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Sample records for clopidogrel response evaluated

  1. Clopidogrel Responsiveness in Patients Undergoing Peripheral Angioplasty

    SciTech Connect

    Pastromas, Georgios Spiliopoulos, Stavros Katsanos, Konstantinos Diamantopoulos, Athanasios Kitrou, Panagiotis Karnabatidis, Dimitrios Siablis, Dimitrios

    2013-12-15

    Purpose: To investigate the incidence and clinical significance of platelet responsiveness in patients receiving clopidogrel after peripheral angioplasty procedures. Materials and Methods: This prospective study included patients receiving antiplatelet therapy with clopidogrel 75 mg after infrainguinal angioplasty or stenting and who presented to our department during routine follow-up. Clopidogrel responsiveness was tested using the VerifyNow P2Y12 Assay. Patients with residual platelet reactivity units (PRU) {>=} 235 were considered as nonresponders (NR group NR), whereas patients with PRU < 235 were considered as normal (responders [group R]). Primary end points were incidence of resistance to clopidogrel and target limb reintervention (TLR)-free survival, whereas secondary end points included limb salvage rates and the identification of any independent predictors influencing clinical outcomes. Results: In total, 113 consecutive patients (mean age 69 {+-} 8 years) with 139 limbs were enrolled. After clopidogrel responsiveness analysis, 61 patients (53.9 %) with 73 limbs (52.5 %) were assigned to group R and 52 patients (46.1 %) with 66 limbs (47.5 %) to group NR. Mean follow-up interval was 27.7 {+-} 22.9 months (range 3-95). Diabetes mellitus, critical limb ischemia, and renal disease were associated with clopidogrel resistance (Fisher's exact test; p < 0.05). According to Kaplan-Meier analysis, TLR-free survival was significantly superior in group R compared with group NR (20.7 vs. 1.9 %, respectively, at 7-year follow-up; p = 0.001), whereas resistance to clopidogrel was identified as the only independent predictor of decreased TLR-free survival (hazard rate 0.536, 95 % confidence interval 0.31-0.90; p = 0.01). Cumulative TLR rate was significantly increased in group NR compared with group R (71.2 % [52 of 73] vs. 31.8 % [21 of 66], respectively; p < 0.001). Limb salvage was similar in both groups. Conclusion: Clopidogrel resistance was related with

  2. Evaluation of clopidogrel response variability and identification of the CYP2C19 polymorphism in Mexican patients.

    PubMed

    Viveros, Martha Eva; Areán, Carlos; Gutiérrez, Sergio; Vázquez, Soledad; Cardiel, Mario Humberto; Taboada, Alejandra; Marín, Gissela; Solorio, Ruben; García, Nalley

    Drug inhibition of platelet P2Y12 adenosine diphosphate receptor has reduced the incidence of adverse cardiovascular events after percutaneous coronary interventions. The analysis of the phosphorylation status of vasodilator-stimulated phosphoprotein by flow cytometry has shown a predictive value for adverse events and stent thrombosis. Polymorphisms of CYP2C19 in high risk patients may also relate to adverse cardiovascular events. Ninety patients were enrolled. Patients received a 600mg clopidogrel loading dose. Blood samples were obtained at the time of the procedure and 24h later, platelet reactivity was assessed by vasodilator-stimulated phosphoprotein phosphorylation measurement using flow cytometry. Low response to clopidogrel was defined as a platelet reactivity index≥50%. The presence of CYP2C19*2 was identified with the restriction enzyme SmaI. Mean platelet reactivity index: 53.45±22.48% in the baseline sample and 57.14±23.08% at 24h (p=0.183); 40% of patients behaved as good responders, the rest behaved as non-responders with 38% of patients showing platelet reactivity indexes between 50-70% and 22% showing indexes above 70%. The CYP2C19*2 polymorphism was found in 17% of patients, with a 3.9% AA homozygous genotype carriers. Response to the clopidogrel loading dose showed a wide variability among patients with 40% responding to the drug according to previously established cut-off values. Our results showed that 3.9% of patients show the AA genotype. To our knowledge, this is the first study involving clopidogrel response by flow citometry and genotype typification in Mexican Mestizo population. Copyright © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. All rights reserved.

  3. Clopidogrel

    MedlinePlus

    ... bleeding, including stomach problems such as ulcers and certain eye problems.tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking clopidogrel, call ...

  4. Interleukin-10 does not modulate clopidogrel platelet response in mice.

    PubMed

    Yin, Q; Tai, T; Ji, J-Z; Mi, Q-Y; Zhang, M-R; Huang, W-J; Cao, C-C; Xie, H-G

    2016-03-01

    ESSENTIALS: It is unclear whether interleukin-10 (IL-10) could affect clopidogrel metabolism and response. The bioactivation of and response to clopidogrel were determined between mice with or without IL-10. Maximum clopidogrel active metabolite levels were the major driver of platelet response to clopidogrel. IL-10 did not modulate maximum levels of clopidogrel active metabolite and its antiplatelet effects. Elevated plasma interleukin-10 (IL-10) levels were observed in patients who responded less to clopidogrel (a prodrug that is required for further metabolic bioactivation in the liver). However, no data are currently available suggesting whether there is such an association. To systematically explore possible differences in the formation of and response to clopidogrel active metabolite (CAM) in mice with or without IL-10 gene expression. A single oral dose of clopidogrel (10 mg kg(-1)) was given to IL-10 knockout (KO) mice and wild-type (WT) control mice, respectively, and pharmacokinetic parameters of clopidogrel and CAM were calculated. Moreover, adenosine diphosphate-induced whole-blood platelet aggregation was measured in mice receiving 0, 5, 10, or 20 mg kg(-1) of clopidogrel, respectively. Compared with IL-10 KO mice, WT mice had significantly lower area under the plasma concentration-time curve (AUC) of CAM as a result of a shorter mean elimination half-life but had significantly higher AUC of clopidogrel due to slower systemic clearance and smaller volume of distribution. Although AUC of CAM was significantly lower in WT mice than in KO mice, antiplatelet effects of clopidogrel did not differ significantly between the two mouse groups, as their maximum plasma concentrations (Cmax ) of CAM were not significantly different. IL-10 expression level affects AUC rather than Cmax of CAM, but the Cmax of CAM is the major driver of antiplatelet effects of clopidogrel in mice. © 2015 International Society on Thrombosis and Haemostasis.

  5. Pharmacokinetic and Pharmacodynamic Responses to Clopidogrel: Evidences and Perspectives

    PubMed Central

    Zhang, Yan-Jiao; Li, Mu-Peng; Tang, Jie; Chen, Xiao-Ping

    2017-01-01

    Clopidogrel has significantly reduced the incidence of recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI). However, recurrence events still remain, which may be partly due to inadequate platelet inhibition by standard clopidogrel therapy. Genetic polymorphisms involved in clopidogrel’s absorption, metabolism, and the P2Y12 receptor may interfere with its antiplatelet activity. Recent evidence indicated that epigenetic modification may also affect clopidogrel response. In addition, non-genetic factors such as demographics, disease complications, and drug-drug interactions can impair the antiplatelet effect of clopidogrel. The identification of factors contributing to the variation in clopidogrel response is needed to improve platelet inhibition and to reduce risk for cardiovascular events. This review encompasses the most recent updates on factors influencing pharmacokinetic and pharmacodynamic responses to clopidogrel. PMID:28335443

  6. Increased Endoplasmic Reticulum Stress Response Is Involved in Clopidogrel-Induced Apoptosis of Gastric Epithelial Cells

    PubMed Central

    Jiang, Zong-Dan; Cao, Wei-Jun; Wang, Zhi-Bing; Hu, Ke-Wei; Gao, Xin; Wang, Shu-Kui; He, Bang-Shun; Zhang, Zhen-Yu; Xie, Hong-Guang

    2013-01-01

    Background The widespread use of clopidogrel alone or in combination with aspirin may result in gastrointestinal mucosal injury, clinically represented as recurrent ulceration and bleeding complications. Our recent work suggested that clopidogrel significantly induced human gastric epithelial cell (GES-1) apoptosis and disrupted gastric mucosal barrier, and that a p38 MAPK inhibitor could attenuate such injury. However, their exact mechanisms are largely unknown. Methods The GES-1 cells were used as a model system, the effects of clopidogrel on the whole gene expression profile were evaluated by human gene expression microarray and gene ontology analysis, changes of the mRNA and protein expression were determined by real-time PCR and Western blot analysis, and cell viability and apoptosis were measured by MTT assay and flow cytometry analysis, respectively. Results Gene microarray analysis identified 79 genes that were differentially expressed (P<0.05 and fold-change >3) when cells were treated with or without clopidogrel. Gene ontology analysis revealed that response to stress and cell apoptosis dysfunction were ranked in the top 10 cellular events being affected, and that the major components of endoplasmic reticulum stress-mediated apoptosis pathway – CHOP and TRIB3– were up-regulated in a concentration- and time-dependent manner when cells were treated with clopidogrel. Pathway analysis demonstrated that multiple MAPK kinases were phosphorylated in clopidogrel-treated GES-1 cells, but that only SB-203580 (a p38-specific MAPK inhibitor) attenuated cell apoptosis and CHOP over-expression, both of which were induced by clopidogrel. Conclusions Increased endoplasmic reticulum stress response is involved in clopidogrel-induced gastric mucosal injury, acting through p38 MAPK activation. PMID:24058556

  7. Comparison of ticagrelor and high-dose clopidogrel on the platelet functions in patients with inadequate response to clopidogrel

    PubMed Central

    Gu, Xinshun; Fu, Xianghua; Wang, Yanbo; Zhang, Wenhui; Fan, Weize; Jiang, Yunfa; Hao, Guozhen; Miao, Qing; Li, Yi; Zhi, Wei

    2017-01-01

    Objective: To evaluate the effects of ticagrelor and high-dose clopidogrel on the platelet functions in patients with inadequate response to clopidogrel. Methods: In this prospective, randomized and controlled study, patients who had been diagnosed as acute coronary syndrome (ACS) with inadequate response to clopidogrel in the Second Hospital of Hebei Medical University from July 2015 to June 2016 were enrolled. Inadequate response to clopidogrel was defined as absolute reduction of platelet aggregation rate (PAR) <30% or PAR >70%. Eligible patients were randomly assigned to two groups, the high-dose group and the ticagrelor group. Clinical information and intervention protocols were compared. The PAR of the two groups were measured at the time of baseline, the 24th hour, 72nd hour, and the 7th day after treatments, the other platelet-related parameters were measured including platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW) at the same time points. Besides, the markers of platelet activation human P-selectin (CD62P) and thromboxane A2 (TXA2) were also recorded to compare. The incidence of major adverse cardiac events (MACE) and the side effects between two groups were followed up for three months. Results: A total of 74 patients were finally enrolled, 38 of whom were assigned to the ticagrelor group and the rest of them to the high-dose clopidogrel group. The baseline clinical and procedural characterists were similar. There were no significant differences in baseline levels of PAR between the two groups [(79.38±11.20)% vs. (73.97±12.74)%, P>0.05]. For both groups, the levels of PAR significantly decreased at each time point (P<0.001). Besides, the levels of PAR in ticagrelor group were lower than those in high-dose clopidogrel group at the 24th hour, 72nd hour and 7th day after treatments: [(25.92±10.31)% vs. (37.95±11.63)%, P<0.001], [(28.02±14.61)% vs. (30.64±10.73)%, P<0.001], [(37.17±11.11)% vs. (36.80±7.26)%, P<0

  8. Aspirin and clopidogrel response variability: review of the published literature.

    PubMed

    Ferguson, Angela D; Dokainish, Hisham; Lakkis, Nasser

    2008-01-01

    Antiplatelet resistance has been proposed as a possible mechanism to explain recurrent cardiovascular events in patients who have coronary artery disease and who are undergoing dual antiplatelet therapy. A comprehensive search on PubMed was conducted for literature that was printed in the English language between January 1996 and November 2007 on aspirin and clopidogrel resistance. Significant traits for aspirin hyporesponsiveness were female sex, older age, and lower levels of hemoglobin. Diabetes mellitus and elevated body mass index showed trends toward a higher incidence of resistance in some aspirin trials but did not reach statistical significance. Clopidogrel studies suggested that patients with type-2 diabetes mellitus are more likely to manifest inadequate response to the medication. Although 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors were initially suspected to decrease response to clopidogrel, later studies refuted this possibility. Patients with a suboptimal response to aspirin or clopidogrel seem to be at increased risk of recurrent cardiovascular events. Large clinical trials with standardized laboratory methods and well-defined protocols are needed to determine whether common features exist in patients with suspected hyporesponsiveness to antiplatelet therapy, and to validate the clinical relevance of response variability. A concise nonarbitrary definition of physiologic "resistance" is needed, and investigators should identify patients as having a variable response to antiplatelet therapy.

  9. Clopidogrel Response Variability: Review of the Literature and Practical Considerations.

    PubMed

    Oliphant, Carrie S; Trevarrow, Brian J; Dobesh, Paul P

    2016-02-01

    Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor is standard therapy following acute coronary syndrome and percutaneous coronary intervention. Despite the use of potent antiplatelet agents, vascular events continue to occur. Lack of response to clopidogrel therapy has been widely investigated using various methods of platelet function testing. These studies have consistently found an association between poor clopidogrel response and an increased risk of vascular events. Strategies to overcome this problem include higher clopidogrel doses or the use of an alternative P2Y12 agent. To date, the majority of studies investigating tailored antiplatelet therapy have failed to show any reduction in clinical events likely due to the low-risk population studied. Despite this lack of benefit from altering therapy, platelet function testing may be done in certain patient populations. Patients at high risk of deleterious outcomes from stent thrombosis may be an appropriate patient population for platelet function testing to ensure adequate response to therapy. In addition, emerging data suggests a potential role for platelet function testing to assess for bleeding risk. The purpose of this article is to review the key studies demonstrating response variability to clopidogrel therapy, strategies to overcome variability, and practical considerations for the clinician.

  10. Genetic and non-genetic factors responsible for antiplatelet effects of clopidogrel in Japanese patients undergoing coronary stent implantation: an algorithm to predict on-clopidogrel platelet reactivity.

    PubMed

    Miura, Go; Ariyoshi, Noritaka; Sato, Yasunori; Yamaguchi, Hiroki; Iwata, Yo; Fujimoto, Yoshihide; Kobayashi, Yoshio; Ishii, Itsuko

    2014-10-01

    Antiplatelet effects of clopidogrel appear to be affected by various factors including genetic polymorphism. So far, there has been little information about the response of clopidogrel in Asians, whose prevalence of a CYP2C19 loss-of-function (LOF) allele is high. We investigated background and clinical factors affecting on-clopidogrel platelet reactivity in Japanese patients undergoing coronary stent implantation (n=114). In univariate analysis, antiplatelet effects of clopidogrel in a steady state were associated with not only CYP2C19 genotypes but also several factors including dyslipidemia. In addition, we developed an algorithm that can estimate P2Y12 Reaction Units (PRU) in a steady state by multiple regression analysis and evaluated the adequacy of the algorithm by the Akaike Information Criterion. We revealed several factors influencing on-clopidogrel platelet reactivity in Japanese patients. We also succeeded in developing an algorithm that estimates PRU in a steady state, although it is uncertain whether the algorithm can be applied to other populations. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. PON1 Q192R genotype influences clopidogrel responsiveness by relative platelet inhibition instead of on-treatment platelet reactivity.

    PubMed

    Li, Xiaoqi; Zhang, Lanning; Chen, Xi; Qu, Fei; Li, Jiayue; Ma, Cong; Yang, Jie; Xu, Bin; Wang, Hongjuan; Xu, Qiang; Zhang, Yuxiao; Li, Yang; Lu, Caiyi; Yin, Tong

    2013-10-01

    paraoxonase-1 (PON1) was recently identified as the crucial enzyme for clopidogrel bioactivation, with PON1 Q192R (rs662) polymorphism determining the clopidogel antiplatelet efficacy. However, subsequent studies showed controversies over the findings. This study aimed to evaluate the impact of PON1 Q192R in parallel to that of CYP2C19*2 (rs4244285) on clopidogrel responsiveness in a cohort of Chinese patients with unstable angina pectoris. One hundred and eighty Chinese-Han patients diagnosed with unstable angina pectoris and treated with clopidogrel were consecutively recruited. Clopidogrel responsiveness, measured by relative platelet inhibition {RI=[(pretreatment aggregation-posttreatment aggregation at 5days)/(pretreatment aggregation)] x100%}, was assessed in relation to PON1 Q192R and CYP2C19*2 genotypes. RI values were stratified into four quartiles, with patients in quartile 1 defined as individuals of clopidogrel non-responsiveness. The contributions of PON1 Q192R and CYP2C19*2 to on-treatment platelet reactivity (OTPR) at 5days maintenance dose of clopidogrel were also evaluated. For PON1 Q192R genotypes, RI values were significantly lower in patients with QR and RR alleles than in patients with QQ alleles (p=0.01). OTPR values at 5days maintenance dose of clopidogrel were similar across all the PON1 Q192R genotypes (p=0.41). PON1 192 QR and RR conferred increased risks for clopidogrel non-responsiveness [OR 3.64; 95% CI (1.21-10.92), p=0.02]. For CYP2C19*2 genotypes, compared to CYP2C19*1/*1 wild type carriers, CYP2C19*2 carriers showed a significantly higher OTPR (p=0.009), and a trend for lower RI values (p=0.06). An increased risk for clopidogrel non-responsiveness was found in patients with CYP2C19*2 genotype [OR 2.02; 95% CI (1.03-3.96), p=0.04]. Both PON1 Q192R and CYP2C19*2 genotypes influence clopidogrel responsiveness, with the impact of PON1 Q192R mainly on relative platelet inhibition instead of OTPR of clopidogrel. © 2013.

  12. Design, development and evaluation of clopidogrel bisulfate floating tablets

    PubMed Central

    Rao, K. Rama Koteswara; Lakshmi, K. Rajya

    2014-01-01

    Objective: The objective of the present work was to formulate and to characterize a floating drug delivery system for clopidogrel bisulphate to improve bioavailability and to minimize the side effects of the drug such as gastric bleeding and drug resistance development. Materials and Methods: Clopidogrel floating tablets were prepared by direct compression technique by the use of three polymers xanthan gum, hydroxypropyl methylcellulose (HPMC) K15M and HPMC K4M in different concentrations (20%, 25% and 30% w/w). Sodium bicarbonate (15% w/w) and microcrystalline cellulose (30% w/w) were used as gas generating agent and diluent respectively. Studies were carried out on floating behavior and influence of type of polymer on drug release rate. All the formulations were subjected to various quality control and in-vitro dissolution studies in 0.1 N hydrochloric acid (1.2 pH) and corresponding dissolution data were fitted to popular release kinetic equations in order to evaluate release mechanisms and kinetics. Results and Discussion: All the clopidogrel floating formulations followed first order kinetics, Higuchi drug release kinetics with diffusion as the dominant mechanism of drug release. As per Korsmeyer-Peppas equation, the release exponent “n” ranged 0.452-0.654 indicating that drug release from all the formulations was by non-Fickian diffusion mechanism. The drug release rate of clopidogrel was found to be affected by the type and concentration of the polymer used in the formulation (P < 0.05). As the concentration of the polymer was increased, the drug release was found to be retarded. Conclusion: Based on the results, clopidogrel floating tablets prepared by employing xanthan gum at concentration 25% w/w (formulation F2) was the best formulation with desired in-vitro floating time and drug dissolution. PMID:24678458

  13. Design, development and evaluation of clopidogrel bisulfate floating tablets.

    PubMed

    Rao, K Rama Koteswara; Lakshmi, K Rajya

    2014-01-01

    The objective of the present work was to formulate and to characterize a floating drug delivery system for clopidogrel bisulphate to improve bioavailability and to minimize the side effects of the drug such as gastric bleeding and drug resistance development. Clopidogrel floating tablets were prepared by direct compression technique by the use of three polymers xanthan gum, hydroxypropyl methylcellulose (HPMC) K15M and HPMC K4M in different concentrations (20%, 25% and 30% w/w). Sodium bicarbonate (15% w/w) and microcrystalline cellulose (30% w/w) were used as gas generating agent and diluent respectively. Studies were carried out on floating behavior and influence of type of polymer on drug release rate. All the formulations were subjected to various quality control and in-vitro dissolution studies in 0.1 N hydrochloric acid (1.2 pH) and corresponding dissolution data were fitted to popular release kinetic equations in order to evaluate release mechanisms and kinetics. All the clopidogrel floating formulations followed first order kinetics, Higuchi drug release kinetics with diffusion as the dominant mechanism of drug release. As per Korsmeyer-Peppas equation, the release exponent "n" ranged 0.452-0.654 indicating that drug release from all the formulations was by non-Fickian diffusion mechanism. The drug release rate of clopidogrel was found to be affected by the type and concentration of the polymer used in the formulation (P < 0.05). As the concentration of the polymer was increased, the drug release was found to be retarded. Based on the results, clopidogrel floating tablets prepared by employing xanthan gum at concentration 25% w/w (formulation F2) was the best formulation with desired in-vitro floating time and drug dissolution.

  14. Clopidogrel, a P2Y12 Receptor Antagonist, Potentiates the Inflammatory Response in a Rat Model of Peptidoglycan Polysaccharide-Induced Arthritis

    PubMed Central

    Rico, Mario C.; Dela Cadena, Raul A.; Kunapuli, Satya P.

    2011-01-01

    The P2Y12 receptor plays a crucial role in the regulation of platelet activation by several agonists, which is irreversibly antagonized by the active metabolite of clopidogrel, a widely used anti-thrombotic drug. In this study, we investigated whether reduction of platelet reactivity leads to reduced inflammatory responses using a rat model of erosive arthritis. We evaluated the effect of clopidogrel on inflammation in Lewis rats in a peptidoglycan polysaccharide (PG-PS)-induced arthritis model with four groups of rats: 1) untreated, 2) clopidogrel-treated, 3) PG-PS-induced, and 4) PG-PS-induced and clopidogrel-treated. There were significant differences between the PG-PS+clopidogrel group when compared to the PG-PS group including: increased joint diameter and clinical manifestations of inflammation, elevated plasma levels of pro-inflammatory cytokines (IL-1 beta, interferon (IFN) gamma, and IL-6), an elevated neutrophil blood count and an increased circulating platelet count. Plasma levels of IL-10 were significantly lower in the PG-PS+clopidogrel group compared to the PG-PS group. Plasma levels of platelet factor 4 (PF4) were elevated in both the PG-PS and the PG-PS+clopidogrel groups, however PF4 levels showed no difference upon clopidogrel treatment, suggesting that the pro- inflammatory effect of clopidogrel may be due to its action on cells other than platelets. Histology indicated an increase in leukocyte infiltration at the inflammatory area of the joint, increased pannus formation, blood vessel proliferation, subsynovial fibrosis and cartilage erosion upon treatment with clopidogrel in PG-PS-induced arthritis animals. In summary, animals treated with clopidogrel showed a pro-inflammatory effect in the PG-PS-induced arthritis animal model, which might not be mediated by platelets. Elucidation of the mechanism of clopidogrel-induced cell responses is important to understand the role of the P2Y12 receptor in inflammation. PMID:22028806

  15. Hypersensitivity to ticagrelor and low response to clopidogrel: a case report

    PubMed Central

    Dai, Jing; Ge, Changjiang

    2017-01-01

    Ticagrelor is widely used to treat acute coronary syndrome. Hypersensitivity reaction of ticagrelor is rarely recognized. A low response to clopidogrel, which occurs in up to 23% of patients, is an independent risk factor for stent thrombosis. Management of patients with a low response to clopidogrel and ticagrelor hypersensitivity who are undergoing antithrombotic therapy remains to be a challenge. Herein, we report a patient with low response to clopidogrel and ticagrelor hypersensitivity, who was successfully managed using aspirin and warfarin. PMID:28154807

  16. The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response.

    PubMed

    Harmsze, Ankie M; Robijns, Karen; van Werkum, Jochem W; Breet, Nicoline J; Hackeng, Christian M; Ten Berg, Jurrien M; Ruven, Hendrik J T; Klungel, Olaf H; de Boer, Anthonius; Deneer, Vera H M

    2010-05-01

    Clopidogrel is a prodrug that has to be converted in vivo to its active metabolite by cytochrome (CYP)P450 iso-enzymes. As calcium channel blockers (CCBs) are inhibitors of CYP3A4, concomitant use of these drugs might play a role in the wide inter-individual variability in the response to clopidogrel. However, some CCBs also have strong inhibitory effects on the drug transporter P-glycoprotein (Pgp), which mediates clopidogrel's intestinal absorption. It was the aim of this study to evaluate the effect of co-administration of Pgp-inhibiting and non-Pgp-inhibiting CCBs on on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective percutaneous coronary intervention (PCI). In a total of 623 consecutive patients undergoing elective PCI treated with clopidogrel and aspirin, platelet reactivity to 5 and 20 muM adenosine diphospate (ADP) and clopidogrel poor-response (defined as > 70% platelet aggregation to 20 muM ADP) were evaluated by light transmittance aggregometry. A total of 222 patients (35.6%) were on CCB treatment, of which 98 used Pgp-inhibiting CCBs (verapamil, nifedipine, diltiazem, barnidipine) and 124 patients used the non-Pgp-inhibiting CCB amlodipine. Adjusted mean ADP-induced on-clopidogrel platelet reactivity was significantly higher in both users of Pgp-inhibiting CCBs and amlodipine as compared to CCB non-users (all p<0.05). However, only the use of amlodipine was significantly associated with a 2.3-fold increased risk of clopidogrel poor-response. This study demonstrates that concomitant use of Pgp-inhibiting CCBs and amlodipine increases on-clopidogrel platelet reactivity. Only amlodipine was associated with clopidogrel poor-response. The drug-drug interaction between clopidogrel and amlodipine might be more clinically relevant as compared to P-glycoprotein-inhibiting CCBs.

  17. Evaluation of Aspirin and Clopidogrel resistance in patients with Acute Coronary Syndrome by using Adenosine Diposphate Test and Aspirin Test

    PubMed Central

    O, Ibrahim; M, Oteh; A, A Syukur; HH, Che Hassan; W, S Fadilah; Rahman, MM

    2013-01-01

    Objectives: To evaluate Aspirin and Clopidogrel resistance/non-responders in patients with acute coronary syndrome (ACS) by using adenosine diposphate and aspirin tests. Methodology: In the study patients with ACS loaded with 300 mg of clopidogrel and 300 mg aspirin and patients on stable daily dose of 75 mg of clopidogrel (more than 3 days) underwent PCI. Response to clopidogrel and Aspirin was assessed by Adenosine Diphosphate (ADP) Test (20 µmol/L) and Aspirin Test (Acetyl Acid) (ASP) 20 µmol/L, respectively, using the Multiplate Platelet Function Analyzer (Dynabyte Medical, Munich, Germany). Results: Sixty four patients were included in this study out of which 57 were with ACS and 7 scheduled for percutaneous coronary intervention (PCI) electively. The proportion of Aspirin good responders and adequate responders were 76.56% and 18.75%, respectively while adequate response and good response to Clopidogrel accounted for 29.7 and 48.4%, respectively Hyperlipidaemia was only co-morbidity associated with higher AUC ADP value (p: 0.046). Hypertriglyceridaemia and serum calcium were weakly correlated with higher AUC ADP serum calcium r=0.08, triglyceride r=0.12. Patients admitted for scheduled PCI and on stable dose of 75mg clopidogrel exhibited lower AUC ADP value as compared to those admitted with acute coronary syndrome given loading dose of 300mg of Clopidogrel. Post loading dose measurement of anti-platelet therapy among ACS patients using the Multiplate Platelet Function Analyzer showed comparable results with other methods. Conclusions : As determined by Multiplate Platelet Function Analyzer, Aspirin resistance/non-responders in this study in acute coronary syndrome patients accounted for 4.69% while Non-responders in Clopidogrel was 21.9%. PMID:24353516

  18. Evaluation of Aspirin and Clopidogrel resistance in patients with Acute Coronary Syndrome by using Adenosine Diposphate Test and Aspirin Test.

    PubMed

    O, Ibrahim; M, Oteh; A, A Syukur; Hh, Che Hassan; W, S Fadilah; Rahman, Mm

    2013-01-01

    To evaluate Aspirin and Clopidogrel resistance/non-responders in patients with acute coronary syndrome (ACS) by using adenosine diposphate and aspirin tests. In the study patients with ACS loaded with 300 mg of clopidogrel and 300 mg aspirin and patients on stable daily dose of 75 mg of clopidogrel (more than 3 days) underwent PCI. Response to clopidogrel and Aspirin was assessed by Adenosine Diphosphate (ADP) Test (20 µmol/L) and Aspirin Test (Acetyl Acid) (ASP) 20 µmol/L, respectively, using the Multiplate Platelet Function Analyzer (Dynabyte Medical, Munich, Germany). Sixty four patients were included in this study out of which 57 were with ACS and 7 scheduled for percutaneous coronary intervention (PCI) electively. The proportion of Aspirin good responders and adequate responders were 76.56% and 18.75%, respectively while adequate response and good response to Clopidogrel accounted for 29.7 and 48.4%, respectively Hyperlipidaemia was only co-morbidity associated with higher AUC ADP value (p: 0.046). Hypertriglyceridaemia and serum calcium were weakly correlated with higher AUC ADP serum calcium r=0.08, triglyceride r=0.12. Patients admitted for scheduled PCI and on stable dose of 75mg clopidogrel exhibited lower AUC ADP value as compared to those admitted with acute coronary syndrome given loading dose of 300mg of Clopidogrel. Post loading dose measurement of anti-platelet therapy among ACS patients using the Multiplate Platelet Function Analyzer showed comparable results with other methods. Conclusions : As determined by Multiplate Platelet Function Analyzer, Aspirin resistance/non-responders in this study in acute coronary syndrome patients accounted for 4.69% while Non-responders in Clopidogrel was 21.9%.

  19. Influence of Genetic Polymorphisms on Clopidogrel Response and Clinical Outcomes in Patients with Acute Ischemic Stroke CYP2C19 Genotype on Clopidogrel Response.

    PubMed

    Han, Yan; Lv, Hui-Hui; Liu, Xu; Dong, Qiang; Yang, Xiao-Li; Li, Shi-Xu; Wu, Shuai; Jiang, Jian-Ming; Luo, Zheng; Zhu, De-Sheng; Zhang, Yi; Zheng, Yi; Guan, Yang-Tai; Xu, Jian-Feng

    2015-09-01

    This study sought to evaluate the influence of the genetic polymorphisms on platelet reactivity and clinical outcomes in acute ischemic stroke patients taking clopidogrel. Little research has been published on relationships between genetic polymorphisms, platelet reactivity, and clinical outcomes in stroke patients treated with clopidogrel. Patients hospitalized in Changhai Hospital with acute ischemic stroke were randomly enrolled into treatment with a 75-mg daily maintenance dose of clopidogrel. Genotyping was detected by the MassARRAY iPLEX genotyping system (Sequenom Inc, San Diego, CA), and platelet reactivity was evaluated by the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, CA). Sixteen single nucleotide polymorphisms (SNPs) within 9 genes were selected and high on-clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) value ≥230. The primary endpoint was ischemic events, including major adverse cardiac events (MACE), recurrence of stroke, transient ischemic attack (TIA), and the composite of vascular death, and the secondary endpoint was bleeding. Of the 345 patients recruited, 275 (79.7%) patients were followed up for 1 year and 122 (35.4%) patients were categorized as HPR. Among the SNPs selected, only the CYP2C19*2 allele and the CYP2C19*3 allele were statistically significantly associated with PRU (P < 0.001 and P = 0.003, respectively). Similarly, the prevalence of HPR was associated with CYP2C19*2 and CYP2C19*3 (P < 0.001 and P = 0.001, respectively). During the 1 year of follow-up, a total of 64 (23.3%) cases of clinical events occurred, including 60 ischemic events and 4 bleeding events. There were no correlation between CYP2C19 variant alleles and clinical outcomes (P > 0.05), but a statistically significant relevance was found between the HPR and the ischemic events in 1 year of follow-up (P = 0.001). CYP2C19*2 and CYP2C19*3 had a significant impact on clopidogrel response, but was not associated with ischemic

  20. Comparison of VerifyNow P2Y12 and thrombelastography for assessing clopidogrel response in stroke patients in China.

    PubMed

    Lv, Hui-Hui; Wu, Shuai; Liu, Xu; Yang, Xiao-Li; Xu, Jian-Feng; Guan, Yang-Tai; Dong, Qiang; Zheng, S Lilly; Jiang, Jian-Ming; Li, Shi-Xu; Luo, Zheng; Li, Li; An, Li-Xian; Han, Yan

    2016-02-01

    Poor response to clopidogrel is often associated with recurrent ischemic events, and reliable platelet function tests are needed to identify clopidogrel low response (CLR). The aim of the study was to compare the consistency of VerifyNow P2Y12 and thrombelastography (TEG) in acute ischemic stroke patients treated with clopidogrel. Patients hospitalized in Changhai Hospital from August 2012 to September 2013 and assigned to treatment with a daily 75-mg dose of clopidogrel. The blood samples were taken on the 5-7th day to assess the capability of VerifyNow P2Y12 and TEG for evaluation of clopidogrel response, and all instrument parameters were used to perform correlation analysis. Patients with CLR were detected by using the methods and criteria published earlier (PRU ≥ 230 assayed by VerifyNow P2Y12 or TEG-Inhib% ≤30 % measured by TEG). Totally 58 patients were enrolled for the study and there were wide varieties in parameters of VerifyNow P2Y12 and TEG. Results showed a total of 17 and 9 patients, respectively, identified as CLR assessed by VerifyNow P2Y12 and TEG, but only three patients were detected to be clopidogrel low responders with both tests. The kappa consistency analysis showed poor consistency between VerifyNow P2Y12 and TEG results in terms of CLR (Kappa = -0.0349, p = 0.7730). Linear regression also demonstrated poor correlation between VerifyNow-PRU/VerifyNow-Inhib% and TEG-Inhib% (p = 0.07901 and p = 0.3788, respectively). Our study demonstrated that there was poor correlation between VerifyNow P2Y12 and TEG results, and VerifyNow P2Y12 showed a larger proportion of CLR than TEG.

  1. Optimizing clopidogrel dose response: a new clinical algorithm comprising CYP2C19 pharmacogenetics and drug interactions

    PubMed Central

    Saab, Yolande B; Zeenny, Rony; Ramadan, Wijdan H

    2015-01-01

    Purpose Response to clopidogrel varies widely with nonresponse rates ranging from 4% to 30%. A reduced function of the gene variant of the CYP2C19 has been associated with lower drug metabolite levels, and hence diminished platelet inhibition. Drugs that alter CYP2C19 activity may also mimic genetic variants. The aim of the study is to investigate the cumulative effect of CYP2C19 gene polymorphisms and drug interactions that affects clopidogrel dosing, and apply it into a new clinical-pharmacogenetic algorithm that can be used by clinicians in optimizing clopidogrel-based treatment. Method Clopidogrel dose optimization was analyzed based on two main parameters that affect clopidogrel metabolite area under the curve: different CYP2C19 genotypes and concomitant drug intake. Clopidogrel adjusted dose was computed based on area under the curve ratios for different CYP2C19 genotypes when a drug interacting with CYP2C19 is added to clopidogrel treatment. A clinical-pharmacogenetic algorithm was developed based on whether clopidogrel shows 1) expected effect as per indication, 2) little or no effect, or 3) clinical features that patients experience and fit with clopidogrel adverse drug reactions. Results The study results show that all patients under clopidogrel treatment, whose genotypes are different from *1*1, and concomitantly taking other drugs metabolized by CYP2C19 require clopidogrel dose adjustment. To get a therapeutic effect and avoid adverse drug reactions, therapeutic dose of 75 mg clopidogrel, for example, should be lowered to 6 mg or increased to 215 mg in patients with different genotypes. Conclusion The implementation of clopidogrel new algorithm has the potential to maximize the benefit of clopidogrel pharmacological therapy. Clinicians would be able to personalize treatment to enhance efficacy and limit toxicity. PMID:26445541

  2. Comparison of current platelet functional tests for the assessment of aspirin and clopidogrel response. A review of the literature.

    PubMed

    Le Quellec, Sandra; Bordet, Jean-Claude; Negrier, Claude; Dargaud, Yesim

    2016-09-27

    The two most widely used antiplatelet drugs in the world are aspirin and clopidogrel. However, some patients on aspirin and/or clopidogrel therapy do not respond appropriately to either aspirin or clopidogrel. This phenomenon is usually called "aspirin/clopidogrel resistance". Several platelet function tests have been used in various studies for the assessment of aspirin and clopidogrel resistance in healthy individuals and patients admitted in cardiology departments. An accurate assessment of platelet response to aspirin/clopidogrel could benefit patients by proposing tailored-antiplatelet therapy based on test results. However, there is a clear lack of standardisation of such techniques and their analytical variability may induce misinterpretation. After a quick report of the mechanisms responsible for aspirin/clopidogrel resistance, we describe the pre-analytical aspects and the analytical performances of current platelet function tests (Light-transmission aggregometry, whole-blood aggregometry, VerifyNow®, Platelet Function Analyzer®, thromboelastography, VASP assay) that are used for the assessment of aspirin/clopidogrel resistance in clinical studies. Considering the different variables that have to be taken into account with each of the platelet function tests, a particular attention should be paid when interpreting results.

  3. Effect of rebamipide on gastric bleeding and ulcerogenic responses induced by aspirin plus clopidogrel under stimulation of acid secretion in rats.

    PubMed

    Takeuchi, Koji; Takayama, Shinichi; Hashimoto, Erika; Itayama, Misaki; Amagase, Kikuko; Izuhara, Chitose

    2014-12-01

    We examined the prophylactic effect of rebamipide on gastric bleeding induced by the perfusion of aspirin (acetylsalicylic acid [ASA]) plus clopidogrel under the stimulation of acid secretion in rats. Under urethane anesthesia, acid secretion was stimulated by the i.v. infusion of histamine (8 mg/kg/h), and the stomach was perfused with 25 mmol/L ASA at a rate of 0.4 mL/min. Gastric bleeding was evaluated as the concentration of hemoglobin in the perfusate. Clopidogrel (30 mg/kg) was given p.o. 24 h before the perfusion. Rebamipide (3-30 mg/kg) or other antiulcer drugs were given i.d. before the ASA perfusion. Slight gastric bleeding or damage was observed with the perfusion of ASA under the stimulation of acid secretion, whereas these responses were significantly increased in the presence of clopidogrel. Both omeprazole and famotidine inhibited acid secretion and prevented these responses to ASA plus clopidogrel. Rebamipide had no effect on acid secretion, but dose-dependently prevented gastric bleeding in response to ASA plus clopidogrel, with the degree of inhibition being almost equivalent to that of the antisecretory drugs, and the same effects were obtained with the gastroprotective drugs, irsogladine and teprenone. These agents also reduced the severity of gastric lesions, although the effects were less than those of the antisecretory drugs. These results suggest that the antiplatelet drug, clopidogrel, increases gastric bleeding induced by ASA under the stimulation of acid secretion, and the gastroprotective drug, rebamipide, is effective in preventing the gastric bleeding induced under such conditions, similar to antisecretory drugs. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  4. Association of CYP2C19*2 polymorphism with clopidogrel response and 1-year major adverse cardiovascular events in a multiethnic population with drug-eluting stents.

    PubMed

    Tan, Shirley Siang Ning; Fong, Alan Yean Yip; Mejin, Melissa; Gerunsin, Jerry; Kong, Khai Liy; Chin, Felicia Yien Yin; Tiong, Lee Len; Lim, Melissa Siaw Han; Asri, Said; Khiew, Ning Zan; Voon, Chi Yen; Mohd Amin, Nor Hanim; Cham, Yee Ling; Koh, Keng Tat; Oon, Yen Yee; Ong, Tiong Kiam

    2017-08-01

    Patients undergoing elective percutaneous coronary intervention (PCI) with drug-eluting stents (DES) who have impaired clopidogrel response, have a higher risk of subsequent major adverse cardiovascular events (MACE). To establish the relationship between CYP2C19 genotype, clopidogrel responsiveness and 1-year MACE. Aspirin/clopidogrel responses were assessed with Multiplate Analyzer and CYP2C19*2 allele by SpartanRx. A total of 42.0% carried ≥1 CYP2C19*2 allele. Prevalences of aspirin and clopidogrel high on-treatment platelet reactivity (HPR; local cutoffs: 300 AU*min for aspirin and 600 AU*min for clopidogrel) were 11.5% and 19.8% respectively. In multivariate ana-lysis, clopidogrel HPR was found to be an independent predictor for 1-year MACE (adj HR: 3.48, p = 0.022 ). Having clopidogrel HPR could be a potentially modifiable risk factor guided by phenotyping.

  5. Does i-T744C P2Y12 Polymorphism Modulate Clopidogrel Response among Moroccan Acute Coronary Syndromes Patients?

    PubMed Central

    Hmimech, Wiam; El Khorb, Nada; Akoudad, Hafid; Habbal, Rachida; Nadifi, Sellama

    2017-01-01

    Background. An interindividual variability in response to Clopidogrel has been widely described in patients with acute coronary syndromes (ACS). The contribution of genetics on modulating this response was widely discussed. The objective of our study was to investigate the potential effect of i-T744C P2Y12 polymorphism on Clopidogrel response in a sample of Moroccan ACS patients. We tried also to determine the frequency of this polymorphism among Moroccan ACS compared to healthy subjects. Methods and Results. 77 ACS patients versus 101 healthy controls were recruited. DNA samples were genotyped by PCR-RFLP method. The VerifyNow assay was used to evaluate platelet function among ACS patients. Our results show that the mutant allele C was more frequent among ACS ST (+) than ST (−) patients (39% versus 19.8%, resp.), when the wild-type allele was more represented in the ACS ST (−) group (80.2%). The C allele frequency was higher among resistant than nonresistant patients (30% versus 20.8%, resp.). Comparison of ACS patients and healthy controls shows higher frequency of mutant C allele among cases compared to controls (22.73% versus 19.31%, resp.); there was a statistically significant association of the recessive and additive transmission models with the ACS development risk (OR [95% CI] = 1.78 [1.58–5.05], P = 0.01 and OR [95% CI] = 1.23 [0.74–2.03], P < 0.001, resp.), increasing thus the association of this polymorphism with the pathology. Conclusion. Our results suggest that this polymorphism may have a potential effect on Clopidogrel response among our Moroccan ACS patients and also on ACS development. PMID:28261502

  6. Paraoxonase-1 activity affects the clopidogrel response in CYP2C19 loss-of-function carriers.

    PubMed

    Nishio, Ryo; Shinke, Toshiro; Otake, Hiromasa; Nakagawa, Masayuki; Inoue, Takumi; Hariki, Hirotoshi; Osue, Tsuyoshi; Taniguchi, Yu; Iwasaki, Masamichi; Hiranuma, Noritoshi; Konishi, Akihide; Kinutani, Hiroto; Kuroda, Masaru; Hirata, Ken-Ichi

    2013-11-01

    The impact of paraoxonase-1 (PON1) activity on the response to clopidogrel may differ in patients treated with drug-eluting stents (DES) in association with CYP2C19 loss-of-function (LOF) polymorphisms. This study included 112 Japanese patients receiving clopidogrel (75 mg/day) and aspirin (100mg/day) who underwent optical coherence tomography (OCT) examination 9 months after DES implantation. The CYP2C19 genotype was analyzed and LOF carriers (1/2, 1/3, 2/2, 3/3, 2/3) were identified. At the 9-month follow-up, platelet reactivity was determined by measuring the P2Y12 reactivity unit (PRU) using a VerifyNow P2Y12 assay, PON1 activity was evaluated and intra-stent thrombus was evaluated by OCT. Of the 112 Japanese patients, 75 were LOF carriers (67.0%). The patients were divided into tertiles according to the PON1 activity (tertile 1; <230 U/L, tertile 2; 230-283U/L, tertile 3; >283 U/L). In the VerifyNowP2Y12 analysis, tertile 1 had a higher PRU than tertiles 2 and 3 in LOF carriers, and there was no difference among tertiles in non-carriers. The highest incidence of intra-stent thrombus was observed in tertile 1 followed by tertiles 2 and 3 in LOF carriers, whereas there was no such difference in non-carriers. Multivariate analysis revealed that LOF carriers and PON1 activity tertile 1 were independent predictors of intra-stent thrombus in all patients. In LOF carriers, tertile 1 was the only independent predictor for intra-stent thrombus. Low PON1 activity is associated with a low response to clopidogrel and a high frequency of intra-stent thrombus only in LOF carriers. © 2013.

  7. Interaction between platelet-derived microRNAs and CYP2C19*2 genotype on clopidogrel antiplatelet responsiveness in patients with ACS.

    PubMed

    Peng, Li; Liu, Jun; Qin, Liuan; Liu, Jia; Xi, Shaozhi; Lu, Caiyi; Yin, Tong

    2017-09-01

    Both platelet-derived microRNAs and the genotype of CYP2C19*2 were implicated for the variability of clopidogrel antiplatelet responsiveness. However, their interaction on the antiplatelet responsiveness of clopidogrel in patients with acute coronary syndrome (ACS) remains unknown. Consecutive clopidogrel-treated patients with ACS were recruited, with their antiplatelet responsiveness evaluated by the relative platelet inhibition (RI), as measured by light transmittance aggregometry (LTA) at baseline and 5days' after the maintenance treatment of clopidogrel. Extreme cases were selected according to the octiles of RI value. Expression of the microRNAs targeting the mRNAs of P2RY12 was analyzed in the platelet of the extreme cases. Genotyping of CYP2C19*2 was performed for each extreme case. Among the included 272 ACS patients, 21 cases were screened as the extremely high-responders with RI>84%, and 18 as the extremely low-responders with RI<10%. Bioinformatics tools predicted the candidate microRNAs of miR-223, miR-221, and miR-21 could bind directly to the mRNA of P2RY12. Compared with the extremely low-responders, the expression of miR-223, miR-221, and miR-21 was significantly higher in the extremely high-responders (miR-223: 7.18±2.95 vs. 0.99±0.64, p=0.022; miR-221: 3.60±2.54 vs. 1.14±0.81, p=0.004; miR-21: 4.36±3.33 vs. 2.31±1.69, p=0.01). ROC curve showed ideal discriminatory power of the platelet-derived miRNAs for the prediction of clopidogrel antiplatelet responsiveness (c-index=0.70 for miR-223; c-index=0.76 for miR-221; c-index=0.79 for miR-21). After stratified by the carrier status of CYP2C19*2, the association between platelet-derived miRNAs and clopidogrel antiplatelet responsiveness could be found only in CYP2C19*2 carriers, but not in non-carriers. Platelet-derived miRNAs (miR-223, miR-221 and miR-21) are independently associated with clopidogrel antiplatelet responsiveness in ACS patients. However, the association could be influenced by the

  8. [Stent thrombosis and clopidogrel response variability: is the genetic test useful in clinical practice?].

    PubMed

    Notarangelo, Maria Francesca; Marziliano, Nicola; Giacalone, Rossella; Demola, Maria Antonietta; Conte, Giulio; Mantovani, Francesco; Ardissino, Diego

    2011-10-01

    The antiplatelet agent clopidogrel is an effective drug for the prevention of thrombotic events in patients with acute coronary syndrome and in those undergoing percutaneous coronary intervention with the deployment of a coronary stent. However, it has been reported that, despite adequate treatment, about 30% of patients continue to show the high degree of platelet reactivity that is central to the development of atherothrombotic complications and poorer clinical outcomes. Up to 13% of those taking clopidogrel experience a recurrent ischemic event during the first year after acute coronary syndrome, 1-3% experience subacute stent thrombosis after percutaneous coronary intervention probably due to a poor drug response, and about 1.5% experience major bleeding mainly due to an enhanced response. Recent research findings have highlighted the role of genetic variations in determining antiplatelet response variability, and this has aroused interest in genotyping all thienopyridine-eligible patients in order to identify those who would be at increased risk of harm if treated with clopidogrel. However, it remains to be determined whether this information is necessary or sufficient for risk stratification. Only when there are clinical data to support the hypothesis that genotype-guided therapy reduces the rate of ischemic and bleeding events will it be possible to justify the use of genetic testing in all potential patients. When that happens, genotype-guided antiplatelet therapy will also be available in the field of cardiovascular medicine.

  9. Clopidogrel resistance: what's new?

    PubMed

    Cuisset, Thomas; Cayla, Guillaume; Silvain, Johanne

    2010-01-01

    The concept of clopidogrel resistance emerged several years ago. Since then, many studies have been performed to elucidate the mechanisms and potential clinical impact of this biological finding. These studies identified complex mechanisms, including drug-drug interactions, genetic polymorphisms and clinical factors, and showed consistently the clinical relevance of the variability of clopidogrel response, with higher ischaemic risk in low-responders or non-responders, and higher bleeding risk in hyper-responders. Several strategies for overcoming clopidogrel resistance have been evaluated in small clinical studies, but the benefit of tailored antiplatelet therapy has yet to be validated in large randomized trials, which are currently ongoing. Upcoming antiplatelet drugs that are more potent will change the field of antiplatelet therapy in acute coronary syndromes. The future of antiplatelet therapy sounds more complex, with different drugs, and tailored therapy based on platelet tests and/or genetic testing, but it will lead us to propose a more individualized therapy, which hopefully will improve patient outcome. Copyright 2010 Elsevier Masson SAS. All rights reserved.

  10. Decreased platelet responsiveness to clopidogrel correlates with CYP2C19 and PON1 polymorphisms in atherosclerotic patients.

    PubMed

    Marchini, J F M; Pinto, M R; Novaes, G C; Badran, A V; Pavão, R B; Figueiredo, G L; Lago, I M; Lima-Filho, M O; Lemos, D C; Tonani, M; Antloga, C M; Oliveira, L; Lorenzi, J C; Marin-Neto, J A

    2017-01-09

    Clopidogrel and aspirin are the most commonly used medications worldwide for dual antiplatelet therapy after percutaneous coronary intervention. However, clopidogrel hyporesponsiveness related to gene polymorphisms is a concern. Populations with higher degrees of genetic admixture may have increased prevalence of clopidogrel hyporesponsiveness. To assess this, we genotyped CYP2C19, ABCB1, and PON1 in 187 patients who underwent percutaneous coronary intervention. Race was self-defined by patients. We also performed light transmission aggregometry with adenosine diphosphate (ADP) and arachidonic acid during dual antiplatelet therapy. We found a significant difference for presence of the CYP2C19*2 polymorphism between white and non-white patients. Although 7% of patients had platelet resistance to clopidogrel, this did not correlate with any of the tested genetic polymorphisms. We did not find platelet resistance to aspirin in this cohort. Multivariate analysis showed that patients with PON1 and CYP2C19 polymorphisms had higher light transmission after ADP aggregometry than patients with native alleles. There was no preponderance of any race in patients with higher light transmission aggregometry. In brief, PON1 and CYP2C19 polymorphisms were associated with lower clopidogrel responsiveness in this sample. Despite differences in CYP2C19 polymorphisms across white and non-white patients, genetic admixture by itself was not able to identify clopidogrel hyporesponsiveness.

  11. Decreased platelet responsiveness to clopidogrel correlates with CYP2C19 and PON1 polymorphisms in atherosclerotic patients

    PubMed Central

    Marchini, J.F.M.; Pinto, M.R.; Novaes, G.C.; Badran, A.V.; Pavão, R.B.; Figueiredo, G.L.; Lago, I.M.; Lima-Filho, M.O.; Lemos, D.C.; Tonani, M.; Antloga, C.M.; Oliveira, L.; Lorenzi, J.C.; Marin-Neto, J.A.

    2017-01-01

    Clopidogrel and aspirin are the most commonly used medications worldwide for dual antiplatelet therapy after percutaneous coronary intervention. However, clopidogrel hyporesponsiveness related to gene polymorphisms is a concern. Populations with higher degrees of genetic admixture may have increased prevalence of clopidogrel hyporesponsiveness. To assess this, we genotyped CYP2C19, ABCB1, and PON1 in 187 patients who underwent percutaneous coronary intervention. Race was self-defined by patients. We also performed light transmission aggregometry with adenosine diphosphate (ADP) and arachidonic acid during dual antiplatelet therapy. We found a significant difference for presence of the CYP2C19*2 polymorphism between white and non-white patients. Although 7% of patients had platelet resistance to clopidogrel, this did not correlate with any of the tested genetic polymorphisms. We did not find platelet resistance to aspirin in this cohort. Multivariate analysis showed that patients with PON1 and CYP2C19 polymorphisms had higher light transmission after ADP aggregometry than patients with native alleles. There was no preponderance of any race in patients with higher light transmission aggregometry. In brief, PON1 and CYP2C19 polymorphisms were associated with lower clopidogrel responsiveness in this sample. Despite differences in CYP2C19 polymorphisms across white and non-white patients, genetic admixture by itself was not able to identify clopidogrel hyporesponsiveness. PMID:28076455

  12. The CYP2C19(∗)1/(∗)2 Genotype Does Not Adequately Predict Clopidogrel Response in Healthy Malaysian Volunteers.

    PubMed

    Nasyuhana Sani, Yanti; Sheau Chin, Lim; Luen Hui, Lim; Mohd Redhuan Shah Edwin, Nur Elyana Yazmin; Teck Hwa, Goh; Serebruany, Victor L; Kah Hay, Yuen

    2013-01-01

    Background. The CYP2C19∗2 allele may be associated with a reduced antiplatelet effect for clopidogrel. Here, we assessed whether CYP2C19∗2 alleles correlate with clopidogrel responsiveness following the administration of clopidogrel in healthy Malaysian volunteers. Methods. Ninety volunteers were genotyped for CYP2C19∗2 and CYP2C19∗3 alleles. Forty-five of 90 volunteers were included in the clopidogrel response studies and triaged into three genotypes, namely, CYP2C19∗1/∗1 (n = 17), CYP2C19∗1/∗2 (n = 21), and CYP2C19∗2/∗2 (n = 7). All subjects received 300 mg of clopidogrel, and platelet reactivity was assessed after a four-hour loading utilizing the VerifyNow-P2Y12 assay. Platelet activity was reported using P2Y12 reaction units (PRUs), and nonresponder status was prespecified at PRU ≥ 230. Results. Following clopidogrel intake, CYP2C19∗2/∗2 carriers had a significantly higher mean PRU compared to the CYP2C19∗1/∗2 and CYP2C19∗1/∗1 (291.0 ± 62.1 versus 232.5 ± 81.4 versus 147.4 ± 87.2 PRU, P < 0.001) carriers. Almost half of the participants (46.7%) were found to be nonresponders (3 were CYP2C19∗1/∗1, 11 were CYP2C19∗1/∗2, and 7 were CYP2C19∗2/∗2). Conclusion. In healthy Malaysian volunteers, CYP2C19∗2 allele was associated with a decrease in platelet responsiveness to clopidogrel. However, clopidogrel nonresponders can be found not only in the carriers of CYP2C19∗2/∗2, but also in the carriers of CYP2C19∗1/∗2 and CYP2C19∗1/∗1. The present paper demonstrated that genotype information does not correlate with clopidogrel response, and genotyping may represent a less robust approach compared to platelet activity testing in guiding clopidogrel therapy.

  13. Management Strategies for Clopidogrel Hypersensitivity.

    PubMed

    Beavers, Craig J; Carris, Nicolas W; Ruf, Kathryn M

    2015-06-01

    Clopidogrel is a cornerstone of dual antiplatelet therapy. Hypersensitivity reactions potentially limit the use of this treatment and present a significant clinical challenge. The authors have developed recommendations for the management of clopidogrel hypersensitivity with consideration for the etiology, pathophysiology, and critical evaluation of potential management strategies. The clopidogrel hypersensitivity reaction is complex in mechanism and presents generally around day 5 of treatment. Generalized reactions are most common, but the reaction may also be localized or systemic. Screening patients for hypersensitivity is not always possible because the type IV delayed reaction is not detected reliably by conventional skin prick, intradermal challenge, or patch testing. Proposed strategies for management of clopidogrel hypersensitivity include treatment of the reaction with corticosteroids, clopidogrel desensitization, substituting an alternative P2Y12 inhibitor, or clopidogrel avoidance. The safety, efficacy, and cost of each potential strategy must be considered when managing a patient with clopidogrel hypersensitivity.

  14. The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study: Variation in Platelet Response to Clopidogrel and Aspirin.

    PubMed

    Bozzi, Laura M; Mitchell, Braxton D; Lewis, Joshua P; Ryan, Kathy A; Herzog, William R; O'Connell, Jeffrey R; Horenstein, Richard B; Shuldiner, Alan R; Yerges-Armstrong, Laura M

    2016-01-01

    Clopidogrel and aspirin are commonly prescribed anti-platelet medications indicated for patients who have experienced, or are at risk for, ischemic cardiovascular events. The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study was designed to characterize determinants of clopidogrel and dual anti-platelet therapy (DAPT) response in a healthy cohort of Old Order Amish from Lancaster, PA. Following a loading dose, clopidogrel was taken once a day for 7 days. One hour after the last dose of clopidogrel, 325 mg of aspirin was given. Ex vivo platelet aggregometry was performed at baseline, post-clopidogrel, and post-DAPT. Platelet aggregation measurements were significantly lower after both interventions for all agonists tested (p <0.05), although there was large inter-individual variation in the magnitude of anti-platelet response. Female sex and older age were associated with higher platelet aggregation at all three time-points. Change in aggregation was correlated among the various agonists at each time point. Heritability (h2) of change in platelet aggregation was significant for most traits at all time-points (range h2=0.14-0.57). Utilization of a standardized, short-term intervention provided a powerful approach to investigate sources of variation in platelet aggregation response due to drug therapy. Further, this short-term intervention approach may provide a useful paradigm for pharmacogenomics studies.

  15. Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response.

    PubMed

    Kreutz, Rolf P; Owens, Janelle; Jin, Yan; Nystrom, Perry; Desta, Zeruesenay; Kreutz, Yvonne; Breall, Jeffrey A; Li, Lang; Chiang, Chienwei; Kovacs, Richard J; Flockhart, David A

    2013-01-01

    Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 μM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.

  16. Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults.

    PubMed

    Jiang, Xi-Ling; Samant, Snehal; Lewis, Joshua P; Horenstein, Richard B; Shuldiner, Alan R; Yerges-Armstrong, Laura M; Peletier, Lambertus A; Lesko, Lawrence J; Schmidt, Stephan

    2016-01-20

    Clopidogrel (Plavix®), is a widely used antiplatelet agent, which shows high inter-individual variability in treatment response in patients following the standard dosing regimen. In this study, a physiology-directed population pharmacokinetic/pharmacodynamic (PK/PD) model was developed based on clopidogrel and clopidogrel active metabolite (clop-AM) data from the PAPI and the PGXB2B studies using a step-wise approach in NONMEM (version 7.2). The developed model characterized the in vivo disposition of clopidogrel, its bioactivation into clop-AM in the liver and subsequent platelet aggregation inhibition in the systemic circulation reasonably well. It further allowed the identification of covariates that significantly impact clopidogrel's dose-concentration-response relationship. In particular, CYP2C19 intermediate and poor metabolizers converted 26.2% and 39.5% less clopidogrel to clop-AM, respectively, compared to extensive metabolizers. In addition, CES1 G143E mutation carriers have a reduced CES1 activity (82.9%) compared to wild-type subjects, which results in a significant increase in clop-AM formation. An increase in BMI was found to significantly decrease clopidogrel's bioactivation, whereas increased age was associated with increased platelet reactivity. Our PK/PD model analysis suggests that, in order to optimize clopidogrel dosing on a patient-by-patient basis, all of these factors have to be considered simultaneously, e.g. by using quantitative clinical pharmacology tools.

  17. C3435T polymorphism of the ABCB1 gene is associated with poor clopidogrel responsiveness in a Mexican population undergoing percutaneous coronary intervention.

    PubMed

    Calderón-Cruz, Beatriz; Rodríguez-Galván, Karen; Manzo-Francisco, Luis Antonio; Vargas-Alarcón, Gilberto; Fragoso, José Manuel; Peña-Duque, Marco Antonio; Reyes-Gómez, Carlos Alberto; Martínez-Ríos, Marco Antonio; De la Peña-Díaz, Aurora

    2015-11-01

    Clopidogrel is a pro-drug and its intestinal absorption is limited by the P-glycoprotein encoded by the ABCB1 gene. It is metabolized hepatically by cytochrome P450 enzymes encoded by CYP genes to produce an active metabolite that antagonizes the P2Y12 platelet receptor. Some patients exhibit poor clopidogrel responsiveness due to polymorphisms, resulting in thrombotic events. The aim of this study was to determine the relationship between poor clopidogrel responsiveness and the ABCB1, CYP and P2RY12 gene polymorphisms among patients undergoing percutaneous coronary intervention (PCI). Two hundred seventy-six patients who underwent PCI were included in this study. Clopidogrel responsiveness was determined via optical aggregometry in platelet-rich plasma using 10 μM ADP. Patients exhibiting a platelet aggregation response higher than 70% were classified as poor responders. The genetic polymorphisms were analyzed via real-time PCR. Poor responsiveness to clopidogrel was noted in 22.1% of the patients. The TT genotype of the C3435T polymorphism of the ABCB1 gene and omeprazole usage were each associated with poor clopidogrel responsiveness (Exp (β) 2.73, p=0.009 and Exp (β) 3.86, p=0.04, respectively). Poor clopidogrel responsiveness is associated with the TT genotype of the C3435T polymorphism of the ABCB1 gene. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Does "smoker's paradox" exist in clopidogrel-treated Turkish patients with acute coronary syndrome.

    PubMed

    Edem, Efe; Kirdök, Ali Hikmet; Kınay, Ahmet Ozan; Tekin, Ümit İlker; Taş, Sedat; Alpaslan, Erkan; Pabuccu, Mustafa Türker; Akdeniz, Bahri

    2016-01-01

    Previously conducted studies revealed that smoking enhanced the efficacy of clopidogrel by increasing formation of the active metabolite (AM) from the prodrug through induction of the cytochrome CYP1A2. The expression of cytochrome enzymes depends on genotype and no data exists in literature conducted in Turkish patients comparing the clopidogrel responsiveness between active smokers and non-active smokers treated with clopidogrel. In this study, our aim was to investigate the clopidogrel responsiveness in clopidogrel-treated Turkish acute coronary syndrome (ACS) patients according to their smoking status. We retrospectively enrolled 258 patients who were hospitalized due to ACS. Clinical variables of the patients, especially smoking status were recorded. Clopidogrel resistance was evaluated by using adenosine diphosphate (ADP) induced platelet aggregometry. Clopidogrel resistance was detected as a change in maximal aggregation ≤20% from baseline. A total of 139 patients were active smokers while 12 were former smokers. 107 patients did not have a history of smoking. Ten of the smokers were hyporesponsive to clopidogrel, whereas 36 of non-smokers were hyporesponsive to clopidogrel (p < 0.001). Receiver-operating characteristic curve analysis demonstrated that Au-min value >612.5 predicted the clopidogrel resistance with a sensitivity of 60% (OR: 100.65, %95 CI = 19.996-506.615 p < 0.001). Results of this study demonstrated that ADP responses were lower in smokers receiving clopidogrel and aspirin than in non-smokers receiving the same drug regimen. This finding indicates that smoking was related to an enhanced clopidogrel responsiveness in Turkish patients hospitalized due to ACS, suggesting that "smoker's paradox" probably exists in Turkish ACS patients.

  19. The variability of platelet response to aspirin and clopidogrel: revisiting the Caprie, Cure, Credo, and Match trials.

    PubMed

    Myers, Robert I

    2005-10-01

    In a significant number of patients, platelets do not respond to aspirin and/or clopidogrel. Furthermore, this lack of response has recently been shown to affect cardiovascular outcome. At the time of the CAPRIE, CURE, CREDO, and MATCH studies, no in vitro assessment was made to determine platelet response. In vitro platelet response should be considered as an important correctable risk factor for atherosclerotic events.

  20. [Pharmacoeconomic evaluation of clopidogrel in acute coronary syndromes. Long-term treatment, secondary prophylaxis, and percutaneous coronary intervention].

    PubMed

    Bramkamp, Matthias; Szucs, Thomas D

    2008-02-01

    Clopidogrel, a thienopyridine antiplatelet agent, is an adenosine diphosphate (ADP) receptor antagonist. Clopidogrel inhibits ADP binding to its platelet receptor and subsequent ADP-mediated activation of the glycoprotein IIb/IIIa complex, thus inhibiting platelet aggregation. Clopidogrel irreversibly modifies the ADP receptor so platelets are affected for the remainder of their life span. The treatment of acute coronary syndromes consists of an inpatient diagnosis and inpatient treatment usually done in an emergency room and intensive care unit and a long-term secondary prophylaxis of the underlying condition, coronary artery disease. Therefore, efficacy of different treatments and their implication on costs have to be examined over a long time period. The cost perspective (hospital, society, country) is another important point. In each country different charges for drugs, medical procedures and hospitalization are existing; varying drug costs may result in a more or less cost-effective ratio of a treatment. Furthermore, not only direct medical costs, but also implications on indirect costs should be taken into account when measuring cost-effectiveness of treatments.Worldwide, cardiovascular diseases account for a significant burden of hospital and societal costs. In particular for colleagues running their own private practice, cost-consciousness has become important in recent times. On the other hand, there has to be carried the duty to accord patients the best possible treatment. This - against the background of ethical responsibility, physicians can come into a conflict - continues to require cost-effectiveness studies in the future. By means of the set-forth results configurations can be seen in which clopidogrel has both, a benefit on the medical and on the economic side of view. From most of the quoted analyses application of clopidogrel was warrantable and the scope of costs within the amount of established cardiovascular therapies.

  1. Positive clinical response to clopidogrel is independent of paraoxonase 1 Q192R and CYP2C19 genetic variants.

    PubMed

    Martínez-Quintana, Efrén; Medina-Gil, José M; Rodríguez-González, Fayna; Garay-Sánchez, Paloma; Limiñana, José M; Saavedra, Pedro; Tugores, Antonio

    2014-08-01

    There is increasing controversy about the influence of serum paraoxonase type 1 and cytochrome CYP2C19 in the conversion of clopidogrel to its pharmaceutically active metabolite. The effect of concomitant medication with the proton pump inhibitor omeprazole has been also subject of intense scrutiny. We present a cohort of 263 patients receiving anti-platelet aggregation treatment with clopidogrel and aspirin for 1 year. The paraoxonase 1 gene Q192R variant along with the presence of CYP2C19*2 and *3 loss of function alleles, concomitant medication with proton pump inhibitors and known cardiovascular risk factors were examined to determine their influence in disease relapse due to an ischaemic event during the 12 month treatment period. The low number of patients suffering a relapse (20 out of 263), indicates that double anti-aggregation therapy with aspirin and clopidogrel was very effective in our patients. Among the relapsers, evidence of coronary heart disease was the most influencial factor affecting response to therapy, while the presence of the paraoxonase 1 Q192R variant, loss of function of CYP2C19, and concomitant medication with omeprazole were non-significant.

  2. Clopidogrel versus aspirin in patients with recent ischemic stroke and established peripheral artery disease: an economic evaluation in a Chinese setting.

    PubMed

    Li, Te; Liu, Maobai; Ben, He; Xu, Zhenxing; Zhong, Han; Wu, Bin

    2015-06-01

    Clopidogrel or aspirin are indicated for patients with recent ischemic stroke (IS) or established peripheral artery disease (PAD). We compared the cost effectiveness of clopidogrel with that of aspirin in Chinese patients with recent IS or established PAD. A discrete-event simulation was developed to evaluate the economic implications of secondary prevention with clopidogrel versus aspirin. All available evidence was derived from clinical studies. Costs from a Chinese healthcare perspective in 2013 US dollars and quality-adjusted life-years (QALYs) were projected over patients' lifetimes. Uncertainties were addressed using sensitivity analyses. Compared with aspirin, clopidogrel yielded a marginally increased life expectancy by 0.46 and 0.21 QALYs at an incremental cost-effectiveness ratio of $US5246 and $US9890 per QALY in patients with recent IS and established PAD, respectively. One-way sensitivity analyses showed that the evaluation of patients with PAD and recent IS was robust except for the parameter of patient age. Given a willingness-to-pay of $US19,877 per QALY gained, clopidogrel had a probability of 90 and 68% of being cost effective in the recent IS or established PAD subgroups compared with aspirin, respectively. The analysis suggests that clopidogrel for secondary prevention is cost effective for patients with either PAD or recent IS in a Chinese setting in comparison with aspirin.

  3. Evidence of platelet sensitization to ADP following discontinuation of clopidogrel therapy in patients with stable coronary artery disease.

    PubMed

    Lordkipanidzé, Marie; Diodati, Jean G; Schampaert, Erick; Palisaitis, Donald A; Pharand, Chantal

    2015-01-01

    Epidemiological studies have linked clopidogrel discontinuation with an increased incidence of ischemic events. This has led to the hypothesis that clopidogrel discontinuation may result in a pharmacological rebound. We evaluated the impact of clopidogrel discontinuation on platelet function. Platelet aggregation was measured by light transmission aggregometry (LTA) in response to adenosine diphosphate (ADP) 0.5, 1, 1.5, 2.5, 5 and 10 µM and by VerifyNow® P2Y12, in 37 clinically stable coronary artery disease (CAD) patients scheduled to discontinue clopidogrel treatment, and 37 clinically stable CAD patients not taking clopidogrel. Platelet function was assessed the day before clopidogrel cessation and 1, 3, 7, 14, 21 and 28 days after. Clopidogrel had been initiated a median of 555 days (ranging from 200 to 2280 days) before the treating cardiologist recommended its discontinuation. All participants were taking aspirin, most commonly 80 mg daily although a minority was prescribed 325 mg daily. Following clopidogrel discontinuation, VerifyNow® P2Y12 did not detect any rebound platelet activity, but ADP-induced LTA showed platelet sensitization to ADP, particularly at low ADP levels. Increased platelet activity was detectable seven days after clopidogrel cessation and remained higher than in controls 28 days after discontinuation. No clinical event occurred in any of the participants during the 28 days following clopidogrel cessation. In conclusion, platelet sensitization to ADP as a consequence of chronic clopidogrel administration may partially explain the recrudescence of ischemic events following clopidogrel discontinuation in otherwise stable coronary artery patients.

  4. The evaluation of clopidogrel use in perioperative general surgery patients: a prospective randomized controlled trial.

    PubMed

    Chu, Edward W; Chernoguz, Artur; Divino, Celia M

    2016-06-01

    The perioperative safety profile of clopidogrel, a potent antiplatelet agent used in the management of cardiovascular disease, is unknown, and there are no evidence-based guidelines recommending for either its interruption or continuation at this time. The aim of this study was to determine whether patients who are maintained on clopidogrel before general surgical procedures are at increased risk of perioperative bleeding complications. Patients receiving clopidogrel at the time of elective general surgery were randomized to either discontinue clopidogrel 1 week before surgery (group A) or continue clopidogrel into surgery (group B). All other antiplatelet and anticoagulant agents were discontinued before surgery. The primary end points were perioperative bleeding requiring intraoperative or postoperative transfusion of blood or blood components and bleeding-related readmission, reoperation, or mortality within 90 days of surgery. The secondary end points were perioperative myocardial infarction or cerebrovascular accidents within 90 days of surgery. Thirty-nine patients were enrolled and underwent 43 general surgical operations. Twenty-one procedures were randomized to group A and 22 to group B. The most commonly performed individual procedures were open inguinal hernia repair (23%), laparoscopic cholecystectomy (21%), open ventral hernia repair (15%), laparoscopic ventral hernia repair (11%), and laparoscopic inguinal hernia repair (9%). No perioperative mortalities, bleeding events requiring blood transfusion, or reoperations occurred. One readmission for intra-abdominal hematoma requiring percutaneous drainage occurred in each group (group A: 4.8% vs group B: 4.5%; P = 1.0). No myocardial infarctions or cerebrovascular accidents were observed or reported. The outcomes from this prospective study suggest that, patients undergoing commonly performed elective general surgical procedures can be safely maintained on clopidogrel without increased perioperative

  5. CYP2C19 polymorphisms and antiplatelet effects of clopidogrel in acute ischemic stroke in China.

    PubMed

    Jia, Dong-mei; Chen, Zhi-bin; Zhang, Mei-juan; Yang, Wen-jie; Jin, Jia-li; Xia, Yong-quan; Zhang, Chun-lei; Shao, Yuan; Chen, Cong; Xu, Yun

    2013-06-01

    Little research regarding genotypes and clopidogrel response related to acute ischemic stroke has been published. This study was conducted to investigate whether the polymorphisms of receptors or enzymes involved in the metabolic process of clopidogrel affect clopidogrel response and prognosis related to acute stroke. A total of 259 patients with acute ischemic stroke were enrolled in this study; all received follow-up evaluations 3 and 6 months after clopidogrel treatment. CYP2C19, CYP3A4, and P2Y12 were screened. The adenosine diphosphate-induced platelet aggregation test, the National Institutes of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS) were used, and blood vascular events were evaluated. The difference before and after clopidogrel treatment on adenosine diphosphate-induced platelet aggregation was significantly smaller in patients carrying 1 or 2 CYP2C19 loss-of-function alleles (*2, *3) compared with patients carrying none. Patients with none had better outcomes than patients with CYP2C19 loss-of-function alleles, as demonstrated by NIHSS and mRS scores at 3 and 6 months after treatment. Regression analysis showed that CYP2C19 was an independent predictor of clopidogrel resistance. CYP2C19 genotypes had significant impact on clopidogrel response and prognosis of patients with stroke. Clinical Trial Registration Information- URL: http://www.chictr.org/. Unique Identifier: ChiCTR-OCH-12002681.

  6. New clopidogrel napadisilate salt and its solid dispersion with improved stability and bioequivalence to the commercial clopidogrel bisulphate salt in beagle dogs.

    PubMed

    Kim, Yong-Il; Kim, Kyung Soo; Suh, Kwee-Hyun; Shanmugam, Srinivasan; Woo, Jong Soo; Yong, Chul Soon; Choi, Han-Gon

    2011-08-30

    The purpose of this study was to develop a novel clopidogrel napadisilate-loaded solid dispersion with improved stability and bioequivalence to the clopidogrel bisulphate-loaded commercial product. Clopidogrel napadisilate prepared in this study appeared as a white crystalline powder unlike clopidogrel base. However, this salt did not improve the solubility of clopidogrel, even with improved stability compared to clopidogrel bisulphate. To improve the solubility of clopidogrel napadisilate, a novel clopidogrel napadisilate-loaded solid dispersion was prepared by the spray-drying technique using HPMC and colloidal silica, and the physicochemical properties, dissolution and bioavailability in beagle dogs were evaluated compared to the clopidogrel bisulphate-loaded commercial product. The solid dispersion composed of clopidogrel napadisilate, HPMC and colloidal silica at a weight ratio of 11.069/3/3.5 improved solubility by 6.5-fold compared to clopidogrel napadisilate, even if it did not improve drug solubility compared to clopidogrel bisulphate. However, unlike clopidogrel bisulphate, this formulation improved the stability of clopidogrel. Furthermore, the clopidogrel napadisilate solid dispersion-loaded tablet showed similar dissolution to the clopidogrel bisulphate-loaded commercial product and was bioequivalent to the commercial product in beagle dogs. Thus, this clopidogrel napadisilate-loaded solid dispersion could be a promising candidate for improving the stability and bioavailability of clopidogrel.

  7. Resistance to Clopidogrel among Iranian Patients Undergoing Angioplasty Intervention

    PubMed Central

    Haji Aghajani, Mohammad; Kobarfard, Farzad; Safi, Olia; Sheibani, Kourosh; Sistanizad, Mohammad

    2013-01-01

    To study the resistance to standard dosage of clopidogrel among Iranian patients following percutaneous coronary intervention measured by platelet aggregation test. Patients undergoing percutaneous coronary intervention in Imam Hussein Medical center, Tehran, Iran, who were under treatment with aspirin, but had no history of clopidogrel usage, entered the study. Patients received standard dosage of clopidogrel (Plavix®, Sanofi, France, 600 mg loading dose and 75 mg/day afterward). Platelet aggregation was measured using light transmission aggregometer. The response to the drug was categorized as complete resistance (platelet aggregation decreased less than 10%), intermediate resistance (platelet aggregation decreased between 10 to 30%) and complete response (platelet aggregation decreased to 30% or more). All patients were evaluated for major adverse cardio vascular events one month after the angioplasty based on MACE criteria by phone contact. Thirty-one patients with a mean age of 59 ± 13 entered the study. Sixty-five percent of patients showed complete response to clopidogrel (95% CI: 45% to 81%), 22% showed intermediate resistance (95% CI: 10-41%) and 13% showed complete resistance (95% CI: 4-30%). One month after the angioplasty, no major adverse cardiovascular event was recorded. Based on our findings, it seems that there is no major difference between Iranian population and other studies regarding the resistance to clopidogrel. Due to the limited number of participants in our study, further investigations with higher number of patients are recommended to more precisely calculate the percentage of resistance among Iranian patients. PMID:24250685

  8. PON1 Q192R genetic variant and response to clopidogrel and prasugrel: pharmacokinetics, pharmacodynamics, and a meta-analysis of clinical outcomes.

    PubMed

    Mega, Jessica L; Close, Sandra L; Wiviott, Stephen D; Man, Michael; Duvvuru, Suman; Walker, Joseph R; Sundseth, Scott S; Collet, Jean-Philippe; Delaney, Jessica T; Hulot, Jean-Sebastien; Murphy, Sabina A; Paré, Guillaume; Price, Matthew J; Sibbing, Dirk; Simon, Tabassome; Trenk, Dietmar; Antman, Elliott M; Sabatine, Marc S

    2016-04-01

    response to clopidogrel, nor was it associated with the response to prasugrel. The meta-analysis reinforced a lack of a significant association between Q192R and cardiovascular outcomes in clopidogrel-treated patients.

  9. Influence of Cyp2c19*2 Gene Variant on Therapeutic Response During Clopidogrel Treatment in Patients with Carotid Artery Stenosis

    PubMed Central

    Ignjatović, Svetlana; Rakićević, Ljiljana; Kusić-Tišma, Jelena; Radojković, Dragica; Čalija, Branko; Strugarević, Evgenija; Radak, Ðorđe; Kovač, Mirjana

    2016-01-01

    Summary Background Despite the proven clinical effect of oral antiplatelet drugs, a considerable number of patients do not have an adequate response to clopidogrel. The aim of our study was to determine the influence of CYP2C19*2 loss-of-function variant allele on clopidogrel responsiveness in patients with carotid artery stenosis. Methods One hundred and twelve patients with carotid artery stenosis undergoing endarterectomy were included in this one-year prospective study. All of them received clopidogrel (75 mg daily) for at least 30 days after the intervention. They were followed from the moment of hospital admission. CYP2C19*2 genotyping was performed by TaqMan Assay. The influence of CYP2C19*2 variant allele on clopidogrel platelet reactivity was determined using multiple-electrode aggregometry (MEA). Results Genotyping results showed that 82 (73.2%) patients were homozygous for wild type, 29 (25.9%) were heterozygous for the CYP2C19*2 allele and 1 (0.9%) was CYP2C19*2 homozygous. After 24 hours, among those with the wild type 29.3% were clopidogrel responders, and in those with the CYP2C19*2 alleles 10%. In the wild type group, 74.4% were clopidogrel responders after 7 days of taking the drug; 82.9% after 30 days of clopidogrel introduction, respectively. In patients with the CYP2C19*2 alleles the number of responders increased up to 46.7% after 7 days; 53.3% after 30 days of taking the drug, respectively. The risk for being a low-responder is higher for the patients heterozygous for the CYP2C19*2 allele vs. wild-type (OR 4.250, 95% CI 1.695-10.658, P<0.01). Conclusions The CYP2C19*2 loss-of-function variant allele has significant influence on clopidogrel response in patients with carotid artery stenosis undergoing endarterectomy. PMID:28356861

  10. Measuring aspirin resistance, clopidogrel responsiveness, and postprocedural markers of myonecrosis in patients undergoing percutaneous coronary intervention.

    PubMed

    Buch, Ashesh N; Singh, Suman; Roy, Probal; Javaid, Aamir; Smith, Kimberly A; George, Christopher E; Pichard, Augusto D; Satler, Lowell F; Kent, Kenneth M; Suddath, William O; Waksman, Ron

    2007-06-01

    Aspirin and clopidogrel are proven to prevent thromboembolic events during percutaneous coronary intervention (PCI). Enzyme release of creatine kinase-MB (CK-MB) enzyme during PCI has been associated with an increased risk of future adverse cardiac events. This study examined the correlation between measurements of aspirin resistance and the level of inhibition of the thienopyridine-specific P2Y12 platelet receptor and CK-MB release after PCI. We prospectively studied 330 patients with elective PCI treated with drug-eluting stents. Patients were pretreated with aspirin and clopidogrel. Patients with positive CK-MB or acute coronary syndrome and those on glycoprotein IIb/IIIa inhibitors were excluded. Serum assays of aspirin resistance (Ultegra Rapid Platelet Function Assay-ASA, Accumetrics) and clopidogrel resistance (Rapid Platelet Function Assay P2Y12, Accumetrics) were performed before PCI. Serum troponinI and CK-MB levels were measured at 8, 16, and 24 hours after PCI. Aspirin resistance unit (ARU) measurement > or =550 was detected in 12 patients (3.7%). Mean platelet reactivity unit (PRU; measurement of inhibition of P2Y12 activity) was 192.2 +/- 95.4 (lower PRU, more inhibition of P2Y12 receptor). There was no correlation between level of ARU or PRU and troponin I or CK-MB release after PCI at any time point. Only multivessel coronary disease was found to be a predictor of any increase in CK-MB in a multivariate analysis (odds ratio 2.2, 95% confidence interval 1.4 to 3.3, p = 0.0003). A positive correlation was found between levels of ARU and PRU. Target vessel revascularization/major adverse cardiac event rate at 6 months was 8.2% with no correlation between ARU or PRU and release of cardiac enzymes or occurrence of adverse cardiac events. In conclusion, this study does not support routine measurements of aspirin and clopidogrel resistance in stable patients undergoing PCI.

  11. Carboxylesterase 1 as a determinant of clopidogrel metabolism and activation.

    PubMed

    Zhu, Hao-Jie; Wang, Xinwen; Gawronski, Brian E; Brinda, Bryan J; Angiolillo, Dominick J; Markowitz, John S

    2013-03-01

    Clopidogrel pharmacotherapy is associated with substantial interindividual variability in clinical response, which can translate into an increased risk of adverse outcomes. Clopidogrel, a recognized substrate of hepatic carboxylesterase 1 (CES1), undergoes extensive hydrolytic metabolism in the liver. Significant interindividual variability in the expression and activity of CES1 exists, which is attributed to both genetic and environmental factors. We determined whether CES1 inhibition and CES1 genetic polymorphisms would significantly influence the biotransformation of clopidogrel and alter the formation of the active metabolite. Coincubation of clopidogrel with the CES1 inhibitor bis(4-nitrophenyl) phosphate in human liver s9 fractions significantly increased the concentrations of clopidogrel, 2-oxo-clopidogrel, and clopidogrel active metabolite, while the concentrations of all formed carboxylate metabolites were significantly decreased. As anticipated, clopidogrel and 2-oxo-clopidogrel were efficiently hydrolyzed by the cell s9 fractions prepared from wild-type CES1 transfected cells. The enzymatic activity of the CES1 variants G143E and D260fs were completely impaired in terms of catalyzing the hydrolysis of clopidogrel and 2-oxo-clopidogrel. However, the natural variants G18V, S82L, and A269S failed to produce any significant effect on CES1-mediated hydrolysis of clopidogrel or 2-oxo-clopidogrel. In summary, deficient CES1 catalytic activity resulting from CES1 inhibition or CES1 genetic variation may be associated with higher plasma concentrations of clopidogrel-active metabolite, and hence may enhance antiplatelet activity. Additionally, CES1 genetic variants have the potential to serve as a biomarker to predict clopidogrel response and individualize clopidogrel dosing regimens in clinical practice.

  12. Comparison of VerifyNow-P2Y12 test and Flow Cytometry for monitoring individual platelet response to clopidogrel. What is the cut-off value for identifying patients who are low responders to clopidogrel therapy?

    PubMed

    Godino, Cosmo; Mendolicchio, Loredana; Figini, Filippo; Latib, Azeem; Sharp, Andrew Sp; Cosgrave, John; Calori, Giliola; Cera, Michela; Chieffo, Alaide; Castelli, Alfredo; Maseri, Attilio; Ruggeri, Zaverio M; Colombo, Antonio

    2009-05-06

    Dual anti-platelet therapy with aspirin and a thienopyridine (DAT) is used to prevent stent thrombosis after percutaneous coronary intervention (PCI). Low response to clopidogrel therapy (LR) occurs, but laboratory tests have a controversial role in the identification of this condition. We studied LR in patients with stable angina undergoing elective PCI, all on DAT for at least 7 days, by comparing: 1) Flow cytometry (FC) to measure platelet membrane expression of P-selectin (CD62P) and PAC-1 binding following double stimulation with ADP and collagen type I either in the presence of prostaglandin (PG) E1; 2) VerifyNow-P2Y12 test, in which results are reported as absolute P2Y12-Reaction-Units (PRU) or % of inhibition (% inhibition). Thirty controls and 52 patients were analyzed. The median percentage of platelets exhibiting CD62P expression and PAC-1 binding by FC evaluation after stimulation in the presence of PG E1 was 25.4% (IQR: 21.4-33.1%) and 3.5% (1.7-9.4%), respectively. Only 6 patients receiving DAT (11.5%) had both values above the 1st quartile of controls, and were defined as LR. Evaluation of the same patients with the VerifyNow-P2Y12 test revealed that the area under the receiver-operating-characteristic (ROC) curve was 0.94 (95% CI: 0.84-0.98, p < 0.0001) for % inhibition and 0.85 (0.72-0.93, p < 0.005) for PRU. Cut-off values of ≤ 15% inhibition or > 213 PRU gave the maximum accuracy for the detection of patients defined as having LR by FC. In conclusion our findings show that a cut-off value of ≤ 15% inhibition or > 213 PRU in the VerifyNow-P2Y12 test may provide the best accuracy for the identification of patients with LR.

  13. Exome sequencing of extreme clopidogrel response phenotypes identifies B4GALT2 as a determinant of on-treatment platelet reactivity.

    PubMed

    Scott, S A; Collet, J-P; Baber, U; Yang, Y; Peter, I; Linderman, M; Sload, J; Qiao, W; Kini, A S; Sharma, S K; Desnick, R J; Fuster, V; Hajjar, R J; Montalescot, G; Hulot, J-S

    2016-09-01

    Interindividual variability in platelet aggregation is common among patients treated with clopidogrel and both high on-treatment platelet reactivity (HTPR) and low on-treatment platelet reactivity (LTPR) increase risks for adverse clinical outcomes. CYP2C19 influences clopidogrel response but only accounts for ∼12% of the variability in platelet reactivity. To identify novel variants implicated in on-treatment platelet reactivity, patients with coronary artery disease (CAD) with extreme pharmacodynamic responses to clopidogrel and wild-type CYP2C19 were subjected to exome sequencing. Candidate variants that clustered in the LTPR subgroup subsequently were genotyped across the discovery cohort (n = 636). Importantly, carriers of B4GALT2 c.909C>T had lower on-treatment P2Y12 reaction units (PRUs; P = 0.0077) and residual platelet aggregation (P = 0.0008) compared with noncarriers, which remained significant after adjusting for CYP2C19 and other clinical variables in both the discovery (P = 0.0298) and replication (n = 160; PRU: P = 0.0001) cohorts. B4GALT2 is a platelet-expressed galactosyltransferase, indicating that B4GALT2 c.909C>T may influence clopidogrel sensitivity through atypical cell-surface glycoprotein processing and platelet adhesion.

  14. Clinical, genetic and confounding factors determine the dynamics of the in vitro response/non response to clopidogrel.

    PubMed

    Gremmel, Thomas; Panzer, Simon

    2011-08-01

    Platelet inhibition by clopidogrel varies from one individual to the next. Further, in vitro high on-treatment residual adenosine-diphosphate inducible platelet reactivity (HRPR) is associated with an increased risk for major adverse cardiovascular events after percutaneous coronary intervention (PCI) with stent implantation. Recent studies identified numerous influencing factors for the antiplatelet effect of clopidogrel. Besides genetic predispositions, diverse clinical conditions as well as pharmacological interactions were shown to significantly impair clopidogrel-mediated platelet inhibition. Consequently, these influencing factors may affect clinical outcome after PCI and it is therefore desirable to identify cofounders of HRPR by platelet reactivity testing. It is apparent, that not all assays are sensitive to the same variables, and only cofounders of HRPR that are repeatedly identified by more than one test system may be clinically meaningful. However, treatment adjustment based on platelet function testing has not been associated with improved patients' outcome. This summary shall provide an overview over current knowledge on influencing factors for clopidogrel-mediated platelet inhibition and aid guidance for critical interpretation of in vitro obtained data on HRPR.

  15. The effects of clopidogrel and omeprazole on platelet function in normal dogs.

    PubMed

    Thames, B E; Lovvorn, J; Papich, M G; Wills, R; Archer, T; Mackin, A; Thomason, J

    2017-04-01

    Omeprazole is used concurrently with clopidogrel to reduce gastrointestinal adverse effects. In humans, the concurrent use of these two drugs can reduce the antiplatelet efficacy of clopidogrel. Our objective was to determine the effects of omeprazole and clopidogrel on platelet function in healthy dogs. A crossover study utilized turbidimetric aggregometry (ADP and collagen) and the PFA-100(®) with the collagen/ADP cartridge to evaluate platelet function in eight healthy dogs during the administration of clopidogrel (1 mg/kg/24 h p.o.), omeprazole (1 mg/kg/24 h p.o.), and a combination of clopidogrel and omeprazole. Drug metabolite concentrations were also measured. Compared to pretreatment, on Days 3 and 5, with ADP as the agonist, there was a significant decrease in maximum amplitude on aggregometry for both clopidogrel and clopidogrel/omeprazole groups. The following revealed no significant differences between clopidogrel and clopidogrel/omeprazole groups when compared on Days 3 and 5: maximum amplitude on aggregometry with ADP or collagen agonists, and PFA-100(®) closure times. When compared to the clopidogrel group, clopidogrel metabolite concentrations in the clopidogrel/omeprazole group were significantly higher on Days 3 and 5. The concurrent administration of omeprazole and clopidogrel in healthy dogs was associated with an increase in the plasma concentration of an inactive metabolite of clopidogrel, but does not significantly alter the antiplatelet effects of clopidogrel.

  16. Clopidogrel reduces the inflammatory response of lung in a rat model of decompression sickness.

    PubMed

    Bao, Xiao-Chen; Chen, Hong; Fang, Yi-Qun; Yuan, Heng-Rong; You, Pu; Ma, Jun; Wang, Fang-Fang

    2015-06-01

    Inflammation and platelet activation are critical phenomena in the setting of decompression sickness. Clopidogrel (Clo) inhibits platelet activation and may also reduce inflammation. The goal of this study was to investigate if Clo had a protective role in decompression sickness (DCS) through anti-inflammation way. Male Sprague-Dawley rats (n=111) were assigned to three groups: control+vehicle group, DCS+vehicle, DCS+Clo group. The experimental group received 50 mg/kg of Clo or vehicle for 3 days, then compressed to 1,600 kPa (150 msw) in 28 s, maintained at 150 msw for 242 s and decompressed to surface at 3m/s. In a control experiment, rats were also treated with vehicle for 3 days and maintained at atmospheric pressure for an equivalent period of time. Clinical assessment took place over a period of 30 min after surfacing. At the end, blood samples were collected for blood cells counts and cytokine detection. The pathology and the wet/dry ratio of lung tissues, immunohistochemical detection of lung tissue CD41 expression, the numbers of P-selectin positive platelets and platelet-leukocyte conjugates in blood were tested. We found that Clo significantly reduced the DCS mortality risk (mortality rate: 11/45 with Clo vs. 28/46 in the untreated group, P<0.01). Clo reduced the lung injury, the wet/dry ratio of lung, the accumulation of platelet and leukocyte in lung, the fall in platelet count, the WBC count, the numbers of activated platelets and platelet-leukocyte complexes in peripheral blood. It was concluded that Clo can play a protective role in decompression sickness through reducing post-decompression platelet activation and inflammatory process. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Genetics Home Reference: clopidogrel resistance

    MedlinePlus

    ... it. Clopidogrel (also known as Plavix) is an antiplatelet drug, which means that it prevents blood cell ... Version: How Blood Clots National Health Service (NHS): Antiplatelets, Clopidogrel (UK) Orphanet: Resistance to clopidogrel Patient Support ...

  18. Drug-drug interactions between clopidogrel and novel cardiovascular drugs.

    PubMed

    Pelliccia, Francesco; Rollini, Fabiana; Marazzi, Giuseppe; Greco, Cesare; Gaudio, Carlo; Angiolillo, Dominick J

    2015-10-15

    The combination of aspirin and the thienopyridine clopidogrel is a cornerstone in the prevention of atherothrombotic events. These two agents act in concert to ameliorate the prothrombotic processes stimulated by plaque rupture and vessel injury complicating cardiovascular disease. Guidelines recommend the use of clopidogrel in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention, and the drug remains the most utilized P2Y12 receptor inhibitor despite the fact that newer antiplatelet agents are now available. In recent years, numerous studies have shown inconsistency in the efficacy of clopidogrel to prevent atherothrombotic events. Studies of platelet function testing have shown variability in the response to clopidogrel. One of the major reason for this phenomenon lies in the interaction between clopidogrel and other drugs that may affect clopidogrel absorption, metabolism, and ultimately its antiplatelet action. Importantly, these drug-drug interactions have prognostic implications, since patients with high on-treatment platelet reactivity associated with reduced clopidogrel metabolism have an increased risk of ischemia. Previous systematic reviews have focused on drug-drug interactions between clopidogrel and specific pharmacologic classes, such as proton pump inhibitors, calcium channel blockers, and statins. However, more recent pieces of scientific evidence show that clopidogrel may also interact with newer drugs that are now available for the treatment of cardiovascular patients. Accordingly, the aim of this review is to highlight and discuss recent data on drug-drug interactions between clopidogrel and third-generation proton pump inhibitors, pantoprazole and lansoprazole, statins, pitavastatin, and antianginal drug, ranolazine.

  19. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment-elevation acute coronary syndromes: a systematic review and economic evaluation.

    PubMed

    Main, C; Palmer, S; Griffin, S; Jones, L; Orton, V; Sculpher, M; Henderson, R; Sudlow, C; Hawkins, N; Riemsma, R

    2004-10-01

    To review systematically the clinical effectiveness and the cost-effectiveness of clopidogrel used in combination with standard therapy including aspirin, compared with standard therapy alone for the treatment of non-ST-segment elevation acute coronary syndromes (ACS). Electronic databases. Manufacturers' submissions. Studies were selected using rigorous criteria. The quality of randomised controlled trials (RCTs) was assessed according to criteria based on NHS CRD Report No. 4, and the quality of systematic reviews was assessed according to the guidelines for the Database of Reviews of Effect (DARE) criteria. The quality of economic evaluations was assessed according to a specifically tailored checklist. The clinical effectiveness and cost-effectiveness of clopidogrel in combination with standard therapy compared with standard therapy alone were synthesised through a narrative review with full tabulation of the results of the included studies. In the economic evaluations, a cost-effectiveness model was constructed using the best available evidence to determine cost-effectiveness in a UK setting. One RCT (the CURE trial) was a randomised, double-blind, placebo-controlled trial of high quality and showed that clopidogrel in addition to aspirin was significantly more effective than placebo plus aspirin in patients with non-ST-segment elevation ACS for the composite outcome of death from cardiovascular causes, non-fatal myocardial infarction or stroke over the 9-month treatment period. However, clopidogrel was associated with a significantly higher number of episodes of both major and minor bleeding. The results from the five systematic reviews that assessed the adverse events associated with long-term aspirin use showed that aspirin was associated with a significantly higher incidence of haemorrhagic stroke, extracranial haemorrhage and gastrointestinal haemorrhage compared with placebo. Of the cost-effectiveness evidence reviewed, only the manufacturer's submission

  20. Tailored antiplatelet therapy to improve prognosis in patients exhibiting clopidogrel low-response prior to percutaneous coronary intervention for stable angina or non-ST elevation acute coronary syndrome.

    PubMed

    Paarup Dridi, Nadia; Johansson, Pär I; Lønborg, Jacob T; Clemmensen, Peter; Radu, Maria D; Qayyum, Abbas; Pedersen, Frants; Kollslid, Rudi; Helqvist, Steffen; Saunamäki, Kari; Kelbæk, Henning; Jørgensen, Erik; Engstrøm, Thomas; Holmvang, Lene

    2015-01-01

    To investigate whether an intensified antiplatelet regimen could improve prognosis in stable or non-ST elevation in acute coronary syndrome (ACS) patients exhibiting high on-treatment platelet reactivity (HTPR) on clopidogrel and treated with percutaneous coronary intervention (PCI). There is a wide variability in the platelet reactivity to clopidogrel and HTPR has been associated with a poor prognosis. In this observational study, 923 consecutive patients without ST-elevation myocardial infarction (STEMI) and adequately pre-treated with clopidogrel were screened for HTPR with multiple electrode aggregometry after assessment of the coronary anatomy. Patients were grouped based on their response to clopidogrel and the assigned antiplatelet strategy. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or stent thrombosis. HTPR was demonstrated in 237 patients (25.7%). Of these, 114 continued on conventional clopidogrel therapy, while the remaining 123 received intensified antiplatelet therapy with either double-dose clopidogrel (150 mg daily, n = 55) or the newer P2Y12-inhibitors, prasugrel or ticagrelor (n = 68) for at least 30 days after the index procedure. The median follow-up was 571 days (interquartile range, 373-746). Intensifying antiplatelet therapy reduced the rate of the composite endpoint (p < 0.001). After adjustment for potential confounders, HTPR in combination with conventional clopidogrel therapy remained independently associated with an increased risk of cardiovascular events (hazard ratio (HR), 2.92; 95% CI, 1.90-4.48), whereas intensified treatment reduced the risk to a level equivalent to that of patients exhibiting normal platelet reactivity (HR, 1.08; 95% CI, 0.59-1.99). Tailored antiplatelet therapy significantly reduced the event rate in patients exhibiting HTPR prior to PCI.

  1. Von Willebrand Factor Antigen Predicts Response to Double Dose of Aspirin and Clopidogrel by PFA-100 in Patients Undergoing Primary Angioplasty for St Elevation Myocardial Infarction

    PubMed Central

    Gianetti, Jacopo; Parri, Maria Serena; Della Pina, Francesca; Marchi, Federica; Koni, Endrin; De Caterina, Alberto; Maffei, Stefano

    2013-01-01

    Von Willebrand factor (VWF) is an emerging risk factor in acute coronary syndromes. Platelet Function Analyzer (PFA-100) with Collagen/Epinephrine (CEPI) is sensitive to functional alterations of VWF and also identifies patients with high on-treatment platelet reactivity (HPR). The objective of this study was to verify the effect of double dose (DD) of aspirin and clopidogrel on HPR detected by PFA-100 and its relation to VWF and to its regulatory metalloprotease ADAMTS-13. Between 2009 and 2011 we enrolled 116 consecutive patients with ST elevation myocardial infarction undergoing primary PCI with HPR at day 5 after PCI. Patients recruited were then randomized between a standard dose (SD, n = 58) or DD of aspirin and clopidogrel (DD, n = 58), maintained for 6 months follow-up. Blood samples for PFA-100, light transmittance aggregometry, and VWF/ADAMTS-13 analysis were collected after 5, 30, and 180 days (Times 0, 1, and 2). At Times 1 and 2 we observed a significantly higher CEPI closure times (CT) in DD as compared to SD (P < 0.001). Delta of CEPI-CT (T1 − T0) was significantly related to VWF (P < 0.001) and inversely related to ADAMTS-13 (0.01). Responders had a significantly higher level of VWF at T0. Finally, in a multivariate model analysis, VWF and ADAMTS-13 in resulted significant predictors of CEPI-CT response (P = 0.02). HRP detected by PFA-100 in acute myocardial infarction is reversible by DD of aspirin and clopidogrel; the response is predicted by basal levels of VWF and ADAMTS-13. PFA-100 may be a useful tool to risk stratification in acute coronary syndromes given its sensitivity to VWF. PMID:24453831

  2. Effects of clopidogrel therapy on whole blood platelet aggregation, the Plateletworks® assay and coagulation parameters in cats with asymptomatic hypertrophic cardiomyopathy: a pilot study.

    PubMed

    den Toom, M L; van Leeuwen, M W; Szatmári, V; Teske, E

    2017-12-01

    Although scientific evidence is limited, clopidogrel is frequently used as prophylaxis for arterial thromboembolism in cats with hypertrophic cardiomyopathy (HCM). Evaluating effects of clopidogrel therapy in asymptomatic cats with HCM on (1) conventional whole blood aggregation (WBA), (2) alternative platelet aggregation assessed with tubes of the Plateletworks® assay and (3) standard coagulation parameters. Prospective, randomized, double-blind, placebo-controlled pilot study. Fourteen asymptomatic HCM cats were randomly allocated to receive placebo (n = 5) or clopidogrel (18.75 mg/cat q24h, n = 9) as part of a larger study. Aggregation responses (to 20 µM adenosine diphosphate (ADP) and 10 µg/ml collagen) in WBA and the Plateletworks® assay and standard coagulation parameters were evaluated at baseline and after seven days of therapy. Clopidogrel therapy significantly reduced aggregation responses to ADP and collagen in the Plateletworks® agonists tubes (ADP and collagen: P < 0.001), but did not significantly reduce aggregation responses to ADP and collagen in the WBA technique (ADP: P = 0.07, collagen: P = 0.30). Clopidogrel therapy did not show a significant effect on prothrombin time, activated partial thromboplastin time, antithrombin, D-dimers and fibrinogen concentrations. Clopidogrel therapy at a dose of 18.75 mg/cat q24h for seven days causes a significant decrease in in vitro platelet aggregation evaluated with the Plateletworks® assay, without affecting standard coagulation parameters in cats with asymptomatic HCM.

  3. Potent and Orally Bioavailable Antiplatelet Agent, PLD-301, with the Potential of Overcoming Clopidogrel Resistance

    PubMed Central

    Chen, Jingyu; Wang, Michael Zhiyan

    2016-01-01

    PLD-301, a phosphate prodrug of clopidogrel thiolactone discovered by Prelude Pharmaceuticals with the aim to overcome clopidogrel resistance, was evaluated for its in vivo inhibitory effect on ADP-induced platelet aggregation in rats. The potency of PLD-301 was similar to that of prasugrel, but much higher than that of clopidogrel. The results of pharmacokinetic analysis showed that the oral bioavailability of clopidogrel thiolactone converted from PLD-301 was 4- to 5-fold higher than that of the one converted from clopidogrel, suggesting that in comparison with clopidogrel, lower doses of PLD-301 could be used clinically. In summary, PLD-301 presents a potent and orally bioavailable antiplatelet agent that might have some advantages over clopidogrel, such as overcoming clopidogrel resistance for CYP2C19-allele loss-of-function carriers, and lowering dose-related toxicity due to a much lower effective dose. PMID:27594816

  4. Relation between clopidogrel active metabolite levels and different platelet aggregation methods in patients receiving clopidogrel and aspirin.

    PubMed

    Liang, Yan; Johnston, Marilyn; Hirsh, Jack; Pare, Guillaume; Li, Chunjian; Mehta, Shamir; Teo, Koon K; Sloane, Debi; Yi, Qilong; Zhu, Jun; Eikelboom, John W

    2012-11-01

    Clopidogrel is a prodrug that undergoes bioconversion via cytochrome P450 system to form an active metabolite (AM) that binds to the platelet ADP receptor. The antiplatelet effect of clopidogrel is commonly assessed by measuring the aggregatory response to 5 μM ADP by light transmission aggregation (LTA) or multiple electrode aggregometry (MEA) or by the vasodilator-stimulated phosphoprotein platelet reactivity index (VASP-PRI). To determine which of these three tests of platelet ADP receptor pathway inhibition most closely correlates with clopidogrel AM levels. We analyzed blood samples from 82 patients with coronary artery disease who were randomized to receive double-dose or standard dose clopidogrel for 2 weeks. We measured peak clopidogrel AM levels, platelet aggregation in response to ADP and VASP-PRI on days 1, and repeated all the measures on days 7 and 14. Linear regression analysis was used to examine the correlation between clopidogrel AM and LTA, MEA and VASP-PRI. Bland-Altman plots were used to explore the agreement between tests of the antiplatelet effects of clopidogrel. Clopidogrel AM on day 1 correlated most closely with VASP-PRI (r = -0.5767) and demonstrated weaker correlations with LTA (r = -0.4656) and MEA (r = -0.3384) (all p < 0.01). Intra-class correlation (ICC) between VASP-PRI and LTA was 0.6446; VASP-PRI and MEA was 0.4720; and LTA and MEA was 0.4693. Similar results were obtained on days 7 and 14. Commonly used pharmacodynamic measures of clopidogrel response are only moderately correlated with clopidogrel AM levels and may not be suitable to measure the adequacy of clopidogrel therapy.

  5. ABCB1 C3435T Polymorphism and Response to Clopidogrel Treatment in Coronary Artery Disease (CAD) Patients: A Meta-Analysis

    PubMed Central

    Su, Jia; Xu, Jin; Li, Xiaojing; Zhang, Han; Hu, Juwei; Fang, Renyuan; Chen, Xiaomin

    2012-01-01

    Background A number of investigators have evaluated the association between the ABCB1 polymorphism and clopidogrel responding, but the results have been inconclusive. To examine the risk of high platelet activity and poor clinical outcomes associated with the ABCB1 C3435T polymorphism in CAD patients on clopidogrel, all available studies were included in the present meta-analysis. Methods We performed a systematic search of PubMed, Scopus and the Cochrane library database for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated by the meta-analysis. Results It was demonstrated that the ABCB1 C3435T variation was associated with the risk of early major adverse cardiovascular events (MACE) (T vs. C OR, 1.34; 95% CI, 1.10 to 1.62; P = 0.003; TT vs. CC: OR, 1.77; 95% CI, 1.19 to 2.63; P = 0.005; CT + TT vs.CC: OR, 1.48; 95% CI, 1.06 to 2.06; P = 0.02) and the polymorphism was also associated with the risk of the long-term MACE in patients on clopidogrel LD 300 mg (T vs. C: OR, 1.28; 95% CI, 1.10 to 1.48; P = 0.001; TT vs. CC: OR, 1.59; 95% CI, 1.19 to 2.13; P = 0.002; CT + TT vs.CC: OR, 1.39; 95% CI, 1.08 to 1.79; P = 0.01). The comparison of TT vs. CC was associated with a reduction in the outcome of bleeding (TT vs. CC: OR, 0.51; 95% CI, 0.40 to 0.66; P<0.00001). However, the association between ABCB1 C3435T polymorphism and platelet activity and other risk of poor clinical outcomes was not significant. Conclusions The evidence from our meta-analysis indicated that the ABCB1 C3435T polymorphism might be a risk factor for the MACE in patients on clopidogrel LD 300 mg, and that TT homozygotes decreased the outcome of bleeding compared with CC homozygotes. PMID:23056288

  6. Paraoxonase 1 Gene Polymorphism Does Not Affect Clopidogrel Response Variability but Is Associated with Clinical Outcome after PCI

    PubMed Central

    Kang, Jeehoon; Jeon, Ki-Hyun; Kang, Si-Hyuck; Han, Jung-Kyu; Lee, Sang Eun; Yang, Han-Mo; Lee, Hae-Young; Kang, Hyun-Jae; Koo, Bon-Kwon; Oh, Byung-Hee; Park, Young-Bae; Kim, Hyo-Soo

    2013-01-01

    Background Paraoxonase (PON) is a high-density-lipoprotein (HDL) associated enzyme with antioxidative and anti-atherogenic property. Its function is associated with coronary artery disease and its activity genetically controlled. We evaluated whether genetic variation of PON-1 is associated with clinical outcome in a large cohort of Korean patients with drug-eluting stents implantation. Methods A total of 1676 patients with drug-eluting stent implantation were enrolled in the prospective CROSS-VERIFY cohort from June 2006 to June 2010. We genotyped the PON1-Q192R gene, measured clopidogrel on-treatment platelet reactivity (OPR), and analyzed lipid profiles. The primary endpoint was the composite of cardiac death, myocardial infarction, and stent thrombosis at 12 months. Results PON-1 genotyping data were available in 1336 patients. Since the Q-allele is associated with decreased PON-activity, we analyzed the outcome between patients with QQ/QR (815 patients, 61%) and those with RR-genotype (521 patients, 39%). After adjustment for common cardiac risk factors, the QQ/QR-genotype was an independent predictor of the primary thrombotic endpoint with an 11-fold increased risk (HR 11.6, 95% CI: 1.55–87.0), but not repeat revascularization (HR 1.12, 95% CI: 0.78–1.61). The QQ/QR-genotype was not associated with OPR (QQ/QR: 231±86 PRU vs. RR 236±82 PRU, p = 0.342) but higher small-dense LDL levels (1.20±0.12 mg/dL vs. 0.76±0.15 mg/dL, p = 0.027). The increased risk of thrombotic outcomes was more profound in acute coronary syndrome (ACS) patients compared with non-ACS patients. Conclusion PON1 Q-allele is an independent predictor of worse cardiovascular outcome independent of platelet function and is associated with significantly higher levels of small dense LDL-C. PMID:23418418

  7. Pharmacodynamic effects of adjunctive high dose atorvastatin on double dose clopidogrel in patients with high on-treatment platelet reactivity depending on diabetes mellitus status.

    PubMed

    Leoncini, Mario; Toso, Anna; Maioli, Mauro; Angiolillo, Dominick J; Giusti, Betti; Marcucci, Rossella; Abbate, Rosanna; Bellandi, Francesco

    2014-05-01

    Diabetes mellitus (DM) is associated with impaired platelet response to clopidogrel. In patients with high on-treatment platelet reactivity (HTPR) while on standard-dose clopidogrel, high-dose atorvastatin enhances the pharmacodynamic (PD) effects of double-dose clopidogrel. It is unknown if similar effects are achieved in patients with DM. This study compare the PD effects of high-dose atorvastatin associated with double dose clopidogrel in HTPR patients with and without DM undergoing elective percutaneous coronary intervention (PCI). This is a post hoc analysis of a prospective randomized PD study that compared double-dose (150 mg) clopidogrel associated with high-dose (80 mg) atorvastatin to double-dose clopidogrel alone in statin naïve patients with HTPR undergoing elective PCI. In this analysis, patients were divided in two groups according to DM (n = 27) and non-DM (n = 49) status. Platelet reactivity was evaluated immediately before PCI and at 30 days using the VerifyNow P2Y12 assay. HTPR was defined as P2Y12 reaction units (PRU) ≥235. Administering high-dose atorvastatin in addition to high-dose clipodogrel, the 30 days absolute PRU changes (106 ± 75 vs 100 ± 42, p = 0.7) and optimal response rates (83 vs 84%; p = 0.9) were similar in DM and non-DM patients. The baseline variables significantly associated with 30-day optimal response to high-dose clopidogrel were: atorvastatin treatment (OR = 7.5 [95% CI 1.19-47]; p = 0.032) in DM patients; PRU values (OR = 0.9 [95% CI 0.95-0.99]; p = 0.031) and creatinine clearance (OR = 1.07 [95% CI 1.008-1.13]; p = 0.025) in non-DM patients. High-dose atorvastatin significantly improved the PD effects of double-dose clopidogrel in DM patients with HTPR undergoing elective PCI.

  8. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.

    PubMed

    Price, Matthew J; Berger, Peter B; Teirstein, Paul S; Tanguay, Jean-François; Angiolillo, Dominick J; Spriggs, Douglas; Puri, Sanjeev; Robbins, Mark; Garratt, Kirk N; Bertrand, Olivier F; Stillabower, Michael E; Stillablower, Michael E; Aragon, Joseph R; Kandzari, David E; Stinis, Curtiss T; Lee, Michael S; Manoukian, Steven V; Cannon, Christopher P; Schork, Nicholas J; Topol, Eric J

    2011-03-16

    High platelet reactivity while receiving clopidogrel has been linked to cardiovascular events after percutaneous coronary intervention (PCI), but a treatment strategy for this issue is not well defined. To evaluate the effect of high-dose compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI. Randomized, double-blind, active-control trial (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety [GRAVITAS]) of 2214 patients with high on-treatment reactivity 12 to 24 hours after PCI with drug-eluting stents at 83 centers in North America between July 2008 and April 2010. High-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (no additional loading dose, 75 mg daily) for 6 months. The primary end point was the 6-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. The key safety end point was severe or moderate bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition. A key pharmacodynamic end point was the rate of persistently high on-treatment reactivity at 30 days. At 6 months, the primary end point had occurred in 25 of 1109 patients (2.3%) receiving high-dose clopidogrel compared with 25 of 1105 patients (2.3%) receiving standard-dose clopidogrel (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.58-1.76; P = .97). Severe or moderate bleeding was not increased with the high-dose regimen (15 [1.4%] vs 25 [2.3%], HR, 0.59; 95% CI, 0.31-1.11; P = .10). Compared with standard-dose clopidogrel, high-dose clopidogrel provided a 22% (95% CI, 18%-26%) absolute reduction in the rate of high on-treatment reactivity at 30 days (62%; 95% CI, 59%-65% vs 40%; 95% CI, 37%-43%; P < .001). Among patients with high on-treatment reactivity after PCI with drug-eluting stents, the use of high-dose clopidogrel compared with standard-dose clopidogrel

  9. Point-of-care platelet function assays demonstrate reduced responsiveness to clopidogrel, but not aspirin, in patients with Drug-Eluting Stent Thrombosis whilst on dual antiplatelet therapy

    PubMed Central

    Hobson, Alex R; Petley, Graham; Morton, Geraint; Dawkins, Keith D; Curzen, Nick P

    2008-01-01

    Background To test the hypothesis that point-of-care assays of platelet reactivity would demonstrate reduced response to antiplatelet therapy in patients who experienced Drug Eluting Stent (DES) ST whilst on dual antiplatelet therapy compared to matched DES controls. Whilst the aetiology of stent thrombosis (ST) is multifactorial there is increasing evidence from laboratory-based assays that hyporesponsiveness to antiplatelet therapy is a factor in some cases. Methods From 3004 PCI patients, seven survivors of DES ST whilst on dual antiplatelet therapy were identified and each matched with two patients without ST. Analysis was performed using (a) short Thrombelastogram PlateletMapping™ (TEG) and (b) VerifyNow Aspirin and P2Y12 assays. TEG analysis was performed using the Area Under the Curve at 15 minutes (AUC15) as previously described. Results There were no differences in responses to aspirin. There was significantly greater platelet reactivity on clopidogrel in the ST group using the Accumetrics P2Y12 assay (183 ± 51 vs. 108 ± 31, p = 0.02) and a trend towards greater reactivity using TEG AUC15 (910 ± 328 vs. 618 ± 129, p = 0.07). 57% of the ST group by TEG and 43% of the ST cases by Accumetrics PRU had results > two standard deviations above the expected mean in the control group. Conclusion This study demonstrates reduced platelet response to clopidogrel in some patients with DES ST compared to matched controls. The availability of point-of-care assays that can detect these responses raises the possibility of prospectively identifying DES patients at risk of ST and manipulating their subsequent risk. PMID:18312665

  10. Drug resistance and secondary treatment of ischaemic stroke: The genetic component of the response to acetylsalicylic acid and clopidogrel.

    PubMed

    Gallego-Fabrega, C; Krupinski, J; Fernandez-Cadenas, I

    2015-01-01

    Cerebrovascular diseases are among the leading causes of death and disability in developed countries. Acetylsalicylic acid (ASA) and clopidogrel are the most widely-used antiplatelet drugs for secondary prevention of recurrent thromboembolic events. However, there have been cases in which antiplatelet drugs did not inhibit platelet activity; this phenomenon is called resistance, and it may be modulated at the genetic level. Following a literature search, we reviewed the current state of antiplatelet therapy and covered the different types of resistance to antiplatelet therapy, how it is measured, current problems and limitations, and any genetic factors that have been associated with resistance. We mainly used the Genome Wide Association Studies in the field of ASA and clopidogrel resistance. We observed an association between different genetic factors and antiplatelet drug resistance as measured by platelet activity. However, there is no evident association between these genetic factors and risk of new thromboembolic events. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  11. Both PON1 Q192R and CYP2C19*2 influence platelet response to clopidogrel and ischemic events in Chinese patients undergoing percutaneous coronary intervention.

    PubMed

    Chen, Yu; Huang, Xiaohong; Tang, Yong; Xie, Yuquan; Zhang, Yachen

    2015-01-01

    Clopidogrel nonresponsiveness increases the recurrence of cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). Previous studies found that genetic variants such as single nucleotide polymorphisms (SNPs) of CYP2C19 and PON1 may influence clopidogrel response, cause high platelet reactivity (HPR) and increase cardiovascular events. However, these studies were inconsistent and inconclusive, especially in the Eastern Asian population. In this study, we investigated the effects of genetic variants on clopidogrel response and clinical outcomes in Chinese patients undergoing PCI. A total of 336 acute coronary syndrome patients undergoing PCI were included, 53 (15.77%) of whom were categorized as HPR. Among the 10 SNPs studied (ABCB1, CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*17, CYP3A4, CYP3A5, ITGB3, P2Y12 and PON1 Q192R), the CYP2C19*4 and P2Y12 variants were not found in our population. The PON1 192Q and CYP2C19*2 alleles were significantly higher in the HPR group compared with the normal platelet reactivity (NPR) group (P=0.033 and 0.038, respectively), while the other SNPs were not significantly different between the two groups. Platelet aggregation of the PON1 192Q allele carriers was significantly higher than that of non-carriers both at baseline and 1 month after PCI (P=0.010 and 0.024, respectively); this was the case for CYP2C19*2 allele carriers, as well (P=0.005 and 0.003, respectively). The risk of major adverse cardiovascular event (MACE) increased with the presence of the PON1 192Q and CYP2C19*2 alleles during 6-month follow-up (P=0.012 and 0.003, respectively). In conclusion, both the PON1 Q192R and CYP2C19*2 variants are associated with HPR and an increased risk of ischemic events in Chinese patients undergoing PCI.

  12. CYP2C19 but not CYP2B6, CYP3A4, CYP3A5, ABCB1, PON1 or P2Y12 genetic polymorphism impacts antiplatelet response after clopidogrel in Koreans.

    PubMed

    Zhang, Hong-Zhe; Kim, Moo Hyun; Guo, Long-Zhe; Serebruany, Victor

    2017-01-01

    Clopidogrel response variability (CRV) is well documented, and may affect clinical outcomes. Impact of genetic polymorphisms is important for assessing and predicting CRV. The extensive evidence indicates the importance of CYP2C19 variants in reducing efficacy of clopidogrel. This study defined the impact of numerous genetic polymorphisms on CRV before and after percutaneous coronary interventions (PCI) exclusively in a Korean cohort assuming less genetic variability noise. One hundred and thirty-six patients of Korean origin undergoing PCI were included. Platelet reactivity was measured by VerifyNow assay before and after PCI. Genetic polymorphism of seven single nucleotides of CYP2B6, CYP2C19, CYP3A4, CYP3A5, ABCB1, PON1, and P2Y12 were evaluated and matched with platelet reactivity. Carriers of at least one CYP2C19*2 or *3 allele uniformly exhibited higher platelet reactivity compared to 0-carrier pre-PCI (odds ratio 3.1, 95% confidence interval 1.4-6.9, P < 0.01) and post-PCI (odds ratio 3.4, 95% confidence interval 1.7-6.8, P < 0.001). The carriers of other gene allele variants lack uniformed impact on CRV. The Korean carriers of CYP2C19*2 or *3 allele are linked to CRV, whereas CYP2B6, CYP3A4, CYP3A5, ABCB1, PON1, and P2Y12 failed to predict CRV. The exact clinical utility of these findings is uncertain, and requires a large randomized national trial for proof of concept.

  13. Intrinsic platelet reactivity before start with clopidogrel as predictor for on-clopidogrel platelet function and long-term clinical outcome.

    PubMed

    Hochholzer, Willibald; Valina, Christian M; Bömicke, Timo; Amann, Michael; Stratz, Christian; Nührenberg, Thomas; Trenk, Dietmar; Neumann, Franz-Josef

    2015-07-01

    High on-clopidogrel platelet reactivity is associated with worse clinical outcome. Previous data suggest that intrinsic platelet reactivity before initiation of clopidogrel contributes significantly to on-clopidogrel platelet reactivity. It is unknown whether intrinsic reactivity can sufficiently predict on-clopidogrel reactivity and therefore identify patients with insufficient response to clopidogrel before initiation of treatment and at risk for worse clinical outcome. This analysis included 765 consecutive patients undergoing elective coronary stent implantation. Platelet reactivity was assessed by light transmission aggregometry (5 µM ADP) before administration of clopidogrel 600mg and after intake of first maintenance dose of clopidogrel on day 1 following coronary stenting. Patients were followed for up to seven years. The combined primary endpoint was death of any cause or non-fatal myocardial infarction. Intrinsic and on-clopidogrel platelet reactivity were significant correlated (r=0.31; p < 0.001). Among all tested clinical and genetic factors including the cytochrome P450 2C19*2 polymorphism, intrinsic platelet reactivity was the strongest predictor for on-clopidogrel platelet reactivity. However, intrinsic platelet reactivity could only explain 8 % of variability of on-clopidogrel platelet function. Only on-treatment platelet reactivity was predictive for long-term clinical outcome (HR 1.47, 95 % CI 1.05-2.05; p = 0.02) whereas intrinsic platelet reactivity was not (HR 1.03, 95 % CI 0.74-1.43; p = 0.86). In conclusion, intrinsic platelet reactivity before initiation of clopidogrel is the strongest predictor of early on-clopidogrel platelet reactivity but can only explain a minor proportion of its variability and is not significantly associated with clinical outcome. Thus, baseline testing cannot substitute on-clopidogrel platelet function testing.

  14. Direct healthcare costs and cost-effectiveness of acute coronary syndrome secondary prevention with ticagrelor compared to clopidogrel: economic evaluation from the public payer's perspective in Poland based on the PLATO trial results.

    PubMed

    Pawęska, Justyna; Macioch, Tomasz; Perkowski, Piotr; Budaj, Andrzej; Niewada, Maciej

    2014-01-01

    Ticagrelor is the first reversibly binding oral P2Y12 receptor antagonist designed to reduce clinical thrombotic events in patients with acute coronary syndrome (ACS). Compared to clopidogrel, ticagrelor has been proven to significantly reduce the rate of death from vascular causes, myocardial infarction (MI), or stroke without an increase in the rate of overall major bleeding in patients who have an ACS with or without ST-segment elevation (STEMI and NSTEMI) or unstable angina (UA). To evaluate the cost-effectiveness and healthcare costs associated with secondary prevention of ACS using ticagrelor or clopidogrel in patients after STEMI, NSTEMI and UA. An economic model based on results from the PLATO trial was used to evaluate the cost-effectiveness of one-year therapy with ticagrelor or clopidogrel. The structure of the model consisted of two parts, i.e. the decision tree with one-year PLATO results and the Markov model with lifelong estimations, which exceeded PLATO follow-up data. The model was adjusted to Polish settings with country-specific data on death rates in the general population and direct medical costs calculated from the public payer's perspective. Costs were derived from the National Health Fund (NHF) and the Ministry of Health and presented in PLN 2013 values. Annual mean costs of second and subsequent years after stroke or MI were obtained from the literature. Uncertainty of assumed parameters was tested in scenarios and probabilistic sensitivity analyses. The adopted model allowed the estimation of an incremental cost-effectiveness ratio for life years gained (LYG) and an incremental cost-utility ratio for quality adjusted life years (QALY). Total direct medical costs to the public payer at a one year horizon were 2,905 PLN higher with ticagrelor than with clopidogrel. However, mean healthcare costs at a one year horizon (excluding drug costs and concomitant drugs) were 690 PLN higher for patients treated with clopidogrel. In a lifetime horizon

  15. High clopidogrel dose in patients with chronic kidney disease having clopidogrel resistance after percutaneous coronary intervention.

    PubMed

    Liang, Jing; Wang, Zhijian; Shi, Dongmei; Liu, Yuyang; Zhao, Yingxin; Han, Hongya; Li, Yueping; Liu, Wei; Zhang, Linlin; Yang, Lixia; Zhou, Yujie

    2015-04-01

    We evaluated the impact of clopidogrel 150 mg/d in patients with chronic kidney disease (CKD) having clopidogrel resistance (CR) after percutaneous coronary intervention (PCI); 1076 consecutive patients with coronary artery disease (CAD) having CKD were enrolled. Maximal platelet aggregation (MPA) was assessed before, 24 hours, and 30 days after a 300-mg loading dose of clopidogrel prior to PCI. After PCI, 370 patients with CR were randomized to receive clopidogrel 75 mg/d (n = 184) or 150 mg/d (n = 186) for 30 days. Stent thrombosis (ST), major adverse cardiac events (MACEs), and bleeding were analyzed after 1 month. Patients in the 150 mg group had significant lower rates of ST and MACE. There was no significant difference in major or minor bleeding. Patients in the 150 mg group had lower MPA and greater inhibition of platelet aggregation. One-month administration of 150 mg/d of clopidogrel decreases the rate of ST and MACE without increasing bleeding in patients with CKD having CR after PCI.

  16. The effect of clopidogrel on platelet activity in patients with and without type-2 diabetes mellitus: a comparative study.

    PubMed

    Schuette, Claudia; Steffens, Daniel; Witkowski, Marco; Stellbaum, Caroline; Bobbert, Peter; Schultheiss, Heinz-Peter; Rauch, Ursula

    2015-02-03

    Although antiplatelet therapy involving clopidogrel is a standard treatment for preventing cardiovascular events after coronary stent implantation, patients can display differential responses. Here, we assessed the effectiveness of clopidogrel on platelet function inhibition in subjects with and without type-2 diabetes and stable coronary artery disease. In addition, we investigated the correlation between platelet function and routine clinical parameters. A total of 64 patients with stable coronary heart disease were enrolled in the study. Among these, 32 had known type-2 diabetes, whereas the remaining 32 subjects were non-diabetics (control group). A loading dose of 300 mg clopidogrel was given to clopidogrel-naïve patients (13 patients in the diabetes group and 14 control patients). All patients were given a daily maintenance dose of 75 mg clopidogrel. In addition, all patients received 100 mg ASA per day. Agonist-induced platelet aggregation measurements were performed on hirudin-anticoagulated blood using an impedance aggregometer (Multiple Platelet Function Analyzer, Dynabyte, Munich, Germany). Blood samples were drawn from the antecubital vein 24 h after coronary angiography with percutaneous coronary intervention. The platelets were then stimulated with ADP alone or ADP and prostaglandin-E (ADP and ADP-PGE tests, respectively) in order to evaluate clopidogrel-mediated inhibition of platelet function. The effectiveness of ASA was measured by stimulation with arachidonic acid (ASPI test). In addition, maximal platelet aggregation was assessed via stimulation with thrombin receptor-activating peptide (TRAP test). Patients with diabetes exhibited significantly less inhibition of platelet function than patients without diabetes (ADP-PGE test p = 0.003; ASPI test p = 0.022). Administering a clopidogrel loading dose of 300 mg did not result in a lower level of ADP-PGE-induced platelet reactivity in comparison to the use of a 75 mg maintenance dose

  17. The influencing factors for clopidogrel-mediated platelet inhibition are assay-dependent.

    PubMed

    Gremmel, Thomas; Steiner, Sabine; Seidinger, Daniela; Koppensteiner, Renate; Panzer, Simon; Kopp, Christoph W

    2011-10-01

    Influencing factors for clopidogrel-mediated platelet inhibition have only been evaluated by one or two different test systems in the same population so far. Since previous studies revealed poor correlations between the various platelet function tests, the identification of influencing variables for clopidogrel response may vary from one test system to the next. We therefore investigated whether the influencing factors for clopidogrel-mediated platelet inhibition depend on the used assay. Adenosine diphosphate (ADP)-inducible platelet reactivity was assessed by light transmission aggregometry (LTA), the VerifyNow P2Y12 assay, the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, multiple electrode aggregometry (MEA), and the Impact-R in 288 patients after angioplasty and stenting for cardiovascular disease. By univariate and multivariate regression analyses, we evaluated the impact of age ≥ 75, gender, body mass index (BMI), diabetes, active smoking, hypertension, hyperlipidemia, C-reactive protein, platelet count, creatinine, use of calcium-channel blockers (CCBs), statins, proton pump inhibitors, beta blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers on clopidogrel-mediated platelet inhibition in each test system. None of the independent influencing variables was consistent through all test systems. Only by LTA and the VerifyNow P2Y12 assay, age ≥ 75 and the use of CCBs were independently associated with higher on-treatment platelet reactivity. Only by the VASP assay and MEA, on-treatment platelet reactivity increased linearly with BMI. Further, only by MEA, residual ADP-inducible platelet reactivity increased linearly with platelet count, whereas an increase in platelet count was independently associated with a decrease in ADP-inducible platelet activation by the Impact-R. The influencing factors for platelet reactivity during clopidogrel therapy are assay-dependent. Copyright © 2011 Elsevier Ltd. All

  18. Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations.

    PubMed

    Ellis, Kyle J; Stouffer, George A; McLeod, Howard L; Lee, Craig R

    2009-11-01

    Antiplatelet therapy with clopidogrel is the current standard of care for coronary artery disease patients undergoing a percutaneous coronary intervention. However, approximately 25% of patients experience a subtherapeutic antiplatelet response. Clopidogrel is a prodrug that undergoes hepatic biotransformation by CYP2C19 into its active metabolite. Several studies have reported that, compared with wild-type individuals, CYP2C19 variant allele carriers exhibit a significantly lower capacity to metabolize clopidogrel into its active metabolite and inhibit platelet activation, and are therefore at significantly higher risk of adverse cardiovascular events. Consequently, the US FDA has recently changed clopidogrel's prescribing information to highlight the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics and clinical response. Future studies remain necessary to develop effective personalized therapeutic strategies for CYP2C19 variant allele carriers and other individuals at risk for clopidogrel nonresponsiveness.

  19. Clopidogrel use After Myocardial Revascularization: Prevalence, Predictors, and One-Year Survival Rate

    PubMed Central

    Prates, Paulo Roberto L.; Williams, Judson B.; Mehta, Rajendra H.; Stevens, Susanna R.; Thomas, Laine; Smith, Peter K.; Newby, L. Kristin; Kalil, Renato A. K.; Alexander, John H.; Lopes, Renato D.

    2016-01-01

    Introduction Antiplatelet therapy after coronary artery bypass graft (CABG) has been used. Little is known about the predictors and efficacy of clopidogrel in this scenario. Objective Identify predictors of clopidogrel following CABG. Methods We evaluated 5404 patients who underwent CABG between 2000 and 2009 at Duke University Medical Center. We excluded patients undergoing concomitant valve surgery, those who had postoperative bleeding or death before discharge. Postoperative clopidogrel was left to the discretion of the attending physician. Adjusted risk for 1-year mortality was compared between patients receiving and not receiving clopidogrel during hospitalization after undergoing CABG. Results At hospital discharge, 931 (17.2%) patients were receiving clopidogrel. Comparing patients not receiving clopidogrel at discharge, users had more comorbidities, including hyperlipidemia, hypertension, heart failure, peripheral arterial disease and cerebrovascular disease. Patients who received aspirin during hospitalization were less likely to receive clopidogrel at discharge (P≤0.0001). Clopidogrel was associated with similar 1-year mortality compared with those who did not use clopidogrel (4.4% vs. 4.5%, P=0.72). There was, however, an interaction between the use of cardiopulmonary bypass and clopidogrel, with lower 1-year mortality in patients undergoing off-pump CABG who received clopidogrel, but not those undergoing conventional CABG (2.6% vs 5.6%, P Interaction = 0.032). Conclusion Clopidogrel was used in nearly one-fifth of patients after CABG. Its use was not associated with lower mortality after 1 year in general, but lower mortality rate in those undergoing off-pump CABG. Randomized clinical trials are needed to determine the benefit of routine use of clopidogrel in CABG. PMID:27556308

  20. Chiral Stability of an Extemporaneously Prepared Clopidogrel Bisulfate Oral Suspension

    PubMed Central

    Tynes, Clay R.; Livingston, Brad; Patel, Hetesh; Arnold, John J.

    2014-01-01

    OBJECTIVES The purpose of this study was to evaluate the chiral stability of clopidogrel bisulfate in an extemporaneously compounded oral suspension for a period of 60 days. METHODS A 5 mg/mL oral suspension of clopidogrel bisulfate was prepared from commercially available Plavix tablets. The clopidogrel suspension was then evenly divided between two light-resistant prescription bottles and stored either under refrigeration (4°C) or at room temperature (25°C). Samples were drawn from the stored suspensions immediately after preparation and on days 7, 14, 28, and 60. Samples were subsequently analyzed at each time point by high-performance liquid chromatography using a reversed-phase column, with chemical stability defined as the retention of at least 90% of the initial intact clopidogrel concentration measured. To determine the chiral stability of the suspension, samples were also analyzed by high-performance liquid chromatography using a chiral column to investigate possible enantiomeric inversion. Chiral stability was defined as the retention of at least 90% of the initial concentration of the suspension as the S-enantiomer, the active moiety of Plavix. RESULTS Regardless of storage conditions, the oral suspension of clopidogrel retained at least 98% of the active S-enantiomer for 60 days after preparation. Compared with the clopidogrel suspension stored in the refrigerator, more chiral inversion was noted in the clopidogrel suspension stored at room temperature. CONCLUSIONS Our investigation of chiral stability indicates that a 5 mg/mL clopidogrel oral suspension stored under refrigeration and at room temperature maintains chiral stability as the active S-enantiomer. PMID:24782688

  1. Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y(12)-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI).

    PubMed

    Leonardi, Sergio; Rao, Sunil V; Harrington, Robert A; Bhatt, Deepak L; Gibson, C Michael; Roe, Matthew T; Kochman, Janusz; Huber, Kurt; Zeymer, Uwe; Madan, Mina; Gretler, Daniel D; McClure, Matthew W; Paynter, Gayle E; Thompson, Vivian; Welsh, Robert C

    2010-07-01

    Despite current dual-antiplatelet therapy with aspirin and clopidogrel, adverse clinical events continue to occur during and after percutaneous coronary intervention (PCI). The failure of clopidogrel to provide optimal protection may be related to delayed onset of action, interpatient variability in its effect, and an insufficient level of platelet inhibition. Furthermore, the irreversible binding of clopidogrel to the P2Y(12) receptor for the life span of the platelet is associated with increased bleeding risk especially during urgent or emergency surgery. Novel antiplatelet agents are required to improve management of patients undergoing PCI. Elinogrel is a potent, direct-acting (ie, non-prodrug), selective, competitive, and reversible P2Y(12) inhibitor available in both intravenous and oral formulations. The INNOVATE-PCI study is a phase 2 randomized, double-blind, clopidogrel-controlled trial to evaluate the safety, tolerability, and preliminary efficacy of this novel antiplatelet agent in patients undergoing nonurgent PCI.

  2. High residual platelet reactivity on clopidogrel: its significance and therapeutic challenges overcoming clopidogrel resistance

    PubMed Central

    Alam, Samir

    2013-01-01

    Over the last decade, dual antiplatelet therapy has been the mainstay of the management of Acute Coronary Syndrome, with clopidogrel therapy providing clear benefits over aspirin monotherapy and becoming the agent of choice for the prevention of stent thrombosis. While newer antiplatelet agents have now become available, clopidogrel is still widely used due to its low cost and efficacy. However, many patients still experience recurrent ischemic events. A poor response of the platelets to clopidogrel, called High Residual Platelet Reactivity (HRPR), has been incriminated to account for this dilemma. Despite the absence of a universal definition of HRPR or the gold standard test to quantify it, persistent high platelet reactivity has consistently been associated with recurrence of ischemic events. Clopidogrel metabolism is highly variable, and genetics, comorbidities and drug interactions can affect it. In this article we review all definitions of HRPR, explore the available tests to quantify it, the clinical outcomes associated with it, as well as strategies that have shown success in overcoming it. PMID:24282742

  3. [Clopidogrel resistance: myth or reality].

    PubMed

    Serebrianyĭ, V L; Malinin, A I; Makarov, L M

    2007-01-01

    The efficacy of clopidogrel, as an established anti-platelet agent for the acute coronary syndrome treatment and for the thrombotic complications prevention after percutaneous coronary angioplasty and coronary artery stenting has been supported by the evidence of several major randomized clinical trials. However, some patients treated with clopidogrel have a minor, but still a risk of coronary artery thrombosis and sudden death. Moreover, clopidogrel was not effective in patients after ischemic stroke, as well as it was not effective for the primary prevention of vascular events. Several authors proposed the theory of " clopidogrel-resistance " . However, this theory is based on a limited number of laboratory findings, and was not supported by the evidence of clinical studies. The phenomena of " clopidogrel-resistance " could be masked by the low patient compliance, while the rate of such patients could exceed 30% after one year of treatment. The offered methods for overcoming clopidogrel-resistance include doubling or tripling of the loading dose (600-900 mg vs. 300mg) or administration one or two more potent antiplatelet agents. However, such approach could not only increase the risk of major and fatal bleedings, but could have a potential to reduce patients compliance, and consequently increase the risk of thrombosis. Only multicenter randomized study with hard outcome or ideally survival endpoint, supported by comprehensive serial platelet assessment, strict compliance rules including measurement of clopidogrel metabolite(s) will determine whether " clopidogrel resistance " is a real danger (as suggested by the platelet biomarkers), or an artificial tool (as suggested by the randomized clinical evidence) introduced to help novel antiplatelet agents to gain the vascular market share.

  4. Clopidogrel and genetic testing: is it necessary for everyone?

    PubMed

    Goswami, Sweta; Cheng-Lai, Angela; Nawarskas, James

    2012-01-01

    Clopidogrel is a widely used antiplatelet agent to treat and prevent a variety of atherothrombotic diseases. More than a decade after its initial Food and Drug Administration approval, studies have emerged raising concerns regarding its possible reduced efficacy in patients who have impaired conversion of clopidogrel to its active metabolite (ie, poor metabolizers). Research has implicated genetic variations in the CYP2C19 isozyme as at least partly responsible for the variable antiplatelet response seen with clopidogrel. Studies have shown that patients possessing genetic variants of the CYP2C19 isozyme may be at increased risk of adverse cardiovascular events due to impaired clopidogrel efficacy, although this has not been definitively demonstrated. The Food and Drug Administration has issued a boxed warning regarding this concern. However, specific recommendations on genetic testing and alternative therapeutic strategies are not currently available. Genetic testing is commercially available to test patients for variability in the CYP2C19 isozyme, but altering antiplatelet therapy based on the results of this testing has not been adequately studied, and it is therefore not clear how to adjust therapy based on the results of this genetic testing. In addition, there are many other factors that may contribute to the variability in antiplatelet effect seen with clopidogrel besides CYP2C19 genetic polymorphisms. Ongoing trials dealing with adjusting antiplatelet therapy based on genetic testing will hopefully provide more useful information on how to appropriately integrate pharmacogenomics with the care of patients with atherothrombotic disease.

  5. Branded versus generic clopidogrel in cardiovascular diseases: a systematic review.

    PubMed

    Caldeira, Daniel; Fernandes, Ricardo M; Costa, João; David, Cláudio; Sampaio, Cristina; Ferreira, Joaquim J

    2013-04-01

    In the United States, patent for branded Plavix has recently expired. Some studies have compared branded and generic clopidogrel in terms of pharmacokinetic parameters in healthy volunteers, but data on patients and clinical outcomes are scarce. We aimed to review efficacy and safety data from studies comparing Plavix with generic clopidogrel in patients with cardiovascular disease. Electronic databases were searched (from inception to May 2012) for prospective studies evaluating branded versus generic clopidogrel in patients with cardiovascular diseases. Studies' characteristics and data estimates were retrieved. Pooled risk ratio (RR) and 95% confidence intervals (95% CIs) were estimated through a random-effects model. Three studies evaluating 760 patients were included: 2 randomized controlled trials and 1 cohort study. The RR for major cardiovascular events was 1.01 (95% CI, 0.67-1.52). Incidence of adverse events was similar between Plavix and generic (RR 0.85; 95% CI, 0.49-1.48). The risks of mortality, bleeding, and drug discontinuation were also not different between groups. There are a limited number of studies comparing Plavix and generic clopidogrel in patients with cardiovascular diseases and reporting hard clinical end points. The available evidence is therefore limited and does not support the existence of differences in efficacy or safety between branded and generic clopidogrel.

  6. Desensitization to clopidogrel: a tailor-made protocol.

    PubMed

    Barreira, P; Cadinha, S; Malheiro, D; Moreira da Silva, J P

    2014-01-01

    Clopidogrel is an antiplatelet drug widely used for treatment and prevention of a variety of cardiovascular diseases. We report a successful desensitization to clopidogrel in a 70-year-old Caucasian man with delayed hypersensitivity (HS) reaction. He developed lip, hand and foot swelling, erythematous papular non-pruritic lesions and arthralgias 2 weeks after starting treatment with clopidogrel 75 mg/d. A 3-hour desensitization protocol was started, achieving a cumulative dose of 154 mg without any reaction, and a daily dose of 75 mg was recommended. On the 4th day, the patient developed skin lesions similar to the previously described. He was treated with topical steroids and oral antihistamines, and the daily dose of clopidogrel was reduced to 20 mg. A new desensitization protocol was established, with a slow dose increment, according to the patient's response. It was only possible to achieve the dose of 75 mg/d after 2 months. Although well tolerated by most patients, HS reactions with clopidogrel may occur and desensitization is rising as a safe alternative in those patients. In delayed reactions with cutaneous lesions, a slower desensitization protocol may be necessary, as in this case.

  7. The role of clopidogrel in the management of ischemic heart disease.

    PubMed

    Homan, David J; Price, Matthew J

    2013-07-01

    Placebo-controlled randomized trials have demonstrated the efficacy of clopidogrel in combination with aspirin across a broad range of clinical presentations. Recent trials have addressed several remaining issues regarding clopidogrel therapy. Three randomized trials examined the role of platelet function testing (PFT) in clopidogrel-treated patients. The results do not support the use of PFT to adjust clopidogrel dose after percutaneous coronary intervention (PCI), particularly in patients with stable angina or ischemia, in whom event rates are low irrespective of on-treatment reactivity. Doses greater than clopidogrel 150  mg daily are required to sufficiently overcome high reactivity in CYP2C19 loss-of-function (LOF) allele carriers. Clopidogrel response variability also influences the time to platelet recovery after drug discontinuation, and a proof-of-principle study supports the concept of using PFT for surgical timing. Unlike its efficacy in the setting of acute coronary syndrome (ACS) and PCI, prasugrel was not superior to clopidogrel in medically treated patients recovering from ACS. Current data do not support routine PFT to guide antiplatelet therapy in patients undergoing nonurgent PCI. The role of PFT to optimize therapy in ACS patients remains unaddressed, and further study is needed to confirm its promise in guiding surgical timing in patients who have discontinued therapy. Clopidogrel remains an important therapeutic option for patients presenting after an ACS who did not undergo initial revascularization.

  8. Effect of long-term adherence to clopidogrel on the VASP-PRI after elective coronary stent implantation: a randomized controlled study.

    PubMed

    Forni Ogna, Valentina; Menetrey, Isabelle; Muller, Olivier; Tousset, Eric; Guihard, Linda; Fontana, Pierre; Eeckhout, Eric; Eap, Chin B; Vrijens, Bernard; Burnier, Michel; Wuerzner, Grégoire

    2016-12-01

    The biological response to clopidogrel is highly variable and a poor responsiveness is associated with major adverse cardiac events. Adherence to therapy is a major cause of poor responsiveness but its impact on long-term platelet inhibition is unknown. The objective of the present study was to evaluate the effect of different programmes monitoring adherence to clopidogrel on platelet reactivity. The study took the form of a monocentric, parallel group, randomized controlled trial. Adults treated with clopidogrel 75 mg after elective coronary stenting were randomized into one of three groups: (i) a standard of care group; (ii) a standard of care + adherence electronic monitoring group, in which drug intake was recorded but kept blinded until the study end; or (iii) an integrated care group, with regular feedback on recorded adherence. Clopidogrel response was assessed with the vasodilator-stimulated phosphoprotein-platelet reactivity index (VASP-PRI) at randomization, 3 months and 6 months. A total of 123 adults were enrolled and randomized. Baseline VASP-PRI was highly variable, with a mean of 48 ± 18.8%. No difference between groups in VASP-PRI was found at 6 months (P = 0.761), despite better adherence to clopidogrel in the integrated care group. However, adherence (P = 0.035) and baseline VASP-PRI (P = 0.015) were associated with VASP-PRI at 3 months and 6 months. The association between adherence and VASP-PRI was lost in patients with baseline VASP-PRI > 50%. Diabetes, CYP2C19*2 carrier status and body mass index were significant predictors of VASP-PRI. The platelet response to clopidogrel during chronic therapy remained highly variable, despite high adherence. Different adherence monitoring programmes did not affect VASP-PRI at 6 months. Poor adherence is associated with lower VASP-PRI only in initial good responders to clopidogrel. © 2016 The British Pharmacological Society.

  9. Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug-Drug Interaction Between Clopidogrel and Dasabuvir.

    PubMed

    Shebley, M; Fu, W; Badri, P; Bow, Daj; Fischer, V

    2017-10-01

    Dasabuvir, a nonnucleoside NS5B polymerase inhibitor, is a sensitive substrate of cytochrome P450 (CYP) 2C8 with a potential for drug-drug interaction (DDI) with clopidogrel. A physiologically based pharmacokinetic (PBPK) model was developed for dasabuvir to evaluate the DDI potential with clopidogrel, the acyl-β-D glucuronide metabolite of which has been reported as a strong mechanism-based inhibitor of CYP2C8 based on an interaction with repaglinide. In addition, the PBPK model for clopidogrel and its metabolite were updated with additional in vitro data. Sensitivity analyses using these PBPK models suggested that CYP2C8 inhibition by clopidogrel acyl-β-D glucuronide may not be as potent as previously suggested. The dasabuvir and updated clopidogrel PBPK models predict a moderate increase of 1.5-1.9-fold for Cmax and 1.9-2.8-fold for AUC of dasabuvir when coadministered with clopidogrel. While the PBPK results suggest there is a potential for DDI between dasabuvir and clopidogrel, the magnitude is not expected to be clinically relevant. © 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  10. Program Evaluation Particularly Responsive Evaluation

    ERIC Educational Resources Information Center

    Stake, Robert E.

    2011-01-01

    In this paper, the author talks about some recent developments in the methodology of program evaluation and about what he calls "responsive evaluation." He discusses two models for program evaluation, namely (1) informal study or self-study; and (2) the pretest/posttest model. Then, he describes an approach that he has been working on, which will…

  11. Impaired bioavailability and antiplatelet effect of high-dose clopidogrel in patients after cardiopulmonary resuscitation (CPR).

    PubMed

    Součková, L; Opatřilová, R; Suk, P; Čundrle, I; Pavlík, M; Zvoníček, V; Hlinomaz, O; Šrámek, V

    2013-03-01

    Bioavailability of clopidogrel in the form of crushed tablets administered via nasogastric tube (NGT) has not been established in patients after cardiopulmonary resuscitation. Therefore, we performed a study comparing pharmacokinetic and pharmacodynamic response to high loading dose of clopidogrel in critically ill patients after cardiopulmonary resuscitation (CPR) with patients scheduled for elective coronary angiography with stent implantation. In the NGT group (nine patients, after cardiopulmonary resuscitation, mechanically ventilated, therapeutic hypothermia), clopidogrel was administered in the form of crushed tablets via NGT. Ten patients undergoing elective coronary artery stenting took clopidogrel per os (po) in the form of intact tablets. Pharmacokinetics of clopidogrel was measured with high-performance liquid chromatography (HPLC) before and at 0.5, 1, 6, 12, 24 h after administration of a loading dose of 600 mg. In five patients in each group, antiplatelet effect was measured with thrombelastography (TEG; Platelet Mapping) before and 24 h after administration. The carboxylic acid metabolite of clopidogrel was detected in all patients in the po group. In eight patients, the maximum concentration was measured in the range of 0.5-1 h after the initial dose. In four patients in the of NGT group, the carboxylic acid metabolite of clopidogrel was undetectable and in the remaining patients was significantly delayed (peak values at 12 h). All patients in the po group reached clinically relevant (>50 %) inhibition of thrombocyte adenosine diphosphate (ADP) receptor after 24 h compared with only two in the NGT group (p = 0.012). There was a close correlation between peak of inactive clopidogrel metabolite plasmatic concentration and inhibition of the ADP receptor (r = 0.79; p < 0.001). The bioavailability of clopidogrel in critically ill patients after cardiopulmonary resuscitation is significantly impaired compared with stable patients. Therefore

  12. Association of Cytochrome P450 Genetic Variants with Clopidogrel Resistance and Outcomes in Acute Ischemic Stroke

    PubMed Central

    Yi, Xingyang; Wang, Yanfen; Zhou, Qiang; Wang, Chun; Cheng, Wen; Chi, Lifen

    2016-01-01

    Aims: Clopidogrel is an antiplatelet drug primarily used to treat or prevent acute ischemic stroke (IS) or myocardial infarction (MI). This prodrug requires biotransformation to an active metabolite by cytochrome P450 (CYP) enzymes, and CYP single nucleotide polymorphisms (SNPs) could affect the efficiency of such biotransformation. Methods: A total of 375 consecutive IS patients were genotyped for eight CYP SNPs using mass spectrometry. Platelet aggregation activity was measured before and after the 7 – 10 day treatment. Gene–gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) analysis. All patients received clopidogrel therapy and were followed up for six months. Primary outcomes were evaluated as a composite of recurrent ischemic stroke (RIS), MI, and death. The secondary outcome was the modified Rankin Scale (mRS). Results: Clopidogrel resistance occurred in 153 patients (40.8%). The frequency of CYP3A5 (rs776746) GG/AG and CYP2C19*2 (rs4244285) AA/AG genotypes was significantly higher in clopidogrel-resistant patients than in sensitive patients. There was a significant gene-gene interaction between CYP3A5 (rs776746) and CYP2C19*2 (rs4244285). CYP2C19*2 AA and its interaction with CYP3A5 GG were independent predictors of clopidogrel resistance and affected the activity of platelet aggregation. Diabetes mellitus, CYP2C19*2 (rs4244285), clopidogrel resistance, and the interaction of CYP2C19*2 with CYP3A5 were all independent risk factors for the primary outcomes of clopidogrel treatment. Clopidogrel-resistant patients were more likely to have poor outcomes (mRS > 2 points) compared with clopidogrel-sensitive patients. Conclusion: CYP SNPs and their interactions are associated with drug resistance and outcomes in acute IS patients. PMID:26961113

  13. Bleeding outcomes associated with coronary artery bypass graft surgery and recent clopidogrel exposure.

    PubMed

    Blais, Danielle M; Zukkoor, Sarah M; Hayes, Charles; Pickworth, Kerry K; Porter, Kyle; Firstenberg, Michael S

    2013-04-01

    Guidelines recommend discontinuing clopidogrel for at least 5 days before elective coronary artery bypass graft surgery (CABG) to limit blood transfusions and for at least 24 hours before urgent CABG to reduce major bleeding complications. Studies have produced conflicting results regarding whether recent exposure to clopidogrel increases bleeding, the need for intraoperative and postoperative blood products, postoperative complications, and hospital length of stay. We evaluated the effect of clopidogrel exposure on major bleeding at our institution within 5 days of CABG. We conducted a retrospective review of patients who underwent CABG at a tertiary academic medical center. The primary outcome was major bleeding, defined as transfusion of 4 units of packed red blood cells (PRBCs) and/or a need for reexploration. Secondary outcomes included non-life-threatening bleeding, defined as transfusion of 2 units but <4 units of PRBCs; postoperative complications; hospital length of stay; readmission within 30 days of the procedure; and hospital mortality. Major bleeding events were analyzed with a logistic regression model that adjusted for covariates of bleeding risk factors. Of the 715 patients we reviewed, 169 patients received clopidogrel within 5 days before CABG, and 546 patients did not. A significantly higher incidence of major bleeding was observed in the clopidogrel group compared with the group not exposed to clopidogrel (32% versus 17%, P = .002). After adjusting for covariates, patients exposed to clopidogrel had significantly higher odds of major bleeding (odds ratio, 2.1; 95% confidence interval, 1.3-3.4; P = .003). The groups were similar with respect to postoperative complications, except for infection. The clopidogrel-exposed group had a significantly higher rate of leg site infections (3% versus 0.2%, P = .003). Clopidogrel exposure within 5 days of CABG is associated with an increased risk of major bleeding.

  14. Sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients.

    PubMed

    Harmsze, Ankie M; Van Werkum, Jochem W; Moral, Fulya; Ten Berg, Jurri N M; Hackeng, Christian M; Klungel, Olaf H; De Boer, Anthonius; Deneer, Vera H M

    2011-01-01

    Clopidogrel is a prodrug that needs to be converted in?vivo by several cytochrome (CYP) P450 iso-enzymes to become active. Both clopidogrel and the oral hypoglycemic drug class sulfonylureas are metabolized by the iso-enzyme CYP2C9. The objective of the study was to evaluate the relationship of sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients undergoing elective coronary stent implantation. In this prospective, observational study, on-clopidogrel platelet reactivity was quantified using adenosine diphosphate (ADP)-induced light transmittance aggregometry in 139 type 2 diabetes mellitus patients undergoing elective coronary stent implantation treated with clopidogrel and aspirin. High on-clopidogrel platelet reactivity was defined as >70.7% platelet reactivity to 20 μmol/L ADP. A total of 53 patients (38.1%) were on concomitant treatment with sulfonylureas. The remaining 86 patients were on other hypoglycemic drugs. On-clopidogrel platelet reactivity was significantly higher in patients with concomitant sulfonylurea treatment as compared to patients without concomitant sulfonylurea treatment (for 5 μmol/L ADP: 46.0% ± 11.8 vs. 40.6% ± 16.0; p=0.035, adjusted p=0.032 and for 20 μmol/L ADP: 64.6% ± 10.8 vs. 58.7% ± 15.5; p=0.019, adjusted p=0.017). The concomitant use of sulfonylureas was associated with a 2.2-fold increased risk of high on-clopidogrel platelet reactivity (OR 2.2, 95% CI 1.1-4.7, p=0.039 and after adjustment for confounders: OR(adj) 2.0, 95% CI 1.0-5.7, p=0.048). Concomitant treatment with sulfonylureas might be associated with decreased platelet inhibition by clopidogrel in type 2 diabetes mellitus patients on dual antiplatelet therapy undergoing elective coronary stent implantation.

  15. Clopidogrel-Paclitaxel Drug-Drug Interaction: A Pharmacoepidemiologic Study.

    PubMed

    Agergaard, K; Mau-Sørensen, M; Stage, T B; Jørgensen, T L; Hassel, R E; Steffensen, K D; Pedersen, J W; Milo, Mlh; Poulsen, S H; Pottegård, A; Hallas, J; Brøsen, K; Bergmann, T K

    2017-09-01

    Paclitaxel is mainly eliminated by CYP2C8 in the liver. CYP2C8 is strongly inhibited by the clopidogrel metabolite acyl-β-D-glucuronide. To determine if this interaction has clinical relevance, we identified 48 patients treated with clopidogrel and paclitaxel using databases and a prescription register. Peripheral sensory neuropathy was retrospectively evaluated from medical charts and compared to that of 88 age- and sex-matched controls treated with paclitaxel and low-dose aspirin. By a cumulative dose of 1,500 mg paclitaxel, 35% of the patients had developed severe neuropathy. The overall hazard ratio between clopidogrel use and severe paclitaxel neuropathy was 1.7 (95% confidence interval, 0.9-3.0). Among those receiving a high-dose paclitaxel regimen, the hazard ratio was 2.3 (95% confidence interval, 1.1-4.5). Our study indicates that clopidogrel is associated with a clinically relevant increased risk of neuropathy in patients treated with high-dose paclitaxel. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  16. National Quality Assessment of Early Clopidogrel Therapy in Chinese Patients With Acute Myocardial Infarction (AMI) in 2006 and 2011: Insights From the China Patient-Centered Evaluative Assessment of Cardiac Events (PEACE)–Retrospective AMI Study

    PubMed Central

    Zhang, Lihua; Desai, Nihar R; Li, Jing; Hu, Shuang; Wang, Qing; Li, Xi; Masoudi, Frederick A; Spertus, John A; Nuti, Sudhakar V; Wang, Sisi; Krumholz, Harlan M; Jiang, Lixin

    2015-01-01

    Background Early clopidogrel administration to patients with acute myocardial infarction (AMI) has been demonstrated to improve outcomes in a large Chinese trial. However, patterns of use of clopidogrel for patients with AMI in China are unknown. Methods and Results From a nationally representative sample of AMI patients from 2006 and 2011, we identified 11 944 eligible patients for clopidogrel therapy and measured early clopidogrel use, defined as initiation within 24 hours of hospital admission. Among the patients eligible for clopidogrel, the weighted rate of early clopidogrel therapy increased from 45.7% in 2006 to 79.8% in 2011 (P<0.001). In 2006 and 2011, there was significant variation in early clopidogrel use by region, ranging from 1.5% to 58.0% in 2006 (P<0.001) and 48.7% to 87.7% in 2011 (P<0.001). While early use of clopidogrel was uniformly high in urban hospitals in 2011 (median 89.3%; interquartile range: 80.1% to 94.5%), there was marked heterogeneity among rural hospitals (median 50.0%; interquartile range: 11.5% to 84.4%). Patients without reperfusion therapy and those admitted to rural hospitals were less likely to be treated with clopidogrel. Conclusions Although the use of early clopidogrel therapy in patients with AMI has increased substantially in China, there is notable wide variation across hospitals, with much less adoption in rural hospitals. Quality improvement initiatives are needed to increase consistency of early clopidogrel use for patients with AMI. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01624883. PMID:26163041

  17. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization.

    PubMed

    Roe, Matthew T; Armstrong, Paul W; Fox, Keith A A; White, Harvey D; Prabhakaran, Dorairaj; Goodman, Shaun G; Cornel, Jan H; Bhatt, Deepak L; Clemmensen, Peter; Martinez, Felipe; Ardissino, Diego; Nicolau, Jose C; Boden, William E; Gurbel, Paul A; Ruzyllo, Witold; Dalby, Anthony J; McGuire, Darren K; Leiva-Pons, Jose L; Parkhomenko, Alexander; Gottlieb, Shmuel; Topacio, Gracita O; Hamm, Christian; Pavlides, Gregory; Goudev, Assen R; Oto, Ali; Tseng, Chuen-Den; Merkely, Bela; Gasparovic, Vladimir; Corbalan, Ramon; Cinteză, Mircea; McLendon, R Craig; Winters, Kenneth J; Brown, Eileen B; Lokhnygina, Yuliya; Aylward, Philip E; Huber, Kurt; Hochman, Judith S; Ohman, E Magnus

    2012-10-04

    The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

  18. An allele-specific PCR system for rapid detection and discrimination of the CYP2C19∗4A, ∗4B, and ∗17 alleles: implications for clopidogrel response testing.

    PubMed

    Scott, Stuart A; Tan, Qian; Baber, Usman; Yang, Yao; Martis, Suparna; Bander, Jeffrey; Kornreich, Ruth; Hulot, Jean-Sébastien; Desnick, Robert J

    2013-11-01

    CYP2C19 is involved in the metabolism of clinically relevant drugs, including the antiplatelet prodrug clopidogrel, which has prompted interest in clinical CYP2C19 genotyping. The CYP2C19∗4B allele is defined by both gain-of-function [c.-806C>T (∗17)] and loss-of-function [c.1A>G (∗4)] variants on the same haplotype; however, current genotyping and sequencing assays are unable to determine the phase of these variants. Thus, the aim of this study was to develop an assay that could rapidly detect and discriminate the related ∗4A, ∗4B, and ∗17 alleles. An allele-specific PCR assay, composed of four unique primer mixes that specifically interrogate the defining ∗17 and ∗4 variants, was developed by using samples (n = 20) with known genotypes, including the ∗4A, ∗4B, and/or ∗17 alleles. The assay was validated by testing 135 blinded samples, and the results were correlated with CYP2C19 genotyping and allele-specific cloning/sequencing. Importantly, among the six ∗4 carriers in the validation cohort, after allele-specific PCR testing both samples with a ∗1/∗4 genotype were reclassified to ∗1/∗4A, all three samples with a ∗4/∗17 genotype were reclassified to ∗1/∗4B, and a sample with a ∗4/∗17/∗17 genotype was reclassified to ∗4B/∗17. In conclusion, this rapid and robust allele-specific PCR assay can refine CYP2C19 genotyping and metabolizer phenotype classification by determining the phase of the defining ∗17 and ∗4 variants, which may have utility when testing CYP2C19 for clopidogrel response.

  19. Evaluator Responsiveness to Stakeholders

    ERIC Educational Resources Information Center

    Azzam, Tarek

    2010-01-01

    A simulation study was conducted in an attempt to examine how evaluators modify their evaluation design in response to differing stakeholder groups. In this study, evaluators were provided with a fictitious description of a school-based program. They were then asked to design an evaluation of the program. After the evaluation design decisions were…

  20. Inflammatory and Antioxidant Pattern Unbalance in “Clopidogrel-Resistant” Patients during Acute Coronary Syndrome

    PubMed Central

    Gori, Anna Maria; Cecchettini, Antonella; Parodi, Guido; Marcucci, Rossella; Parolini, Marina; Romagnuolo, Ilaria; Citti, Lorenzo; Abbate, Rosanna

    2015-01-01

    Background. In acute coronary syndrome (ACS), inflammation and redox response are associated with increased residual platelet reactivity (RPR) on clopidogrel therapy. We investigated whether clopidogrel interaction affects platelet function and modulates factors related to inflammation and oxidation in ACS patients differently responding to clopidogrel. Material and Methods. Platelet aggregation was measured in 29 ACS patients on dual (aspirin/clopidogrel) antiplatelet therapy. Nonresponders (NR) were defined as RPR ≥70% by ADP. Several inflammatory and redox parameters were assayed and platelet proteome was determined. Results. Eight (28%) out of 29 ACS patients resulted NR to clopidogrel. At 24 hours, the levels of Th2-type cytokines IL-4, IFNγ, and MCP-1 were higher in NR, while blood GSH (r-GSHbl) levels were lower in NR than responders (R). Proteomic analysis evidenced an upregulated level of platelet adhesion molecule, CD226, and a downregulation of the antioxidant peroxiredoxin-4. In R patients the proinflammatory cytokine IL-6 decreased, while the anti-inflammatory cytokine IL-1Ra increased. Conclusions. In patients with high RPR on clopidogrel therapy, an unbalance of inflammatory factors, platelet adhesion molecules, and circulatory and platelet antioxidant molecules was observed during the acute phase. Proinflammatory milieu persists in nonresponders for a long time after the acute event while antioxidant blood factors tend to conform to normal responsiveness. PMID:25873769

  1. Uric acid and high-residual platelet reactivity in patients treated with clopidogrel or ticagrelor.

    PubMed

    Barbieri, L; Verdoia, M; Pergolini, P; Nardin, M; Rolla, R; Marino, P; Bellomo, G; Suryapranata, H; De Luca, G

    2016-04-01

    High residual platelet reactivity (HRPR) is still an important challenge, despite the advent of new potent ADP-antagonists. Therefore it is of extreme importance to identify factors that can influence platelet activation. Serum uric acid (SUA) has been largely addressed in the past as a possible risk factor for coronary artery disease, with a possible association with platelets hyperreactivity. So far no studies have assessed the role of serum uric acid on the response to dual antiplatelet therapy. Therefore, the aim of our study was to evaluate the impact of uric acid levels on platelet function in patients treated with dual antiplatelet therapy (DAPT) with clopidogrel or ticagrelor. We scheduled for platelet function assessment at 30-90 days post-discharge patients treated with DAPT (ASA + clopidogrel or ticagrelor) for an ACS or elective percutaneous coronary intervention (PCI). Platelet function was assessed by whole blood impedance aggregometry (Multiplate(®)-Roche Diagnostics AG), HRPR was considered for ASPI test >862 AU(∗)min (for ASA) and ADP test values ≥417 AU* min (for ADP-antagonists). We included a total of 493 patients (262 were on ASA and clopidogrel and 231 on ASA and ticagrelor). Patients were divided according to quartiles of serum uric acid levels measured at the time of platelet aggregation assessment (Group 1 <4.6 mg/dL, n = 114; Group 2, 4.7-5.8 mg/dL, n = 133; Group 3, 5.9-6.8 mg/dL, n = 124; Group 4, >6.9, n = 122). Patients with higher uric acid levels were older, more often smokers, with history of hypertension and previous coronary artery bypass surgery and renal failure and were more often on therapy with diuretics at admission. Patients with higher SUA had higher triglycerides and fibrinogen. Uric acid levels did not influence ASPI, COL, TRAP and ADP tests. High residual platelet reactivity (HRPR) was observed in 1.5% of patients treated with ASA, with no difference according to SUA quartiles (p = 0.60), confirmed at multivariate

  2. Switching from Clopidogrel to Prasugrel in patients undergoing PCI: A meta-analytic overview.

    PubMed

    Verdoia, Monica; Barbieri, Lucia; Suryapranata, Harry; De Luca, Giuseppe

    2016-01-01

    Despite the demonstrated benefits of Prasugrel, a new generation thienopyridine, in the prevention of thrombotic complications after percutaneous coronary interventions (PCI) for Acute Coronary Syndromes (ACS), its use is still precluded to those many patients arriving to the cath lab pre-treated with Clopidogrel. Conclusive data on the strategy of switching from Clopidogrel to Prasugrel are still missing, therefore we aimed to perform a meta-analysis of current studies evaluating the safety and efficacy of switching from Clopidogrel to Prasugrel (PS) as compared to a standard thienopyridine therapy with Clopidogrel or Prasugrel in patients undergoing PCI. Literature archives and main scientific sessions' abstracts were scanned for studies comparing a switching strategy from Clopidogrel to Prasugrel vs. Prasugrel or Clopidogrel. Primary efficacy endpoint was overall mortality. Secondary endpoints were: non-fatal myocardial infarction and definite/probable stent thrombosis. Safety endpoint was the rate of major bleedings according to a per-protocol definition. A total of 12 studies, involving 3956 patients, were included. Among them, 1396 patients (35.3%), received Prasugrel after a Clopidogrel treatment (PS), while 2560 (64.7%) received either Prasugrel or Clopidogrel. The switch from Clopidogrel to Prasugrel was in the majority of the studies periprocedural. The mortality was numerically lower, but not statistically significant, in the PS group as compared with patients who did not switch (1.7% vs. 3.8%, OR [95% CI] = 0.68 [0.40,1.15], p = 0.15, phet = 0.61), without any relationship with patients' risk profile (r = -0.68 [-2.09, 0.73], p = 0.35). Similar results were obtained for secondary efficacy endpoints and at sensitivity analysis in the majority of subgroups evaluated. Moreover, the PS strategy did not increase major bleedings as compared with standard therapy (1.4% vs. 2.5%, OR [95% CI = 0.70 [0.39, 1.25], p = 0.23, phet = 0.6). The present meta

  3. Responsive Evaluation: An Interpretation.

    ERIC Educational Resources Information Center

    Lewy, Arieh

    1977-01-01

    Stake's concept of responsive evaluation is designed to provide various decision makers with the kind of information desired and in the form most helpful for making decisions. Compared with formal research procedures, this approach has both advantages and disadvantages. It may also provide a valuable supplement to formal evaluation. (CTM)

  4. Clopidogrel IBS Patients Have Higher Incidence of Gastrointestinal Symptoms Influenced by Age and Gender.

    PubMed

    Soghomonyan, Suren; Abdel-Rasoul, Mahmoud; Zuleta-Alarcon, Alix; Grants, Iveta; Davila, Victor; Yu, Jeffrey; Zhang, Cheng; Whitaker, Emmett E; Bergese, Sergio D; Stoicea, Nicoleta; Arsenescu, Razvan; Christofi, Fievos L

    2017-08-24

    Clopidogrel is an irreversible antagonist of P2Y12 receptors (P2Y12Rs) used as an antiplatelet drug to reduce risk of thrombosis. P2Y12Rs are expressed in gastrointestinal (GI) tract where they might regulate GI function. To evaluate if blockade of P2Y12Rs by clopidogrel is associated with higher incidence of GI symptoms in patients with irritable bowel syndrome (IBS). A retrospective analysis of our institutional database was conducted for a 13-year period. IBS patients were identified, and their demographics, GI symptoms and clopidogrel therapy were collected. Logistic regression models were used to characterize symptoms in clopidogrel versus no-clopidogrel IBS-groups, adjusting for Age and Sex differences. An additional study characterized the P2Y12R distribution in human gut. The search identified 7217 IBS patients (6761 no-clopidogrel/456 clopidogrel). There were a higher proportion of patients with GI symptoms on clopidogrel (68%) compared to controls (60%, p = 0.0011) that were Females (70 vs. 60%, p = 0.0003) not Males (61 vs. 60%; p = 0.8312). In Females, clopidogrel was associated with higher incidence of GI symptoms (Age adjusted; p < 0.0001) for pain, constipation, gastroparesis (p ≤ 0.0001) and psychogenic pain (p = 0.0006). Age or Sex (adjusted models) influenced one or more GI symptoms (i.e., pain, p < 0.0001; constipation, p < 0.0001/p = 0.008; diarrhea, flatulence, p = 0.01). P2Y12R immunoreactivity was abundant in human ENS; glial-to-neuron ratio of P2Y12Rs expressed in Females ≫ Males. Irreversible blockade of P2Y12R by clopidogrel is associated with higher incidence of GI symptoms in Female IBS patients, although Age or Sex alone contributes to symptomatology. Prospective studies can determine clinical implications of P2Y12Rs in IBS.

  5. Effects of genetic factors to stent thrombosis due to clopidogrel resistance after coronary stent placement.

    PubMed

    Kirac, D; Erdem, A; Avcilar, T; Yesilcimen, K; Guney, A I; Emre, A; Yazici, S; Terzi, S; Kaspar, E C; Cetin, S E; Isbir, T

    2016-01-19

    Stent thrombosis (ST) is considered as a multifactorial problem which is mostly occurs due to clopidogrel resistance. It may be due to some CYP450 enzyme deficiencies which play role in clopidogrel metabolism. Therefore the aim of this study is to detect the mutations in CYP2C19 and CYP2C9 genes which may cause ST, and to investigate the relation between other risk factors and ST. 50 individuals who have stent thrombosis and 50 individuals who haven't got any complication were enrolled as patient and control group respectively. *2,*3,*4,*5,*17 mutations in CYP2C19 gene and *2 ve *3 mutations in CYP2C9 gene were investigated with RT-PCR. Clopidogrel and aspirin resistance were investigated with multiple electrode platelet aggregometry. Results were evaluated statistically. CYP2C19*2 mutation was found statistically higher in patients (% 18), whereas CYP2C19*17 was found statistically higher in controls (% 36)(p<0.05). Additionally, it was found that patients who have clopidogrel and/or aspirin resistance also have CYP2C19*1/*2 or CYPC19*2/*2 genotype. These relations were also found statistically significant. (p=0,000005 for clopidogrel resistance and p=0,000059 for aspirin resistance). In conclusion, it was suggested that there is a relation between CYP2C19*2 mutations and ST due to clopidogrel resistance, and CYP2C19*17 may have a protective role in this process. The use of novel and more potent drug or high clopidogrel maintenance dosing before stent implantation may be beneficial treatment options for antiplatelet therapy in CYP2C19*2 carriers.

  6. Increased Postoperative Bleeding Risk among Patients with Local Flap Surgery under Continued Clopidogrel Therapy

    PubMed Central

    Eichhorn, Wolfgang; Haase, Martina; Kluwe, Lan; Zeuch, Jürgen; Smeets, Ralf; Hanken, Henning; Wehrmann, Manfred; Gröbe, Alexander; Heiland, Max; Birkelbach, Moritz; Rendenbach, Carsten

    2015-01-01

    Purpose. The purpose of the study was to evaluate the influence of a continued antiplatelet therapy with clopidogrel on postoperative bleeding risk in patients undergoing skin tumor resection and reconstruction with local flaps or skin grafts under outpatient conditions. Patients and Methods. The authors designed and implemented a retrospective clinical cohort study at the General Hospital Balingen. The primary endpoint was the bleeding ratio in patients with clopidogrel treatment in comparison to patients without any anticoagulant or antiplatelet therapy. Wound healing was evaluated on days 1, 3, 5, 7, 10, and 14. Results. 650 procedures were performed, 123 of them under continued clopidogrel therapy. There were significantly more postoperative bleeding complications among patients with continued antiplatelet therapy. Regarding the whole study population, malignant lesions, a larger defect size, and skin grafts were accompanied by a higher rate of bleeding incidents. However, there were no significant findings in the univariate analysis of the clopidogrel group. All bleeding incidents were easily manageable. Conclusion. Despite an increased bleeding ratio among patients under continued clopidogrel therapy, the performance of simple surgical procedures can be recommended. However, cautious preparation and careful hemostasis are indispensable. PMID:26345612

  7. Efficacy of Clopidogrel and Clinical Outcome When Clopidogrel Is Coadministered With Atorvastatin and Lansoprazole

    PubMed Central

    Zhang, Jian-rong; Wang, Di-qing; Du, Jun; Qu, Guang-su; Du, Jian-lin; Deng, Song-bai; Liu, Ya-jie; Cai, Jin-xi; She, Qiang

    2015-01-01

    Abstract This prospective, randomized, nonblind, controlled trial evaluated the effects of clopidogrel on platelet function upon coadministration with atorvastatin and lansoprazole. One hundred four adult patients with non-ST-segment elevated acute coronary syndrome (NSTE-ACS) who underwent percutaneous coronary intervention (PCI) with drug-eluting stent implantation were included. All patients were treated with standard dual antiplatelet therapy (DAPT) plus rosuvastatin 10 mg daily after the operation. On the sixth day after PCI, patients were randomly divided into 4 groups, Group A: DAPT + atorvastatin 20 mg daily (a change from rosuvastatin to atorvastatin) + lansoprazole 30 mg daily, Group B: DAPT + atorvastatin 20 mg daily (a change from rosuvastatin to atorvastatin), Group C: DAPT + lansoprazole 30 mg daily (continuing to take rosuvastatin), Group D is the control group. Additional drugs were used according to the situation of patients. Platelet function and concentrations of platelet activation markers (granular membrane protein 140 (P-selectin), thromboxane B2 (TXB2), and human soluble cluster of differentiation 40 ligand (sCD40L)) were assessed before randomization and at 15- and 30-day follow-up visits. All patients were maintained on treatment for 6 months and observed for bleeding and ischemic events. A total of 104 patients were enrolled, 27 patients in group A, 26 patients in Group B/C, 25 patients in Group D separately, and all the patients were analyzed. There were no differences in platelet function and the levels of platelet activation markers (P-selectin, TXB2, and sCD40L) among or within the 4 groups at the 3 time points of interest (P > 0.05). In the subsequent 6 months, no significant bleeding events occurred, and 12 patients experienced ischemic events, these results were also not significantly different among the groups (P > 0.05). In patients diagnosed with NSTE-ACS who have had drug-eluting stent

  8. Clopidogrel and bleeding after general surgery procedures.

    PubMed

    Ozao-Choy, Junko; Tammaro, Yolanda; Fradis, Martin; Weber, Kaare; Divino, Celia M

    2008-08-01

    Although many studies in the cardiothoracic literature exist about the relationship between clopidogrel and postoperative bleeding, there is scarce data in the general surgery literature. We assessed whether there are increased bleeding complications, morbidity, mortality, and resource utilization in patients who are on clopidogrel (Plavix) within 1 week before undergoing a general surgery procedure. Fifty consecutive patient charts were retrospectively reviewed after identifying patients who had pharmacy orders for clopidogrel and who underwent a general surgery procedure between 2003 and 2007. Patients who took clopidogrel within 6 days before surgery (group I, n = 28) were compared with patients who stopped clopidogrel for 7 days or more (group II, n = 22). A larger percentage of patients who took their last dose of clopidogrel within 1 week of surgery (21.4% vs 9.5%) had significant bleeding after surgery requiring blood transfusion. However, there were no significant differences between the groups in operative or postoperative blood transfusions (P = 0.12, 0.53), decreases in hematocrit (P = 0.21), hospital stay (P = 0.09), intensive care unit stay (P = 0.41), late complications (P = 0.45), or mortality (P = 0.42). Although our cohort is limited in size, these results suggest that in the case of a nonelective general surgery procedure where outcomes depend on timely surgery, clopidogrel taken within 6 days before surgery should not be a reason to delay surgery. However, careful attention must be paid to meticulous hemostasis, and platelets must be readily available for transfusion in the operating room.

  9. Pharmacogenetic Selection of Volunteers Increases Stringency of Bioequivalence Studies; The Case of Clopidogrel

    PubMed Central

    Garcés-Eisele, J.; Ruiz-Argüelles, A.; Estrada-Marín, Larisa; Reyes-Núñez, Virginia; Vázquez-Pérez, R.; Guzmán-García, Olga; Coutiño-Medina, R.; Acosta-Sandria, Leticia; Cedillo-Carvallo, Beatriz

    2014-01-01

    Clinical response to clopidogrel varies widely due to under-dosing, drug interactions and intrinsic interindividual differences resulting from genetic polymorphisms. Cytochrome P450-2C19 is the principal enzyme involved in the activation of the prodrug and loss-of-function alleles have been described. Upon expiration of the pharmaceutical patent of clopidogrel, generic manufacturers have started to subject interchangeable formulations to bioequivalence studies. The purpose of the current investigation was to study the effect of selection of volunteers homozygous for the CYP2C19*1 haplotype on the bioavailability of clopidogrel. A regular 2×2 bioequivalence study between two formulations of clopidogrel was performed in volunteers selected and unselected for relevant CYP2C19 haplotypes for the Mexican population. It was found that selection of volunteers homozygous for the CYP2C19*1 haplotype, increased the stringency of bioequivalence statistics and resulted in bioinequivalence of a generic clopidogrel compound that otherwise proved equivalent when tested in an open unselected population. Augmentation of bioequivalence strictness is expected to result from pharmacogenetic selection of volunteers. PMID:25284925

  10. Pharmacogenetic selection of volunteers increases stringency of bioequivalence studies; the case of clopidogrel.

    PubMed

    Garcés-Eisele, J; Ruiz-Argüelles, A; Estrada-Marín, Larisa; Reyes-Núñez, Virginia; Vázquez-Pérez, R; Guzmán-García, Olga; Coutiño-Medina, R; Acosta-Sandria, Leticia; Cedillo-Carvallo, Beatriz

    2014-07-01

    Clinical response to clopidogrel varies widely due to under-dosing, drug interactions and intrinsic interindividual differences resulting from genetic polymorphisms. Cytochrome P450-2C19 is the principal enzyme involved in the activation of the prodrug and loss-of-function alleles have been described. Upon expiration of the pharmaceutical patent of clopidogrel, generic manufacturers have started to subject interchangeable formulations to bioequivalence studies. The purpose of the current investigation was to study the effect of selection of volunteers homozygous for the CYP2C19*1 haplotype on the bioavailability of clopidogrel. A regular 2×2 bioequivalence study between two formulations of clopidogrel was performed in volunteers selected and unselected for relevant CYP2C19 haplotypes for the Mexican population. It was found that selection of volunteers homozygous for the CYP2C19*1 haplotype, increased the stringency of bioequivalence statistics and resulted in bioinequivalence of a generic clopidogrel compound that otherwise proved equivalent when tested in an open unselected population. Augmentation of bioequivalence strictness is expected to result from pharmacogenetic selection of volunteers.

  11. Clopidogrel inhibition of stent, graft, and vascular thrombogenesis with antithrombotic enhancement by aspirin in nonhuman primates.

    PubMed

    Harker, L A; Marzec, U M; Kelly, A B; Chronos, N R; Sundell, I B; Hanson, S R; Herbert, J M

    1998-12-01

    aspirin and clopidogrel need to be evaluated in patients at risk of vascular thrombosis.

  12. Stent Thrombosis Patients with Hyporesponsiveness to Clopidogrel, Prasugrel, and Ticagrelor: A Case Series Using Short Thromboelastography

    PubMed Central

    Sambu, Nalyaka; Mahmoudi, Michael; Curzen, Nick

    2016-01-01

    Patients after percutaneous coronary intervention (PCI) with stent implantation and functional hyporesponsiveness to P2Y12 inhibitors are at higher risk of ischaemic events, particularly stent thrombosis (ST). It is currently not routine practice to assess the functional response to these agents. However, concern over functional hyporesponsiveness to clopidogrel has led to widespread uptake of prasugrel and ticagrelor as the default P2Y12 inhibitor after stent implantation in patients with acute coronary syndrome. Here we report, for the first time, 3 cases in which patients who have had ST exhibit hyporesponsiveness to clopidogrel, prasugrel, and ticagrelor. PMID:27799942

  13. Preformulation investigation of some clopidogrel addition salts.

    PubMed

    Zupančič, Vinko; Smrkolj, Matej; Benkič, Promož; Simonič, Igor; Plevnik, Miha; Ritlop, Gregor; Kristl, Albin; Vrečer, Franc

    2010-06-01

    Physico-chemical properties of active substances such as solubility, dissolution rate, chemical stability, pharmaceutical processibility, etc. can be improved by salt formation of active substances. Characterization of physical properties of such salts is important for selection of an optimal salt having required biopharmaceutical properties, stability and manufacturability. The present study deals with the preformulation study of selected clopidogrel acid addition salts, i.e. hydrogen sulfate, hydrochloride (HCl), hydrobromide (HBr), besylate and (-)-camphor-10-sulfonate salt (CSA) and two commercially available polymorphic forms of hydrogen sulphate salt, i.e. form 1 (HS F1) and form 2 (HS F2). Clopidogrel salts were characterized by means of thermal analysis (TG, DSC), X-ray powder diffraction (XRPD), infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), dynamic vapor sorption (DVS), true density, scanning electron microscopy (SEM) and solubility. Distinct differences in tested parameters were found among acid addition salts and crystalline forms of clopidogrel. Higher melting point of both hydrogen sulphate salt was attributed to presence of hydrogen bonds among HS anions, connecting them into a chain. All salts included in the present study were anhydrous, except HBr which was in the form of monohydrate. The two tested polymorphic forms of clopidogrel HS salt are enantiotropically related to each other and showed the highest hygroscopicity among the tested salts. This is important for development of solid dosage form containing both polymorphic forms and for selection of primary packaging. Solubility studies in different aqueous media showed comparable solubility for clopidogrel hydrogen sulfate (polymorphic forms 1 and 2), hydrochloride (form 1) and hydrobromide hydrate (form 1) whereas clopidogrel camphorsulfonate (CSA) and besylate salt showed slightly lower solubility.

  14. Evaluation of two Japanese regulatory actions using medical information databases: a 'Dear Doctor' letter to restrict oseltamivir use in teenagers, and label change caution against co-administration of omeprazole with clopidogrel.

    PubMed

    Hanatani, T; Sai, K; Tohkin, M; Segawa, K; Antoku, Y; Nakashima, N; Yokoi, H; Ohe, K; Kimura, M; Hori, K; Kawakami, J; Saito, Y

    2014-08-01

    The implementation of appropriate epidemiological methodology using medical information databases (MIDs) to evaluate the effects of regulatory actions has been highly anticipated. To assess scientific methods for active pharmacovigilance using MIDs, we conducted a quantitative assessment of the impact of two regulatory actions by the Japanese government: (i) restriction of use of oseltamivir in teenagers in March 2007 and (ii) caution against the co-administration of omeprazole (OPZ) with clopidogrel (CPG) in April 2010. Data were obtained from four hub hospitals in Japan. We measured the seasonal proportion of patients prescribed oseltamivir to those prescribed neuraminidase inhibitors for the 2002/2003 to 2010/2011 seasons. The monthly proportion of patients co-administered OPZ and CPG (OPZ+CPG) to those prescribed CPG was measured from May 2009 to April 2011. We evaluated the changes observed with implementation of the regulatory actions. To estimate the impact of the actions, we conducted segmented regression analysis using interrupted time series data. The impact was assessed by two parameter estimates of the regression model: the change in level for short-term effects and change in trend for long-term effects. The use of oseltamivir in the target 10-19 years age group showed a significant and large decline (63·16%) immediately after the intervention (P = 0·0008). No change was observed in OPZ+CPG, although there was a relative inhibitory trend for OPZ+CPG compared with co-administration of lansoprazole or rabeprazole with CPG as the control group. When restricted to new users of CPG, the stratified results were consistent with the overall results. The current analysis demonstrates the effectiveness of two regulatory actions. The results of the current study indicate that MID research can contribute to assessing and improving pharmacovigilance activities. © 2014 John Wiley & Sons Ltd.

  15. Additive antithrombotic effect of ASP6537, a selective cyclooxygenase (COX)-1 inhibitor, in combination with clopidogrel in guinea pigs.

    PubMed

    Sakata, Chinatsu; Suzuki, Ken-Ichi; Morita, Yoshiaki; Kawasaki, Tomihisa

    2017-03-05

    Clopidogrel (Plavix(®), Sanofi-Aventis), the adenosine diphosphate P2Y12 receptor antagonist, is reported to be effective in the prevention of cardiovascular events and is often used in combination with aspirin, particularly in high-risk patients. ASP6537 is a reversible cyclooxygenase (COX)-1 inhibitor that is under investigation as an anti-platelet agent. First, we investigated the reversibility of the antiplatelet effect of ASP6537 and its interaction with ibuprofen to compare the usability of ASP6537 with that of aspirin. We then evaluated the antithrombotic effect of ASP6537 in combination with clopidogrel using a FeCl3-induced thrombosis model in guinea pigs. ASP6537 exerted reversible antiplatelet activity, and no pharmacodynamic interaction with ibuprofen was noted. When administered as monotherapy, ASP6537 exerted a significant antithrombotic effect at ≥3mg/kg, while aspirin inhibited thrombosis at 100mg/kg. ASP6537 exerted significant additive effects in combination with clopidogrel, and the minimum antithrombotic dose was reduced by concomitant administration of clopidogrel. Our study showed that ASP6537 did not interact with ibuprofen and has clear additive effects in combination with clopidogrel. ASP6537 may therefore represent a promising antiplatelet agent for use in clinical settings in combination with clopidogrel.

  16. Antithrombotic potency of ticagrelor versus clopidogrel in type-2 diabetic patients with cardiovascular disease.

    PubMed

    Zafar, M Urooj; Baber, Usman; Smith, Donald A; Sartori, Samantha; Contreras, Johanna; Rey-Mendoza, Juan; Linares-Koloffon, Carlos A; Escolar, Gines; Mehran, Roxana; Fuster, Valentin; Badimon, Juan J

    2017-08-24

    Type-2 Diabetes Mellitus [T2DM] is associated with increased platelet reactivity and hypo-response to antiplatelet drugs. Ticagrelor, with its faster and more potent antiplatelet effects, was shown to reduce adverse events more than clopidogrel in the overall CAD patient population of PLATO trial, but the benefits did not reach statistical significance in the T2DM subgroup. To better understand these findings, we compared the antithrombotic effects of ticagrelor versus with clopidogrel in T2DM patients with cardiovascular disease. In a randomized, 2 treatment-sequence, crossover-design, T2DM patients (n=20, 57±8 years, 60 % male) received a loading-dose [LD] plus one week of daily-therapy [DT] of clopidogrel or ticagrelor. Treatment effects were assessed by measuring thrombus formation (Badimon Chamber) and platelet aggregation (Multiple Electrode Aggregometry (MEA) Analyzer and VerifyNow®) at 2- and 6-hour post-LD and on Day-7 of DT, in comparison with pre-treatment baseline. After 2 weeks of washout, patients switched to the second treatment under identical testing conditions. Ticagrelor significantly reduced thrombus formation versus baseline at 2- and 6-hour post-LD and Day-7 of DT (33 %, 40 % and 31 %, respectively, p<0.01 for all) whereas thrombus reductions with clopidogrel were much lower and significant only at 6-hour post-LD (16 %, 20 % and 17 %, respectively). Antithrombotic effect of ticagrelor at 6-hour was significantly stronger than clopidogrel (p<0.05). Platelet aggregation (MEA and VerifyNow®) was inhibited by both treatments but effects of ticagrelor were significantly stronger at each time-point. Ticagrelor exhibits a faster and more potent antithrombotic effect than clopidogrel in T2DM patients with cardiovascular disease, supporting its use in this population.

  17. [Impact of pharmacotherapeutic warnings on the prescription of clopidogrel and proton pump inhibitors in hospitalised patients].

    PubMed

    Sánchez Ruiz-Gordoa, M; Tenías Burillo, J M; Ruiz Martín de la Torre, R; Valenzuela Gámez, J C

    2012-01-01

    To estimate the frequency of clopidogrel prescriptions in association with proton pump inhibitors (PPIs) in patients hospitalised with circulatory pathologies, after the publication of several warnings about this association. To identify and quantify the magnitude of the factors related to the prescription of both drugs. Observational, analytical, longitudinal, and retrospective study assessing changes in prescription of clopidogrel-PPIs association after and before the first official warning (about these drugs' interactions) was published. We selected all patients with a code indicating a circulatory system disease in the Minimum Basic Data Set, who had been prescribed clopidogrel during hospital admission. We also evaluated proton pump inhibitor use in these patients (omeprazole and pantoprazole). 5678 patients diagnosed with circulatory diseases were admitted during 2009, and clopidogrel was prescribed in 13.6% of them. In the pre-warning period, clopidogrel-PPIs prescriptions were significantly higher than in the post-warning period (80, 8% vs 48, 6%), especially in omeprazole. The combined prescription was lower if the circulatory diagnosis was the main cause for hospitalisation, if the patient had heart disease, if the patient was admitted in Internal Medicine/Cardiology or Intensive care units, and if the period of time was further from warning. Combined prescription has decreased since the first warning, above all in patients with a primary circulatory heart disease. Omeprazole is a potent CYP2C19 inhibitor, so it was used in lower rates than pantoprazole in association with clopidogrel. Medical departments related to cardiovascular disease followed the warning more than others. Copyright © 2011 SEFH. Published by Elsevier Espana. All rights reserved.

  18. Determination of clopidogrel resistance by whole blood platelet aggregometry and inhibitors of the P2Y12 receptor.

    PubMed

    Ivandic, Boris T; Schlick, Philipp; Staritz, Peter; Kurz, Kerstin; Katus, Hugo A; Giannitsis, Evangelos

    2006-03-01

    Inhibition of platelet aggregation by clopidogrel may be insufficient in up to 30% of users. These nonresponders carry an increased risk of cardiovascular events. We reported here a simple assay to study clopidogrel responsiveness. Electrical impedance aggregometry was performed in diluted whole blood in the presence of 5 and 20 micromol/L ADP. Some samples were incubated with 0.1 mmol/L methyl-S-adenosine monophosphate (MeSAMP), a P2Y12 receptor blocker, to maximize inhibition of aggregation before aggregometry. To validate the assay, we analyzed 6-min impedance in 21 healthy probands and 244 patients with coronary artery disease (CAD). At 5 micromol/L ADP, the imprecision of the assay was 11%. Mean (SD) impedance of the healthy cohort was 12.2 (2.2) Omega. The mean - 3 SD was used to define the cutoff for clopidogrel responsiveness: responders and nonresponders exhibited a 6-min impedance < or =5 Omega and >5 Omega, respectively. Samples from nonresponders were incubated with MeSAMP and analyzed again to distinguish pharmacokinetic and pharmacodynamic types of resistance. Sixteen percent of CAD patients were classified as nonresponders (38 and 2 cases of pharmacokinetic and pharmacodynamic resistance, respectively). Female sex was strongly associated with clopidogrel resistance (P = 0.0002, Fisher exact test). A higher clopidogrel loading dose (P = 0.0353, Mann-Whitney U-test) was given to responders (median, 450 mg) than nonresponders (median, 300 mg). Age and cardiovascular diagnosis showed no significant associations. Impedance aggregometry using 5 mumol/L ADP is a useful tool for studying clopidogrel responsiveness. MeSAMP allows characterization of responsiveness "on treatment" and may be useful for optimizing clopidogrel dosing.

  19. The efficacy and safety of clopidogrel in vascular surgery patients with immediate postoperative asymptomatic troponin T release for the prevention of late cardiac events: Rationale and design of the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo-VII (DECREASE-VII) trial.

    PubMed

    van Kuijk, Jan-Peter; Voute, Michiel T; Flu, Willem-Jan; Schouten, Olaf; Chonchol, Michel; Hoeks, Sanne E; Boersma, Eric E; Verhagen, Hence J M; Bax, Jeroen J; Poldermans, Don

    2010-09-01

    Major vascular surgery patients are at high risk for developing asymptomatic perioperative myocardial ischemia reflected by a postoperative troponin release without the presence of chest pain or electrocardiographic abnormalities. Long-term prognosis is severely compromised and characterized by an increased risk of long-term mortality and cardiovascular events. Current guidelines on perioperative care recommend single antiplatelet therapy with aspirin as prophylaxis for cardiovascular events. However, as perioperative surgical stress results in a prolonged hypercoagulable state, the postoperative addition of clopidogrel to aspirin within 7 days after perioperative asymptomatic cardiac ischemia could provide improved effective prevention for cardiovascular events. DECREASE-VII is a phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial designed to evaluate the efficacy and safety of early postoperative dual antiplatelet therapy (aspirin and clopidogrel) for the prevention of cardiovascular events after major vascular surgery. Eligible patients undergoing a major vascular surgery (abdominal aorta or lower extremity vascular surgery) who developed perioperative asymptomatic troponin release are randomized 1:1 to clopidogrel or placebo (300-mg loading dose, followed by 75 mg daily) in addition to standard medical treatment with aspirin. The primary efficacy end point is the composite of cardiovascular death, stroke, or severe ischemia of the coronary or peripheral arterial circulation leading to an intervention. The evaluation of long-term safety includes bleeding defined by TIMI criteria. Recruitment began early 2010. The trial will continue until 750 patients are included and followed for at least 12 months. DECREASE-VII is evaluating whether early postoperative dual antiplatelet therapy for patients developing asymptomatic cardiac ischemia after vascular surgery reduces cardiovascular events with a favorable safety profile. 2010 Mosby

  20. Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008)

    PubMed Central

    Zakarija, Anaadriana; Kwaan, Hau C.; Moake, Joel L.; Bandarenko, Nicholas; Pandey, Dilip K.; McKoy, June M.; Yarnold, Paul R.; Raisch, Dennis W.; Winters, Jeffrey L.; Raife, Thomas J.; Cursio, John F.; Luu, Thanh Ha; Richey, Elizabeth A.; Fisher, Matthew J.; Ortel, Thomas L.; Tallman, Martin S.; Zheng, X. Long; Matsumoto, Masanori; Fujimura, Yoshihiro; Bennett, Charles L.

    2012-01-01

    Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions. PMID:19180126

  1. [Effect of drug interaction between clopidogrel and omeprazole in hospital readmision of patients by a recurrent acute coronary syndrome: a case-control study].

    PubMed

    Amariles, Pedro; Holguín, Héctor; Angulo, Nancy Yaneth; Betancourth, Piedad Maria; Ceballos, Mauricio

    2014-10-01

    To evaluate the effect of drug interaction between omeprazol and clopidogrel in hospital readmission of patients with acute coronary syndrome (ACS). Case-control study. University Clinic LeonXIII, Medellin, Colombia. We selected from a prevalent population, between 2009-2010, use of clopidogrel patients on an outpatient basis (less than one year and more than 30days), and hospital stay for ACS or the presence of a previous ACS. A case-patient was defined as one who had a recurrence of ACS and a patient-control is defined as one that no recurrence of ACS. Both groups used ambulatory prior clopidogrel due to ACS. As defined risk factor the joint use of omeprazole and clopidogrel outpatients. During the study, 1680patients clopidogrel formulated. This group identified 50cases readmitted with ACS and 76controls. No statistically significant association was found between use of clopidogrel-omeprazole and increased risk of hospital readmission for ACS (OR: 1.05; 95%CI: 0.516-2.152; P=.8851). In this small group of patients with previous SCA, the simultaneous use of clopidogrel with omeprazole does not increase the risk of a readmission by recurrence of this type of coronary event. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  2. Evaluating vendor responses.

    PubMed

    Williams, F L; Tucker, S R

    1982-05-01

    The process of evaluating computer vendors' responses to a request for proposal (RFP) is described. The steps involved are (1) reviewing vendor proposals, (2) attending vendor presentations (3) reviewing references, (4) visiting vendor clients, (5) reviewing vendor stability, and (6) making the decision. The primary purpose of reviewing proposals is to reduce the number of vendors under consideration. Vendors' proposals should be attended by representatives of all affected departments, and each vendor's presentation should be discussed with the RFP or RFP extension as a guide. Interviewing users of a system helps determine how the system works in practice and how accurately the vendor has represented his product. Likewise, visiting selective vendor clients, without the vendor representative being present, helps establish whether the persons actually using the system like it and find it easy to use. A vendor's stability can be best determined by examining its financial stability and its commitment to the pharmacy product. Making the selection requires elimination of vendors that do not meet minimum requirements, rating the remaining vendors numerically, and deciding which features of each system are most desirable. The vendor selection process provides an opportunity to thoroughly study an operation and helps set priorities for the department.

  3. Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel

    PubMed Central

    Zhong, W‐P; Wu, H; Chen, J‐Y; Li, X‐X; Lin, H‐M; Zhang, B; Zhang, Z‐W; Ma, D‐L; Sun, S; Li, H‐P; Mai, L‐P; He, G‐D; Wang, X‐P; Lei, H‐P; Zhou, H‐K; Tang, L; Liu, S‐W

    2017-01-01

    Genetic variants in the pharmacokinetic (PK) mechanism are the main underlying factors affecting the antiplatelet response to clopidogrel. Using a genomewide association study (GWAS) to identify new genetic loci that modify antiplatelet effects in Chinese patients with coronary heart disease, we identified novel variants in two transporter genes (SLC14A2 rs12456693, ATP‐binding cassette [ABC]A1 rs2487032) and in N6AMT1 (rs2254638) associated with P2Y12 reaction unit (PRU) and plasma active metabolite (H4) concentration. These new variants dramatically improved the predictability of PRU variability to 37.7%. The associations between these loci and PK parameters of clopidogrel and H4 were observed in additional patients, and its function on the activation of clopidogrel was validated in liver S9 fractions (P < 0.05). Rs2254638 was further identified to exert a marginal risk effect for major adverse cardiac events in an independent cohort. In conclusion, new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment. PMID:27981573

  4. Pivotal Bioequivalence Study of Clopacin®, a Generic Formulation of Clopidogrel 75 mg Film-Coated Tablets.

    PubMed

    McGregor, Gerard Patrick

    2016-02-01

    Clopacin(®) (Acino Pharma AG) is a proprietary, besylate salt and lactose-free formulation of the widely-used anti-platelet treatment, clopidogrel. This study aimed to evaluate the bioequivalence of Clopacin(®) with the originator as reference drug, using a guideline-compliant trial design: open-labeled, randomized, single-dose (clopidogrel 75 mg tablet), two-period, crossover trial in 48 healthy male volunteers, with a 7 day wash-out period. Plasma samples were collected at intervals and extracted before quantifying clopidogrel concentrations using a fully validated LC-MS/MS method. Bioequivalence of Clopacin(®) and the reference drug was established by comparison of the primary pharmacokinetic parameters, C max, AUC0-t, and AUC0-∞. The parameter values were similar for the two products (analysis of variance) and provided Clopacin/reference ratios (least squares means) of >90% and 90% confidence intervals (CIs 84.64-105.50%, 90.43-111.22%, 88.75-110.71%, respectively) that were well within the limits set for defining bioequivalence, according to international guidelines. The respective Clopacin(®) and reference drug values for mean time to maximal plasma clopidogrel concentration (t max) were 0.83 and 0.91 h, and for terminal elimination half-life were 3.99 and 3.51 h. The intra-subject coefficients of variability for maximal plasma clopidogrel concentration (C max), area under the plasma clopidogrel concentration versus time curve, at 48 h (AUC0-t) and extrapolated to infinity (AUC0-∞) were 32.2%, 30.2%, and 28.9% (least square means), respectively, and the respective power values were 99.5%, 97.1%, and 95.3%. This bioequivalence study provided robust clopidogrel pharmacokinetic data that established the bioequivalence of Clopacin(®) and the reference originator drug. Acino Pharma AG (formerly Cimex AG).

  5. Non-Carriers of Reduced-Function CYP2C19 Alleles are Most Susceptible to Impairment of the Anti-Platelet Effect of Clopidogrel by Proton-Pump Inhibitors: A Pilot Study

    PubMed Central

    Lee, Jen-Kuang; Wu, Cho-Kai; Juang, Jyh-Ming; Tsai, Chia-Ti; Hwang, Juey-Jen; Lin, Jiuun-Lee; Chiang, Fu-Tien

    2016-01-01

    Background The phenomenon of CYP2C19 polymorphism affects the metabolism of both clopidogrel and proton-pump inhibitors (PPI). However, concomitant use of both drugs may reduce the desired therapeutic effects. In this study, we evaluated whether individuals with different numbers of reduced-function CYP2C19 alleles were equally affected and whether PPIs with different dependencies on CYP2C19 metabolism were equally involved. Methods Thirty healthy volunteers were recruited to a six-week regimen of clopidogrel. Three PPIs with different metabolic dependencies on CYP2C19 were included and separately administered in this order. Each PPI was given for a week, followed by a one-week washout period before the intervention of the next PPI. The anti-platelet effect was examined by Thromboelastography Platelet MappingTM (TEG®) and vasodilator-stimulated phosphoprotein (VASP) assays. Results Both TEG® and VASP tests showed the same general qualitative trend, but TEG® detected a statistically significant fluctuation of platelet aggregation in response to different drug interventions. The TEG® results also demonstrated that non-carriers experienced the most significant impairment of anti-platelet effect of clopidogrel after concomitant use of PPIs. This impairment was closely related to the metabolic dependence on CYP2C19 of PPI. Conclusions Our study indicated that non-carriers of reduced-function CYP2C19 alleles are most susceptible to impairment of the anti-platelet effect of clopidogrel after concomitant PPI use. Individual subjects are not equally affected, and PPIs are not equally involved. However, large-scale randomized clinical trials are needed to evaluate the clinical outcome. PMID:27122952

  6. Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction.

    PubMed

    Schulz, Stefanie; Richardt, Gert; Laugwitz, Karl-Ludwig; Morath, Tanja; Neudecker, Julia; Hoppmann, Petra; Mehran, Roxana; Gershlick, Anthony H; Tölg, Ralph; Anette Fiedler, K; Abdel-Wahab, Mohamed; Kufner, Sebastian; Schneider, Simon; Schunkert, Heribert; Ibrahim, Tareq; Mehilli, Julinda; Kastrati, Adnan

    2014-09-07

    Whether prasugrel plus bivalirudin is a superior strategy to unfractionated heparin plus clopidogrel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) has never been assessed in specifically designed randomized trials. The Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 study is an investigator-initiated, randomized, open-label, multicentre trial, designed to test the hypothesis that in STEMI patients with planned primary PCI a strategy based on prasugrel plus bivalirudin is superior to a strategy based on clopidogrel plus heparin in terms of net clinical outcome. Owing to slow recruitment, the trial was stopped prematurely after enrolment of 548 of 1240 planned patients. At 30 days, the primary composite endpoint of death, myocardial infarction, unplanned revascularization of the infarct related artery, stent thrombosis, stroke, or bleeding was observed in 42 patients (15.6%) randomized to prasugrel plus bivalirudin and 40 patients (14.5%) randomized to clopidogrel plus heparin [relative risk, 1.09; one-sided 97.5% confidence interval (CI) 0-1.79, P = 0.680]. The composite ischaemic endpoint of death, myocardial infarction, unplanned revascularization of the infarct-related artery, stent thrombosis, or stroke occurred in 13 patients (4.8%) in the prasugrel plus bivalirudin group and 15 patients (5.5%) in the clopidogrel plus heparin group (relative risk, 0.89; 95% CI 0.40-1.96, P = 0.894). Bleeding according to the HORIZONS-AMI definition was observed in 38 patients (14.1%) in the prasugrel plus bivalirudin group and 33 patients (12.0%) in the clopidogrel plus heparin group (relative risk, 1.18; 95% CI 0.74-1.88, P = 0.543). Results were consistent across various subgroups of patients. In this randomized trial of STEMI patients, we were unable to demonstrate significant differences in net clinical outcome between prasugrel plus bivalirudin and clopidogrel plus heparin. Neither the

  7. Clopidogrel and bleeding after coronary artery bypass graft surgery.

    PubMed

    Leong, Jee-Yoong; Baker, Robert A; Shah, Pallav J; Cherian, Vijit K; Knight, John L

    2005-09-01

    There is evidence that clopidogrel (with or without aspirin) confers superior outcomes in patients with coronary artery disease. The purpose of this study is to review the effect of preoperative clopidogrel administration on clinical outcome, bleeding complications and resource utilization after coronary artery bypass graft surgery. Patient data were prospectively collected from 919 patients who had isolated coronary surgery during the period 2000 to 2003. Outcome comparisons were studied, firstly between patients who received preoperative clopidogrel with those who did not, and secondly between patients on clopidogrel only, aspirin only, both or neither medications. Twenty-four patients (2.6%) were on clopidogrel only, 598 (65.1%) were on aspirin only, 61 (6.6%) were on both, and 236 (25.7%) were on neither. Clopidogrel (n = 85) versus no clopidogrel (n = 834): there were no significant differences in the off-pump patients. In the on-pump patients, the clopidogrel group had significantly increased bleeding (p = 0.02), blood transfused (p = 0.01), intensive care (p = 0.03), and hospital stays (p = 0.03). There were no significant differences in surgical reexploration, perioperative myocardial infarction, intraoperative balloon pump use, inotropic support or 30-day mortality. Clopidogrel versus aspirin versus both versus neither: patients on both clopidogrel and aspirin had significantly more postoperative bleeding than patients on aspirin alone or on neither medication. The preoperative use of clopidogrel in patients undergoing coronary artery bypass graft surgery showed limited clinical benefits; however, its use significantly increased the risk of bleeding, blood transfusion, and resource utilization.

  8. Multi-parameter assessment of platelet inhibition and its stability during aspirin and clopidogrel therapy

    PubMed Central

    Timur, A. Anil; Murugesan, Gurunathan; Zhang, Li; Barnard, John; Bhatt, Deepak L.; Kottke-Marchant, Kandice

    2014-01-01

    Introduction Poor response to antiplatelet drugs is associated with adverse outcomes. We assessed platelet inhibition and its stability and tested correlation and agreement between platelet function assays. Methods Peripheral blood from 58 patients on both aspirin and clopidogrel who underwent percutaneous coronary intervention (PCI) was collected at hospital discharge (visit-1) and at 30–90 days (visit-2). Platelet function was measured using light transmission aggregometry (LTA-AA and LTA-ADP), VerifyNow (Aspirin; ARU and P2Y12; PRU), ex vivo TxB2, urinary 11dhTxB2, and VASP (PRI) assays. Data were analyzed as continuous, quartiles and binary. Patients were defined as aspirin poor responder (PR) with ARU ≥550, LTA-AA maximum ≥20%, TxB2 ≥1 ng/mL or 11dhTxB2 ≥1,500 pg/mg of creatinine and as clopidogrel PR with PRU ≥240, PRU ≥208, LTA-ADP maximum ≥40%, PRI ≥50%, or PRI ≥66%. Results Aspirin PR was 3–33% and clopidogrel PR was 10–35% in visit-1. LTA-AA, 11dhTxB2, and all clopidogrel-response measures showed correlation and agreement between visit-1 and visit-2. The highest agreement between two visits was revealed by PRU ≥240 and PRI ≥66% (PRU-κ=0.7, 95% CI=0.47, 0.93; PRI-κ=0.69, 95% CI=0.42, 0.95, p-values<0.001). Comparison of platelet function assays in a single visit (Visit-1) revealed a poor correlation between LTA-AA and 11dhTxB2 assays and no agreement among aspirin-response assays. The highest correlation and agreement were obtained between VerifyNow P2Y12 and VASP assays (rho=0.7, p-value<0.001 and PRU ≥208-PRI-κ=0.41–0.42, 95% CI=0.13, 0.69, p-values<0.001). Conclusions Platelet inhibition is stable during aspirin and clopidogrel treatment. Clopidogrel-response assays correlate and agree with each other better than aspirin-response assays. PMID:24852729

  9. Cost-effectiveness of clopidogrel plus aspirin for stroke prevention in patients with atrial fibrillation in whom warfarin is unsuitable.

    PubMed

    Coleman, Craig I; Straznitskas, Andrew D; Sobieraj, Diana M; Kluger, Jeffrey; Anglade, Moise W

    2012-04-01

    Guidelines for atrial fibrillation (AF) recommend clopidogrel plus aspirin as an alternative stroke prevention strategy in patients in whom warfarin is unsuitable. A Markov model was conducted from a Medicare prospective using data from the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A) trial and other published studies. Base-case analysis evaluated patients 65 years old with AF, a CHADS(2) (congestive heart failure, 1 point; hypertension defined as blood pressure consistently >140/90 mm Hg or antihypertension medication, 1 point; age ≥75 years, 1 point; diabetes mellitus, 1 point; previous stroke or transient ishemic attack, 2 points) score of 2, and a lower risk for major bleeding. Patients received clopidogrel 75 mg/day plus aspirin or aspirin alone. Patients were followed for up to 35 years. Outcomes included quality-adjusted life-years (QALYs), costs (in 2011 American dollars), and incremental cost-effectiveness ratios. Quality-adjusted life expectancy and costs were 9.37 QALYs and $88,751 with clopidogrel plus aspirin and 9.01 QALYs and $79,057 with aspirin alone. Incremental cost-effectiveness ratio for clopidogrel plus aspirin was $26,928/QALY. With 1-way sensitivity analysis using a willingness-to-pay threshold of $50,000/QALY, clopidogrel plus aspirin was no longer cost effective when the CHADS(2) score was ≤1, major bleeding risk with aspirin was ≥2.50%/patient-year, the relative risk decrease for ischemic stroke with clopidogrel plus aspirin versus aspirin alone was <25%, and the utility of being healthy with AF on combination therapy decreased to 0.95. Monte Carlo simulation demonstrated that clopidogrel plus aspirin was cost effective in 55% and 73% of 10,000 iterations assuming willingness-to-pay thresholds of $50,000 and $100,000/QALY. In conclusion, clopidogrel plus aspirin appears cost-effective compared to aspirin alone for stroke prevention in patients with AF with a CHADS(2) of ≥2

  10. Review of aspirin and clopidogrel resistance in peripheral arterial disease.

    PubMed

    Guirgis, Mina; Thompson, Peter; Jansen, Shirley

    2017-09-08

    Aspirin resistance (AR) and clopidogrel resistance (CR) are terms used to describe a reduction in the medication's efficacy in inhibiting platelet aggregation despite regular dosing. This review gives context to the clinical role and implications of antiplatelet resistance in peripheral arterial disease (PAD). A review of English-language literature on AR and CR in PAD involving human subjects using PubMed and MEDLINE databases was performed in April 2017. A total of 2075 patients in 22 relevant studies were identified. To give this issue context, a review of the larger, more established literature on antiplatelet resistance in coronary disease was undertaken, identifying significant research associating resistance to major adverse cardiovascular events (MACEs). Studies in the coronary arterial disease literature have strongly associated antiplatelet resistance with increased MACE. Prevalence of AR or CR in coronary disease appears to be >55% for each in some studies. Meta-analyses of >50 studies revealed that AR and CR are significantly associated with MACE (relative risk of 2.09 and 2.8, respectively). This adds further weight to the literature reporting antiplatelet resistance as an independent predictor of and a threefold risk factor for major adverse cardiovascular events. The prevalence of resistance in PAD in this review was comparable to that in the coronary disease literature, with AR and CR prevalence up to 60% and 65%, respectively. There is evidence that the adverse effects of antiplatelet resistance are significant in PAD. In fact, research directly studying stent thrombosis populations with either coronary arterial disease or PAD revealed more significantly impaired platelet responsiveness to clopidogrel and aspirin in PAD compared with similar individuals with coronary disease. AR in PAD was found in studies to be a significant risk factor for iliofemoral stent reocclusion (P = .0093) and stroke in patients with symptomatic carotid disease (P

  11. The Evaluator's Responsibility for Utilization.

    ERIC Educational Resources Information Center

    Patton, Michael Quinn

    1988-01-01

    The role of the evaluator in insuring utilization and quality of evaluation results is discussed. Topics covered include a utilization-focused vision of accountability, overcoming staff fears of evaluation, eliciting the right information from users, situational responsiveness, and advocacy. (TJH)

  12. Online Course Evaluations Response Rates

    ERIC Educational Resources Information Center

    Guder, Faruk; Malliaris, Mary

    2013-01-01

    This paper studies the reasons for low response rates in online evaluations. Survey data are collected from the students to understand factors that might affect student participation in the course evaluation process. When course evaluations were opened to the student body, an email announcement was sent to all students, and a reminder email was…

  13. "Influence of methadone on clopidogrel in addicts on methadone maintenance therapy" Drug interaction between methadone and clopidogrel

    PubMed Central

    Fallah, Ferigol; Hamidikenari, Abolhasan; Sajadi, Seyed Navid; Sajadi, Seyed Rohollah; Shiran, Mohammadreza

    2016-01-01

    Background: Clopidogrel is a prodrug that converts in the liver to an active thiol metabolite, which irreversibly inhibits the platelet P2Y12 adenosine diphosphate receptor. It seems that methadone as CYP2C19 inhibitor affects ticlopidine activity in vivo. This study aimed to test the ability of methadone in changing ticlopidine pharmacokinetics. Methods: We conducted a case–control study in 10 subjects. The cases (5 subjects) in our study were addicts who were receiving methadone maintenance treatment (MMT) for preventing opium withdrawal symptoms. The control group were opiate users before starting MMT. In both groups, the patients received clopidogrel (75mg/day) for 5 days. On the 6th day, the subjects returned to the clinic, blood samples were taken up to 12 hours following clopidogrel dosing in case and control groups. Plasma concentration of clopidogrel was measured by GC-MAS. Noncompartmental pharmacokinetic analysis was performed using Microsoft Excel software to estimate PK parameters. Results: In this study, methadone decreased clopidogrel clearance by 25% and increased the AUC0-inf nearly 1.3 fold during the coadministration of clopidogrel as an antiplatelet drug. Conclusion: A significant decrease in the clearance of clopidogrel during the coadministration of methadone consistent with a decrease in clopidogrel conversion to its active metabolite and this may decrease its efficacy and may have life-threatening consequences for the patients undergoing clopidogerel maintenance therapy. PMID:27386066

  14. "Influence of methadone on clopidogrel in addicts on methadone maintenance therapy" Drug interaction between methadone and clopidogrel.

    PubMed

    Fallah, Ferigol; Hamidikenari, Abolhasan; Sajadi, Seyed Navid; Sajadi, Seyed Rohollah; Shiran, Mohammadreza

    2016-01-01

    Clopidogrel is a prodrug that converts in the liver to an active thiol metabolite, which irreversibly inhibits the platelet P2Y12 adenosine diphosphate receptor. It seems that methadone as CYP2C19 inhibitor affects ticlopidine activity in vivo. This study aimed to test the ability of methadone in changing ticlopidine pharmacokinetics. We conducted a case-control study in 10 subjects. The cases (5 subjects) in our study were addicts who were receiving methadone maintenance treatment (MMT) for preventing opium withdrawal symptoms. The control group were opiate users before starting MMT. In both groups, the patients received clopidogrel (75mg/day) for 5 days. On the 6(th) day, the subjects returned to the clinic, blood samples were taken up to 12 hours following clopidogrel dosing in case and control groups. Plasma concentration of clopidogrel was measured by GC-MAS. Noncompartmental pharmacokinetic analysis was performed using Microsoft Excel software to estimate PK parameters. In this study, methadone decreased clopidogrel clearance by 25% and increased the AUC0-inf nearly 1.3 fold during the coadministration of clopidogrel as an antiplatelet drug. A significant decrease in the clearance of clopidogrel during the coadministration of methadone consistent with a decrease in clopidogrel conversion to its active metabolite and this may decrease its efficacy and may have life-threatening consequences for the patients undergoing clopidogerel maintenance therapy.

  15. Postpolypectomy bleeding in patients undergoing colonoscopy on uninterrupted clopidogrel therapy.

    PubMed

    Singh, Mandeep; Mehta, Nilesh; Murthy, Uma K; Kaul, Vivek; Arif, Asma; Newman, Nancy

    2010-05-01

    The risk of postpolypectomy bleeding (PPB) in patients undergoing colonoscopy on uninterrupted clopidogrel therapy has not been established. To assess the PPB rate and outcome and identify risk factors associated with PPB in patients taking clopidogrel. Single-center, retrospective study. Demographics, clinical parameters, polyp characteristics, polypectomy techniques, and postpolypectomy events in the groups were compared by univariate analysis. Stepwise logistic regression analyses identified independent risk factors associated with PPB. Veterans Affairs Medical Center. A total of 142 patients (375 polypectomies) taking clopidogrel (cases) and 1243 patients (3226 polypectomies) not taking clopidogrel (controls). None. Postpolypectomy bleeding, hospitalization, and mortality. The immediate (intraprocedural) bleeding rate was similar in the 2 groups (2.1% vs 2.1%). Delayed (postprocedural) PPB rate was higher in the group taking clopidogrel (3.5% vs 1.0%, P = .02). Delayed bleeding of significance requiring hospitalization and transfusion/intervention was also higher in patients taking clopidogrel (2.1% vs 0.4%, P = .04). The length of hospital stay and interventions for PPB were comparable between the 2 groups. There was no mortality. Concomitant use of clopidogrel and aspirin/other nonsteroidal anti-inflammatory drugs (odds ratio 3.7; 95% CI, 1.6-8.5) and the number of polyps removed (OR 1.3; 95% CI, 1.2-1.4) were the only significant risk factors associated with PPB. Clopidogrel alone was not an independent risk factor for PPB. Retrospective study and small number of patients with PPB. The PPB rate is significantly higher in patients undergoing polypectomy while taking clopidogrel and concomitant aspirin/nonsteroidal anti-inflammatory drugs; however, the risk is small and the outcome is favorable. Routine cessation of clopidogrel in patients before colonoscopy/polypectomy is not necessary. 2010 American Society for Gastrointestinal Endoscopy. Published by Mosby

  16. The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes

    PubMed Central

    Kim, Ho‐Sook; Lim, Younghae; Oh, Minkyung; Ghim, Jong‐lyul; Kim, Eun‐Young; Kim, Dong‐Hyun

    2015-01-01

    Aim The primary objective of the present study was to evaluate the pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to the CYP2C19 and CYP3A5 genotypes. Methods In a randomized, three‐way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg) or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4‐dehydrocilostazol and 4″‐trans‐hydroxycilostazol), and adenosine diphosphate‐induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment. Results The area under the plasma concentration–time curve (AUC) of the active thiol metabolite of clopidogrel was highest in the CYP2C19 extensive metabolizers (EM) and lowest in the poor metabolizers (PM). Cilostazol decreased the thiol metabolite AUC by 29% in the CYP3A5*1/*3 genotype [geometric mean ratio (GMR) 0.71; 90% confidence interval (CI) 0.58, 0.86; P = 0.020] but not in the CYP3A5*3/*3 genotype (GMR 0.93; 90% CI 0.80, 1.10; P = 0.446). Known effects of the CYP2C19 and CYP3A5 genotypes on the exposure of cilostazol and its metabolites were observed but there was no significant difference in the AUC of cilostazol and 3,4‐dehydrocilostazol between cilostazol and clopidogrel + cilostazol. The inhibition of platelet aggregation from 4 h to 24 h (IPA4–24) following the administration of clopidogrel alone was highest in the CYP2C19 EM genotype and lowest in the CYP2C19 PM genotype (59.05 ± 18.95 vs. 36.74 ± 13.26, P = 0.023). However, the IPA of the CYP2C19 PM following co‐administration of clopidogrel and cilostazol was comparable with that of the CYP2C19 EM and intermediate metabolizers (IM) only in CYP3A5*3/*3 subjects. Conclusions The additive antiplatelet effect of cilostazol plus clopidogrel is maximized in subjects with both the CYP2C19 PM and CYP3A5*3/*3 genotypes because

  17. Eight-year follow-up of the Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) trial.

    PubMed

    Hage, Ali; Voisine, Pierre; Erthal, Fernanda; Larose, Éric; Glineur, David; Chow, Benjamin; Tremblay, Hugo; Fortier, Jacqueline; Ko, Gifferd; Une, Dai; Farkouh, Michael; Mesana, Thierry G; LeMay, Michel; Kulik, Alexander; Ruel, Marc

    2017-06-24

    In this 8 years' follow-up study, we evaluated the long-term outcomes of the addition of clopidogrel to aspirin during the first year after coronary artery bypass grafting, versus aspirin plus placebo, with respect to survival, major adverse cardiac, or major cerebrovascular events, including revascularization, functional status, graft patency, and native coronary artery disease progression. In the initial Clopidogrel After Surgery for Coronary Artery Disease trial, 113 patients were randomized to receive either daily clopidogrel (n = 56) or placebo (n = 57), in addition to aspirin, in a double-blind fashion for 1 year after coronary artery bypass grafting. All patients were re-evaluated to collect long-term clinical data. Surviving patients with a glomerular filtration rate > 30 mL/min were asked to undergo a coronary computed tomography angiogram to evaluate the late saphenous vein graft patency and native coronary artery disease progression. At a median follow-up of 7.6 years, survival rate was 85.5% ± 3.8% (P = .23 between the 2 groups). A trend toward enhanced freedom from all-cause death or major adverse cardiac or cerebrovascular events, including revascularization, was observed in the aspirin-clopidogrel group (P = .11). No difference in functional status or freedom from angina was observed between the 2 groups (P > .57). The long-term patency of saphenous vein graft was 89.11% in the aspirin-clopidogrel group versus 91.23% in the aspirin-placebo group (P = .79). A lower incidence of moderate to severe native disease progression was observed in the aspirin-clopidogrel group versus the aspirin-placebo group (7 out of 122 vs 13 out of 78 coronary segments that showed progression, respectively [odds ratio, 0.3 ± 0.2; 95% confidence interval, 0.1-0.8; P = .02]). At 8 years' follow-up, the addition of clopidogrel to aspirin during the first year after coronary artery bypass grafting exhibited a lower incidence of moderate to severe

  18. A randomized, double-blind, placebo-controlled study of rebamipide for gastric mucosal injury taking aspirin with or without clopidogrel.

    PubMed

    Tozawa, Katsuyuki; Oshima, Tadayuki; Okugawa, Takuya; Ogawa, Tomohiro; Ohda, Yoshio; Tomita, Toshihiko; Hida, Nobuyuki; Fukui, Hirokazu; Hori, Kazutoshi; Watari, Jiro; Nakamura, Shiro; Miwa, Hiroto

    2014-08-01

    Antithrombotic drugs, such as low-dose aspirin (LDA) and clopidogrel, can cause upper gastrointestinal complications. The goal of the present study was to investigate whether a mucosal-protective agent, rebamipide, could prevent gastric mucosal injuries induced by LDA with or without clopidogrel in healthy subjects. A randomized, double-blind, placebo-controlled trial was performed with 32 healthy male volunteers. Subjects were randomly assigned to a 14-day course of one of the following regimens: group A, placebo (tid) + LDA; group B, rebamipide (100 mg tid) + LDA (100 mg once-daily); group C, placebo + LDA + clopidogrel (75 mg once-daily); or group D, rebamipide + LDA + clopidogrel. The grade of gastric mucosal injuries was evaluated by esophagogastroduodenoscopy before and after dosing (on day 0 and day 14), and the grade of gastric mucosal injury was assessed according to the modified Lanza score. Subjective symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS). A rapid urease test was performed on day 0, and blood tests were performed on day 0 and day 14. Rebamipide significantly inhibited gastric mucosal injury induced by LDA alone or by LDA plus clopidogrel when compared with placebo in healthy subjects. GSRS score and hemoglobin level were not significantly different among the four groups. Rebamipide is useful for the primary prevention of gastric mucosal injury induced by LDA alone or by LDA plus clopidogrel in healthy subjects.

  19. Efficacy of Leflunomide, Telmisartan, and Clopidogrel for Immunoglobulin A Nephropathy: A Randomized Controlled Trial

    PubMed Central

    Wu, Jie; Duan, Shu-Wei; Sun, Xue-Feng; Li, Wen-Ge; Wang, Ya-Ping; Liu, Wen-Hu; Zhang, Jian-Rong; Lun, Li-De; Li, Xue-Mei; Zhou, Chun-Hua; Li, Ji-Jun; Liu, Shu-Wen; Xie, Yuan-Sheng; Cai, Guang-Yan; Ma, Lu; Huang, Wen; Wu, Hua; Jia, Qiang; Chen, Xiang-Mei

    2016-01-01

    Background: The efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for immunoglobulin A nephropathy (IgAN) are unclear. This study was designed to evaluate the efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for IgAN. Methods: It is a multicenter, prospective, double-dummy randomized controlled trial. Primary IgAN patients were recruited in 13 renal units across Beijing, China, from July 2010 to June 2012. After a 4-week telmisartan (80 mg/d) wash-in, 400 patients continuing on 80 mg/d telmisartan were randomly assigned to additionally receive placebo (Group A), 50 mg/d clopidogrel (Group B), 20 mg/d leflunomide (Group C), or 50 mg/d clopidogrel and 20 mg/d leflunomide (Group D). The 24-week intervention was completed by 360 patients. The primary endpoint was change in 24-h proteinuria at 24 weeks. A linear mixed-effect model was used to analyze the changes at 4, 12, and 24 weeks. Generalized estimating equations were used to evaluate changes in hematuria grade. This trial was registered at the Chinese Clinical Trial Registry. Results: The effects of telmisartan combined with leflunomide on changes in proteinuria (0.36 [95% confidence interval (CI) 0.18–0.55] g/d, P < 0.001), in serum uric acid (76.96 [95% CI 57.44–96.49] μmol/L, P < 0.001), in serum creatinine (9.49 [95% CI 6.54–12.44] μmol/L, P < 0.001), and in estimated glomerular filtration rate (−6.72 [95% CI −9.46 to −3.98] ml∙min−1∙1.73 m−2, P < 0.001) were statistically significant, whereas they were not statistically significant on changes in systolic and diastolic blood pressure and weight (P > 0.05). Telmisartan combined with clopidogrel had no statistical effect on any outcome, and there was no interaction between the interventions. No obvious adverse reactions were observed. Conclusions: Telmisartan combined with leflunomide, not clopidogrel, is safe and effective for decreasing proteinuria in certain

  20. Efficacy of Leflunomide, Telmisartan, and Clopidogrel for Immunoglobulin A Nephropathy: A Randomized Controlled Trial.

    PubMed

    Wu, Jie; Duan, Shu-Wei; Sun, Xue-Feng; Li, Wen-Ge; Wang, Ya-Ping; Liu, Wen-Hu; Zhang, Jian-Rong; Lun, Li-De; Li, Xue-Mei; Zhou, Chun-Hua; Li, Ji-Jun; Liu, Shu-Wen; Xie, Yuan-Sheng; Cai, Guang-Yan; Ma, Lu; Huang, Wen; Wu, Hua; Jia, Qiang; Chen, Xiang-Mei

    2016-08-20

    The efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for immunoglobulin A nephropathy (IgAN) are unclear. This study was designed to evaluate the efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for IgAN. It is a multicenter, prospective, double-dummy randomized controlled trial. Primary IgAN patients were recruited in 13 renal units across Beijing, China, from July 2010 to June 2012. After a 4-week telmisartan (80 mg/d) wash-in, 400 patients continuing on 80 mg/d telmisartan were randomly assigned to additionally receive placebo (Group A), 50 mg/d clopidogrel (Group B), 20 mg/d leflunomide (Group C), or 50 mg/d clopidogrel and 20 mg/d leflunomide (Group D). The 24-week intervention was completed by 360 patients. The primary endpoint was change in 24-h proteinuria at 24 weeks. A linear mixed-effect model was used to analyze the changes at 4, 12, and 24 weeks. Generalized estimating equations were used to evaluate changes in hematuria grade. This trial was registered at the Chinese Clinical Trial Registry. The effects of telmisartan combined with leflunomide on changes in proteinuria (0.36 [95% confidence interval (CI) 0.18-0.55] g/d, P < 0.001), in serum uric acid (76.96 [95% CI 57.44-96.49] μmol/L, P < 0.001), in serum creatinine (9.49 [95% CI 6.54-12.44] μmol/L, P < 0.001), and in estimated glomerular filtration rate (-6.72 [95% CI-9.46 to -3.98] ml·min-1·1.73 m-2, P < 0.001) were statistically significant, whereas they were not statistically significant on changes in systolic and diastolic blood pressure and weight (P > 0.05). Telmisartan combined with clopidogrel had no statistical effect on any outcome, and there was no interaction between the interventions. No obvious adverse reactions were observed. Telmisartan combined with leflunomide, not clopidogrel, is safe and effective for decreasing proteinuria in certain IgAN patients. chictr.org.cn, ChiCTR-TRC-10000776; http

  1. EVALUATING HYDROLOGICAL RESPONSE TO ...

    EPA Pesticide Factsheets

    Studies of future management and policy options based on different assumptions provide a mechanism to examine possible outcomes and especially their likely benefits or consequences. Planning and assessment in land and water resource management are evolving toward complex, spatially explicit regional assessments. These problems have to be addressed with distributed models that can compute runoff and erosion at different spatial and temporal scales. The extensive data requirements and the difficult task of building input parameter files, however, have long been an obstacle to the timely and cost-effective use of such complex models by resource managers. The U.S. EPA Landscape Ecology Branch in collaboration with the USDA-ARS Southwest Watershed Research Center has developed a geographic information system (GIS) tool to facilitate this process. A GIS provides the framework within which spatially distributed data are collected and used to prepare model input files, and model results are evaluated. The Automated Geospatial Watershed Assessment (AGWA) tool uses widely available standardized spatial datasets that can be obtained via the internet at no cost to the user. The data are used to develop input parameter files for KINEROS2 and SWAT, two watershed runoff and erosion simulation models that operate at different spatial and temporal scales. AGWA automates the process of transforming digital data into simulation model results and provides a visualization tool

  2. Antiplatelet efficacy of prasugrel in patients with high on-clopidogrel treatment platelet reactivity and a history of coronary stenting.

    PubMed

    Bernlochner, Isabell; Mayer, Katharina; Morath, Tanja; Orban, Martin; Schulz, Stefanie; Schömig, Albert; Braun, Siegmund; Kastrati, Adnan; Sibbing, Dirk

    2013-03-01

    Little is known about the antiplatelet action of the 3 rd generation thienopyridine prasugrel in patients showing high platelet reactivity (PR) levels on clopidogrel. Thus, we aimed to determine the antiplatelet efficacy of prasugrel loading (LD) and maintenance dose (MD) treatment in a registry of patients with high PR levels on clopidogrel and a consecutive switch over to prasugrel in a setting of routine platelet function testing. In our registry of patients treated by percutaneous coronary intervention (n=73) with high levels of PR on clopidogrel, the ADP-induced platelet aggregation (PA, in AU x min) was assessed on a Multiplate analyser 1) after clopidogrel LD, 2) after prasugrel LD and 3) on prasugrel MD (5 vs. 10 mg/day). In patients with high PR levels on clopidogrel, prasugrel LD resulted in significantly lower PA values (574 [462-698] vs. 156 [89-234] AU x min; p<0.0001). Only 2.7% of patients showed high PR (HPR, ≥468 AU x min) following prasugrel LD. On prasugrel MD, PA was significantly higher as compared to prasugrel LD (248 [145-406] vs. 156 [89-234] AU x min; p<0.0001) with more patients showing HPR on MD vs. LD (16.4% vs. 2.7%; p=0.009). For prasugrel MD, HPR rates were higher in 5 vs. 10 mg/day treated patients (46.2% vs. 10.0%; p=0.006). In conclusion, for patients with high PR levels on clopidogrel, prasugrel LD abolished this status in the majority of patients. However, prasugrel response variability was detected, being more pronounced on prasugrel MD vs. LD treatment. The clinical impact of these findings warrants further investigation.

  3. Cangrelor inhibits the binding of the active metabolites of clopidogrel and prasugrel to P2Y12 receptors in vitro.

    PubMed

    Judge, Heather M; Buckland, Robert J; Jakubowski, Joseph A; Storey, Robert F

    2016-01-01

    Cangrelor is a rapid-acting, direct-binding, and reversible P2Y12 antagonist which has been studied for use during percutaneous coronary intervention (PCI) in patients with or without pretreatment with an oral P2Y12 antagonist. As cangrelor is administered intravenously, it is necessary to switch to an oral P2Y12 antagonist following PCI, such as the thienopyridines clopidogrel, and prasugrel or the non-pyridine ticagrelor. Previous studies have suggested a negative pharmacodynamic interaction between cangrelor and thienopyridines. This in vitro study evaluated the receptor-level interaction between cangrelor and the active metabolite (AM) of clopidogrel or prasugrel by assessing functional P2Y12 receptor number using a (33)P-2MeSADP binding assay. All P2Y12 antagonists studied resulted in strong P2Y12 receptor blockade (cangrelor: 93.6%; clopidogrel AM: 93.0%; prasugrel AM: 97.9%). Adding a thienopyridine AM in the presence of cangrelor strongly reduces P2Y12 receptor blockade by the AM (clopidogrel AM: 7%, prasugrel AM: 3.2%). The thienopyridine AMs had limited ability to compete with cangrelor for binding to P2Y12 (% P2Y12 receptor blockade after co-incubation with cangrelor 1000 nmol/L: 11.7% for clopidogrel AM 3 µmol/L; 34.1% for prasugrel AM 3 µmol/L). In conclusion, in vitro cangrelor strongly inhibits the binding of clopidogrel and prasugrel AMs to the P2Y12 receptor, consistent with the previous observation of a negative pharmacodynamic interaction. Care may need to be taken to not overlap exposure to thienopyridine AMs and cangrelor in order to reduce the risk of thrombotic complications following PCI.

  4. Sustained increase in platelet aggregation after the cessation of clopidogrel.

    PubMed

    Djukanovic, Nina; Todorovic, Zoran; Zamaklar-Trifunovic, Danijela; Protic, Dragana; Dzudovic, Boris; Ostojic, Miodrag; Obradovic, Slobodan

    2016-02-01

    This study shows that the abrupt cessation of one-year clopidogrel treatment was not associated with thrombotic events in a prospective, multicentre study that enrolled 200 patients subjected to coronary stent implantation and treated with aspirin + clopidogrel 1 year after the stent placement. The aim of the study was to investigate the causes of a sustained increase of platelet aggregability, considering that the values of platelet aggregation stimulated with ADP + PGE1 (ADPHS values) significantly increased 10-90 days after the cessation of clopidogrel. Values of platelet aggregation induced by thrombin receptor activating peptide (TRAP values) and arachidonic acid (ASPI values) were divided into quartiles on the basis of ADPHS values 10 days after stopping clopidogrel (ADPHS10 ). There was a significant difference between TRAP values divided into quartiles according to ADPHS10 , 10, 45 and 90 days after stopping clopidogrel (P < 0.001, all), and ASPI values across the same quartiles 10 and 45 days after the cessation of clopidogrel (P = 0.028 and 0.003). The results of the study indicate that patients with early pronounced rebound phenomena to clopidogrel termination have a long-term (at least 90 days) increased platelet aggregation to other agonists such as thrombin-related activated protein and arachidonic acid, suggesting the complex mutual relationship of various factors/agonists influencing the function of platelets.

  5. Cytochrome allelic variants and clopidogrel metabolism in cardiovascular diseases therapy.

    PubMed

    Jarrar, Mohammed; Behl, Shalini; Manyam, Ganiraju; Ganah, Hany; Nazir, Mohammed; Nasab, Reem; Moustafa, Khaled

    2016-06-01

    Clopidogrel and aspirin are among the most prescribed dual antiplatelet therapies to treat the acute coronary syndrome and heart attacks. However, their potential clinical impacts are a subject of intense debates. The therapeutic efficiency of clopidogrel is controlled by the actions of hepatic cytochrome P450 (CYPs) enzymes and impacted by individual genetic variations. Inter-individual polymorphisms in CYPs enzymes affect the metabolism of clopidogrel into its active metabolites and, therefore, modify its turnover and clinical outcome. So far, clinical trials fail to confirm higher or lower adverse cardiovascular effects in patients treated with combinations of clopidogrel and proton pump inhibitors, compared with clopidogrel alone. Such inconclusive findings may be due to genetic variations in the cytochromes CYP2C19 and CYP3A4/5. To investigate potential interactions/effects of these cytochromes and their allele variants on the treatment of acute coronary syndrome with clopidogrel alone or in combination with proton pump inhibitors, we analyze recent literature and discuss the potential impact of the cytochrome allelic variants on cardiovascular events and stent thrombosis treated with clopidogrel. The diversity of CYP2C19 polymorphisms and prevalence span within various ethnic groups, subpopulations and demographic areas are also debated.

  6. Grapefruit juice inhibits the metabolic activation of clopidogrel.

    PubMed

    Holmberg, M T; Tornio, A; Neuvonen, M; Neuvonen, P J; Backman, J T; Niemi, M

    2014-03-01

    Cytochrome P450 (CYP) enzymes, including CYP2C19 and CYP3A4, participate in the bioactivation of clopidogrel. Grapefruit juice constituents potently inactivate intestinal CYP3A4 and have been shown to inhibit CYP2C19 as well. In a randomized crossover study, 14 healthy volunteers ingested 200 ml of grapefruit juice or water three times daily for 3 days. On day 3, they ingested a single 600-mg dose of clopidogrel. Grapefruit juice reduced the peak plasma concentration (Cmax) of the active metabolite of clopidogrel to 13% of the control (range 11-17%, P < 0.001) and the area under the plasma concentration-time curve from 0 to 3 h to 14% (range 12-17%, P < 0.001) of the control, but it had no significant effect on the parent clopidogrel. Moreover, grapefruit juice markedly decreased the platelet-inhibitory effect of clopidogrel, as assessed with the VerifyNow P2Y12 test in two of the participants. In conclusion, concomitant use of grapefruit juice may impair the efficacy of clopidogrel. Therefore, the use of grapefruit juice is best avoided during clopidogrel therapy.

  7. Information Science and Responsive Evaluation

    ERIC Educational Resources Information Center

    Stake, Robert E.

    2014-01-01

    Responsive evaluation builds upon the methods of informal evaluation in disciplined ways: getting personally acquainted with the evaluand, observation of activities, interviewing people who are in different ways familiar with the evaluand, searching documents that reveal what happened in the past or somewhere else. It calls for sustained effort to…

  8. Information Science and Responsive Evaluation

    ERIC Educational Resources Information Center

    Stake, Robert E.

    2014-01-01

    Responsive evaluation builds upon the methods of informal evaluation in disciplined ways: getting personally acquainted with the evaluand, observation of activities, interviewing people who are in different ways familiar with the evaluand, searching documents that reveal what happened in the past or somewhere else. It calls for sustained effort to…

  9. Development of a Multiplex and Cost-Effective Genotype Test toward More Personalized Medicine for the Antiplatelet Drug Clopidogrel

    PubMed Central

    Jeong, Hye-Eun; Lee, Su-Jun; Cha, Eun-Young; Kim, Eun-Young; Kim, Ho-Sook; Song, Young Hwan; Shin, Jae-Gook

    2014-01-01

    There has been a wide range of inter-individual variations in platelet responses to clopidogrel. The variations in response to clopidogrel can be driven by genetic polymorphisms involved in the pathway of absorption, distribution, metabolism, excretion, and the target receptor P2Y12. A set of genetic variants known for causing variations in clopidogrel responses was selected, which included CYP2C19*2, *3, *17, CYP2B6*4, *6, *9, CYP3A4*18, CYP3A5*3, MDR1 2677G > T/A, 3435C > T, and P2Y12 H2 (742T > C). The simultaneous detection of these 10 variants was developed by using a multiplex PCR and single-base extension (MSSE) methodology. The newly developed genotyping test was confirmed by direct DNA sequencing in the representative positive control samples and validated in an extended set of 100 healthy Korean subjects. Genotyping results from the developed MSSE exhibited a perfect concordance with the direct DNA sequencing data and all of variants tested in 100 healthy Korean subjects were in agreement with Hardy-Weinberg equilibrium (p > 0.05). The present molecular diagnostic studies provide an accurate, convenient, and fast genotyping method for the detection of multiple variants. This would be helpful for researchers, as well as clinicians, to use genetic information toward more personalized medicine of clopidogrel and other antiplatelet drugs in the future. PMID:24857912

  10. Purpuric herpes zoster in patients in therapy with clopidogrel.

    PubMed

    Veraldi, S; Vaira, F; Nazzaro, G

    2015-08-01

    Clopidogrel is an adenosine diphosphate receptor antagonist used for the prevention of vascular events in patients with atherothrombotic diseases manifested by recent myocardial infarction, ischemic stroke or peripheral arterial disease. Diarrhoea, rash and pruritus are rather common side effects of clopidogrel. Other side effects include epistaxis, nausea, abdominal pain, vomiting, gastritis, gastric and duodenal ulcer. Thrombocytopenia is the most common laboratory abnormality. Leucopenia and neutropenia are rare. We report three cases of purpuric herpes zoster in patients in therapy with clopidogrel. To our knowledge, only one case of haemorrhagic herpes zoster has been published in a patient in therapy with this drug.

  11. Antiplatelet effects of clopidogrel and aspirin after interventional patent foramen ovale/ atrium septum defect closure.

    PubMed

    Polzin, Amin; Dannenberg, Lisa; Sophia Popp, Valérie-; Kelm, Malte; Zeus, Tobias

    2016-06-01

    The optimal antiplatelet therapy after patent foramen ovale (PFO)/ atrium septum defect (ASD) closure is a matter of discussion. It is challenging as inter-individual responses to antiplatelet medication vary significantly and common complications are bleeding and ischemic events. In this study, we aimed to analyze the incidence of high on-treatment platelet reactivity (HTPR) to antiplatelet medication in patients undergoing PFO/ASD closure as well as clinical complications and thrombus formation on the occluder during six-month follow-up. This hypothesis generating pilot study was observed, which included 140 patients undergoing PFO/ASD closure. The primary endpoint was pharmacodynamic response to antiplatelet medication. A composite of death, myocardial infarction, bleeding, stroke and thrombus formation on the occluder during six-month follow-up was the secondary endpoint. HTPR to clopidogrel was analyzed using the vasodilator-stimulated protein phosphorylation (VASP), HTPR to aspirin by light-transmission aggregometry (LTA). In 71% of patients HTPR to clopidogrel was detected, HTPR to aspirin in only 4%. We observed 12 complications, 9 bleeding events (including 3 major bleeding events) and 3 transient ischemic attacks. No stroke and no thrombus formation on the occluder occurred. The primary endpoint was not associated with the secondary endpoint. The incidence of HTPR to clopidogrel in PFO/ASD closure patients is very high. Despite this high incidence, no stroke or thrombus formation on the occluder occurred at all. This leads to the hypothesis, that the benefit of additional clopidogrel medication is questionable and has to be investigated in large-scale clinical trials.

  12. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.

    PubMed

    1996-11-16

    Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate. CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years. 19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favour of clopidogrel (95% Cl 0.3-16.5). Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten (0.10%) patients in the clopidogrel group

  13. Antiplatelet Agents in Cardiology: A Report on Aspirin, Clopidogrel, Prasugrel, and Ticagrelor.

    PubMed

    Dobesh, Paul P; Varnado, Sara; Doyle, Meagan

    2016-01-01

    Antiplatelet drugs are the cornerstone of therapy in many cardiovascular conditions. With the current success and increased use of transcatheter aortic valve implantation (TAVI), the use of antiplatelet therapy is considered part of the medical therapy for these patients. Clinicians caring for these patients need to have a thorough understanding of the pharmacology, pharmacokinetics, pharmacodynamic, and clinical efficacy and safety of commonly used antiplatelet therapy. While aspirin therapy is widely used, dual antiplatelet therapy with clopidogrel has become part of standard of care. Despite the extensive experience with clopidogrel, there are limitations such as drug interactions, metabolism genetic polymorphisms, and variability in the antiplatelet response. More predictable and more potent antiplatelet agents, prasugrel and ticagrelor, have demonstrated superior reductions in ischemic endpoints as part of dual antiplatelet therapy compared to clopidogrel, but at the cost of more major bleeding in patients with an acute coronary syndrome. Significant research needs to be conducted in the setting of TAVI to help define the optimal antiplatelet regimen.

  14. Clopidogrel Within Few Hours of Coronary Artery Bypass Grafting Does Significantly Increase the Risk of Bleeding

    PubMed Central

    Hijazi, Emad M.; Musleh, Ghassan S

    2012-01-01

    Background Postoperative bleeding after coronary artery surgery is partly related to platelet dysfunction. The aim of this study was to evaluate the effects of a single loading dose of clopidogrel (300 mg) before coronary angiography on bleeding and use of blood and blood products after emergency coronary artery bypass surgery (CABG). Methods This is a nonrandomized observational prospective study between January, 2006 till December 2009, at a university hospital, we compare the results of a cohort of 65 patients who received 300 mg clopidogrel during coronary angiography that was followed by emergency CABG (group A or study group) to a cohort of 206 patients who underwent elective coronary artery bypass surgery during the same period by the same surgeons in whom clopidogrel was stopped 7 days before surgery (Group B or control group). Emergency surgery was done because of critical coronary anatomy or because of ongoing chest pain. All patients in the two groups were kept on 100 mg of aspirin until the day of surgery. Outcome data used to compare the two groups, Chest tube drainage in first 12 hours (12 h), need for re-exploration and use of blood and blood product transfusion were prospectively collected. Results Postoperative bleeding, reoperation rates for bleeding and use of blood products are significantly more in those who received a loading dose of clopedogril within few hours of CABG (group A) compared to those who stopped clopedogril for a week before CABG. Conclusions Preoperative 300 mg of clopidogrel is associated with significant increase in post operative bleeding, need for surgical exploration and use of blood and blood product transfusion after CABG. PMID:28348689

  15. Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study.

    PubMed

    Siller-Matula, J M; Delle-Karth, G; Lang, I M; Neunteufl, T; Kozinski, M; Kubica, J; Maurer, G; Linkowska, K; Grzybowski, T; Huber, K; Jilma, B

    2012-04-01

    Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies. To compare different assays for prediction of events during long-term follow-up. In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator-stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA-100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12-month follow-up. Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c-index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA-100 (c-index < 0.70; P > 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c-index < 0.56; P > 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra-metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status.  Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping. © 2012 International Society on Thrombosis and Haemostasis.

  16. Role of phenotypic and genetic testing in managing clopidogrel therapy.

    PubMed

    Chan, Noel C; Eikelboom, John W; Ginsberg, Jeffrey S; Lauw, Mandy N; Vanassche, Thomas; Weitz, Jeffrey I; Hirsh, Jack

    2014-07-31

    The P2Y12 inhibitors, clopidogrel, prasugrel, and ticagrelor, are administered in fixed doses without laboratory monitoring. Randomized trials in acute coronary syndrome have shown that prasugrel and ticagrelor are more effective than standard-dose clopidogrel. Nonetheless, standard-dose clopidogrel remains widely used because it causes less bleeding and is less expensive. Patients treated with standard-dose clopidogrel have substantial variability in platelet inhibition, which is partly explained by genetic polymorphisms encoding CYP2C19, the hepatic enzyme involved in biotransformation of clopidogrel to its active metabolite. Some advocate tailoring P2Y12 inhibitor therapy according to the results of routine laboratory testing. Although there is good evidence for analytic, biological, and clinical validity of several phenotypic and genotypic biomarkers, the benefit of a management strategy that incorporates routine biomarker testing over standard of care without such testing remains unproven. Appropriately designed, adequately powered trials are needed but face the challenges of feasibility, cost, and the progressive switch from clopidogrel to prasugrel or ticagrelor.

  17. Temporal variability in the antiplatelet effects of clopidogrel and aspirin after elective drug-eluting stent implantation. An ADAPT-DES substudy.

    PubMed

    Nührenberg, Thomas G; Stratz, Christian; Leggewie, Stefan; Hochholzer, Willibald; Valina, Christian M; Gick, Michael; Kirtane, Ajay J; Stone, Gregg W; Neumann, Franz-Josef; Trenk, Dietmar

    2015-11-01

    Given conflicting data on temporal variability in pharmacodynamic platelet responses to clopidogrel, we investigated platelet reactivity on clopidogrel and aspirin for up to six months after elective percutaneous coronary intervention (PCI) with drug-eluting stents. Platelet reactivity was determined in 102 patients before loading with clopidogrel and aspirin, and on maintenance therapy after PCI on day 1, at one month and six months by VerifyNow™ P2Y12 and Aspirin assays and by residual platelet aggregation (RPA) on light transmission aggregometry using adenosine diphosphate and arachidonic acid. By VerifyNow testing, median (interquartile range) P2Y12 reaction units (PRU) on clopidogrel were 166 (90-234), 195 (124-257), and 198 (141-252) on day 1, one month and six months after PCI, respectively (p=0.005 day 1 to 1 month, and p=0.86 1 month to 6 months). Using a cut-off of > 208 PRU, 35 % of patients had high platelet reactivity (HPR) to clopidogrel on day 1, 43 % at one month, and 46 % at six months after PCI. Between day 1 and six months after PCI, 38.2 % of patients changed clopidogrel responder status at least once. Other cut-offs and RPA yielded similar results. Platelet inhibition by aspirin was consistent over time with only five patients being characterised as having HPR. Considerable variation in individual on-clopidogrel platelet reactivity was present during both the subacute and the late phases of maintenance therapy after elective PCI. Hence, the utility of contemporary platelet function testing to guide antiplatelet therapy may be limited.

  18. Synergistic Effects of Clopidogrel and Fufang Danshen Dripping Pills by Modulation of the Metabolism Target and Pharmacokinetics

    PubMed Central

    Ma, Shitang; Ju, Wenzheng; Dai, Guoliang; Zhao, Wenzhu; Cheng, Xiaogui; Fang, Zhuyuan; Tan, Hengshan; Wang, Xiaoxiao

    2014-01-01

    Background and Objective. The aim was to evaluate the synergistic effects of clopidogrel and FDDP by modulating the metabolism target and the pharmacokinetics. Methods. The inhibition effect of FDDP on the CES1 was first investigated by the molecular simulation method, and the synergistic effects on the pharmacokinetics of CPGS were studied as follows: SD rats were treated with oral clopidogrel alone at a dosage of 30 mg/kg or the combination of clopidogrel and FDDP at dosages of 30 mg/kg and 324 mg/kg, respectively, for 21 days. The concentrations of CPGS in the blood plasma samples were determined and the calculated concentrations were used to determine the pharmacokinetic parameters. Results. 20 compounds in FDDP potentially interacted with CES1 target. The CPGS showed a two-compartment model pharmacokinetic profile. The concentration-time course of CPGS was not changed by FDDP, but FDDP decreased the peak plasma concentration and area under the curve of CPGS. Conclusion. The CES1's activity could be partly inhibited by FDDP through the molecular simulation investigation. The concentration-time course of CPGS was altered slightly by FDDP. The results demonstrated the synergistic effects of clopidogrel and FDDP by modulating both the pharmacokinetics and the target metabolism. PMID:25530790

  19. Angiotensin-Converting Enzyme Inhibitors' Influence on Antiplatelet Therapy of Clopidogrel in ACS.

    PubMed

    Yang, Shuo; Cui, Chanjuan; Zhang, Jie; Qiao, Rui

    2016-10-01

    Clopidogrel is a prodrug, the minority of which is converted to an active metabolite by hepatic cytochrome P450 (CYP2C19), however, most of it is metabolized to inactive substance by hepatic carboxylesterase1 (CES1). Meanwhile angiotensin-converting enzyme inhibitors (ACEIs) are mostly metabolized by CES1. We aimed to assess the impact of ACEIs on platelet inhibition by clopidogrel. We genotyped variants CES1, CYP2C19*2 and *3 in 502 patients with acute coronary syndrome (ACS) receiving clopidogrel therapy, and analyzed the effects of ACEIs on responsiveness to clopidogrel by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and ADP-stimulated impedance whole blood platelet aggregation assay. It showed that the allele frequency of CES1 c.428A was 0% in these patients. 45.22% (227/502) of these patients were carriers of CYP2C19*2 or CYP2C9*3 loss-of-function alleles. Among them, 57.71% (131/227) of the patients with CYP2C19 variants received ACEIs therapy. In a total of 502 patients, there was no difference in the VASP-PRI or the impedance whole blood platelet aggregation assay between the ACEIs group and non-ACEIs group [56.26 ± 14.55% versus 57.76 ± 13.56%, p = 0.241; 0 (0 - 2) Ω vs. 0 (0 - 2) Ω, p = 0.856]. In the CYP2C19 variant patients, there was no difference in the VASP-PRI or the impedance whole blood platelet aggregation assay between ACEIs group and non-ACEIs group [57.24 ± 15.12% versus 58.07 ± 13.90%, p = 0.667; 0 (0 - 2) Ω versus 0 (0 - 2) Ω, p = 0.536]. In the subgroups of ACS patients (unstable angina, non-ST-segment elevation myocardial infarction, ST-segment elevation myocardial infarction), there was no difference in the VASP-PRI between the ACEIs group and non-ACEIs group [55.81 ± 15.24% versus 58.37 ± 13.31%, p = 0.103; 55.76 ± 15.20% versus 49.09 ± 15.22%, p = 0.098; 58.13 ± 11.48% versus 61.87 ± 10.34%, p = 0.221], and there was no difference in the impedance whole blood platelet aggregation assay between

  20. The pharmacogenetic control of antiplatelet response: candidate genes and CYP2C19.

    PubMed

    Yang, Yao; Lewis, Joshua P; Hulot, Jean-Sébastien; Scott, Stuart A

    2015-01-01

    Aspirin, clopidogrel, prasugrel and ticagrelor are antiplatelet agents for the prevention of ischemic events in patients with acute coronary syndromes (ACS), percutaneous coronary intervention (PCI) and other indications. Variability in response is observed to different degrees with these agents, which can translate to increased risks for adverse cardiovascular events. As such, potential pharmacogenetic determinants of antiplatelet pharmacokinetics, pharmacodynamics and clinical outcomes have been actively studied. This article provides an overview of the available antiplatelet pharmacogenetics literature. Evidence supporting the significance of candidate genes and their potential influence on antiplatelet response and clinical outcomes are summarized and evaluated. Additional focus is directed at CYP2C19 and clopidogrel response, including the availability of clinical testing and genotype-directed antiplatelet therapy. The reported aspirin response candidate genes have not been adequately replicated and few candidate genes have thus far been implicated in prasugrel or ticagrelor response. However, abundant data support the clinical validity of CYP2C19 and clopidogrel response variability among ACS/PCI patients. Although limited prospective trial data are available to support the utility of routine CYP2C19 testing, the increased risks for reduced clopidogrel efficacy among ACS/PCI patients that carry CYP2C19 loss-of-function alleles should be considered when genotype results are available.

  1. The Pharmacogenetic Control of Antiplatelet Response: Candidate Genes and CYP2C19

    PubMed Central

    Yang, Yao; Lewis, Joshua P.; Hulot, Jean-Sébastien; Scott, Stuart A.

    2016-01-01

    Introduction Aspirin, clopidogrel, prasugrel and ticagrelor are antiplatelet agents for the prevention of ischemic events in patients with acute coronary syndromes (ACS), percutaneous coronary intervention (PCI), and other indications. Variability in response is observed to different degrees with these agents, which can translate to increased risks for adverse cardiovascular events. As such, potential pharmacogenetic determinants of antiplatelet pharmacokinetics, pharmacodynamics and clinical outcomes have been actively studied. Areas covered This article provides an overview of the available antiplatelet pharmacogenetics literature. Evidence supporting the significance of candidate genes and their potential influence on antiplatelet response and clinical outcomes are summarized and evaluated. Additional focus is directed at CYP2C19 and clopidogrel response, including the availability of clinical testing and genotype-directed antiplatelet therapy. Expert opinion The reported aspirin response candidate genes have not been adequately replicated and few candidate genes have thus far been implicated in prasugrel or ticagrelor response. However, abundant data supports the clinical validity of CYP2C19 and clopidogrel response variability among ACS/PCI patients. Although limited prospective trial data are available to support the utility of routine CYP2C19 testing, the increased risks for reduced clopidogrel efficacy among ACS/PCI patients that carry CYP2C19 loss-of-function alleles should be considered when genotype results are available. PMID:26173871

  2. Clopidogrel in infants with systemic-to-pulmonary-artery shunts.

    PubMed

    Wessel, David L; Berger, Felix; Li, Jennifer S; Dähnert, Ingo; Rakhit, Amit; Fontecave, Sylvie; Newburger, Jane W

    2013-06-20

    Infants with cyanotic congenital heart disease palliated with placement of a systemic-to-pulmonary-artery shunt are at risk for shunt thrombosis and death. We investigated whether the addition of clopidogrel to conventional therapy reduces mortality from any cause and morbidity related to the shunt. In a multicenter, double-blind, event-driven trial, we randomly assigned infants 92 days of age or younger with cyanotic congenital heart disease and a systemic-to-pulmonary-artery shunt to receive clopidogrel at a dose of 0.2 mg per kilogram of body weight per day (467 infants) or placebo (439 infants), in addition to conventional therapy (including aspirin in 87.9% of infants). The primary efficacy end point was a composite of death or heart transplantation, shunt thrombosis, or performance of a cardiac procedure due to an event considered to be thrombotic in nature before 120 days of age. The rate of the composite primary end point did not differ significantly between the clopidogrel group (19.1%) and the placebo group (20.5%) (absolute risk difference, 1.4 percentage points; relative risk reduction with clopidogrel, 11.1%; 95% confidence interval, -19.2 to 33.6; P=0.43), nor did the rates of the three components of the composite primary end point. There was no significant benefit of clopidogrel treatment in any subgroup, including subgroups defined by shunt type. Clopidogrel recipients and placebo recipients had similar rates of overall bleeding (18.8% and 20.2%, respectively) and severe bleeding (4.1% and 3.4%, respectively). Clopidogrel therapy in infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary-artery shunt, most of whom received concomitant aspirin therapy, did not reduce either mortality from any cause or shunt-related morbidity. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00396877.).

  3. Variability of platelet aggregation in patients with clopidogrel treatment and hip fracture: A retrospective case-control study on 112 patients

    PubMed Central

    Clareus, Anna; Fredriksson, Inga; Wallén, Håkan; Gordon, Max; Stark, André; Sköldenberg, Olof

    2015-01-01

    AIM: To identify the rate of non-responders to clopidogrel treatment in hip fracture patients and study how non-responders differ from controls. METHODS: In a retrospective case-control study we included 28 cases of acute proximal femoral fracture with clopidogrel treatment 2011 to 2013. Eighty-four controls from the same time period were included. Data collected included response to clopidogrel measured with multiple electrode aggregometry (MEA), intraoperative bleeding, erythrocyte transfusion, time to surgery and the incidence of adverse events up to 3 mo after surgery. RESULTS: Eight (29%) of the 28 cases were non-responders. The median intraoperative bleeding was 300 mL (range, 0-1500), and was lower for non-responders (50 mL) but did not reach statistical significance. Erythrocyte transfusions did not differ between responders, non-responders and controls. Forty-five (40%) of 112 patients had adverse events postoperatively but the rate did not differ between patients with and without clopidogrel treatment. CONCLUSION: Almost one-third of patients with clopidogrel treatment and an acute proximal femoral fracture are non-responders to antiplatelet therapy and can be operated without delay. PMID:26085986

  4. Using Responsive Evaluation To Evaluate a Professional Conference.

    ERIC Educational Resources Information Center

    Speigel, Amy N.; Bruning, Roger H.; Giddings, Lisa

    1999-01-01

    Incorporated responsive evaluation methods into the structure of a professional conference and illustrated the usefulness of these techniques in evaluating conferences. Discusses the implications of this pilot study of responsive evaluation. (SLD)

  5. Clopidogrel generic formulations in the era of new antiplatelets: a systematic review.

    PubMed

    Tsoumani, Maria E; Kalantzi, Kallirroi I; Goudevenos, Ioannis A; Tselepis, Alexandros D

    2014-01-01

    Clopidogrel is a thienopyridine that selectively and irreversibly inhibits the ADP purinergic receptor P2Y12 and the subsequent ADP-mediated platelet activation. Clopidogrel has been approved for clinical use as clopidogrel hydrogen sulfate (bisulfate) salt. The clinical usefulness of clopidogrel bisulfate salt has been proved in a wide variety of large scale clinical trials, thus clopidogrel bisulfate has been extensively used in a large spectrum of patients been under thrombotic risk. Recently, several generic clopidogrel formulations have been approved for clinical use. Consequently, clopidogrel is currently a cost-effective antiplatelet agent. Only small studies have compared the pharmacokinetic and pharmacodynamic properties of various clopidogrel generic salt formulations with the innovator bisulfate salt. In addition few data are available concerning the clinical efficacy and safety of these generic clopidogrel formulations in order to guide clinicians in deciding when generic substitution is appropriate. The aim of this review is to summarize the physicochemical properties as well as the pharmacokinetic and pharmacodynamic characteristics of the generic clopidogrel salts. We also critically present existing data on the clinical efficacy and safety of the generic clopidogrel formulations compared with the innovator clopidogrel bisulfate salt in patients with cardiovascular disease.

  6. Effect of clopidogrel on bleeding after coronary artery bypass surgery.

    PubMed

    Yende, S; Wunderink, R G

    2001-12-01

    Platelet dysfunction is a common cause of bleeding after coronary artery bypass graft surgery. This study explores the effects of clopidogrel on bleeding complications after coronary artery bypass graft surgery. Prospective observational study of patients undergoing coronary artery bypass graft. Tertiary care center. A total of 247 patients undergoing coronary artery bypass graft surgery. None. Primary end point was need for reexploration secondary to bleeding. Secondary end points included need for transfusion of blood products and chest tube output. Eight (3.3%) of 247 patients required reexploration secondary to bleeding. Clopidogrel recipients had higher incidence of reexploration for bleeding (9.8 vs. 1.6, p =.01) with an odds ratio of 6.9 (95% confidence interval, 1.6-30). Clopidogrel also increased the percentage of patients receiving packed red blood cell transfusion (72.6 vs. 51.6%, p =.007), the number of packed red blood cell units (3 vs. 1.6, p =0.0004), and the number of cryoprecipitate units (2.4 vs. 1.2, p =.04) transfused after coronary artery bypass graft surgery. Among clopidogrel recipients, a trend for increased transfusion of platelet units (4.3 vs. 1.7, p =.05) and fresh frozen plasma units (1.1 vs. 0.6, p =.08) also was found. Preoperative use of clopidogrel in combination with aspirin is associated with increased need for surgical reexploration as well as risk of packed red blood cell and cryoprecipitate transfusions after coronary artery bypass graft surgery.

  7. Revaluation of clopidogrel: let the data speak for themselves.

    PubMed

    Liu, Li; Zeng, Fandian; Zeng, Xiaohua; Xue, Qingmei; Nie, Shaoping; Kang, Cailian; Wu, Jianhong; Kang, Qingyun; Wang, Xingao; Liu, Xiaoqing; Li, Tao; Chen, Jun; Li, Qing; Xu, Rong; Yang, Xiaoyan; Kang, Hui; Jiang, Fagang; Li, Zongtao; Wang, Xuwu; Zhang, Li; Long, Yu

    2010-06-01

    Clopidogrel was believed to be superior to aspirin by the well-known CAPRIE trial. However, no other large clinical trials demonstrated the same results, but all focused on the combination use of clopidogrel with aspirin, and combination therapy in CREDO was called the "Emperor's New Clothes". However, no one overturned the results of these clinical trials by quantitatively analyzing them. We reviewed ten large-scale clinical trials about clopidogrel. On the basis of results of CAPRIE, CREDO and CHARISMA trials, we re-estimated their minimal sample sizes and their powers by three well-established statistical methodologies. From the results of CAPRIE, we inferred that the minimal sample size should be 85 086 or 84 968 but its power was only 30.70%. A huge gap existed. The same was also true of CREDO and CHARISMA trials. Moreover, in CAPRIE trial, 0 was included in the 95% confidence interval and 1 was included in the 95% confidence interval for the relative risk. There were some paradoxical data in CAPRIE trial. We are led to conclude that the results in CAPRIE, CREDO, and from the subgroup analysis in CHARISMA trials were questionable. These results failed to demonstrate that clopidogrel was superior to aspirin or that clopidogrel used in combination with aspirin was better than aspirin alone. The cost-effectiveness analyses by some previous studies were not reliable.

  8. Counterintuitive compaction behavior of clopidogrel bisulfate polymorphs.

    PubMed

    Khomane, Kailas S; More, Parth K; Bansal, Arvind K

    2012-07-01

    Being a density violator, clopidogrel bisulfate (CLP) polymorphic system (forms I and II) allows us to study individually the impact of molecular packing (true density) and thermodynamic properties such as heat of fusion on the compaction behavior. These two polymorphs of CLP were investigated for in-die and out-of-die compaction behavior using CTC profile, Heckel, and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. Detailed examinations of the molecular packing of each form revealed that arrangement of the sulfate anion differs significantly in both crystal forms, thus conferring different compaction behavior to two forms. Close cluster packing of molecules in form I offers a rigid structure, which has poor compressibility and hence resists deformation under compaction pressure. This results into lower densification, higher yield strength, and mean yield pressure, as compared with form II at a given pressure. However, by virtue of higher bonding strength, form I showed superior tabletability, despite its poor compressibility and deformation behavior. Form I, having higher true density and lower heat of fusion showed higher bonding strength. Hence, true density and not heat of fusion can be considered predictor of bonding strength of the pharmaceutical powders.

  9. Controversy of proton pump inhibitor and clopidogrel interaction: a review.

    PubMed

    Tan, H J

    2010-12-01

    A proton pump inhibitor (PPI) is often co-prescribed with clopidogrel to reduce the gastrointestinal risk of bleeding ulcers in patients following acute coronary syndrome or a stent implant. However, the safety issue of such practice has been scrutinized after some studies reporting an increased incidence of cardiovascular events and mortality, although there have also been contrary research reports. This has lead to a warning statement from the US Food and Drug Administration cautioning the concomitant use of PPI and clopidogrel. This review examines the evidence of PPI as gastroprotective agent, histamine H(2) antagonists as an alternative therapy, the influence of PPI on the antiplatelet effect of clopidogrel, and the controversies of various studies. © 2010 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

  10. The extent of P2Y12 inhibition by clopidogrel in diabetes mellitus patients with acute coronary syndrome is not related to glycaemic control: roles of white blood cell count and body weight.

    PubMed

    Morel, Olivier; El Ghannudi, Soraya; Hess, Sebastien; Reydel, Antje; Crimizade, Ulun; Jesel, Laurence; Radulescu, Bogdan; Wiesel, Marie L; Gachet, Christian; Ohlmann, Patrick

    2012-08-01

    It was the study objective to determine whether glycaemic control affects the extent of platelet inhibition by thienopyridines as assessed by vasodilator-stimulated phosphoprotein flow cytometry (VASP-FCT) in patients with diabetes mellitus (DM) undergoing percutaneous coronary intervention (PCI) during acute coronary syndrome (ACS). Although the proportion of high on-treatment residual platelet reactivity is higher in DM, the contributions of glycaemic control and other factors associated with DM, such as excess body weight and inflammation, to this impaired platelet inhibition by thienopyridines have not yet been fully characterised. In this study, the extent of P2Y12 ADP receptor pathway inhibition was evaluated by the VASP-FCT. Platelet activation was expressed as the platelet reactivity index (PRI). Low response to clopidogrel (LR) was defined as a PRI of >61%. Four hundred forty-five consecutive ACS patients (DM = 160, NDM = 285) were enrolled. The proportion of LR was higher in DM patients (50 vs. 37.5%). In DM, PRI was not correlated with glycosylated haemoglobin (HbA1c) or glycaemia. In a univariate analysis, LR was associated with age, male sex, overweight, and white blood cell count (WBC). In a multivariate analysis, WBC >10,000 and body weight >80 kg were the sole independent predictors of LR to clopidogrel (hazard ratio (HR) 3.02 [1.36-6.68], p=0.006 and HR 2.47 [1.14-5.35], p = 0.021, respectively). Conversely, in non-DM patients, ST-elevation myocardial infarction was the sole independent predictor of LR. In conclusion, in ACS DM patients undergoing PCI, the extent of P2Y12 inhibition by clopidogrel is not related to glycaemic control but is related to body weight and inflammatory status as assessed by the WBC.

  11. Relationship between pharmacokinetics and pharmacodynamics of clopidogrel in patients undergoing percutaneous coronary intervention: comparison between vasodilator-stimulated phosphoprotein phosphorylation assay and multiple electrode aggregometry.

    PubMed

    Danese, E; Fava, C; Beltrame, F; Tavella, D; Calabria, S; Benati, M; Gelati, M; Gottardo, R; Tagliaro, F; Guidi, G C; Cattaneo, M; Minuz, P

    2016-02-01

    ESSENTIALS: The reliability of platelet tests as markers of the variable bioavailability of clopidogrel is not yet defined. Kinetics of clopidogrel active metabolite (CAM) and platelet response were studied in ischemic heart disease. CAM plasma maximum concentration (Cmax ) predicted vasodilator-stimulated phosphoprotein (VASP-P). Timely performed VASP-P, not an aggregation-based test, may be a surrogate for clopidogrel bioavailability. The high inter-individual variability in the inhibition of platelet function by clopidogrel is mostly explained by high variability in its transformation to an active metabolite (CAM). Objective We investigated the relations between pharmacokinetics and pharmacodynamics of CAM by comparing two methods of platelet function. We enrolled 14 patients undergoing percutaneous coronary interventions for non-ST-segment elevation acute coronary syndrome or inducible myocardial ischemia. Plasma concentrations of clopidogrel and CAM, phosphorylation of vasodilator-stimulated phosphoprotein (VASP-P), expressed as a platelet reactivity index (PRI) and whole-blood platelet aggregation (multiple electrode aggregometer, MEA) were measured before and after a 600-mg clopidogrel loading dose (nine time-points) and before and after 75-mg maintenance doses on days 2, 7 and 30. Plasma concentrations of clopidogrel and CAM were highly variable. CAM reached maximal concentration (Cmax ) (median, 110.8 nm; range, 41.9-484.8) 0.5-2 h after the loading dose. A sigmoid dose-response curve defined the relations between CAMCmax and PRI after 3 to 24 h (IC50 , 459.6 nm; 95% confidence interval, 453.4-465.7; R(2) = 0.82). PRI was unchanged from baseline in patients with the lowest CAMCmax (< 83 nm, n = 7), indicating low sensitivity of VASP-P. PRI values were also predicted by CAMCmax at days 2, 7 and 30. Platelet aggregation measured by MEA did not show significant relations with either PRI or with CAM pharmacokinetics at any time-point. After 600 mg clopidogrel

  12. A Cost-Effectiveness Analysis of Clopidogrel for Patients with Non-ST-Segment Elevation Acute Coronary Syndrome in China.

    PubMed

    Cui, Ming; Tu, Chen Chen; Chen, Er Zhen; Wang, Xiao Li; Tan, Seng Chuen; Chen, Can

    2016-09-01

    There are a number of economic evaluation studies of clopidogrel for patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) published from the perspective of multiple countries in recent years. However, relevant research is quite limited in China. We aimed to estimate the long-term cost effectiveness for up to 1-year treatment with clopidogrel plus acetylsalicylic acid (ASA) versus ASA alone for NSTEACS from the public payer perspective in China. This analysis used a Markov model to simulate a cohort of patients for quality-adjusted life years (QALYs) gained and incremental cost for lifetime horizon. Based on the primary event rates, adherence rate, and mortality derived from the CURE trial, hazard functions obtained from published literature were used to extrapolate the overall survival to lifetime horizon. Resource utilization, hospitalization, medication costs, and utility values were estimated from official reports, published literature, and analysis of the patient-level insurance data in China. To assess the impact of parameters' uncertainty on cost-effectiveness results, one-way sensitivity analyses were undertaken for key parameters, and probabilistic sensitivity analysis (PSA) was conducted using the Monte Carlo simulation. The therapy of clopidogrel plus ASA is a cost-effective option in comparison with ASA alone for the treatment of NSTEACS in China, leading to 0.0548 life years (LYs) and 0.0518 QALYs gained per patient. From the public payer perspective in China, clopidogrel plus ASA is associated with an incremental cost of 43,340 China Yuan (CNY) per QALY gained and 41,030 CNY per LY gained (discounting at 3.5% per year). PSA results demonstrated that 88% of simulations were lower than the cost-effectiveness threshold of 150,721 CYN per QALY gained. Based on the one-way sensitivity analysis, results are most sensitive to price of clopidogrel, but remain well below this threshold. This analysis suggests that treatment with

  13. Long-term clopidogrel administration following severe coronary injury reduces proliferation and inflammation via inhibition of nuclear factor-kappaB and activator protein 1 activation in pigs.

    PubMed

    Pels, K; Schwimmbeck, P L; Rosenthal, P; Loddenkemper, C; Dang-Heine, C; Rauch, U; Martens, H; Schultheiss, H-P; Dechend, R; Deiner, C

    2009-03-01

    The optimal duration of clopidogrel treatment following percutaneous coronary intervention (PCI) and the patient population that would benefit most are still unknown. In a porcine coronary injury model, we tested two different durations of clopidogrel treatment on severely or moderately injured arteries and examined the arterial response to injury. To understand the molecular mechanism, we also investigated the effects on transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1). In 24 cross-bred pigs, one coronary artery was only moderately injured by percutaneous transluminal coronary angioplasty (PTCA) and one coronary artery was severely injured by PTCA and subsequent beta-irradiation (Brachy group). Animals received 325 mg aspirin daily for 3 months and 75 mg clopidogrel daily for either 28 days [short-term (ST) clopidogrel group] or 3 months [long-term (LT) clopidogrel group]. After 3 months, the number of proliferating cells per cross-section differed significantly between ST and LT in both injury groups (PTCA(ST) 90.2 +/- 10.3 vs. PTCA(LT )19.2 +/- 4.7, P < 0.05; Brachy(ST) 35.8 +/- 8.4 vs. Brachy(LT) 7.5 +/- 2.0, P < 0.05). Similar results were seen for inflammatory cells (CD3(+) cells): PTCA(ST) 23.5 +/- 3.55 vs. PTCA(LT )4.67 +/- 0.92, P < 0.05; Brachy(ST) 83.17 +/- 11.17 vs. Brachy(LT) 20 +/- 4.82, P < 0.05). Long-term administration also reduced the activity of NF-kappaB and AP-1 by 62-64% and 42-58%, respectively. However, the effects of different durations of clopidogrel administration on artery dimensions were not statistically significant. Regarding inflammation and transcription factor activity at the PCI site, long-term clopidogrel administration is superior to short-term administration, especially in severely injured arteries. Transferring our results to the human situation, patients with more severely diseased arteries may benefit from a prolonged clopidogrel medication after PCI.

  14. Changing CS Features Alters Evaluative Responses in Evaluative Conditioning

    ERIC Educational Resources Information Center

    Unkelbach, Christian; Stahl, Christoph; Forderer, Sabine

    2012-01-01

    Evaluative conditioning (EC) refers to changes in people's evaluative responses toward initially neutral stimuli (CSs) by mere spatial and temporal contiguity with other positive or negative stimuli (USs). We investigate whether changing CS features from conditioning to evaluation also changes people's evaluative response toward these CSs. We used…

  15. Changing CS Features Alters Evaluative Responses in Evaluative Conditioning

    ERIC Educational Resources Information Center

    Unkelbach, Christian; Stahl, Christoph; Forderer, Sabine

    2012-01-01

    Evaluative conditioning (EC) refers to changes in people's evaluative responses toward initially neutral stimuli (CSs) by mere spatial and temporal contiguity with other positive or negative stimuli (USs). We investigate whether changing CS features from conditioning to evaluation also changes people's evaluative response toward these CSs. We used…

  16. Sub-Tenon's anesthesia with aspirin, warfarin, and clopidogrel.

    PubMed

    Kumar, Nishant; Jivan, Sharmila; Thomas, Peter; McLure, Hamish

    2006-06-01

    To review the frequency of hemorrhagic complications with sub-Tenon's anesthesia in patients on aspirin, warfarin or clopidogrel. St. James's University Hospital, Leeds, United Kingdom. Data were collected prospectively for patients having elective phacoemulsification under sub-Tenon's anesthesia. Seventy-five patients were on aspirin, 65 were on warfarin, and 40 were on clopidogrel. Seventy-five patients on no anticoagulants were used as the control group. No changes in the anticoagulant regimen were made prior to surgery. No sight-threatening hemorrhagic complications were noted, and no surgery was postponed or cancelled due to an anesthesic complication. Subconjunctival hemorrhage occurred in 19% in the control group, 40% in the clopidogrel group, 35% in the warfarin group, and 21% in the aspirin group. The warfarin and clopidogrel groups had the highest incidence of subconjunctival hemorrhage (P<.05). The incidence of hemorrhages involving more than 1 quadrant was highest in these 3 groups; however, this did not achieve statistical significance (P = .37, Fisher exact test). Data from this study support the continued use of anticoagulant agents among routine users during cataract surgery using a sub-Tenon's block.

  17. Clopidogrel Enhances Mesenchymal Stem Cell Proliferation Following Periodontitis

    PubMed Central

    Coimbra, L.S.; Steffens, J.P.; Alsadun, S.; Albiero, M.L.; Rossa, C.; Pignolo, R.J.; Spolidorio, L.C.; Graves, D.T.

    2015-01-01

    Bone formation is dependent on the differentiation of osteoblasts from mesenchymal stem cells (MSCs). In addition to serving as progenitors, MSCs reduce inflammation and produce factors that stimulate tissue formation. Upon injury, MSCs migrate to the periodontium, where they contribute to regeneration. We examined the effect of clopidogrel and aspirin on MSCs following induction of periodontitis in rats by placement of ligatures. We showed that after the removal of ligatures, which induces resolution of periodontal inflammation, clopidogrel had a significant effect on reducing the inflammatory infiltrate. It also increased the number of osteoblasts and MSCs. Mechanistically, the latter was linked to increased proliferation of MSCs in vivo and in vitro. When given prior to inducing periodontitis, clopidogrel had little effect on MSC or osteoblasts numbers. Applying aspirin before or after induction of periodontitis did not have a significant effect on the parameters measured. These results suggest that clopidogrel may have a positive effect on MSCs in conditions where a reparative process has been initiated. PMID:26220958

  18. Effect of antiplatelet agents clopidogrel, aspirin, and cilostazol on circulating tissue factor procoagulant activity in patients with peripheral arterial disease.

    PubMed

    Rao, A Koneti; Vaidyula, Vijender R; Bagga, Shagun; Jalagadugula, Gauthami; Gaughan, John; Wilhite, Douglas B; Comerota, Anthony J

    2006-12-01

    Tissue factor (TF) is the physiological initiating mechanism for blood coagulation. Platelets play an important role in monocyte TF expression, thrombosis and inflammation. Aspirin, clopidogrel and cilostazol, which inhibit platelet responses by different mechanisms, are widely used in patients with arterial diseases. We tested the hypothesis that platelet-inhibiting agents inhibit the levels of circulating TF procoagulant activity (TF-PCA) in patients with peripheral arterial disease (PAD). Twenty-six patients with lower extremity PAD, average age 65.9 +/- 8.4 years (mean +/- SEM), were studied at baseline and following sequential two-week treatment regimens with aspirin (325 mg daily), clopidogrel (75 mg daily) or a phosphodiesterase inhibitor cilostazol (100 mg twice daily) singly, and with each possible combination of these agents. Circulating TF-PCA in whole blood, and plasma factor VIIa, prothrombin fragment F1.2, thrombin-antithrombin complexes (TAT), and P-selectin were measured. Baseline TF-PCA levels in the patients were elevated (131 +/- 19 U/ml) compared to control subjects (23 +/- 2, p < 0.0001). TF-PCA levels declined following treatment with clopidogrel alone, and with combinations of clopidogrel with aspirin or cilostazol, with the lowest levels being with the triple-drug combination. Plasma P-selectin declined in all treatment groups. No changes were noted in plasma factor VIIa, F1.2 or TAT. In conclusion, treatment of PAD patients with antiplatelet agents decreases circulating TF, a molecule with prothrombotic and proinflammatory effects. These findings suggest an unrecognized mechanism, beyond inhibiting aggregation responses, for the efficacy of antiplatelet drugs in patients with arterial diseases.

  19. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes.

    PubMed

    Mehta, Shamir R; Bassand, Jean-Pierre; Chrolavicius, Susan; Diaz, Rafael; Eikelboom, John W; Fox, Keith A A; Granger, Christopher B; Jolly, Sanjit; Joyner, Campbell D; Rupprecht, Hans-Jurgen; Widimsky, Petr; Afzal, Rizwan; Pogue, Janice; Yusuf, Salim

    2010-09-02

    Clopidogrel and aspirin are widely used for patients with acute coronary syndromes and those undergoing percutaneous coronary intervention (PCI). However, evidence-based guidelines for dosing have not been established for either agent. We randomly assigned, in a 2-by-2 factorial design, 25,086 patients with an acute coronary syndrome who were referred for an invasive strategy to either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. The primary outcome occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (hazard ratio, 0.94; 95% confidence interval [CI], 0.83 to 1.06; P=0.30). Major bleeding occurred in 2.5% of patients in the double-dose group and in 2.0% in the standard-dose group (hazard ratio, 1.24; 95% CI, 1.05 to 1.46; P=0.01). Double-dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis among the 17,263 patients who underwent PCI (1.6% vs. 2.3%; hazard ratio, 0.68; 95% CI, 0.55 to 0.85; P=0.001). There was no significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome (4.2% vs. 4.4%; hazard ratio, 0.97; 95% CI, 0.86 to 1.09; P=0.61) or major bleeding (2.3% vs. 2.3%; hazard ratio, 0.99; 95% CI, 0.84 to 1.17; P=0.90). In patients with an acute coronary syndrome who were referred for an invasive strategy, there was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, myocardial infarction, or

  20. Ticagrelor versus clopidogrel in patients with acute coronary syndromes.

    PubMed

    Wallentin, Lars; Becker, Richard C; Budaj, Andrzej; Cannon, Christopher P; Emanuelsson, Håkan; Held, Claes; Horrow, Jay; Husted, Steen; James, Stefan; Katus, Hugo; Mahaffey, Kenneth W; Scirica, Benjamin M; Skene, Allan; Steg, Philippe Gabriel; Storey, Robert F; Harrington, Robert A; Freij, Anneli; Thorsén, Mona

    2009-09-10

    Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an

  1. [Efficacy of clopidogrel as ADP-dependent platelet aggregation inhibitor. Study on individuals with coronary artery disease].

    PubMed

    Izaguirre Avila, R; de la Peña, A; González Pacheco, H; Ramírez Gutiérrez, A; González Valdez, H; Quiroz, A; Cortina, E; Huerta, M; Lupi, E

    2000-01-01

    Acetyl-salicylic acid inhibits thromboxane A2 production and reduces the risk of vascular occlusive events by 20 to 25%. Ticlopidine inhibits ADP-dependent platelet aggregation and reduces the same risk by 30 to 35%, but produces some adverse effects. Clopidogrel is a ticlopidin-derived antiplatelet-drug, with the same mechanism of action; reduces the expression of the glycoprotein IIb/IIIa, the fibrinogen receptor on the platelet surface. Clopidogrel has the same clinical efficacy of ticlopidin and lowers the incidence of adverse effects. In this study, we evaluated the effects of one daily dosis of 75 mg of clopidogrel on platelet function in 33 subjects with coronary artery disease. Before treatment and after the 6th and 12th week, the following parameters were evaluated: 5 microM-ADP and 20 micrograms/mL collagen-induced platelet aggregation, bleeding time and fibrinogen concentration. In basal and in the 6th and 12th week samples, ADP-induced platelet aggregation was 90.7% +/- 13.2, 54.6% +/- 23.2 and 49.2% +/- 23.7 respectively, that represents a significant reduction of 38.6% and 44.4%. Reduction of collagen-induced platelet aggregation was not significative. Plasmatic fibrinogen did not suffer variation during treatment. Bleeding time was significant prolonged from 4.1 minutes to 15.4 and 14.6 minutes (3.7-3.5 times compared with the test before treatment). There were no haemorrhagic complications, only digestive discomfort in fewer than 3% of patients. We concluded that clopidogrel is a safe and efficacious drug for patients, it efficiently reduces ADP-induced platelet aggregation and prolongs bleeding time.

  2. Actively using clopidogrel correlates with an increased risk of acute pancreatitis in Taiwan.

    PubMed

    Lai, Shih-Wei; Lin, Cheng-Li; Liao, Kuan-Fu

    2015-03-15

    The aim of this study is to assess whether there is an association between clopidogrel use and risk of acute pancreatitis in Taiwan. We conducted a case-control study using the database of the Taiwan National Health Insurance Program from 2000 to 2011. There were 5644 subjects aged 20-84 years with a first-time attack of acute pancreatitis as the case group and 22,576 randomly selected sex-matched and age-matched subjects without acute pancreatitis as the control group. We defined clopidogrel use as "actively using" if the final clopidogrel prescription was filled between 0 and 7 days before the date of diagnosing acute pancreatitis, or "not actively using" if the final clopidogrel prescription was filled ≧ 8 days before the date of diagnosing acute pancreatitis. Subjects who never used clopidogrel were defined as never used. The multivariable logistic regression model was used to calculate the odds ratio (OR) and 95% confidence interval (CI) of acute pancreatitis associated with clopidogrel use. Comparing the subjects actively using clopidogrel to those who never used clopidogrel, the adjusted OR of acute pancreatitis was 8.46 (95%CI 5.25, 13.7). The adjusted OR decreased to 1.16 among subjects not actively using clopidogrel (95%CI 0.95, 1.43). Persons actively using clopidogrel are at an increased risk of acute pancreatitis. Further studies are necessary to prove the causal relationship.

  3. Clopidogrel hypersensitivity: a novel multi-day outpatient oral desensitization regimen.

    PubMed

    Fajt, Merritt; Petrov, Andrej

    2010-01-01

    Clopidogrel hypersensitivity has posed a problem for the acute treatment and long-term care of a particular patient population with coronary artery disease and stent placement. Patients with clopidogrel hypersensitivity have had an increased risk of hypersensitivity reactions, including anaphylaxis, if they ingest clopidogrel without undergoing an oral desensitization procedure. The previously published desensitization protocols have either been performed in the intensive care unit, requiring significant cost and healthcare utilization, or have required a full-day outpatient commitment on behalf of the patient. To determine whether a multi-day outpatient oral clopidogrel desensitization protocol is effective and safe for patients with clopidogrel hypersensitivity. We retrospectively assessed the efficacy of a 10-dose outpatient multi-day clopidogrel desensitization protocol performed in a university allergy-immunology center from April 2006 to October 2008 in patients with clopidogrel hypersensitivity. Patients were desensitized over 2-3 half-day clinical visits and were able to go home between desensitization sessions. A preliminary cost analysis was performed using the average of actual costs for the outpatient clopidogrel desensitization procedure and was compared with the average cost for an inpatient oral desensitization completed at our institution. Eight patients with coronary artery disease, cardiac stent placement, and clopidogrel hypersensitivity underwent an outpatient multi-day oral clopidogrel desensitization procedure. All patients were successfully desensitized with the multi-day protocol without complications. No patient had recurrence of allergic reaction 3 months after the procedure. A preliminary cost analysis demonstrated a lower cost for the outpatient compared to the inpatient oral clopidogrel desensitization protocol. This outpatient 10-dose multi-day clopidogrel desensitization protocol is a safe and effective novel approach for the

  4. Misrepresentation of vital status follow-up: challenging the integrity of the PLATO trial and the claimed mortality benefit of ticagrelor versus clopidogrel.

    PubMed

    DiNicolantonio, James J; Tomek, Ales

    2013-10-30

    Ticagrelor, a novel, reversible, and oral P2Y12 receptor antagonist, was claimed to reduce all-cause mortality compared to clopidogrel in the PLATO trial. We sought to ascertain vital status follow-up for clopidogrel and ticagrelor to determine if any discrepancy existed by reviewing data from the FDA Complete Response Review. The FDA Complete Response Review indicated misrepresentation of vital status follow-up by the sponsor's presenter at the Cardiovascular and Renal Drugs Advisory Committee. Instead of five patients with missing vital status follow-up, the FDA primary efficacy reviewer indicated that there was a minimum of 106 patients. Additionally and more concerning was the fact that significantly more patients on ticagrelor (3.1%, n = 289 patients) had incomplete vital status follow-up versus clopidogrel (2.6%, n = 242 patients, p = 0.04 for the difference). The Advisory Committee that voted in favor to approve ticagrelor was given misrepresented data, which may have affected the approval of ticagrelor. The fact that significantly more patients on ticagrelor had incomplete vital status follow-up versus clopidogrel challenges the claimed mortality benefit of ticagrelor and the approval of the PLATO trial. © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Aligning Collaborative and Culturally Responsive Evaluation Approaches

    ERIC Educational Resources Information Center

    Askew, Karyl; Beverly, Monifa Green; Jay, Michelle L.

    2012-01-01

    The authors, three African-American women trained as collaborative evaluators, offer a comparative analysis of collaborative evaluation (O'Sullivan, 2004) and culturally responsive evaluation approaches (Frierson, Hood, & Hughes, 2002; Kirkhart & Hopson, 2010). Collaborative evaluation techniques immerse evaluators in the cultural milieu…

  6. Improving Beta Test Evaluation Response Rates: A Meta-Evaluation

    ERIC Educational Resources Information Center

    Russ-Eft, Darlene; Preskill, Hallie

    2005-01-01

    This study presents a meta-evaluation of a beta-test of a customer service training program. The initial evaluation showed a low response rate. Therefore, the meta-evaluation focused on issues related to the conduct of the initial evaluation and reasons for nonresponse. The meta-evaluation identified solutions to the nonresponse problem as related…

  7. The Practice and Politics of Responsive Evaluation

    ERIC Educational Resources Information Center

    Abma, Tineke

    2006-01-01

    Responsive evaluation offers a perspective in which evaluation is reframed from the assessment of program interventions on the basis of policy makers' goals to an engagement with and among all stakeholders about the value and meaning of their practice. Responsive evaluators have to be extra sensitive to power relations given the deliberate…

  8. Effects of CYP2C19 Polymorphism on Endothelial Function, Arterial Stiffness and Inflammation in Coronary Artery Disease Patients Under Clopidogrel Treatment.

    PubMed

    Siasos, Gerasimos; Zaromitidou, Marina; Oikonomou, Evangelos; Mourouzis, Konstantinos; Tsalamandris, Sotiris; Kioufis, Stamatios; Kokkou, Eleni; Vavuranakis, Manolis; Zografos, Theodoros; Antonopoulos, Alexis; Dimitropoulos, Stathis; Stefanadis, Christodoulos; Papavassiliou, Athanasios G; Tousoulis, Dimitris

    2015-01-01

    Clopidogrel's ability to inhibit platelet function determined its clinical usefulness. The role of CYP2C19*2 genotype on antiplatelet treatment is recently under question. Arterial wall properties and inflammation are key players in atherosclerosis development. Hence, we evaluated the impact of CYP2C19*2 genetic polymorphism on endothelial function, arterial stiffness and inflammation in coronary artery disease (CAD) patients receiving clopidogrel treatment. In this study we enrolled 408 consecutive patients with stable CAD under dual antiplatelet therapy (clopidogrel 75mg/day, aspirin 100mg/day), 30 days after percutaneous coronary intervention. Measurement of flow-mediated dilation (FMD) of the brachial artery was used to evaluate endothelial function. Carotid-femoral pulse wave velocity (PWV) and augmentation index (AIx) was measured to estimate arterial stiffness. Real time polymerase chain reaction was used for the genotyping of CYP2C19*2. Levels of tumor necrosis factor alpha (TNF-a) and interleukin 6 (IL-6) were measured with ELISA. We found no difference in basic clinical and demographic characteristics nor in FMD, PWV, AIx and inflammatory status (p=NS for all) between CYP2C19 homozygotes for the wild type; carriers of reduced function allele and homozygotes for the reduced function allele. CYP2C19*2 loss of action polymorphism causes no impact on vascular function and inflammatory status in stable CAD patients receiving clopidogrel treatment.

  9. Design and rationale for the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial.

    PubMed

    Berger, Jeffrey S; Katona, Brian G; Jones, W Schuyler; Patel, Manesh R; Norgren, Lars; Baumgartner, Iris; Blomster, Juuso; Mahaffey, Kenneth W; Held, Peter; Millegård, Marcus; Heizer, Gretchen; Reist, Craig; Fowkes, F Gerry; Hiatt, William R

    2016-05-01

    Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y12 receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events. EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction-defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur. The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Clopidogrel effectively suppresses endothelial microparticle generation induced by indoxyl sulfate via inhibition of the p38 mitogen-activated protein kinase pathway.

    PubMed

    Ryu, Jung-Hwa; Kim, Seung-Jung

    2011-01-01

    Endothelial microparticles (EMPs) are closely associated with vascular dysfunction. We investigated the effects of several drugs on EMP generation in human umbilical vein endothelial cells (HUVECs), and the involvement of the mitogen-activated protein kinase (MAPK) in EMP generation. CD31+CD42-EMP counts were measured by flow cytometry in supernatants of HUVECs incubated with indoxyl sulfate. The EMP responses to losartan, lovastatin, clopidogrel, and mesoglycan were examined. We then measured the effects of MAPK inhibitors on EMPs. (1) Indoxyl sulfate induced EMP release in HUVECs in a dose-dependent fashion; (2) all drugs (10-50 μM) inhibited EMP generation induced by indoxyl sulfate, with clopidogrel being the most effective; (3) the p38 MAPK inhibitor suppressed EMP generation induced by indoxyl sulfate, and (4) clopidogrel significantly suppressed MAPK signaling activated by indoxyl sulfate, with the most potency on p38. The p38 signaling involves EMP generation induced by indoxyl sulfate and is effectively suppressed by clopidogrel. Copyright © 2011 S. Karger AG, Basel.

  11. Prior chronic clopidogrel therapy is associated with increased adverse events and early stent thrombosis.

    PubMed

    Asher, Elad; Fefer, Paul; Sabbag, Avi; Herscovici, Romana; Regev, Ehud; Mazin, Israel; Shlomo, Nir; Zahger, Doron; Atar, Shaul; Hammerman, Haim; Polak, Arthur; Beigel, Roy; Matetzky, Shlomi

    2016-01-01

    Despite the growing use of clopidogrel, limited data exist regarding the prognostic significance of chronic clopidogrel therapy in patients sustaining acute coronary syndrome (ACS). Our aim was to determine whether patients sustaining ACS while on chronic clopidogrel therapy have a worse prognosis than clopidogrel-naïve patients. A total of 5,386 consecutive ACS patients were prospectively characterised and followed-up for 30 days. Of them, 680 (13%) were treated with clopidogrel prior to the index ACS. Major adverse cardiovascular events (MACE) were defined as death, recurrent ACS, stroke and/or stent thrombosis. Compared with clopidogrel-naïve, chronic clopidogrel-treated patients were older (66 ± 12 vs 63 ± 13, respectively; p<0.01), suffered more from diabetes mellitus, hypertension, dyslipidaemia, prior cardiovascular history, including prior myocardial infarction, revascularisation, coronary artery bypass graft and stroke (p<0.01 for all), and were less likely to present with ST-elevation myocardial infarction (21% vs 45%; respectively; p < 0.001). Prior clopidogrel therapy was associated with a two-fold increase in in-hospital (1.6% vs 0.6%, respectively; p =0.006) as well as 30-day stent thrombosis (2.2% vs 1.0%, respectively; p=0.007). MACE at 30 days was also higher among chronic clopidogrel-treated compared with clopidogrel-naïve patients [12.3% vs 9.4%, respectively; p<0.01]. In multivariate log regression analysis chronic clopidogrel treatment was an independent predictor of stent thrombosis [OR=2.6 (95%CI 1.2-5.6), p=0.001]. Patients sustaining ACS while on chronic clopidogrel treatment are at higher risk for in-hospital and 30-day adverse outcomes, including stent thrombosis.

  12. Comparison of high-resolution melting analysis, TaqMan Allelic discrimination assay, and sanger sequencing for Clopidogrel efficacy genotyping in routine molecular diagnostics.

    PubMed

    Zhang, Lina; Cui, Guanglin; Li, Zongzhe; Wang, Haoran; Ding, Hu; Wang, Dao Wen

    2013-09-01

    Clopidogrel, as a routine antiplatelet drug, is widely used in patients to reduce cardiovascular events following percutaneous coronary intervention. Because of genetic variation, patients undergoing percutaneous coronary intervention show differing responses to clopidogrel therapy. Recently, five single nucleotide polymorphisms (SNPs) within CYP2C19 (rs4244285, rs4986893, rs12248560), ABCB1 (rs1045642), and ITGB3 (rs5918) were identified that contribute prominently to variability in response to clopidogrel. Given that Sanger sequencing is labor intensive and time consuming, rapid genotyping methods for SNP detection are urgently required before clopidogrel therapy. Accordingly, we developed a high-resolution melting analysis (HRMA) and TaqMan allelic discrimination assay (TaqMan) to genotype those five SNPs, and compared these two assays with Sanger sequencing on accuracy of genotyping as well as operational characteristics. These two assays showed high accuracy (0.995, 95% CI 0.991 to 0.998 for HRMA; 0.997, 95% CI 0.994 to 0.999 for TaqMan, respectively), sensitivity (0.996, 95% CI 0.989 to 1.002 for HRMA; 0.998, 95% CI 0.993 to 1.002 for TaqMan, respectively), and specificity (0.995, 95% CI 0.991 to 0.999 for HRMA; 0.996, 95% CI 0.993 to 1.000 for TaqMan, respectively). Our study indicates that HRMA and TaqMan are easier to operate and obviously faster than Sanger sequencing. In conclusion, HRMA and TaqMan are rapid, convenient, and reliable assays for clopidogrel efficacy genotyping.

  13. Effect of clopidogrel on platelet aggregation and intimal hyperplasia following carotid endarterectomy in the rat.

    PubMed

    Bledsoe, Shelly L; Brown, Aliza T; Davis, Joseph A; Chen, Hongjiang; Eidt, John F; Moursi, Mohammed M

    2005-01-01

    Intimal hyperplasia results in significant morbidity and mortality following vascular intervention. Both platelets and elevated homocysteine have been implicated in the development of intimal hyperplasia. We previously demonstrated that a locally applied antiplatelet agent decreases the development of intimal hyperplasia. We were therefore interested in a systemic antiplatelet agent, clopidogrel. We hypothesized that clopidogrel would decrease platelet aggregation and activity and intimal hyperplasia. Male Sprague-Dawley rats underwent carotid endarterectomy (CEA) and treatment with either placebo or varying regimens of clopidogrel, including chronic, pre-CEA bolus, chronic plus pre-CEA bolus, and chronic plus post-CEA bolus; a homocystine diet was used to elevate both plasma homocysteine and the degree of intimal hyperplasia. Platelet aggregation, platelet activity, and intimal hyperplasia were then assessed. Platelet aggregation was not decreased with chronic clopidogrel; however, it was decreased with pre-CEA bolus clopidogrel. Similarly, platelet activity was not inhibited by chronic clopidogrel but was inhibited by pre-CEA and chronic plus pre-CEA bolus clopidogrel. Neither chronic, pre-CEA bolus, chronic plus pre-CEA bolus, nor chronic plus post-CEA bolus clopidogrel resulted in a decrease in intimal hyperplasia. Although pre-CEA bolus clopidogrel resulted in a decrease in both platelet aggregation and activity, it was unable to decrease the development of intimal hyperplasia at any dose. Additional factors must therefore contribute to the pathologic development of intimal hyperplasia.

  14. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (review of Technology Appraisal No. 90): a systematic review and economic analysis.

    PubMed

    Greenhalgh, J; Bagust, A; Boland, A; Martin Saborido, C; Oyee, J; Blundell, M; Dundar, Y; Dickson, R; Proudlove, C; Fisher, M

    2011-09-01

    Occlusive vascular events such as myocardial infarction (MI), ischaemic stroke and transient ischaemic attack (TIA) are the result of a reduction in blood flow associated with an artery becoming narrow or blocked through atherosclerosis and atherothrombosis. Peripheral arterial disease is the result of narrowing of the arteries that supply blood to the muscles and other tissues, usually in the lower extremities. The primary objective in the treatment of all patients with a history of occlusive vascular events and peripheral arterial disease is to prevent the occurrence of new occlusive vascular events. To assess the clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole (MRD) alone or with aspirin (ASA) compared with ASA (and each other where appropriate) in the prevention of occlusive vascular events in patients with a history of MI, ischaemic stroke/TIA or established peripheral arterial disease. To consider the clinical effectiveness and cost-effectiveness of clopidogrel in patients with multivascular disease. This review is an update of the evidence base for the National Institute for Health and Clinical Excellence (NICE) guidance Technology Appraisal No. 90 (TA90) entitled Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (2005). Four electronic databases (EMBASE, MEDLINE, Web of Science and The Cochrane Library) were searched for randomised controlled trials (RCTs) and economic evaluations. Submissions to NICE by the manufacturers of the interventions were also considered. A systematic review of clinical effectiveness and cost-effectiveness was conducted. To manage heterogeneity between trials, indirect analysis (using a mixed-treatment methodology) was performed on selected clinical outcomes. A new economic model was developed to assess incremental costs per life-year gained [quality-adjusted life-years (QALYs)]. For evidence of clinical effectiveness, four RCTs were

  15. Response Bias in Hospice Evaluation.

    ERIC Educational Resources Information Center

    Hayslip, Bert, Jr.; And Others

    1991-01-01

    Analyzed response bias among 34 recipients of care in hospice. Found nonrespondents to have better bereavement prognoses and tended to care for patients who were younger, male, and in program for shorter time. Nonrespondents were in contact with staff less than were respondents. Data are consistent with earlier research showing significant…

  16. A Ranking Method for Evaluating Constructed Responses

    ERIC Educational Resources Information Center

    Attali, Yigal

    2014-01-01

    This article presents a comparative judgment approach for holistically scored constructed response tasks. In this approach, the grader rank orders (rather than rate) the quality of a small set of responses. A prior automated evaluation of responses guides both set formation and scaling of rankings. Sets are formed to have similar prior scores and…

  17. A Ranking Method for Evaluating Constructed Responses

    ERIC Educational Resources Information Center

    Attali, Yigal

    2014-01-01

    This article presents a comparative judgment approach for holistically scored constructed response tasks. In this approach, the grader rank orders (rather than rate) the quality of a small set of responses. A prior automated evaluation of responses guides both set formation and scaling of rankings. Sets are formed to have similar prior scores and…

  18. Rationale and Design for a Randomized Comparison of Efficacy and Safety between Aspirin and Clopidogrel in Atrial Fibrillation Patients with Low Stroke Risk: CESAC-AF trial.

    PubMed

    Park, Sang Min; Jeong, Haemin; Jung, Mi-Hyang; Hong, Kyung Soon; Hong, Myeong-Ki; Bang, Chang Seok; Kim, Christopher Y

    2017-09-01

    Atrial fibrillation (AF) increases the risk of thromboembolic stroke. An oral anticoagulant should be administrated to prevent stroke in patients with moderate stroke risk (ie, CHA2DS2-VASc score>2). If the stroke risk is low (i.e. the score=1), however, antiplatelet agent such as aspirin is widely used. Aspirin can cause peptic ulcer disease (PUD) while its alternative, clopidogrel, theoretically does not. To elucidate the efficacy and safety between aspirin and clopidogrel, a multicenter randomized controlled trial was designed in AF patients with low stroke risk. According to sample size estimation based on previous literature, a total of 1560 AF patients with low stroke risk will be randomly assigned into 4 different groups dependent upon initial esophagogastroduodenoscopy (EGD) results: two mono-antiplatelet treatment groups with either aspirin 100mg or clopidogrel 75mg for 1year; two antiplatelet agent and proton pump inhibitor (PPI) combination groups. Follow-up EGD will be performed at 1year. The clinical follow-up will be performed for 1year after enrollment. The primary efficacy endpoint is to compare the annual stroke rate between aspirin and clopidogrel treatment groups. The primary safety endpoint is to compare the prevalence of drug-induced gastrointestinal (GI) and intracranial hemorrhage and upper-GI response including PUD based on EGD after 1year. This trial will determine whether clopidogrel is noninferior in stroke prevention and superior in reduction of GI events including PUD to aspirin in AF patients with low stroke risk. (ClinicalTrials.gov: NCT02960126). Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy

    PubMed Central

    Wang, Zhi-Yu; Chen, Meng; Zhu, Ling-Ling; Yu, Lu-Shan; Zeng, Su; Xiang, Mei-Xiang; Zhou, Quan

    2015-01-01

    Background Coprescribing of clopidogrel and other drugs is common. Available reviews have addressed the drug–drug interactions (DDIs) when clopidogrel is as an object drug, or focused on combination use of clopidogrel and a special class of drugs. Clinicians may still be ignorant of those DDIs when clopidogrel is a precipitant drug, the factors determining the degree of DDIs, and corresponding risk management. Methods A literature search was performed using PubMed, MEDLINE, Web of Science, and the Cochrane Library to analyze the pharmacokinetic DDIs of clopidogrel and new P2Y12 receptor inhibitors. Results Clopidogrel affects the pharmacokinetics of cerivastatin, repaglinide, ferulic acid, sibutramine, efavirenz, and omeprazole. Low efficacy of clopidogrel is anticipated in the presence of omeprazole, esomeprazole, morphine, grapefruit juice, scutellarin, fluoxetine, azole antifungals, calcium channel blockers, sulfonylureas, and ritonavir. Augmented antiplatelet effects are anticipated when clopidogrel is coprescribed with aspirin, curcumin, cyclosporin, St John’s wort, rifampicin, and angiotensin-converting enzyme inhibitors. The factors determining the degree of DDIs with clopidogrel include genetic status (eg, cytochrome P540 [CYP]2B6*6, CYP2C19 polymorphism, CYP3A5*3, CYP3A4*1G, and CYP1A2-163C.A), species differences, and dose strength. The DDI risk does not exhibit a class effect, eg, the effects of clopidogrel on cerivastatin versus other statins, the effects of proton pump inhibitors on clopidogrel (omeprazole, esomeprazole versus pantoprazole, rabeprazole), the effects of rifampicin on clopidogrel versus ticagrelor and prasugrel, and the effects of calcium channel blockers on clopidogrel (amlodipine versus P-glycoprotein-inhibiting calcium channel blockers). The mechanism of the DDIs with clopidogrel involves modulating CYP enzymes (eg, CYP2B6, CYP2C8, CYP2C19, and CYP3A4), paraoxonase-1, hepatic carboxylesterase 1, P-glycoprotein, and organic anion

  20. Safety of Continued Clopidogrel Use in the Preoperative Course of Gastrointestinal Surgery: A Retrospective Cohort Study.

    PubMed

    Jupiter, Daniel C; Fang, Xiao; Adhikari, Deepak; Mehta, Hemalkumar B; Riall, Taylor S

    2017-02-01

    Our study aimed to estimate postoperative bleeding risk in older adults taking clopidogrel before gastrointestinal (GI) surgery, to aid surgeons in decisions regarding clopigogrel cessation. Balancing risks of postoperative bleeding associated with continued clopidogrel use and those associated with cessation is difficult for GI surgeons. Using 100% Texas Medicare Claims Data from 2006 to 2011, we identified patients undergoing emergent GI surgery. We propensity score matched patients on clopidogrel before surgery to patients not on clopidogrel. Using conditional logistic regression, we compared risks of bleeding events at 1-month postdischarge between groups, adjusting for bleeding risk factors. In total, 1240 patients undergoing emergent GI surgery while treated with clopidogrel were matched to emergency GI surgery patients not treated with clopidogrel. The only significant preoperative differences between groups were higher percent of clopidogrel-treated patients with congestive heart failure, cholecystectomy, and lower percent of clopidogrel-treated patients with colectomy. Mean age was 76.91 (±7.06) and 76.70 (±7.05) years (P = 0.47), and 63.84% and 59.41% of operations were cholecystectomy, in the clopidogrel and nonclopidogrel groups (P = 0.18). In multivariable analyses adjusting for Elixhauser index, hyperlipidemia, confounding drugs, and surgery type, odds ratio for bleeding within 30 days of discharge in those exposed to clopidogrel compared with those not exposed was 1.60 (95% confidence interval, 1.08-2.38), with raw rates of bleeding 6.85% and 4.84%. Clopidogrel use in older adults through the preoperative period of GI surgery does not significantly increase bleeding events in the month after surgery.

  1. Cost-effectiveness analysis of short-term clopidogrel therapy for ST elevation myocardial infarction.

    PubMed

    Gibler, Kyle B; Huskamp, Haiden A; Sabatine, Marc S; Murphy, Sabina A; Cohen, David J; Cannon, Christopher P

    2010-03-01

    Clopidogrel improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and is recommended in the guidelines. We sought to determine the incremental cost-effectiveness of clopidogrel therapy in this patient population. We used primary patient-level resource use and clinical outcomes data from 3491 STEMI patients treated with fibrinolysis and either clopidogrel or placebo prior to a diagnostic coronary angiogram in the Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial. Costs for each patient were calculated based on diagnosis-related groups-specific Medicare reimbursement rates for all hospitalizations and the average wholesale price of clopidogrel. Cost per event prevented and cost per life year gained (LYG) were calculated using standard methods. The estimate of LYG due to clopidogrel therapy was based on recurrent myocardial infarction and death outcomes. The bootstrap method was used to produce bias-corrected confidence intervals for cost and efficacy estimates as well as the cost per LYG ratio. Total costs and resource use were not significantly different for the clopidogrel and placebo groups ($8128 vs. $8134), indicating that short-term clopidogrel therapy is an economically dominant treatment strategy. Even in a sensitivity analysis accounting for higher long-term medical costs due to greater life expectancy, clopidogrel remained under $6000 per LYG. Clopidogrel therapy was dominant in 35% of the bootstrap simulations and cost less than $50,000 per LYG in 67% of simulations. In conclusion, this analysis finds short-term clopidogrel therapy to be a highly economically attractive therapy, improving patient outcomes at no increase in costs.

  2. Cost-effectiveness of clopidogrel, prasugrel and ticagrelor for dual antiplatelet therapy after acute coronary syndrome: a decision-analytic model

    PubMed Central

    Abdel-Qadir, Husam; Roifman, Idan; Wijeysundera, Harindra C.

    2015-01-01

    Background: The use of prasugrel or ticagrelor as part of dual antiplatelet therapy with acetylsalicylic acid after acute coronary syndrome (ACS) improves clinical outcomes relative to clopidogrel. The relative cost-effectiveness of these agents are unknown. We conducted an economic analysis evaluating 12 months of treatment with clopidogrel, prasugrel or ticagrelor after ACS. Methods: We developed a fully probabilistic Markov cohort decision-analytic model using a lifetime horizon, from the perspective of the Ontario Ministry of Health and Long-Term Care. The model incorporated risks of death, recurrent ACS, heart failure, major bleeding and other adverse effects of treatment. Data on probabilities and utilities were obtained from the published literature where available. The primary outcome was quality-adjusted life-years (QALYs). Results: Treatment with clopidogrel was associated with the lowest effectiveness (7.41 QALYs, 95% confidence interval [CI] 1.05-14.79) and the lowest cost ($39 601, 95% CI $8434-$111 186). Ticagrelor treatment had an effectiveness of 7.50 QALYs (95% CI 1.13-14.84) at a cost of $40 649 (95% CI $9327-$111 881). The incremental cost-effectiveness ratio (ICER) for ticagrelor relative to clopidogrel was $12 205 per QALY gained. Prasugrel had an ICER of $57 630 per QALY gained relative to clopidogrel. Ticagrelor was the preferred option in 90% of simulations at a willingness-to-pay threshold of $50 000 per QALY gained. Interpretation: Ticagrelor was the most cost-effective agent when used as part of dual antiplatelet therapy after ACS. This conclusion was robust to wide variations in model parameters. PMID:26770967

  3. Culturally Responsive Evaluation Meets Systems-Oriented Evaluation

    ERIC Educational Resources Information Center

    Thomas, Veronica G.; Parsons, Beverly A.

    2017-01-01

    The authors of this article each bring a different theoretical background to their evaluation practice. The first author has a background of attention to culturally responsive evaluation (CRE), while the second author has a background of attention to systems theories and their application to evaluation. Both have had their own evolution of…

  4. Culturally Responsive Evaluation Meets Systems-Oriented Evaluation

    ERIC Educational Resources Information Center

    Thomas, Veronica G.; Parsons, Beverly A.

    2017-01-01

    The authors of this article each bring a different theoretical background to their evaluation practice. The first author has a background of attention to culturally responsive evaluation (CRE), while the second author has a background of attention to systems theories and their application to evaluation. Both have had their own evolution of…

  5. Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease.

    PubMed

    Hiatt, William R; Fowkes, F Gerry R; Heizer, Gretchen; Berger, Jeffrey S; Baumgartner, Iris; Held, Peter; Katona, Brian G; Mahaffey, Kenneth W; Norgren, Lars; Jones, W Schuyler; Blomster, Juuso; Millegård, Marcus; Reist, Craig; Patel, Manesh R

    2017-01-05

    Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease. In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow-up was 30 months. The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49). In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZeneca; EUCLID ClinicalTrials.gov number

  6. Variation in thromboxane B2 concentrations in serum and plasma in patients taking regular aspirin before and after clopidogrel therapy.

    PubMed

    Good, Richard I S; McGarrity, Anne; Sheehan, Rory; James, Tina E; Miller, Helen; Stephens, Jonathan; Watkins, Stuart; McConnachie, Alex; Goodall, Alison H; Oldroyd, Keith G

    2015-01-01

    Dual antiplatelet therapy with aspirin and a P2Y12 antagonist is widely prescribed for the prevention of thrombotic events in patients with an acute coronary syndrome or undergoing percutaneous coronary intervention (PCI). It is recognised that there is inter-individual variation in the antiplatelet effects of both drugs. Recent data also suggest that P2Y12 antagonists can affect the response to aspirin. A direct indicator of the effect of aspirin on platelets is their ability to generate thromboxane, which if measured as the difference between the level of thromboxane B2 in serum and plasma ([TxB2]S-P) avoids the confounding effect of endogenous TxB2 production from other cells. We therefore analysed [TxB2]S-P as a measure of aspirin response in a group of 123 patients undergoing elective PCI before and after the introduction of clopidogrel. In a subgroup of 40 patients taking aspirin alone, we compared [TxB2]S-P and VerifyNow Aspirin for the assessment of aspirin response. There was a wide variation in plasma and serum TxB2 concentrations both before and after clopidogrel therapy but only 3.5% of patients had residual serum concentration of TxB2 > 10 ng/ml. There was a strong correlation between the pre and post clopidogrel levels of TxB2 (r ≥ 0.78; p = 0.001) and no significant difference in [TxB2]S-P. There was no correlation between the magnitude of response to clopidogrel response and the generation of thromboxane B2. Correlation between [TxB2]S-P and VerifyNow Aspirin was poor. We conclude that the use of a P2Y12 antagonist does not influence the effect of aspirin on the ability of platelets to generate thromboxane. Therefore, measurement of TxB2 levels in serum, after subtracting the contribution from plasma, provides a measure of the response to aspirin in patients taking dual antiplatelet therapy.

  7. Effect of Ginkgo Biloba Extract on the Pharmacokinetics and Metabolism of Clopidogrel in Rats.

    PubMed

    Deng, Ying; Mo, Yu-Fei; Chen, Xin-Meng; Zhang, Lv-Zhao; Liao, Chao-Feng; Song, Yu; Xu, Chenshu

    2016-11-01

    Ginkgo biloba extract (GBE), a traditional herbal product used worldwide as both medicine and supplement, is often supplied with clopidogrel for the treatment of cerebrovascular diseases. The aim of the current study was to explore the effect of GBE on the metabolism and pharmacokinetics of clopidogrel. The in vitro study using rat liver microsomes revealed that GBE significantly induced the conversion of clopidogrel into its active metabolite. The effect of GBE on the pharmacokinetics of clopidogrel was also investigated in vivo. Compared to rats without GBE pretreatment, administration of 4 mg/kg, 20 mg/kg, and 100 mg/kg of GBE significantly decreased the Cmax and the AUC0-∞ of clopidogrel in a dose-dependent manner. As expected, pretreatment of high dose GBE significantly increased the Cmax and AUC0-∞ of the clopidogrel active metabolite. However, no marked change was observed following medium and low dose of GBE, suggesting that the biotransformation of clopidogrel was altered differently by high dose of GBE. Our study suggested that the awareness of the potential herb-drug interactions between GBE and clopidogrel should be increased in clinical practice. Copyright © 2016 John Wiley & Sons, Ltd.

  8. Anti-atherosclerotic effect of atorvastatin and clopidogrel alone and in combination in rats.

    PubMed

    Srinivas, Martha; Annapurna, Akula; Reddy, Yellu Narsimha

    2008-10-01

    Atherosclerosis is a disease affecting arterial blood vessels due to the accumulation of macrophage white blood cells and low density lipoproteins. Effects of atorvastatin, a recently introduced lipid lowering statin was studied alone and in combination with clopidogrel in high fat diet fed atherosclerotic rats orally. Results showed significant reduction in total serum cholesterol and malondialdehyde levels and significant improvement in urine creatinine levels. Aortic cross sections of rats treated with clopidogrel alone showed reversal of atherosclerotic calcification. The same effect was observed with the combined treatment of clopidogrel and atorvastatin. Only atorvastatin treatment did not show any histological atheroprotective effect. Atorvastatin and clopidogrel alone and in combination have offered significant atheroprotective effect. No specific advantage was seen with combined treatment of atorvastatin and clopidogrel, moreover the advantages seen with independent drug administration also reduced with combined treatment.

  9. Bleeding tendency in dual antiplatelet therapy with aspirin/clopidogrel: rescue of the template bleeding time in a single-center prospective study

    PubMed Central

    2012-01-01

    Background Patients with heightened platelet reactivity in response to antiplatelet agents are at an increased risk of recurrent ischemic events. However, there is a lack of diagnostic criteria for increased response to combined aspirin/clopidogrel therapy. The challenge is to identify patients at risk of bleeding. This study sought to characterize bleeding tendency in patients treated with aspirin and clopidogrel. Patients/methods In a single-center prospective study, 100 patients under long-term aspirin/clopidogrel treatment, the effect of therapy was assayed by template bleeding time (BT) and the inhibition of platelet aggregation (IPA) by light transmission aggregometry (LTA). Arachidonic acid (0.625 mmol/L) and adenosine diphosphate (ADP; 2, 4, and 8 μmol/L) were used as platelet agonists. Results Bleeding episodes (28 nuisance, 2 hematuria [1 severe], 1 severe proctorrhagia, 1 severe epistaxis) were significantly more frequent in patients with longer BT. Template BT ≥ 24 min was associated with bleeding episodes (28 of 32). Risk of bleeding increased 17.4% for each 1 min increase in BT. Correlation was found between BT and IPAmax in response to ADP 2 μmol/L but not to ADP 4 or 8 μmol/L. Conclusion In patients treated with dual aspirin/clopidogrel therapy, nuisance and internal bleeding were significantly associated with template BT and with IPAmax in response to ADP 2 μmol/L but not in response to ADP 4 μmol/L or 8 μmol/L. PMID:22236361

  10. Clopidogrel Therapy Discontinuation Following Drug Eluting Stent Implantation in Real World Practice in Israel

    PubMed Central

    Blich, Miry; Shwiri, Tawfiq Zeidan; Petcherski, Sirouch; Osherov, Azriel B; Hammerman, Haim

    2012-01-01

    Background Incidence and predictors of clopidogrel discontinuation after drug eluting stent (DES) implantation, in real world practice, are poorly known. Methods Prospective study included all patients who underwent implantation of at least one DES between February 2006 and January 2007. Predictors of clopidogrel discontinuation were assessed by a multivariable analysis. Results In 269 patients, mean period for clopidogrel therapy was 13.2 ± 7.2 month. Twenty eight patients (10.4%) discontinued clolopidogrel prematurely (< 3 months). Early clopidogrel discontinuation was a predictor of late stent thrombosis (P = 0.005) and urgent target vessel revascularization (P = 0.05). There was a trend for higher cardiac mortality among that group (P = 0.07). By 12 months, 173 patients (64.3%) have discontinued clopidogrel therapy. The most frequent circumstance to stop clopidogrel before 12 months was recommendation of family physician. Patients that were followed by cardiologist were more encouraged to longer clopidogrel therapy. In multivariable analysis being non Jew (OR 19.2, 95% CI 2.4 to 142, P = 0.005), not followed by cardiologist (OR 4.7, 95% CI 1 to 23.1, P = 0.05) and lack of information regarding the importance of clopidogrel maintenance at discharge from hospital (OR 10.8, 95% CI 2.7 to 42.9, P = 0.001) were independent predictors of early clopidogrel discontinuation. Conclusions Clopidogrel discontinuation, in real world practice is not unusual and related to poor outcome. Education for general physicians, clear instructions about the importance of antiplatelet maintenance at discharge and follow up by an expert cardiologist are opportunities to improve adherence do antiplatelet therapy following DES implantation.

  11. Response Evaluation in Computer Based Tutorials.

    ERIC Educational Resources Information Center

    Smyth, Timothy

    1987-01-01

    Describes a computer program that allows undergraduate students to undertake nomenclature tutorials in organic chemistry, where user response is evaluated based on a set of rules that determine appropriate feedback. Design of the software is described, including the use of computer graphics, and results of students' evaluations are briefly…

  12. Use of Responsive Evaluation in Statewide Program Evaluation

    ERIC Educational Resources Information Center

    Kalman, Marjorie

    1976-01-01

    A summer school program stressing basic skills for migrant children in a rural Illinois community was assessed according to Stake's responsive evaluation model. Informal communication, program activities, audience needs, and participant values were emphasized in this case study. This evaluation method provided useful information for the state's…

  13. Use of Responsive Evaluation in Statewide Program Evaluation.

    ERIC Educational Resources Information Center

    Kalman, Marjorie

    The objective of this paper is to discuss the utilization of Stake's theory of responsive evaluation by a unit in state government charged with the evaluation of the Illinois Migrant Program. Through interviews with state and local Title I staff, we were able to discover program purposes and concerns and to later conceptualize these concerns into…

  14. Design of the Dialysis Access Consortium (DAC) Clopidogrel Prevention of Early AV Fistula Thrombosis Trial.

    PubMed

    Dember, Laura M; Kaufman, James S; Beck, Gerald J; Dixon, Bradley S; Gassman, Jennifer J; Greene, Tom; Himmelfarb, Jonathan; Hunsicker, Lawrence G; Kusek, John W; Lawson, Jeffrey H; Middleton, John P; Radeva, Milena; Schwab, Steve J; Whiting, James F; Feldman, Harold I

    2005-01-01

    The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes. The autogenous arteriovenous fistula created by direct connection of native artery to vein is the recommended vascular access for hemodialysis. However, it fails frequently due to clotting after surgery. The DAC Early AV Fistula Thrombosis Trial tests the hypothesis that clopidogrel can prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access. This is one of two initial and concurrent trials being performed by the DAC. The companion trial investigates pharmacologic approaches to prevent venous stenosis leading to AV graft failure. This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1,284 patients over four years. Patients undergoing creation of a new native arteriovenous (AV) fistula are randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery. The primary outcome is fistula patency at six weeks. The major secondary outcome is fistula suitability for dialysis. This paper examines key aspects of this study that have broad relevance to trial design including: 1) the selection of an intermediate event as the primary outcome, 2) timing of the intervention to balance efficacy and safety concerns, 3) ethical considerations arising from required modifications of concomitant drug therapy, and 4) choosing an efficacy or effectiveness evaluation of the intervention. This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent early AV fistula failure and promote more usable fistulas for hemodialysis. The methodologic challenges identified and addressed during the development of this trial should help to inform the design of future vascular access trials, and are relevant to clinical trials addressing a wide range of questions.

  15. Aspirin and clopidogrel: a sweeping combination in cardiology.

    PubMed

    Manolis, Antonis S; Tzeis, Stylianos; Andrikopoulos, George; Koulouris, Spyros; Melita, Helen

    2005-07-01

    Platelets play a pivotal role in the pathogenesis of atherothrombosis, believed to be integrally involved in both the development and progression of atherosclerotic heart disease, as well as in its acute thrombotic complications. Antiplatelet therapy constitutes the cornerstone in the management of patients with acute coronary syndromes and generally high-risk patients with atherothrombosis. Until recently, long-term antiplatelet therapy for the treatment and prevention of the complications of atherothrombotic disease was traditionally limited to aspirin. The availability of the thienopyridines, in particular clopidogrel, represents an important addition to the physician's armamentarium. Clopidogrel is currently one of the most widely prescribed drugs for the treatment of symptomatic coronary artery disease. Aspirin and clopidogrel interfere with platelet activation in complementary, but separate pathways. Aspirin irreversibly inhibits cyclooxygenase, thus preventing the production of thromboxane A(2), which is a prothrombotic and vasoconstrictive substance. Clopidogrel, a newer thienopyridine which has largely supplanted ticlopidine due to a more favorable safety profile, irreversibly prevents platelet activation by blocking one of the three known adenosine 5'-diphosphate (ADP) receptors (the P2Y(12) receptor) on the platelet surface, thus interfering with platelet activation, degranulation and aggregation. Both these antiplatelet agents have a potent protective effect against adverse vascular events, but the combination of these two agents has an even stronger antiplatelet effect translating into superior antithrombotic protection in coronary, cerebral or peripheral arterial disease, without an inordinate increase in bleeding complications. A number of seminal clinical trials have demonstrated and confirmed the incremental benefit and efficacy of the combination of clopidogrel and aspirin therapy above and beyond that of aspirin alone, with multiple other

  16. Effect of Clopidogrel and Aspirin vs Aspirin Alone on Migraine Headaches After Transcatheter Atrial Septal Defect Closure: The CANOA Randomized Clinical Trial.

    PubMed

    Rodés-Cabau, Josep; Horlick, Eric; Ibrahim, Reda; Cheema, Asim N; Labinaz, Marino; Nadeem, Najaf; Osten, Mark; Côté, Mélanie; Marsal, Josep Ramon; Rivest, Donald; Marrero, Alier; Houde, Christine

    2015-11-24

    The occurrence of new-onset migraine attacks is a complication of transcatheter atrial septal defect (ASD) closure. It has been suggested that clopidogrel may reduce migraine attacks after ASD closure. To assess the efficacy of clopidogrel, used in addition to taking aspirin, for the prevention of migraine attacks following ASD closure. Randomized, double-blind clinical trial performed in 6 university hospitals in Canada. Participants were 171 patients with an indication for ASD closure and no history of migraine. Patients were randomized (1:1) to receive dual antiplatelet therapy (aspirin + clopidogrel [the clopidogrel group], n = 84) vs single antiplatelet therapy (aspirin + placebo [the placebo group], n = 87) for 3 months following transcatheter ASD closure. The first patient was enrolled in December 2008, and the last follow-up was completed in February 2015. The primary efficacy outcome was the monthly number of migraine days within the 3 months following ASD closure in the entire study population. The incidence and severity of new-onset migraine attacks, as evaluated by the Migraine Disability Assessment questionnaire, were prespecified secondary end points. A zero-inflated Poisson regression model was used for data analysis. The mean (SD) age of the participants was 49 (15) years and 62% (106) were women. Patients in the clopidogrel group had a reduced mean (SD) number of monthly migraine days within the 3 months following the procedure (0.4 [95% CI, 0.07 to 0.69] days) vs the placebo group (1.4 [95% CI, 0.54 to 2.26] days; difference, -1.02 days [95% CI, -1.94 to -0.10 days]; incident risk ratio [IRR], 0.61 [95% CI, 0.41 to 0.91]; P = .04) and a lower incidence of migraine attacks following ASD closure (9.5% for the clopidogrel group vs 21.8% for the placebo group; difference, -12.3% [95% CI, -23% to -1.6%]; odds ratio [OR], 0.38 [95% CI, 0.15 to 0.89]; P = .03). Among patients with migraines, those in the clopidogrel group had less

  17. Impact of CYP2C19 Variants on Clinical Efficacy of Clopidogrel and 1-Year Clinical Outcomes in Coronary Heart Patients Undergoing Percutaneous Coronary Intervention

    PubMed Central

    Sun, Hong; Qu, Qiang; Chen, Zhen-Fan; Tan, Sheng-Lan; Zhou, Hai-Jun; Qu, Jian; Chen, Hui

    2016-01-01

    The impact of pharmacogenetic variants of cytochrome P450 2C19 (CYP2C19) on clopidogrel-mediated effects on platelet inhibition, inflammatory response and endothelial function, as well as risk of major adverse cardiovascular events (MACE), in coronary heart patients undergoing percutaneous coronary intervention (PCI) was investigated. To this end, we assessed the residual platelet aggregation rate (RPA), maximal aggregation rate (MAR) and plasma levels of sCD40L, sP-selectin, MMP-9, sVCAM-1 and sE-selectin after 24 h of PCI in 559 patients treated with clopidogrel and followed up for 1 year for evidence of MACE. CYP2C19 *2 and *3 variants were identified using a clopidogrel-sensitive gene detection kit. Our results showed higher RPA and MAR as well as increased sE-selectin, sCD40L, sP-selectin, MMP-9, and sVCAM-1 levels in CYP2C19 intermediate metabolizer (IM, CYP2C19*1/*2, or *1/*3), poor metabolizer (PM, CYP2C19*2/*2, *2/*3, or *3/*3) and combined IM+PM groups, relative to those in extensive metabolizers (EM, CYP2C19*1/*1). In total, 519 patients completed 1 year of follow-up, among which 69 (13.3%) experienced MACE. The risk of MACE in CYP2C19 IM+PM patients was 2.664 times higher than that in CYP2C19 EM patients (OR = 2.664 (1.397–5.193), P = 0.004). The data suggest that CYP2C19*2 and *3 variants modulate the drug efficacy of clopidogrel in coronary heart patients undergoing PCI and further enhance the risk of MACE. Accordingly, CYP2C19 pharmacogenetic profiling may be beneficial for coronary heart patients undergoing PCI to predict the efficacy of treatment with clopidogrel. We propose that IM and PM patients should benefit from treatment with higher clopidogrel doses to improve efficacy and reduce the incidence of MACE. PMID:27932982

  18. Postoperative Bleeding Risk for Oral Surgery under Continued Clopidogrel Antiplatelet Therapy

    PubMed Central

    Zeuch, Jürgen; Haase, Martina; Semmusch, Jan; Eichhorn, Wolfgang

    2015-01-01

    Object. To determine the incidence of postoperative bleeding for oral osteotomy carried out under continued monoantiplatelet therapy with clopidogrel and dual therapy with clopidogrel/aspirin. Design. Retrospective single center observatory study of two study groups and a control group. Methods. A total of 64 and 60 oral osteotomy procedures carried out under continued monoclopidogrel therapy and dual clopidogrel/aspirin therapy, respectively, were followed for two weeks for postoperative bleeding. Another 281 similar procedures were also followed as a control group. All oral osteotomy procedures were carried out on an outpatient basis. Results. We observed postoperative bleeding in 2/281 (0.7%) cases in the control group, in 1/64 (1.6%) cases in the clopidogrel group, and in 2/60 (3.3%) cases in the dual clopidogrel/aspirin group. The corresponding 95% confidence intervals are 0–1.7%, 0–4.7%, and 0–7.8%, respectively, and the incidences did not differ significantly among the three groups (P > 0.09). Postoperative hemorrhage was treated successfully in all cases with local measures. No changes of antiplatelet medication, transfusion, nor hospitalisation were necessary. No major cardiovascular events were recorded. Conclusions. Our results indicate that minor oral surgery can be performed safely under continued monoantiplatelet medication with clopidogrel or dual antiplatelet medication with clopidogrel/aspirin. PMID:25632402

  19. Combination of clopidogrel and everolimus dramatically reduced the development of transplant arteriosclerosis in murine aortic allografts.

    PubMed

    Eckl, Sebastian; Heim, Christian; Abele-Ohl, Silke; Hoffmann, Julia; Ramsperger-Gleixner, Martina; Weyand, Michael; Ensminger, Stephan M

    2010-09-01

    Our group has shown that platelet inhibition with clopidogrel, an antagonist of the P2Y12 adenosine diphosphate receptor on platelets, reduced the formation of transplant arteriosclerosis. The aim of this study was to investigate whether a combination of cyclosporin or everolimus with clopidogrel has a beneficial effect on the development of transplant arteriosclerosis. Fully MHC mismatched C57Bl/6 (H2(b)) donor aortas were transplanted into CBA.J (H2(k)) recipients and mice received either clopidogrel alone (1 mg/kg/day) or in combination with cyclosporin (2 mg/kg/day) or everolimus (0.05 mg/kg/day). Grafts were analysed by histology and morphometry on day 30 after transplantation. In mice treated with clopidogrel alone, transplant arteriosclerosis was significantly reduced [intima proliferation 56 +/- 11% vs. 81 +/- 7% (control)/n = 7]. Daily application of everolimus reduced the development of transplant arteriosclerosis compared with untreated controls [intima proliferation of 29 +/- 9% vs. 81 +/- 7% (control)/n = 7]. Strikingly, combination of clopidogrel and everolimus almost abolished the formation of transplant arteriosclerosis [intima proliferation: 11 +/- 8% vs. 81 +/- 7% (control)/n = 7]. By contrast, combination of cyclosporin and clopidogrel compared with clopidogrel alone showed no additive effect. These results demonstrate that combination of platelet- and mammalian target of Rapamycin-inhibition can dramatically reduce the development of transplant arteriosclerosis.

  20. The risk of endoscopic mucosal resection in the setting of clopidogrel use.

    PubMed

    Namasivayam, Vikneswaran; Prasad, Ganapathy A; Lutzke, Lori S; Dunagan, Kelly T; Borkenhagen, Lynn S; Okoro, Ngozi I; Tomizawa, Yutaka; Buttar, Navtej S; Michel, Wongkeesong Louis; Wang, Kenneth K

    2014-01-01

    Objective. Guidelines on antiplatelet medication use during endoscopy are based on limited evidence. We investigate the risk of bleeding and ischemic events in patients undergoing endoscopic mucosal resection (EMR) of esophageal lesions in the setting of scheduled cessation and prompt resumption of clopidogrel. Design. Single centre retrospective review. Patients. Patients undergoing EMR of esophageal lesions. Interventions. Use of clopidogrel before EMR and resumption after EMR. Patients cease antiplatelets and anticoagulants 7 days before EMR and resume clopidogrel 2 days after EMR in average risk patients. Main Outcomes. Gastrointestinal bleeding (GIB) and ischemic events (IE) within 30 days of EMR. Results. 798 patients underwent 1716 EMR. 776 EMR were performed on patients on at least 1 antiplatelet/anticoagulant (APAC). 17 EMR were performed following clopidogrel cessation. There were 14 GIB and 2 IE. GIB risk in the setting of recent clopidogrel alone (0%) was comparable to those not on APAC (1.1%) (P = 1.0). IE risk on clopidogrel (6.3%) was higher than those not on APAC (0.1%) (P = 0.03). Limitations. Retrospective study. Conclusions. Temporary cessation of clopidogrel before EMR and prompt resumption is not associated with an increased risk of gastrointestinal bleeding but may be associated with increased ischemic events.

  1. The Risk of Endoscopic Mucosal Resection in the Setting of Clopidogrel Use

    PubMed Central

    Namasivayam, Vikneswaran; Prasad, Ganapathy A.; Lutzke, Lori S.; Dunagan, Kelly T.; Borkenhagen, Lynn S.; Okoro, Ngozi I.; Tomizawa, Yutaka; Buttar, Navtej S.; Michel, Wongkeesong Louis; Wang, Kenneth K.

    2014-01-01

    Objective. Guidelines on antiplatelet medication use during endoscopy are based on limited evidence. We investigate the risk of bleeding and ischemic events in patients undergoing endoscopic mucosal resection (EMR) of esophageal lesions in the setting of scheduled cessation and prompt resumption of clopidogrel. Design. Single centre retrospective review. Patients. Patients undergoing EMR of esophageal lesions. Interventions. Use of clopidogrel before EMR and resumption after EMR. Patients cease antiplatelets and anticoagulants 7 days before EMR and resume clopidogrel 2 days after EMR in average risk patients. Main Outcomes. Gastrointestinal bleeding (GIB) and ischemic events (IE) within 30 days of EMR. Results. 798 patients underwent 1716 EMR. 776 EMR were performed on patients on at least 1 antiplatelet/anticoagulant (APAC). 17 EMR were performed following clopidogrel cessation. There were 14 GIB and 2 IE. GIB risk in the setting of recent clopidogrel alone (0%) was comparable to those not on APAC (1.1%) (P = 1.0). IE risk on clopidogrel (6.3%) was higher than those not on APAC (0.1%) (P = 0.03). Limitations. Retrospective study. Conclusions. Temporary cessation of clopidogrel before EMR and prompt resumption is not associated with an increased risk of gastrointestinal bleeding but may be associated with increased ischemic events. PMID:24944824

  2. Prevalence of CYP2C19 variant alleles and pharmacodynamic variability of aspirin and clopidogrel in Native Americans.

    PubMed

    Oestreich, Julie H; Best, Lyle G; Dobesh, Paul P

    2014-03-01

    The prevalence of variant alleles of the CYP2C19 gene has been determined for most population groups, but not Native Americans. Furthermore, the overall effectiveness of clopidogrel and aspirin has not been well studied in Native Americans, although this group has high mortality rates for cardiovascular disease and diabetes. We recruited 50 volunteers from the Oglala Sioux Tribe with coronary artery disease taking aspirin and clopidogrel. Whole blood was collected for analysis using the VerifyNow P2Y12 and aspirin tests. Samples from the coronary artery disease patients and 50 additional tribal volunteers (n = 100 total) were genotyped for CYP2C19 variants *2, *3, and *17. The allele frequencies for CYP2C19*2 and CYP2C19*17 in the population group were 11% (95% CI 7%-16%) and 9% (95% CI 5%-13%), respectively. No subjects carried the CYP2C19*3 allele. The median PRU (P2Y12 reaction units) in the population group was 194 with wide variability (range 29-400). There was no significant effect of genotype on platelet aggregation as measured by the VerifyNow P2Y12 test (P = .77). The median ARU (aspirin reaction units) for the group was 437 (range 350-659), and 73% had aspirin reaction unit values <550. The prevalence of variant CYP2C19 alleles is low in Native Americans of the Oglala Sioux Tribe compared with certain HapMap populations. The variable response to aspirin and clopidogrel in the Oglala Sioux Tribe is consistent with reported values for other groups as measured by the VerifyNow assay (Accumetrics, San Diego, CA). © 2014.

  3. Impact of clopidogrel on bleeding complications and survival in off-pump coronary artery bypass grafting.

    PubMed

    Bittner, Hartmuth B; Lehmann, Sven; Rastan, Ardawan; Mohr, Friedrich W

    2012-03-01

    This study investigated the impact of preoperative clopidogrel on bleeding complications and survival during and after off-pump coronary artery bypass grafting (OPCABG) and assessed the possible role of the antifibrinolytic agent aprotinin for attenuating blood loss after clopidogrel exposure. Prospectively collected data of 753 consecutive adult patients undergoing OPCABG were retrospectively reviewed; 139 (18.5%) patients received clopidogrel preoperatively. Statistical methods used were student paired t-test, Mann-Whitney U, Kruskal-Wallis, chi-square analysis and Kaplan-Meier with log-rank analysis. Clopidogrel was associated with a significant increase in perioperative blood loss (P = 0.003) and more excessive postoperative haemorrhage (P = 0.04). Overall transfusion rates (P = 0.02) and the amount of administered blood products (P = 0.01) were also higher after clopidogrel exposure. Intraoperative aprotinin reduced postoperative bleeding significantly in patients administered clopidogrel [18.7% after 24 h (P = 0.006) and 15.2% after 48 h (P = 0.03)] and attenuated excessive postoperative haemorrhaging. Five-year survival was markedly improved in clopidogrel-treated patients. Preoperative clopidogrel exposure does increase perioperative blood loss and blood transfusion requirements in patients undergoing OPCABG but has an otherwise excellent safety profile with a 94% 5-year survival rate. Aprotinin attenuated this blood loss. Based on these results a recommendation to discontinue clopidogrel prior to coronary artery bypass grafting cannot be maintained, if OPCABG strategies are considered.

  4. Preoperative Use of Clopidogrel Does Not Affect Outcomes for Femoral Neck Fractures Treated With Hemiarthroplasty.

    PubMed

    Ghanem, Elie S; Richard, Raveesh D; Wingert, Nathaniel C H; Gotoff, James R; Graham, Jove H; Bowen, Thomas R

    2017-07-01

    The antiplatelet effect of clopidogrel on blood loss and perioperative complications after surgical intervention remains ambiguous. The purpose of this study was to determine if patients on clopidogrel before hemiarthroplasty for femoral neck fracture are predisposed to greater surgical bleeding and perioperative complications compared with those not taking clopidogrel before surgery. We conducted a review of our electronic medical record from 2006-2013 and identified 602 patients who underwent 623 hemiarthroplasty procedures for displaced femoral neck fracture, of which 54 cases (9%) were taking clopidogrel before hospital admission. Patient demographics and comorbidities, operative and surgical variables, and perioperative complications at 90 days were compared between the clopidogrel and nonclopidogrel user groups. The 2 groups of patients had similar baseline characteristics, but patients taking clopidogrel preoperatively were sicker with higher American Society of Anesthesiologists scores (P = .049) and age-adjusted Charlson index (P = .001). They also had a greater incidence of cerebrovascular disease (P = .01), chronic obstructive pulmonary disease (P = .03), diabetes (0.03), and malignancy (P < .001). There was no significant difference between the 2 patient groups with respect to 90-day postoperative medical readmissions (P = .85), surgical readmissions (P = .26), infection (P = .99), and mortality (P = .89). Patients taking clopidogrel who present with a displaced femoral neck fracture can safely undergo a hemiarthroplasty while actively on clopidogrel without an increase in medical or surgical complications and mortality. We do not recommend delaying surgical intervention until the antiplatelet effects of clopidogrel subside. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Gastroduodenal tolerance of 75 mg clopidogrel versus 325 mg aspirin in healthy volunteers. A gastroscopic study.

    PubMed

    Fork, F T; Lafolie, P; Tóth, E; Lindgärde, F

    2000-05-01

    Clopidogrel is a new antiplatelet agent that offers increased protection over aspirin in preventing vascular ischaemic events in patients with symptomatic atherosclerosis. In a large, randomized, international study of clopidogrel and aspirin (n = 19,185 patients) clopidogrel was associated with a lower incidence of gastrointestinal adverse events, including gastrointestinal haemorrhage and hospitalizations because of gastrointestinal haemorrhage. The aim of the study was to determine whether macroscopic differences in the gastric mucosa between aspirin- and clopidogrel-treated subjects could be detected by gastroscopy after short-term treatment. Thirty-six healthy volunteers were randomized in a double-blind, double-dummy, parallel design, to 75 mg/day of clopidogrel or 325 mg/day of aspirin for 8 days. Gastroscopy was performed at base line before administration of study drug and directly after treatment completion. Gastroduodenal effects were measured in accordance with a modified Lanza scale. At base line no difference between the groups was detected (median Lanza score, 0.0 in both groups). At the end of treatment the aspirin group showed a median score of 7.5, and the clopidogrel group showed an unchanged median score of 0.0 (P < 0.001). In the aspirin group 13 individuals reported 19 adverse events versus 8 individuals and 13 adverse events for clopidogrel, with approximately half of the adverse events being gastrointestinal in each group. No serious adverse events were reported. In contrast to aspirin, short-term treatment with clopidogrel does not induce macroscopic changes in the gastroduodenal mucosa. The study results show that in patients without gastroduodenal disease clopidogrel, but not aspirin, does not induce any gastroscopically evident erosions during short-term treatment.

  6. Prolonged application of clopidogrel reduces inflammation after percutaneous coronary intervention in the porcine model.

    PubMed

    Ayral, Yunus; Rauch, Ursula; Goldin-Lang, Petra; Stellbaum, Caroline; Deiner, Carolin; Schwimmbeck, Peter L; Schultheiss, Heinz-Peter; Pels, Klaus

    2007-01-01

    We determined the effect of prolonged treatment with clopidogrel on C-reactive protein (CRP) concentrations and blood thrombogenicity after percutaneous transluminal coronary angioplasty followed by intracoronary brachytherapy in the porcine model. ANIMAL MODEL: All 48 pigs received antiplatelet therapy, including aspirin (325 mg, daily) and clopidogrel (300 mg, loading dose) 1 day before PCI, followed by a daily dose of clopidogrel (75 mg/day) in addition to aspirin. During PCI, one of two balloon-injured arteries was randomly assigned to receive immediate radiation treatment. Animals were sacrificed after 24 h, 1 month, and 3 months post-PCI. The pigs, which were sacrificed 3 months post-PCI, were divided into two groups. The first group received clopidogrel in addition to aspirin for 3 months, and the second group received clopidogrel in addition to aspirin for only 1 month after PCI and then aspirin alone. Blood was taken from all pigs before intervention, immediately after intervention, and before sacrifice. Serum CRP was measured by enzyme-linked immunosorbent assay. To analyze the procoagulant effects of PCI on blood thrombogenicity, a one-stage clotting assay was performed. Clopidogrel treatment for 3 months reduced CRP levels more than did clopidogrel therapy for 1 month only at 3 months post-PCI (27.9+/-3.9 vs. 56.6+/-11.3 microg/ml; P=.019). Baseline CRP levels were found to be 50.4+/-4.8 microg/ml. Plasma clotting was not affected by prolonged clopidogrel therapy (322.8+/-59.3 s vs. 295.2+/-52.5 s; P=ns). Prolonged treatment with clopidogrel reduced CRP levels post-PCI.

  7. [Clopidogrel--proton pump inhibitors drug interaction: implications to clinical practice].

    PubMed

    Fontes-Carvalho, Ricardo; Albuquerque, Aníbal

    2010-10-01

    Recent studies have raised the concern that proton pump inhibitors (PPIs) could potentially interfere with clopidogrel antiplatelet effect. This association is frequent in clinical practice and is recommended by recent consensus guidelines in patients taking dual antiplatelet therapy to prevent gastrointestinal (GI) bleeding. Clopidogrel is a pro-drug which needs to be metabolized into its active metabolite, by cytochrome P450, especially by CYP2C19 isoenzyme. Various PPIs can inhibit CYP2C19, which could possibly decrease clopidogrel bioactivation process and, therefore, its antiplatelet effect. Various platelet function studies have shown that omeprazol can significantly decrease clopidogrel inhibitory effect on platelet P2Y12 receptor, leading to an increase in the number of patients who are "nonresponders" to clopidogrel. These pharmacokinetic studies also shown that this is not probably a class effect of PPIs, because they are metabolized to varying degrees by CYP2C19. The clinical impact of these observations remains uncertain, because various observational studies have shown conflicting results, and remains to demonstrate if PPIs can really increase the risk of cardiovascular events in patients taking clopidogrel. In this review we will discuss the pharmacokinetic basis underlying this drug interaction, the effect of different PPIs on platelet function tests and we will analyze in detail the potential clinical implications of using this association, both on cardiovascular and gastrointestinal events. Until further data is available, some clinical strategies can be recommended: (1) individual gastrointestinal risk assessment, with PPIs administration only to patients on dual anti-platelet therapy with additional GI risk factors; (2) preferential use of PPIs that have shown less interference with clopidogrel efficacy; (3) wide separation of PPI and clopidogrel dosing to minimize the risk of interaction (PPI may be given before breakfast and clopidogrel at

  8. Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo.

    PubMed

    Heim, Christian; Gebhardt, Julia; Ramsperger-Gleixner, Martina; Jacobi, Johannes; Weyand, Michael; Ensminger, Stephan M

    2016-05-01

    The anti-platelet drug clopidogrel has been shown to modulate adhesion molecule and cytokine expression, both playing an important role in the pathogenesis of atherosclerosis. The aim of this study was to investigate the impact of clopidogrel on the development and progression of atherosclerosis. ApoE(-/-) mice fed an atherogenic diet (cholesterol: 1 %) for 6 months received a daily dose of clopidogrel (1 mg/kg) by i.p. injection. Anti-platelet treatment was started immediately in one experimental group, and in another group clopidogrel was started 2 month after beginning of the atherogenic diet. Blood was analysed at days 30, 60 and 120 to monitor the lipid profile. After 6 months the aortic arch and brachiocephalic artery were analysed by Sudan IV staining for plaque size and by morphometry for luminal occlusion. Serum levels of various adhesion molecules were investigated by ELISA and the cellular infiltrate was analysed by immunofluorescence. After daily treatment with 1 mg/kg clopidogrel mice showed a significant reduction of atherosclerotic lesions in the thoracic aorta and within cross sections of the aortic arch [plaque formation 55.2 % (clopidogrel/start) vs. 76.5 % (untreated control) n = 8, P < 0.05]. After treatment with clopidogrel P-/E-selectin levels and cytokine levels of MCP-1 and PDGFβ were significantly reduced as compared to controls. The cellular infiltrate showed significantly reduced macrophage and T-cell infiltration in clopidogrel-treated animals. These results show that clopidogrel can effectively delay the development and progression of 'de-novo' atherosclerosis. However, once atherosclerotic lesions were already present, anti-platelet treatment alone did not result in reverse remodelling of these lesions.

  9. Clopidogrel-Associated Thrombotic Thrombocytopenic Purpura following Endovascular Treatment of Spontaneous Carotid Artery Dissection

    PubMed Central

    Rubano, Jerry A.; Chen, Kwan; Sullivan, Brianne; Vosswinkel, James A.; Jawa, Randeep S.

    2015-01-01

    Thrombotic thrombocytopenic purpura (TTP) is a life-threatening multisystem disease secondary to platelet aggregation. We present a patient who developed profound thrombocytopenia and anemia 8 days following initiation of therapy with clopidogrel after stent placement for carotid artery dissection. She did not have a disintegrin and metalloproteinase with thrombospondin domain 13 (ADAMTS 13) deficiency. Management included steroids and therapeutic plasma exchange. Clopidogrel has rarely been associated with TTP. Unlike other causes of acquired TTP, the diagnosis of early clopidogrel-associated TTP is largely clinical given the infrequent reduction in ADAMTS 13 activity. PMID:26623244

  10. Clopidogrel treatment during pregnancy: a case report and a review of literature.

    PubMed

    De Santis, Marco; De Luca, Carmen; Mappa, Ilenia; Cesari, Elena; Mazza, Andrea; Quattrocchi, Tomasella; Caruso, Alessandro

    2011-01-01

    Management of ischemic heart disease in pregnant women is still difficult, as there is little experience with many of the newer treatments such as clopidogrel. The safety of clopidogrel in pregnancy is unknown, especially in combination with aspirin. Its use during gestation has been described in a few case reports. We describe the case of a 36-year-old woman in her 9th week of pregnancy with a history of chronic hypertension, dyslipidemia and CAD, who required antiplatelet treatment. Clopidogrel and aspirin were administrated until one week before delivery and a healthy child was born at 36 weeks of pregnancy by caesarean section, without any complication.

  11. Safety and efficacy of minimal biliary sphincterotomy with papillary balloon dilation (m-EBS+EPBD) in patients using clopidogrel or anticoagulation

    PubMed Central

    Mok, Shaffer R. S.; Arif, Murtaza; Diehl, David L; Khara, Harshit S; Ho, Henry C; Elfant, Adam B

    2017-01-01

    Background and study aims Endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (EBS) or endoscopic papillary balloon dilation (EPBD) are common techniques of biliary decompression. Potential risks include gastrointestinal hemorrhage, which can be increased by antiplatelet agents, anticoagulants (AC) and/or novel oral anticoagulants (NOACs) (ie. apixaban, dabigatran and rivaroxaban). The study aim is to evaluate the safety/efficacy of an alternative technique, minimal-EBS plus EPBD (m-EBS + EPBD), in individuals for whom clopidogrel, AC, and/or NOACs cannot be interrupted due to high cardiovascular or thromboembolic risk. Patients and methods Patients undergoing m-EBS + EPBD while taking clopidogrel and/or AC were retrospectively evaluated at two United States tertiary care centers for efficacy, GIB and procedure-related, cardiovascular and thromboembolic adverse events (AE). Results Ninety-five patients were identified [55 = clopidogrel and 45 = AC (31.1 % NOACs)]. The main indication for ERCP was choledocholithiasis (34 %). 100 % clinical improvement and 97.9 % endoscopic success were found. The incidence of AE was 5.3 %. There was a 4.2 % incidence of gastrointestinal hemorrhage (2 cases requiring endoscopic intervention). Both severe gastrointestinal hemorrhages also experienced the cases of post-ERCP pancreatitis, and 2 /3 of cholangitis (all aspirin + AC). There was 1cardiovascular event (non-ST elevation myocardial infarction), and no thromboembolic events. Conclusions Minimal-EBS + EPBD is an effective and safe therapy with an incidence of gastrointestinal hemorrhage of 4.2 %, (2.1 % requiring endoscopic intervention), for patients on clopidogrel and/or AC, with a high risk for cardiovascular/thromboembolic events. PMID:28337485

  12. Platelet factor XIIIa release during platelet aggregation and plasma clot strength measured by thrombelastography in patients with coronary artery disease treated with clopidogrel.

    PubMed

    Kreutz, Rolf P; Owens, Janelle; Lu, Deshun; Nystrom, Perry; Jin, Yan; Kreutz, Yvonne; Desta, Zeruesenay; Flockhart, David A

    2015-01-01

    It has been estimated that up to half of circulating factor XIIIa (FXIIIa) is stored in platelets. The release of FXIIIa from platelets upon stimulation with adenosine diphosphate (ADP) in patients with coronary artery disease treated with dual antiplatelet therapy has not been previously examined. Samples from 96 patients with established coronary artery disease treated with aspirin and clopidogrel were examined. Platelet aggregation was performed by light transmittance aggregometry in platelet-rich plasma (PRP), with platelet-poor plasma (PPP) as reference, and ADP 5 µM as agonist. Kaolin-activated thrombelastography (TEG) was performed in citrate PPP. PRP after aggregation was centrifuged and plasma supernatant (PSN) collected. FXIIIa was measured in PPP and PSN. Platelet aggregation after stimulation with ADP 5 µM resulted in 24% additional FXIIIa release in PSN as compared to PPP (99.3 ± 27 vs. 80.3 ± 24%, p < 0.0001). FXIIIa concentration in PSN correlated with maximal plasma clot strength (TEG-G) (r = 0.48, p < 0.0001), but not in PPP (r = 0.15, p = 0.14). Increasing quartiles of platelet-derived FXIIIa were associated with incrementally higher TEG-G (p = 0.012). FXIIIa release was similar between clopidogrel responders and non-responders (p = 0.18). In summary, platelets treated with aspirin and clopidogrel release a significant amount of FXIIIa upon aggregation by ADP. Platelet-derived FXIIIa may contribute to differences in plasma TEG-G, and thus, in part, provide a mechanistic explanation for high clot strength observed as a consequence of platelet activation. Variability in clopidogrel response does not significantly influence FXIIIa release from platelets.

  13. [Comparative assessment of antiaggregant efficacy of acetylsalicylic acid and clopidogrel in peripheral atherosclerosis].

    PubMed

    Kuznetsov, M R; Sergeeva, N A; Koshkin, V M; Boldin, B V; Rodionov, S V; Virganskiĭ, A O; Kosykh, I V; Lisenkov, O P; Kuznetsova, V F

    2014-01-01

    Presented in the article are the results of studying antiaggregate activity of acetylsalicylic acid and clopidogrel in a total of 36 patients suffering from various-severity chronic arterial insufficiency of lower limbs on the background of atherosclerosis obliterans. The study was conducted prior to treatment for correct selection of a particular antiplatelet agent. The obtained results showed that clopidogrel was not always more efficient than acetylsalicylic acid, since there is individual sensitivity of each patients to a particular antiplatelet agent. Therefore, an individual approach is necessary to conservative therapy of arterial insufficiency of lower limbs. For some patients it is preferable to administer clopidogrel, for others - acetylsalicylic acid. In a series of cases combined treatment is justified, while some patients having low sensitivity to both acetylsalicylic acid and clopidogrel require careful selection of alternative agents influencing other thrombocyte receptors.

  14. Clopidogrel-Induced Thrombotic Thrombocytopenic Purpura–Hemolytic Uremic Syndrome After Coronary Artery Stenting

    PubMed Central

    Manor, Shawn M; Guillory, Gregory S; Jain, Suresh P

    2004-01-01

    The antiplatelet drug clopidogrel has largely replaced ticlopidine, due to an association between ticlopidine and thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP-HUS). Clopidogrel at first was thought to be void of this potentially fatal adverse effect, but recent case reports have called that assumption into question. Even with proper treatment (plasma exchange), TTP-HUS can persist for weeks. Clinicians should be aware of this possible adverse effect because prompt therapy is imperative for patients' survival. Earlier reports of clopidogrel-related TTP-HUS have involved patients who had received at least 72 hours of therapy. We describe a case of TTP-HUS in a patient who had received only a 300-mg loading dose of clopidogrel. PMID:15162901

  15. Implementation of Cell Samples as Controls in National Proficiency Testing for Clopidogrel Therapy-Related CYP2C19 Genotyping in China: A Novel Approach

    PubMed Central

    Zhang, Kuo; Wang, Lunan; Zhang, Rui; Xie, Jiehong; Li, Jinming

    2015-01-01

    Laboratories are increasingly requested to perform CYP2C19 genetic testing when managing clopidogrel therapy, especially in patients with acute coronary syndrome undergoing percutaneous coronary intervention. To ensure high quality molecular testing and ascertain that the referring clinician has the correct information for CYP2C19 genotype–directed antiplatelet therapy, a proficiency testing scheme was set up to evaluate the laboratory performance for the entire testing process. Proficiency panels of 10 cell samples encompassing the common CYP2C19 genetic polymorphisms were distributed to 62 participating laboratories for routine molecular testing and the responses were analyzed for accuracy of genotyping and the reporting of results. Data including the number of samples tested, the accreditation/certification status, and test methodology of each individual laboratory were also reviewed. Fifty-seven of the 62 participants correctly identified the CYP2C19 variants in all samples. There were six genotyping errors, with a corresponding analytical sensitivity of 98.5% (333/338 challenges; 95% confidence interval: 96.5–99.5%) and an analytic specificity of 99.6% (281/282; 95% confidence interval: 98.0–99.9%). Reports of the CYP2C19 genotyping results often lacked essential information. In conclusion, clinical laboratories demonstrated good analytical sensitivity and specificity; however, the pharmacogenetic testing community requires additional education regarding the correct reporting of CYP2C19 genetic test results. PMID:26218263

  16. VerifyNow and VASP phosphorylation assays give similar results for patients receiving clopidogrel, but they do not always correlate with platelet aggregation.

    PubMed

    Bidet, Audrey; Jais, Catherine; Puymirat, Etienne; Coste, Pierre; Nurden, Alan; Jakubowski, Joseph; Nurden, Paquita

    2010-01-01

    Point-of-care testing permits an evaluation of the efficacy of drugs used in the treatment of acute coronary syndromes (ACS). An increased risk of thrombosis after coronary stenting for ACS patients treated with aspirin and clopidogrel has been linked to high platelet reactivity and, for certain patients, poor drug response. The objective of our study was to compare the VerifyNow-P2Y12 device with the VASP (vasodilator-stimulated phosphoprotein) phosphorylation assay and ADP-induced platelet aggregation as assessed by light transmission aggregometry in a group of 81 ACS patients (100 tests) treated in our hospital. There was a good correlation between VerifyNow-P2Y12 and VASP especially during the chronic phase of one month or more after the ischemic event, whereas discordance was sometimes seen with platelet aggregometry. The rapidity and ease of use of the VerifyNow device suggests that it has a valuable place in point-of-care testing of ACS patients.

  17. Clopidogrel inhibits angiogenesis of gastric ulcer healing via downregulation of vascular endothelial growth factor receptor 2.

    PubMed

    Luo, Jiing-Chyuan; Peng, Yen-Ling; Chen, Tseng-Shing; Huo, Teh-Ia; Hou, Ming-Chih; Huang, Hui-Chun; Lin, Han-Chieh; Lee, Fa-Yauh

    2016-09-01

    Although clopidogrel does not cause gastric mucosal injury, it does not prevent peptic ulcer recurrence in high-risk patients. We explored whether clopidogrel delays gastric ulcer healing via inhibiting angiogenesis and to elucidate the possible mechanisms. Gastric ulcers were induced in Sprague Dawley rats, and ulcer healing and angiogenesis of ulcer margin were compared between clopidogrel-treated rats and controls. The expressions of the proangiogenic growth factors and their receptors including basic fibroblast growth factor (bFGF), bFGF receptor (FGFR), vascular endothelial growth factor (VEGF), VEGFR1, VEGFR2, platelet-derived growth factor (PDGF)A, PDGFB, PDGFR A, PDGFR B, and phosphorylated form of mitogenic activated protein kinase pathways over the ulcer margin were compared via western blot and reverse transcription polymerase chain reaction. In vitro, human umbilical vein endothelial cells (HUVECs) were used to elucidate how clopidogrel inhibited growth factors-stimulated HUVEC proliferation. The ulcer sizes were significantly larger and the angiogenesis of ulcer margin was significantly diminished in the clopidogrel (2 and 10 mg/kg/d) treated groups. Ulcer induction markedly increased the expression of phosphorylated form of extracellular signal-regulated kinase (pERK), FGFR2, VEGF, VEGFR2, and PDGFRA when compared with those of normal mucosa. Clopidogrel treatment significantly decreased pERK, FGFR2, VEGF, VEGFR2, and PDGFRA expression at the ulcer margin when compared with those of the respective control group. In vitro, clopidogrel (10(-6)M) inhibited VEGF-stimulated (20 ng/mL) HUVEC proliferation, at least, via downregulation of VEGFR2 and pERK. Clopidogrel inhibits the angiogenesis of gastric ulcer healing at least partially by the inhibition of the VEGF-VEGFR2-ERK signal transduction pathway. Copyright © 2015. Published by Elsevier B.V.

  18. Effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel in rats.

    PubMed

    Chen, Xinmeng; Jin, Jing; Chen, Yaobin; Peng, Lingling; Zhong, Guoping; Li, Jiali; Bi, Huichang; Cai, Yefeng; Huang, Min

    2015-01-01

    Erigeron breviscapus (Vant.) Hand-Mazz, a traditional Chinese medicine, is often co-prescribed with clopidogrel for the treatment of ischemic vascular diseases. Scutellarin is the representative bioactive flavonoid isolated from this herb. The aim of this study was to explore the effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel. The in vitro studies using rat liver microsomes showed that scutellarin significantly inhibited the metabolism of clopidogrel. The IC50 value was 2.1 µM. Ten male rats were employed to investigate the effect of scutellarin on the pharmacokinetics of clopidogrel in vivo. After pretreatment with scutellarin, there were significant increases in the AUC0-∞ (from 0.9 ± 0.4 to 1.7 ± 0.6 ng/ml h; p <0.05) and Cmax (from 0.4 ± 0.1 to 0.9 ± 0.1 ng/ml; p <0.05) of clopidogrel. The pharmacokinetic data for clopidogrel active metabolite showed significant decreases in AUC0-∞ (18.2 ± 5.6 to 11.4 ± 3.7 ng/ml h; p <0.05) and Cmax (from 8.2 ± 1.2 to 4.3 ± 0.3 ng/ml; p <0.05) after pretreatment with scutellarin. Collectively, the metabolism and pharmacokinetics of clopidogrel were significantly affected by scutellarin. This study indicated that potential herb-drug interaction between scutellarin and clopidogrel should be taken into consideration in clinical use.

  19. Trends in the coprescription of proton pump inhibitors with clopidogrel: an ecological analysis

    PubMed Central

    Juurlink, David N.; Gomes, Tara; Paterson, J. Michael; Hellings, Chelsea; Mamdani, Muhammad M.

    2015-01-01

    Background: In early 2009, 2 observational studies and a US Food and Drug Administration (FDA) advisory addressed the drug interaction between proton pump inhibitors (PPIs) and clopidogrel. One study suggested that pantoprazole could be used safely in this setting, whereas the other study and the FDA advisory did not distinguish among PPIs. We examined trends in PPI prescribing among clopidogrel recipients in the period following these events. Methods: We conducted a population-based time series analysis of Ontario residents aged 66 years or older for whom clopidogrel was prescribed between Apr. 1, 1999, and Sept. 30, 2013. We determined the proportion of clopidogrel recipients dispensed a PPI during each quarter and the proportions who received pantoprazole or other PPIs. The outcome of interest was change in the use of pantoprazole. Results: In the final quarter of 2008, pantoprazole represented 23.7% of all PPI prescriptions dispensed to patients receiving clopidogrel. Following the publications and FDA advisory in early 2009, pantoprazole use increased substantially. By the end of 2009, this medication accounted for 52.5% of all PPI prescriptions issued to patients receiving clopidogrel; by the end of the study period, it accounted for 71.0% of all PPI prescriptions dispensed to such patients (p < 0. 001). We also observed a modest drop in overall PPI use among clopidogrel recipients beginning in early 2009. Interpretation: In 2009, the prescribing of PPIs with clopidogrel changed substantially in Ontario, with pantoprazole rapidly becoming the most commonly prescribed agent in its class. However, a modest decline in overall PPI use also occurred that may reflect suboptimal translation of emerging drug safety information to clinical practice. PMID:26770965

  20. [ASA and clopidogrel for urological operations. Perioperative management].

    PubMed

    Fischer, C; Lümmen, G

    2013-11-01

    In a systematic overview and meta-analysis among more than 50,000 patients at risk for coronary artery disease, not adhering to or discontinuing aspirin (acetylsalicylic acid, ASA) was associated with a significantly increased risk of non-fatal myocardial infarction or death. Withdrawal of low dose aspirin was correlated with a threefold increase in the risk of adverse cardiovascular events. This risk is present irrespective of the length of time patients had been taking low dose aspirin. Therefore, in patients on chronic low dose aspirin for secondary prevention of cardiovascular disease, aspirin should never be discontinued. In the few available studies in urological surgery the increase in bleeding does not translate into a significant increase in specific morbidity. This seems to be also true for the additional administration of clopidogrel to aspirin. Nevertheless, in patients with drug-eluting stents and dual antiplatelet therapy, urologists should ensure a multidisciplinary management of the perioperative course.

  1. Comparative risk of ischemic stroke among users of clopidogrel together with individual proton pump inhibitors

    PubMed Central

    Bilker, Warren B.; Brensinger, Colleen M.; Flockhart, David A.; Freeman, Cristin P.; Kasner, Scott E.; Kimmel, Stephen E.; Hennessy, Sean

    2015-01-01

    Background and Purpose There is controversy and little information concerning whether individual proton pump inhibitors (PPIs) differentially alter the effectiveness of clopidogrel in reducing ischemic stroke risk. We therefore aimed to elucidate the risk of ischemic stroke among concomitant users of clopidogrel and individual PPIs. Methods We conducted a propensity score-adjusted cohort study of adult new users of clopidogrel, using 1999–2009 Medicaid claims from 5 large states. Exposures were defined by prescriptions for esomeprazole, lansoprazole, omeprazole, rabeprazole and pantoprazole—with pantoprazole serving as the referent. The endpoint was hospitalization for acute ischemic stroke, defined by International Classification of Diseases 9th Revision Clinical Modification codes in the principal position on inpatient claims, within 180 days of concomitant therapy initiation. Results Among 325,559 concomitant users of clopidogrel and a PPI, we identified 1,667 ischemic strokes for an annual incidence of 2.4% (95% confidence interval: 2.3–2.5). Adjusted hazard ratios for ischemic stroke vs. pantoprazole were: 0.98 (0.82–1.17) for esomeprazole; 1.06 (0.92–1.21) for lansoprazole; 0.98 (0.85–1.15) for omeprazole; and 0.85 (0.63–1.13) for rabeprazole. Conclusions PPIs of interest did not increase the rate of ischemic stroke among clopidogrel users when compared to pantoprazole, a PPI thought to be devoid of the potential to interact with clopidogrel. PMID:25657176

  2. How to test the effect of aspirin and clopidogrel in patients on dual antiplatelet therapy?

    PubMed

    Bagoly, Zsuzsa; Homoródi, Nóra; Kovács, Emese Gyöngyvér; Sarkady, Ferenc; Csiba, László; Édes, István; Muszbek, László

    2016-01-01

    Dual antiplatelet therapy with clopidogrel and aspirin is frequently used for the prevention of recurrent ischemic events. Various laboratory methods are used to detect the effect of these drugs administered in monotherapy, however their value in dual therapy has not been explored. Here, we determined which methods used for testing the effect of clopidogrel or aspirin are influenced by the other antiplatelet agent. One arm of the study included 53 ischemic stroke patients being on clopidogrel monotherapy showing effective inhibition of the P2Y12 ADP receptor. Laboratory tests routinely used for the detection of aspirin resistance (arachidonic acid (AA)-induced platelet aggregation/secretion, AA-induced thromboxane B2 (TXB2) production in platelet-rich plasma and VerifyNow Aspirin assay) were carried out on samples obtained from these patients. The other arm of the study involved 52 patients with coronary artery disease being on aspirin monotherapy. Methods used for testing the effect of clopidogrel (ADP-induced platelet aggregation and secretion, flow cytometric analysis of vasodilator-stimulated phosphoprotein (VASP) phosphorylation and a newly developed P2Y12-specific platelet aggregation (ADP[PGE1] test)) were performed on samples obtained from these patients. Clopidogrel monotherapy significantly inhibited AA-induced platelet aggregation and secretion, moreover, AA-induced TXB2 production was also significantly decreased. VASP phosphorylation and AA-induced platelet aggregation showed fair correlation in patients taking clopidogrel only. Clopidogrel did not inhibit the VerifyNow Aspirin test significantly. Aspirin monotherapy influenced ADP-induced platelet aggregation and secretion, but did not have an effect on VASP phosphorylation and on the ADP[PGE1] platelet aggregation test.

  3. A comparison of INNOVANCE® PFA P2Y and VerifyNow P2Y12 assay for the assessment of clopidogrel resistance in patients undergoing percutaneous coronary intervention.

    PubMed

    Jang, Jiyoung; Lim, Jihyang; Chang, Kiyuk; Kim, Yonggoo; Kim, Myungshin; Park, Hae Il; Kim, Jayoung; Shin, Soyoung

    2012-07-01

    VerifyNow P2Y12 is commonly used to measure responsiveness to clopidogrel. We sought to compare the results obtained from novel INNOVANCE® PFA P2Y and VerifyNow P2Y12 assay to assess the clopidogrel resistance in patients undergoing percutaneous coronary intervention. A total of 255 patients undergoing percutaneous coronary intervention, preliminarily treated with 100 mg/day of aspirin followed by coadministration of clopidogrel (loading dose, 600 mg; maintenance dose, 75 mg/day), were enrolled in this study. Platelet aggregation was measured by INNOVANCE® PFA P2Y and VerifyNow P2Y12. INNOVANCE® PFA P2Y and VerifyNow P2Y12 assay showed moderate correlations with INNOVANCE® PFA P2Y vs. VerifyNow%inhibition: r = 0.412, P < 0.0001; INNOVANCE® PFA P2Yvs.VerifyNow P2Y12 reaction units (PRU): r = -0.402, P < 0.0001. The agreement between INNOVANCE® PFA P2Y and VerifyNow%inhibition was 85% and that of INNOVANCE® PFA P2Y and VerifyNow PRU was 79%. The k statistics between INNOVANCE® PFA P2Y and VerifyNow%inhibition and PRU were 0.52 and 0.44, respectively. The sensitivity of INNOVANCE® PFA P2Y in detecting clopidogrel resistance is comparable to that of VerifyNow P2Y12 assay. As the PFA-100® system is already widely used, the new test cartilage may be a useful tool for the assessment of clopidogrel effects. Additional clinical correlation studies are required to validate the effectiveness of INNOVANCE® PFA P2Y in predicting long-term clinical outcomes. © 2012 Wiley Periodicals, Inc.

  4. Changes in Practice Patterns of Clopidogrel in Combination with Proton Pump Inhibitors after an FDA Safety Communication

    PubMed Central

    Guérin, Annie; Mody, Reema; Carter, Valerie; Ayas, Charles; Patel, Haridarshan; Lasch, Karen; Wu, Eric

    2016-01-01

    Objectives In 2009, the FDA issued a warning that omeprazole–a proton pump inhibitor (PPI)–reduces the antithrombotic effect of clopidogrel by almost half when taken concomitantly. This study aims to analyze the impact of the FDA Safety Communications on prescribing clopidogrel together with PPIs. Methods This retrospective study identified clopidogrel users from the Truven Health Analytics MarketScan Databases (01/2006–12/2012). Rates of clopidogrel-PPI combination therapy were estimated in 6-month intervals for patients with ≥1 clopidogrel prescription fill, then were analyzed pre- and post-safety communication (11/17/2009). Analyses were also conducted by grouping PPIs into CYP2C19 inhibitors (omeprazole and esomeprazole) and CYP2C19 non-inhibitors (pantoprazole, lansoprazole, dexlansoprazole, and rabeprazole). Results Overall, 483,074 patients met the selection criteria; of these, 157,248 used a clopidogrel-PPI combination. On average, 30.5% of patients in the pre- and 19.9% in the post-communication period used a clopidogrel-PPI combination therapy. Among clopidogrel users, the probability of using clopidogrel-PPI combinations fell by over 40% in the post-communication period (OR = 0.57; p<0.001); the proportion of patients using esomeprazole fell from 12.9% to 5.3%, and the proportion using omeprazole fell from 10.1% to 6.3%. Among combination therapy users, the probability of patients using a combination with a CYP2C19 inhibitor decreased by 53% (OR = 0.47; p<0.001); however, 31.5% of patients were still prescribed a clopidogrel-PPI combination therapy. Trends were similar for all and newly treated patients, regardless of clopidogrel indication and physician specialty. Conclusions The FDA Safety Communication resulted in a reduction in the number of patients undergoing combination therapy; however approximately one-third of patients still used combination therapy post-communication. PMID:26727382

  5. Protocol for the comparison of triflusal and clopidogrel in secondary prevention of stroke based on cytochrome P450 2C19 genotyping (MASETRO study): A multicenter, randomized, open-label, parallel-group trial.

    PubMed

    Han, Sang Won; Kim, Yong-Jae; Ahn, Seong Hwan; Seo, Woo-Keun; Yu, Sungwook; Oh, Seung-Hun; Kim, Youn Nam; Lee, Kyung-Yul

    2016-06-01

    The antiplatelet effect of clopidogrel is reportedly influenced by cytochrome P450 2C19 (CYP2C19) polymorphisms. However, there is no data concerning the relationship between stroke recurrence and CYP2C19 polymorphisms in patients treated with clopidogrel for secondary prevention of ischemic stroke. Triflusal may be an alternative therapy for clopidogrel in patients with poor genotype. The Comparison of Triflusal and Clopidogrel Effects in Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping (MAESTRO) study will investigate the effect of antiplatelet agents based on CYP2C19 polymorphisms in secondary prevention of ischemic stroke. Assuming that 55% of patients belong to the poor genotype group, the required sample size is 1080 patients with at least 24 months of follow-up. This study is designed as a prospective, multicenter, randomized, parallel-group, open-label, and blind genotype trial. Patients who experience their first non-cardiogenic ischemic stroke within 30 days prior to screening are eligible. Patients received 300 mg triflusal twice a day or 75 mg clopidogrel once daily during the trial. The study is registered with ClinicalTrials.gov (NCT01174693). The primary outcome is recurrent ischemic stroke or hemorrhagic stroke. Secondary outcomes consist of composite major vascular events including stroke, myocardial infarction, coronary revascularization, or vascular death. Personalized medicine may be essential for patients according to individual drug metabolism abilities. MAESTRO is the first prospective study designed to evaluate the effect of CYP2C19 polymorphism in secondary stroke prevention and will resolve several questions regarding preventive antiplatelet agents for recurrent stroke. © 2016 World Stroke Organization.

  6. Evaluation of TV commercials using neurophysiological responses.

    PubMed

    Yang, Taeyang; Lee, Do-Young; Kwak, Youngshin; Choi, Jinsook; Kim, Chajoong; Kim, Sung-Phil

    2015-04-24

    In recent years, neuroscientific knowledge has been applied to marketing as a novel and efficient means to comprehend the cognitive and behavioral aspects of consumers. A number of studies have attempted to evaluate media contents, especially TV commercials using various neuroimaging techniques such as electroencephalography (EEG). Yet neurophysiological examination of detailed cognitive and affective responses in viewers is still required to provide practical information to marketers. Here, this study develops a method to analyze temporal patterns of EEG data and extract affective and cognitive indices such as happiness, surprise, and attention for TV commercial evaluation. Twenty participants participated in the study. We developed the neurophysiological indices for TV commercial evaluation using classification model. Specifically, these model-based indices were customized using individual EEG features. We used a video game for developing the index of attention and four video clips for developing indices of happiness and surprise. Statistical processes including one-way analyses of variance (ANOVA) and the cross validation scheme were used to select EEG features for each index. The EEG features were composed of the combinations of spectral power at selected channels from the cross validation for each individual. The Fisher's linear discriminant classifier (FLDA) was used to estimate each neurophysiological index during viewing four different TV commercials. Post hoc behavioral responses of preference, short-term memory, and recall were measured. Behavioral results showed significant differences for all preference, short-term memory rates, and recall rates between commercials, leading to a 'high-ranked' commercial group and a 'low-ranked' group (P < 0.05). Neural estimation of happiness results revealed a significant difference between the high-ranked and the low-ranked commercials in happiness index (P < 0.01). The order of rankings based on happiness and

  7. Evaluation of allergic response using dynamic thermography

    NASA Astrophysics Data System (ADS)

    Rokita, E.; Rok, T.; Tatoń, G.

    2015-03-01

    Skin dynamic termography supplemented by a mathematical model is presented as an objective and sensitive indicator of the skin prick test result. Termographic measurements were performed simultaneously with routine skin prick tests. The IR images were acquired every 70 s up to 910 s after skin prick. In the model histamine is treated as the principal mediator of the allergic reaction. Histamine produces vasolidation and the engorged vessels are responsible for an increase in skin temperature. The model parameters were determined by fitting the analytical solutions to the spatio-temporal distributions of the differences between measured and baseline temperatures. The model reproduces experimental data very well (coefficient of determination = 0.805÷0.995). The method offers a set of parameters to describe separately skin allergic reaction and skin reactivity. The release of histamine after allergen injection is the best indicator of allergic response. The diagnostic parameter better correlates with the standard evaluation of a skin prick test (correlation coefficient = 0.98) than the result of the thermographic planimetric method based on temperature and heated area determination (0.81). The high sensitivity of the method allows for determination of the allergic response in patients with the reduced skin reactivity.

  8. Point-of-care measurements of platelet inhibition after clopidogrel loading in patients with acute coronary syndrome: comparison of generic and branded clopidogrel bisulfate.

    PubMed

    Seo, Kyoung-Woo; Tahk, Seung-Jea; Yang, Hyoung-Mo; Yoon, Myeong-Ho; Shin, Joon-Han; Choi, So-Yeon; Lim, Hong-Seok; Hwang, Gyo-Seung; Choi, Byoung-Joo; Park, Jin-Sun; Shin, Jeoung-Sook; Lee, You-Hong; Choi, Yong-Woo; Park, Se-Jun; Jin, Xiong-Jie

    2014-11-01

    Platelet-function suppression with antiplatelet therapy is effective in preventing and treating cardiovascular disease. Clopidogrel is a thienopyridine derivative that blocks platelet activation by adenosine diphosphate receptor binding. This study demonstrates the effects of generic clopidogrel bisulfate in comparison to branded clopidogrel bisulfate in patients with acute coronary syndromes. This prospective, 2-arm, single-center, open-label trial used 1:1 randomization to assign patients to receive generic or branded clopidogrel bisulfate. Patients with unstable angina or non-ST-segment elevation myocardial infarction and scheduled to undergo coronary angiography were enrolled. Platelet function was measured with a P2Y12 assay and reported in P2Y12 reaction units (PRU) and aspirin reaction units (ARU) after randomization. Platelet function was measured at 2, 4, 8, and 24 hours after 600-mg clopidogrel loading. The clinical outcome was checked at 1 month after coronary angiography. Ninety-five patients were enrolled and randomized to the generic or branded group. Ninety patients (62 men [69%], 28 women [31%]; mean age, 58 years) completed the study protocol. The clinical characteristics were similar between the 2 groups. The difference in the baseline PRU measurements between the generic and branded groups was not significant (274.8 [59.7] vs 285.4 [62.4], respectively; P = 0.414). There were significant differences in 2-hour PRU (231.1 [71.3] vs 266.9 [67.4]; P = 0.017) and 4-hour PRU (227.3 [80.4] vs 265.7 [71.0]; P = 0.020); however, 24-hour PRU (200.5 [82.1] vs 220.6 [75.8]; P = 0.253) was similar. No death, myocardial infarction, target lesion revascularization, stent thrombosis, or Thrombolysis in Myocardial Infarction-defined major bleeding complications were reported during in-hospital stay or 1-month follow-up. In patients with ACS, loading of generic clopidogrel bisulfate was associated with an antiplatelet effect comparable to that of branded

  9. Temporal trends and patterns of early clopidogrel use across the spectrum of acute coronary syndromes.

    PubMed

    Rao, Rajeev V; Goodman, Shaun G; Yan, Raymond T; Spencer, Frederick A; Fox, Keith A; DeYoung, J Paul; Rose, Barry; Grondin, François R; Gallo, Richard; Gore, Joel M; Yan, Andrew T

    2009-04-01

    Randomized trials have established efficacy of clopidogrel in various types of acute coronary syndromes (ACS). The objective of this study was to examine the temporal trends and patterns of early clopidogrel use (within the first 24 hours of hospitalization) across the spectrum of patients with ACS in Canada. Using the multinational, prospective GRACE (Global Registry of Acute Coronary Events) and GRACE(2), we identified 11,177 patients who were admitted for ACS from January 2003 to December 2007 in Canada. Demographic information, clinical features, and treatment were recorded. We examined the early use of clopidogrel over time and in relation to the type of ACS, clinical features on presentation, and the mode of reperfusion therapy. Of the 11,177 patients with ACS, 3,091 (27.7%) had ST-elevation myocardial infarction (STEMI), 5,194 (46.5%) had non-STEMI, and 2,892 (25.9%) had unstable angina; the rates of early clopidogrel administration were 63.0%, 66.6%, and 57.2%, respectively (P < .001). Overall, there was a significant increase in clopidogrel use over the period studied (P for trend < .001). In patients with non-ST-elevation ACS (non-STEMI and unstable angina), clopidogrel use was higher among those with positive cardiac biomarkers compared to those without (67.1% vs 59.8%, P < .001) but similar in the groups with and without ST deviation. There was an inverse relationship between GRACE risk score and rates of early clopidogrel administration. In patients with STEMI receiving fibrinolytic therapy, only 55.7% of patients <65 years old received clopidogrel compared with 47.0% and 42.6% of patients 65 to 74 and >75 years old, respectively (P for trend < .001). Although early use of clopidogrel therapy has increased over time across the spectrum of ACS, a significant proportion of eligible patients still do not receive this evidence-based therapy. There is a need to optimize the use of proven antiplatelet therapies to improve clinical outcome.

  10. Clopidogrel reduces migraine with aura after transcatheter closure of persistent foramen ovale and atrial septal defects

    PubMed Central

    Wilmshurst, P T; Nightingale, S; Walsh, K P; Morrison, W L

    2005-01-01

    Objective: To report the clinical events leading to alteration of an anticoagulation regimen for patients undergoing transcatheter closure of an atrial shunt and how this affected migraine symptoms after the closure procedure. Method: Audit of a change of anticoagulant regimen. Results: In the first few weeks after a closure procedure migraine frequency and severity increased despite treatment with aspirin for six months in 71 patients. Severe attacks of migraine with aura, including status migrainosus, in the first few weeks after transcatheter closure were terminated by addition of clopidogrel to aspirin treatment. Therefore, the anticoagulant regimen was changed with addition of clopidogrel for the first month after the closure procedure (90 procedures in 89 patients). Fewer patients had migraine with aura in the first month after transcatheter closure when taking the combination of clopidogrel and aspirin compared with aspirin alone (11 of 90 (12.2%) v 30 of 71 (42.3%), p < 0.001). Episodes of migraine with aura were more severe and more frequent in patients taking aspirin alone. Conclusion: The combination of clopidogrel for four weeks and aspirin for six months is superior to aspirin alone for six months for preventing migraine with aura after transcatheter closure of an atrial shunt. This beneficial effect of a powerful inhibitor of platelet aggregation suggests that platelets may have a role in pathogenesis of migraine. This may be because of an effect on serotonin stores. Whether clopidogrel has a role in treatment of migraine in other clinical situations requires investigation. PMID:16103551

  11. A retrospective review of clopidogrel as primary therapy for migraineurs with right to left shunt lesions.

    PubMed

    Spencer, Barbara T; Qureshi, Yasir; Sommer, Robert J

    2014-10-01

    The association of patient foramen ovale (PFO) and migraine headache (migraine) with aura (MA) is well established. Current research suggests a mechanistic link between platelet activation, paradoxical embolization and migraine in some patients. Clopidogrel, a platelet inhibitor, was added to existing migraine therapy, as a 4-week open-label trial in 15 women, aged 16-56 years, with severe migraine and documented right to left shunt (RLS). 13/15 had > 50% reduction or complete elimination of migraine symptoms. After completing the trial period, five responders remain on clopidogrel with ongoing benefit at 11.9 ± 4.5 months (6.5-20), one stopped clopidogrel because of side effects. Nine other responders underwent PFO closure and clopidogrel discontinuation. Eight of nine have had ongoing benefit. Clopidogrel may have a primary prophylactic role in migraine/RLS patients, but may also help select candidates who would benefit from PFO closure. A randomized clinical trial is being established. © International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  12. [Identification of the polymorphs of clopidogrel bisulfate based on the steric morphology parameters of crystals].

    PubMed

    Chen, Long; Wang, Liu-yi; Yin, Xian-zhen; Wang, Jin-can; Liu, Rui-hao; Wang, Dan; Li, Hai-yan; Zhu, Wei-feng; Zhang, Ji-wen

    2013-09-01

    The crystal form of solid substance had intrinsic correlation with its three dimensional crystal morphology. Based on the characterization of the three dimensional crystal morphology of clopidogrel bisulfate, this research is to establish a model based on the three dimensional morphological parameters. The granular samples composed of polymorphs of clopidogrel bisulfate and microcrystalline cellulose (MCC) were scanned by synchrotron radiation X-ray microscopic CT technology (SR-microCT) and the three dimensional structural models for which were constructed. Seven groups of three dimensional morphological parameters were calculated. Finally, the mathematical model was established with the multi-layer perception (MLP) artificial neutral network methods to identify and predict the polymorphs of clopidogrel bisulfate. The success rate of the model prediction for the polymorphs of clopidogrel bisulfate was 92.7% and the area under the ROC curve was 96.2%. The polymorphs of drugs could be identified and predicted through the numerical description of the three dimensional morphology. The volume, number of the vertices and the surface area were the major determinants for the identification of the polymorphs of clopidogrel bisulfate.

  13. Quantitative Analysis of Clopidogrel Bisulphate and Aspirin by First Derivative Spectrophotometric Method in Tablets

    PubMed Central

    Game, Madhuri D.; Gabhane, K. B.; Sakarkar, D. M.

    2010-01-01

    A simple, accurate and precise spectrophotometric method has been developed for simultaneous estimation of clopidogrel bisulphate and aspirin by employing first order derivative zero crossing method. The first order derivative absorption at 232.5 nm (zero cross point of aspirin) was used for clopidogrel bisulphate and 211.3 nm (zero cross point of clopidogrel bisulphate) for aspirin.Both the drugs obeyed linearity in the concentration range of 5.0 μg/ml to 25.0 μg/ml (correlation coefficient r2<1). No interference was found between both determined constituents and those of matrix. The method was validated statistically and recovery studies were carried out to confirm the accuracy of the method. PMID:21969765

  14. Comparison of antiplatelet effect and tolerability of clopidogrel resinate with clopidogrel bisulfate in patients with coronary heart disease (CHD) or CHD-equivalent risks: a phase IV, prospective, double-dummy, parallel-group, 4-week noninferiority trial.

    PubMed

    Suh, Jung-Won; Seung, Ki-Bae; Gwak, Chung-Hwan; Kim, Kwon-Sam; Hong, Soon-Jun; Park, Tae-Ho; Kim, Sang-Hyun; Choi, Young-Jin; Joo, Seung-Jea; Tahk, Seung-Jea; Kim, Hyo-Soo

    2011-08-01

    Clopidogrel resinate is a resinate complex of (+)-clopidogrel optical isomer, wherein the (+)-clopidogrel isomer binds to a water-soluble cation exchange resin via sulfonic acid groups. It was approved by the Korean Food and Drug Administration on the basis of a Phase I study that demonstrated the bioequivalence of clopidogrel resinate and clopidogrel bisulfate. However, there are no available data regarding efficacy and tolerability in patients with vascular disease. The goal of this study was to investigate the antiplatelet efficacy and tolerability of clopidogrel resinate in patients with coronary heart disease (CHD) or CHD-equivalent risks. This study was a Phase IV, randomized, double-blind, double-dummy, parallel-group, noninferiority trial. We prospectively recruited patients in 10 centers between March 2008 and July 2008. Patients who had documented CHD or CHD-equivalent risks were randomly assigned to 1 of 3 groups: group A, aspirin (100 mg) + clopidogrel bisulfate placebo + clopidogrel resinate placebo; group B, aspirin (100 mg) + clopidogrel bisulfate placebo + clopidogrel resinate (75 mg); or group C, aspirin (100 mg) + clopidogrel bisulfate (75 mg) + clopidogrel resinate placebo. The primary outcome was the percent P2Y(12) inhibition after medication, assessed by using a point-of-care assay. If the 1-sided 90% upper confidence limit for the difference was less than the prespecified delta value (-5.7), clopidogrel resinate would be considered noninferior to clopidogrel bisulfate. The secondary outcome, the prevalence of adverse events (AEs) associated with study medications, was assessed at each visit by direct interview. A total of 314 patients (mean [SD] age, 62.2 [9.0] years; male 63.7%; weight, 67.3 [13.6] kg [range, 45-102 kg]; all Asian) were enrolled, and 287 patients finished the study (group A, n = 97; group B, n = 90; and group C, n = 100). Eight patients took no study medications and were excluded from the tolerability and efficacy analyses

  15. High Platelet Reactivity in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: Randomised Controlled Trial Comparing Prasugrel and Clopidogrel

    PubMed Central

    Geisler, Tobias; Booth, Jean; Tavlaki, Elli; Karathanos, Athanasios; Müller, Karin; Droppa, Michal; Gawaz, Meinrad; Yanez-Lopez, Monica; Davidson, Simon J.; Stables, Rod H.; Banya, Winston; Zaman, Azfar; Flather, Marcus; Dalby, Miles

    2015-01-01

    Background Prasugrel is more effective than clopidogrel in reducing platelet aggregation in acute coronary syndromes. Data available on prasugrel reloading in clopidogrel treated patients with high residual platelet reactivity (HRPR) i.e. poor responders, is limited. Objectives To determine the effects of prasugrel loading on platelet function in patients on clopidogrel and high platelet reactivity undergoing percutaneous coronary intervention for acute coronary syndrome (ACS). Patients Patients with ACS on clopidogrel who were scheduled for PCI found to have a platelet reactivity ≥40 AUC with the Multiplate Analyzer, i.e. “poor responders” were randomised to prasugrel (60 mg loading and 10 mg maintenance dose) or clopidogrel (600 mg reloading and 150 mg maintenance dose). The primary outcome measure was proportion of patients with platelet reactivity <40 AUC 4 hours after loading with study medication, and also at one hour (secondary outcome). 44 patients were enrolled and the study was terminated early as clopidogrel use decreased sharply due to introduction of newer P2Y12 inhibitors. Results At 4 hours after study medication 100% of patients treated with prasugrel compared to 91% of those treated with clopidogrel had platelet reactivity <40 AUC (p = 0.49), while at 1 hour the proportions were 95% and 64% respectively (p = 0.02). Mean platelet reactivity at 4 and 1 hours after study medication in prasugrel and clopidogrel groups respectively were 12 versus 22 (p = 0.005) and 19 versus 34 (p = 0.01) respectively. Conclusions Routine platelet function testing identifies patients with high residual platelet reactivity (“poor responders”) on clopidogrel. A strategy of prasugrel rather than clopidogrel reloading results in earlier and more sustained suppression of platelet reactivity. Future trials need to identify if this translates into clinical benefit. Trial Registration ClinicalTrials.gov NCT01339026 PMID:26317618

  16. Prevalence of CYP2C19 alleles, pharmacokinetic and pharmacodynamic variation of clopidogrel and prasugrel in Bangladeshi population.

    PubMed

    Bin Sayeed, Muhammad Shahdaat; Hasan Apu, Mohd Nazmul; Munir, Maliha Tabassum; Ahmed, Maizbha Uddin; Islam, Mohammad Safiqul; Haq, M Maksumul; Ahsan, Chowdhury H; Rashid, M A; Shin, Jae Gook; Hasnat, Abul

    2015-05-01

    The extent to which cytochrome P450 (CYP) 2C19 genotype influences the effectiveness of clopidogrel remains uncertain due to considerable heterogeneity between studies. We used the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method for genotyping loss of function (LOF) allele, CYP2C19*2 and gain of function (GOF) allele, CYP2C19*17 in 163 patients undergoing PCI and 165 healthy volunteers from an ethnically distinctive Bangladeshi population. Thirty-eight patients took prasugrel and 125 patients took clopidogrel among whom 30 patients had their clopidogrel active metabolites (CAM) determined by LC-MS/MS 1-1.5 h after clopidogrel intake. All patients who underwent PCI had their P2Y12 per cent inhibition (PRI) measured by VerifyNow System. The impact of different genotypes on CAM and PRI were also determined. We did not find significant variation of CYP2C19*2 (P > 0.05) and CYP2C9*17 (P > 0.05) alleles among healthy volunteers and patients. CAM concentration as well as PRI by clopidogrel varied significantly (P < 0.05) based on genotypic variation of CYP2C19*2 and CYP2C19*17 individually. Such influence was not observed in case of prasugrel. Genotypic variation did not impact PRI but as a whole PRI by prasugrel was better than that of clopidogrel (P < 0.05). Due to presence of both of alleles the effect on PRI by clopidogrel could not be predicted, effectively indicating possible involvement of other factors. Genotype guided clopidogrel dose adjustment would be beneficial and therefore we propose mandatory genotyping before clopidogrel dosing. Prasugrel proved to be less affected by genotypic variability, but due to lack of sufficient long-term toxicity data, caution would be adopted before substituting clopidogrel.

  17. Influence of low-dose proton pump inhibitors administered concomitantly or separately on the anti-platelet function of clopidogrel.

    PubMed

    Furuta, Takahisa; Sugimoto, Mitsushige; Kodaira, Chise; Nishino, Masafumi; Yamade, Mihoko; Uotani, Takahiro; Sahara, Shu; Ichikawa, Hitomi; Kagami, Takuma; Iwaizumi, Moriya; Hamaya, Yasushi; Osawa, Satoshi; Sugimoto, Ken; Umemura, Kazuo

    2017-04-01

    Proton pump inhibitors (PPIs) at low doses can effectively prevent gastrointestinal bleeding due to aspirin and are widely used in Japan for gastroprotection in patients taking anti-platelet agents. We examined the influence of different PPIs at low doses administered concomitantly or separately on anti-platelet functions of clopidogrel. In 41 healthy Japanese volunteers with different CYP2C19 genotypes who took clopidogrel 75 mg in the morning alone, or with omeprazole 10 mg, esomeprazole 10 mg, lansoprazole 15 mg, or rabeprazole 10 mg, either concomitantly in the morning or separately in the evening, we measured the inhibition of platelet aggregation (IPA, %) using VerifyNow P2Y12 assay at 4 h after the last clopidogrel dose on Day 7 of each regimen. IPA by clopidogrel with rabeprazole administered at lunchtime, approximately 4 h after clopidogrel, was also measured. Mean IPAs in those concomitantly receiving omeprazole, esomeprazole, lansoprazole or rabeprazole (47.2 ± 21.1%, 43.2 ± 20.2%, 46.4 ± 18.8%, and 47.3 ± 19.2%, respectively) were significantly decreased compared with those receiving clopidogrel alone (56.0%) (all ps < 0.001). This decrease was observed when PPIs were administered separately in the evening. However, IPA by clopidogrel with rabeprazole administered at lunchtime was 51.6%, which was markedly similar to that of clopidogrel alone (p = 0.114). All tested PPIs reduce the efficacy of clopidogrel when administered concomitantly. Our preliminary data suggest that administration of rabeprazole 4 h following clopidogrel may minimize potential drug-drug interactions.

  18. Prolonged clopidogrel application reduces tissue factor expression after percutaneous coronary intervention in the porcine model.

    PubMed

    Ayral, Yunus; Rauch, Ursula; Goldin-Lang, Petra; Eisenreich, Andreas; Pepke, Wojciech; Deiner, Carolin; Schwimmbeck, Peter L; Schultheiss, Heinz-Peter; Pels, Klaus

    2011-01-01

    Late thrombotic events are important complications associated with intracoronary brachytherapy (ICBT) using ionizing radiation (IR) or with antiproliferative treatment modalities such as drug-eluting stents (DES). The mechanism mediating these thrombotic events is not well understood. This study assessed the effect of prolonged clopidogrel treatment on tissue factor (TF) expression in coronary arteries and on the circulating TF level after percutaneous transluminal coronary angioplasty /ICBT in a porcine coronary model. Pigs were treated with aspirin plus a 300 mg loading dose of clopidogrel one day before percutaneous coronary intervention (PCI), followed by a daily dose of clopidogrel and aspirin. During PCI one of the two balloon-injured arteries was treated by brachytherapy. Animals were sacrificed at different time points. The pigs, which were sacrificed 3 months post-PCI, were divided into two groups (Group I: clopidogrel for 3 months; Group II: clopidogrel for 1 month). Plasma TF was measured by enzyme-linked immunosorbent assay in blood samples taken from all pigs before and immediately after intervention and before sacrifice. Morphometric analysis was performed on digitalized images employing the software LUCIA G for TF staining. Vascular TF expression levels were assessed by quantitative real-time polymerase chain reaction. Prolonged clopidogrel application significantly reduced coronary TF at the protein (Group I vs. II, 8.975 ± 3.947% vs. 26.44 ± 5.375%, P = .007) and mRNA level [Group I vs. II, (0.3501 ± 0.0519) × 10(-3) vs. (0.7073 ± 0.0436) × 10(-3), P<.0005]. Circulating TF protein tended to be lower after 3 months than after 1 month clopidogrel treatment post-PCI (Group I vs. Group II, 488.3 ± 35.37 pg/ml vs. 572.3 ± 39.9 pg/ml, P = .130). Prolonged clopidogrel treatment reduced coronary TF expression and tended to reduce the blood TF level post-PCI, thus possibly modulating the risk of late thrombosis. Copyright © 2011 Elsevier Inc. All

  19. Comparative pharmacodynamic effects of two clopidogrel formulations under steady-state conditions in healthy Thai volunteers
.

    PubMed

    Nakkam, Nontaya; Tiamkao, Somsak; Kanjanawart, Sirimas; Phunikhom, Kutcharin; Tiamkao, Siriporn; Vannaprasaht, Suda; Tassaneeyakul, Wongwiwat; Tassaneeyakul, Wichittra

    2017-02-01

    Clopidogrel is a commonly used antiplatelet aggregation agent. Compared with the reference clopidogrel product, most commercially available generic clopidogrel products contain different crystalline forms of clopidogrel. This study was aimed to compare the pharmacodynamics of a commonly used generic clopidogrel product in Thailand with the reference clopidogrel product under steady state conditions. A multiple-dose, randomized 2-way crossover study was conducted in 32 healthy male Thai volunteers. The subjects were assigned to receive 75 mg once daily of the test or the reference product for 7 days with a 2-week wash out period. Blood samples were collected on days 1, 5, 6, and 7 prior to drug administration and at 1, 2, 3, 4, 8, 12, and 24 hours after the last dose administered. The antiplatelet aggregation effects of clopidogrel were determined by using two different ex-vivo platelet aggregation tests including the whole blood impedance assay (WBA) and the VerifyNow® P2Y12 assay. Both pharmacodynamic parameters, the maximal antiplatelet effect (Emax) and the areas under the antiplatelet effect-time curve (AUEC0-24h), were calculated. Neither the mean values of Emax (90.70 ± 15.15 vs. 89.50 ± 10.71% inhibition) nor of AUEC0-24h (1,892.84 ± 657.22 vs. 1,853.58 ± 673.95% inhibition × h) under steady-state conditions obtained using the WBA method of these two clopidogrel products were significantly different. The results obtained using the VerifyNow® P2Y12 assay were consistent with those of the WBA assay. This study clearly demonstrated that ex-vivo antiplatelet aggregation effect under steady-state conditions of the test product was not significantly different from the reference product.
.

  20. CYP2C19 polymorphisms in acute coronary syndrome patients undergoing clopidogrel therapy in Zhengzhou population.

    PubMed

    Guo, Y M; Zhao, Z C; Zhang, L; Li, H Z; Li, Z; Sun, H L

    2016-05-25

    The goal of this study was to explore the polymorphisms of CYP2C19 (CYP2C19*2, CYP2C19*3) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) on clopidogrel therapy in Zhengzhou city for guidance on clinical medication and reduction in the incidence of thromboembolic events. Two hundred and thirty-four ACS patients undergoing PCI were included in the study, including 171 males (average age = 64.13 ± 12 years) and 63 females (average age = 67.86 ± 10.20 years). Pyrosequencing analysis detected CYP2C19*2/*3 genotypes, which were divided into wild-type homozygous C/C, mutant heterozygous C/T, and mutant homozygous T/T. This study further explored the relationship between CYP2C19 polymorphisms and clopidogrel resistance in ACS patients. Gene frequencies of C/C, C/T, and T/T for CYP2C19*2 were 39.74, 50, and 10.26%, respectively, while the frequencies of C/C, C/T, and T/T for CYP2C19*3 were 94.02, 5.55, and 0.43%, respectively. According to platelet aggregation analysis, 203 cases normally responded to clopidogrel (86.8%) and 31 cases were clopidogrel resistant (13.2%). There was a correlation between gender and genotype distribution but none between age and genotype. In addition, patients with clopidogrel resistance were treated with ticagrelor antiplatelet therapy instead of clopidogrel, and only 1 case in all patients suffered thrombotic events during a 3-12 month follow-up. In conclusion, CYP2C19*2/*3 polymorphisms may be associated with clopidogrel resistance. Wild-type homozygote and single mutant heterozygote of CYP2C19*2/*3 can be given a normal dose of clopidogrel, while carriers with single mutant homozygote or double mutant heterozygote require ticagrelor antiplatelet therapy as an alternative.

  1. Pharmacodynamics and pharmacokinetics of single doses of prasugrel 30 mg and clopidogrel 300 mg in healthy Chinese and white volunteers: an open-label trial.

    PubMed

    Small, David S; Payne, Christopher D; Kothare, Prajakti; Yuen, Eunice; Natanegara, Fanni; Teng Loh, Mei; Jakubowski, Joseph A; Richard Lachno, D; Li, Ying G; Winters, Kenneth J; Farid, Nagy A; Ni, Lan; Salazar, Daniel E; Tomlin, Molly; Kelly, Ronan

    2010-02-01

    Prasugrel is an oral antiplatelet agent approved for the reduction of atherothrombotic cardiovascular events in patients presenting with acute coronary syndrome and undergoing percutaneous coronary intervention. Although the approved loading dose is 60 mg, earlier studies of prasugrel suggested that active-metabolite exposure and pharmacodynamic response may be higher in Asian subjects than in white subjects. This study compared the pharmacodynamic response to a single 30-mg dose of prasugrel in healthy Chinese and white subjects and the response to a single 30-mg dose of prasugrel and a single 300-mg dose of clopidogrel in healthy Chinese subjects. The pharmacokinetics and tolerability of both drugs were also assessed. This was an open-label, single-dose study conducted in Singapore. Chinese subjects were randomly allocated to receive prasugrel 30 mg or clopidogrel 300 mg; after a 14-day washout period, they received the alternative drug. White subjects received only prasugrel 30 mg. Blood samples for pharmaco-dynamic assessments were collected before dosing and at 0.5, 1, 2, 4, and 24 hours after dosing. Three methods were used to measure inhibition of platelet aggregation (IPA)-traditional light transmission aggregometry (LTA), the Verify Now P2Y12 (VN-P2Y12) assay, and a vasodilator-stimulated phosphoprotein (VASP) phosphorylation flow cytometry assay-and their results were compared. Blood samples for pharmacokinetic assessments were collected at 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 hours after dosing. Concentrations of the active metabolite of prasugrel were measured using a validated LC-MS/MS method. The study enrolled 18 Chinese subjects and 14 white subjects. Chinese subjects had a mean (SD) age of 31 (10) years and a mean body weight of 65.2 (8.9) kg; 83% were male. The corresponding values for white subjects were 30 (10) years, 77.2 (12.4) kg, and 86%. Thirty of the 32 enrolled subjects completed the study. Two Chinese men were withdrawn from the study

  2. Current status of high on-treatment platelet reactivity in patients with coronary or peripheral arterial disease: Mechanisms, evaluation and clinical implications

    PubMed Central

    Spiliopoulos, Stavros; Pastromas, Georgios

    2015-01-01

    Antiplatelet therapy with aspirin or clopidogrel or both is the standard care for patients with proven coronary or peripheral arterial disease, especially those undergoing endovascular revascularization procedures. However, despite the administration of the antiplatelet regiments, some patients still experience recurrent cardiovascular ischemic events. So far, it is well documented by several studies that in vitro response of platelets may be extremely variable. Poor antiplatelet effect of clopidogrel or high on-treatment platelet reactivity (HTPR) is under investigation by numerous recent studies. This review article focuses on methods used for the ex vivo evaluation of HTPR, as well as on the possible underlying mechanisms and the clinical consequences of this entity. Alternative therapeutic options and future directions are also addressed. PMID:26730297

  3. Platelet reactivity in response to loading dose of atorvastatin or rosuvastatin in patients with stable coronary disease before percutaneous coronary intervention: The STATIPLAT randomized study.

    PubMed

    Godino, Cosmo; Pavon, Anna Giulia; Mangieri, Antonio; Salerno, Anna; Cera, Michela; Monello, Alberto; Chieffo, Alaide; Magni, Valeria; Cappelletti, Alberto; Margonato, Alberto; Colombo, Antonio

    2017-08-01

    The acute effects of statin loading dose (LD) on platelet reactivity in patients with chronic stable angina (CSA) are not completely clear. We hypothesized that LDs of atorvastatin and rosuvastatin have different pharmacodynamic acute effects on platelet aggregability in CSA patients with baseline normal platelet reactivity while on dual antiplatelet therapy (DAPT). From September 2011 to February 2014, all consecutive CSA patients on chronic DAPT (aspirin and clopidogrel) were evaluated before elective percutaneous coronary intervention (PCI). An initial assessment of platelet reactivity in response to thrombin receptor agonist, ADP, and ASP (respectively, indicative of the response to clopidogrel and aspirin) was performed with impedance aggregometry. Patients with high platelet reactivity to ADP test (area under the curve >47) were excluded. The remaining patients were randomized into 3 treatment groups: Group A, atorvastatin LD 80 mg; Group B, rosuvastatin LD 40 mg; and Group C, no statin LD (control group). A second assessment of platelet reactivity was performed ≥12 hours after statin LD. 682 patients were screened and 145 were randomized into the 3 groups. At baseline and after statin LD, no significant difference was found in platelet reactivity in response to 3 different agonists between the 3 groups. Subgroup analysis showed that platelet reactivity to ADP test was significantly lower in patients chronically treated with low-dose statins (n = 94) compared with statin-naïve patients (n = 51; 15.32 ± 1.50 vs 18.59 ± 1.30; P = 0.007). Loading dose of atorvastatin (80 mg) or rosuvastatin (40 mg) did not induce significant variation in platelet reactivity in CSA patients with baseline reduced platelet reactivity as in chronic DAPT. Our data confirm that chronic concomitant treatment with low-dose statins and clopidogrel resulted in significantly lower platelet reactivity compared with clopidogrel alone. © 2017 Wiley Periodicals, Inc.

  4. Evaluating Potential Response-Modifying Factors for ...

    EPA Pesticide Factsheets

    Epidemiologic and experimental studies have demonstrated a variety of health effects in response to ozone (O3) exposure. Studies have demonstrated that some populations may be at increased risk of O3-related health effects. Objectives: To identify populations and lifestages potentially at increased risk of O3-related health effects by applying a novel strength of evidence approach for identifying and classifying factors associated with increased risk. Methods: Epidemiologic, experimental, and exposure science studies of populations potentially at increased risk of O3-related health effects were identified and evidence was integrated across disciplines to evaluate consistency, coherence, and biological plausibility of effects. The factors identified were then classified using a strength of evidence approach to conclude whether a population or lifestage is at increased risk of O3-related health effects. Discussion: We found “adequate” evidence that populations with certain genotypes, different lifestages, populations with preexisting asthma, populations with reduced intake of certain nutrients, and outdoor workers are at increased risk of O3 related health effects. Additionally, we identified other factors (i.e., sex, SES, and obesity) for which there was “suggestive” evidence of increased risk of O3-related health effects. Conclusions: We identified a diverse group of factors that potentially result in an increased risk of O3-related health effects.

  5. Clopidogrel enhances periodontal repair in rats through decreased inflammation

    PubMed Central

    Coimbra, Leila S; Steffens, Joao Paulo; Rossa, Carlos; Graves, Dana T; Spolidorio, Luis C.

    2014-01-01

    Aim We hypothesized that platelet inactivation induced by drugs might interfere with periodontal repair in experimental periodontitis by suppressing the release of biological mediators from platelets at the site of injury. Material and Methods 60 rats were randomly assigned to 6 groups (n=10) and ligatures were placed around lower first molars of three groups. The other three groups were used as negative controls. Ligatures were removed after 10 days of periodontitis induction and all groups were submitted to treatment with aspirin (Asp) (30 mg/kg), clopidogrel (Clop) (75 mg/kg) or NaCl 0.9% intragastrically once daily for 3 days. Periodontal tissue was assessed by the measurement of CXCL12, CXCL4, CCL5 and PDGF by ELISA; histomorphometric analysis of PMN infiltration, attachment loss, bone loss and osteoclast numbers and quantification of blood vessels by imunnohistochemistry. Results During periodontal repair and treatment with NaCl 0.9%, CCL5 was decreased and CXCL12 increased when compared to negative control groups. Asp and Clop did not affect CCL5 expression, decreased CXCL12 but only Clop decreased CXCL4 and PDGF content compared to saline-treated animals. Clop increased blood vessel number, reduced PMN count, and decreased attachment and bone loss, also decreased osteoclast number in animals submitted or not to periodontal repair. Conclusion Systemic administration of Clop during 3 days improved the repair process associated with experimental periodontal disease, suggesting that it may have therapeutic value under situations where tissues undergo a transition from inflammation to repair. PMID:24433307

  6. Aspirin and clopidogrel resistance using the cone and plate(let) analyser in Indian patients with coronary artery disease.

    PubMed

    Koshy, Sudeep Kurien; Salahuddin, Salman; Karunakaran, Bijoy; Nalakath, Sajid Yoonus; Bhaskaran, Jayesh; Haridas, Padinjare Veloor; Mandalay, Asishkumar; Faizal, Ali

    2014-01-01

    Resistance to antiplatelet drugs is a well-known entity. However, data for aspirin and clopidogrel resistance, and its clinical significance, in Indian patients are meagre. We sought to determine the prevalence of resistance to aspirin and clopidogrel in Indian patients with stable coronary heart disease (CHD), using the cone and plate(let) analyser (CPA) technology. A single centre prospective study in a cohort of patients with stable CHD on chronic aspirin and clopidogrel therapy attending the cardiology outpatient clinic of a tertiary care hospital in Southern India. Platelet function was measured using the Impact-R device (DiaMed, Cressier, Switzerland). Resistance to aspirin and clopidogrel was measured in a cohort of 100 patients with stable documented CHD. Relation of antiplatelet resistance to various clinical comorbidities was also assessed. Of the 100 patients, 85% were men, and 15% were above 65 years of age. 47% patients had diabetes, 29% of patients were hypertensive and 16% were smokers. Using the CPA, 12 patients (12%) were found to be resistant to aspirin and 19 patients (19%) were clopidogrel resistant. In addition, 10 patients (10%) were resistant to both aspirin and clopidogrel. There was no significant correlation between the presence of antiplatelet resistance and several baseline clinical variables, including age, sex, diabetes, hypertension and smoking. Resistance to aspirin and clopidogrel and dual antiplatelet resistance are prevalent in Indian patients, comparable with the prevalence worldwide. The CPA is a feasible assay to determine antiplatelet resistance.

  7. Antiplatelet Therapy of Cilostazol or Sarpogrelate with Aspirin and Clopidogrel after Percutaneous Coronary Intervention: A Retrospective Cohort Study Using the Korean National Health Insurance Claim Database.

    PubMed

    Noh, Yoojin; Lee, Jimin; Shin, Sooyoung; Lim, Hong-Seok; Bae, Soo Kyung; Oh, Euichul; Kim, Grace Juyun; Kim, Ju Han; Lee, Sukhyang

    2016-01-01

    Addition of cilostazol or sarpogrelate to the standard dual antiplatelet therapy of aspirin and clopidogrel has been implemented in patients that underwent percutaneous coronary intervention (PCI) with stents in Korea. This study aimed to evaluate the efficacy and safety of triple antiplatelet therapies. This retrospective cohort study was performed using the Korean National Insurance Claim Data of the Health Insurance Review and Assessment Service from January 1, 2009 to December 31, 2014. The study cohort population consisted of patients with ischemic heart diseases and a history of PCI. They were treated with antiplatelet therapy of aspirin, clopidogrel (AC); aspirin, clopidogrel, cilostazol (ACCi); or aspirin, clopidogrel, sarpogrelate (ACSa) during the index period from January 1, 2010 to December 31, 2011. During the follow-up period up to December 31, 2014, the major adverse cardiac or cerebral events (MACCE) including death, myocardial infarction, target lesion revascularization, and ischemic stroke were assessed. Bleeding complications were also evaluated as adverse drug events. Out of 93,876 patients with PCI during the index period, 69,491 patients started dual (AC) or triple therapy (ACSa or ACCi). The clinical outcomes of comparing ACSa and ACCi therapy showed beneficial effects in the ACSa group in the prevention of subsequent cardiac or cerebral events. After Propensity score-matching between ACSa and ACCi groups, there were significant differences in MI and revascularization, with corresponding HR of 0.38 (95% CI, 0.20-0.73) and 0.66 (95% CI, 0.53-0.82) in ACSa vs. ACCi at 12 months, respectively. At the 24-month follow-up, the triple therapy groups (ACS or ACC) had a higher incidence of MACCE compared to the dual therapy (AC) group; ACSa vs. AC HR of 1.69 (95% CI, 1.62-1.77); ACC vs. AC HR of 1.22 (95% CI, 1.06-1.41). There was no significant difference in severe or life-threatening bleeding risk among three groups; ACSa vs. AC, HR of 0.68 (95% CI

  8. Clopidogrel use is associated with an increased prevalence of cerebral microbleeds in a stroke-free population: the Rotterdam study.

    PubMed

    Darweesh, Sirwan K L; Leening, Maarten J G; Akoudad, Saloua; Loth, Daan W; Hofman, Albert; Ikram, M Arfan; Vernooij, Meike W; Stricker, Bruno H

    2013-09-26

    Although clopidogrel reduces the incidence of atherothrombotic events, its use is associated with an increased risk of major bleeding. Cerebral microbleeds (CMBs) are indicative of subclinical microangiopathy in the brain and may prelude symptomatic intracerebral hemorrhage. We examined the association between use of clopidogrel and CMBs in persons without a history of stroke. We performed a cross-sectional analysis using data from the Rotterdam Study, a prospective population-based cohort of persons aged 45 years and older. Among 4408 stroke-free individuals who underwent brain magnetic resonance imaging for the detection of CMBs, we identified 121 ever-users and 4287 never-users of clopidogrel before magnetic resonance imaging. We used multiple logistic regression to analyze the association between clopidogrel and CMBs with adjustment for age, sex, cardiovascular risk factors, and common cardiovascular medication. Users of clopidogrel had a higher prevalence of CMBs (odd ratio 1.55, 95% CI 1.01 to 2.37) than nonusers and more often had a high number (> 4) of CMBs (odds ratio 3.19, 95% CI 1.52 to 6.72). Clopidogrel use was associated with a significantly higher prevalence of deep or infratentorial CMBs (odd ratio 1.90, 95% CI 1.05 to 3.45). Among clopidogrel users, we were unable to demonstrate differences in the prevalence of CMBs by indication of prescription, history of coronary heart disease, or common genetic variants in CYP2C19. In stroke-free individuals, clopidogrel use was associated with a higher prevalence and higher number of CMBs. Whether this association is causal requires confirmation in prospective studies, especially given the small number of participants taking clopidogrel and the possibility of residual confounding in this study.

  9. Clopidogrel Use Is Associated With an Increased Prevalence of Cerebral Microbleeds in a Stroke‐Free Population: The Rotterdam Study

    PubMed Central

    Darweesh, Sirwan K.L.; Leening, Maarten J.G.; Akoudad, Saloua; Loth, Daan W.; Hofman, Albert; Arfan Ikram, M.; Vernooij, Meike W.; Stricker, Bruno H.

    2013-01-01

    Background Although clopidogrel reduces the incidence of atherothrombotic events, its use is associated with an increased risk of major bleeding. Cerebral microbleeds (CMBs) are indicative of subclinical microangiopathy in the brain and may prelude symptomatic intracerebral hemorrhage. We examined the association between use of clopidogrel and CMBs in persons without a history of stroke. Methods and Results We performed a cross‐sectional analysis using data from the Rotterdam Study, a prospective population‐based cohort of persons aged 45 years and older. Among 4408 stroke‐free individuals who underwent brain magnetic resonance imaging for the detection of CMBs, we identified 121 ever‐users and 4287 never‐users of clopidogrel before magnetic resonance imaging. We used multiple logistic regression to analyze the association between clopidogrel and CMBs with adjustment for age, sex, cardiovascular risk factors, and common cardiovascular medication. Users of clopidogrel had a higher prevalence of CMBs (odd ratio 1.55, 95% CI 1.01 to 2.37) than nonusers and more often had a high number (>4) of CMBs (odds ratio 3.19, 95% CI 1.52 to 6.72). Clopidogrel use was associated with a significantly higher prevalence of deep or infratentorial CMBs (odd ratio 1.90, 95% CI 1.05 to 3.45). Among clopidogrel users, we were unable to demonstrate differences in the prevalence of CMBs by indication of prescription, history of coronary heart disease, or common genetic variants in CYP2C19. Conclusions In stroke‐free individuals, clopidogrel use was associated with a higher prevalence and higher number of CMBs. Whether this association is causal requires confirmation in prospective studies, especially given the small number of participants taking clopidogrel and the possibility of residual confounding in this study. PMID:24072532

  10. Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome

    PubMed Central

    Roe, Matthew T.; Cyr, Derek D.; Eckart, Debra; Schulte, Phillip J.; Morse, Michael A.; Blackwell, Kimberly L.; Ready, Neal E.; Zafar, S. Yousuf; Beaven, Anne W.; Strickler, John H.; Onken, Jane E.; Winters, Kenneth J.; Houterloot, Lisa; Zamoryakhin, Dmitry; Wiviott, Stephen D.; White, Harvey D.; Prabhakaran, Dorairaj; Fox, Keith A. A.; Armstrong, Paul W.; Ohman, E. Magnus

    2016-01-01

    Aims Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS. Methods and results The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77–1.42; P = 0.79). Conclusions Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel

  11. Behavioral Response Research Evaluation Workshop (BRREW)

    DTIC Science & Technology

    2015-09-30

    N000141512664 http://www.creem.st-and.ac.uk LONG-TERM GOALS The behavioral response of marine mammals to Navy sonar exposure has been a research...The overall objective is to review the status and future of research into behavioral responses of marine mammals to naval sonar exposure in order to...are to: 1. undertake a science-based synthesis of the current state of knowledge on the behavioral response of marine mammals to Navy sonar exposure

  12. Regional Anesthesia in Patients of Aged 99 Years in Clopidogrel Use

    PubMed Central

    Brasileiro, Bruno; Imbelloni, Luiz Eduardo

    2017-01-01

    The risk of neuraxial block in patients treated with antiplatelet drugs are uncertain. Elderly patients often have low physiological reserve, delaying surgery can lead to a high rate of morbidity and mortality. The aim of this paper is to present a case of a patient with 99 years using clopidogrel undergoing regional anesthesia for surgical treatment of hip fracture without complications. PMID:28298798

  13. Investigating Real-World Clopidogrel Pharmacogenetics in Stroke Using a Bioresource Linked to Electronic Medical Records.

    PubMed

    Tornio, Aleksi; Flynn, Rob; Morant, Steve; Velten, Elena; Palmer, Colin N A; MacDonald, Thomas M; Doney, Alex S F

    2017-06-27

    Clopidogrel efficacy is influenced by genetic variation of CYP2C19, however few studies have considered stroke patients. We used electronic medical records (EMR) linked to a bioresource to examine real-world implications of clopidogrel pharmacogenetics in stroke. Patients hospitalized for any arterial thrombo-occlusive event (ATO) who subsequently redeemed clopidogrel prescriptions in the community were entered into the study (n=651). During 24 months follow-up the primary endpoint of recurrent ATO or death occurred in 299 (46%) patients. CYP2C19*2 loss-of-function allele carriers had an increased risk, hazard ratio (HR) 1.29 (95% confidence interval 1.04-1.59, P=0.019). In the ischemic stroke subgroup (n=94) the estimate of risk was greater (HR 2.23, 95% confidence interval 1.17-4.24, P=0.015) further supported by a meta-analysis of available studies. In conclusion, we have demonstrated the clinical impact of CYP2C19*2 on clopidogrel efficacy using a purely EMR approach. This suggests that the risk in the ischemic stroke population may be particularly high. This article is protected by copyright. All rights reserved. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  14. In-stent thrombosis when switching ticagrelor to clopidogrel after percutaneous coronary intervention.

    PubMed

    Brice, Aaron E; Hernandez, Gabriel A; Sanchez, Mariluz; Haynick, Marshall; Mendoza, Cesar E

    2017-05-01

    Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker has been proven to reduce subsequent cardiovascular events and in-stent thrombosis in patients undergoing percutaneous coronary intervention. Newer P2Y12 antagonists with faster onset and greater inhibition of platelet activity have improved cardiovascular outcomes but have created uncertainty with the appropriate dosing when switching between agents. Currently, there are no evidence-based guidelines to aid clinicians when switching between P2Y12 receptor blockers. Here we describe two patients that developed in-stent thrombosis when switching from ticagrelor to clopidogrel using a 300 mg clopidogrel loading dose. Both patients presented with ST elevation myocardial infarction and underwent stent placement but then developed in-stent thrombosis 48 hours after switching from ticagrelor to clopidogrel. These cases illustrate the severe consequences of suboptimal platelet inhibition and the need for prospective trials thoroughly powered to assess clinical outcomes in order to determine the most appropriate strategy when switching from ticagrelor to clopidogrel.

  15. Clopidogrel in the management of acute coronary syndromes: indications, results, obstacles.

    PubMed

    Amsterdam, Ezra A

    2009-06-01

    Atherothrombosis is the underlying pathology of the acute coronary syndromes (ACS), in which platelet activation plays a key role. Therefore, antiplatelet therapy is an essential component of guideline-recommended ACS management. Considerable evidence clearly demonstrates the benefits of the antiplatelet agent clopidogrel in reducing mortality, decreasing recurrent cardiovascular events, and increasing arterial patency in ACS patients. Despite this evidence, data from patient registries and clinical initiatives such as CRUSADE (Can Rapid stratification of Unstable angina Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines) and GRACE (Global Registry of Acute Coronary Events) indicate that clopidogrel is underused in patients with ACS. This is especially true for patients receiving conservative medical management, many of whom have significant risk for recurrent ischemic events. The purpose of this review is to compare "real-life" clopidogrel therapy with evidence-based guidelines, and to highlight clinical factors that drive clopidogrel implementation or provide barriers to its use in ACS patients.

  16. Operative delay for orthopedic patients on clopidogrel (plavix): a complete lack of consensus.

    PubMed

    Lavelle, William F; Demers Lavelle, Elizabeth A; Uhl, Richard

    2008-04-01

    : Because of its irreversible nature, Plavix (clopidogrel) has become a double edged sword in the care of some of our sickest patients, particularly when surgical intervention is required. Platelets exposed to a single dose of clopidogrel are affected for the remainder of their lifespan and recover normal platelet function at a rate consistent with platelet turnover, which is within 5 days to 7 days (1-3) with the generation of new platelets not influenced by the drug; however, delay of surgical fixation for orthopedic patients, particularly patients with hip fractures may lead to increased morbidity and mortality. : A Web-based survey was created and administered to the program directors of academic orthopedic surgery programs. : Seventy-three percent of orthopedic residency programs responded that waiting 3 days or less for urgent but nonemergent operative interventions on patients on clopidogrel is acceptable with 23% feeling that no delay at all is necessary. For emergent surgery, the vast majority of programs 66 (89%) reported no delay to the operating room for patients on clopidogrel. : The majority of orthopedic surgery residency programs who responded to the survey wait less than 3 days for urgent surgery and do not delay surgery for emergency cases for patients on clopidogrel. At this point we feel that an early intervention that occurs within approximately 2 days, with the acceptance of the possibility of increased blood loss is in the patient's best interest. Based on the reviewed physiology, a perioperative platelet transfusion may be of some benefit as the transfused platelets would be effective in forming a viable plug.

  17. Recurrent Ischemic Lesions After Acute Atherothrombotic Stroke: Clopidogrel Plus Aspirin Versus Aspirin Alone.

    PubMed

    Hong, Keun-Sik; Lee, Seung-Hoon; Kim, Eung Gyu; Cho, Ki-Hyun; Chang, Dae Il; Rha, Joung-Ho; Bae, Hee-Joon; Lee, Kyung Bok; Kim, Dong Eog; Park, Jong-Moo; Kim, Hahn-Young; Cha, Jae-Kwan; Yu, Kyung-Ho; Lee, Yong-Seok; Lee, Soo Joo; Choi, Jay Chol; Cho, Yong-Jin; Kwon, Sun U; Kim, Gyeong-Moon; Sohn, Sung-Il; Park, Kwang-Yeol; Kang, Dong-Wha; Sohn, Chul-Ho; Lee, Jun; Yoon, Byung-Woo

    2016-09-01

    In patients with acute ischemic stroke caused by large artery atherosclerosis, clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia. However, there is no clear evidence. In this multicenter, double-blind, placebo-controlled trial, we randomized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel (75 mg/d without loading dose) plus aspirin (300-mg loading followed by 100 mg/d) or to aspirin alone (300-mg loading followed by 100 mg/d) for 30 days. The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days. Secondary outcomes were 30-day functional disability, clinical stroke recurrence, and composite of major vascular events. Safety outcome was any bleeding. Of 358 patients enrolled, 334 (167 in each group) completed follow-up magnetic resonance imaging. The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups (36.5% versus 35.9%; relative risk, 1.02; 95% confidence interval, 0.77-1.35; P=0.91). Of the recurrent ischemic lesions, 94.2% were clinically asymptomatic. There were no differences in secondary outcomes between the 2 groups. Any bleeding were more frequent in the combination group than in the aspirin monotherapy group, but the difference was not significant (16.7% versus 10.7%; P=0.11). One hemorrhagic stroke occurred in the clopidogrel plus aspirin group. Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00814268. © 2016 American Heart Association, Inc.

  18. Bioequivalence of two tablet formulations of clopidogrel in healthy Argentinian volunteers: a single-dose, randomized-sequence, open-label crossover study.

    PubMed

    Di Girolamo, Guillermo; Czerniuk, Paola; Bertuola, Roberto; Keller, Guillermo A

    2010-01-01

    Platelet activation is a major component in the pathogenesis of coronary thrombosis and myocardial infarction. Thienopyridines, particularly clopidogrel, are highly effective in reducing in-stent thrombosis and functional inhibition of adenosine diphosphate-induced platelet activation. The aim of this study was to evaluate the bioequivalence of a new generic formulation of clopidogrel 75-mg tablets (test) and the available branded formulation (reference) to meet regulatory criteria for marketing the test product in Argentina. This was a randomized-sequence, open-label, 2-period crossover study conducted in healthy white volunteers in the fasted state. A single oral dose of the test or reference formulation was followed by a 7-day washout period, after which subjects received the alternative formulation. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after dosing. Clopidogrel concentrations were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% CI of the geometric mean ratios (test:reference) for C(max) and AUC(0-last) were within the range from 80% to 125%. Adverse events were monitored throughout the study based on clinical parameters and patient reports. Twenty-four volunteers (13 male, 11 female; mean [SD] age, 33.7 [5.2] years [range, 21-42 years]; weight, 72.4 [6.83] kg [range, 59-82 kg]) were enrolled in and completed the study. The geometric mean C(max) for the test and reference formulations was 877.76 and 913.49 pg/mL, respectively. The geometric mean AUC(0-t) was 1911.53 and 2053.09 pg . h/mL, and the geometric mean AUC(0-infinity)) was 2021.33 and 2188.25 pg . h/mL. The geometric mean ratios (test:reference) for C(max), AUC(0-t), and AUC(0-infinity)) were 96.09% (90% CI, 90.71-101.78), 93.10% (90% CI, 85.57-101.3), and 92.37% (90% CI, 85.06-100.31), respectively. There were no significant differences in pharmacokinetic parameters between groups

  19. Response Style Contamination of Student Evaluation Data

    ERIC Educational Resources Information Center

    Dolnicar, Sara; Grun, Bettina

    2009-01-01

    Student evaluation surveys provide instructors with feedback regarding development opportunities and they form the basis of promotion and tenure decisions. Student evaluations have been extensively studied, but one dimension hitherto neglected is the actual measurement aspect: which questions to ask, how to ask them, and what answer options to…

  20. Response Style Contamination of Student Evaluation Data

    ERIC Educational Resources Information Center

    Dolnicar, Sara; Grun, Bettina

    2009-01-01

    Student evaluation surveys provide instructors with feedback regarding development opportunities and they form the basis of promotion and tenure decisions. Student evaluations have been extensively studied, but one dimension hitherto neglected is the actual measurement aspect: which questions to ask, how to ask them, and what answer options to…

  1. A randomized two-by-two comparison of high-dose bolus tirofiban versus abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary revascularization and stent placement: the tirofiban evaluation of novel dosing versus abciximab with clopidogrel and inhibition of thrombin (TENACITY) study trial.

    PubMed

    Moliterno, David J

    2011-06-01

    In the absence of high-dose thienopyridines, placebo-controlled trials have demonstrated a reduction in ischemic events with intravenous glycoprotein IIb/IIIa antagonists during percutaneous coronary intervention (PCI). One head-to-head trial comparing abciximab and tirofiban among PCI patients found tirofiban to be inferior, and laboratory evidence confirmed that the bolus dose of tirofiban tested in that trial to be less effective than abciximab. Whether a higher bolus dose of tirofiban would be as efficacious as abciximab during PCI is uncertain. Patients undergoing PCI were randomized equally to abciximab or to tirofiban, given as high-dose bolus (25 μg/kg) plus 12-hr infusion (0.15 μg/kg/min). All patients received aspirin and clopidogrel and were additionally randomized to unfractionated heparin or bivalirudin. Approximately 8,000 patients were to be studied, but after 383 were enrolled, the study sponsor discontinued the trial for financial reasons. The primary endpoint of 30-day death, myocardial infarction, or urgent target vessel revascularization occurred in 8.8% of patients randomized to abciximab and 6.9% of those randomized to tirofiban. The respective rates of major bleeding were 1.5 and 1.6%. Additionally, the primary endpoint occurred in 8.1% of patients randomized to unfractionated heparin and 7.6% of those randomized to bivalirudin. The respective rates of major bleeding were 2.5% and 0.5%. With limited assessment, this direct comparison of high-dose bolus tirofiban versus abciximab produced encouraging results and suggests that further study of this tirofiban dose regimen is warranted. The limited assessments comparing heparin and bivalirudin are consistent with prior observations. Copyright © 2010 Wiley-Liss, Inc.

  2. Politics in evaluation: Politically responsive evaluation in high stakes environments.

    PubMed

    Azzam, Tarek; Levine, Bret

    2015-12-01

    The role of politics has often been discussed in evaluation theory and practice. The political influence of the situation can have major effects on the evaluation design, approach and methods. Politics also has the potential to influence the decisions made from the evaluation findings. The current study focuses on the influence of the political context on stakeholder decision making. Utilizing a simulation scenario, this study compares stakeholder decision making in high and low stakes evaluation contexts. Findings suggest that high stakes political environments are more likely than low stakes environments to lead to reduced reliance on technically appropriate measures and increased dependence on measures better reflect the broader political environment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. X-ray crystal structure of the cytochrome P450 2B4 active site mutant F297A in complex with clopidogrel: insights into compensatory rearrangements of the binding pocket.

    PubMed

    Shah, Manish B; Jang, Hyun-Hee; Zhang, Qinghai; David Stout, C; Halpert, James R

    2013-02-15

    Prior X-ray crystal structures of cytochrome P450 2B4 revealed the pivotal role of rearrangement of the side chains of residues F206 and F297 in the active site in accommodating various inhibitors or substrates. To explore the role of these residues, 2B4 F206A and F297A were created by site-directed mutagenesis and characterized functionally. The structure of F297A with clopidogrel demonstrated the reorientation of the ligand such that the methyl ester group is oriented toward the heme, whereas the thiophene moiety now extends to the additional void in the F297A mutant. Most interestingly, movement of the I helix and several amino acid side chains within the active site was observed in apparent response to the altered binding orientation. Results of flexible docking using the 2B4 wild type or the F297A-virtual mutant positioned either the thiophene or chlorophenyl group closer to heme. However, docking of clopidogrel using the real F297A mutant or a virtual mutant with the I-helix re-positioned oriented clopidogrel preferentially with either the methyl ester or the chlorophenyl group closest to heme. The study provides insight into how the altered active site adapts to accommodate and interact with the substrate in a distinct orientation while maintaining the overall closed protein conformation. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Measurement and evaluation techniques for automated demand response demonstration

    SciTech Connect

    Motegi, Naoya; Piette, Mary Ann; Watson, David S.; Sezgen, Osman; ten Hope, Laurie

    2004-08-01

    The recent electricity crisis in California and elsewhere has prompted new research to evaluate demand response strategies in large facilities. This paper describes an evaluation of fully automated demand response technologies (Auto-DR) in five large facilities. Auto-DR does not involve human intervention, but is initiated at a facility through receipt of an external communications signal. This paper summarizes the measurement and evaluation of the performance of demand response technologies and strategies in five large facilities. All the sites have data trending systems such as energy management and control systems (EMCS) and/or energy information systems (EIS). Additional sub-metering was applied where necessary to evaluate the facility's demand response performance. This paper reviews the control responses during the test period, and analyzes demand savings achieved at each site. Occupant comfort issues are investigated where data are available. This paper discusses methods to estimate demand savings and results from demand response strategies at five large facilities.

  5. Concomitant Use of Proton Pump Inhibitors and Clopidogrel Is Not Associated with Adverse Outcomes after Ischemic Stroke in Chinese Population.

    PubMed

    Yi, Xingyang; Zhou, Qiang; Wang, Chun; Lin, Jing; Cheng, Wen; Chi, Lifen

    2016-12-01

    Conflicting data exist as to whether proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel. We, therefore, assessed the effect of concomitant PPI use in ischemic stroke (IS) patients receiving clopidogrel. We consecutively enrolled 535 IS patients receiving clopidogrel, 166 of whom were concomitantly taking PPIs. Platelet aggregation was measured before and after 7-10 days of treatment with clopidogrel. Single nucleotide polymorphisms of CYP3A4, CYP3A5, CYP2C19*2, and CYP2C19*3 were examined. The primary outcome was a composite of recurrent ischemic stroke (RIS), myocardial infarction (MI), and vascular death occurring during the 6-month follow-up. The secondary outcome was the modified Rankin Scale score at the end of follow-up. The primary outcome occurred in 45 patients and the frequency did not differ in patients with or without PPI treatment. The percentage inhibition of platelet aggregation and the frequency of clopidogrel resistance were similar between patients treated with or without PPIs after clopidogrel treatment. However, for patients carrying a reduced-function CYP2C19*2 (AG/AA genotype) or CYP3A5 (GG/AG genotype), the inhibition of platelet aggregation was significantly lower in patients treated with PPIs. Cox regression analysis showed that diabetes mellitus, clopidogrel resistance, CYP2C19*2 AG/AA genotype, and patients carrying two loss-of-function variant alleles were independent risk factors for the primary outcome, but not the use of PPIs. The concomitant use of PPIs and clopidogrel in patients with IS may not be associated with an increased risk of RIS, MI, or vascular death. Further well-designed randomized controlled studies are necessary to confirm our current results. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  6. St. John's Wort in patients non-responders to clopidogrel undergoing percutaneous coronary intervention: a single-center randomized open-label trial (St. John's Trial).

    PubMed

    Trana, Catalina; Toth, Gabor; Wijns, William; Barbato, Emanuele

    2013-06-01

    We assessed if St. John's Wort (SJW) improves platelet response in patients (pts) resistant to clopidogrel after percutaneous coronary intervention (PCI). Stable angina pts non-responders to 600 mg clopidogrel (P2Y12 reaction units (PRU) >240) were randomized (2:1) to SJW (n = 15) or placebo (n = 8). SJW (300 mg × 3/day) was administrated for 2 weeks after PCI. Platelet reactivity was assessed by VerifyNowTM before (BL), 2 (T1), and 4 weeks (T2) after PCI. PRU significantly changed during protocol in SJW (BL (316 ± 60) vs. T1 (170 ± 87) vs. T2 (220 ± 96), p < 0.0001) and placebo group (BL (288 ± 36) vs. T1 (236 ± 31) vs. T2 (236 ± 62), p = 0.046). Yet, PRU changes from BL were higher at T1 in SJW than in placebo group (Δ%, -47 ± 24 vs. -16 ± 15, p = 0.0033), with no differences at T2 between the groups (Δ%, -30 ± 29 vs. -17 ± 24, p = 0.30). Residual platelet reactivity improved with SJW during the first month post-PCI.

  7. Transient receptor potential ankyrin 1 (TRPA1) channel activation by the thienopyridine-type drugs ticlopidine, clopidogrel, and prasugrel.

    PubMed

    Schulze, Anja; Hartung, Philipp; Schaefer, Michael; Hill, Kerstin

    2014-04-01

    Transient receptor potential A1 (TRPA1) is widely expressed throughout the human and animal organism, including the dorsal root ganglia as well as the bladder, stomach and small intestine. Here, we examined the effect of three platelet aggregation inhibitors on TRPA1: ticlopidine, clopidogrel and prasugrel. Utilising fluorometric Ca(2+) influx analysis and electrophysiological whole cell measurements in TRPA1-expressing HEK293 and in human enterochromaffin-like QGP-1 cells, we found that ticlopidine, clopidogrel and prasugrel are direct activators of TRPA1. Although this polymodal channel commonly contributes to the perception of pain, temperature and chemical irritants, recent studies provide evidence for its involvement in the release of serotonin (5-HT) from enterochromaffin cells. Therefore, we further investigated the ability of ticlopidine, clopidogrel and prasugrel to stimulate 5-HT release from QGP-1 cells. We could determine 5-HT in supernatants from cultured QGP-1 cells upon treatment with ticlopidine and clopidogrel but not with prasugrel. These findings indicate that a robust TRPA1 activation by ticlopidine and clopidogrel correlates with the stimulatory effect on the secretion of 5-HT. As recipients of ticlopidine and clopidogrel frequently complain about gastrointestinal adverse events such as nausea, vomiting and diarrhoea, an activation of TRPA1 may contribute to adverse effects of such drugs in the digestive system.

  8. Use of prasugrel in the setting of clopidogrel hypersensitivity: Case report and systematic review of the literature.

    PubMed

    Siu, Henry; Kaliyadan, Antony; Fischman, David L; Nardone, Evan; Poll, David; Savage, Michael P

    2016-12-01

    Allergic reactions to clopidogrel soon after coronary stent implantation pose an important and challenging clinical problem. We describe a 44-year-old man who developed a diffuse maculopapular rash four days after initiation of clopidogrel with drug-eluting coronary stent placement. An initial treat-through strategy was unsuccessful due to patient intolerance to corticosteroids. Because of persistent hypersensitivity, clopidogrel was substituted with prasugrel which was continued successfully for one year without reaction. A systematic review of the literature was performed which identified 10 prior case reports of patients with clopidogrel hypersensitivity who were subsequently treated with prasugrel. Patient characteristics and clinical outcomes of these patients plus the current case were reviewed. There were 9 men and 2 women with ages from 44 to 76 years. All patients had undergone coronary stent procedures. Prasugrel was successfully used without cross-reactivity in 9 of the 11 patients (82%). Cross-reactivity was reported in two patients who developed hypersensitivity reactions to prasugrel similar to those experienced on clopidogrel. In conclusion, prasugrel can be used successfully in most patients with a history of clopidogrel hypersensitivity. However, potential cross-reactivity between these two thienopyridines may occur in some patients.

  9. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke.

    PubMed

    Sacco, Ralph L; Diener, Hans-Christoph; Yusuf, Salim; Cotton, Daniel; Ounpuu, Stephanie; Lawton, William A; Palesch, Yuko; Martin, Reneé H; Albers, Gregory W; Bath, Philip; Bornstein, Natan; Chan, Bernard P L; Chen, Sien-Tsong; Cunha, Luis; Dahlöf, Björn; De Keyser, Jacques; Donnan, Geoffrey A; Estol, Conrado; Gorelick, Philip; Gu, Vivian; Hermansson, Karin; Hilbrich, Lutz; Kaste, Markku; Lu, Chuanzhen; Machnig, Thomas; Pais, Prem; Roberts, Robin; Skvortsova, Veronika; Teal, Philip; Toni, Danilo; Vandermaelen, Cam; Voigt, Thor; Weber, Michael; Yoon, Byung-Woo

    2008-09-18

    Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.) 2008 Massachusetts Medical Society

  10. Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke

    PubMed Central

    Sacco, Ralph L.; Diener, Hans-Christoph; Yusuf, Salim; Cotton, Daniel; Ôunpuu, Stephanie; Lawton, William A.; Palesch, Yuko; Martin, Reneé H.; Albers, Gregory W.; Bath, Philip; Bornstein, Natan; Chan, Bernard P.L.; Chen, Sien-Tsong; Cunha, Luis; Dahlöf, Björn; De Keyser, Jacques; Donnan, Geoffrey A.; Estol, Conrado; Gorelick, Philip; Gu, Vivian; Hermansson, Karin; Hilbrich, Lutz; Kaste, Markku; Lu, Chuanzhen; Machnig, Thomas; Pais, Prem; Roberts, Robin; Skvortsova, Veronika; Teal, Philip; Toni, Danilo; VanderMaelen, Cam; Voigt, Thor; Weber, Michael; Yoon, Byung-Woo

    2009-01-01

    BACKGROUND Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens — aspirin plus extendedrelease dipyridamole (ASA–ERDP) versus clopidogrel. METHODS In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. RESULTS A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA–ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA–ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA–ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA–ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). CONCLUSIONS The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA–ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. PMID:18753638

  11. Children's Responses to the Medical Evaluation for Child Sexual Abuse.

    ERIC Educational Resources Information Center

    Dubowitz, Howard

    1998-01-01

    Addresses three issues: (1) how children respond to the medical evaluation for sexual abuse; (2) how the trauma of the evaluation experienced by some children can be minimized and the benefits maximized; and (3) how children's responses to the medical evaluation for sexual abuse can be interpreted. (DB)

  12. [Clopidogrel before and after percutaneous coronary intervention: the PCI-CURE and CREDO studies do not support long-term therapy. Shorter treatment saves millions].

    PubMed

    Eriksson, Peter

    2003-10-09

    The ideal time to start treatment with clopidogrel prior to a percutaneous coronary intervention, the most efficacious loading-dose and the optimal duration of treatment following the procedure are not known in detail. PCI-CURE and CREDO both support pre-treatment with clopidogrel. Extended treatment beyond the first few months after the procedure is not, however, supported by the data. Accordingly, 300 mg clopidogrel should be given at least 6 hours and ideally 12 hours before the procedure. If the intervention must be undertaken sooner, a doubling of the loading-dose is recommended. After the procedure, clopidogrel 75 mg once daily should be continued for one to three months.

  13. Evaluating Detection and Diagnostic Decision Support Systems for Bioterrorism Response

    PubMed Central

    Sundaram, Vandana; McDonald, Kathryn M.; Smith, Wendy M.; Szeto, Herbert; Schleinitz, Mark D.; Owens, Douglas K.

    2004-01-01

    We evaluated the usefulness of detection systems and diagnostic decision support systems for bioterrorism response. We performed a systematic review by searching relevant databases (e.g., MEDLINE) and Web sites for reports of detection systems and diagnostic decision support systems that could be used during bioterrorism responses. We reviewed over 24,000 citations and identified 55 detection systems and 23 diagnostic decision support systems. Only 35 systems have been evaluated: 4 reported both sensitivity and specificity, 13 were compared to a reference standard, and 31 were evaluated for their timeliness. Most evaluations of detection systems and some evaluations of diagnostic systems for bioterrorism responses are critically deficient. Because false-positive and false-negative rates are unknown for most systems, decision making on the basis of these systems is seriously compromised. We describe a framework for the design of future evaluations of such systems. PMID:15078604

  14. Sharing stories: narrative and dialogue in responsive nursing evaluation.

    PubMed

    Abma, T A; Widdershoven, G A M

    2005-03-01

    Responsive evaluation is an emerging vision and rationale for nursing evaluation. In this vision, evaluation is redefined as an engagement with all stakeholders about the value and meaning of their practice as a vehicle for learning, understanding, and improvement. In this article, the authors aim to illustrate the utility of a particular version of responsive evaluation, one that is connected with recent ideas about narrative and dialogue. They concentrate on methodological issues and use a case example to illustrate these issues. The case concerns a responsive evaluation of the quality of palliative care for cancer patients in a Dutch region. Methodological issues include the collection of stories through the use of conversational interviews. Stories can reveal the meaning and ambiguity of everyday situations. If evaluators listen to different stories and facilitate a dialogue about stories, this will enhance mutual understandings and promote respect, inclusiveness, and social equity.

  15. Imaging in evaluation of response to neoadjuvant breast cancer treatment

    PubMed Central

    Ollivier, L; Balu-Maestro, C; Leclère, J

    2005-01-01

    The role of imaging for patients treated with neoadjuvant therapy for breast cancer is not only to evaluate the therapeutic response in terms of tumour shrinkage, but also to predict the histological response to chemotherapy, which is correlated to survival. Surgery and histopathological analysis after neoadjuvant therapy allow for an objective assessment of the accuracy of imaging techniques in evaluating response. The aim of this study is to compare the value of the different conventional and functional imaging techniques for determining response to neoadjuvant chemotherapy in breast cancer treatment. PMID:16154816

  16. Combination of aspirin and clopidogrel for the prevention of thrombosis: implications for the dental practitioner.

    PubMed

    Shah, Paulomi R; Yepes, Juan F; Valenza, John A

    2007-01-01

    The use of aspirin and clopidogrel as effective antiplatelet therapy in preventing secondary thromboembolic events is well-established. However, there is controversy among dentists and physicians regarding the appropriate dental management of patients receiving dual antiplatelet therapy due to the lack of clinical studies about hemorrhagic risk in these patients. Indications for modifying dual antiplatelet therapy--whether it is done by altering doses, switching to monotherapy, or discontinuing it completely--occur infrequently, as most patients can be treated in a dental office setting. In all cases, patients must be managed jointly by the dentist and physician, taking into account the patient's medical and dental history. This article reviews the current use of aspirin and clopidogrel as combination therapy, examining their effect on platelet function, the associated hemorrhagic risk during dental procedures for patients using this therapy, and how oral health care providers can manage these patients safely and effectively.

  17. Measurement of platelet P-selectin for remote testing of platelet function during treatment with clopidogrel and/or aspirin.

    PubMed

    Fox, S C; May, J A; Shah, A; Neubert, U; Heptinstall, S

    2009-06-01

    There is great interest in assessing the efficacy of treatment with clopidogrel and aspirin in patients with cardiovascular disease using procedures that can be used in a remote setting. Here we have established methods to assess the effects of clopidogrel and aspirin on platelets based on measurements of platelet P-selectin. Platelets were stimulated in whole blood by adding the combination of adenosine diphosphate and the TXA(2) mimetic U46619 (ADP/U4, designed to assess P2Y(12) inhibition) or the combination of arachidonic acid and epinephrine (AA/Epi, designed to assess COX-1 inhibition). The stimulated samples were then fixed using a fixative solution that provides stability for at least 9 days, and sent to a central laboratory for analysis of P-selectin by flow cytometry. Measurements were performed in blood from healthy volunteers and patients with cardiovascular disease. The inhibitory effects of clopidogrel and aspirin were assessed ex vivo and the effects of the direct acting P2Y(12) antagonist cangrelor and aspirin were assessed in vitro. Measurements of platelet aggregation were also performed for comparison. In healthy volunteers clopidogrel ex vivo and cangrelor in vitro markedly inhibited P-selectin expression induced by ADP/U4. Aspirin did not inhibit and did not interfere with the effects of clopidogrel or cangrelor using this test. There was very little overlap of results obtained in the absence and presence of clopidogrel or cangrelor. In contrast, over half of 42 patients with cardiovascular disease did not respond well to clopidogrel treatment, although cangrelor was still effective. Aspirin markedly inhibited P-selectin expression induced by AA/Epi. Clopidogrel had much less effect and did not interfere with the effects of aspirin. There was no overlap of results obtained in the absence and presence of aspirin. Aspirin provided near-complete inhibition in 29 of 30 patients with cardiovascular disease. Aggregometry measurements agreed well with

  18. Randomised, double-blind trial on the value of tapered discontinuation of clopidogrel maintenance therapy after drug-eluting stent implantation. Intracoronary Stenting and Antithrombotic Regimen: CAUTION in Discontinuing Clopidogrel Therapy--ISAR-CAUTION.

    PubMed

    Fiedler, K Anette; Mehilli, Julinda; Kufner, Sebastian; Schlichting, Anna; Ibrahim, Tareq; Sibbing, Dirk; Ott, Ilka; Schunkert, Heribert; Laugwitz, Karl-Ludwig; Kastrati, Adnan; Schulz, Stefanie

    2014-06-01

    There is little evidence on the optimal mode of clopidogrel discontinuation. Epidemiological studies observed clustering of thrombotic events after cessation of chronic clopidogrel therapy. The underlying mechanism has been ascribed to transient platelet hyper-reactivity. Gradual tapering of clopidogrel may have the potential to attenuate this phenomenon. The objective of the present study was to assess whether in patients with drug-eluting stents (DES) gradual discontinuation of clopidogrel maintenance therapy is superior to conventional, abrupt discontinuation. Patients with planned discontinuation of chronic clopidogrel therapy after DES implantation were randomised in a double-blinded fashion to either gradual discontinuation (according to a tapering schema over four weeks) or abrupt discontinuation (after continued clopidogrel therapy for additional four weeks). The primary endpoint was the composite of cardiac death, myocardial infarction, stroke, stent thrombosis, major bleeding or rehospitalisation due to an acute coronary syndrome at 90 days. Enrollment of 3,000 patients was planned. The study was stopped prematurely due to slow recruitment after enrollment of 782 patients. At 90 days, nine of 392 patients (2.3%) with tapered cessation reached the primary endpoint compared to five of 390 patients (1.3%) with abrupt cessation (p=0.284). The composite of death or myocardial infarction occurred in three patients with tapered and three patients with abrupt discontinuation (p=0.764). In conclusion, tapered discontinuation of chronic clopidogrel therapy is not superior to abrupt discontinuation regarding the primary endpoint in this study. However, the results must be interpreted in view of the premature termination of the trial and low event rates.

  19. Effect of clopidogrel administration to healthy volunteers on platelet phosphorylation events triggered by ADP.

    PubMed

    Contreres, Jean O; Dupuy, Evelyne; Job, Bernard; Habib, Aïda; Bryckaert, Margke; Rosa, Jean P; Simoneau, Guy; Herbert, Jean M; Savi, Pierre; Levy-Toledano, Sylviane

    2003-02-01

    The action of clopidogrel on platelet receptors was analysed using platelets obtained from 11 healthy volunteers given 75 mg of clopidogrel daily for 8 d. Samples of blood were taken before treatment and after 8 d of medication. Determination of 2-methylthioadenosine diphosphate trisodium (2MesADP)-induced platelet aggregation, serine/threonine and tyrosine phosphorylations were performed in the absence or presence of the P2Y1-receptor-specific antagonist: adenosine 3'-phosphate 5'-phosphate (A3P5P) or the strong inhibitor of GPIIb/IIIa activation: SR121566. 1). Serine and threonine phosphorylations of the myosin light chain (P20) and pleckstrin (P47) do not behave similarly, although they are both recognized as the result of phospholipase C pathway stimulation triggered by the P2Y1 receptor. P47 is strongly affected by the A3P5P, and this appears to be highly dependent on P2Y12. However, P20 phosphorylation occurs in the presence of A3P5P, suggesting that the P2Y12 receptor signal contributes to P20 phosphorylation mediated by a calcium-independent pathway. The results suggest that P2Y1 and P2Y12 receptors interact to modulate the phosphorylation of P20 and P47. 2). The inside-out signalling dependent on both P2Y12 and P2Y1 is necessary for GPIIb/IIIa activation. 3). Clopidogrel and SR121566 inhibited the increase in tyrosine phosphorylation induced by 2MesADP and concomitantly inhibited platelet aggregation, indicating that most of the phosphorylations are GPIIb/IIIa dependent. However, neither clopidogrel nor SR121566 inhibited the first wave of 80 kDa substrate (cortactin) which is involved in the reorganization of the cytoskeleton necessary for shape change and which appeared to be essentially P2Y1 dependent.

  20. Clopidogrel, prasugrel or ticagrelor in patients with acute coronary syndromes undergoing percutaneous coronary intervention.

    PubMed

    Yudi, M B; Clark, D J; Farouque, O; Eccleston, D; Andrianopoulos, N; Duffy, S J; Brennan, A; Lefkovits, J; Ramchand, J; Yip, T; Oqueli, E; Reid, C M; Ajani, A E

    2016-05-01

    Guidelines recommend prasugrel or ticagrelor instead of clopidogrel in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary interventions (PCI). We sought to describe the trends in uptake of the newer agents and analyse the clinical characteristics and short-term outcomes of patients treated with clopidogrel, prasugrel or ticagrelor. We analysed the temporal trends of antiplatelet use since the availability of prasugrel (2009-2013) in patients with ACS from the Melbourne Interventional Group registry. To assess clinical characteristics and outcomes, we included 1850 patients from 2012 to 2013, corresponding to the time all three agents were available. The primary outcome was major adverse cardiovascular events (MACE). The safety end-point was in-hospital bleeding. For the period of 2009-2013, the majority of patients were treated with clopidogrel (72%) compared with prasugrel (14%) or ticagrelor (14%). There was a clear trend towards ticagrelor by the end of 2013. Patients treated with clopidogrel were more likely to present with non-ST-elevation ACS, be older, and have more comorbidities. There was no difference in unadjusted 30-day mortality (0.9 vs 0.5 vs 1.0%, P = 0.76), myocardial infarction (2 vs 1 vs 2%, P = 0.52) or MACE (3 vs 3 vs 4%, P = 0.57) between the three agents. There was no difference in in-hospital bleeding (3 vs 2 vs 2%, P = 0.64). Prasugrel and ticagrelor are increasingly used in ACS patients treated with PCI, predominantly in a younger cohort with less comorbidity. Although antiplatelet therapy should still be individualised based on the thrombotic and bleeding risk, our study highlights the safety of the new P2Y12 inhibitors in contemporary Australian practice. © 2016 Royal Australasian College of Physicians.

  1. Overcoming Aspirin Resistance with Loading Clopidogrel Earlier in Elective Percutaneous Coronary Intervention

    PubMed Central

    Ozcan, Ozgur Ulas; Tutar, Eralp; Candemir, Basar; Ustun, Elif Ezgi; Erol, Cetin

    2015-01-01

    We aimed to analyze the clinical effect of clopidogrel loading time on adverse cardiovascular events among patients with aspirin resistance. Recurrent adverse events may still occur despite dual antiplatelet therapy after coronary stenting. Aspirin resistance is one of the possible reasons of this trouble. Optimal antiplatelet strategy for coronary stenting is unknown among patients with aspirin resistance. A total of 980 patients scheduled for elective coronary stenting were enrolled and allocated into two groups according to the loading time of clopidogrel more or less than 6 hours before coronary intervention (early- or late-loaded groups, respectively). Aspirin resistance was determined according to the urinary levels of 11-dehydrothromboxane B2. Overall 240 patients who were allocated to early- and late-loaded groups were identified as aspirin resistant according to the urinary levels of 11-dehydrothromboxane B2. After a follow-up period of 12 months major adverse cardiac events were observed among 16 patients (13.9%) in the early-loaded group and 30 patients (25.8%) in the late-loaded group (p = 0.02). Early loading of clopidogrel was an independent predictor of lower rate of cardiac events (hazard ratio = 0.46 [0.32–0.76, 95% confidence interval], p = 0.001). The rates of bleeding events and periprocedural myocardial infarction were similar in early- and late-loaded groups. The current study demonstrated that loading of clopidogrel earlier than 6 hours before elective coronary stenting among aspirin-resistant patients was associated with increased benefits for ischemic events with similar bleeding rates. PMID:25780324

  2. Costs and consequences of direct-to-consumer advertising for clopidogrel in Medicaid.

    PubMed

    Law, Michael R; Soumerai, Stephen B; Adams, Alyce S; Majumdar, Sumit R

    2009-11-23

    Direct-to-consumer advertising (DTCA) is assumed to be a major driver of rising pharmaceutical costs. Yet, research on how it affects costs is limited. Therefore, we studied clopidogrel, a commonly used and heavily marketed antiplatelet agent, which was first sold in 1998 and first direct-to-consumer advertised in 2001. We examined pharmacy data from 27 Medicaid programs from 1999 through 2005. We used interrupted time series analysis to analyze changes in the number of units dispensed, cost per unit dispensed, and total pharmacy expenditures after DTCA initiation. In 1999 and 2000, there was no DTCA for clopidogrel; from 2001 through 2005, DTCA spending exceeded $350 million. Direct-to-consumer advertising did not change the preexisting trend in the number of clopidogrel units dispensed per 1000 enrollees (P = .10). However, there was a sudden and sustained increase in cost per unit of $0.40 after DTCA initiation (95% confidence interval, $0.31-$0.49; P < .001), leading to an additional $40.58 of pharmacy costs per 1000 enrollees per quarter thereafter (95% confidence interval, $22.61-$58.56; P < .001). Overall, this change resulted in an additional $207 million in total pharmacy expenditures. Direct-to-consumer advertising was not associated with an increase in clopidogrel use over and above preexisting trends. However, Medicaid pharmacy expenditures increased substantially after the initiation of DTCA because of a concomitant increase in the cost per unit. If drug price increases after DTCA initiation are common, there are important implications for payers and for policy makers in the United States and elsewhere.

  3. ASA failure: does the combination ASA/clopidogrel confer better long-term vascular protection?

    PubMed

    Côté, Robert; Zhang, Yu; Hart, Robert G; McClure, Leslie A; Anderson, David C; Talbert, Robert L; Benavente, Oscar R

    2014-02-04

    To assess whether adding clopidogrel to acetylsalicylic acid (ASA) has a long-term protective vascular effect in patients with lacunar stroke while taking ASA. Post hoc analysis of 838 patients with ASA failure and recent lacunar stroke from the Secondary Prevention of Small Subcortical Strokes Trial (SPS3) cohort randomly allocated to aspirin (325 mg/day) and clopidogrel (75 mg/day) or placebo. Primary efficacy outcome was stroke recurrence (ischemic and intracranial hemorrhage) and main safety outcome was major extracranial hemorrhage. Patients were followed for a mean period of 3.5 years. The ASA failure group had a significantly higher risk of vascular events including ischemic stroke when compared with the non-ASA failure group (n = 2,151) in SPS3 (p = 0.03). Mean age was 65.6 years and 65% were men. The risk of recurrent stroke was not reduced in the dual antiplatelet group, 3.1% per year, compared to the aspirin-only group, 3.3% per year (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.61-1.37). There was also no difference between groups for ischemic stroke (HR 0.90; 95% CI 0.59-1.38). The risk of gastrointestinal bleeding was higher in the dual antiplatelet group (HR 2.7; 95% CI 1.1-6.9); however, the risk of intracranial hemorrhage was not different. In patients with a recent lacunar stroke while taking ASA, the addition of clopidogrel did not result in reduction of vascular events vs continuing ASA only. This study provides Class I evidence that for patients with recent lacunar stroke while taking ASA, adding clopidogrel as compared to continuing ASA alone does not reduce the risk of recurrent stroke.

  4. Species Comparison of Pre-systemic Bioactivation of Vicagrel, a New Acetate Derivative of Clopidogrel

    PubMed Central

    Qiu, Zhi-xia; Gao, Wen-chao; Dai, Yu; Zhou, Su-feng; Zhao, Jie; Lu, Yang; Chen, Xi-jing; Li, Ning

    2016-01-01

    Previously we have found vicagrel, a new acetate derivative of clopidogrel, underwent hydrolysis to 2-oxo-clopidogrel and subsequent conversions to its pharmacological active metabolite (AM) and inactive carboxylic acid metabolite (CAM). This study demonstrated the interspecies differences of the vicagrel bioactivation by comparing the critical vicagrel metabolites formation in rats, dogs and human. The pharmacokinetic studies with rats and dogs were conducted after intragastric administration of vicagrel, followed by in vitro metabolism investigation in venous system, intestinal/hepatic microsomes from rats, dogs and human. An obvious disparity was observed in system exposure to AM (99.0 vs. 635.1 μg⋅h/L, p < 0.05) and CAM (10119 vs. 2634 μg⋅h/L, p < 0.05) in rats and dogs. It was shown that the cleavage of vicagrel was almost completed in intestine with great different clearance (53.28 vs. 3.643 L⋅h-1⋅kg-1, p < 0.05) in rats and dogs. With no further hydrolysis to CAM, the greatest clearance of AM (3.26 mL⋅h-1⋅kg-1) was found in dog intestine. In rat plasma, 2-oxo-clopidogrel was much more extensively hydrolyzed to CAM than in dog and human. Albeit similar hydrolysis clearance and AM production was observed among hepatic microsomes of the three species, the production velocity of CAM ranked highest in dogs (7.55 pmol/min/mg protein). Therefore, the unconformity of AM and CAM exposure cross species mainly came from the metabolism of 2-oxo-clopidogrel associated largely with tissue specificity and interspecies differences of esterases. In human, the pharmacokinetics of vicagrel might be more optimistic due to less inactivation hydrolysis before reaching liver. PMID:27774067

  5. Development and validation of an HPLC–MS/MS method to determine clopidogrel in human plasma

    PubMed Central

    Liu, Gangyi; Dong, Chunxia; Shen, Weiwei; Lu, Xiaopei; Zhang, Mengqi; Gui, Yuzhou; Zhou, Qinyi; Yu, Chen

    2015-01-01

    A quantitative method for clopidogrel using online-SPE tandem LC–MS/MS was developed and fully validated according to the well-established FDA guidelines. The method achieves adequate sensitivity for pharmacokinetic studies, with lower limit of quantifications (LLOQs) as low as 10 pg/mL. Chromatographic separations were performed on reversed phase columns Kromasil Eternity-2.5-C18-UHPLC for both methods. Positive electrospray ionization in multiple reaction monitoring (MRM) mode was employed for signal detection and a deuterated analogue (clopidogrel-d4) was used as internal standard (IS). Adjustments in sample preparation, including introduction of an online-SPE system proved to be the most effective method to solve the analyte back-conversion in clinical samples. Pooled clinical samples (two levels) were prepared and successfully used as real-sample quality control (QC) in the validation of back-conversion testing under different conditions. The result showed that the real samples were stable in room temperature for 24 h. Linearity, precision, extraction recovery, matrix effect on spiked QC samples and stability tests on both spiked QCs and real sample QCs stored in different conditions met the acceptance criteria. This online-SPE method was successfully applied to a bioequivalence study of 75 mg single dose clopidogrel tablets in 48 healthy male subjects. PMID:26904399

  6. Aspirin and clopidogrel resistance using the cone and plate(let) analyser in Indian patients with coronary artery disease

    PubMed Central

    Koshy, Sudeep Kurien; Salahuddin, Salman; Karunakaran, Bijoy; Nalakath, Sajid Yoonus; Bhaskaran, Jayesh; Haridas, Padinjare Veloor; Mandalay, Asishkumar; Faizal, Ali

    2014-01-01

    Background Resistance to antiplatelet drugs is a well-known entity. However, data for aspirin and clopidogrel resistance, and its clinical significance, in Indian patients are meagre. Aims and objectives We sought to determine the prevalence of resistance to aspirin and clopidogrel in Indian patients with stable coronary heart disease (CHD), using the cone and plate(let) analyser (CPA) technology. Setting and design A single centre prospective study in a cohort of patients with stable CHD on chronic aspirin and clopidogrel therapy attending the cardiology outpatient clinic of a tertiary care hospital in Southern India. Methods Platelet function was measured using the Impact-R device (DiaMed, Cressier, Switzerland). Resistance to aspirin and clopidogrel was measured in a cohort of 100 patients with stable documented CHD. Relation of antiplatelet resistance to various clinical comorbidities was also assessed. Results Of the 100 patients, 85% were men, and 15% were above 65 years of age. 47% patients had diabetes, 29% of patients were hypertensive and 16% were smokers. Using the CPA, 12 patients (12%) were found to be resistant to aspirin and 19 patients (19%) were clopidogrel resistant. In addition, 10 patients (10%) were resistant to both aspirin and clopidogrel. There was no significant correlation between the presence of antiplatelet resistance and several baseline clinical variables, including age, sex, diabetes, hypertension and smoking. Conclusions Resistance to aspirin and clopidogrel and dual antiplatelet resistance are prevalent in Indian patients, comparable with the prevalence worldwide. The CPA is a feasible assay to determine antiplatelet resistance. PMID:27326196

  7. Non-antiplatelet effect of clopidogrel: improving endothelial function in Chinese healthy subjects with different CYP2C19 genotype.

    PubMed

    Zhang, Yin-Zhuang; Chen, Bi-Lian; Zhang, Wei; Cao, Xin

    2015-01-01

    Clopidogrel has been shown to improve endothelial function in vitro and in patients with coronary artery disease. However, it remains unclear whether such an effect of clopidogrel is associated with CYP2C19 polymorphisms that determine the antiplatelet effect of clopidogrel. After genotyping, 12 healthy participants were enrolled in the study. Among them, six participants were CYP2C19*1/*1 (extensive metabolizers; EM) and the other six participants were CYP2C19*2/*2 or *3 (poor metabolizers; PM). All participants received 300 mg clopidogel orally. Endothelial function was assessed by measurement of flow-mediated dilation of the brachial artery, and adenosine diphosphate-induced platelet aggregation was determined by using optical aggregometry at 0, 4 and 24 h after administration of 300 mg clopidogrel. Flow-mediated dilation was significantly higher at 4 and 24 h after a loading-dose administration of clopidogrel in both the CYP2C19 EM and PM groups, but showed no significant difference between the two groups. Adenosine diphosphate-induced platelet aggregation was significantly inhibited at 4 and 24 h after administration of clopidogrel in the CYP2C19 EM group. However, there was no statistical correlation between the change in flow-mediated dilation and adenosine diphosphate-induced platelet aggregation in the two CYP2C19 groups. This is the first study to report that clopidogrel improves endothelial function in healthy Chinese subjects, which is unrelated with the CYP2C19 genotype and independent of antiplatelet action.

  8. Combination antiplatelet therapy with aspirin and clopidogrel: the role of antecedent and concomitant doses of aspirin. An analysis of 711 patients.

    PubMed

    Serebruany, Victor L; Malinin, Alex I; Atar, Dan

    2007-01-01

    Numerous randomized studies have shown that the combination of clopidogrel with aspirin yields better clinical outcomes than monotherapy in patients with acute vascular events. However, the impact of the aspirin dose on the antiplatelet potency of clopidogrel is unclear. We sought to compare the antiplatelet profile of aspirin 81 mg (n = 252) versus aspirin 325 mg (n = 459) before and during conventional clopidogrel loading (300 mg), and/or clopidogrel maintenance (75 mg/daily) therapy. Secondary post hoc analysis of an existing dataset consisting of 711 patients after coronary stenting (n = 601) and ischemic stroke (n = 110) treated previously with aspirin for at least 1 month, and then with aspirin + clopidogrel for at least 7 days was performed. Platelet assessments include conventional and whole blood aggregometry, rapid cartridge-based analyzers, and expression of platelet/endothelial cell adhesion molecule-1, P-selectin, and GPIIb/IIIa activity by flow cytometry measured before and after addition of clopidogrel. There was a small but consistent yet non-significant trend towards more potent platelet inhibition with aspirin 325 mg compared to aspirin 81 mg for every platelet activation parameter before addition of clopidogrel. However, after loading and/or 1 week of chronic treatment with clopidogrel + aspirin, measured platelet parameters became very similar between the groups, and identical for collagen-induced aggregation and PFA-100 analyzer readings. Before addition of clopidogrel, aspirin 325 mg has a tendency to provide stronger platelet inhibition than aspirin 81 mg. However, when clopidogrel and aspirin are used in combination, the higher aspirin dose does not translate into superior antiplatelet action. Given that the existing body of evidence supports the comparable efficacy and, particularly, superior safety of lower versus higher doses of aspirin, aspirin 81 mg should be the dose used in combination with clopidogrel. 2007 S. Karger AG, Basel

  9. Comparative Efficacy and Safety of Prasugrel, Ticagrelor, and Standard-Dose and High-Dose Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention: A Network Meta-analysis.

    PubMed

    Singh, Sukhchain; Singh, Mukesh; Grewal, Navsheen; Khosla, Sandeep

    2016-01-01

    Authors aimed to compare efficacy and safety of prasugrel, ticagrelor, and standard-dose (SD) and high-dose (HD) clopidogrel in patients undergoing percutaneous coronary intervention (PCI). PubMed, EMBASE, CENTRAL, and clinicaltrials.gov were searched for studies comparing prasugrel, ticagrelor, SD and HD clopidogrel in patients undergoing PCI. Frequentist and Bayesian network meta-analyses were performed besides direct pairwise comparisons. Thirty trials, comprising 34,563 person-year data, were included. Prasugrel emerged as a best drug to prevent definite or probable stent thrombosis, followed by HD clopidogrel and ticagrelor, with SD clopidogrel being the worst. Myocardial infarction was least likely to be prevented by SD clopidogrel after PCI, and remaining 3 were superior to it with little difference among them. SD clopidogrel was least effective in preventing cardiovascular deaths after PCI. Prasugrel was most effective in preventing cardiovascular deaths, although having only small advantage over ticagrelor and HD clopidogrel. Ticagrelor reduced all-cause mortality by a small margin compared with rest of treatments. SD clopidogrel, followed by ticagrelor, resulted in significantly lower thrombolysis in myocardial infarction major bleeding complications compared with prasugrel. Analysis of any bleeding revealed similar trend. HD clopidogrel performed better than prasugrel in terms of bleeding complications. In conclusion, Prasugrel is likely most effective drug to prevent post-PCI ischemic events but at the expense of higher bleeding. Ticagrelor followed by HD clopidogrel seems to strike the right balance between efficacy and safety. HD clopidogrel can be considered as an alternative to newer P2Y12 inhibitors.

  10. Effects of clopidogrel on mortality, cardiovascular and bleeding outcomes in patients with chronic kidney disease - data from Taiwan acute coronary syndrome full spectrum registry.

    PubMed

    Lin, Tsung-Hsien; Lai, Wen-Ter; Hsin, Ho-Tsung; Li, Ai-Hsien; Wang, Chun-Li; Kuo, Chi-Tai; Hwang, Juey-Jen; Chiang, Fu-Tien; Chang, Shu-Chen

    2013-01-01

    The efficacy of clopidogrel is inconclusive in the chronic kidney disease (CKD) population with acute coronary syndrome (ACS). Furthermore, CKD patients are prone to bleeding with antiplatelet therapy. We investigated the efficacy and safety of clopidogrel in patients with ACS and CKD. In a Taiwan national-wide registry, 2819 ACS patients were enrolled. CKD is defined as an estimated glomerular filtration rate of less than 60 ml/min per 1.73 m(2). The primary endpoints are the combined outcomes of death, non-fatal myocardial infarction and stroke at 12 months. Overall 949 (33.7%) patients had CKD and 2660 (94.36%) patients received clopidogrel treatment. CKD is associated with increased risk of the primary endpoint at 12 months (HR 2.39, 95% CI 1.82 to 3.15, p<0.01). Clopidogrel use is associated with reduced risk of the primary endpoint at 12 months (HR 0.42, 95% CI: 0.29-0.60, p<0.01). Cox regression analysis showed that clopidogrel reduced death and primary endpoints for CKD population (HR 0.35, 95% CI: 0.21-0.61 and HR 0.48, 95% CI: 0.30-0.77, respectively, both p<0.01). Patients with clopidogrel(-)/CKD(-), clopidogrel(+)/CKD(+) and clopidogrel(-)/CKD(+) have 2.4, 3.0 and 10.4 fold risk to have primary endpoints compared with those receiving clopidogrel treatment without CKD (all p<0.01). Clopidogrel treatment was not associated with increased in-hospital Thrombolysis In Myocardial Infarction (TIMI) bleeding in CKD population. Clopidogrel could decrease mortality and improve cardiovascular outcomes without increasing risk of bleeding in ACS patients with CKD.

  11. 40 CFR 265.93 - Preparation, evaluation, and response.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 26 2011-07-01 2011-07-01 false Preparation, evaluation, and response. 265.93 Section 265.93 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID..., STORAGE, AND DISPOSAL FACILITIES Ground-Water Monitoring § 265.93 Preparation, evaluation, and...

  12. Evaluation Responsibility and Leadership in the Face of Failing Democracies

    ERIC Educational Resources Information Center

    McKegg, Kate

    2013-01-01

    In a world faced with unprecedented rising levels of inequality and injustice, is there a responsibility for our evaluation organizations to take on a leadership role in promoting inclusive, evaluative dialog and deliberation about the state of our democracies in relation to key democratic principles and ideals? In this forum, I question whether…

  13. Cytochrome P450 Gene Variants, Race, and Mortality Among Clopidogrel Treated Patients Following Acute Myocardial Infarction

    PubMed Central

    Cresci, Sharon; Depta, Jeremiah P.; Lenzini, Petra A.; Li, Allie Y.; Lanfear, David E.; Province, Michael A.; Spertus, John A.; Bach, Richard G.

    2014-01-01

    Background Clopidogrel is recommended after acute myocardial infarction (AMI) but has variable efficacy and safety, in part related to the effect of cytochrome P450 (CYP) polymorphisms on its metabolism. The effect of CYP polymorphisms on cardiovascular events among clopidogrel-treated patients after AMI remains controversial, and no studies to date have investigated the association of CYP variants with outcomes in African American patients. Methods and Results 2732 subjects (2062 Caucasians; 670 African Americans) hospitalized with AMI enrolled in the prospective, multicenter TRIUMPH study were genotyped for CYP polymorphisms. The majority of Caucasians (79%) and African Americans (64.4%) were discharged on clopidogrel. Among Caucasians, carriers of the loss-of-function CYP2C19*2 allele had significantly increased 1-year mortality (adjusted HR: 1.70; CI: 1.01 to 2.86; p=0.046), and a trend toward increased rate of recurrent MI (adjusted HR: 2.10; CI 0.95 to 4.63; p= 0.066). Among African Americans, increased 1-year mortality was associated with the gain of function CYP2C19*17 allele (adjusted HR for *1/*17 vs. *1/*1: 2.02; CI: 0.92 to 4.44; *17/*17 vs. *1/*1: 8.97; CI: 3.34 to 24.10; p< 0.0001) and the CYP1A2*1C allele (adjusted HR for *1/*1C vs. *1/*1: 1.89; CI: 0.85 to 4.22; *1C/*1C vs. *1/*1: 4.96; CI: 1.69 to 14.56; p= 0.014). Bleeding events were significantly more common among African American carriers of CYP2C19*17 or CYP1A2*1C. Conclusions Both loss of function and gain of function CYP polymorphisms affecting clopidogrel metabolism are associated with increased mortality among clopidogrel treated patients following AMI; the specific polymorphism and the putative mechanism vary according to race. PMID:24762860

  14. Clinical bioequivalence of a dose of clopidogrel Leti Cravid tablets 75 mg versus clopidogrel Sanofi Plavix tablets 75 mg administered on a daily dose for 7 days on healthy volunteers: a clinical trial.

    PubMed

    Müller, Aixa; Octavio, José; González, María Y; Contreras, Jesús; Méndez, Gisela; Portillo, Milagros; Valero, Zuleima

    2010-01-01

    Patients undergoing percutaneous coronary intervention procedures, as in patients with coronary disease, should receive treatment indefinitely with acetylsalicylic acid and clopidogrel. New brands of clopidogrel have been developed at lower costs, for helping to avoid premature suspension of antiplatelet therapy, as Cravid Leti Laboratories clopidogrel. Its effectiveness and safety must be compared with Plavix international standard. A prospective, comparative, cross-over, and randomized study was conducted in healthy volunteers. Each group received 1 tablet of Clopidogrel Leti or Clopidogrel Sanofi, 75 mg in a single dose daily for 7 days, followed by 7-day washout period before administration of second treatment. Platelet aggregation was measured at the start of each period and at 7 days of treatment through optical aggregometry, using an optical aggregometer 490-2D Chrono-Log, with a self-calibration system working with platelet-rich plasma with readings 0%-100% of light transmission. An important decrease of platelet aggregation was observed in both groups at 7 days of treatment of more than 50%, independent of adenosine diphosphate reactive (Helena and Chrono-Log) used for aggregation (P < 0.05). The relationship between the mean and 90% confidence interval ratio obtained with the 2 different adenosine diphosphate brands were between 80% and 125%, therefore, it can be considered that both brands are bioequivalent and perfectly exchangeable.

  15. Short-term bleeding events observed with clopidogrel loading in acute ischemic stroke patients.

    PubMed

    Leung, Lester Y; Albright, Karen C; Boehme, Amelia K; Tarsia, Joseph; Shah, Kamal R; Siegler, James E; Jones, Erica M; Pletsch, Gayle R; Beasley, Timothy M; Martin-Schild, Sheryl

    2013-10-01

    The Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence trial raised concern that loading doses of clopidogrel may increase hemorrhagic complications. We investigated if similar rates of hemorrhage occur in patients with acute ischemic stroke (AIS) of varying severity. Patients meeting inclusion criteria were divided into 2 groups: the LOAD group and non-LOAD group. The LOAD group was defined as patients who were administered a loading dose of 300 mg or more of clopidogrel with or without aspirin within 24 hours of admission. The non-LOAD group was devised using propensity score (PS): 55 patients who received a loading dose of clopidogrel of 300 mg or more were matched on PS to 55 patients who did not receive loading doses. These patients were taken from a pool of 341 consecutive ischemic patients ineligible for intravenous or intra-arterial fibrinolysis, 162 of whom received a clopidogrel loading dose and the remainder of whom did not. The frequency of hemorrhage was compared between the 2 groups using Student t test and chi-square. Logistic regression was used to assess the relationship between loading dose and serious bleeding events (symptomatic intracerebral hemorrhage [sICH] or transfusion for systemic bleeding). AIS patients (N = 596) were screened during the 31-month period of this retrospective study. Of this sample, 170 patients were excluded: 149 patients were excluded because they were treated with intravenous tissue plasminogen activator (IV t-PA) alone, 11 were excluded because they were treated with IV t-PA combined with intra-arterial therapy (IAT), and 10 were excluded for treatment with IAT alone. An additional 85 patients were excluded because they were not admitted to the stroke service or because they had an in-hospital stroke. Baseline characteristics of the groups were well matched. There were no significant differences in the rates of sICH, transfusion, hemorrhagic transformation, or systemic bleeding

  16. Physician Perspectives of CYP2C19 and Clopidogrel Drug-Gene Interaction Active Clinical Decision Support Alerts

    PubMed Central

    Nishimura, Adam A.; Shirts, Brian H.; Salama, Joseph; Smith, Joe W.; Devine, Beth; Tarczy-Hornoch, Peter

    2015-01-01

    Objective To determine if physicians find clinical decision support alerts for pharmacogenomic drug-gene interactions useful and assess their perceptions of usability aspects that impact usefulness. Materials and Methods 52 physicians participated in an online simulation and questionnaire involving a prototype alert for the clopidogrel and CYP2C19 drug-gene interaction. Results Only 4% of participants stated they would override the alert. 92% agreed that the alerts were useful. 87% found the visual interface appropriate, 91% felt the timing of the alert was appropriate and 75% were unfamiliar with the specific drug-gene interaction. 80% of providers preferred the ability to order the recommended medication within the alert. Qualitative responses suggested that supplementary information is important, but should be provided as external links, and that the utility of pharmacogenomic alerts depends on the broader ecosystem of alerts. Principal Conclusions Pharmacogenomic alerts would be welcomed by many physicians, can be built with minimalist design principles, and are appropriately placed at the end of the prescribing process. Since many physicians lack familiarity with pharmacogenomics but have limited time, information and educational resources within the alert should be carefully selected and presented in concise ways. PMID:26642939

  17. Clopidogrel-related refractory bleeding after coronary artery bypass graft surgery: a rationale for the use of coagulation factor concentrates?

    PubMed

    von Heymann, C; Schoenfeld, H; Sander, M; Ziemer, S; Grubitzsch, H; Spies, C

    2005-01-01

    Clopidogrel, an irreversible ADP-receptor antagonist, inhibits platelet aggregation mediated by reduced activation of glycoprotein receptor IIb/IIIa. Clopidogrel in combination with aspirin has been shown to be superior to aspirin alone for treating unstable angina, but clopidogrel recipients have shown increases in blood loss, transfusion requirements, and rate of reoperation after cardiac surgery. We describe a patient who had taken clopidogrel 75 mg daily until the day prior to coronary artery bypass graft surgery. Severe postoperative bleeding developed and was refractory to conventional hemostatic therapy consisting of 19 units of packed red blood cell concentrates, 16 of fresh frozen plasma, 8 of platelet apheresis concentrates plus high-dose treatment with aprotinin (500.000 kallikrein-inhibiting units/h) and administration of 0.3 microg/kg 1-deamino-8-D-arginine vasopressin (DDAVP). Two reoperations were performed, but surgical hemostasis was not achieved, so 100 microg/kg recombinant activated factor VII was applied to generate sufficient thrombin to stop the bleeding. This treatment approach reduced the bleeding. Then, to promote clot formation and firmness, 2 g of fibrinogen and 1250 IU of factor XIII were administered, and the bleeding finally stopped. No further transfusions were required, and the patient was discharged from the hospital on day 10 after the operation. This case suggests that in clopidogrel-related bleeding refractory to conventional hemostatic therapy, hemostasis may be achieved by a stepwise administration of coagulation factor concentrates.

  18. Multiple Recurrent Stent Thrombosis in a Patient with Coexisting Clopidogrel Resistance and Increased Anticardiolipin Antibodies: A Case Report

    PubMed Central

    Middlebrooks, Erik H.; Panda, Mukta

    2010-01-01

    The antiphospholipid syndrome (APS) is a common cause of both arterial and venous thrombosis. While studies exist demonstrating the role of APS in coronary artery bypass graft failure, its role in stent thrombosis is less clearly documented. Also, a literature search of PubMed did not reveal any articles regarding the coexistence of clopidogrel resistance and APS despite increasing awareness of resistance to clopidogrel treatment. We present a case of a 59-year-old male having recurrent myocardial infarction after subacute restenosis of multiple drug-eluting stents despite anticoagulant therapy. The patient had in-stent thrombosis of seven drug-eluting stents in a course of eight days. He was subsequently found to have mild elevation of IgG anticardiolipin (aCL) antibody titers and resistance to clopidogrel. Long-term anticoagulation with a combination of low-molecular-weight heparin, clopidogrel, and aspirin has been effective. While the patient's aCL titer level was not elevated above the level required by the current diagnostic criteria for APS, we believe that this patient suffers from the antiphospholipid syndrome. We will discuss some of the controversies surrounding the diagnosis of APS as well as appropriate treatment and recognition of the coexistence of APS and clopidogrel resistance in patients with stent thrombosis. PMID:20592997

  19. The risk of clopidogrel resistance is associated with ABCB1 polymorphisms but not promoter methylation in a Chinese Han population

    PubMed Central

    Su, Jia; Yu, Qinglin; Zhu, Hao; Li, Xiaojing; Cui, Hanbin; Du, Weiping; Ji, Lindan; Tong, Maoqing; Zheng, Yibo; Xu, Hongyu; Zhang, Jianjiang; Zhu, Yunyun; Xia, Yezi; Liu, Ting; Yao, Qi; Yang, Jun; Chen, Xiaomin; Yu, Jingbo

    2017-01-01

    The goal of our study was to investigate the contribution of ABCB1 expression to the risk of clopidogrel resistance (CR). Platelets functions were measured using the Verify-Now P2Y12 assay. Applying Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR-RFLP), the single-nucleotide polymorphisms (SNPs) was tested. Using bisulphite pyrosequencing assay, we investigated the association of the ABCB1 DNA methylation levels and CR. It was shown that female, hypertension, and lower albumin levels increased the risk of CR (P<0.05). If patients did not have hypoproteinaemia or had hypertension, the SNP in rs1045642 was associated with CR (CC vs. TT: albumin ≥35, P = 0.042; hypertension, P = 0.045; C vs. T: albumin ≥35, P = 0.033; hypertension, P = 0.040). Additionally, the platelet inhibition of the CT+TT genotype in rs1128503 was larger than that of the CC genotype (P = 0.021). Multivariate logistic regression analysis showed that male, higher albumin and hsCRP decreased the risk of CR, and the stent size maybe positively correlated with CR. The SNP in rs1045642 was related to all-cause mortality (P = 0.024). We did not find any relationship between the methylation levels of the ABCB1 promoter and CR. In conclusions, our study indicated that ABCB1 polymorphisms might be useful in further evaluating the pathogenesis of CR. PMID:28358842

  20. [Response evaluation in nuclear medicine : Criteria, results and pitfalls].

    PubMed

    Hoffend, J; Sachpekidis, C; Dimitrakopoulou-Strauss, A

    2017-09-05

    Established criteria to categorize metabolic tumor response to cytotoxic chemotherapies may not be suited to capture the effects of therapy with immune checkpoint inhibitors (ICI) or with kinase inhibitors (KI), such as BRAF or MEK inhibitors. To assess the metabolic response to cytotoxic chemotherapy by positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG), the criteria of the European Organization for Research and Treatment of Cancer (EORTC) and the positron emission tomography response criteria in solid tumors (PERCIST) were conceived. The salient features of both criteria are detailed in a comparative way. To date only retrospective data exist for the evaluation of therapies with either ICI or KI. They show that response to ICI cannot be reliably determined using the established criteria. Employing the EORTC criteria the responses to KI can be adequately ascertained so that the metabolic tumor response in FDG-PET is regarded as a surrogate marker for the efficacy of these drugs. Tumor response to therapy with ICI cannot at present be assessed with FDG-PET. Responses to BRAF and MEK inhibitors are, however, assessable using the criteria that were originally developed to evaluate responses to cytotoxic chemotherapy.

  1. Pharmacodynamic effects of a new fixed-dose clopidogrel-aspirin combination compared with separate administration of clopidogrel and aspirin in patients treated with coronary stents: The ACCEL-COMBO trial.

    PubMed

    Koh, Jin-Sin; Park, Yongwhi; Tantry, Udaya S; Ahn, Jong-Hwa; Kang, Min Gyu; Kim, Kyehwan; Jang, Jeong Yoon; Park, Hyun Woong; Park, Jeong Rang; Hwang, Seok-Jae; Kwak, Choong Hwan; Hwang, Jin-Yong; Gurbel, Paul A; Jeong, Young-Hoon

    2017-03-01

    Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely prescribed regimen to prevent ischemic events in patients undergoing percutaneous coronary intervention (PCI). A fixed-dose combination (FDC) capsule (HCP0911) has been developed to provide dosing convenience and improve adherence. We compared the antiplatelet effects of single daily dose HCP0911 with separate treatment with daily 75 mg clopidogrel plus 100 mg aspirin. This was a randomized, open-label, two-period, crossover, non-inferiority study conducted in stented patients who had been treated for at least 6 months with clopidogrel and aspirin. Thirty patients were randomly assigned to receive either daily 75 mg clopidogrel plus 100 mg aspirin treatment or HCP0911 for 2 weeks and then were crossed over to the other treatment for 2 weeks. Pharmacodynamic effects were measured with VerifyNow, light transmittance aggregometry (LTA), and thromboelastography (TEG(®)). The primary endpoint was P2Y12 Reaction Units (PRU) measured by VerifyNow. PRUs during treatment with HCP0911 were not inferior to those during separate treatment (202 ± 52 vs. 207 ± 60 PRU; mean difference, -5 PRU; 90% confidence interval of difference, -23 to 13 PRU; P for non-inferiority = 0.015 for predetermined limit). "BASE" and Aspirin Reaction Units by VerifyNow did not differ between the two treatments. During each treatment, there were no differences in maximal and final platelet aggregations by LTA (all P values ≥0.822) and TEG(®) measurements. In conclusion, in stented patients, the antiplatelet effect of a fixed-dose clopidogrel-aspirin combination, HCP0911, was not inferior to separate administration of clopidogrel and aspirin.

  2. Non-Hodgkin lymphoma response evaluation with MRI texture classification

    PubMed Central

    Harrison, Lara CV; Luukkaala, Tiina; Pertovaara, Hannu; Saarinen, Tuomas O; Heinonen, Tomi T; Järvenpää, Ritva; Soimakallio, Seppo; Kellokumpu-Lehtinen, Pirkko-Liisa I; Eskola, Hannu J; Dastidar, Prasun

    2009-01-01

    Background To show magnetic resonance imaging (MRI) texture appearance change in non-Hodgkin lymphoma (NHL) during treatment with response controlled by quantitative volume analysis. Methods A total of 19 patients having NHL with an evaluable lymphoma lesion were scanned at three imaging timepoints with 1.5T device during clinical treatment evaluation. Texture characteristics of images were analyzed and classified with MaZda application and statistical tests. Results NHL tissue MRI texture imaged before treatment and under chemotherapy was classified within several subgroups, showing best discrimination with 96% correct classification in non-linear discriminant analysis of T2-weighted images. Texture parameters of MRI data were successfully tested with statistical tests to assess the impact of the separability of the parameters in evaluating chemotherapy response in lymphoma tissue. Conclusion Texture characteristics of MRI data were classified successfully; this proved texture analysis to be potential quantitative means of representing lymphoma tissue changes during chemotherapy response monitoring. PMID:19545438

  3. Simultaneous Two-Vessel Subacute Stent Thrombosis Caused by Clopidogrel Resistance from CYP2C19 Polymorphism

    PubMed Central

    Patel, Bimal; Patel, Neel; Sattur, Sudhakar; Patel, Vinod

    2016-01-01

    Clopidogrel resistance from CYP2C19 polymorphism has been associated with stent thrombosis in patients undergoing percutaneous coronary intervention with drug-eluting stents. We present a case of a 76-year-old male who received drug-eluting stents to the right coronary artery and left anterior descending artery for non-ST elevation myocardial infarction and was discharged on dual antiplatelet therapy with aspirin and clopidogrel. He subsequently presented with chest pain from anterior, anteroseptal, and inferior ST segment elevation myocardial infarction. An emergent coronary angiogram revealed acute stent thrombosis with 100% occlusion of RCA and LAD that was successfully treated with thrombus aspiration and angioplasty. Although he was compliant with his dual antiplatelet therapy, he developed stent thrombosis, which was confirmed as clopidogrel resistance from homozygous CYP2C19 polymorphism. PMID:27555873

  4. Standard problems to evaluate piping response computer codes

    SciTech Connect

    Bezler, P.; Subudhi, M.

    1984-01-01

    A program has been underway to evaluate the analysis methods used by industry to qualify nuclear power plant piping. Two objectives of this program are to develop physical benchmarks for validating the accuracy of computer codes used to simulate piping response and to develop improved procedures for calculating the response of multiple supported piping with independent seismic inputs. The status of the program in these two areas is reviewed.

  5. Pharmacokinetics and relative bioavailability of fixed-dose combination of clopidogrel and aspirin versus coadministration of individual formulations in healthy Korean men

    PubMed Central

    Choi, Hyang-Ki; Ghim, Jong-Lyul; Shon, Jihong; Choi, Young-Kyung; Jung, Jin Ah

    2016-01-01

    Background Simultaneous prescription of clopidogrel and low-dose aspirin is recommended for the treatment of acute coronary syndrome because of improvements in efficacy and patient compliance. In this study, the pharmacokinetics of a fixed-dose combination (FDC) of clopidogrel and aspirin was compared with coadministration of individual formulations to clarify the equivalence of the FDC. Methods This was a randomized, open-label, two-period, two-treatment, crossover study in healthy Korean men aged 20–55 years. Subjects received two FDC capsules of clopidogrel/aspirin 75/100 mg (test) or two tablets of clopidogrel 75 mg and two capsules of aspirin 100 mg (reference) with a 14-day washout period. Plasma concentrations of clopidogrel, aspirin, and salicylic acid were measured using validated ultraperformance liquid chromatography–tandem mass spectrometry. Bioequivalence was assessed by analysis of variance and calculation of the 90% confidence intervals (CIs) of the ratios of the geometric means (GMRs) for AUClast and Cmax for clopidogrel and aspirin. Results Sixty healthy subjects were enrolled, and 53 completed the study. Clopidogrel, aspirin, and salicylic acid showed similar absorption profiles and no significant differences in Cmax, AUClast, and Tmax between FDC administration and coadministration of individual formulations. The GMRs (90% CI) for the Cmax and AUClast of clopidogrel were 1.08 (0.95, 1.23) and 0.93 (0.84, 1.03), respectively. The GMRs (90% CI) for the Cmax and AUClast of aspirin were 0.98 (0.84, 1.13) and 0.98 (0.93, 1.04), respectively. Both treatments were well tolerated in the study subjects. Conclusion The FDC of clopidogrel and aspirin was bioequivalent to coadministration of each individual formulation. The FDC capsule exhibited similar safety and tolerability profiles to the individual formulations. Therefore, clopidogrel/aspirin 75 mg/100 mg FDC capsules can be prescribed to improve patient compliance. PMID:27822013

  6. Evaluation of the Emergency Response Dose Assessment System(ERDAS)

    NASA Technical Reports Server (NTRS)

    Evans, Randolph J.; Lambert, Winifred C.; Manobianco, John T.; Taylor, Gregory E.; Wheeler, Mark M.; Yersavich, Ann M.

    1996-01-01

    The emergency response dose assessment system (ERDAS) is a protype software and hardware system configured to produce routine mesoscale meteorological forecasts and enhanced dispersion estimates on an operational basis for the Kennedy Space Center (KSC)/Cape Canaveral Air Station (CCAS) region. ERDAS provides emergency response guidance to operations at KSC/CCAS in the case of an accidental hazardous material release or an aborted vehicle launch. This report describes the evaluation of ERDAS including: evaluation of sea breeze predictions, comparison of launch plume location and concentration predictions, case study of a toxic release, evaluation of model sensitivity to varying input parameters, evaluation of the user interface, assessment of ERDA's operational capabilities, and a comparison of ERDAS models to the ocean breeze dry gultch diffusion model.

  7. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study.

    PubMed

    Storey, Robert F; James, Stefan K; Siegbahn, Agneta; Varenhorst, Christoph; Held, Claes; Ycas, Joseph; Husted, Steen E; Cannon, Christopher P; Becker, Richard C; Steg, Ph Gabriel; Åsenblad, Nils; Wallentin, Lars

    2014-01-01

    In the PLATelet inhibition and patient Outcomes (PLATO) study of patients with acute coronary syndromes, ticagrelor reduced mortality compared to clopidogrel but the mechanisms for this mortality reduction remain uncertain. We analysed adverse events (AEs) consistent with either pulmonary infection or sepsis, and subsequent mortality, in 18,421 PLATO patients treated with ticagrelor or clopidogrel. AEs occurring within 7 days of last dose of study medication were defined as "on-treatment". Serial measurements of blood leukocyte counts, C-reactive protein and interleukin-6 were performed. Fewer on-treatment pulmonary AEs occurred in the ticagrelor compared to the clopidogrel group (275 vs. 331 respectively; p = 0.019), with fewer deaths following these AEs (33 vs. 71; p < 0.001), particularly in those who remained on study medication three days after AE onset (10 vs. 43; p < 0.001). There were fewer deaths attributed to sepsis in the ticagrelor group (7 vs. 23; p = 0.003). Leukocyte counts were lower in the clopidogrel group during treatment (p < 0.0001 at 1, 3 and 6 months) but not at 1 month post-discontinuation. C-reactive protein increased more at discharge in the ticagrelor group (28.0 ± 38.0 vs. 26.1 ± 36.6 mg/l; p < 0.001) and interleukin-6 remained higher during the first month of treatment with ticagrelor. We conclude that the mortality risk following pulmonary AEs and sepsis in acute coronary syndrome patients appears to be lower during ticagrelor compared to clopidogrel therapy. Further work should assess whether ticagrelor and clopidogrel have differential effects on immune signalling.

  8. Inhibition of platelet function with clopidogrel is associated with a reduction of inflammation in patients with peripheral artery disease.

    PubMed

    Meyer, Alexander; Weithaeuser, Alice; Steffens, Daniel; Bobbert, Peter; Hassanein, Adel; Ayral, Yunus; Schultheiss, Heinz-Peter; Rauch, Ursula

    2016-01-01

    The reactivity of platelets is increased in patients with peripheral artery disease (PAD). RANTES and sCD40L are chemokines which are stored in the alpha-granules of platelets. Clopidogrel inhibits and thus reduces platelet reactivity. Whether a treatment with clopidogrel is associated with an inhibition of systemic inflammation in patients with PAD has not been thoroughly explored. This study examined the effect of clopidogrel on platelet reactivation and the release of inflammatory chemokines in patients with PAD. 40 patients with PAD were randomized into two groups. In the first group A the patients were treated with 100mg acetylsalicylic acid (ASA) and additional placebo for 4weeks. The patients in group B received 75mg/d clopidogrel in addition to ASA 100mg for 4weeks. After obtaining blood at days 0, 7 and 28 the platelet activation was determined by measuring the surface protein expression of CD63, CD62p and thrombospondin (TSP) after stimulation with TRAP and ADP. The release of the chemokines RANTES and sCD40L from platelets was analyzed by ELISA. Platelet activation markers (CD62p and CD63) and chemokine RANTES were significantly reduced in patients with PAD after 7 and 28days after treatment with clopidogrel. No alterations were found in TSP expression and sCD40L during the treatment. The treatment with clopidogrel leads to a reduction of platelet reactivity and release of RANTES from the platelets of patients with PAD. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Relation between the Change in Mean Platelet Volume and Clopidogrel Resistance in Patients Undergoing Percutaneous Coronary Intervention.

    PubMed

    Koh, Young-Youp; Kim, Hyung Ho; Choi, Dong-Hyun; Lee, Young-Min; Ki, Young-Jae; Kang, Seong-Ho; Park, Geon; Chung, Joong-Wha; Chang, Kyong-Sig; Hong, Soon-Pyo

    2015-01-01

    We aimed to determine the association between the change in mean platelet volume (MPV) over time and aspirin/ clopidogrel resistance in patients undergoing percutaneous coronary intervention (PCI). The MPV and platelet function were analysed in 302 patients who underwent PCI. MPV changes were associated with increased aspirin reaction units (ARU, r = 0.114; P = 0.047), increased P2Y12 reaction units (PRU, r = 0.193; P = 0.001), and decreased P2Y12% inhibition (PI%, r = - 0.273; P < 0.001). The group with increasing MPV values showed significantly higher PRU values and lower PI% compared with the group with decreasing MPV values (222.5 ± 73.9 vs. 195.6 ± 63.7 PRU, P = 0.001; 24.1 ± 21.0 vs. 32.8 ± 18.5 PI%, P < 0.001, respectively). The clopidogrel resistant group (≥235 PRU or ≤15% of PI%) showed a significantly higher positive change in MPV (ΔMPV) values than the clopidogrel responder group (0.53 ± 0.78 vs. 0.13 ± 0.69 fL, P < 0.001). When the ΔMPV cut-off level was set at 0.20 fL using the receiver operating characteristic curve, the sensitivity and specificity for differentiating between the clopidogrel resistant and responder groups were 72.6% and 59.3%, respectively. After adjusting for traditional risk factors, the odds ratio in the clopidogrel resistant group with ΔMPV ≥0.2 fL was 4.10 (95% confidence interval; 1.84-9.17). In conclusion, ΔMPV was associated with PRU and PI%; a positive ΔMPV was an independent predictive marker for clopidogrel resistance after PCI.

  10. Cost-effectiveness of ticagrelor versus clopidogrel in patients with acute coronary syndromes in Canada

    PubMed Central

    Grima, Daniel T; Brown, Stephen T; Kamboj, Laveena; Bainey, Kevin R; Goeree, Ron; Oh, Paul; Ramanathan, Krishnan; Goodman, Shaun G

    2014-01-01

    Background Ticagrelor demonstrated a significant reduction in major cardiac events in patients with acute coronary syndrome (ACS) compared with clopidogrel in the Platelet Inhibition and Patient Outcomes (PLATO) trial. The objective of this study was to assess the cost-effectiveness of ticagrelor compared with clopidogrel in ACS patients from the perspective of the Canadian publicly funded health care system. Methods A two-part model was developed consisting of a 1-year decision tree and a lifetime Markov model. Within the decision tree, patients remained event-free, experienced a nonfatal myocardial infarction, a nonfatal stroke, or death due to vascular or nonvascular related causes based on data from the PLATO trial. The lifetime Markov model followed these patients and allowed for subsequent myocardial infarction, stroke, and death. Patient utility and resource use were derived from the PLATO trial. Transition probabilities and specific Canadian unit costs were derived from published sources. Univariate and probabilistic sensitivity analyses were conducted. Results In the base case lifetime analysis, treatment with ticagrelor resulted in more years of life per person (0.097), more quality-adjusted life years per person (QALYs, 0.084), and an incremental cost per QALY gained of $9,745 (Canadian$), assuming a generic cost for clopidogrel. A probabilistic sensitivity analysis demonstrated the robustness of the base case analysis, with a 93% probability of being below $20,000 per QALY gained and a 99% probability of being below $30,000 per QALY gained. Conclusion Ticagrelor is a clinically superior and cost-effective option for the prevention of thrombotic events among ACS patients in Canada. PMID:24493930

  11. 40 CFR 265.93 - Preparation, evaluation, and response.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., STORAGE, AND DISPOSAL FACILITIES Ground-Water Monitoring § 265.93 Preparation, evaluation, and response... an outline of a ground-water quality assessment program. The outline must describe a more comprehensive ground-water monitoring program (than that described in §§ 265.91 and 265.92) capable of...

  12. 40 CFR 265.93 - Preparation, evaluation, and response.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., STORAGE, AND DISPOSAL FACILITIES Ground-Water Monitoring § 265.93 Preparation, evaluation, and response... an outline of a ground-water quality assessment program. The outline must describe a more comprehensive ground-water monitoring program (than that described in §§ 265.91 and 265.92) capable of...

  13. Student Evaluation of Audience Response Technology in Large Lecture Classes

    ERIC Educational Resources Information Center

    MacGeorge, Erina L.; Homan, Scott R.; Dunning, John B., Jr.; Elmore, David; Bodie, Graham D.; Evans, Ed; Khichadia, Sangeetha; Lichti, Steven M.; Feng, Bo; Geddes, Brian

    2008-01-01

    In the past few years, audience response technology (ART) has been widely adopted on college campuses, and is especially popular among instructors of large lecture classes. Claims regarding ART's benefits to students have received only limited empirical evaluation, and prior studies exhibit methodological limitations. The current study provides a…

  14. An Evaluation of Response Prompts for Teaching Behavior Chains

    ERIC Educational Resources Information Center

    Seaver, Jessica L.; Bourret, Jason C.

    2014-01-01

    Individuals who have been diagnosed with autism spectrum disorders can have difficulty acquiring new skills, and teaching procedures found to be efficient with 1 individual may not be efficient with others. However, relatively little research has evaluated methods to identify efficient, individualized response-prompt and prompt-fading procedures.…

  15. Evaluation of the Response to the Fukushima Accident.

    PubMed

    Miska, Horst

    2016-08-01

    The cause for the severity of the Fukushima nuclear accident is explained, and the radiological consequences are assessed. Moreover, the non-radiological effects are critically evaluated and failures in onsite and offsite emergency response highlighted. In conclusion, disregarding the principle of justification, the evacuation of residents and hospital patients was implemented too rigorously, resulting in unnecessary fatalities due to the protective action.

  16. Student Evaluation of Audience Response Technology in Large Lecture Classes

    ERIC Educational Resources Information Center

    MacGeorge, Erina L.; Homan, Scott R.; Dunning, John B., Jr.; Elmore, David; Bodie, Graham D.; Evans, Ed; Khichadia, Sangeetha; Lichti, Steven M.; Feng, Bo; Geddes, Brian

    2008-01-01

    In the past few years, audience response technology (ART) has been widely adopted on college campuses, and is especially popular among instructors of large lecture classes. Claims regarding ART's benefits to students have received only limited empirical evaluation, and prior studies exhibit methodological limitations. The current study provides a…

  17. Notification: OIG Evaluation of EPA's Response to Erroneous Laboratory Data

    EPA Pesticide Factsheets

    Project #OPE-FY12-0023, August 14, 2012. The purpose of this memorandum is to notify you that the Office of Inspector General (OIG) plans to begin preliminary.research on an evaluation of EPA's response to erroneous laboratory data.

  18. Evaluating Item Fit for Multidimensional Item Response Models

    ERIC Educational Resources Information Center

    Zhang, Bo; Stone, Clement A.

    2008-01-01

    This research examines the utility of the s-x[superscript 2] statistic proposed by Orlando and Thissen (2000) in evaluating item fit for multidimensional item response models. Monte Carlo simulation was conducted to investigate both the Type I error and statistical power of this fit statistic in analyzing two kinds of multidimensional test…

  19. Evaluating the Response of the Terrestrial Biosphere to Significant Drought

    NASA Astrophysics Data System (ADS)

    Shiach, I.; Baker, I. T.; Denning, A.

    2011-12-01

    The response of terrestrial fluxes of energy, water, and carbon to drought is evaluated. Major droughts should be clearly evident in reanalyzed precipitation data, although this is not always the case. With reduced precipitation we can expect a suppression in Gross Primary Photosynthesis (GPP) if physiological stress is sufficient, with atttendant changes in energy partitioning due to stomatal closure. There may also be a response in respiratory release of CO2 with temperature increase. This study aimed to investigate the behavior of the terrestrial biosphere using the Simple Biosphere Model (SiB3) during and following times of drought and to identify any model responses inconsistent with observational relationships. The Standardized Precipitation Index (SPI) was evaluated from 1983 to 2006 in order to evaluate historical drought maps, and to facilitate a qualitative analysis of modeled drought behavior. Standardized and raw anomaly maps were produced for modeled physiological variables (GPP, transpiration, respiration, heat fluxes, carbon flux, and stress factors) in order to determine general response patterns for comparison with observations. The SiB model was determined to be generally accurate in its representation of significant drought, with regard to perturbations in Bowen ratio, GPP, and CO2 respiration. However, model response was heterogeneous, and did not always respond in a manner consistent with published descriptions of drought.

  20. Cytochromes P450 catalyze both steps of the major pathway of clopidogrel bioactivation, whereas paraoxonase catalyzes the formation of a minor thiol metabolite isomer.

    PubMed

    Dansette, Patrick M; Rosi, Julien; Bertho, Gildas; Mansuy, Daniel

    2012-02-20

    The mechanism generally admitted for the bioactivation of the antithrombotic prodrug, clopidogrel, is its two-step enzymatic conversion into a biologically active thiol metabolite. The first step is a classical cytochrome P450 (P450)-dependent monooxygenation of its thiophene ring leading to 2-oxo-clopidogrel, a thiolactone metabolite. The second step was described as a P450-dependent oxidative opening of the thiolactone ring of 2-oxo-clopidogrel, with intermediate formation of a reactive sulfenic acid metabolite that is eventually reduced to the corresponding thiol 4b. A very recent paper published in Nat. Med. (Bouman et al., (2011) 17, 110) reported that the second step of clopidogrel bioactivation was not catalyzed by P450 enzymes but by paraoxonase-1(PON-1) and that PON-1 was a major determinant of clopidogrel efficacy. The results described in the present article show that there are two metabolic pathways for the opening of the thiolactone ring of 2-oxo-clopidogrel. The major one, that was previously described, results from a P450-dependent redox bioactivation of 2-oxo-clopidogrel and leads to 4b cis, two previously reported thiol diastereomers bearing an exocyclic double bond. The second, minor one, results from a hydrolysis of 2-oxo-clopidogrel, which seems to be dependent on PON-1, and leads to an isomer of 4b cis, 4b "endo", in which the double bond has migrated from an exocyclic to an endocyclic position in the piperidine ring. These results were obtained from a detailed study of the metabolism of 2-oxo-clopidogrel by human liver microsomes and human sera and analysis by HPLC-MS under conditions allowing a complete separation of the thiol metabolite isomers, either as such or after derivatization with 3'-methoxy phenacyl bromide or N-ethyl maleimide (NEM). These results also show that the major bioactive thiol isomer found in the plasma of clopidogrel-treated patients derives from 2-oxo-clopidogrel by the P450-dependent pathway. Finally, chemical

  1. Moral Knowledge and Responsibilities in Evaluation Implementation: When Critical Theory and Responsive Evaluation Collide

    ERIC Educational Resources Information Center

    Freeman, Melissa; Preissle, Judith; Havick, Steven

    2010-01-01

    An external evaluation documented what occurred in an inaugural summer camp to teach high school students how to preserve religious freedom by learning about and acting on the history and current state of church-state separation and other first amendment issues. Camp designers hoped to promote religious diversity values and civic engagement in…

  2. Comparison of modified Thrombelastograph and Plateletworks whole blood assays to optical platelet aggregation for monitoring reversal of clopidogrel inhibition in elective surgery patients.

    PubMed

    Craft, Robert M; Chavez, Jack J; Snider, Carolyn C; Muenchen, Robert A; Carroll, Roger C

    2005-06-01

    Clinically monitoring recovery from clopidogrel and nonsteroidal anti-inflammatory drug (NSAID) inhibition requires whole blood assays corresponding to a standard methodology such as platelet-rich plasma aggregation monitored optically (OPA). We compared OPA, using an ED 50 dose of adenosine diphosphate activation, with 2 whole blood assays, Plateletworks (PWA) and modified Thrombelastograph (TEG). Two sets of assays were performed on 43 surgery patients while on clopidogrel and off clopidogrel to determine the reversal of absolute and relative inhibition. The modified TEG had Spearman correlations with OPA for absolute (rho = .424; P = .006) and relative inhibition (rho = .742; P < .0001). PWA correlations with OPA gave absolute (rho = .28; P = .08) and relative inhibition (rho = .46; P = .004) values. Bland-Altman analysis indicated agreement of both tests with OPA, showing constant biases of about 18% and some dependency on mean magnitude error. Cohen effect size thresholds defined nonresponders as < 7.7% clopidogrel inhibition relative to baseline recovery of full platelet function. Apparent nonresponse to clopidogrel or lack of platelet recovery did not correlate with statin or NSAID therapies. These PWA and modified TEG whole blood assays could prove useful for monitoring the reversal of clopidogrel and NSAID inhibition before surgery. More important, these assays done at baseline and after beginning clopidogrel therapy could monitor the effectiveness for the individual patients with cardiovascular disease and help identify the need for alternative therapies.

  3. A Multicenter Cohort Comparison Study of the Safety, Efficacy, and Cost of Ticagrelor Compared to Clopidogrel in Aneurysm Flow Diverter Procedures.

    PubMed

    Moore, Justin M; Adeeb, Nimer; Shallwani, Hussain; Gupta, Raghav; Patel, Apar S; Griessenauer, Christoph J; Youn, Roy; Siddiqui, Adnan; Ogilvy, Christopher S; Thomas, Ajith J

    2017-10-01

    Thromboembolic and hemorrhagic complications are among the most feared adverse events in the endovascular treatment of aneurysms, and this is particularly the case for flow diverter devices. Dual antiplatelet therapy has become standard of care; however, the safety, efficacy, and cost profiles of newer antiplatelet agents are not well characterized in the neurovascular context. To compare the safety, efficacy, and cost of one of these newer agents, ticagrelor, to the most frequently used agent, clopidogrel. A multicenter, retrospective, cohort comparison study design of consecutively treated aneurysms with flow diverter embolization device and treated with either ticagrelor or clopidogrel was performed. Data were collected on patient demographics and risk factors, procedural details, antiplatelet treatment regime, complications, and angiographic and functional outcomes. Fifty patients undergoing flow diverter device deployment and treatment with ticagrelor were compared to 53 patients undergoing flow diversion and treatment with clopidogrel. The patients' age, sex, smoking status, aneurismal morphology and size, and procedural details did not differ between the 2 groups; neither did the rate of thromboembolic and hemorrhagic complications, angiographical, and functional outcomes. Ticagrelor was more expensive when compared to clopidogrel. Ticagrelor is a safe and effective agent for prevention of thromboembolic complications following flow diverter deployment when compared to clopidogrel. However, ticagrelor remains significantly more expensive than clopidogrel, and, thus, we would advise ticagrelor be reserved for patients who are hyporesponsive to clopidogrel.

  4. Effects of Paclitaxel on the Ability of Aspirin and Clopidogrel to Inhibit Platelet Aggregation.

    PubMed

    Zhang, Shu; Sun, Changli; Hu, Hai; He, Yarong; Yao, Yuanchang; Cao, Yu; Zeng, Zhi

    2016-10-01

    The aim of this study was to investigate the effects of different paclitaxel concentrations on platelet aggregation induced by adenosine diphosphate (ADP). This experiment involved platelet suspensions that were obtained from fasting morning blood specimens from healthy adult male volunteers aged 22 to 28 years. The effect of paclitaxel on platelet aggregation induced by ADP and the inhibition rate of platelet aggregation were calculated in 6 groups with varying concentrations of paclitaxel, respectively. The optimal incubation time and concentration of ADP were 10 minutes and 10 μmol/mL, respectively. When the concentration of paclitaxel increased, platelet aggregation induced by ADP increased accordingly. When the concentration of paclitaxel exceeded 0.1 ng/mL, the ability of ADP to induce platelet aggregation increased significantly with increasing paclitaxel concentrations. In all the 3 experimental groups, that is A, C, and AC groups, the ability to inhibit platelet aggregation was weakened as paclitaxel concentration increased. Paclitaxel can enhance platelet aggregation induced by ADP, and this ability was observed to increase as paclitaxel concentration increased. In conclusion, paclitaxel can reduce the ability of aspirin, clopidogrel, and aspirin combined with clopidogrel to inhibit platelet aggregation. Furthermore, the ability to inhibit platelet aggregation was weakened as paclitaxel concentration increased in all 3 experimental groups. © The Author(s) 2015.

  5. Aspirin Versus Clopidogrel for Type 2 Diabetic Patients with First-Ever Noncardioembolic Acute Ischemic Stroke: Ten-Year Survival Data from the Athens Stroke Outcome Project.

    PubMed

    Milionis, Haralampos; Ntaios, George; Papavasileiou, Vasileios; Spengos, Konstantinos; Manios, Efstathios; Elisaf, Moses; Vemmos, Konstantinos

    2017-07-27

    Diabetes mellitus is associated with an increased risk of stroke and poor outcome following a stroke event. We assessed the impact of discharge treatment with aspirin versus clopidogrel on the 10-year survival of patients with type 2 diabetes after a first-ever noncardioembolic acute ischemic stroke (AIS). This was a post hoc analysis of the Athens Stroke Outcome Project. Study outcomes included death, stroke recurrence, and a composite cardiovascular disease (CVD) end point (recurrent stroke, myocardial infarction, unstable angina, coronary revascularization, aortic aneurysm rupture, or sudden death). Kaplan-Meier survival curve and Cox regression analyses were performed. A total of 304 (93 women) diabetic patients receiving either aspirin (n = 197) or clopidogrel (n = 107) were studied. The 10-year survival was better in clopidogrel-treated patients than in aspirin-treated patients (19 deaths [17.7%] for clopidogrel versus 55 deaths [27.9%] for aspirin; log-rank test: 4.91, P = .027). Similarly, clopidogrel was associated with a favorable impact on recurrent stroke (12 events [11.2%] for clopidogrel versus 39 events [19.7%] for aspirin; log-rank test: 4.46, P = .035) and on the composite CVD end point (21 events [19.6%] for clopidogrel versus 54 events [27.4%] for aspirin; log-rank test: 4.17, P = .041). In the multivariable analysis, the beneficial effect of clopidogrel over aspirin on both primary and secondary end points was independent of age, gender, the presence of CVD or CVD risk factors, and stroke severity. Our findings indicate a favorable effect of clopidogrel at discharge compared with aspirin in preventing death, recurrent stroke, and CVD events in diabetic patients with a first-ever noncardioembolic AIS. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  6. Evaluation of Piloted Inputs for Onboard Frequency Response Estimation

    NASA Technical Reports Server (NTRS)

    Grauer, Jared A.; Martos, Borja

    2013-01-01

    Frequency response estimation results are presented using piloted inputs and a real-time estimation method recently developed for multisine inputs. A nonlinear simulation of the F-16 and a Piper Saratoga research aircraft were subjected to different piloted test inputs while the short period stabilator/elevator to pitch rate frequency response was estimated. Results show that the method can produce accurate results using wide-band piloted inputs instead of multisines. A new metric is introduced for evaluating which data points to include in the analysis and recommendations are provided for applying this method with piloted inputs.

  7. Effects of the short-term application of pantoprazole combined with aspirin and clopidogrel in the treatment of acute STEMI

    PubMed Central

    Wei, Peng; Zhang, Yi-Gang; Ling, Lin; Tao, Zi-Qi; Ji, Li-Ya; Bai, Jie; Zong, Bin; Jiang, Chun-Ying; Zhang, Qian; Fu, Qiang; Yang, Xiang-Jun

    2016-01-01

    The aim of the present study was to determine the effects of the short-term application of pantoprazole on the co-treatment of acute ST-segment elevation myocardial infarction (STEMI) with aspirin and clopidogrel. A total of 207 acute patients showing primary symptoms of STEMI, who received successful emergent percutaneous coronary intervention treatment during hospitalization were randomly divided into two groups. In the test group proton pump inhibitors (PPIs), the patients were treated with a combination of aspirin and clopidogrel and pantoprazole, while those in the control group were treated only with aspirin and clopidogrel. Gastrointestinal bleeding events and major adverse cardiac events (MACEs) were observed in the two groups. Gastrointestinal bleeding events of the two groups mostly occurred within the first week of hospitalization, although the incidence in the PPIs group was significantly higher than that in the control group (p<0.05). However, no significant difference was observed for the incidence of MACEs between the two groups (p>0.05). In conclusion, the results of the present study have shown that the short-term application of pantoprazole combined with aspirin and clopidogrel does not increase the incidence of MACEs in patients with acute STEMI, reduces the risk of gastrointestinal bleeding, and is thus worth promoting clinically, particularly for high-risk groups. PMID:27882086

  8. Routine Screening for CYP2C19 Polymorphisms for Patients being Treated with Clopidogrel is not Recommended

    PubMed Central

    Hong, Robert A; Khan, Zia R; Valentin, Mona R; Badawi, Ramy A

    2015-01-01

    Recent efforts directed at potential litigation in Hawai‘i have resulted in a renewed interest for genetic screening for cytochrome P450 2C19 (CYP2C19) polymorphisms in patients treated with clopidogrel. Clopidogrel is an antiplatelet agent, frequently used in combination with aspirin, for the prevention of thrombotic complications with acute coronary syndrome and in patients undergoing percutaneous coronary interventions. Cytochrome P-450 (CYP) 2C19 is an enzyme involved in the bioactivation of clopidogrel from a pro-drug to an active inhibitor of platelet action. Patients of Asian and Pacific Island background have been reported to have an increase in CYP2C19 polymorphisms associated with loss-of-function of this enzyme when compared to other ethnicities. This has created an interest in genetic testing for CYP2C19 polymorphisms in Hawai‘i. Based upon our review of the current literature, we do not feel that there is support for the routine screening for CYP2C19 polymorphisms in patients being treated with clopidogrel; furthermore, the results of genetic testing may not be helpful in guiding therapeutic decisions. We recommend that decisions on the type of antiplatelet treatment be made based upon clinical evidence of potential differential outcomes associated with the use of these agents rather than on the basis of genetic testing. PMID:25628978

  9. Reliability evaluation of microgrid considering incentive-based demand response

    NASA Astrophysics Data System (ADS)

    Huang, Ting-Cheng; Zhang, Yong-Jun

    2017-07-01

    Incentive-based demand response (IBDR) can guide customers to adjust their behaviour of electricity and curtail load actively. Meanwhile, distributed generation (DG) and energy storage system (ESS) can provide time for the implementation of IBDR. The paper focus on the reliability evaluation of microgrid considering IBDR. Firstly, the mechanism of IBDR and its impact on power supply reliability are analysed. Secondly, the IBDR dispatch model considering customer’s comprehensive assessment and the customer response model are developed. Thirdly, the reliability evaluation method considering IBDR based on Monte Carlo simulation is proposed. Finally, the validity of the above models and method is studied through numerical tests on modified RBTS Bus6 test system. Simulation results demonstrated that IBDR can improve the reliability of microgrid.

  10. Therapy response evaluation with positron emission tomography-computed tomography.

    PubMed

    Segall, George M

    2010-12-01

    Positron emission tomography-computed tomography with F-18-fluorodeoxyglucose is widely used for evaluation of therapy response in patients with solid tumors but has not been as readily adopted in clinical trials because of the variability of acquisition and processing protocols and the absence of universal response criteria. Criteria proposed for clinical trials are difficult to apply in clinical practice, and gestalt impression is probably accurate in individual patients, especially with respect to the presence of progressive disease and complete response. Semiquantitative methods of determining tissue glucose metabolism, such as standard uptake value, can be a useful descriptor for levels of tissue glucose metabolism and changes in response to therapy if technical quality control measures are carefully maintained. The terms partial response, complete response, and progressive disease are best used in clinical trials in which the terms have specific meanings and precise definitions. In clinical practice, it may be better to use descriptive terminology agreed upon by imaging physicians and clinicians in their own practice.

  11. Development of Metrics to Evaluate Effectiveness of Emergency Response Operations

    DTIC Science & Technology

    2005-06-01

    00-00-2005 4. TITLE AND SUBTITLE Development of Metrics to Evaluate Efectiveness of Emergency Response Operations 5a. CONTRACT NUMBER 5b. GRANT...population and/or property. Furthermore, the disaster will be characterized as being large enough that the resources the community has to mitigate the...disaster are stretched beyond the limits of their capacity. Such events that a community can readily cope with, such as small fires, individual

  12. Building an Evaluation Scale using Item Response Theory

    PubMed Central

    Lalor, John P.; Wu, Hao; Yu, Hong

    2016-01-01

    Evaluation of NLP methods requires testing against a previously vetted gold-standard test set and reporting standard metrics (accuracy/precision/recall/F1). The current assumption is that all items in a given test set are equal with regards to difficulty and discriminating power. We propose Item Response Theory (IRT) from psychometrics as an alternative means for gold-standard test-set generation and NLP system evaluation. IRT is able to describe characteristics of individual items - their difficulty and discriminating power - and can account for these characteristics in its estimation of human intelligence or ability for an NLP task. In this paper, we demonstrate IRT by generating a gold-standard test set for Recognizing Textual Entailment. By collecting a large number of human responses and fitting our IRT model, we show that our IRT model compares NLP systems with the performance in a human population and is able to provide more insight into system performance than standard evaluation metrics. We show that a high accuracy score does not always imply a high IRT score, which depends on the item characteristics and the response pattern.1 PMID:28004039

  13. Primary healthcare response to family violence: a Delphi evaluation tool.

    PubMed

    Gear, Claire; Koziol-McLain, Jane; Wilson, Denise; Rae, Ngaire; Samuel, Hayley; Clark, Faye; McNeill, Edith

    2012-01-01

    Family violence is identified as a significant yet preventable public health problem internationally and in Aotearoa, New Zealand. Despite this, responses to family violence within New Zealand primary healthcare settings are generally limited and ad hoc. Along with guidelines and resources, a systems approach is indicated to support a safe and effective response to those who experience violence in the home. To modify an existing United States evaluation tool to guide implementation of family violence intervention programmes within New Zealand primary healthcare. Twenty-nine expert panelists, representing diverse family violence prevention and intervention organisations across New Zealand, participated in three rounds of a modified Delphi method to identify ideal primary healthcare family violence response programme indicators. In Round One, tool scope and context issues for New Zealand were identified; in Round Two, expert panelists identified ideal indicators and rated indicator importance, and in Round Three, expert panelists attended a one-day workshop to achieve consensus on tool categories, indicators, scoring and measurement notes. The developed tool was subsequently piloted at six volunteer primary healthcare sites for performance, clarity and usefulness. The final tool encompasses 143 indicators organised within 10 categories. Pilot sites found the tool and evaluation experience useful in guiding programme development. The evaluation tool represents a best practice standard enabling focused family violence intervention programme development and quality improvement within primary healthcare settings. A standardised evaluation tool may be useful in guiding programme development. Future evaluations will enable individual and national benchmarking activities, using category, overall and target scores to measure progress across settings and over time.

  14. Evaluation of the biological response of wear debris.

    PubMed

    Chang, Bong-Soon; Brown, Phillip Rand; Sieber, Ann; Valdevit, Antonio; Tateno, Kei; Kostuik, John Philip

    2004-01-01

    An animal study was conducted to evaluate the biological response to titanium particles from an artificial intervertebral disc in terms of serology and histologic changes. To determine the biological response to wear debris in the retroperitoneal and epidural space. Few wear studies exist about mechanical artificial discs. Twenty-three New Zealand white rabbits were used for two approaches of the lumbar spine. In a retroperitoneal group (10 rabbits), lateral flank approach at the L2-L3 area was used. In an epidural group (13 rabbits), a dorsal laminotomy of L2 was performed. The wear debris was obtained from mechanical test cycling of the implantable intervertebral disc. At 4 and 12 weeks postoperatively, five or six animals from each group were killed. The tissues, including deposition site, regional lymph nodes and major organs, were evaluated with hematoxylin and eosin staining. At death all rabbits were found to be healthy. Blood results from the predeath samples were found to be consistent with the preoperative blood work values. Scar tissue was minimal with good healing. All organs were found to be normal in appearance. On histopathology sections, adverse reactions such as fibrosis, granuloma formation or necrosis were not found in any tissues. Free particles were found sparingly in all tissue sections with minimal cellular response. No remarkable difference was found according to groups or time intervals. Smaller particles were found to be engulfed in macrophages without adverse biological consequences. Titanium particles traveled from the sites of deposition but elicited no to minimal biological response.

  15. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes.

    PubMed

    Storey, Robert F; Becker, Richard C; Harrington, Robert A; Husted, Steen; James, Stefan K; Cools, Frank; Steg, Philippe Gabriel; Khurmi, Nardev S; Emanuelsson, Håkan; Cooper, Anna; Cairns, Richard; Cannon, Christopher P; Wallentin, Lars

    2011-12-01

    AIMS To describe the incidence of dyspnoea and its associations with demographic characteristics and clinical outcomes in patients with acute coronary syndromes (ACS) treated with ticagrelor or clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) study. METHODS AND RESULTS In the PLATO study, 18 624 patients were randomized to receive either clopidogrel [300-600 mg loading dose (LD), 75 mg daily] or ticagrelor (180 mg LD, 90 mg b.i.d.). The occurrence of reported dyspnoea adverse events (AEs) was analysed in the 18 421 patients who received at least one dose of study medication in relation to demographic characteristics, clinical outcomes and other associations of patients with and without dyspnoea. A total of 1339 ticagrelor-treated patients (14.5%) and 798 clopidogrel-treated patients (8.7%) had a dyspnoea AE following randomization, with respectively 39 (0.4%) and 24 (0.3%) classified as severe in intensity. Excluding dyspnoea AEs occurring after the secondary endpoint of myocardial infarction (MI), the yearly rates of the efficacy endpoints in dyspnoea AE patients in the ticagrelor and clopidogrel groups were: for the primary composite of CV death, MI, and stroke, 8.8 and 10.4% (unadjusted P = 0.25; adjusted P = 0.54); for CV death, 3.1 and 4.8% (unadjusted P = 0.024; adjusted P = 0.18); and for total death 3.7 and 6.2% (unadjusted P = 0.004; adjusted P = 0.06), respectively. CONCLUSIONS Ticagrelor-related dyspnoea is usually mild or moderate in intensity and does not appear to be associated with differences concerning any efficacy or safety outcomes with ticagrelor compared with clopidogrel therapy in ACS patients.

  16. Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis.

    PubMed

    Pan, Yuesong; Chen, Weiqi; Xu, Yun; Yi, Xingyang; Han, Yan; Yang, Qingwu; Li, Xin; Huang, Li'an; Johnston, S Claiborne; Zhao, Xingquan; Liu, Liping; Zhang, Qi; Wang, Guangyao; Wang, Yongjun; Wang, Yilong

    2017-01-03

    The association of genetic polymorphisms and clopidogrel efficacy in patients with ischemic stroke or transient ischemic attack (TIA) remains controversial. We performed a systematic review and meta-analysis to assess the association between genetic polymorphisms, especially CYP2C19 genotype, and clopidogrel efficacy for ischemic stroke or TIA. We conducted a comprehensive search of PubMed and EMBASE from their inceptions to June 24, 2016. Studies that reported clopidogrel-treated patients with stroke or TIA and with information on genetic polymorphisms were included. The end points were stroke, composite vascular events, and any bleeding. Among 15 studies of 4762 patients with stroke or TIA treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles (*2, *3, and *8) were at increased risk of stroke in comparison with noncarriers (12.0% versus 5.8%; risk ratio, 1.92, 95% confidence interval, 1.57-2.35; P<0.001). Composite vascular events were also more frequent in carriers of CYP2C19 loss-of-function alleles than in noncarriers (13.7% versus 9.4%; risk ratio, 1.51, 95% confidence interval, 1.10-2.06; P=0.01), whereas bleeding rates were similar (2.4% versus 3.1%; risk ratio, 0.89, 95% confidence interval, 0.58-1.35; P=0.59). There was no evidence of statistical heterogeneity among the included studies for stroke, but there was for composite vascular events. Genetic variants other than CYP2C19 were not associated with clinical outcomes, with the exception that significant associations of PON1, P2Y12, and COX-1 with outcomes were observed in 1 study. Carriers of CYP2C19 loss-of-function alleles are at greater risk of stroke and composite vascular events than noncarriers among patients with ischemic stroke or TIA treated with clopidogrel. © 2016 American Heart Association, Inc.

  17. Associations Between Chronic Kidney Disease and Outcomes With Use of Prasugrel Versus Clopidogrel in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: A Report From the PROMETHEUS Study.

    PubMed

    Baber, Usman; Chandrasekhar, Jaya; Sartori, Samantha; Aquino, Melissa; Kini, Annapoorna S; Kapadia, Samir; Weintraub, William; Muhlestein, Joseph B; Vogel, Birgit; Faggioni, Michela; Farhan, Serdar; Weiss, Sandra; Strauss, Craig; Toma, Catalin; DeFranco, Anthony; Baker, Brian A; Keller, Stuart; Effron, Mark B; Henry, Timothy D; Rao, Sunil; Pocock, Stuart; Dangas, George; Mehran, Roxana

    2017-07-27

    The study sought to compare clinical outcomes in a contemporary acute coronary syndrome (ACS) percutaneous coronary intervention (PCI) cohort stratified by chronic kidney disease (CKD) status. Patients with CKD exhibit high risks for both thrombotic and bleeding events, thus complicating decision making regarding antiplatelet therapy in the setting of ACS. The PROMETHEUS study was a multicenter observational study comparing outcomes with prasugrel versus clopidogrel in ACS PCI patients. Major adverse cardiac events (MACE) at 90 days and at 1 year were defined as a composite of death, myocardial infarction, stroke, or unplanned revascularization. Clinically significant bleeding was defined as bleeding requiring transfusion or hospitalization. Cox regression multivariable analysis was performed for adjusted associations between CKD status and clinical outcomes. Hazard ratios for prasugrel versus clopidogrel treatment were generated using propensity score stratification. The total cohort included 19,832 patients, 28.3% with and 71.7% without CKD. CKD patients were older with greater comorbidities including diabetes and multivessel disease. Prasugrel was less often prescribed to CKD versus non-CKD patients (11.0% vs. 24.0%, respectively; p < 0.001). At 1 year, CKD was associated with higher adjusted risk of MACE (1.27; 95% confidence interval: 1.18 to 1.37) and bleeding (1.46; 95% confidence interval: 1.24 to 1.73). Although unadjusted rates of 1-year MACE were lower with prasugrel versus clopidogrel in both CKD (18.3% vs. 26.5%, p < 0.001) and non-CKD (10.9% vs. 17.9%; p < 0.001) patients, associations were attenuated after propensity stratification. Similarly, unadjusted differences in 1-year bleeding with prasugrel versus clopidogrel (6.0% vs. 7.4%, p = 0.18 in CKD patients; 2.6% vs. 3.5%, p = 0.008 in non-CKD patients) were not significant after propensity score adjustment. Although risks for 1-year MACE were significantly higher in ACS PCI patients with

  18. Video methods for evaluating physiologic monitor alarms and alarm responses.

    PubMed

    Bonafide, Christopher P; Zander, Miriam; Graham, Christian Sarkis; Weirich Paine, Christine M; Rock, Whitney; Rich, Andrew; Roberts, Kathryn E; Fortino, Margaret; Nadkarni, Vinay M; Lin, Richard; Keren, Ron

    2014-01-01

    False physiologic monitor alarms are extremely common in the hospital environment. High false alarm rates have the potential to lead to alarm fatigue, leading nurses to delay their responses to alarms, ignore alarms, or disable them entirely. Recent evidence from the U.S. Food and Drug Administration (FDA) and The Joint Commission has demonstrated a link between alarm fatigue and patient deaths. Yet, very little scientific effort has focused on the rigorous quantitative measurement of alarms and responses in the hospital setting. We developed a system using multiple temporarily mounted, minimally obtrusive video cameras in hospitalized patients' rooms to characterize physiologic monitor alarms and nurse responses as a proxy for alarm fatigue. This allowed us to efficiently categorize each alarm's cause, technical validity, actionable characteristics, and determine the nurse's response time. We describe and illustrate the methods we used to acquire the video, synchronize and process the video, manage the large digital files, integrate the video with data from the physiologic monitor alarm network, archive the video to secure servers, and perform expert review and annotation using alarm "bookmarks." We discuss the technical and logistical challenges we encountered, including the root causes of hardware failures as well as issues with consent, confidentiality, protection of the video from litigation, and Hawthorne-like effects. The description of this video method may be useful to multidisciplinary teams interested in evaluating physiologic monitor alarms and alarm responses to better characterize alarm fatigue and other patient safety issues in clinical settings.

  19. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke.

    PubMed

    Benavente, Oscar R; Hart, Robert G; McClure, Leslie A; Szychowski, Jeffrey M; Coffey, Christopher S; Pearce, Lesly A

    2012-08-30

    Lacunar infarcts are a frequent type of stroke caused mainly by cerebral small-vessel disease. The effectiveness of antiplatelet therapy for secondary prevention has not been defined. We conducted a double-blind, multicenter trial involving 3020 patients with recent symptomatic lacunar infarcts identified by magnetic resonance imaging. Patients were randomly assigned to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. The participants had a mean age of 63 years, and 63% were men. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P<0.001). Among classifiable recurrent ischemic strokes, 71% (133 of 187) were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P=0.004); this difference was not accounted for by fatal hemorrhages (9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone). Among patients with recent lacunar strokes, the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly

  20. Clopidogrel, prasugrel, ticagrelor or vorapaxar in patients with renal impairment: do we have a winner?

    PubMed

    Serebruany, Victor L; Tomek, Ales; Pokov, Alex N; Kim, Moo Hyun

    2015-12-01

    The optimal utilization of antiplatelet therapy in patients with renal impairment (RI) following acute coronary syndromes (ACS) represents an urgent, unmet and yet unsolved need with regards to the choice of agents, duration of treatment and potential dose/regimen adjustment. The lack of any large randomized trials designed and powered specifically in such high-risk patients, absence of the uniformed efficacy and safety data reporting policy to the FDA and endless overoptimistic publications based on post hoc analyses of primary trials sometimes exaggerating benefits and hiding risks, clouds reality. In addition, triaging RI patients is problematic due to ongoing kidney deterioration and the fact that such patients are prone to both vascular occlusions and bleeding. The authors summarize available FDA-confirmed evidence from the latest trials with approved antiplatelet agents, namely clopidogrel (CAPRIE, CURE, CREDO, CLARITY, CHARISMA); prasugrel (TRITON, TRILOGY); ticagrelor (PLATO, and PEGASUS); and vorapaxar (TRACER and TRA2P) in RI patient cohorts on top of aspirin as part of dual antiplatelet therapy (DAPT). We deliberately avoided any results unless they were verified by the FDA, with the exception of the recent PEGASUS, since Agency reviews are not yet available. Despite differences among the trials and DAPT choices, RI patients universally experience much higher (HR = 1.3-3.1) rates of primary endpoint events, and bleeding risks (HR = 1.7-3.6). However, only ticagrelor increases creatinine and uric acid levels above that of clopidogrel; has the worst incidence of serious adverse events, more adverse events, and inferior outcomes in patients with severe (eGFR <30 ml/min), especially in the lowest (eGFR <15 ml/min) RI subsets. Clopidogrel, prasugrel and vorapaxar appear safer. Moreover, less aggressive half dose (5 mg/daily) prasugrel and strict DAPT, are well justified in RI, but not predominantly triple strategies with vorapaxar as tested in TRA2P and

  1. Evaluation of polydimethylsiloxane modification methods for cell response.

    PubMed

    Pakstis, L M; Dunkers, J P; Zheng, A; Vorburger, T V; Quinn, T P; Cicerone, M T

    2010-02-01

    Many methods exist in the literature to modify surfaces with extracellular matrix (ECM) proteins prior to cell seeding. However, there are few studies that systematically characterize and compare surface properties and cell response results among modification methods that use different bonding mechanisms. In this work, we compare cell response and physical characterization results from fibronectin or laminin attached to polydimethylsiloxane (PDMS) elastomer surfaces by physical adsorption, chemisorption, and covalent attachment to determine the best method to modify a deformable surface. We evaluate modification methods based on completeness and uniformity of coverage, surface roughness, and hydrophilicity of attached ECM protein. Smooth muscle cell adhesion, proliferation, morphology, and phenotype were also evaluated. We found that chemisorption methods resulted in higher amounts of protein attachment than physical adsorption and covalent bonding of the ECM proteins. Cell response to protein-modified surfaces was similar with respect to cell adhesion, area, aspect ratio, and phenotype. When all the data are considered, the chemisorption methods, most notably silane_70, provide the best surface properties and highest cell proliferation. (c) 2009 Wiley Periodicals, Inc.

  2. Cancer Education Program Evaluation: A Responsive Approach to Planning an Evaluation and Initial Results.

    ERIC Educational Resources Information Center

    Pearsol, James A.

    This paper describes evaluation planning for the Cancer Education Program (CEP) at Ohio State University (OSU). The three-year OSU CEP project was designed as a multidisciplinary cancer education program. A responsive method, which trades off some measurement precision in order to increase the usefulness of the findings, was employed in the…

  3. Cancer Education Program Evaluation: A Responsive Approach to Planning an Evaluation and Initial Results.

    ERIC Educational Resources Information Center

    Pearsol, James A.

    This paper describes evaluation planning for the Cancer Education Program (CEP) at Ohio State University (OSU). The three-year OSU CEP project was designed as a multidisciplinary cancer education program. A responsive method, which trades off some measurement precision in order to increase the usefulness of the findings, was employed in the…

  4. Probability effects on stimulus evaluation and response processes

    NASA Technical Reports Server (NTRS)

    Gehring, W. J.; Gratton, G.; Coles, M. G.; Donchin, E.

    1992-01-01

    This study investigated the effects of probability information on response preparation and stimulus evaluation. Eight subjects responded with one hand to the target letter H and with the other to the target letter S. The target letter was surrounded by noise letters that were either the same as or different from the target letter. In 2 conditions, the targets were preceded by a warning stimulus unrelated to the target letter. In 2 other conditions, a warning letter predicted that the same letter or the opposite letter would appear as the imperative stimulus with .80 probability. Correct reaction times were faster and error rates were lower when imperative stimuli confirmed the predictions of the warning stimulus. Probability information affected (a) the preparation of motor responses during the foreperiod, (b) the development of expectancies for a particular target letter, and (c) a process sensitive to the identities of letter stimuli but not to their locations.

  5. Probability effects on stimulus evaluation and response processes

    NASA Technical Reports Server (NTRS)

    Gehring, W. J.; Gratton, G.; Coles, M. G.; Donchin, E.

    1992-01-01

    This study investigated the effects of probability information on response preparation and stimulus evaluation. Eight subjects responded with one hand to the target letter H and with the other to the target letter S. The target letter was surrounded by noise letters that were either the same as or different from the target letter. In 2 conditions, the targets were preceded by a warning stimulus unrelated to the target letter. In 2 other conditions, a warning letter predicted that the same letter or the opposite letter would appear as the imperative stimulus with .80 probability. Correct reaction times were faster and error rates were lower when imperative stimuli confirmed the predictions of the warning stimulus. Probability information affected (a) the preparation of motor responses during the foreperiod, (b) the development of expectancies for a particular target letter, and (c) a process sensitive to the identities of letter stimuli but not to their locations.

  6. Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis

    PubMed Central

    Cardoso, Rhanderson N; Benjo, Alexandre M; DiNicolantonio, James J; Garcia, Daniel C; Macedo, Francisco Y B; El-Hayek, Georges; Nadkarni, Girish N; Gili, Sebastiano; Iannaccone, Mario; Konstantinidis, Ioannis; Reilly, John P

    2015-01-01

    Background Dual antiplatelet therapy is the standard of care after coronary stent placement but increases the bleeding risk. The effects of proton pump inhibitors (PPIs) on clopidogrel metabolism have been described, but the clinical significance is not yet definitive. We aimed to do an updated meta-analysis comparing outcomes in patients receiving clopidogrel with and without PPIs. Methods We systematically searched PubMed, Scopus and the Cochrane Central Register of Controlled Trials for randomised controlled trials (RCTs) and controlled observational studies in patients taking clopidogrel stratified by concomitant PPI use. Heterogeneity was examined with the Cochran Q test and I2 statistics; p values inferior to 0.10 and I2 >25% were considered significant for heterogeneity. Results We included 39 studies with a total of 214 851 patients, of whom 73 731 (34.3%) received the combination of clopidogrel and a PPI. In pooled analysis, all-cause mortality, myocardial infarction, stent thrombosis and cerebrovascular accidents were more common in patients receiving both drugs. However, among 23 552 patients from eight RCTs and propensity-matched studies, there were no significant differences in mortality or ischaemic events between groups. The use of PPIs in patients taking clopidogrel was associated with a significant reduction in the risk of gastrointestinal bleeding. Conclusions The results of our meta-analysis suggest that PPIs are a marker of increased cardiovascular risk in patients taking clopidogrel, rather than a direct cause of worse outcomes. The pharmacodynamic interaction between PPIs and clopidogrel most likely has no clinical significance. Furthermore, PPIs have the potential to decrease gastrointestinal bleeding in clopidogrel users. PMID:26196021

  7. Comparison of a new P2Y12 receptor specific platelet aggregation test with other laboratory methods in stroke patients on clopidogrel monotherapy.

    PubMed

    Bagoly, Zsuzsa; Sarkady, Ferenc; Magyar, Tünde; Kappelmayer, János; Pongrácz, Endre; Csiba, László; Muszbek, László

    2013-01-01

    Clinical studies suggest that 10-50% of patients are resistant to clopidogrel therapy. ADP induced platelet aggregation, a widely used test to monitor clopidogrel therapy, is affected by aspirin and is not specific for the P2Y12 receptor inhibited by clopidogrel. To develop a P2Y12-specific platelet aggregation test and to compare it with other methods used for monitoring clopidogrel therapy. Study population included 111 patients with the history of ischemic stroke being on clopidogrel monotherapy and 140 controls. The effect of clopidogrel was tested by a newly developed ADP(PGE1) aggregation test in which prostaglandin E1 treated platelets are used. Results of conventional ADP induced platelet aggregation, VerifyNow P2Y12 assay and ADP(PGE1) aggregation were compared to those obtained by flow cytometric analysis of vasodilator stimulated phosphoprotein (VASP) phosphorylation. Reference intervals for all assays were determined according to the guidelines of Clinical Laboratory Standards Institute. The P2Y12-specificity of ADP(PGE1) test was proven by comparing it with ADP aggregation in the presence of P2Y1 antagonist, adenosine 3', 5'-diphosphate. The method was not influenced by aspirin treatment. Approximately 50% of patients were clopidogrel resistant by conventional ADP aggregation and VerifyNow tests. The ADP(PGE1) method and the VASP phosphorylation assay identified 25.9% and 11.7% of patients as non-responders, respectively. ADP(PGE1) aggregation showed good correlation with VASP phosphorylation and had high diagnostic efficiency. The new ADP(PGE1) method is a reliable test for monitoring P2Y12 receptor inhibition by platelet aggregation. As a subset of patients are non-responders, monitoring clopidogrel therapy by adequate methods is essential.

  8. Triple cage olfactometer for evaluating mosquito (Diptera: Culicidae) attraction responses.

    PubMed

    Posey, K H; Barnard, D R; Schreck, C E

    1998-05-01

    A triple cage olfactometer for evaluating mosquito attraction responses is described. The olfactometer is designed for easy access for interior cleaning, has a mechanism that allows synchronous operation of the port doors on each cage, and requires 0.8 m2 of floor space. It is constructed of clear acrylic, contains 3 test chambers in a tiered configuration, has paired removable sleeves and mosquito traps on each cage, and is equipped with a filtered external air supply system that has temperature and relative humidity control.

  9. Clopidogrel Resistance by P2Y12 Platelet Function Testing in Patients Undergoing Neuroendovascular Procedures

    PubMed Central

    Nordeen, Jerah D.; Patel, Alden V.; Darracott, Robert M.; Johns, Gretchen S.; Taussky, Philipp; Tawk, Rabih G.; Miller, David A.; Freeman, William D.; Hanel, Ricardo A.

    2013-01-01

    Purpose: The purpose of the study was to assess clopidogrel resistance and whether “intensified” antiplatelet therapy guided by platelet inhibition tests during neuroendovascular procedures would reduce ischemic complications. Methods: We conducted a retrospective review of patients at Mayo Clinic in Jacksonville, Florida, who underwent neuroendovascular (NV) procedures and had P2Y12 platelet function testing from October 1, 2009, to September 30, 2010. The primary end-point was to determine P2Y12 resistance to antiplatelet therapy in patients who underwent NV procedures. Secondary objectives included incidence of hemorrhagic and ischemic events and a correlation between resistance and genetic CYP2C19 testing. Results: 160 patients underwent P2Y12 platelet function tests. Eighty-one patients (81/160, 50.6%) met inclusion criteria. Platelet function tests identified 64 patients (79%) as non-resistant (≥20% P2Y12 inhibition) and 17 (21%) as resistant (<20% inhibition) after initial clopidogrel loading. There was an increased rate of death when a complication occurred in the resistant group by 30 day (17% versus 3%; p=0.059) and 90 day follow-up (23% versus 4%; p=0.032). There was no significant association found between complication and loading dose (p=0.0721). Conclusions: 21% of patients undergoing NV procedures were resistant to clopidogrel. Intensifying antiplatelet therapy to achieve ≥20% inhibition on platelet function testing did not result in higher numbers of ischemic or hemorrhagic events, but there was a trend toward more death in the resistant group by 30 and 90 days of those experiencing complication(s). Author Justifications: Jerah D. Nordeen, Pharm.D.: Primary author Alden V. Patel, Pharm.D.: Contributor of professional content, study design Robert M. Darracott, Pharm.D.: Contributor of professional content, study design Gretchen S. Johns, M.D.: Contributor of professional content, study design Philipp Taussky, M.D.: Contributor of professional

  10. Clopidogrel-induced refractory thrombotic thrombocytopenic purpura successfully treated with rituximab.

    PubMed

    Khodor, Sara; Castro, Miguel; McNamara, Colin; Chaulagain, Chakra P

    2016-06-01

    Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder characterized by microvascular aggregation of platelets and fibrin strands causing thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction. TTP can develop as a result of a deficiency in ADAMTS13 enzyme activity due to either a genetic defect or, more commonly, the development of anti-ADAMTS13 autoantibodies. TTP can also be associated with pregnancy, organ transplant, lupus, infections, and drugs. Here, we present a case of TTP that developed shortly after the start of clopidogrel treatment for acute ischemic stroke and acute myocardial infarction, and describe the clinical presentation, refractory course of the disease, and successful induction of remission through the use of rituximab in a setting of pre-existing autoimmune diseases.

  11. Six Versus Twelve Months Clopidogrel Therapy After Drug-Eluting Stenting in Patients With Acute Coronary Syndrome: An ISAR-SAFE Study Subgroup Analysis.

    PubMed

    Lohaus, Raphaela; Michel, Jonathan; Mayer, Katharina; Lahmann, Anna Lena; Byrne, Robert A; Wolk, Annabelle; Ten Berg, Jurrien M; Neumann, Franz-Josef; Han, Yaling; Adriaenssens, Tom; Tölg, Ralph; Seyfarth, Melchior; Maeng, Michael; Zrenner, Bernhard; Jacobshagen, Claudius; Wöhrle, Jochen; Kufner, Sebastian; Morath, Tanja; Ibrahim, Tareq; Bernlochner, Isabell; Fischer, Marcus; Schunkert, Heribert; Laugwitz, Karl-Ludwig; Mehilli, Julinda; Kastrati, Adnan; Schulz-Schüpke, Stefanie

    2016-09-14

    In patients presenting with acute coronary syndrome (ACS) the optimal duration of dual-antiplatelet therapy after drug-eluting stent (DES) implantation remains unclear. At 6 months after intervention, patients receiving clopidogrel were randomly assigned to either a further 6-month period of placebo or clopidogrel. The primary composite endpoint was death, myocardial infarction, stent thrombosis, stroke, or major bleeding 9 months after randomization. The ISAR-SAFE trial was terminated early due to low event rates and slow recruitment. 1601/4000 (40.0%) patients presented with ACS and were randomized to 6 (n = 794) or 12 months (n = 807) clopidogrel. The primary endpoint occurred in 14 patients (1.8%) receiving 6 months of clopidogrel and 17 patients (2.2%) receiving 12 months; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.41-1.68, P = 0.60. There were 2 (0.3%) cases of stent thrombosis in each group; HR 1.00, 95% CI 0.14-7.09, P = >0.99. Major bleeding occurred in 3 patients (0.4%) receiving 6 months clopidogrel and 5 (0.6%) receiving 12 months; HR 0.60, 95% CI 0.15-2.49, P = 0.49. There was no significant difference in net clinical outcomes after DES implantation in ACS patients treated with 6 versus 12 months clopidogrel. Ischaemic and bleeding events were low beyond 6-months.

  12. Occurrence, causes, and outcome after switching from ticagrelor to clopidogrel in a real-life scenario: data from a prospective registry.

    PubMed

    Biscaglia, Simone; Campo, Gianluca; Pavasini, Rita; Tebaldi, Matteo; Tumscitz, Carlo; Ferrari, Roberto

    2016-07-01

    In randomized clinical trials, ticagrelor has been substituted in roughly one-third of the patients during follow-up. To date, there are no studies addressing safety and modalities of switching from ticagrelor to clopidogrel. The aim of our study is to describe the occurrence, causes, and outcome of the switch from ticagrelor to clopidogrel in a real-life scenario. From June 2013 to March 2015, 586 patients were treated with ticagrelor in our centre. Overall, 101 (17%) patients were switched to clopidogrel through a standardized protocol, and they were followed-up for 12 months. Ischemic and bleeding events were prospectively recorded. The switch from ticagrelor to clopidogrel occurred mostly after discharge (69 ± 40 days), and the most frequent cause was the need of oral anticoagulation treatment, followed by bleeding events. Patients requiring ticagrelor discontinuation were older, more frequently female, with lower body mass index and creatinine clearance if compared to the "non-switched" group. In the 10 days after the switch, we did not observe ischemic adverse events. No definite/probable stent thrombosis was recorded. Before the switch, there was a significant higher occurrence of BARC bleedings in the "switched" group, particularly BARC 1 and 2. Our data confirm that the switch from ticagrelor to clopidogrel is common, and it occurs for several reasons. Our analysis did not demonstrate a significant increase in adverse cardiovascular events in the days following the switch from ticagrelor to clopidogrel, although larger studies are needed to validate our findings.

  13. Effects of omeprazole and genetic polymorphism of CYP2C19 on the clopidogrel active metabolite.

    PubMed

    Boulenc, Xavier; Djebli, Nassim; Shi, Juan; Perrin, Laurent; Brian, William; Van Horn, Robert; Hurbin, Fabrice

    2012-01-01

    Clopidogrel is an antiplatelet agent widely used in cardiovascular diseases and an inactive prodrug that needs to be converted to an active metabolite in two sequential metabolic steps. Several CYP450 isoforms involved in these two steps have been described, although the relative contribution in vivo of each enzyme is still under debate. CYP2C19 is considered to be the major contributor to active metabolite formation. In the current study, net CYP2C19 contribution to the active metabolite formation was determined from exposure of the active metabolite in two clinical studies (one phase I study with well balanced genetic polymorphic populations and a meta-analysis with a total of 396 healthy volunteers) at different clopidogrel doses. CYP2C19 involvements were estimated to be from 58 to 67% in intermediate metabolizers (IMs), from 58 to 72% in extensive metabolizers (EMs), and from 56 to 74% in ultrarapid metabolizers (UMs), depending on the study and the dose. For this purpose, a static model was proposed to estimate the net contribution of a given enzyme to the secondary metabolite formation. This static model was compared with a dynamic approach (Simcyp model) and showed good consistency. In parallel, in vitro investigations showed that omeprazole is a mechanism-based inhibitor of CYP2C19 with K(I) of 8.56 μM and K(inact) of 0.156 min(-1). These values were combined with the net CYP2C19 contribution to the active metabolite formation, through a static approach, to predict the inhibitory effect at 80-mg omeprazole doses in EM, IM, and UM CYP2C19 populations, with good consistency, compared with observed clinical values.

  14. Recombinant activated factor VII does not reduce bleeding in rabbits treated with aspirin and clopidogrel.

    PubMed

    Hindy-François, Clemence; Bachelot-Loza, Christilla; Le Bonniec, Bernard; Grelac, Francoise; Dizier, Blandine; Godier, Anne; Emmerich, Joseph; Gaussem, Pascale; Samama, Charles-Marc

    2010-10-01

    Combined antiplatelet agents (cAPA), aspirin plus clopidogrel, increase the risk of bleeding. We hypothesised that recombinant activated FVIIa (rFVIIa), which normalises thrombin generation in platelet-rich plasma from patients treated with cAPA, could limit this bleeding risk. It was the objective of this study to investigate the efficacy and safety of rFVIIa compared to placebo, in a bleeding and thrombosis model in rabbits treated with aspirin and clopidogrel. New-Zealand rabbits, randomised into two groups (Placebo1, n=36 ; cAPA, n=34), were anaesthetised, ventilated and monitored for blood pressure, temperature and carotid blood flow. The Folts model was applied to a carotid artery. Cyclic flow reductions (CFR) were recorded over a first 20-min period (Obs1). Each rabbit was then randomly assigned into one of three subgroups (Placebo2, 40μg/kg rFVIIa, 160 μg/kg rFVIIa) and CFR were monitored for a second 20-min period (Obs2). Ear bleeding time (BT) was measured at the end of each period. Hepatosplenic (HS) section was performed at the end of the experiment and HS blood loss defines the primary endpoint. Secondary endpoints were thrombosis (CFR), prothrombin time, platelet aggregation, and thrombin generation. Non- parametric statistical tests were used (p<0.05). cAPA significantly increased HS blood loss, BT and suppressed CFR compared to Placebo1 (p<0.05). rFVIIa injection did not modify HS blood loss, BT or CFR rate in Placebo1 rabbits nor in cAPA animals. These effects were unaffected by either rFVIIa dose. rFVIIa accelerated thrombin generation but had no effect on platelet aggregation in citrated platelet-rich plasma. rFVIIa did not modify HS blood loss associated with cAPA in rabbits.

  15. Combined clopidogrel-aspirin treatment for high risk TIA or minor stroke does not increase cerebral microbleeds.

    PubMed

    Wang, Zhiming; Xu, Chenghua; Wang, Peng; Wang, Yilong; Xin, Huaping

    2015-11-01

    To study whether Clopidogrel-Aspirin combined treatment for high risk transient ischaemic attack (TIA) or minor stroke results in increased number of lesions associated with anti-thrombotic cerebral haemorrhage or cerebral micro-bleeds (CMB) than aspirin alone treatment. The patients recruited in CHANCE test in our hospital participated in this study. We made a comparison between treatments Aspirin-Clopidogrel combined group and the Aspirin alone group in the numbers of CMB and subsequent cerebral haemorrhages. In addition, we analysed the association between the increased numbers of CMB and subsequent intracerebral haemorrhages. All 129 patients with high risk TIA with microbleeds or minor stroke within 24 hours after the onset (average age 65.9 ± 9.3, 48.7% were male patients) were divided randomly into two groups: (1) 67 patients were given combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, then 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days);(2) the rest patients were given aspirin treatment (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75-300 mg on the first day. The CMB were found in 52.7% of all patients in both groups. There was no siginificant difference between the Aspirin group and the Aspirin-clopidogrel treated group, though the latter showed some slight increase in CMB (Odds ratios (OR) = 1.16, 95% confidence intervals (CI) = 0.54-2.47, P = 0.71). But the numbers of CMB were remarkably associated with the number of primary existing CMB (OR = 6.46, 95%CI 2.57-16.23, P < 0.001), especially that of primary existing CMB ≥  3.In addition, the increasing numbers of CMB associated with primary CMB lesions, which located in corticosubcortical area (CSC) (OR = 4.69, 95%CI 1.51-14.53, P = 0.007). For the treatment of high-risk TIA or minor stroke patients, the

  16. VASP phosphorylation and genetic polymorphism for clopidogrel resistance in Chinese patients with non-cardioembolic ischemic stroke.

    PubMed

    Zhang, Shijun; Lai, Xinqiang; Li, Wenxian; Xiong, Zhilin; Xu, Anding; Xu, Anding; Huang, Li'an

    2014-12-01

    Clopidogrel resistance(CR)is found in non-cardioembolic ischemic stroke (NCIS) patients. However, it is still largely unknown how to identify CR in NCIS patients by laboratory and genetic characteristics. A total of 95 patients with acute NCIS were recruited. Phosphorylation of the vasodilator stimulated phosphoprotein (VASP) was detected using flow cytometry, and genes(CYP2C19,CYP3A4) were detected using the Sanger method. The baseline of platelet reactivity index (BPRI) before clopidogrel treatment and the platelet reactivity index with clopidogrel treatment (CPRI) for 7 days were measured. Laboratory clopidogrel resistance (LCR) was defined as CPRI of ≥ 50%. Clinical clopidogrel resistance (CCR) was defined as the presence of progressive stroke during hospitalization, stroke recurrence or occurrence of other ischemic vascular events within 6 months. The incidence of LCR was 41.05% and 18.95% developed CCR. The incidence of LCR was significantly higher in GA/AA patients with CYP2C19 (681G > A) (χ2 = 11.16, P = 0.001) and CYP2C19 (636G > A) (χ2 = 4.829, P = 0.028) than in wildtype GG patients. CYP2C19 (681G > A) (OR 6.272, 95%CI 2.162,18.199,P = 0.001) and CYP2C19 (636G > A) (OR: 5.625,95%CI 1.439, 21.583,P = 0.013) were risk factors for LCR. patients with LCR were more likely to develop CCR (χ2 = 6.021, P = 0.014). The probability of CCR was markedly increased in GA/AA patients with CYP2C19 (681G > A) (χ2 = 10.341, P = 0.001). We identified CYP2C19 (681G > A) (OR 7.814, 95%CI 1.816, 33.618 P = 0.006), Essen score (OR 8.351, 95%CI 1.848, 37.745 P = 0.006), and LCR (OR 5.881, 95%CI 1.373, 25.192, P = 0.017) as risk factors for CCR. In clinical practice,LCR and CYP2C19 gene polymorphism should be assessed in NCIS patients receiving clopidogrel treatment.

  17. Neural attention and evaluative responses to gay and lesbian couples.

    PubMed

    Dickter, Cheryl L; Forestell, Catherine A; Mulder, Blakely E

    2015-01-01

    The goal of the current study was to examine whether differential neural attentional capture and evaluative responses for out-group homosexual relative to in-group heterosexual targets occur during social categorization. To this end, 36 heterosexual participants were presented with pictures of heterosexual and homosexual couples in a picture-viewing task that was designed to assess implicit levels of discomfort toward homosexuality and explicit evaluations of pleasantness toward the images. Neural activity in the form of electroencephalogram was recorded during the presentation of the pictures, and event-related potentials resulting from these stimuli were examined. Participants also completed questionnaires that assessed the degree to which they socialized with gays and lesbians. Results demonstrated that relative to straight couples, larger P2 amplitude was observed in response to gay but not to lesbian couples. However, both gay and lesbian couples yielded a larger late positive potential than straight couples. Moreover, the degree to which participants differentially directed early neural attention to out-group lesbian versus in-group straight couples was related to their familiarity with homosexual individuals. This work, which provides an initial understanding of the neural underpinnings of attention toward homosexual couples, suggests that differences in the processing of sexual orientation can occur as early as 200 ms and may be moderated by familiarity.

  18. Evaluating linear response in active systems with no perturbing field

    NASA Astrophysics Data System (ADS)

    Szamel, Grzegorz

    2017-03-01

    We present a method for the evaluation of time-dependent linear response functions for systems of active particles propelled by a persistent (colored) noise from unperturbed simulations. The method is inspired by the Malliavin weights sampling method proposed by Warren and Allen (Phys. Rev. Lett., 109 (2012) 250601) for out-of-equilibrium systems of passive Brownian particles. We illustrate our method by evaluating two linear response functions for a single active particle in an external harmonic potential. As an application, we calculate the time-dependent mobility function and an effective temperature, defined through the Einstein relation between the self-diffusion and mobility coefficients, for a system of many active particles interacting via a screened Coulomb potential. We find that this effective temperature decreases with increasing persistence time of the self-propulsion. Initially, for not too large persistence times, it changes rather slowly, but then it decreases markedly when the persistence length of the self-propelled motion becomes comparable with the particle size.

  19. Evaluation of a hospice rapid response community service: a controlled evaluation

    PubMed Central

    2012-01-01

    Background While most people faced with a terminal illness would prefer to die at home, less than a third in England are enabled to do so with many dying in National Health Service hospitals. Patients are more likely to die at home if their carers receive professional support. Hospice rapid response teams, which provide specialist palliative care at home on a 24/7 on-call basis, are proposed as an effective way to help terminally ill patients die in their preferred place, usually at home. However, the effectiveness of rapid response teams has not been rigorously evaluated in terms of patient, carer and cost outcomes. Methods/Design The study is a pragmatic quasi-experimental controlled trial. The primary outcome for the quantitative evaluation for patients is dying in their preferred place of death. Carers’ quality of life will be evaluated using postal questionnaires sent at patient intake to the hospice service and eight months later. Carers’ perceptions of care received and the patient’s death will be assessed in one to one interviews at 6 to 8 months post bereavement. Service utilisation costs including the rapid response intervention will be compared to those of usual care. Discussion The study will contribute to the development of the evidence base on outcomes for patients and carers and costs of hospice rapid response teams operating in the community. Trial registration: Current controlled trials ISRCTN32119670. PMID:22846107

  20. Critical Evaluation of Ayurvedic Plants for Stimulating Intrinsic Antioxidant Response

    PubMed Central

    Shukla, Sunil Dutt; Bhatnagar, Maheep; Khurana, Sukant

    2012-01-01

    Oxidative damage caused by free radicals plays an important role in the causation and progression of many diseases, including aging. Free-radical damage is countered by many mechanisms, including both active antioxidant enzymatic activity in our body and passive antioxidants. Antioxidant response of our body can accommodate increased oxidative damage in diseased states to a level but beyond that level, additional antioxidants are required to combat the increased stress. Apart from the regular dietary sources of antioxidants, many traditional herbal medicines demonstrate a potential to boost antioxidant activity. Rasayana chikitsa that deals with rejuvenation and revitalization is a branch of the Indian traditional medical system of ayurveda. We review some select herbs described in rasayana chikitsa that have been assessed by modern means for stimulating intrinsic antioxidant responses in humans. A critical evaluation of rasayana chikitsa will likely provide urgently needed, actual stimulants of our physiological antioxidant responses and not just more passive antioxidants to add to an already large catalog. PMID:22855669

  1. Evaluating Satiated Copepod Behavioral Responses to Thin Layer Flow Structure

    NASA Astrophysics Data System (ADS)

    True, Aaron C.; Webster, Donald R.; Weissburg, Marc J.; Yen, Jeannette

    2011-11-01

    Zooplankton exploit a variety of chemical and fluid mechanical cues in foraging, mate-seeking, and habitat partitioning contexts. To examine the influence of environmental cues on zooplankton aggregations in coastal marine thin layers, a laboratory thin layer mimic was built. The apparatus uses a laminar, planar jet (the Bickley jet) to produce ecologically-relevant layers of chemical (beneficial and harmful phytoplankton) and fluid mechanical (shear strain rate) cues for zooplankton behavioral assays. Particle image velocimetry (PIV) and laser-induced fluorescence (LIF) were employed to fully quantify the spatial structure of the chemical and fluid mechanical cues, ensuring a close match to in situ conditions and allowing for investigations into threshold cue levels responsible for inducing behavioral responses. Evaluating the effect of hunger level on behavioral responses is particularly important for producing accurate individual-based simulations of zooplankton population dynamics. Behavioral assays with the calanoid copepod Temora longicornis have produced digitized trajectories and, subsequently, path kinematics. Observed behaviors include increased turn frequency and decreased relative swimming speed, which result in increased residence time in the free jet shear layer. Cue-induced individual behaviors have the potential to produce population-scale aggregations.

  2. Acute Coronary Syndromes, Gastrointestinal Protection, and Recommendations Regarding Concomitant Administration of Proton-Pump Inhibitors (Omeprazol/Esomeprazole) and Clopidogrel.

    PubMed

    Lozano, Iñigo; Sanchez-Insa, Esther; de Leiras, Sergio Rodríguez; Carrillo, Pilar; Ruiz-Quevedo, Valeriano; Pinar, Eduardo; Gopar-Gopar, Silvia; Bayon, Jeremías; Mañas, Pilar; Lasa, Garikoitz; CruzGonzalez, Ignacio; Hernandez, Felipe; Fernandez-Portales, Javier; Fernandez-Fernandez, Javier; Pérez-Serradilla, Ana; de la Torre Hernandez, José M; Gomez-Jaume, Alfredo

    2016-02-01

    The Food and Drug Administration and the European Medicines Agency sent a warning in 2010 discouraging the concomitant use of clopidogrel with omeprazole or esomeprazole. The purpose is to know the gastroprotective approach in patients with acute coronary syndrome (ACS) and the level of follow-up of the alert. In 17 hospitals with catheterization laboratory in Spain, 1 per region, we studied 25 consecutive patients per hospital whose diagnosis of discharge since October 1, 2013, had been any type of ACS. We analyzed their baseline clinical profile, the gatroprotective agents at admission and discharge and the antiplatelet therapy at discharge. The number of patients included was 425: age 67.2 ± 12.5 years, women 29.8%, diabetes 36.5%. The patients presented unstable angina in 21.6%, non-ST-elevation myocardial infarction in 35.3% and ST-elevation myocardial infarction in 43.1%. Conservative approach was chosen in 17.9%, bare-metal stents 32.2%, ≥ 1 drug-eluting stent 48.5%, and surgery 1.4%. Aspirin was indicated in 1.9%, aspirin + clopidogrel 73.6%, aspirin + prasugrel 17.6%, and aspririn + ticagrelor 6.8%. Gastroprotective agents were present in 40.2% patients at admission and this percentage increased to 93.7% at discharge. Of the 313 (73.6%) on clopidogrel in 96 (30.6%) was combined with omeprazole and 3 (0.95%) with esomeprazole, whereas the most commonly used was pantoprazole with 190 patients (44.7%). In conclusion, almost the totality of the patients with an ACS receive gastroprotective agents at the moment of discharge, most of them with proton-pump inhibitors. In one every 3 cases of the patients who are on clopidogrel, the recommendation of the Food and Drug Administration and the European Medicines Agency is not followed. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Clopidogrel use and cancer-specific mortality: a population-based cohort study of colorectal, breast and prostate cancer patients.

    PubMed

    Hicks, Blánaid M; Murray, Liam J; Hughes, Carmel; Cardwell, Chris R

    2015-08-01

    Concerns were raised about the safety of antiplatelet thienopyridine derivatives after a randomized control trial reported increased risks of cancer and cancer deaths in prasugrel users. We investigate whether clopidogrel, a widely used thienopyridine derivative, was associated with increased risk of cancer-specific or all-cause mortality in cancer patients. Colorectal, breast and prostate cancer patients, newly diagnosed from 1998 to 2009, were identified from the National Cancer Data Repository. Cohorts were linked to the UK Clinical Practice Research Datalink, providing prescription records, and to the Office of National Statistics mortality data (up to 2012). Unadjusted and adjusted hazard ratios (HRs) for cancer-specific and all-cause mortality in post-diagnostic clopidogrel users were calculated using time-dependent Cox regression models. The analysis included 10 359 colorectal, 17 889 breast and 13 155 prostate cancer patients. There was no evidence of an increase in cancer-specific mortality in clopidogrel users with colorectal (HR = 0.98 95% confidence interval (CI) 0.77, 1.24) or prostate cancer (HR = 1.03 95%CI 0.82, 1.28). There was limited evidence of an increase in breast cancer patients (HR = 1.22 95%CI 0.90, 1.65); however, this was attenuated when removing prescriptions in the year prior to death. This novel study of large population-based cohorts of colorectal, breast and prostate cancer patients found no evidence of an increased risk of cancer-specific mortality among colorectal, breast and prostate cancer patients using clopidogrel. Copyright © 2015 John Wiley & Sons, Ltd.

  4. Haplotype of platelet receptor P2RY12 gene is associated with residual clopidogrel on-treatment platelet reactivity*

    PubMed Central

    Nie, Xiao-yan; Li, Jun-lei; Zhang, Yong; Xu, Yang; Yang, Xue-li; Fu, Yu; Liang, Guang-kai; Lu, Yun; Liu, Jian; Shi, Lu-wen

    2017-01-01

    Objective: To investigate a possible association between common variations of the P2RY12 and the residual clopidogrel on-treatment platelet reactivity after adjusting for the influence of CYP2C19 tested by thromboelastography (TEG). Methods: One hundred and eighty patients with acute coronary syndrome (ACS) treated with clopidogrel and aspirin were included and platelet function was assessed by TEG. Five selected P2RY12 single nucleotide polymorphisms (SNPs; rs6798347, rs6787801, rs6801273, rs6785930, and rs2046934), which cover the common variations in the P2RY12 gene and its regulatory regions, and three CYP2C19 SNPs (*2,*3,*17) were genotyped and possible haplotypes were analyzed. Results: The high on-treatment platelet reactivity (HTPR) prevalence defined by a platelet inhibition rate <30% by TEG in adenosine diphosphate (ADP)-channel was 69 (38.33%). Six common haplotypes were inferred from four of the selected P2RY12 SNPs (denoted H0 to H5) according to the linkage disequilibrium R square (except for rs2046934). Haplotype H1 showed a significantly lower incidence of HTPR than the reference haplotype (H0) in the total study population while haplotypes H1 and H2 showed significantly lower incidences of HTPR than H0 in the nonsmoker subgroup after adjusting for CYP2C19 effects and demographic characteristics. rs2046934 (T744C) did not show any significant association with HTPR. Conclusions: The combination of common P2RY12 variations including regulatory regions rather than rs2046934 (T744C) that related to pharmacodynamics of clopidogrel in patients with ACS was independently associated with residual on-clopidogrel platelet reactivity. This is apart from the established association of the CYP2C19. This association seemed more important in the subgroup defined by smoking. PMID:28070995

  5. Plasma and whole blood clot strength measured by thrombelastography in patients treated with clopidogrel during acute coronary syndromes.

    PubMed

    Lu, Deshun; Owens, Janelle; Kreutz, Rolf P

    2013-08-01

    Treatment with clopidogrel, a selective platelet P2Y12 receptor antagonist, reduces risk of recurrent ischemic events in patients with acute coronary syndrome (ACS), by limiting platelet aggregation and activation. Stable whole blood clot formation requires activation of platelets, generation of fibrin and final fibrin crosslinks. In this study we intended to compare plasma and whole blood thrombelastography (TEG) measurements in patients during ACS. Whole blood and plasma samples from 32 patients with non-ST segment elevation myocardial infarction (NSTEMI) were collected after administration of clopidogrel. Whole blood and plasma fibrin clot strength (MA) were determined by TEG. Platelet aggregation was determined by light transmittance aggregometry (LTA) using adenosine 5'-diphosphate (ADP), thrombin receptor activation peptide (TRAP), or collagen as agonists. Fibrinogen and C-reactive protein (CRP) concentrations were measured by ELISA. Heightened plasma fibrin clot strength was associated with increased platelet reactivity stimulated by ADP (ρ=0.536; p=0.002), TRAP (ρ=0.481; p=0.007), and collagen (ρ=0.538; p=0.01). In contrast to plasma fibrin MA, whole blood MA did not correlate with platelet aggregation. Platelet count was the primary contributor to the difference in thrombin induced whole blood MA and plasma fibrin MA. Increasing levels of CRP were associated with increased plasma fibrin clot strength and platelet reactivity. Our data suggest that inflammation is associated with increased plasma fibrin clot strength and lower platelet inhibition by clopidogrel during ACS. Platelet count is a main contributor to additional contractile force of whole blood TEG as compared to plasma TEG during treatment with clopidogrel. © 2013 Elsevier Ltd. All rights reserved.

  6. Spectral response of the Viking lander camera: Preliminary evaluation

    NASA Technical Reports Server (NTRS)

    Kelly, W. L., IV; Huck, F. O.; Arvidson, R. E.

    1975-01-01

    One of the objectives of the Viking lander imaging investigation is to obtain color and near-infrared multispectral panoramas of the Martian surface using six spectral channels in the 0.4 to 1.1 microns wavelength range. This data can be compared with data obtained by imaging a reference test chart to construct approximate spectral reflectance curves that can then be matched to laboratory standards to aid in identifying surface materials. Some channels exhibit appreciable out-of-band spectral responses, making data reduction and interpretation difficult. A preliminary evaluation of predicted multispectral data for eight geological materials reveals that fairly good reflectance estimates can be made for those materials which have monotonically increasing or decreasing reflectances. Reflectance estimates for materials with more complex reflectances often do not reveal important spectral features and sometimes provide misleading results.

  7. 209-E Building -- Response to ventilation failure evaluation

    SciTech Connect

    Foust, D.J.

    1998-07-27

    This document provides an evaluation and recommendations for radiological workplace air monitoring and response to ventilation failure for the Critical Mass Laboratory, 209-E Building. The Critical Mass Laboratory, part of the 209-E Building, was designed to provide a heavily shielded room where plutonium and uranium liquid solutions could be brought into various critical configurations under readily controlled and monitored conditions. The facility is contained within a one-story L-shaped concrete block and reinforced concrete building. One wing houses offices, a control room, shops, and a common area while the other wing includes an equipment room, the change room, work areas, and the two-story Critical Assembly Room (CAR). Three of the rooms contain radiologically contaminated equipment and materials.

  8. Fear of negative evaluation modulates electrocortical and behavioral responses when anticipating social evaluative feedback

    PubMed Central

    Van der Molen, Melle J. W.; Poppelaars, Eefje S.; Van Hartingsveldt, Caroline T. A.; Harrewijn, Anita; Gunther Moor, Bregtje; Westenberg, P. Michiel

    2014-01-01

    Cognitive models posit that the fear of negative evaluation (FNE) is a hallmark feature of social anxiety. As such, individuals with high FNE may show biased information processing when faced with social evaluation. The aim of the current study was to examine the neural underpinnings of anticipating and processing social-evaluative feedback, and its correlates with FNE. We used a social judgment paradigm in which female participants (N = 31) were asked to indicate whether they believed to be socially accepted or rejected by their peers. Anticipatory attention was indexed by the stimulus preceding negativity (SPN), while the feedback-related negativity and P3 were used to index the processing of social-evaluative feedback. Results provided evidence of an optimism bias in social peer evaluation, as participants more often predicted to be socially accepted than rejected. Participants with high levels of FNE needed more time to provide their judgments about the social-evaluative outcome. While anticipating social-evaluative feedback, SPN amplitudes were larger for anticipated social acceptance than for social rejection feedback. Interestingly, the SPN during anticipated social acceptance was larger in participants with high levels of FNE. None of the feedback-related brain potentials correlated with the FNE. Together, the results provided evidence of biased information processing in individuals with high levels of FNE when anticipating (rather than processing) social-evaluative feedback. The delayed response times in high FNE individuals were interpreted to reflect augmented vigilance imposed by the upcoming social-evaluative threat. Possibly, the SPN constitutes a neural marker of this vigilance in females with higher FNE levels, particularly when anticipating social acceptance feedback. PMID:24478667

  9. Visible hyperspectral imaging evaluating the cutaneous response to ultraviolet radiation

    NASA Astrophysics Data System (ADS)

    Ilias, Michail A.; Häggblad, Erik; Anderson, Chris; Salerud, E. Göran

    2007-02-01

    In vivo diagnostics of skin diseases as well as understanding of the skin biology constitute a field demanding characterization of physiological and anatomical parameters. Biomedical optics has been successfully used, to qualitatively and quantitatively estimate the microcirculatory conditions of superficial skin. Capillaroscopy, laser Doppler techniques and spectroscopy, all elucidate different aspects of microcirculation, e.g. capillary anatomy and distribution, tissue perfusion and hemoglobin oxygenation. We demonstrate the use of a diffuse reflectance hyperspectral imaging system for spatial and temporal characterization of tissue oxygenation, important to skin viability. The system comprises: light source, liquid crystal tunable filter, camera objective, CCD camera, and the decomposition of the spectral signature into relative amounts of oxy- and deoxygenized hemoglobin as well as melanin in every pixel resulting in tissue chromophore images. To validate the system, we used a phototesting model, creating a graded inflammatory response of a known geometry, in order to evaluate the ability to register spatially resolved reflectance spectra. The obtained results demonstrate the possibility to describe the UV inflammatory response by calculating the change in tissue oxygen level, intimately connected to a tissue's metabolism. Preliminary results on the estimation of melanin content are also presented.

  10. Blue gum gaming machine: an evaluation of responsible gambling features.

    PubMed

    Blaszczynski, Alexander; Gainsbury, Sally; Karlov, Lisa

    2014-09-01

    Structural characteristics of gaming machines contribute to persistence in play and excessive losses. The purpose of this study was to evaluate the effectiveness of five proposed responsible gaming features: responsible gaming messages; a bank meter quarantining winnings until termination of play; alarm clock facilitating setting time-reminders; demo mode allowing play without money; and a charity donation feature where residual amounts can be donated rather than played to zero credits. A series of ten modified gaming machines were located in five Australian gambling venues. The sample comprised 300 patrons attending the venue and who played the gaming machines. Participants completed a structured interview eliciting gambling and socio-demographic data and information on their perceptions and experience of play on the index machines. Results showed that one-quarter of participants considered that these features would contribute to preventing recreational gamblers from developing problems. Just under half of the participants rated these effects to be at least moderate or significant. The promising results suggest that further refinements to several of these features could represent a modest but effective approach to minimising excessive gambling on gaming machines.

  11. Simultaneous quantitation of acetylsalicylic acid and clopidogrel along with their metabolites in human plasma using liquid chromatography tandem mass spectrometry.

    PubMed

    Chhonker, Yashpal S; Pandey, Chandra P; Chandasana, Hardik; Laxman, Tulsankar Sachin; Prasad, Yarra Durga; Narain, V S; Dikshit, Madhu; Bhatta, Rabi S

    2016-03-01

    The interest in therapeutic drug monitoring has increased over the last few years. Inter- and intra-patient variability in pharmacokinetics, plasma concentration related toxicity and success of therapy have stressed the need of frequent therapeutic drug monitoring of the drugs. A sensitive, selective and rapid liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous quantification of acetylsalicylic acid (aspirin), salicylic acid, clopidogrel and carboxylic acid metabolite of clopidogrel in human plasma. The chromatographic separations were achieved on Waters Symmetry Shield(TM) C18 column (150 × 4.6 mm, 5 µm) using 3.5 mm ammonium acetate (pH 3.5)-acetonitrile (10:90, v/v) as mobile phase at a flow rate of 0.75 mL/min. The present method was successfully applied for therapeutic drug monitoring of aspirin and clopidogrel in 67 patients with coronary artery disease.

  12. Evaluating Melanoma Drug Response and Therapeutic Escape with Quantitative Proteomics*

    PubMed Central

    Rebecca, Vito W.; Wood, Elizabeth; Fedorenko, Inna V.; Paraiso, Kim H. T.; Haarberg, H. Eirik; Chen, Yi; Xiang, Yun; Sarnaik, Amod; Gibney, Geoffrey T.; Sondak, Vernon K.; Koomen, John M.; Smalley, Keiran S. M.

    2014-01-01

    The evolution of cancer therapy into complex regimens with multiple drugs requires novel approaches for the development and evaluation of companion biomarkers. Liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) is a versatile platform for biomarker measurement. In this study, we describe the development and use of the LC-MRM platform to study the adaptive signaling responses of melanoma cells to inhibitors of HSP90 (XL888) and MEK (AZD6244). XL888 had good anti-tumor activity against NRAS mutant melanoma cell lines as well as BRAF mutant cells with acquired resistance to BRAF inhibitors both in vitro and in vivo. LC-MRM analysis showed HSP90 inhibition to be associated with decreased expression of multiple receptor tyrosine kinases, modules in the PI3K/AKT/mammalian target of rapamycin pathway, and the MAPK/CDK4 signaling axis in NRAS mutant melanoma cell lines and the inhibition of PI3K/AKT signaling in BRAF mutant melanoma xenografts with acquired vemurafenib resistance. The LC-MRM approach targeting more than 80 cancer signaling proteins was highly sensitive and could be applied to fine needle aspirates from xenografts and clinical melanoma specimens (using 50 μg of total protein). We further showed MEK inhibition to be associated with signaling through the NFκB and WNT signaling pathways, as well as increased receptor tyrosine kinase expression and activation. Validation studies identified PDGF receptor β signaling as a potential escape mechanism from MEK inhibition, which could be overcome through combined use of AZD6244 and the PDGF receptor inhibitor, crenolanib. Together, our studies show LC-MRM to have unique value as a platform for the systems level understanding of the molecular mechanisms of drug response and therapeutic escape. This work provides the proof-of-principle for the future development of LC-MRM assays for monitoring drug responses in the clinic. PMID:24760959

  13. Clopidogrel pretreatment of patients with ST-elevation myocardial infarction does not affect platelet reactivity after subsequent prasugrel-loading: platelet reactivity in an observational study.

    PubMed

    Nührenberg, Thomas G; Trenk, Dietmar; Leggewie, Stefan; Ristau, Inga; Amann, Michael; Stratz, Christian; Hochholzer, Willibald; Valina, Christian M; Neumann, Franz-Josef

    2013-01-01

    Current guidelines recommend prasugrel or ticagrelor for patients undergoing percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI). Whereas available data support ticagrelor independent of pretreatment with clopidogrel, corresponding data for prasugrel are missing. Here, we investigated platelet reactivity after loading with prasugrel in clopidogrel-naïve vs. clopidogrel-pretreated patients. Forty-seven consecutive patients with STEMI referred for primary PCI were enrolled. Use of GPIIb/IIIa inhibitors and known contraindications to prasugrel served as exclusion criteria. A total of 31 patients were already treated with a loading dose of clopidogrel 600 mg by the emergency medical system before admission, while 16 patients were P2Y12 antagonist naïve. All patients received a loading dose of prasugrel 60 mg immediately before PCI. Adenosine diphosphate (ADP) induced platelet reactivity was determined by VerifyNow™ P2Y12 assay, by light transmission aggregometry (LTA) and by multiple electrode impedance aggregometry (MEIA; Multiplate™ analyser). No differences in platelet reactivity were observed at day 1 after PCI between the bolus-on-bolus treatment regimen and single prasugrel loading. Platelet reactivity was profoundly decreased to 10 [8-31] platelet reactivity unit (PRU; median [interquartile range]) in patients on clopidogrel + prasugrel vs. 9 [6-60] PRU in patients on prasugrel only (p = 0.916). Consistent results were obtained by LTA and MEIA. The proportion of patients reaching a MEIA associated with increased risk bleeding (<188 AU*min) was also similar between the two study groups. The level of platelet reactivity at day 1 after the 60 mg loading dose of prasugrel was independent of pretreatment with clopidogrel. Our results do not support withholding prasugrel in patients pretreated with clopidogrel who undergo PCI for STEMI.

  14. Impact of concomitant use of proton pump inhibitors and clopidogrel or ticagrelor on clinical outcomes in patients with acute coronary syndrome

    PubMed Central

    Yan, Yan; Wang, Xiao; Fan, Jing-Yao; Nie, Shao-Ping; Raposeiras-Roubín, Sergio; Abu-Assi, Emad; Henriques, Jose P Simao; D'Ascenzo, Fabrizio; Saucedo, Jorge; González-Juanatey, José R; Wilton, Stephen B; Kikkert, Wouter J; Nuñez-Gil, Iván; Ariza-Sole, Albert; Song, Xian-Tao; Alexopoulos, Dimitrios; Liebetrau, Christoph; Kawaji, Tetsuma; Moretti, Claudio; Huczek, Zenon; Fujii, Toshiharu; Correia, Luis C; Kawashiri, Masa-aki; Kedev, Sasko

    2016-01-01

    Background There is great debate on the possible adverse interaction between proton pump inhibitors (PPIs) and clopidogrel. In addition, whether the use of PPIs affects the clinical efficacy of ticagrelor remains less known. We aimed to determine the impact of concomitant administration of PPIs and clopidogrel or ticagrelor on clinical outcomes in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). Methods We retrospectively analyzed data from a “real world”, international, multi-center registry between 2003 and 2014 (n = 15,401) and assessed the impact of concomitant administration of PPIs and clopidogrel or ticagrelor on 1-year composite primary endpoint (all-cause death, re-infarction, or severe bleeding) in patients with ACS after PCI. Results Of 9429 patients in the final cohort, 54.8% (n = 5165) was prescribed a PPI at discharge. Patients receiving a PPI were older, more often female, and were more likely to have comorbidities. No association was observed between PPI use and the primary endpoint for patients receiving clopidogrel (adjusted HR: 1.036; 95% CI: 0.903–1.189) or ticagrelor (adjusted HR: 2.320; 95% CI: 0.875–6.151) (Pinteraction = 0.2004). Similarly, use of a PPI was not associated with increased risk of all-cause death, re-infarction, or a decreased risk of severe bleeding for patients treated with either clopidogrel or ticagrelor. Conclusions In patients with ACS following PCI, concomitant use of PPIs was not associated with increased risk of adverse outcomes in patients receiving either clopidogrel or ticagrelor. Our findings indicate it is reasonable to use a PPI in combination with clopidogrel or ticagrelor, especially in patients with a higher risk of gastrointestinal bleeding. PMID:27103915

  15. Secondary prevention of cardiogenic arterial thromboembolism in the cat: The double-blind, randomized, positive-controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT).

    PubMed

    Hogan, Daniel F; Fox, Philip R; Jacob, Kristin; Keene, Bruce; Laste, Nancy J; Rosenthal, Steven; Sederquist, Kimberly; Weng, Hsin-Yi

    2015-12-01

    To determine if clopidogrel administration is associated with a reduced likelihood of recurrent cardiogenic arterial thromboembolism (CATE) in cats compared to aspirin administration. Secondary aims were to determine if clopidogrel administration had an effect on the composite endpoint of recurrent CATE and cardiac death and to identify adverse effects of chronic clopidogrel or aspirin therapy. Seventy-five cats that survived a CATE event. Multicenter, double-blind, randomized, positive-controlled study. Cats were assigned to clopidogrel (18.75 mg/cat PO q 24 h) or aspirin (81 mg/cat PO q 72 h). Kaplan-Meier survival curves were created for each endpoint and the log rank test performed to compare treatment groups with respect to time to event and the likelihood of the event occurring. The mean age of all cats was 8.0 ± 3.5 yr and 57/75 (76%) were male (p < 0.001); 62/75 (83%) were mixed breed with the remainder including Persian, Abyssinian, American Shorthair, Bengal, Birman, Himalayan, Maine Coon, Ragdoll, Snowshoe, and Sphynx breeds. Only 15% (11/75) of cats had a history of heart disease recorded prior to the CATE event. Clopidogrel administration was associated with significantly reduced likelihood of recurrent CATE compared to aspirin (p = 0.024) and had a longer median time to recurrence [443 (95% CI 185-990) days vs. 192 (95% CI 62-364) days, respectively]. Clopidogrel was also associated with a significantly reduced likelihood of the composite endpoint of recurrent CATE or cardiac death (p = 0.033) with a longer median time to event [346 (95% CI 146-495) days vs. 128 (95% CI 58-243) days]. Clopidogrel administration significantly reduces the likelihood of recurrent CATE compared with aspirin in cats; both drugs were well tolerated. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease.

    PubMed

    Jones, W Schuyler; Baumgartner, Iris; Hiatt, William R; Heizer, Gretchen; Conte, Michael S; White, Christopher J; Berger, Jeffrey S; Held, Peter; Katona, Brian G; Mahaffey, Kenneth W; Norgren, Lars; Blomster, Juuso; Millegård, Marcus; Reist, Craig; Patel, Manesh R; Fowkes, F Gerry R

    2017-01-17

    In patients with symptomatic peripheral artery disease with a history of limb revascularization, the optimal antithrombotic regimen for long-term management is unknown. The EUCLID trial (Examining Use of Ticagrelor In PAD) randomized 13 885 patients with peripheral artery disease to treatment with ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle-brachial index ≤0.80 or a previous lower extremity revascularization. This analysis focuses on the 7875 (57%) patients enrolled based on the previous lower extremity revascularization criterion. Patients could not be enrolled within 30 days of most recent revascularization, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. Patients with a previous revascularization had a mean age of 66 years, 73% were male, and the median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on previous revascularization had similar rates of the primary composite end point (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.98-1.23, P=0.12) and statistically significantly higher rates of myocardial infarction (HR 1.29, 95% CI 1.08-1.55, P=0.005) and acute limb ischemia (HR 4.23, 95% CI 2.86-6.25, P<0.001) when compared with patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor- versus clopidogrel-treated patients were found for the primary efficacy end point (11.4% vs 11.3%; HR 1.01, 95% CI 0.88-1.15; P=0.90), all-cause mortality (9.2% vs 9.2%; HR 0.99, 95% CI 0.86-1.15; P=0.93), acute limb ischemia (2.5% vs 2.5%; HR 1.03, 95% CI 0.78-1.36; P=0.84), or major bleeding (1.9% vs 1.8%; HR 1.15, 95% CI 0.83-1.59; P=0.41). The median duration of follow-up was ≈30 months. After adjustment for baseline

  17. What Do We Do Now That the Evaluation Is Over? Methods for Transitioning the Responsibility of Evaluation to Program Staff.

    ERIC Educational Resources Information Center

    Cassata, Jennifer Coyne; Siddens, Stephanie K.

    This paper describes the methods engaged in by an internal evaluation unit within a large school district to transition program staff from participating in a formal program evaluation to continuing the responsibility of program monitoring once an evaluation ends. Formal multiyear program evaluations can provide program managers and staff with…

  18. Evaluation of acute cardiorespiratory responses to hydraulic resistance exercise.

    PubMed

    Katch, F I; Freedson, P S; Jones, C A

    1985-02-01

    Accurate evaluation of the acute responses to resistance exercise training depends on the stability of the criterion measures. This is particularly true for maximal effort exercise where continuous "all-out" effort for each repetition is encouraged. The present study evaluated reliability of repetition number (repN), respiratory gas parameters (VO2, VCO2, VE), and heart rate (HR) for shoulder (SE), chest (CE), and leg (LE) exercise performed maximally on a single-unit, 3-station hydraulic resistance exercise machine (Hydra-Fitness, Belton, TX). On 2 separate days, 20 college men completed three 20-s bouts of SE, CE, and LE with a 20-s rest between bouts and 5 min between exercise modes. There were no significant differences between bouts or test days for repN, gas measures, or HR. Subjects performed 17, 19, and 21 reps during SE, LE, and CE. VO2 was 1.7 l . min-1 (24.3 ml . kg-1 . min-1) for SE, 1.87 l . min-1 (25.5 ml . kg-1 . min-1) for CE, and 2.1 l . min-1 (28.6 ml . kg-1 . min-1) for LE. These values, averaged, represented 52.8% of the max VO2 determined on a continuous cycle ergometer test. The corresponding HR's during hydraulic exercise averaged 84.6% of HR max. Test-retest reliability coefficients ranged from r = .67 to .87 for repN, r = .41 to .83 for gas measures, and r = .72 to .89 for HR.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Defining hormesis: evaluation of a complex concentration response phenomenon.

    PubMed

    Kendig, Eric L; Le, Hoa H; Belcher, Scott M

    2010-01-01

    Hormesis describes dose-response relationships characterized by a reversal of response between low and high doses of chemicals, biological molecules, physical stressors, or other initiators of a response. Acceptance of hormesis as a viable dose-response theory has been limited until recently, in part, because of poor conceptual understanding, ad hoc and inappropriate use, and lack of a defined mechanism. By examining the history of this dose-response theory, it is clear that both pharmacological and toxicological studies provide evidence for hormetic dose responses, but retrospective examination of studies can be problematic at best. Limited scientific evidence and lack of a common lexicon with which to describe these responses have left hormesis open to inappropriate application to unrelated dose-response relationships. Future studies should examine low-dose effects using unbiased, descriptive criteria to further the scientific understanding of this dose response. A clear, concise definition is required to further the limited scientific evidence for hormetic dose responses.

  20. Implicit misattribution of evaluative responses: contingency-unaware evaluative conditioning requires simultaneous stimulus presentations.

    PubMed

    Hütter, Mandy; Sweldens, Steven

    2013-08-01

    Recent research has shown that evaluative conditioning (EC) procedures can change attitudes without participants' awareness of the contingencies between conditioned and unconditioned stimuli (Hütter, Sweldens, Stahl, Unkelbach, & Klauer, 2012). We present a theoretical explanation and boundary condition for the emergence of unaware EC effects based on the implicit misattribution of evaluative responses from unconditioned to conditioned stimuli. We hypothesize that such misattribution is only possible when conditioned and unconditioned stimuli are perceived simultaneously. Therefore we manipulate the simultaneity of the stimulus presentations and apply a process dissociation procedure to distinguish contingency-aware from contingency-unaware EC effects. A multinomial model indicates that with sequential presentations, EC effects do not occur without contingency awareness. However, unaware EC effects do occur with simultaneous presentations. The findings support dual-process theories of learning. PsycINFO Database Record (c) 2013 APA, all rights reserved.

  1. Platelet-to-lymphocyte ratio but not neutrophil-to-lymphocyte ratio predicts high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndrome

    PubMed Central

    Efe, Edem; Kocayiğit, Ibrahim; Türker, Pabuccu Mustafa; Murat, Küçükukur; Erkan, Alpaslan; Sedat, Taş; Alper, Çil; Necati, Aksoy Murat; Gökhan, Vural Mustafa; Bahri, Akdeniz

    2016-01-01

    Objectives: Dual antiplatelet therapy (DAPT), consisting of clopidogrel and aspirin, is the main-stay treatment of acute coronary syndromes (ACS). However, major adverse cardiovascular events may occur even in patients undergoing DAPT, and this has been related to the variable pharmacodynamic efficacy of these drugs, especially clopidogrel. Platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) are novel inflammatory markers for cardiovascular risk stratification, which may reflect an inflammatory state and thus high on-treatment platelet reactivity (HPR). Methods: We investigated the usefulness of PLR and NLR in predicting HPR in clopidogrel-treated patients with ACS. A total of 244 patients were enrolled in this study, and 43 of them were nonresponsive to clopidogrel. Results: Logistic regression analysis indicated that PLR was significantly associated with HPR (P < 0.001). Using a cutoff level of 331, PLR predicted HPR with a sensitivity of 73% and a specificity of 69% (odds ratio: 376.15, 95% confidence interval = 37.813–3741.728 P < 0.001, receiver operating characteristic curve: 0.885). Conclusions: We suggest that more attention should be paid to the PLR values of these patients on admission to identify individuals who may not benefit from clopidogrel during the course of ACS. PMID:27756943

  2. Development and validation of a liquid chromatographic method for purity control of clopidogrel-acetylsalicylic acid in combined oral dosage forms.

    PubMed

    Kahsay, Getu; Van Schepdael, Ann; Adams, Erwin

    2012-03-05

    A reversed phase liquid chromatographic method with UV detection for the simultaneous determination of clopidogrel and acetylsalicylic acid and their related substances in combined oral formulations was developed and validated. Good separation was achieved on a Luna C18 column (150 mm × 4.6 mm, 3 μm) using gradient elution at a flow rate of 1 mL/min and a column temperature of 35 °C. UV detection was performed at 220 nm. The validation was performed according to the ICH guidelines. The method proved to be specific, sensitive (LOQ=0.975 μg/mL and 0.0384 μg/mL for clopidogrel and acetylsalicylic acid, respectively), linear in the concentration range from LOQ to 325 μg/mL for clopidogrel and from LOQ to 650 μg/mL for acetylsalicylic acid, precise (RSD values for intermediate precision <1%) and accurate with mean recovery values of 100.7% and 100.2% for clopidogrel and acetylsalicylic acid, respectively. Moreover, the solution stability and method robustness were examined. The method gives satisfactory separation of impurities of clopidogrel and acetylsalicylic acid and so it is suitable for quantification of the related substances as well as for the assay of the actives.

  3. Molecular structure and vibrational spectroscopic analysis of an antiplatelet drug; clopidogrel hydrogen sulphate (form 2) - A combined experimental and quantum chemical approach

    NASA Astrophysics Data System (ADS)

    Srivastava, Anubha; Mishra, Soni; Tandon, Poonam; Patel, Sarasvatkumar; Ayala, A. P.; Bansal, A. K.; Siesler, H. W.

    2010-02-01

    Clopidogrel hydrogen sulphate which belongs to a class of medicine called antiplatelet drugs. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno [3,2- c] pyridine-5-acetate hydrogen sulphate having the empirical formula C 16H 17ClNO 2S.HSO 4 and molecular mass 321.82 g/mol. The present study is confined to vibrational spectroscopy of the polymorph identified as form 2 of the clopidogrel hydrogen sulphate. The vibrational analysis of clopidogrel hydrogen sulphate salt (form 2) considering separately the two counterions has been performed. We also report a theoretical and experimental study of the molecular conformation and vibrational dynamics of the independent moieties of the clopidogrel hydrogen sulphate salt. The equilibrium geometry, harmonic vibrational frequencies, infrared intensities and activities of Raman scattering were calculated by ab initio Hartree-Fock and density functional theory employing B3LYP with complete relaxation in the potential energy surface using 6-311++G(d,p) basis set. The calculated wavenumbers after a proper scaling show a very good agreement with the observed values. A complete vibrational assignment is provided for the observed Raman and infrared spectra of clopidogrel hydrogen sulphate form 2.

  4. Evaluations of indoor noise criteria systems based on human response

    NASA Astrophysics Data System (ADS)

    Bowden, Erica E.; Wang, Lily M.

    2005-09-01

    The goal of this research is to examine human response to background noise, and relate results to indoor noise criteria. In previous work by the authors, subjects completed perception surveys, typing tasks, and proofreading tasks under typical heating, ventilating, and air-conditioning (HVAC) noise conditions. Results were correlated with commonly used indoor noise criteria systems including noise criteria (NC), room criteria (RC) and others. The findings suggested that the types of tasks used and the length of exposure can impact the results. To examine these two issues, the authors conducted a new study in which each test subject completed 38 total hours of testing over multiple days. Subjects were exposed to several background noise exposures over 20, 40, 80, and 240 minute trials. During the trials, subjects completed a variety of performance tasks and answered questions about their perception of the noise, the thermal environment, and various other factors. Findings from this study were used to determine optimum testing conditions for on-going research examining the effects of tonal or fluctuating background noise on performance, annoyance, and spectral perception. Results are being used to evaluate the effectiveness of commonly used indoor noise criteria systems. [Work supported by INCE and ASHRAE.

  5. A definition and ethical evaluation of overdiagnosis: response to commentaries.

    PubMed

    Carter, Stacy M; Doust, Jenny; Degeling, Chris; Barratt, Alexandra

    2016-08-29

    It is a privilege to have respected colleagues engage with our definition and ethical evaluation of overdiagnosis. In our response to the commentaries, we first deal with paradigmatic issues: the place of realism, the relationship between diagnostic standards and correctness and the distinction between overdiagnosis and both false-positives and medicalisation. We then discuss issues arising across the commentaries in turn. Our definition captures the range of different types of overdiagnosis, unlike a definition limited to diagnosis of harmless disease. Certain implications do flow from our definition, as noted by commentators, but we do not view them as problematic: overdiagnoses can become beneficial diagnoses as medical knowledge and practice changes over time; inadequate systems of healthcare can produce tragic overdiagnosis, and the effectiveness of treatment partly determines whether overdiagnosis occurs. Complexity and uncertainty in balancing benefits and harms is unfortunate, but not a reason to avoid making a judgement (ideally one that reflects multiple perspectives). We reaffirm that overdiagnosis, for the foreseeable future, must be estimated at a population level and defend the importance of good-quality risk communication for individuals. We acknowledge that a lot turns on the relevance of professional communities in our definition and expand our reasoning in this regard then conclude with a note on the difference between intentions and goals. We expect that it will be some time before these matters are settled and we look forward to continue debating these matters with our colleagues.

  6. CYP2C19 loss-of-function alleles are not associated with clinical outcome of clopidogrel therapy in patients treated with newer-generation drug-eluting stents

    PubMed Central

    Choi, Ik Jun; Koh, Yoon-Seok; Park, Mahn-Won; Her, Sung Ho; Choi, Yun-Seok; Park, Chul-Soo; Park, Hun-Jun; Kim, Pum-Joon; Chung, Wook-Sung; Kim, Ho-Sook; Shin, Jae-Gook; Seung, Ki-Bae; Chang, Kiyuk

    2016-01-01

    Abstract CYP2C19 loss-of-function (LOF) alleles adversely affect clinical outcome of clopidogrel therapy. Recent introduction of a newer-generation drug-eluting stent (DES) has significantly reduced the occurrence of stent thrombosis. The aim of this study was to evaluate the impact of CYP2C19 LOF alleles on clinical outcome in patients treated with the newer-generation DES. The effects of CYP2C19 genotypes were evaluated on clinical outcome of clopidogrel therapy in 2062 patients treated with percutaneous coronary intervention using either first-generation DES (sirolimus- and paclitaxel-eluting stent, n = 1349) or newer-generation DES (everolimus- and zotarolimus-eluting stent, n = 713). The primary clinical outcome was major cardiac and cerebrovascular event (MACCE) including cardiac death, nonfatal myocardial infarction, stroke, and stent thrombosis during 1 year of follow-up. CYP2C19 LOF alleles were significantly associated with a higher risk of MACCE in patients treated with first-generation DES (hazard ratio [HR] 2.599, 95% confidence interval [CI] 1.047–6.453; P = 0.034). In contrast, CYP2C19 LOF alleles were not associated with primary outcome in newer-generation DES (HR 0.716, 95% CI 0.316–1.622; P = 0.522). In the further multivariate analysis, CYP2C19 LOF alleles were not associated with MACCE in patients receiving newer-generation DES (adjusted HR 0.540, 95% CI 0.226–1.291; P = 0.166), whereas they were demonstrated to be an independent risk factor for MACCE in those implanted with first-generation DES (adjusted HR 3.501, 95% CI 1.194–10.262; P = 0.022). In contradiction to their clinical impact in first-generation DES era, CYP2C19 LOF alleles may not affect clinical outcome of clopidogrel therapy in patients treated with newer-generation DES. PMID:27368038

  7. Monoclinic form I of clopidogrel hydrogen sulfate from powder diffraction data

    PubMed Central

    Chernyshev, Vladimir V.; Pirogov, Sergey V.; Shishkina, Irina N.; Velikodny, Yurii A.

    2010-01-01

    The asymmetric unit of the title compound, C16H17ClNO2S+·HSO4 −, (I) [systematic name: (+)-(S)-5-[(2-chloro­phen­yl)(meth­oxy­carbon­yl)meth­yl]-4,5,6,7-tetra­hydro­thieno[3,2-c]pyridin-5-ium hydrogen sulfate], contains two independent cations of clopidogrel and two independent hydrogensulfate anions. The two independent cations are of similar conformation; however, this differs from that observed in ortho­rhom­bic form (II) [Bousquet et al. (2003 ▶). US Patent No. 6 504 030]. The H—N—Cchiral—H fragment shows a trans conformation in both independent cations in (I) and a gauche conformation in (II). In (I), classical inter­molecular N—H⋯O and O—H⋯O hydrogen bonds link two independent cations and two independent anions into an isolated cluster, in which two cations inter­act with one anion only via N—H⋯O hydrogen bonds. Weak inter­molecular C—H⋯O hydrogen bonds further consolidate the crystal packing. PMID:21588394

  8. Visualization and quantification of deformation behavior of clopidogrel bisulfate polymorphs during tableting.

    PubMed

    Yin, Xian-Zhen; Wu, Li; Li, Ying; Guo, Tao; Li, Hai-Yan; Xiao, Ti-Qiao; York, Peter; Nangia, Ashwini; Gui, Shuang-Ying; Zhang, Ji-Wen

    2016-02-25

    The deformation behavior of particles under pressure dominates the mechanical properties of solid dosage forms. In this study, the in situ 3D deformation of two polymorphs (I and II) of clopidogrel bisulfate (CLP) was determined to illustrate pressure distribution profiles within the tablet by the deformation of the crystalline particles for the first time. Synchrotron radiation X-ray computed microtomography (SR-μCT) was utilized to visualize and quantify the morphology of thousands crystalline particles of CLP I and CLP II before and after compression. As a result, the deformation was examined across scale dimensions from microns to the size of the final dosage form. Three dimensional parameters such as volume, sphericity, oblate and prolate of individual particle and distributions were computed and analyzed for quantitative comparison to CLP I and CLP II. The different degrees of deformation under the same compression conditions of CLP I and CLP II were observed and characterized quantitatively. The map of deformation degrees within the tablet illustrated the heterogeneous pressure distribution in various regions of the compacted tablet. In conclusion, the polymorph deformation behaviors demonstrated by SR-μCT quantitative structure analysis deepen understanding of tableting across dimensions from microns to millimeters for the macrostrcuture of tablet.

  9. Design and Development of Clopidogrel Bisulfate Gastroretentive Osmotic Formulation Using Quality by Design Tools.

    PubMed

    Desai, Nilesh; Purohit, Ravindra

    2017-02-28

    Clopidogrel bisulfate (CBS) is antiplatelet drug and it is becoming a drug of choice in the treatment and management of prevention of heart attacks and strokes. CBS is stable and soluble in acidic pH; therefore, retention in stomach for prolonged period appears to be beneficial for controlling the bioavailability. The gastroretentive osmotic system (GROS) facilitates prolonged retention of drug in stomach and provides zero-order drug release. A complex formulation like GROS poses many challenges, and QbD tools can help in designing robust formulation which takes all aspects of product and process development in order to deliver a robust product. The GROS was formulated in three steps: core tablet, osmotic tablet, and gastroretentive osmotic tablet. The design of experiment was used for screening and optimization of formulation and process-related parameters. The dissolution study was carried out to analyze the release pattern of tablet. The optimized batch O-4 showed cumulative drug release of 19.43, 30.49, 64.41, and 85.11% at 2, 4, 8, and 12 h which is in the range of QTPP predictions. The novel technique of GROS was implemented successfully which demonstrates robust design giving consistent and desired results.

  10. Visualization and quantification of deformation behavior of clopidogrel bisulfate polymorphs during tableting

    PubMed Central

    Yin, Xian-Zhen; Wu, Li; Li, Ying; Guo, Tao; Li, Hai-Yan; Xiao, Ti-Qiao; York, Peter; Nangia, Ashwini; Gui, Shuang-Ying; Zhang, Ji-Wen

    2016-01-01

    The deformation behavior of particles under pressure dominates the mechanical properties of solid dosage forms. In this study, the in situ 3D deformation of two polymorphs (I and II) of clopidogrel bisulfate (CLP) was determined to illustrate pressure distribution profiles within the tablet by the deformation of the crystalline particles for the first time. Synchrotron radiation X-ray computed microtomography (SR-μCT) was utilized to visualize and quantify the morphology of thousands crystalline particles of CLP I and CLP II before and after compression. As a result, the deformation was examined across scale dimensions from microns to the size of the final dosage form. Three dimensional parameters such as volume, sphericity, oblate and prolate of individual particle and distributions were computed and analyzed for quantitative comparison to CLP I and CLP II. The different degrees of deformation under the same compression conditions of CLP I and CLP II were observed and characterized quantitatively. The map of deformation degrees within the tablet illustrated the heterogeneous pressure distribution in various regions of the compacted tablet. In conclusion, the polymorph deformation behaviors demonstrated by SR-μCT quantitative structure analysis deepen understanding of tableting across dimensions from microns to millimeters for the macrostrcuture of tablet. PMID:26911359

  11. Visualization and quantification of deformation behavior of clopidogrel bisulfate polymorphs during tableting

    NASA Astrophysics Data System (ADS)

    Yin, Xian-Zhen; Wu, Li; Li, Ying; Guo, Tao; Li, Hai-Yan; Xiao, Ti-Qiao; York, Peter; Nangia, Ashwini; Gui, Shuang-Ying; Zhang, Ji-Wen

    2016-02-01

    The deformation behavior of particles under pressure dominates the mechanical properties of solid dosage forms. In this study, the in situ 3D deformation of two polymorphs (I and II) of clopidogrel bisulfate (CLP) was determined to illustrate pressure distribution profiles within the tablet by the deformation of the crystalline particles for the first time. Synchrotron radiation X-ray computed microtomography (SR-μCT) was utilized to visualize and quantify the morphology of thousands crystalline particles of CLP I and CLP II before and after compression. As a result, the deformation was examined across scale dimensions from microns to the size of the final dosage form. Three dimensional parameters such as volume, sphericity, oblate and prolate of individual particle and distributions were computed and analyzed for quantitative comparison to CLP I and CLP II. The different degrees of deformation under the same compression conditions of CLP I and CLP II were observed and characterized quantitatively. The map of deformation degrees within the tablet illustrated the heterogeneous pressure distribution in various regions of the compacted tablet. In conclusion, the polymorph deformation behaviors demonstrated by SR-μCT quantitative structure analysis deepen understanding of tableting across dimensions from microns to millimeters for the macrostrcuture of tablet.

  12. Evaluating Educational Programmes: The Need and the Response.

    ERIC Educational Resources Information Center

    Stake, Robert E.

    This survey of recent developments in educational program evaluation is intended for persons who commission, implement, direct, or carry out evaluation studies. The attitudes of government officials, educators, and researchers toward assessment and their own evaluation needs are discussed. Various approaches to evaluation are briefly described;…

  13. Will They Like Me? Adolescents' Emotional Responses to Peer Evaluation

    ERIC Educational Resources Information Center

    Guyer, Amanda E.; Caouette, Justin D.; Lee, Clinton C.; Ruiz, Sarah K.

    2014-01-01

    Relative to children and adults, adolescents are highly focused on being evaluated by peers. This increased attention to peer evaluation has implications for emotion regulation in adolescence, but little is known about the characteristics of the evaluatee and evaluator that influence emotional reactions to evaluative outcomes. The present study…

  14. Will They Like Me? Adolescents' Emotional Responses to Peer Evaluation

    ERIC Educational Resources Information Center

    Guyer, Amanda E.; Caouette, Justin D.; Lee, Clinton C.; Ruiz, Sarah K.

    2014-01-01

    Relative to children and adults, adolescents are highly focused on being evaluated by peers. This increased attention to peer evaluation has implications for emotion regulation in adolescence, but little is known about the characteristics of the evaluatee and evaluator that influence emotional reactions to evaluative outcomes. The present study…

  15. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms.

    PubMed

    Rumi, Elisa; Cazzola, Mario

    2017-02-09

    Philadelphia-negative classical myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 revision of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues includes new criteria for the diagnosis of these disorders. Somatic mutations in the 3 driver genes, that is, JAK2, CALR, and MPL, represent major diagnostic criteria in combination with hematologic and morphological abnormalities. PV is characterized by erythrocytosis with suppressed endogenous erythropoietin production, bone marrow panmyelosis, and JAK2 mutation. Thrombocytosis, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation are the main diagnostic criteria for ET. PMF is characterized by bone marrow megakaryocytic proliferation, reticulin and/or collagen fibrosis, and presence of JAK2, CALR, or MPL mutation. Prefibrotic myelofibrosis represents an early phase of myelofibrosis, and is characterized by granulocytic/megakaryocytic proliferation and lack of reticulin fibrosis in the bone marrow. The genomic landscape of MPNs is more complex than initially thought and involves several mutant genes beyond the 3 drivers. Comutated, myeloid tumor-suppressor genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive disorders. Patients with myeloid neoplasms are at variable risk of vascular complications, including arterial or venous thrombosis and bleeding. Current prognostic models are mainly based on clinical and hematologic parameters, but innovative models that include genetic data are being developed for both clinical and trial settings. In perspective, molecular profiling of MPNs might also allow for accurate evaluation and monitoring of response to innovative drugs that target the mutant clone.

  16. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms

    PubMed Central

    2017-01-01

    Philadelphia-negative classical myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 revision of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues includes new criteria for the diagnosis of these disorders. Somatic mutations in the 3 driver genes, that is, JAK2, CALR, and MPL, represent major diagnostic criteria in combination with hematologic and morphological abnormalities. PV is characterized by erythrocytosis with suppressed endogenous erythropoietin production, bone marrow panmyelosis, and JAK2 mutation. Thrombocytosis, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation are the main diagnostic criteria for ET. PMF is characterized by bone marrow megakaryocytic proliferation, reticulin and/or collagen fibrosis, and presence of JAK2, CALR, or MPL mutation. Prefibrotic myelofibrosis represents an early phase of myelofibrosis, and is characterized by granulocytic/megakaryocytic proliferation and lack of reticulin fibrosis in the bone marrow. The genomic landscape of MPNs is more complex than initially thought and involves several mutant genes beyond the 3 drivers. Comutated, myeloid tumor-suppressor genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive disorders. Patients with myeloid neoplasms are at variable risk of vascular complications, including arterial or venous thrombosis and bleeding. Current prognostic models are mainly based on clinical and hematologic parameters, but innovative models that include genetic data are being developed for both clinical and trial settings. In perspective, molecular profiling of MPNs might also allow for accurate evaluation and monitoring of response to innovative drugs that target the mutant clone. PMID:28028026

  17. Content-Responsive Program Evaluation: An Integrated Preservice Example.

    ERIC Educational Resources Information Center

    Costner, Kelly M.; Wagner, Sigrid; Owens, Douglas T.

    This paper discusses the lack of and the need for program evaluation models for mathematics education and points out generic approaches to program evaluation. This project attempts to develop a mathematical approach to program evaluation that can be applied to an integrated preservice program for mathematics, science, and technology education…

  18. On Messes, Systems Thinking, and Evaluation: A Response to Patton

    ERIC Educational Resources Information Center

    Miller, Robin Lin

    2016-01-01

    To help evaluation professionals better understand what an authentic attempt at Developmental Evaluation (DE) ought to look like and when it is appropriate to use, Michael Patton's provocative essay (this issue) offers evaluators eight sensitizing concepts to call on as guides. Patton states these concepts succinctly define DE and persuasively…

  19. On Messes, Systems Thinking, and Evaluation: A Response to Patton

    ERIC Educational Resources Information Center

    Miller, Robin Lin

    2016-01-01

    To help evaluation professionals better understand what an authentic attempt at Developmental Evaluation (DE) ought to look like and when it is appropriate to use, Michael Patton's provocative essay (this issue) offers evaluators eight sensitizing concepts to call on as guides. Patton states these concepts succinctly define DE and persuasively…

  20. Accreditation Stimuli and Evaluation Responses in a Clinical Training Program.

    ERIC Educational Resources Information Center

    Wood, David; And Others

    Assessment and evaluation skills are significant goals of clinical training, yet many clinical and counseling students lack personal experiences with applied program evaluation. Clinical psychology graduate students responded to successive impending accreditation visits by conducting in-house evaluations. Students in 1977 (N=38) and 1980 (N=35)…

  1. Aspirin Versus Aspirin Plus Clopidogrel as Antithrombotic Treatment Following Transcatheter Aortic Valve Replacement With a Balloon-Expandable Valve: The ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation) Randomized Clinical Trial.

    PubMed

    Rodés-Cabau, Josep; Masson, Jean-Bernard; Welsh, Robert C; Garcia Del Blanco, Bruno; Pelletier, Marc; Webb, John G; Al-Qoofi, Faisal; Généreux, Philippe; Maluenda, Gabriel; Thoenes, Martin; Paradis, Jean-Michel; Chamandi, Chekrallah; Serra, Vicenç; Dumont, Eric; Côté, Mélanie

    2017-07-10

    The aim of this study was to compare aspirin plus clopidogrel with aspirin alone as antithrombotic treatment following transcatheter aortic valve replacement (TAVR) for the prevention of ischemic events, bleeding events, and death. Few data exist on the optimal antithrombotic therapy following TAVR. This was a randomized controlled trial comparing aspirin (80 to 100 mg/day) plus clopidogrel (75 mg/day) (dual antiplatelet therapy [DAPT]) versus aspirin alone (single-antiplatelet therapy [SAPT]) in patients undergoing TAVR with a balloon-expandable valve. The primary endpoint was the occurrence of death, myocardial infarction (MI), stroke or transient ischemic attack, or major or life-threatening bleeding (according to Valve Academic Research Consortium 2 definitions) within the 3 months following the procedure. The trial was prematurely stopped after the inclusion of 74% of the planned study population. A total of 222 patients were included, 111 allocated to DAPT and 111 to SAPT. The composite of death, MI, stroke or transient ischemic attack, or major or life-threatening bleeding tended to occur more frequently in the DAPT group (15.3% vs. 7.2%, p = 0.065). There were no differences between groups in the occurrence of death (DAPT, 6.3%; SAPT, 3.6%; p = 0.37), MI (DAPT, 3.6%; SAT, 0.9%; p = 0.18), or stroke or transient ischemic attack (DAPT, 2.7%; SAPT, 0.9%; p = 0.31) at 3 months. DAPT was associated with a higher rate of major or life-threatening bleeding events (10.8% vs. 3.6% in the SAPT group, p = 0.038). There were no differences between groups in valve hemodynamic status post-TAVR. This small trial showed that SAPT (vs. DAPT) tended to reduce the occurrence of major adverse events following TAVR. SAPT reduced the risk for major or life-threatening events while not increasing the risk for MI or stroke. Larger studies are needed to confirm these results. (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation: The ARTE

  2. Six Versus Twelve Months Clopidogrel Therapy After Drug-Eluting Stenting in Patients With Acute Coronary Syndrome: An ISAR-SAFE Study Subgroup Analysis

    PubMed Central

    Lohaus, Raphaela; Michel, Jonathan; Mayer, Katharina; Lahmann, Anna Lena; Byrne, Robert A.; Wolk, Annabelle; ten Berg, Jurrien M.; Neumann, Franz-Josef; Han, Yaling; Adriaenssens, Tom; Tölg, Ralph; Seyfarth, Melchior; Maeng, Michael; Zrenner, Bernhard; Jacobshagen, Claudius; Wöhrle, Jochen; Kufner, Sebastian; Morath, Tanja; Ibrahim, Tareq; Bernlochner, Isabell; Fischer, Marcus; Schunkert, Heribert; Laugwitz, Karl-Ludwig; Mehilli, Julinda; Kastrati, Adnan; Schulz-Schüpke, Stefanie

    2016-01-01

    In patients presenting with acute coronary syndrome (ACS) the optimal duration of dual-antiplatelet therapy after drug-eluting stent (DES) implantation remains unclear. At 6 months after intervention, patients receiving clopidogrel were randomly assigned to either a further 6-month period of placebo or clopidogrel. The primary composite endpoint was death, myocardial infarction, stent thrombosis, stroke, or major bleeding 9 months after randomization. The ISAR-SAFE trial was terminated early due to low event rates and slow recruitment. 1601/4000 (40.0%) patients presented with ACS and were randomized to 6 (n = 794) or 12 months (n = 807) clopidogrel. The primary endpoint occurred in 14 patients (1.8%) receiving 6 months of clopidogrel and 17 patients (2.2%) receiving 12 months; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.41–1.68, P = 0.60. There were 2 (0.3%) cases of stent thrombosis in each group; HR 1.00, 95% CI 0.14–7.09, P = >0.99. Major bleeding occurred in 3 patients (0.4%) receiving 6 months clopidogrel and 5 (0.6%) receiving 12 months; HR 0.60, 95% CI 0.15–2.49, P = 0.49. There was no significant difference in net clinical outcomes after DES implantation in ACS patients treated with 6 versus 12 months clopidogrel. Ischaemic and bleeding events were low beyond 6-months. PMID:27624287

  3. Prasugrel Results in Higher Decrease in High-Sensitivity C-Reactive Protein Level in Patients Undergoing Percutaneous Coronary Intervention Comparing to Clopidogrel

    PubMed Central

    Hajsadeghi, Shokoufeh; Chitsazan, Mandana; Chitsazan, Mitra; Salehi, Negar; Amin, Ahmad; Bidokhti, Arash Amin; Babaali, Nima; Bordbar, Armin; Hejrati, Maral; Moghadami, Samar

    2016-01-01

    OBJECTIVES A growing body of clinical and laboratory evidence indicates that inflammation plays a crucial role in atherosclerosis. In the present study, we compared the effects of clopidogrel and prasugrel on high-sensitivity C-reactive protein (hs-CRP) in patients undergoing percutaneous coronary intervention (PCI). METHODS The present randomized, double-blind clinical trial included 120 patients who underwent PCI. Eligible patients were randomly assigned 2:1 to one of the two groups: 80 patients in the first group received clopidogrel (Plavix®; loading dose and maintenance dose of 300 and 75 mg daily, respectively) and 40 patients in the second group received prasugrel (Effient®; loading dose and maintenance dose of 60 and 10 mg, respectively) for 12 weeks. The hs-CRP levels between baseline and 12th week were compared. RESULTS Of the 120 patients, 69 patients (57.5%) were male. Pretreatment hs-CRP level was statistically comparable in clopidogrel (median, 15.10 mg/dL; interquartile range [IQR], 9.62–23.75 mg/dL) and prasugrel groups (median, 18 mg/dL; IQR, 14.25–22 mg/dL; P = 0.06). Patients taking clopidogrel showed a significant reduction in hs-CRP level compared with the baseline values (P < 0.001). Prasugrel administration also resulted in a significant reduction in hs-CRP level (P < 0.001). A significant 73% overall reduction in the hs-CRP level was seen with prasugrel compared with 39% overall reduction in hs-CRP level with clopidogrel (P = 0.002). CONCLUSION Prasugrel seems to be superior to clopidogrel in the reduction of hs-CRP in patients undergoing PCI. PMID:27597810

  4. Crop insurance evaluation in response to extreme events

    NASA Astrophysics Data System (ADS)

    Moriondo, Marco; Ferrise, Roberto; Bindi, Marco

    2013-04-01

    Crop yield insurance has been indicated as a tool to manage the uncertainties of crop yields (Sherrick et al., 2004) but the changes in crop yield variability as expected in the near future should be carefully considered for a better quantitative assessment of farmer's revenue risk and insurance values in a climatic change regime (Moriondo et al., 2011). Under this point of view, mechanistic crop growth models coupled to the output of General/Regional Circulation Models (GCMs, RCMs) offer a valuable tool to evaluate crop responses to climatic change and this approach has been extensively used to describe crop yield distribution in response to climatic change considering changes in both mean climate and variability. In this work, we studied the effect of a warmer climate on crop yield distribution of durum wheat (Triticum turgidum L. subsp durum) in order to assess the economic significance of climatic change in a risk decision context. Specifically, the outputs of 6 RCMs (Tmin, Tmax, Rainfall, Global Radiation) (van der Linden and Mitchell 2009) have been statistically downscaled by a stochastic weather generator over eight sites across the Mediterranean basin and used to feed the crop growth model Sirius Quality. Three time slices were considered i) the present period PP (average of the period 1975-1990, [CO2]=350 ppm), 2020 (average of the period 2010-2030, SRES scenario A1b, [CO2]=415 ppm) and 2040 (average of the period 2030-2050, SRES scenario A1b, [CO2]=480 ppm). The effect of extreme climate events (i.e. heat stress at anthesis stage) was also considered. The outputs of these simulations were used to estimate the expected payout per hectare from insurance triggered when yields fall below a specific threshold defined as "the insured yield". For each site, the threshold was calculated as a fraction (70%) of the median of yield distribution under PP that represents the percentage of median yield above which indemnity payments are triggered. The results

  5. Cost-effectiveness analysis of ticagrelor compared to clopidogrel for the treatment of patients with acute coronary syndrome in Colombia.

    PubMed

    Mejía, Aurelio; Senior, Juan Manuel; Ceballos, Mateo; Atehortúa, Sara; Toro, Juan Manuel; Saldarriaga, Clara; Mejía, María Elena; Ramírez, Carolina

    2015-01-01

    Acute coronary syndrome is one of the most frequent medical emergencies in developing countries. To determine, from the perspective of the Colombian health system, the cost-effectiveness of ticagrelor compared to clopidogrel for the treatment of patients with acute coronary syndrome. We conducted a cost-effectiveness analysis from the perspective of the Colombian health system comparing ticagrelor and clopidogrel for the treatment of patients with acute coronary syndrome. To estimate the expected costs and outcomes, a Markov model was constructed in which patients could remain stable without experiencing new cardiovascular events, suffer from a new event, or die. For the baseline case, a 10-year time horizon and a discount ratio of 3% for costs and benefits were adopted. The transition probabilities were extracted from the PLATO (Platelet Inhibition and Patient Outcomes) clinical trial. Vital statistics were drawn from the Departmento Administrativo Nacional de Estadística (DANE) and additional information from Colombian patients included in the Access registry. To identify and measure resource use, a standard case was built by consulting guidelines and protocols. Unit costs were obtained from Colombian rate lists. A probabilistic sensitivity analysis was conducted in which costs were represented by a triangular distribution, and the effectiveness through a beta distribution. In the base case, the additional cost per quality-adjusted life-year gained with ticagrelor was COP$ 28,411,503. The results were sensitive to changes in the time horizon and the unit cost of clopidogrel. For a willingness-to-pay equivalent to three times the Colombian per capita gross domestic product, the probability of ticagrelor being cost-effective was 75%. Ticagrelor is a cost-effective strategy for the treatment of patients with acute coronary syndrome in Colombia.

  6. Prediction of high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndromes.

    PubMed

    Podda, G M; Grossi, E; Palmerini, T; Buscema, M; Femia, E A; Della Riva, D; de Servi, S; Calabrò, P; Piscione, F; Maffeo, D; Toso, A; Palmieri, C; De Carlo, M; Capodanno, D; Genereux, P; Cattaneo, M

    2017-08-01

    About 40% of clopidogrel-treated patients display high platelet reactivity (HPR). Alternative treatments of HPR patients, identified by platelet function tests, failed to improve their clinical outcomes in large randomized clinical trials. A more appealing alternative would be to identify HPR patients a priori, based on the presence/absence of demographic, clinical and genetic factors that affect PR. Due to the complexity and multiplicity of these factors, traditional statistical methods (TSMs) fail to identify a priori HPR patients accurately. The objective was to test whether Artificial Neural Networks (ANNs) or other Machine Learning Systems (MLSs), which use algorithms to extract model-like 'structure' information from a given set of data, accurately predict platelet reactivity (PR) in clopidogrel-treated patients. A complete set of fifty-nine demographic, clinical, genetic data was available of 603 patients with acute coronary syndromes enrolled in the prospective GEPRESS study, which showed that HPR after 1month of clopidogrel treatment independently predicted adverse cardiovascular events in patients with Syntax Score >14. Data were analysed by MLSs and TSMs. ANNs identified more variables associated PR at 1month, compared to TSMs. ANNs overall accuracy in predicting PR, although superior to other MLSs was 63% (95% CI 59-66). PR phenotype changed in both directions in 35% of patients across the 3 time points tested (before PCI, at hospital discharge and at 1month). Despite their ability to analyse very complex non-linear phenomena, ANNs or MLS were unable to predict PR accurately, likely because PR is a highly unstable phenotype. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. [Clopidogrel resistance of patients with coronary artery disease and its correlation with platelet count and mean platelet volume].