PATCH: platelet transfusion in cerebral haemorrhage: study protocol for a multicentre, randomised, controlled trial.

PubMed

de Gans, Koen; de Haan, Rob J; Majoie, Charles B; Koopman, Maria M; Brand, Anneke; Dijkgraaf, Marcel G; Vermeulen, Marinus; Roos, Yvo B

2010-03-18

Patients suffering from intracerebral haemorrhage have a poor prognosis, especially if they are using antiplatelet therapy. Currently, no effective acute treatment option for intracerebral haemorrhage exists. Limiting the early growth of intracerebral haemorrhage volume which continues the first hours after admission seems a promising strategy. Because intracerebral haemorrhage patients who are on antiplatelet therapy have been shown to be particularly at risk of early haematoma growth, platelet transfusion may have a beneficial effect. The primary objective is to investigate whether platelet transfusion improves outcome in intracerebral haemorrhage patients who are on antiplatelet treatment. The PATCH study is a prospective, randomised, multi-centre study with open treatment and blind endpoint evaluation. Patients will be randomised to receive platelet transfusion within six hours or standard care. The primary endpoint is functional health after three months. The main secondary endpoints are safety of platelet transfusion and the occurrence of haematoma growth. To detect an absolute poor outcome reduction of 20%, a total of 190 patients will be included. To our knowledge this is the first randomised controlled trial of platelet transfusion for an acute haemorrhagic disease.

Subarachnoid haemorrhage with "Ecstasy" abuse in a young adult.

PubMed

Auer, J; Berent, R; Weber, T; Lassnig, E; Eber, B

2002-10-01

Abuse of the drugs like amphetamine, cocaine and "Ecstasy" may be complicated by intracerebral, subdural or subarachnoid haemorrhage. Contrary to historical opinion, drug-related intracranial haemorrhage (ICH) is frequently related to an underlying vascular malformation. We report the case of an 18-year-old man with a history of Ecstasy abuse preceding the onset of severe occipital headache. Cerebral computed tomography revealed right-sided subarachnoid haemorrhage and cerebral angiography showed right-sided middle cerebral artery aneurysm of 1 cm diameter. The patient was treated surgically with aneurysm clipping. Three weeks after onset of intracranial haemorrhage, neurological examination demonstrated normal findings. A history of severe headache immediately after using amphetamine, Ecstasy, or cocaine should alert doctors to the possibility of intracerebral haemorrhage. Arteriography should be part of the evaluation of most young patients with stroke or non-traumatic ICH.

Methamphetamine-related brainstem haemorrhage.

PubMed

Chiu, Zelia K; Bennett, Iwan E; Chan, Patrick; Rosenfeld, Jeffrey V

2016-10-01

We report the case of an otherwise healthy 29-year-old woman who presented with a brainstem haemorrhage following intravenous methamphetamine use. Extensive investigation did not reveal an underlying pathology, and the development of symptoms was temporally related to methamphetamine injection. Although intracerebral haemorrhage secondary to methamphetamine use is well documented, this report describes a haemorrhage within the brainstem which is a rare location. While animal studies have demonstrated the potential of methamphetamines to produce brainstem haemorrhages, there has only been one previous report describing a haemorrhage in this location due to amphetamine use in humans. We conclude with a brief discussion of the clinical features and aetiology of methamphetamine-related stroke. Copyright © 2016 Elsevier Ltd. All rights reserved.

Risk of long-term anticoagulation under sustained severe arterial hypertension: A translational study comparing warfarin and the new oral anticoagulant apixaban

PubMed Central

Pfeilschifter, Waltraud; Steinstraesser, Thurid; Paulus, Patrick; Zeiner, Pia Susan; Bohmann, Ferdinand; Theisen, Alf; Lindhoff-Last, Edelgard; Penski, Cornelia; Wagner, Marlies; Mittelbronn, Michel

2016-01-01

New oral anticoagulants for the prevention of stroke and systemic embolism in patients with atrial fibrillation have recently been introduced. In this translational study, we explored the risk of long-term anticoagulation on intracerebral hemorrhage under sustained severe arterial hypertension. We initiated anticoagulation with warfarin or apixaban in spontaneously hypertensive rats prone to develop severe hypertension and subsequent intracerebral bleeding complications. A non-anticoagulated group served as control. During an 11-week-study period, blood pressure, anticoagulation parameters, and clinical status were determined regularly. The incidence of histopathologically proven intracerebral hemorrhage was defined as the primary endpoint. Both warfarin and apixaban anticoagulation was fairly stable during the study period, and all rats developed severe hypertension. Intracerebral hemorrhage was determined in 29% (4/14) of warfarin rats and in 10% (1/10) of apixaban rats. Controls did not show cerebral bleeding complications (chi-square not significant). Mortality rate at study termination was 33% (2/6) in controls, 43% (6/14) in the warfarin group, and 60% (6/10) in the apixaban group. Animals died from extracerebral complications in most cases. Our study describes an experimental intracerebral hemorrhage model in the context of sustained hypertension and long-term anticoagulation. Extracerebral bleeding complications occurred more often in warfarin-treated animals compared with apixaban and control rats. PMID:27189904

Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial.

PubMed

Sprigg, Nikola; Flaherty, Katie; Appleton, Jason P; Al-Shahi Salman, Rustam; Bereczki, Daniel; Beridze, Maia; Christensen, Hanne; Ciccone, Alfonso; Collins, Ronan; Czlonkowska, Anna; Dineen, Robert A; Duley, Lelia; Egea-Guerrero, Juan Jose; England, Timothy J; Krishnan, Kailash; Laska, Ann Charlotte; Law, Zhe Kang; Ozturk, Serefnur; Pocock, Stuart J; Roberts, Ian; Robinson, Thompson G; Roffe, Christine; Seiffge, David; Scutt, Polly; Thanabalan, Jegan; Werring, David; Whynes, David; Bath, Philip M

2018-05-26

Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage. We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214. We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic

Prevention of haematoma progression by tranexamic acid in intracerebral haemorrhage patients with and without spot sign on admission scan: a statistical analysis plan of a pre-specified sub-study of the TICH-2 trial.

PubMed

Ovesen, Christian; Jakobsen, Janus Christian; Gluud, Christian; Steiner, Thorsten; Law, Zhe; Flaherty, Katie; Dineen, Rob A; Bath, Philip M; Sprigg, Nikola; Christensen, Hanne

2018-06-13

We present the statistical analysis plan of a prespecified Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 sub-study aiming to investigate, if tranexamic acid has a different effect in intracerebral haemorrhage patients with the spot sign on admission compared to spot sign negative patients. The TICH-2 trial recruited above 2000 participants with intracerebral haemorrhage arriving in hospital within 8 h after symptom onset. They were included irrespective of radiological signs of on-going haematoma expansion. Participants were randomised to tranexamic acid versus matching placebo. In this subgroup analysis, we will include all participants in TICH-2 with a computed tomography angiography on admission allowing adjudication of the participants' spot sign status. Primary outcome will be the ability of tranexamic acid to limit absolute haematoma volume on computed tomography at 24 h (± 12 h) after randomisation among spot sign positive and spot sign negative participants, respectively. Within all outcome measures, the effect of tranexamic acid in spot sign positive/negative participants will be compared using tests of interaction. This sub-study will investigate the important clinical hypothesis that spot sign positive patients might benefit more from administration of tranexamic acid compared to spot sign negative patients. Trial registration ISRCTN93732214 ( http://www.isrctn.com ).

Volume and functional outcome of intracerebral hemorrhage according to oral anticoagulant type

PubMed Central

Wilson, Duncan; Charidimou, Andreas; Shakeshaft, Clare; Ambler, Gareth; White, Mark; Cohen, Hannah; Yousry, Tarek; Al-Shahi Salman, Rustam; Lip, Gregory Y.H.; Brown, Martin M.; Jäger, Hans Rolf

2016-01-01

Objective: To compare intracerebral hemorrhage (ICH) volume and clinical outcome of non–vitamin K oral anticoagulants (NOAC)–associated ICH to warfarin-associated ICH. Methods: In this multicenter cross-sectional observational study of patients with anticoagulant-associated ICH, consecutive patients with NOAC-ICH were compared to those with warfarin-ICH selected from a population of 344 patients with anticoagulant-associated ICH. ICH volume was measured by an observer blinded to clinical details. Outcome measures were ICH volume and clinical outcome adjusted for confounding factors. Results: We compared 11 patients with NOAC-ICH to 52 patients with warfarin-ICH. The median ICH volume was 2.4 mL (interquartile range [IQR] 0.3–5.4 mL) for NOAC-ICH vs 8.9 mL (IQR 4.0–21.3 mL) for warfarin-ICH (p = 0.0028). In univariate linear regression, use of warfarin (difference in cube root volume 1.61; 95% confidence interval [CI] 0.69 to 2.53) and lobar ICH location (compared with nonlobar ICH; difference in cube root volume 1.52; 95% CI 2.20 to 0.85) were associated with larger ICH volumes. In multivariable linear regression adjusting for confounding factors (sex, hypertension, previous ischemic stroke, white matter disease burden, and premorbid modified Rankin Scale score [mRS]), warfarin use remained independently associated with larger ICH (cube root) volumes (coefficient 0.64; 95% CI 0.24 to 1.25; p = 0.042). Ordered logistic regression showed an increased odds of a worse clinical outcome (as measured by discharge mRS) in warfarin-ICH compared with NOAC-ICH: odds ratio 4.46 (95% CI 1.10 to 18.14; p = 0.037). Conclusions: In this small prospective observational study, patients with NOAC-associated ICH had smaller ICH volumes and better clinical outcomes compared with warfarin-associated ICH. PMID:26718576

Volume and functional outcome of intracerebral hemorrhage according to oral anticoagulant type.

PubMed

Wilson, Duncan; Charidimou, Andreas; Shakeshaft, Clare; Ambler, Gareth; White, Mark; Cohen, Hannah; Yousry, Tarek; Al-Shahi Salman, Rustam; Lip, Gregory Y H; Brown, Martin M; Jäger, Hans Rolf; Werring, David J

2016-01-26

To compare intracerebral hemorrhage (ICH) volume and clinical outcome of non-vitamin K oral anticoagulants (NOAC)-associated ICH to warfarin-associated ICH. In this multicenter cross-sectional observational study of patients with anticoagulant-associated ICH, consecutive patients with NOAC-ICH were compared to those with warfarin-ICH selected from a population of 344 patients with anticoagulant-associated ICH. ICH volume was measured by an observer blinded to clinical details. Outcome measures were ICH volume and clinical outcome adjusted for confounding factors. We compared 11 patients with NOAC-ICH to 52 patients with warfarin-ICH. The median ICH volume was 2.4 mL (interquartile range [IQR] 0.3-5.4 mL) for NOAC-ICH vs 8.9 mL (IQR 4.0-21.3 mL) for warfarin-ICH (p = 0.0028). In univariate linear regression, use of warfarin (difference in cube root volume 1.61; 95% confidence interval [CI] 0.69 to 2.53) and lobar ICH location (compared with nonlobar ICH; difference in cube root volume 1.52; 95% CI 2.20 to 0.85) were associated with larger ICH volumes. In multivariable linear regression adjusting for confounding factors (sex, hypertension, previous ischemic stroke, white matter disease burden, and premorbid modified Rankin Scale score [mRS]), warfarin use remained independently associated with larger ICH (cube root) volumes (coefficient 0.64; 95% CI 0.24 to 1.25; p = 0.042). Ordered logistic regression showed an increased odds of a worse clinical outcome (as measured by discharge mRS) in warfarin-ICH compared with NOAC-ICH: odds ratio 4.46 (95% CI 1.10 to 18.14; p = 0.037). In this small prospective observational study, patients with NOAC-associated ICH had smaller ICH volumes and better clinical outcomes compared with warfarin-associated ICH. © 2015 American Academy of Neurology.

Role of surgery in the management of patients with supratentorial spontaneous intracerebral hematoma: Critical appraisal of evidence.

PubMed

Akhigbe, Taiwo; Zolnourian, Ardalan

2017-05-01

Whether surgery improves the outcome more than medical management alone continues to be a subject of intense debate and controversy. However, there is optimism that the management of spontaneous supratentorial intracerebral haemorrhage will change in future based new insight and better understanding of the acute pathophysiology of hematomas and its dynamics. Craniotomy as a surgical approach has been the most studied intervention for spontaneous supratentorial intracerebral haemorrhage but with no significant benefit when compared to best medical management. A literature search was conducted using electronic data bases including the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane library, MEDLINE and EMBASE. In addition, critical appraisal of most current evidences was carried out. About 1387 articles identified through database search over 10-year period of which one systematic review and two randomised controlled trials most relevant to this review were critically appraised. The role of surgery in the management of spontaneous intracerebral haemorrhage still remains a matter of debate. There is insufficient evidence to justify a general policy of early surgery for patients with spontaneous intracerebral haemorrhage compared to initial medical management but STICH did demonstrate that patients with superficial hematoma might benefit from craniotomy. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Excessive work and risk of haemorrhagic stroke: a nationwide case-control study.

PubMed

Kim, Beom Joon; Lee, Seung-Hoon; Ryu, Wi-Sun; Kim, Chi Kyung; Chung, Jong-Won; Kim, Dohoung; Park, Hong-Kyun; Bae, Hee-Joon; Park, Byung-Joo; Yoon, Byung-Woo

2013-10-01

Adverse effect of excessive work on health has been suggested previously, but it was not documented in cerebrovascular diseases. The authors investigated whether excessive working conditions would associate with increased risk of haemorrhagic stroke. A nationwide matched case-control study database, which contains 940 cases of incident haemorrhagic stroke (498 intracerebral haemorrhages and 442 sub-arachnoid haemorrhages) with 1880 gender- and age- (± 5-year) matched controls, was analysed. Work-related information based on the regular job situation, including type of occupation, regular working time, duration of strenuous activity during regular work and shift work, was gathered through face-to-face interviews. Conditional logistic regression analyses were used for the multivariable analyses. Compared with white-collar workers, blue-collar workers had a higher risk for haemorrhagic stroke (odds ratio, 1.33 [95% confidence interval, 1.06-1.66]). Longer regular working time was associated with increased risk of haemorrhagic stroke [odds ratio, 1.38 (95% confidence interval, 1.05-1.81) for 8-12 h/day; odds ratio, 1.95 (95% confidence interval, 1.33-2.86) for ≥ 13 h/day; compared with ≤ 4 h/day]. Exposure to ≥ 8 h/week of strenuous activity also associated haemorrhagic stroke risk [odds ratio, 1.61 (95% confidence interval, 1.26-2.05); compared with no strenuous activity]. Shift work was not associated with haemorrhagic stroke (P = 0.98). Positive associations between working condition indices and haemorrhagic stroke risk were consistent regardless of haemorrhagic stroke sub-types and current employment status. Blue-collar occupation, longer regular working time and extended duration of strenuous activity during work may relate to an increased risk of haemorrhagic stroke. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.

Catastrophic cerebral antiphospholipid syndrome presenting as cerebral infarction with haemorrhagic transformation after sudden withdrawal of warfarin in a patient with primary antiphospholipid syndrome

PubMed Central

Wani, Abdul Majid; Hussain, Waleed Mohd; Mejally, Mousa Ali Al; Ali, Khaled Shawkat; Raja, Sadeya Hanif; Maimani, Wael Al; Bafaraj, Mazen G; Bashraheel, Ashraf; Akhtar, Mubeena; Khoujah, Amer Mohd

2010-01-01

Catastrophic antiphospholipid syndrome (APS) is caused by thrombotic vascular occlusions that affect both small and large vessels, producing ischaemia in the affected organs. The “catastrophic” variant of the antiphospholipid syndrome (cAPS) develops over a short period of time. Although patients with cAPS represent <1% of all patients with APS, they are usually life threatening with a 50% mortality rate. A strong association with concomitant infection is thought to act as the main trigger of microthromboses in cAPS. Several theories have been proposed to explain these physiopathological features. Some of them suggest the possibility of molecular mimicry between components of infectious microorganisms and natural anticoagulants, which might be involved in the production of cross-reacting antiphospholipid antibodies. We present a case of catastrophic cerebral APS characterised by massive temporal lobe infarction and subsequent haemorrhagic transformation after sudden withdrawal of warfarin. PMID:22242060

Higher mortality in patients with right hemispheric intracerebral haemorrhage: INTERACT1 and 2.

PubMed

Sato, Shoichiro; Heeley, Emma; Arima, Hisatomi; Delcourt, Candice; Hirakawa, Yoichiro; Pamidimukkala, Vijaya; Li, Zhendong; Tao, Qingling; Xu, Yuehong; Hennerici, Michael G; Robinson, Thompson; Tzourio, Christophe; Lindley, Richard I; Chalmers, John; Anderson, Craig S; Anderson, C S; Huang, Y; Wang, J G; Arima, H; Neal, B; Peng, B; Heeley, E; Skulina, C; Parsons, M W; Kim, J S; Tao, Q L; Li, Y C; Jiang, J D; Tai, L W; Zhang, L J; Xu, E; Cheng, Y; Heritier, S; Morgenstern, L B; Chalmers, J

2015-12-01

Controversy exists over the prognostic significance of the affected hemisphere in stroke. We aimed to determine the relationship between laterality of acute intracerebral haemorrhage (ICH) and poor clinical outcomes. A subsidiary analysis of the INTERACT Pilot and INTERACT2 studies--randomised controlled trials of patients with spontaneous acute ICH with elevated systolic blood pressure (BP), randomly assigned to intensive (target systolic BP <140 mm Hg) or guideline-based (<180 mm Hg) BP management. Outcomes were the combined and separate end points of death and major disability (modified Rankin scale (mRS) scores of 3-6, 6 and 3-5, respectively) at 90 days. A total of 2708 patients had supratentorial/hemispheric ICH and information on mRS at 90 days. Patients with right hemispheric ICH (1327, 49%) had a higher risk of death at 90 days compared to those with left hemispheric ICH after adjustment for potential confounding variables (OR, 1.77 (95% CI 1.33 to 2.37)). There were no differences between patients with right and left hemispheric ICH regarding the combined end point of death or major disability or major disability in the multivariable-adjusted models (1.07 (0.89 to 1.29) and 0.85 (0.72 to 1.01), respectively). Right hemispheric lesion was associated with increased risk of death in patients with acute ICH. The laterality of the ICH does not appear to affect the level of disability in survivors. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00226096 and NCT00716079. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Adiposity and risk of ischaemic and haemorrhagic stroke in 0·5 million Chinese men and women: a prospective cohort study.

PubMed

Chen, Zhengming; Iona, Andri; Parish, Sarah; Chen, Yiping; Guo, Yu; Bragg, Fiona; Yang, Ling; Bian, Zheng; Holmes, Michael V; Lewington, Sarah; Lacey, Ben; Gao, Ruqin; Liu, Fang; Zhang, Zengzhi; Chen, Junshi; Walters, Robin G; Collins, Rory; Clarke, Robert; Peto, Richard; Li, Liming

2018-06-01

China has high stroke rates despite the population being relatively lean. Uncertainty persists about the relevance of adiposity to risk of stroke types. We aimed to assess the associations of adiposity with incidence of stroke types and effect mediation by blood pressure in Chinese men and women. The China Kadoorie Biobank enrolled 512 891 adults aged 30-79 years from ten areas (five urban and five rural) during 2004-08. During a median 9 years (IQR 8-10) of follow-up, 32 448 strokes (about 90% confirmed by neuroimaging) were recorded among 489 301 participants without previous cardiovascular disease. Cox regression analysis was used to produce adjusted hazard ratios (HRs) for ischaemic stroke (n=25 210) and intracerebral haemorrhage (n=5380) associated with adiposity. Mean baseline body-mass index (BMI) was 23·6 kg/m 2 (SD 3·2), and 331 723 (67·8%) participants had a BMI of less than 25 kg/m 2 . Throughout the range examined (mean 17·1 kg/m 2 [SD 0·9] to 31·7 kg/m 2 [2·0]), each 5 kg/m 2 higher BMI was associated with 8·3 mm Hg (SE 0·04) higher systolic blood pressure. BMI was positively associated with ischaemic stroke, with an HR of 1·30 (95% CI 1·28-1·33 per 5 kg/m 2 higher BMI), which was generally consistent with that predicted by equivalent differences in systolic blood pressure (1·25 [1·24-1·26]). The HR for intracerebral haemorrhage (1·11 [1·07-1·16] per 5 kg/m 2 higher BMI) was less extreme, and much weaker than that predicted by the corresponding difference in systolic blood pressure (1·48 [1·46-1·50]). Other adiposity measures showed similar associations with stroke types. After adjustment for usual systolic blood pressure, the positive associations with ischaemic stroke were attenuated (1·05 [1·03-1·07] per 5 kg/m 2 higher BMI); for intracerebral haemorrhage, they were reversed (0·73 [0·70-0·77]). High adiposity (BMI >23 kg/m 2 ) accounted for 14·7% of total stroke (16·5% of ischaemic stroke and 6·7% of

Pentadecapeptide BPC 157 Reduces Bleeding and Thrombocytopenia after Amputation in Rats Treated with Heparin, Warfarin, L-NAME and L-Arginine.

PubMed

Stupnisek, Mirjana; Kokot, Antonio; Drmic, Domagoj; Hrelec Patrlj, Masa; Zenko Sever, Anita; Kolenc, Danijela; Radic, Bozo; Suran, Jelena; Bojic, Davor; Vcev, Aleksandar; Seiwerth, Sven; Sikiric, Predrag

2015-01-01

BPC 157 is a stable gastric pentadecapeptide recently implicated with a role in hemostasis. While NO is largely implicated in hemostatic mechanisms, in tail-amputation-models under heparin- and warfarin-administration, both the NO-synthase (NOS)-blocker, L-NAME (prothrombotic) and the NOS-substrate L-arginine (antithrombotic), were little investigated. Objective. To investigate the effect of L-NAME and L-arginine on hemostatic parameters, and to reveal the effects of BPC 157 on the L-NAME- and L-arginine-induced hemostatic actions under different pathological condition: tail amputation without or with anticoagulants, heparin or warfarin. Tail amputation, and/or i.v.-heparin (10 mg/kg), i.g.-warfarin (1.5 mg/kg/day for 3 days) were used in rats. Treatment includes BPC 157, L-NAME, L-arginine, per se and their combination. After (tail) amputation, with or without i.v.-heparin or i.g.-warfarin, BPC 157 (10 μg/kg, 10 ng/kg, i.p., i.v. (heparin), 10 μg/kg i.g. (warfarin)) always reduced bleeding time and/or haemorrhage and counteracted thrombocytopenia. As for L-NAME and/or L-arginine, we noted: L-arginine (100 mg/kg i.p.)-rats: more bleeding, less/no thrombocytopenia; L-NAME (5 mg/kg i.p.)-rats: less bleeding (amputation only), but present thrombocytopenia; L-NAME+L-arginine-rats also exhibited thrombocytopenia: L-NAME counteracted L-arginine-increased bleeding, L-arginine did not counteract L-NAME-thrombocytopenia. All animals receiving BPC 157 in addition (BPC 157 μg+L-NAME; BPC 157 μg+L-arginine, BPC 157 μg+L-NAME+L-arginine), exhibited decreased haemorrhage and markedly counteracted thrombocytopenia. L-NAME (thrombocytopenia), L-arginine (increased haemorrhage) counteraction and BPC 157 (decreased haemorrhage, counteracted thrombocytopenia) with rescue against two different anticoagulants, implicate a BPC 157 modulatory and balancing role with rescued NO-hemostatic mechanisms.

The REstart or STop Antithrombotics Randomised Trial (RESTART) after stroke due to intracerebral haemorrhage: study protocol for a randomised controlled trial.

PubMed

Al-Shahi Salman, Rustam; Dennis, Martin S; Murray, Gordon D; Innes, Karen; Drever, Jonathan; Dinsmore, Lynn; Williams, Carol; White, Philip M; Whiteley, William N; Sandercock, Peter A G; Sudlow, Cathie L M; Newby, David E; Sprigg, Nikola; Werring, David J

2018-03-05

For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs results in an increase in the risk of recurrent ICH or a beneficial net reduction of all serious vascular events compared to avoiding antiplatelet drugs. The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, randomised, open, assessor-blind, parallel-group, randomised trial comparing starting versus avoiding antiplatelet drugs for adults surviving antithrombotic-associated ICH at 122 hospital sites in the United Kingdom. RESTART uses a central, web-based randomisation system using a minimisation algorithm, with 1:1 treatment allocation to which central research staff are masked. Central follow-up includes annual postal or telephone questionnaires to participants and their general (family) practitioners, with local provision of information about adverse events and outcome events. The primary outcome is recurrent symptomatic ICH. The secondary outcomes are: symptomatic haemorrhagic events; symptomatic vaso-occlusive events; symptomatic stroke of uncertain type; other fatal events; modified Rankin Scale score; adherence to antiplatelet drug(s). The magnetic resonance imaging (MRI) sub-study involves the conduct of brain MRI according to a standardised imaging protocol before randomisation to investigate heterogeneity of treatment effect according to the presence of brain microbleeds. Recruitment began on 22 May 2013. The target sample size is at least 720 participants in the main trial (at least 550 in the MRI sub-study). Final results of RESTART will be analysed and disseminated in 2019. ISRCTN71907627 ( www.isrctn.com/ISRCTN71907627 ). Prospectively registered on 25 April 2013.

Intracranial haemorrhage and use of selective serotonin reuptake inhibitors

PubMed Central

de Abajo, Francisco J; Jick, Hershel; Derby, Laura; Jick, Susan; Schmitz, Stephen

2000-01-01

Aims In the past few years an increasing number of bleeding disorders have been reported in association with the use of selective serotonin reuptake inhibitors (SSRIs), including serious cases of intracranial haemorrhage, raising concerns about the safety of this class of drugs. The present study was performed to test the hypothesis of an increased risk of intracranial haemorrhage associated with the use of SSRIs. Methods We carried out a case-control study nested in a cohort of antidepressants users with the UK-based General Practice Research Database (GPRD) as the primary source of information. The study cohort encompassed subjects aged between 18 and 79 years who received a first-time prescription for any antidepressant from January, 1990 to October, 1997. Patients with presenting conditions or treatments that could be associated with an increased risk of intracranial haemorrhage were excluded from the cohort. Patients were followed-up until the occurrence of an idiopathic intracranial haemorrhage. Up to four controls per case, matched on age, sex, calendar time and practice were randomly selected from the study cohort. We estimated adjusted odds ratios and 95% confidence intervals of intracranial haemorrhage with current use of SSRIs and other antidepressants as compared with nonuse using conditional logistic regression. Results We identified 65 cases of idiopathic intracranial haemorrhage and 254 matched controls. Current exposure to SSRIs was ascertained in 7 cases (10.8%) and 24 controls (9.7%) resulting in an adjusted OR (95%CI) of 0.8 (0.3,2.3). The estimate for ‘other antidepressants’ was 0.7 (0.3,1.6). The effect measures were not modified by gender or age. No effect related to dose or treatment duration was detected. The risk estimates did not change according to the location of bleeding (intracerebral or subarachnoid). Conclusions Our results are not compatible with a major increased risk of intracranial haemorrhage among users of SSRIs or other

Two novel cases of cerebral haemorrhages at the neonatal period associated with inherited factor VII deficiency, one of them revealing a new nonsense mutation (Ser52Stop).

PubMed

Giansily-Blaizot, Muriel; Aguilar-Martinez, Patricia; Briquel, Marie-Elisabeth; d'Oiron, Roseline; De Maistre, Emmanuel; Epelbaum, Serge; Schved, Jean-François

2003-02-01

Factor VII (FVII) is a plasma glycoprotein that plays a key role in the initiation of blood coagulation cascade. Inherited FVII deficiency is a rare autosomal recessive disorder with a wide heterogeneous clinical pattern. The severe form may be associated with intracranial haemorrhages occurring closely to birth with a high mortality rate. In the present article, we report two novel cases of neonatal intracerebral bleeding associated with FVII activity levels below 1% of normal. FVII genotyping investigations revealed particular genotypes including the deleterious Cys135Arg mutation and a novel Ser52Stop nonsense mutation at the homozygous state. Both mutations, through different mechanisms, are expected to be inconsistent with the production of functional FVII. These putative mechanisms are discussed through a review of the literature on phenotypic and genotypic characteristics of cerebral haemorrhages in severe inherited FVII deficiency.

Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.

PubMed

Mant, Jonathan; Hobbs, F D Richard; Fletcher, Kate; Roalfe, Andrea; Fitzmaurice, David; Lip, Gregory Y H; Murray, Ellen

2007-08-11

Anticoagulants are more effective than antiplatelet agents at reducing stroke risk in patients with atrial fibrillation, but whether this benefit outweighs the increased risk of bleeding in elderly patients is unknown. We assessed whether warfarin reduced risk of major stroke, arterial embolism, or other intracranial haemorrhage compared with aspirin in elderly patients. 973 patients aged 75 years or over (mean age 81.5 years, SD 4.2) with atrial fibrillation were recruited from primary care and randomly assigned to warfarin (target international normalised ratio 2-3) or aspirin (75 mg per day). Follow-up was for a mean of 2.7 years (SD 1.2). The primary endpoint was fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage, or clinically significant arterial embolism. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN89345269. There were 24 primary events (21 strokes, two other intracranial haemorrhages, and one systemic embolus) in people assigned to warfarin and 48 primary events (44 strokes, one other intracranial haemorrhage, and three systemic emboli) in people assigned to aspirin (yearly risk 1.8%vs 3.8%, relative risk 0.48, 95% CI 0.28-0.80, p=0.003; absolute yearly risk reduction 2%, 95% CI 0.7-3.2). Yearly risk of extracranial haemorrhage was 1.4% (warfarin) versus 1.6% (aspirin) (relative risk 0.87, 0.43-1.73; absolute risk reduction 0.2%, -0.7 to 1.2). These data support the use of anticoagulation therapy for people aged over 75 who have atrial fibrillation, unless there are contraindications or the patient decides that the benefits are not worth the inconvenience.

Audit of CT reporting standards in cases of intracerebral haemorrhage at a comprehensive stroke centre in Australia.

PubMed

Barras, Christen D; Asadi, Hamed; Phal, Pramit M; Tress, Brian M; Davis, Stephen M; Desmond, Patricia M

2016-12-01

Multiple CT-derived biomarkers that are predictive of intracerebral haemorrhage (ICH) growth and outcome have been described in the literature, but the extent to which these appear in imaging reports of ICH is unknown. The aim of this retrospective process audit was to determine which of the known predictors of ICH outcome was recorded in reports of the disease, with a view to providing reporting recommendations, as appropriate. We examined the initial CT report of patients diagnosed with ICH presenting to a metropolitan comprehensive stroke centre and meeting inclusion criteria during the audit period between 1 March 2013 and 28 February 2014. Each report was assessed for the inclusion of the following ICH characteristics: the number of measurement dimensions; volume; location; hydrocephalus; shape; density; 'CTA spot sign' (where CTA was performed). A total of 100 patients met audit inclusion criteria. At least one ICH dimension was recorded in 90% of reports; however, 39% did not include the measurements in three dimensions and volume was reported in just 6%. No ICH dimension was recorded in 10% of reports. With the exception of density and shape, reporting of other CT features exceeded 95%. Where CTA was performed (58%), 14 (24%) of 58 reported the 'CTA spot sign' status. In this audit, volume was the most under-reported of the established ICH characteristics predictive of ICH outcome. Readily calculated from multiplanar reformats using the ABC/2 technique, the routine reporting of ICH volume is recommended. More reporting attention to ICH density heterogeneity and shape irregularity is encouraged, given their emerging importance. Where acute CTA is performed, the presence of any dynamic haemorrhage (CTA spot sign) should be reported. © 2016 The Royal Australian and New Zealand College of Radiologists.

Pharmacogenetic association study of warfarin safety endpoints in Puerto Ricans.

PubMed

Valentín, Isa I; Rivera, Giselle; Nieves-Plaza, Mariely; Cruz, Iadelisse; Renta, Jessica Y; Cadilla, Carmen L; Feliu, Juan F; Seip, Richard L; Ruaño, Gualberto; Duconge, Jorge

2014-09-01

This study was intended to determine the incidence rate of warfarin-related adverse events (e.g., bleeding) in Puerto Ricans and whether a genetic association between warfarin pharmacogenes and any of these adverse events was observed over the initiation period (i.e., the first 90 days of therapy). We conducted an observational, retrospective cohort study of pharmacogenetic association in 122 warfarin-treated, male, Puerto Rican patients (69.9 +/- 9.6 years) from the Veterans Affair Caribbean Healthcare System (VACHS) who consented to participate. Genotyping was performed using the CYP2C9 and VKORC1 assays by Luminex. Event-free survival curves were estimated using the Kaplan-Meier method and analyzed by log-rank test. Cox regression models were constructed and hazard ratios (HR) calculated. Carriers of functional CYP2C9 and VKORC1 polymorphisms demonstrated a higher incidence rate of multiple adverse events (i.e., 5.2 vs. 1.0 cases per 100 patient-months; RR = 4.8, p = 0.12) than did wild types. A significant association was observed between multiple adverse events and carrier status (HR = 2.5; 95% CI: 1.0-6.3, p = 0.04). However, no significant associations between genotypes and individual outcomes over the first 90 days of therapy were found. The association of CYP2C9 and VKORC1 genotypes and risks for adverse events due to exposure to warfarin was examined for the first time in Puerto Ricans. Despite a lack of association with individual events in this study population, our findings revealed a potential utility of genotyping for the prevention of multiple adverse events during warfarin therapy.

Pharmacogenetic Association Study of Warfarin Safety Endpoints in Puerto Ricans

PubMed Central

Valentín, Isa I.; Rivera, Giselle; Nieves-Plaza, Mariely; Cruz, Iadelisse; Renta, Jessica Y.; Cadilla, Carmen L.; Feliu, Juan F.; Seip, Richard L.; Ruaño, Gualberto; Duconge, Jorge

2014-01-01

Objective This study was intended to determine the incidence rate of warfarin-related adverse events (e.g., bleeding) in Puerto Ricans and whether a genetic association between warfarin pharmacogenes and any of these adverse events was observed over the initiation period (i.e., the first 90 days of therapy). Methods We conducted an observational, retrospective cohort study of pharmacogenetic association in 122 warfarin-treated, male, Puerto Rican patients (69.9 ±9.6 years) from the Veterans Affair Caribbean Healthcare System (VACHS) who consented to participate. Genotyping was performed using the CYP2C9 and VKORC 1 assays by Luminex. Event-free survival curves were estimated using the Kaplan–Meier method and analyzed by log-rank test. Cox regression models were constructed and hazard ratios (HR) calculated. Results Carriers of functional CYP2C9 and VKORC1 polymorphisms demonstrated a higher incidence rate of multiple adverse events (i.e., 5.2 vs. 1.0 cases per 100 patient-months; RR = 4.8, p = 0.12) than did wild types. A significant association was observed between multiple adverse events and carrier status (HR = 2.5; 95% CI : 1.0–6.3, p = 0.04). However, no significant associations between genotypes and individual outcomes over the first 90 days of therapy were found. Conclusion The association of CYP2C9 and VKORC1 genotypes and risks for adverse events due to exposure to warfarin was examined for the first time in Puerto Ricans. Despite a lack of association with individual events in this study population, our findings revealed a potential utility of genotyping for the prevention of multiple adverse events during warfarin therapy. PMID:25244877

Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2.

PubMed

Morihara, Ryuta; Yamashita, Toru; Kono, Syoichiro; Shang, Jingwei; Nakano, Yumiko; Sato, Kota; Hishikawa, Nozomi; Ohta, Yasuyuki; Heitmeier, Stefan; Perzborn, Elisabeth; Abe, Koji

2017-09-01

This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin (0.2 mg/kg/day), low-dose rivaroxaban (60 mg/kg/day), high-dose rivaroxaban (120 mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90 min, followed by reperfusion with tPA (10 mg/kg/10 ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Pentadecapeptide BPC 157 Reduces Bleeding and Thrombocytopenia after Amputation in Rats Treated with Heparin, Warfarin, L-NAME and L-Arginine

PubMed Central

Stupnisek, Mirjana; Kokot, Antonio; Drmic, Domagoj; Hrelec Patrlj, Masa; Zenko Sever, Anita; Kolenc, Danijela; Radic, Bozo; Suran, Jelena; Bojic, Davor; Vcev, Aleksandar; Seiwerth, Sven; Sikiric, Predrag

2015-01-01

Background BPC 157 is a stable gastric pentadecapeptide recently implicated with a role in hemostasis. While NO is largely implicated in hemostatic mechanisms, in tail-amputation-models under heparin- and warfarin-administration, both the NO-synthase (NOS)-blocker, L-NAME (prothrombotic) and the NOS-substrate L-arginine (antithrombotic), were little investigated. Objective. To investigate the effect of L-NAME and L-arginine on hemostatic parameters, and to reveal the effects of BPC 157 on the L-NAME- and L-arginine-induced hemostatic actions under different pathological condition: tail amputation without or with anticoagulants, heparin or warfarin. Methods Tail amputation, and/or i.v.-heparin (10 mg/kg), i.g.-warfarin (1.5 mg/kg/day for 3 days) were used in rats. Treatment includes BPC 157, L-NAME, L-arginine, per se and their combination. Results After (tail) amputation, with or without i.v.-heparin or i.g.-warfarin, BPC 157 (10 μg/kg, 10 ng/kg, i.p., i.v. (heparin), 10 μg/kg i.g. (warfarin)) always reduced bleeding time and/or haemorrhage and counteracted thrombocytopenia. As for L-NAME and/or L-arginine, we noted: L-arginine (100 mg/kg i.p.)–rats: more bleeding, less/no thrombocytopenia; L-NAME (5 mg/kg i.p.)-rats: less bleeding (amputation only), but present thrombocytopenia; L-NAME+L-arginine-rats also exhibited thrombocytopenia: L-NAME counteracted L-arginine-increased bleeding, L-arginine did not counteract L-NAME-thrombocytopenia. All animals receiving BPC 157 in addition (BPC 157μg+L-NAME; BPC 157μg+L-arginine, BPC 157μg+L-NAME+L-arginine), exhibited decreased haemorrhage and markedly counteracted thrombocytopenia. Conclusions L-NAME (thrombocytopenia), L-arginine (increased haemorrhage) counteraction and BPC 157 (decreased haemorrhage, counteracted thrombocytopenia) with rescue against two different anticoagulants, implicate a BPC 157 modulatory and balancing role with rescued NO-hemostatic mechanisms. PMID:25897838

Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial.

PubMed

Alexander, John H; Lopes, Renato D; Thomas, Laine; Alings, Marco; Atar, Dan; Aylward, Philip; Goto, Shinya; Hanna, Michael; Huber, Kurt; Husted, Steen; Lewis, Basil S; McMurray, John J V; Pais, Prem; Pouleur, Hubert; Steg, Philippe Gabriel; Verheugt, Freek W A; Wojdyla, Daniel M; Granger, Christopher B; Wallentin, Lars

2014-01-01

We assessed the effect of concomitant aspirin use on the efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation (AF). In ARISTOTLE, 18 201 patients were randomized to apixaban 5 mg twice daily or warfarin. Concomitant aspirin use was left to the discretion of the treating physician. In this predefined analysis, simple and marginal structured models were used to adjust for baseline and time-dependent confounders associated with aspirin use. Outcome measures included stroke or systemic embolism, ischaemic stroke, myocardial infarction, mortality, major bleeding, haemorrhagic stroke, major or clinically relevant non-major bleeding, and any bleeding. On Day 1, 4434 (24%) patients were taking aspirin. Irrespective of concomitant aspirin use, apixaban reduced stroke or systemic embolism [with aspirin: apixaban 1.12% vs. warfarin 1.91%, hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.39-0.85 vs. without aspirin: apixaban 1.11% vs. warfarin 1.32%, HR 0.84, 95% CI 0.66-1.07; P interaction = 0.10] and caused less major bleeding than warfarin (with aspirin: apixaban 3.10% vs. warfarin 3.92%, HR 0.77, 95% CI 0.60-0.99 vs. without aspirin: apixaban 1.82% vs. warfarin 2.78%, HR without aspirin 0.65, 95% CI 0.55-0.78; P interaction = 0.29). Similar results were seen in the subgroups of patients with and without arterial vascular disease. Apixaban had similar beneficial effects on stroke or systemic embolism and major bleeding compared with warfarin, irrespective of concomitant aspirin use.

Race influences warfarin dose changes associated with genetic factors

PubMed Central

Brown, Todd M.; Yan, Qi; Thigpen, Jonathan L.; Shendre, Aditi; Liu, Nianjun; Hill, Charles E.; Arnett, Donna K.; Beasley, T. Mark

2015-01-01

Warfarin dosing algorithms adjust for race, assigning a fixed effect size to each predictor, thereby attenuating the differential effect by race. Attenuation likely occurs in both race groups but may be more pronounced in the less-represented race group. Therefore, we evaluated whether the effect of clinical (age, body surface area [BSA], chronic kidney disease [CKD], and amiodarone use) and genetic factors (CYP2C9*2, *3, *5, *6, *11, rs12777823, VKORC1, and CYP4F2) on warfarin dose differs by race using regression analyses among 1357 patients enrolled in a prospective cohort study and compared predictive ability of race-combined vs race-stratified models. Differential effect of predictors by race was assessed using predictor-race interactions in race-combined analyses. Warfarin dose was influenced by age, BSA, CKD, amiodarone use, and CYP2C9*3 and VKORC1 variants in both races, by CYP2C9*2 and CYP4F2 variants in European Americans, and by rs12777823 in African Americans. CYP2C9*2 was associated with a lower dose only among European Americans (20.6% vs 3.0%, P < .001) and rs12777823 only among African Americans (12.3% vs 2.3%, P = .006). Although VKORC1 was associated with dose decrease in both races, the proportional decrease was higher among European Americans (28.9% vs 19.9%, P = .003) compared with African Americans. Race-stratified analysis improved dose prediction in both race groups compared with race-combined analysis. We demonstrate that the effect of predictors on warfarin dose differs by race, which may explain divergent findings reported by recent warfarin pharmacogenetic trials. We recommend that warfarin dosing algorithms should be stratified by race rather than adjusted for race. PMID:26024874

Race influences warfarin dose changes associated with genetic factors.

PubMed

Limdi, Nita A; Brown, Todd M; Yan, Qi; Thigpen, Jonathan L; Shendre, Aditi; Liu, Nianjun; Hill, Charles E; Arnett, Donna K; Beasley, T Mark

2015-07-23

Warfarin dosing algorithms adjust for race, assigning a fixed effect size to each predictor, thereby attenuating the differential effect by race. Attenuation likely occurs in both race groups but may be more pronounced in the less-represented race group. Therefore, we evaluated whether the effect of clinical (age, body surface area [BSA], chronic kidney disease [CKD], and amiodarone use) and genetic factors (CYP2C9*2, *3, *5, *6, *11, rs12777823, VKORC1, and CYP4F2) on warfarin dose differs by race using regression analyses among 1357 patients enrolled in a prospective cohort study and compared predictive ability of race-combined vs race-stratified models. Differential effect of predictors by race was assessed using predictor-race interactions in race-combined analyses. Warfarin dose was influenced by age, BSA, CKD, amiodarone use, and CYP2C9*3 and VKORC1 variants in both races, by CYP2C9*2 and CYP4F2 variants in European Americans, and by rs12777823 in African Americans. CYP2C9*2 was associated with a lower dose only among European Americans (20.6% vs 3.0%, P < .001) and rs12777823 only among African Americans (12.3% vs 2.3%, P = .006). Although VKORC1 was associated with dose decrease in both races, the proportional decrease was higher among European Americans (28.9% vs 19.9%, P = .003) compared with African Americans. Race-stratified analysis improved dose prediction in both race groups compared with race-combined analysis. We demonstrate that the effect of predictors on warfarin dose differs by race, which may explain divergent findings reported by recent warfarin pharmacogenetic trials. We recommend that warfarin dosing algorithms should be stratified by race rather than adjusted for race. © 2015 by The American Society of Hematology.

Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design.

PubMed

Pullicino, Patrick; Thompson, John L P; Barton, Bruce; Levin, Bruce; Graham, Susan; Freudenberger, Ronald S

2006-02-01

Warfarin is widely prescribed for patients with heart failure without level 1 evidence, and an adequately powered randomized study is needed. The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction study is a National Institutes of Health-funded, randomized, double-blind clinical trial with a target enrollment of 2860 patients. It is designed to test with 90% power the 2-sided primary null hypothesis of no difference between warfarin (International Normalized Ratio 2.5-3) and aspirin (325 mg) in 3- to 5-year event-free survival for the composite endpoint of death, or stroke (ischemic or hemorrhagic) among patients with cardiac ejection fraction < or =35% who do not have atrial fibrillation or mechanical prosthetic heart valves. Secondary analyses will compare warfarin and aspirin for reduction of all-cause mortality, ischemic stroke, and myocardial infarction (MI), balanced against the risk of intracerebral hemorrhage, among women and African Americans; and compare warfarin and aspirin for prevention of stroke alone. Randomization is stratified by site, New York Heart Association (NYHA) heart class (I vs II-IV), and stroke or transient ischemic attack (TIA) within 1 year before randomization versus no stroke or TIA in that period. NYHA class I patients will not exceed 20%, and the study has a target of 20% (or more) patients with stroke or TIA within 12 months. Randomized patients receive active warfarin plus placebo or active aspirin plus placebo, double-blind. The results should help guide the selection of optimum antithrombotic therapy for patients with left ventricular dysfunction.

Effectiveness and safety of apixaban versus warfarin in non-valvular atrial fibrillation patients in "real-world" clinical practice. A propensity-matched analysis of 76,940 patients.

PubMed

Li, Xiaoyan Shawn; Deitelzweig, Steve; Keshishian, Allison; Hamilton, Melissa; Horblyuk, Ruslan; Gupta, Kiran; Luo, Xuemei; Mardekian, Jack; Friend, Keith; Nadkarni, Anagha; Pan, Xianying; Lip, Gregory Y H

2017-06-02

The ARISTOTLE trial showed a risk reduction of stroke/systemic embolism (SE) and major bleeding in non-valvular atrial fibrillation (NVAF) patients treated with apixaban compared to warfarin. This retrospective study used four large US claims databases (MarketScan, PharMetrics, Optum, and Humana) of NVAF patients newly initiating apixaban or warfarin from January 1, 2013 to September 30, 2015. After 1:1 warfarin-apixaban propensity score matching (PSM) within each database, the resulting patient records were pooled. Kaplan-Meier curves and Cox proportional hazards models were used to estimate the cumulative incidence and hazard ratios (HRs) of stroke/SE and major bleeding (identified using the first listed diagnosis of inpatient claims) within one year of therapy initiation. The study included a total of 76,940 (38,470 warfarin and 38,470 apixaban) patients. Among the 38,470 matched pairs, 14,563 were from MarketScan, 7,683 were from PharMetrics, 7,894 were from Optum, and 8,330 were from Humana. Baseline characteristics were balanced between the two cohorts with a mean (standard deviation [SD]) age of 71 (12) years and a mean (SD) CHA 2 DS 2 -VASc score of 3.2 (1.7). Apixaban initiators had a significantly lower risk of stroke/SE (HR: 0.67, 95 % CI: 0.59-0.76) and major bleeding (HR: 0.60, 95 % CI: 0.54-0.65) than warfarin initiators. Different types of stroke/SE and major bleeding - including ischaemic stroke, haemorrhagic stroke, SE, intracranial haemorrhage, gastrointestinal bleeding, and other major bleeding - were all significantly lower for apixaban compared to warfarin treatment. Subgroup analyses (apixaban dosage, age strata, CHA 2 DS 2 -VASc or HAS-BLED score strata, or dataset source) all show consistently lower risks of stroke/SE and major bleeding associated with apixaban as compared to warfarin treatment. This is the largest "real-world" study on apixaban effectiveness and safety to date, showing that apixaban initiation was associated with

Early hyperglycaemia and the early-term death in patients with spontaneous intracerebral haemorrhage: a meta-analysis.

PubMed

Tan, X; He, J; Li, L; Yang, G; Liu, H; Tang, S; Wang, Y

2014-03-01

Stroke is often accompanied by hyperglycaemia, and this has an important impact on prognosis. The aim of this study was to investigate the relationship between early hyperglycaemia and the outcome of spontaneous intracerebral haemorrhage (sICH). A systematic literature search on PubMed, Embase, Cochran, WANFANG DATA, VIP and CNKI databases was conducted, and eight eligible studies were retrieved. Relative risks and 95% confidence interval (CI) in the hyperglycaemia group compared with the non-hyperglycaemia group were calculated and meta-analysed when possible. Eight controlled trials and cohort studies totalling 3756 patients addressing early hyperglycaemia and the outcome of sICH were compiled for this meta-analysis. Cut-off points for defining hyperglycaemia was 6.1-8.3 mmol/L, and the median cut-off value was 7.5 mmol/L. Studies were assigned to one of the two subgroups: the group A (for studies with the values of glucose concentrations above the median cut-off) and the group B (for studies with the values of glucose concentrations below the median cut-off). The RR for short-term death associated with hyperglycaemia was 3.65 (95% confidence interval (CI) (3.08, 4.33); P < 0.0001). In the subgroup analysis, the relative risk values were 3.46 (95% CI (1.66, 7.20); P = 0.0009) and 3.53 (95% CI (2.92, 4.26); P < 0.00001) for the groups A and B respectively. The publication bias showed that Egger's test (P > 0.1), Begg's test (P > 0.05) and Nfs0.05 exceeded included studies. Early hyperglycaemia can significantly increase the rate of early-term death in patients with sICH, independent of the cut-off points for hyperglycaemia. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

Warfarin-induced Venous Limb Gangrene

PubMed Central

Grim Hostetler, Sarah; Sopkovich, Jennifer; Dean, Steven

2012-01-01

Warfarin is a commonly used anticoagulant that has been associated with several significant cutaneous side effects, most notably warfarin-induced skin necrosis. A lesser known adverse reaction to warfarin is warfarin-induced venous limb gangrene. Both cutaneous adverse effects share the same pathophysiology, but are clinically quite different. The majority of cases of warfarin-induced venous limb gangrene has been in patients with cancer or heparin-induced thrombocytopenia. However, other hypercoagulable disease states, such as the antiphospholipid antibody syndrome, can be associated with venous limb gangrene. In order to increase recognition of this important condition, the authors report a case of warfarin-induced venous limb gangrene in a patient with presumed antiphospholipid antibody syndrome and review the literature on warfarin-induced venous limb gangrene. PMID:23198012

Patient Attitudinal and Behavioral Factors Associated with Warfarin Non-adherence at Outpatient Anticoagulation Clinics

PubMed Central

Localio, A. Russell; Platt, Alec B.; Brensinger, Colleen M.; Christie, Jason D.; Gross, Robert; Parker, Catherine S.; Price, Maureen; Metlay, Joshua P.; Cohen, Abigail; Newcomb, Craig W.; Strom, Brian L.; Kimmel, Stephen E.

2010-01-01

Background Warfarin is an anticoagulant effective in preventing stroke, but it has a narrow therapeutic range requiring optimal adherence to achieve the most favorable effects. Purpose The goal of this study was to examine specific patient factors that might help explain warfarin non-adherence at outpatient anticoagulation clinics. Method In a prospective cohort study of 156 adults, we utilized logistic regression analyses to examine the relationship between the five Treatment Prognostics scales from the Millon Behavioral Medicine Diagnostic (MBMD), as well as three additional MBMD scales (Depression, Future Pessimism, and Social Isolation), and daily warfarin non-adherence assessed using electronic medication event monitoring systems caps over a median of 139 days. Results Four of the five Treatment Prognostic scales and greater social isolation were associated with warfarin non-adherence. When controlling for pertinent demographic and medical variables, the Information Discomfort scale remained significantly associated with warfarin non-adherence over time. Conclusion Although several factors were related to warfarin non-adherence, patients reporting a lack of receptivity to details regarding their medical illness seemed most at risk for warfarin non-adherence. This information might aid in the development of interventions to enhance warfarin adherence and perhaps reduce adverse medical events. PMID:19579066

Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study.

PubMed

Perera, Minoli A; Cavallari, Larisa H; Limdi, Nita A; Gamazon, Eric R; Konkashbaev, Anuar; Daneshjou, Roxana; Pluzhnikov, Anna; Crawford, Dana C; Wang, Jelai; Liu, Nianjun; Tatonetti, Nicholas; Bourgeois, Stephane; Takahashi, Harumi; Bradford, Yukiko; Burkley, Benjamin M; Desnick, Robert J; Halperin, Jonathan L; Khalifa, Sherief I; Langaee, Taimour Y; Lubitz, Steven A; Nutescu, Edith A; Oetjens, Matthew; Shahin, Mohamed H; Patel, Shitalben R; Sagreiya, Hersh; Tector, Matthew; Weck, Karen E; Rieder, Mark J; Scott, Stuart A; Wu, Alan H B; Burmester, James K; Wadelius, Mia; Deloukas, Panos; Wagner, Michael J; Mushiroda, Taisei; Kubo, Michiaki; Roden, Dan M; Cox, Nancy J; Altman, Russ B; Klein, Teri E; Nakamura, Yusuke; Johnson, Julie A

2013-08-31

VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 -1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10(-8) in the discovery cohort and p<0·0038 in the replication cohort. The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10(-8)). This association was confirmed in the replication cohort (p=5·04×10(-5)); analysis of the two cohorts together produced a p value of 4·5×10(-12). Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent

Congenital Dandy Walker malformation associated with first trimester warfarin: a case report and literature review.

PubMed

Kaplan, L C

1985-12-01

While the warfarin embryopathy is well defined, central nervous system abnormalities associated with gestational warfarin exposure require further definition. Based on the timing of warfarin exposure in humans, it has been proposed that second- and third-trimester exposure predisposes to CNS abnormalities while first-trimester exposure more typically is associated with the warfarin embryopathy. A case is presented of a liveborn male with Dandy Walker malformation, agenesis of the corpus callosum, and Peter anomaly of the right eye who was exposed to warfarin between the 8th and 12th weeks of gestation who had none of the stigmata of the warfarin embryopathy. His is the first known case of exposure confined to the first trimester, and the fifth case of Dandy Walker malformation among a total of 15 CNS cases associated with this drug. This case offers evidence that Dandy Walker malformation may represent a distinct complication of in utero first-trimester exposure, and consideration of these particular abnormalities with exposure limited to a period prior to the known appearance of vitamin K-dependent clotting factors suggests that warfarin has a direct teratogenic effect on central nervous system morphogenesis.

Determinants and Prognostic Significance of Hematoma Sedimentation Levels in Acute Intracerebral Hemorrhage.

PubMed

Sato, Shoichiro; Delcourt, Candice; Zhang, Shihong; Arima, Hisatomi; Heeley, Emma; Zheng, Danni; Al-Shahi Salman, Rustam; Stapf, Christian; Tzourio, Christophe; Robinson, Thompson; Lindley, Richard I; Chalmers, John; Anderson, Craig S

2016-01-01

This study aimed at identifying the determinants and prognostic significance of a sedimentation level (fluid-blood level) in the hematoma among patients with acute intracerebral hemorrhage (ICH) who participated in the main Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). Post-hoc analysis of the INTERACT2 dataset, a randomized controlled trial of patients with acute ICH with elevated systolic blood pressure (SBP), randomly assigned to intensive (target SBP <140 mm Hg) or guideline-based (<180 mm Hg) BP management. Patients with a sedimentation level at baseline assessment on CT, and modified Rankin Scale score at 90-day, were included in these analyses. Factors associated with a sedimentation level and its significance in relation to 90-day clinical outcomes were assessed in univariable and multivariable logistic regression models. Of 2,065 participants, 19 (1%) had sedimentation level on baseline CT, which was independently associated with warfarin use (p = 0.006) and lobar ICH (p = 0.025). Sedimentation level was also associated with death or major disability at 90-day in both crude (84 vs. 53%; p = 0.014) and multivariable analyses adjusted for age, gender, Chinese region, warfarin use, baseline National Institutes of Health Stroke Scale score, onset to CT time, volume and location of ICH, intraventricular extension, and randomized intensive BP lowering (OR 3.94, 95% CI 1.01-15.37; p = 0.049). The presence of hematoma sedimentation level on baseline CT is associated with warfarin use and lobar location of ICH, and predicts a worse outcome. Although uncommon, sedimentation level is an easily detectable prognostic factor in acute ICH. © 2015 S. Karger AG, Basel.

Protocol for Birmingham Atrial Fibrillation Treatment of the Aged study (BAFTA): a randomised controlled trial of warfarin versus aspirin for stroke prevention in the management of atrial fibrillation in an elderly primary care population [ISRCTN89345269

PubMed Central

Mant, Jonathan WF; Richards, Suzanne H; Hobbs, FD Richard; Fitzmaurice, David; Lip, Gregory YH; Murray, Ellen; Banting, Miriam; Fletcher, Kate; Rahman, Joy; Allan, Teresa; Raftery, James; Bryan, Stirling

2003-01-01

Background Atrial fibrillation (AF) is an important independent risk factor for stroke. Randomised controlled trials have shown that this risk can be reduced substantially by treatment with warfarin or more modestly by treatment with aspirin. Existing trial data for the effectiveness of warfarin are drawn largely from studies in selected secondary care populations that under-represent the elderly. The Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) study will provide evidence of the risks and benefits of warfarin versus aspirin for the prevention of stroke for older people with AF in a primary care setting. Study design A randomised controlled trial where older patients with AF are randomised to receive adjusted dose warfarin or aspirin. Patients will be followed up at three months post-randomisation, then at six monthly intervals there after for an average of three years by their general practitioner. Patients will also receive an annual health questionnaire. 1240 patients will be recruited from over 200 practices in England. Patients must be aged 75 years or over and have AF. Patients will be excluded if they have a history of any of the following conditions: rheumatic heart disease; major non-traumatic haemorrhage; intra-cranial haemorrhage; oesophageal varices; active endoscopically proven peptic ulcer disease; allergic hypersensitivity to warfarin or aspirin; or terminal illness. Patients will also be excluded if the GP considers that there are clinical reasons to treat a patient with warfarin in preference to aspirin (or vice versa). The primary end-point is fatal or non-fatal disabling stroke (ischaemic or haemorrhagic) or significant arterial embolism. Secondary outcomes include major extra-cranial haemorrhage, death (all cause, vascular), hospital admissions (all cause, vascular), cognition, quality of life, disability and compliance with study medication. PMID:12939169

A clinical characteristic analysis of pregnancy-associated intracranial haemorrhage in China.

PubMed

Liang, Zhu-Wei; Lin, Li; Gao, Wan-Li; Feng, Li-Min

2015-03-30

Intracerebral haemorrhage (ICH) occurring during pregnancy and the puerperium is an infrequent but severe complication with a high mortality and poor prognosis. Until recently, previous studies have mainly focused on the effect of different treatments on prognosis. However, few studies have provided solid evidence to clarify the key predisposing factors affecting the prognosis of ICH. In the present study, based on a unique sample with a high ICH incidence and mortality rate, we described the main clinical characteristics of ICH patients and found that the prognosis of patients who underwent surgical intervention was not better than that of patients who received other treatment modalities. However, pre-eclampsia patients had higher maternal and neonatal mortality rates than other aetiology groups. Furthermore, univariate regression analysis identified onset to diagnosis time (O-D time) and pre-eclampsia as the only factors showing independent correlation with poor maternal outcomes (modified Rankin Scale, mRS ≥ 3), and only O-D time was identified as a predictor of maternal mortality. These results revealed that the aetiology of ICH and O-D time might be crucial predisposing factors to prognosis, especially for patients with pre-eclampsia. The study highlighted a novel direction to effectively improve the prognosis of pregnancy-associated ICH.

Warfarin Pharmacogenetics

PubMed Central

Johnson, Julie A.; Cavallari, Larisa H.

2014-01-01

The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. However, clinical trials evaluating genotype-guided warfarin dosing produced mixed results, calling into question the utility of this approach. Recent trials used surrogate markers as endpoints rather than clinical endpoints, further complicating translation of the data to clinical practice. The present data do not support genetic testing to guide warfarin dosing, but in the setting where genotype data are available, use of such data in those of European ancestry is reasonable. Outcomes data are expected from an on-going trial, observational studies continue, and more work is needed to define dosing algorithms that incorporate appropriate variants in minority populations; all these will further shape guidelines and recommendations on the clinical utility of genotype-guided warfarin dosing. PMID:25282448

Intracerebral hemorrhage (image)

MedlinePlus

Intracerebral hemorrhage may be caused by trauma (brain injury) or abnormalities of the blood vessels (aneurysm or angioma), but it is most commonly associated with high blood pressure (hypertensive intracerebral hemorrhage).

Reasons for non-recruitment of eligible patients to a randomised controlled trial of secondary prevention after intracerebral haemorrhage: observational study.

PubMed

Maxwell, Amy E; MacLeod, Mary Joan; Joyson, Anu; Johnson, Sharon; Ramadan, Hawraman; Bellfield, Ruth; Byrne, Anthony; McGhee, Caroline; Rudd, Anthony; Price, Fiona; Vasileiadis, Evangelos; Holden, Melinda; Hewitt, Jonathan; Carpenter, Michael; Needle, Ann; Valentine, Stacey; Patel, Farzana; Harrington, Frances; Mudd, Paul; Emsley, Hedley; Gregary, Bindu; Kane, Ingrid; Muir, Keith; Tiwari, Divya; Owusu-Agyei, Peter; Temple, Natalie; Sekaran, Lakshmanan; Ragab, Suzanne; England, Timothy; Hedstrom, Amanda; Jones, Phil; Jones, Sarah; Doherty, Mandy; McCarron, Mark O; Cohen, David L; Tysoe, Sharon; Al-Shahi Salman, Rustam

2017-04-05

Recruitment to randomised prevention trials is challenging, not least for intracerebral haemorrhage (ICH) associated with antithrombotic drug use. We investigated reasons for not recruiting apparently eligible patients at hospital sites that keep screening logs in the ongoing REstart or STop Antithrombotics Randomised Trial (RESTART), which seeks to determine whether to start antiplatelet drugs after ICH. By the end of May 2015, 158 participants had been recruited at 108 active sites in RESTART. The trial coordinating centre invited all sites that kept screening logs to submit screening log data, followed by one reminder. We checked the integrity of data, focused on the completeness of data about potentially eligible patients and categorised the reasons they were not randomised. Of 108 active sites, 39 (36%) provided usable screening log data over a median of ten (interquartile range = 5-13) months of recruitment per site. During this time, sites screened 633 potentially eligible patients and randomised 53 (8%) of them. The main reasons why 580 patients were not randomised were: 43 (7%) patients started anticoagulation, 51 (9%) patients declined, 148 (26%) patients' stroke physicians were not uncertain about using antiplatelet drugs, 162 (28%) patients were too unwell and 176 (30%) patients were not randomised due to other reasons. RESTART recruited ~8% of eligible patients. If more physicians were uncertain about the therapeutic dilemma that RESTART is addressing, RESTART could have recruited up to four times as many participants. The trial coordinating centre continues to engage with physicians about their uncertainty. EU Clinical Trials, EudraCT 2012-003190-26 . Registered on 3 July 2012.

Emergency admissions for major haemorrhage associated with direct oral anticoagulants.

PubMed

Bouget, Jacques; Oger, Emmanuel

2015-12-01

To describe the population admitted in an emergency department of a teaching hospital for severe bleeding associated with direct oral anticoagulants (DOAC). During a three-year period (2012-2014) patients older than 16 years were prospectively identified by haemorrhagic symptoms from computerised requests. At least one of the following criteria defined major haemorrhage: haemorrhagic shock, unstable haemodynamic, need for transfusion or haemostatic procedure, or a life threatening location. Fifty four patients, 23 receiving dabigatran, 30 rivaroxaban and one apixaban were included, 2 in 2012, 35 in 2013 and 17 in 2014. Median age was 84 years (range 63-99) with a sex ratio of 1.16. Haemorrhagic complications were gastrointestinal (n=27), intracranial (n=12) or miscellaneous (n=15). Indication of DOAC was stroke prevention in atrial fibrillation in 49 cases and deep vein thrombosis in 5 cases. Hospitalization was required for 45 patients (83%) with a mean length of stay of 8.5 days. Sixteen patients needed intensive care. Reversal therapy was prescribed in 11 patients. At 1 month, overall mortality was 24%, reaching 41.7% for intracranial haemorrhage. Among surviving patients, DOAC was stopped in 10 cases, continued in 17 patients and switched for other antithrombotic in 17 patients. Our study contributes to the post marketing surveillance of major haemorrhagic complications associated with DOAC. It takes part to the knowledge about the course of this severe event in emergencies. Careful awareness in risk benefit assessment, especially in elderly, is needed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pharmacogenetics of warfarin: challenges and opportunities

PubMed Central

Ta Michael Lee, Ming; Klein, Teri E

2014-01-01

Since the introduction in the 1950s, warfarin has become the commonly used oral anticoagulant for the prevention of thromboembolism in patients with deep vein thrombosis, atrial fibrillation or prosthetic heart valve replacement. Warfarin is highly efficacious; however, achieving the desired anticoagulation is difficult because of its narrow therapeutic window and highly variable dose response among individuals. Bleeding is often associated with overdose of warfarin. There is overwhelming evidence that an individual's warfarin maintenance is associated with clinical factors and genetic variations, most notably polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase subunit 1. Numerous dose-prediction algorithms incorporating both genetic and clinical factors have been developed and tested clinically. However, results from major clinical trials are not available yet. This review aims to provide an overview of the field of warfarin which includes information about the drug, genetics of warfarin dose requirements, dosing algorithms developed and the challenges for the clinical implementation of warfarin pharmacogenetics. PMID:23657428

Warfarin-induced eosinophilic pleurisy.

PubMed

Kuwahara, T; Hamada, M; Inoue, Y; Aono, S; Hiwada, K

1995-08-01

A 51-year-old man was admitted to our hospital because of dry cough and low grade fever with right-sided pleural fluid and blood eosinophilia. Warfarin had been prescribed following coronary artery bypass grafting. After the discontinuation of warfarin the clinical and chest X-ray findings improved; readministration of the drug caused recurrent blood eosinophilia and pleural effusion in the other lung. Since no other specific etiologies for eosinophilia and pleural effusion were determined by extensive evaluation, warfarin seemed to be associated with his illness. This is the first report of warfarin-induced eosinophilic pleurisy.

Intracranial haemorrhage associated with ingestion of 'ecstasy'.

PubMed Central

Hughes, J C; McCabe, M; Evans, R J

1993-01-01

A case of a patient with intracranial haemorrhage thought to have been associated with ingestion of 'Ecstasy' [3-4 methylenedioxymethamphetamine (MDMA)] is presented. The case illustrates the importance of drug analysis in cases involving illicit drug use. Images Fig. 1 PMID:7906517

Factors associated with failure to correct the international normalised ratio following fresh frozen plasma administration among patients treated for warfarin-related major bleeding. An analysis of electronic health records.

PubMed

Menzin, J; White, L A; Friedman, M; Nichols, C; Menzin, J; Hoesche, J; Bergman, G E; Jones, C

2012-04-01

This study assessed the frequency and factors associated with failure to correct international normalised ratio (INR) in patients administered fresh frozen plasma (FFP) for warfarin-related major bleeding. This retrospective database analysis used electronic health records from an integrated health system. Patients who received FFP between 01/01/2004 and 01/31/2010, and who met the following criteria were selected: major haemorrhage diagnosis the day before to the day after initial FFP administration; INR ≥2 on the day before or the day of FFP and another INR result available; warfarin prescription within 90 days. INR correction (defined as INR ≤1.3) was evaluated at the last available test up to one day following FFP. A total of 414 patients met selection criteria (mean age 75 years, 53% male, mean Charlson score 2.5). Patients presented with gastrointestinal bleeding (58%), intracranial haemorrhage (38%) and other bleed types (4%). The INR of 67% of patients remained uncorrected at the last available test up to one day following receipt of FFP. In logistic regression analysis, the INR of patients who were older, those with a Charlson score of 4 or greater, and those with non-ICH bleeds (odds ratio vs. intracranial bleeding 0.48; 95% confidence interval 0.31-0.76) were more likely to remain uncorrected within one day following FFP administration. In an alternative definition of correction, (INR ≤1.5), 39% of patients' INRs remained uncorrected. For a substantial proportion of patients, the INRs remain inadequately or uncorrected following FFP administration, with estimates varying depending on the INR threshold used.

Identification of novel variants associated with warfarin stable dosage by use of a two-stage extreme phenotype strategy.

PubMed

Luo, Z; Li, X; Zhu, M; Tang, J; Li, Z; Zhou, X; Song, G; Liu, Z; Zhou, H; Zhang, W

2017-01-01

Essentials Required warfarin doses for mechanical heart valves vary greatly. A two-stage extreme phenotype design was used to identify novel warfarin dose associated mutation. We identified a group of variants significantly associated with extreme warfarin dose. Four novel identified mutations account for 2.2% of warfarin dose discrepancies. Background The variation among patients in warfarin response complicates the management of warfarin therapy, and an improper therapeutic dose usually results in serious adverse events. Objective To use a two-stage extreme phenotype strategy in order to discover novel warfarin dose-associated mutations in heart valve replacement patients. Patients/method A total of 1617 stable-dose patients were enrolled and divided randomly into two cohorts. Stage I patients were genotyped into three groups on the basis of VKORC1-1639G>A and CYP2C9*3 polymorphisms; only patients with the therapeutic dose at the upper or lower 5% of each genotype group were selected as extreme-dose patients for resequencing of the targeted regions. Evaluation of the accuracy of the sequence data and the potential value of the stage I-identified significant mutations were conducted in a validation cohort of 420 subjects. Results A group of mutations were found to be significantly associated with the extreme warfarin dose. The validation work finally identified four novel mutations, i.e. DNMT3A rs2304429 (24.74%), CYP1A1 rs3826041 (47.35%), STX1B rs72800847 (7.01%), and NQO1 rs10517 (36.11%), which independently and significantly contributed to the overall variability in the warfarin dose. After addition of these four mutations, the estimated regression equation was able to account for 56.2% (R 2 Adj = 0.562) of the overall variability in the warfarin maintenance dose, with a predictive accuracy of 62.4%. Conclusion Our study provides evidence linking genetic variations in STX1B, DNMT3A and CYP1A1 to warfarin maintenance dose. The newly identified mutations

A Retroperitoneal Leiomyosarcoma Presenting as an Adrenal Incidentaloma in a Subject on Warfarin

PubMed Central

Khan, Ishrat N.; Adlan, Mohamed A.; Stechman, Michael J.; Premawardhana, Lakdasa D.

2015-01-01

Adrenal incidentalomas (AIs) are mostly benign and nonsecretory. Management algorithms lack sensitivity when assessing malignant potential, although functional status is easier to assess. We present a subject whose AI was a retroperitoneal leiomyosarcoma (RL). Case Presentation. A woman on warfarin with SLE and the antiphospholipid syndrome, presented with left loin pain. She was normotensive and clinically normal. Ultrasound scans demonstrated left kidney scarring, but CT scans revealed an AI. MRI scans later confirmed the AI without significant fat and no interval growth. Cortisol after 1 mg dexamethasone, urinary free cortisol and catecholamines, plasma aldosterone renin ratio, and 17-hydroxyprogesterone were within the reference range. Initially, adrenal haemorrhage was diagnosed because of warfarin therapy and the acute presentation. However, she underwent adrenalectomy because of interval growth of the AI. Histology confirmed an RL. The patient received adjuvant radiotherapy. Discussion. Our subject presented with an NSAI. However, we highlight the following: (a) the diagnosis of adrenal haemorrhage in this anticoagulated woman was revised because of interval growth; (b) the tumour, an RL, was relatively small at diagnosis; (c) this subject has survived well over 60 months despite an RL perhaps because of her acute presentation and early diagnosis of a small localised tumour. PMID:26064705

A Retroperitoneal Leiomyosarcoma Presenting as an Adrenal Incidentaloma in a Subject on Warfarin.

PubMed

Khan, Ishrat N; Adlan, Mohamed A; Stechman, Michael J; Premawardhana, Lakdasa D

2015-01-01

Adrenal incidentalomas (AIs) are mostly benign and nonsecretory. Management algorithms lack sensitivity when assessing malignant potential, although functional status is easier to assess. We present a subject whose AI was a retroperitoneal leiomyosarcoma (RL). Case Presentation. A woman on warfarin with SLE and the antiphospholipid syndrome, presented with left loin pain. She was normotensive and clinically normal. Ultrasound scans demonstrated left kidney scarring, but CT scans revealed an AI. MRI scans later confirmed the AI without significant fat and no interval growth. Cortisol after 1 mg dexamethasone, urinary free cortisol and catecholamines, plasma aldosterone renin ratio, and 17-hydroxyprogesterone were within the reference range. Initially, adrenal haemorrhage was diagnosed because of warfarin therapy and the acute presentation. However, she underwent adrenalectomy because of interval growth of the AI. Histology confirmed an RL. The patient received adjuvant radiotherapy. Discussion. Our subject presented with an NSAI. However, we highlight the following: (a) the diagnosis of adrenal haemorrhage in this anticoagulated woman was revised because of interval growth; (b) the tumour, an RL, was relatively small at diagnosis; (c) this subject has survived well over 60 months despite an RL perhaps because of her acute presentation and early diagnosis of a small localised tumour.

Comparison of endoscopic evacuation, stereotactic aspiration and craniotomy for the treatment of supratentorial hypertensive intracerebral haemorrhage: study protocol for a randomised controlled trial.

PubMed

Xu, Xinghua; Zheng, Yi; Chen, Xiaolei; Li, Fangye; Zhang, Huaping; Ge, Xin

2017-06-28

Hypertensive intracerebral haemorrhage (HICH) is the most common form of haemorrhagic stroke with the highest morbidity and mortality of all stroke types. The choice of surgical or conservative treatment for patients with HICH remains controversial. In recent years, minimally invasive surgeries, such as endoscopic evacuation and stereotactic aspiration, have been attempted for haematoma removal and offer promise. However, research evidence on the benefits of endoscopic evacuation or stereotactic aspiration is still insufficient. A multicentre, randomised controlled trial will be conducted to compare the efficacy of endoscopic evacuation, stereotactic aspiration and craniotomy in the treatment of supratentorial HICH. About 1350 eligible patients from 10 neurosurgical centres will be randomly assigned to an endoscopic group, a stereotactic group and a craniotomy group at a 1:1:1 ratio. Randomisation is undertaken using a 24-h randomisation service accessed by telephone or the Internet. All patients will receive the corresponding surgery based on their grouping. They will be followed-up at 1, 3 and 6 months after surgery. The primary outcome is the modified Rankin Scale at 6-month follow-up. Secondary outcomes include: haematoma clearance rate; Glasgow Coma Scale 7 days after surgery; rebleeding rate; intracranial infection rate; hospitalisation time; mortality at 1 month and 3 months after surgery; the Barthel Index and the WHO quality of life at 3 months and 6 months after surgery. The trial aims to investigate whether endoscopic evacuation and stereotactic aspiration could improve the outcome of supratentorial HICH compared with craniotomy. The trial will help to determine the best surgical method for the treatment of supratentorial HICH. ClinicalTrials.gov, ID: NCT02811614 . Registered on 20 June 2016.

Genetic polymorphisms are associated with variations in warfarin maintenance dose in Han Chinese patients with venous thromboembolism.

PubMed

Zhang, Wei; Zhang, Wei-Juan; Zhu, Jin; Kong, Fan-Cui; Li, Yan-Yan; Wang, He-Yao; Yang, Yuan-Hua; Wang, Chen

2012-02-01

Warfarin is a clinical anticoagulant that requires periodic monitoring because it is associated with adverse outcomes. Personalized medicine, which is based on pharmacogenetics, holds great promise in solving these types of problems. It aims to provide the tools and knowledge to tailor drug therapy to an individual patient, with the potential of increasing safety and efficacy of medications. In the present study we analyzed genotypes of 14 SNPs for seven genes using DNA from 297 Han Chinese venous thromboembolism patients treated with warfarin. Multiple regression analyses revealed that CYP2C9 genotype (p = 0.001), VKORC1 genotype (p < 0.001), age (p < 0.01) and weight (p < 0.001) were all associated with warfarin dose requirements, which can explain 37.4% of the variability of warfarin dose among Han Chinese patients. Meanwhile, in the validation cohort, the predicted warfarin daily dose was calculated using the best model with a 64.5% predicted dose being acceptable (-1 mg/day ≤Δwarfarin dose ≤1 mg/day). We developed a pharmacogenetic dose algorithm for warfarin treatment that uses genotypes from two genes (VKORC1 and CYP2C9) and clinical variables to predict therapeutic maintenance doses in Chinese patients with venous thromboembolism. The validity of the dosing algorithm was confirmed in a cohort of venous thromboembolism patients on warfarin therapy.

Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial.

PubMed

Held, Claes; Hylek, Elaine M; Alexander, John H; Hanna, Michael; Lopes, Renato D; Wojdyla, Daniel M; Thomas, Laine; Al-Khalidi, Hussein; Alings, Marco; Xavier, Dennis; Ansell, Jack; Goto, Shinya; Ruzyllo, Witold; Rosenqvist, Mårten; Verheugt, Freek W A; Zhu, Jun; Granger, Christopher B; Wallentin, Lars

2015-05-21

In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced the risk of stroke, major bleed, and death in patients with atrial fibrillation. In this ancillary study, we evaluated clinical consequences of major bleeds, as well as management and treatment effects of warfarin vs. apixaban. Major International Society on Thrombosis and Haemostasis bleeding was defined as overt bleeding accompanied by a decrease in haemoglobin (Hb) of ≥2 g/dL or transfusion of ≥2 units of packed red cells, occurring at a critical site or resulting in death. Time to event [death, ischaemic stroke, or myocardial infarction (MI)] was evaluated by Cox regression models. The excess risk associated with bleeding was evaluated by separate time-dependent indicators for intracranial (ICH) and non-intracranial haemorrhage. Major bleeding occurred in 848 individuals (4.7%), of whom 126 (14.9%) died within 30 days. Of 176 patients with an ICH, 76 (43.2%) died, and of the 695 patients with major non-ICH, 64 (9.2%) died within 30 days of the bleeding. The risk of death, ischaemic stroke, or MI was increased roughly 12-fold after a major non-ICH bleeding event within 30 days. Corresponding risk of death following an ICH was markedly increased, with HR 121.5 (95% CI 91.3-161.8) as was stroke or MI with HR 21.95 (95% CI 9.88-48.81), respectively. Among patients with major bleeds, 20.8% received vitamin K and/or related medications (fresh frozen plasma, coagulation factors, factor VIIa) to stop bleeding within 3 days, and 37% received blood transfusion. There was no interaction between apixaban and warfarin and major bleeding on the risk of death, stroke, or MI. Major bleeding was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following ICH, and this risk was similarly elevated regardless of treatment with apixaban or warfarin. These results underscore the

Clinical and genetic factors associated with warfarin maintenance dose in northern Chinese patients with mechanical heart valve replacement

PubMed Central

Liu, Rui; Cao, Jian; Zhang, Qian; Shi, Xin-Miao; Pan, Xiao-Dong; Dong, Ran

2017-01-01

Abstract The effects of genetic variants on warfarin dosing vary among different ethnic groups, especially in the Chinese population. The objective of this study was to recruit patients through a rigorous experimental design and to perform a comprehensive screen to identify gene polymorphisms that may influence warfarin dosing in northern Han Chinese patients with mechanical heart valve replacement. Consenting patients (n = 183) with a stable warfarin dose were included in this study. Ninety-six single nucleotide polymorphisms (SNPs) in 30 genes involved in warfarin pharmacological pathways were genotyped using the Illumina SNP GoldenGate Assay, and their associations with warfarin dosing were assessed using univariate regression analysis with post hoc comparison using least significant difference analysis. Multiple linear regression was performed by incorporating patients’ clinical and genetic data to create a new algorithm for warfarin dosing. From the 96 SNPs analyzed, VKORC1 rs9923231, CYP1A2 rs2069514, CYP3A4 rs28371759, and APOE rs7412 were associated with higher average warfarin maintenance doses, whereas CYP2C9 rs1057910, EPHX1 rs2260863, and CYP4F2 rs2189784 were associated with lower warfarin doses (P < 0.05). Multiple linear regression analysis could estimate 44.4% of warfarin dose variability consisting of, in decreasing order, VKORC1 rs9923231 (14.2%), CYP2C9∗3 (9.6%), body surface area (6.7%), CYP1A2 rs2069514 (3.7%), age (2.7%), CYP3A4 rs28371759 (2.5%), CYP4F2 rs2108622 (1.9%), APOE rs7412 (1.7%), and VKORC1 rs2884737 (1.4%). In the dosing algorithm we developed, we confirmed the strongest effects of VKORC1, CYP2C9 on warfarin dosing. In the limited sample set, we also found that novel genetic predictors (CYP1A2, CYP3A4, APOE, EPHX1, CYP4F2, and VKORC1 rs2884737) may be associated with warfarin dosing. Further validation is needed to assess our results in larger independent northern Chinese samples. PMID:28079798

Buccofacial apraxia and left cerebral haemorrhage.

PubMed

Maeshima, S; Truman, G; Smith, D S; Dohi, N; Itakura, T; Komai, N

1997-11-01

We examined 33 patients with left intracerebral haemorrhage to investigate the relations to buccofacial apraxia (BFA). BFA was present in 18 cases at 1 month and disappeared in 3 cases and persisted in 15 cases at 6 month from the onset. The existence of BFA seems to be partially dependent the haematoma volume which may cause the organic damage in lenticulate nucleus, insula, posterior limb or internal capsule and anterior portion of paraventricle white matter. All patients with BFA had aphasia (Broca 6, Wernicke 1, Total 10, Amnestic 1). Aphasia of the patients with transient BFA improved as well as the patients without BFA after BFA disappeared. We suspected that improvement or aphasia might be affected by BFA.

Warfarin use and the risk of valvular calcification.

PubMed

Lerner, R G; Aronow, W S; Sekhri, A; Palaniswamy, C; Ahn, C; Singh, T; Sandhu, R; McClung, J A

2009-12-01

Warfarin affects the synthesis and function of the matrix Gla-protein, a vitamin K-dependent protein, which is a potent inhibitor of tissue calcification. To investigate the incidence of mitral valve calcium (MVC), mitral annular calcium (MAC) and aortic valve calcium (AVC) in patients with non-valvular atrial fibrillation (AF) treated with warfarin vs. no warfarin. Of 1155 patients, mean age 74 years, with AF, 725 (63%) were treated with warfarin and 430 (37%) without warfarin. The incidence of MVC, MAC and AVC was investigated in these 1155 patients with two-dimensional echocardiograms. Unadjusted logistic regression analysis was conducted to examine the association between the use of warfarin and the incidence of MVC, MAC or AVC. Logistic regression analyses were also conducted to investigate whether the relationship stands after adjustment for confounding risk factors such as age, sex, race, ejection fraction, smoking, hypertension, diabetes, dyslipidemia, coronary artery disease (CAD), glomerular filtration rate, calcium, phosphorus, calcium-phosphorus product, alkaline phosphatase, use of aspirin, beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins. There was a significant association between the use of warfarin and the risk of calcification [unadjusted odds ratio = 1.71, 95% CI = (1.34-2.18)]. The association still stands after adjustment for confounding risk factors. MVC, MAC or AVC was present in 473 of 725 patients (65%) on warfarin vs. 225 of 430 patients (52%) not on warfarin (P < 0.0001). Whether this is a causal relationship remains unknown. Use of warfarin in patients with AF is associated with an increased prevalence of MVC, MAC or AVC.

Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation.

PubMed

Lau, Wallis C Y; Chan, Esther W; Cheung, Ching-Lung; Sing, Chor Wing; Man, Kenneth K C; Lip, Gregory Y H; Siu, Chung-Wah; Lam, Joanne K Y; Lee, Alan C H; Wong, Ian C K

2017-03-21

The risk of osteoporotic fracture with dabigatran use in patients with nonvalvular atrial fibrillation (NVAF) is unknown. To investigate the risk of osteoporotic fracture with dabigatran vs warfarin in patients with NVAF. Retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with NVAF from 2010 through 2014 and prescribed dabigatran or warfarin were matched by propensity score at a 1:2 ratio with follow-up until July 31, 2016. Dabigatran or warfarin use during the study period. Risk of osteoporotic hip fracture and vertebral fracture was compared between dabigatran and warfarin users using Poisson regression. The corresponding incidence rate ratio (IRR) and absolute risk difference (ARD) with 95% CIs were calculated. Among 51 496 patients newly diagnosed with NVAF, 8152 new users of dabigatran (n = 3268) and warfarin (n = 4884) were matched by propensity score (50% women; mean [SD] age, 74 [11] years). Osteoporotic fracture developed in 104 (1.3%) patients during follow-up (32 dabigatran users [1.0%]; 72 warfarin users [1.5%]). Results of Poisson regression analysis showed that dabigatran use was associated with a significantly lower risk of osteoporotic fracture compared with warfarin (0.7 vs 1.1 per 100 person-years; ARD per 100 person-years, -0.68 [95% CI, -0.38 to -0.86]; IRR, 0.38 [95% CI, 0.22 to 0.66]). The association with lower risk was statistically significant in patients with a history of falls, fractures, or both (dabigatran vs warfarin, 1.6 vs 3.6 per 100 person-years; ARD per 100 person-years, -3.15 [95% CI, -2.40 to -3.45]; IRR, 0.12 [95% CI, 0.04 to 0.33]), but not in those without a history (0.6 vs 0.7 per 100 person-years; ARD per 100 person-years, -0.04 [95% CI, 0.67 to -0.39]; IRR, 0.95 [95% CI, 0.45 to 1.96]) (P value for interaction, <.001). Among adults with NVAF receiving anticoagulation, the use of dabigatran compared with warfarin was associated with a

Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.

PubMed

Phuah, Chia-Ling; Dave, Tushar; Malik, Rainer; Raffeld, Miriam R; Ayres, Alison M; Goldstein, Joshua N; Viswanathan, Anand; Greenberg, Steven M; Jagiella, Jeremiasz M; Hansen, Björn M; Norrving, Bo; Jimenez-Conde, Jordi; Roquer, Jaume; Pichler, Alexander; Enzinger, Christian; Montaner, Joan; Fernandez-Cadenas, Israel; Lindgren, Arne; Slowik, Agnieszka; Schmidt, Reinhold; Biffi, Alessandro; Rost, Natalia; Langefeld, Carl D; Markus, Hugh S; Mitchell, Braxton D; Worrall, Brad B; Kittner, Steven J; Woo, Daniel; Dichgans, Martin; Rosand, Jonathan; Anderson, Christopher D

2017-10-01

Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary

Protective role of free and quercetin-loaded nanoemulsion against damage induced by intracerebral haemorrhage in rats.

PubMed

Galho, A R; Cordeiro, M F; Ribeiro, S A; Marques, M S; Antunes, M F D; Luz, D C; Hädrich, G; Muccillo-Baisch, A L; Barros, D M; Lima, J V; Dora, C L; Horn, A P

2016-04-29

Intracerebral haemorrhage (ICH) is a worldwide public health problem. Experimental studies have shown that oxidative stress plays an important role in the pathogenesis of ICH and could represent a target for its treatment. However, the blood-brain barrier is an obstacle to be overcome, as it hampers the administration of compounds to the central nervous system. In this study, we compared the effects of a quercetin-loaded nanoemulsion (QU-N) with the free form of the drug (QU-SP) in a collagenase-induced ICH rat model. Quercetin (QU) is a polyphenol that has an antioxidant effect in vitro, but due to its high lipophilicity, it has low bioavailability in vivo. In this study, animals submitted or not to ICH were treated with a single intraperitoneal QU dose (free or nanoemulsion) of 30 mg kg(-1). Motor assessment was evaluated by the open field, foot fault and beam walking behavioural tests. 72 h after surgery the haematoma size was evaluated and biochemical measurements were performed. Animals treated with QU-N had a significant improvement in the beam walking and open field tests. Also, QU-N was able to reduce the size of the haematoma, preserving the activity of glutathione S-transferase (GST), increasing GSH content, and the total antioxidant capacity. QU-SP recovered locomotor activity and increased the GSH content and the total antioxidant capacity. Thus, it can be observed that QU presented antioxidant activity in both formulations, but the incorporation into nanoemulsions increased its antioxidant effect, which was reflected in the improvement of the motor skills and in the haematoma size decrement. These results suggest that the nanoemulsion containing QU developed in this study could be promising for future studies on treatments for ICH.

Protective role of free and quercetin-loaded nanoemulsion against damage induced by intracerebral haemorrhage in rats

NASA Astrophysics Data System (ADS)

Galho, A. R.; Cordeiro, M. F.; Ribeiro, S. A.; Marques, M. S.; Antunes, M. F. D.; Luz, D. C.; Hädrich, G.; Muccillo-Baisch, A. L.; Barros, D. M.; Lima, J. V.; Dora, C. L.; Horn, A. P.

2016-04-01

Intracerebral haemorrhage (ICH) is a worldwide public health problem. Experimental studies have shown that oxidative stress plays an important role in the pathogenesis of ICH and could represent a target for its treatment. However, the blood-brain barrier is an obstacle to be overcome, as it hampers the administration of compounds to the central nervous system. In this study, we compared the effects of a quercetin-loaded nanoemulsion (QU-N) with the free form of the drug (QU-SP) in a collagenase-induced ICH rat model. Quercetin (QU) is a polyphenol that has an antioxidant effect in vitro, but due to its high lipophilicity, it has low bioavailability in vivo. In this study, animals submitted or not to ICH were treated with a single intraperitoneal QU dose (free or nanoemulsion) of 30 mg kg-1. Motor assessment was evaluated by the open field, foot fault and beam walking behavioural tests. 72 h after surgery the haematoma size was evaluated and biochemical measurements were performed. Animals treated with QU-N had a significant improvement in the beam walking and open field tests. Also, QU-N was able to reduce the size of the haematoma, preserving the activity of glutathione S-transferase (GST), increasing GSH content, and the total antioxidant capacity. QU-SP recovered locomotor activity and increased the GSH content and the total antioxidant capacity. Thus, it can be observed that QU presented antioxidant activity in both formulations, but the incorporation into nanoemulsions increased its antioxidant effect, which was reflected in the improvement of the motor skills and in the haematoma size decrement. These results suggest that the nanoemulsion containing QU developed in this study could be promising for future studies on treatments for ICH.

Association of warfarin with congestive heart failure and peripheral artery occlusive disease in hemodialysis patients with atrial fibrillation.

PubMed

Lee, Kuo-Hua; Li, Szu-Yuan; Liu, Jin-Sin; Huang, Chi-Ting; Chen, Ying-Ying; Lin, Yao-Ping; Hsu, Chih-Cheng; Tarng, Der-Cherng

2017-05-01

The effect of warfarin on the risk of cardiovascular (CV) disease is unknown among chronic hemodialysis patients with atrial fibrillation (HD-AF). Population-based propensity score and prescription time-distribution matched cohort study including 6719 HD-AF patients with CHA 2 DS 2 -VASc score ≥ 2 were divided into warfarin users and nonusers and followed-up for CV events and death. Warfarin treatment in HD-AF patients with AF preceding HD was associated with higher risks of developing congestive heart failure [hazard ratio (HR)=1.82, 95% confidence interval (CI)=1.29-2.58, p<0.01], peripheral artery occlusive disease (HR=3.42, 95% CI=1.86-6.31, p<0.01), and aortic valve stenosis (HR=3.20, 95% CI=1.02-9.98, p<0.05). Warfarin users were not associated with risks of ischemic or hemorrhagic stroke and all-cause mortality as compared to nonusers. Warfarin may be associated with vascular calcification, increasing the risks of congestive heart failure and peripheral artery occlusive disease among HD-AF patients. Copyright © 2017. Published by Elsevier Taiwan LLC.

Acute convexity subarachnoid haemorrhage and cortical superficial siderosis in probable cerebral amyloid angiopathy without lobar haemorrhage.

PubMed

Charidimou, Andreas; Boulouis, Grégoire; Fotiadis, Panagiotis; Xiong, Li; Ayres, Alison M; Schwab, Kristin M; Gurol, Mahmut Edip; Rosand, Jonathan; Greenberg, Steve M; Viswanathan, Anand

2018-04-01

Acute non-traumatic convexity subarachnoid haemorrhage (cSAH) is increasingly recognised in cerebral amyloid angiopathy (CAA). We investigated: (a) the overlap between acute cSAH and cortical superficial siderosis-a new CAA haemorrhagic imaging signature and (b) whether acute cSAH presents with particular clinical symptoms in patients with probable CAA without lobar intracerebral haemorrhage. MRI scans of 130 consecutive patients meeting modified Boston criteria for probable CAA were analysed for cortical superficial siderosis (focal, ≤3 sulci; disseminated, ≥4 sulci), and key small vessel disease markers. We compared clinical, imaging and cortical superficial siderosis topographical mapping data between subjects with versus without acute cSAH, using multivariable logistic regression. We included 33 patients with probable CAA presenting with acute cSAH and 97 without cSAH at presentation. Patients with acute cSAH were more commonly presenting with transient focal neurological episodes (76% vs 34%; p<0.0001) compared with patients with CAA without cSAH. Patients with acute cSAH were also more often clinically presenting with transient focal neurological episodes compared with cortical superficial siderosis-positive, but cSAH-negative subjects with CAA (76% vs 30%; p<0.0001). Cortical superficial siderosis prevalence (but no other CAA severity markers) was higher among patients with cSAH versus those without, especially disseminated cortical superficial siderosis (49% vs 19%; p<0.0001). In multivariable logistic regression, cortical superficial siderosis burden (OR 5.53; 95% CI 2.82 to 10.8, p<0.0001) and transient focal neurological episodes (OR 11.7; 95% CI 2.70 to 50.6, p=0.001) were independently associated with acute cSAH. This probable CAA cohort provides additional evidence for distinct disease phenotypes, determined by the presence of cSAH and cortical superficial siderosis. © Article author(s) (or their employer(s) unless otherwise stated in the

Effectiveness and safety of rivaroxaban versus warfarin for treatment and prevention of recurrence of venous thromboembolism.

PubMed

Coleman, Craig I; Bunz, Thomas J; Turpie, Alexander G G

2017-10-05

The efficacy and safety or rivaroxaban versus enoxaparin/vitamin K antagonist for treatment and prevention recurrence of venous thromboembolism (VTE) was demonstrated in the randomised EINSTEIN trials. We assessed the effectiveness and safety of rivaroxaban versus warfarin in VTE patients managed in routine practice. Using US MarketScan claims from 1/2012-6/2015, we included adults with a primary diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE) during a hospitalisation/emergency department visit, newly-initiated on rivaroxaban or warfarin within 30-days after the VTE and with ≥180-days of continuous medical/prescription benefits prior to the VTE (baseline). Patients with a claim for anticoagulation at baseline were excluded. Recurrent VTE, major bleeding, intracranial haemorrhage (ICH) and gastrointestinal bleeding (GIB) were assessed. Differences in baseline characteristics between cohorts were adjusted for using inverse probability of treatment weights based on propensity-scores. Patients had a maximum of 12-months period of follow-up post-VTE or until endpoint occurrence, switch/discontinuation of index anticoagulation, insurance disenrollment or end-of-follow-up. Cox regression was performed and reported as hazard ratios (HRs) with 95 % confidence intervals (CIs). In total, 13,609 rivaroxaban and 32,244 warfarin users experiencing VTE were included. Rivaroxaban was associated with an 19 % (95 %CI=10-27 %) reduction in recurrent VTE and a 21 % (95 %CI=4-35 %) reduction in major bleeding hazard versus warfarin. Rivaroxaban was also associated with significantly decreased hazards of ICH (HR=0.40) and GIB (HR=0.72). Rivaroxaban appears to reduce patients' hazard of both recurrent VTE and major bleeding in routine practice. These results appear consistent with EINSTEIN and post-marketing registry studies.

Healthcare costs associated with rivaroxaban or warfarin use for the treatment of venous thromboembolism.

PubMed

Coleman, Craig I; Baugh, Christopher; Crivera, Concetta; Milentijevic, Dejan; Wang, Sheng-Wei; Lu, Lang; Nelson, Winnie W

2017-02-01

Rivaroxaban has been shown to have similar efficacy but less major bleeding than warfarin in randomized trials of patients experiencing venous thromboembolism (VTE). This report sought to assess healthcare costs up to 12-months following an index VTE in patients prescribed either rivaroxaban or warfarin. This study analyzed claims from the MarketScan Commercial Claims and Encounters Database from November 2011-July 2015. It selected adults newly-diagnosed with VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) if they had an outpatient prescription claim for rivaroxaban or warfarin within 7-days of the index event. Warfarin users were 2:1 propensity-score matched to rivaroxaban users and followed until the end of insurance coverage, end of data availability or 12-months of follow-up. Total per patient healthcare costs, including inpatient, outpatient, and overall pharmacy costs, were compared using a multivariable generalized linear model. In total, 10,929 rivaroxaban patients were matched to 21,858 warfarin patients. Mean follow-up for rivaroxaban and warfarin patients was 317- and 321-days for those experiencing an index DVT, and 313- and 318-days for those with PE. Mean overall treatment costs per patient were lower for rivaroxaban vs warfarin users (-$1,116, p = .0016). This cost difference was driven by lower inpatient (-$622) and outpatient (-$1,156) treatment costs, and the higher pharmacy costs ($661) were, therefore, fully offset. Results were similar when analysis was restricted to DVT patients. No significant difference in total costs was observed in patients experiencing an index PE. Claims databases are subject to inaccuracies and missing data. Prescription claims may not fully reflect actual medication utilization. Despite propensity-score matching and regression, residual confounding cannot be excluded. Rivaroxaban was associated with significantly lower total per patient VTE treatment costs, despite higher pharmacy costs. These savings

Outcomes Associated With Resuming Warfarin Treatment After Hemorrhagic Stroke or Traumatic Intracranial Hemorrhage in Patients With Atrial Fibrillation.

PubMed

Nielsen, Peter Brønnum; Larsen, Torben Bjerregaard; Skjøth, Flemming; Lip, Gregory Y H

2017-04-01

The increase in the risk for bleeding associated with antithrombotic therapy causes a dilemma in patients with atrial fibrillation (AF) who sustain an intracranial hemorrhage (ICH). A thrombotic risk is present; however, a risk for serious harm associated with resumption of anticoagulation therapy also exists. To investigate the prognosis associated with resuming warfarin treatment stratified by the type of ICH (hemorrhagic stroke or traumatic ICH). This nationwide observational cohort study included patients with AF who sustained an incident ICH event during warfarin treatment from January 1, 1998, through February 28, 2016. Follow-up was completed April 30, 2016. Resumption of warfarin treatment was evaluated after hospital discharge. No oral anticoagulant treatment or resumption of warfarin treatment, included as a time-dependent exposure. One-year observed event rates per 100 person-years were calculated, and treatment strategies were compared using time-dependent Cox proportional hazards regression models with adjustment for age, sex, length of hospital stay, comorbidities, and concomitant medication use. A total of 2415 patients with AF in this cohort (1481 men [61.3%] and 934 women [38.7%]; mean [SD] age, 77.1 years [9.1 years]) sustained an ICH event. Of these events, 1325 were attributable to hemorrhagic stroke and 1090 were secondary to trauma. During the first year, 305 patients with a hemorrhagic stroke (23.0%) died, whereas 210 in the traumatic ICH group (19.3%) died. Among patients with hemorrhagic stroke, resuming warfarin therapy was associated with a lower rate of ischemic stroke or systemic embolism (SE) (adjusted hazard ratio [AHR], 0.49; 95% CI, 0.24-1.02) and an increased rate of recurrent ICH (AHR, 1.31; 95% CI, 0.68-2.50) compared with not resuming warfarin therapy, but these differences did not reach statistical significance. For patients with traumatic ICH, resuming warfarin therapy also was associated with a lower rate of ischemic stroke

Outcomes Associated With Resuming Warfarin Treatment After Hemorrhagic Stroke or Traumatic Intracranial Hemorrhage in Patients With Atrial Fibrillation

PubMed Central

Larsen, Torben Bjerregaard; Skjøth, Flemming; Lip, Gregory Y. H.

2017-01-01

Importance The increase in the risk for bleeding associated with antithrombotic therapy causes a dilemma in patients with atrial fibrillation (AF) who sustain an intracranial hemorrhage (ICH). A thrombotic risk is present; however, a risk for serious harm associated with resumption of anticoagulation therapy also exists. Objective To investigate the prognosis associated with resuming warfarin treatment stratified by the type of ICH (hemorrhagic stroke or traumatic ICH). Design, Setting, and Participants This nationwide observational cohort study included patients with AF who sustained an incident ICH event during warfarin treatment from January 1, 1998, through February 28, 2016. Follow-up was completed April 30, 2016. Resumption of warfarin treatment was evaluated after hospital discharge. Exposures No oral anticoagulant treatment or resumption of warfarin treatment, included as a time-dependent exposure. Main Outcomes and Measures One-year observed event rates per 100 person-years were calculated, and treatment strategies were compared using time-dependent Cox proportional hazards regression models with adjustment for age, sex, length of hospital stay, comorbidities, and concomitant medication use. Results A total of 2415 patients with AF in this cohort (1481 men [61.3%] and 934 women [38.7%]; mean [SD] age, 77.1 years [9.1 years]) sustained an ICH event. Of these events, 1325 were attributable to hemorrhagic stroke and 1090 were secondary to trauma. During the first year, 305 patients with a hemorrhagic stroke (23.0%) died, whereas 210 in the traumatic ICH group (19.3%) died. Among patients with hemorrhagic stroke, resuming warfarin therapy was associated with a lower rate of ischemic stroke or systemic embolism (SE) (adjusted hazard ratio [AHR], 0.49; 95% CI, 0.24-1.02) and an increased rate of recurrent ICH (AHR, 1.31; 95% CI, 0.68-2.50) compared with not resuming warfarin therapy, but these differences did not reach statistical significance. For patients with

Use of warfarin in long-term care: a systematic review

PubMed Central

2012-01-01

Background The use of warfarin in older patients requires special consideration because of concerns with comorbidities, interacting medications, and the risk of bleeding. Several studies have suggested that warfarin may be underused or inconsistently prescribed in long-term care (LTC); no published systematic review has evaluated warfarin use for stroke prevention in this setting. This review was conducted to summarize the body of published original research regarding the use of warfarin in the LTC population. Methods A systematic literature search of the PubMed, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library was conducted from January 1985 to August 2010 to identify studies that reported warfarin use in LTC. Studies were grouped by (1) rates of warfarin use and prescribing patterns, (2) association of resident and institutional characteristics with warfarin prescribing, (3) prescriber attitudes and concerns about warfarin use, (4) warfarin management and monitoring, and (5) warfarin-related adverse events. Summaries of study findings and quality assessments of each study were developed. Results Twenty-two studies met the inclusion criteria for this review. Atrial fibrillation (AF) was the most common indication for warfarin use in LTC and use of warfarin for stroke survivors was common. Rates of warfarin use in AF were low in 5 studies, ranging from 17% to 57%. These usage rates were low even among residents with high stroke risk and low bleeding risk. Scored bleeding risk had no apparent association with warfarin use in AF. In physician surveys, factors associated with not prescribing warfarin included risk of falls, dementia, short life expectancy, and history of bleeding. International normalized ratio was in the target range approximately half of the time. The combined overall rate of warfarin-related adverse events and potential events was 25.5 per 100 resident months on warfarin therapy. Conclusions Among residents with AF

Ultraearly hematoma growth in active intracerebral hemorrhage

PubMed Central

Coscojuela, Pilar; Rubiera, Marta; Hill, Michael D.; Dowlatshahi, Dar; Aviv, Richard I.; Silva, Yolanda; Dzialowski, Imanuel; Lum, Cheemun; Czlonkowska, Anna; Boulanger, Jean-Martin; Kase, Carlos S.; Gubitz, Gord; Bhatia, Rohit; Padma, Vasantha; Roy, Jayanta; Tomasello, Alejandro; Demchuk, Andrew M.; Molina, Carlos A.

2016-01-01

Objective: To determine the association of ultraearly hematoma growth (uHG) with the CT angiography (CTA) spot sign, hematoma expansion, and clinical outcomes in patients with acute intracerebral hemorrhage (ICH). Methods: We analyzed data from 231 patients enrolled in the multicenter Predicting Haematoma Growth and Outcome in Intracerebral Haemorrhage Using Contrast Bolus CT study. uHG was defined as baseline ICH volume/onset-to-CT time (mL/h). The spot sign was used as marker of active hemorrhage. Outcome parameters included significant hematoma expansion (>33% or >6 mL, primary outcome), rate of hematoma expansion, early neurologic deterioration, 90-day mortality, and poor outcome. Results: uHG was higher in spot sign patients (p < 0.001) and in patients scanned earlier (p < 0.001). Both uHG >4.7 mL/h (p = 0.002) and the CTA spot sign (p = 0.030) showed effects on rate of hematoma expansion but not its interaction (2-way analysis of variance, p = 0.477). uHG >4.7 mL/h improved the sensitivity of the spot sign in the prediction of significant hematoma expansion (73.9% vs 46.4%), early neurologic deterioration (67.6% vs 35.3%), 90-day mortality (81.6% vs 44.9%), and poor outcome (72.8% vs 29.8%), respectively. uHG was independently related to significant hematoma expansion (odds ratio 1.06, 95% confidence interval 1.03–1.10) and clinical outcomes. Conclusions: uHG is a useful predictor of hematoma expansion and poor clinical outcomes in patients with acute ICH. The combination of high uHG and the spot sign is associated with a higher rate of hematoma expansion, highlighting the need for very fast treatment in ICH patients. PMID:27343067

Benefit, risk and cost of new oral anticoagulants and warfarin in atrial fibrillation; A multicriteria decision analysis.

PubMed

Mendoza-Sanchez, Jose; Silva, Federico; Rangel, Lady; Jaramillo, Linda; Mendoza, Leidy; Garzon, Jenny; Quiroga, Andrea

2018-01-01

Warfarin and new oral anticoagulants are effective in reducing stroke in atrial fibrillation; however, the benefits and risks rates in clinical trials show heterogeneity for each anticoagulant, and is unknown the cost influence on a model considering most of the treatment consequences. We designed a benefit-risk and cost assessment of oral anticoagulants. We followed the roadmap proposed by IMI-PROTECT and the considerations of emerged good practice to perform Multi-Criteria Decision Analysis (MCDA). The roadmap defines the following steps: (1) planning, (2) evidence gathering and data preparation, (3) analyses, (4) explorations, and (5) conclusions. We defined two reference points (0-100) to allocate numerical values for scores and weights, and used an analogue numeric scale to assess physicians' preferences. As benefits of the anticoagulant therapy, we included reductions in stroke and all-cause mortality; intracranial haemorrhage, gastrointestinal haemorrhage, minor bleeding and myocardial infarction were considered risks. We also made an estimation of the annual drug cost per person. The scores were: Apixaban 33, Dabigatrán 25, warfarin 18 and Rivaroxaban 14 this score reveals the most preferred up to the less preferred option, considering the benefit-risk ratio and drug costs altogether. The relative model weights were: 51.1% for risks, 40.4% for benefits and 8.5% for cost. The sensitivity analysis confirms the model robustness. From this analysis, apixaban should be considered as the preferred anticoagulant option -due to a better benefit-risk balance and a minor cost influence- followed by dabigatran, warfarin and rivaroxaban.

Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.

PubMed

Ruff, Christian T; Giugliano, Robert P; Braunwald, Eugene; Hoffman, Elaine B; Deenadayalu, Naveen; Ezekowitz, Michael D; Camm, A John; Weitz, Jeffrey I; Lewis, Basil S; Parkhomenko, Alexander; Yamashita, Takeshi; Antman, Elliott M

2014-03-15

Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes. We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71,683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity. 42,411 participants received a new oral anticoagulant and 29,272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73-0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38-0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85-0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39-0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01-1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the

Antithrombotic drug use, cerebral microbleeds, and intracerebral hemorrhage: a systematic review of published and unpublished studies.

PubMed

Lovelock, Caroline E; Cordonnier, Charlotte; Naka, Hiromitsu; Al-Shahi Salman, Rustam; Sudlow, Cathie L M; Sorimachi, Takatoshi; Werring, David J; Gregoire, Simone M; Imaizumi, Toshio; Lee, Seung-Hoon; Briley, Dennis; Rothwell, Peter M

2010-06-01

Cerebral microbleeds (MB) are potential risk factors for intracerebral hemorrhage (ICH), but it is unclear if they are a contraindication to using antithrombotic drugs. Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with ICH and ischemic stroke (IS)/transient ischemic attack (TIA). We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with ICH; (2) antithrombotic users vs nonusers with IS/TIA; and (3) ICH vs ischemic events stratified by antithrombotic use. We also analyzed published and unpublished follow-up data to determine the risk of ICH in antithrombotic users with MB. In a pooled analysis of 1460 ICH and 3817 IS/TIA, MB were more frequent in ICH vs IS/TIA in all treatment groups, but the excess increased from 2.8 (odds ratio; range, 2.3-3.5) in nonantithrombotic users to 5.7 (range, 3.4-9.7) in antiplatelet users and 8.0 (range, 3.5-17.8) in warfarin users (P difference=0.01). There was also an excess of MB in warfarin users vs nonusers with ICH (OR, 2.7; 95% CI, 1.6-4.4; P<0.001) but none in warfarin users with IS/TIA (OR, 1.3; 95% CI, 0.9-1.7; P=0.33; P difference=0.01). There was a smaller excess of MB in antiplatelet users vs nonusers with ICH (OR, 1.7; 95% CI, 1.3-2.3; P<0.001), but findings were similar for antiplatelet users with IS/TIA (OR, 1.4; 95% CI, 1.2-1.7; P<0.001; P difference=0.25). In pooled follow-up data for 768 antithrombotic users, presence of MB at baseline was associated with a substantially increased risk of subsequent ICH (OR, 12.1; 95% CI, 3.4-42.5; P<0.001). The excess of MB in warfarin users with ICH compared to other groups suggests that MB increase the risk of warfarin-associated ICH. Limited prospective data corroborate these findings, but larger prospective studies are urgently required.

Acute Methanol Poisoning: Prevalence and Predisposing Factors of Haemorrhagic and Non-Haemorrhagic Brain Lesions.

PubMed

Zakharov, Sergey; Kotikova, Katerina; Vaneckova, Manuela; Seidl, Zdenek; Nurieva, Olga; Navratil, Tomas; Caganova, Blazena; Pelclova, Daniela

2016-08-01

The purpose was to study the prevalence and predisposing factors of brain lesions in survivors of acute methanol poisoning. Clinical data on 106 patients with methanol poisoning were collected during the Czech mass poisoning outbreak. Of 83 survivors, in 46 (55%) patients, follow-up examinations including magnetic resonance imaging of brain (MR) were performed 3-8 and 24-28 months after discharge from the hospital. Of 46 patients with a median age of 49 (interquartile range, 35-57) years, 24 (52%) patients had a total of 40 abnormal brain findings with haemorrhagic lesions detected in 15 (33%) and non-haemorrhagic lesions found in 9 (19%) patients. The patients with haemorrhagic brain lesions were more acidemic (lower arterial blood pH, higher base deficit) and had higher glycaemia and lactacidaemia on admission than those without haemorrhages (all p < 0.05). Thirteen of 32 (41%) of patients with systemic anticoagulation and 2 of 14 (14%) of patients without it had haemorrhagic lesions (p = 0.080). Bleeding complications during the treatment occurred in 4 of 15 (27%) patients, and 5 of 15 (33%) patients had conditions predisposing to haemorrhage in the group with haemorrhagic lesions. In three cases with a series of computer tomography (CT)/MR performed during hospitalization, the necrotic lesions in the brain remained non-haemorrhagic during hospitalization and haemorrhagic lesions were detected on the follow-up MR examinations only. No association between brain haemorrhages and systemic anticoagulation during dialysis was found: brain haemorrhages might occur in severely poisoned patients treated without systemic anticoagulation, whereas treatment with high doses of heparin might not lead to brain haemorrhages. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Lack of Early Improvement Predicts Poor Outcome Following Acute Intracerebral Hemorrhage.

PubMed

Yogendrakumar, Vignan; Smith, Eric E; Demchuk, Andrew M; Aviv, Richard I; Rodriguez-Luna, David; Molina, Carlos A; Silva Blas, Yolanda; Dzialowski, Imanuel; Kobayashi, Adam; Boulanger, Jean-Martin; Lum, Cheemun; Gubitz, Gord; Padma, Vasantha; Roy, Jayanta; Kase, Carlos S; Bhatia, Rohit; Ali, Myzoon; Lyden, Patrick; Hill, Michael D; Dowlatshahi, Dar

2018-04-01

There are limited data as to what degree of early neurologic change best relates to outcome in acute intracerebral hemorrhage. We aimed to derive and validate a threshold for early postintracerebral hemorrhage change that best predicts 90-day outcomes. Derivation: retrospective analysis of collated clinical stroke trial data (Virtual International Stroke Trials Archive). retrospective analysis of a prospective multicenter cohort study (Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign [PREDICT]). Neurocritical and ICUs. Patients with acute intracerebral hemorrhage presenting less than 6 hours. Derivation: 552 patients; validation: 275 patients. None. We generated a receiver operating characteristic curve for the association between 24-hour National Institutes of Health Stroke Scale change and clinical outcome. The primary outcome was a modified Rankin Scale score of 4-6 at 90 days; secondary outcomes were other modified Rankin Scale score ranges (modified Rankin Scale, 2-6, 3-6, 5-6, 6). We employed Youden's J Index to select optimal cut points and calculated sensitivity, specificity, and predictive values. We determined independent predictors via multivariable logistic regression. The derived definitions were validated in the PREDICT cohort. Twenty-four-hour National Institutes of Health Stroke Scale change was strongly associated with 90-day outcome with an area under the receiver operating characteristic curve of 0.75. Youden's method showed an optimum cut point at -0.5, corresponding to National Institutes of Health Stroke Scale change of greater than or equal to 0 (a lack of clinical improvement), which was seen in 46%. Early neurologic change accurately predicted poor outcome when defined as greater than or equal to 0 (sensitivity, 65%; specificity, 73%; positive predictive value, 70%; adjusted odds ratio, 5.05 [CI, 3.25-7.85]) or greater than or equal to 4 (sensitivity, 19%; specificity

Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.

PubMed

Wallentin, Lars; Yusuf, Salim; Ezekowitz, Michael D; Alings, Marco; Flather, Marcus; Franzosi, Maria Grazia; Pais, Prem; Dans, Antonio; Eikelboom, John; Oldgren, Jonas; Pogue, Janice; Reilly, Paul A; Yang, Sean; Connolly, Stuart J

2010-09-18

Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2·0-3·0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2·0-3·0. Median follow-up was 2·0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. The quartiles of cTTR for patients in the warfarin group were: less than 57·1%, 57·1-65·5%, 65·5-72·6%, and greater than 72·6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0·89) or 150 mg dabigatran (interaction p=0·20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0·71) or 150 mg dabigatran (interaction p=0·89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0·03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all

Association of Proton Pump Inhibitors with Reduced Risk of Warfarin-related Serious Upper Gastrointestinal Bleeding

PubMed Central

Ray, Wayne A.; Chung, Cecilia P.; Murray, Katherine T.; Smalley, Walter E.; Daugherty, James R.; Dupont, William D.; Stein, C. Michael

2016-01-01

Background & Aims Proton-pump inhibitors (PPIs) might reduce the risk of serious warfarin-related upper gastrointestinal bleeding, but the evidence of their efficacy for this indication is limited. A gastroprotective effect of PPIs would be particularly important for patients who take warfarin with antiplatelet drugs or nonselective non-steroidal anti-inflammatory drugs (NSAIDs), which further increase the risk of gastrointestinal bleeding. Methods This retrospective cohort study of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample identified 97,430 new episodes of warfarin treatment with 75,720 person-years of follow up. The study endpoints were hospitalizations for upper gastrointestinal bleeding potentially preventable by PPIs and for bleeding at other sites. Results Patients who took warfarin without PPI co-therapy had 119 hospitalizations for upper gastrointestinal bleeding per 10,000 person-years of treatment. The risk decreased by 24% among patients who received PPI co-therapy (adjusted hazard ratio [HR], 0.76; 95% CI, 0.63–0.91). There was no significant reduction in the risk of other gastrointestinal bleeding hospitalizations (HR, 1.07; 95% CI, 0.94–1.22) or non-gastrointestinal bleeding hospitalizations (HR, 0.98; 95% CI, 0.84–1.15) in this group. Among patients concurrently using antiplatelet drugs or NSAIDs, those without PPI co-therapy had 284 upper gastrointestinal bleeding hospitalizations per 10,000 person-years of warfarin treatment. The risk decreased by 45% (HR, 0.55; 95% CI, 0.39–0.77) with PPI co-therapy. PPI co-therapy had no significant protective effect for warfarin patients not using antiplatelet drugs or NSAIDs (HR, 0.86; 95% CI, 0.70-1.06). Findings were similar in both study populations. Conclusions In an analysis of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample, PPI co-therapy was associated with reduced risk of warfarin-related upper

Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years.

PubMed

Haaland, Gry S; Falk, Ragnhild S; Straume, Oddbjørn; Lorens, James B

2017-12-01

In cancer models, warfarin inhibits AXL receptor tyrosine kinase-dependent tumorigenesis and enhances antitumor immune responses at doses not reaching anticoagulation levels. This study investigates the association between warfarin use and cancer incidence in a large, unselected population-based cohort. To examine the association between warfarin use and cancer incidence. This population-based cohort study with subgroup analysis used the Norwegian National Registry coupled with the Norwegian Prescription Database and the Cancer Registry of Norway. The cohort comprised all persons (N = 1 256 725) born between January 1, 1924, and December 31, 1954, who were residing in Norway from January 1, 2006, through December 31, 2012. The cohort was divided into 2 groups-warfarin users and nonusers; persons taking warfarin for atrial fibrillation or atrial flutter were the subgroup. Data were collected from January 1, 2004, to December 31, 2012. Data analysis was conducted from October 15, 2016, to January 31, 2017. Warfarin use was defined as taking at least 6 months of a prescription and at least 2 years from first prescription to any cancer diagnosis. If warfarin treatment started after January 1, 2006, each person contributed person-time in the nonuser group until the warfarin user criteria were fulfilled. Cancer diagnosis of any type during the 7-year observation period (January 1, 2006, through December 31, 2012). Of the 1 256 725 persons in the cohort, 607 350 (48.3%) were male, 649 375 (51.7%) were female, 132 687 (10.6%) had cancer, 92 942 (7.4%) were classified as warfarin users, and 1 163 783 (92.6%) were classified as nonusers. Warfarin users were older, with a mean (SD) age of 70.2 (8.2) years, and were predominantly men (57 370 [61.7%]) as compared with nonusers, who had a mean (SD) age of 63.9 (8.6) years and were mostly women (613 803 [52.7%]). Among warfarin users and compared with nonusers, there was a significantly lower age- and sex

Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.

PubMed

Hemphill, J Claude; Greenberg, Steven M; Anderson, Craig S; Becker, Kyra; Bendok, Bernard R; Cushman, Mary; Fung, Gordon L; Goldstein, Joshua N; Macdonald, R Loch; Mitchell, Pamela H; Scott, Phillip A; Selim, Magdy H; Woo, Daniel

2015-07-01

The aim of this guideline is to present current and comprehensive recommendations for the diagnosis and treatment of spontaneous intracerebral hemorrhage. A formal literature search of PubMed was performed through the end of August 2013. The writing committee met by teleconference to discuss narrative text and recommendations. Recommendations follow the American Heart Association/American Stroke Association methods of classifying the level of certainty of the treatment effect and the class of evidence. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Oversight Committee and Stroke Council Leadership Committee. Evidence-based guidelines are presented for the care of patients with acute intracerebral hemorrhage. Topics focused on diagnosis, management of coagulopathy and blood pressure, prevention and control of secondary brain injury and intracranial pressure, the role of surgery, outcome prediction, rehabilitation, secondary prevention, and future considerations. Results of new phase 3 trials were incorporated. Intracerebral hemorrhage remains a serious condition for which early aggressive care is warranted. These guidelines provide a framework for goal-directed treatment of the patient with intracerebral hemorrhage. © 2015 American Heart Association, Inc.

Risk Profile of Symptomatic Lacunar Stroke Versus Nonlobar Intracerebral Hemorrhage.

PubMed

Morotti, Andrea; Paciaroni, Maurizio; Zini, Andrea; Silvestrelli, Giorgio; Del Zotto, Elisabetta; Caso, Valeria; Dell'Acqua, Maria Luisa; Simone, Anna Maria; Lanari, Alessia; Costa, Paolo; Poli, Loris; De Giuli, Valeria; Gamba, Massimo; Ciccone, Alfonso; Ritelli, Marco; Di Castelnuovo, Augusto; Iacoviello, Licia; Colombi, Marina; Agnelli, Giancarlo; Grassi, Mario; de Gaetano, Giovanni; Padovani, Alessandro; Pezzini, Alessandro

2016-08-01

Although lacunar stroke (LS) and deep intracerebral hemorrhage (dICH) represent acute manifestations of the same pathological process involving cerebral small vessels (small vessel disease), it remains unclear what factors predispose to one phenotype rather than the other at individual level. Consecutive patients with either acute symptomatic LS or dICH were prospectively enrolled as part of a multicenter Italian study. We compared the risk factor profile of the 2 subgroups using multivariable logistic regression. During a time course of 9.5 years, 1931 subjects (1434 LS and 497 dICH; mean age, 71.3±13.3 years; males, 55.5%) qualified for the analysis. Current smoking was associated with LS (odds ratio [OR], 2.17; P<0.001). Conversely, dICH cases were more likely to be hypertensive (OR, 1.87; P<0.001), excessive alcohol consumers (OR, 1.70; P=0.001), and more frequently under treatment with warfarin (OR, 2.05; P=0.010) and statins (OR, 3.10; P<0.001). Hypercholesterolemia, diabetes mellitus, and antiplatelet treatment were not associated with a specific small vessel disease manifestation. The risk factor profile of dICH differs from that associated with LS. This might be used for disease risk stratification at individual level. © 2016 American Heart Association, Inc.

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.

PubMed

Hanley, Daniel F; Lane, Karen; McBee, Nichol; Ziai, Wendy; Tuhrim, Stanley; Lees, Kennedy R; Dawson, Jesse; Gandhi, Dheeraj; Ullman, Natalie; Mould, W Andrew; Mayo, Steven W; Mendelow, A David; Gregson, Barbara; Butcher, Kenneth; Vespa, Paul; Wright, David W; Kase, Carlos S; Carhuapoma, J Ricardo; Keyl, Penelope M; Diener-West, Marie; Muschelli, John; Betz, Joshua F; Thompson, Carol B; Sugar, Elizabeth A; Yenokyan, Gayane; Janis, Scott; John, Sayona; Harnof, Sagi; Lopez, George A; Aldrich, E Francois; Harrigan, Mark R; Ansari, Safdar; Jallo, Jack; Caron, Jean-Louis; LeDoux, David; Adeoye, Opeolu; Zuccarello, Mario; Adams, Harold P; Rosenblum, Michael; Thompson, Richard E; Awad, Issam A

2017-02-11

Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9

Reduced anticoagulation variability in patients on warfarin monitored with Fiix-prothrombin time associates with reduced thromboembolism: The Fiix-trial.

PubMed

Oskarsdóttir, Alma Rut; Gudmundsdottir, Brynja R; Indridason, Olafur S; Lund, Sigrun H; Arnar, David O; Bjornsson, Einar S; Magnusson, Magnus K; Jensdottir, Hulda M; Vidarsson, Brynjar; Francis, Charles W; Onundarson, Pall T

2017-05-01

Fiix-prothrombin time (Fiix-PT) differs from traditional PT in being affected by reduced factor (F) II or FX only. In the randomized controlled Fiix-trial, patients on warfarin monitored with Fiix-PT (Fiix-warfarin patients) had fewer thromboembolisms (TE), similar major bleeding (MB) and more stable anticoagulation than patients monitored with PT (PT-warfarin patients). In the current Fiix-trial report we analyzed how reduced anticoagulation variability during Fiix-PT monitoring was reflected in patients with TE or bleeding. Data from 1143 randomized patients was used. We analyzed the groups for anticoagulation intensity (time within target range; TTR), international normalized ratio (INR) variability (variance growth rate B 1 ; VGR) and dose adjustment frequency. We assessed how these parameters associated with clinically relevant vascular events (CRVE), ie TE or MB or clinically relevant non-MB. TTR was highest in Fiix-warfarin patients without CRVE (median 82%;IQR 72-91) and lowest in PT-warfarin patients with TE (62%;56-81). VGR was lowest in Fiix-warfarin patients without CRVE (median VGR B 1 0.17; 95% CI 0.08-0.38) and with TE (0.20;0.07-0.26) and highest in PT-warfarin patients with TE (0.50;0.27-0.90) or MB (0.59;0.07-1.36). The mean annual dose adjustment frequency was lowest in Fiix-warfarin patients with TE (mean 5.4;95% CI 3.9-7.3) and without CRVE (mean 6.0; 5.8-6.2) and highest in PT-warfarin patients with TE (14.2;12.2-16.3). Frequent dose changes predicted MB in both study arms. Compared to patients monitored with PT, high anticoagulation stability in Fiix-warfarin patients coincided with their low TE rate. Those with bleeding had high variability irrespective of monitoring method. Thus, although further improvements are needed to reduce bleeding, stabilization of anticoagulation by Fiix-PT monitoring associates with reduced TE.

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study

PubMed Central

Claudio-Campos, Karla; Labastida, Aurora; Ramos, Alga; Gaedigk, Andrea; Renta-Torres, Jessicca; Padilla, Dariana; Rivera-Miranda, Giselle; Scott, Stuart A.; Ruaño, Gualberto; Cadilla, Carmen L.; Duconge-Soler, Jorge

2017-01-01

Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study.

PubMed

Claudio-Campos, Karla; Labastida, Aurora; Ramos, Alga; Gaedigk, Andrea; Renta-Torres, Jessicca; Padilla, Dariana; Rivera-Miranda, Giselle; Scott, Stuart A; Ruaño, Gualberto; Cadilla, Carmen L; Duconge-Soler, Jorge

2017-01-01

Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9 * 2 and CYP2C9 * 3 . Although, CYP2C9 * 2 and CYP2C9 * 3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs 2860905 in a regression model ( R 2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1 -1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9 * 2 and CYP2C9 * 3 combined (partial R 2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of

Association of Proton Pump Inhibitors With Reduced Risk of Warfarin-Related Serious Upper Gastrointestinal Bleeding.

PubMed

Ray, Wayne A; Chung, Cecilia P; Murray, Katherine T; Smalley, Walter E; Daugherty, James R; Dupont, William D; Stein, C Michael

2016-12-01

Proton pump inhibitors (PPIs) might reduce the risk of serious warfarin-related upper gastrointestinal bleeding, but the evidence of their efficacy for this indication is limited. A gastroprotective effect of PPIs would be particularly important for patients who take warfarin with antiplatelet drugs or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which further increase the risk of gastrointestinal bleeding. This retrospective cohort study of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample identified 97,430 new episodes of warfarin treatment with 75,720 person-years of follow-up. The study end points were hospitalizations for upper gastrointestinal bleeding potentially preventable by PPIs and for bleeding at other sites. Patients who took warfarin without PPI co-therapy had 119 hospitalizations for upper gastrointestinal bleeding per 10,000 person-years of treatment. The risk decreased by 24% among patients who received PPI co-therapy (adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63-0.91). There was no significant reduction in the risk of other gastrointestinal bleeding hospitalizations (HR, 1.07; 95% CI, 0.94-1.22) or non-gastrointestinal bleeding hospitalizations (HR, 0.98; 95% CI, 0.84-1.15) in this group. Among patients concurrently using antiplatelet drugs or NSAIDs, those without PPI co-therapy had 284 upper gastrointestinal bleeding hospitalizations per 10,000 person-years of warfarin treatment. The risk decreased by 45% (HR, 0.55; 95% CI, 0.39-0.77) with PPI co-therapy. PPI co-therapy had no significant protective effect for warfarin patients not using antiplatelet drugs or NSAIDs (HR, 0.86; 95% CI, 0.70-1.06). Findings were similar in both study populations. In an analysis of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample, PPI co-therapy was associated with reduced risk of warfarin-related upper gastrointestinal bleeding; the

Post-polypectomy bleeding and thromboembolism risks associated with warfarin vs direct oral anticoagulants.

PubMed

Yanagisawa, Naohiro; Nagata, Naoyoshi; Watanabe, Kazuhiro; Iida, Tatsuhiro; Hamada, Mariko; Kobayashi, Sakurako; Shimbo, Takuro; Akiyama, Junichi; Uemura, Naomi

2018-04-14

To verify the validity of the endoscopy guidelines for patients taking warfarin or direct oral anticoagulants (DOAC). We collected data from 218 patients receiving oral anticoagulants (73 DOAC users, 145 warfarin users) and 218 patients not receiving any antithrombotics (age- and sex-matched controls) who underwent polypectomy. (1) We evaluated post-polypectomy bleeding (PPB) risk in patients receiving warfarin or DOAC compared with controls; (2) we assessed the risks of PPB and thromboembolism between three AC management methods: Discontinuing AC with heparin bridge (HPB) (endoscopy guideline recommendation), continuing AC, and discontinuing AC without HPB. PPB rate was significantly higher in warfarin users and DOAC users compared with controls (13.7% and 13.7% vs 0.9%, P < 0.001), but was not significantly different between rivaroxaban (13.2%), dabigatran (11.1%), and apixaban (13.3%) users. Two thromboembolic events occurred in warfarin users, but none in DOAC users. Compared with the continuing anticoagulant group, the discontinuing anticoagulant with HPB group (guideline recommendation) had a higher PPB rate (10.8% vs 19.6%, P = 0.087). These findings were significantly evident in warfarin but not DOAC users. One thrombotic event occurred in the discontinuing anticoagulant with HPB group and the discontinuing anticoagulant without HPB group; none occurred in the continuing anticoagulant group. PPB risk was similar between patients taking warfarin and DOAC. Thromboembolism was observed in warfarin users only. The guideline recommendations for HPB should be re-considered.

Stroke in Heart Failure in Sinus Rhythm: The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial

PubMed Central

Pullicino, Patrick M.; Thompson, John L.P.; Sacco, Ralph L.; Sanford, Alexandra R.; Qian, Min; Teerlink, John R.; Haddad, Haissam; Diek, Monika; Freudenberger, Ronald S.; Labovitz, Arthur J.; Di Tullio, Marco R.; Lok, Dirk J.; Ponikowski, Piotr; Anker, Stefan D.; Graham, Susan; Mann, Douglas L.; Mohr, J.P.; Homma, Shunichi

2014-01-01

Background The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses. Methods We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions. Results Twenty-nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3–5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic

Stroke in heart failure in sinus rhythm: the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial.

PubMed

Pullicino, Patrick M; Thompson, John L P; Sacco, Ralph L; Sanford, Alexandra R; Qian, Min; Teerlink, John R; Haddad, Haissam; Diek, Monika; Freudenberger, Ronald S; Labovitz, Arthur J; Di Tullio, Marco R; Lok, Dirk J; Ponikowski, Piotr; Anker, Stefan D; Graham, Susan; Mann, Douglas L; Mohr, J P; Homma, Shunichi

2013-01-01

The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses. We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions. Twenty-nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3-5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic, possible cardioembolic and

Case Series Analysis of New Zealand Reports of Rapid Intense Potentiation of Warfarin by Roxithromycin.

PubMed

Savage, Ruth L; Tatley, Michael V

2018-05-01

We undertook an analysis of all the reports to the New Zealand Centre for Adverse Reactions Monitoring of a roxithromycin/warfarin interaction after two recent reports described intense rapid warfarin potentiation. The interaction was first published in 1995. Cytochrome P450 3A4 inhibition has been the proposed mechanism but has limited biologic plausibility. There are suggestions that the clinical significance of the interaction may be increased by severe illness, polypharmacy, renal dysfunction, older age and increased warfarin sensitivity. To investigate the potentiating effect of warfarin on roxithromycin in this New Zealand case series, the reports were reviewed to identify patients at risk, compare the reporting pattern with published Australian data and evaluate the appropriateness of current prescribing advice. Thirty patient reports were identified. The age range was 23-88 years, mean 66.8, median 73.0 (standard deviation 17.7) and the international normalised ratios after roxithromycin commencement ranged from 3.6 to 16.7 (mean 7.6, median 7.6, standard deviation 3.6). For eight patients with measurements on day 3, international normalised ratios were 4.3-16.7 (mean 10.4, median 8.8, standard deviation 4.4). Four patients had serious haemorrhage. Indications for roxithromycin were a range of respiratory tract infections. Anticoagulation was stable for most patients prior to acute infection. Serious infection occurred in 54.5% (12 of 22 patients with information). Polypharmacy (five or more medicines daily) was used by 36.7% of patients long term, increasing acutely to 83.3%, including additional potentially interacting medicines. Warfarin daily dose (1.5-13.0 mg, mean 4.4, median 4.0, standard deviation 2.2) was moderate to low. Pre-roxithromycin international normalised ratio values ranged from 1.4 to 3.7, mean and median 2.5, standard deviation 0.5. A high proportion of interactions were observed between warfarin and roxithromycin compared with other

Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans.

PubMed

Cavallari, Larisa H; Perera, Minoli; Wadelius, Mia; Deloukas, Panos; Taube, Gelson; Patel, Shitalben R; Aquino-Michaels, Keston; Viana, Marlos A G; Shapiro, Nancy L; Nutescu, Edith A

2012-02-01

Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the γ-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements greater than 7.5 mg/day in an African American population. A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA)n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes were tested for their association with dose requirements greater than 7.5 mg/day alone and in the context of other variables known to influence dose variability. The GGCX rs10654848 (CAA)16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring greater than 7.5 mg/day versus those who required lower doses (12 vs. 3%, P=0.003; odds ratio 4.0, 95% confidence interval, 1.5-10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA)16 repeat frequency of only 0.27% (P=0.008 compared with African Americans). These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA)16/17 repeat compared with Caucasians.

12/15-Lipoxygenase Inhibition or Knockout Reduces Warfarin-Associated Hemorrhagic Transformation After Experimental Stroke.

PubMed

Liu, Yu; Zheng, Yi; Karatas, Hulya; Wang, Xiaoying; Foerch, Christian; Lo, Eng H; van Leyen, Klaus

2017-02-01

For stroke prevention, patients with atrial fibrillation typically receive oral anticoagulation. The commonly used anticoagulant warfarin increases the risk of hemorrhagic transformation (HT) when a stroke occurs; tissue-type plasminogen activator treatment is therefore restricted in these patients. This study was designed to test the hypothesis that 12/15-lipoxygenase (12/15-LOX) inhibition would reduce HT in warfarin-treated mice subjected to experimental stroke. Warfarin was dosed orally in drinking water, and international normalized ratio values were determined using a Coaguchek device. C57BL6J mice or 12/15-LOX knockout mice were subjected to transient middle cerebral artery occlusion with 3 hours severe ischemia (model A) or 2 hours ischemia and tissue-type plasminogen activator infusion (model B), with or without the 12/15-LOX inhibitor ML351. Hemoglobin was determined in brain homogenates, and hemorrhage areas on the brain surface and in brain sections were measured. 12/15-LOX expression was detected by immunohistochemistry. Warfarin treatment resulted in reproducible increased international normalized ratio values and significant HT in both models. 12/15-LOX knockout mice suffered less HT after severe ischemia, and ML351 reduced HT in wild-type mice. When normalized to infarct size, ML351 still independently reduced hemorrhage. HT after tissue-type plasminogen activator was similarly reduced by ML351. In addition to its benefits in infarct size reduction, 12/15-LOX inhibition also may independently reduce HT in warfarin-treated mice. ML351 should be further evaluated as stroke treatment in anticoagulated patients suffering a stroke, either alone or in conjunction with tissue-type plasminogen activator. © 2017 American Heart Association, Inc.

The acute management of intracerebral hemorrhage: a clinical review.

PubMed

Elliott, Justine; Smith, Martin

2010-05-01

Intracerebral hemorrhage (ICH) is a devastating disease with high rates of mortality and morbidity. The major risk factors for ICH include chronic arterial hypertension and oral anticoagulation. After the initial hemorrhage, hematoma expansion and perihematoma edema result in secondary brain damage and worsened outcome. A rapid onset of focal neurological deficit with clinical signs of increased intracranial pressure is strongly suggestive of a diagnosis of ICH, although cranial imaging is required to differentiate it from ischemic stroke. ICH is a medical emergency and initial management should focus on urgent stabilization of cardiorespiratory variables and treatment of intracranial complications. More than 90% of patients present with acute hypertension, and there is some evidence that acute arterial blood pressure reduction is safe and associated with slowed hematoma growth and reduced risk of early neurological deterioration. However, early optimism that outcome might be improved by the early administration of recombinant factor VIIa (rFVIIa) has not been substantiated by a large phase III study. ICH is the most feared complication of warfarin anticoagulation, and the need to arrest intracranial bleeding outweighs all other considerations. Treatment options for warfarin reversal include vitamin K, fresh frozen plasma, prothrombin complex concentrates, and rFVIIa. There is no evidence to guide the specific management of antiplatelet therapy-related ICH. With the exceptions of placement of a ventricular drain in patients with hydrocephalus and evacuation of a large posterior fossa hematoma, the timing and nature of other neurosurgical interventions is also controversial. There is substantial evidence that management of patients with ICH in a specialist neurointensive care unit, where treatment is directed toward monitoring and managing cardiorespiratory variables and intracranial pressure, is associated with improved outcomes. Attention must be given to fluid

Warfarin Safety: A Cross-Sectional Study of the Factors Associated with the Consumption of Medicinal Plants in a Brazilian Anticoagulation Clinic.

PubMed

Leite, Paula Mendonça; de Freitas, Aline A; Mourão, Aline de O Magalhães; Martins, Maria A P; Castilho, Rachel O

2018-06-01

The aim of this study was to analyze factors associated with the consumption of medicinal plants by patients being treated with warfarin in a Brazilian anticoagulation clinic and to study the safety of medicinal plant use in patients on warfarin therapy. The study was performed as an observational cross-sectional analysis. Study participants were outpatients on long-term warfarin therapy for at least 2 months for atrial fibrillation or prosthetic cardiac valves. Interviews were carried out concerning information about the habits of medicinal herb consumption, and logistic regression analysis was performed to identify factors associated with the consumption of herbs. The scientific names of the medicinal plants were identified to search for information on the effects on the hemostasis of the interactions between the medicinal herbs reported and warfarin. The mean age of the 273 patients included was 60.8 years; 58.7% were women. Medicinal plants were used by 67% of the participants. No association between demographic and clinical data and the use of medicinal plants was identified. Patients reported a total of 64 different plants, primarily consumed in the form of tea. The plants were mainly used to treat respiratory tract and central nervous system disorders. About 40% of the plants cited have been reported to potentially interfere with the anticoagulation therapy, principally by potentiating the effects of warfarin, which could, increase the risk of bleeding. The use of medicinal plants was highly common and widespread in patients receiving warfarin as an anticoagulation therapy. Univariate analysis of variables associated with the consumption of herbs showed no statistically significant difference in the consumption of medicinal plants for any of the sociodemographic and clinical data. The medicinal plants that were reportedly consumed by the patients could affect hemostasis. This study reinforces the need for further studies evaluating the habits of patients

Inappropriate combination of warfarin and aspirin.

PubMed

Turan, Burak; Demir, Hakan; Mutlu, Ayhan; Daşlı, Tolga; Erkol, Ayhan; Erden, İsmail

2016-03-01

A combination of warfarin and aspirin is associated with increased bleeding compared with warfarin monotherapy. The aim of the study was to investigate the incidence and appropriateness of the combination of warfarin and aspirin in patients with atrial fibrillation (AF) or mechanical heart valve (MHV). This cross-sectional study included consecutive patients with AF or MHV on chronic warfarin therapy (>3 months) without acute coronary syndrome or have not undergone a revascularization procedure in the preceding year. Medical history, concomitant diseases, and treatment data were acquired through patient interviews and from hospital records. Three hundred and sixty patients (213 with AF, 147 with MHV) were included. In those with AF, a significantly higher warfarin-aspirin combination was observed with concomitant vascular disease (38.8% vs. 14.6%), diabetes (36.6% vs. 16.3%), statin therapy (40% vs. 16.9%), left ventricular systolic dysfunction (33.3% vs. 17.5%) (p<0.05 for all). The use of combination therapy was similar between different CHADS-VASc scores. In patients with MHV, higher combination therapy was observed in males (41% vs. 26.7% in females; p=0.070), concomitant vascular disease (47.8% vs. 29.8%; p=0.091), and AF (56.3% vs. 29.8%; p=0.033). Independent predictors of warfarin-aspirin combination were concomitant vascular disease, diabetes, and (younger) age in patients with AF and were concomitant AF and male sex in patients with MHV. Interestingly, the incidence of combination therapy was found to increase with a higher HAS-BLED score in both patients with AF and MHV (p<0.001). The combination of warfarin and aspirin was found to be prescribed to patients with AF mainly for the prevention of cardiovascular events, for which warfarin monotherapy usually suffices. On the other hand, co-treatment with aspirin appeared to be underused in patients with MHV.

Validation of Clinical Testing for Warfarin Sensitivity

PubMed Central

Langley, Michael R.; Booker, Jessica K.; Evans, James P.; McLeod, Howard L.; Weck, Karen E.

2009-01-01

Responses to warfarin (Coumadin) anticoagulation therapy are affected by genetic variability in both the CYP2C9 and VKORC1 genes. Validation of pharmacogenetic testing for warfarin responses includes demonstration of analytical validity of testing platforms and of the clinical validity of testing. We compared four platforms for determining the relevant single nucleotide polymorphisms (SNPs) in both CYP2C9 and VKORC1 that are associated with warfarin sensitivity (Third Wave Invader Plus, ParagonDx/Cepheid Smart Cycler, Idaho Technology LightCycler, and AutoGenomics Infiniti). Each method was examined for accuracy, cost, and turnaround time. All genotyping methods demonstrated greater than 95% accuracy for identifying the relevant SNPs (CYP2C9 *2 and *3; VKORC1 −1639 or 1173). The ParagonDx and Idaho Technology assays had the shortest turnaround and hands-on times. The Third Wave assay was readily scalable to higher test volumes but had the longest hands-on time. The AutoGenomics assay interrogated the largest number of SNPs but had the longest turnaround time. Four published warfarin-dosing algorithms (Washington University, UCSF, Louisville, and Newcastle) were compared for accuracy for predicting warfarin dose in a retrospective analysis of a local patient population on long-term, stable warfarin therapy. The predicted doses from both the Washington University and UCSF algorithms demonstrated the best correlation with actual warfarin doses. PMID:19324988

Activated Prothrombin Complex Concentrate versus Plasma for Reversal of Warfarin-Associated Hemorrhage.

PubMed

Rowe, Anthony Shaun; Mahbubani, Pinky S; Bucklin, Mason H; Clark, Christopher T; Hamilton, Leslie A

2016-11-01

To evaluate the efficacy and safety of an activated four-factor prothrombin complex concentrate (aPCC) versus plasma for the reversal of warfarin-associated hemorrhage. Single-center, retrospective cohort analysis of adult patients with warfarin-associated hemorrhage treated with either aPCC or plasma. Patients received either aPCC or plasma as treatment for warfarin-associated hemorrhage between January 1, 2011, and July 1, 2013. Patients with missing data points were excluded from the final analysis. Of the 276 patients included in the final analysis, 128 received aPCC and 148 received plasma. None. Those patients who received aPCC achieved a lower posttreatment INR (1.1 [0.1] vs 1.6 [0.5]; p<0.05). In addition, patients who received aPCC had a 4.3 times higher odds of achieving an INR of less than 1.4 (97 [75.8%] vs 65 [43.9%]; p<0.05; odds ratio [OR] = 4.3 [95% confidence interval (CI) 2.6-7.3]). When controlling for vitamin K administration, history of diabetes mellitus, receipt of the recommended reversal agent dose, and pretreatment INR, aPCC administration remained an independent predictor for achieving an international normalized ratio (INR) of less than 1.4 in the first 24 hours after treatment (OR = 3.75 [95% CI 2.11-6.65]; p<0.001). In addition, there was no statistical difference between the groups with regard to occurrences of infusion reaction, pulmonary embolism, deep vein thrombosis, stroke, or myocardial infarction. Compared with patients who received plasma, patients who received aPCC achieved a lower posttreatment INR, had a larger INR change, and were more likely to achieve an INR less than the prespecified goal. Those patients who received aPCC did not have a higher incidence of thromboembolic events. © 2016 Pharmacotherapy Publications, Inc.

Warfarin sensitivity genotyping: a review of the literature and summary of patient experience.

PubMed

Moyer, Thomas P; O'Kane, Dennis J; Baudhuin, Linnea M; Wiley, Carmen L; Fortini, Alexandre; Fisher, Pamela K; Dupras, Denise M; Chaudhry, Rajeev; Thapa, Prabin; Zinsmeister, Alan R; Heit, John A

2009-12-01

The antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to achieve steady-state dose, variations in INR, and allelic variance. Results were compared with those previously reported in the literature for 637 patients. The relationships between allelic variants and warfarin sensitivity found in our study of Mayo Clinic patients are fundamentally the same as in those reported by others. The Mayo Clinic population is predominantly white and shows considerable allelic variability in CYP2C9 and VKORC1. Certain of these alleles are associated with increased sensitivity to warfarin. Polymorphisms in CYP2C9 and VKORC1 have a considerable effect on warfarin dose in white people. A correlation between steady-state warfarin dose and allelic variants of CYP2C9 and VKORC1 has been demonstrated by many previous reports and is reconfirmed in this report. The allelic variants found to most affect warfarin sensitivity are CYP2C9*1*1-VKORC1BB (less warfarin sensitivity than typical); CYP2C9*1*1-VKORC1AA (considerable variance in INR throughout initiation); CYP2C9*1*2-VKORC1AB (more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1

Warfarin Pharmacogenomics in Diverse Populations.

PubMed

Kaye, Justin B; Schultz, Lauren E; Steiner, Heidi E; Kittles, Rick A; Cavallari, Larisa H; Karnes, Jason H

2017-09-01

Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as African Americans and Latinos, have greater variability in warfarin dose requirements and are at greater risk for experiencing warfarin-related adverse events compared with individuals of European ancestry. Although these data suggest that patients of diverse populations may benefit from improved warfarin dose estimation, the vast majority of literature on genotype-guided warfarin dosing, including data from prospective randomized trials, is in populations of European ancestry. Despite differing frequencies of variants by race/ethnicity, most evidence in diverse populations evaluates variants that are most common in populations of European ancestry. Algorithms that do not include variants important across race/ethnic groups are unlikely to benefit diverse populations. In some race/ethnic groups, development of race-specific or admixture-based algorithms may facilitate improved genotype-guided warfarin dosing algorithms above and beyond that seen in individuals of European ancestry. These observations should be considered in the interpretation of literature evaluating the clinical utility of genotype-guided warfarin dosing. Careful consideration of race/ethnicity and additional evidence focused on improving warfarin dosing algorithms across race/ethnic groups will be necessary for successful clinical implementation of warfarin pharmacogenomics. The evidence for warfarin pharmacogenomics has a broad significance for pharmacogenomic testing, emphasizing the consideration of race/ethnicity in discovery of gene-drug pairs and development of clinical recommendations for pharmacogenetic testing. © 2017 Pharmacotherapy Publications, Inc.

Correlations between the enantio- and regio-selective metabolisms of warfarin.

PubMed

Takahashi, Harumi; Ohara, Minami; Shibata, Soichi; Lee, Ming Ta Michael; Cavallari, Larisa H; Nutescu, Edith A; Scordo, Maria G; Pengo, Vittorio; Padrini, Roberto; Atsuda, Koichiro; Matsubara, Hajime; Chen, Yuan Tsong; Echizen, Hirotoshi

2017-01-01

To clarify whether the activities of multiple CYPs associated with warfarin metabolism would be correlated with each other. Oral clearances (CLpo) of warfarin enantiomers were estimated in 378 Chinese, Caucasians and African-Americans. The partial metabolic clearances (CLm) for 7-hydroxywarfarin enantiomers were also measured. In addition, CLpo and CLm were determined in a patient on warfarin and rifampicin. Correlations between CLpo for warfarin enantiomers existed across the three populations. In addition, there was a significant correlation between the CLm for 7-hydroxylation of warfarin enantiomers. Under induced conditions by rifampicin, there were significant correlations between the enantio- and regio-selective metabolisms of warfarin. Metabolic activities of CYP2C9, CYP1A2 and CYP3A4 may be regulated by common transcriptional mechanism(s).

Risk factors for computed tomography angiography spot sign in deep and lobar intracerebral hemorrhage are shared.

PubMed

Radmanesh, Farid; Falcone, Guido J; Anderson, Christopher D; Battey, Thomas W K; Ayres, Alison M; Vashkevich, Anastasia; McNamara, Kristen A; Schwab, Kristin; Romero, Javier M; Viswanathan, Anand; Greenberg, Steven M; Goldstein, Joshua N; Rosand, Jonathan; Brouwers, H Bart

2014-06-01

Patients with intracerebral hemorrhage (ICH) who present with a spot sign on computed tomography angiography are at increased risk of hematoma expansion and poor outcome. Because primary ICH is the acute manifestation of chronic cerebral small vessel disease, we investigated whether different clinical or imaging characteristics predict spot sign presence, using ICH location as a surrogate for arteriolosclerosis- and cerebral amyloid angiopathy-related ICH. Patients with primary ICH and available computed tomography angiography at presentation were included. Predictors of spot sign were assessed using uni- and multivariable regression, stratified by ICH location. Seven hundred forty-one patients were eligible, 335 (45%) deep and 406 (55%) lobar ICH. At least one spot sign was present in 76 (23%) deep and 102 (25%) lobar ICH patients. In multivariable regression, warfarin (odds ratio [OR], 2.42; 95% confidence interval [CI], 1.01-5.71; P=0.04), baseline ICH volume (OR, 1.20; 95% CI, 1.09-1.33, per 10 mL increase; P<0.001), and time from symptom onset to computed tomography angiography (OR, 0.89; 95% CI, 0.80-0.96, per hour; P=0.009) were associated with the spot sign in deep ICH. Predictors of spot sign in lobar ICH were warfarin (OR, 3.95; 95% CI, 1.87-8.51; P<0.001) and baseline ICH volume (OR, 1.20; 95% CI, 1.10-1.31, per 10 mL increase; P<0.001). The most potent associations with spot sign are shared between deep and lobar ICH, suggesting that the acute bleeding process that arises in the setting of different chronic small vessel diseases shares commonalities. © 2014 American Heart Association, Inc.

Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial.

PubMed

Halvorsen, Sigrun; Atar, Dan; Yang, Hongqiu; De Caterina, Raffaele; Erol, Cetin; Garcia, David; Granger, Christopher B; Hanna, Michael; Held, Claes; Husted, Steen; Hylek, Elaine M; Jansky, Petr; Lopes, Renato D; Ruzyllo, Witold; Thomas, Laine; Wallentin, Lars

2014-07-21

The risk of stroke in patients with atrial fibrillation (AF) increases with age. In the ARISTOTLE trial, apixaban when compared with warfarin reduced the rate of stroke, death, and bleeding. We evaluated these outcomes in relation to patient age. A total of 18 201 patients with AF and a raised risk of stroke were randomized to warfarin or apixaban 5 mg b.d. with dose reduction to 2.5 mg b.d. or placebo in 831 patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, or creatinine ≥133 μmol/L. We used Cox models to compare outcomes in relation to patient age during 1.8 years median follow-up. Of the trial population, 30% were <65 years, 39% were 65 to <75, and 31% were ≥75 years. The rates of stroke, all-cause death, and major bleeding were higher in the older age groups (P < 0.001 for all). Apixaban was more effective than warfarin in preventing stroke and reducing mortality across all age groups, and associated with less major bleeding, less total bleeding, and less intracranial haemorrhage regardless of age (P interaction >0.11 for all). Results were also consistent for the 13% of patients ≥80 years. No significant interaction with apixaban dose was found with respect to treatment effect on major outcomes. The benefits of apixaban vs. warfarin were consistent in patients with AF regardless of age. Owing to the higher risk at older age, the absolute benefits of apixaban were greater in the elderly. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial

PubMed Central

Halvorsen, Sigrun; Atar, Dan; Yang, Hongqiu; De Caterina, Raffaele; Erol, Cetin; Garcia, David; Granger, Christopher B.; Hanna, Michael; Held, Claes; Husted, Steen; Hylek, Elaine M.; Jansky, Petr; Lopes, Renato D.; Ruzyllo, Witold; Thomas, Laine; Wallentin, Lars

2014-01-01

Aims The risk of stroke in patients with atrial fibrillation (AF) increases with age. In the ARISTOTLE trial, apixaban when compared with warfarin reduced the rate of stroke, death, and bleeding. We evaluated these outcomes in relation to patient age. Methods and results A total of 18 201 patients with AF and a raised risk of stroke were randomized to warfarin or apixaban 5 mg b.d. with dose reduction to 2.5 mg b.d. or placebo in 831 patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, or creatinine ≥133 μmol/L. We used Cox models to compare outcomes in relation to patient age during 1.8 years median follow-up. Of the trial population, 30% were <65 years, 39% were 65 to <75, and 31% were ≥75 years. The rates of stroke, all-cause death, and major bleeding were higher in the older age groups (P < 0.001 for all). Apixaban was more effective than warfarin in preventing stroke and reducing mortality across all age groups, and associated with less major bleeding, less total bleeding, and less intracranial haemorrhage regardless of age (P interaction >0.11 for all). Results were also consistent for the 13% of patients ≥80 years. No significant interaction with apixaban dose was found with respect to treatment effect on major outcomes. Conclusion The benefits of apixaban vs. warfarin were consistent in patients with AF regardless of age. Owing to the higher risk at older age, the absolute benefits of apixaban were greater in the elderly. PMID:24561548

Alveolar hemorrhage associated with warfarin therapy: a case report and literature review.

PubMed

Erdogan, Dogan; Kocaman, Orhan; Oflaz, Huseyin; Goren, Taner

2004-04-01

A 75-year-old man was admitted to our clinic with the complaints of palpitation, fever, severe dyspnea, dizziness and bloody sputum associated with coughing. Chest radiographs revealed that the lungs were bilaterally infiltrated. A high resolution computed tomographic study of the thorax disclosed diffuse alveolar hemorrhage, of which presence was proved by histopathological study of bronchoalveolar lavage material. The hemorrhage occured at 8th day of 5 mg daily warfarin therapy, which was given for frequent atrial fibrillation attacks was controlled by fresh frozen plasma and vitamin K. Alveolar hemorrhage is difficult to diagnose and has high mortality if the treatment was not started as soon as possible. This is the first report of alveolar hemorrhage caused by 5 mg daily warfarin therapy. We propose that the patient's age, nutritional status, used drugs should be taken into consideration for true management of patients with atrial fibrillation.

A Pharmacogenetics-Based Warfarin Maintenance Dosing Algorithm from Northern Chinese Patients

PubMed Central

Luo, Fang; Wang, Jin'e; Shi, Yi; Tan, Yu; Chen, Qianlong; Zhang, Yu; Hui, Rutai; Wang, Yibo

2014-01-01

Inconsistent associations with warfarin dose were observed in genetic variants except VKORC1 haplotype and CYP2C9*3 in Chinese people, and few studies on warfarin dose algorithm was performed in a large Chinese Han population lived in Northern China. Of 787 consenting patients with heart-valve replacements who were receiving long-term warfarin maintenance therapy, 20 related Single nucleotide polymorphisms were genotyped. Only VKORC1 and CYP2C9 SNPs were observed to be significantly associated with warfarin dose. In the derivation cohort (n = 551), warfarin dose variability was influenced, in decreasing order, by VKORC1 rs7294 (27.3%), CYP2C9*3(7.0%), body surface area(4.2%), age(2.7%), target INR(1.4%), CYP4F2 rs2108622 (0.7%), amiodarone use(0.6%), diabetes mellitus(0.6%), and digoxin use(0.5%), which account for 45.1% of the warfarin dose variability. In the validation cohort (n = 236), the actual maintenance dose was significantly correlated with predicted dose (r = 0.609, P<0.001). Our algorithm could improve the personalized management of warfarin use in Northern Chinese patients. PMID:25126975

Educational Placement After Pediatric Intracerebral Hemorrhage.

PubMed

Hawks, Charlotte; Jordan, Lori C; Gindville, Melissa; Ichord, Rebecca N; Licht, Daniel J; Beslow, Lauren A

2016-08-01

This study describes educational placement of school-aged children after spontaneous intracerebral hemorrhage and examines whether educational placement is associated with severity of neurological deficits. Children with spontaneous intracerebral hemorrhage presenting from 2007 to 2013 were prospectively enrolled at three tertiary children's hospitals. The Pediatric Stroke Outcome Measure and parental interview gathered information about neurological outcome, school attendance, and educational placement. The cohort of 92 enrolled children included 42 school-aged children (6 to 17 years) with intracerebral hemorrhage. Four children died; one was excluded because of preexisting cognitive deficits. Thirty-seven children completed three-month follow-up, and 30 completed 12-month follow-up. At 12 months, 14 children (46.7%) received regular age-appropriate programming, 12 (40%) attended school with in-class services, three (10%) were in special education programs, and one child (3.3%) received home-based services because of intracerebral hemorrhage-related deficits. Of 30 children with three- and 12-month follow-up, 14 (46.7%) improved their education status, 13 (43.3%) remained at the same education level, and three (10%) began to receive in-class services. An increasing Pediatric Stroke Outcome Measure score predicted the need for educational modifications at three months (odds ratio, 3.3; 95% confidence interval, 1.4 to 7.9; P = 0.007) and at 12 months (odds ratio, 2.1; 95% confidence interval, 1.1 to 3.9; P = 0.025). Most children returned to school within a year after intracerebral hemorrhage, and many had a reduction in the intensity of educational support. However, a great need for educational services persisted at 12 months after intracerebral hemorrhage with fewer than half enrolled in regular age-appropriate classes. Worse deficits on the Pediatric Stroke Outcome Measure were associated with remedial educational placement. Copyright © 2016 Elsevier

Influence of Sampling on the Determination of Warfarin and Warfarin Alcohols in Oral Fluid

PubMed Central

Lomonaco, Tommaso; Ghimenti, Silvia; Piga, Isabella; Biagini, Denise; Onor, Massimo; Fuoco, Roger; Di Francesco, Fabio

2014-01-01

Background and Objective The determination of warfarin, RS/SR- and RR/SS-warfarin alcohols in oral fluid may offer additional information to the INR assay. This study aimed to establish an optimized sampling technique providing the best correlation between the oral fluid and the unbound plasma concentrations of these compounds. Materials and Methods Samples of non-stimulated and stimulated oral fluid, and blood were collected from 14 patients undergoing warfarin therapy. After acidification, analytes were extracted with a dichloromethane/hexane mixture and determined by HPLC with fluorescence detection. Plasma samples were also ultrafiltered for the determination of the unbound fraction. The chromatographic separation was carried out in isocratic conditions with a phosphate buffer/methanol mobile phase on a C-18 reversed-phase column. The absence of interfering compounds was verified by HPLC-ESI-Q-TOF. Results Stimulation generally increased the oral fluid pH to values close to blood pH in about 6 minutes. The concentration of warfarin and RS/SR-warfarin alcohols in oral fluid followed the same trend, whereas the concentration of RR/SS-warfarin alcohols was not affected. Six minute stimulation with chewing gum followed by collection with a polyester swab was the best sampling procedure, with a good repeatability (RSD <10%) and relatively low inter-subject variability (RSD  = 30%) of the oral fluid to plasma ratio. This procedure provided strong correlations between the measured oral fluid and unbound plasma concentration of warfarin (r  =  0.92, p <0.001) and RS/SR-warfarin alcohols (r  =  0.84, p <0.001), as well as between stimulated oral fluid and total plasma concentration of warfarin (r  =  0.78, p <0.001) and RS/SR-warfarin alcohols (r  =  0.81, p <0.001). Conclusion The very good correlation between oral fluid and unbound plasma concentration of warfarin and RS/SR-warfarin alcohols suggests that oral fluid analysis could provide

Inappropriate combination of warfarin and aspirin

PubMed Central

Turan, Burak; Demir, Hakan; Mutlu, Ayhan; Daşlı, Tolga; Erkol, Ayhan; Erden, İsmail

2016-01-01

Objective: A combination of warfarin and aspirin is associated with increased bleeding compared with warfarin monotherapy. The aim of the study was to investigate the incidence and appropriateness of the combination of warfarin and aspirin in patients with atrial fibrillation (AF) or mechanical heart valve (MHV). Methods: This cross-sectional study included consecutive patients with AF or MHV on chronic warfarin therapy (>3 months) without acute coronary syndrome or have not undergone a revascularization procedure in the preceding year. Medical history, concomitant diseases, and treatment data were acquired through patient interviews and from hospital records. Results: Three hundred and sixty patients (213 with AF, 147 with MHV) were included. In those with AF, a significantly higher warfarin-aspirin combination was observed with concomitant vascular disease (38.8% vs. 14.6%), diabetes (36.6% vs. 16.3%), statin therapy (40% vs. 16.9%), left ventricular systolic dysfunction (33.3% vs. 17.5%) (p<0.05 for all). The use of combination therapy was similar between different CHADS-VASc scores. In patients with MHV, higher combination therapy was observed in males (41% vs. 26.7% in females; p=0.070), concomitant vascular disease (47.8% vs. 29.8%; p=0.091), and AF (56.3% vs. 29.8%; p=0.033). Independent predictors of warfarin-aspirin combination were concomitant vascular disease, diabetes, and (younger) age in patients with AF and were concomitant AF and male sex in patients with MHV. Interestingly, the incidence of combination therapy was found to increase with a higher HAS-BLED score in both patients with AF and MHV (p<0.001). Conclusion: The combination of warfarin and aspirin was found to be prescribed to patients with AF mainly for the prevention of cardiovascular events, for which warfarin monotherapy usually suffices. On the other hand, co-treatment with aspirin appeared to be underused in patients with MHV. (Anatol J Cardiol 2016; 16: 189-96) PMID:26467380

Topical Antimycotics for Oral Candidiasis in Warfarin Users.

PubMed

Hellfritzsch, Maja; Pottegård, Anton; Pedersen, Andreas James Thestrup; Burghle, Alaa; Mouaanaki, Fatima; Hallas, Jesper; Grove, Erik Lerkevang; Damkier, Per

2017-04-01

Treatment for oral candidiasis in warfarin users may be complicated by drug-drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross-over study with the objective to evaluate the potential DDIs between warfarin and miconazole oral gel or nystatin oral solution. The cohort consisted of individuals using warfarin in the period of 1998-2012 (n ≈ 7400). We collected data on cohort members' measurements of the international normalized ratio (INR) from a clinical database, and obtained information on their use of topically applied miconazole and nystatin from a regional prescription register. Potential DDIs were assessed by comparing INR values before and after initiation of an antimycotic drug. Among 17 warfarin users exposed to miconazole oral gel, the mean INR increased from 2.5 (95% CI: 2.1-2.8) to 3.8 (95% CI: 2.8-4.8) after exposure, corresponding to a mean INR increase of 1.4 (95% CI: 0.3-2.4). Among 30 warfarin users exposed to nystatin oral solution, the mean INR was 2.7 (95% CI: 2.3-3.1) before and 2.5 (95% CI: 2.2-2.9) after exposure. In conclusion, we found evidence supporting a clinically relevant drug-drug interaction between warfarin and miconazole oral gel. In contrast, we did not find any indication of an interaction between warfarin and nystatin oral solution. Nystatin rather than miconazole should be preferred when treating warfarin users for oral candidiasis. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Azathioprine-Induced Warfarin Resistance

PubMed Central

Vazquez, Sara R; Rondina, Matthew T; Pendleton, Robert C

2011-01-01

OBJECTIVE To describe a case of azathioprine-induced warfarin resistance, present a literature review on warfarin–azathioprine interactions, and provide recommendations on appropriate management of this clinically significant interaction. CASE SUMMARY A 29-year-old female with Cogan’s syndrome experienced thrombosis of the left internal carotid artery. She was treated with an average weekly warfarin dose of 39 mg (5.5 mg daily) prior to beginning azathioprine therapy. Three weeks following initiation of azathioprine 150 mg daily, the international normalized ratio (INR) decreased from 1.9 (prior to the medication change) to 1.0 without any change in the warfarin dose or other relevant factors. Over several weeks, the patient’s warfarin dose was titrated up to 112 mg weekly (16 mg daily) to achieve an INR of 2.5 (a 188%, or 2.9-fold dose increase). Because of elevated liver enzyme levels, the azathioprine dosage was decreased to 100 mg daily. Within 2 weeks following that decrease, warfarin requirements decreased to 105 mg weekly (15 mg daily). DISCUSSION Azathioprine was the probable causative agent of warfarin resistance according to the Naranjo probability scale, and a possible causative agent according to the Drug Interaction Probability Scale. A literature search (PubMed, 1966–December 2007) revealed 8 case reports of this drug interaction and 2 cases involving a similar effect with 6-mercaptopurine, the active metabolite of azathioprine. The exact mechanism of the interaction remains unknown. Previously published case reports point to a rapid onset and offset of the warfarin–azathioprine interaction and a dose-dependent increase of at least 2.5-fold in warfarin dose requirement with the initiation of azathioprine 75–200 mg daily. CONCLUSIONS This case report and several others point toward azathioprine as a clinically significant inducer of warfarin resistance. Providers should anticipate the need for higher warfarin doses, warfarin dose adjustment

[The current role of warfarin].

PubMed

Michalcová, Jana; Buliková, Alena; Zavřelová, Jiřina; Prudková, Marie; Penka, Miroslav

Well-managed warfarin therapy remains an important method of anticoagulation in the 21st century, despite the introduction of new antithrombotics into the clinical practice. The main advantages of warfarin are decades of treatment experience, the possibility to monitor its anticoagulant effect using the INR and the last, but not least, the low cost. Currently, approximately 75 % of anticoagulated patients in the Czech Republic are treated with warfarin and warfarin remains the only option for oral anticoagulant therapy in certain clinical conditions (particularly in patients with valvular atrial fibrillation or mechanical heart valves). For physicians across specialties it is still indispensable to master the basics of safe and effective warfarin therapy, including the management of treatment complications.Key words: anticoagulant therapy - INR - thrombosis - warfarin.

Validation of clinical testing for warfarin sensitivity: comparison of CYP2C9-VKORC1 genotyping assays and warfarin-dosing algorithms.

PubMed

Langley, Michael R; Booker, Jessica K; Evans, James P; McLeod, Howard L; Weck, Karen E

2009-05-01

Responses to warfarin (Coumadin) anticoagulation therapy are affected by genetic variability in both the CYP2C9 and VKORC1 genes. Validation of pharmacogenetic testing for warfarin responses includes demonstration of analytical validity of testing platforms and of the clinical validity of testing. We compared four platforms for determining the relevant single nucleotide polymorphisms (SNPs) in both CYP2C9 and VKORC1 that are associated with warfarin sensitivity (Third Wave Invader Plus, ParagonDx/Cepheid Smart Cycler, Idaho Technology LightCycler, and AutoGenomics Infiniti). Each method was examined for accuracy, cost, and turnaround time. All genotyping methods demonstrated greater than 95% accuracy for identifying the relevant SNPs (CYP2C9 *2 and *3; VKORC1 -1639 or 1173). The ParagonDx and Idaho Technology assays had the shortest turnaround and hands-on times. The Third Wave assay was readily scalable to higher test volumes but had the longest hands-on time. The AutoGenomics assay interrogated the largest number of SNPs but had the longest turnaround time. Four published warfarin-dosing algorithms (Washington University, UCSF, Louisville, and Newcastle) were compared for accuracy for predicting warfarin dose in a retrospective analysis of a local patient population on long-term, stable warfarin therapy. The predicted doses from both the Washington University and UCSF algorithms demonstrated the best correlation with actual warfarin doses.

Vitamin K for improved anticoagulation control in patients receiving warfarin.

PubMed

Mahtani, Kamal R; Heneghan, Carl J; Nunan, David; Roberts, Nia W

2014-05-15

range. Only one study (70 participants) reported the mean time in therapeutic range as a percentage. This study found that in the group of participants deemed to have poor INR control, the addition of 150 micrograms (mcg) oral vitamin K significantly improved anticoagulation control in those with unexplained instability of response to warfarin. The second study (30 participants) reported the effect of 175 mcg oral vitamin K versus placebo on participants with high variability in their INR levels. The study concluded that vitamin K supplementation did not significantly improve the stability of anticoagulation for participants on chronic anticoagulation therapy. However, the study was only available in abstract form, and communication with the lead author confirmed that there were no further publications. Therefore, we interpreted this conclusion with caution. Neither study reported any thromboembolic events, haemorrhage, or death from the addition of vitamin K supplementation. Two included studies in this review compared whether the addition of a low dose (150 to 175 mcg) of vitamin K given to participants with a high-variability response to warfarin improved their INR control. One study demonstrated a significant improvement, while another smaller study (published in abstract only) suggested no overall benefit. Currently, there are insufficient data to suggest an overall benefit. Larger, higher quality trials are needed to examine if low-dose vitamin K improves INR control in those starting or already taking warfarin.

Acute management of stroke patients taking non-vitamin K antagonist oral anticoagulants Addressing Real-world Anticoagulant Management Issues in Stroke (ARAMIS) Registry: Design and rationale.

PubMed

Xian, Ying; Hernandez, Adrian F; Harding, Tina; Fonarow, Gregg C; Bhatt, Deepak L; Suter, Robert E; Khan, Yosef; Schwamm, Lee H; Peterson, Eric D

2016-12-01

Non-vitamin K antagonist oral anticoagulants (NOACs, dabigatran, rivaroxaban, apixaban, and edoxaban) have been increasingly used as alternatives to warfarin for stroke prophylaxis in patients with atrial fibrillation. Yet there is substantial lack of information on how patients on NOACs are currently treated when they have an acute ischemic stroke and the best strategies for treating intracerebral hemorrhage for those on chronic anticoagulation with warfarin or a NOAC. These are critical unmet needs for real world clinical decision making in these emergent patients. The ARAMIS Registry is a multicenter cohort study of acute stroke patients who were taking chronic anticoagulation therapy prior to admission and are admitted with either an acute ischemic stroke or intracerebral hemorrhage. Built upon the existing infrastructure of American Heart Association/American Stroke Association Get With the Guidelines Stroke, the ARAMIS Registry will enroll a total of approximately 10,000 patients (5000 with acute ischemic stroke who are taking a NOAC and 5000 with anticoagulation-related intracerebral hemorrhage who are on warfarin or a NOAC). The primary goals of the ARAMIS Registry are to provide a comprehensive picture of current treatment patterns and outcomes of acute ischemic stroke patients on NOACs, as well as anticoagulation-related intracerebral hemorrhage in patients on either warfarin or NOACs. Beyond characterizing the index hospitalization, up to 2500 patients (1250 ischemic stroke and 1250 intracerebral hemorrhage) who survive to discharge will be enrolled in an optional follow-up sub-study and interviewed at 3 and 6 months after discharge to assess longitudinal medication use, downstream care, functional status, and patient-reported outcomes. The ARAMIS Registry will document the current state of management of NOAC treated patients with acute ischemic stroke as well as contemporary care and outcome of anticoagulation-related intracerebral hemorrhage. These

Gastrointestinal bleeding and intracranial hemorrhage in concomitant users of warfarin and antihyperlipidemics.

PubMed

Leonard, Charles E; Brensinger, Colleen M; Bilker, Warren B; Kimmel, Stephen E; Han, Xu; Nam, Young Hee; Gagne, Joshua J; Mangaali, Margaret J; Hennessy, Sean

2017-02-01

Drug interactions, particularly those involving warfarin, are a major clinical and public health problem. Minimizing serious bleeding caused by anticoagulants is a recent major focus of the United States (US) Department of Health and Human Services. This study quantified the risk of gastrointestinal bleeding (GIB) and intracranial hemorrhage (ICH) among concomitant users of warfarin and individual antihyperlipidemics. The authors conducted a high-dimensional propensity score-adjusted cohort study of new concomitant users of warfarin and an antihyperlipidemic, among US Medicaid beneficiaries from five states during 1999-2011. Exposure was defined by concomitant use of warfarin plus one of eight antihyperlipidemics. The primary outcome measure was a composite of GIB/ICH within the first 30days of concomitant use. As a secondary outcome measure, GIB/ICH was examined within the first 180days of concomitant use. Among 236,691 persons newly-exposed to warfarin and an antihyperlipidemic, the crude incidence of GIB/ICH was 13.2 (95% confidence interval 12.7 to 13.8) per 100person-years. Users were predominantly older, female, and Caucasian. Adjusted hazard ratios (aHRs) for warfarin and individual statins were consistent with no association. Warfarin+gemfibrozil was associated with an 80% increased risk of GIB/ICH within the first month of concomitant use (aHR=1.8, 1.4 to 2.4). Warfarin+fenofibrate was associated with a similar increased risk (aHR=1.8, 1.2 to 2.7), yet with an onset during the second month of concomitant use. Among warfarin-treated persons, the use of fibrates-but not statins-increases the risk of hospital presentation for GIB/ICH. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

One-year adherence to warfarin treatment for venous thromboembolism in high-risk patients and its association with long-term risk of recurrent events.

PubMed

Chen, Shih-Yin; Wu, Ning; Gulseth, Michael; LaMori, Joyce; Bookhart, Brahim K; Boulanger, Luke; Fields, Larry; Schein, Jeff

2013-05-01

Warfarin is the predominant oral anticoagulant used for the prevention of recurrent venous thromboembolism (VTE) events. However, its long-term use is complicated by the need to manage the drug within a narrow therapeutic range and by possible food and drug interactions. To examine the association between 1-year adherence, measured through compliance with and persistence on warfarin treatment for VTE, and long-term risk of recurrent events among patients at high risk. Medical and pharmacy claims for patients with commercial or Medicare supplemental insurance in the Thomson Reuters MarketScan database were analyzed. Adult patients with medical claims with an associated VTE diagnosis between January 1, 2006, and March 31, 2008, were identified. The index date was defined as the date of the first observed VTE claim or the date of discharge if the index event was a hospital stay. High-risk patients (patients with cancer, or noncancer patients who did not have reversible risk factors during the 3-month period prior to the index date) who filled a warfarin prescription within 2 weeks of the index date were included. Persistence was evaluated in terms of discontinuation, defined as a 90-day gap in warfarin supply during a 1-year assessment period following the index date. Compliance was measured by the proportion of days covered (PDC) over the 1-year assessment period, with PDC less than 0.8 defined as noncompliance. Recurrent VTE events were identified as hospitalizations where VTE was the primary diagnosis after the 1-year assessment period and until patients were lost to follow-up. The association between adherence to warfarin therapy and VTE recurrence was evaluated descriptively via Kaplan-Meier curves and a Cox proportional hazards model, adjusted for patient demographic and clinical characteristics. A similar analysis using the medication possession ratio (MPR) as a measure of compliance was also performed in a subset of patients who had filled at least 2 warfarin

Dabigatran versus warfarin in patients with atrial fibrillation.

PubMed

Connolly, Stuart J; Ezekowitz, Michael D; Yusuf, Salim; Eikelboom, John; Oldgren, Jonas; Parekh, Amit; Pogue, Janice; Reilly, Paul A; Themeles, Ellison; Varrone, Jeanne; Wang, Susan; Alings, Marco; Xavier, Denis; Zhu, Jun; Diaz, Rafael; Lewis, Basil S; Darius, Harald; Diener, Hans-Christoph; Joyner, Campbell D; Wallentin, Lars

2009-09-17

Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number

Prescribing Warfarin Appropriately to Meet Patient Safety Goals

PubMed Central

Dharmarajan, Lekshmi; Dharmarajan, T.S.

2008-01-01

The anticoagulant warfarin is increasingly used in a variety of disorders associated with risk of thromboembolism. The drug is undoubtedly effective but is linked to numerous nutrient, disease, and drug interactions; safe use of warfarin therefore necessitates close patient monitoring, using the international normalized ratio. The predominant adverse effect is bleeding, and individuals respond to warfarin in different ways. Both high and subtherapeutic international normalized ratios warrant attention, whereas a high international normalized ratio, with or without bleeding, mandates prompt patient evaluation. The 2008 National Patient Safety Goals require medical institutions to develop processes to ensure the safe use and monitoring of anticoagulant use. Last August, the US Food and Drug Administration revised the prescribing information for warfarin to include genetic testing before initiating therapy, although this is still not covered by most health plans. PMID:25126243

Response to warfarin and other oral anticoagulants: effects of disease states.

PubMed

Demirkan, K; Stephens, M A; Newman, K P; Self, T H

2000-05-01

Warfarin is associated with numerous drug and food interactions, and much attention has been appropriately focused on this subject. Because several disease states may also affect response to oral anticoagulants, we present a summary of the literature. We searched MEDLINE for original articles on the effect of disease states on response to warfarin. Liver disease and thyroid dysfunction are well-documented as affecting warfarin response. Further study is needed to establish whether febrile illness, congestive heart failure, and other disease states enhance the effect of warfarin in some patients. Careful monitoring of anticoagulant therapy in patients with diseases that have the potential to affect warfarin response could increase safety and efficacy of this important agent.

Predictors of intracerebral hemorrhage severity and its outcome in Japanese stroke patients.

PubMed

Hosomi, Naohisa; Naya, Takayuki; Ohkita, Hiroyuki; Mukai, Mao; Nakamura, Takehiro; Ueno, Masaki; Dobashi, Hiroaki; Murao, Koji; Masugata, Hisashi; Miki, Takanori; Kohno, Masakazu; Kobayashi, Shotai; Koziol, James A

2009-01-01

The aim of this investigation was to determine the factors influencing acute intracerebral hemorrhage severity on admission and clinical outcomes at discharge. Sixty acute stroke hospitals throughout Japan participated in the Japan Standard Stroke Registry Study (JSSRS), documenting the in-hospital course of 16,630 consecutive patients with acute stroke from January 2001 to March 2004. We identified 2,840 adult patients from the JSSRS who had intracerebral hemorrhage. Intracerebral hemorrhage severity on admission was strongly related to age, previous stroke history, and hemorrhage size in a monotone fashion [chi(2)(9) = 374.5, p < 0.0001]. Drinking history was also predictive of intracerebral hemorrhage severity on admission, but the association was not monotone. Interestingly, intracerebral hemorrhage severity on admission was increased in nondrinking and heavy drinking compared to mild drinking (p < 0.05). Unsuccessful outcome (modified Rankin scale score = 3-6) was related to age, previous stroke history, hemorrhage size, and intracerebral hemorrhage severity on admission [chi(2)(9) = 830.4, p < 0.0001]. Mortality was related to hemorrhage size, intraventricular hemorrhage, intracerebral hemorrhage severity on admission, and surgical operation [chi(2)(7) = 540.4, p < 0.0001]. We could find four varied factors associated with intracerebral hemorrhage severity and its outcomes. Interestingly, intracerebral hemorrhage severity tended to be greater in nondrinking and heavy drinking than mild drinking. Additionally, surgical operation decreased intracerebral hemorrhage mortality. Copyright 2008 S. Karger AG, Basel.

Warfarin resistance associated with genetic polymorphism of VKORC1: linking clinical response to molecular mechanism using computational modeling.

PubMed

Lewis, Benjamin C; Nair, Pramod C; Heran, Subash S; Somogyi, Andrew A; Bowden, Jeffrey J; Doogue, Matthew P; Miners, John O

2016-01-01

The variable response to warfarin treatment often has a genetic basis. A protein homology model of human vitamin K epoxide reductase, subunit 1 (VKORC1), was generated to elucidate the mechanism of warfarin resistance observed in a patient with the Val66Met mutation. The VKORC1 homology model comprises four transmembrane (TM) helical domains and a half helical lid domain. Cys132 and Cys135, located in the N-terminal end of TM-4, are linked through a disulfide bond. Two distinct binding sites for warfarin were identified. Site-1, which binds vitamin K epoxide (KO) in a catalytically favorable orientation, shows higher affinity for S-warfarin compared with R-warfarin. Site-2, positioned in the domain occupied by the hydrophobic tail of KO, binds both warfarin enantiomers with similar affinity. Displacement of Arg37 occurs in the Val66Met mutant, blocking access of warfarin (but not KO) to Site-1, consistent with clinical observation of warfarin resistance.

Factor VII R353Q genetic polymorphism is associated with altered warfarin sensitivity among CYP2C9 *1/*1 carriers.

PubMed

Mlynarsky, Liat; Bejarano-Achache, Idit; Muszkat, Mordechai; Caraco, Yoseph

2012-05-01

Warfarin responsiveness is characterized by marked interindividual variability. A major portion of this variability is attributed to CYP2C9 and VKORC1 polymorphisms, but almost 50% is still unaccounted for. This paper reports the first prospective study on the association between factor VII R353Q polymorphism and warfarin responsiveness during induction. Genotyping for factor VII R353Q and 323D/I polymorphisms was performed in a cohort consisting of 374 patients (198 CYP2C9*1/*1) treated with warfarin who were prospectively followed from warfarin initiation. Compared with *1/*1-R/R and *1/*1-R/Q genotype carriers, *1/*1-Q/Q homozygotes achieved higher International Normalized Ratio (INR) values while consuming lower warfarin doses. The greater sensitivity was illustrated by 82.1% higher Warfarin Sensitivity Index During Induction (WSIDI) (0.14 ± 0.11 vs. 0.08 ± 0.50 mg⁻¹ Mann-Whitney, P = 0.043). Multiple regression analysis consisting of both genetic and nongenetic factors explained 26% of WSIDI variability, with R353Q genetic polymorphism having a modest yet significant effect and accounting for 1.7% of the overall variability. Moreover, the incidence of overanticoagulation (i.e., INR > 4) was 6.94-fold higher among *1/*1-Q/Q vs. *1/*1-R/R&R/Q carriers during warfarin induction (Pearson chi-square, P = 0.005). These findings were not accounted for by a chance difference in the distribution of VKORC1 genotypes. Analysis of these parameters among the entire cohort, including CYP2C9*2 and CYP2C9*3 variant allele carriers, did not reach statistical significance. Warfarin responsiveness during induction was unrelated to factor VII 323D/I genetic polymorphism. The response to warfarin during induction is influenced by factor VII R353Q polymorphism. The prospective use of this polymorphism, along with CYP2C9 and VKORC1, may enhance the accuracy of warfarin loading. However, the impact of R353Q polymorphism on overall warfarin response is subtle, and it is therefore

Risk of stroke/systemic embolism, major bleeding and associated costs in non-valvular atrial fibrillation patients who initiated apixaban, dabigatran or rivaroxaban compared with warfarin in the United States Medicare population.

PubMed

Amin, Alpesh; Keshishian, Allison; Trocio, Jeffrey; Dina, Oluwaseyi; Le, Hannah; Rosenblatt, Lisa; Liu, Xianchen; Mardekian, Jack; Zhang, Qisu; Baser, Onur; Vo, Lien

2017-09-01

To compare the risk and cost of stroke/systemic embolism (SE) and major bleeding between each direct oral anticoagulant (DOAC) and warfarin among non-valvular atrial fibrillation (NVAF) patients. Patients (≥65 years) initiating warfarin or DOACs (apixaban, rivaroxaban, and dabigatran) were selected from the Medicare database from 1 January 2013 to 31 December 2014. Patients initiating each DOAC were matched 1:1 to warfarin patients using propensity score matching to balance demographics and clinical characteristics. Cox proportional hazards models were used to estimate the risks of stroke/SE and major bleeding of each DOAC vs. warfarin. Two-part models were used to compare the stroke/SE- and major-bleeding-related medical costs between matched cohorts. Of the 186,132 eligible patients, 20,803 apixaban-warfarin pairs, 52,476 rivaroxaban-warfarin pairs, and 16,731 dabigatran-warfarin pairs were matched. Apixaban (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.31, 0.53) and rivaroxaban (HR = 0.72; 95% CI 0.63, 0.83) were significantly associated with lower risk of stroke/SE compared to warfarin. Apixaban (HR = 0.51; 95% CI 0.44, 0.58) and dabigatran (HR = 0.79; 95% CI 0.69, 0.91) were significantly associated with lower risk of major bleeding; rivaroxaban (HR = 1.17; 95% CI 1.10, 1.26) was significantly associated with higher risk of major bleeding compared to warfarin. Compared to warfarin, apixaban ($63 vs. $131) and rivaroxaban ($93 vs. $139) had significantly lower stroke/SE-related medical costs; apixaban ($292 vs. $529) and dabigatran ($369 vs. $450) had significantly lower major bleeding-related medical costs. Among the DOACs in the study, only apixaban is associated with a significantly lower risk of stroke/SE and major bleeding and lower related medical costs compared to warfarin.

Heparin Induced Thrombocytopenia and Re-Thrombosis Associated with Warfarin and Fondaparinux in a Child

PubMed Central

Maurer, Scott H.; Wilimas, Judith A.; Wang, Winfred C.; Reiss, Ulrike M.

2016-01-01

An 11 year-old female developed heparin induced thrombocytopenia (HIT) with thrombosis during therapy for lower extremity deep vein thrombosis and pulmonary embolism. Transition from bivalirudin, a direct thrombin inhibitor (DTI), to warfarin resulted in extensive re-thrombosis, and fondaparinux therapy similarly failed. She was then treated with argatroban, and transitioned successfully to warfarin after nine weeks. The risk of re-thrombosis was ultimately reduced by allowing time for the thrombogenic potential to abate. The argatroban/warfarin transition was monitored with chromogenic factor X levels. This case highlights several difficult problems in pediatric thrombosis. PMID:19415734

Warfarin Use in Hemodialysis Patients With Atrial Fibrillation: A Systematic Review of Stroke and Bleeding Outcomes

PubMed Central

Tsai, Chieh; Marcus, Laura Quinn; Patel, Priya; Battistella, Marisa

2017-01-01

Background: Given the lack of clear indications for the use of warfarin in the treatment of atrial fibrillation (AF) in patients on hemodialysis and the potential risks that accompany warfarin use in these patients, we systematically reviewed stroke and bleeding outcomes in hemodialysis patients treated with warfarin for AF. Objective: To systematically review the stroke and bleeding outcomes associated with warfarin use in the hemodialysis population to treat AF. Design: Systematic review. Setting: All adult hemodialysis patients. Patients: Patients on hemodialysis receiving warfarin for the management of AF. Measurements: Any type of stroke and/or bleeding outcomes. Methods: MEDLINE(R) In-Process & Other Non-Indexed Citations and MEDLINE(R) via OVID (1946 to January 11, 2017), and EMBASE via OVID (1974 to January 11, 2017) were searched for relevant literature. Inclusion criteria were randomized controlled trials, observational studies, and case series in English that examined stroke and bleeding outcomes in adult population of patients (over 18 years old) who are on hemodialysis and taking warfarin for AF. Studies with less than 10 subjects, case reports, review articles, and editorials were excluded. Quality of selected articles was assessed using Newcastle-Ottawa Scale (NOS). Results: Of the 2340 titles and abstracts screened, 7 met the inclusion criteria. Two studies showed an association between warfarin use and an increased risk of stroke (Hazard Ratio: 1.93-3.36) but no association with an increased risk of bleed (HR: 0.85-1.04), while 4 studies showed no association between warfarin and stroke outcomes (HR: 0.12-1.17) but identified an association between warfarin and increased bleeding outcome (HR: 1.41-3.96). And 1 study reported neither beneficial nor harmful effects associated with warfarin use. Limitations: The major limitation to this review is that the 7 included studies were observational cohort studies, and thus the outcome measures were not

Leptospirosis pulmonary haemorrhage syndrome is associated with linear deposition of immunoglobulin and complement on the alveolar surface.

PubMed

Croda, J; Neto, A N D; Brasil, R A; Pagliari, C; Nicodemo, A C; Duarte, M I S

2010-06-01

Leptospirosis is a zoonotic infection associated with severe diseases such as leptospirosis pulmonary haemorrhage syndrome (LPHS). The cause of pulmonary haemorrhage is unclear. Understanding which mechanisms and processes are involved in LPHS will be important in treatment regimens under development for this life-threatening syndrome. In the present study, we evaluated 30 lung specimens from LPHS patients and seven controls using histology and immunohistochemistry (detection of IgM, IgG, IgA and C3) in order to describe the pathological features associated with this syndrome. Immunoglobulin deposits were detected on the alveolar surface in 18/30 LPHS patients. Three staining patterns were observed for the immunoglobulins and C3 in the lung tissues of LPHS patients: AS, delicate linear staining adjacent to the alveolar surface, which was indicative of a membrane covering the luminal surface of type I and II pneumocyte cells; S, heterogeneous staining which was sporadically distributed along the alveolar septum; and IA, weak, focal intra-alveolar granular staining. Human LPHS is associated with individual and unique histological patterns that differ from those of other causes of pulmonary haemorrhage. In the present study, it was found that the linear deposition of immunoglobulins (IgA, IgG and IgM) and complement on the alveolar surface may play a role in the pathogenesis of pulmonary haemorrhage in human leptospirosis.

Outcomes associated with warfarin use in older patients with heart failure and atrial fibrillation and a cardiovascular implantable electronic device: findings from the ADHERE registry linked to Medicare claims.

PubMed

Hess, Paul L; Greiner, Melissa A; Fonarow, Gregg C; Klaskala, Winslow; Mills, Roger M; Setoguchi, Soko; Al-Khatib, Sana M; Hernandez, Adrian F; Curtis, Lesley H

2012-11-01

Warfarin use and associated outcomes in patients with heart failure and atrial fibrillation and a cardiovascular implantable electronic device have not been described previously. We hypothesized that warfarin is underused and is associated with lower risks of mortality, thromboembolic events, and myocardial infarction. Using data from a clinical registry linked with Medicare claims, we examined warfarin use at discharge and 30-day and 1-year Kaplan-Meier estimates of all-cause mortality and cumulative incidence rates of mortality, thromboembolic events, myocardial infarction, and bleeding events in patients 65 years or older, with a history of atrial fibrillation and a cardiovascular implantable electronic device admitted with heart failure between 2001 and 2006, who were naïve to anticoagulation therapy at admission. We compared outcomes between patients who were or were not prescribed warfarin at discharge and tested associations between treatment and outcomes. Of 2586 eligible patients in 252 hospitals, 2049 were discharged without a prescription for warfarin. At 1 year, the group discharged without warfarin had a higher mortality rate after discharge (37.4% vs 28.8%; P < 0.001) but similar rates of thromboembolism, myocardial infarction, and bleeding events. After adjustment, treatment with warfarin was associated with lower risk of all-cause death 1 year after discharge (hazard ratio: 0.76, 95% confidence interval: 0.63-0.92). Among older patients with heart failure and atrial fibrillation and a cardiovascular implantable electronic device, 4 of 5 were discharged without a prescription for warfarin. Warfarin nonuse was associated with a higher risk of death 1 year after discharge. Clin. Cardiol. 2011 DOI: 10.1002/clc.22064 Damon M. Seils, MA, Duke University, assisted with manuscript preparation. Mr. Seils did not receive compensation for his assistance apart from his employment at the institution where the study was conducted. This study was supported by a

Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions.

PubMed

Monaco, Luca; Biagi, Chiara; Conti, Valentino; Melis, Mauro; Donati, Monia; Venegoni, Mauro; Vaccheri, Alberto; Motola, Domenico

2017-07-01

Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase. Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P ≤ 0.05 were statistically significant. We retrieved 32 972 reports. We identified 204 ADRs with a ROR >1 (P ≤ 0.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47-1.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28-0.34)]. We identified other potential signals that have not been associated with DOACs previously. As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred. © 2017 The British Pharmacological Society.

R-warfarin clearances from plasma associated with polymorphic cytochrome P450 2C19 and simulated by individual physiologically based pharmacokinetic models for 11 cynomolgus monkeys.

PubMed

Utoh, Masahiro; Kusama, Takashi; Miura, Tomonori; Mitsui, Marina; Kawano, Mirai; Hirano, Takahiro; Shimizu, Makiko; Uno, Yasuhiro; Yamazaki, Hiroshi

2018-02-01

1. Cynomolgus monkey cytochrome P450 2C19 (formerly known as P450 2C75), homologous to human P450 2C19, has been identified as R-warfarin 7-hydroxylase. In this study, simulations of R-warfarin clearance in individual cynomolgus monkeys genotyped for P450 2C19 p.[(Phe100Asn; Ala103Val; Ile112Leu)] were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling. 2. Pharmacokinetic parameters and absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearances for individual PBPK models were estimated for eleven cynomolgus monkeys. 3. One-way ANOVA revealed significant effects of the genotype (p < 0.01) on the observed elimination half-lives and areas under the curves of R-warfarin among the homozygous mutant, heterozygous mutant, and wild-type groups. R-Warfarin clearances in individual cynomolgus monkeys genotyped for P450 2C19 were simulated by simplified PBPK modeling. The modeled hepatic intrinsic clearances were significantly associated with the P450 2C19 genotypes. The liver microsomal elimination rates of R-warfarin for individual animals after in vivo administration showed significant reductions associated with the genotype (p < 0.01). 4. This study provides important information to help simulate clearances of R-warfarin and related medicines associated with polymorphic P450 2C19 in individual cynomolgus monkeys, thereby facilitating calculation of the fraction of hepatic clearance.

Quality of Anticoagulation Control in Preventing Adverse Events in Heart Failure Patients in Sinus Rhythm: A Warfarin Aspirin Reduced Cardiac Ejection Fraction Trial (WARCEF) Substudy

PubMed Central

Homma, Shunichi; Thompson, John L.P.; Qian, Min; Ye, Siqin; Di Tullio, Marco R.; Lip, Gregory Y.H.; Mann, Douglas L.; Sacco, Ralph L.; Levin, Bruce; Pullicino, Patrick M.; Freudenberger, Ronald S.; Teerlink, John R.; Graham, Susan; Mohr, J.P.; Labovitz, Arthur J.; Buchsbaum, Richard; Estol, Conrado J.; Lok, Dirk J.; Ponikowski, Piotr; Anker, Stefan D.

2015-01-01

Background The aim of this study is to examine the relationship between time in therapeutic range (TTR) and clinical outcomes in heart failure (HF) patients in sinus rhythm (SR) treated with warfarin. Methods and Results We used data from the Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction Trial (WARCEF) to assess the relationship of TTR with the WARCEF primary outcome (ischemic stroke, intracerebral hemorrhage, or death); with death alone; ischemic stroke alone; major hemorrhage alone; and net clinical benefit (primary outcome and major hemorrhage combined). Multivariable Cox models were used to examine how the event risk changed with TTR and to compare the high TTR, low TTR, and aspirin patients, with TTR being treated as a time-dependent covariate. 2,217 patients were included in the analyses, among whom 1,067 were randomized to warfarin and 1,150 were randomized to aspirin. The median (IQR) follow-up duration was 3.6 (2.0–5.0) years. Mean (±SD) age was 61±11.3 years, with 80% being men. The mean (±SD) TTR was 57% (±28.5%). Increasing TTR was significantly associated with reduction in primary outcome (adjusted p<0.001), death alone (adjusted p=0.001), and improved net clinical benefit (adjusted p<0.001). A similar trend was observed for the other two outcomes but significance was not reached (adjusted p=0.082 for ischemic stroke, adjusted p=0.109 for major hemorrhage). Conclusions In HF patients in SR, increasing TTR is associated with better outcome and improved net clinical benefit. Patients in whom good quality anticoagulation can be achieved may benefit from the use of anticoagulants. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938. PMID:25850425

The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study

PubMed Central

Talarico, Anna; Fabbri, Matteo; Bertocco, Cesare; Vigliano, Marco; Moratelli, Stefano; Cuneo, Antonio; Serino, Maria Luisa; Avato, Francesco Maria

2016-01-01

Objectives Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3’-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis. Methods 133 OAT patients were recruited and assessed for warfarin/3’-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups Results In the whole OAT group both warfarin and 3’-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3’-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3’-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; p<0.0001). Interestingly, 3’-hydroxywarfarin reached a strong correlation at c4 respect to warfarin (r2 = 0.2157 and r2 = 0.0549; p = 0.0005 and p = 0.0944 respectively) seeming less affected by drug adjustments in the subgroup of 52 patients who started OAT. The multivariate analyses aimed at estimating the true contribution of 3’-hydroxywarfarin on INR value ascribed it the unique significant value (p = 0.0021) in spite of warfarin who lost association. The pharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and

The Active Metabolite of Warfarin (3'-Hydroxywarfarin) and Correlation with INR, Warfarin and Drug Weekly Dosage in Patients under Oral Anticoagulant Therapy: A Pharmacogenetics Study.

PubMed

Gemmati, Donato; Burini, Francesco; Talarico, Anna; Fabbri, Matteo; Bertocco, Cesare; Vigliano, Marco; Moratelli, Stefano; Cuneo, Antonio; Serino, Maria Luisa; Avato, Francesco Maria; Tisato, Veronica; Gaudio, Rosa Maria

2016-01-01

Warfarin oral anticoagulant therapy (OAT) requires regular and frequent drug adjustment monitored by INR. Interindividual variability, drug and diet interferences, and genetics (VKORC1 and CYP2C9) make the maintenance/reaching of stable INR a not so easy task. HPLC assessment of warfarin/enantiomers was suggested as a valid monitoring-tool along with INR, but definite results are still lacking. We evaluated possible correlations between INR, warfarin/3'-hydroxywarfarin, and drug weekly dosage aimed at searching novel alternatives to OAT monitoring. VKORC1/CYP2C9 pharmacogenetics investigation was performed to account for the known influence on warfarin homeostasis. 133 OAT patients were recruited and assessed for warfarin/3'-hydroxywarfarin serum levels (HPLC), INR, and VKORC1 and CYP2C9 genotypes. A subgroup of 52 patients were monitored in detail (5 consecutive controls; c0-c4) till the target INR was reached. Correlation analyses were performed in both groups. In the whole OAT group both warfarin and 3'-hydroxywarfarin correlate with INR at comparable degree (r2 = 0.0388 and 0.0362 respectively). Conversely, warfarin weekly dosage better correlates with warfarin than with 3'-hydroxywarfarin (r2 = 0.0975 and r2 = 0.0381 respectively), but considering together warfarin plus 3'-hydroxywarfarin the correlation strongly increased (r2 = 0.1114; p<0.0001). Interestingly, 3'-hydroxywarfarin reached a strong correlation at c4 respect to warfarin (r2 = 0.2157 and r2 = 0.0549; p = 0.0005 and p = 0.0944 respectively) seeming less affected by drug adjustments in the subgroup of 52 patients who started OAT. The multivariate analyses aimed at estimating the true contribution of 3'-hydroxywarfarin on INR value ascribed it the unique significant value (p = 0.0021) in spite of warfarin who lost association. The pharmacogenetics studies confirmed that patients carrying the VKORC1 variant-allele required lower warfarin maintenance dosage and that the combination of VKORC1 and CYP2C

Is rivaroxaban associated with lower inpatient costs compared to warfarin among patients with non-valvular atrial fibrillation?

PubMed

Laliberté, François; Pilon, Dominic; Raut, Monika K; Nelson, Winnie W; Olson, William H; Germain, Guillaume; Schein, Jeff R; Lefebvre, Patrick

2014-08-01

Warfarin has been the mainstay treatment used by patients with a moderate-to-high risk of stroke due to non-valvular atrial fibrillation (NVAF). Unlike rivaroxaban, laboratory monitoring to allow the attainment of the prothrombin time international normalized ratio goal is required with warfarin, thereby potentially increasing a patient's hospitalization costs. To compare hospitalization costs between hospitalized NVAF patients using rivaroxaban versus warfarin in a real-world setting. A retrospective claims analysis was conducted using the Premier Perspective Comparative Hospital Database from November 2010 to September 2012. The study included adult patients hospitalized for NVAF after November 2011. Patients using rivaroxaban during hospitalization were matched with up to four warfarin users by propensity score analyses. Hospitalization costs were compared between the matched cohorts using generalized estimating equations. A sub-analysis was performed for patients who were first administered their treatment on day three or later of their hospital stay. Sensitivity analyses were conducted on matched cohorts with a primary diagnosis of AF. The matched cohorts' (2809 rivaroxaban and 11,085 warfarin users) characteristics were well balanced. The mean age of cohorts was 71 years and 49% of patients were female. The average hospitalization cost of rivaroxaban users was $11,993 compared to $13,255 for warfarin users. The cost difference was significantly lower by $1284 (P < 0.001). Patients who were administered rivaroxaban treatment on day three or after incurred significantly lower hospitalization costs (cost difference: $4350; P < 0.001) compared to warfarin users. Rivaroxaban users with a primary diagnosis of AF also had significantly lower costs compared to warfarin users. These included possible inaccuracies or omissions in diagnoses, completeness of baseline characteristics, and a study population that included patients newly initiated on and patients

Clopidogrel and warfarin pharmacogenetic tests: what is the evidence for use in clinical practice?

PubMed Central

Shahin, Mohamed H.A.; Johnson, Julie A.

2013-01-01

Purpose of review To review the most promising genetic markers associated with the variability in the safety or efficacy of warfarin and clopidogrel and highlight the verification and validation initiatives for translating clopidogrel and warfarin pharmacogenetic tests to clinical practice. Recent findings Rapid advances in pharmacogenetics, continuous decrease in genotyping cost, development of point-of-care devices and the newly established clinical genotyping programs at several institutions hold the promise of individualizing clopidogrel and warfarin based on genotype. Guidelines have been established to assist clinicians in prescribing clopidogrel or warfarin dose based on genotype. However, the clinical utility of clopidogrel and warfarin is still limited. Accordingly, large randomized clinical trials are underway to define the role of clopidogrel and warfarin pharmacogenetics in clinical practice. Summary Pharmacogenetics has offered compelling evidence toward the individualization of clopidogrel and warfarin therapies. The rapid advances in technology make the clinical implementation of clopidogrel and warfarin pharmacogenetics possible. The clinical genotyping programs and the ongoing clinical trials will help in overcoming some of the barriers facing the clinical implementation of clopidogrel and warfarin pharmacogenetics. PMID:23478884

Comparative effectiveness of dabigatran and rivaroxaban versus warfarin for the treatment of non-valvular atrial fibrillation

PubMed Central

Bengtson, Lindsay GS; Lutsey, Pamela L.; Chen, Lin Y.; MacLehose, Richard F.; Alonso, Alvaro

2016-01-01

Background Effectiveness data on novel oral anticoagulants (NOACs) versus warfarin for stroke prevention in non-valvular atrial fibrillation (NVAF) by prior warfarin use are limited. Methods We used data from the US MarketScan databases from 2009–2012. NVAF patients initiating dabigatran or rivaroxaban were matched with up to 5 warfarin users. Propensity score-adjusted Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (95%CI) for relevant endpoints in NOACs versus warfarin users. Separate analyses were conducted to compare anticoagulant-naïve users of NOACs and those switching from warfarin. Results Among 32,918 dabigatran, 3,301 rivaroxaban, and 109,447 warfarin users with NVAF, 225 intracranial bleeds, 1035 ischemic strokes, 958 myocardial infarctions, and 1842 gastrointestinal bleeds were identified. Compared to warfarin users, patients initiating NOACs had similar ischemic stroke rates and lower intracranial bleeding rates, while the gastrointestinal bleeding rate was higher in dabigatran users than warfarin users. Associations of dabigatran with ischemic stroke risk differed between anticoagulant-naïve initiators and patients switching from warfarin; dabigatran was associated with lower ischemic stroke rates in naïve users (HR 0.65, 95%CI 0.52–0.82) but not in switchers (HR 1.20, 95%CI 0.95–1.51), compared to warfarin. Risk of stroke and bleeding was not different between rivaroxaban and warfarin users. Conclusions Real-world effectiveness of NOACs (compared to warfarin) for diverse outcomes was comparable to efficacy reported in published clinical trials. However, harms and benefits of switching from warfarin to dabigatran need to be evaluated. PMID:27889397

Use of warfarin therapy among residents who developed venous thromboembolism in the nursing home.

PubMed

Reardon, Gregory; Pandya, Naushira; Nutescu, Edith A; Lamori, Joyce; Damaraju, Chandrasekhar V; Schein, Jeff; Bookhart, Brahim K

2012-12-01

Treatment of venous thromboembolism (VTE) in long-term care (LTC) settings has received little empirical study. Among residents with VTE in nursing homes, this analysis evaluated frequency of anticoagulant use, the proportion of residents newly started on warfarin who persisted on therapy (≥3 months), and the association of key resident characteristics, including bleeding risk, with warfarin use and persistence. Using the AnalytiCare LTC database (US), eligible residents had deep vein thrombosis or pulmonary embolism coded in the Minimum Data Set (MDS) 2.0 during the uptake period April 1, 2007 through December 31, 2008 (earliest VTE was index date) and had 1 or more MDS assessment(s) over the 90-day preindex period, each negative for VTE. Logistic regression evaluated the association of resident characteristics with warfarin use. Cox regression evaluated persistence with warfarin therapy. The median age of residents with VTE included in the analysis (N = 489) was 80 years; 73% received anticoagulant therapy and 66% were prescribed warfarin ±45 days of the index date. Multivariate logistic regression identified several factors significantly associated with warfarin use: location in South Central region (odds ratio [OR] = 1.94, P = 0.019) and the Western region (OR = 2.53, P = 0.005) [both vs reference South Atlantic]; body mass index categories normal (OR = 2.73, P = 0.045), overweight (OR = 4.21, P = 0.005), and obese (OR = 3.82, P = 0.010) (both vs reference underweight); Alzheimer's/dementia (OR = 0.52, P = 0.024); cancer (OR = 0.39, P = 0.008); and moderate-dependent versus independent physical functioning (OR = 2.59, P = 0.003). Of residents newly started on warfarin therapy with no history of cancer (n = 149), 28% discontinued warfarin within 90 days of initiation. Peripheral vascular disease (PVD) (OR = 4.07, P < 0.001), Alzheimer's disease/dementia (OR = 2.55, P = 0.046), and antipsychotic use (OR = 4.60, P < 0.001) were all significantly associated with

Fecal hemoglobin excretion in elderly patients with atrial fibrillation: combined aspirin and low-dose warfarin vs conventional warfarin therapy.

PubMed

Blackshear, J L; Baker, V S; Holland, A; Litin, S C; Ahlquist, D A; Hart, R G; Ellefson, R; Koehler, J

1996-03-25

Antithrombotic prophylaxis using combined aspirin and low-dose warfarin is under evaluation in several clinical trials. However, therapy may result in increased gastrointestinal blood loss and clinical bleeding vs conventional single-agent antithrombotic therapy. To assess differences in gastrointestinal blood loss, we measured quantitative fecal hemoglobin equivalents (HemoQuant, Mayo Medical Laboratory, Rochester, Minn) in 117 patients, mean age 71 years, 1 month after initiation of assigned therapy in the Stroke Prevention in Atrial Fibrillation III Study. Sixty-three of these patients who had characteristics for high risk of stroke were randomly assigned to conventional adjusted-dose warfarin therapy (international normalized ratio, 2.0 to 3.0) or low-dose combined therapy (warfarin [international normalization ratio,<1.5] plus 325 mg/d of enteric-coated aspirin). The remaining 54 patients with low risk of stroke received 325 mg/d of enteric-coated aspirin. Among the 63 at high risk of stroke, abnormal values (>2mg of hemoglobin per gram of stool) were detected in 11% and values greater than 4 mg of hemoglobin per gram of stool were found in 8%. Mean ( +/- SD) values were more for those randomly assigned to receive combined therapy (1.7 +/- 3.3 mg of hemoglobin per gram of stool vs adjusted-dose warfarin therapy, 1.0 +/- 1.9 mg/g; P=.003). The 54 nonrandomized patients with low risk of stroke receiving aspirin alone had a mean (+/- SD) HemoQuant value of 0.8 +/- 0.7mg of hemoglobin per gram of stool 1 month after entry in the study. Abnormal levels of fecal hemoglobin excretion were common in elderly patients with high risk of atrial fibrillation 1 month after randomization to prophylactic antithrombotic therapy. Combined warfarin and aspirin therapy was associated with greater fecal hemoglobin excretion than standard warfarin therapy, suggesting the potential for increased gastrointestinal hemorrhage.

Effect of statins on intracerebral hemorrhage outcome and recurrence.

PubMed

FitzMaurice, Emilie; Wendell, Lauren; Snider, Ryan; Schwab, Kristin; Chanderraj, Rishi; Kinnecom, Cathrine; Nandigam, Kaveer; Rost, Natalia S; Viswanathan, Anand; Rosand, Jonathan; Greenberg, Steven M; Smith, Eric E

2008-07-01

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been associated with improved outcome after ischemic stroke and subarachnoid hemorrhage but an increased risk of incident intracerebral hemorrhage (ICH). We investigated (1) whether statin use before ICH was associated with functional independence at 90 days, and (2) whether survivors exposed to statins after ICH had an increased risk of recurrence. We analyzed 629 consecutive ICH patients with 90-day outcome data enrolled in a prospective cohort study between 1998 to 2005. Statin use was determined by patient interview at the time of ICH and supplemented by medical record review. Independent status was defined as Glasgow Outcome Scale 4 or 5. ICH survivors were followed by telephone interview every 6 months. Statins were used by 149/629 (24%) before ICH. There was no effect of pre-ICH statin use on the rates of functional independence (28% versus 29%, P=0.84) or mortality (46% versus 45%, P=0.93). Medical comorbidities and warfarin use were more common in statin users. Hematoma volumes were similar (median 28 cm(3) in pre-ICH statin users compared to 22 cm(3) in nonusers, P=0.18). The multivariable-adjusted odds ratio for independent status in pre-ICH statin users was 1.16 (95% CI 0.65 to 2.10, P=0.62). ICH survivors treated with statins after discharge did not have a higher risk of recurrence (adjusted HR 0.82, 95% CI 0.34 to 1.99, P=0.66). Pre-ICH statin use is not associated with improved ICH functional outcome or mortality. Post-ICH statin use is not associated with an increased risk of ICH recurrence.

The association between GGCX, miR-133 genetic polymorphisms and warfarin stable dosage in Han Chinese patients with mechanical heart valve replacement.

PubMed

Tang, X-Y; Zhang, J; Peng, J; Tan, S-L; Zhang, W; Song, G-B; Liu, L-M; Li, C-L; Ren, H; Zeng, L; Liu, Z-Q; Chen, X-P; Zhou, X-M; Zhou, H-H; Hu, J-X; Li, Z

2017-08-01

Warfarin is a widely used anticoagulant with a narrow therapeutic index. Polymorphisms in the VKORC1, CYP2C9 and CYP4F2 genes have been verified to correlate with warfarin stable dosage (WSD). Whether any other genes or variants affect the dosage is unknown. The aim of our study was to investigate the relationship between GGCX, miR-133 variants and the WSD in Han Chinese patients with mechanical heart valve replacement (MHVR). A total of 231 patients were enrolled in the study. Blood samples were collected for genotyping. The average WSD among subjects with different GGCX or miR-133 genotypes was compared. Regression analyses were performed to test for any association of genetic polymorphisms with WSD. The warfarin dosage in patients with the GGCX rs699664 TT and rs12714145 TT genotypes was 3.77±0.93 (95% CI: 3.35-4.19) mg/d and 3.70±1.00 (95% CI: 3.32-4.09) mg/d, respectively. The GGCX rs699664 and rs12714145 genotypes were significantly associated with WSD (P<.05). But they were ruled out in the multivariate regression analysis. There were no significant differences in the average warfarin stable dosage between subjects with MIR133B rs142410335 wild-type and variant genotypes (P>.05). The genotypes of GGCX rs699644 and rs12714145 were significantly associated with WSD (P<.05), but their contributions were not significant after accounting for other factors. MIR133B rs142410335 makes no significant contributions to warfarin stable dosage in Han Chinese patients with MHVR neither in univariate regression nor in multivariate regression analyses. © 2017 John Wiley & Sons Ltd.

Association of subdural hematoma with increased mortality in lobar intracerebral hemorrhage.

PubMed

Patel, Pratik V; FitzMaurice, Emilie; Nandigam, R N Kaveer; Auluck, Pavan; Viswanathan, Anand; Goldstein, Joshua N; Rosand, Jonathan; Greenberg, Steven M; Smith, Eric E

2009-01-01

To determine the prevalence of subdural hematoma (SDH) in patients presenting with primary nontraumatic lobar intracerebral hemorrhage (ICH) and characteristics associated with the presence of SDH. Retrospective analysis of data collected in a prospective cohort study. Hospital. Consecutive sample of 200 patients with primary lobar ICH and 75 patients with deep hemispheric ICH. Presence of SDH and mortality. Subdural hematoma was present in 40 of 200 patients (20%) with primary lobar ICH. By contrast, SDH was not present in any of 75 consecutive patients with deep hemispheric ICH (P < .001 for comparison with lobar ICH). Intracerebral hemorrhage volume higher than 60 cm3 was the only independent predictor of SDH (odds ratio [OR], 2.69; 95% confidence interval [CI], 1.14-6.34; P = .02). Subdural hematoma thickness more than 5 mm was an independent predictor of increased 30-day mortality (OR, 7.60; 95% CI, 1.86-30.99; P = .005) after controlling for other factors including ICH volume. Further analysis showed that the effect of SDH on mortality depended on ICH volume, with larger odds for mortality in those with low ICH volume (OR, 12.85; 95% CI, 2.42-68.23; P = .003 for those with ICH volume <30 cm3). Cerebral amyloid angiopathy was present in 8 of 9 patients with pathological specimens. Nontraumatic SDH frequently accompanies primary lobar ICH and is associated with higher 30-day mortality, particularly when the ICH volume is relatively low. Rupture of an amyloid-laden leptomeningeal vessel, with extravasation into the brain parenchyma and subdural space, may be the pathogenic mechanism.

Thromboembolic and Major Bleeding Events With Rivaroxaban Versus Warfarin Use in a Real-World Setting.

PubMed

Russo-Alvarez, Giavanna; Martinez, Kathryn A; Valente, Megan; Bena, James; Hu, Bo; Luxenburg, Jennifer; Chaitoff, Alexander; Ituarte, Catherine; Brateanu, Andrei; Rothberg, Michael B

2018-01-01

Although randomized trials demonstrate the noninferiority of rivaroxaban compared with warfarin in the context of nonvalvular atrial fibrillation (AF), little is known about how these drugs compare in practice. To assess the relative effectiveness and safety of rivaroxaban versus warfarin in a large health system and to evaluate this association by time in therapeutic range (TTR). We conducted a retrospective cohort study with propensity matching in the Cleveland Clinic Health System. The study included patients initiated on warfarin or rivaroxaban for thromboembolic prevention in nonvalvular AF between January 2012 and July 2016. The main outcomes were thromboembolic events and major bleeds. Analyses were stratified by warfarin patients' TTR. The cohort consisted of 472 propensity-matched pairs. The mean age was 73.6 years (SD = 11.7), and the mean CHADS 2 score was 1.8. The median TTR for warfarin patients was 64%. In the propensity-matched analysis, there was no significant difference in thromboembolic or major bleeding events between groups. Among warfarin patients with a TTR <64% and their matched rivaroxaban pairs, there was also no significant difference in thromboembolic or major bleeding events. Under real-world conditions, warfarin and rivaroxaban were associated with similar safety and effectiveness, even among those with suboptimal therapeutic control. Individualized decision making, taking into account the nontherapeutic tradeoffs associated with these medications (eg, monitoring, half-life, cost) is warranted.

Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer

PubMed Central

Shen, Guomin; Cui, Weidong; Zhang, Hao; Zhou, Fengbo; Huang, Wei; Liu, Qian; Yang, Yihu; Li, Shuang; Bowman, Gregory R.; Sadler, J. Evan; Gross, Michael L.; Li, Weikai

2017-01-01

Although warfarin is the most widely used anticoagulant worldwide, the mechanism by which warfarin inhibits its target, human vitamin K epoxide reductase (hVKOR), remains unclear. Here we show that warfarin blocks a dynamic electron-transfer process in hVKOR. A major fraction of cellular hVKOR is at an intermediate redox state of this process containing a Cys51-Cys132 disulfide, a characteristic accommodated by a four-transmembrane-helix structure of hVKOR. Warfarin selectively inhibits this major cellular form of hVKOR, whereas disruption of the Cys51-Cys132 disulfide impairs warfarin binding and causes warfarin resistance. Relying on binding interactions identified by cysteine alkylation footprinting and mass spectrometry coupled with mutagenesis analysis, we are able to conduct structure simulations to reveal a closed warfarin-binding pocket stabilized by the Cys51-Cys132 linkage. Understanding the selective warfarin inhibition of a specific redox state of hVKOR should enable the rational design of drugs that exploit the redox chemistry and associated conformational changes in hVKOR. PMID:27918545

A Population-Based Assessment of the Drug Interaction Between Levothyroxine and Warfarin

PubMed Central

Pincus, D; Gomes, T; Hellings, C; Zheng, H; Paterson, JM; Mamdani, MM; Juurlink, DN

2013-01-01

Most drug interaction resources suggest that levothyroxine can dramatically potentiate the effect of warfarin. However, the mechanistic basis of the interaction is speculative, and little evidence supports a meaningful drug interaction. We conducted a population-based nested case–control study to examine the risk of hospitalization for hemorrhage following the initiation of levothyroxine in a cohort of 260,076 older patients receiving warfarin. In this group, we identified 10,532 case subjects hospitalized for hemorrhage and 40,595 controls. In the primary analysis, we found no association between hospitalization for hemorrhage during warfarin therapy and initiation of levothyroxine in the preceding 30 days (adjusted odds ratio 1.11, 95% confidence interval 0.67–1.86). Secondary analyses using more remote initiation of levothyroxine also found no association. These findings suggest that concerns about a clinically meaningful levothyroxine–warfarin drug interaction are not justified. Drug interaction resources that presently characterize this interaction as important should reevaluate this classification. PMID:23093318

Warfarin

MedlinePlus

... forming or growing larger in your blood and blood vessels. It is prescribed for people with certain types ... symptoms You should know that warfarin may cause necrosis or gangrene (death of skin or other body ...

Use of Warfarin at Discharge Among Acute Ischemic Stroke Patients With Nonvalvular Atrial Fibrillation in China.

PubMed

Yang, Xiaomeng; Li, Zixiao; Zhao, Xingquan; Wang, Chunjuan; Liu, Liping; Wang, Chunxue; Pan, Yuesong; Li, Hao; Wang, David; Hart, Robert G; Wang, Yilong; Wang, Yongjun

2016-02-01

Guidelines recommend oral anticoagulation for ischemic stroke patients with atrial fibrillation, and previous studies have shown the underuse of anticoagulation for these patients in China. We sought to explore the underlying reasons and factors that currently affect the use of warfarin in China. From June 2012 to January 2013, 19 604 patients with acute ischemic stroke were admitted to 219 urban hospitals voluntarily participating in the China National Stroke Registry II. Multivariable logistic regression models using the generalized estimating equation method were used to identify patient/hospital factors independently associated with warfarin use at discharge. Among the 952 acute ischemic stroke patients with nonvalvular atrial fibrillation, 19.4% were discharged on warfarin. The risk of bleeding (52.8%) and patient refusal (31.9%) were the main reasons for not prescribing anticoagulation. Larger/teaching hospitals were more likely to prescribe warfarin. Older patients, heavy drinkers, patients with higher National Institutes of Health Stroke Scale score on admission were less likely to be given warfarin, whereas patients with history of heart failure and an international normalized ratio between 2.0 and 3.0 during hospitalization were significantly associated with warfarin use at discharge. The rate of warfarin use remains low among patients with ischemic stroke and known nonvalvular atrial fibrillation in China. Hospital size and academic status together with patient age, heart failure, heavy alcohol drinking, international normalized ratio in hospital, and stroke severity on admission were each independently associated with the use of warfarin at discharge. There is much room for improvement for secondary stroke prevention in nonvalvular atrial fibrillation patients in China. © 2015 American Heart Association, Inc.

Warfarin use and the risk of mortality, stroke, and bleeding in hemodialysis patients with atrial fibrillation.

PubMed

Kai, Brandon; Bogorad, Yuliya; Nguyen, Leigh-Anh N; Yang, Su-Jau; Chen, Wansu; Spencer, Hillard T; Shen, Albert Y-J; Lee, Ming-Sum

2017-05-01

The optimal management of stroke prophylaxis in hemodialysis patients with atrial fibrillation is controversial. The purpose of this study was to determine the risk of mortality, stroke, and bleeding associated with the use of warfarin in hemodialysis patients with atrial fibrillation. This was a retrospective, population-based study of hemodialysis patients with atrial fibrillation between January 1, 2006, and September 30, 2015. Association of warfarin use with mortality, stroke, and bleeding was determined by propensity score-matched, Cox proportional hazard models. Among the 4286 patients with atrial fibrillation on hemodialysis, 989 (23%) were prescribed warfarin. Propensity score matching was used to identify 888 matched pairs with similar baseline characteristics. Warfarin use was associated with lower risk of all-cause death (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.69-0.84) and lower risk of ischemic stroke (HR 0.68, 95% CI 0.52-0.91). Warfarin use was not associated with a higher risk of hemorrhagic stroke (HR 1.2, 95% CI 0.6-2.2) or gastrointestinal bleeding (HR 0.97, 95% CI 0.77-1.2). The treatment effect was largest in the group with the best international normalized ratio control as measured by time in therapeutic range. Subgroup analyses showed warfarin use was associated with survival benefit in most subgroups. The 2 subgroups that did not benefit were patients with a history of hemorrhagic stroke and patients with concurrent aspirin use. Warfarin use is associated with lower all-cause mortality and ischemic stroke, without significantly increasing the risk of bleeding in hemodialysis patients with atrial fibrillation. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Predictors of warfarin use in atrial fibrillation in the United States: a systematic review and meta-analysis

PubMed Central

2012-01-01

Background Despite warfarin's marked efficacy, not all eligible patients receive it for stroke prevention in AF. The aim of this meta-analysis was to evaluate the association between prescriber and/or patient characteristics and subsequent prescription of warfarin for stroke prevention in patients with atrial fibrillation (AF). Methods Observational studies conducted in the US using multivariate analysis to determine the relationship between characteristics and the odds of receiving warfarin for stroke prevention were identified in MEDLINE, EMBASE and a manual review of references. Effect estimates of prescriber and/or patient characteristics from individual studies were pooled to calculate odds ratios (ORs) with 95% confidence intervals. Results Twenty-eight studies reporting results of 33 unique multivariate analyses were identified. Warfarin use across studies ranged from 9.1%-79.8% (median = 49.1%). There was a moderately-strong correlation between warfarin use and year of study (r = 0.60, p = 0.002). Upon meta-analysis, characteristics associated with a statistically significant increase in the odds of warfarin use included history of cerebrovascular accident (OR = 1.59), heart failure (OR = 1.36), and male gender (OR = 1.12). Those associated with a significant reduction in the odds of warfarin use included alcohol/drug abuse (OR = 0.62), perceived barriers to compliance (OR = 0.87), contraindication(s) to warfarin (OR = 0.81), dementia (OR = 0.32), falls (OR = 0.60), gastrointestinal hemorrhage (OR = 0.47), intracranial hemorrhage (OR = 0.39), hepatic (OR = 0.59), and renal impairment (OR = 0.69). While age per 10-year increase (OR = 0.78) and advancing age as a dichotomized variable (cut-off varied by study) (OR = 0.57) were associated with significant reductions in warfarin use; qualitative review of results of studies evaluating age as a categorical variable did not confirm this relationship. Conclusions Warfarin use has increased somewhat over time. The

Warfarin-acetaminophen drug interaction revisited.

PubMed

Shek, K L; Chan, L N; Nutescu, E

1999-10-01

Physicians and pharmacists routinely advise patients receiving warfarin to take acetaminophen for pain or fever because of its relative safety; however, a recent study questioned the safety of such practice. A comprehensive search of MEDLINE and IPA for human studies and case reports from 1966-1999 revealed evidence that acetaminophen may potentiate the effect of warfarin by a mechanism that has yet to be elucidated. Due to lack of a safer alternative, acetaminophen still should be the analgesic and antipyretic of choice in patients taking warfarin, as long as excessive amounts and prolonged administration (> 1.3 g acetaminophen/day for > 2 wks) are avoided. With the high degree of interpatient variability and the unpredictability of various drug-drug interactions with warfarin, close and frequent monitoring of international normalized ratios is the key for safe oral anticoagulation therapy.

Low Ambient Temperature and Intracerebral Hemorrhage: The INTERACT2 Study.

PubMed

Zheng, Danni; Arima, Hisatomi; Sato, Shoichiro; Gasparrini, Antonio; Heeley, Emma; Delcourt, Candice; Lo, Serigne; Huang, Yining; Wang, Jiguang; Stapf, Christian; Robinson, Thompson; Lavados, Pablo; Chalmers, John; Anderson, Craig S

2016-01-01

Rates of acute intracerebral hemorrhage (ICH) increase in winter months but the magnitude of risk is unknown. We aimed to quantify the association of ambient temperature with the risk of ICH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) participants on an hourly timescale. INTERACT2 was an international, open, blinded endpoint, randomized controlled trial of patients with spontaneous ICH (<6h of onset) and elevated systolic blood pressure (SBP, 150-220 mmHg) assigned to intensive (target SBP <140 mmHg) or guideline-recommended (SBP <180 mmHg) BP treatment. We linked individual level hourly temperature to baseline data of 1997 participants, and performed case-crossover analyses using a distributed lag non-linear model with 24h lag period to assess the association of ambient temperature and risk of ICH. Results were presented as overall cumulative odds ratios (ORs) and 95% CI. Low ambient temperature (≤10°C) was associated with increased risks of ICH: overall cumulative OR was 1.37 (0.99-1.91) for 10°C, 1.92 (1.31-2.81) for 0°C, 3.13 (1.89-5.19) for -10°C, and 5.76 (2.30-14.42) for -20°C, as compared with a reference temperature of 20°C.There was no clear relation of low temperature beyond three hours after exposure. Results were consistent in sensitivity analyses. Exposure to low ambient temperature within several hours increases the risk of ICH. ClinicalTrials.gov NCT00716079.

Warfarin interaction with Matricaria chamomilla

PubMed Central

Segal, Robert; Pilote, Louise

2006-01-01

No cases have been reported of Matricaria chamomilla potentiating the effects of warfarin. Nevertheless there is a theoretical risk for potentiation, since the herb is thought to be a coumarin constituent. We describe the case of a 70-year-old woman who, while being treated with warfarin, was admitted to hospital with multiple internal hemorrhages after having used chamomile products (tea and body lotion) to soothe upper respiratory tract symptoms. Patient education on the potential risk of taking chamomile products while being treated with warfarin is necessary to avoid such occurrences. PMID:16636327

Updates on the Clinical Evidenced Herb-Warfarin Interactions

PubMed Central

Ge, Beikang; Zhang, Zhen; Zuo, Zhong

2014-01-01

Increasing and inadvertent use of herbs makes herb-drug interactions a focus of research. Concomitant use of warfarin, a highly efficacious oral anticoagulant, and herbs causes major safety concerns due to the narrow therapeutic window of warfarin. This paper presents an update overview of clinical findings regarding herb-warfarin interaction, highlighting clinical outcomes, severity of documented interactions, and quality of clinical evidence. Among thirty-eight herbs, Cannabis, Chamomile, Cranberry, Garlic, Ginkgo, Grapefruit, Lycium, Red clover, and St. John's wort were evaluated to have major severity interaction with warfarin. Herbs were also classified on account of the likelihood of their supporting evidences for interaction. Four herbs were considered as highly probable to interact with warfarin (level I), three were estimated as probable (level II), and ten and twenty-one were possible (level III) and doubtful (level IV), respectively. The general mechanism of herb-warfarin interaction almost remains unknown, yet several pharmacokinetic and pharmacodynamic factors were estimated to influence the effectiveness of warfarin. Based on limited literature and information reported, we identified corresponding mechanisms of interactions for a small amount of “interacting herbs.” In summary, herb-warfarin interaction, especially the clinical effects of herbs on warfarin therapy should be further investigated through multicenter studies with larger sample sizes. PMID:24790635

Association of Subdural Hematoma With Increased Mortality in Lobar Intracerebral Hemorrhage

PubMed Central

Patel, Pratik V.; FitzMaurice, Emilie; Kaveer Nandigam, R. N.; Auluck, Pavan; Viswanathan, Anand; Goldstein, Joshua N.; Rosand, Jonathan; Greenberg, Steven M.; Smith, Eric E.

2011-01-01

Objective To determine the prevalence of subdural hematoma (SDH) in patients presenting with primary non-traumatic lobar intracerebral hemorrhage (ICH) and characteristics associated with the presence of SDH. Design Retrospective analysis of data collected in a prospective cohort study. Setting Hospital. Patients Consecutive sample of 200 patients with primary lobar ICH and 75 patients with deep hemispheric ICH. Main Outcome Measures Presence of SDH and mortality. Results Subdural hematoma was present in 40 of 200 patients (20%) with primary lobar ICH. By contrast, SDH was not present in any of 75 consecutive patients with deep hemispheric ICH (P<.001 for comparison with lobar ICH). Intracerebral hemorrhage volume higher than 60 cm3 was the only independent predictor of SDH (odds ratio [OR], 2.69; 95% confidence interval [CI], 1.14–6.34; P=.02). Subdural hematoma thickness more than 5 mm was an independent predictor of increased 30-day mortality (OR, 7.60; 95% CI, 1.86–30.99; P=.005) after controlling for other factors including ICH volume. Further analysis showed that the effect of SDH on mortality depended on ICH volume, with larger odds for mortality in those with low ICH volume (OR, 12.85; 95% CI, 2.42–68.23; P=.003 for those with ICH volume <30 cm3). Cerebral amyloid angiopathy was present in 8 of 9 patients with pathological specimens. Conclusions Nontraumatic SDH frequently accompanies primary lobar ICH and is associated with higher 30-day mortality, particularly when the ICH volume is relatively low. Rupture of an amyloid-laden leptomeningeal vessel, with extravasation into the brain parenchyma and subdural space, may be the pathogenic mechanism. PMID:19139303

Warfarin Poisoning with Delayed Rebound Toxicity.

PubMed

Berling, Ingrid; Mostafa, Ahmed; Grice, Jeffrey E; Roberts, Michael S; Isbister, Geoffrey K

2017-02-01

Intentional poisoning with warfarin is not the same as over-anticoagulation, for which guidelines exist. The coagulopathy resulting from a warfarin overdose is reversed with vitamin K 1 , the dose and timing of which is often guided by experience with the management of over-anticoagulation with warfarin therapy, rather than acute overdose. We report a case of a 50-year-old man who ingested an unknown amount of his warfarin, venlafaxine, and paracetamol. He presented with an international normalized ratio (INR) of 2.5, which steadily increased over 24 h to 7, despite receiving an initial 1 mg of vitamin K 1 . He was then treated with 5 mg vitamin K 1 , and once the INR returned to 4.5, 40 h post ingestion, he was discharged home. He was also treated with a full course of acetylcysteine for the paracetamol overdose. The following day his INR rebounded to 8.5 and he suffered a spontaneous epistaxis requiring readmission; he was treated with low titrated doses of vitamin K 1 . The warfarin concentration was 74.6 μg/mL 26 h post ingestion and decreased to 3.7 μg/mL over 72 h. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Our case highlights the risk of a rebound elevated INR even 3 days after acute warfarin overdose despite treatment with vitamin K 1 . Understanding the pharmacokinetics of vitamin K 1 in comparison with warfarin, repeat INR testing, and continued treatment with oral vitamin K 1 may help avoid complications of rebound coagulopathy in warfarin overdose. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Factors Associated with Fever in Intracerebral Hemorrhage.

PubMed

Gillow, Sabreena J; Ouyang, Bichun; Lee, Vivien H; John, Sayona

2017-06-01

Fever is common in patients with intracerebral hemorrhage (ICH). We sought to identify predictors of fever in patients hospitalized with ICH, and compare infectious fever with noninfectious fever. A retrospective review on consecutive spontaneous ICH patients from April 2009 to March 2010 was performed. Fever was defined as temperature 100.9°F or higher and attributed to infectious versus noninfectious etiology, based upon the National Healthcare Safety Network criteria. Univariate analysis and multivariable logistic regression model were used to determine factors associated with fever and with infection. Among the 351 ICH patients, 136 (39%) developed fever. Factors associated with fever included mean ICH volume, intraventricular hemorrhage (IVH), external ventricular drain (EVD) placement or surgical evacuation, positive microbial cultures, longer length of stay (LOS), and higher in-hospital mortality. Among patients with fever, 96 (71%) were noninfectious and 40 (29%) were infectious. Infectious fever was associated with higher LOS. Noninfectious fever was associated with higher in-hospital mortality. In multivariable analysis, ICH volume (OR = 1.01, P = .04), IVH (OR = 2.0, P = .03), EVD (OR = 3.7, P < .0001), and surgical evacuation (OR = 6.78, P < .0001) were significant predictors of fever. Infectious fever (OR = 5.26, P = .004), EVD (OR = 4.86, P = .01), and surgical evacuation (OR = 4.77, P = .04) correlated with prolonged LOS when dichotomized using a median of 15 days. Fever is common in ICH patients and is not associated with a clear infectious etiology in the majority of patients. Patients with noninfectious fever have higher in-hospital mortality, but survivors have shorter LOS. Further studies are warranted to better understand fevers in ICH. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Rationale, design, and preliminary results of the Quebec Warfarin Cohort Study.

PubMed

Perreault, Sylvie; Shahabi, Payman; Côté, Robert; Dumas, Stéphanie; Rouleau-Mailloux, Étienne; Feroz Zada, Yassamin; Provost, Sylvie; Mongrain, Ian; Dorais, Marc; Huynh, Thao; Kouz, Simon; Diaz, Ariel; Blostein, Mark; de Denus, Simon; Turgeon, Jacques; Ginsberg, Jeffrey; Lelorier, Jacques; Lalonde, Lyne; Busque, Lambert; Kassis, Jeannine; Talajic, Mario; Tardif, Jean-Claude; Dubé, Marie-Pierre

2018-05-01

Over- and undercoagulation with warfarin are associated with hemorrhagic and thromboembolic events, respectively. Genetic and clinical factors affect warfarin response, and the causes of this variability remain unclear. We present descriptive statistics and test for predictors of poor anticoagulation control. The Quebec Warfarin Cohort (QWC) comprises 1059 new warfarin users, with prospective follow-up using telephone questionnaires every 3 months for 1 year, and using healthcare administrative databases (RAMQ and Med-Echo) for 5 years prior to cohort entry and up to 10 years following active patient participation. Genetic material was collected, and genotyping of CYP2C9 and VKORC1 genes was conducted. Measured outcomes included the percentage of time patients spent within therapeutic range, anticoagulation control, warfarin dose, bleeding, and thromboembolic events. We report baseline characteristics and outcomes after 1 year of follow-up. Poor anticoagulation control was defined as time in therapeutic range <60% in the 3- to 12-month interval. Participants had a mean age of 71 years, and 62% were men. The most common indication for warfarin was atrial fibrillation (87%). Mean time in therapeutic range was 56% (±25%) in the 3 months following warfarin initiation, and 70% (±21%) in the 3- to 12-month interval. During follow-up, the rate of stroke or systemic embolism was 1.8 events per 100 person-years; for major bleeding events, 3.3 events per 100 person-years. Independent predictors of poor anticoagulation control were chronic kidney disease, heart failure, dyslipidemia, and age. The QWC represents a good research cohort to investigate clinical and genetic factors in a warfarin-anticoagulated population. © 2018 Wiley Periodicals, Inc.

Oesophageal ulcer caused by warfarin.

PubMed Central

Loft, D. E.; Stubington, S.; Clark, C.; Rees, W. D.

1989-01-01

Oesophageal injury is a well recognized complication of certain oral medications but warfarin has not been implicated previously. We present a case of an oesophageal ulcer occurring in a patient with mitral regurgitation taking warfarin, and demonstrate a delayed oesophageal tablet transit time. PMID:2594605

Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation.

PubMed

Yao, Xiaoxi; Abraham, Neena S; Sangaralingham, Lindsey R; Bellolio, M Fernanda; McBane, Robert D; Shah, Nilay D; Noseworthy, Peter A

2016-06-13

The introduction of non-vitamin K antagonist oral anticoagulants has been a major advance for stroke prevention in atrial fibrillation; however, outcomes achieved in clinical trials may not translate to routine practice. We aimed to evaluate the effectiveness and safety of dabigatran, rivaroxaban, and apixaban by comparing each agent with warfarin. Using a large US insurance database, we identified privately insured and Medicare Advantage patients with nonvalvular atrial fibrillation who were users of apixaban, dabigatran, rivaroxaban, or warfarin between October 1, 2010, and June 30, 2015. We created 3 matched cohorts using 1:1 propensity score matching: apixaban versus warfarin (n=15 390), dabigatran versus warfarin (n=28 614), and rivaroxaban versus warfarin (n=32 350). Using Cox proportional hazards regression, we found that for stroke or systemic embolism, apixaban was associated with lower risk (hazard ratio [HR] 0.67, 95% CI 0.46-0.98, P=0.04), but dabigatran and rivaroxaban were associated with a similar risk (dabigatran: HR 0.98, 95% CI 0.76-1.26, P=0.98; rivaroxaban: HR 0.93, 95% CI 0.72-1.19, P=0.56). For major bleeding, apixaban and dabigatran were associated with lower risk (apixaban: HR 0.45, 95% CI 0.34-0.59, P<0.001; dabigatran: HR 0.79, 95% CI 0.67-0.94, P<0.01), and rivaroxaban was associated with a similar risk (HR 1.04, 95% CI 0.90-1.20], P=0.60). All non-vitamin K antagonist oral anticoagulants were associated with a lower risk of intracranial bleeding. In patients with nonvalvular atrial fibrillation, apixaban was associated with lower risks of both stroke and major bleeding, dabigatran was associated with similar risk of stroke but lower risk of major bleeding, and rivaroxaban was associated with similar risks of both stroke and major bleeding in comparison to warfarin. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Warfarin: history, tautomerism and activity

NASA Astrophysics Data System (ADS)

Porter, William R.

2010-06-01

The anticoagulant drug warfarin, normally administered as the racemate, can exist in solution in potentially as many as 40 topologically distinct tautomeric forms. Only 11 of these forms for each enantiomer can be distinguished by selected computational software commonly used to estimate octanol-water partition coefficients and/or ionization constants. The history of studies on warfarin tautomerism is reviewed, along with the implications of tautomerism to its biological properties (activity, protein binding and metabolism) and chemical properties (log P, log D, p K a). Experimental approaches to assessing warfarin tautomerism and computational results for different tautomeric forms are presented.

Prostate cancer-specific survival among warfarin users in the Finnish Randomized Study of Screening for Prostate Cancer.

PubMed

Kinnunen, Pete T T; Murtola, Teemu J; Talala, Kirsi; Taari, Kimmo; Tammela, Teuvo L J; Auvinen, Anssi

2017-08-29

Venous thromboembolic events (VTE) are common in cancer patients and associated with higher mortality. In vivo thrombosis and anticoagulation might be involved in tumor growth and progression. We studied the association of warfarin and other anticoagulant use as antithrombotic medication and prostate cancer (PCa) death in men with the disease. The study included 6,537 men diagnosed with PCa during 1995-2009. Information on anticoagulant use was obtained from a national reimbursement registry. Cox regression with adjustment for age, PCa risk group, primary therapy and use of other medication was performed to compare risk of PCa death between warfarin users with 1) men using other types of anticoagulants and 2) non-users of anticoagulants. Medication use was analyzed as a time-dependent variable to minimize immortal time bias. In total, 728 men died from PCa during a median follow-up of 9 years. Compared to anticoagulant non-users, post-diagnostic use of warfarin was associated with an increased risk of PCa death (overall HR 1.47, 95% CI 1.13-1.93). However, this was limited to low-dose, low-intensity use. Otherwise, the risk was similar to anticoagulant non-users. Additionally, we found no risk difference between warfarin and other types of anticoagulants. Pre-diagnostic use of warfarin was not associated with the risk of PCa death. We found no reduction in risk of PCa death associated with warfarin use. Conversely, the risk was increased in short-term use, which is probably explained by a higher risk of thrombotic events prompting warfarin use in patients with terminal PCa.

Peri-procedural interrupted oral anticoagulation for atrial fibrillation ablation: comparison of aspirin, warfarin, dabigatran, and rivaroxaban

PubMed Central

Winkle, Roger A.; Mead, R. Hardwin; Engel, Gregory; Kong, Melissa H.; Patrawala, Rob A.

2014-01-01

Aims Atrial fibrillation ablation requires peri-procedural oral anticoagulation (OAC) to prevent thromboembolic events. There are several options for OAC. We evaluate peri-procedural AF ablation complications using a variety of peri-procedural OACs. Methods and results We examined peri-procedural OAC and groin, bleeding, and thromboembolic complications for 2334 consecutive AF ablations using open irrigated-tip radiofrequency (RF) catheters. Pre-ablation OAC was warfarin in 1113 (47.7%), dabigatran 426 (18.3%), rivaroxaban 187 (8.0%), aspirin 472 (20.2%), and none 136 (5.8%). Oral anticoagulation was always interrupted and intraprocedural anticoagulation was unfractionated heparin (activated clotting time, ACT = 237 ± 26 s). Pre- and post-OAC drugs were the same for 1591 (68.2%) and were different for 743 (31.8%). Following ablation, 693 (29.7%) were treated with dabigatran and 291 (12.5%) were treated with rivaroxaban. There were no problems changing from one OAC pre-ablation to another post-ablation. Complications included 12 (0.51%) pericardial tamponades [no differences for dabigatran (P = 0.457) or rivaroxaban (P = 0.163) compared with warfarin], 12 (0.51%) groin complications [no differences for rivaroxaban (P = 0.709) and fewer for dabigatran (P = 0.041) compared with warfarin]. Only 5 of 2334 (0.21%) required blood transfusions. There were two strokes (0.086%) and no transient ischaemic attacks (TIAs) in the first 48 h post-ablation. Three additional strokes (0.13%), and two TIAs (0.086%) occurred from 48 h to 30 days. Only one stroke had a residual deficit. Compared with warfarin, the neurologic event rate was not different for dabigatran (P = 0.684) or rivaroxaban (P = 0.612). Conclusion Using interrupted OAC, low target intraprocedural ACT, and irrigated-tip RF, the rate of peri-procedural groin, haemorrhagic, and thromboembolic complications was extremely low. There were only minimal differences between OACs. Low-risk patients may remain on aspirin

Vitamin K2 for the reversal of warfarin-related coagulopathy.

PubMed

Hifumi, Toru; Takada, Hiroaki; Ogawa, Daisuke; Suzuki, Kenta; Hamaya, Hideyuki; Shinohara, Natsuyo; Abe, Yuko; Takano, Koshiro; Kawakita, Kenya; Hagiike, Masanobu; Koido, Yuichi; Kuroda, Yasuhiro

2015-08-01

The American Heart Association/American College of Cardiology Foundation recommends vitamin K1 for warfarin-related coagulopathy. In Japan, vitamin K2 is used more commonly for such purpose. The difference between vitamins K1 and K2 in reversing warfarin-related coagulopathy has not been discussed. Herein, we report a case that was reversed with vitamin K2; alterations in vitamins K1 and K2 levels and coagulation markers are also presented.

Impact on survival of warfarin in patients with pulmonary arterial hypertension receiving subcutaneous treprostinil.

PubMed

Ascha, Mona; Zhou, Xuan; Rao, Youlan; Minai, Omar A; Tonelli, Adriano R

2017-10-01

Anticoagulation is a common treatment modality in patients with pulmonary arterial hypertension (PAH). Further studies are needed to appropriately assess the risk/benefit ratio of anticoagulation, particularly in PAH patients receiving PAH-specific therapies. We use observational long-term data on PAH patients treated with subcutaneous (SQ) treprostinil from a large open-label study. Patients were followed for up to 4 years. The use of warfarin and bleeding events were recorded. At total of 860 patients (age [mean±SD] 46±15 years, 76% female, 83% Caucasian, 49% idiopathic PAH, and 76% New York Heart Association [NYHA] functional class III) were included. All patients received SQ treprostinil (15% also other pulmonary hypertension [PH]-therapies) and 590 (69%) received warfarin during the study. The proportions of women, African American, and idiopathic pulmonary hypertension (IPAH) patients were higher in the group receiving warfarin. A higher proportion of patients with congenital heart disease and portopulmonary hypertension did not receive warfarin. There were no differences in unadjusted long-term survival between PAH patients receiving warfarin or not (log-rank test, P value=.69), even when only considering idiopathic PAH (P=.32). In addition, no difference was found in adjusted long-term survival both in PAH (P=.84) and idiopathic PAH patients (P=.44) based on the use of warfarin. Furthermore, no survival difference based on the use of warfarin were noted between propensity score-matched PAH patients (P=.37). Long-term anticoagulation with warfarin was not associated with any significant effect on survival in PAH or idiopathic PAH patients treated with SQ treprostinil. © 2017 John Wiley & Sons Ltd.

Association Between Hypodensities Detected by Computed Tomography and Hematoma Expansion in Patients With Intracerebral Hemorrhage

PubMed Central

Boulouis, Gregoire; Morotti, Andrea; Brouwers, H. Bart; Charidimou, Andreas; Jessel, Michael J.; Auriel, Eitan; Pontes-Neto, Octávio; Ayres, Alison; Vashkevich, Anastasia; Schwab, Kristin M.; Rosand, Jonathan; Viswanathan, Anand; Gurol, Mahmut E.; Greenberg, Steven M.; Goldstein, Joshua N.

2017-01-01

IMPORTANCE Hematoma expansion is a potentially modifiable predictor of poor outcome following an acute intracerebral hemorrhage (ICH). The ability to identify patients with ICH who are likeliest to experience hematoma expansion and therefore likeliest to benefit from expansion-targeted treatments remains an unmet need. Hypodensities within an ICH detected by noncontrast computed tomography (NCCT) have been suggested as a predictor of hematoma expansion. OBJECTIVE To determine whether hypodense regions, irrespective of their specific patterns, are associated with hematoma expansion in patients with ICH. DESIGN, SETTING, AND PARTICIPANTS We analyzed a large cohort of 784 patients with ICH (the development cohort; 55.6% female), examined NCCT findings for any hypodensity, and replicated our findings on a different cohort of patients (the replication cohort; 52.7% female). Baseline and follow-up NCCT data from consecutive patients with ICH presenting to a tertiary care hospital between 1994 and 2015 were retrospectively analyzed. Data analyses were performed between December 2015 and January 2016. MAIN OUTCOMES AND MEASURES Hypodensities were analyzed by 2 independent blinded raters. The association between hypodensities and hematoma expansion (>6 cm3 or 33% of baseline volume) was determined by multivariable logistic regression after controlling for other variables associated with hematoma expansion in univariate analyses with P ≤ .10. RESULTS A total of 1029 patients were included in the analysis. In the development and replication cohorts, 222 of 784 patients (28.3%) and 99 of 245 patients (40.4%; 321 of 1029 patients [31.2%]), respectively, had NCCT scans that demonstrated hypodensities at baseline (κ = 0.87 for interrater reliability). In univariate analyses, hypodensities were associated with hematoma expansion (86 of 163 patients with hematoma expansion had hypodensities [52.8%], whereas 136 of 621 patients without hematoma expansion had hypodensities [21

Cohort-specific imputation of gene expression improves prediction of warfarin dose for African Americans.

PubMed

Gottlieb, Assaf; Daneshjou, Roxana; DeGorter, Marianne; Bourgeois, Stephane; Svensson, Peter J; Wadelius, Mia; Deloukas, Panos; Montgomery, Stephen B; Altman, Russ B

2017-11-24

Genome-wide association studies are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into "gene level" effects. Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression-on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals. We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations. Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions. MATLAB code is available at https://github.com/assafgo/warfarin-cohort.

Warfarin

Integrated Risk Information System (IRIS)

Warfarin ; CASRN 81 - 81 - 2 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Effects )

Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population.

PubMed

Lee, Soo-Chin; Ng, Swee-Siang; Oldenburg, Johannes; Chong, Pei-Yi; Rost, Simone; Guo, Jia-Yi; Yap, Hui-Ling; Rankin, Sheila Clare; Khor, Hui-Boon; Yeo, Tiong-Cheng; Ng, Kheng-Siang; Soong, Richie; Goh, Boon-Cher

2006-03-01

Chinese and Malay subjects have been reported to require less maintenance warfarin than Indians that could not be accounted for by cytochrome P450 (CYP) 2C9 variants. Vitamin K epoxide reductase complex 1 (VKORC1) is the target enzyme of warfarin, and VKORC1 intronic variants and haplotypes have recently been shown to influence VKORC1 activity and warfarin requirements. We sequenced the coding regions of CYP2C9 and VKORC1 and inferred VKORC1 haplotype from 10 intronic variants in 147 Chinese, 85 Malay, and 43 Indian patients receiving maintenance warfarin. The mean weight-normalized warfarin dose was lower for Chinese and Malays than for Indians (0.058 +/- 0.025 mg/kg, 0.059 +/- 0.023 mg/kg, and 0.089 +/- 0.036 mg/kg, respectively; P < .001 for comparisons between Chinese and Malays with Indians). CYP2C9*2 and VKORC1 coding region variants were rare (<2%), whereas CYP2C9*3 associated with lower warfarin requirements was less common in Chinese and Malays (7% and 9%, respectively) than in Indians (18%) and could not account for their lower warfarin requirements. VKORC1 H1 and H7/H8/H9 haplotypes were associated with lower and higher warfarin requirements, respectively (0.050 +/- 0.019 mg/kg and 0.092 +/- 0.057 mg/kg, respectively; P < .001). VKORC1 H1 haplotype (requiring low warfarin doses) was common in Chinese (87%) and Malays (65%) but uncommon in Indians (12%), whereas H7, H8, and H9 haplotypes (requiring high warfarin doses) were rare in Chinese (9%), intermediate in Malays (30%), and common in Indians (82%). The interethnic difference in warfarin requirements became nonsignificant when adjusted for VKORC1 haplotype. Interethnic difference in VKORC1 haplotypes accounts for the difference in warfarin requirements between Chinese, Malays, and Indians, providing interesting insights into genetic variation between ethnogeographically distinct Asian groups.

Feasibility of implementing a comprehensive warfarin pharmacogenetics service.

PubMed

Nutescu, Edith A; Drozda, Katarzyna; Bress, Adam P; Galanter, William L; Stevenson, James; Stamos, Thomas D; Desai, Ankit A; Duarte, Julio D; Gordeuk, Victor; Peace, David; Kadkol, Shrihari S; Dodge, Carol; Saraf, Santosh; Garofalo, John; Krishnan, Jerry A; Garcia, Joe G N; Cavallari, Larisa H

2013-11-01

To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Prospective observational study. A 438-bed tertiary care hospital affiliated with a large academic institution. Eighty patients who started warfarin therapy and were managed by a newly implemented pharmacogenetics service. All patients received routine warfarin genotyping and clinical pharmacogenetics consultation. The primary outcomes were percentage of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders placed during the first 6 months of the service, 190 (44%) were deemed appropriate. For the 80 patients on the service who consented to data collection, 76% of the genotypes were available prior to the second warfarin dose. The median (range) time from genotype order to genotype result was 26 hours (7-80 hrs), and the time to genotype-guided dose recommendation was 30 hours (7-80 hrs). A total of 73% of warfarin doses ordered by the medical staff were within 0.5 mg of the daily dose recommended by the pharmacogenetics consult service. Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with most genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff. © 2013 Pharmacotherapy Publications, Inc.

Feasibility of Implementing a Comprehensive Warfarin Pharmacogenetics Service

PubMed Central

Nutescu, Edith A.; Drozda, Katarzyna; Bress, Adam P.; Galanter, William L.; Stevenson, James; Stamos, Thomas D.; Desai, Ankit A.; Duarte, Julio D.; Gordeuk, Victor; Peace, David; Kadkol, ShriHari S.; Dodge, Carol; Saraf, Santosh; Garofalo, John; Krishnan, Jerry A.; Garcia, Joe G.N.; Cavallari, Larisa H.

2013-01-01

Objective To determine the procedural feasibility of a pharmacist-led interdisciplinary service for providing genotype-guided warfarin dosing for hospitalized patients newly starting warfarin. Design Prospective observational study Setting 483-bed hospital affiliated with a large academic institution Participants Eighty patients started on warfarin and managed by a newly implemented pharmacogenetics service. Intervention Routine warfarin genotyping and clinical pharmacogenetics consultation Measurements and Main Results The primary outcomes were percent of genotype-guided dose recommendations available prior to the second warfarin dose and adherence of the medical staff to doses recommended by the pharmacogenetics service. Of 436 genotype orders during the first 6 months of the service, 190 were deemed appropriate. For 80 patients on the service who consented to data collection, 77% of genotypes were available prior to the second warfarin dose. The median (range) time from the genotype order to the genotype result was 26 (7 to 80) hours, and the time to genotype-guided dosing recommendation was 30 (7 to 80) hours. Seventy-three percent of warfarin doses ordered by the medical staff were within 0.5 mg of the dose recommended by the pharmacogenetics consult service. Conclusions Providing routine genotype-guided warfarin dosing supported by a pharmacogenetics consult service is feasible from a procedural standpoint, with the majority of genotypes available prior to the second warfarin dose and good adherence to genotype-guided dose recommendations by the medical staff. PMID:23864527

Prevalence of Drug Combinations Increasing Bleeding Risk Among Warfarin Users With and Without Alzheimer's Disease.

PubMed

Taipale, Heidi; Vuorikari, Hanna; Tanskanen, Antti; Koponen, Marjaana; Tiihonen, Jari; Kettunen, Raimo; Hartikainen, Sirpa

2015-11-01

The aim of this study was to analyse the prevalence and predictors of drug combinations increasing bleeding risk among warfarin users with and without Alzheimer's disease (AD). This retrospective observational study utilised data from the Finnish MEDALZ-2005 cohort. The MEDALZ-2005 study included all community-dwelling persons with a clinically verified diagnosis of AD at the end of 2005, and one comparison person without AD for each case. Data on drug use was collected from the Prescription Register. We included persons who were warfarin users during the study period 2006-2009. Drug combinations increasing bleeding risk with warfarin included selective serotonin reuptake inhibitors (SSRIs), non-steroidal anti-inflammatory agents (NSAIDs), other antithrombotic drugs and tramadol. Factors associated with combination use were investigated with logistic regression. During the follow-up, 3385 persons with AD and 4830 persons without AD used warfarin. Drug combinations increasing bleeding risk were more common in warfarin users with AD than without AD [35.9 and 30.5%, respectively (p < 0.0001)]. The most common combination was SSRIs and warfarin, which was more common among persons with AD (23.8%) than among persons without AD (10.9%). NSAIDs and warfarin combination was more common among persons without AD. Combination use was associated with AD, female gender, younger age, diabetes mellitus, rheumatoid arthritis and asthma/chronic obstructive pulmonary disease (COPD). Use of drug combinations increasing bleeding risk was more common among warfarin users with AD. Special attention should be paid to minimise the duration of concomitant use and to find safer alternatives without increased bleeding risk.

[Administration of idarucizumab in spontaneous intracerebral hemorrhage under dabigatran-therapy].

PubMed

Bereczki, Dániel; Szilágyi, Géza; Kakuk, Ilona; Szakács, Zoltán; May, Zsolt

2017-09-30

Introduction - Among antidotes in development for reversal of novel oral anticoagulants, dabigatran-specific idarucizumab was the first one to reach the market. Case presentation - We present the first Hungarian case of intracerebral hemorrhage under treatment with dabigatran, where idarucizumab was administered to suspend anticoagulation. Discussion - Our report is concordant with prior publications, confirming the efficacy of the antidote in reversing the effect of dabigatran, and thus, preventing intracerebral hematoma progression in the acute phase. Conclusion - Since there is no proven alternative to idarucizumab, conducting randomized clinical trials would be unethical. Therefore, besides case reports, positive results of prospective studies could help us revise therapeutic guidelines, and thus, improve the prognosis of dabigatran-associated intracerebral hemorrhages.

Direct oral anticoagulants compared with warfarin in patients with severe blunt trauma.

PubMed

Feeney, James M; Neulander, Matthew; DiFiori, Monica; Kis, Lilla; Shapiro, David S; Jayaraman, Vijay; Marshall, William T; Montgomery, Stephanie C

2017-01-01

We queried our Trauma Quality Improvement Program registry for patients who presented between 6/1/2011 and 9/1/2015 with severe (injury severity score (ISS)>15) blunt traumatic injury during anticoagulant use. Patients were then grouped into those prescribed warfarin and patients prescribed any of the available novel Direct Oral Anticoagulants (DOAC) medications. We excluded severe (AIS≧4) head injuries. There were no differences between DOAC and warfarin groups in terms of age, gender mean ISS, median hospital or intensive care unit lengths of stay, complication proportions, numbers of complications per patient, or the proportion of patients requiring transfusion. Finally, excluding patients who died, the observed proportion of discharge to skilled nursing facility was similar. In our sample of trauma patients, DOAC use was associated with significantly lower mortality (DOAC group 8.3% vs. warfarin group 29.5%, p<0.015). The ratio of units transfused per patient was also lower in the DOAC group (2.8±1.8 units/patient in the DOAC group vs. 6.7±6.4 units per patient in the warfarin group; p=0.001). In conclusion, we report an association with decrease in mortality and a decrease in transfused blood products in severely injured trauma patients with likely minimal or no head injury taking novel DOACs over those anticoagulated with warfarin for outpatient anticoagulation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Post-operative re-bleeding in patients with hypertensive ICH is closely associated with the CT blend sign.

PubMed

Wu, Guofeng; Shen, Zhengkui; Wang, Likun; Sun, Shujie; Luo, Jinbiao; Mao, Yuanhong

2017-07-06

Intracranial post-operative re-haemorrhage is an important complication in patients with hypertensive intracerebral haemorrhage (ICH). The purpose of the present study was to determine the value of the computed tomography (CT) blend sign in predicting post-operative re-haemorrhage in patients with ICH. A total of 126 patients with ICH were included in the present study. All the patients underwent standard stereotactic minimally invasive surgery(MIS) to remove the ICH within 24 h following admission. There were 41 patients with a blend sign on initial CT and 85 patients without a blend sign on the initial CT. Multivariable logistic regression analyses were performed to assess the relationship between the presence of the blend sign on the non-enhanced admission CT scan and post-operative re-haemorrhage. Post-operative re-haemorrhage occurred in 24 of the 41 patients with the blend sign, and in 9 of the 85 patients without the blend sign. The incidence of re-haemorrhage was significantly different between the groups. The multivariate logistic regression analysis demonstrated that the initial Glasgow coma scale score (p = 0.002) and blend sign (P < 0.00) on the initial CT scan are independent predictors of post-operative re-haemorrhage. The sensitivity, specificity, and positive and negative predictive values of the blend sign for predicting post-operative re-haemorrhage were 72.7, 81.7, 58.5 and 89.4%, respectively. The presence of the blend sign on the initial CT scan is closely associated with post-operative re-haemorrhage in patients with ICH who undergo stereotactic MIS.

Patterns of international normalized ratio values among new warfarin patients with nonvalvular atrial fibrillation.

PubMed

Nelson, Winnie W; Milentijevic, Dejan; Wang, Li; Baser, Onur; Damaraju, C V; Schein, Jeffrey R

2016-12-01

Limited information exists regarding the relationship between international normalized ratio (INR) control/stability and the discontinuation of warfarin therapy among patients with nonvalvular atrial fibrillation (NVAF). This study evaluated the association between INR stabilization and warfarin discontinuation and assessed INR patterns before and after INR stabilization among patients (≥18 years) with NVAF who newly initiated warfarin (Veterans Health Administration datasets; October 1, 2007 through September 30, 2012). Achievement of INR stabilization (≥3 consecutive in-range therapeutic INR measurements ≥7 days apart) was examined from warfarin initiation through the end of warfarin exposure. Proportion of time in therapeutic range during warfarin exposure was calculated (Rosendaal method) and categorized as at least 60% or less than 60%. Among 34 346 patients, 49.4% achieved INR stabilization (mean time to stabilization, 98 days). Approximately 40% of INR values were out-of-range, even after achieving stabilization. During 30 days following an INR 4.0 or higher, patients had more INR testing than the overall mean (2.51 vs. 1.67 tests). Warfarin discontinuation was 4.2 times more likely among patients without INR stabilization versus those with INR stabilization (P < 0.00001). Patients with poor INR control (time in therapeutic range <60%) were 1.76 times more likely to discontinue warfarin within 1 year (P < 0.0001). INR stabilization is a better predictor of warfarin discontinuation than poor INR control. Improved approaches are necessary to maintain appropriate anticoagulation levels among patients with NVAF.

[Enantioselective determinination of R-warfarin/S-warfarin in human plasma using liquid chromatography-tandem mass spectrometry and its application in a drug-drug interaction study].

PubMed

Jin, Shu; Zhang, Yi-Fan; Chen, Xiao-Yan; Liu, Ke; Zhong, Da-Fang

2012-01-01

To study the drug-drug interaction of morinidazole and warfarin and its application, a sensitive and rapid liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the determination of R-warfarin/S-warfarin in human plasma. In a random, two-period crossover study, 12 healthy volunteers received a single oral dose of 5 mg racemic warfarin in the absence and presence of morinidazole. Blood samples were collected according to a pre-designed time schedule. R-warfarin, S-warfarin and methyclothiazide were extracted with ethylether : methylenechloride (3 : 2), then separated on a Astec Chirobiotic V (150 mm x 4.6 mm ID, 5 microm) column using 5 mmol x L(-1) ammonium acetate (pH 4.0) - acetonitrile as mobile phase at a flow-rate of 1.5 mL x min(-1). The mobile phase was splitted and 0.5 mL x min(-1) was introduced into MS. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the negative ion mode. Quantification was performed using multiple reaction monitoring (MRM). The resolution of warfarin enantiomers is 1.56. The linear calibration curves for R-warfarin and S-warfarin both were obtained in the concentration range of 5 - 1 000 ng x mL(-1). Intra- and inter-day relative standard deviation (RSD) for R-warfarin and S-warfarin over the entire concentration range across three validation runs was both less than 10%, and relative error (RE) ranged from -4.9% to 0.7%, separately. The method herein described is effective and convenient, and suitable for the study of metabolic interaction between morinidazole and warfarin. The results showed that coadministration of warfarin with morinidazole did not affect the pharmacokinetics of either R-warfarin or S-warfarin.

Administrative claims analysis of the relationship between warfarin use and risk of hemorrhage including drug-drug and drug-disease interactions.

PubMed

Zhang, Kui; Young, Christopher; Berger, Jan

2006-10-01

Despite the risk of hemorrhage, warfarin is the most commonly used oral anticoagulant today, both as monotherapy and when taken in combination with selected drugs. Warfarin is used most commonly for irregular heartbeat, after a heart attack, and after joint or heart valve replacement surgery. To evaluate the relative risk of hemorrhage in health plan members who received warfarin concomitant with a drug known to cause an interaction or after diagnosis of liver disease or heart failure (HF). A cohort study sample was drawn from an administrative database comprising medical and pharmacy claims for 1.7 million health plan members. A health plan member was defined as anyone who was eligible for pharmacy and medical benefits at any time from October 1, 2003, to September 30, 2004. To be included in the study, a member must have received at least 1 pharmacy claim for warfarin during the study period and been younger than 100 years. Hemorrhage was defined as a diagnosed bleeding episode recorded on a medical claim within 7 calendar days of a fill date for a pharmacy claim (new or refill) for warfarin. The following variables were used to predict the outcome measures: type of drug-drug or drug-disease interaction, patient age and gender, number of unique prescribers during the year for all drugs, specialty of the first prescriber for warfarin, average dose of warfarin, and days of warfarin therapy. Because individuals were followed only during the calendar year under study, the authors have interpreted the days of therapy measured primarily as a control on exposure. The outcome measures are prevalence of drug and disease interactions among members receiving warfarin therapy and the per-patient-per-year and per-member-per-month (PMPM) cost of medical treatment of hemorrhage associated with warfarin therapy including drug and disease interactions. Costs are defined as the total paid amount for a procedure or service after negotiated provider discounts and subtraction of

Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans.

PubMed

Hernandez, W; Gamazon, E R; Aquino-Michaels, K; Smithberger, E; O'Brien, T J; Harralson, A F; Tuck, M; Barbour, A; Cavallari, L H; Perera, M A

2017-04-01

Essentials Genetic variants controlling gene regulation have not been explored in pharmacogenomics. We tested liver expression quantitative trait loci for association with warfarin dose response. A novel predictor for increased warfarin dose response in African Americans was identified. Precision medicine must take into account population-specific variation in gene regulation. Background Warfarin is commonly used to control and prevent thromboembolic disorders. However, because of warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs). Objectives We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs. Patients/Methods We identified a total of 56 expression quantitative trait loci (eQTLs) for CYP2C9, VKORC1 and CALU derived from human livers and evaluated their association with warfarin dose response in two independent AA warfarin patient cohorts. Results We found that rs4889606, a strong cis-eQTL for VKORC1 (log 10 Bayes Factor = 12.02), is significantly associated with increased warfarin daily dose requirement (β = 1.1; 95% confidence interval [CI] 0.46 to 1.8) in the discovery cohort (n = 305) and in the replication cohort (β = 1.04; 95% CI 0.33 -1.7; n = 141) after conditioning on relevant covariates and the VKORC1 -1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes and clinical variables, explained 31% of the inter-patient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and European Americans, which may explain the increased dose requirement found in AAs. Conclusion

Infrastructure and clinical practice for the detection and management of trauma-associated haemorrhage and coagulopathy.

PubMed

Driessen, A; Schäfer, N; Albrecht, V; Schenk, M; Fröhlich, M; Stürmer, E K; Maegele, M

2015-08-01

Early detection and management of post-traumatic haemorrhage and coagulopathy have been associated with improved outcomes, but local infrastructures, logistics and clinical strategies may differ. To assess local differences in infrastructure, logistics and clinical management of trauma-associated haemorrhage and coagulopathy, we have conducted a web-based survey amongst the delegates to the 15th European Congress of Trauma and Emergency Surgery (ECTES) and the 2nd World Trauma (WT) Congress held in Frankfurt, Germany, 25-27 May 2014. 446/1,540 delegates completed the questionnaire yielding a response rate of 29%. The majority specified to work as consultants/senior physicians (47.3%) in general (36.1%) or trauma/orthopaedic surgery (44.5%) of level I (70%) or level II (19%) trauma centres. Clinical assessment (>80%) and standard coagulation assays (74.6%) are the most frequently used strategies for early detection and monitoring of bleeding trauma patients with coagulopathy. Only 30% of the respondents declared to use extended coagulation assays to better characterise the bleeding and coagulopathy prompted by more individualised treatment concepts. Most trauma centres (69%) have implemented local protocols based on international and national guidelines using conventional blood products, e.g. packed red blood cell concentrates (93.3%), fresh frozen plasma concentrates (93.3%) and platelet concentrates (83%), and antifibrinolytics (100%). 89% considered the continuous intake of anticoagulants including "new oral anticoagulants" and platelet inhibitors as an increasing threat to bleeding trauma patients. This study confirms differences in infrastructure, logistics and clinical practice for the detection and management of trauma-haemorrhage and trauma-associated coagulopathy amongst international centres. Ongoing work will focus on geographical differences.

Impact of Body Mass Index and Genetics on Warfarin Major Bleeding Outcomes in a Community Setting.

PubMed

Hart, Ragan; Veenstra, David L; Boudreau, Denise M; Roth, Joshua A

2017-02-01

Several studies have demonstrated an association between body mass index (BMI) and warfarin therapeutic dose, but none evaluated the association of BMI with the clinically important outcome of major bleeding in a community setting. To address this evidence gap, we conducted a case-control study to evaluate the association between BMI and major bleeding risk among patients receiving warfarin. We used a case-control study design to evaluate the association between obesity (BMI >30.0 kg/m 2 ) and major bleeding risk among 265 cases and 305 controls receiving warfarin at Group Health, an integrated healthcare system in Washington State. Multivariate logistic regression was used to adjust for potential confounders derived from health plan records and a self-report survey. In exploratory analyses we evaluated the interaction between genetic variants potentially associated with warfarin bleeding (CYP2C9, VKORC1, and CYP4F2) and obesity on the risk of major bleeding. Overall, the sample was 55% male, 94% Caucasian, and mean age was 70 years. Cases and controls had an average of 3.4 and 3.7 years of warfarin use, respectively. Obese patients had significantly lower major bleeding risk relative to non-obese patients (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.39-0.92). The OR was 0.56 (95% CI 0.35-0.90) in patients with ≥1 year of warfarin use, and 0.78 (95% CI 0.40-1.54) in patients with <1 year of warfarin use. An exploratory analysis indicated a statistically significant interaction between CYP4F2*3 genetic status and obesity (P = .049), suggesting a protective effect of obesity on the risk of major bleeding among those wild type for CYP4F2*3, but not among variants. Our findings suggest that BMI is an important clinical factor in assessing and managing warfarin therapy. Future studies should confirm the major bleeding associations, including the interaction between obesity and CYP4F2*3 status identified in this study, and evaluate potential mechanisms

Warfarin interaction with erythromycin.

PubMed

Sato, R I; Gray, D R; Brown, S E

1984-12-01

The drug interaction between warfarin and erythromycin is not well known. We report a case in which erythromycin was observed to markedly potentiate warfarin anticoagulation, resulting in hemorrhage in a patient treated for Legionella pneumonia. The morbidity of this drug interaction is enhanced in elderly patients who have infection accompanied by anorexia and/or fever and who are receiving intravenous erythromycin. The well-documented, temporal relationship established erythromycin as the interacting drug.

Non-valvular atrial fibrillation patients with none or one additional risk factor of the CHA2DS2-VASc score. A comprehensive net clinical benefit analysis for warfarin, aspirin, or no therapy.

PubMed

Lip, Gregory Y H; Skjøth, Flemming; Nielsen, Peter B; Larsen, Torben Bjerregaard

2015-10-01

Oral anticoagulation (OAC) to prevent stroke has to be balanced against the potential harm of serious bleeding, especially intracranial haemorrhage (ICH). We determined the net clinical benefit (NCB) balancing effectiveness and safety of no antithrombotic therapy, aspirin and warfarin in AF patients with none or one stroke risk factor. Using Danish registries, we determined NCB using various definitions intrinsic to our cohort (Danish weights at 1 and 5 year follow-up), with risk weights which were derived from the hazard ratio (HR) of death following an event, relative to HR of death after ischaemic stroke. When aspirin was compared to no treatment, NCB was neutral or negative for both risk strata. For warfarin vs no treatment, NCB using Danish weights was neutral where no risk factors were present and using five years follow-up. For one stroke risk factor, NCB was positive for warfarin vs no treatment, for one year and five year follow-up. For warfarin vs aspirin use in patients with no risk factors, NCB was positive with one year follow-up, but neutral with five year follow-up. With one risk factor, NCB was generally positive for warfarin vs aspirin. In conclusion, we show a positive overall advantage (i.e. positive NCB) of effective stroke prevention with OAC, compared to no therapy or aspirin with one additional stroke risk factor, using Danish weights. 'Low risk' AF patients with no additional stroke risk factors (i.e.CHA2DS2-VASc 0 in males, 1 in females) do not derive any advantage (neutral or negative NCB) with aspirin, nor with warfarin therapy in the long run.

Hemorrhagic Transformation After Large Cerebral Infarction in Rats Pretreated With Dabigatran or Warfarin.

PubMed

Kwon, Il; An, Sunho; Kim, Jayoung; Yang, Seung-Hee; Yoo, Joonsang; Baek, Jang-Hyun; Nam, Hyo Suk; Kim, Young Dae; Lee, Hye Sun; Choi, Hyun-Jung; Heo, Ji Hoe

2017-10-01

It is uncertain whether hemorrhagic transformation (HT) after large cerebral infarction is less frequent in dabigatran users than warfarin users. We compared the occurrence of HT after large cerebral infarction among rats pretreated with dabigatran, warfarin, or placebo. This was a triple-blind, randomized, and placebo-controlled experiment. After treatment with warfarin (0.2 mg/kg), dabigatran (20 mg/kg), or saline for 7 days, Wistar rats were subjected to transient middle cerebral artery occlusion. As the primary outcome, HT was determined by gradient-recalled echo imaging. For the secondary outcome, intracranial hemorrhage was assessed via gradient-recalled echo imaging in surviving rats and via autopsy for dead rats. Of 62 rats, there were 33 deaths (53.2%, 17 technical reasons). Of the intention-to-treat population, 33 rats underwent brain imaging. HT was less frequent in the dabigatran group than the warfarin group (placebo 2/14 [14%], dabigatran 0/10 [0%], and warfarin 9/9 [100%]; dabigatran versus warfarin; P <0.001). In all 62 rats, compared with the placebo (2/14 [14.3%]), the incidence of intracranial hemorrhage was significantly higher in the warfarin group (19/29 [65.5%]; P =0.003), but not in the dabigatran group (6/19 [31.6%]; P =0.420). Mortality was significantly higher in the warfarin group than the dabigatran group (79.3% versus 47.4%; P =0.022), but not related to the hemorrhage frequency. The risk of HT after a large cerebral infarction was significantly increased in rats pretreated with warfarin than those with dabigatran. However, the results here may not have an exact clinical translation. © 2017 American Heart Association, Inc.

Determination of total and unbound warfarin and warfarin alcohols in human plasma by high performance liquid chromatography with fluorescence detection.

PubMed

Lomonaco, Tommaso; Ghimenti, Silvia; Piga, Isabella; Onor, Massimo; Melai, Bernardo; Fuoco, Roger; Di Francesco, Fabio

2013-11-01

Two analytical procedures are presented for the determination of the total content and unbound fraction of both warfarin and warfarin alcohols in human plasma. Chromatographic separation was carried out in isocratic conditions at 25°C on a C-18 reversed-phase column with a mobile phase consisting of a 70% buffer phosphate 25mM at pH=7, 25% methanol and 5% acetonitrile at a flow rate of 1.2mL/min. Fluorescence detection was performed at 390nm (excitation wavelength 310nm). Neither method showed any detectable interference or matrix effect. Inter-day recovery of the total warfarin and warfarin alcohols at a concentration level of 1000ng/mL was 89±3% and 73±3%, respectively, whereas for their unbound fraction (at a concentration level of 10ng/mL) was 66±8% and 90±7%, respectively. The intra- and inter-day precision (assessed as relative standard deviation) was <10% for both methods. The limits of detection were 0.4 and 0.2ng/mL for warfarin and warfarin alcohols, respectively. The methods were successfully applied to a pooled plasma sample obtained from 69 patients undergoing warfarin therapy. Copyright © 2013 Elsevier B.V. All rights reserved.

Pharmacometabonomics Technique to Identify Warfarin Response Using Nuclear Magnetic Resonance Spectroscopy.

PubMed

Bawadikji, Abdulkader A; Teh, Chin-Hoe; Kader, Muhamad A B S A; Sulaiman, Syed A S; Ibrahim, Baharudin

2017-01-01

Warfarin, an anticoagulant medication, is prescribed regularly despite of its bleeding tendency for the prevention and/or treatment of various thromboembolic conditions, such as deep vein thrombosis, and complications associated with atrial fibrillation, and myocardial infarction, but because of its narrow therapeutic window, it has a lot of interactions with drugs and diet. Warfarin relies on regular monitoring of International Normalized Ratio which is a standardized test to measure prothrombin time and appropriate dose adjustment. Pharmacometabonomics is a novel scientific field which deals with identification and quantification of the metabolites present in the metabolome using spectroscopic techniques such as Nuclear Magnetic Resonance (NMR). Pharmacometabonomics helps to indicate perturbation in the levels of metabolites in the cells and tissues due to drug or ingestion of any substance. NMR is one of the most widely-used spectroscopic techniques in metabolomics because of its reproducibility and speed. There are many factors that influence the metabolism of warfarin, making changes in drug dosage common, and clinical factors like drug-drug interactions, dietary interactions and age explain for the most part the variability in warfarin dosing. Some studies have showed that pharmacogenetic testing for warfarin dosing does not improve health outcomes, and around 26% of the variation in warfarin dose requirements remains unexplained yet. Many recent pharmacometabonomics studies have been conducted to identify novel biomarkers of drug therapies such as paracetamol, aspirin and simvastatin. Thus, a technique such as NMR based pharmacometabonomics to find novel biomarkers in plasma and urine might be useful to predict warfarin outcome. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Low Ambient Temperature and Intracerebral Hemorrhage: The INTERACT2 Study

PubMed Central

Zheng, Danni; Arima, Hisatomi; Sato, Shoichiro; Gasparrini, Antonio; Heeley, Emma; Delcourt, Candice; Lo, Serigne; Huang, Yining; Wang, Jiguang; Stapf, Christian; Robinson, Thompson; Lavados, Pablo; Chalmers, John; Anderson, Craig S.

2016-01-01

Background Rates of acute intracerebral hemorrhage (ICH) increase in winter months but the magnitude of risk is unknown. We aimed to quantify the association of ambient temperature with the risk of ICH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) participants on an hourly timescale. Methods INTERACT2 was an international, open, blinded endpoint, randomized controlled trial of patients with spontaneous ICH (<6h of onset) and elevated systolic blood pressure (SBP, 150–220 mmHg) assigned to intensive (target SBP <140 mmHg) or guideline-recommended (SBP <180 mmHg) BP treatment. We linked individual level hourly temperature to baseline data of 1997 participants, and performed case-crossover analyses using a distributed lag non-linear model with 24h lag period to assess the association of ambient temperature and risk of ICH. Results were presented as overall cumulative odds ratios (ORs) and 95% CI. Results Low ambient temperature (≤10°C) was associated with increased risks of ICH: overall cumulative OR was 1.37 (0.99–1.91) for 10°C, 1.92 (1.31–2.81) for 0°C, 3.13 (1.89–5.19) for -10°C, and 5.76 (2.30–14.42) for -20°C, as compared with a reference temperature of 20°C.There was no clear relation of low temperature beyond three hours after exposure. Results were consistent in sensitivity analyses. Conclusions Exposure to low ambient temperature within several hours increases the risk of ICH. Trial Registration ClinicalTrials.gov NCT00716079 PMID:26859491

Edoxaban versus warfarin in patients with atrial fibrillation.

PubMed

Giugliano, Robert P; Ruff, Christian T; Braunwald, Eugene; Murphy, Sabina A; Wiviott, Stephen D; Halperin, Jonathan L; Waldo, Albert L; Ezekowitz, Michael D; Weitz, Jeffrey I; Špinar, Jindřich; Ruzyllo, Witold; Ruda, Mikhail; Koretsune, Yukihiro; Betcher, Joshua; Shi, Minggao; Grip, Laura T; Patel, Shirali P; Patel, Indravadan; Hanyok, James J; Mercuri, Michele; Antman, Elliott M

2013-11-28

=0.32). Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.).

Computed Tomographic Blend Sign Is Associated With Computed Tomographic Angiography Spot Sign and Predicts Secondary Neurological Deterioration After Intracerebral Hemorrhage.

PubMed

Sporns, Peter B; Schwake, Michael; Schmidt, Rene; Kemmling, André; Minnerup, Jens; Schwindt, Wolfram; Cnyrim, Christian; Zoubi, Tarek; Heindel, Walter; Niederstadt, Thomas; Hanning, Uta

2017-01-01

Significant early hematoma growth in patients with intracerebral hemorrhage is an independent predictor of poor functional outcome. Recently, the novel blend sign (BS) has been introduced as a new imaging sign for predicting hematoma growth in noncontrast computed tomography. Another parameter predicting increasing hematoma size is the well-established spot sign (SS) visible in computed tomographic angiography. We, therefore, aimed to clarify the association between established SS and novel BS and their values predicting a secondary neurological deterioration. Retrospective study inclusion criteria were (1) spontaneous intracerebral hemorrhage confirmed on noncontrast computed tomography and (2) noncontrast computed tomography and computed tomographic angiography performed on admission within 6 hours after onset of symptoms. We defined a binary outcome (secondary neurological deterioration versus no secondary deterioration). As secondary neurological deterioration, we defined (1) early hemicraniectomy under standardized criteria or (2) secondary decrease of Glasgow Coma Scale of >3 points, both within the first 48 hours after symptom onset. Of 182 patients with spontaneous intracerebral hemorrhage, 37 (20.3%) presented with BS and 39 (21.4%) with SS. Of the 81 patients with secondary deterioration, 31 (38.3%) had BS and SS on admission. Multivariable logistic regression analysis identified hematoma volume (odds ratio, 1.07 per mL; P≤0.001), intraventricular hemorrhage (odds ratio, 3.08; P=0.008), and the presence of BS (odds ratio, 11.47; P≤0.001) as independent predictors of neurological deterioration. The BS, which is obtainable in noncontrast computed tomography, shows a high correlation with the computed tomographic angiography SS and is a reliable predictor of secondary neurological deterioration after spontaneous intracerebral hemorrhage. © 2016 American Heart Association, Inc.

CYP2C9 Genotype-Dependent Warfarin Pharmacokinetics: Impact of CYP2C9 Genotype on R- and S-Warfarin and Their Oxidative Metabolites.

PubMed

Flora, Darcy R; Rettie, Allan E; Brundage, Richard C; Tracy, Timothy S

2017-03-01

Multiple factors can impact warfarin therapy, including genetic variations in the drug-metabolizing enzyme cytochrome P450 2C9 (CYP2C9). Compared with individuals with the wild-type allele, CYP2C9*1, carriers of the common *3 variant have significantly impaired CYP2C9 metabolism. Genetic variations in CYP2C9, the primary enzyme governing the metabolic clearance of the more potent S-enantiomer of the racemic anticoagulant warfarin, may impact warfarin-drug interactions. To establish a baseline for such studies, plasma and urine concentrations of R- and S-warfarin and 10 warfarin metabolites were monitored for up to 360 hours following a 10-mg warfarin dose in healthy subjects with 4 different CYP2C9 genotypes: CYP2C9*1/*1 (n = 8), CYP2C9*1/*3 (n = 9), CYP2C9*2/*3 (n = 3), and CYP2C9*3/*3 (n = 4). Plasma clearance of S-warfarin, but not R-warfarin, decreased multiexponentially and in a CYP2C9 gene-dependent manner: 56%, 70%, and 75% for CYP2C9*1/*3, CYP2C9*2/*3, and CYP2C9*3/*3 genotypes, respectively, compared with CYP2C9*1/*1, resulting in pronounced differences in the S:R ratio that identified warfarin-sensitive genotypes. CYP2C9 was the primary P450 enzyme contributing to S-warfarin metabolism and a minor contributor to R-warfarin metabolism. In the presence of a defective CYP2C9 allele, switching of warfarin metabolism to other oxidative pathways and P450 enzymes for the metabolic elimination of S-warfarin was not observed. The 10-hydroxywarfarin metabolites, whose detailed pharmacokinetics are reported for the first time, exhibited a prolonged half-life with no evidence of renal excretion and displayed elimination rate-limited kinetics. Understanding the impact of CYP2C9 genetics on warfarin pharmacokinetics lays the foundation for future genotype-dependent warfarin-drug interaction studies. © 2016, The American College of Clinical Pharmacology.

Pharmacogenomics of warfarin in populations of African descent

PubMed Central

Suarez-Kurtz, Guilherme; Botton, Mariana R

2013-01-01

Warfarin is the most commonly prescribed oral anticoagulant worldwide despite its narrow therapeutic index and the notorious inter- and intra-individual variability in dose required for the target clinical effect. Pharmacogenetic polymorphisms are major determinants of warfarin pharmacokinetic and dynamics and included in several warfarin dosing algorithms. This review focuses on warfarin pharmacogenomics in sub-Saharan peoples, African Americans and admixed Brazilians. These ‘Black’ populations differ in several aspects, notably their extent of recent admixture with Europeans, a factor which impacts on the frequency distribution of pharmacogenomic polymorphisms relevant to warfarin dose requirement for the target clinical effect. Whereas a small number of polymorphisms in VKORC1 (3673G > A, rs9923231), CYP2C9 (alleles *2 and *3, rs1799853 and rs1057910, respectively) and arguably CYP4F2 (rs2108622), may capture most of the pharmacogenomic influence on warfarin dose variance in White populations, additional polymorphisms in these, and in other, genes (e.g. CALU rs339097) increase the predictive power of pharmacogenetic warfarin dosing algorithms in the Black populations examined. A personalized strategy for initiation of warfarin therapy, allowing for improved safety and cost-effectiveness for populations of African descent must take into account their pharmacogenomic diversity, as well as socio-economical, cultural and medical factors. Accounting for this heterogeneity in algorithms that are ‘friendly’ enough to be adopted by warfarin prescribers worldwide requires gathering information from trials at different population levels, but demands also a critical appraisal of racial/ethnic labels that are commonly used in the clinical pharmacology literature but do not accurately reflect genetic ancestry and population diversity. PMID:22676711

Retroperitoneal Haematoma in a Patient with Dengue Haemorrhagic Fever: A Rare Case Report.

PubMed

Singh, Jasminder; Singh, Harpreet; Sukhija, Gagandeep; Jagota, Ruchi; Bala, Saroj

2016-11-01

Dengue Haemorrhagic Fever (DHF) has diverse manifestations ranging from asymptomatic petechial skin haemorrhages to life threatening cerebral, pulmonary, gastrointestinal and genitourinary haemorrhages. However, the association of spontaneous retroperitoneal haematomas with DHF is not well documented in literature. We report a rare case of spontaneous retroperitoneal haematoma complicating DHF.

Ebola haemorrhagic fever

PubMed Central

Feldmann, Heinz; Geisbert, Thomas W

2012-01-01

Ebola viruses are the causative agents of a severe form of viral haemorrhagic fever in man, designated Ebola haemorrhagic fever, and are endemic in regions of central Africa. The exception is the species Reston Ebola virus, which has not been associated with human disease and is found in the Philippines. Ebola virus constitutes an important local public health threat in Africa, with a worldwide effect through imported infections and through the fear of misuse for biological terrorism. Ebola virus is thought to also have a detrimental effect on the great ape population in Africa. Case-fatality rates of the African species in man are as high as 90%, with no prophylaxis or treatment available. Ebola virus infections are characterised by immune suppression and a systemic inflammatory response that causes impairment of the vascular, coagulation, and immune systems, leading to multiorgan failure and shock, and thus, in some ways, resembling septic shock. PMID:21084112

Neonatal intraventricular haemorrhage associated with maternal use of paroxetine

PubMed Central

Duijvestijn, Yvonne C M; Kalmeijer, Mathijs D; Passier, Anneke L M; Dahlem, Peter; Smiers, Frans

2003-01-01

Selective serotonin reuptake inhibitors (SSRIs) have been reported to inhibit serotonin uptake into platelets, resulting in decreased platelet function. We report a case of a large intraventricular haemorrhage in a 6-h-old boy, whose mother used paroxetine during pregnancy. PMID:14651736

Identifying Drug-Drug Interactions by Data Mining: A Pilot Study of Warfarin-Associated Drug Interactions.

PubMed

Hansen, Peter Wæde; Clemmensen, Line; Sehested, Thomas S G; Fosbøl, Emil Loldrup; Torp-Pedersen, Christian; Køber, Lars; Gislason, Gunnar H; Andersson, Charlotte

2016-11-01

Knowledge about drug-drug interactions commonly arises from preclinical trials, from adverse drug reports, or based on knowledge of mechanisms of action. Our aim was to investigate whether drug-drug interactions were discoverable without prior hypotheses using data mining. We focused on warfarin-drug interactions as the prototype. We analyzed altered prothrombin time (measured as international normalized ratio [INR]) after initiation of a novel prescription in previously INR-stable warfarin-treated patients with nonvalvular atrial fibrillation. Data sets were retrieved from clinical work. Random forest (a machine-learning method) was set up to predict altered INR levels after novel prescriptions. The most important drug groups from the analysis were further investigated using logistic regression in a new data set. Two hundred and twenty drug groups were analyzed in 61 190 novel prescriptions. We rediscovered 2 drug groups having known interactions (β-lactamase-resistant penicillins [dicloxacillin] and carboxamide derivatives) and 3 antithrombotic/anticoagulant agents (platelet aggregation inhibitors excluding heparin, direct thrombin inhibitors [dabigatran etexilate], and heparins) causing decreasing INR. Six drug groups with known interactions were rediscovered causing increasing INR (antiarrhythmics class III [amiodarone], other opioids [tramadol], glucocorticoids, triazole derivatives, and combinations of penicillins, including β-lactamase inhibitors) and two had a known interaction in a closely related drug group (oripavine derivatives [buprenorphine] and natural opium alkaloids). Antipropulsives had an unknown signal of increasing INR. We were able to identify known warfarin-drug interactions without a prior hypothesis using clinical registries. Additionally, we discovered a few potentially novel interactions. This opens up for the use of data mining to discover unknown drug-drug interactions in cardiovascular medicine. © 2016 American Heart Association

Resource use and cost implications of switching among warfarin formulations in atrial fibrillation patients.

PubMed

Kwong, Winghan Jacqueline; Kamat, Siddhesh; Fang, Christy

2012-12-01

Despite the uncertainty surrounding the safety of switching warfarin formulations, limited data exist on the resource use and costs associated with this switching pattern. To evaluate health care resource use and costs associated with switching warfarin formulations among patients with atrial fibrillation (AF) in a managed care organization. Patients diagnosed with AF (ICD-9 427.31) between July 2004 and August 2008 and who received warfarin therapy were identified in the HealthCore Integrated Research Database and categorized into 3 groups: users of generic warfarin formulations from a single drug manufacturer (generic-only group), users of branded warfarin formulations only (brand-only group), and patients who used generic and branded warfarin therapy interchangeably or who may have used generic drugs from 1 or more manufacturers (generic/brand switching group). Patients were followed 12 months or longer after their index warfarin prescription date to compare all-cause resource use and costs using multivariable regression analysis. The analysis included 12,908 patients: 71.82% were in the genericonly group, 9.61% were in the brand-only group, and 18.57% were in the generic/brand switching group. Patients in the generic/brand switching group were more likely to be hospitalized (relative risk [RR] = 1.43, p < 0.0001) or to use emergency department services (RR = 1.20, p < 0.01), compared to the brand-only users. Hospitalizations were more likely (RR = 1.26, p < 0.001) to occur among generic-only users versus brand-only users. Adjusted mean pharmacy costs per member per month were lower in the generic/brand switching group compared to the brand-only group ($257 vs $273, p = 0.038), but inpatient costs were higher ($1250 vs $972, p < 0.001), resulting in higher ($2125 vs $1847, p < 0.001) total costs. Generic-only users had lower pharmacy costs compared to brand-only users ($246 vs $273, p < 0.001), but total health care costs trended to be higher in the generic

Medical cost reductions associated with the usage of novel oral anticoagulants vs warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF, and ARISTOTLE trials.

PubMed

Deitelzweig, Steve; Amin, Alpesh; Jing, Yonghua; Makenbaeva, Dinara; Wiederkehr, Daniel; Lin, Jay; Graham, John

2012-01-01

The randomized clinical trials, RE-LY, ROCKET-AF, and ARISTOTLE, demonstrate that the novel oral anticoagulants (NOACs) are effective options for stroke prevention among non-valvular atrial fibrillation (AF) patients. This study aimed to evaluate the medical cost reductions associated with the use of individual NOACs instead of warfarin from the US payer perspective. Rates for efficacy and safety clinical events for warfarin were estimated as the weighted averages from the RE-LY, ROCKET-AF and ARISTOTLE trials, and event rates for NOACs were determined by applying trial hazard ratios or relative risk ratios to such weighted averages. Incremental medical costs to a US health payer of an AF patient experiencing a clinical event during 1 year following the event were obtained from published literature and inflation adjusted to 2010 cost levels. Medical costs, excluding drug costs, were evaluated and compared for each NOAC vs warfarin. Sensitivity analyses were conducted to determine the influence of variations in clinical event rates and incremental costs on the medical cost reduction. In a patient year, the medical cost reduction associated with NOAC usage instead of warfarin was estimated to be -$179, -$89, and -$485 for dabigatran, rivaroxaban, and apixaban, respectively. When clinical event rates and costs were allowed to vary simultaneously, through a Monte Carlo simulation, the 95% confidence interval of annual medical costs differences ranged between -$424 and +$71 for dabigatran, -$301 and +$135 for rivaroxaban, and -$741 and -$252 for apixaban, with a negative number indicating a cost reduction. Of the 10,000 Monte-Carlo iterations 92.6%, 79.8%, and 100.0% were associated with a medical cost reduction >$0 for dabigatran, rivaroxaban, and apixaban, respectively. Usage of the NOACs, dabigatran, rivaroxaban, and apixaban may be associated with lower medical (excluding drug costs) costs relative to warfarin, with apixaban having the most substantial medical cost

Warfarin for stroke prevention in octogenarians with atrial fibrillation.

PubMed

Howard, P A; Ellerbeck, E F; Engelman, K K; Dunn, M I

2001-01-01

The authors examined warfarin use in elderly patients with atrial fibrillation. Medical records were abstracted from a random sample of Medicare beneficiaries with atrial fibrillation who were discharged from Kansas hospitals. Data were analyzed for warfarin and aspirin use and risk factors for stroke or bleeding in patients 65-79 years of age or 80 years and older. Stroke risk factors other than age and atrial fibrillation were seen in 98% of 142 patients less than 80 years of age and 100% of 141 octogenarians. Warfarin use was similar in the younger and older age groups (50% vs. 45%, respectively; p = ns) and was not associated with the number of stroke or bleeding risk factors. Compared to patients less than 80 years of age, octogenarians were less likely to receive aspirin (38% vs. 27%, respectively; p < 0.05). Anticoagulation rates for high-risk patients with atrial fibrillation were low and poorly explained by stroke or bleeding risks.

Pharmacogenomics of warfarin in populations of African descent.

PubMed

Suarez-Kurtz, Guilherme; Botton, Mariana R

2013-02-01

Warfarin is the most commonly prescribed oral anticoagulant worldwide despite its narrow therapeutic index and the notorious inter- and intra-individual variability in dose required for the target clinical effect. Pharmacogenetic polymorphisms are major determinants of warfarin pharmacokinetic and dynamics and included in several warfarin dosing algorithms. This review focuses on warfarin pharmacogenomics in sub-Saharan peoples, African Americans and admixed Brazilians. These 'Black' populations differ in several aspects, notably their extent of recent admixture with Europeans, a factor which impacts on the frequency distribution of pharmacogenomic polymorphisms relevant to warfarin dose requirement for the target clinical effect. Whereas a small number of polymorphisms in VKORC1 (3673G > A, rs9923231), CYP2C9 (alleles *2 and *3, rs1799853 and rs1057910, respectively) and arguably CYP4F2 (rs2108622), may capture most of the pharmacogenomic influence on warfarin dose variance in White populations, additional polymorphisms in these, and in other, genes (e.g. CALU rs339097) increase the predictive power of pharmacogenetic warfarin dosing algorithms in the Black populations examined. A personalized strategy for initiation of warfarin therapy, allowing for improved safety and cost-effectiveness for populations of African descent must take into account their pharmacogenomic diversity, as well as socio-economical, cultural and medical factors. Accounting for this heterogeneity in algorithms that are 'friendly' enough to be adopted by warfarin prescribers worldwide requires gathering information from trials at different population levels, but demands also a critical appraisal of racial/ethnic labels that are commonly used in the clinical pharmacology literature but do not accurately reflect genetic ancestry and population diversity. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Low cerebral blood flow is a risk factor for severe intraventricular haemorrhage

PubMed Central

Meek, J.; Tyszczuk, L.; Elwell, C.; Wyatt, J

1999-01-01

AIMS—To investigate the relation between cerebral blood flow on the first day of postnatal life and the severity of any subsequent germinal matrix haemorrhage-intraventricular haemorrhage (GMH-IVH).
METHODS—Cerebral blood flow was measured in 24 babies during the first 24 hours of life using near infrared spectroscopy. Repeated cerebral ultrasound examination was performed to define the maximum extent of GMH-IVH. Infants were classified as: normal scan, minor periventricular haemorrhage (haemorrhage that resolved), or severe GMH-IVH (haemorrhage distending the ventricles, that progressed to either post haemorrhagic dilatation or porencephalic cyst formation).
RESULTS—Cerebral blood flow was significantly lower in the infants with GMH-IVH (median 7.0 ml/100 g/min) than those without haemorrhage (median 12.2 ml/100 g/min), despite no difference in carbon dioxide tension and a higher mean arterial blood pressure. On subgroup analysis, those infants with severe GMH-IVH had the lowest cerebral blood flow.
CONCLUSION—A low cerebral blood flow on the first day of life is associated with the subsequent development of severe intraventricular haemorrhage.

 PMID:10375356

Locations and Mucosal Lesions Responsible for Major Gastrointestinal Bleeding in Patients on Warfarin or Dabigatran.

PubMed

Kolb, Jennifer M; Flack, Kathryn Friedman; Chatterjee-Murphy, Prapti; Desai, Jay; Wallentin, Lars C; Ezekowitz, Michael; Connolly, Stuart; Reilly, Paul; Brueckmann, Martina; Ilgenfritz, John; Aisenberg, James

2018-03-27

Different oral anticoagulants may be associated with gastrointestinal bleeding (GIB) from different locations or mucosal lesions. We aimed to test this hypothesis. Two blinded gastroenterologists independently analyzed source documents from the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial of dabigatran 150 mg BID (D150), dabigatran 110 mg BID (D110) versus warfarin in non-valvular atrial fibrillation (NVAF). Major GIB events (total n = 546) and life-threatening GIB events (n = 258) were more common with D150 versus warfarin (RR 1.57 [1.28-1.92] and RR 1.62 [1.20-2.18], respectively) and similar for D110 compared to warfarin (RR 1.11 [0.89-1.38] and RR 1.16 [0.84-1.61], respectively). Fatal bleeding was similarly rare across treatment groups. Lower GI major bleeding and life-threatening bleeding were more common with D150 compared to warfarin (RR 2.23 [1.47, 3.38] and RR 2.64 [1.36, 5.13], respectively) and with D110 compared to warfarin (RR 1.78 [1.16, 2.75] and RR 2.00 [1.00, 4.00], respectively). MGIB from colonic angiodysplasia was increased with dabigatran versus warfarin (P < 0.01 for both dose comparisons). Subacute and chronic MGIB events were more common with D150 than with warfarin (RR 1.72 [1.06, 2.78] and RR 1.66 [1.12, 2.45], respectively), as were hematochezia or melena (RR 1.67 [1.18, 2.36] and RR 1.72 [1.20, 2.47], respectively). In a chronic NVAF population, D150 but not D110 is associated with increased major and life-threatening GI bleeding in comparison with warfarin. At both dabigatran doses, increased bleeding from the colorectum, in particular from angiodysplasia, is seen.

Warfarin Initiation, Atrial Fibrillation, and Kidney Function: Comparative Effectiveness and Safety of Warfarin in Older Adults With Newly Diagnosed Atrial Fibrillation.

PubMed

Jun, Min; James, Matthew T; Ma, Zhihai; Zhang, Jianguo; Tonelli, Marcello; McAlister, Finlay A; Manns, Braden J; Ravani, Pietro; Quinn, Robert R; Wiebe, Natasha; Perkovic, Vlado; Wilton, Stephen B; Winkelmayer, Wolfgang C; Hemmelgarn, Brenda R

2017-06-01

The effectiveness and safety of warfarin use among patients with atrial fibrillation (AF) and reduced kidney function are uncertain. Community-based retrospective cohort study (May 1, 2003, to March 31, 2012) using province-wide laboratory and administrative data in Alberta, Canada. 14,892 adults 66 years or older with new AF and a measurement of kidney function. Long-term dialysis patients or kidney transplant recipients were excluded. Propensity scores were used to construct a matched-pairs cohort of patients with AF who did and did not have a warfarin prescription within a 60-day period surrounding their AF diagnosis. Within 1 year of initiating warfarin therapy (or the matched date for nonusers): (1) the composite of all-cause death, ischemic stroke, or transient ischemic attack (also assessed as separate end points) and (2) first hospitalization or emergency department visit for a major bleeding episode defined as an intracranial, upper or lower gastrointestinal, or other bleeding. Baseline glomerular filtration rate (GFR) was estimated using the CKD-EPI creatinine equation. Patients were matched within estimated GFR (eGFR) categories: ≥90, 60 to 89, 45 to 59, 30 to 44, and <30mL/min/1.73m 2 . Information for baseline characteristics (sociodemographics, comorbid conditions, and prescription drug use) was obtained. Across eGFR categories, warfarin therapy initiation was associated with lower risk for the composite outcome compared to nonuse (adjusted HRs [95% CI] for eGFR categories ≥ 90, 60-89, 45-59, 30-44, and <30mL/min/1.73m 2 : 0.59 [0.35-1.01], 0.61 [0.54-0.70], 0.55 [0.47-0.65], 0.54 [0.44-0.67], and 0.64 [0.47-0.87] mL/min/1.73m 2 , respectively). Compared to nonuse, warfarin therapy was not associated with higher risk for major bleeding except for those with eGFRs of 60 to 89mL/min/1.73m 2 (HR, 1.36; 95% CI, 1.13-1.64). Selection bias. Among older adults with AF, warfarin therapy initiation was associated with a significantly lower 1-year risk

New high-performance liquid chromatography method for the determination of (R)-warfarin and (S)-warfarin using chiral separation on a glycopeptide-based stationary phase.

PubMed

Malakova, Jana; Pavek, Petr; Svecova, Lucie; Jokesova, Iveta; Zivny, Pavel; Palicka, Vladimir

2009-10-01

Warfarin is a well-known anticoagulant agent that occurs in two enantiomers, (R)-(+)-warfarin and (S)-(-)-warfarin. A new liquid chromatography method for the determination of both enantiomers was developed, validated and applied in in vitro studies with the aim of evaluating the accumulation of (R)-warfarin and (S)-warfarin in the hepatoma HepG2 cell line. OptiMEM cell cultivation medium samples and cellular lysates were purified using Waters Oasis MAX extraction cartridges. The chiral separation of warfarin and the internal standard p-chlorowarfarin enantiomers was performed on an Astec Chirobiotic V2 column at a flow rate of 1.2mL/min. The mobile phase was composed of 31% acetonitrile, 5% of methanol and 64% of ammonium acetate buffer (10mmol/L, pH 4.1). The enantiomers were quantified using a fluorescence detector (lambda(excit)=320nm, lambda(emiss)=415nm). The limit of detection was found to be 0.121micromol/L of (S)-warfarin and 0.109micromol/L of (R)-warfarin. The range of applicability and linearity was estimated from 0.25 to 100micromol/L. The precision ranged from 1.3% to 12.2% of the relative standard deviation, and the accuracy reached acceptable values from 95.5% to 108.4%. The new bioanalytical method confirmed the same accumulation of (R)-warfarin and (S)-warfarin in the hepatoma HepG2 cell line.

Evaluation of Bleeding Events Requiring Hospitalization in Patients With Atrial Fibrillation Receiving Dabigatran, Warfarin, or Antiplatelet Therapy.

PubMed

Riley, Tanya R; Gauthier-Lewis, Mary L; Sanchez, Chelsea K; Riley, Treavor T

2017-04-01

To determine the incidence and severity of bleeding events requiring hospitalization among patients with atrial fibrillation (AF) receiving anticoagulants (dabigatran or warfarin) or antiplatelet agents (eg, aspirin and clopidogrel). This was a single-center, retrospective cohort study involving 1494 patients with AF hospitalized from November 1, 2010, to November 1, 2011, with prior warfarin, dabigatran, or antiplatelet therapy. Overall bleeding events in the dabigatran group compared to the warfarin group were 24% and 12%, respectively ( P = .004). Of these events, individually, there were no significant differences in major (56% vs 58%, P = .88), life-threatening (25% vs 36%, P = .38), or minor bleeding (44% vs 42%, P = .06). Gastrointestinal (GI) bleeding occurred more in the dabigatran group compared to the warfarin group ( P = .02). Intracranial bleeding occurred in 15% of patients in the warfarin group and did not occur at all in the dabigatran group. Warfarin patients had significantly more overall bleeding events compared to antiplatelet therapy ( P < .001), with an increasing trend seen in major bleeding ( P = .06). GI bleeding, however, favored the warfarin group over the antiplatelet group (48% vs 73%, P = .04). Anticoagulation with dabigatran was associated with an overall increased occurrence of bleeding requiring hospital admission compared to warfarin. GI bleeding was more prevalent with dabigatran and antiplatelets than with warfarin. There were more intracranial hemorrhages seen in the warfarin group.

Concurrent Use of Warfarin and Antibiotics and the Risk of Bleeding in Older Adults

PubMed Central

Baillargeon, Jacques; Holmes, Holly M.; Lin, Yu-li; Raji, Mukaila A.; Sharma, Gulshan; Kuo, Yong-Fang

2011-01-01

Background Antibiotic medications are associated with an increased risk of bleeding among patients receiving warfarin. The recent availability of data from the Medicare Part D prescription drug program provides an opportunity to assess the association of antibiotic medications and the risk of bleeding in a national population of older adults receiving warfarin. Methods We conducted a case-control study nested within a cohort of 38,762 patients aged 65 years and older who were continuous warfarin users, using enrollment and claims data for a 5% national sample of Medicare beneficiaries with Part D benefits. Cases were defined as persons hospitalized for a primary diagnosis of bleeding and were matched with three control subjects on age, race, gender, and indication for warfarin. Logistic regression analysis was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the risk of bleeding associated with prior exposure to antibiotic medications. Results Exposure to any antibiotic agent within the 15 days of the event/index date was associated with an increased risk of bleeding (aOR 2.01; 95% CI, 1.62-2.50). All six specific antibiotic drug classes examined [azole antifungals (aOR, 4.57; 95% CI, 1.90-11.03), macrolides (aOR, 1.86; 95% CI, 1.08-3.21), quinolones (aOR, 1.69; 95% CI, 1.09-2.62), cotrimoxazole (aOR, 2.70; 95% CI, 1.46-5.05), penicillins (aOR, 1.92; 95% CI, 1.21-2.07) and cephalosporins (aOR, 2.45; 95% CI, 1.52-3.95) were associated with an increased risk of bleeding. Conclusion Among older continuous warfarin users, exposure to antibiotic agents—particularly azole antifungals—was associated with an increased risk of bleeding. PMID:22269622

Warfarinized Patients with Proximal Femoral Fractures: Survey of UK Clinical Practice.

PubMed

Starks, Ian; Cooke, Stephen; Docker, Charles; Raine, Andrew

2009-06-01

In an aging population, anticoagulation in patients with musculoskeletal injuries is increasingly prevalent. The North American literature indicates an absence of consensus concerning the most appropriate management for this group. We aim to test the hypothesis that there is a lack of consensus in the UK regarding the perioperative management of patients with hip fractures on long-term warfarin therapy. A representative group of 400 consultant orthopedic surgeons was surveyed by postal questionnaire regarding their policy on the reversal of anticoagulation in warfarinized patients with hip fractures. The consultants contacted were selected to represent a geographical spread throughout the UK. There were 159 respondents (40% response rate), of which 79% (126) had a trauma commitment. 95 (75%) of these had a protocol for the reversal of anticoagulation prior to surgery. The commonest method used was to simply withhold warfarin and wait (70%). Other methods included FFP (16%), and low-dose (23%) and high-dose (14%) vitamin K. Some respondents used more than onemethod. Although nearly all respondents preferred an INR < 2.0 prior to surgery, 55% preferred an INR < 1.5. Hip fracture in the presence of long-term warfarin use is associated with significantly increased morbidity. This problem is likely to increase. Our results demonstrate variation in approach throughout the UK with regard to warfarin reversal and the acceptable INR at which to operate in this group of patients. We propose that low-dose vitamin K is considered more widely as a safe and effective method of warfarin reversal in this group.

Warfarin Use in Patients With Atrial Fibrillation Undergoing Hemodialysis: A Nationwide Population-Based Study.

PubMed

Yoon, Chang-Yun; Noh, Juhwan; Jhee, Jong Hyun; Chang, Tae Ik; Kang, Ea Wha; Kee, Youn Kyung; Kim, Hyoungnae; Park, Seohyun; Yun, Hae-Ryong; Jung, Su-Young; Oh, Hyung Jung; Park, Jung Tak; Han, Seung Hyeok; Kang, Shin-Wook; Kim, Changsoo; Yoo, Tae-Hyun

2017-09-01

The aim of this study is to elucidate the effects of warfarin use in patients with atrial fibrillation undergoing dialysis using a population-based Korean registry. Data were extracted from the Health Insurance Review and Assessment Service, which is a nationwide, mandatory social insurance database of all Korean citizens enrolled in the National Health Information Service between 2009 and 2013. Thromboembolic and hemorrhagic outcomes were analyzed according to warfarin use. Overall and propensity score-matched cohorts were analyzed by Cox proportional hazards models. Among 9974 hemodialysis patients with atrial fibrillation, the mean age was 66.6±12.2 years, 5806 (58.2%) were men, and 2921 (29.3%) used warfarin. After propensity score matching to adjust for all described baseline differences, 5548 subjects remained, and differences in baseline variables were distributed equally between warfarin users and nonusers. During a mean follow-up duration of 15.9±11.1 months, ischemic and hemorrhagic stroke occurred in 678 (6.8%) and 227 (2.3%) patients, respectively. In a multiple Cox model, warfarin use was significantly associated with an increased risk of hemorrhagic stroke (hazard ratio, 1.44; 95% confidence interval, 1.09-1.91; P =0.010) in the overall cohort. Furthermore, a significant relationship between warfarin use and hemorrhagic stroke was found in propensity-matched subjects (hazard ratio, 1.56; 95% confidence interval, 1.10-2.22; P =0.013). However, the ratios for ischemic stroke were not significantly different in either the propensity-matched (hazard ratio, 0.95; 95% confidence interval, 0.78-1.15; P =0.569) or overall cohort (hazard ratio, 1.06; 95% confidence interval, 0.90-1.26; P =0.470). Our findings suggest that warfarin should be used carefully in hemodialysis patients, given the higher risk of hemorrhagic events and the lack of ability to prevent thromboembolic complications. © 2017 American Heart Association, Inc.

Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program.

PubMed

Witt, Daniel M; Tillman, Donald J; Evans, Christy M; Plotkin, Tatyana V; Sadler, Melanie A

2003-03-01

Substitution of generic warfarin initially was discouraged because of concerns regarding therapeutic failure or toxicity. Although subsequent research with AB-rated (i.e., bioequivalent) warfarin did not confirm initial concerns, the issue is not settled for all clinicians. We sought to provide additional information regarding the clinical and economic impact of warfarin conversion by analyzing a real-life sample of patients receiving long-term anticoagulation therapy who were switched from brand name to generic warfarin. Patients who had been taking warfarin for at least 180 days and had received uninterrupted oral anticoagulation 90 days before and 90 days after switching to generic warfarin were included. The switch date was based on the first time generic warfarin was dispensed from our pharmacies. The primary end point was the calculated amount of time each patient's international normalized ratio (INR) values were within the patient-specific target INR range in the 90 days before and after the switch. Data regarding adverse events and medical resource utilization were also collected. Pharmacoeconomic analyses were performed. The analysis included 2299 patients. The overall difference in calculated time INR values were below (22.6% before vs 26.1% after switch, p<0.0001) and within (65.9% before vs 63.3% after switch, p=0.0002) the therapeutic INR range was statistically but not clinically significant. Only 28.0% of patients experienced a change in therapeutic INR control of 10% or less, 33.1% experienced INR control that improved by greater than 10%, and 38.9% experienced INR control that worsened by more than 10%. The difference in total treatment costs associated with brand name and generic warfarin was 3128 dollars/100 patient-years in favor of the generic product. Sensitivity analyses revealed that cost savings associated with warfarin conversion in this health care system were highly dependent on the difference between warfarin costs and cost of treating

Polymorphisms of vitamin K-related genes (EPHX1 and VKORC1L1) and stable warfarin doses.

PubMed

Chung, Jee-Eun; Lee, Kyung Eun; Chang, Byung Chul; Gwak, Hye Sun

2018-01-30

The aim of this study was to investigate the possible effects of EPHX1 and VKORC1L1 polymorphisms on variability of responses to warfarin. Sixteen single nucleotide polymorphisms (SNPs) in 201 patients with stable warfarin doses were analyzed including genes of VKORC1, CYP2C9, CYP4F2, GGCX, EPHX1 and VKORC1L1. Univariate analysis was conducted for the association of genotypes with stable warfarin doses. Multiple linear regression analysis was used to investigate factors that independently affected the inter-individual variability of warfarin dose requirements. The rs4072879 of VKORC1L1 (A>G) was significantly associated with stable warfarin doses; wild homozygote carriers (AA) required significantly lower stable warfarin doses than those with the variant G allele (5.02±1.56 vs. 5.96±2.01mg; p=0.001). Multivariate analysis showed that EPHX1 rs1877724 and VKORC1L1 rs4072879 accounted for 1.5% and 1.3% of the warfarin dose variability. Adding EPHX1 and VKORC1L1 SNPs to the base model including non-genetic variables (operation age, body weight and the therapy of ACEI or ARB) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 34. This study showed that polymorphisms of EPHX1 and VKORC1L1 could be determinants of stable warfarin doses. Copyright © 2017. Published by Elsevier B.V.

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.

PubMed

Patel, Manesh R; Mahaffey, Kenneth W; Garg, Jyotsna; Pan, Guohua; Singer, Daniel E; Hacke, Werner; Breithardt, Günter; Halperin, Jonathan L; Hankey, Graeme J; Piccini, Jonathan P; Becker, Richard C; Nessel, Christopher C; Paolini, John F; Berkowitz, Scott D; Fox, Keith A A; Califf, Robert M

2011-09-08

The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).

Pharmacokinetic and pharmacodynamic interactions of aspirin with warfarin in beagle dogs.

PubMed

Shen, Chenlin; Huang, Xiaohui; Li, Jun; Zhang, Ping; Li, Lin; Zhang, Wei; Hu, Tingting; Pappoe, Faustina; Huang, Jihan; Tang, Haiqin

2016-01-01

1. Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin-aspirin therapy, the safety and side effect of combined therapy remains unclear. 2. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses. 3. Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC(0-t)) and maximum plasma concentration (Cmax) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC(0-t) and Cmax and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC(0-t) and Emax of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin. 4. Coadministration of warfarin had no markedly effects on the AUC(0-t) and Cmax of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC(0-t) and Emax of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin. 5. Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug-drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin-aspirin drug interactions in healthy volunteers or patients.

Impact of Aspirin on Warfarin Control as Measured by Time in Therapeutic Range.

PubMed

Boyce, Michelle L; Zayac, Alexa; Davis, Arie; Badrick, Tony; Anoopkumar-Dukie, Shailendra; Bernaitis, Nijole

2018-05-12

Warfarin is an oral anticoagulant widely prescribed for a variety of thromboembolic indications including venous thromboembolism (VTE) deep vein thrombosis (DVT) and the prevention of stroke associated for atrial fibrillation (AF). 1 Warfarin requires ongoing monitoring of Internationalised Normalised Ratio (INR) due to a narrow therapeutic index and interactions with numerous drugs. 2 The time in therapeutic range (TTR) is often used to indicate the quality of warfarin therapy due to the established correlation between higher mean TTR and reduced complications such as bleeding and thromboembolism. 3 This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Unclear-onset intracerebral hemorrhage: Clinical characteristics, hematoma features, and outcomes.

PubMed

Inoue, Yasuteru; Miyashita, Fumio; Koga, Masatoshi; Minematsu, Kazuo; Toyoda, Kazunori

2017-12-01

Background and purpose Although unclear-onset ischemic stroke, including wake-up ischemic stroke, is drawing attention as a potential target for reperfusion therapy, acute unclear-onset intracerebral hemorrhage has been understudied. Clinical characteristics, hematoma features, and outcomes of patients who developed intracerebral hemorrhage during sleep or those with intracerebral hemorrhage who were unconscious when witnessed were determined. Methods Consecutive intracerebral hemorrhage patients admitted within 24 hours after onset or last-known normal time were classified into clear-onset intracerebral hemorrhage and unclear-onset intracerebral hemorrhage groups. Outcomes included initial hematoma volume, initial National Institutes of Health Stroke Scale score, hematoma growth on 24-hour follow-up computed tomography, and vital and functional prognoses at 30 days. Results Of 377 studied patients (122 women, 69 ± 11 years old), 147 (39.0%) had unclear-onset intracerebral hemorrhage. Patients with unclear-onset intracerebral hemorrhage had larger hematoma volumes (p = 0.044) and higher National Institutes of Health Stroke Scale scores (p < 0.001) than those with clear-onset intracerebral hemorrhage after multivariable adjustment for risk factors and comorbidities. Hematoma growth was similarly common between the two groups (p = 0.176). There were fewer patients with modified Rankin Scale (mRS) scores of 0-2 (p = 0.033) and more patients with mRS scores of 5-6 (p = 0.009) and with fatal outcomes (p = 0.049) in unclear-onset intracerebral hemorrhage group compared with clear-onset intracerebral hemorrhage as crude values, but not after adjustment. Conclusions Patients with unclear-onset intracerebral hemorrhage presented with larger hematomas and higher National Institutes of Health Stroke Scale scores at emergent visits than those with clear-onset intracerebral hemorrhage, independent of underlying characteristics. Unclear

Continued Use of Warfarin in Veterans with Atrial Fibrillation After Dementia Diagnosis.

PubMed

Orkaby, Ariela R; Ozonoff, Al; Reisman, Joel I; Miller, Donald R; Zhao, Shibei; Rose, Adam J

2017-02-01

To determine the effectiveness of warfarin in older adults with dementia. Retrospective cohort study. Department of Veterans Affairs national healthcare system. Veterans aged 65 and older (73% aged ≥75, 99% male, 91% white) who had been receiving warfarin for nonvalvular atrial fibrillation for at least 6 months, were newly diagnosed with dementia in fiscal year 2007 or 2008, and were not enrolled in Medicare Advantage (n = 2,572). The onset of dementia was defined according to International Classification of Diseases, Ninth Revision, code. Participants were followed for up to 4 years for persistence of warfarin therapy, anticoagulation control, major hemorrhage, ischemic stroke, and all-cause mortality. The average CHADS2 score was 3.3 ± 1.3. After a diagnosis of dementia, 405 individuals (16%) persisted on warfarin therapy. Unadjusted Cox proportional hazards analysis demonstrated a protective effect of warfarin in prevention of ischemic stroke (hazard ratio (HR) = 0.64, 95% confidence interval (CI) = 0.46-0.89, P = .008), major bleeding (HR = 0.72, 95% CI = 0.55-0.94, P = .02), and all-cause mortality (HR = 0.66, 95% CI = 0.55-0.79, P < .001). Using propensity score matching, the protective effect of continuing warfarin persisted in prevention of stroke (HR = 0.74, 95% CI = 0.54-0.996, P = .047) and mortality (HR = 0.72, 95% CI = 0.60-0.87, P < .001), with no statistically significant decrease in risk of major bleeding (HR = 0.78, 95% CI = 0.61-1.01, P = .06). Discontinuing warfarin after a diagnosis of dementia is associated with a significant increase in stroke and mortality. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

The use of antidepressants and the risk of haemorrhagic stroke: a nested case control study

PubMed Central

Douglas, Ian; Smeeth, Liam; Irvine, David

2011-01-01

AIM To investigate whether selective serotonin re-uptake inhibitor (SSRI) use is associated with an increased risk of haemorrhagic stroke in a cohort of antidepressant users. METHODS We conducted a case control study, nested within a cohort of antidepressant users in the United Kingdom General Practice Research Database. A cohort of 365 195 patients prescribed either an SSRI or tricyclic antidepressant between 1992 and 2006 was identified. Three hundred and fifty-seven cases of haemorrhagic stroke were observed and 1631 control patients without haemorrhagic stroke were selected. RESULTS The primary analysis showed no evidence of an association between current SSRI or TCA use and haemorrhagic stroke. Current use of an SSRI compared with no use at the time of haemorrhagic stroke was associated with an adjusted odds ratio of 1.11 (95% confidence interval (CI) 0.82, 1.50). For current tricyclic use the equivalent odds ratio was 0.73 (0.52, 1.02). There was no evidence that prior cerebrovascular events modified the effect of either SSRIs or TCAs. CONCLUSIONS We found no evidence that SSRIs are associated with an increased risk of haemorrhagic stroke, regardless of prior history of cerebrovascular events. PMID:21143507

Association between p75 neurotrophin receptor gene expression and cell apoptosis in tissues surrounding hematomas in rat models of intracerebral hemorrhage.

PubMed

He, Baixiang; Bao, Gang; Guo, Shiwen; Xu, Gaofeng; Li, Qi; Wang, Ning

2012-03-15

Animal models of intracerebral hemorrhage were established by injection of autologous blood into the caudate nucleus in rats. Cell apoptosis was measured by flow cytometry and immunohistochemical staining of the p75 neurotrophin receptor. p75 neurotrophin receptor protein was detected by immunohistochemistry. p75 neurotrophin receptor mRNA was examined by quantitative real-time polymerase chain reactions. At 24 hours after modeling, cellular apoptosis occured around hematoma with upregulation of p75 neurotrophin receptor protein and mRNA was observed, which directly correlated to apoptosis. This observation indicated that p75 neurotrophin receptor upregulation was associated with cell apoptosis around hematomas after intracerebral hemorrhage.

Bilateral eyelid ecchymosis and subconjunctival haemorrhage manifesting as presenting feature in a case of dengue haemorrhagic fever.

PubMed

Jain, Sparshi; Goswami, Anup; Singh, Nidhi; Kaur, Savleen

2015-10-01

We report a case of bilateral eyelid ecchymosis and subconjunctival haemorrhage, a rare presenting feature of dengue haemorrhagic fever. A 17-year-old boy presented to the emergency department with complaints of redness in both eyes and vomiting. He had bilateral eyelid ecchymosis with subconjunctival haemorrhage. Complete blood count revealed a significantly reduced platelet count of 11000/µL suggestive of dengue haemorrhagic fever (DHF). Ocular manifestations were followed by other systemic haemorrhagic manifestations of dengue later on which violates the usual sequence of events of dengue fever. Bilateral eyelid ecchymosis is a rare clinical manifestation and a rare presenting feature of dengue fever and one has to keep high index of suspicion for presence of dengue whenever a case of fever presents with lid ecchymosis/haemorrhage. © The Author(s) 2014.

Major bleeding caused by warfarin in a genetically susceptible patient.

PubMed

Bloch, Aharon; Ben-Chetrit, Eldad; Muszkat, Mordechai; Caraco, Yoseph

2002-01-01

A 90-year-old woman was hospitalized for gastrointestinal bleeding. Although she had been receiving only warfarin 5 mg/day, her international normalized ratio (INR) was 66. Warfarin was discontinued, and her INR fell to 3.7 after transfusion of fresh-frozen plasma. However, it rose again spontaneously to 7.5. Eleven days after the last dose of warfarin had been administered, it was still detectable in the patient's plasma, indicating that impaired warfarin clearance may have caused an enhanced anticoagulation effect. Genetic analysis of the cytochrome P450 (CYP) isoenzyme 2C9, which mediates the major deactivating pathway of S-warfarin, revealed that the patient was a compound heterozygote carrying two variant alleles: CYP2C9*2 and CYP2C9*3. The patient's enhanced sensitivity to warfarin 5 mg/day can be ascribed to decreased clearance of S-warfarin secondary to genetic alteration of the gene encoding CYP2C9, resulting in a life-threatening complication.

Warfarin therapy: in need of improvement after all these years

PubMed Central

Kimmel, Stephen E

2010-01-01

Background Warfarin therapy has been used clinically for over 60 years, yet continues to be problematic because of its narrow therapeutic index and large inter-individual variability in patient response. As a result, warfarin is a leading cause of serious medication-related adverse events, and its efficacy is also suboptimal. Objective To review factors that are responsible for variable response to warfarin, including clinical, environmental, and genetic factors, and to explore some possible approaches to improving warfarin therapy. Results Recent efforts have focused on developing dosing algorithms that included genetic information to try to improve warfarin dosing. These dosing algorithms hold promise, but have not been fully validated or tested in rigorous clinical trials. Perhaps equally importantly, adherence to warfarin is a major problem that should be addressed with innovative and cost-effective interventions. Conclusion Additional research is needed to further test whether interventions can be used to improve warfarin dosing and outcomes. PMID:18345947

Factors influencing warfarin control in Australia and Singapore.

PubMed

Bernaitis, Nijole; Ching, Chi Keong; Teo, Siew Chong; Chen, Liping; Badrick, Tony; Davey, Andrew K; Crilly, Julia; Anoopkumar-Dukie, Shailendra

2017-09-01

Warfarin is widely used for patients with non-valvular atrial fibrillation (NVAF). Variations in warfarin control, as measured by time in therapeutic range (TTR), have been reported across different regions and ethnicities, particularly between Western and Asian countries. However, there is limited data on comparative factors influencing warfarin control in Caucasian and Asian patients. Therefore, the aim of this study was to determine warfarin control and potential factors influencing this in patients with NVAF in Australia and Singapore. Retrospective data was collected for patients receiving warfarin for January to June 2014 in Australia and Singapore. TTR was calculated for individuals with mean patient TTR used for analysis. Possible influential factors on TTR were analysed including age, gender, concurrent co-morbidities, and concurrent medication. The mean TTR was significantly higher in Australia (82%) than Singapore (58%). At both sites, chronic kidney disease significantly lowered this TTR. Further factors influencing control were anaemia and age<60years in Australia, and vascular disease, CHA 2 DS 2 -VASc score of 6, and concurrent platelet inhibitor therapy in Singapore. Warfarin control was significantly higher in Australia compared to Singapore, however chronic kidney disease reduced control at both sites. The different levels of control in these two countries, together with patient factors further reducing control may impact on anticoagulant choice in these countries with better outcomes from warfarin in Australia compared to Singapore. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Creating an Optimal Warfarin Nomogram (CROWN) Study

PubMed Central

Perlstein, Todd S.; Goldhaber, Samuel Z.; Nelson, Kerrie; Joshi, Victoria; Morgan, T. Vance; Lesko, Lawrence J.; Lee, Joo-Yeon; Gobburu, Jogarao; Schoenfeld, David; Kucherlapati, Raju; Freeman, Mason W.; Creager, Mark A.

2014-01-01

A significant proportion of warfarin dose variability is explained by variation in the genotypes of the cytochrome P450 CYP2C9 and the vitamin K epoxide reductase complex, VKORC1, enzymes that influence warfarin metabolism and sensitivity, respectively. We sought to develop an optimal pharmacogenetic warfarin dosing algorithm that incorporated clinical and genetic information. We enroled patients initiating warfarin therapy. Genotyping was performed of the VKORC1, –1639G>A, the CYP2C9*2, 430C>T, and the CYP2C9*3, 1075C>A genotypes. The initial warfarin dosing algorithm (Algorithm A) was based upon established clinical practice and published warfarin pharmacogenetic information. Subsequent dosing algorithms (Algorithms B and Algorithm C) were derived from pharmacokinetic / pharmacodynamic (PK/PD) modelling of warfarin dose, international normalised ratio (INR), clinical and genetic factors from patients treated by the preceding algorithm(s). The primary outcome was the time in the therapeutic range, considered an INR of 1.8 to 3.2. A total of 344 subjects are included in the study analyses. The mean percentage time within the therapeutic range for each subject increased progressively from Algorithm A to Algorithm C from 58.9 (22.0), to 59.7 (23.0), to 65.8 (16.9) percent (p = 0.04). Improvement also occurred in most secondary endpoints, which included the per-patient percentage of INRs outside of the therapeutic range (p = 0.004), the time to the first therapeutic INR (p = 0.07), and the time to achieve stable therapeutic anticoagulation (p < 0.001). In conclusion, warfarin pharmacogenetic dosing can be optimised in real time utilising observed PK/PD information in an adaptive fashion. Clinical Trial Registration ClinicalTrials.gov (NCT00401414) PMID:22116191

In Potential Stroke Patients on Warfarin, the International Normalized Ratio Predicts Ischemia.

PubMed

Cao, Cathy; Martinelli, Ashley; Spoelhof, Brian; Llinas, Rafael H; Marsh, Elisabeth B

2017-01-01

Stroke can occur in patients on warfarin despite anticoagulation. Patients with a low international normalized ratio (INR) should theoretically be at greater risk for ischemia than those who are therapeutic. Therefore, INR may be able to indicate whether new neurological deficits are more likely strokes or stroke mimics in patients on warfarin. This study evaluates the association and predictive value of INR in determining the likelihood of ischemia. Patients were identified using the acute stroke registry at a Primary Stroke Center from January 2013 through December 2014. All adult patients undergoing evaluation for acute stroke with prior documented use of warfarin and an INR level at presentation were included. Data were collected regarding patient demographics, medical comorbidities, stroke severity, reason for anticoagulation, and laboratory studies including INR. Student t tests and χ2 analysis were used to evaluate factors associated with increased likelihood of ischemia (stroke or transient ischemic attack) versus mimic. Significant results were entered into a multivariable regression analysis. Sensitivity and specificity analyses were conducted to determine the predictive value of INR for ischemic risk. 116 patients were included; 46 were diagnosed with ischemia, 70 were diagnosed as mimics. 75% of patients were on warfarin for atrial fibrillation versus 25% for venous thrombosis. A statistically significant difference in mean INR for patients with ischemia (n = 46) versus mimics (n = 70) was observed (1.7 vs. 2.8; p < 0.001). In multivariable analysis, both sub-therapeutic INR (p < 0.001) and atrial fibrillation (p = 0.014) were predictors of ischemia. In patients with an INR ≥2, the predictive value of having a non-ischemic etiology was 79%. No patient with an INR of ≥3.6 was found to have ischemia. Sub-therapeutic INR and atrial fibrillation are strongly associated with ischemia in patients on warfarin presenting with acute neurologic symptoms

Supervised Patient Self-Testing of Warfarin Therapy Using an Online System

PubMed Central

2013-01-01

Background Point-of-care international normalized ratio (INR) monitoring devices simplify warfarin management by allowing selected patients to monitor their own therapy in their homes. Patient self-testing (PST) has been shown to improve the clinical outcomes of warfarin therapy compared to usual care. Objective To compare management of warfarin therapy using PST combined with online supervision by physicians via a custom system with usual warfarin management, which involved laboratory testing and physician dosing. Methods Interested patients were recruited via community pharmacies to participate in a warfarin PST training program. Participants were required to have a long-term indication for warfarin, have been taking warfarin for at least 6 months, and have Internet access in their home. The training involved two sessions covering theoretical aspects of warfarin therapy, use of the CoaguChek XS, and the study website. Following training, patients monitored their INR once weekly for up to 3 months. Patients and physicians utilized a secure website to communicate INR values, dosage recommendations, and clinical incidents. Physicians provided a 6-12 month history of INR results for comparison with study results. The percentage of time spent within the therapeutic INR range (TTR) was the primary outcome, with participants acting as their own historical controls. The percentage of INR tests in range and participant satisfaction were secondary outcomes. Results Sixteen patients completed training requirements. The mean age of participants was 69.8 (SD 10.1) years. TTR improved significantly from 66.4% to 78.4% during PST (P=.01), and the number of tests within the target range also improved significantly (from 66.0% at prior to the study to 75.9% during PST; P=.04). Patients and physicians expressed a high degree of satisfaction with the monitoring strategy and online system. Conclusions PST supported by an online system for supervision was associated with improved INR

Risk factors for severe post partum haemorrhage in Mulago hospital, Kampala, Uganda.

PubMed

Wandabwa, J; Doyle, P; Todd, J; Ononge, S; Kiondo, P

2008-02-01

To determine the risk factors for severe postpartum haemorrhage. A case control study. Mulago hospital labour wards, Kampala, Uganda. One hundred and six mothers with severe postpartum haemorrhage were recruited between 15th November 2001 and 30th November 2002 and were compared with 500 women who had normal delivery. The predictors for postpartum haemorrhage were co-existing hypertension (O.R 9.3, 95% CI: 1.7-51.7), chronic anaemia (OR 17.3, 95% CI: 9.5-31.7), low socio economic background (OR 5.3, 95% CI: 3.0, 9.2), past history of postpartum haemorrhage (OR 3.6, 95% CI: 1.1-11.8), previous delivery by Caesarean section (OR 7.5, 95% CI: 3.5-14.3), long birth interval of more than sixty months (OR 5.2, 95% CI: 2.1-13.0), prolonged third stage (OR 49.1, 95% CI: 8.8-342.8) and non use of oxytocics (OR 4.3%, 95% CI: 1.2-15.3). Severe postpartum haemorrhage is common in our environment and is associated with a high maternal morbidity and mortality. The determinants of postpartum haemorrhage are useful in identifying mothers at risk and together with the services of a skilled birth attendant at delivery will prevent postpartum haemorrhage and reduce the maternal morbidity and mortality associated with this condition. In our study, the following risk factors were identified: pre-existing hypertension, chronic anaemia, low socio-economic background, history of postpartum haemorrhage, previous delivery by Caesarean section, longbirth interval of more than sixty months, prolonged third stage and non use of oxytocics were found to be significant.

Shorter Hospital Stays and Lower Costs for Rivaroxaban Compared With Warfarin for Venous Thrombosis Admissions.

PubMed

Margolis, Jay M; Deitelzweig, Steven; Kline, Jeffrey; Tran, Oth; Smith, David M; Bookhart, Brahim; Crivera, Concetta; Schein, Jeff

2016-10-06

% confidence interval, $8035-$8739]; warfarin $10 275 [95% confidence interval, $9842-$10 708]). Rivaroxaban was associated with significantly shorter hospital LOS and lower hospitalization costs compared with warfarin. © 2016 The Authors, Janssen Scientific Affairs, LLC, and Truven Health Analytics. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study.

PubMed

Gulløv, A L; Koefoed, B G; Petersen, P; Pedersen, T S; Andersen, E D; Godtfredsen, J; Boysen, G

1998-07-27

Despite the efficacy of warfarin sodium therapy for stroke prevention in atrial fibrillation, many physicians hesitate to prescribe it to elderly patients because of the risk for bleeding complications and because of inconvenience for the patients. The Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study was a randomized, controlled trial examining the following therapies: warfarin sodium, 1.25 mg/d; warfarin sodium, 1.25 mg/d, plus aspirin, 300 mg/d; and aspirin, 300 mg/d. These were compared with adjusted-dose warfarin therapy (international normalized ratio of prothrombin time [INR], 2.0-3.0). Stroke or a systemic thromboembolic event was the primary outcome event. Transient ischemic attack, acute myocardial infarction, and death were secondary events. Data were handled as survival data, and risk factors were identified using the Cox proportional hazards model. The trial was scheduled for 6 years from May 1, 1993, but due to scientific evidence of inefficiency of low-intensity warfarin plus aspirin therapy from another study, our trial was prematurely terminated on October 2, 1996. We included 677 patients (median age, 74 years). The cumulative primary event rate after 1 year was 5.8% in patients receiving minidose warfarin; 7.2%, warfarin plus aspirin; 3.6%, aspirin; and 2.8%, adjusted-dose warfarin (P = .67). After 3 years, no difference among the groups was seen. Major bleeding events were rare. Although the difference was insignificant, adjusted-dose warfarin seemed superior to minidose warfarin and to warfarin plus aspirin after 1 year of treatment. The results do not justify a change in the current recommendation of adjusted-dose warfarin (INR, 2.0-3.0) for stroke prevention in atrial fibrillation.

Anticoagulation Use and Clinical Outcomes Following Major Bleeding on Dabigatran or Warfarin in Atrial Fibrillation

PubMed Central

Hernandez, Inmaculada; Zhang, Yuting; Brooks, Maria M.; Chin, Paul K.L.; Saba, Samir

2016-01-01

Background and Purpose Little is known about the clinical outcomes associated with post-hemorrhage anticoagulation resumption for atrial fibrillation. This study had two objectives: first, to evaluate anticoagulation use after a first major bleed on warfarin or dabigatran; and second, to compare effectiveness and safety outcomes between patients discontinuing anticoagulation after a major bleed and patients restarting warfarin or dabigatran. Methods Using 2010-2012 Medicare Part D data, we identified atrial fibrillation patients who experienced a major bleeding event while using warfarin (n=1135) or dabigatran (n=404) and categorized them by their post-hemorrhage use of anticoagulation. We followed them until an ischemic stroke, recurrent hemorrhage, or death through December 31, 2012. We constructed logistic regression models to evaluate factors impacting anticoagulation resumption, and Cox Proportional Hazard models to compare the combined risk of ischemic stroke and all-cause mortality, and the risk of recurrent bleeding between treatment groups. Results Resumption of anticoagulation with warfarin (hazard ratio (HR) 0.76; 95%CI, 0.59-0.97) or dabigatran (HR0.66; 95%CI 0.44-0.99) was associated with lower combined risk of ischemic stroke and all-cause mortality than anticoagulation discontinuation. The incidence of recurrent major bleeding was higher for patients prescribed warfarin after the event than for those prescribed dabigatran (HR2.31; 95%CI, 1.19-4.76) or whose anticoagulation ceased (HR1.56; 95%CI, 1.10-2.22), but did not differ between patients restarting dabigatran and those discontinuing anticoagulation (HR0.66; 95% CI, 0.32-1.33). Conclusions Dabigatran was associated with a superior benefit/risk ratio than warfarin and anticoagulation discontinuation in the treatment of atrial fibrillation patients who have survived a major bleed. PMID:27909200

Economic Evaluation of the Combined Use of Warfarin and Low-dose Aspirin Versus Warfarin Alone in Mechanical Valve Prostheses.

PubMed

El-Hamamsy, Manal H; Elsisi, Gihan H; Eldessouki, Randa; Elmazar, Mohamed M; Taha, Ahmed S; Awad, Basma F; Elmansy, Hossam

2016-08-01

The use of combined therapy of antiplatelet and anticoagulant versus anticoagulant alone to reduce instances of thromboembolic events in patients with heart valve prostheses is an established standard of care in many countries but not in Egypt. A previous Markov model cost-effectiveness study on Egyptian patients aged 50-60 years demonstrated that the combined therapy reduces the overall treatment cost. However, due to the lack of actual real-world data on cost-effectiveness and the limitation of the Markov model study to 50- to 60-year-old patients, the Egyptian medical community is still questioning whether the added benefit is worth the cost. To assess, from the perspective of the Egyptian health sector, the cost-effectiveness of the combined use of warfarin and low-dose aspirin (75 mg) versus that of warfarin alone in patients with mechanical heart valve prostheses who began therapy between the age of 15 and 50 years. An economic evaluation was conducted alongside a randomized, controlled trial to assess the cost-effectiveness of the combined therapy in patients with mechanical valve prostheses. A total of 316 patients aged between 15 and 50 years were included in the study and randomly assigned to a group treated with both warfarin and aspirin or a group treated with warfarin alone. The patients in the combined therapy group exhibited a significantly longer duration of protection against the first event. Fewer primary events were observed in the patients treated with warfarin plus aspirin than in those treated with warfarin alone (1.4 %/year, vs. 4.8 %/year), and a higher mean quality-adjusted life-years (QALYs) value over 4 years was obtained for the group treated with warfarin plus aspirin (difference 0.058; 95 % CI 0.013-0.118), although this difference did not reach a conventional level of statistical significance. The total costs over a 4-year period were lower with the combined therapy (difference -US$244; 95 % CI -US$483.1 to -US$3.8), which

Dabigatran versus warfarin in patients with mechanical heart valves.

PubMed

Eikelboom, John W; Connolly, Stuart J; Brueckmann, Martina; Granger, Christopher B; Kappetein, Arie P; Mack, Michael J; Blatchford, Jon; Devenny, Kevin; Friedman, Jeffrey; Guiver, Kelly; Harper, Ruth; Khder, Yasser; Lobmeyer, Maximilian T; Maas, Hugo; Voigt, Jens-Uwe; Simoons, Maarten L; Van de Werf, Frans

2013-09-26

Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves. In this phase 2 dose-validation study, we studied two populations of patients: those who had undergone aortic- or mitral-valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier. Patients were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin. The selection of the initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter. The warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk. The primary end point was the trough plasma level of dabigatran. The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding. The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.).

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review

PubMed Central

2016-01-01

Background Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing. Objective To explore the prevalence of CYP2C9 and VKORC1 variants in MENA, and the effect of these variants along with other non-genetic factors in predicting warfarin dose. Methods In this systematic review, we included observational cross sectional and cohort studies that enrolled patients on stable warfarin dose and had the genetics and non-genetics factors associated with mean warfarin dose as the primary outcome. We searched PubMed, Medline, Scopus, PharmGKB, PHGKB, Google scholar and reference lists of relevant reviews. Results We identified 17 studies in eight different populations: Iranian, Israeli, Egyptian, Lebanese, Omani, Kuwaiti, Sudanese and Turkish. Most common genetic variant in all populations was the VKORC1 (-1639G>A), with a minor allele frequency ranging from 30% in Egyptians and up to 52% and 56% in Lebanese and Iranian, respectively. Variants in the CYP2C9 were less common, with the highest MAF for CYP2C9*2 among Iranians (27%). Variants in the VKORC1 and CYP2C9 were the most significant predictors of warfarin dose in all populations. Along with other genetic and non-genetic factors, they explained up to 63% of the dose variability in Omani and Israeli patients. Conclusion Variants of VKORC1 and CYP2C9 are the strongest predictors of warfarin dose variability among the different populations from MENA. Although many of those populations share the same ancestry and are similar in their warfarin dose predictors, a population specific dosing algorithm is

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review.

PubMed

Bader, Loulia Akram; Elewa, Hazem

2016-01-01

Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing. To explore the prevalence of CYP2C9 and VKORC1 variants in MENA, and the effect of these variants along with other non-genetic factors in predicting warfarin dose. In this systematic review, we included observational cross sectional and cohort studies that enrolled patients on stable warfarin dose and had the genetics and non-genetics factors associated with mean warfarin dose as the primary outcome. We searched PubMed, Medline, Scopus, PharmGKB, PHGKB, Google scholar and reference lists of relevant reviews. We identified 17 studies in eight different populations: Iranian, Israeli, Egyptian, Lebanese, Omani, Kuwaiti, Sudanese and Turkish. Most common genetic variant in all populations was the VKORC1 (-1639G>A), with a minor allele frequency ranging from 30% in Egyptians and up to 52% and 56% in Lebanese and Iranian, respectively. Variants in the CYP2C9 were less common, with the highest MAF for CYP2C9*2 among Iranians (27%). Variants in the VKORC1 and CYP2C9 were the most significant predictors of warfarin dose in all populations. Along with other genetic and non-genetic factors, they explained up to 63% of the dose variability in Omani and Israeli patients. Variants of VKORC1 and CYP2C9 are the strongest predictors of warfarin dose variability among the different populations from MENA. Although many of those populations share the same ancestry and are similar in their warfarin dose predictors, a population specific dosing algorithm is needed for the prospective estimation of warfarin

Evaluation of the effect of torsemide on warfarin dosage requirements.

PubMed

Lai, Sophia; Momper, Jeremiah D; Yam, Felix K

2017-08-01

Background According to drug interaction databases, torsemide may potentiate the effects of warfarin. Evidence for this drug-drug interaction, however, is conflicting and the clinical significance is unknown. Objective The aim of this study is to evaluate the impact of torsemide initiation on warfarin dosage requirements. Setting This study was conducted at the Veterans Affairs Healthcare System in San Diego, California. Method A retrospective cohort study was conducted using Veterans Affairs data from patients who were converted from bumetanide to torsemide between March 2014 and July 2014. Patients were also prescribed and taking warfarin during the observation period. Warfarin dosage requirements were evaluated to determine if any changes occurred within the first 3 months of starting torsemide. Main outcome measure The primary outcome was the average weekly warfarin dose before and after torsemide initiation. Results Eighteen patients met study inclusion criteria. The weekly warfarin dose before and after initiation of torsemide was not significantly different (34 ± 15 and 34 ± 13 mg, p > 0.05). Of those eighteen patients, only two experienced elevations in INR that required a decrease in warfarin dosage after torsemide initiation. Between those two patients, dosage reductions ranged from 5.3 to 18%. Conclusion These results indicated that most patients did not require any warfarin dosage adjustments after torsemide was initiated. The potential for interaction, however, still exists. While empiric warfarin dosage adjustments are not recommended when initiating torsemide, increased monitoring is warranted to minimize the risk of adverse effects.

UK guidelines on the management of variceal haemorrhage in cirrhotic patients

PubMed Central

Tripathi, Dhiraj; Stanley, Adrian J; Hayes, Peter C; Patch, David; Millson, Charles; Mehrzad, Homoyon; Austin, Andrew; Ferguson, James W; Olliff, Simon P; Hudson, Mark; Christie, John M

2015-01-01

These updated guidelines on the management of variceal haemorrhage have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines which this document supersedes were written in 2000 and have undergone extensive revision by 13 members of the Guidelines Development Group (GDG). The GDG comprises elected members of the BSG liver section, representation from British Association for the Study of the Liver (BASL) and Liver QuEST, a nursing representative and a patient representative. The quality of evidence and grading of recommendations was appraised using the AGREE II tool. The nature of variceal haemorrhage in cirrhotic patients with its complex range of complications makes rigid guidelines inappropriate. These guidelines deal specifically with the management of varices in patients with cirrhosis under the following subheadings: (1) primary prophylaxis; (2) acute variceal haemorrhage; (3) secondary prophylaxis of variceal haemorrhage; and (4) gastric varices. They are not designed to deal with (1) the management of the underlying liver disease; (2) the management of variceal haemorrhage in children; or (3) variceal haemorrhage from other aetiological conditions. PMID:25887380

The impact of pre-injury direct oral anticoagulants compared to warfarin in geriatric G-60 trauma patients.

PubMed

Barletta, J F; Hall, S; Sucher, J F; Dzandu, J K; Haley, M; Mangram, A J

2017-08-01

Pre-injury oral anticoagulants are associated with worse outcomes in geriatric (G-60) trauma patients, but there are limited data comparing warfarin with direct oral anticoagulants (DOAC). We sought to compare outcomes in G-60 trauma patients taking pre-injury DOACs vs. warfarin. All trauma patients, age ≥60 who were admitted to the hospital and taking an oral anticoagulant pre-injury were retrospectively identified. Patients were excluded if their reason for admission was a suicide attempt or penetrating extremity injury. Outcome measures included blood transfusions, hospital LOS, and mortality. A second analysis was performed, whereby patients were matched using ISS and age. There were 3,941 patients identified; 331 had documentation of anticoagulant use, pre-injury (warfarin, n = 237; DOAC, n = 94). Demographics were similar, but ISS [9 (4-13) vs. 8 (4-9), p = .027], initial INR [2.2 (1.8-2.9) vs. 1.2 (1.1-1.5), p < .001], and the use of pharmacologic reversal agents (48 vs. 14%, p < .001) were higher in the warfarin group. There was no difference in the use of blood transfusions (24 vs. 17%, p = .164) or mortality (5.9 vs. 4.3%, p = .789) between warfarin and DOAC groups, respectively. However, LOS was longer in the warfarin group [5 (3-7.5) vs. 4 (2-6.3) days, p = .02]. Matched analysis showed no difference in blood transfusions (23 vs. 17%, p = .276), mortality (2.1 vs. 4.3%, p = .682) or LOS [5 (3-7) vs. 4 (2-6.3) days, p = .158] between warfarin and DOAC groups, respectively. Pre-injury DOACs are not associated with worse clinical outcomes compared to warfarin in G-60 trauma patients. Higher use of pharmacologic reversal agents with warfarin may be related to differences in mechanism of action and effect on INR.

Warfarin - Fluoroquinolones, Sulfonamides, or Azole Antifungals Interactions and the Risk of Hospitalization for Gastrointestinal Bleeding

PubMed Central

Schelleman, Hedi; Bilker, Warren B.; Brensinger, Colleen M.; Han, Xiaoyan; Kimmel, Stephen E.; Hennessy, Sean

2008-01-01

Objective To determine whether a potential pharmacokinetic interaction between warfarin and orally administered anti-infectives increases the risk of hospitalization for gastrointestinal (GI) bleeding in warfarin users. Methods We conducted a nested case-control and case-crossover study in US Medicaid data. Logistic regression was used to determine the association between GI bleeding and prior use of ciprofloxacin, levofloxacin, gatifloxacin, cotrimoxazole, or fluconazole, all versus no exposure and versus cephalexin, which would not be expected to interact with warfarin. Results All anti-infectives examined exhibited an elevated odds ratio (OR) vs. no exposure. Using cephalexin as the reference category, ORs for cotrimoxazole (OR:1.68 [95% CI:1.21–2.33] in the prior 6–10 days) and fluconazole (OR:2.09 [95% CI:1.34–3.26] in the prior 11–15 days) were significantly elevated. Conclusions Warfarin users who had received an anti-infective agent showed a substantially increased risk of GI bleeding. Nonetheless, a drug-drug interaction with warfarin was evident only for cotrimoxazole and fluconazole. PMID:18685566

Admission blood glucose predicted haemorrhagic shock in multiple trauma patients.

PubMed

Kreutziger, Janett; Rafetseder, Andreas; Mathis, Simon; Wenzel, Volker; El Attal, René; Schmid, Stefan

2015-01-01

Admission blood glucose is known to be a predictor for outcome in several disease patterns, especially in critically ill trauma patients. The underlying mechanisms for the association of hyperglycaemia and poor outcome are still not proven. It was hypothesised that hyperglycaemia upon hospital admission is associated with haemorrhagic shock and in-hospital mortality. Data was extracted from an observational trauma database of the level 1 trauma centre at Innsbruck Medical University hospital. Trauma patients (≥18 years) with multiple injuries and an Injury Severity Score ≥17 were included and analysed. In total, 279 patients were analysed, of which 42 patients (15.1%) died. With increasing blood glucose upon hospital admission, the rate of patients with haemorrhagic shock rose significantly [from 4.4% (glucose 4.1-5.5mmol/L) to 87.5% (glucose >15mmol/L), p<0.0001]. Mortality was also associated with initial blood glucose [≤5.50mmol/L 8.3%; 5.51-7.50mmol/L 10.9%, 7.51-10mmol/L 12.4%; 10.01-15mmol/L 32.0%; ≥15.01mmol/L 12.5%, p=0.008]. Admission blood glucose was a better indicator for haemorrhagic shock (cut-off 9.4mmol/L, sensitivity 67.1%, specificity 83.9%) than haemoglobin, base excess, bicarbonate, pH, lactate, or vital parameters. Regarding haemorrhagic shock, admission blood glucose is more valuable during initial patient assessment than the second best predictive parameter, which was admission haemoglobin (cut-off value 6.5mmol/L (10.4g/dL): sensitivity 61.3%, specificity 83.9%). In multiple trauma, non-diabetic patients, admission blood glucose predicted the incidence of haemorrhagic shock. Admission blood glucose is an inexpensive, rapidly and easily available laboratory value that might help to identify patients at risk for haemorrhagic shock during initial evaluation upon hospital admission. Copyright © 2014 Elsevier Ltd. All rights reserved.

Warfarin monitoring in nursing homes assessed by case histories. Do recommendations and electronic alerts affect judgements?

PubMed

Teruel, Reyes Serrano; Thue, Geir; Fylkesnes, Svein Ivar; Sandberg, Sverre; Kristoffersen, Ann Helen

2017-09-01

Older adults treated with warfarin are prone to complications, and high-quality monitoring is essential. The aim of this case history based study was to assess the quality of warfarin monitoring in a routine situation, and in a situation with an antibiotic-warfarin interaction, before and after receiving an electronic alert. In April 2014, a national web-based survey with two case histories was distributed among Norwegian nursing home physicians and general practitioners working part-time in nursing homes. Case A represented a patient on stable warfarin treatment, but with a substantial INR increase within the therapeutic interval. Case B represented a more challenging patient with trimethoprim sulfamethoxazole (TMS) treatment due to pyelonephritis. In both cases, the physicians were asked to state the next warfarin dose and the INR recall interval. In case B, the physicians could change their suggestions after receiving an electronic alert on the TMS-warfarin interaction. Three hundred and ninety eight physicians in 292 nursing homes responded. Suggested INR recall intervals and warfarin doses varied substantially in both cases. In case A, 61% gave acceptable answers according to published recommendations, while only 9% did so for case B. Regarding the TMS-warfarin interaction in case history B, the electronic alert increased the percentage of respondents correctly suggesting a dose reduction from 29% to 53%. Having an INR instrument in the nursing home was associated with shortened INR recall times. Practical advice on handling of warfarin treatment and drug interactions is needed. Electronic alerts as presented in electronic medical records seem insufficient to change practice. Availability of INR instruments may be important regarding recall time.

Patterns of Warfarin Use in Subgroups of Patients with Atrial Fibrillation: A Cross-Sectional Analysis of 430 General Practices in the United Kingdom

PubMed Central

Mohammed, Mohammed A.; Marshall, Tom; Nirantharakumar, Krishnarajah; Stevens, Andrew; Fitzmaurice, David

2013-01-01

Background Despite the proven efficacy of warfarin, its use in patients with Atrial Fibrillation (AF) is reportedly low. We investigated the underuse and overuse of warfarin in the management of AF in general practices in the United Kingdom (UK) against the National Institute of Clinical Excellence (NICE, UK) guidelines whilst seeking to identify subgroups of AF patients to inform efforts to optimise warfarin use. Methodology A retrospective database analysis to determine warfarin prescribing using tree models based on 50361 patients with AF (classified as low, moderate and high risk of stroke using CHADS2) from 430 general practices in the UK. Results Over one-third (37.0%, 4573/12351) of low risk AF patients were on warfarin, compared with 47.1% (8349/17709) moderate risk AF patients and 54.9% (11142/20301) high risk AF patients. Clinical subgroups (n = 15 low risk subgroups, n = 15 medium risk subgroups, n = 22 high risk subgroups) were identified. Several factors not supported by current guidelines (age, BMI, dementia, gender) were associated with the use of warfarin. Gender and BMI were associated with warfarin use in low and medium risk AF patients but not in high risk AF patients. Conclusion Whilst NICE guidelines suggest that all high risk AF patients should be on warfarin, half of those at moderate risk should be on warfarin and none of those at low risk should be on warfarin, we found evidence of over and under use of warfarin. Interventions to optimise warfarin therapy tailored to and targeting specific subgroups of AF patients identified by the tree models are required. PMID:23658703

Interaction of quercetin and its metabolites with warfarin: Displacement of warfarin from serum albumin and inhibition of CYP2C9 enzyme.

PubMed

Poór, Miklós; Boda, Gabriella; Needs, Paul W; Kroon, Paul A; Lemli, Beáta; Bencsik, Tímea

2017-04-01

Flavonoids are ubiquitous molecules in nature with manifold pharmacological effects. Flavonoids interact with several proteins, and thus potentially interfere with the pharmacokinetics of various drugs. Though much is known about the protein binding characteristics of flavonoid aglycones, the behaviour of their metabolites, which are extensively formed in the human body has received little attention. In this study, the interactions of the flavonoid aglycone quercetin and its main metabolites with the albumin binding of the oral anticoagulant warfarin were investigated by fluorescence spectroscopy and ultrafiltration. Furthermore, the inhibitory effects of these flavonoids on CYP2C9 enzyme were tested because the metabolic elimination of warfarin is catalysed principally by this enzyme. Herein, we demonstrate that each tested flavonoid metabolite can bind to human serum albumin (HSA) with high affinity, some with similar or even higher affinity than quercetin itself. Quercetin metabolites are able to strongly displace warfarin from HSA suggesting that high quercetin doses can strongly interfere with warfarin therapy. On the other hand, tested flavonoids showed no or weaker inhibition of CYP2C9 compared to warfarin, making it very unlikely that quercetin or its metabolites can significantly inhibit the CYP2C9-mediated inactivation of warfarin. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Cost-effectiveness of apixaban versus warfarin and aspirin in Sweden for stroke prevention in patients with atrial fibrillation.

PubMed

Lanitis, Tereza; Kongnakorn, Thitima; Jacobson, Lena; De Geer, Anna

2014-08-01

Atrial fibrillation (AF), one of the major risk factors for stroke, imposing a substantial burden to the Swedish health care system. Apixaban has demonstrated superiority to warfarin and aspirin in stroke prevention amongst patients with AF in two large randomised clinical trials. The aim of this study was to assess the economic implications of apixaban against warfarin and aspirin in these patients from a Swedish societal perspective. A Markov cohort model was constructed to characterise the consequences of anticoagulant treatment with regards to thromboembolic and bleeding events, as well as the associated health care costs, life-years and quality-adjusted life years (QALYs) for patients with AF treated with apixaban, warfarin or aspirin. Incremental cost-effectiveness ratios (ICERs) per QALY gained of apixaban relative to warfarin (among patients suitable for warfarin treatment) and aspirin (among patients unsuitable for warfarin treatment) were calculated. Costs (in 2011 SEKs) and QALYs were discounted at 3% per annum. The model estimated the ICER of apixaban versus warfarin amongst patients who are suitable for warfarin therapy to be SEK 33,458/QALY gained and that of apixaban versus aspirin amongst those unsuitable for warfarin therapy to be SEK 41,453/QALY gained. Probabilistic sensitivity analyses indicate that apixaban is an optimal treatment option compared with warfarin and aspirin, when the willingness-to-pay is above SEK 35,000 and SEK 45,000 per QALY, respectively. Apixaban was found to be a cost-effective alternative to warfarin and aspirin for stroke prevention in patients with AF in Sweden. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Apixaban Versus Warfarin for Mechanical Heart Valve Thromboprophylaxis in a Swine Aortic Heterotopic Valve Model.

PubMed

Lester, Patrick A; Coleman, Dawn M; Diaz, Jose A; Jackson, Tatum O; Hawley, Angela E; Mathues, Angela R; Grant, Brandon T; Knabb, Robert M; Ramacciotti, Eduardo; Frost, Charles E; Song, Yan; Wakefield, Thomas W; Myers, Daniel D

2017-05-01

Warfarin is the current standard for oral anticoagulation therapy in patients with mechanical heart valves, yet optimal therapy to maximize anticoagulation and minimize bleeding complications requires routine coagulation monitoring, possible dietary restrictions, and drug interaction monitoring. As alternatives to warfarin, oral direct acting factor Xa inhibitors are currently approved for the prophylaxis and treatment of venous thromboembolism and reduction of stroke and systemic embolization. However, no in vivo preclinical or clinical studies have been performed directly comparing oral factor Xa inhibitors such as apixaban to warfarin, the current standard of therapy. A well-documented heterotopic aortic valve porcine model was used to test the hypothesis that apixaban has comparable efficacy to warfarin for thromboprophylaxis of mechanical heart valves. Sixteen swine were implanted with a bileaflet mechanical aortic valve that bypassed the ligated descending thoracic aorta. Animals were randomized to 4 groups: control (no anticoagulation; n=4), apixaban oral 1 mg/kg twice a day (n=5), warfarin oral 0.04 to 0.08 mg/kg daily (international normalized ratio 2-3; n=3), and apixaban infusion (n=4). Postmortem valve thrombus was measured 30 days post-surgery for control-oral groups and 14 days post-surgery for the apixaban infusion group. Control thrombus weight (mean) was significantly different (1422.9 mg) compared with apixaban oral (357.5 mg), warfarin (247.1 mg), and apixiban 14-day infusion (61.1 mg; P <0.05). Apixaban is a promising candidate and may be a useful alternative to warfarin for thromboprophylaxis of mechanical heart valves. Unlike warfarin, no adverse bleeding events were observed in any apixaban groups. © 2017 American Heart Association, Inc.

Direct Oral Anticoagulant- or Warfarin-Related Major Bleeding: Characteristics, Reversal Strategies, and Outcomes From a Multicenter Observational Study.

PubMed

Xu, Yan; Schulman, Sam; Dowlatshahi, Dar; Holbrook, Anne M; Simpson, Christopher S; Shepherd, Lois E; Wells, Philip S; Giulivi, Antonio; Gomes, Tara; Mamdani, Muhammad; Khuu, Wayne; Frymire, Eliot; Johnson, Ana P

2017-07-01

Direct oral anticoagulants (DOACs) have expanded the armamentarium for antithrombotic therapy. Although DOAC-related major bleeding was associated with favorable outcomes compared with warfarin in clinical trials, warfarin effects were reversed in < 40% of cases, raising concerns about the generalizability of this finding. Consecutive patients ≥ 66 years presented to five tertiary care hospitals across three cities in Ontario, Canada from October 2010 to March 2015 with diagnoses that included hemorrhage. Charts were screened for association with DOAC or warfarin use; eligible cases were abstracted and linked to administrative databases. Among 19,061 records screened, 2,002 (460 receiving DOAC, 1,542 receiving warfarin) were eligible. Reversal agents (72.9% vitamin K, 40.7% prothrombin complex concentrates) were frequently used in warfarin bleeding events. Red blood cell transfusions occurred more often in DOAC bleeding events than in warfarin events (52.0% vs 39.5%; adjusted relative risk [aRR], 1.32; 95% CI, 1.19-2.47). However, units of blood products transfused were not different between the two groups. Thirty-four DOAC cases (7.4%) received activated prothrombin complex concentrates or recombinant factor VIIa. In-hospital mortality was lower following DOAC bleeding events (9.8% vs 15.2%; aRR, 0.66; 95% CI, 0.49-0.89), although differences in 30-day mortality did not reach statistical significance (12.6% vs 16.3%; aRR, 0.79; 95% CI, 0.61-1.03). In this unselected cohort of patients with oral anticoagulant-related hemorrhage with high rates of warfarin reversal, in-hospital mortality was lower among DOAC-associated bleeding events. These findings support the safety of DOACs in routine care and present useful baseline measures for evaluations of DOAC-specific reversal agents. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomised controlled trial.

PubMed

Derman, Richard J; Kodkany, Bhalchandra S; Goudar, Shivaprasad S; Geller, Stacie E; Naik, Vijaya A; Bellad, M B; Patted, Shobhana S; Patel, Ashlesha; Edlavitch, Stanley A; Hartwell, Tyler; Chakraborty, Hrishikesh; Moss, Nancy

2006-10-07

Postpartum haemorrhage is a major cause of maternal mortality in the developing world. Although effective methods for prevention and treatment of such haemorrhage exist--such as the uterotonic drug oxytocin--most are not feasible in resource-poor settings where many births occur at home. We aimed to investigate whether oral misoprostol, a potential alternative to oxytocin, could prevent postpartum haemorrhage in a community home-birth setting. In a placebo-controlled trial undertaken between September, 2002, and December, 2005, 1620 women in rural India were randomised to receive oral misoprostol (n=812) or placebo (n=808) after delivery. 25 auxiliary nurse midwives undertook the deliveries, administered the study drug, and measured blood loss. The primary outcome was the incidence of acute postpartum haemorrhage (defined as > or =500 mL bleeding) within 2 h of delivery. Analysis was by intention-to-treat. The trial was registered with the US clinical trials database (http://www. clinicaltrials.gov) as number NCT00097123. Oral misoprostol was associated with a significant reduction in the rate of acute postpartum haemorrhage (12.0% to 6.4%, p<0.0001; relative risk 0.53 [95% CI 0.39-0.74]) and acute severe postpartum haemorrhage (1.2% to 0.2%, p<0.0001; 0.20 [0.04-0.91]. One case of postpartum haemorrhage was prevented for every 18 women treated. Misoprostol was also associated with a decrease in mean postpartum blood loss (262.3 mL to 214.3 mL, p<0.0001). Postpartum haemorrhage rates fell over time in both groups but remained significantly higher in the placebo group. Women taking misoprostol had a higher rate of transitory symptoms of chills and fever than the control. Oral misoprostol was associated with significant decreases in the rate of acute postpartum haemorrhage and mean blood loss. The drug's low cost, ease of administration, stability, and a positive safety profile make it a good option in resource-poor settings.

R- and S-Warfarin Were Transported by Breast Cancer Resistance Protein: From In Vitro to Pharmacokinetic-Pharmacodynamic Studies.

PubMed

Yang, Meng-Syuan; Yu, Chung-Ping; Chao, Pei-Dawn Lee; Lin, Shiuan-Pey; Hou, Yu-Chi

2017-05-01

Warfarin, a racemate of R- and S-warfarin, is an important oral anticoagulant with narrow therapeutic window. Being an acidic drug, warfarin (pKa = 4.94) exists mainly as anion under physiological pH. We hypothesized that the transport of warfarin anion across cell membrane was mediated by breast cancer resistance protein (BCRP), an efflux transporter having a variety of acidic substrates. This study aimed at verifying that warfarin was a substrate of BCRP. Cell lines and mice were used for transport assay and pharmacokinetic-pharmacodynamic studies, respectively. The concentrations of R- and S-warfarin were simultaneously determined by liquid chromatography-mass spectrometry method. Transport assay showed that the intracellular concentrations of R- and S-warfarin in MDCKII-BCRP were significantly lower than those in MDCKII. In addition, Ko143, a potent BCRP inhibitor, significantly inhibited the efflux transport of R- and S-warfarin in MDCKII-BCRP, but not in MDCKII. Pharmacokinetic study showed that the plasma concentrations of R- and S-warfarin in Bcrp -/- mice were significantly higher than those in wild-type mice at 6 h after dosing. Anticoagulation measurement showed that the international normalized ratio in Bcrp -/- mice was significantly higher than that in wild-type mice at 24 h after dosing. In conclusion, R- and S-warfarin were transported by BCRP. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Outcomes of Dabigatran and Warfarin for Atrial Fibrillation in Contemporary Practice: A Retrospective Cohort Study.

PubMed

Go, Alan S; Singer, Daniel E; Toh, Sengwee; Cheetham, T Craig; Reichman, Marsha E; Graham, David J; Southworth, Mary Ross; Zhang, Rongmei; Izem, Rima; Goulding, Margie R; Houstoun, Monika; Mott, Katrina; Sung, Sue Hee; Gagne, Joshua J

2017-12-19

Dabigatran (150 mg twice daily) has been associated with lower rates of stroke than warfarin in trials of atrial fibrillation, but large-scale evaluations in clinical practice are limited. To compare incidence of stroke, bleeding, and myocardial infarction in patients receiving dabigatran versus warfarin in practice. Retrospective cohort. National U.S. Food and Drug Administration Sentinel network. Adults with atrial fibrillation initiating dabigatran or warfarin therapy between November 2010 and May 2014. Ischemic stroke, intracranial hemorrhage, extracranial bleeding, and myocardial infarction identified from hospital claims among propensity score-matched patients starting treatment with dabigatran or warfarin. Among 25 289 patients starting dabigatran therapy and 25 289 propensity score-matched patients starting warfarin therapy, those receiving dabigatran did not have significantly different rates of ischemic stroke (0.80 vs. 0.94 events per 100 person-years; hazard ratio [HR], 0.92 [95% CI, 0.65 to 1.28]) or extracranial hemorrhage (2.12 vs. 2.63 events per 100 person-years; HR, 0.89 [CI, 0.72 to 1.09]) but were less likely to have intracranial bleeding (0.39 vs. 0.77 events per 100 person-years; HR, 0.51 [CI, 0.33 to 0.79]) and more likely to have myocardial infarction (0.77 vs. 0.43 events per 100 person-years; HR, 1.88 [CI, 1.22 to 2.90]). However, the strength and significance of the association between dabigatran use and myocardial infarction varied in sensitivity analyses and by exposure definition (HR range, 1.13 [CI, 0.78 to 1.64] to 1.43 [CI, 0.99 to 2.08]). Older patients and those with kidney disease had higher gastrointestinal bleeding rates with dabigatran. Inability to examine outcomes by dabigatran dose (unacceptable covariate balance between matched patients) or quality of warfarin anticoagulation (few patients receiving warfarin had available international normalized ratio values). In matched adults with atrial fibrillation treated in

Prophylactic ethamsylate for periventricular haemorrhage.

PubMed Central

Cooke, R W; Morgan, M E

1984-01-01

Drug prophylaxis with ethamsylate for periventricular haemorrhage in very low birthweight infants significantly reduced the incidence of periventricular haemorrhage in survivors. A reduction in abnormalities at follow up and in insertion of ventriculoperitoneal shunts was also noted. PMID:6696506

Can We Predict Daily Adherence to Warfarin?

PubMed Central

Platt, Alec B.; Localio, A. Russell; Brensinger, Colleen M.; Cruess, Dean G.; Christie, Jason D.; Gross, Robert; Parker, Catherine S.; Price, Maureen; Metlay, Joshua P.; Cohen, Abigail; Newcomb, Craig W.; Strom, Brian L.; Laskin, Mitchell S.

2010-01-01

Background: Warfarin is the primary therapy to prevent stroke and venous thromboembolism. Significant periods of nonadherence frequently go unreported by patients and undetected by providers. Currently, no comprehensive screening tool exists to help providers assess the risk of nonadherence at the time of initiation of warfarin therapy. Methods: This article reports on a prospective cohort study of adults initiating warfarin therapy at two anticoagulation clinics (university- and Veterans Affairs-affiliated). Nonadherence, defined by failure to record a correct daily pill bottle opening, was measured daily by electronic pill cap monitoring. A multivariable logistic regression model was used to develop a point system to predict daily nonadherence to warfarin. Results: We followed 114 subjects for a median of 141 days. Median nonadherence of the participants was 14.4% (interquartile range [IQR], 5.8-33.8). A point system, based on nine demographic, clinical, and psychosocial factors, distinguished those demonstrating low vs high levels of nonadherence: four points or fewer, median nonadherence 5.8% (IQR, 2.3-14.1); five points, 9.1% (IQR, 5.9-28.6); six points, 14.5% (IQR, 7.1-24.1); seven points, 14.7% (IQR, 7.0-34.7); and eight points or more, 29.3% (IQR, 15.5-41.9). The model produces a c-statistic of 0.66 (95% CI, 0.61-0.71), suggesting modest discriminating ability to predict day-level warfarin nonadherence. Conclusions: Poor adherence to warfarin is common. A screening tool based on nine demographic, clinical, and psychosocial factors, if further validated in other patient populations, may help to identify groups of patients at lower risk for nonadherence so that intensified efforts at increased monitoring and intervention can be focused on higher-risk patients. PMID:19903973

Factors influencing warfarin response in hospitalized patients

PubMed Central

Abdel-Aziz, Mahmoud I.; Ali, Mostafa A. Sayed; Hassan, Ayman K.M.; Elfaham, Tahani H.

2015-01-01

The objective of this study was to investigate the influence of simultaneous factors that potentially keep patients far from achieving target INR range at discharge in hospitalized patients. Prospective cross-sectional observational study conducted at the Cardiology Department and Intensive Care Unit (ICU) of the Assiut University Hospitals. One-hundred and twenty patients were enrolled in the study from July 2013 to January 2014. Outcome measures were discharge INRs, bleeding and thromboembolic episodes. Bivariate analysis and multinomial logistic regression were conducted to determine independent risk factors that can keep patients outside target INR range. Patients who were newly initiated warfarin on hospital admission were given low initiation dose (2.8 mg ± 0.9). They were more likely to have INR values below 1.5 during hospital stay, 13 (27.7%) patients compared with 9 (12.3%) previously treated patients, respectively (p = .034). We found that the best predictors of achieving below target INR range relative to within target INR range were; shorter hospital stay periods (OR, 0.82 for every day increase [95% CI, 0.72–0.94]), being a male patient (OR, 2.86 [95% CI, 1.05–7.69]), concurrent infection (OR, 0.21 [95% CI, 0.07–0.59]) and new initiation of warfarin therapy on hospital admission (OR, 3.73 [95% CI, 1.28–10.9]). Gender, new initiation of warfarin therapy on hospital admission, shorter hospital stay periods and concurrent infection can have a significant effect on discharge INRs. Initiation of warfarin without giving loading doses increases the risk of having INRs below 1.5 during hospital stay and increases the likelihood of a patient to be discharged with INR below target range. Following warfarin dosing nomograms and careful monitoring of the effect of various factors on warfarin response should be greatly considered. PMID:26702259

The Time in Therapeutic Range and Bleeding Complications of Warfarin in Different Geographic Regions of Turkey: A Subgroup Analysis of WARFARIN-TR Study.

PubMed

Kılıç, Salih; Çelik, Ahmet; Çakmak, Hüseyin Altuğ; Afşin, Abdülmecit; Tekkeşin, Ahmet İlker; Açıksarı, Gönül; Memetoğlu, Mehmet Erdem; Özpamuk Karadeniz, Fatma; Şahan, Ekrem; Alıcı, Mehmet Hayri; Dereli, Yüksel; Sinan, Ümit Yaşar; Zoghi, Mehdi

2017-08-04

The time in therapeutic range values may vary between different geographical regions of Turkey in patients vitamin K antagonist therapy. To evaluate the time in therapeutic range percentages, efficacy, safety and awareness of warfarin according to the different geographical regions in patients who participated in the WARFARIN-TR study (The Awareness, Efficacy, Safety and Time in Therapeutic Range of Warfarin in the Turkish population) in Turkey. Cross-sectional study. The WARFARIN-TR study includes 4987 patients using warfarin and involved regular international normalized ratio monitoring between January 1, 2014 and December 31, 2014. Patients attended follow-ups for 12 months. The sample size calculations were analysed according to the density of the regional population and according to Turkish Statistical Institute data. The time in therapeutic range was calculated according to F.R. Roosendaal's algorithm. Awareness was evaluated based on the patients' knowledge of the effect of warfarin and food-drug interactions with simple questions developed based on a literature review. The Turkey-wide time in therapeutic range was reported as 49.5%±22.9 in the WARFARIN-TR study. There were statistically significant differences between regions in terms of time in therapeutic range (p>0.001). The highest rate was reported in the Marmara region (54.99%±20.91) and the lowest was in the South-eastern Anatolia region (41.95±24.15) (p>0.001). Bleeding events were most frequently seen in Eastern Anatolia (41.6%), with major bleeding in the Aegean region (5.11%) and South-eastern Anatolia (5.36%). There were statistically significant differences between the regions in terms of awareness (p>0.001). Statistically significant differences were observed in terms of the efficacy, safety and awareness of warfarin therapy according to different geographical regions in Turkey.

Warfarin Toxicity and Individual Variability—Clinical Case

PubMed Central

Piatkov, Irina; Rochester, Colin; Jones, Trudi; Boyages, Steven

2010-01-01

Warfarin is a widely used anticoagulant in the treatment and prevention of thrombosis, in the treatment for chronic atrial fibrillation, mechanical valves, pulmonary embolism, and dilated cardiomyopathy. It is tasteless and colorless, was used as a poison, and is still marketed as a pesticide against rats and mice. Several long-acting warfarin derivatives—superwarfarin anticoagulants—such as brodifacoum, diphenadione, chlorophacinone, bromadiolone, are used as pesticides and can produce profound and prolonged anticoagulation. Several factors increase the risk of warfarin toxicity. However, polymorphisms in cytochrome P450 genes and drug interactions account for most of the risk for toxicity complications. Each person is unique in their degree of susceptibility to toxic agents. The toxicity interpretation and the health risk of most toxic substances are a subject of uncertainty. Genetically determined low metabolic capacity in an individual can dramatically alter the toxin and metabolite levels from those normally expected, which is crucial for drugs with a narrow therapeutic index, like warfarin. Personalized approaches in interpretation have the potential to remove some of the scientific uncertainties in toxicity cases. PMID:22069565

Measurement of blood loss during postpartum haemorrhage.

PubMed

Lilley, G; Burkett-St-Laurent, D; Precious, E; Bruynseels, D; Kaye, A; Sanders, J; Alikhan, R; Collins, P W; Hall, J E; Collis, R E

2015-02-01

We set out to validate the accuracy of gravimetric quantification of blood loss during simulated major postpartum haemorrhage and to evaluate the technique in a consecutive cohort of women experiencing major postpartum haemorrhage. The study took part in a large UK delivery suite over a one-year period. All women who experienced major postpartum haemorrhage were eligible for inclusion. For the validation exercise, in a simulated postpartum haemorrhage scenario using known volumes of artificial blood, the accuracy of gravimetric measurement was compared with visual estimation made by delivery suite staff. In the clinical observation study, the blood volume lost during postpartum haemorrhage was measured gravimetrically according to our routine institutional protocol and was correlated with fall in haemoglobin. The main outcome measure was the accuracy of gravimetric measurement of blood loss. Validation exercise: the mean percentage error of gravimetrically measured blood volume was 4.0±2.7% compared to visually estimated blood volume with a mean percentage error of 34.7±32.1%. Clinical observation study: 356 out of 6187 deliveries were identified as having major postpartum haemorrhage. The correlation coefficient between measured blood loss and corrected fall in haemoglobin for all patients was 0.77; correlation was stronger (0.80) for postpartum haemorrhage >1500mL, and similar during routine and out-of-hours working. The accuracy of the gravimetric method was confirmed in simulated postpartum haemorrhage. The clinical study shows that gravimetric measurement of blood loss is correlated with the fall in haemoglobin in postpartum haemorrhage where blood loss exceeds 1500mL. The method is simple to perform, requires only basic equipment, and can be taught and used by all maternity services during major postpartum haemorrhage. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats

PubMed Central

John, J; John, M; Wu, L; Hsiao, C; Abobo, CV; Liang, D

2013-01-01

Background and Purpose Warfarin is often used with etravirine (ETV) to prevent HIV-related thromboembolic events. As both warfarin and ETV bind to plasma proteins and are metabolized by hepatic cytochrome P450s, they are likely to interact. Hence, we evaluated the effect of ETV on the pharmacokinetics and blood clotting time of racemic warfarin in rats. Experimental Approach Two groups of male Sprague-Dawley rats, in which the jugular vein had been cannulated, were studied. The control group (n = 10) received 1 mg·kg−1 racemic warfarin i.v., and the test group (n = 13) 1 mg·kg−1 of racemic warfarin followed by 25 mg·kg−1 ETV i.v. Serial blood samples were collected for up to 144 h and the blood clotting time (calculated as international normalized ratio [INR]) measured in blood plasma at each sample point. Plasma concentrations of R-warfarin, S-warfarin, R-7-hydroxywarfarin and S-7-hydroxywarfarin were measured by a LC/MS/MS method using a chiral lux cellulose-1 column. Pharmacokinetic parameters were analysed using non-compartmental methods. Key Results ETV significantly increased, by threefold, the systemic clearance and volume of distribution of S-warfarin, but not those of R-warfarin. ETV decreased the total AUC of warfarin, but had no effect on its elimination half-life. ETV also increased the systemic clearance of both R-7-hydroxywarfarin and S-7-hydroxywarfarin but only increased the volume of distribution of R-7-hydroxywarfarin. Interestingly, the effect of warfarin on blood clotting time (INR) was significantly increased in the presence of etravirine. Conclusion and Implications Our data suggest that etravirine may potentiate the anticoagulant effect of warfarin and this could have clinical significance. PMID:23215758

Effects of VKORC1 Genetic Polymorphisms on Warfarin Maintenance Dose Requirement in a Chinese Han Population

PubMed Central

Yan, Xiaojuan; Yang, Feng; Zhou, Hanyun; Zhang, Hongshen; Liu, Jianfei; Ma, Kezhong; Li, Yi; Zhu, Jun; Ding, Jianqiang

2015-01-01

Background VKORC1 is reported to be capable of treating several diseases with thrombotic risk, such as cardiac valve replacement. Some single-nucleotide polymorphisms (SNPs) in VKORC1 are documented to be associated with clinical differences in warfarin maintenance dose. This study explored the correlations of VKORC1–1639 G/A, 1173 C/T and 497 T/G genetic polymorphisms with warfarin maintenance dose requirement in patients undergoing cardiac valve replacement. Material/Methods A total of 298 patients undergoing cardiac valve replacement were recruited. During follow-up, clinical data were recorded. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was applied to detect VKORC1–1639 G/A, 1173 C/T and 497 T/G polymorphisms, and genotypes were analyzed. Results Correlations between warfarin maintenance dose and baseline characteristics revealed statistical significances of age, gender and operation methods with warfarin maintenance dose (all P<0.05). Warfarin maintenance dose in VKORC1–1639 G/A AG + GG carriers was obviously higher than in AA carriers (P<0.001). As compared with patients with TT genotype in VKORC1 1173 C/T, warfarin maintenance dose was apparently higher in patients with CT genotype (P<0.001). Linear regression analysis revealed that gender, operation method, method for heart valve replacement, as well as VKORC1–1639 G/A and 1173 C/T gene polymorphisms were significantly related to warfarin maintenance dose (all P<0.05). Conclusions VKORC1 gene polymorphisms are key genetic factors to affect individual differences in warfarin maintenance dose in patients undergoing cardiac valve replacement; meanwhile, gender, operation method and method for heart valve replacement might also be correlate with warfarin maintenance dose. PMID:26583785

Estimation of the impact of warfarin's time-in-therapeutic range on stroke and major bleeding rates and its influence on the medical cost avoidance associated with novel oral anticoagulant use-learnings from ARISTOTLE, ROCKET-AF, and RE-LY trials.

PubMed

Amin, Alpesh; Deitelzweig, Steve; Jing, Yonghua; Makenbaeva, Dinara; Wiederkehr, Daniel; Lin, Jay; Graham, John

2014-01-01

Warfarin's time-in-therapeutic range (TTR) is highly variable among patients with nonvalvular atrial fibrillation (NVAF). The objective of this study was to estimate the impact of variations in wafarin's TTR on rates of stroke/systemic embolism (SSE) and major bleedings among NVAF patients in the ARISTOTLE, ROCKET-AF, and RE-LY trials. Additionally, differences in medical costs for clinical endpoints when novel oral anticoagulants (NOACs) were used instead of warfarin at different TTR values were estimated. Quartile ranges of TTR values and corresponding event rates (%/patient - year = %/py) of SSE and major bleedings among NVAF patients treated with warfarin were estimated from published literature and FDA documents. The associations of SSE and major bleeding rates with TTR values were evaluated by regression analysis and then the calculated regression coefficients were used in analysis of medical cost differences associated with use of each NOAC versus warfarin (2010 costs; US payer perspective) at different TTRs. Each 10 % increase in warfarin's TTR correlated with a -0.32%/py decrease in SSE rate (R(2) = 0.61; p < 0.001). Although, the rate of major bleedings decreased as TTR increased, it was not significant (-0.035%/py, p = 0.63). As warfarin's TTR increased from 30 to 90% the estimated medical cost decreased from -$902 to -$83 for apixaban, from -$506 to +$314 for rivaroxaban, and from -$596 to +$223 for dabigatran. Among NVAF patients there is a significant negative correlation between warfarin's TTR and SSE rate, but not major bleedings. The variations in warfarin's TTR impacted the economic comparison of use of individual NOACs versus warfarin.

Lack of effect of lacosamide on the pharmacokinetic and pharmacodynamic profiles of warfarin.

PubMed

Stockis, Armel; van Lier, Jan Jaap; Cawello, Willi; Kumke, Thomas; Eckhardt, Klaus

2013-07-01

The aim of this study was to evaluate the effect of the antiepileptic drug lacosamide on the pharmacokinetics and pharmacodynamics of the anticoagulant warfarin. In this open-label, two-treatment crossover study, 16 healthy adult male volunteers were randomized to receive a single 25-mg dose of warfarin alone in one period and lacosamide 200 mg twice daily on days 1-9 with a single 25 mg dose of warfarin coadministered on day 3 in the other period. There was a 2-week washout between treatments. Pharmacokinetic end points were area under the plasma concentration-time curve (AUC(0,last) and AUC(0,∞) ) and maximum plasma concentration (Cmax ) for S- and R-warfarin. Pharmacodynamic end points were area under the international normalized ratio (INR)-time curve (AUCINR ), maximum INR (INRmax ), maximum prothrombin time (PTmax ) and area under the PT-time curve (AUCPT ). Following warfarin and lacosamide coadministration, Cmax and AUC of S- and R-warfarin, as well as peak value and AUC of PT and INR, were equivalent to those after warfarin alone. In particular, the AUC(0,∞) ratio (90% confidence interval) for coadministration of warfarin and lacosamide versus warfarin alone was 0.97 (0.94-1.00) for S-warfarin and 1.05 (1.02-1.09) for R-warfarin, and the AUCINR ratio was 1.04 (1.01-1.06). All participants completed the study. Coadministration of lacosamide 400 mg/day did not alter the pharmacokinetics of warfarin 25 mg or the anticoagulation level. These results suggest that there is no need for dose adjustment of warfarin when coadministered with lacosamide. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Medication persistence and discontinuation of rivaroxaban versus warfarin among patients with non-valvular atrial fibrillation.

PubMed

Nelson, Winnie W; Song, Xue; Coleman, Craig I; Thomson, Erin; Smith, David M; Damaraju, C V; Schein, Jeffrey R

2014-12-01

To compare real-world persistence and discontinuation among non-valvular atrial fibrillation (NVAF) patients on rivaroxaban and warfarin in the US. A large nationally representative US claims database was used to conduct a retrospective cohort analysis of patients with NVAF treated with rivaroxaban or warfarin from 1 July 2010 through 31 March 2013. Index date was the date of the first prescription of rivaroxaban or warfarin. All patients were followed until the earliest of inpatient death, end of continuous enrollment, or end of study period. Rivaroxaban patients were matched 1:1 by propensity scores. Medication persistence was defined as absence of refill gap of ≥ 60 days. Discontinuation was defined as no additional refill for at least 90 days and until the end of follow-up. Cox proportional hazards models were estimated to examine the adjusted hazard ratios (aHRs) of rivaroxaban vs. warfarin on non-persistence and discontinuation. A total of 32,886 NVAF patients on rivaroxaban or warfarin met the study inclusion criteria. Each of the 7259 rivaroxaban patients identified were matched 1:1 to warfarin patients. Patients on rivaroxaban had a significantly better rate of persistence (aHR: 0.63, 95% CI 0.59-0.68) and lower rate of discontinuation (aHR: 0.54, 95% CI 0.49-0.58) compared to warfarin recipients. Claims data may have contained inaccuracies and miscoding. Confounding may remain even after propensity score matching and additional adjustments in model. Refill data may not fully reflect actual medication use. Longer follow-up may produce more precise estimates of persistence and discontinuation. This matched cohort analysis indicated that rivaroxaban was associated with significantly higher medication persistence and lower discontinuation rates compared to warfarin.

Intracerebral Hemorrhage with Herniation in a Second-Trimester Pregnant Female.

PubMed

MacMillan, Donald S

A 30-year-old woman, gravida 1, para 2, in her second trimester presented to the local emergency department complaining of an atraumatic headache described as the worst headache of her life. While undergoing evaluation, she became unresponsive with signs of herniation, including a blown pupil and bradycardia. Emergent imaging identified an intracerebral hemorrhage requiring immediate surgical decompression. The patient was transferred by helicopter to tertiary care. Upon arrival, the patient was taken directly to the operating room and underwent a decompressive craniotomy. This article reviews the considerations for transporting pregnant patients with intracerebral hemorrhage. Copyright © 2018 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.

Noninvasive detection of intracerebral hemorrhage using near-infrared spectroscopy (NIRS)

NASA Astrophysics Data System (ADS)

Hennes, Hans-Juergen; Lott, Carsten; Windirsch, Michael; Hanley, Daniel F.; Boor, Stephan; Brambrink, Ansgar; Dick, Wolfgang

1998-01-01

Intracerebral Hemorrhage (IH) is an important cause of secondary brain injury in neurosurgical patients. Early identification and treatment improve neurologic outcome. We have tested Near Infrared Spectroscopy (NIRS) as an alternative noninvasive diagnostic tool compared to CT-Scans to detect IH. We prospectively studied 212 patients with neurologic symptoms associated with intracranial pathology before performing a CT-scan. NIRS signals indicated pathologies in 181 cases (sensitivity 0.96; specificity 0.29). In a subgroup of subdural hematomas NIRS detected 45 of 46 hematomas (sensitivity 0.96; specificity 0.79). Identification of intracerebral hemorrhage using NIRS has the potential to allow early treatment, thus possibly avoiding further injury.

Noninvasive detection of intracerebral hemorrhage using near-infrared spectroscopy (NIRS)

NASA Astrophysics Data System (ADS)

Hennes, Hans J.; Lott, C.; Windirsch, Michael; Hanley, Daniel F.; Boor, Stephan; Brambrink, Ansgar; Dick, Wolfgang

1997-12-01

Intracerebral Hemorrhage (IH) is an important cause of secondary brain injury in neurosurgical patients. Early identification and treatment improve neurologic outcome. We have tested Near Infrared Spectroscopy (NIRS) as an alternative noninvasive diagnostic tool compared to CT-Scans to detect IH. We prospectively studied 212 patients with neurologic symptoms associated with intracranial pathology before performing a CT-scan. NIRS signals indicated pathologies in 181 cases (sensitivity 0.96; specificity 0.29). In a subgroup of subdural hematomas NIRS detected 45 of 46 hematomas (sensitivity 0.96; specificity 0.79). Identification of intracerebral hemorrhage using NIRS has the potential to allow early treatment, thus possibly avoiding further injury.

Comparison of the Effectiveness and Safety of Apixaban, Dabigatran, Rivaroxaban, and Warfarin in Newly Diagnosed Atrial Fibrillation.

PubMed

Hernandez, Inmaculada; Zhang, Yuting; Saba, Samir

2017-11-15

No studies have performed direct pairwise comparisons of the effectiveness and safety of warfarin and the new oral anticoagulants (NOACs) apixaban, dabigatran, and rivaroxaban. Using 2013 to 2014 claims from a 5% random sample of Medicare beneficiaries, we identified patients newly diagnosed with atrial fibrillation who initiated apixaban, dabigatran, rivaroxaban, warfarin, or no oral anticoagulation therapy in 2013 to 2014. Outcomes included the composite of ischemic stroke, systemic embolism (SE) and death, any bleeding event, gastrointestinal bleeding, intracranial bleeding, and treatment persistence. We constructed Cox proportional hazard models to compare outcomes between each pair of treatment groups. The composite risk of ischemic stroke, SE, and death was lower for NOACs than for warfarin: hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76 to 0.98 for apixaban; 0.73, 95% CI 0.63 to 0.86 for dabigatran; and 0.82, 95% CI 0.75 to 0.89 for rivaroxaban, all compared with warfarin. There were no differences in effectiveness across NOACs. The risk of any bleeding was lower with apixaban than with warfarin, but higher with rivaroxaban than with warfarin. Apixaban (HR 0.69, 95% CI 0.60 to 0.79) and dabigatran (HR 0.79, 95% CI 0.69 to 0.92) were associated with lower bleeding risk than rivaroxaban. Treatment persistence was highest for apixaban (82%), and lowest for dabigatran and warfarin (64%) (p value <0.001). Compared with warfarin, NOACs are more effective in preventing stroke but their risk of bleeding varies, with rivaroxaban having higher risk than warfarin. Altogether, apixaban had the most favorable effectiveness, safety, and persistence profile. Copyright © 2017 Elsevier Inc. All rights reserved.

Influence of warfarin therapy on the occurrence of postoperative endoleaks and aneurysm sac enlargement after endovascular abdominal aortic aneurysm repair.

PubMed

Seike, Yoshimasa; Tanaka, Hiroshi; Fukuda, Tetsuya; Itonaga, Tatsuya; Morita, Yoshiaki; Oda, Tatsuya; Inoue, Yosuke; Sasaki, Hiroaki; Minatoya, Kenji; Kobayashi, Junjiro

2017-04-01

This study aims to determine whether warfarin therapy influences the occurrence of endoleaks or aneurysm sac enlargement after endovascular aortic repair (EVAR). A total of 367 patients who underwent EVAR for abdominal aortic aneurysm between 2007 and 2013 were recruited for this study. Satisfactory follow-up data including completed computed tomography scan follow-up for more than 2 years were available for 209 patients, and the mean follow-up time was 37 ± 12 months. Twenty-nine (16%) patients were on warfarin therapy (warfarin group), whereas 180 (84%) patients were not on warfarin therapy (control group). Two- and four-year freedom rates for persistent type II endoleaks were significantly lower in patients of the warfarin group compared with the control group (85 and 49% vs 93 and 91%, respectively; P = 0.0001). Similarly, 2- and 4-year freedom rates for sac enlargement (>5 mm) were significantly lower in patients of the warfarin group compared with the control group (83 and 61% vs 92 and 82%, respectively; P = 0.0036). Using Cox regression analysis, the warfarin therapy was identified to be an independent positive predictor of sac enlargement after EVAR [hazard ratio (HR): 2.4; 95% confidence interval (CI): 1.08-5.40; P = 0.032], together with persistent type II endoleak. Warfarin therapy was also an independent predictor for persistent type II endoleak (HR: 3.7; 95% CI: 1.81-7.41; P < 0.0001) together with the number of patent lumbar arteries. Results suggested that warfarin therapy was significantly associated with an increased risk for persistent II endoleak and sac enlargement after EVAR. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Tranexamic acid for acute intracerebral hemorrhage growth predicted by spot sign trial: Rationale and design.

PubMed

Liu, Liping; Wang, Yilong; Meng, Xia; Li, Na; Tan, Ying; Nie, Ximing; Liu, Dacheng; Zhao, Xingquan

2017-04-01

Rationale Acute intracerebral hemorrhage inflicts a high-economic and -health burden. Computed tomography angiography spot sign is a predictor of hematoma expansion, is associated with poor clinical outcome and is an important stratifying variable for patients treated with haemostatic therapy. Aims We aim to compare the effect of treatment with tranexamic acid to placebo for the prevention of hemorrhage growth in patients with high-risk acute intracerebral hemorrhage with a positive spot sign. Design The tranexamic acid for acute intracerebral hemorrhage growth predicted by spot sign (TRAIGE) is a prospective, multicenter, placebo-controlled, double-blind, investigator-led, randomized clinical trial that will include an estimated 240 participants. Patients with intracerebral hemorrhage demonstrating symptom onset within 8 h and with the spot sign as a biomarker for ongoing hemorrhage, and no contraindications for antifibrinolytic therapy, will be enrolled to receive either tranexamic acid or placebo. The primary outcome measure is the presence of hemorrhage growth defined as an increase in intracerebral hemorrhage volume >33% or >6 ml from baseline to 24 ± 2 h. The secondary outcomes include safety and clinical outcomes. Conclusion The TRAIGE trial evaluates the efficacy of haemostatic therapy with tranexamic acid in the prevention of hemorrhage growth among high-risk patients with acute intracerebral hemorrhage.

Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.

PubMed

Granger, Christopher B; Lopes, Renato D; Hanna, Michael; Ansell, Jack; Hylek, Elaine M; Alexander, John H; Thomas, Laine; Wang, Junyuan; Bahit, M Cecilia; Verheugt, Freek; Lawrence, Jack; Xavier, Denis; Wallentin, Lars

2015-01-01

We sought to assess the occurrence of events after blinded study drug discontinuation and transition to open-label vitamin K antagonist (VKA) in ARISTOTLE. At the end of ARISTOTLE, blinded study drug was stopped, and open-label VKA was recommended. For patients completing the trial on blinded study drug, a 2-day bridging period with apixaban or apixaban placebo was recommended (while beginning open-label VKA). Outcomes were assessed during the 30 days after stopping blinded study drug. Of the 6,809 patients in the apixaban group and 6,588 in the warfarin group who completed the trial on study drug, there were 21 strokes or systemic emboli (4.02%/year) and 26 major bleeding (4.97%/year) events in the apixaban group (transitioning to VKA) and 5 strokes or systemic emboli (0.99%/year) and 10 major bleeding (1.97%/year) events in the warfarin group (continuing on VKA), with most of the imbalance between groups being after the first week. Similar results were seen in the first 30 days of the trial where warfarin-naive patients starting warfarin had a higher rate of stroke or systemic emboli (5.41%/year) than warfarin-experienced patients (1.42%/year), a pattern not seen when starting apixaban. No similar increase in events with apixaban versus warfarin was seen during temporary or permanent study drug discontinuation during the trial. The excess in thrombotic and bleeding events in the apixaban group after study drug discontinuation appears to be related to an increased risk associated with the initiation of a VKA rather than a direct effect of apixaban. Whether ≥2 days of apixaban bridging improves outcomes during VKA transition is unknown and deserves further evaluation. Copyright © 2014 Elsevier Inc. All rights reserved.

Pharmacokinetics of warfarin in rats: role of serum protein binding and tissue distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheung, W.K.

The purpose of this study was to explore the role of serum protein binding and tissue distribution in the non-linear pharmacokinetics of warfarin in rats. The first phase of the research was an attempt to elucidate the causes of intersubject differences in serum protein binding of warfarin in rats. It was found that the distribution of S-warfarin between blood and liver, kidneys, muscle, or fatty tissue was non-linear. Based on the tissue distribution data obtained, a physiologically-based pharmacokinetic model was developed to describe the time course of S-warfarin concentrations in the serum and tissues of rats. The proposed model wasmore » able to display the dose-dependent pharmacokinetics of warfarin in rats. Namely a lower clearance and a smaller apparent volume of distribution with increasing dose, which appear to be due to the presence of capacity-limited, high-affinity binding sites for warfarin in various tissues. To determine if the binding of warfarin to the high-affinity binding sites in the liver of rats is reversible, concentrations of S-warfarin in the liver and serum of rats were monitored for a very long time after an intravenous injection of a 1 mg/kg dose. In another study in rats, non-radioactive warfarin was found to be able to displace tissue-bound C/sup 14/-warfarin which was administered about 200 hours before the i.v. injection of the non-radioactive warfarin, showing that the binding of warfarin to the high-affinity binding sites in the body is persistent and reversible.« less

Late post pancreatectomy haemorrhage. Risk factors and modern management.

PubMed

Sanjay, Pandanaboyana; Fawzi, Ali; Fulke, Jennifer L; Kulli, Christoph; Tait, Iain S; Zealley, Iain A; Polignano, Francesco M

2010-05-05

Current management of late post-pancreatectomy haemorrhage in a university hospital. Haemorrhage after pancreaticoduodenectomy is a serious complication. We report on risk factors and outcome following management by radiological intervention. Tertiary care centre in Scotland. Sixty-seven consecutive patients who underwent pancreaticoduodenectomy. All pancreaticoduodenectomies over a 3-year period were reviewed. International Study Group on Pancreatic Surgery (ISGPS) definition of post-pancreatectomy haemorrhage was used. Endpoints were incidence of haemorrhage, pancreaticojejunal anastomosis leak, methicillin-resistant Staphylococcus aureus (MRSA) infection and mortality. Seven patients (10.4%) developed post-pancreatectomy haemorrhage out of 67 pancreaticoduodenectomies. Median age was 71 years. All post-pancreatectomy haemorrhage were late onset (median 23 days; range: 3-35 days), extraluminal and ISGPS grade C. Post-pancreatectomy haemorrhage arose from hepatic artery (n=4), superior mesenteric artery (n=1), jejunal artery (n=1), and splenic artery (n=1). Angiographic treatment was successful in all patients by embolisation (n=5) or stent grafting (n=2). Pancreatic fistula rate was similar in post-pancreatectomy haemorrhage and "no-haemorrhage" groups (57.1% vs. 40.0%; P=0.440); MRSA infection was significantly higher in post-pancreatectomy haemorrhage group (57.1% vs. 16.7%; P=0.030). Mortality from post-pancreatectomy haemorrhage despite successful haemostasis was 42.9%. Univariate and multivariate analysis identified MRSA infection as a risk factor for post-pancreatectomy haemorrhage. CT angiogram followed by conventional catheter angiography is effective for treatment of late extraluminal post-pancreatectomy haemorrhage. MRSA infection in the abdominal drain fluid increases its risk and therefore aggressive treatment of MRSA and high index of suspicion are indicated.

Ethnicity and Onset of Cardiovascular Disease: A CALIBER Study

ClinicalTrials.gov

2017-06-07

Abdominal Aortic Aneurysm; Coronary Heart Disease; Sudden Cardiac Death; Intracerebral Haemorrhage; Heart Failure; Ischemic Stroke; Myocardial Infarction; Stroke; Peripheral Arterial Disease; Stable Angina Pectoris; Subarachnoid Haemorrhage; Transient Ischemic Attack; Unstable Angina; Cardiac Arrest

Educating patients about warfarin therapy using information technology: A survey on healthcare professionals’ perspectives

PubMed Central

Nasser, Sayeed; Mullan, Judy; Bajorek, Beata

Objective To explore healthcare professionals' views about the benefits and challenges of using information technology (IT) resources for educating patients about their warfarin therapy. Methods A cross-sectional survey of both community and hospital-based healthcare professionals (e.g., doctors, pharmacists and nurses) involved using a purpose-designed questionnaire. The questionnaires were distributed using a multi-modal approach to maximise response rates. Results Of the total 300 questionnaires distributed, 109 completed surveys were received (43.3% response rate). Over half (53.2%) of the healthcare participants were aged between 40-59 years, the majority (59.5%) of whom were female. Fifty nine (54.1%) participants reported having had no access to warfarin-specific IT-based patient education resources, and a further 19 (38.0%) of the participants who had IT-access reported that they never used such resources. According to the healthcare participants, the main challenges associated with educating their patients about warfarin therapy included: patient-related factors, such as older age, language barriers, cognitive impairments and/or ethnic backgrounds or healthcare professional factors, such as time constraints. The healthcare professionals reported that there were several aspects about warfarin therapy which they found difficult to educate their patients about which is why they identified computers and interactive touch screen kiosks as preferred IT devices to deliver warfarin education resources in general practices, hospital-based clinics and community pharmacies. At the same time, the healthcare professionals also identified a number of facilitators (e.g., to reinforce warfarin education, to offer reliable and easily comprehensible information) and barriers (e.g., time and costs of using IT resources, difficulty in operating the resources) that could impact on the effective implementation of these devices in educating patients about their warfarin therapy

Factors influencing medication knowledge and beliefs on warfarin adherence among patients with atrial fibrillation in China.

PubMed

Zhao, Shujuan; Zhao, Hongwei; Wang, Xianpei; Gao, Chuanyu; Qin, Yuhua; Cai, Haixia; Chen, Boya; Cao, Jingjing

2017-01-01

Warfarin is often used for ischemic stroke prevention in patients with atrial fibrillation (AF), but the factors affecting patient adherence to warfarin therapy have not been fully understood. A cross-sectional survey was conducted in AF patients undergoing warfarin therapy at least 6 months prior to the study. The clinical data collected using questionnaires by phone interviews included the following: 1) self-reported adherence measured by the Morisky Medication Adherence Scale-8 © ; 2) beliefs about medicines surveyed by Beliefs about Medicines Questionnaire (BMQ); and 3) drug knowledge as measured by the Warfarin Related Knowledge Test (WRKT). Demographic and clinical factors associated with warfarin adherence were identified using a logistic regression model. Two hundred eighty-eight patients completed the survey and 93 (32.3%) of them were classified as nonadherent (Morisky Medication Adherence Scale-8 score <6). Major factors predicting warfarin adherence included age, cardiovascular disorders, WRKT, and BMQ; WRKT and BMQ were independently correlated with adherence to warfarin therapy by multivariate logistic regression analysis. Adherents were more likely to have greater knowledge scores and stronger beliefs in the necessity of their specific medications ([odds ratio {OR} =1.81, 95% confidence interval {CI} =1.51-2.15] and [OR =1.17, 95% CI =1.06-1.29], respectively). Patients with greater concerns about adverse reactions and more negative views of general harm were more likely to be nonadherent ([OR =0.76, 95% CI =0.69-0.84] and [OR =0.82, 95% CI =0.73-0.92], respectively). BMK and WRKT are related with patient behavior toward warfarin adherence. BMQ can be applied to identify patients at increased risk of nonadherence.

Clinical and Genetic Determinants of Warfarin Pharmacokinetics and Pharmacodynamics during Treatment Initiation

PubMed Central

Gong, Inna Y.; Schwarz, Ute I.; Crown, Natalie; Dresser, George K.; Lazo-Langner, Alejandro; Zou, GuangYong; Roden, Dan M.; Stein, C. Michael; Rodger, Marc; Wells, Philip S.; Kim, Richard B.; Tirona, Rommel G.

2011-01-01

Variable warfarin response during treatment initiation poses a significant challenge to providing optimal anticoagulation therapy. We investigated the determinants of initial warfarin response in a cohort of 167 patients. During the first nine days of treatment with pharmacogenetics-guided dosing, S-warfarin plasma levels and international normalized ratio were obtained to serve as inputs to a pharmacokinetic-pharmacodynamic (PK-PD) model. Individual PK (S-warfarin clearance) and PD (Imax) parameter values were estimated. Regression analysis demonstrated that CYP2C9 genotype, kidney function, and gender were independent determinants of S-warfarin clearance. The values for Imax were dependent on VKORC1 and CYP4F2 genotypes, vitamin K status (as measured by plasma concentrations of proteins induced by vitamin K absence, PIVKA-II) and weight. Importantly, indication for warfarin was a major independent determinant of Imax during initiation, where PD sensitivity was greater in atrial fibrillation than venous thromboembolism. To demonstrate the utility of the global PK-PD model, we compared the predicted initial anticoagulation responses with previously established warfarin dosing algorithms. These insights and modeling approaches have application to personalized warfarin therapy. PMID:22114699

Influence of NR3C1 and VDR polymorphisms on stable warfarin dose in patients with mechanical cardiac valves.

PubMed

Lee, Kyung Eun; Chung, Jee Eun; Yi, Boram; Cho, Yoon Jeong; Kim, Hyun Jeong; Lee, Gwan Yung; Kim, Joo Hee; Chang, Byung Chul; Gwak, Hye Sun

2017-06-01

The aim of this study was to evaluate the associations between polymorphisms of VKORC1, CYP2C9, CYP4F2, NR3C1 and VDR genes and stable warfarin doses in Korean patients with mechanical heart valves. Seventeen single-nucleotide polymorphisms (SNPs) in 204 patients with stable warfarin dose were analyzed: VKORC1 (rs9934438), CYP2C9 (rs1057910), CYP4F2 (rs2108622), NR3C1 (rs41423247, rs1800445, rs56149945, rs10052957, rs6198, rs33388, rs6196, and rs244465), and VDR (rs1544410, rs11568820, rs731236, rs757343, rs7975232, and rs2228570). Statistical analyses were conducted to evaluate the associations of gene variations with stable warfarin dose. Number needed to genotype was obtained by calculating the percentage of patients whose predicted dose was at least 20% higher or lower than the actual stable dose. The combined genotypes of rs7975232 and rs2228570 of the VDR gene revealed a significant association with stable warfarin dose, along with VKORC1, CYP2C9, and CYP4F2 polymorphisms. Patients with the genotype combination GT,TT/CT,CC of VDR rs7975232/rs2228570 required significantly higher stable warfarin dose (5.79±2.02mg) than those with the other genotypic combinations (5.19±1.78mg, p=0.034). Multivariate analysis showed that VDR rs7975232/rs2228570 explained 2.0% of the 47.5% variability in overall warfarin dose. Adding VDR SNP combinations to the base model including non-genetic variables (age, sex, and body weight) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 41. This study showed that stable warfarin dose is associated with VDR SNPs along with VKORC1, CYP2C9, and CYP4F2 SNPs. Copyright © 2017 Elsevier B.V. All rights reserved.

Neurocutaneous Melanosis in Association with Dandy-Walker Complex with Extensive Intracerebral and Spinal Cord Involvement

PubMed Central

Sung, Kyoung-Su

2014-01-01

Neurocutaneous melanosis (NCM) is a rare congenital syndrome consisting of benign or malignant melanotic tumors of the central nervous system with large or numerous cutaneous melanocytic nevi. The Dandy-Walker complex (DWC) is characterized by an enlarged posterior fossa with high insertion of the tentorium, hypoplasia or aplasia of the cerebellar vermis, and cystic dilatation of the fourth ventricle. These each two conditions are rare, but NCM associated with DWC is even more rare. Most patients of NCM with DWC present neurological symptoms early in life such as intracranial hemorrhage, hydrocephalus, and malignant transformation of the melanocytes. We report a 14-year-old male patient who was finally diagnosed as NCM in association with DWC with extensive intracerebral and spinal cord involvement. PMID:25289129

Reducing warfarin medication interactions: an interrupted time series evaluation.

PubMed

Feldstein, Adrianne C; Smith, David H; Perrin, Nancy; Yang, Xiuhai; Simon, Steven R; Krall, Michael; Sittig, Dean F; Ditmer, Diane; Platt, Richard; Soumerai, Stephen B

2006-05-08

Computerized decision support reduces medication errors in inpatients, but limited evidence supports its effectiveness in reducing the coprescribing of interacting medications, especially in the outpatient setting. The usefulness of academic detailing to enhance the effectiveness of medication interaction alerts also is uncertain. This study used an interrupted time series design. In a health maintenance organization with an electronic medical record, we evaluated the effectiveness of electronic medical record alerts and group academic detailing to reduce the coprescribing of warfarin and interacting medications. Participants were 239 primary care providers at 15 primary care clinics and 9910 patients taking warfarin. All 15 clinics received electronic medical record alerts for the coprescription of warfarin and 5 interacting medications: acetaminophen, nonsteroidal anti-inflammatory medications, fluconazole, metronidazole, and sulfamethoxazole. Seven clinics were randomly assigned to receive group academic detailing. The primary outcome, the interacting prescription rate (ie, the number of coprescriptions of warfarin-interacting medications per 10 000 warfarin users per month), was analyzed with segmented regression models, controlling for preintervention trends. At baseline, nearly a third of patients had an interacting prescription. Coinciding with the alerts, there was an immediate and continued reduction in the warfarin-interacting medication prescription rate (from 3294.0 to 2804.2), resulting in a 14.9% relative reduction (95% confidence interval, -19.5 to -10.2) at 12 months. Group academic detailing did not enhance alert effectiveness. This study, using a strong and quasi-experimental design in ambulatory care, found that medication interaction alerts modestly reduced the frequency of coprescribing of interacting medications. Additional efforts will be required to further reduce rates of inappropriate prescribing of warfarin with interacting drugs.

Anxiety, Depression, and Adverse Clinical Outcomes in Patients With Atrial Fibrillation Starting Warfarin: Cardiovascular Research Network WAVE Study.

PubMed

Baumgartner, Christine; Fan, Dongjie; Fang, Margaret C; Singer, Daniel E; Witt, Daniel M; Schmelzer, John R; Williams, Marc S; Gurwitz, Jerry H; Sung, Sue Hee; Go, Alan S

2018-04-14

Anxiety and depression are associated with worse outcomes in several cardiovascular conditions, but it is unclear whether they affect outcomes in atrial fibrillation (AF). In a large diverse population of adults with AF, we evaluated the association of diagnosed anxiety and/or depression with stroke and bleeding outcomes. The Cardiovascular Research Network WAVE (Community-Based Control and Persistence of Warfarin Therapy and Associated Rates and Predictors of Adverse Clinical Events in Atrial Fibrillation and Venous Thromboembolism) Study included adults with AF newly starting warfarin between 2004 and 2007 within 5 health delivery systems in the United States. Diagnosed anxiety and depression and other patient characteristics were identified from electronic health records. We identified stroke and bleeding outcomes from hospitalization databases using validated International Classification of Diseases, Ninth Revision ( ICD-9 ), codes. We used multivariable Cox regression to assess the relation between anxiety and/or depression with outcomes after adjustment for stroke and bleeding risk factors. In 25 570 adults with AF initiating warfarin, 490 had an ischemic stroke or intracranial hemorrhage (1.52 events per 100 person-years). In multivariable analyses, diagnosed anxiety was associated with a higher adjusted rate of combined ischemic stroke and intracranial hemorrhage (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28). Results were not materially changed after additional adjustment for patient-level percentage of time in therapeutic anticoagulation range on warfarin (hazard ratio, 1.56; 95% confidence interval, 1.03-2.36). In contrast, neither isolated depression nor combined depression and anxiety were significantly associated with outcomes. Diagnosed anxiety was independently associated with increased risk of combined ischemic stroke and intracranial hemorrhage in adults with AF initiating warfarin that was not explained by differences in risk factors

Medical costs in the US of clinical events associated with oral anticoagulant (OAC) use compared to warfarin among non-valvular atrial fibrillation patients ≥75 and <75 years of age, based on the ARISTOTLE, RE-LY, and ROCKET-AF trials.

PubMed

Deitelzweig, Steve; Amin, Alpesh; Jing, Yonghua; Makenbaeva, Dinara; Wiederkehr, Daniel; Lin, Jay; Graham, John

2013-09-01

Based on clinical trials the oral anticoagulants (OACs) apixaban, dabigatran, and rivaroxaban are efficacious for reducing stroke risk for non-valvular atrial fibrillation (NVAF) patients. Based on the clinical trials, this study evaluated the medical costs for clinical events among NVAF patients ≥75 and <75 years of age treated with individual OACs vs warfarin. Rates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients receiving warfarin or each of the OACs were determined for NVAF populations aged ≥75 years and <75 years of age from the OAC vs warfarin trials. One-year incremental costs among patients with clinical events were obtained from published literature and inflation adjusted to 2010 costs. Medical costs, excluding medication costs, for clinical events associated with each OAC and warfarin were then estimated and compared. Among NVAF patients aged ≥75, compared to warfarin, use of either apixaban or rivaroxaban was associated with a reduction in medical costs per patient year (apixaban = -$825, rivaroxaban =-$23), while dabigatran use was associated with increased medical costs of $180 per patient year. Among NVAF patients <75 years of age medical costs per patient year were estimated to be reduced -$254, -$367, and -$88, for apixaban, dabigatran, and rivaroxaban, respectively, in comparison to warfarin. This economic analysis was based on clinical trial data and, therefore, the direct application of the results to routine clinical practice will require further assessment. Difference in medical costs between OAC and warfarin treated NVAF patients vary by age group and individual OACs. Although reductions in medical costs for NVAF patients aged ≥75 and <75 were observed for those using either apixaban or rivaroxaban vs warfarin, the reductions were greater per patient year for both the older and younger NVAF populations using apixaban.

Evaluation of SAMe-TT2R2 Score on Predicting Success With Extended-Interval Warfarin Monitoring.

PubMed

Hwang, Andrew Y; Carris, Nicholas W; Dietrich, Eric A; Gums, John G; Smith, Steven M

2018-06-01

In patients with stable international normalized ratios, 12-week extended-interval warfarin monitoring can be considered; however, predictors of success with this strategy are unknown. The previously validated SAMe-TT 2 R 2 score (considering sex, age, medical history, treatment, tobacco, and race) predicts anticoagulation control during standard follow-up (every 4 weeks), with lower scores associated with greater time in therapeutic range. To evaluate the ability of the SAMe-TT 2 R 2 score in predicting success with extended-interval warfarin follow-up in patients with previously stable warfarin doses. In this post hoc analysis of a single-arm feasibility study, baseline SAMe-TT 2 R 2 scores were calculated for patients with ≥1 extended-interval follow-up visit. The primary analysis assessed achieved weeks of extended-interval follow-up according to baseline SAMe-TT 2 R 2 scores. A total of 47 patients receiving chronic anticoagulation completed a median of 36 weeks of extended-interval follow-up. The median baseline SAMe-TT 2 R 2 score was 1 (range 0-5). Lower SAMe-TT 2 R 2 scores appeared to be associated with greater duration of extended-interval follow-up achieved, though the differences between scores were not statistically significant. No individual variable of the SAMe-TT 2 R 2 score was associated with achieved weeks of extended-interval follow-up. Analysis of additional patient factors found that longer duration (≥24 weeks) of prior stable treatment was significantly associated with greater weeks of extended-interval follow-up completed ( P = 0.04). Conclusion and Relevance: This pilot study provides limited evidence that the SAMe-TT 2 R 2 score predicts success with extended-interval warfarin follow-up but requires confirmation in a larger study. Further research is also necessary to establish additional predictors of successful extended-interval warfarin follow-up.

Racial background is a determinant factor in the maintenance dosage of warfarin.

PubMed

Gan, Gin Gin; Teh, Alan; Goh, Kim Yen; Chong, Heng Thay; Pang, Kang Wah

2003-07-01

Warfarin is a drug commonly used in the prevention of thromboembolic events. There have been reports suggesting that racial background may influence warfarin dose requirements. Malaysia is a multiracial country in which there are 3 major races, Malay, Chinese, and Indian. We examined 100 patients from our hospital on stable maintenance doses of warfarin, with international normalized ratio (INR) of 2.0 to 3.5. We found that the mean warfarin dose for Indian patients (n = 19) was 6.9 mg, for Chinese patients (n = 55) was 3.6 mg, and for Malay patients (n = 26) was 3.2 mg. The results showed that the Indian patients required a statistically significantly higher warfarin dose than did patients of the other 2 races (P < .0005). Age was also found to affect the daily warfarin maintenance dose.

Improving Warfarin Management Within the Medical Home: A Health-System Approach.

PubMed

Rose, Anne E; Robinson, Erin N; Premo, Joan A; Hauschild, Lori J; Trapskin, Philip J; McBride, Ann M

2017-03-01

Anticoagulation clinics have been considered the optimal strategy for warfarin management with demonstrated improved patient outcomes through increased time in therapeutic international normalized ratio (INR) range, decreased critical INR values, and decreased anticoagulation-related adverse events. However, not all health systems are able to support a specialized anticoagulation clinic or may see patient volume exceed available anticoagulation clinic resources. The purpose of this study was to utilize an anticoagulation clinic model to standardize warfarin management in a primary care clinic setting. A warfarin management program was developed that included standardized patient assessment, protocolized warfarin-dosing algorithm, and electronic documentation and reporting tools. Primary care clinics were targeted for training and implementation of this program. The warfarin management program was applied to over 2000 patients and implemented at 39 clinic sites. A total of 160 nurses and 15 pharmacists were trained on the program. Documentation of warfarin dose and date of the next INR increased from 70% to 90% (P <.0001), documentation occurring within 24 hours of the INR result increased from 75% to 87% (P <.0001), and monitoring the INR at least every 4 weeks increased from 71% to 83% (P <.0001) per patient encounter. Time in therapeutic INR range improved from 65% to 75%. Incorporating a standardized approach to warfarin management in the primary care setting significantly improves warfarin-related documentation and time in therapeutic INR range. Copyright © 2016 Elsevier Inc. All rights reserved.

Atrial Fibrillation Patients Treated With Long-Term Warfarin Anticoagulation Have Higher Rates of All Dementia Types Compared With Patients Receiving Long-Term Warfarin for Other Indications.

PubMed

Bunch, T Jared; May, Heidi T; Bair, Tami L; Crandall, Brian G; Cutler, Michael J; Day, John D; Jacobs, Victoria; Mallender, Charles; Osborn, Jeffrey S; Stevens, Scott M; Weiss, J Peter; Woller, Scott C

2016-07-11

The mechanisms behind the association of atrial fibrillation (AF) and dementia are unknown. We previously found a significantly increased risk of dementia in AF patients taking warfarin with a low percentage of time in therapeutic range. The purpose of this study was to determine the extent to which AF itself increases dementia risk, in addition to long-term anticoagulation exposure. A total of 10 537 patients anticoagulated with warfarin (target INR 2-3), managed by the Clinical Pharmacist Anticoagulation Service with no history of dementia were included. Warfarin indication was for AF (n=4460), thromboembolism (n=5868), and mechanical heart valve(s) (n=209). Patients in the latter 2 categories were included only if they had no prior history of AF. The primary outcome was dementia. Patients with AF were older and had higher rates of hypertension, diabetes, heart failure, and stroke. AF patients experienced higher rates of total dementia (5.8% versus 1.6%, P<0.0001), Alzheimer disease (2.8% versus 0.9%, P<0.0001), and vascular dementia (1.0% versus 0.2%, P<0.0001). A propensity analysis of 6030 patients was performed to account for baseline demographics differences. Long-term risk of dementia remained significant in AF patients compared with matched non-AF patients (total dementia: hazard ratio [HR]=2.42 [1.85-3.18], P<0.0001; Alzheimer: HR=2.04 [1.40-2.98], P<0.0001; senile: HR=2.46 [1.58-3.86], P<0.0001). Low percent therapeutic range compared with a higher percent therapeutic range was associated with dementia risk in both AF (26-50% versus >75%: HR=2.51, P=0.005) and non-AF groups (≤25% versus >75%: HR=3.92, P<0.0001). The presence of AF significantly increases risk of dementia, including Alzheimer's disease, compared with matched patients receiving warfarin anticoagulation for other reasons. Quality of anticoagulation management remains an important risk factor for dementia in all patients. © 2016 The Authors. Published on behalf of the American Heart

Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study.

PubMed

Jun, Min; Lix, Lisa M; Durand, Madeleine; Dahl, Matt; Paterson, J Michael; Dormuth, Colin R; Ernst, Pierre; Yao, Shenzhen; Renoux, Christel; Tamim, Hala; Wu, Cynthia; Mahmud, Salaheddin M; Hemmelgarn, Brenda R

2017-10-17

Objective  To determine the safety of direct oral anticoagulant (DOAC) use compared with warfarin use for the treatment of venous thromboembolism. Design  Retrospective matched cohort study conducted between 1 January 2009 and 31 March 2016. Setting  Community based, using healthcare data from six jurisdictions in Canada and the United States. Participants  59 525 adults (12 489 DOAC users; 47 036 warfarin users) with a new diagnosis of venous thromboembolism and a prescription for a DOAC or warfarin within 30 days of diagnosis. Main outcome measures  Outcomes included hospital admission or emergency department visit for major bleeding and all cause mortality within 90 days after starting treatment. Propensity score matching and shared frailty models were used to estimate adjusted hazard ratios of the outcomes comparing DOACs with warfarin. Analyses were conducted independently at each site, with meta-analytical methods used to estimate pooled hazard ratios across sites. Results  Of the 59 525 participants, 1967 (3.3%) had a major bleed and 1029 (1.7%) died over a mean follow-up of 85.2 days. The risk of major bleeding was similar for DOAC compared with warfarin use (pooled hazard ratio 0.92, 95% confidence interval 0.82 to 1.03), with the overall direction of the association favouring DOAC use. No difference was found in the risk of death (pooled hazard ratio 0.99, 0.84 to 1.16) for DOACs compared with warfarin use. There was no evidence of heterogeneity across centres, between patients with and without chronic kidney disease, across age groups, or between male and female patients. Conclusions  In this analysis of adults with incident venous thromboembolism, treatment with DOACs, compared with warfarin, was not associated with an increased risk of major bleeding or all cause mortality in the first 90 days of treatment. Trial registration  Clinical trials NCT02833987. Published by the BMJ Publishing Group Limited. For permission to use (where not

Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial.

PubMed

Breithardt, Günter; Baumgartner, Helmut; Berkowitz, Scott D; Hellkamp, Anne S; Piccini, Jonathan P; Stevens, Susanna R; Lokhnygina, Yuliya; Patel, Manesh R; Halperin, Jonathan L; Singer, Daniel E; Hankey, Graeme J; Hacke, Werner; Becker, Richard C; Nessel, Christopher C; Mahaffey, Kenneth W; Fox, Keith A A; Califf, Robert M

2014-12-14

We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial. ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55-1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75-1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05-1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94-1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban. Many patients with 'non-valvular atrial fibrillation' have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial

PubMed Central

Breithardt, Günter; Baumgartner, Helmut; Berkowitz, Scott D.; Hellkamp, Anne S.; Piccini, Jonathan P.; Stevens, Susanna R.; Lokhnygina, Yuliya; Patel, Manesh R.; Halperin, Jonathan L.; Singer, Daniel E.; Hankey, Graeme J.; Hacke, Werner; Becker, Richard C.; Nessel, Christopher C.; Mahaffey, Kenneth W.; Fox, Keith A. A.; Califf, Robert M.

2014-01-01

Aims We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial. Methods and results ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55–1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75–1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05–1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94–1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban. Conclusions Many patients with ‘non-valvular atrial fibrillation’ have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants. PMID:25148838

Out-of-range INR values and outcomes among new warfarin patients with non-valvular atrial fibrillation.

PubMed

Nelson, Winnie W; Wang, Li; Baser, Onur; Damaraju, Chandrasekharrao V; Schein, Jeffrey R

2015-02-01

Although efficacious in stroke prevention in non-valvular atrial fibrillation, many warfarin patients are sub-optimally managed. To evaluate the association of international normalized ratio control and clinical outcomes among new warfarin patients with non-valvular atrial fibrillation. Adult non-valvular atrial fibrillation patients (≥18 years) initiating warfarin treatment were selected from the US Veterans Health Administration dataset between 10/2007 and 9/2012. Valid international normalized ratio values were examined from the warfarin initiation date through the earlier of the first clinical outcome, end of warfarin exposure or death. Each patient contributed multiple in-range and out-of-range time periods. The relative risk ratios of clinical outcomes associated with international normalized ratio control were estimated. 34,346 patients were included for analysis. During the warfarin exposure period, the incidence of events per 100 person-years was highest when patients had international normalized ratio <2:13.66 for acute coronary syndrome; 10.30 for ischemic stroke; 2.93 for transient ischemic attack; 1.81 for systemic embolism; and 4.55 for major bleeding. Poisson regression confirmed that during periods with international normalized ratio <2, patients were at increased risk of developing acute coronary syndrome (relative risk ratio: 7.9; 95 % confidence interval 6.9-9.1), ischemic stroke (relative risk ratio: 7.6; 95 % confidence interval 6.5-8.9), transient ischemic attack (relative risk ratio: 8.2; 95 % confidence interval 6.1-11.2), systemic embolism (relative risk ratio: 6.3; 95 % confidence interval 4.4-8.9) and major bleeding (relative risk ratio: 2.6; 95 % confidence interval 2.2-3.0). During time periods with international normalized ratio >3, patients had significantly increased risk of major bleeding (relative risk ratio: 1.5; 95 % confidence interval 1.2-2.0). In a Veterans Health Administration non-valvular atrial fibrillation population

Cytochrome P450 2C9 gene polymorphism and warfarin maintenance dosage in pediatric patients: A systematic review and meta-analysis.

PubMed

Zhang, Jinhua; Tian, Lihong; Huang, Jinlong; Huang, Sihan; Chai, Tingting; Shen, Jianzhen

2017-02-01

To assess the effect of Cytochrome P450 2C9 (CYP2C9) gene polymorphism on pediatric warfarin maintenance dosage requirement. A previously developed search strategy was conducted in PubMed, EMBASE, and the Cochrane Library. Eligible studies published prior to January 27, 2016, were identified and compared against strict inclusion/exclusion criteria. Required data were extracted, and researchers were consulted for additional data if needed. Review Manager version 5.2.3 software was used to analyze the relationship between CYP2C9 polymorphisms and warfarin maintenance doses in pediatric patients. Eight articles with a combined total of 507 pediatric patients were included in the meta-analysis. Maintenance warfarin doses in patients with CYP2C9 *1/*2 genotype, CYP2C9 *1/*3 genotype, and CYP2C9 variant carriers which contain at least one variant allele (*2 or *3) were from 15% to 41% lower than doses in patients with the wild-type allele (CYP2C9 *1/*1): All differences were significant with P-values <.05. The Fontan procedure as a medical indication for anticoagulation was also associated with a lower warfarin maintenance dose; however, target INR range was not. We found that CYP2C9 gene polymorphism (referring to the presence of *1/*2, *1/*3, and variant genotypes in the population in addition to the wild type) was significantly associated with decreased warfarin maintenance dose requirements. Additionally, a specific indication for warfarin, the Fontan procedure, was associated with a lower daily warfarin dose. However, the results of our study require confirmation from more research with larger numbers of pediatric patients. © 2016 John Wiley & Sons Ltd.

Clinical Prediction Model for Time in Therapeutic Range While on Warfarin in Newly Diagnosed Atrial Fibrillation.

PubMed

Williams, Brent A; Evans, Michael A; Honushefsky, Ashley M; Berger, Peter B

2017-10-12

Though warfarin has historically been the primary oral anticoagulant for stroke prevention in newly diagnosed atrial fibrillation (AF), several new direct oral anticoagulants may be preferred when anticoagulation control with warfarin is expected to be poor. This study developed a prediction model for time in therapeutic range (TTR) among newly diagnosed AF patients on newly initiated warfarin as a tool to assist decision making between warfarin and direct oral anticoagulants. This electronic medical record-based, retrospective study included newly diagnosed, nonvalvular AF patients with no recent warfarin exposure receiving primary care services through a large healthcare system in rural Pennsylvania. TTR was estimated as the percentage of time international normalized ratio measurements were between 2.0 and 3.0 during the first year following warfarin initiation. Candidate predictors of TTR were chosen from data elements collected during usual clinical care. A TTR prediction model was developed and temporally validated and its predictive performance was compared with the SAMe-TT 2 R 2 score (sex, age, medical history, treatment, tobacco, race) using R 2 and c-statistics. A total of 7877 newly diagnosed AF patients met study inclusion criteria. Median (interquartile range) TTR within the first year of starting warfarin was 51% (32, 67). Of 85 candidate predictors evaluated, 15 were included in the final validated model with an R 2 of 15.4%. The proposed model showed better predictive performance than the SAMe-TT 2 R 2 score ( R 2 =3.0%). The proposed prediction model may assist decision making on the proper mode of oral anticoagulant among newly diagnosed AF patients. However, predicting TTR on warfarin remains challenging. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Factors influencing medication knowledge and beliefs on warfarin adherence among patients with atrial fibrillation in China

PubMed Central

Zhao, Shujuan; Zhao, Hongwei; Wang, Xianpei; Gao, Chuanyu; Qin, Yuhua; Cai, Haixia; Chen, Boya; Cao, Jingjing

2017-01-01

Objectives Warfarin is often used for ischemic stroke prevention in patients with atrial fibrillation (AF), but the factors affecting patient adherence to warfarin therapy have not been fully understood. Methods A cross-sectional survey was conducted in AF patients undergoing warfarin therapy at least 6 months prior to the study. The clinical data collected using questionnaires by phone interviews included the following: 1) self-reported adherence measured by the Morisky Medication Adherence Scale-8©; 2) beliefs about medicines surveyed by Beliefs about Medicines Questionnaire (BMQ); and 3) drug knowledge as measured by the Warfarin Related Knowledge Test (WRKT). Demographic and clinical factors associated with warfarin adherence were identified using a logistic regression model. Results Two hundred eighty-eight patients completed the survey and 93 (32.3%) of them were classified as nonadherent (Morisky Medication Adherence Scale-8 score <6). Major factors predicting warfarin adherence included age, cardiovascular disorders, WRKT, and BMQ; WRKT and BMQ were independently correlated with adherence to warfarin therapy by multivariate logistic regression analysis. Adherents were more likely to have greater knowledge scores and stronger beliefs in the necessity of their specific medications ([odds ratio {OR} =1.81, 95% confidence interval {CI} =1.51–2.15] and [OR =1.17, 95% CI =1.06–1.29], respectively). Patients with greater concerns about adverse reactions and more negative views of general harm were more likely to be nonadherent ([OR =0.76, 95% CI =0.69–0.84] and [OR =0.82, 95% CI =0.73–0.92], respectively). Conclusion BMK and WRKT are related with patient behavior toward warfarin adherence. BMQ can be applied to identify patients at increased risk of nonadherence. PMID:28223782

Effect of Warfarin Treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL)

PubMed Central

Preston, Ioana R.; Roberts, Kari E.; Miller, Dave P.; Sen, Ginny P.; Selej, Mona; Benton, Wade W.; Hill, Nicholas S.

2015-01-01

Background— Long-term anticoagulation is recommended in idiopathic pulmonary arterial hypertension (IPAH). In contrast, limited data support anticoagulation in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc-PAH). We assessed the effect of warfarin anticoagulation on survival in IPAH and SSc-PAH patients enrolled in Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a longitudinal registry of group I PAH. Methods and Results— Patients who initiated warfarin on study (n=187) were matched 1:1 with patients never on warfarin, by enrollment site, etiology, and diagnosis status. Descriptive analyses were conducted to compare warfarin users and nonusers by etiology. Survival analyses with and without risk adjustment were performed from the time of warfarin initiation or a corresponding quarterly update in matched pairs to avoid immortal time bias. Time-varying covariate models were used as sensitivity analyses. Mean warfarin treatment was 1 year; mean international normalized ratios were 1.9 (IPAH) and 2.0 (SSc-PAH). Two-thirds of patients initiating warfarin discontinued treatment before the last study assessment. There was no survival difference with warfarin in IPAH patients (adjusted hazard ratio, 1.37; P=0.21) or in SSc-PAH patients (adjusted hazard ratio, 1.60; P=0.15) in comparison with matched controls. However, SSc-PAH patients receiving warfarin within the previous year (hazard ratio, 1.57; P=0.031) or any time postbaseline (hazard ratio, 1.49; P=0.046) had increased mortality in comparison with warfarin-naïve patients. Conclusions— No significant survival advantage was observed in IPAH patients who started warfarin. In SSc-PAH patients, long-term warfarin was associated with poorer survival than in patients not receiving warfarin, even after adjusting for confounders. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214. PMID:26510696

Effect of Warfarin Treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL).

PubMed

Preston, Ioana R; Roberts, Kari E; Miller, Dave P; Sen, Ginny P; Selej, Mona; Benton, Wade W; Hill, Nicholas S; Farber, Harrison W

2015-12-22

Long-term anticoagulation is recommended in idiopathic pulmonary arterial hypertension (IPAH). In contrast, limited data support anticoagulation in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc-PAH). We assessed the effect of warfarin anticoagulation on survival in IPAH and SSc-PAH patients enrolled in Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a longitudinal registry of group I PAH. Patients who initiated warfarin on study (n=187) were matched 1:1 with patients never on warfarin, by enrollment site, etiology, and diagnosis status. Descriptive analyses were conducted to compare warfarin users and nonusers by etiology. Survival analyses with and without risk adjustment were performed from the time of warfarin initiation or a corresponding quarterly update in matched pairs to avoid immortal time bias. Time-varying covariate models were used as sensitivity analyses. Mean warfarin treatment was 1 year; mean international normalized ratios were 1.9 (IPAH) and 2.0 (SSc-PAH). Two-thirds of patients initiating warfarin discontinued treatment before the last study assessment. There was no survival difference with warfarin in IPAH patients (adjusted hazard ratio, 1.37; P=0.21) or in SSc-PAH patients (adjusted hazard ratio, 1.60; P=0.15) in comparison with matched controls. However, SSc-PAH patients receiving warfarin within the previous year (hazard ratio, 1.57; P=0.031) or any time postbaseline (hazard ratio, 1.49; P=0.046) had increased mortality in comparison with warfarin-naïve patients. No significant survival advantage was observed in IPAH patients who started warfarin. In SSc-PAH patients, long-term warfarin was associated with poorer survival than in patients not receiving warfarin, even after adjusting for confounders. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214. © 2015 The Authors.

VKORC1 polymorphisms and warfarin maintenance dose in population of Sakha (Yakuts).

PubMed

Chertovskikh, Y V; Malova, E U; Maksimova, N R; Popova, N V; Sychev, D A

2015-01-01

.13 (SD ± 1.5). Differences are of borderline significance (p = 0.054). Of the 41 patients who required warfarin doses of less than 5 mg, 28 (63%) were found to be AA carriers and 14 (37%) were GG, GA carriers. Differences were not quite significant (p = 0.072). Among 31 homozygous polymorphism carriers 2 (4%) patients developed overanticoagulation (INR >4.0), while among 22 normal and heterozygous polymorphisms carriers only 3 (6%) patients developed overanticoagulation (INR >4.0). Differences were not statistically significant (p = 0.36). No significant association between VKORC1 polymorphisms and the frequency of excess anticoagulation (INR >4.0) was found. This may be explained by the number of cases included. AA polymorphisms compared to other polymorphisms shows borderline difference in the warfarin dose. The results can be used for the development of a pharmacogenetic-guided warfarin dosing algorithm.

Health literacy and warfarin therapy at two anticoagulation clinics in Brazil

PubMed Central

Martins, Maria Auxiliadora Parreiras; Costa, Josiane Moreira; Mambrini, Juliana Vaz de Melo; Ribeiro, Antonio Luiz Pinho; Benjamin, Emelia J; Brant, Luisa Campos Caldeira; Paasche-Orlow, Michael K; Magnani, Jared W

2017-01-01

Objective Health literacy has been related to health-related conditions and health outcomes. Studies examining the association of health literacy and anticoagulation have had variable results. We sought to investigate the relations of health literacy and percentage of time in therapeutic range (TTR) in a vulnerable Brazilian cohort at two hospital-based anticoagulation clinics. Methods We measured health literacy with the Short Assessment of Health Literacy for Portuguese-speaking Adults (SAHLPA-18) in 2015–2016. We identified the demographic and clinical characteristics associated with health literacy and related health literacy to TTR. Results We enrolled 422 adults prescribed chronic warfarin therapy in our observational study (median age 62.1 years; 58.8% women; monthly income $200.00). The prevalence of inadequate health literacy (score 0–14 points) was 72.3% with a median score of 12 (quartiles, Q1=10; Q3=15) on the SAHLPA-18. The median TTR was 66.1%. In the multivariable logistic analysis, cognitive impairment and assistance with taking warfarin were associated with inadequate health literacy. Prosthetic heart valves and more school years were associated with adequate health literacy. Our analyses showed no significant relation between health literacy and TTR, analysing health literacy as a categorical (adjusted OR 1.05; 95% CI 0.65 to 1.70) or continuous variable (Spearman’s coefficient 0.02; p=0.70). Conclusions Inadequate health literacy was highly prevalent in this impoverished Brazilian cohort receiving anticoagulation with warfarin. However, we did not identify an association between health literacy and TTR. Future investigations may consider the systemic factors that contribute towards successful anticoagulation outcomes for vulnerable patient cohorts with inadequate health literacy. PMID:28258243

Overall Survival After Whole-Brain Radiation Therapy for Intracerebral Metastases from Testicular Cancer.

PubMed

Rades, Dirk; Dziggel, Liesa; Veninga, Theo; Bajrovic, Amira; Schild, Steven E

2016-09-01

To identify predictors and develop a score for overall survival of patients with intracerebral metastasis from testicular cancer. Whole-brain radiation therapy program, age, Karnofsky performance score (KPS), number of intracerebral metastases, number of other metastatic sites and time between testicular cancer diagnosis and radiation therapy were analyzed for their association with overall survival in eight patients. KPS of 80-90% was significantly associated with better overall survival (p=0.006), one or no other metastatic sites showed a trend for a better outcome (p=0.10). The following scores were assigned: KPS 60-70%=0 points, KPS 80-90%=1 point, ≥2 other metastatic sites=0 points, 0-1 other metastatic sites=1 point. Two groups, with 0 and with 1-2 points, were formed. Overall survival rates were 33% vs. 100% at 6 months and 0% vs. 100% at 12 months (p=0.006), respectively. A simple instrument enabling physicians to judge the overall survival of patients with intracerebral metastasis from testicular cancer is provided. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Cost-Effectiveness of Apixaban Compared with Warfarin for Stroke Prevention in Atrial Fibrillation

PubMed Central

Lee, Soyon; Mullin, Rachel; Blazawski, Jon; Coleman, Craig I.

2012-01-01

Background Apixaban was shown to be superior to adjusted-dose warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (AF) and at least one additional risk factor for stroke, and associated with reduced rates of hemorrhage. We sought to determine the cost-effectiveness of using apixaban for stroke prevention. Methods Based on the results from the Apixaban Versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) trial and other published studies, we constructed a Markov model to evaluate the cost-effectiveness of apixaban versus warfarin from the Medicare perspective. The base-case analysis assumed a cohort of 65-year-old patients with a CHADS2 score of 2.1 and no contraindication to oral anticoagulation. We utilized a 2-week cycle length and a lifetime time horizon. Outcome measures included costs in 2012 US$, quality-adjusted life-years (QALYs), life years saved and incremental cost-effectiveness ratios. Results Under base case conditions, quality adjusted life expectancy was 10.69 and 11.16 years for warfarin and apixaban, respectively. Total costs were $94,941 for warfarin and $86,007 for apixaban, demonstrating apixaban to be a dominant economic strategy. Upon one-way sensitivity analysis, these results were sensitive to variability in the drug cost of apixaban and various intracranial hemorrhage related variables. In Monte Carlo simulation, apixaban was a dominant strategy in 57% of 10,000 simulations and cost-effective in 98% at a willingness-to-pay threshold of $50,000 per QALY. Conclusions In patients with AF and at least one additional risk factor for stroke and a baseline risk of ICH risk of about 0.8%, treatment with apixaban may be a cost-effective alternative to warfarin. PMID:23056642

Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation.

PubMed

Raunsø, Jakob; Selmer, Christian; Olesen, Jonas Bjerring; Charlot, Mette Gitz; Olsen, Anne-Marie S; Bretler, Ditte-Marie; Nielsen, Jørn Dalsgaard; Dominguez, Helena; Gadsbøll, Niels; Køber, Lars; Gislason, Gunnar H; Torp-Pedersen, Christian; Hansen, Morten Lock

2012-08-01

It is presently unknown whether patients with atrial fibrillation (AF) are at increased risk of thrombo-embolic adverse events after interruption of warfarin treatment. The purpose of this study was to assess the risk and timing of thrombo-embolism after warfarin treatment interruption. A retrospective, nationwide cohort study of all patients in Denmark treated with warfarin after a first hospitalization with AF in the period 1997-2008. Incidence rate ratios (IRRs) of thrombo-embolic events and all-cause mortality were calculated using the Poisson regression analyses. In total, 48 989 AF patients receiving warfarin treatment were included. Of these, 35 396 patients had at least one episode of warfarin treatment interruption. In all, 8255 deaths or thrombo-embolic events occurred during treatment interruption showing an initial clustering of events with 2717, 835, 500, and 427 events occurring during 0-90, 91-180, 181-270, and 271-360 days after treatment interruption, respectively. Correspondingly, the crude incidence rates were 31.6, 17.7, 12.3, and 11.4 events per 100 patient-years. In a multivariable analysis, the first 90-day interval of treatment interruption was associated with a markedly higher risk of death or thrombo-embolism (IRR 2.5; 95% confidence interval 2.3-2.8) vs. the interval of 271-360 days. In patients with AF, an interruption of warfarin treatment is associated with a significantly increased short-term risk of death or thrombo-embolic events within the first 90 days of treatment interruption.

Ezetimibe enhances and stabilizes anticoagulant effect of warfarin.

PubMed

Hashikata, Takehiro; Yamaoka-Tojo, Minako; Kakizaki, Ryota; Nemoto, Teruyoshi; Fujiyoshi, Kazuhiro; Namba, Sayaka; Kitasato, Lisa; Hashimoto, Takuya; Ishii, Shunsuke; Kameda, Ryo; Shimohama, Takao; Tojo, Taiki; Ako, Junya

2017-01-01

Ezetimibe reduces plasma levels of low-density lipoprotein cholesterol by inhibiting Niemann-Pick C1-like protein 1 (NPC1L1). A recent study demonstrated that NPC1L1 plays an important role in absorption of fat-soluble vitamins including vitamin K. We evaluated whether the add-on treatment of ezetimibe affects anticoagulation in patients taking warfarin. Between October 2007 and March 2015, the administration of ezetimibe was started to a total of 101 outpatients who were already on oral anticoagulation with warfarin. We retrospectively analyzed blood lipid levels, prothrombin time international normalized ratio (PT-INR) and time in therapeutic INR range (TTR). Seventy-one patients (70 %) showed increase in PT-INR after ezetimibe treatment (1.96 ± 0.45 to 2.20 ± 0.61, p < 0.001). It was necessary to reduce the warfarin dose in 9 of 101 patients for clinical indication. There was a significant positive correlation between change in PT-INR and statin usage at baseline (p = 0.03). The mean value of changes in PT-INR of patients with taking statin was significantly larger than that of patients without taking statin (0.34 ± 0.54 vs. 0.06 ± 0.36, p = 0.03). There was an increase in the TTR (52 ± 26 to 61 ± 23 %, p < 0.0001) and a decrease in the frequency to change the dose of warfarin after the ezetimibe treatment [45 times of 735 examination days (6 %) to 20 times of 695 examination days (3 %), p = 0.02]. Our data suggest possible drug interaction between warfarin and ezetimibe. Ezetimibe may increase and stabilize the anticoagulant effect of warfarin, especially in patients taking statins.

Interaction between gemfibrozil and warfarin: case report and review of the literature.

PubMed

Dixon, Dave L; Williams, Virginia G

2009-06-01

Possible procoagulant effects can occur when lipid-lowering fibric acid derivatives, such as gemfibrozil and fenofibrate, are taken concomitantly with warfarin. Although there are several detailed reports of fenofibrate potentiating the anticoagulant effects of warfarin, few case reports have been published regarding an interaction between gemfibrozil and warfarin. We describe a 62-year-old man who was taking warfarin for paroxysmal atrial fibrillation and came to the anticoagulation clinic for a routine follow-up. For 9 months, the patient's international normalized ratio (INR) had been stable (target range 2.0-3.0) with warfarin 45 mg/week. At this clinic visit, however, his INR was supratherapeutic at 5.8; the only identified change in his drug therapy was the addition of gemfibrozil 600 mg twice/day, started 3 weeks earlier. The patient denied any changes in his dietary intake of vitamin K, alcohol use, or addition of nonprescription or herbal agents. Recent laboratory tests revealed no signs of thyroid abnormalities and only an insignificant elevation in his alanine aminotransferase level. His warfarin dose was decreased to 35-37.5 mg/week (a 22% reduction), and a therapeutic INR was maintained until gemfibrozil was later discontinued because of myalgia. After consecutive subtherapeutic INRs, his warfarin dose was increased to 45 mg/week and a therapeutic INR was maintained. Use of the Drug Interaction Probability Scale indicated that the likelihood of the gemfibrozil-warfarin interaction was probable. The exact mechanism of the proposed interactions between fibric acid derivatives and warfarin remains unknown but may be multifactorial through inhibition of cytochrome P450 isoenzymes, displacement from protein binding sites, or changes in coagulation factor synthesis. Regardless of the fibric acid derivative chosen, an empiric dosage reduction of 20% and close INR monitoring are warranted in patients receiving warfarin.

Heart Rate and Initial Presentation of Cardiovascular Diseases (Caliber)

ClinicalTrials.gov

2013-09-17

Abdominal Aortic Aneurysm; Coronary Heart Disease NOS; Unheralded Coronary Death; Intracerebral Haemorrhage; Heart Failure; Ischemic Stroke; Myocardial Infarction; Stroke; Peripheral Arterial Disease; Stable Angina Pectoris; Subarachnoid Haemorrhage; Transient Ischemic Attack; Unstable Angina; Cardiac Arrest, Sudden Cardiac Death

Social Deprivation and Initial Presentation of 12 Cardiovascular Diseases: a CALIBER Study

ClinicalTrials.gov

2013-09-03

Abdominal Aortic Aneurysm; Coronary Heart Disease NOS; Unheralded Corronary Death; Intracerebral Haemorrhage; Heart Failure; Ischemic Stroke; Myocardial Infarction; Stroke; Peripheral Arterial Disease; Stable Angina Pectoris; Subarachnoid Haemorrhage; Transient Ischemic Attack; Unstable Angina; Cardiac Arrest, Sudden Cardiac Death

Preserved arterial flow secures hepatic oxygenation during haemorrhage in the pig

PubMed Central

Rasmussen, Allan; Skak, Claus; Kristensen, Michael; Ott, Peter; Kirkegaard, Preben; Secher, Niels H

1999-01-01

This study examined the extent of liver perfusion and its oxygenation during progressive haemorrhage. We examined hepatic arterial flow and hepatic oxygenation following the reduced portal flow during haemorrhage in 18 pigs. The hepatic surface oxygenation was assessed by near-infrared spectroscopy and the hepatic metabolism of oxygen, lactate and catecholamines determined the adequacy of the hepatic flow. Stepwise haemorrhage until circulatory collapse resulted in proportional reductions in cardiac output and in arterial, central venous and pulmonary wedge pressures. While heart rate increased, pulmonary arterial pressure remained stable. In addition, renal blood flow decreased, renal vascular resistance increased and there was elevated noradrenaline spill-over. Further, renal surface oxygenation was lowered from the onset of haemorrhage. Similarly, the portal blood flow was reduced in response to haemorrhage, and, as for the renal flow, the reduced splanchnic blood flow was associated with an elevated noradrenaline spill-over. In contrast, hepatic arterial blood flow was only slightly reduced by haemorrhage, and surface oxygenation did not change. The hepatic oxygen uptake was maintained until the blood loss represented more than 30 % of the estimated blood volume. At 30 % reduced blood volume, hepatic catecholamine uptake was reduced, and the lactate uptake approached zero. Subsequent reduction of cardiac output and portal blood flow elicited a selective dilatation of the hepatic arterial vascular bed. Due to this dilatation liver blood flow and hepatic cell oxygenation and metabolism were preserved prior to circulatory collapse. PMID:10087351

International normalized ratio stability in warfarin-experienced patients with nonvalvular atrial fibrillation.

PubMed

Nelson, Winnie W; Desai, Sunita; Damaraju, Chandrasekharrao V; Lu, Lang; Fields, Larry E; Wildgoose, Peter; Schein, Jeffery R

2015-06-01

Maintaining stable levels of anticoagulation using warfarin therapy is challenging. Few studies have examined the stability of the international normalized ratio (INR) in patients with nonvalvular atrial fibrillation (NVAF) who have had ≥6 months' exposure to warfarin anticoagulation for stroke prevention. Our objective was to describe INR control in NVAF patients who had been receiving warfarin for at least 6 months. Using retrospective patient data from the CoagClinic™ database, we analyzed data from NVAF patients treated with warfarin to assess the quality of INR control and possible predictors of poor INR control. Time within, above, and below the recommended INR range (2.0-3.0) was calculated for patients who had received warfarin for ≥6 months and had three or more INR values. The analysis also assessed INR patterns and resource utilization of patients with an INR >4.0. Logistic regression models were used to determine factors associated with poor INR control. Patients (n = 9433) had an average of 1.6 measurements per 30 days. Mean follow-up time was 544 days. Approximately 39% of INR values were out of range, with 23% of INR values being <2.0 and 16% being >3.0. Mean percent time with INR in therapeutic range was 67%; INR <2.0 was 19% and INR >3.0 was 14%. Patients with more than one reading of INR >4.0 (~39%) required an average of one more visit and took 3 weeks to return to an in-range INR. Male sex and age >75 years were predictive of better INR control, whereas a history of heart failure or diabetes were predictive of out-of-range INR values. However, patient characteristics did not predict the likelihood of INR >4.0. Out-of-range INR values remain frequent in patients with NVAF treated with warfarin. Exposure to high INR values was common, resulting in increased resource utilization.

Dabigatran exhibits low intensity of left atrial spontaneous echo contrast in patients with nonvalvular atrial fibrillation as compared with warfarin.

PubMed

Watanabe, Tetsuya; Shinoda, Yukinori; Ikeoka, Kuniyasu; Inui, Hirooki; Fukuoka, Hidetada; Sunaga, Akihiro; Kanda, Takashi; Uematsu, Masaaki; Hoshida, Shiro

2017-03-01

The presence of spontaneous echo contrast (SEC) in the left atrium has been reported to be an independent predictor of thromboembolic risk in patients with atrial fibrillation (AF). Dabigatran was associated with lower rates of stroke and systemic embolism as compared with warfarin when administered at a higher dose. Between July 2011 and October 2015, nonvalvular AF patients treated with warfarin or dabigatran who had transesophageal echocardiography prior to ablation therapy for AF were enrolled. The intensity of SEC was classified into four grades, from 0 to 3. Univariate and multivariate analysis was performed to analyze factors associated with SEC. Sixty-five patients were on dabigatran and 65 were on warfarin, with the prothrombin time in therapeutic range. There were no significant differences in the age, CHADS2 score, left atrial dimension, and left atrial appendage flow between the two groups. However, there were more grade 2 or higher patients with left atrial SEC in the warfarin group (n = 20) than in the dabigatran group (n = 2) (p < 0.001). When multivariate regression analysis was performed, grade 2 or higher left atrial SEC was independently associated with no dabigatran usage in addition to high brain natriuretic peptide level and high incidence of diabetes mellitus or persistent AF. Thus, dabigatran exhibited low intensity of left atrial SEC in nonvalvular AF patients as compared with warfarin.

Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects

PubMed Central

Lilja, Jari J; Backman, Janne T; Neuvonen, Pertti J

2005-01-01

Aims Case reports suggest that gemfobrozil can increase the anticoagulant effect of warfarin. Because gemfibrozil inhibits CYP2C9 in vitro, we studied its effects on the pharmacokinetics and pharmacodynamics of racemic warfarin. Methods In a randomized cross-over study, 10 healthy subjects ingested 600 mg gemfibrozil or placebo twice daily for 8 days. On day 3, they were administered a single dose of 10 mg racemic R-S-warfarin orally. The concentrations of R- and S-warfarin in plasma and thromboplastin time were monitored up to 168 h. Results Gemfibrozil decreased the mean (±SD) area under the plasma concentration-time curve [AUC(0–∞)] of S-warfarin by 11%, from 19.9 ± 5.2 mg l−1 h to 17.6 ± 4.7 mg l−1 h (95% CI on the difference −3.7, −0.78; P < 0.01) and that of R-warfarin by 6% from 31.3 ± 7.5 mg l−1 h during the gemfibrozil phase to 29.5 ± 6.9 mg l−1 h during the placebo phase (95% CI −3.3, −0.33; P < 0.05). There were no significant differences in the elimination half-lives of S- or R-warfarin between the phases. Gemfibrozil did not alter the anticoagulant effect of warfarin. Conclusion Unexpectedly, gemfibrozil slightly decreased the plasma concentrations of R- and S-warfarin. Displacement of warfarin from plasma albumin by gemfibrozil or its interference with the absorption of warfarin could explain the present findings. Usual therapeutic doses of gemfibrozil seem to have limited effects on the pharmacokinetics and pharmacodynamics of single dose warfarin in healthy subjects. PMID:15801938

Prognostic Significance of Hyponatremia in Acute Intracerebral Hemorrhage: Pooled Analysis of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial Studies.

PubMed

Carcel, Cheryl; Sato, Shoichiro; Zheng, Danni; Heeley, Emma; Arima, Hisatomi; Yang, Jie; Wu, Guojun; Chen, Guofang; Zhang, Shihong; Delcourt, Candice; Lavados, Pablo; Robinson, Thompson; Lindley, Richard I; Wang, Xia; Chalmers, John; Anderson, Craig S

2016-07-01

To determine the association of hyponatremia at presentation with clinical and imaging outcomes in patients with acute intracerebral hemorrhage. Retrospective pooled analysis of prospectively collected data from 3,243 participants of the pilot and main phases of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials 1 and 2 (international, multicenter, open, blinded endpoint, randomized controlled trials designed to assess the effects of early intensive blood pressure lowering in patients with acute intracerebral hemorrhage). Clinical hospital sites in 21 countries. Patients with predominantly mild-moderate severity of spontaneous intracerebral hemorrhage within 6 hours of onset and elevated systolic blood pressure (150-220 mm Hg) were included in the study. Patients were assigned to receive intensive (target systolic blood pressure, < 140 mm Hg within 1 hr) or guideline-recommended (target systolic blood pressure, < 180 mm Hg) blood pressure-lowering therapy. Presentation hyponatremia was defined as serum sodium less than 135 mEq/L. The primary outcome was death at 90 days. Multivariable logistic regression was used to assess the association of hyponatremia with important clinical events. Of 3,002 patients with available data, 349 (12%) had hyponatremia. Hyponatremia was associated with death (18% vs 11%; multivariable-adjusted odds ratio, 1.81; 95% CI, 1.28-2.57; p < 0.001) and larger baseline intracerebral hemorrhage volume (multivariable adjusted, p = 0.046) but not with baseline perihematomal edema volume nor with growth of intracerebral hemorrhage or perihematomal edema during the initial 24 hours. Hyponatremia at presentation is associated with increased mortality in patients with predominantly deep and modest volume intracerebral hemorrhage through mechanisms that seem independent of growth in intracerebral hemorrhage or perihematomal edema.

Oral warfarin intake affects skin inflammatory cytokine responses in rats.

PubMed

Aleksandrov, Aleksandra Popov; Mirkov, Ivana; Zolotarevski, Lidija; Ninkov, Marina; Mileusnic, Dina; Kataranovski, Dragan; Kataranovski, Milena

2017-09-01

Warfarin is an anticoagulant used in prevention/prophylaxis of thromboembolism. Besides the effects on coagulation, non-hemorrhagic reactions have also been documented. Although cutaneous reactions were reported in some patients, the impact on skin immunity was not explored. In the present paper, the effect of 30-day oral warfarin intake on skin cytokine responses in rats was analyzed. Increased release of inflammatory cytokines (TNF, IL-1β and IL-10) was noted by skin explants from rats which received warfarin, but without effect on IL-6. No impact on epidermal cell cytokine secretion was seen, except a tendency of an increase of IL-6 response to stimulation with microbial product lipopolysaccharide (LPS). Topical application of contact allergen dinitrochlorobenzene (DNCB) resulted in slight (numerical solely) increase of TNF release by skin explants of warfarin-treated animals, while epidermal cells responded by increased secretion of all four cytokines examined. The data presented provide new information on the potential of oral warfarin to modulate skin innate immune activity. Copyright © 2017 Elsevier B.V. All rights reserved.

The Cost Differential Between Warfarin Versus Aspirin Treatment After a Fontan Procedure.

PubMed

Schilling, Chris; Dalziel, Kim; Iyengar, Ajay J; d'Udekem, Yves

2017-08-01

The use of aspirin versus warfarin for treatment of patients after a Fontan procedure remains contentious. Current preference-based models of treatment across Australia and New Zealand show variation in care that is unlikely to reflect patient differences and/or clinical risk. We combine data from the Australian and New Zealand Fontan Registry and a home INR (International Normalised Ratio) monitoring program (HINRMP) from the Royal Children's Hospital (RCH) Melbourne, to estimate the cost difference for Fontan recipients receiving aspirin versus warfarin for 2015. We adopt a societal perspective to costing which includes cost to the health system (e.g. medical consults, pathology tests) and costs to patients and carers (e.g. travel and time), but excludes costs of adverse events. Costs are presented in Australian 2015 dollars; any costs from previous years have been inflated using appropriate rates from the Australian Bureau of Statistics. We find that warfarin patients face additional costs of $825 per annum, with the majority ($584 or 71%) of those borne by the patient or family. If aspirin is as clinically as effective as warfarin, Fontan recipients could be enjoying far less costly, invasive and time-consuming treatment. While achieving such clinical consensus can be difficult, economics shows us that there are large costs associated with a failure to achieve it. Copyright © 2017. Published by Elsevier B.V.

Drug interactions and risk of acute bleeding leading to hospitalisation or death in patients with chronic atrial fibrillation treated with warfarin.

PubMed

Gasse, Christiane; Hollowell, Jennifer; Meier, Christoph R; Haefeli, Walter E

2005-09-01

Although drug interactions with warfarin are an important cause of excessive anticoagulation, their impact on the risk of serious bleeding is unknown. We therefore performed a cohort study and a nested case-control analysis to determine the risk of serious bleeding in 4152 patients (aged 40-84 years) with nonvalvular atrial fibrillation (AF) taking long-term warfarin (> 3 months). The study population was drawn from the UK General Practice Research Database. More than half (58%) of eligible patients used potentially interacting drugs during continuous warfarin treatment. Among 45 identified cases of incident idiopathic bleeds (resulting in hospitalisation within 30 days or death within 7 days) and 143 matched controls, more cases than controls took > or = 1 potentially interacting drug within the preceding 30 days (62.2% vs. 35.7%) and used > 4 drugs (polypharmacy) within the preceding 90 days (80.0% vs. 66.4%). Conditional logistic regression analysis yielded an odds ratio (OR) of 3.4 (95% confidence interval [CI]: 1.4-8.5) for the risk of serious bleeding in patients treated with warfarin and > or = 1 drugs potentially increasing the effect of warfarin vs. warfarin alone adjusted for polypharmacy, diabetes, hypertension, heart failure, and thyroid disease; the adjusted OR for the combined use of warfarin and aspirin vs. warfarin alone was 4.5 (95% CI: 1.1-18.1). We conclude that concurrent use of potentially interacting drugs with warfarin is associated with a 3 to 4.5-fold increased risk of serious bleeding in long-term warfarin users.

Cost Effectiveness of Genotype-Guided Warfarin Dosing in Patients with Mechanical Heart Valve Replacement Under the Fee-for-Service System.

PubMed

Kim, Dong-Jin; Kim, Ho-Sook; Oh, Minkyung; Kim, Eun-Young; Shin, Jae-Gook

2017-10-01

Although studies assessing the cost effectiveness of genotype-guided warfarin dosing for the management of atrial fibrillation, deep vein thrombosis, and pulmonary embolism have been reported, no publications have addressed genotype-guided warfarin therapy in mechanical heart valve replacement (MHVR) patients or genotype-guided warfarin therapy under the fee-for-service (FFS) insurance system. The aim of this study was to evaluate the cost effectiveness of genotype-guided warfarin dosing in patients with MHVR under the FFS system from the Korea healthcare sector perspective. A decision-analytic Markov model was developed to evaluate the cost effectiveness of genotype-guided warfarin dosing compared with standard dosing. Estimates of clinical adverse event rates and health state utilities were derived from the published literature. The outcome measure was the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were performed to explore the range of plausible results. In a base-case analysis, genotype-guided warfarin dosing was associated with marginally higher QALYs than standard warfarin dosing (6.088 vs. 6.083, respectively), at a slightly higher cost (US$6.8) (year 2016 values). The ICER was US$1356.2 per QALY gained. In probabilistic sensitivity analysis, there was an 82.7% probability that genotype-guided dosing was dominant compared with standard dosing, and a 99.8% probability that it was cost effective at a willingness-to-pay threshold of US$50,000 per QALY gained. Compared with only standard warfarin therapy, genotype-guided warfarin dosing was cost effective in MHVR patients under the FFS insurance system.

Healthcare utilization and costs for patients initiating Dabigatran or Warfarin.

PubMed

Reynolds, Shannon L; Ghate, Sameer R; Sheer, Richard; Gandhi, Pranav K; Moretz, Chad; Wang, Cheng; Sander, Stephen; Costantino, Mary E; Annavarapu, Srinivas; Andrews, George

2017-06-21

Novel oral anticoagulants (NOAC) such as dabigatran, when compared to warfarin, have been shown to potentially reduce the risk of stroke in patients with non-valvular atrial fibrillation (NVAF) together with lower healthcare resource utilization (HCRU) and similar total costs. This study expands on previous work by comparing HCRU and costs for patients newly diagnosed with NVAF and newly initiated on dabigatran or warfarin, and is the first study specifically in a Medicare population. A retrospective matched-cohort study was conducted using data from administrative health care claims during the study period 01/01/2010-12/31/2012. Cox regression analyses were used to compare all-cause risk of first hospitalizations and emergency room (ER) visits. Medical, pharmacy, and total costs per-patient-per-month (PPPM) were compared between dabigatran and warfarin users. A total of 1110 patients initiated on dabigatran were propensity score-matched with corresponding patients initiated on warfarin. The mean number of hospitalizations (0.92 vs. 1.13, P = 0.012), ER visits (1.32 vs. 1.56, P < 0.01), office visits (21.43 vs. 29.41; P < 0.01), and outpatient visits (10.86 vs. 22.02; P < 0.01) were lower among dabigatran compared to warfarin users. Patients initiated on dabigatran had significantly lower risk of first all-cause ER visits [hazard ratio (HR): 0.84, 95% confidence interval (CI): 0.73-0.98] compared to those initiated on warfarin. Adjusted mean pharmacy costs PPPM were significantly greater for dabigatran users ($510 vs. $250, P < 0.001); however, mean medical costs PPPM ($1912 vs. $1956, P = 0.55) and mean total costs PPPM ($2381 vs. $2183, P = 0.10) were not significantly different compared to warfarin users. Dabigatran users had significantly lower HCRU compared to warfarin users. In addition, dabigatran users had lower risk of all-cause ER visits. Despite higher pharmacy costs, the two cohorts did not differ significantly in medical or total all

Anti-inflammatory effects of Simvastatin in patients with acute intracerebral hemorrhage in an intensive care unit

PubMed Central

Zhou, Xiurong; Chen, Jiafeng; Wang, Chengdong; Wu, Lili

2017-01-01

Intracerebral hemorrhage is one of the most common types of cerebrovascular disease in humans and often causes paralysis, a vegetative state and even death. Patients with acute intracerebral hemorrhage are frequently monitored in intensive care units (ICUs). Spontaneous intracerebral hemorrhage is associated with a higher rate of mortality and morbidity than other intracephalic diseases. The expression levels of inflammatory factors have important roles in inflammatory responses indicative of changes in a patient's condition and are therefore important in the monitoring and treatment of affected patients at the ICU as well as the development of therapeutic strategies for acute cerebral hemorrhage. The present study investigated the anti-inflammatory effects of Simvastatin in patients with acute intracerebral hemorrhage at an ICU, and inflammatory factors and cellular changes were systematically analyzed. The plasma concentrations of inflammatory factors, including interleukin (IL)-4, IL-6, IL-8 and IL-10, were evaluated by ELISAs. The plasma concentrations of inflammatory cellular changes were detected by using flow cytometry. The results demonstrated that after Simvastatin treatment of patients with acute cerebral hemorrhage at the ICU, the plasma concentrations of IL-4, IL-6, IL-8 and IL-10 were downregulated compared with those in placebo-treated controls. In addition, Simvastatin treatment at the ICU decreased lymphocytes, granulocytes and mononuclear cells in patients with acute cerebral hemorrhage. The levels of inflammatory factors were associated with brain edema in patients with acute cerebral hemorrhage treated at the ICU. In addition, the amount of bleeding was reduced in parallel with the inflammatory cell plasma concentration of lymphocytes, granulocytes and mononuclear cells. Importantly, Simvastatin treatment produced beneficial outcomes by improving brain edema and reducing the amount of bleeding. In conclusion, the present study demonstrated the

Warfarin Management and Outcomes in Patients with Nonvalvular Atrial Fibrillation Within an Integrated Health Care System.

PubMed

An, JaeJin; Niu, Fang; Zheng, Chengyi; Rashid, Nazia; Mendes, Robert A; Dills, Diana; Vo, Lien; Singh, Prianka; Bruno, Amanda; Lang, Daniel T; Le, Paul T; Jazdzewski, Kristin P; Aranda, Gustavus

2017-06-01

Warfarin is a common treatment option to manage patients with nonvalvular atrial fibrillation (NVAF) in clinical practice. Understanding current pharmacist-led anticoagulation clinic management patterns and associated outcomes is important for quality improvement; however, currently little evidence associating outcomes with management patterns exists. To (a) describe warfarin management patterns and (b) evaluate associations between warfarin treatment and clinical outcomes for patients with NVAF in an integrated health care system. A retrospective cohort study was conducted among NVAF patients with warfarin therapy between January 1, 2006, and December 31, 2011, using Kaiser Permanente Southern California data, and followed until December 31, 2013. Management patterns related to international normalized ratio (INR) monitoring, anticoagulation clinic pharmacist intervention (consultation), and warfarin dose adjustments were investigated along with yearly attrition rates, time-in-therapeutic ranges (TTRs), and clinical outcomes (stroke or systemic embolism and major bleeding). Descriptive statistics and multivariable Cox proportional hazard models were used to determine associations between TTR and clinical outcomes. A total of 32,074 NVAF patients on warfarin treatment were identified and followed for a median of 3.8 years. About half (49%) of the patients were newly initiating warfarin therapy. INR monitoring and pharmacist interventions were conducted roughly every 3 weeks after 6 months of warfarin treatment. Sixty-three percent of the study population had ≥ 1 warfarin dose adjustments with a mean (SD) of 6.7 (6.3) annual dose adjustments. Warfarin dose adjustments occurred at a median of 1 day (interquartile ranges [IQR] 1-3) after the INR measurement. Yearly attrition rate was from 3.3% to 6.3% during the follow-up, and median (IQR) TTR was 61% (46%-73%). Patients who received frequent INR monitoring (≥ 27 times per year), pharmacist interventions (≥ 24

Effect of Genetic Variants, Especially CYP2C9 and VKORC1, on the Pharmacology of Warfarin

PubMed Central

Fung, Erik; Patsopoulos, Nikolaos A.; Belknap, Steven M.; O’Rourke, Daniel J.; Robb, John F.; Anderson, Jeffrey L.; Shworak, Nicholas W.; Moore, Jason H.

2014-01-01

The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin. Together with patient demographics and clinical information, they account for approximately one-half of the warfarin dose variance in individuals of European descent. Recent prospective and randomized controlled trial data support pharmacogenetic guidance with their use in warfarin dose initiation and titration. Benefits from pharmacogenetics-guided warfarin dosing have been reported to extend beyond the period of initial dosing, with supportive data indicating benefits to at least 3 months. The genetic effects of VKORC1 and CYP2C9 in African and Asian populations are concordant with those in individuals of European ancestry; however, frequency distribution of allelic variants can vary considerably between major populations. Future randomized controlled trials in multiethnic settings using population-specific dosing algorithms will allow us to further ascertain the generalizability and cost-effectiveness of pharmacogenetics-guided warfarin therapy. Additional genome-wide association studies may help us to improve and refine dosing algorithms and potentially identify novel biological pathways. PMID:23041981

Health literacy and knowledge in a cohort of Australian patients taking warfarin.

PubMed

Yiu, Angela W; Bajorek, Beata V

2018-01-01

To 1) characterise older patients taking warfarin, 2) assess these patients' level of warfarin knowledge, and 3) describe their strengths and limitations in health literacy, and 4) explore relationships between participants' characteristics, warfarin knowledge and health literacy. A warfarin knowledge questionnaire and Health Literacy Questionnaire (HLQ) were administered to older patients (aged >65 years, N=34) taking warfarin in an Australian general practice setting. Key gaps in participant knowledge pertained to the consequences of an international normalized ratio (INR) being below the target INR range and safety issues such as when to seek medical attention. A limitation for participants with a lower level of health literacy was the ability to appraise health information. Patients who needed assistance in completing the HLQs had significantly lower warfarin knowledge scores (p=0.03). Overseas-born participants and those taking 5 or more long-term medications had lower HLQ scores for specific scales (p<0.05). In this study warfarin knowledge gaps and a limitation of health literacy amongst a small sample of older patients were identified. The findings suggest that education and resources may need to be tailored to the needs of older patients taking warfarin and their carers to address these knowledge gaps and limitations in health literacy. Patients who may need greater support include those that need assistance in completing the HLQ, are overseas-born, or are taking 5 or more long-term medications.

A new warfarin dosing algorithm including VKORC1 3730 G > A polymorphism: comparison with results obtained by other published algorithms.

PubMed

Cini, Michela; Legnani, Cristina; Cosmi, Benilde; Guazzaloca, Giuliana; Valdrè, Lelia; Frascaro, Mirella; Palareti, Gualtiero

2012-08-01

Warfarin dosing is affected by clinical and genetic variants, but the contribution of the genotype associated with warfarin resistance in pharmacogenetic algorithms has not been well assessed yet. We developed a new dosing algorithm including polymorphisms associated both with warfarin sensitivity and resistance in the Italian population, and its performance was compared with those of eight previously published algorithms. Clinical and genetic data (CYP2C9*2, CYP2C9*3, VKORC1 -1639 G > A, and VKORC1 3730 G > A) were used to elaborate the new algorithm. Derivation and validation groups comprised 55 (58.2% men, mean age 69 years) and 40 (57.5% men, mean age 70 years) patients, respectively, who were on stable anticoagulation therapy for at least 3 months with different oral anticoagulation therapy (OAT) indications. Performance of the new algorithm, evaluated with mean absolute error (MAE) defined as the absolute value of the difference between observed daily maintenance dose and predicted daily dose, correlation with the observed dose and R(2) value, was comparable with or slightly lower than that obtained using the other algorithms. The new algorithm could correctly assign 53.3%, 50.0%, and 57.1% of patients to the low (≤25 mg/week), intermediate (26-44 mg/week) and high (≥ 45 mg/week) dosing range, respectively. Our data showed a significant increase in predictive accuracy among patients requiring high warfarin dose compared with the other algorithms (ranging from 0% to 28.6%). The algorithm including VKORC1 3730 G > A, associated with warfarin resistance, allowed a more accurate identification of resistant patients who require higher warfarin dosage.

Health literacy and warfarin therapy at two anticoagulation clinics in Brazil.

PubMed

Martins, Maria Auxiliadora Parreiras; Costa, Josiane Moreira; Mambrini, Juliana Vaz de Melo; Ribeiro, Antonio Luiz Pinho; Benjamin, Emelia J; Brant, Luisa Campos Caldeira; Paasche-Orlow, Michael K; Magnani, Jared W

2017-07-01

Health literacy has been related to health-related conditions and health outcomes. Studies examining the association of health literacy and anticoagulation have had variable results. We sought to investigate the relations of health literacy and percentage of time in therapeutic range (TTR) in a vulnerable Brazilian cohort at two hospital-based anticoagulation clinics. We measured health literacy with the Short Assessment of Health Literacy for Portuguese-speaking Adults (SAHLPA-18) in 2015-2016. We identified the demographic and clinical characteristics associated with health literacy and related health literacy to TTR. We enrolled 422 adults prescribed chronic warfarin therapy in our observational study (median age 62.1 years; 58.8% women; monthly income $200.00). The prevalence of inadequate health literacy (score 0-14 points) was 72.3% with a median score of 12 (quartiles, Q1=10; Q3=15) on the SAHLPA-18. The median TTR was 66.1%. In the multivariable logistic analysis, cognitive impairment and assistance with taking warfarin were associated with inadequate health literacy. Prosthetic heart valves and more school years were associated with adequate health literacy. Our analyses showed no significant relation between health literacy and TTR, analysing health literacy as a categorical (adjusted OR 1.05; 95% CI 0.65 to 1.70) or continuous variable (Spearman's coefficient 0.02; p=0.70). Inadequate health literacy was highly prevalent in this impoverished Brazilian cohort receiving anticoagulation with warfarin. However, we did not identify an association between health literacy and TTR. Future investigations may consider the systemic factors that contribute towards successful anticoagulation outcomes for vulnerable patient cohorts with inadequate health literacy. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Vascular access site complication in transfemoral coronary angiography between uninterrupted warfarin and heparin bridging.

PubMed

Wongcharoen, Wanwarang; Pinyosamosorn, Kittipong; Gunaparn, Siriluck; Boonnayhun, Suchada; Thonghong, Tasalak; Suwannasom, Pannipa; Phrommintikul, Arintaya

2017-08-01

Warfarin discontinuation with heparin bridging is a common practice in patients receiving warfarin prior to elective coronary angiography (CAG). The uninterrupted warfarin strategy has been suggested to be alternative option for patients with high thromboembolic risk. Therefore, we aimed to assess the safety of elective transfemoral CAG during uninterrupted warfarin therapy compared to heparin bridging. This study was a randomized open-label design with blinded event evaluation. The 110 consecutive patients (age ≥ 18 years) receiving warfarin before the planned transfemoral CAG were randomly assigned to either heparin bridging or uninterrupted warfarin with targeted INR (2.0-3.0). The primary outcome was the incidence of major vascular access site complications. The baseline characteristics were comparable between two groups (mean age was 60.1 ± 7.8 years, 49 males). The mean INR on the day of CAG of heparin bridging and uninterrupted warfarin groups was 1.2 ± 0.3 and 2.2 ± 0.5 (P < 0.001). The major vascular access site complications occurred in 3 of 55 (5.5%) heparin-bridging patients and in none of 55 uninterrupted warfarin patients (P = 0.243). The total vascular access site complications occurred in 6 (10.9%) heparin-bridging and one (1.8%) uninterrupted warfarin patients (P = 0.113). No patient developed either other bleeding or thromboembolic events during 7 days after CAG. We demonstrated that an uninterrupted warfarin strategy did not increase vascular access site complications in patients undergoing transfemoral CAG compared to heparin bridging therapy. Due to the safety and the ease of uninterrupted warfarin strategy, this approach should be encouraged in patients receiving long-term warfarin who undergo elective transfemoral CAG. © 2017, Wiley Periodicals, Inc.

Dermoscopy of subungual haemorrhage: its usefulness in differential diagnosis from nail-unit melanoma.

PubMed

Mun, J-H; Kim, G-W; Jwa, S-W; Song, M; Kim, H-S; Ko, H-C; Kim, B-S; Kim, M-B

2013-06-01

Subungual haemorrhages are characterized by well-circumscribed dots or blotches with a red to red-black pigmentation, but some cases can be difficult to distinguish from subungual melanoma by the naked eye alone. Dermoscopy has proven to be a useful, noninvasive tool in the diagnosis of pigmented lesions in the nail; however, few dermoscopic studies of subungual haemorrhages have been reported. To investigate characteristic dermoscopic patterns of subungual haemorrhages, and to find distinctive features that can differentiate them from nail-unit melanomas. Patients with a confirmed diagnosis of either subungual haemorrhage or nail-unit melanoma at a tertiary university hospital were included in the study. Clinical features and dermoscopic patterns were evaluated. Sixty-four patients with a total of 90 lesions of subungual haemorrhage were enrolled in the study. The majority of cases (84%) showed combinations of more than one colour, while 16% had only one colour. The most common colour of the subungual haemorrhages was purple-black, in 37% of cases. A homogeneous pattern was observed in 92% of cases, globular patterns in 42% and streaks in 39%. Peripheral fading and periungual haemorrhages were found in 54% and 22% of cases, respectively. Destruction or dystrophy of the nail plate was observed in 16% of cases. In the 16 cases of nail-unit melanomas, Hutchinson sign, longitudinal irregular bands or lines, triangular shape of bands, vascular pattern, and ulcerations were found in 100%, 81%, 25%, 6% and 81% of cases, respectively. In contrast, these features were not found in subungual haemorrhages. Dermoscopy provides valuable information for the diagnosis of subungual haemorrhage and aids in the differential diagnosis from nail-unit melanoma. © 2013 The Authors. BJD © 2013 British Association of Dermatologists.

Secondary stroke prevention with ximelagatran versus warfarin in patients with atrial fibrillation: pooled analysis of SPORTIF III and V clinical trials.

PubMed

Akins, Paul T; Feldman, Harvey A; Zoble, Robert G; Newman, David; Spitzer, Stefan G; Diener, Hans-Christoph; Albers, Gregory W

2007-03-01

Patients with nonvalvular atrial fibrillation and prior stroke or transient ischemic attack (TIA) are at high risk for recurrent stroke. We investigated whether ximelagatran was noninferior to warfarin in patients with prior stroke or TIA. We analyzed pooled data from the SPORTIF III and V trials in patients with prior stroke/TIA. The primary outcome was the composite annual rate of both ischemic and hemorrhagic strokes and systemic embolic events. Secondary analyses considered ischemic and hemorrhagic strokes separately, bleeding, and nonrandomized, concomitant therapy with aspirin < or =100 mg/d. Patients from SPORTIF III (n=3407) and SPORTIF V (n=3922) trials were categorized by prior stroke/TIA (21%) versus no prior stroke/TIA (79%) and by treatment group (ximelagatran vs warfarin). The primary event rate in patients with prior stroke/TIA was 2.83%/y with ximelagatran and 3.27%/y with warfarin (absolute difference, -0.44%; 95% CI, -1.88 to1.01; P=0.625). In those without prior stroke/TIA, the primary event rate was 1.31%/y with ximelagatran and 1.26%/y with warfarin (P=NS). Ischemic strokes outnumbered cerebral hemorrhages with both warfarin (31 of 36) and ximelagatran (30 of 32) treatment (difference between treatments was not significant). Combining aspirin with either anticoagulant was associated with higher rates of major bleeding (1.5%/y with warfarin and 4.95%/y with warfarin plus aspirin, P=0.004; 2.35%/y with ximelagatran and 5.09%/y with ximelagatran plus aspirin, P=0.046) but not lower rates of primary events. Ximelagatran was at least as effective as well-controlled warfarin for the secondary prevention of stroke. The nonrandomized, concomitant treatment with aspirin and anticoagulation was associated with increased bleeding without evidence of a reduction in primary outcome events.

Patient satisfaction with extended-interval warfarin monitoring.

PubMed

Carris, Nicholas W; Hwang, Andrew Y; Smith, Steven M; Taylor, James R; Sando, Karen; Powell, Jason; Rosenberg, Eric I; Zumberg, Marc S; Gums, John G; Dietrich, Eric A; Anderson, Katherine Vogel

2016-11-01

Extended-interval monitoring of warfarin has been proposed to reduce follow-up burden and improve patient satisfaction. We aimed to make an initial assessment of anticoagulation satisfaction before and after an extended-interval warfarin monitoring intervention. We conducted a translational prospective single-arm pilot study of extended-interval warfarin monitoring in five pharmacist-managed anticoagulation clinics. Patients meeting CHEST guideline criteria for extended-interval warfarin monitoring began progressive extended-interval follow-up (6, 8, and 12 weeks thereafter). The Duke Anticoagulation Satisfaction Scale (DASS) was administered at baseline and at end-of-study or study removal (in patients no longer appropriate for extended interval follow-up). Forty-six patients had evaluable pre- and post-intervention DASS survey data. Mean age of patients was 66.5 years, 74 % were non-Hispanic whites, and 48 % were men. Patients completed a mean ± SD of 34 ± 22 weeks of follow-up. Mean ± SD total DASS score at baseline was 45.2 ± 14.2 versus 49.1 ± 14.9 at end-of-study (mean change, +3.9 [95 % CI -0.6-8.4; p = 0.09]), indicating no benefit-and trending toward decrement-to anticoagulation satisfaction. Change in anticoagulation satisfaction varied substantially following extended-interval monitoring, with no evidence of improved satisfaction. Plausible reasons for patients not preferring extended-interval monitoring include increased anxiety and disengagement from self-management activities, both potentially related to less frequent feedback and reassurance during extended interval-monitoring. Additional research is needed to identify who is likely to benefit most from extended-interval monitoring. Anticoagulation satisfaction should be considered with clinical factors and shared-decision making when implementing extended-interval warfarin monitoring.

Cytochrome P450-mediated warfarin metabolic ability is not a critical determinant of warfarin sensitivity in avian species: In vitro assays in several birds and in vivo assays in chicken.

PubMed

Watanabe, Kensuke P; Kawata, Minami; Ikenaka, Yoshinori; Nakayama, Shouta M M; Ishii, Chihiro; Darwish, Wageh Sobhi; Saengtienchai, Aksorn; Mizukawa, Hazuki; Ishizuka, Mayumi

2015-10-01

Coumarin-derivative anticoagulant rodenticides used for rodent control are posing a serious risk to wild bird populations. For warfarin, a classic coumarin derivative, chickens have a high median lethal dose (LD50), whereas mammalian species generally have much lower LD50. Large interspecies differences in sensitivity to warfarin are to be expected. The authors previously reported substantial differences in warfarin metabolism among avian species; however, the actual in vivo pharmacokinetics have yet to be elucidated, even in the chicken. In the present study, the authors sought to provide an in-depth characterization of warfarin metabolism in birds using in vivo and in vitro approaches. A kinetic analysis of warfarin metabolism was performed using liver microsomes of 4 avian species, and the metabolic abilities of the chicken and crow were much higher in comparison with those of the mallard and ostrich. Analysis of in vivo metabolites from chickens showed that excretions predominantly consisted of 4'-hydroxywarfarin, which was consistent with the in vitro results. Pharmacokinetic analysis suggested that chickens have an unexpectedly long half-life despite showing high metabolic ability in vitro. The results suggest that the half-life of warfarin in other bird species could be longer than that in the chicken and that warfarin metabolism may not be a critical determinant of species differences with respect to warfarin sensitivity. © 2015 SETAC.

Warfarin time in therapeutic range and its impact on healthcare resource utilization and costs among patients with nonvalvular atrial fibrillation.

PubMed

Deitelzweig, Steve; Evans, Michael; Hillson, Eric; Trocio, Jeffrey; Bruno, Amanda; Tan, Wilson; Lingohr-Smith, Melissa; Singh, Prianka; Lin, Jay

2016-01-01

Warfarin is efficacious for reducing stroke risk among patients with nonvalvular atrial fibrillation (NVAF). However, the efficacy and safety of warfarin are influenced by its time in therapeutic range (TTR). To assess differences in healthcare resource utilization and costs among NVAF patients with low (<60%) and high (≥60%) warfarin TTRs in an integrated delivery network (IDN) setting. Patients with NVAF were identified from an electronic medical record database. Patients were required to have ≥6 international normalized prothrombin time ratio (INR) tests. NVAF patients were grouped into two cohorts: those with warfarin TTR <60% (low TTR) and those with warfarin TTR ≥60% (high TTR). Healthcare resource utilization and costs were evaluated during a 12 month follow-up period. Multivariable regressions were used to assess the impact of different warfarin TTRs on healthcare costs. Among the study population, greater than half (54%, n = 1595) had a low TTR, and 46% (n = 1356) had a high TTR. Total all-cause healthcare resource utilization was higher among patients in the low TTR cohort vs. the high TTR cohort (number of encounters: 70.2 vs. 56.1, p < 0.001). After adjusting for patient characteristics, total all-cause healthcare costs and stroke-related healthcare costs were $2398 (p < 0.001) and $687 (p = 0.02) higher, respectively, for patients in the low TTR cohort vs. the high TTR cohort. In this retrospective study, we were only able to evaluate the association and not the causality between healthcare resource utilization and costs with the different warfarin TTRs. Many warfarin-treated NVAF patients have a low warfarin TTR. NVAF patients with low vs. patients with high warfarin TTR used healthcare resources to a greater extent, which was reflected in higher healthcare costs.

Rivaroxaban Versus Dabigatran or Warfarin in Real-World Studies of Stroke Prevention in Atrial Fibrillation: Systematic Review and Meta-Analysis.

PubMed

Bai, Ying; Deng, Hai; Shantsila, Alena; Lip, Gregory Y H

2017-04-01

This study was designed to evaluate the effectiveness and safety of rivaroxaban in real-world practice compared with effectiveness and safety of dabigatran or warfarin for stroke prevention in atrial fibrillation through meta-analyzing observational studies. Seventeen studies were included after searching in PubMed for studies reporting the comparative effectiveness and safety of rivaroxaban versus dabigatran (n=3), rivaroxaban versus Warfarin (n=11), or both (n=3) for stroke prevention in atrial fibrillation. Overall, the risks of stroke/systematic thromboembolism with rivaroxaban were similar when compared with those with dabigatran (stroke/thromboembolism: hazard ratio, 1.02; 95% confidence interval, 0.91-1.13; I 2 =70.2%, N=5), but were significantly reduced when compared with those with warfarin (hazard ratio, 0.75; 95% confidence interval, 0.64-0.85; I 2 =45.1%, N=9). Major bleeding risk was significantly higher with rivaroxaban than with dabigatran (hazard ratio, 1.38; 95% confidence interval, 1.27-1.49; I 2 =26.1%, N=5), but similar to that with warfarin (hazard ratio, 0.99; 95% confidence interval, 0.91-1.07; I 2 =0.0%, N=6). Rivaroxaban was associated with increased all-cause mortality and gastrointestinal bleeding, but similar risk of acute myocardial infarction and intracranial hemorrhage when compared with dabigatran. When compared with warfarin, rivaroxaban was associated with similar risk of any bleeding, mortality, and acute myocardial infarction, but a higher risk of gastrointestinal bleeding and lower risk of intracranial hemorrhage. In this systematic review and meta-analysis, rivaroxaban was as effective as dabigatran, but was more effective than warfarin for the prevention of stroke/thromboembolism in atrial fibrillation patients. Major bleeding risk was significantly higher with rivaroxaban than with dabigatran, as was all-cause mortality and gastrointestinal bleeding. Rivaroxaban was comparable to warfarin for major bleeding, with an

Sol-gel Derived Warfarin - Silica Composites for Controlled Drug Release.

PubMed

Dolinina, Ekaterina S; Parfenyuk, Elena V

2017-01-01

Warfarin, commonly used anticoagulant in clinic, has serious shortcomings due to its unsatisfactory pharmacodynamics. One of the efficient ways for the improvement of pharmacological and consumer properties of drugs is the development of optimal drug delivery systems. The aim of this work is to synthesize novel warfarin - silica composites and to study in vitro the drug release kinetics to obtain the composites with controlled release. The composites of warfarin with unmodified (UMS) and mercaptopropyl modified silica (MPMS) were synthesized by sol-gel method. The composite formation was confirmed by FTIR spectra. The concentrations of warfarin released to media with pH 1.6, 6.8 and 7.4 were measured using UV spectroscopy. The drug release profiles from the solid composites were described by a series of kinetic models which includes zero order kinetics, first order kinetics, the modified Korsmeyer-Peppas model and Hixson-Crowell model. The synthesized sol-gel composites have different kinetic behavior in the studied media. In contrast to the warfarin composite with unmodified silica, the drug release from the composite with mercaptopropyl modified silica follows zero order kinetics for 24 h irrespective to the release medium pH due to mixed mechanism (duffusion + degradation and/or disintegration of silica matrix). The obtained results showed that warfarin - silica sol-gel composites have a potential application for the development of novel oral formulation of the drug with controlled delivery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

International normalized ratio stabilization in newly initiated warfarin patients with nonvalvular atrial fibrillation.

PubMed

Nelson, Winnie W; Desai, Sunita; Damaraju, C V; Lu, Lang; Fields, Larry E; Wildgoose, Peter; Schein, Jeff R

2014-12-01

Warfarin is effective for stroke prevention in patients with atrial fibrillation (AF), but international normalized ratio (INR) levels fluctuate and frequent monitoring is necessary. This study used data from a large anticoagulation management service database to analyze the relationship between INR stabilization and warfarin utilization for >1 year in patients with nonvalvular AF (NVAF). Anticoagulation records from a large US electronic database collected from 2006 to 2010 were analyzed. Patients with NVAF and ≥ 3 INR values in the dataset were identified (n = 15,276). INR stabilization was defined as the first three consecutive INR values between 2.0 and 3.0 after warfarin initiation. One quarter of patients (n = 3809) failed to reach INR stabilization. After initial stabilization, 30% of subsequent INR values were out of range. The mean (± standard deviation [SD]) follow-up time from stabilization to the end of study for these patients was 494.2 ± 418.1 days. Age ≥ 75 years (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.08-1.27), hypertension (OR = 1.19, 95% CI = 1.10-1.29), or prior stroke (OR = 1.29, 95% CI = 1.04-1.61) were positively associated with achieving stabilization; heart failure was negatively associated with stabilization (OR = 0.78, 95% CI = 0.70-0.87). Male gender (p < 0.0001) and hypertension were associated with earlier stabilization (p = 0.0013); heart failure was associated with later stabilization (p = 0.0098). Patients who achieved INR stabilization within 1 year were 10 times more likely to remain on warfarin than patients who did not achieve it. Observational data may contain incomplete records. Data on adherence, concurrent medications, vitamin K intake, genotype, reasons for discontinuation of monitoring, and patient outcomes were not available in the dataset. The study findings were generalizable only to patients with AF who were managed by anticoagulation clinics. Given the importance of stroke prevention among

Suboptimal Anticoagulant Management in Japanese Patients with Nonvalvular Atrial Fibrillation Receiving Warfarin for Stroke Prevention.

PubMed

Hirano, Teruyuki; Kaneko, Hirokazu; Mishina, Sari; Wang, Feng; Morita, Satoshi

2017-10-01

Atrial fibrillation (AF) is the most common cardiac arrhythmia, with increasing prevalence in Japan. Although prothrombin time-international normalized ratio (PT-INR) targets for monitoring warfarin therapy in patients with nonvalvular AF (NVAF) are well defined, real-world patient characteristics and PT-INR levels remain unknown among Japanese patients with NVAF who initiate and continue warfarin (warfarin maintainers) versus those who switch from warfarin to direct oral anticoagulants (DOACs; warfarin switchers). Patients with NVAF receiving oral anticoagulants between February 2013 and June 2015 were identified using a nationwide electronic medical record (EMR) database from 69 hospitals in Japan. Demographics and characteristics of patients, PT-INR, time in therapeutic range (TTR), and frequency in range (FIR) of PT-INR between warfarin maintainers and warfarin switchers were assessed. A total of 1705 patients met inclusion criteria and were examined (1501 warfarin maintainers versus 204 warfarin switchers). CHADS 2 , CHA 2 DS 2 -VASc, and HAS-BLED scores were comparable between groups. However, these scores were significantly higher among warfarin switchers at the time of switching than at the time of warfarin initiation. Furthermore, TTR and FIR of PT-INR were lower in warfarin switchers than in maintainers. Nevertheless, TTR and FIR were below 50% (PT-INR, 1.6-2.6) in both patient groups. In this EMR-based clinical study, patients who switched to DOACs had both poor or inadequate PT-INR control and higher risk factors of stroke. Many patients receiving warfarin did not achieve sufficient PT-INR therapeutic range. DOACs could be recommended in Japanese patients with NVAF with inadequate PT-INR control and increased risk of stroke. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Algorithms for monitoring warfarin use: Results from Delphi Method.

PubMed

Kano, Eunice Kazue; Borges, Jessica Bassani; Scomparini, Erika Burim; Curi, Ana Paula; Ribeiro, Eliane

2017-10-01

Warfarin stands as the most prescribed oral anticoagulant. New oral anticoagulants have been approved recently; however, their use is limited and the reversibility techniques of the anticoagulation effect are little known. Thus, our study's purpose was to develop algorithms for therapeutic monitoring of patients taking warfarin based on the opinion of physicians who prescribe this medicine in their clinical practice. The development of the algorithm was performed in two stages, namely: (i) literature review and (ii) algorithm evaluation by physicians using a Delphi Method. Based on the articles analyzed, two algorithms were developed: "Recommendations for the use of warfarin in anticoagulation therapy" and "Recommendations for the use of warfarin in anticoagulation therapy: dose adjustment and bleeding control." Later, these algorithms were analyzed by 19 medical doctors that responded to the invitation and agreed to participate in the study. Of these, 16 responded to the first round, 11 to the second and eight to the third round. A 70% consensus or higher was reached for most issues and at least 50% for six questions. We were able to develop algorithms to monitor the use of warfarin by physicians using a Delphi Method. The proposed method is inexpensive and involves the participation of specialists, and it has proved adequate for the intended purpose. Further studies are needed to validate these algorithms, enabling them to be used in clinical practice.

Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach.

PubMed

Martín-Pérez, Mar; Gaist, David; de Abajo, Francisco J; Rodríguez, Luis A García

2018-03-01

 To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels.  Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 ( N  = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t -test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2-3).  Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of -0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%).  Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users. Schattauer GmbH Stuttgart.

Transcranial Duplex Sonography Predicts Outcome following an Intracerebral Hemorrhage.

PubMed

Camps-Renom, P; Méndez, J; Granell, E; Casoni, F; Prats-Sánchez, L; Martínez-Domeño, A; Guisado-Alonso, D; Martí-Fàbregas, J; Delgado-Mederos, R

2017-08-01

Several radiologic features such as hematoma volume are related to poor outcome following an intracerebral hemorrhage and can be measured with transcranial duplex sonography. We sought to determine the prognostic value of transcranial duplex sonography in patients with intracerebral hemorrhage. We conducted a prospective study of patients diagnosed with spontaneous intracerebral hemorrhage. Transcranial duplex sonography examinations were performed within 2 hours of baseline CT, and we recorded the following variables: hematoma volume, midline shift, third ventricle and lateral ventricle diameters, and the pulsatility index in both MCAs. We correlated these data with the CT scans and assessed the prognostic value of the transcranial duplex sonography measurements. We assessed early neurologic deterioration during hospitalization and mortality at 1-month follow-up. We included 35 patients with a mean age of 72.2 ± 12.8 years. Median baseline hematoma volume was 9.85 mL (interquartile range, 2.74-68.29 mL). We found good agreement and excellent correlation between transcranial duplex sonography and CT when measuring hematoma volume ( r = 0.791; P < .001) and midline shift ( r = 0.827; P < .001). The logistic regression analysis with transcranial duplex sonography measurements showed that hematoma volume was an independent predictor of early neurologic deterioration (OR, 1.078; 95% CI, 1.023-1.135) and mortality (OR, 1.089; 95% CI, 1.020-1.160). A second regression analysis with CT variables also demonstrated that hematoma volume was associated with early neurologic deterioration and mortality. When we compared the rating operation curves of both models, their predictive power was similar. Transcranial duplex sonography showed an excellent correlation with CT in assessing hematoma volume and midline shift in patients with intracerebral hemorrhage. Hematoma volume measured with transcranial duplex sonography was an independent predictor of poor outcome. © 2017 by

Serious Bleeding Events due to Warfarin and Antibiotic Co-prescription In a Cohort of Veterans

PubMed Central

Lane, Michael A.; Zeringue, Angelique; McDonald, Jay R.

2014-01-01

Background Antibiotics may interact with warfarin, increasing the risk for significant bleeding events. Methods Retrospective cohort study of veterans prescribed warfarin for ≥ 30 days without interruption through the VA between October 1, 2002 and September 1, 2008. Antibiotics considered to be high-risk for interaction with warfarin include: trimethoprim/sulfamethoxazole (TMP/SMX), ciprofloxacin, levofloxacin, metronidazole, fluiconazole, azithromycin, and clarithromycin. Low-risk antibiotics include: clindamycin and cephalexin. Risk of bleeding event within 30 days of antibiotic exposure was measured using Cox proportional hazards regression, adjusted for demographic characteristics, comorbid conditions and receipt of other medications interacting with warfarin. Results A total of 22,272 patients met inclusion criteria with 14,078 and 8,194 receiving high- and low-risk antibiotics, respectively. There were 93 and 36 bleeding events in the high- and low-risk groups, respectively. Receipt of a high-risk antibiotic (HR 1.48, 95% CI 1.00-2.19) and azithromycin (HR 1.93, 95% CI 1.13-3.30) were associated with increased risk of bleeding as a primary diagnosis. TMP/SMX (HR 2.09, 95% CI 1.45-3.02), ciprofloxacin (HR 1.87, 95% CI 1.42-2.50), levofloxacin (HR 1.77, 95% CI 1.22-2.50), azithromycin (HR 1.64, 95% CI 1.16-2.33), and clarithromycin (HR 2.40, 95% CI 1.16-4.94) were associated with serious bleeding as a primary or secondary diagnosis. INR alterations were common; 9.7% of patients prescribed fluconazole had INR value >6. Patients who had INR performed 3-14 days of co-prescription were at a decrease risk of serious bleeding (HR 0.61, 95% CI 0.42-0.88). Conclusions Warfarin users who are prescribed high-risk antibiotics are at higher risk for serious bleeding events. Early INR evaluation may mitigate this risk. PMID:24657899

Concurrent Hand and Penile Gangrene following Prolonged Warfarin Use; a Case Report

PubMed Central

Mahdizadeh, Fatemeh; Safari, Saeed

2017-01-01

Warfarin induced skin necrosis (WISN) is a rare but important side effect of warfarin. Early diagnosis may lessen the amount of permanent tissue damage and can prevent progression to full thickness skin necrosis. So, physicians should be aware of such a complication. Screening for protein C or S or anti-thrombin deficiencies, or presence of anti-phospholipid antibodies before beginning warfarin therapy, could be helpful to avoid high levels of international normalized ratio (INR). Here, we report a 54-year-old man who presented to the emergency department with acral and penile gangrene following prolonged use of warfarin. PMID:29201953

Concurrent Hand and Penile Gangrene following Prolonged Warfarin Use; a Case Report.

PubMed

Mahdizadeh, Fatemeh; Safari, Saeed

2017-01-01

Warfarin induced skin necrosis (WISN) is a rare but important side effect of warfarin. Early diagnosis may lessen the amount of permanent tissue damage and can prevent progression to full thickness skin necrosis. So, physicians should be aware of such a complication. Screening for protein C or S or anti-thrombin deficiencies, or presence of anti-phospholipid antibodies before beginning warfarin therapy, could be helpful to avoid high levels of international normalized ratio (INR). Here, we report a 54-year-old man who presented to the emergency department with acral and penile gangrene following prolonged use of warfarin.

Lack of a meaningful effect of anacetrapib on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

PubMed Central

Krishna, Rajesh; Stypinski, Daria; Ali, Melissa; Garg, Amit; Cote, Josee; Maes, Andrea; DeGroot, Bruce; Liu, Yang; Li, Susie; Connolly, Sandra M; Wagner, John A; Stoch, S Aubrey

2012-01-01

AIM Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted. METHODS In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 × 10 mg CoumadinTM) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of anacetrapib (1 × 100 mg) beginning on day −14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 × 10 mg) on day 1. All anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied. RESULTS Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC(0–∞) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(−) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin Cmax were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(−) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC(0–168 h) was 0.93 (0.89, 0.96). CONCLUSION The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not

Combined low-dose aspirin and warfarin anticoagulant therapy of postoperative atrial fibrillation following mechanical heart valve replacement.

PubMed

Wang, Jian-tang; Dong, Ming-feng; Song, Guang-min; Ma, Zeng-shan; Ma, Sheng-jun

2014-12-01

The safety and efficacy of combined low dose aspirin and warfarin therapy in patients with atrial fibrillation after mechanical heart valve replacement were evaluated. A total of 1016 patients (620 females, mean age of 36.8±7.7 years) admitted for cardiac valve replacement and complicated with atrial fibrillation after surgery were randomly divided into study (warfarin plus 75-100 mg aspirin) or control (warfarin only) groups. International normalized ratio (INR) and prothrombin time were maintained at 1.8-2.5 and 1.5-2.0 times the normal values, respectively. Thromboembolic events and major bleedings were registered during the follow-up period. Patients were followed up for 24±9 months. The average dose of warfarin in the study and control groups was 2.91±0.83 mg and 2.88±0.76 mg, respectively (P>0.05). The incidence of overall thromboembolic events in study group was lower than that in control group (2.16% vs. 4.35%, P=0.049). No statistically significant differences were found in hemorrhage events (3.53% vs. 3.95%, P=0.722) or mortality (0.20% vs. 0.40%, P=0.559) between the two groups. Combined low dose aspirin and warfarin therapy in the patients with atrial fibrillation following mechanical heart valve replacement significantly decreased thromboembolic events as compared with warfarin therapy alone. This combined treatment was not associated with an increase in the risk of major bleeding or mortality.

The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors.

PubMed

Lane, Steven; Al-Zubiedi, Sameh; Hatch, Ellen; Matthews, Ivan; Jorgensen, Andrea L; Deloukas, Panos; Daly, Ann K; Park, B Kevin; Aarons, Leon; Ogungbenro, Kayode; Kamali, Farhad; Hughes, Dyfrig; Pirmohamed, Munir

2012-01-01

Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet. To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy. Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability. Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h⁻¹ (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h⁻¹ (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19

Bleeding risk of apixaban, dabigatran, and low-dose rivaroxaban compared with warfarin in Japanese patients with non-valvular atrial fibrillation: a propensity matched analysis of administrative claims data.

PubMed

Kohsaka, Shun; Murata, Tatsunori; Izumi, Naoko; Katada, Jun; Wang, Feng; Terayama, Yasuo

2017-11-01

There is scarce evidence comparing novel oral anticoagulants (NOACs) with warfarin in real-world settings in Japan. This study compared the risk of bleeding events among patients with non-valvular atrial fibrillation (NVAF) initiating treatment with NOACs versus warfarin. A retrospective cohort study was conducted using a de-identified electronic health record based database of health claims and Diagnosis Procedure Combination data from 275 consenting hospitals in Japan. NVAF patients newly initiated on oral anticoagulants were eligible. Based on the first prescription, patients were assigned to 5/2.5 mg BID apixaban, 150/110 mg BID dabigatran, 15/10 mg QD rivaroxaban (approved dose lower in Japan compared to Western countries [20/15 mg QD]) or warfarin groups. One-to-one propensity score matching (PSM) was used to balance patient characteristics between warfarin and each NOAC. Patients were followed up to 1 year post-first prescription. Among 38,662 eligible patients, a total of 5977, 5090, and 6726 matched pairs were identified for warfarin versus apixaban, warfarin versus dabigatran, and warfarin versus rivaroxaban, respectively after PSM. Compared to warfarin, apixaban (hazard ratio [HR] 0.586; 95% CI 0.421-0.815), dabigatran (HR 0.617; 0.425-0.895) and rivaroxaban (HR 0.693; 0.514-0.933) were associated with a significantly lower risk of major bleeding. The risk of any bleeding was significantly lower for apixaban (HR 0.782; 0.682-0.896), but not for dabigatran (HR 0.988; 0.860-1.135) or rivaroxaban (HR 0.938; 0.832-1.057) when comparing to warfarin. Among Japanese patients with NVAF, treatment with apixaban 5/2.5 mg BID was associated with a significantly lower risk of major bleeding and any bleeding when compared to warfarin. Treatment with dabigatran 150/110 mg BID or rivaroxaban 15/10 mg QD was associated with a significantly lower risk of major bleeding, but not any bleeding, than warfarin. The potential benefit of individual NOACs in real

Subarachnoid and Intracerebral Hemorrhage in Patients with Churg-Strauss Syndrome: Two Case Reports

PubMed Central

Go, Myeong Hoon; Park, Jeong Un; Kang, Jae Gyu

2012-01-01

Churg-Strauss syndrome (CSS) is a systemic necrotizing vasculitis of the small and medium vessels, associated with extravascular eosinophilic granulomas, peripheral eosinophilia, and asthma. The exact etiology of CSS is unknown. This syndrome commonly affects the lungs, peripheral nerves, skin, heart, and gastrointestinal tract, but rarely the central nervous system. Subarachnoid and intracerebral hemorrhage in CSS patients is extremely rare; however, clinicians should consider that CSS may be a cause of intracranial hemorrhage and its high rate of mortality and morbidity. The authors report on two cases of subarachnoid and intracerebral hemorrhage with CSS and discuss a brief review of CSS. PMID:23210058

Warfarin or aspirin in embolism prevention in patients with mitral valvulopathy and atrial fibrillation.

PubMed

Lavitola, Paulo de Lara; Sampaio, Roney Orismar; Oliveira, Walter Amorim de; Bôer, Berta Napchan; Tarasoutchi, Flavio; Spina, Guilherme Sobreira; Grinberg, Max

2010-12-01

Atrial fibrillation (AF) associated to rheumatic mitral valve disease (RMVD) increases the incidence of thromboembolism (TE), with warfarin being the standard therapy, in spite of difficulties in treatment adherence and therapeutic control. To compare the effectiveness of Aspirin vs Warfarin in TE prevention in patients with AF and RMVD. A total of 229 patients (pts) with AF and RMVD were followed in a prospective and randomized study. The first group consisted of 110 pts receiving Aspirin - 200 mg/day (Group Aspirin - GA) and the second group consisted of 119 pts receiving Warfarin at individually-adjusted doses (Group Warfarin - GW). There were 15 embolic events in GA and 24 in GW (p = 0.187), of which 21 presented INR < 2.0. Thus, after excluding patients with inadequate INR, there was a higher number of embolic events in GA than in GW (15 vs 3) (p < 0.0061). The GW showed lower treatment adherence (p = 0.001). Neither group presented episodes of major bleeding. Small bleeding episodes were more frequent in the GW (p < 0.01). Increased serum levels of cholesterol and triglycerides constituted a risk factor for a higher number of thromboembolic events in the studied population, with no difference between the groups. In patients presenting RMVD with AF for less than a year and no previous embolism, Aspirin is little effective in preventing TE. Patients with lower-risk mitral valvulopathy (mitral regurgitation and mitral biological prosthesis), especially in cases presenting contraindication to or low adherence to Warfarin, Aspirin use can present some benefit in TE prevention.

Renal function in atrial fibrillation patients switched from warfarin to a direct oral anticoagulant.

PubMed

Minhas, Anum S; Jiang, Qingmei; Gu, Xiaokui; Haymart, Brian; Kline-Rogers, Eva; Almany, Steve; Kozlowski, Jay; Krol, Gregory D; Kaatz, Scott; Froehlich, James B; Barnes, Geoffrey D

2016-11-01

All available direct oral anticoagulants (DOACs) are at least partially eliminated by the kidneys. These agents are increasingly being used as alternatives to warfarin for stroke prevention in patients with atrial fibrillation. The aim of this study was to identify changes in renal function and associated DOAC dosing implications in a multicenter cohort of atrial fibrillation patients switched from warfarin to DOAC treatment. We included all patients in the Michigan Anticoagulation Quality Improvement Initiative cohort who switched from warfarin to a DOAC with atrial fibrillation as their anticoagulant indication between 2009 and 2014, and who had at least two creatinine values. Compliance with FDA-recommended dosing based on renal function was assessed. Of the 189 patients switched from warfarin to a DOAC, 34 (18.0 %) had a baseline creatinine clearance <50 mL/min and 23 (12.2 %) experienced important fluctuations in renal function. Of these 23 patients, 6 (26.1 %) should have impacted the DOAC dosing, but only 1 patient actually received an appropriate dose adjustment. Additionally, 15 (7.9 %) of patients on DOACs had a dose change performed, but only one patient demonstrated a change in renal function to justify the dose adjustment. Most atrial fibrillation patients who switched from warfarin to a DOAC had stable renal function. However, the majority of patients who had a change in renal function did not receive the indicated dose change. As the use of DOACs expands, monitoring of renal function and appropriate dose adjustments are critical.

Comparative effectiveness of rivaroxaban versus warfarin or dabigatran for the treatment of patients with non-valvular atrial fibrillation.

PubMed

Norby, Faye L; Bengtson, Lindsay G S; Lutsey, Pamela L; Chen, Lin Y; MacLehose, Richard F; Chamberlain, Alanna M; Rapson, Ian; Alonso, Alvaro

2017-09-06

Rivaroxaban is an oral anticoagulant approved in the US for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). We determined the effectiveness and associated risks of rivaroxaban versus other oral anticoagulants in a large real-world population. We selected NVAF patients initiating oral anticoagulant use in 2010-2014 enrolled in MarketScan databases. Rivaroxaban users were matched with warfarin and dabigatran users by age, sex, enrolment date, anticoagulant initiation date, and high-dimensional propensity score. Study endpoints, including ischemic stroke, intracranial bleeding (ICB), myocardial infarction (MI), and gastrointestinal (GI) bleeding, were identified from inpatient diagnostic codes. Multivariable Cox models were used to assess associations between type of anticoagulant and outcomes. The analysis included 44,340 rivaroxaban users matched to 89,400 warfarin and 16,957 dabigatran users (38% female, mean age 70) with 12 months of mean follow-up. Anticoagulant-naïve rivaroxaban initiators, but not those switching from warfarin, had lower risk of ischemic stroke [hazard ratio (HR) (95% confidence interval (CI)): 0.75 (0.62, 0.91)] and ICB [HR (95%CI): 0.55, (0.39, 0.78)] than warfarin users. In contrast, anticoagulant-experienced rivaroxaban initiators had higher risk of GI bleeding than warfarin users [HR (95%CI): 1.55 (1.32, 1.83)]. Endpoint rates were similar when comparing anticoagulant-naïve rivaroxaban and dabigatran initiators, with the exception of higher GI bleeding risk in rivaroxaban users [HR (95%CI) 1.28 (1.06, 1.54)]. There were no significant differences in the risk of MI among the comparison groups. In this large real-world sample of NVAF patients, effectiveness and risks of rivaroxaban versus warfarin differed by prior anticoagulant status, while effectiveness of rivaroxaban versus dabigatran differed in GI bleeding risk.

Comparison of Nine Statistical Model Based Warfarin Pharmacogenetic Dosing Algorithms Using the Racially Diverse International Warfarin Pharmacogenetic Consortium Cohort Database

PubMed Central

Liu, Rong; Li, Xi; Zhang, Wei; Zhou, Hong-Hao

2015-01-01

Objective Multiple linear regression (MLR) and machine learning techniques in pharmacogenetic algorithm-based warfarin dosing have been reported. However, performances of these algorithms in racially diverse group have never been objectively evaluated and compared. In this literature-based study, we compared the performances of eight machine learning techniques with those of MLR in a large, racially-diverse cohort. Methods MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied in warfarin dose algorithms in a cohort from the International Warfarin Pharmacogenetics Consortium database. Covariates obtained by stepwise regression from 80% of randomly selected patients were used to develop algorithms. To compare the performances of these algorithms, the mean percentage of patients whose predicted dose fell within 20% of the actual dose (mean percentage within 20%) and the mean absolute error (MAE) were calculated in the remaining 20% of patients. The performances of these techniques in different races, as well as the dose ranges of therapeutic warfarin were compared. Robust results were obtained after 100 rounds of resampling. Results BART, MARS and SVR were statistically indistinguishable and significantly out performed all the other approaches in the whole cohort (MAE: 8.84–8.96 mg/week, mean percentage within 20%: 45.88%–46.35%). In the White population, MARS and BART showed higher mean percentage within 20% and lower mean MAE than those of MLR (all p values < 0.05). In the Asian population, SVR, BART, MARS and LAR performed the same as MLR. MLR and LAR optimally performed among the Black population. When patients were grouped in terms of warfarin dose range, all machine learning techniques except ANN and LAR showed significantly

[The randomized study of efficiency and safety of antithrombotic therapy in nonvalvular atrial fibrillation: warfarin compared with aspirin].

PubMed

Hu, Da-yi; Zhang, He-ping; Sun, Yi-hong; Jiang, Li-qing

2006-04-01

To investigate whether warfarin is more effective and superior to aspirin for the prevention of thromboembolism in nonvalvular atrial fibrillation in Chinese. In a multicenter randomized trial, the patients diagnosed as nonvalvular atrial fibrillation were randomized to receive aspirin 150 mg - 160 mg once daily or adjusted-dose warfarin (international normalized ratio, 2.0 - 3.0). We compared the effect of the two therapy on the primary end point of ischemic stroke or death from any cause and on the combined end-point (stroke, death, peripheral arteries embolism, TIA, acute myocardial infarction, serious bleeding) during a median follow-up period of 19 months. Of the 704 patients, 420 (59.7%) were male. The average patient age was (63.3 +/- 9.9) years. The median follow-up period is 19 months. The mean dose of warfarin was (3.2 +/- 0.7) mg. Compared with aspirin, the primary end point of death or ischemic stroke was reduced by warfarin (2.7% vs 6.0%, P = 0.03, OR 0.44, 95% CI 0.198 - 0.960) and the relative risk decreased by 56%. The thromboembolism event in the aspirin group was significantly higher than that in warfarin group (10.6% vs 5.4%, P = 0.01, OR 0.48, 95% CI 0.269 - 0.858). There was no significant differences of the mortality rate between the two groups (1.2% vs 2.2%, P > 0.05). The secondary end point was nonsignificantly reduced in warfarin group than that in aspirin group, while the combined end point is statistically decreased by adjusted-dose warfarin (8.4% vs 13.0%, P = 0.047). Warfarin treatment was associated with increased bleeding rate compared to aspirin (6.9% vs 2.4%, P < 0.05), although the major bleeding rate is rather low (1.5%). All the major bleeding events occurred with INR above 3.0. Randomized control study demonstrated that anticoagulation with adjusted-dosed warfarin (INR 2.0 - 3.0) can significantly reduced the risk of thromboembolism event with slightly increased hemorrhage, compared to aspirin in Chinese population. Under

Effects of folic acid supplementation on the pharmacokinetics and anticoagulant effect of warfarin: an open-label, prospective study of long-term administration in adults.

PubMed

Muszkat, Mordechai; Bialer, Omer; Blotnick, Simcha; Adar, Liat; Xie, Hong-Guang; Ufer, Mike; Cascorbi, Ingolf; Caraco, Yoseph

2010-02-01

Folic acid supplementation in patients with folic acid deficiency has been associated with increased clearance of phenytoin to its cytochrome P450 (CYP) 2C9-mediated metabolite, 5-(4'-hydroxyphenyl)-5-phenylhydantoin. The aim of this study was to determine whether folic acid supplementation increases the dosage requirement of the CYP2C9 substrate warfarin, and the formation clearance of the CYP2C9-mediated product, (S)-7-hydroxywarfarin. Patients aged >or=18 years with folic acid deficiency who were receiving long-term treatment with a stable dosage of warfarin were studied prospectively, before and 30 to 60 days after the initiation of supplementation with folic acid. Warfarin dosage and international normalized ratio (INR) were documented, and the formation clearance of (S)- and (R)-7-hydroxywarfarin and the oral clearance of (S)- and (R)-warfarin were determined. Twenty-four white patients (14 males; mean (SD) age, 55.0 [19.7] years; body mass index, 30.64 [6.8] kg/m(2)) were enrolled. Treatment with folic acid was associated with a significantly increased mean (SD) formation clearance of (S)-7-hydroxywarfarin (1.096 [0.816] vs 1.608 [1.302] mL/min; P = 0.048). Before folic acid supplementation, the mean (SD) warfarin dosage was 5.98 (2.12) mg/d, and the INR was 2.51 (0.55). During supplementation, the warfarin dosage was 6.17 (2.31) mg/d and the INR was 2.63 (0.65) (both, P = NS vs before supplementation). Folic acid supplementation was associated with significantly increased formation clearance of (S)-7-hydroxywarfarin. Changes in warfarin dosage requirements and INR were nonsignificant. Copyright 2010. Published by EM Inc USA.

Monotherapy of aspirin or warfarin for prevention of ischemic stroke in low-risk atrial fibrillation: A Easter Asian population-based study.

PubMed

Liu, Chieh-Yu; Chen, Hui-Chun

2018-05-02

This study aimed to investigate the effectiveness of monotherapy aspirin and warfarin for stroke prevention in low-risk atrial fibrillation (AF) by using a population-based cohort study in Taiwan. A newly diagnosed low-risk AF patient cohort were identified by using National Health Insurance Research Database (NHIRD) in Taiwan in 2008. The study cohort was observed with a follow-up of 2 years to examine the onset of ischemic stroke (IS) (to 2010). The longitudinal data were analyzed by using generalized estimation equations (GEE). A total of 8,065 newly-diagnosed low-risk AF patients were identified in 2008. 7.4% were prescribed with aspirin and 4.6% were prescribed with warfarin. The GEE results showed that low-risk AF patients with hypertension who received warfarin were associated with a statistically significant 58.4% reduction of IS risk (OR = 0.416, p = 0.024, 95% CI 0.194-0.891). Additionally, low-risk AF patients with hyperlipidemia who received warfarin were associated with a 69.3% reduction of IS risk (OR = 0.307, p = 0.044, 95% CI 0.097-0.969). Warfarin is suggested to be prescribed in preventing ischemic stroke for low-stroke-risk atrial fibrillation patients with hypertension and hyperlipidemia.

Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic-Americans and African-Americans.

PubMed

Bress, Adam; Patel, Shitalben R; Perera, Minoli A; Campbell, Richard T; Kittles, Rick A; Cavallari, Larisa H

2012-12-01

The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. The following were assessed in a cohort of 260 African-Americans and 53 Hispanic-Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs 0.18; p < 0.05) allele frequencies were higher in Hispanic-Americans compared with African-Americans. Multiple regression analysis in the Hispanic-American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African-Americans after adjusting for known genetic and clinical predictors. In our cohort of inner-city Hispanic-Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic-Americans.

Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic–Americans and African–Americans

PubMed Central

Bress, Adam; Patel, Shitalben R; Perera, Minoli A; Campbell, Richard T; Kittles, Rick A; Cavallari, Larisa H

2013-01-01

Aim The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. Patients & methods The following were assessed in a cohort of 260 African–Americans and 53 Hispanic–Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Results Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs. 0.18; p < 0.05) allele frequencies were higher in Hispanic–Americans compared with African–Americans. Multiple regression analysis in the Hispanic–American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African–Americans after adjusting for known genetic and clinical predictors. Conclusion In our cohort of inner-city Hispanic–Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic–Americans. PMID:23215885

Oral warfarin affects peripheral blood leukocyte IL-6 and TNFα production in rats.

PubMed

Popov, Aleksandra; Belij, Sandra; Subota, Vesna; Zolotarevski, Lidija; Mirkov, Ivana; Kataranovski, Dragan; Kataranovski, Milena

2013-01-01

Warfarin is a Vitamin K (VK) antagonist that affects Vitamin K-dependent (VKD) processes, including blood coagulation, as well as processes unrelated to hemostasis such as bone growth, calcification, and growth of some cell types. In addition, warfarin exerts influence on some non-VKD-related activities, including anti-tumor and immunomodulating activity. With respect to the latter, both immune stimulating and suppressive effects have been noted in different experimental systems. To explore the in vivo immunomodulatory potential of warfarin on one type of activity (i.e., cytokine production) in two different immune cell populations (i.e., mononuclear or polymorphonuclear cells), effects of subchronic oral warfarin intake in rats on pro-inflammatory cytokine (i.e., TNFα, IL-6) production by peripheral blood mononuclear and polymorphonuclear cells (granulocytes) was examined. Differential effects of warfarin intake on TNFα and IL-6 were noted, depending on the type of peripheral blood leukocytes and on the cytokine examined. Specifically, a lack of effect on TNFα and a priming of IL-6 production by mononuclear cells along with a decrease in TNFα and a lack of effect on IL-6 in polymorphonuclear cells were seen in warfarin-exposed hosts. The cell- and cytokine-dependent effects from subchronic oral warfarin intake on peripheral blood leukocytes demonstrated in this study could, possibly, differentially affect reactions mediated by these cells. Ultimately, the observed effects in rats might have implications for those humans who are on long-term/prolonged warfarin therapy.

Genetics Home Reference: warfarin sensitivity

MedlinePlus

... it thins the blood, preventing blood clots from forming . Warfarin is often prescribed to prevent blood clots ... much drug to prevent clots because their clot forming process is already slower than average and can ...

The future of warfarin pharmacogenetics in under-represented minority groups

PubMed Central

Cavallari, Larisa H; Perera, Minoli A

2012-01-01

Genotype-based dosing recommendations are provided in the US FDA-approved warfarin labeling. However, data that informed these recommendations were from predominately Caucasian populations. Studies show that variants contributing to warfarin dose requirements in Caucasians provide similar contributions to dose requirements in US Hispanics, but significantly lesser contributions in African–Americans. Further data demonstrate that variants occurring commonly in individuals of African ancestry, but rarely in other racial groups, significantly influence dose requirements in African–Americans. These data suggest that it is important to consider variants specific for African–Americans when implementing genotype-guided warfarin dosing in this population. PMID:22871196

Acquired absolute vitamin K deficiency in a patient undergoing warfarin therapy.

PubMed

Takada, Hiroaki; Toru, Hifumi; Bunya, Naofumi; Kiriu, Nobuaki; Kato, Hiroshi; Koido, Yuichi; Yasuhiro, Kuroda

2014-06-01

We report a case of absolute vitamin K deficiency (VKD) diagnosed by measuring serum VK levels in an elderly woman undergoing warfarin therapy. A 78-year-old woman was admitted to our hospital because of dyspnea and sore throat diagnosed as pharyngitis 1 week before admission. On admission, the sore throat had exacerbated and dyspnea developed. She had history of atrial fibrillation, for which warfarin 1.5 mg/d was started approximately 10 years prior and her international normalized ratio (INR) had been maintained at an acceptable therapeutic level. Blood results revealed unmeasurable INR and abnormally prolonged activated partial thromboplastin time (APTT). She was diagnosed with adenoiditis and warfarin-related coagulopathy and administered intravenous VK (20 mg) and fresh frozen plasma (FFP; 4 U), which improved INR and APTT. Since the coagulopathy responded to intravenous VK administration, the patient was clinically diagnosed with warfarin-related relative VKD. Approximately 1 month later, she returned with complaints of sore throat. Blood results indicated abnormal INR (7.22) and APTT (N80.0 s). She was diagnosed with recurrent adenoiditis and VK deficient coagulopathy. The patient’s serum VK levels were low (VK1 level, 0.13 ng/mL; VK2 levels, 0.85 ng/mL). Initial treatment of VK (20 mg) and FFP followed by intravenous VK (20 mg/d) for 6 days, her symptoms dissipated. Warfarin was suspected to have caused absolute VKD. Severe coagulopathy in patients undergoing warfarin therapy is primarily caused by, relative VKD. However, the possibility of warfarin-related absolute VKD should be suspected when INRis not sufficiently improved by intravenous VK administration.

Development of Novel Warfarin-Silica Composite for Controlled Drug Release.

PubMed

Parfenyuk, Elena V; Dolinina, Ekaterina S

2017-04-01

The work is devoted to synthesis and study of warfarin composites with unmodified, methyl and phenyl modified silica in order to develop controlled release formulation of the anticoagulant. The composites were prepared by two routes, adsorption and sol-gel, and characterized with FTIR spectroscopy, dynamic light scattering and DSC methods. The drug release behavior from the composites in media with pH 1.6, 6.8 and 7.4 was analyzed in vitro. The release kinetics of the warfarin - silica composites prepared by the two routes was compared among each other and with analogous silica composites with water soluble drug molsidomine. The comparative analysis showed that in general the kinetic regularities and mechanisms of release for both drugs are similar and determined by nonuniform distribution of the drugs over the silica matrixes and stability of the matrixes in the studied media for the adsorbed composites and uniformly distributed drug and more brittle structure for the sol-gel composites. The sol-gel composite of warfarin - phenyl modified silica is perspective for further development of novel warfarin formulation with controlled release because it releases warfarin according to zero-order kinetic law with approximately equal rate in the media imitating different segments of gastrointestinal tract.

Does chronic warfarin cause increased blood loss and transfusion during lumbar spinal surgery?

PubMed

Young, Ernest Y; Ahmadinia, Kasra; Bajwa, Navkirat; Ahn, Nicholas U

2013-10-01

The use of oral anticoagulation therapy such as warfarin is projected to increase significantly as the population ages and the prevalence of cardiovascular disease increases. Current recommendations state that warfarin be discontinued before surgery and the international normalized ratio (INR) normalized. To determine if stopping warfarin 7 days before surgery and correcting INR had any effect on intraoperative blood loss or the requirements for blood product transfusion. This was a retrospective cohort study in a high-volume tertiary care center. Sample comprised 263 consecutive patients who underwent elective lumbar spinal surgery. The outcome measures were intraoperative blood loss, intraoperative blood transfusion, postoperative blood transfusion, and the number of blood products transfused. The records of patients undergoing elective spinal surgery were analyzed for patient demographic data, comorbidities, coagulation panel laboratory findings, operative characteristics, blood loss, and blood transfusion requirements. These included patients undergoing full laminectomies with or without posterolateral fusion and instrumentation. Patients on warfarin were analyzed for the mean dosage of warfarin and underlying pathology that required anticoagulation. All patients on warfarin had their anticoagulation therapy stopped 7 days before surgery and their INR checked preoperatively to confirm normalization. Both univariate and multiple linear regression analyses were performed. The patients on warfarin had a mean intraoperative blood loss of 839 mL compared with 441 mL for patients not on warfarin (p<.01). Multiple regression analysis determined that warfarin and number of spinal levels decompressed/fused/instrumented were predictors for increased blood loss (R(2)=0.37). Patients on warfarin also had increased postoperative blood transfusions (23.1% compared with 7.4%, p=.04). There was no significant difference between groups in terms of intraoperative blood

Cost-effectiveness of apixaban vs. current standard of care for stroke prevention in patients with atrial fibrillation

PubMed Central

Dorian, Paul; Kongnakorn, Thitima; Phatak, Hemant; Rublee, Dale A.; Kuznik, Andreas; Lanitis, Tereza; Liu, Larry Z.; Iloeje, Uchenna; Hernandez, Luis; Lip, Gregory Y.H.

2014-01-01

Aims Warfarin, a vitamin K antagonist (VKA), has been the standard of care for stroke prevention in patients with atrial fibrillation (AF). Aspirin is recommended for low-risk patients and those unsuitable for warfarin. Apixaban is an oral anticoagulant that has demonstrated better efficacy than warfarin and aspirin in the ARISTOTLE and AVERROES studies, respectively, and causes less bleeding than warfarin. We evaluated the potential cost-effectiveness of apixaban against warfarin and aspirin from the perspective of the UK payer perspective. Results and methods A lifetime Markov model was developed to evaluate the pharmacoeconomic impact of apixaban compared with warfarin and aspirin in VKA suitable and VKA unsuitable patients, respectively. Clinical events considered in the model include ischaemic stroke, haemorrhagic stroke, intracranial haemorrhage, other major bleed, clinically relevant non-major bleed, myocardial infarction, cardiovascular hospitalization and treatment discontinuations; data from the ARISTOTLE and AVERROES trials and published mortality rates and event-related utility rates were used in the model. Apixaban was projected to increase life expectancy and quality-adjusted life years (QALYs) compared with warfarin and aspirin. These gains were expected to be achieved at a drug acquisition-related cost increase over lifetime. The estimated incremental cost-effectiveness ratio was £11 909 and £7196 per QALY gained with apixaban compared with warfarin and aspirin, respectively. Sensitivity analyses indicated that results were robust to a wide range of inputs. Conclusions Based on randomized trial data, apixaban is a cost-effective alternative to warfarin and aspirin, in VKA suitable and VKA unsuitable patients with AF, respectively. PMID:24513791

Immunological abnormalities associated with hereditary haemorrhagic telangiectasia.

PubMed

Guilhem, A; Malcus, C; Clarivet, B; Plauchu, H; Dupuis-Girod, S

2013-10-01

Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder related to mutations in one of the coreceptors to the transforming growth factor-β superfamily (ALK1 or endoglin). Besides the obvious vascular symptoms (epistaxis and arteriovenous malformations), patients have an unexplained high risk of severe bacterial infections. The aim of the study was to assess the main immunological functions of patients with HHT using the standard biological tests for primary immunodeficiencies. A prospective single-centre study of 42 consecutive adult patients with an established diagnosis of HHT was conducted at the National French HHT Reference Center (Lyon). Lymphocyte subpopulations and proliferation capacity, immunoglobulin levels and neutrophil and monocyte phagocytosis, oxidative burst and chemotaxis were assessed. Innate immunity was not altered in patients with HHT. With regard to adaptive immunity, significant changes were seen in immunological parameters: primarily, a lymphopenia in patients with HHT compared with healthy control subjects affecting mean CD4 (642 cells μL(-1) vs. 832 cells μL(-1) , P < 0.001), CD8 (295 cells μL(-1) vs. 501 cells μL(-1) , P < 0.0001) and natural killer (NK) cells (169 cells μL(-1) vs. 221 cells μL(-1) , P < 0.01), associated with increased levels of immunoglobulins G and A. This lymphopenia mainly concerned naïve T cells. Proliferation capacities of lymphocytes were normal. Lymphopenic patients had a higher frequency of iron supplementation but no increase in infection rate. Lower levels of immunoglobulin M and a higher rate of pulmonary arteriovenous malformations were found amongst patients with a history of severe infection. Patients with HHT exhibit immunological abnormalities including T CD4, T CD8 and NK cell lymphopenia and increased levels of immunoglobulins G and A. The observed low level of immunoglobulin M requires further investigation to determine whether it is a specific risk factor for infection in HHT. �

Evaluation of 16 genotype-guided Warfarin Dosing Algorithms in 310 Korean Patients Receiving Warfarin Treatment: Poor Prediction Performance in VKORC1 1173C Carriers.

PubMed

Yang, Mina; Choi, Rihwa; Kim, June Soo; On, Young Keun; Bang, Oh Young; Cho, Hyun-Jung; Lee, Soo-Youn

2016-12-01

The purpose of this study was to evaluate the performance of 16 previously published warfarin dosing algorithms in Korean patients. The 16 algorithms were selected through a literature search and evaluated using a cohort of 310 Korean patients with atrial fibrillation or cerebral infarction who were receiving warfarin therapy. A large interindividual variation (up to 11-fold) in warfarin dose was observed (median, 25 mg/wk; range, 7-77 mg/wk). Estimated dose and actual maintenance dose correlated well overall (r range, 0.52-0.73). Mean absolute error (MAE) of the 16 algorithms ranged from -1.2 to -20.1 mg/wk. The percentage of patients whose estimated dose fell within 20% of the actual dose ranged from 1.0% to 49%. All algorithms showed poor accuracy with increased MAE in a higher dose range. Performance of the dosing algorithms was worse in patients with VKORC1 1173TC or CC than in total (r range, 0.38-0.61 vs 0.52-0.73; MAE range, -2.6 to -28.0 mg/wk vs -1.2 to -20.1 mg/wk). The algorithms had comparable prediction abilities but showed limited accuracy depending on ethnicity, warfarin dose, and VKORC1 genotype. Further studies are needed to develop genotype-guided warfarin dosing algorithms with greater accuracy in the Korean population. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Integrating In Vitro, Modeling, and In Vivo Approaches to Investigate Warfarin Bioequivalence

PubMed Central

Wen, H; Fan, J; Vince, B; Li, T; Gao, W; Kinjo, M; Brown, J; Sun, W; Jiang, W; Lionberger, R

2017-01-01

We demonstrate the use of modeling and simulation to investigate bioequivalence (BE) concerns raised about generic warfarin products. To test the hypothesis that the loss of isopropyl alcohol and slow dissolution in acidic pH has significant impact on the pharmacokinetics of warfarin sodium tablets, we conducted physiologically based pharmacokinetic absorption modeling and simulation using formulation factors or in vitro dissolution profiles as input parameters. Sensitivity analyses indicated that warfarin pharmacokinetics was not sensitive to solubility, particle size, density, or dissolution rate in pH 4.5, but was affected by dissolution rate in pH 6.8 and potency. Virtual BE studies suggested that stressed warfarin sodium tablets with slow dissolution rate in pH 4.5 but having similar dissolution rate in pH 6.8 would be bioequivalent to the unstressed warfarin sodium tablets. A four‐way, crossover, single‐dose BE study in healthy subjects was conducted to test the same hypothesis and confirmed the simulation conclusion. PMID:28379643

Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients.

PubMed

Ramos, Alga S; Seip, Richard L; Rivera-Miranda, Giselle; Felici-Giovanini, Marcos E; Garcia-Berdecia, Rafael; Alejandro-Cowan, Yirelia; Kocherla, Mohan; Cruz, Iadelisse; Feliu, Juan F; Cadilla, Carmen L; Renta, Jessica Y; Gorowski, Krystyna; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

2012-12-01

This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better 'ideal dose' estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R(2) = 51%). Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients.

Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients

PubMed Central

Ramos, Alga S; Seip, Richard L; Rivera-Miranda, Giselle; Felici-Giovanini, Marcos E; Garcia-Berdecia, Rafael; Alejandro-Cowan, Yirelia; Kocherla, Mohan; Cruz, Iadelisse; Feliu, Juan F; Cadilla, Carmen L; Renta, Jessica Y; Gorowski, Krystyna; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

2012-01-01

Aim This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. Patients & methods A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. Results The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better ‘ideal dose’ estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R2 = 51%). Conclusion Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients. PMID:23215886

Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects

PubMed Central

Moore, Kenneth Todd; Byra, William; Vaidyanathan, Seema; Natarajan, Jaya; Ariyawansa, Jay; Salih, Hiba; Turner, Kenneth C

2015-01-01

Aims The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives. Methods An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2–4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0–3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban. Results During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (Emax) for INR after co-administration was 2.79–4.15 (mean PT Emax 41.0–62.7 s), compared with 1.41–1.74 (mean PT Emax 20.1–25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug. Conclusions The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR. PMID:25475601

Genetics Home Reference: warfarin resistance

MedlinePlus

... J, Müller CR, Rost S, Watzka M, Bevans CG. Comparative genetics of warfarin resistance. Hamostaseologie. 2014;34(2): ... in Brazilian patients with thrombosis: a prospective cohort study. Mol Diagn Ther. 2014 Dec;18(6):675- ...

Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose.

PubMed

King, Cristi R; Porche-Sorbet, Rhonda M; Gage, Brian F; Ridker, Paul M; Renaud, Yannick; Phillips, Michael S; Eby, Charles

2008-06-01

Initiation of warfarin therapy is associated with bleeding owing to its narrow therapeutic window and unpredictable therapeutic dose. Pharmacogenetic-based dosing algorithms can improve accuracy of initial warfarin dosing but require rapid genotyping for cytochrome P-450 2C9 (CYP2C9) *2 and *3 single nucleotide polymorphisms (SNPs) and a vitamin K epoxide reductase (VKORC1) SNP. We evaluated 4 commercial systems: INFINITI analyzer (AutoGenomics, Carlsbad, CA), Invader assay (Third Wave Technologies, Madison, WI), Tag-It Mutation Detection assay (Luminex Molecular Diagnostics, formerly Tm Bioscience, Toronto, Canada), and Pyrosequencing (Biotage, Uppsala, Sweden). We genotyped 112 DNA samples and resolved any discrepancies with bidirectional sequencing. The INFINITI analyzer was 100% accurate for all SNPs and required 8 hours. Invader and Tag-It were 100% accurate for CYP2C9 SNPs, 99% accurate for VKORC1 -1639/3673 SNP, and required 3 hours and 8 hours, respectively. Pyrosequencing was 99% accurate for CYP2C9 *2, 100% accurate for CYP2C9 *3, and 100% accurate for VKORC1 and required 4 hours. Current commercial platforms provide accurate and rapid genotypes for pharmacogenetic dosing during initiation of warfarin therapy.

[Clinical applications of dosing algorithm in the predication of warfarin maintenance dose].

PubMed

Huang, Sheng-wen; Xiang, Dao-kang; An, Bang-quan; Li, Gui-fang; Huang, Ling; Wu, Hai-li

2011-12-27

To evaluate the feasibility of clinical application for genetic based dosing algorithm in the predication of warfarin maintenance dose in Chinese population. The clinical data were collected and blood samples harvested from a total of 126 patients undergoing heart valve replacement. The genotypes of VKORC1 and CYP2C9 were determined by melting curve analysis after PCR. They were divided randomly into the study and control groups. In the study group, the first three doses of warfarin were prescribed according to the predicted warfarin maintenance dose while warfarin was initiated at 2.5 mg/d in the control group. The warfarin doses were adjusted according to the measured international normalized ratio (INR) values. And all subjects were followed for 50 days after an initiation of warfarin therapy. At the end of a 50-day follow-up period, the proportions of the patients on a stable dose were 82.4% (42/51) and 62.5% (30/48) for the study and control groups respectively. The mean durations of reaching a stable dose of warfarin were (27.5 ± 1.8) and (34.7 ± 1.8) days and the median durations were (24.0 ± 1.7) and (33.0 ± 4.5) days in the study and control groups respectively. Significant differences existed in the durations of reaching a stable dose between the two groups (P = 0.012). Compared with the control group, the hazard ratio (HR) for the duration of reaching a stable dose was 1.786 in the study group (95%CI 1.088 - 2.875, P = 0.026). The predicted dosing algorithm incorporating genetic and non-genetic factors may shorten the duration of achieving efficiently a stable dose of warfarin. And the present study validates the feasibility of its clinical application.

Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy.

PubMed

Shaw, Kaitlyn; Amstutz, Ursula; Kim, Richard B; Lesko, Lawrence J; Turgeon, Jacques; Michaud, Veronique; Hwang, Soomi; Ito, Shinya; Ross, Colin; Carleton, Bruce C

2015-08-01

To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results? A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus. Testing of VKORC1 (-1639G>A), CYP2C9*2, and CYP2C9*3 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C9*5, *6, *8, or *11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose. This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotype-guided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.

Comparison of Direct Oral Anticoagulants and Warfarin in the Treatment of Deep Venous Thrombosis in the Chronic Phase.

PubMed

Wakakura, Shingo; Hara, Fumihiko; Fujino, Tadashi; Hamai, Asami; Ohara, Hiroshi; Kabuki, Takayuki; Harada, Masahiko; Ikeda, Takanori

2018-01-27

We assessed the efficacy and safety of direct oral anticoagulants (DOACs) for the treatment of deep venous thrombosis (DVT) in the chronic phase through comparison with conventional warfarin therapy.A total of 807 consecutive patients who were diagnosed with having DVT in the chronic phase were included (484 patients to warfarin therapy and 323 patients to DOAC therapy). The condition of leg veins was assessed 3 to 6 months after starting the therapies by ultrasound examination. Major bleeding and mortality during the therapies were followed-up.There was no significant difference between the two groups in the thrombosis improvement rate (DOAC group: 91.2% versus warfarin group: 88.9%). There was no significant difference between the two groups in major bleeding (DOAC group: 1.8% versus warfarin group: 1.8%). In patients with active cancer, the DOAC group had a borderline higher thrombosis improvement rate than the warfarin group (92.1% versus 80.0%, P = 0.05). The proportion of major bleeding in the patients with active cancer was slightly higher in the warfarin group than in the DOAC group (4.3% versus 2.8%; P = 0.71). Active cancer was not an independent risk factor for major bleeding and recurrence in the DOAC group (OR 2.68, 95% CI 0.51-14.1; P = 0.24 and OR 0.65, 95% CI 0.20-2.07; P = 0.47).In treatment using oral anticoagulants for DVT in the chronic phase, DOACs exhibited equal efficacy and safety as warfarin did. Particularly DOACs appear to be an attractive therapeutic option for cancer-associated DVT in chronic phase, with relatively low anticipated rates of recurrence and major bleeding.

Administration of human recombinant activated protein C is not associated with pancreatic parenchymal haemorrhage in L-arginine-induced experimental acute pancreatitis.

PubMed

Jamdar, Saurabh; Babu, Benoy I; Nirmalan, Mahesh; Jeziorska, Maria; McMahon, Raymond F T; Siriwardena, Ajith K

2013-11-10

Microvascular thrombosis is a critical event in severe acute pancreatitis. Human recombinant activated protein C (Xigris®, Eli Lilly, Indianapolis, IN, USA) modulates the interplay between pro-inflammatory and pro-coagulant pathways and maintains microvascular patency. However, the anticoagulant properties of Xigris® may precipitate bleeding from the inflamed pancreas. This study tests the hypothesis that Xigris® can ameliorate experimental acute pancreatitis without causing pancreatic haemorrhage. Sprague Dawley rats were allocated as follows: Group 1: control (n=7); Group 2: acute pancreatitis (n=6); Group 3: administration of Xigris® 500 µg/kg body weight before induction of acute pancreatitis (n=6); and Group 4: Administration of Xigris® 500 µg/kg body weight 30 minutes after induction of acute pancreatitis (n=6). Acute pancreatitis was induced by intraperitoneal administration of L-arginine 300 mg/100 g body weight. Animals were sacrificed at 48 hours and biochemical, haematological, and histological markers of pancreatic haemorrhage and inflammation assessed. Median lipase in animals with acute pancreatitis was 10 U/mL (range: 7-16 U/mL) compared to 5.5 (range: 3-8 U/mL) in controls (P=0.028). Lipase was also elevated in animals given Xigris® both before (12 U/mL, range: 8-22 U/mL; P=0.031 vs. control group) and after (46 U/mL, range: 9-71 U/mL; P=0.015 vs. control group) induction of acute pancreatitis). Haemoglobin levels were similar among all groups (P=0.323). There was no histological evidence of pancreatic haemorrhage in animals treated with Xigris®. Pre-treatment with Xigris® was associated with a significant reduction in pancreatic injury. This effect was absent when Xigris® was administered after induction of acute pancreatitis. Xigris® did not lead to pancreatic haemorrhage in experimental acute pancreatitis. Administration of Xigris® prior to induction of acute pancreatitis was associated with amelioration of injury. This effect was

Haemorrhagic Fevers, Viral

MedlinePlus

... Filoviridae (Ebola and Marburg) and Flaviviridae (yellow fever, dengue, Omsk haemorrhagic fever, Kyasanur forest disease). General information ... the Ebola vaccine trials in Guinea What is dengue and how is it treated? Fact sheets Crimean- ...

Effects of CYP4F2 polymorphism on response to warfarin during induction phase: a prospective, open-label, observational cohort study.

PubMed

Bejarano-Achache, Idit; Levy, Liran; Mlynarsky, Liat; Bialer, Meir; Muszkat, Mordechai; Caraco, Yoseph

2012-04-01

The cytochrome P450 (CYP) 4F2 isozyme has been reported to metabolize vitamin K(1) in vitro, and the V433M polymorphism in the CYP4F2 gene has been associated with reduced vitamin K(1) metabolism and the need for a higher maintenance dosage in patients receiving warfarin. The purpose of the present study was to evaluate the effects of V433M polymorphism on warfarin response during the induction phase. Warfarin-naive white patients in whom warfarin was scheduled to be initiated with a target INR of 2 to 3 were enrolled into the study. On enrollment, a single blood sample for the genotyping of CYP4F2, CYP2C9, and VKORC1 was drawn. The international normalized ratio (INR) was followed daily during induction and twice weekly until stable anticoagulation was reached. The relationships between several markers of warfarin response during induction and CYP4F2 polymorphism were determined. The cohort consisted of 241 patients (115 men; mean [SD] age, 55.2 [19.4] years; weight, 79.5 [18.3] kg). Most of the patients were carriers of the CYP4F2 CC genotype (112 patients) or the CT genotype (104 patients). In carriers of the TT genotype (25 patients), INR >3 was >4-fold lower compared with that in carriers of the CC or CT genotype, suggesting that patients with the TT genotype were less sensitive to warfarin during induction. Also in TT carriers, the extent of excessive anticoagulation was >10-fold lower than in the other carriers. Both of these findings had a nominal P value of <0.05. After adjustment for false discovery rate, none of the findings remained significant at a threshold q value of <0.05. Among CC carriers, the concurrent use of a statin was associated with a 1-mg/d reduction in warfarin maintenance dosage. No similar effect was noted in the CT or TT carriers, suggesting a possible genetic influence on warfarin-statin interaction. These preliminary findings suggest that among white patients treated with warfarin, CYP4F2 polymorphism had a measurable effect on

Gene polymorphisms and the risk of warfarin-induced bleeding complications at therapeutic international normalized ratio (INR)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pourgholi, Leyla

Background: Bleeding episodes commonly occur in patients on warfarin treatment even in those within therapeutic range of international normalized ratio (INR). The objective of this study was to investigate the effects of the 8 examined polymorphisms on the risk of bleeding complications in a sample of Iranian patients. Methods: A total of 552 warfarin treated patients who maintained on a target INR level of 2.0–3.5 for at least three consecutive intervals were enrolled from those attended our anticoagulation clinics. Ninety-two bleeding events were observed in 87 patients. The presences of the examined polymorphisms were analyzed using polymerase chain reaction-based restrictionmore » fragment length polymorphism (PCR-RFLP). Results: Patients with the T allele in NQO1*2 (CT or TT genotypes) had a higher risk of bleeding than patients with the CC genotype (adjusted OR: 2.25, 95% CI: 1.37 to 3.70, P = 0.001). Those who were carriers of CYP2C9 one-variant haplotypes (*1/*2 or *1/*3) were also found to be associated with the higher risk of bleeding events. Compared to reference group (*1/*1), the odds of bleeding increased for carriers of one variant allele (*1/*2 or *1/*3) (adjusted OR: 1.75, 95% CI: 1.03 to 2.97, P = 0.039). Variant VKORC1, Factor VII, and EPHX1 genotypes were not significantly associated with the risk of bleeding events. Conclusion: The SNP C609T within NQO1 and haplotypes of CYP2C9 (1*2 or 1*3) are independently associated to bleeding complications of warfarin at normal INR. Further studies are required to confirm such associations in diverse racial and ethnic populations. - Highlights: • NQO1 C609T variant is associated with warfarin induced bleeding at therapeutic INR. • Haplotypes of CYP2C9 (1*2 or 1*3) are also associated with bleeding events. • VKORC1, Factor VII, and EPHX1 genotypes were not associated with bleeding risk.« less

Patients' perspectives on taking warfarin: qualitative study in family practice

PubMed Central

Dantas, Guilherme Coelho; Thompson, Barbara V; Manson, Judith A; Tracy, C Shawn; Upshur, Ross EG

2004-01-01

Background Despite the well-documented benefits of using warfarin to prevent stroke, physicians remain reluctant to initiate therapy, and especially so with the elderly owing to the higher risk of hemorrhage. Prior research suggests that patients are more accepting of the risk of bleeding than are physicians, although there have been few qualitative studies. The aim of this study was to employ qualitative methods to investigate the experience and perspective of individuals taking warfarin. Methods We conducted face-to-face interviews with 21 older patients (12 male, 9 female) who had been taking warfarin for a minimum of six months. Participants were patients at a family practice clinic situated in a large, tertiary care teaching hospital. We used a semistructured interview guide with four main thematic areas: decision-making, knowledge/education, impact, and satisfaction. Data were analysed according to the principles of content analysis. Results and Discussion Participants tended to have minimal input into the decision to initiate warfarin therapy, instead relying in great part on physicians' expertise. There appeared to be low retention of information received regarding the therapy; half the patients in our sample possessed only a superficial level of understanding of the risks and benefits. This notwithstanding, participants reported a high level of satisfaction with the care provided and a low level of impact on their day-to-day lives. Conclusions Minimal patient involvement in the initial decision and modest knowledge did not appear to diminish satisfaction with warfarin management. At the same time, care providers exert a tremendous influence on the initiation of warfarin therapy and should strive to incorporate patient preferences and expectations into the decision-making process. PMID:15268764

Quality of warfarin control in atrial fibrillation patients in South East Queensland, Australia.

PubMed

Bernaitis, N; Badrick, T; Davey, A K; Anoopkumar-Dukie, S

2016-08-01

Warfarin is widely prescribed to decrease the risk of stroke in atrial fibrillation (AF) patients. Due to patient variability in response, regular monitoring is required, and time in therapeutic range (TTR) used to indicate quality of warfarin control with a TTR>60% is recommended. Recently, an Australian Government review of anticoagulants identified the need to establish current warfarin control and determine the potential place of the newer oral anticoagulants. To determine warfarin control by a pathology practice in Queensland, Australia and identify factors influencing TTR. Retrospective data were collected from Sullivan Nicolaides Pathology, a major pathology practice offering a warfarin care programme in Australia. Patients enrolled in their programme as of September 2014 were included in the study. TTR was calculated using INR test results, and test dates using the Rosendaal method with mean patient TTR were used for analysis and comparison. Exclusions were target therapeutic range outside 2.0-3.0, less than two INR tests and programme treatment time of less than 30 days. The eligible 3692 AF patients had 73.6% of INR tests within the therapeutic range. The mean TTR was 81%, with 97% of patients above a TTR of 60%. TTR was not significantly influenced by age, gender or socioeconomic factors. The observed mean TTR of over 80% is superior to the minimum recommended threshold of 60%. The TTR achieved by the Queensland pathology practice demonstrates that dedicated warfarin programmes can produce high-quality warfarin care, ensuring the full benefit of warfarin for Australian patients. © 2016 Royal Australasian College of Physicians.

Net clinical benefit of warfarin in individuals with atrial fibrillation across stroke risk and across primary and secondary care

PubMed Central

Banerjee, Amitava; Shah, Anoop Dinesh; Patel, Riyaz; Denaxas, Spiros; Casas, Juan-Pablo; Hemingway, Harry

2017-01-01

Objective To investigate net clinical benefit (NCB) of warfarin in individuals with atrial fibrillation (AF) across stroke risk and across primary and secondary care. Methods We conducted a linked electronic health record cohort study of 70 206 individuals with initial record of diagnosis of AF in primary (n=29 568) or secondary care (n=40 638) in England (1998–2010). We defined stroke risk according to the CHA2DS2-VASc score, and followed individuals over a median 2.2 years for 7005 ischaemic strokes (IS) and for 906 haemorrhagic strokes (HS). We calculated incidence rates (IRs) and 95% CIs per 100 person-years (PYs) (IR (95% CI)/100 PY) of IS and HS, with and without use of warfarin, and the NCB (ie, number of IS avoided) per 100 PYs of warfarin use (NCB (95% CI)/100 PY). Results Compared with individuals with initial record of diagnosis in secondary care, those in primary care had lower scores of IS risk (CHA2DS2-VASc≤2: 30.8% vs 20.6%), and lower overall incidence of IS (IR (95% CI)/100 PY: 2.3 (2.2 to 2.4) vs 4.3 (4.2 to 4.4), p value=0.00); however among individuals with CHA2DS2-VASc=0, 1 or 2 there were no differences in IS rate between those with initial record of diagnosis in primary care or secondary care (IR (95% CI)/100 PY: 0.2 (0.1 to 0.3) vs 0.3 (0.2 to 0.5), p value=0.16), (IR (95% CI)/100 PY: 0.6 (0.4 to 0.7) vs 0.7 (0.6 to 0.9), p value=0.08) and (IR (95% CI)/100 PY: 1.1 (1.00 to 1.3) vs 1.4 (1.2 to 1.6), p value=0.05), respectively. For CHA2DS2-VASc=0, 1 and 2, IRs of IS with versus without warfarin were (IR (95% CI)/100 PY: 0.4 (0.2 to 0.8) vs 0.2 (0.1 to 0.3), p value=0.16), (IR (95% CI)/100 PY: 0.4 (0.3 to 0.7) vs 0.7 (0.6 to 0.8), p value=0.03) and (IR (95% CI)/100 PY: 0.8 (0.7 to 1.0) vs 1.4 (1.3 to 1.6), p value=0.00), respectively. We found a significant positive NCB of warfarin from CHA2DS2-VASc≥2 in men (NCB (95% CI)/100 PY: 0.5 (0.1 to 0.9)) and from CHA2DS2-VASc≥3 in women (NCB (95% CI)/100 PY: 1.5 (1

Warfarin and bosentan interaction in a patient with pulmonary hypertension secondary to bilateral pulmonary emboli.

PubMed

Spangler, Mikayla L; Saxena, Shailendra

2010-01-01

Bosentan is an endothelin-receptor antagonist that reportedly induces both cytochrome P450 (CYP) 3A4 and CYP2C9 enzymes, which are also involved in warfarin metabolism. We present a case report describing a probable drug interaction between warfarin and bosentan in a patient with pulmonary hypertension. A 52-year-old black female (weight, 77 kg) diagnosed with pulmonary hypertension secondary to bilateral pulmonary emboli had a stable international normalized ratio (INR; target range, 2-3) with a weekly warfarin dose of 52.5 mg for 2 months before the initiation of bosentan therapy. Other concurrent medications included telmisartan/ hydrochlorothiazide 40/12.5 mg once daily and a daily multivitamin (which contained no vitamin K). Three weeks after starting bosentan 62.5 mg BID, a therapeutic INR concentration was reached with a weekly warfarin dose 14% higher (an increase of 7.5 mg/wk) than her weekly warfarin dose before initiation of bosentan. After a brief discontinuation (7 days) and retitration of bosentan and warfarin, the final weekly warfarin dose (75 mg/wk) was 43% greater (an increase of 22.5 mg/wk) than the previously stable dose, which enabled the patient to reach her therapeutic INR goal range of 2 to 3. Bosentan has CYP3A4- and CYP2C9-inducing properties and is therefore likely to cause decreased concentrations of warfarin. We describe here a probable drug interaction between bosentan and warfarin that resulted in a 43% increase in warfarin dose to maintain the patient's therapeutic INR.

Genetic epidemiology of pharmacogenetic variations in CYP2C9, CYP4F2 and VKORC1 genes associated with warfarin dosage in the Indian population.

PubMed

Giri, Anil K; Khan, Nazir M; Grover, Sandeep; Kaur, Ismeet; Basu, Analabha; Tandon, Nikhil; Scaria, Vinod; Kukreti, Ritushree; Brahmachari, Samir K; Bharadwaj, Dwaipayan

2014-07-01

Warfarin, a widely used anticoagulant, exhibits large interindividual variability in dose requirements. CYP2C9 and VKORC1 polymorphisms in various ethnic groups have been extensively studied as genetic markers associated with variable drug response. However, allele frequencies of these variants have not been assessed in major ethnic groups in the Indian population. To study the functional variants known to affect warfarin dosing, we reanalyzed genotype microarray datasets generated as a part of genome-wide association studies as well as data from the Indian Genome Variation database. We examined data from 2680 individuals across 24 ethnically diverse Indian subpopulations. Allelic distribution of VKORC1 (-1639G>A) showed a greater degree of variation across Indian subpopulations, with frequencies as low as 6.5% in an out-group subpopulation to >70% in Tibeto-Burmans. Risk allele frequency of CYP4F2*3 (V433M) was higher in north Indians (0.30-0.44), as compared with other world populations, such as African-American (0.12), Caucasian (0.34) and Hispanic (0.23). TheVKORC1 variant (-1639A) was shown to be prevalent amongst Tibeto-Burmans, whereas CYP2C9 (R144C, I359L) and CYP4F2 (V433M) variants were observed in considerable variability amongst Indo-Europeans. The frequency of CYP2C9*3 (I359L) in north Indians was found to be higher than in most Asian populations. Furthermore, geographical distribution patterns of these variants in north India showed an increased trend of warfarin extensive metabolizers from the Himalayan to Gangetic region. Combined allele frequency (CYP2C9*3 and CYP4F2*3) data suggest that poor metabolizers varied in the range of 0.38-1.85% in Indo-Europeans. Based on genotypic distribution, the majority of the Indian subpopulation might require higher doses for stable anticoagulation, whereas careful assessment is required for Tibeto-Burmans who are expected to have intermediate dose requirement. This is the largest global genetic epidemiological

Prospective evaluation of a bivalirudin to warfarin transition nomogram.

PubMed

Hohlfelder, Benjamin; Sylvester, Katelyn W; Rimsans, Jessica; DeiCicchi, David; Connors, Jean M

2017-05-01

Bivalirudin may cause a falsely prolonged international normalized ratio (INR) that complicates the discontinuation of bivalirudin when used as a bridge to warfarin. To prospectively validate our novel bivalirudin to warfarin transition nomogram, adult patients who received bivalirudin as a bridge to warfarin between July 2015 and June 2016 were prospectively evaluated, utilizing our predictive nomogram. The major outcome of our analysis was the correlation between the predicted change in INR upon bivalirudin discontinuation based on the nomogram, and the actual change in INR upon bivalirudin discontinuation. The major outcome was analyzed using the Pearson's correlation test. A Pearson's correlation coefficient >0.6 was considered to be a strong correlation. Bivalirudin was used as a bridge to warfarin in 29 patients. The majority of patients (86%) included in the analysis had a ventricular assist device. The median initial bivalirudin rate was 0.07 mg/kg/h and the mean increase in INR when starting bivalirudin was 0.6. The mean final weight-based bivalirudin rate was 0.08 mg/kg/h and the mean change in INR after stopping bivalirudin was 0.7. The Pearson correlation coefficient between the predicted change in INR upon bivalirudin discontinuation and the actual change in INR upon bivalirudin discontinuation was 0.86 (p < 0.001). After bivalirudin discontinuation, 68% of patients had a therapeutic INR. The results of this prospective analysis successfully validated our novel bivalirudin to warfarin transition nomogram. There was a very strong correlation between the predicted change and actual change in INR upon bivalirudin discontinuation.

[Distribution of variant alleles association with warfarin pharmacokinetics and pharmacodynamics in the Han population in China].

PubMed

Liu, Yuan; Zhong, Shi-long; Yang, Min; Tan, Hong-hong; Fei, Hong-wen; Chen, Ji-yan; Yu, Xi-yong; Lin, Shu-guang

2011-12-18

To investigate distribution of CYP2C9, CYP3A4, VKORC1 and GGCX gene polymorphisms in the Han population of Guangdong. The subjects included were 970 Chinese Han patients who received long-term warfarin anticoagulant therapy orally after valve replacement in Guangdong General Hospital between 2000 and 2008. By selecting and analyzing the 12 single nucleotide polymorphisms (SNPs) loci, rs12572351 G>A, rs9332146 G>A, rs4917639 G>T, rs1057910 A>C (CYP2C9*3), rs1934967 G>T, rs1934968 G>A, rs2242480 T>C, rs2246709 G>A, rs9923231 C>T (VKORC1-1639 G>A), rs2359612 G>A (VKORC1*2), rs10871454 C>T, and rs699664 T>C, in 4 genes including CYP2C9, CYP3A4, VKORC1 and GGCX that were possibly correlated with warfarin pharmacodynamics and pharmacokinetics through literature retrieval, the distribution of mutation frequencies of the 12 SNPs loci in Chinese Han population were obtained systematically. SNaPshot technique was used to detect gene SNPs, Hardy-Weinberg genetic equilibrium test was used to test population representativeness. The allelic mutation frequency at CYP2C9 gene rs12572351 G>A, rs9332146 G>A, rs4917639 C>A, rs1057910 A>C (*3), rs1934967 G>T and rs1934968 G>A loci was 32.53%, 2.16%, 8.25%, 3.61%, 19.18% and 37.37%, respectively; the allelic mutation frequency at CYP3A4 gene rs2242480 T>C and rs2246709 G>A loci was 29.07% and 40.41%, respectively; the allelic mutation frequency at VKORC1 gene rs9923231 C>T, rs2359612 G>A and rs10871454 C>T SNPs loci was 87.99%, 87.94% and 91.34%, respectively; the allelic mutation frequency at GGCX gene rs699664 T>C locus was 31.86%. It is of important clinical significance in individualized warfarin therapy to systematically study distribution of mutation frequencies at 12 polymorphisms loci in 4 genes including CYP2C9, CYP3A4 , VKORC1 and GGCX related to warfarin pharmacodynamics and pharmacokinetics in the Chinese Han population receiving valve replacement.

Out-of-range international normalized ratio values and healthcare cost among new warfarin patients with non-valvular atrial fibrillation.

PubMed

Nelson, Winnie W; Wang, Li; Baser, Onur; Damaraju, C V; Schein, Jeffrey R

2015-05-01

Patients with out-of-range international normalized ratio (INR) values <2.0 and >3.0 have been associated with increased risk of thromboembolic and bleeding events. INR monitoring is costly, because of associated physician and nurse time, laboratory resource use, and dose adjustments. This study assessed the healthcare cost burden associated with out-of-range INR among warfarin initiator patients diagnosed with non-valvular atrial fibrillation (NVAF) in the US Veterans Health Administration (VHA) population. Adult NVAF patients (≥18 years) initiating warfarin were selected from the VHA dataset for the study period October 1, 2007-September 30, 2012. Only valid INR measurements (0.5 ≤ INR ≤ 20) were examined for the follow-up period, from the index date (warfarin initiation date) until the end of warfarin exposure or death. All-cause healthcare costs within 30 days were measured starting from the second month (31 days post-index date) to the end of the study period. Costs for inpatient stays, emergency room, outpatient facility, physician office visits, and other services were computed separately. Multiple regression was performed using the generalized linear model for overall cost analysis. In total, 29,463 patients were included in the study sample. Mean costs for out-of-range INR ranged from $3419 to $5126. Inpatient, outpatient, outpatient pharmacy, and total costs were significantly higher after patients experienced out-of-range results (INR < 2, INR > 3), compared with in-range INR (2 ≤ INR ≤ 3). When exposed to out-of-range INR, patients also incurred higher mean total costs within 2-6 months ($3840-$5820) than after the first 6 months ($2789-$3503) of warfarin therapy. In the VHA population, INR measures outside of the 2-3 range were associated with significantly higher healthcare costs. Increased costs were especially apparent when INR values were below 2, although INR measures above 3 were also associated with higher costs

Timing of oral anticoagulant therapy in acute ischemic stroke with atrial fibrillation: study protocol for a registry-based randomised controlled trial.

PubMed

Åsberg, Signild; Hijazi, Ziad; Norrving, Bo; Terént, Andreas; Öhagen, Patrik; Oldgren, Jonas

2017-12-02

Oral anticoagulation therapy is recommended for the prevention of recurrent ischemic stroke in patients with atrial fibrillation (AF). Current guidelines do not provide evidence-based recommendations on optimal time-point to start anticoagulation therapy after an acute ischemic stroke. Non-vitamin K antagonist oral anticoagulants (NOACs) may offer advantages compared to warfarin because of faster and more predictable onset of action and potentially a lower risk of intracerebral haemorrhage also in the acute phase after an ischemic stroke. The TIMING study aims to establish the efficacy and safety of early vs delayed initiation of NOACs in patients with acute ischemic stroke and AF. The TIMING study is a national, investigator-led, registry-based, multicentre, open-label, randomised controlled study. The Swedish Stroke Register is used for enrolment, randomisation and follow-up of 3000 patients, who are randomised (1:1) within 72 h from ischemic stroke onset to either early (≤ 4 days) or delayed (≥ 5-10 days) start of NOAC therapy. The primary outcome is the composite of recurrent ischemic stroke, symptomatic intracerebral haemorrhage, or all-cause mortality within 90 days after randomisation. Secondary outcomes include: individual components of the primary outcome at 90 and 365 days; major haemorrhagic events; functional outcome by the modified Rankin Scale at 90 days; and health economics. In an optional biomarker sub-study, blood samples will be collected after randomisation from approximately half of the patients for central analysis of cardiovascular biomarkers after study completion. The study is funded by the Swedish Medical Research Council. Enrolment of patients started in April 2017. The TIMING study addresses the ongoing clinical dilemma of when to start NOAC after an acute ischemic stroke in patients with AF. By the inclusion of a randomisation module within the Swedish Stroke Register, the advantages of a prospective randomised study design

Comparison of the prevalence of enteric viruses in healthy dogs and those with acute haemorrhagic diarrhoea by electron microscopy.

PubMed

Schulz, B S; Strauch, C; Mueller, R S; Eichhorn, W; Hartmann, K

2008-02-01

To evaluate prevalence of enteric viruses in healthy dogs and to compare it with prevalences in dogs with acute haemorrhagic diarrhoea. Faecal samples were collected from 200 healthy dogs and examined by electron microscopy for presence of viral particles. Data were compared with viral prevalences that had been determined retrospectively by electron microscopy for 936 dogs with acute haemorrhagic diarrhoea. There were significantly more negative faecal samples among the healthy dogs (82.0 per cent) compared with 55.8 per cent in dogs with acute haemorrhagic diarrhoea (P<0.001). With a prevalence of 17.5 per cent, significantly more healthy dogs were shedding coronavirus compared with 11.6 per cent in dogs with acute haemorrhagic diarrhoea (P=0.034). Parvovirus was only detected in one healthy dog (0.5 per cent), thus with a prevalence that was significantly lower than 16.0 per cent detected in the dogs with acute haemorrhagic diarrhoea (P<0.001). Paramyxovirus was not found in any of the healthy dogs but was found in 9.3 per cent of dogs with acute haemorrhagic diarrhoea (P<0.001). Results suggest that shedding of parvovirus and paramyxovirus is strongly associated with acute haemorrhagic diarrhoea. However, coronavirus seems to be even more prevalent among healthy dogs, raising the need for further studies to investigate the strain-associated pathogenicity of this virus.

Warfarin metabolism and anticoagulant effect: a prospective, observational study of the impact of CYP2C9 genetic polymorphism in the presence of drug-disease and drug-drug interactions.

PubMed

Muszkat, Mordechai; Blotnik, Simcha; Elami, Amir; Krasilnikov, Irena; Caraco, Yoseph

2007-03-01

Cytocbrome P450 (CYP) 2C9 polymorphism affects the warfarin dosage requirement in stable outpatients. However, it is not known whether the CYP2C9 genotype contributes to the variability in warfarin dosage in the presence of drug-disease and drug-drug interactions. The aim of this study was to examine the effects of CYP2C9 genetic polymorphism on warfarin dosage requirements in patients with severe comorbid conditions and those treated with medications that potentially interact with warfarin. This prospective, observational study was conducted at Hadassah University Hospital, Jerusalem, Israel. Data from consecutive patients treated with warfarin for at least 3 months and admitted to the internal medicine ward were eligible for inclusion. Clinical data, international normalized ratio (INR), and warfarin dosage were recorded from medical records. The CYP2C9 genotype was determined using polymerase chain reaction restriction fragment length polymorphism, and plasma concentrations of (S)- and (R)-warfarin were determined by high-performance liquid chromatography using chiral methods. One hundred nineteen subjects (52% women) were studied. Mean age was 65.8 years (95% CI, 63.1-68.4), and weight was 74.9 kg (95% CI, 72.1-77.7). The mean warfarin dosage was 33% lower in patients with the CYP2C9-*1/*3 genotype (mean [SEM], 0.045 [0.006] mg/kg x d(-1)) compared with the CYP2C9-*1/*1 genotype (0.067 [0.004] mg/kg x d(-1)) (P=0.008); an intermediate value was found for the CYP2C9-*1/*2 genotype (0.062 [0.008] mg/kg x d(-1)). However, despite the lower dosage, INR was significantly higher in patients with the *1/*3 genotype (mean [95% CI], 3.29 [2.44-4.14]) (n=18) compared with the *1/*1 genotype (2.52 [2.34-2.71]) (n=64) (P=0.029). In addition to genotype, older age, congestive heart failure (CHF), and treatment with antibiotics were associated with lower warfarin dosages, whereas treatment with drug-metabolism inducers was associated with higher warfarin dosages. In addition

Age-specific association between blood pressure and vascular and non-vascular chronic diseases in 0·5 million adults in China: a prospective cohort study.

PubMed

Lacey, Ben; Lewington, Sarah; Clarke, Robert; Kong, Xiang Ling; Chen, Yiping; Guo, Yu; Yang, Ling; Bennett, Derrick; Bragg, Fiona; Bian, Zheng; Wang, Shaojie; Zhang, Hua; Chen, Junshi; Walters, Robin G; Collins, Rory; Peto, Richard; Li, Liming; Chen, Zhengming

2018-06-01

The age-specific association between blood pressure and vascular disease has been studied mostly in high-income countries, and before the widespread use of brain imaging for diagnosis of the main stroke types (ischaemic stroke and intracerebral haemorrhage). We aimed to investigate this relationship among adults in China. 512 891 adults (59% women) aged 30-79 years were recruited into a prospective study from ten areas of China between June 25, 2004, and July 15, 2008. Participants attended assessment centres where they were interviewed about demographic and lifestyle characteristics, and their blood pressure, height, and weight were measured. Incident disease was identified through linkage to local mortality records, chronic disease registries, and claims to the national health insurance system. We used Cox regression analysis to produce adjusted hazard ratios (HRs) relating systolic blood pressure to disease incidence. HRs were corrected for regression dilution to estimate associations with long-term average (usual) systolic blood pressure. During a median follow-up of 9 years (IQR 8-10), there were 88 105 incident vascular and non-vascular chronic disease events (about 90% of strokes events were diagnosed using brain imaging). At ages 40-79 years (mean age at event 64 years [SD 9]), usual systolic blood pressure was continuously and positively associated with incident major vascular disease throughout the range 120-180 mm Hg: each 10 mm Hg higher usual systolic blood pressure was associated with an approximately 30% higher risk of ischaemic heart disease (HR 1·31 [95% CI 1·28-1·34]) and ischaemic stroke (1·30 [1·29-1·31]), but the association with intracerebral haemorrhage was about twice as steep (1·68 [1·65-1·71]). HRs for vascular disease were twice as steep at ages 40-49 years than at ages 70-79 years. Usual systolic blood pressure was also positively associated with incident chronic kidney disease (1·40 [1·35-1·44]) and diabetes (1·14 [1�

The changing characteristics of atrial fibrillation patients treated with warfarin.

PubMed

Putnam, Andrew; Gu, Xiaokui; Haymart, Brian; Kline-Rogers, Eva; Almany, Steve; Kozlowski, Jay; Krol, Gregory D; Kaatz, Scott; Froehlich, James B; Barnes, Geoffrey D

2015-11-01

It has been suggested that direct oral anticoagulants are being preferentially used in low risk atrial fibrillation (AF) patients. Understanding the changing risk profile of new AF patients treated with warfarin is important for interpreting the quality of warfarin delivery through an anticoagulation clinic. Six anticoagulation clinics participating in the Michigan Anticoagulation Quality Improvement Initiative enrolled 1293 AF patients between 2010 and 2014 as an inception cohort. Abstracted data included demographics, comorbidities, medication use and all INR values. Risk scores including CHADS2, CHA2DS2-VASc, HAS-BLED, SAMe-TT2R2, and Charlson comorbidity index (CCI) were calculated for each patient at the time of warfarin initiation. The quality of anticoagulation was assessed using the Rosendaal time in the therapeutic range (TTR) during the first 6 months of treatment. Between 2010 and 2014, patients initiating warfarin therapy for AF had an increasing mean CHADS2 (2.0 ± 1.1 to 2.2 ± 1.4, p = 0.02) and CCI (4.7 ± 1.8 to 5.1 ± 2.0, p = 0.03), and a trend towards increasing mean CHA2DS2-VASc, HAS-BLED, and SAMe-TT2R2 scores. The actual TTR remained unchanged over the study period (62.6 ± 18.2 to 62.7 ± 17.0, p = 0.98), and the number of INR checks did not change (18.9 ± 5.2 to 18.5 ± 5.1, p = 0.06). Between 2010 and 2014, AF patients newly starting warfarin had mild increases in risk for stroke and death with sustained quality of warfarin therapy.

Warfarin genotyping in a single PCR reaction for microchip electrophoresis.

PubMed

Poe, Brian L; Haverstick, Doris M; Landers, James P

2012-04-01

Warfarin is the most commonly prescribed oral anticoagulant medication but also is the second leading cause of emergency room visits for adverse drug reactions. Genetic testing for warfarin sensitivity may reduce hospitalization rates, but prospective genotyping is impeded in part by the turnaround time and costs of genotyping. Microfluidics-based assays can reduce reagent consumption and analysis time; however, no current assay has integrated multiplexed allele-specific PCR for warfarin genotyping with electrophoretic microfluidics hardware. Ideally, such an assay would use a single PCR reaction and, without further processing, a single microchip electrophoresis (ME) run to determine the 3 single-nucleotide polymorphisms (SNPs) affecting warfarin sensitivity [i.e., CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) *2, CYP2C9 *3, and the VKORC1 (vitamin K epoxide reductase complex 1) A/B haplotype]. We designed and optimized primers for a fully multiplexed assay to examine 3 biallelic SNPs with the tetraprimer amplification refractory mutation system (T-ARMS). The assay was developed with conventional PCR equipment and demonstrated for microfluidic infrared-mediated PCR. Genotypes were determined by ME on the basis of the pattern of PCR products. Thirty-five samples of human genomic DNA were analyzed with this multiplex T-ARMS assay, and 100% of the genotype determinations agreed with the results obtained by other validated methods. The sample population included several genotypes conferring warfarin sensitivity, with both homozygous and heterozygous genotypes for each SNP. Total analysis times for the PCR and ME were approximately 75 min (1-sample run) and 90 min (12-sample run). This multiplexed T-ARMS assay coupled with microfluidics hardware constitutes a promising avenue for an inexpensive and rapid platform for warfarin genotyping.

Intracerebral dendritic cells critically modulate encephalitogenic versus regulatory immune responses in the CNS

PubMed Central

Zozulya, Alla L.; Ortler, Sonja; Lee, JangEun; Weidenfeller, Christian; Sandor, Matyas; Wiendl, Heinz; Fabry, Zsuzsanna

2010-01-01

Dendritic cells (DCs) appear in higher numbers within the CNS as a consequence of inflammation associated with autoimmune disorders, such as multiple sclerosis (MS), but the contribution of these cells to the outcome of disease is not yet clear. Here we show that stimulatory or tolerogenic functional states of intracerebral DCs regulate the systemic activation of neuroantigen-specific T cells, the recruitment of these cells into the CNS and the onset and progression of experimental autoimmune encephalomyelitis (EAE). Intracerebral microinjection of stimulatory DCs exacerbated the onset and clinical course of EAE, accompanied with an early T-cell infiltration and a decreased proportion of regulatory FoxP3-expressing cells in the brain. In contrast, the intracerebral microinjection of DCs modified by tumor necrosis factor alpha (TNF-α) induced their tolerogenic functional state and delayed or prevented EAE onset. This triggered the generation of interleukin 10 (IL-10)-producing neuroantigen-specific lymphocytes in the periphery and restricted IL-17 production in the CNS. Our findings suggest that DCs are a rate-limiting factor for neuroinflammation. PMID:19129392

CYP2C9*3 polymorphism presenting as lethal subdural hematoma with low-dose warfarin

PubMed Central

Karnik, Niteen D.; Sridharan, Kannan; Tiwari, D.; Gupta, V.

2014-01-01

Warfarin is the most common and cheap oral anticoagulant currently used in clinical practice. A high inter-individual variation is seen in the response to warfarin. Recently, pharmacogenetics has gained importance in managing patients on warfarin, both in predicting the optimum required dose as well as in decreasing the risk of bleeding. This case report is a description of a 49-year-old patient who had a lethal subdural hematoma with low-dose warfarin. He was subsequently found to have CYP2C9 gene polymorphism (*1/*3). This case report stresses the importance of pre-prescription assessment of genetic analysis for those initiated on warfarin. PMID:25298588

Warfarin hypersensitivity due to gluten-sensitive enteropathy: a case study.

PubMed

Kwolek, Sara; Deming, Paula

2012-01-01

A 53 year old female who was maintained on long-term warfarin therapy due to history of pulmonary embolism, repeatedly presents with an abnormally prolonged Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT). After many asymptomatic episodes were corrected with Vitamin K therapy to temporarily reverse the effects of the warfarin, the cause of the apparent coagulopathy was further investigated. Factor Activity Assays of the common pathway factors II, IX, and X all revealed critically low values; below the threshold even a loading dose of warfarin is typically capable of eliciting. The patient tested strongly positive for Tissue Transglutaminase IgA, which is highly suggestive of a gluten-sensitive enteropathy. One effect of this condition is malabsorption due to flattened intestinal villi. The patient was determined to have an acquired vitamin K deficiency secondary to gluten-sensitive enteropathy. Her condition was exacerbated by the long-term warfarin therapy, resulting in the prolonged PT and PTT. The patient was treated with vitamin K therapy, which reversed the deficiency and corrected her abnormal coagulation results.

Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.

PubMed

1996-09-07

Adjusted-dose warfarin is highly efficacious for prevention of ischaemic stroke in patients with atrial fibrillation (AF). However, this treatment carries a risk of bleeding and the need for frequent medical monitoring. We sought an alternative that would be safer and easier to administer to patients with AF who are at high-risk of thromboembolism. 1044 patients with AF and with at least one thromboembolic risk factor (congestive heart failure or left ventricular fractional shortening < or = 25%, previous thromboembolism, systolic blood pressure of more than 160 mm Hg at study enrollment, or being a woman aged over 75 years) were randomly assigned either a combination of low-intensity, fixed-dose warfarin (international normalised ratio [INR] 1.2-1.5 for initial dose adjustment) and aspirin (325 mg/day) or adjusted-dose warfarin (INR 2.0-3.0). Drugs were given open-labelled. The mean INR during follow-up of patients taking combination therapy (n = 521) was 1.3, compared with 2.4 for those taking adjusted-dose warfarin (n = 523). During follow-up, 54% of INRs in patients taking combination therapy were 1.2-1.5 and 34% were less than 1.2. The trial was stopped after a mean, follow-up of 1.1 years when the rate of ischaemic stroke and systemic embolism (primary events) in patients given combination therapy (7.9% per year) was significantly higher than in those given adjusted-dose warfarin (1.9% per year) at an interim analysis (p < 0.0001), an absolute reduction of 6.0% per year (95% Cl 3.4, 8.6) by adjusted-dose warfarin. The annual rates of disabling stroke (5.6% vs 1.7%, p = 0.0007) and of primary event or vascular death (11.8% vs 6.4%, p = 0.002), were also higher with combination therapy. The rates of major bleeding were similar in both treatment groups. Low-intensity, fixed-dose warfarin plus aspirin in this regimen is insufficient for stroke prevention in patients with non-valvular AF at high-risk for thromboembolism; adjusted-dose warfarin (target INR 2