Warfarin In Clinical Practice Research Articles

Impact of VKORC1, CYP2C9, CYP1A2, UGT1A1, and GGCX polymorphisms on warfarin maintenance dose: Exploring a new algorithm in South Chinese patients accept mechanical heart valve replacement.

Background:Warfarin is the most recommended oral anticoagulant after artificial mechanical valve replacement therapy. However, the narrow therapeutic window and varying safety and efficacy in individuals make dose determination difficult. It may cause adverse events such as hemorrhage or thromboembolism. Therefore, advanced algorithms are urgently required for the use of warfarin.Objective:To establish a warfarin dose model for patients after prosthetic mechanical valve replacement in southern China in combination with clinical and genetic variables, and to improve the accuracy and ideal prediction percentage of the model.Methods:Clinical data of 476 patients were tracked and recorded in detail. The gene polymorphisms of VKORC1 (rs9923231, rs9934438, rs7196161, and rs7294), CYP2C9 (rs1057910), CYP1A2 (rs2069514), GGCX (rs699664), and UGT1A1 (rs887829) were determined using Sanger sequencing. Multiple linear regressions were used to analyze the gene polymorphisms and the contribution of clinical data variables; the variables that caused multicollinearity were screened stepwise and excluded to establish an algorithm model for predicting the daily maintenance dose of warfarin. The ideal predicted percentage was used to test clinical effectiveness.Results:A total of 395 patients were included. Univariate linear regression analysis suggested that CYP1A2 (rs2069514) and UGT1A1 (rs887829) were not associated with the daily maintenance dose of warfarin. The new algorithm model established based on multiple linear regression was as follows: Y = 1.081 − 0.011 (age) + 1.532 (body surface area)-0.807 (rs9923231 AA) + 1.788 (rs9923231 GG) + 0.530 (rs1057910 AA)-1.061 (rs1057910 AG)-0.321 (rs699664 AA). The model accounted for 61.7% of individualized medication differences, with an ideal prediction percentage of 69%.Conclusion:GGCX (rs699664) may be a potential predictor of warfarin dose, and our newly established model is expected to guide the individualized use of warfarin in clinical practice in southern China.

The Prevalence and Risks of Inappropriate Combination of Aspirin and Warfarin in Clinical Practice: Results From WARFARIN-TR Study

Background:The use of warfarin and aspirin in combination is restricted to limited patients under relevant guidelines.Aims:To evaluate the prevalence of the inappropriate combination of aspirin and warfarin therapy in daily practice and its risks.Study Design:Cross-sectional study.Methods:The awareness, efficacy, safety, and time in the therapeutic range of warfarin in the Turkish population study is a multi-center observational study that includes 4987 patients using warfarin for any reason between January 1, 2014, and December 31, 2014. To determine the prevalence of inappropriate combination use in daily practice, all patients who had a history of atherosclerotic disease (ischemic heart disease, peripheral artery disease) or cerebrovascular disease (n=1498) were excluded. The data of 3489 patients were analyzed. We defined inappropriate combination as all patients who received aspirin and warfarin regardless of the indication for warfarin use, under the direction of the European Society of Cardiology guideline recommendation.Results:The mean age of patients was 59.2±13.8 years (41.8% male). The prevalence of the inappropriate use of warfarin and aspirin combination was 20.0%. The prevalence of combination therapy in patients with a primary indication for mechanical heart valve, non-valvular atrial fibrillation, and other reasons was 20.5%, 18.7%, and 21.0%, respectively. Multivariate logistic regression analysis revealed that age (odds ratio, 1.009; 95% confidence interval, 1.002-1.015; p=0.010), heart failure (odds ratio, 1.765; 95% confidence interval, 1.448-2.151; p<0.001), smoking (odds ratio, 1.762; 95% confidence interval, 1.441-1.153; p<0.010), chronic kidney disease (odds ratio, 2.057; 95% confidence interval, 1.494-2.833; p<0.001), and deep vein thrombosis (odds ratio, 0.463; 95% confidence interval, 0.229-0.718; p=0.001) were independent predictors of combination therapy (r2=0.66). The mean time in therapeutic range of patients receiving combination therapy was significantly lower than in those on warfarin monotherapy (51.6±27.05 vs. 54.7±23.93; p=0.006). Overall, 19.4% (n=677) of patients had a bleeding event (major bleeding 13.0%, n=88) within a year. Percentages of patients with combination therapy were significantly higher in patients with major bleeding than in patients without major bleeding (29.5% vs. 19.7%; p=0.023).Conclusion:Our study demonstrated that 20.0% of patients taking warfarin use concomitant aspirin inappropriately in daily practice. Patients receiving aspirin with warfarin were demonstrated to have more comorbidities, lower time in therapeutic range levels, and higher bleeding rates.

Acute Lower Gastrointestinal Bleeding in Patients Treated With Non-Vitamin K Antagonist Oral Anticoagulants Compared With Warfarin in Clinical Practice: Characteristics and Clinical Outcome.

BackgroundAcute lower gastrointestinal bleeding (ALGIB) can occur in patients on anticoagulant therapy (either warfarin or non-vitamin K oral anticoagulants (NOACs)). Use of NOACs has been increasing compared to warfarin in recent years. We analyzed patients with ALGIB on anticoagulation therapy and compared characteristics, management and clinical outcome in patients treated with NOACs versus warfarin.MethodsAll patients with ALGIB on anticoagulation therapy treated in two (affiliated) centers during a 7-year period were evaluated. Characteristics and clinical outcome were compared between patients on warfarin and patients on NOACs.ResultsOut of the 587 patients identified with ALGIB during the study period, 43 (7.3%) were on NOACs and 68 (11.6%) on warfarin. Mean age was 75.9 ± 9.5 and 77.1 ± 7.9 years respectively. Site of bleeding was located in the small bowel in 2/43 of NOAC patients and 6/68 of warfarin group. Vascular ectasias (8/43 vs. 6/68, P = 0.010) and polyps/neoplasia (13/43 vs. 6/68, P = 0.025) were more commonly causes of bleeding in patients on NOACs. While endoscopic hemostasis was more commonly needed in patients on NOACs (17/43 vs. 14/68, P = 0.049), they required less hospitalization days (4.5 ± 3.6 vs. 6.1 ± 4.2, P = 0.032). Blood transfusions and need for other interventions (embolization and/or surgery) as well as recurrence of bleeding and mortality were not statistically different.ConclusionsAlthough NOAC patients with ALGIB exhibit some differences on certain clinical characteristics when compared to warfarin patients, they share a similar clinical outcome.

Dabigatran, rivaroxaban and apixaban vs. high TTR warfarin in atrial fibrillation

IntroductionNew oral anticoagulants are non-inferior compared with warfarin regarding stroke prevention in atrial fibrillation, with similar or decreased risk of bleeding. However, it is unclear whether high TTR warfarin is as effective and safe as NOACs. Our objective was to investigate efficacy and safety of apixaban, dabigatran or rivaroxaban compared with warfarin in clinical practice. Materials and methodsNationwide retrospective cohort study based on Swedish quality registries. Atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin between 2013-01-01 and 2015-12-31 were included. Main outcome measures were all-cause stroke and systemic embolism, all-cause stroke, ischemic stroke, hemorrhagic stroke; major bleeding, intracranial bleeding, gastrointestinal bleeding, other bleeding (fatal or requiring hospital care); all-cause mortality; myocardial infarction. ResultsThe study included 64,382 patients corresponding to 81,176 treatment years. Of these, 37,174 patients were instituted on warfarin, 6574 on dabigatran, 8323 on rivaroxaban and 12,311 on apixaban. In warfarin treated patients, the time in therapeutic range was 71.4%. After propensity score matching, there was no significant difference in risk of stroke or systemic embolism between NOAC and warfarin treated patients. Hazard ratios for major bleeding events were 0.63(95%CI 0.52–0.75) for apixaban, 0.74(0.62–0.87) for dabigatran and 1.06(0.92–1.23) for rivaroxaban, compared with warfarin. ConclusionsThis study showed no difference between apixaban, dabigatran, or rivaroxaban compared to high TTR warfarin treatment regarding stroke prevention. However, fewer bleeding events were seen for apixaban and dabigatran, but not for rivaroxaban. Further studies are needed on the comparability of individual NOACs with respect to bleeding risks.

CV3 - Comparative Effectiveness of Direct Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation

Atrial fibrillation (AF) management focuses on the prevention of blood clots to reduce the risk of stroke. Warfarin has successfully reduced the risk of stroke and mortality. Since 2010, a new class of medications, direct oral anticoagulants (DOACs), entered the market. Clinical trials provide good evidence that DOACs compare favorably to warfarin on a variety of outcomes, including mortality. Initial observational studies have concluded these medications may also be cost-effective. Our research objective was to compare the effectiveness of DOACs to warfarin in clinical practice. This is a retrospective observational study of data from patient-level administrative and claims data from the Veterans Health Administration (VHA) and Medicare. We identified patients with a new diagnosis of AF who initiated warfarin or a DOAC between 2011 and 2015 (N=35,478). We examined the relationship between initiating warfarin or a DOAC on mortality using a two-stage residual inclusion approach, using facility-level prescribing patterns as an instrumental variable. Models controlled for facility quality measures, patient demographic variables, comorbidities, and stroke risk. Eighty percent of the sample initiated warfarin with the remainder initiating the DOACs. The average follow-up time was 1.97 years. In the first stage model, facility prescribing patterns significantly predicted the likelihood of receiving a DOAC (OR=6.04, 95% CI=2.5-13.8). In the second-stage, Cox proportional hazard models that control for selection bias, Veterans who started on a DOAC had significantly lower risk of mortality (hazard ratio=0.34, C.I.=0.22-0.53). Naïve models and propensity score models that don’t explicitly account for unobserved selection bias have hazard ratios of 0.66 (CI=0.61-0.71) and 0.70 (CI=0.65-0.76), respectively. Veterans who initiate a DOAC compared to warfarin have significantly lower risk of death. The ease of administration and monitoring advantages for DOACs suggest these drugs may be the preferred option for treatment in clinical populations with significant comorbidities.

Management of Major Bleeding in Patients With Atrial Fibrillation Treated With Non–Vitamin K Antagonist Oral Anticoagulants Compared With Warfarin in Clinical Practice (from Phase II of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF II

Non-vitamin K antagonist oral anticoagulants (NOACs) are effective at preventing stroke in patients with atrial fibrillation (AF). However, little is known about the management of bleeding in contemporary, clinical use of NOACs. We aimed to assess the frequency, management, and outcomes of major bleeding in the setting of community use of NOACs. Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry, we analyzed rates of International Society on Thrombosis and Haemostasis major bleeding and subsequent outcomes in patients treated with NOACs versus warfarin. Outcomes of interest included acute and chronic bleeding management, recurrent bleeding, thromboembolic events, and death. In total, 344 patients with atrial fibrillation experienced major bleeding events over a median follow-up of 360days follow-up: n= 273 on NOAC (3.3 per 100 patient-years) and n= 71 on warfarin (3.5 per 100 patient-years). Intracranial bleeding was uncommon but similar (0.34 per 100 patient-years for NOAC vs 0.44 for warfarin, p= 0.5), as was gastrointestinal bleeding (1.8 for NOAC vs 1.3 for warfarin, p= 0.1). Blood products and correction agents were less commonly used in NOAC patients with major bleeds compared with warfarin-treated patients (53% vs 76%, p= 0.0004 for blood products; 0% vs 1.5% for recombinant factor; p= 0.0499); no patients received pharmacologic hemostatic agents (aminocaproic acid, tranexamic acid, desmopressin, aprotinin). Within 30days, 23 NOAC-treated patients (8.4%) died versus 5 (7.0%) on warfarin (p= 0.7). At follow-up, 126 NOAC-treated (46%) and 29 warfarin-treated patients (41%) were not receiving any anticoagulation. In conclusion, rates of major bleeding are similar in warfarin and NOAC-treated patients in clinical practice. However, NOAC-related bleeds require less blood product administration and rarely require factor replacement.

Potential impact of new oral anticoagulants on the management of atrial fibrillation‐related stroke in primary care

AimAnticoagulant prophylaxis with vitamin K antagonists (such as warfarin) is effective in reducing the risk of stroke in patients with atrial fibrillation (AF). New oral anticoagulants have emerged as potential alternatives to traditional oral agents. The purpose of this review was to summarise the effectiveness and safety of rivaroxaban, dabigatran and apixaban in stroke prevention in patients with AF in phase III trials, evaluate their cost-effectiveness and consider the implications for primary care.MethodologyA literature search was performed between 2007 and 2012, selecting all phase III trials (ROCKET AF, RE-LY and ARISTOTLE) of new oral anticoagulants and relevant cost–benefit studies.ResultsEvidence shows that all three agents are at least as effective as warfarin in the prevention of stroke and systemic emboli, with similar safety profiles. Cost–benefit studies of rivaroxaban and dabigatran further confirm their potential use as alternatives to warfarin in clinical practice. These observations may allow stratification of the general practice AF population, to help prioritise which patients may benefit from receiving a new oral anticoagulant.ConclusionThe clinical and economic benefits of the new oral anticoagulants, along with appropriate risk stratification, may enable a higher number of patients with AF to receive effective and convenient prophylaxis for stroke prevention.

New Challenges Ahead for the Newer Oral Thrombin Inhibitors that Aim at Replacing Warfarin in Clinical Practice—Any Role for Scientific Societies in the Debate?

New Challenges Ahead for the Newer Oral Thrombin Inhibitors that Aim at Replacing Warfarin in Clinical Practice—Any Role for Scientific Societies in the Debate?

Novel drugs for oral anticoagulation pharmacotherapy

Long-term anticoagulation with warfarin is the mainstay of treatment in patients with diseases with high thromboembolic potential, such as atrial fibrillation. However, warfarin therapy carries a number of inherent limitations, including slow onset and offset of action, interindividual variability, food and drug interactions, lack of selectivity and a narrow therapeutic window. Recently developed oral anticoagulants that selectively block key factors in the coagulation cascade, with no need for monitoring or dose adjustment, have the potential to replace warfarin in clinical practice. The safety and efficacy of these agents in patients with atrial fibrillation, venous thromboembolisms and acute coronary syndromes have been the object of numerous recent large-scale clinical investigations. This article provides an overview of the evidence currently available on the use of novel, orally available, selective anticoagulants in patients at risk for thromboembolic events.

The pharmacogenetics of warfarin in clinical practice

The pharmacogenetics of warfarin in clinical practice

Role of pharmacodiagnostic of CYP2C9 variants in the optimization of warfarin therapy in Malaysia: A 6-month follow-up study

1. A retrospective study was conducted to explore the importance of CYP2C9 genotyping for the initiation and maintenance therapy of warfarin in clinical practice. A total of 191 patients on warfarin therapy in a local hospital were recruited after written informed consent. Their medical records were reviewed and no intervention of warfarin dose was performed.2. A total of 5 ml of blood were taken from each subject for DNA extraction and identification of *1, *2, *3 and *4 CYP2C9 alleles, using a nested-allele-specific-multiplex-polymerase chain reaction (PCR). Half the patients were Malays and the remaining were Chinese.3. Two genotypes were detected; 93.2% had CYP2C9*1/*1 and 6.8% were CYP2C9*1/* 3. Warfarin doses were higher in patients with CYP2C9*1/*1. Patients with the *1/* 3 genotype experienced a higher rate of serious and life-threatening bleeding; 15.4 versus 6.2 per 100 patients per 6 months.4. The observation clearly highlights the inadequacy of the current dosing regimens and the need to move toward a more individualized approach to warfarin therapy. Prospective clinical studies are now being conducted to assess dosing algorithms that incorporate the contribution of the genotype to allow the individualization of warfarin dose.

Pre-admission warfarin use in patients with acute ischemic stroke and atrial fibrillation: The appropriate use and barriers to oral anticoagulant therapy

Introduction Warfarin reduces the risk of stroke in patients with atrial fibrillation. Despite strong guideline recommendations, studies continue to demonstrate the under-use of warfarin in clinical practice. Purpose To determine the prevalence and predictors of warfarin use in patients presenting with atrial fibrillation and acute ischemic stroke who do not have a documented contraindication to anticoagulants. Methods We conducted a retrospective chart review of all patients admitted to the Hamilton General Hospital with a primary diagnosis of ischemic stroke and a coded diagnosis of atrial fibrillation between 1999 and 2004. Using a standardized data abstraction form, the following variables were recorded: baseline demographics, past medical history including risk factors for stroke and major bleeding and known predictors of warfarin under-use. In cases where warfarin was not prescribed, charts were also reviewed for documented contraindications to warfarin use. The following were considered valid contraindications to warfarin: patient refusal, non-compliance with INR monitoring, bleeding diathesis, history of major bleeding or significant alcohol consumption. Results In total, 196 patients with ischemic stroke and atrial fibrillation were identified. Of these patients, 106 were considered to be appropriate candidates for anticoagulation after excluding patients with no known diagnosis of atrial fibrillation prior to admission ( N = 59), a valid contraindication to warfarin use ( N = 18), a CHADS2 score < 1 ( N = 6) or a competing diagnosis for warfarin use ( N = 7). Of the patients deemed to be suitable candidates for warfarin, 57 (54%) were receiving warfarin therapy on admission. On multivariable analyses, increasing age (OR 0.7; 95% CI 0.5–0.9) was associated with a reduced odds of warfarin use while a history of stroke or TIA (OR 2.6; 95% CI 1.1–6.5) and a history of congestive heart failure (OR 3.2; 95% CI 1.1–9.0) were associated with an increased odds of warfarin use in patients without a contraindication to warfarin. While 75% of patients < 75 years old were anticoagulated, only 33% of those > 85 years were prescribed warfarin on admission to hospital. Conclusions early half of all patients presenting with atrial fibrillation and acute ischemic stroke who were suitable candidates for anticoagulation were not prescribed warfarin. In patients not prescribed warfarin, very few had a documented contraindication. Advanced age appears to be the strongest predictor of warfarin non-use.

Stroke prophylaxis in nonvalvular atrial fibrillation.

Nonvalvular atrial fibrillation is the most prevalent dysrrhythmia, and carries with it an at least fivefold increased risk of ischaemic stroke. Currently, the implementation and optimization of prophylactic therapy (with warfarin or acetylsalicylic acid) is the most effective approach, at the population level, to optimize outcomes in patients with atrial fibrillation. Therefore, clinical trial evidence regarding warfarin and acetylsalicylic acid in stroke prophylaxis is highlighted. Recently, considerable data have emerged that indicate suboptimal use of warfarin in clinical practice (both in terms of the prescription and titration of therapy). Narrowing this gap between research evidence and clinical practice may be accomplished by identifying those patients who are eligible for prophylaxis, and then maintaining them at an adequate level of anticoagulation.