Randomized Evaluation Of Long-Term Anticoagulation Therapy Research Articles

Cost-effectiveness of dabigatran etexilate in the prevention of stroke and systemic embolism in patients with atrial fibrillation in Belgium

Objective:To assess the cost-effectiveness of dabigatran etexilate (‘dabigatran’) vs vitamin K antagonists (VKAs) in the Belgian healthcare setting for the prevention of stroke and systemic embolism (SE) in patients with non-valvular atrial fibrillation (AF).Research design and methods:A Markov model was used to calculate the cost-effectiveness of dabigatran vs VKAs in Belgium, whereby warfarin was considered representative for the VKA class. Efficacy and safety data were taken from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial and a network meta-analysis. Local resource use and unit costs were included in the model. Effectiveness was expressed in Quality Adjusted Life-Years (QALYs). The model outcomes were total costs, total QALYs, incremental costs, incremental QALYs and the incremental cost-effectiveness ratio (ICER). The level of International Normalized Ratio (INR) control and the use of other antithrombotic therapies observed in Belgian clinical practice were reflected in two scenario analyses.Results:In the base case analysis, total costs per patient were €13,333 for dabigatran and €12,454 for warfarin. Total QALYs per patient were 9.51 for dabigatran and 9.19 for warfarin. The corresponding ICER was €2807/QALY. The ICER of dabigatran was €970/QALY vs warfarin with real-world INR control and €5296/QALY vs a mix of warfarin, aspirin, and no treatment. Results were shown to be robust in one-way and probabilistic sensitivity analyses.Limitations:The analysis does not include long-term costs for clinical events, as these data were not available for Belgium. As in any economic model based on data from a randomized clinical trial, several assumptions had to be made when extrapolating results to routine clinical practice in Belgium.Conclusion:This analysis suggests that dabigatran, a novel oral anticoagulant, is a cost-effective treatment for the prevention of stroke and SE in patients with non-valvular AF in the Belgian healthcare setting.

Letter by Bonaque et al Regarding Article, “Cardiac Biomarkers Are Associated With an Increased Risk of Stroke and Death in Patients With Atrial Fibrillation: A Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Substudy”

We have read with great interest the article “Cardiac Biomarkers Are Associated With an Increased Risk of Stroke and Death in Patients with Atrial Fibrillation: A Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Substudy,”1 where the authors suggest using cardiac biomarkers troponin I and N-terminal pro-B-type natriuretic peptide (NT-ProBNP) for better risk prediction in patients with atrial fibrillation, combining both markers in an independent manner to increase the possibility of predicting death and stroke. The discoveries made from …

Response to Letter Regarding Article, “Cardiac Biomarkers Are Associated With an Increased Risk of Stroke and Death in Patients With Atrial Fibrillation: A Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Substudy”

We thank Gonzales et al for their valuable comments on the article on biomarkers from The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.1 The RE-LY trial included 18 113 patients with atrial fibrillation, cardiac biomarkers were analyzed from plasma samples obtained at randomization in 6189 of the participants. The results showed that both N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin I were strongly and independently related to thromboembolic outcomes regardless of clinical risk factors including heart failure. At randomization, all patients were classified as either having heart failure or not based on New York Heart Association class and on available information regarding previous measurements of left ventricular ejection fraction based on echocardiography, radionuclide, or angiogram assessments.2 NT-proBNP is a sensitive biomarker of left ventricular function, clinical heart failure, and a predictor of …

AHA 2012: Prevention a key focus of meeting

The American Heart Association (AHA) Scientific Sessions 2012 brought together leading experts from around the world to discuss successes and new initiatives aimed at reducing the burden of cardiovascular disease (CVD). A key focus of the meeting was on treatments aimed at preventing cardiovascular events. In addition, the meeting discussed the efficacy of novel therapies and safety of marketed treatments. A review of select late-breaking trials and other presentations will be covered in this article.

Waiting for the new oral anticoagulants: questions and answers about dabigatran

Dabigatran is the first oral thrombin inhibitor approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and one or more risk factors for stroke. Dabigatran has also been approved in several countries for the prevention of venous thrombosis in patients undergoing total knee or hip replacement. The RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) study has shown that dabigatran 150 mg twice daily is superior to warfarin, and dabigatran 110 mg twice daily is non-inferior to warfarin, for the prevention of stroke and systemic embolism. Interestingly, the incidence of hemorrhagic stroke was significantly lower with dabigatran than with warfarin. Waiting for the introduction of dabigatran in the market in Italy for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, several issues related to the use of dabigatran in clinical practice need to be addressed. The aim of this article is to clarify some practical issues concerning the use of this innovative drug.

Cardiovascular outcomes during treatment with dabigatran: comprehensive analysis of individual subject data by treatment

BackgroundDabigatran 150 mg twice daily was shown to be superior to warfarin in preventing stroke in subjects with nonvalvular atrial fibrillation (SPAF) in the RE-LY (Randomized Evaluation of Long-term anticoagulation therapY) trial. Numerically, more myocardial infarctions occurred in patients receiving dabigatran compared with well-controlled warfarin. This observation prompted a comprehensive analysis of cardiovascular outcomes, including myocardial infarction, in all completed Phase II and III trials of dabigatran etexilate.MethodsThe analysis included comparisons of dabigatran with warfarin, enoxaparin, and placebo. Data were analyzed for the occurrence of cardiovascular events from 14 comparative trials (n = 42,484) in five different indications. Individual study data were evaluated, as well as pooled subject-level data grouped by comparator.ResultsIn the pooled analysis of individual patient data comparing dabigatran with warfarin (SPAF and venous thromboembolism treatment indications), myocardial infarction occurrence favored warfarin (odds ratio [OR] 1.30, 95% confidence interval [CI] 0.96–1.76 for dabigatran 110 mg twice daily and OR 1.42, 95% CI 1.07–1.88 for dabigatran 150 mg twice daily). The clinically relevant composite endpoint of myocardial infarction, total stroke, and vascular death demonstrated numerically fewer events in dabigatran 150 mg patients (OR 0.87, 95% CI 0.77–1.00), but was similar for dabigatran 110 mg (OR 0.99, 95% CI 0.87–1.13). Dabigatran had similar myocardial infarction rates when compared with enoxaparin or placebo.ConclusionThese analyses suggest a more protective effect of well-controlled warfarin, but not enoxaparin, compared with dabigatran in preventing myocardial infarction in multiple clinical settings. Dabigatran showed an overall positive benefit-risk ratio for multiple clinically important cardiovascular composite endpoints in all evaluated clinical indications. In conclusion, these data suggest that myocardial infarction is not an adverse drug reaction associated with use of dabigatran.

Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Trial

The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial showed that dabigatran etexilate 150 mg BID was superior and dabigatran etexilate 110 mg BID was noninferior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation. In this subgroup analysis, we assess the efficacy and safety of dabigatran in patients who did and did not receive concomitant antiplatelets. All comparisons used a Cox proportional hazards model with adjustments made for risk factors for bleeding. A time-dependent analysis was performed when comparing patients with concomitant antiplatelets with those without. Of 18 113 patients, 6952 (38.4%) received concomitant aspirin or clopidogrel at some time during the study. Dabigatran etexilate 110 mg BID was noninferior to warfarin in reducing stroke and systemic embolism, whether patients received antiplatelets (hazard ratio [HR], 0.93; 95% confidence interval [95% CI], 0.70-1.25) or not (HR, 0.87; 95% CI, 0.66-1.15; interaction P=0.738). There were fewer major bleeds than warfarin in both subgroups (HR, 0.82; 95% CI, 0.67-1.00 for patients who used antiplatelets; HR, 0.79; 95% CI, 0.64-0.96 for patients who did not; interaction P=0.794). Dabigatran etexilate 150 mg BID reduced the primary outcome of stroke and systemic embolism in comparison with warfarin. This effect seemed attenuated among patients who used antiplatelets (HR, 0.80; 95% CI, 0.59-1.08) in comparison with those who did not (HR, 0.52; 95% CI, 0.38-0.72; P for interaction=0.058). Major bleeding was similar to warfarin regardless of antiplatelet use (HR, 0.93; 95% CI, 0.76-1.12 for patients who used antiplatelets; HR, 0.94; 95% CI, 0.78-1.15 for patients who did not; P for interaction=0.875). In the time-dependent analysis, concomitant use of a single antiplatelet seemed to increase the risk of major bleeding (HR, 1.60; 95% CI, 1.42-1.82). Dual antiplatelet seemed to increased this even more (HR, 2.31; 95% CI, 1.79-2.98). The absolute risks were lowest on dabigatran etexilate 110 mg BID in comparison with dabigatran etexilate 150 mg BID or warfarin. Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE-LY without affecting the advantages of dabigatran over warfarin. Choosing between dabigatran etexilate 110 mg BID and dabigatran etexilate 150 mg BID requires a careful assessment of characteristics that influence the balance between benefit and harm. URL: http://clinicaltrials.gov. Unique identifier: NCT00262600.

Do Ingredients Make the Difference?

In clinical practice, the need to add 1 or 2 antiplatelet agents to an oral anticoagulant (OAC) often arises in patients with atrial fibrillation (AF). The indications can be diverse, from primary prevention in patients at high risk for an ischemic atherosclerotic event to secondary prevention after an acute coronary syndrome (ACS) to prevention of stent thrombosis.1,2 Unfortunately, adding antiplatelet agents to OACs increases bleeding risk, and although this risk is highest early after initiation of combination therapy, there appears to be no safe therapeutic window.1 The difficulty lies in balancing thromboembolic risk and bleeding risk in the individual patient. Because many new agents have come on the market recently, there is a wide variety of possible strategies with regard to not only the number and type of agents but also the intensity of anticoagulation and duration of the combination treatment. Article see p 634 Although ample guidance is available for preventing thromboembolic events and bleeding complications related to anticoagulant therapy on the one hand and for preventing ischemic events with antiplatelet agents on the other hand, there are few data from prospective studies on the combined use of antiplatelets with warfarin or one of the new OACs. Because the wide variety of clinical scenarios in which combination therapy is indicated can hardly be studied prospectively in dedicated clinical trials, we have to turn to post hoc analyses from trials such as the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) to obtain a better understanding of the benefits and risk of adding 1 or 2 antiplatelet agents to an OAC. In the RE-LY study, dabigatran at a dose of 110 mg twice daily reduced the risk of major bleeding and was noninferior to warfarin in preventing systemic emboli, whereas the 150-mg twice-daily dose reduced the risk …

Adverse Effects of Dabigatran

Letters18 December 2012Adverse Effects of DabigatranPatricio A. Pazmiño, MD, PhDPatricio A. Pazmiño, MD, PhDFrom Nephrology, Internal Medicine and Hypertension Center, El Paso, TX 79902-3503.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-157-12-201212180-00016 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I read Radecki's article (1) with interest and agree with his concerns. Some of the potential harms stem from dabigatran's use for unapproved indications and in populations that have not been well-studied. The approval of dabigatran in the United States was based mostly on the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial involving more than 18 000 patients (2). Unfortunately, this trial did not include patients with creatinine clearances less than 30 mL/min per 1.73 m2, which is common in the elderly and in patients with stage 4 or 5 chronic kidney disease.The ...

Variation in Warfarin Dose Adjustment Practice Is Responsible for Differences in the Quality of Anticoagulation Control Between Centers and Countries

Background— The outcome of atrial fibrillation patients on warfarin partially depends on maintaining adequate time in therapeutic International Normalized Ratio range (TTR). Large differences in TTR have been reported between centers and countries. The association between warfarin dosing practice, TTR, and clinical outcomes was evaluated in Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial patients receiving warfarin. Methods and Results— RE-LY provided an algorithm for warfarin dosing, recommending no change for in-range, and 10% to 15% weekly dose changes for out-of-range International Normalized Ratio values. We determined whether dose adjustments were consistent with algorithm recommendations but could not verify whether providers used the algorithm. Using multilevel regression models to adjust for patient, center, and country characteristics, we assessed whether algorithm-consistent warfarin dosing could predict patient TTR and the composite outcome of stroke, systemic embolism, or major hemorrhage. We included 6022 nonvalvular atrial fibrillation patients from 912 centers in 44 countries. We found a strong association between the proportion of algorithm-consistent warfarin doses and mean country TTR ( R 2 =0.65). The degree of algorithm-consistency accounted for 87% of the between-center and 55% of the between-country TTR variation. Each 10% increase in center algorithm-consistent dosing independently predicted a 6.12% increase in TTR (95% confidence interval, 5.65–6.59) and an 8% decrease in rate of the composite clinical outcome (hazard ratio, 0.92; 95% confidence interval, 0.85–1.00). Conclusions— Adherence, intentional or not, to a simple warfarin dosing algorithm predicts improved TTR and accounts for considerable TTR variation between centers and countries. Systems facilitating algorithm-based warfarin dosing could optimize anticoagulation quality and improve clinical outcomes in atrial fibrillation on a global scale. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00262600.

How country-specific should a country-specific cost-effectiveness analysis be?

This editorial refers to ‘Cost-effectiveness of dabigatran compared with warfarin for patients with atrial fibrillation in Sweden’†, by T. Davidson et al. , on page 177 and ‘Cost-effectiveness of treating acute coronary syndrome patients with ticagrelor for 12 months: results from the PLATO study’‡, by E. Nikolic et al. , on page 220 Two recent cost-effectiveness analyses published in the European Heart Journal add to a growing evidence base regarding the costs and health outcomes associated with dabigatran vs. warfarin for patients with atrial fibrillation1 and ticagrelor vs. clopidogrel for patients with acute coronary syndromes.2 Conducted from the perspective of the Swedish healthcare system, both analyses are trial-based economic evaluations augmented with decision models to extrapolate short-term trial outcomes to longer term estimates of costs and quality-adjusted survival. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) provided primary data for the cost-effectiveness analysis of dabigatran vs. warfarin.3 The Platelet Inhibition and Patient Outcomes (PLATO) trial provided primary data for the cost-effectiveness analysis of ticagrelor vs. clopidogrel.4 Both trials were large, multinational, randomized controlled studies. RE-LY enrolled 18 113 patients in 44 countries, and PLATO enrolled 18 624 patients in 43 countries. In both analyses, the analysts relied on clinical data that were pooled across all countries represented in the trial. To inform decision making in Sweden, …

Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin

Background— Dabigatran reduces ischemic stroke in comparison with warfarin; however, given the lack of antidote, there is concern that it might increase bleeding when surgery or invasive procedures are required. Methods and Results— The current analysis was undertaken to compare the periprocedural bleeding risk of patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial treated with dabigatran and warfarin. Bleeding rates were evaluated from 7 days before until 30 days after invasive procedures, considering only the first procedure for each patient. A total of 4591 patients underwent at least 1 invasive procedure: 24.7% of patients received dabigatran 110 mg, 25.4% received dabigatran 150 mg, and 25.9% received warfarin, P =0.34. Procedures included: pacemaker/defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%), and joint replacement (6.2%). Among patients assigned to either dabigatran dose, the last dose of study drug was given 49 (35–85) hours before the procedure on comparison with 114 (87–144) hours in patients receiving warfarin, P <0.001. There was no significant difference in the rates of periprocedural major bleeding between patients receiving dabigatran 110 mg (3.8%) or dabigatran 150 mg (5.1%) or warfarin (4.6%); dabigatran 110 mg versus warfarin: relative risk, 0.83; 95% CI, 0.59 to 1.17; P =0.28; dabigatran 150 mg versus warfarin: relative risk, 1.09; 95% CI, 0.80 to 1.49; P =0.58. Among patients having urgent surgery, major bleeding occurred in 17.8% with dabigatran 110 mg, 17.7% with dabigatran 150 mg, and 21.6% with warfarin: dabigatran 110 mg; relative risk, 0.82; 95% CI, 0.48 to 1.41; P =0.47; dabigatran 150 mg: relative risk, 0.82; 95% CI, 0.50 to 1.35; P =0.44. Conclusions— Dabigatran and warfarin were associated with similar rates of periprocedural bleeding, including patients having urgent surgery. Dabigatran facilitated a shorter interruption of oral anticoagulation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00262600.

Letter by Stöllberger and Finsterer Regarding Article, “Intracranial Hemorrhage in Patients With Atrial Fibrillation During Anticoagulation With Warfarin or Dabigatran: The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial”

To the Editor: We read with interest the article by Hart et al1 on intracranial hemorrhage (IH) in patients with atrial fibrillation undergoing anticoagulation treatment with warfarin or dabigatran. They analyzed retrospectively the clinical spectrum of 154 IHs in 18 113 participants of the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial and found that the rates of IHs were lower in dabigatran-treated patents than in those treated with warfarin. However, several points need to be addressed by the authors before one can accept the conclusion that dabigatran is indeed safer than warfarin with respect to the most feared complication of anticoagulant therapy, cerebral bleeding. In particular, the following questions need to be answered: How was it ascertained in the RE-LY study that the patients randomly chosen for the dabigatran group actually …

Dabigatran for the Prevention of Thromboembolic Complications in the Elderly: A RE-LY-able Alternative to Warfarin?

On October 19, 2010, the Food and Drug Administration approved dabigatran (Pradaxa) for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). The use of warfarin sodium has been considered a mainstay therapy for the prevention of thromboembolic complications secondary to AF. Despite its efficacy among oral antithrombotic agents for the prevention of thromboembolic complications secondary to AF, only about 67% of candidates for warfarin receive appropriate antithrombotic therapy. Dosed twice daily, dabigatran offers recipients the ability to forego regular international normalized ratio coagulation monitoring as well as eliminating dietary restrictions (i.e., vitamin K) associated with warfarin therapy. In a 2011 guideline update, dabigatran has been recognized by the American College of Cardiology and the American Heart Association as a useful alternative to warfarin in patients with AF who are at risk for thromboembolic complications and who are without severe renal or hepatic impairment. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study is the only direct, prospective, comparative clinical trial of dabigatran versus warfarin to date that enrolled subjects for the purpose of examining the ability of dabigatran to prevent stroke and thromboembolic complications associated with nonvalvular AF. Currently, the published literature has not adequately defined which patient populations would be most suitable to treat with dabigatran. While dabigatran has a place in the therapeutic prevention stroke and systemic embolism associated with AF, careful consideration of the risks and benefits of therapy is recommended.

Novel Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: Focus on Apixaban

Stroke prevention in atrial fibrillation (AF) has been challenging over decades, mostly due to a number of difficulties associated with oral vitamin K antagonists (VKAs), which have been the most effective stroke prevention treatment for a long time. The oral direct thrombin inhibitors (e.g., dabigatran) and oral direct inhibitors of factor Xa (e.g., rivaroxaban, apixaban) have emerged recently as an alternative to VKAs for stroke prevention in AF. These drugs act rapidly, and have a predictable and stable dose-related anticoagulant effect with a few clinically relevant drug-drug interactions. The novel oral anticoagulants are used in fixed doses with no need for regular laboratory monitoring of anticoagulation intensity. However, each of these drugs has distinct pharmacological properties that could influence optimal use in clinical practice. The following phase 3 randomized trials with novel oral anticoagulants versus warfarin for stroke prevention in AF have been completed: the Randomized Evaluation of Long-term Anticoagulant therapy (RE-LY) trial with dabigatran, 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 with rivaroxaban, and the Apixaban for Reduction of Stroke and Other Thromboembolism Events in Atrial Fibrillation (ARISTOTLE) trial with apixaban. Moreover, the Apixaban Versus Acetylsalicylic Acid to prevent Strokes (AVERROES) trial included patients with AF who have failed or were unsuitable for warfarin, and compared apixaban versus aspirin for stroke prevention in AF. Overall, apixaban has two large trials for stroke prevention in AF showing benefits not only over warfarin, but also over aspirin among those patients who have failed or refused warfarin. In the ARISTOTLE trial, apixaban was superior to warfarin in the reduction of stroke or systemic embolism, major bleeding, intracranial hemorrhage, and all-cause mortality, with a similar reduction in the rate of ischemic stroke and better tolerability. When compared with aspirin in the AVERROES trial, apixaban was associated with more effective reduction of stroke, a similar risk of major bleeding, and better tolerability. In this review article, the authors summarize the current knowledge on novel oral anticoagulants and discuss the clinical aspects of their use for stroke prevention in AF, with particular emphasis on apixaban.

EP News: Clinical

Hohnloser et al (Circulation 2012;125:669–676, PMID 22215856) evaluated the rates of myocardial infarction (MI), unstable angina, cardiac arrest, and cardiac death and the prespecified net clinical benefit and treatment effects of dabigatran (D) vs warfarin (W) in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study. MI occurred at annual rates of 0.82% and 0.81% with D 110 or 150 mg bid compared with 0.64% with W (hazard ratio [HR] 1.29, P = .09 for D 110 mg; HR 1.27, P = .12 for D 150 mg).

Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With Warfarin or Dabigatran

Intracranial hemorrhage is the most devastating complication of anticoagulation. Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined. Analysis of 18 113 participants with atrial fibrillation in the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial assigned to adjusted-dose warfarin (target international normalized ratio, 2-3) or dabigatran (150 mg or 110 mg, both twice daily). During a mean of 2.0 years of follow-up, 154 intracranial hemorrhages occurred in 153 participants: 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of intracranial hemorrhage were 0.76%, 0.31%, and 0.23% per year among those assigned to warfarin, dabigatran 150 mg, and dabigatran 110 mg, respectively (P<0.001 for either dabigatran dose versus warfarin). Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg (n=13 and n=11, respectively) versus warfarin (n=32; P<0.01 for both). Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran (11 patients with each dose) compared with warfarin (24 patients; P<0.05 for both dabigatran doses versus warfarin). Independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk, 2.9; P<0.001), aspirin use (relative risk, 1.6; P=0.01), age (relative risk, 1.1 per year; P<0.001), and previous stroke/transient ischemic attack (relative risk, 1.8; P=0.001). The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran. Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin. Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage.

Cardiac Biomarkers Are Associated With an Increased Risk of Stroke and Death in Patients With Atrial Fibrillation

Background— Cardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated the prevalence of elevated troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their association to cardiovascular events in atrial fibrillation (AF) patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Methods and Results— Biomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Cox proportional hazards models adjusting for established cardiovascular risk factors and the CHADS 2 and CHA 2 DS 2 -VASc risk scores. Patients were stratified based on troponin I concentrations: &lt;0.010 μg/L, n=2663; 0.010 to 0.019 μg/L, n=2006; 0.020 to 0.039 μg/L, n=1023; ≥0.040 μg/L, n=497; and on NT-proBNP concentration quartiles: &lt;387; 387 to 800; 801 to 1402; &gt;1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.17–3.39]; P =0.0040), and to NT-proBNP with 2.30%/year versus 0.92% in the highest versus lowest NT-proBNP quartile groups, (HR, 2.40 [95% CI, 1.41–4.07]; P =0.0014). Vascular mortality was also independently related to biomarker levels with 6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR, 4.38 [95% CI, 3.05–6.29]; P &lt;0.0001), and 5.00%/year in the highest and 0.61%/year in the lowest NT-proBNP quartile groups (HR, 6.73 [3.95–11.49]; P &lt;0.0001). Biomarkers increased the C-statistic from 0.68 to 0.72, P &lt;0.0001, for a composite of thromboembolic events. Conclusions— Elevations of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond currently used clinical variables. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00262600.

New Oral Anticoagulants for Atrial Fibrillation: A Review of Clinical Trials

BackgroundWarfarin had been the only oral anticoagulant for stroke prevention in patients with atrial fibrillation (AF) for decades. Direct thrombin inhibitors and factor Xa inhibitors are new anticoagulants recently approved for prevention of stroke or systemic embolism in patients with AF. ObjectiveThe aim of this article was to provide a systematic review of recently published clinical data on the direct thrombin inhibitors and factor Xa inhibitors in the management of AF. MethodsA search of the ClinicalTrials.gov registry was conducted using the subject terms dabigatran, rivaroxaban, and apixaban. Each search was limited to clinical trials that included patients with AF. Completed studies with warfarin as the main comparator were identified. From the yielded results, the national clinical trial identifier was inputted in PubMed (1966–November 2011) for a search of published literature. ResultsThree Phase III clinical trials reported the efficacy of each agent in patients who have AF and risk factors for stroke or embolic complications. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study reported dabigatran 150 mg was associated with a lower rate of stroke and systemic embolism, whereas dabigatran 110 mg was associated with a similar rate for such events when compared with warfarin (relative risk = 0.66; 95% confidence interval [CI], 0.53–0.82; P < 0.001; and relative risk = 0.91; 95% CI, 0.74–1.11; P = 0.34, respectively). From the intention-to-treat analysis of 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) study, rivaroxaban was reported to be noninferior to warfarin in reducing stroke or systemic embolism (2.1% vs 2.4% per year; hazard ratio = 0.88; 95% CI, 0.75–1.03; P < 0.001). The Apixaban for Reduction in Stroke and Other Thrombotic Events in Atrial Fibrillation (ARISTOTLE) trial reported that apixaban reduced stroke or systemic embolic events by 21% when compared with warfarin (1.27% vs 1.60% per year, respectively; hazard ratio = 0.79; 95% CI, 0.66–0.95; P < 0.001). All 3 agents were associated with similar bleeding when compared with warfarin. ConclusionsPublished data suggest that all 3 agents are at least as efficacious as dose-adjusted warfarin, with similar major bleeding profiles. For patients who are unwilling to adhere to regular coagulation monitoring or whose therapeutic effect using warfarin is not optimal despite adequate monitoring and management, the inhibitors of direct thrombin or factor Xa may provide alternative choices in anticoagulation.

Alcance de los últimos subestudios del RE-LY: implicaciones clínicas

The approval of the use of dabiatran in stroke prevention in patients with nonvalvular atrial fibrilation (NVAF) is based on the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, one of the largest studies to date in this entity. In this trial, dabigatran showed similar safety and efficacy to warfarin in primary and secondary prevention of stroke in patients with AF. At a dose of 150mg twice daily, dabigatran was superior to warfarin in the prevention of stroke or systemic embolism and the 110mg dose twice daily showed similar eficacy and greater safety, given the lower incidence of hemorrhage. These results were consistently found in the various subanalyses, with some slight differences of interest for clinical practice. The ideal candidates for dabiatran are patients with NVAF suitable for cardioversion, who require short periods of anticoagulation, patients in remote geographical areas with difficulty in achieving good anticoagulation control or good control with anti-vitamin K treatment due to IRN fluctuations, and patients with a low risk of hemorrhage and a CHADS score ≥3 and/or with prior stroke, whenever there are no contraindications. The choice of dabigatran dose should be evaluated according to the patient's individual characteristics (caution must be exercised when prescribing this drug in the elderly and in renal insufficiency) and embolic and/or hemorrhagic risk. Studies of the long-term safety of this drug, pharmacoeconomic analyses in Spain and post-commercialization pharmacovigilance data are required before the definitive uses of this drug can be established.