Randomized Evaluation Of Long-Term Anticoagulation Therapy Trial Research Articles

Personalizing the decision of dabigatran versus warfarin in atrial fibrillation: A secondary analysis of the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) trial.

The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial demonstrated that higher-risk patients with atrial fibrillation had lower rates of stroke or systemic embolism and a similar rate of major bleeding, on average, when treated with dabigatran 150mg compared to warfarin. Since population-level averages may not apply to individual patients, estimating the heterogeneity of treatment effect can improve application of RE-LY in clinical practice. For 18040 patients randomized in RE-LY, we used patient-level data to develop multivariable models to predict the risk for stroke or systemic embolism and for major bleeding including all three treatment groups (dabigatran 110mg, dabigatran 150mg, and warfarin) over a median follow up of 2.0 years. The mean predicted absolute risk reduction (ARR) for stroke/systemic embolism with dabigatran 150mg compared to warfarin was 1.32% (range 11.6% lower to 3.30% higher risk). The mean predicted ARR for bleeding was 0.41% (range 8.93% lower to 63.4% higher risk). Patients with increased stroke/systemic embolism risk included those with prior stroke/TIA (OR 2.01), diabetics on warfarin (OR 2.00), and older patients on dabigatran 150mg (OR 1.68 for every 10-year increase). Major bleeding risk was higher in patients on aspirin (OR 1.25), with a history of diabetes (OR 1.34) or prior stroke/TIA (OR 1.22), those with heart failure on dabigatran 110mg (OR 1.52), older patients on either dabigatran 110mg or 150mg (OR 1.57 and 1.93, respectively, for each 10-year increase), and heavier patients on dabigatran 110mg or 150mg; patients in a region outside the United States and Canada and with better renal function had lower bleeding risk. There is substantial heterogeneity in the benefits and risks of dabigatran relative to warfarin among patients with atrial fibrillation. Using individualized estimates may enable shared decision making and facilitate more appropriate use of dabigatran; as such, it should be prospectively tested. www.clinicaltrials.gov number, NCT00262600.

Evaluation of the prognostic value of GDF-15, ABC-AF-bleeding score and ABC-AF-death score in patients with atrial fibrillation across different geographical areas

ObjectivesGrowth differentiation factor 15 (GDF-15) is a biomarker independently associated with bleeding and death in anticoagulated patients with atrial fibrillation (AF). GDF-15 is also used as one component in the...

Evaluation of the Age, Biomarkers, and Clinical History–Bleeding Risk Score in Patients With Atrial Fibrillation With Combined Aspirin and Anticoagulation Therapy Enrolled in the ARISTOTLE and RE-LY Trials

Most patients with atrial fibrillation (AF) and coronary artery disease have indications for preventing stroke with oral anticoagulation therapy and preventing myocardial infarction and stent thrombosis with platelet inhibition. To evaluate whether the recently developed ABC (age, biomarkers, and clinical history)-bleeding risk score might be useful to identify patients with AF with different risks of bleeding during concomitant aspirin and anticoagulation therapy. The biomarkers in the ABC-bleeding risk score (growth differentiation factor 15, hemoglobin, and troponin) were measured in blood samples collected at randomization between 2006 and 2010 in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial and between 2005 and 2009 in the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial, both of which were multinational randomized clinical trials. The trials were reported 2011 and 2009, respectively. A total of 24 349 patients with AF (14 980 patients from the ARISTOTLE trial and 9369 patients from the RE-LY trial) were analyzed in the present cohort study. The median (interquartile range) length of follow-up was 1.8 (1.3-2.3) years in the ARISTOTLE cohort and 2.0 (1.6-2.3) years in the RE-LY cohort. Data analysis was performed from February 2018 to June 2019. Concomitant aspirin treatment during study follow-up. Time to first occurrence of a major bleeding was determined according to International Society on Thrombosis and Hemostasis definition. Hazard ratios were estimated with Cox models adjusted for ABC-bleeding risk score and randomized treatment. The median (interquartile range) age was 70 (63-76) years in the ARISTOTLE cohort and 72 (67-77) years in the RE-LY cohort (5238 patients [35.6%] in the ARISTOTLE cohort and 3086 patients [36.4%] in the RE-LY cohort were women). The total number of patients with a first major bleeding event was 651 (207 with aspirin and 444 without) in ARISTOTLE and 463 (238 with aspirin and 225 without) in RE-LY. For both cohorts, in those with a low ABC-bleeding risk score, the absolute bleeding rate was low even with concomitant aspirin treatment, whereas in those with a higher ABC-bleeding risk score, the rate of bleeding was higher with concomitant aspirin compared with oral anticoagulation alone (ARISTOTLE, hazard ratio, 1.65; 95% CI, 1.40-1.95; P < .001; RE-LY, hazard ratio, 1.70; 95% CI, 1.42-2.04; P < .001). Thus, a low annual ABC-bleeding risk (eg, 0.5% without aspirin use) would with concomitant aspirin result in an annual rate of 0.8%, and a high estimated ABC-bleeding risk (eg, 3.0%) would result in a substantially higher rate of 5.0%. These findings suggest that the ABC-bleeding risk score identifies patients with different risks of bleeding when combining aspirin and oral anticoagulation. The ABC-bleeding risk score may, therefore, be a useful tool for decision support concerning intensity and duration of combination antithrombotic treatment in patients with AF and coronary artery disease.

Growth-differentiation factor 15 and risk of major bleeding in atrial fibrillation: Insights from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial

To evaluate and validate the prognostic value of growth-differentiation factor 15 (GDF-15) beyond clinical characteristics and other biomarkers concerning bleeding and stroke outcomes in patients with atrial fibrillation in the RE-LY trial. GDF-15 was measured in samples collected at randomization in 8,474 patients with a median follow-up time of 1.9 years. Patients were stratified based on predefined GDF-15 cutoffs: group 1, <1,200 ng/L (the 90th percentile in healthy individuals); group 2, 1,200-1,800; and group 3, >1,800 ng/L (high-risk individuals). Efficacy and safety outcomes were compared across groups of GDF-15 in Cox models adjusted for baseline characteristics, cardiac (N-terminal pro-b-type natriuretic peptide, high-sensitive troponin T), inflammatory (interleukin 6, C-reactive protein) and coagulation (D-dimer) biomarkers, and randomized treatment. GDF-15 concentrations were <1,200 ng/L in 2,647 (31.2%), between 1,200 and 1,800 ng/L in 2,704 (31.9%), and >1,800 ng/L in 3,123 (36.9%) participants, respectively. Annual rates of stroke, major bleeding, and mortality increased with higher GDF-15 levels. The prognostic value of GDF-15 was independent of clinical characteristics for these outcomes. In models also adjusted for biomarkers, GDF-15 remained significantly associated with major bleeding (hazard ratio [95% CI] group 3 vs group 1 1.76 [1.28-2.42], P < .0005) and all-cause mortality (hazard ratio 1.72 [1.30-2.29], P < .0005). GDF-15 improved the c index of both the HAS-BLED (0.62-0.69) and ORBIT (0.68-0.71) bleeding risk scores. In patients with atrial fibrillation, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but not for stroke. Therefore, GDF-15 seems useful as a specific marker of bleeding in patients with AF on oral anticoagulant treatment.

A Review of the Clinical Subgroup Analyses From the RE-LY Trial

Dabigatran was the first direct-acting oral anticoagulant approved by the US Food and Drug Administration for prevention of stroke and systemic embolism in people with atrial fibrillation, based on data from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Over 18,000 patients with nonvalvular atrial fibrillation and a moderate-to-high risk of thromboembolic stroke were randomized to warfarin or dabigatran. With respect to the primary endpoints for efficacy and safety, dabigatran was superior to warfarin in the prevention of stroke and thromboembolism and noninferior with respect to major bleeding. Although unified by a common arrhythmia and a similar thromboembolic stroke risk, this large patient population is also significantly heterogeneous with respect to other demographics and comorbidities that raise important questions about the efficacy and safety of dabigatran in specific patient populations. Furthermore, there were significant differences between the warfarin and dabigatran groups with respect to several important secondary endpoints. Understanding the differences in outcomes between specific patient subgroups from the RE-LY trial can better inform the practicing clinician's ability to offer the best anticoagulation options to individual patients.

Changes in Renal Function in Patients With Atrial Fibrillation: An Analysis From the RE-LY Trial

BackgroundVitamin K–dependent factors protect against vascular and renovascular calcification, and vitamin K antagonists may be associated with a decreased glomerular filtration rate (GFR). ObjectivesThis study analyzed changes in GFR during long-term treatment with warfarin or dabigatran etexilate (DE) in patients enrolled in the RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy) trial. MethodsOf the 18,113 patients in the RE-LY study randomized to receive DE (110 mg or 150 mg twice daily) or warfarin, 16,490 patients with atrial fibrillation had creatinine values measured at baseline and at least 1 follow-up visit. Changes in GFR for up to 30 months were evaluated. ResultsGFR declined in all treatment groups. After an average of 30 months, the mean ± SE decline in GFR was significantly greater with warfarin (–3.68 ± 0.24 ml/min) compared with DE 110 mg (–2.57 ± 0.24 ml/min; p = 0.0009 vs. warfarin) and DE 150 mg (–2.46 ± 0.23 ml/min; p = 0.0002 vs. warfarin). A decrease in GFR >25% was less likely with DE 110 mg (hazard ratio: 0.81 [95% confidence interval: 0.69 to 0.96]; p = 0.017) or DE 150 mg (hazard ratio: 0.79 [95% confidence interval: 0.68 to 0.93]; p = 0.0056) than with warfarin in the observation period >18 months. Patients with poor international normalized ratio control (i.e., time in therapeutic range <65%) exhibited a faster decline in GFR. A more pronounced decline in GFR was associated with previous warfarin use and with the presence of diabetes. ConclusionsPatients with atrial fibrillation receiving oral anticoagulation exhibited a decline in renal function that was greater in those taking warfarin versus DE, and it was amplified by diabetes and previous vitamin K antagonist use. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600)

ACP Journal Club. In atrial fibrillation, dabigatran had similar efficacy to warfarin but caused less bleeding in higher GFR.

Source Citation Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: A RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation. 2014;129:961-70. 24323795

Cost-Effectiveness of Apixaban Versus Other New Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation

BackgroundApixaban (5 mg BID), dabigatran (available as 150 mg and 110 mg BID in Europe), and rivaroxaban (20 mg once daily) are 3 novel oral anticoagulants (NOACs) currently approved for stroke prevention in patients with atrial fibrillation (AF). ObjectiveThe objective of this study was to evaluate the cost-effectiveness of apixaban against other NOACs from the perspective of the United Kingdom National Health Services. MethodsA Markov model was developed to evaluate the pharmacoeconomic impact of apixaban versus other NOACs over a lifetime. Pair-wise indirect treatment comparisons were conducted against other NOACs by using ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), and ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial results for the following end points: ischemic stroke, hemorrhagic stroke, intracranial hemorrhage, other major bleeds, clinically relevant nonmajor bleeds, myocardial infarction, and treatment discontinuations. Outcomes were life-years, quality-adjusted life years gained, direct health care costs, and incremental cost-effectiveness ratios. ResultsApixaban was projected to increase life expectancy versus other NOACs, including dabigatran (both doses) and rivaroxaban. A small increase in therapeutic management costs was observed with apixaban due to projected gains in life expectancy and lower discontinuation rates anticipated on apixaban versus other NOACs through lifetime. The estimated incremental cost-effectiveness ratio was £9611, £4497, and £5305 per quality-adjusted life-year gained with apixaban compared with dabigatran 150 mg BID, dabigatran 110 mg BID, and rivaroxaban 20 mg once daily, respectively. Sensitivity analyses indicated that results were robust over a wide range of inputs. ConclusionsAlthough our analysis was limited by the absence of head-to-head trials, based on the indirect comparison data available, our model projects that apixaban may be a cost-effective alternative to dabigatran 150 mg BID, dabigatran 110 mg BID, and rivaroxaban 20 mg once daily for stroke prevention in AF patients from the perspective of the United Kingdom National Health Services.

Thromboembolism in a Patient With a Mechanical Mitral Valve During Anticoagulation With Dabigatran Etexilate

Recently, several new anticoagulants have been used instead of warfarin for preventing thromboembolism. In the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, the direct thrombin inhibitor dabigatran etexilate was as an effective and safe as dose-adjusted warfarin for prevention of stroke in high-risk patients with atrial fibrillation. However, the safety and efficacy of thromboprophylaxis after mechanical valve replacement is uncertain. We report a 57-year-old man with a mechanical heart valve who experienced acute upper limb thromboembolism during dabigatran intake. Dabigatran might be inadequate for thromboprophylaxis after mechanical valve replacement.

The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy)

The goal of this study was to analyze the impact of dabigatran plasma concentrations, patient demographics, and aspirin (ASA) use on frequencies of ischemic strokes/systemic emboli and major bleeds in atrial fibrillation patients. The efficacy and safety of dabigatran etexilate were demonstrated in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, but a therapeutic concentration range has not been defined. In a pre-specified analysis of RE-LY, plasma concentrations of dabigatran were determined in patients treated with dabigatran etexilate 110 mg twice daily (bid) or 150 mg bid and correlated with the clinical outcomes of ischemic stroke/systemic embolism and major bleeding using univariate and multivariate logistic regression and Cox regression models. Patient demographics and ASA use were assessed descriptively and as covariates. Plasma concentrations were obtained from 9,183 patients, with 112 ischemic strokes/systemic emboli (1.3%) and 323 major bleeds (3.8%) recorded. Dabigatran levels were dependent on renal function, age, weight, and female sex, but not ethnicity, geographic region, ASA use, or clopidogrel use. A multiple logistic regression model (c-statistic 0.657, 95% confidence interval [CI]: 0.61 to 0.71) showed that the risk of ischemic events was inversely related to trough dabigatran concentrations (p = 0.045), with age and previous stroke (both p < 0.0001) as significant covariates. Multiple logistic regression (c-statistic 0.715, 95% CI: 0.69 to 0.74) showed major bleeding risk increased with dabigatran exposure (p < 0.0001), age (p < 0.0001), ASA use (p < 0.0003), and diabetes (p = 0.018) as significant covariates. Ischemic stroke and bleeding outcomes were correlated with dabigatran plasma concentrations. Age was the most important covariate. Individual benefit-risk might be improved by tailoring dabigatran dose after considering selected patient characteristics. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600).

Dabigatran: Is There a Role for Coagulation Assays in Guiding Therapy?

To determine the usefulness of coagulation assay monitoring for dabigatran etexilate in certain high-risk clinical situations. Literature retrieval was accessed through MEDLINE (1948-February 2013), Web of Science (1980-February 2013), International Pharmaceutical Abstracts (1977-February 2013), and Google Scholar using the terms dabigatran, dabigatran etexilate, BIBR 1048, BIBR 953, direct thrombin inhibitor, therapeutic monitoring, and atrial fibrillation. In addition, abstracts presented at the 2011-2012 American Society of Hematology, American College of Cardiology, International Society of Thrombosis and Haemostasis, and European Society of Cardiology annual meetings were reviewed. A search of Clinicaltrials.gov was performed to identify relevant ongoing or completed research. All English-language articles identified from the data sources were evaluated for inclusion. Priority was placed on all data derived from controlled clinical studies. Of the 6 published Phase 3 studies, only the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial evaluated the safety and efficacy of dabigatran for the prevention of stroke in patients with nonvalvular atrial fibrillation. Post hoc analyses of the RE-LY trial have provided additional information in special situations. Several published reports highlight the potential for complications with dabigatran, the importance of determining the most optimal candidates, and the need for therapeutic monitoring. Activated partial thromboplastin time and thrombin time are effective qualitative assays for dabigatran. Ecarin clotting time and the dilute thrombin time (ie, Hemoclot direct thrombin inhibitor) assays are suitable for quantitative measurement. The correlation between coagulation-based assays and clinical out comes among dabigatran-treated patients has not been definitively established. However, coagulation-based assays may be useful in the management of several clinical scenarios.

Response to Letters Regarding Article, “Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin: Results From the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial”

RE-LY is the largest randomized experience reporting outcomes after interruption of anticoagulant therapy.1 There was no excess of bleeding in patients taking dabigatran, including those having major or urgent surgery.1 David and colleagues correctly state that the majority of procedures performed during the RE-LY trial were minor. Nonetheless, our analysis included 1482 major procedures that had a 6% to 8% rate of major bleeding,1 which was numerically lower among dabigatran-treated patients.1 Hjemdahl et al opine that the high rate of major bleeding in RE-LY patients assigned to dabigatran 150 mg twice daily who had interruption for >72 hours before surgery suggests accumulation of dabigatran in patients with renal impairment. However, data from RE-LY do not support this interpretation, because the same pattern …

Letter by Hjemdahl et al Regarding Article, “Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin: Results From the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial”

To the Editor: We read with interest the report by Healy and coworkers1 on periprocedural bleeding and thromboembolic events in the RE-LY trial, which indicates that 10% to 15% of atrial fibrillation patients on oral anticoagulants may need a surgical operation or other invasive procedure annually. There is concern in these situations about how to avoid and how to manage serious bleeds during anticoagulant treatment, especially with new oral anticoagulants such as dabigatran, which lacks a specific antidote.2–4 It is difficult to evaluate the intensity of anticoagulation in dabigatran-treated patients. Routinely used coagulation tests such as the activated partial thromboplastin time are not sufficiently reliable. More specific tests (ecarin …

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 …

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.

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 ...

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.

Myocardial Ischemic Events in Patients With Atrial Fibrillation Treated With Dabigatran or Warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) Trial

There is a modest risk of myocardial infarction (MI) and myocardial ischemic events in patients with atrial fibrillation. Data from the RE-LY study (Randomized Evaluation of Long-Term Anticoagulation Therapy) were used to report rates of MI, unstable angina, cardiac arrest, and cardiac death and the prespecified net clinical benefit and treatment effects of dabigatran versus warfarin. MI occurred at annual rates of 0.82% and 0.81% with dabigatran 110 or 150 mg BID compared with 0.64% with warfarin (hazard ratio [HR] 1.29, 95% confidence interval [CI] 0.96-1.75, P=0.09 for dabigatran 110 mg; HR 1.27, 95% CI 0.94-1.71, P=0.12 for dabigatran 150 mg). Annual rates of a composite of MI, unstable angina, cardiac arrest, and cardiac death were 3.16% per year with dabigatran 110 mg, 3.33% per year with dabigatran 150 mg, and 3.41% per year with warfarin (HR versus warfarin 0.93, 95% CI 0.80-1.06, P=0.28 for dabigatran 110 mg and HR 0.98, 95% CI 0.85-1.12, P=0.77 for dabigatran 150 mg). Events prespecified as "net clinical benefit" (all strokes, systemic embolism, MI, pulmonary embolism, major bleeding, and all-cause death) occurred at a rate of 7.34% per year with dabigatran 110 mg, 7.11% per year with dabigatran 150 mg, and 7.91% per year with warfarin (HR 0.92, 95% CI 0.84-1.01, P=0.09 for dabigatran 110 mg and HR 0.90, 95% CI 0.82-0.99, P=0.02 for dabigatran 150 mg). The relative effects of dabigatran versus warfarin on myocardial ischemic events were consistent in patients with or without a baseline history of MI or coronary artery disease. There was a nonsignificant increase in MI with dabigatran compared with warfarin, but other myocardial ischemic events were not increased. Treatment effects of dabigatran were consistent in patients at higher and lower risk of myocardial ischemic events.

Dabigatran For Stroke Prevention In Patients With Atrial Fibrillation and Previous Stroke Or Transient Ischemic Attack: Does Dose Matter?

Evaluation of: Diener HC, Connolly SJ, Ezekowitz MD et al.: Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol. 9(12), 1157–1163 (2010). This study aimed to assess the efficacy and safety of daibgatran in two doses (110 and 150 mg) compared with warfarin in a prespecified subgroup analysis of patients with previous stroke or transient ischemic attack in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. There were nonsignificant risk reductions for the primary outcome (stroke and systemic embolism) for both doses of dabigatran compared with warfarin in this subgroup of patients. However, the 110-mg dose of dabigatran provided significantly greater reductions of mortality and higher net clinical benefit compared with warfarin. This was not seen in the 150-mg dose. The bleeding complication rates of this subgroup were consistent with the main RE-LY trial. In the warfarin group, patients with previous history of stroke or transient ischemic attack developed more intracranial bleeding than patients without this history, but this was not the case in dabigatran treatment groups.

Newly Identified Events in the RE-LY Trial

To the Editor: We wish to update our article about the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (Sept. 17, 2009, issue).1 After the database was locked on August 15, 2009, we identified several additional primary efficacy and safety outcome events during routine clinical site closure visits. These events included two systemic embolic events and nine major hemorrhages. Subsequently, after discussions with the Food and Drug Administration, the primary and secondary efficacy and safety data were checked for consistency, and the study database was reevaluated for possible underreporting of events. To achieve this, all free text, outcomes, and adverse . . .