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Randomized Evaluation of Long-Term Anticoagulant Therapy - RE-LY
Contribution To Literature:
The RE-LY trial showed that dabigatran 150 mg twice daily was superior to warfarin at reducing stroke or systemic embolism.
Description:
The goal of the trial was to evaluate the efficacy and safety of two doses of the novel oral direct thrombin inhibitor dabigatran compared with warfarin among patients with atrial fibrillation.
Study Design
- Randomized
- Parallel
Patients Enrolled: 18,113
Follow-up: Median 2.0 years
Mean Patient Age: 71 years
Female: 37%
Patient Populations:
Atrial fibrillation documented with electrocardiogram on the day of screening or within the prior 6 months, and at least one of the following: prior stroke or transient ischemic attack, left ventricular ejection fraction <40%, New York Heart Association class II or higher heart failure within 6 months before screening, age ≥75 years or age 65-74 plus diabetes, hypertension, or coronary artery disease
Exclusions:
Presence of severe heart valve disorder, stroke within 14 days or severe stroke within 6 months, a condition that increased risk of hemorrhage, creatinine clearance <30 ml/min, or active liver disease
Primary Endpoints:
Efficacy: Stroke or systemic embolism, evaluated for noninferiority of each dose of dabigatran compared with warfarin
Safety: Major hemorrhage
Secondary Endpoints:
All stroke, systemic embolism, and death
Drug/Procedures Used:
Patients were randomized to one of two doses of dabigatran twice daily (110 mg, n = 6,015; 150 mg, n = 6,076; blinded to study drug dose) or to open-label warfarin (n = 6,022). Warfarin was dose-adjusted to a target international normalized ratio (INR) of 2.0-3.0; INR was to be measured at least monthly.
Principal Findings:
At study entry, type of atrial fibrillation was evenly divided as persistent (32%), paroxysmal (33%), and permanent (35%). Half of the patients in the trial were on long-term vitamin K antagonist (VKA) therapy, defined as ≥61 days during their lifetime. Mean CHADS2 score was 2.1. The mean percentage of time with an INR in the therapeutic range in the warfarin group was 64%. Study drug discontinuation at 2 years was 21% in the dabigatran groups and 16.6% in the warfarin group.
The primary endpoint of stroke or systemic embolism occurred in 1.53%/year in the dabigatran 110 mg group and 1.11%/year in the dabigatran 150 mg group compared with 1.69%/year in the warfarin group, meeting the criteria for noninferiority in both groups. The dabigatran 150 mg group also met superiority criteria (relative risk [RR] 0.66, 95% confidence interval [CI] 0.53-0.82, p < 0.001). There was no evidence for interaction by age with either dose of dabigatran versus warfarin. Patients with prosthetic heart valves, significant mitral stenosis, and valvular disease requiring intervention were excluded; however, patients with other types of valvular heart disease could be enrolled. The interpretation for the primary outcome was the same among those with valvular heart disease.
The secondary endpoint of stroke was also significantly lower in the dabigatran 150 mg group (1.01%/year) compared with warfarin (1.57%/year, RR 0.64, 95% CI 0.51-0.81, p < 0.001).
Death from vascular causes was lower in the dabigatran 150 mg group (2.28%/year) compared with warfarin (2.69%/year, RR 0.85, 95% CI 0.72-0.99, p = 0.04), but the dabigatran 110 mg group was not (2.43%/year, RR 0.90, 95% CI 0.77-1.06, p = 0.21). Results were similar for all-cause mortality: warfarin 4.13%/year, dabigatran 150 mg group 3.64%/year (RR 0.88, 95% CI 0.77-1.00, p = 0.051), dabigatran 110 mg 3.75%/year, (RR 0.91, 95% CI 0.80-1.03, p = 0.13).
The primary safety endpoint of major bleeding occurred at a rate of 3.36%/year in the warfarin group, which was higher than the dabigatran 110 mg group (2.71%/year, RR 0.80, 95% CI 0.69-0.93, p = 0.003), but did not differ from the dabigatran 150 mg group (3.11%/year, RR 0.93, 95% CI 0.81-1.07, p = 0.31). There was an interaction effect between age and major bleeding. Patients <75 years of age had less major bleeding and extracranial major bleeding with either dose of dabigatran compared with warfarin. There was no interaction effect between age and intracranial bleeding.
GI bleeding was more frequent in the dabigatran 150 mg group compared with warfarin (1.51%/year vs. 1.02%/year, p < 0.001). Both doses of dabigatran had significantly lower rates of major or minor bleeding compared with warfarin (14.62%/year for dabigatran 110 mg, 16.42%/year for dabigatran 150 mg, and 18.15%/year for warfarin). Bleeding outcomes remained the same, irrespective of the degree of INR control at individual centers.
The net clinical benefit outcome, which was a composite of stroke, systemic embolism, pulmonary embolism, myocardial infarction, death, or major bleeding, favored the dabigatran 150 mg group over warfarin (RR 0.91, 95% CI 0.82-1.00, p = 0.04), but did not differ between the dabigatran 110 mg group versus warfarin (RR 0.92, 95% CI 0.84-1.02, p = 0.10). Dyspepsia occurred more frequently with dabigatran than warfarin (11.8% in the 110 mg group and 11.3% in the 150 mg group vs. 5.8% in the warfarin group, p < 0.001). There was no difference in liver function tests.
Cardiovascular outcomes and achieved blood pressure:
Among patients with achieved systolic blood pressure (SBP) <110 mm Hg versus 120 to <130 mm Hg, all-cause death was increased (hazard ratio [HR] 2.78, 95% CI 2.28-3.38) and major bleeding was increased (HR 2.17, 95% CI 1.71-2.75).
Among patients with achieved SBP ≥160 mm Hg versus 120 to <130 mm Hg, all-cause death was increased (HR 1.79, 95% CI 1.24-2.60); however, major bleeding was not increased (HR 1.37, 95% CI 0.91-2.06).
Findings were the same for diastolic blood pressure categories.
Interpretation:
Among patients with atrial fibrillation, treatment with the novel oral direct thrombin inhibitor dabigatran at the 150 mg dose was superior to warfarin in reducing stroke or systemic embolism, with a similar bleeding profile; treatment with dabigatran at the 110 mg dose was noninferior to warfarin for stroke or systemic embolism, but was associated with lower bleeding rates. Dabigatran was associated with fewer intracranial bleeding events versus warfarin across the age spectrum. For other bleeding events, this relationship was more complex. Either dose of dabigatran was associated with fewer major bleeding and extracranial major bleeding events versus warfarin for younger patients, while among older patients, either dose of dabigatran was associated with more major bleeding and extracranial major bleeding events versus warfarin.
There was a J-shape relationship between SBP and adverse events such that all-cause mortality and major bleeding were increased with the lowest on-treatment SBP category. All-cause mortality but not major bleeding was increased with the highest on-treatment SBP category.
Warfarin therapy, which is recommended for patients with atrial fibrillation who are at risk for stroke, reduces the risk of stroke, but can be difficult to keep in the target therapeutic range and is associated with increased bleeding complications. Alternatives to warfarin have been difficult to develop. Another direct thrombin inhibitor, ximelagatran, showed promise in terms of efficacy and bleeding, but was associated with severe hepatotoxicity. Dabigatran did not appear to have a hepatotoxic effect in the trial, but did show a favorable efficacy and bleeding profile.
References:
Böhm M, Brueckmann M, Eikelboom JW, et al. Cardiovascular outcomes, bleeding risk, and achieved blood pressure in patients on long-term anticoagulation with the thrombin antagonist dabigatran or warfarin: data from the RE-LY trial. Eur Heart J 2020;41:2848-59.
Lauw MN, Eikelboom JW, Coppens M, et al. Effects of dabigatran according to age in atrial fibrillation. Heart 2017;103:1015-23.
Ezekowitz MD, Nagarakanti R, Noack H, et al. Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy). Circulation 2016;134:589-98.
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.
Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. Circulation 2011;123:2363-72.
Presented by Dr. Lars Wallentin at the American Heart Association Scientific Sessions, Orlando, FL, November 15, 2009.
Presented by Dr. Stuart Connolly at the European Society of Cardiology Congress, Barcelona, Spain, August 2009.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Hypertension
Keywords: Vitamin K, Risk, Coronary Artery Disease, Myocardial Infarction, Stroke, Pulmonary Embolism, Warfarin, Electrocardiography, Dyspepsia, International Normalized Ratio, Liver Function Tests, beta-Alanine, Azetidines, Benzylamines, Benzimidazoles, Heart Failure, Stroke Volume, Atrial Fibrillation, Hypertension, Diabetes Mellitus, Heart Valve Diseases, Anticoagulants, Hemorrhage, Blood Pressure
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