Randomized Evaluation of Long-Term Anticoagulant Therapy - RE-LY

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.

Contribution to the Literature: The RE-LY trial showed that dabigatran 150 mg twice daily was superior to warfarin at reducing stroke or systemic embolism.

Study Design

  • Randomized
  • Parallel

Patients Enrolled: 18,113
Mean 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). 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 younger than 75 years of age had less major bleeding with either dose of dabigatran compared with warfarin. Among patients 75 years of age or older, there was similar major bleeding with the dabigatran 110 group compared with the warfarin group; however, there was a trend toward more bleeding with the dabigatran 150 group compared with the warfarin group.

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.

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. While dabigatran 150 mg twice daily would appear to be preferential in younger patients, there was a trend toward more bleeding in older patients compared with warfarin, which might make the 110 mg twice daily dose more attractive in this group.

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:

Ezekowitz MD, Nagarakanti R, Noack H, et al. Comparison of Dabigatran versus Warfarin in Patients with Atrial Fibrillation and Valvular Heart Disease: The RE-LY Trial. Circulation 2016;Aug 5:[Epub ahead of print].

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, 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


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