Dabigatran is non-inferior to warfarin in patients with atrial fibrillation: Results of the RE-LY trial

September 3, 2009 by Katherine Ogando

ESC Congress 2009- Barcelona, ES: Among patients with atrial fibrillation (AF), dabigatran is non-inferior to warfarin in lowering the risk of stroke and systemic embolism, according to the results of the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial. Dr. Stuart J. Connolly, on behalf of the RE-LY investigators, presented the results at the annual ESC Congress Hotline Session.

Background
The goal of the RE-LY trial was to assess the effectiveness of 110 mg and 150 mg of dabigatran against warfarin in patients presenting with AF and at least one risk factor for stroke. Prior studies have demonstrated that vitamin K antagonists (VKAs) such as warfarin are effective at significantly reducing the risk of stroke in AF patients. Vitamin K antagonists such as coumadin must be monitored carefully when administered due to an increased risk of bleeding risk and the inconsistency in maintaining the international normalized ratio (INR). The RE-LY investigators hypothesized that dabigatran, at the dosages pre-determined by phase 2 clinical trials, would be non-inferior to warfarin in efficacy and safety.

Methods
RE-LY recruited 18,113 patients from 44 countries in the phase 3, prospective, randomized and open label trial. 6,022 patients were randomized to warfarin (open-label), 6,015 patients were randomized to 110 mg of dabigatran and 6,076 patients were randomized to 150 mg of dabigatran twice daily (blinded). Participating patients had documented atrial fibrillation within 6 months of enrollment and a history of stroke or transient ischemic attack (TIA), left ventricular ejection fraction less than 40%, or a New York Heart Association (NYHA) class II within 6 months. Other inclusion criteria included age of at least 75 years, or 65-74 years if presenting with diabetes mellitus, hypertension, or coronary artery disease (CAD). Patients who had experienced stroke within 14 days of enrollment or severe stroke within 6 months, severe heart-valve disease, were at an increased risk of hemorrhage, or had a creatinine clearance under 30 ml per minute were excluded from trial participation.

The primary endpoint was stroke or systemic embolism assessed for both doses of dabigatran and compared to the standard warfarin. Secondary endpoints included all stroke, systemic embolism, and mortality. The safety endpoint was major bleeding, or hemorrhage. The trial investigators specified the non-inferiority margin as 1.46.

Results
The mean age of the study participants was 71 years. The average CHADS score was 2.1 and the median follow-up period for the trial was 2 years. About half of the patients enrolled were warfarin-naïve and an average of 64% of the warfarin patients were in therapeutic range. The inclusion criteria permitted the use of aspirin, and the proportion of patients receiving 110 mg of dabigatran, 150 mg of dabigatran, and warfarin treated with aspirin throughout the duration of the study was 21.1%, 19.6%, and 20.8% of patients, respectively.

Both doses of dabigatran fell below the non-inferiority margin, with 150 mg of dabigatran actually reaching superiority over warfarin. The primary outcome was observed in 1.53% of patients treated with 110 mg of dabigatran (n=182) and 1.11% of patients treated with 150 mg of dabigatran (n=134), compared to 1.69% of patients treated with warfarin (n=199) (RR 0.91 [95% CI: 0.74-1.11]; p=0.34 ; RR 0.66 [95% CI: 0.53-0.82]; p<0.001 for dabigatran 110mg and 150 mg vs. warfarin, respectively). The dabigatran 150 mg group also experienced lower rates than the warfarin group for the secondary endpoint of stroke, at a rate of 1.01% per year, compared to 1.57% per year (RR 0.64 [95% CI: 0.51-0.81] p<0.001). The rates for dabigatran 110 mg, 1.4% per year,  were not significantly different from warfarin (RR 0.92 [95% CI: 0.74-1.13] p=0.41).

Dabigatran was also associated with a decreased rate of hemorrhagic stroke, with 0.12% and 0.10% in the dabigatran 110 mg (RR 0.31 [95% CI 0.17-0.56] p<0.001) and 150 mg (RR 0.26 [95% CI: 0.14-0.49] p<0.001), respectively, compared to 0.38% per year in warfarin patients. All-cause mortality rates were 4.13% per year for warfarin, compared to 3.75% with 110 mg and 3.64% with 150 mg of dabigatran (RR 0.91 [95% CI: 0.80-1.03] p=0.13; RR 0.88 [95% CI: 0.77-1.00] p=0.051, respectively). Dabigatran was associated with higher myocardial infarction (MI) rates than warfarin, with the 110 mg group at 0.72% per year (RR 1.35 [95% CI: 0.98-1.87] p=0.07) and the 150 mg group at 0.74% per year (RR 1.38 [95% CI: 1.00-1.91] p=0.048), compared to 0.53% rate with warfarin.

Bleeding rates for the warfarin group were 3.36% per year, compared to 2.71% in patients who were administered 110 mg dabigatran (RR 0.80 [95% CI 0.69-0.93] p=0.003) and 3.11% in the 150 mg dabigatran group (RR 0.93 [95% CI 0.81-1.07] p=0.31). Higher rates of gastrointestinal (GI) bleeding were observed in the 150 mg dabigatran group than with the warfarin group (1.5% vs 1.0% respectively; RR 1.50 [95% CI 1.19-1.89] p<0.001). The composite of MI, death, major bleed net clinical benefit supported dabigatran therapy: the rates for warfarin were 7.64%, and 7.09% for 110 mg dabigatran (RR 0.92 [95% CI 0.84-1.02] p=0.10) and 6.91% for 150 mg dabigatran (RR 0.91 [95% CI 0.82-1.00] p=0.04). The adverse event that occurred most frequently on dabigatran patients was dyspepsia (11.8%, 11.3%, 5.8% on dabigatran 110 mg, 150 mg, and warfarin [p<0.001], respectively).

Interpretation
The results suggest that a therapy of 150 mg of dabigatran twice daily is associated with lower stroke and systemic embolism events, while maintaining similar bleeding rates to warfarin. 110 mg of dabigatran twice daily is associated with lower bleeding rates than warfarin. The patients to whom dabigatran was administered did not experience excess hepatotoxicity, although the results show higher rates of dyspepsia. The dyspepsia is thought to be due to the tartaric acid coating of the dabigatrin pill that creates an acidic microenvironment to improve the bioabsorption of dabigatrin.

Interpretation
The RE-LY trial is the first to demonstrate a safe and effective alternative to warfarin, and with 18,113 patients enrolled, it is the largest trial to date that explores alternatives in AF stroke prevention. Prior research on alternative pharmacotherapy have had limited success due to inferiority with respect to efficacy and safety, or an association with adverse side effects. The investigators noted that this is the first study of its kind to include equal numbers of patients who were and were not treated with long-term VKA therapy. The use of two doses of dabigatran was also unusual, though it allowed for further research on therapy modification to fit specific patient characteristics.

Dabigatrin is a factor II inhibitor.

Sponsorship
The RE-LY trial was sponsored by Boehringer-Ingelheim.

PowerPoint Presentation
[[Media:RELY.ppt]]