Background
Phase 3 randomized, partially blinded (dabigatran arms blinded to each other; warfarin open-label). 18,113 patients with non-valvular AF and ≥1 stroke risk factor (CHADS2 ≥1) in 44 countries. Dabigatran etexilate (Pradaxa) is a direct oral thrombin (factor IIa) inhibitor. RE-LY was the pivotal trial establishing the DOAC class for AF anticoagulation. Randomized to 3 arms. Primary stroke prevention. Median follow-up 2 years.
Interventions and follow up
Arm A: Dabigatran 150 mg orally twice daily
Arm B: Warfarin (open-label, dose-adjusted INR 2.0–3.0)
Primary endpoint: Stroke (ischemic or hemorrhagic) or systemic embolism
mFollow up: 2 years (median)
Arm B: Warfarin (open-label, dose-adjusted INR 2.0–3.0)
Primary endpoint: Stroke (ischemic or hemorrhagic) or systemic embolism
mFollow up: 2 years (median)
Results
Stroke/systemic embolism (150mg vs warfarin): 1.11%/yr vs 1.69%/yr, RR 0.66 (95% CI 0.53–0.82), P<.001 for superiority
Major bleeding (150mg vs warfarin): 3.11%/yr vs 3.36%/yr (P=.31)
Intracranial hemorrhage: 0.30%/yr vs 0.74%/yr, P<.001 — significantly lower with dabigatran 150mg
GI bleeding: 1.51%/yr vs 1.02%/yr (150mg higher than warfarin, P<.001)
Mortality: 3.64%/yr vs 4.13%/yr (P=.051)
Major bleeding (150mg vs warfarin): 3.11%/yr vs 3.36%/yr (P=.31)
Intracranial hemorrhage: 0.30%/yr vs 0.74%/yr, P<.001 — significantly lower with dabigatran 150mg
GI bleeding: 1.51%/yr vs 1.02%/yr (150mg higher than warfarin, P<.001)
Mortality: 3.64%/yr vs 4.13%/yr (P=.051)
Adverse events
Main adverse events: Dyspepsia 11.8% (dabigatran 150mg) vs 5.8% (warfarin). GI bleeding higher with dabigatran 150mg. ICH significantly lower vs warfarin. No hepatotoxicity (unlike ximelagatran). MI: numerically higher with dabigatran (0.74% vs 0.53%/yr, P=.048) — clinical significance debated. No routine monitoring needed for dabigatran. Requires renal dose adjustment.
Conclusions
Dabigatran 150 mg BID was superior to warfarin for stroke prevention in AF with similar major bleeding, and significantly lower ICH risk, establishing the first DOAC as superior to warfarin for AF stroke prevention.
Key Limitations
Key Limitations: Warfarin arm was open-label (unblinded) — warfarin TTR was only 64%, below many real-world specialized clinics; this may have inflated the benefit of dabigatran vs optimally-managed warfarin. Dyspepsia with dabigatran led to 9% discontinuation. GI bleeding higher with 150mg. MI signal (debated). No direct reversal agent at time of trial (idarucizumab approved 2015). Renal impairment requires dose reduction; not studied in CrCl <30 mL/min.
Clinical Context
FDA approved October 2010 (Pradaxa) for non-valvular AF. RE-LY launched the DOAC era in AF. Dabigatran 150mg preferred for younger patients at high stroke risk; 110mg (not FDA-approved, used in EU/Canada) preferred in elderly or high bleeding-risk patients. Specific reversal: idarucizumab (Praxbind, 2015). ARISTOTLE (apixaban) and ROCKET-AF (rivaroxaban) demonstrated class benefit; apixaban is now most widely used DOAC for AF in the US.
References