Background
Phase 3 double-blind, double-dummy non-inferiority RCT (RE-COVER). 2,564 patients with acute symptomatic VTE (proximal DVT or PE), receiving initial parenteral anticoagulation (heparin or LMWH, median 9 days). Randomized to 6 months of dabigatran vs warfarin. Dabigatran requires initial parenteral therapy (cannot be started without it — unlike rivaroxaban/apixaban which have oral lead-in doses). Double-blind design with matched placebos. Median follow-up 6 months.
Interventions and follow up
Arm A: Dabigatran 150 mg orally twice daily (after initial heparin/LMWH ≥5 days)
Arm B: Warfarin dose-adjusted to INR 2.0–3.0 (after initial heparin/LMWH)
Primary endpoint: Recurrent symptomatic VTE or VTE-related death at 6 months (non-inferiority margin: HR <2.75 or <3.0, absolute difference <1.55%)
mFollow up: 6 month
Arm B: Warfarin dose-adjusted to INR 2.0–3.0 (after initial heparin/LMWH)
Primary endpoint: Recurrent symptomatic VTE or VTE-related death at 6 months (non-inferiority margin: HR <2.75 or <3.0, absolute difference <1.55%)
mFollow up: 6 month
Results
Recurrent VTE or VTE death: 2.4% (dabigatran) vs 2.1% (warfarin), HR 1.10 (95% CI 0.65–1.84) — non-inferior (P<.001 for NI)
Major bleeding: 1.6% vs 1.9% (HR 0.82, P=.39) — not significantly different
Clinically relevant non-major bleeding: 5.6% vs 8.8%, P<.001
Any bleeding: 16.1% vs 21.9%, P<.001
Major bleeding: 1.6% vs 1.9% (HR 0.82, P=.39) — not significantly different
Clinically relevant non-major bleeding: 5.6% vs 8.8%, P<.001
Any bleeding: 16.1% vs 21.9%, P<.001
Adverse events
Main adverse events: Overall bleeding substantially lower with dabigatran. Dyspepsia 2.9% vs 0.6%. ICH: none in dabigatran vs 1 in warfarin. GI bleeding not significantly different. No hepatotoxicity. Discontinuation due to AEs: 9.0% vs 6.8%. Renal dose adjustment required (GFR <30 mL/min excluded).
Conclusions
Dabigatran was non-inferior to warfarin for VTE treatment with significantly lower overall and clinically relevant non-major bleeding, establishing dabigatran as an effective alternative to warfarin for acute VTE management.
Key Limitations
Key Limitations: Requires initial parenteral anticoagulation (unlike EINSTEIN and AMPLIFY rivaroxaban/apixaban which have oral lead-in), adding complexity. Non-inferiority design — cannot claim superiority for efficacy. Warfarin TTR 60%. RE-COVER II (similarly designed, N=2568) confirmed non-inferiority. Dyspepsia rate higher. No specific dose for DVT vs PE (unlike rivaroxaban's higher initiation dose for 21 days). Not preferred over rivaroxaban/apixaban in VTE due to parenteral requirement.
Clinical Context
FDA approved for VTE treatment April 2014 (Pradaxa). Dabigatran requires parenteral bridging, making it less convenient than rivaroxaban or apixaban for VTE treatment in outpatient settings. EINSTEIN-DVT/PE (rivaroxaban) and AMPLIFY (apixaban) subsequently showed similar or superior outcomes with all-oral regimens without initial parenteral therapy, making rivaroxaban and apixaban the preferred DOACs for acute VTE treatment in most guidelines.
References