RE-COVER II

Dabigatran versus warfarin in the treatment of acute venous thromboembolism II (2013)

Condition

Treatment of acute VTE

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Objective

To compare the efficacy and safety of dabigatran vs. warfarin in the treatment of acute VTE and to confirm the results of RE-COVER I

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Trial design

Randomized, double-blind, double-dummy phase III non-inferiority study (same design as RE-COVER I, duplicate trials)
Active treatment: dabigatran 150 mg p.o. twice daily for 6 months plus warfarin placebo after an initial treatment with a parenteral anticoagulant (low molecular weight or unfractionated heparin) plus warfarin placebo (sham INR) for at least 5 days and until the sham INR had been ≥2.0 for 2 consecutive measurements (n=1279)
Control treatment: dose-adjusted warfarin (INR 2.0–3.0) for 6 months, starting after randomization, plus dabigatran placebo, starting after at least 5 days parenteral anticoagulation and until the INR had been ≥2.0 for 2 consecutive measurements (n=1289)

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Endpoints

Primary efficacy endpoint: 6-month incidence of recurrent symptomatic VTE and deaths related to VTE
Secondary efficacy endpoints: symptomatic VTE, symptomatic non-fatal PE, VTE-related death, all deaths
Safety endpoints: bleeding events, acute coronary syndromes, other adverse events, and liver function parameters

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Trial participants

2568 patients ≥18 years with acute VTE

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Results

Efficacy outcome: At 6 months, of 1279 patients randomized to dabigatran, 30 (2.3%) had recurrent fatal or non-fatal VTE compared with 28 (2.2%) of 1289 patients randomized to warfarin (hazard ratio for dabigatran 1.08; p<0.001 for non-inferiority)
Safety outcome: Major bleeding events occurred in 15 patients (1.2%) treated with dabigatran and 22 patients (1.7%) receiving warfarin (hazard ratio 0.69). Rates of any bleeding favored dabigatran, with 200 bleeding events in the dabigatran group (15.6%) and 285 bleeding events in the warfarin group (22.1%) (hazard ratio 0.67). The frequency of reported ACS events was less than 1% in the trial, with more cases in the dabigatran treatment group (4 vs. 2; difference not statistically significant). There were 25 deaths in each treatment arm, and serious adverse events were similar in both groups

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Summary

The results of the trial confirm that the direct thrombin inhibitor dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with well-controlled warfarin for the treatment of acute VTE. Pooled analysis of this study RE-COVER II and the RE-COVER trial gave hazard ratios for recurrent VTE of 1.09, for major bleeding of 0.73, and for any bleeding of 0.70

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Reference

Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129:764-772; published online December 16, 2013; doi: 10.1161/CIRCULATIONAHA.113.004450

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Corresponding author

Sam Schulman, M.D., Ph.D., Thrombosis Service, HHS-General Hospital, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada, e-mail: schulms@mcmaster.ca

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