Treatment of Acute Venous Thromboembolism with Dabigatran or Warfarin and Pooled Analysis

Schulman S, Kakkar AK, Goldhaber SZ, et al.for the RE-COVER II trial investigators
Circulation. 2013 Dec 16. [Epub ahead of print]

Background

Venous thromboembolism (VTE) is increasingly prevalent in the United States, and its prevalence is expected to continue to rise [1]. Novel oral thrombin- or factor Xa inhibitors can be used for long-term anticoagulation in patients with VTE [2-4], atrial fibrillation [5-7] or acute coronary syndromes [8]. Because they do not need laboratory monitoring or dose adjustments, they may be convenient alternatives for vitamin K antagonists.
Dabigatran etexilate is an oral direct thrombin inhibitor with similar efficacy to warfarin in the treatment and secondary prevention of VTE, with a reduced risk for major and clinically relevant nonmajor bleeding [4,9]. The RE-COVER II study aimed to confirm the results of the RE-COVER study, in which a low rate of recurrent VTE was observed, and to expand the results with more precise subgroup analyses. RE-COVER II was a randomised, double-blind, double-dummy trial to compare dabigatran 150 mg twice daily with warfarin (INR 2.0-3.0) for 6 months, after initial parenteral anticoagulation, involving around 1280 patients in each group.

Main results

• Recurrent fatal or nonfatal VTE was observed in 30 patients in the dabigatran group (2.3%) and in 28 patients (2.2%) in the warfarin group (HR: 1.08: 95%CI: 0.64-1.80). The risk difference was 0.2 percentage points (95%CI: -1.0 to 1.3) in favour of warfarin.
  Dabigatran was non-inferior to warfarin for the prevention of recurrent or fatal VTE. Efficacy results were consistent in all predefined subgroups.
• Fifteen patients on dabigatran (1.2%) and 22 on warfarin (1.7%) had major bleeding events (HR: 0.69, 95%CI: 0.36-1.32). The difference in risk was -0.6 percentage points (95%CI: -1.6 to 0.3). Major and clinically relevant nonmajor bleeding were less often observed in the dabigatran group than in the warfarin group (HR: 0.62, 95%CI: 0.45-0.84). A similar HR was found for any bleeding (HR: 0.67, 95%CI: 0.45-0.84).
• Different categories of adverse events were seen at similar incidences in both groups, with the exception of dyspepsia that was more common with dabigatran (1.0%) than with warfarin (0.2%).
• Data on the efficacy and safety outcomes from this and the previous trial that compared dabigatran and warfarin for treatment of acute VTE were combined. The pooled HR for recurrent VTE was 1.09 (HR: 0.76-1.57) for dabigatran vs. warfarin.
• The safety outcome of clinically relevant bleeding showed that the risk reduction with dabigatran was influenced by age, such that younger patients benefitted from a higher risk reduction, while patients of about 85 years of age on warfarin tended to have a higher risk reduction than with dabigatran. A possible effect of age on efficacy of dabigatran was not as clear.

Conclusion

These results confirm earlier observations in RE-COVER that dabigatran is non-inferior to warfarin in the prevention of recurrent VTE and superior to warfarin for clinically relevant bleedings, or any bleeding. RE-COVER II included more Asians than RE-COVER (20% vs 3%), and fewer patients with previous VTE (18% vs. 26%), but efficacy was maintained in pooled analyses of both studies.

Editorial comment [10]

RE-COVER II confirms RE-COVER with an identical design and shows that parenteral heparin followed by dabigatran was as effective as heparin overlapped with and followed by warfarin. This study completes the phase III clinical development program of dabigatran in VTE, and it is the last of a series of phase III trials in the acute treatment of VTE.All direct oral anticoagulants (DOACs) were consistently shown to be non-inferior compared to well-managed warfarin and to cause less bleeding. Specific caution is still needed for patient populations not appropriately represented in the clinical studies. Possible dose adjustment needs to be examined in frail patients like the very elderly and those with high drug exposure due to impaired renal function.
The authors predict that DOACs that do not require monitoring will be a treatment shift for patients with VTE, as they offer patients, physicians and healthcare systems an effective, safer, and more convenient treatment for acute VTE.

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