Dabigatran vs. Warfarin in the Extended Treatment of VTE - RE-MEDY

Aug 06, 2011
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Date Presented:
01/01/2011
Date Published:
01/01/2013
Date Updated:
08/06/2011
Original Posted Date:
08/06/2011
References

Description:

NOTE: See the combined RE-MEDY and RE-SONATE trial update at: http://www.cardiosource.org/Science-And-Quality/Clinical-Trials/R/REMEDY-and-RESONATE.aspx.

Many patients with venous thromboembolism (VTE) require longer-term anticoagulation, sometimes life-long, due to nonmodifiable risk factors. Traditionally, these patients have been treated with long-term warfarin. However, warfarin is associated with a high risk of bleeding (about 1-2% risk of major bleeding). Dabigatran is a novel direct antithrombin inhibitor, and has been demonstrated to have a similar safety profile as warfarin, with a lower risk of bleeding in various subgroups of patients. The current trial sought to study the safety and efficacy of dabigatran as compared with warfarin in patients with confirmed VTE requiring long-term anticoagulation due to high risk of recurrent VTE.

Hypothesis:

Dabigatran would be noninferior to warfarin for the primary endpoint of recurrent symptomatic VTE and deaths related to VTE during the treatment period.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Documented VTE
  • Need for long-term anticoagulation

    Number of enrollees: 2,866
    Duration of follow-up: 36 months

Primary Endpoints:

  • Composite of recurrent symptomatic VTE or VTE-related deaths

Secondary Endpoints:

  • Incidence of bleeding events (BEs)
  • Major bleeding events (MBEs)
  • Clinically relevant bleeding events (CRBEs): major bleeding and other clinically relevant nonmajor bleeding
  • Any BEs: MBEs, CRBEs, and nuisance bleeds

Drug/Procedures Used:

Patients who had been on warfarin for at least 3-6 months, and required another 18 months of anticoagulation (amended to 3-12 months pretreatment, up to 36 months of anticoagulation) were randomized after a washout period of 1 week (international normalized ratio [INR], ≤2.3) in a 1:1 fashion to either 150 mg twice daily of dabigatran etexilate with warfarin placebo or INR-adjusted warfarin (goal INR 2-3).

Principal Findings:

A total of 2,866 patients were randomized, 1,435 to dabigatran and 1,430 to warfarin. The full analysis set was comprised of 2,856 patients (1,430 to dabigatran, 1,426 to warfarin). Baseline characteristics were fairly similar between the two arms. In the warfarin arm, median overall time in therapeutic INR range was 65.3%.

The primary endpoint of recurrent symptomatic VTE or VTE-related deaths was similar between the dabigatran and warfarin arms (1.8% vs. 1.3%, hazard ratio 1.44, 95% confidence interval 0.78-2.64, p for noninferiority = 0.027). The secondary endpoint of major bleeding was similar (0.9% vs. 1.8%, p = 0.06), whereas any bleeding was significantly lower in the dabigatran arm (19.4% vs. 26.2%, p < 0.0001). Overall mortality was similar between the two arms (0.8% vs. 1.3%, p = NS).

Adverse events were similar, including severe ones (10% vs. 10.6%). Definite and likely acute coronary syndrome (ACS) was significantly higher in the dabigatran arm compared with the warfarin arm (0.9% vs. 0.2%, p = 0.02), including definite MIs (9 vs. 1). There were no cardiovascular deaths in either arm.

Interpretation:

Dabigatran is a newer univalent direct thrombin inhibitor, which differs from bivalent direct thrombin inhibitors such as bivalirudin, in binding only to the active site of thrombin. In the current trial, dabigatran 150 mg BID was noninferior to warfarin in reducing recurrent symptomatic VTE or VTE-related deaths compared with warfarin, with a reduction in bleeding events, in patients with confirmed VTE requiring long-term anticoagulation.

These results add to those noted in the RE-LY trial in patients with atrial fibrillation, and the RE-COVER trial in patients with acute VTE needing anticoagulation for 3-6 months. The higher rate of ACS with dabigatran versus warfarin is concerning, and deserves closer study.

References:

Schulman S, Kearon C, Kakkar AK, et al., on behalf of the Re-MEDY and RE-SONATE Trials Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709-18.

Presented by Dr. Sam Schulman at the XXIII Congress of the International Society on Thrombosis and Haemostasis, Kyoto, Japan, July 2011.

 

Keywords: International Normalized Ratio, Acute Coronary Syndrome, Follow-Up Studies, Thrombin, beta-Alanine, Benzimidazoles, Warfarin, Venous Thromboembolism, Pyridines, Risk Factors


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