Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism - RE-MEDY and RE-SONATE

Description:

Dabigatran is an oral direct thrombin inhibitor that has been shown to be noninferior to warfarin for the initial treatment of venous thromboembolism (VTE) (6 months). Two parallel complementary trials were designed for extended duration of treatment in these patients: RE-MEDY comparing dabigatran to warfarin, and RE-SONATE comparing dabigatran to placebo.

Hypothesis:

Dabigatran would be noninferior to warfarin, but superior to placebo in reducing recurrent long-term VTE events in patients with an initial episode of VTE.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • ≥18 years of age
  • Objectively confirmed symptomatic proximal DVT or PE
  • Treated with approved anticoagulant
  • Treatment with dabigatran for short-term treatment of VTE in the RE-COVER and RE-COVER II trials

    Number of enrollees: 2,866 (RE-MEDY), 1,353 (RE-SONATE)
    Duration of follow-up: 36 months (RE-MEDY), 12 months (RE-SONATE)
    Mean patient age: 55 years (RE-MEDY), 56 years (RE-SONATE)
    Percentage female: 39% (RE-MEDY), 45% (RE-SONATE)

Exclusions:

 

Primary Endpoints:

  • Efficacy: Recurrent symptomatic or fatal VTE; unexplained death also was included in this definition for RE-SONATE
  • Safety: Major bleeding; clinically relevant nonmajor bleeding

Secondary Endpoints:

  • Symptomatic DVT
  • Symptomatic nonfatal PE
  • Fatal VTE
  • All-cause mortality

Drug/Procedures Used:

RE-MEDY: Patients who had completed 3-12 months of active treatment with an approved anticoagulant and had an international normalized ratio [INR] <2.3 were randomized to receive either dabigatran 150 mg BID or warfarin with a goal INR 2.0-3.0.

RE-SONATE: Patients who had completed 6-18 months of active treatment with an approved anticoagulant were randomized to receive either dabigatran 150 mg BID or matching placebo. No INR checks were required.

Principal Findings:

RE-MEDY: A total of 2,856 patients were randomized from 265 sites in 33 countries, 1,430 to dabigatran and 1,426 to warfarin. Baseline characteristics were similar between the two arms. The index event was DVT only in 65%, pulmonary embolism (PE) only in 23%, and a combination of both in 12%. Approximately 7% had transient or permanent immobility, 18% had known thrombophilia, and 4% had active cancer. The median treatment duration with an anticoagulant was 199 days before randomization, whereas the median duration of study drug exposure was 474 days. Overall adherence was >98%.

The primary endpoint of recurrent symptomatic or fatal VTE was similar between the dabigatran and warfarin arms (1.8% vs. 1.3%, hazard ratio [HR] 1.44, 95% confidence interval [CI] 0.78-2.64; p for noninferiority = 0.01). Individual endpoints including symptomatic deep-vein thrombosis (DVT) (1.2% vs. 0.9%), fatal VTE (0.1% vs. 0.1%), and all-cause mortality (1.2% vs. 1.3%) were all similar between the two arms. Major or clinically relevant bleeding events (5.6% vs. 10.2%, p < 0.001) and any bleeding event (19.4% vs. 26.2%, p < 0.001) were significantly reduced in the dabigatran arm. An acute coronary syndrome during treatment was more frequent with dabigatran (0.9% vs. 0.2%, p = 0.02).

RE-SONATE: A total of 1,353 patients were randomized from 147 sites in 21 countries, 681 to dabigatran and 662 to placebo. Baseline characteristics were similar between the two arms. The index event was DVT only in 65%, PE only in 27%, and a combination of both in 6%. About 6% had transient or permanent immobility, 11% had known thrombophilia, and 6% had prior cancer. The median treatment duration with an anticoagulant was 296 days before randomization, while the median duration of study drug exposure was 164 days. Overall adherence was 96.5%.

The primary endpoint of recurrent symptomatic or fatal VTE was significantly lower in the dabigatran arm compared with placebo (0.4% vs. 5.6%, HR 0.08, 95% CI 0.02-0.25; p < 0.001). Individual endpoints including symptomatic DVT (0.3% vs. 3.3%), symptomatic nonfatal PE (0.1% vs. 2.1%), and unexplained death (0% vs. 0.3%) were all reduced in the dabigatran arm. Major or clinically relevant bleeding events (5.3% vs. 1.8%, p = 0.001) and any bleeding event (10.5% vs. 5.9%, p = 0.003) were all significantly higher in the dabigatran arm. An acute coronary syndrome during treatment was similar (0.1% vs. 0.2%).

Interpretation:

The results of the complementary RE-MEDY and RE-SONATE trials indicate that in patients with an index VTE event, extended duration of anticoagulation with dabigatran 150 mg BID is noninferior to warfarin (median duration of treatment 15.6 months beyond initial period of anticoagulation), but superior to placebo (median duration of treatment 5.4 months beyond initial period of anticoagulation) in reducing recurrent VTE events. Dabigatran is, however, associated with a reduced risk of major bleeding as compared with warfarin, but an increased risk of major bleeding as compared with placebo. Although complementary, these patient populations are obviously different; in the RE-MEDY trial, clinicians believed that extended duration of anticoagulation was necessary beyond the initial 3-12 months of treatment following the index VTE event.

In the active comparator trial (RE-MEDY), it is important to note that although criteria for noninferiority for the primary endpoint were met for dabigatran versus warfarin, rates were numerically higher in the dabigatran arm (1.8% vs. 1.2%). Moreover, the prespecified upper boundary of the one-sided CI for noninferiority was quite high (2.85). This meant that dabigatran could increase the risk of recurrent VTE by nearly threefold and yet meet criteria for noninferiority. Also, in RE-MEDY, dabigatran increased the risk of acute coronary syndrome as compared with warfarin, as has been noted in other dabigatran trials as well. The exact mechanism of this is not yet fully understood, but might be a reason for caution in patients with pre-existing coronary artery disease.

Finally, in the placebo-controlled trial (RE-SONATE), the high rates of recurrent VTE in the placebo arm suggest that closer monitoring is necessary in all VTE patients, even if their risk of recurrent VTE is deemed to be low. In addition, longer-term/indefinite anticoagulation might be necessary in higher-risk patients such as those with known thrombophilias. The utility of routine risk-stratification with biomarkers such as d-Dimer in these patients also needs to be further studied.

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.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Anticoagulation Management and ACS, Anticoagulation Management and Venothromboembolism, Novel Agents

Keywords: Coronary Artery Disease, Neoplasms, Acute Coronary Syndrome, Follow-Up Studies, Pulmonary Embolism, Warfarin, Venous Thromboembolism, International Normalized Ratio, beta-Alanine, Biological Markers, Thrombophilia, Benzimidazoles, Fibrin Fibrinogen Degradation Products, Confidence Intervals


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