Efficacy and Safety of Dabigatran Compared to Warfarin for 6-Month Treatment of Acute Symptomatic Venous Thromboembolism - RE-COVER

Dec 18, 2009
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Boehringer Ingelheim
Date Published:
01/01/2009
Date Updated:
12/18/2009
Original Posted Date:
12/18/2009
References

Description:

Dabigatran is an orally active direct thrombin inhibitor, and has been evaluated in a number of settings including prevention of deep vein thrombosis (DVT) in patients undergoing orthopedic surgery. Recently, it was found that dabigatran 150 mg bid had superior efficacy with similar safety when compared with warfarin, when used in preventing stroke in patients with atrial fibrillation. The current trial sought to study the safety and efficacy of dabigatran compared with warfarin for the treatment of acute venous thromboembolism (VTE).

Hypothesis:

Dabigatran would be noninferior to warfarin for the treatment of acute VTE, with a superior safety profile.

Study Design

Patients Enrolled: 2,539
Mean Follow Up: 6 months
Mean Patient Age: 55.0 years
Female: 42

Patient Populations:

  • Age >18 years
  • Acute symptomatic, objectively verified proximal DVT of the legs, or PE
  • Appropriate candidate for 6 months of anticoagulation

Exclusions:

  • Duration of symptoms >14 days
  • PE with hemodynamic instability, or requiring thrombolytic therapy
  • Another indication for warfarin
  • Recent unstable cardiovascular disease
  • High risk of bleeding
  • Liver disease, with ALT >2 x ULN
  • Estimated creatinine clearance <30 ml/min
  • Life expectancy <6 months
  • Requirement for >100 mg of ASA or other long-term antiplatelet therapy
  • Contraindication to heparin or radiographic contrast material
  • Pregnancy or risk of becoming pregnant

Primary Endpoints:

  • Efficacy: Composite of symptomatic VTE or death due to VTE
  • Safety: Major bleeding

Drug/Procedures Used:

Patients received dabigatran 150 mg twice daily orally, in addition to placebo or warfarin (goal international normalized ratio [INR] 2-3), in addition to placebo, in a double-dummy fashion.

Concomitant Medications:

Patients were initially treated with either intravenous unfractionated heparin or subcutaneous low molecular weight heparin.

Principal Findings:

A total of 2,539 patients were randomized: 1,274 to dabigatran, and 1,265 to warfarin. Baseline characteristics were fairly similar between the two arms. Parenteral anticoagulation was given for 10 days in both arms. Mean number of INR checks in the warfarin group in 6 months was 16, with 60% of the INRs being in the therapeutic range. Average estimated creatinine clearance was 105 ml/min in both arms. The main indications for use of anticoagulation were DVT (69%), pulmonary embolism (PE) (21%), and DVT and PE (10%). About 25% of the patients had a history of VTE.

The primary outcome of recurrent VTE or death due to recurrent VTE was noted in 2.4% of patients in the dabigatran arm, and 2.1% of patients in the warfarin arm (hazard ratio [HR] 1.1, 95% confidence interval [CI] 0.65-1.84, p < 0.001 for noninferiority). All-cause mortality was also similar between the two arms (1.6% vs. 1.7%, p > 0.05).

Major bleeding was similar between the dabigatran and warfarin arms (1.6% vs. 1.9%, HR 0.82, 95% CI 0.45-1.48, p = 0.38). The combined endpoint of major or clinically relevant nonmajor bleeding was lower in the dabigatran arm (5.6% vs. 8.8%, p = 0.002).

An adverse event leading to study discontinuation was more common with dabigatran (9.0% vs. 6.8%, p = 0.05). Common adverse events included diarrhea (4.5% vs. 3.0%), headache (6.2% vs. 7.0%), and dyspepsia (3.1 vs. 0.7%). The incidence of acute coronary syndromes (0.4% vs. 0.2%, p = 0.73) and transaminitis (alanine aminotransferase [ALT] >3 ULN) (3.4% vs. 3.8%, p = 0.68) was similar between the two arms.

Interpretation:

The results of the RE-COVER study indicate that dabigatran 150 mg bid orally is noninferior in efficacy to warfarin in patients with acute VTE, with a similar to slightly better bleeding profile. In addition, toxic effects on the liver, as noted with ximelagatran, were not present.

This important study indicates that fixed-dose dabigatran could be used in lieu of warfarin in patients with VTE. Dabigatran appears to be a more convenient drug to take, with no known significant food and medication interactions unlike warfarin. There is also no need to routinely monitor blood for efficacy, unlike with warfarin, where an average of 16 INR checks were necessary over the 6-month duration of this trial. Although data on the long-term safety of dabigatran and its cost-effectiveness are necessary, dabigatran has the potential to radically change the management of patients requiring long-term anticoagulation.

References:

Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52.

Keywords: Acute Coronary Syndrome, Stroke, Pulmonary Embolism, Diarrhea, Warfarin, Venous Thromboembolism, Creatinine, Orthopedics, Headache, Dyspepsia, International Normalized Ratio, beta-Alanine, Benzimidazoles, Azetidines, Benzylamines, Liver, Venous Thrombosis, Confidence Intervals


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