Similar Efficacy, Less Bleeding With Dabigatran vs. Warfarin in VTE Patients

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Dabigatran has a similar effect on the recurrence of acute venous thromboembolism (VTE) and a lower bleeding risk compared with warfarin, according to a study published online December 26, 2013, ahead of print in Circulation.

Findings from the RE-COVER study, published December 2009 in the New England Journal of Medicine, found similar effectiveness with dabigatran compared with warfarin in protecting patients with acute VTE against recurrent events with equivalent or less bleeding risk. The trial included 2,564 patients with acute symptomatic VTE who were randomized to a fixed dose of dabigatran 150 mg twice daily or warfarin dose-adjusted to achieve an international normalized ratio (INR) of 2.0 to 3.0 for 6 months.

For the RE-COVER 2 trial, researchers led by Sam Schulman, MD, PhD, of McMaster University (Hamilton, Canada), randomized 2,568 patients with acute VTE to low molecular weight or unfractionated heparin (5-11 days) plus dabigatran (n = 1,279) or warfarin (n = 1,289) using the same doses as in RE-COVER.

The study drug was stopped before planned treatment completion in 14.7% of the dabigatran group and in 14.1% of the warfarin group. The planned observation time for analysis of efficacy was not completed in 9.8% of the dabigatran group nor in 9.0% of the warfarin group.

Similar Efficacy, Better Safety

Recurrent nonfatal or fatal VTE occurred in 2.3% of patients on dabigatran and 2.2% on warfarin (HR 1.08; 95% CI 0.64 to 1.80), and the difference in risk was 0.2% (95% CI -1.0 to 1.3) in favor of warfarin. Hence, dabigatran met noninferiority criteria for the prevention of recurrent or fatal VTE compared with warfarin (P < 0.001). Efficacy results were consistent in all predefined subgroups.

Major bleeding was reported in 1.2% of the dabigatran group and 1.7% of the warfarin group (HR 0.69; 95% CI 0.36 to 1.32), and the difference in risk was -0.6% (95% CI -1.6 to 0.3). Gastrointestinal bleeding was the most common bleeding event in both study cohorts.

Compared with warfarin, patients on dabigatran reported less major or clinically relevant non-major bleeding (HR 0.62; 95% CI 0.45-0.84), as well as any bleeding (HR 0.67; 95% CI 0.56-0.81). Adverse event rates were similar between the 2 drugs.

In a pooled analysis of both trials, dabigatran had a similar effect on VTE recurrence and mortality and a lower risk of bleeding compared with warfarin at 6 months (table 1).

Table 1. Pooled Analysis of RE-COVER and RE-COVER 2

6 Month Outcomes

(n = 2,553)

(n = 2,554)

HR 95% CI

Recurrent VTE



1.09 (0.76-1.57)




1.0 (0.67-1.51)

Major Bleeding



0.73 (0.48-1.11)

Any Bleeding



0.70 (0.61-0.79)

Using age as a continuous variable in the pooled analysis, there was evidence that the efficacy of dabigatran may be somewhat lower in younger patients and higher in older patients, with equal efficacy at about age 60, compared with warfarin. However, this difference was not statistically significant. Similarly, the safety of dabigatran was influenced by age compared with warfarin (P = 0.010 for interaction), with greater risk reduction in patients younger than 85.

Results Should Be Compared with Other Xa Inhibitor Studies

The study “confirms the results of RE-COVER,” Dr. Schulman and colleagues write. “The RE-COVER II and RE-COVER studies differed in ethnic composition of the study populations, with more Asians in the current trial (20% vs. 3%). There were also fewer patients with previous VTE in the current study (18% vs. 26% in RE-COVER).”

There is “no need for dose adjustment of dabigatran according to demographic characteristics or concomitant medication use” per the pooled analysis, they continue.

Going forward, the authors say the results can be compared with published trials of other factor Xa inhibitors like apixaban (AMPLIFY), rivaroxaban (EINSTEIN-PE and EINSTEIN DVT), and edoxaban (Hokusai-VTE).

“For patients with pronounced symptoms of [VTE] and/or with a large thrombus burden, where the clinician feels that initial hospitalization with parenteral anticoagulation is indicated, dabigatran would be an alternative to other approved oral anticoagulants when the patient is ready for discharge home,” they conclude. “Conversely, when the symptoms and/or thrombosis burden on first examination are limited and the patient is suitable for outpatient management with only oral therapy, dabigatran—as opposed to rivaroxaban—is not recommended since it has not been evaluated for monotherapy.”

Study Details

In the warfarin group, the mean time in the therapeutic range (INR 2.0 to 3.0) was 57%, increasing from 51% at 1 month and 56% at 2 months, to between 59% and 62% per month at 3-6 months. The INR was below the therapeutic range 24% of the time and above the therapeutic range 19% of the time.


Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2013;Epub ahead of print.



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  • The RE-COVER and RE-COVER II trials were funded by Boehringer Ingelheim.
  • Dr. Schulman reports receiving consulting fees from Boehringer Ingelheim and research grant support from Bayer Healthcare.