Dabigatran Noninferior to Warfarin for Extended VTE Therapy: RE-MEDY Published

February 21, 2013

BOSTON — New-age dabigatran etexilate (Pradaxa, Boehringer Ingelheim) was noninferior to old-guard warfarin for long-term, extended antithrombotic therapy in a trial of patients who had already received at least three months of anticoagulation for venous thromboembolism (VTE) [1]. The oral direct thrombin inhibitor and the oral vitamin-K antagonist fared about the same for preventing recurrent VTE, but patients who took the newer agent experienced significantly fewer important bleeding complications.

Adding something of a placebo control to that trial, a complementary, similarly designed study of extended therapy showed, unsurprisingly, that patients taking the newer agent experienced far fewer recurrent VTEs but more bleeding than patients on placebo.

The two international trials--RE-MEDY, which pit dabigatran against warfarin, and RE-SONATE, in which dabigatran was compared with placebo--were presented separately at a July 2011 conference and reported by heartwire at the time. They are published together February 20 in the New England Journal of Medicine with first author Dr Sam Schulman (McMaster University, Hamilton, ON) and essentially the same numbers and conclusions.

RE-MEDY randomized 1430 patients to dabigatran and 1426 to warfarin, and RE-SONATE 681 to dabigatran and 662 to placebo; the direct thrombin inhibitor was given at 150 mg twice daily in both studies.

Over a follow-up of six to 36 months, dabigatran's hazard ratio (HR) for the primary end point of recurrent or fatal VTE, compared with warfarin, was 1.44 (95% CI 0.78-2.64, p=0.01 for noninferiority).

Major or clinically relevant bleeding was significantly reduced in the dabigatran group, with HR 0.54 (95% CI 0.41–0.71, p<0.001).

Of note, there were significantly more cases of acute coronary syndrome (ACS) in the dabigatran group, for rates of 0.9% vs 0.2% for those who took warfarin (p=0.02). That's reminiscent of a much-debated finding in the RE-LY trial that established dabigatran for nonvalvular atrial fibrillation: a 35% (p=0.07) increased MI risk for the 110-mg twice-daily dose vs warfarin and a 38% (p=0.048) increased MI risk for patients on the 150-mg twice-daily dose. Still, MI and other ACS were rare in all the trials.

In the dabigatran-placebo comparison, the HR for the same primary end point was 0.08 (95% CI 0.02–0.25, p<0.001) and major or clinically relevant bleeding was 2.92 (95% CI 1.52–5.60, p=0.001), with one case of ACS in each arm.

Appearing alongside RE-MEDY and RE-SONATE in the same journal issue is the AMPLIFY-EXT trial, a randomized comparison of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), an oral factor Xa inhibitor, vs warfarin for extended therapy after VTE or pulmonary embolism [3].

The trial was presented at a December 8, 2012 meeting and simultaneously published online and covered by heartwire before today's print publication.

In an editorial accompanying both reports [2], Dr Jean M Connors (Brigham and Women’s Hospital, Boston, MA) writes of the two new oral anticoagulants and a competing one, rivaroxaban (Xarelto, Bayer/ Janssen), "One might argue that direct comparison of these agents with one another and with warfarin and aspirin is needed to determine which confers the greatest protection from recurrent venous thromboembolism with the lowest rate of bleeding complications."

The editorial also states that "the increase in the rate of acute coronary events with dabigatran as compared with warfarin . . . requires further evaluation."

RE-MEDY and RE-SONATE were supported by Boehringer Ingelheim. AMPLIFY-EXT was supported by Bristol-Myers Squibb and Pfizer. Disclosures for the authors and editorialist can be found at www.nejm.org.