September 1st, 2013

Disappointing Results with Dabigatran for Mechanical Valves

For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.

Despite being more durable than bioprosthetic valves, mechanical heart valves are often not chosen because of the requirement for lifelong anticoagulant therapy. It has been hoped that the newer generation of oral anticoagulants might eventually replace warfarin, making anticoagulation more tolerable and better accepted, since these agents don’t require continuous monitoring and have much fewer serious interactions with other drugs and food. So far, however, there has been no convincing demonstration that the the newer agents are as safe and effective as warfarin for this indication.

RE-ALIGN was a phase 2 dose-validation study of dabigatran in patients with mechanical heart valves. Results of the trial were presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in the New England Journal of Medicine.  Patients in the trial were randomized to dabigatran or warfarin.

After 252 patients had been randomized, the trial was stopped early due to an increase in thromboembolic and bleeding events in the dabigatran group:

  • Among the 162 patients who received dabigatran there were nine ischemic or unspecified strokes and three MIs, compared with no strokes or MIs among the 84 patients randomized to warfarin.
  • Major bleeding occurred in seven (4%) patients in the dabigatran group versus two (2%) in the warfarin group. Twenty-seven percent of patients in the dabigatran group had a bleeding episode of any type, compared with 12% in the warfarin group. All the major bleeding episodes took place in the first two weeks after surgery.

The trial investigators reported that one-third of the dabigatran patients either discontinued treatment or required a dose adjustment. They speculated that warfarin may be more effective than dabigatran at suppressing the specific coagulation activity associated with valve surgery.

“The results of our study indicate that dabigatran is not appropriate as an alternative to warfarin for the prevention of thromboembolic complicaitons in patients who require anticoagulation after the implantation of a prosthetic heart valve,” they wrote. They also warned that the same fate may befall the factor Xa inhibitors, including rivaroxaban and apixaban, which, like dabigatran, have been approved as an alternative to warfarin for use in atrial fibrillation.

In an accompanying editorial, Elaine Hylek writes that the results may be explained in part by the high percentage of patients with recent surgery. “The early postoperative period may have been less than optimal for testing a new fixed dose regimen because of the enhanced thrombogenicity inherent in such patients.”

Hylek writes that another possible explanation is the use of target trough levels based on the RE-LY trial in patients with AF. “Translation of dose across indications is challenging, given the different mechanisms of thrombus formation in different vascular beds, differences in flow and shear stress… and patients’ characteristics.”

She strongly discourages the clinical use of the newer anticoagulants for this indication at the present time, but holds out hope for their eventual success: “Off-label use will place patients at undue risk and is rightfully prohibited. The results of RE-ALIGN are disappointing, but there is a palpable downside as well to potential premature abandonment of research into the use of such drugs in patients with mechanical heart valves.”

For a clinician’s perspective on the RE-ALIGN trial, click here.

Comments are closed.