Study of dabigatran with mechanical heart valves halted due to excess complications

Dabigatran caused more thromboembolic and bleeding complications than warfarin in patients with mechanical heart valves, according to a study that was prematurely halted as a result.

The phase II, manufacturer-sponsored study included patients who had undergone aortic- or mitral-valve replacement either within a week prior to drug initiation or more than three months earlier. They were randomly assigned to warfarin (adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 depending on thromboembolic risk) or dabigatran (an initial dose of 150, 220 or 300 mg twice daily based on kidney function). Results were published online by the New England Journal of Medicine on Sept. 1.

The study was halted after enrollment of 252 patients, 162 of whom were treated with dabigatran. Fifty-two of those patients required adjustment or discontinuation of their dabigatran dose. More dabigatran patients than warfarin patients had ischemic or unspecified strokes (5% vs. zero) or major bleeding (4% vs. 2%, all pericardial bleeds). Study authors concluded that the drug showed no benefit and excess risk compared to warfarin.

They noted that most thromboembolic events occurred in the dabigatran group who started the drug within a week of surgery. The higher risk of thromboembolism might be due to inadequate plasma levels of the drug (although higher levels might have led to even more bleeding complications) or the difference in the two treatments' mechanisms of action (because dabigatran is less able to suppress coagulation resulting from exposure to artificial surfaces). The results show that dabigatran is not an acceptable alternative to warfarin for this indication and that the effectiveness of factor Xa inhibitors at preventing strokes in patients with atrial fibrillation should not be extrapolated to patients with mechanical valves, the authors concluded.

An accompanying editorial noted several aspects of the study that could explain the failure of dabigatran, including the timing of drug initiation and the lower-than-projected plasma levels of the drug. While agreeing that the use of dabigatran for this indication would place patients at undue risk, the editorialist added, “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.”