December 12th, 2012

Boehringer Ends Phase 2 Trial of Dabigatran in Mechanical Valve Patients

Boehringer Ingelheim today announced that it had discontinued a phase 2 trial of its anticoagulant drug dabigatran (Pradaxa) in patients with mechanical heart valves. As reported here in October, the company had previously terminated one arm of the study after an interim review of the data by the trial’s Data Safety Monitoring Board.

The RE-ALIGN trial was an open-label, 12-week randomized comparison of warfarin and dabigatran in 400 patients who received a mechanical valve. The first arm randomized patients during their initial hospital stay; the second arm randomized patients more than 3 months after their surgery.

Despite the recent advent of novel oral anticoagulants, the much-maligned warfarin remains the only current option available for patients who have received a mechanical valve. Now the first trial to explore this indication for one of the newer oral anticoagulants has been stopped.

In October, Boehringer told members of its speakers’ bureau that the post-surgery arm of the trial had been terminated because of “lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes).” At that time, the company said the second arm of the trial would continue.

Dabigatran has been approved in Europe, but not in the United States, for venous thromboemoblism (VTE) prevention after knee- and hip-replacement surgery. Rivaroxaban (Xarelto) has been approved for both VTE prevention in the United States and Europe. To date there have been no head-to-head comparisons of the newer anticoagulants.

According to a recent study in Circulation: Cardiovascular Quality and Outcomesdabigatran now has about 19% of the oral anticoagulant market, mostly for the approved treatment of AF “but increasingly for off-label indications” as well. A recent letter in the Journal of the American College of Cardiology provided information about the off-label use of dabigatran in two mechanical valve patients. Both patients developed thrombosis after switching to dabigatran from warfarin. The authors noted that “while there is a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, these data are unavailable for dabigatran.” Although newer anticoagulants “hold tremendous promise for mechanical valve anticoagulation… there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting.”

2 Responses to “Boehringer Ends Phase 2 Trial of Dabigatran in Mechanical Valve Patients”

  1. Kasim Salim, MBBS MD MRCP FRCP MRCpath FRCpath says:

    It is really disheartening to see the gradual and impending exit of Dabigatran like it’s predecessor from long term anticoagulation programmes. In mechanical heart valve scenario it was thrombosis and not bleeding as expected. As we can’t expect under dosing for the thrombotic turn, we may have to focus on endothelial dysfunction from defective signalling through the PAR1 caused by continuous Thrombin inhibition. This may not be the outcome of the newer Xa inhibitors as already we have seen excellent bridging effect of LMWH in patients with mechanical Heart valves on long term Warfarin when the latter medicine need to be discontinued for short periods for invasive procedures etc. My hope is in the newer oral Xa inhibitors for patients with mechanical Heart valves in the near future in case we are discarding our old friend Warfarin.

  2. Juergen Schiefermueller, MD says:

    I suppose the nice phrase “imbalance in reports” translates as “higher rates of”…. ?