AMSTERDAM – The complete failure of the oral direct thrombin inhibitor dabigatran in the RE-ALIGN trial spells big trouble for efforts to use the novel oral factor Xa inhibitors for anticoagulation in patients with a mechanical heart valve, RE-ALIGN steering committee cochair Dr. Frans Van de Werf cautioned at the annual congress of the European Society of Cardiology.
"It would not be wise for a cardiologist to prescribe these agents for a patient with a mechanical heart valve," declared Dr. Van de Werf, professor and chairman of the department of cardiovascular medicine at the Catholic University at Leuven (Belgium).
Bruce Jancin/IMNG Medical Media
Dr. Franz Van de Werf
Dabigatran (Pradaxa) is approved as a more effective and convenient alternative to warfarin for prevention of stroke and other systemic embolism in patients with nonvalvular atrial fibrillation. RE-ALIGN (the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement) was an effort to expand the drug’s indications to include prevention of thromboembolic events in patients with mechanical heart valves.
The study was halted prematurely late last year when an interim analysis showed that dabigatran was both less safe and less protective than standard warfarin therapy. Shortly afterwards, the Food and Drug Administration and the European regulatory agency warned that dabigatran is contraindicated in patients with mechanical heart valves. Dr. Van de Werf’s report in Amsterdam, however, was the first presentation of the actual data.
RE-ALIGN was stopped after 252 patients with mechanical heart valves had been randomized 2:1 to dabigatran or warfarin. Dabigatran dosing was adjusted on the basis of creatinine clearance to achieve a trough plasma level of at least 50 ng/mL.
The study halt came in response to an interim analysis showing a 5% stroke rate in the dabigatran group, compared with 0% with warfarin. This was accompanied by a 4% rate of major bleeding with dabigatran, compared with 2% with warfarin, and a 27% rate of any bleeding with dabigatran versus 12% with warfarin. All dabigatran-treated patients with major bleeding had pericardial bleeding and were in the subgroup of participants who started on the direct thrombin inhibitor within 7 days post surgery.
Other unwelcome outcomes in the interim analysis included a 2% MI rate and 3% rate of valve thrombosis without symptoms in the dabigatran group, versus no such events in the warfarin arm.
"Overall, this study was clearly negative: more thrombotic events and more bleeding complications in spite of adjusting the dose of dabigatran based upon renal function," Dr. Van de Werf observed.
Simultaneous with his presentation of the RE-ALIGN findings at the ESC congress in Amsterdam, the results were published online (N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJMoa1300615].
In an accompanying editorial, Dr. Elaine M. Hylek of Boston University said the most likely explanation for the disappointing results in RE-ALIGN was that blood levels of dabigatran were inadequate (N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJMe1310399]).
Dr. Van de Werf, however, rejected that as unlikely. Given that there were excesses of both thromboembolic and bleeding events, other dosing regimens would surely have sent rates of one type of complication or the other even higher, he argued.
Instead, he and his coinvestigators believe that the most likely explanation for the negative results lies in the differences in the mechanisms of action of dabigatran and warfarin. Dabigatran acts near the tail end of the coagulation cascade, on thrombin. In patients with a mechanical heart valve, thrombin is generated by exposure of blood to the artificial surface of the valve leaflets, activating what is known as the contact pathway of coagulation. Thrombin also is generated by the release of tissue factor from tissues injured during the valve surgery. Warfarin acts at both the contact pathway and tissue injury levels; dabigatran doesn’t address either.
The novel oral factor Xa inhibitors don’t act at the contact pathway and tissue injury levels, either, which is why Dr. Van de Werf cautioned against their off-label use in patients with a mechanical valve.
Discussant Dr. Alec Vahanian said that he "fully agrees" with Dr. Van de Werf’s interpretation that the negative results most likely stemmed from dabigatran’s absence of efficacy on the contact pathway.
"It sounds from this study that there is no future for dabigatran with this indication. We should not give this agent to a patient with a mechanical prosthesis, and personally I would extend that further and say we should not give this agent to patients with a bioprosthesis or other high-risk patients with severe valve disease. We don’t have the evidence for that yet," said Dr. Vahanian, head of cardiology at Bichat Hospital, Paris.