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RE-ALIGN: Strokes, bleeds, thrombi with dabigatran and mechanical valves
Amsterdam, the Netherlands - The different mechanism of thrombosis in patients with mechanical heart valves, as compared with patients with atrial fibrillation, may explain the failure of dabigatran in RE-ALIGN, conclude investigators. Full details on the trial, which was stopped in two phases late last year, are being released for the first time here at the European Society of Cardiology 2013 Congress.
Dr Fran Van de Werf (University Hospitals Leuven, Belgium) will present the results during the first hot-line session of the meeting later this morning; RE-ALIGN is also published simultaneously, with first author Dr John Eikelboom (McMaster University, Hamilton, ON), in the New England Journal of Medicine (NEJM) [1].
As previously reported by heartwire, an early glimpse at the disappointing results came from the FDA in December 2012, warning, as did the European Medicines Agency (EMA), that dabigatran was contraindicated in mechanical heart valves as a result of an increase in strokes, MI, and thrombosis forming on the valves seen in RE-ALIGN.
Numbers behind the news
The numbers reported in the NEJM today show that ischemic or unspecified stroke occurred in nine (5%) patients in the dabigatran-treated patients but in no warfarin-treated patients. Major bleeding occurred in seven (4%) dabigatran-treated patients compared with two (2%) warfarin-treated patients. Of note, all patients with major bleeding had pericardial bleeding. Asymptomatic valve thrombosis was detected in five patients (3%) in the dabigatran group; none were found in warfarin-treated patients.
The dabigatran group actually included two types of patients—those randomized at the time of their valve implantation (a bileaflet mitral valve, bileaflet aortic valve, or both) or patients who were randomized more than three months after undergoing their initial valve procedure. Importantly, the authors note, while increased bleeding was seen in both types of dabigatran-treated patients, only those patients who had had their valve implants within one week of randomization experienced major bleeding.
A horse of a different color
In the paper, Eikelboom et al note that while thrombi tend to form in the left atrial appendage in patients with AF, in patients with mechanical valves, the process appears to originate from damaged valve tissue.
That difference, they say, "may partly explain the high risk of early thromboembolic complications." The leaflets and sewing ring are also likely sources of thrombin generation, particularly in the early weeks; warfarin may be better at suppressing coagulation activation related to these foreign materials, the authors write.
They conclude that dabigatran "is not appropriate as an alternative to warfarin" in the setting of mechanical heart valves. Moreover, they say, "the results may be relevant to studies of other new oral anticoagulants in patients with mechanical heart valves."
More questions to answer
In an accompanying editorial entitled "Not as easy as we hoped" [2], Dr Elaine M Hylek (Boston University School of Medicine, MA) proposed a range of reasons behind dabigatran's failure in this setting:
The fact that 80% of patients received dabigatran early after surgery, when thrombogenicity is "enhanced."
The choice of 50 ng/mL as the dabigatran trough target. This level correlated with stroke prevention in AF patients in RE-LY but may not have been appropriate in this indication.
The lower-than-projected plasma levels of dabigatran with the first four weeks, which may point to suboptimal absorption of the drug.
"Thus, there are calculable reasons for the failure of RE-ALIGN," she writes. And despite the FDA and EMA decisions to contraindicate dabigatran in mechanical-valve patients, she argues that the door on further research in this field should not be considered closed.
"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," she concludes.
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