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RE-ALIGN: Dabigatran use not supported in patients with mechanical heart valves
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AMSTERDAM — Use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic events and bleeding complications in the RE-ALIGN study.
The phase 2, dose-validation study focused on two patient populations: those who had undergone aortic or mitral valve replacement within the week before the study and those who had undergone replacement at least 3 months before the study.
Patients were assigned in a 2:1 ratio to dabigatran (Pradaxa, Boehringer Ingelheim; n=168) or warfarin (n=84). Initial dabigatran dose selection (150, 220 or 300 mg twice daily) was based on kidney function. Dabigatran dose was adjusted to obtain a trough plasma level of ≤50 ng/mL; warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 based on thromboembolic risk. After the 12-week study, patients could stop the study drug and switch to a vitamin K antagonist or could enroll in the RE-ALIGN-EX extension trial and continue to receive the assigned study drug for up to 84 months, according to the study details. The trial’s primary outcome was trough plasma level of dabigatran.
“The primary aim of RE-ALIGN was to validate a new regimen for the administration of dabigatran to prevent thromboembolic complications in patients with mechanical heart valves,” the investigators wrote in The New England Journal of Medicine.
The study was terminated early after enrollment of 252 patients showed an excess of thromboembolic and bleeding events in the dabigatran group, although fewer deaths were reported with dabigatran. In December 2012, the FDA and European Medicines Agency issued a contraindication for dabigatran in this patient population after the trial was stopped.
In total, 99 patients in the dabigatran group and 59 in the warfarin group participated in the extension trial.
Frans Van de Werf
According to results from the as-treated analysis presented at ESC Congress 2013 by Frans Van de Werf, MD, PhD, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecific stroke was reported in 5% of the dabigatran group compared with none in the warfarin group. Major bleeding was reported in 4% of the dabigatran group vs. 2% of the warfarin group. Pericardial bleeding was observed in all patients with major bleeding. Most thromboembolic events among patients in the dabigatran group occurred in patients who started a study drug within 7 days after valve surgery, while excess bleeding events among patients assigned dabigatran occurred in both patient populations, according to the researchers.
“The conclusion of this small, negative study is that this agent must not be prescribed to patients with a mechanical valve,” Van de Werf, from the department of cardiovascular sciences at University Hospitals Leuven, Belgium, said at a press conference.
However, “dabigatran etexilate has been shown to be effective and safe in other indications, and there are several potential reasons for these disappointing results,” he said. Possible explanations he cited include inadequate blood levels of dabigatran; pay of chance with relatively few events observed in the warfarin arm; or differences in the mechanism of action of dabigatran as compared with warfarin.
“The consequence could also be that factor Xa inhibitors such as rivaroxaban [Xarelto, Janssen Pharmaceuticals] or apixaban [Eliquis, Bristol-Myers Squibb/Pfizer] won’t work for this indication and that patients with a mechanical heart valve will have to take warfarin or other vitamin K antagonists for the next 5 to 10 years,” he stated in the release. – by Katie Kalvaitis
For more information:
Van de Werf F. Hot Line I: Late breaking trials on thrombosis. Presented at: the European Society of Cardiology Congress; Aug. 31-Sept. 4, 2013; Amsterdam.
Eikelboom JW. N Engl J Med. 2013;doi:10.1056/NEJMoa1300615.
Disclosure: Van de Werf reports grants, personal fees, and nonfinancial support and travel support from Boehringer Ingelheim.