Randomised, phase II study to Evaluate the sAfety and pharmacokinetics of oraL
dabIGatran etexilate in patients after heart valve replacemeNt (2013)


Heart valve replacement

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To identify doses of dabigatran that are expected to be safe and effective for the prevention of thromboembolic complications in patients with with a bileaflet mechanical heart valve

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Trial design

Prospective randomized phase II dose-validation study with open-label design and blinded endpoint adjudication
Active treatment: dabigatran for 12 weeks with a starting dose of 150, 220 or 300 mg twice daily (n=168). The initial doses based on the estimated creatinine clearance and were adjusted to obtain a trough plasma level ≥50 ng/ml at steady state. If a patient receiving 150 mg twice a day had a plasma level of <50 ng/ml, the dose was up-titrated to 220 mg twice a day. Similarly, the 220 mg dose was up-titrated to 300 mg. Patients with a plasma level of <50 ng/ml despite receiving 300 mg twice a day were switched to receive non-study vitamin K antagonist or be withdrawn from the study treatment
Control treatment: warfarin for 12 weeks to maintain an INR level 2.0–3.0 in patients at low thromboembolic risk and 2.5–3.5 in patients at intermediate to high thromboembolic risk (n=84)

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Primary outcome: trough plasma level of dabigatran, as determined on high-performance liquid chromatography-tandem mass spectrometry
Secondary outcome: stroke, systemic embolism, transient ischemic attack, valve thrombosis, bleeding, venous thromboembolism, myocardial infarction, and death

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Trial participants

252 patients aged ≥18 years and ≤75 years, either undergoing implantation of a mechanical bileaflet valve (aortic or mitral or both) during the current hospital stay or having undergone implantation of a mitral bileaflet valve >3 months before randomization. A total of 74 patients (29%) were deemed to be at low risk for thromboembolic complications, and 178 patients (71%) were deemed to be at intermediate or high risk

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The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. All participating patients discontinued the assigned study drug and were switched to a non-study vitamin K antagonist
Primary outcome: The initial dose of dabigatran was 150 mg twice daily in 15% of patients, 220 mg twice daily in 54%, and 300 mg twice daily in 31%. The dose was increased in 39 of 162 patients (24%), and discontinuation of dabigatran therapy was required in 13 patients (8%) who had a trough plasma level <50 ng/ml despite treatment with dabigatran at a dose of 300 mg twice daily. The targeted plasma level of 50 ng/ml was reached for an average of 86% of the time
Secondary outcome: In the dabigatran group, ischemic or unspecified stroke occurred in 9 patients (5%) and myocardial infarction occurred in 3 patients (2%), whereas there were no cases of stroke or myocardial infarction in the warfarin group. Major bleeding was seen in 7 patients (4%) and 2 patients (2%), respectively; and bleeding of any type occurred in 45 patients (27%) and 10 patients (12%), respectively (HR 2.45; p=0.01). All patients with major bleeding had pericardial bleeding

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Dabigatran is not appropriate as an alternative to warfarin for the prevention of thromboembolic complications in patients who require anticoagulation after the implantation of a prosthetic heart valve. The use of dabigatran was associated with increased rates of thromboembolic and bleeding complications, thus showing no benefit and an excess risk

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Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML, Van de Werf F; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369:1206-1214

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Corresponding author

Frans Van de Werf, MD, University Hospitals Leuven, Department of Cardiovascular Medicine, Herestraat 49, B-3000 Leuven, Belgium, e-mail:



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