The RE-ALIGN trial: Dabigatran vs. warfarin for mechanical heart valves [Classics Series]

1. In patients with mechanical heart valves, anticoagulation with dabigatran was associated with significantly higher rates of stroke and major bleeding when compared to warfarin.

2. Based on these findings, patients with mechanical heart valves should be anticoagulated with warfarin, as opposed to dabigatran.

Original Date of Publication: September 2013

Study Rundown: Prosthetic heart valve replacement is sometimes recommended for patients with severe valvular heart disease. While mechanical valves are more durable than bioprosthetic ones, they are associated with a higher risk of thromboembolic disease and lifelong anticoagulation is typically needed. Warfarin provides excellent protection against thromboembolic complications in patients with mechanical heart valves, but one major downside of the drug is that regular monitoring is required. Dabigatran is an oral direct thrombin inhibitor that was shown to be effective as an anticoagulant in the treatment of various conditions, including stroke prophylaxis in patients with atrial fibrillation and for the treatment of acute venous thromboembolism. The Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN) trial sought to determine whether dabigatran would be effective in preventing thromboembolism in patients with mechanical heart valves, as compared with warfarin. The trial was terminated prematurely due to a significantly higher rate of ischemic or unspecified stroke in the dabigatran group. Moreover, there were significantly higher rates of bleeding in the dabigatran group when compared to those on warfarin. A large proportion of the patients in the dabigatran group discontinued their medications or required dosage adjustments. In summary, the use of dabigatran in patients with mechanical heart valves was linked with significantly higher rates of stroke and bleeding when compared to warfarin therapy. Patients with mechanical heart valves should continue to be anticoagulated with warfarin on the basis of these findings.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: The RE-ALIGN trial was a multicenter, prospective, randomized, phase II, open-label trial with blinded end-point adjudication. Patients were eligible for the trial if they were between 18 and 75 years of age and were undergoing mechanical aortic and/or mitral valve replacement or had undergone mechanical mitral valve replacement >3 months prior to randomization. Patients were randomized in a 2:1 ratio to treatment with dabigatran and warfarin. For patients in the dabigatran group, starting dose was determined based on creatinine clearance and trough levels were determined at prespecified timepoints; dose adjustments were made to achieve a trough plasma level ≥50 ng/mL. Patients in the warfarin group had their international normalized ratios (INR) checked at prespecified timepoints to ensure they were in target. The primary outcome was the trough level of dabigatran. Efficacy and safety outcomes included rates of stroke, systemic embolism, transient ischemic attack, valve thrombosis, bleeding, venous thromboembolism, and death.

At the interim analysis, 252 patients had undergone randomization, with 168 in the dabigatran group and 84 in the warfarin group. Interim analysis demonstrated that patients being treated with dabigatran had significantly higher risk of bleeding as compared to those on warfarin (RR 2.45; 95%CI 1.23-4.86; p = 0.01). Moreover, 9 patients (5%) experienced stroke and 3 patients (2%) had myocardial infarctions in the dabigatran group, while no strokes or myocardial infarctions were observed in those taking warfarin. The dose of dabigatran was incresd in 24% of patients and the drug was discontinued in 8% of patients, as they did not attain trough plasma levels ≥50 ng/mL, despite being on the highest dose.

Image: PD

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