Is Dabigatran Better Than Warfarin in Patients with Mechanical Heart Valves?
Abstract & Commentary
By Harold L. Karpman, MD, FACC, FACP
Clinical Professor of Medicine, UCLA School of Medicine
Dr. Karpman reports no financial relationships relevant to this field of study.
Synopsis: The use of dabigatran in patients with mechanical heart valves compared with patients receiving warfarin was associated with increased rates of thromboembolic and bleeding complications, thus demonstrating no benefit and an excess risk.
Source: Eikelboom JW, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013; 369:1206-1214.
Prosthetic heart valve replacement is performed worldwide on several hundred thousand patients with severe valvular heart disease each year.1 Mechanical valves are more durable than bioprosthetic valves,2 but the latter are frequently selected by the patient and the attending physician because mechanical valve implantation requires lifelong anticoagulant therapy, which requires lifelong coagulation monitoring and restrictions on the intake of certain foods, alcohol, and drugs. Dabigatran is a new oral direct thrombin inhibitor that has been shown to be as effective as warfarin in the treatment of patients with atrial fibrillation.3 In addition, it is a simple oral anticoagulant that requires no coagulation monitoring, which makes it an appealing alternative to warfarin.
Because promising studies in animals demonstrated the efficacy of dabigatran in preventing mechanical valve thrombosis,3-5 Eikelboom and colleagues did a study to validate a new regimen for the administration of dabigatran to prevent thromboembolic complication in patients after mechanical heart valve implantation. The warfarin dose in the study was adjusted to obtain an international normalized ratio (INR) of 2.0-3.5 based on the thromboembolic risk. The initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. After enrollment of 252 patients, the trial was terminated prematurely because of excess thromboembolic and bleeding events among patients in the dabigatran group. The study concluded that the use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications when compared with patients on warfarin, thus showing no benefits and an excess risk.
It must be recognized that the Eikelboom study was limited to two populations of patients: those who had undergone aortic or mitral valve replacement within the previous 7 days and those who had undergone a valve replacement at least 3 months earlier.6 Most of the thromboembolic events in the study occurred in patients in the dabigatran group who started the study drug within 7 days after the valve surgery, with fewer episodes occurring in the patients who had undergone valve implantation more than 3 months previously. Bleeding episodes conceivably may have been diminished if lower doses of dabigatran had been used for the first 3 months after valve implantation and then increased to higher doses (of course only if renal function was adequate). Other oral anticoagulants (rivaroxaban) have been successfully tested for the prevention of thromboembolic complications associated with mechanical heart valves in preclinical studies,7 but the Eikelboom study did not provide evidence of the safety and efficacy of the selected dabigatran dosing algorithm despite the favorable results observed in the preclinical studies.6,8,9 Since all episodes of major bleeding in the dabigatran group were in the pericardium, Eikelboom et al suggested that these occurrences might be explained by the relative inability of dabigatran to suppress activation of coagulation that occurs when blood is exposed to the artificial surfaces of the valve prosthesis. Dabigatran and other direct factor Xa inhibitors are effective for stroke prevention in patients with atrial fibrillation,10,11 but these data cannot be extrapolated to patients with mechanical heart valves probably because the mechanisms of thrombosis are different.
In summary, the results of the current study indicated that, at the present time, 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 mechanical heart valve. However, it must be clearly recognized that additional clinical trials, possibly including those that change the time of the initiation of the drug and/or which use other dosing regimens, are necessary before drawing final conclusions. Also, it must be recognized that one or several of the other newer anticoagulant drugs may not exhibit the untoward effects demonstrated by dabigatran in the present study.
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