Prosthetic heart-valve replacement is recommended for many patients with severe valvular heart disease and is performed in several hundred thousand patients worldwide each year.1 Mechanical valves are more durable than bioprosthetic valves2 but typically require lifelong anticoagulant therapy. The use of vitamin K antagonists provides excellent protection against thromboembolic complications in patients with mechanical heart valves3 but requires restrictions on food, alcohol, and drugs and lifelong coagulation monitoring. Because of the limitations of vitamin K antagonists, many patients opt for a bioprosthesis rather than a mechanical valve, despite the higher risk of premature valve failure requiring repeat valve-replacement surgery with bioprostheses.

Dabigatran etexilate (dabigatran) is an oral direct thrombin inhibitor that was shown to be effective as an anticoagulant in the treatment of patients with atrial fibrillation in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study.4-6 Prompted by these data and the promising results of studies in animals, which showed the efficacy of dabigatran in preventing valve thrombosis,7-9 we conducted the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN). 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

DISCUSSION

The primary goal of RE-ALIGN was to validate a new dabigatran dosing regimen for the prevention of thromboembolic complications in patients with mechanical heart valves. However, the trial was stopped early because of an excess of thromboembolic and bleeding events in the dabigatran group, as compared with the warfarin group. Most thromboembolic events among patients in the dabigatran group occurred in population A (patients who had started a study drug within 7 days after valve surgery), with fewer occurring in population B (patients who had undergone valve implantation more than 3 months before randomization). Excess bleeding events among patients receiving dabigatran occurred in the two study populations.

Possible explanations for the increase in thromboembolic complications with dabigatran include inadequate plasma levels of the drug and a mechanism of action that differs from that of warfarin. Trough plasma levels of dabigatran in population A were lower during the first few weeks after surgery than they were subsequently, and low drug levels soon after valve surgery may have allowed for early formation of blood clots that were not clinically manifested until later. However, thromboembolic events also occurred among patients with higher trough plasma levels of dabigatran early after surgery and among those in population B who had higher plasma levels than those in population A, suggesting that lower-than-expected drug levels cannot fully explain the increase in the rate of thromboembolic events.

The choice of a target trough plasma level of 50 ng of dabigatran per milliliter was primarily based on data from the RE-LY trial, in which dabigatran at a dose of 150 mg twice daily, as compared with warfarin, had superior efficacy and similar safety in patients with atrial fibrillation. We cannot exclude the possibility that targeting a higher trough level of dabigatran would have been more effective for the prevention of thromboembolic complications. At the same time, it is likely that the use of higher dabigatran doses would have led to unacceptably high bleeding rates, since dabigatran caused excess bleeding at the doses studied. It is also possible that more frequent administration of dabigatran (e.g., three times a day) without an increase in the total daily dose might have resulted in higher trough and lower peak levels, thereby increasing antithrombotic efficacy and reducing bleeding, but this approach was not tested.

Differences in the mechanisms of action of dabigatran and warfarin may also in part explain our findings. In patients with atrial fibrillation, thrombi form in the left atrial appendage under low-flow, low-shear conditions in which thrombin generation is believed to be triggered by stasis and endothelial dysfunction.19 In contrast, in patients with a mechanical heart valve, coagulation activation and thrombin generation induced by the release of tissue factor from damaged tissues during surgery may partly explain the high risk of early thromboembolic complications. In addition, thrombin generation can be triggered by exposure of the blood to the artificial surface of the valve leaflets and sewing ring, which induce activation of the contact pathway of coagulation. The majority of thrombi in patients with prosthetic heart valves appear to arise from the sewing ring,20 which does not undergo endothelialization for at least several weeks after surgery. It is thought that the sewing ring becomes less thrombogenic once endothelial tissue has formed around it. Warfarin is likely to be more effective than dabigatran at suppressing coagulation activation because it inhibits the activation of both tissue factor–induced coagulation (by inhibiting the synthesis of coagulation factor VII) and contact pathway–induced coagulation by inhibiting the synthesis of factor IX), as well as inhibiting the synthesis of factor X and thrombin in the common pathway,21 whereas dabigatran exclusively inhibits thrombin.22 If contact activation is intense, the resulting thrombin generation may overwhelm local levels of dabigatran, which can lead to thrombus formation on the surface of the valve and related embolic complications.

RE-ALIGN was an open-label trial and thus subject to reporting biases. However, clinical outcomes were prespecified, objectively defined, and independently adjudicated by experts who were unaware of the study-group assignments, all factors that minimize the potential for bias.

The results of our study indicate that 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 results may also be relevant to studies of other new oral anticoagulants in patients with mechanical heart valves. Like dabigatran, the direct factor Xa inhibitors are effective for stroke prevention in patients with atrial fibrillation,23,24 but these data cannot be extrapolated to patients with mechanical heart valves because the mechanisms of thrombosis are different. Rivaroxaban has been successfully tested for the prevention of thromboembolic complications associated with mechanical heart valves in preclinical studies,25 but our study did not provide evidence of the safety and efficacy of the selected dosing algorithm, despite favorable results of preclinical studies.7-9

In conclusion, the results of our phase 2 study indicate that at the doses tested, dabigatran was not as effective as warfarin for the prevention of thromboembolic complications in patients with mechanical heart valves and was associated with an increased risk of bleeding. These results 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. The use of dabigatran has no positive value and was associated with excess risk in patients with mechanical heart valves.

Source: NEJM