Dabigatran Not Safe For Prosthetic Heart Valves
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD
Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco
Source: Eikelboom JW, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369:1206-1214.
Dabigatran is a novel anticoagulant that has been shown to be at least as good as warfarin at preventing thromboembolism in atrial fibrillation (AF). It is an oral direct thrombin inhibitor that requires no blood tests to monitor its effectiveness. Thus, it has distinct advantages over warfarin. Patients with mechanical heart valves require lifelong anticoagulation with warfarin. If dabigatran proved to be equivalent to warfarin, it would be an attractive alternative for patients with mechanical valves. Eikelboom and colleagues performed a randomized, controlled clinical trial of dabigatran vs warfarin in patients with mechanical heart valves. They separated their study sample into two cohorts: cohort A, who were randomized within the first week after mitral or aortic valve replacement surgery, and cohort B who were randomized at least 3 months after surgery. These cohorts were randomized 2:1 to receive dabigatran or warfarin. Interestingly, the dose of dabigatran was higher than used in the AF trials. Initial dosing began at 150 mg, 220 mg, or 300 mg twice daily, depending on renal function, and then the dose was escalated to maintain a serum trough level of over 50 ng/ml. Warfarin was dosed to an INR of 2.0-3.0, or 2.5-3.5 depending on thromboembolic risk.
The data safety monitoring board terminated the trial early because the dabigatran group had an excess of both thromboembolic and bleeding events. Two hundred and fifty-two patients were enrolled. The mechanical valve locations were aortic in 68%, mitral in 28%, and both in 4%. Ischemic stroke occurred in 5% of the dabigatran group and none in the warfarin group. Thrombosis of the mechanical valve without symptoms was detectable in 5% of the dabigatran group and none of the warfarin group. The composite endpoint of stroke, transient ischemic attack, systemic embolism, myocardial infarction (MI), or death occurred in 9% of the dabigatran group and 5% of the warfarin group (hazard ratio [HR], 1.94; 95% confidence interval [CI], 0.64-5.86; P = 0.24). Major bleeding occurred in 4% of the dabigatran group and 2% of the warfarin group. It is noteworthy that all major bleeding was pericardial and all occurred in cohort A (early after surgery). Bleeding of any type occurred in 27% vs 12% of the dabigatran and warfarin groups, respectively (HR, 2.45; 95% CI, 1.23-4.86; P = 0.01). The authors conclude that the use of dabigatran in patients with mechanical heart valves was associated with increased rates of both thrombo-embolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk.
The results of this study are a blow to those on lifelong warfarin for mechanical heart valves. The ease of use of dabigatran compared to warfarin is a major step forward for many patients. But this is exactly the reason we do clinical trials. One cannot extrapolate that effectiveness in one disease state or indication for a drug will necessarily mean that it will be effective in another.
The reason for the failure of dabigatran in both thromboembolic and bleeding endpoints deserves some discussion. The achievement of adequate serum trough levels was less in the early group (cohort A) and this group had higher thrombo-embolic complications. However, they also had higher major bleeding rates, suggesting that it is it not purely a dosing problem. Dabigatran is successful in AF, where thrombosis occurs in the left atrial appendage under conditions of low flow due to stasis and endothelial dysfunction. But in patients undergoing valve surgery, there are large amounts of tissue factor released due to the trauma of surgery, and exposure to the sewing ring and prosthetic valve leaflets can activate the contact pathway of thrombosis. Warfarin acts at multiple sites in the coagulation cascade, including the tissue factor and contact pathways (factors VII and IX), as well as inhibiting the final common pathway, including thrombin. In contrast, dabigatran only inhibits thrombin. The authors suggest that the activation of multiple pathways may lead to an overwhelming amount of thrombin that dabigatran at these doses cannot inhibit. Warfarin’s less specific mechanism of action may be the reason it is more effective in patients with mechanical heart valves.
It should be noted that this was a phase 2 study designed to assess the serum trough levels of dabigatran. It was not designed to test efficacy of the drug. However, the data safety monitoring board terminated the study due to the excess number of endpoints in the dabigatran group. It is technically underpowered to accurately determine the magnitude of event rates, but the direction of both thromboembolic and bleeding event rates were clearly against dabigatran. For now, this means that the novel anticoagulants must not be used in lieu of warfarin for mechanical heart valves.
