Anticoagulant Options — Why the FDA Approved a Higher but Not a Lower Dose of Dabigatran
The following are 10 points to remember about anticoagulant options:
1. In this article, the Food and Drug Administration (FDA) explains why it approved the 150 mg twice daily dosing of dabigatran for atrial fibrillation, but not the lower dose of 110 mg twice daily. This explanation was necessary because many believe that both doses should have been approved, with the dose decision left to patients and their physicians based on the available evidence and their individual concerns and needs.
2. Dabigatran (Pradaxa®) is a novel anticoagulant (direct thrombin inhibitor) approved by the FDA as an alternative to warfarin for the reduction of the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
3. Approval was based on a multicenter, active-control trial, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY), a noninferiority study in which patients were randomly assigned to receive twice daily 150 mg of dabigatran or 110 mg of dabigatran, or warfarin. Warfarin was titrated to achieve an international normalized ratio (INR) of 2.0-3.0. Both dabigatran regimens were noninferior to warfarin, but the 150 mg regimen was significantly superior to warfarin and to the 110 mg regimen.
4. With respect to major bleeding, 110 mg of dabigatran was superior to warfarin, whereas 150 mg was similar to warfarin. Thus, 150 mg reduced the risk of stroke and systemic embolism greater than the 110 mg dose, but with the risk of greater bleeding.
5. The FDA acknowledges that in patients for whom there is reason for heightened concern about bleeding, the lower dose might have seemed desirable, even at the cost of increased risk of stroke. For many patients who refuse to take warfarin because of fear of bleeding, 110 mg of dabigatran might have provided an attractive option—an option clearly preferable to no treatment at all.
6. To determine whether there was evidence for a benefit/risk of the low- versus high-dose dabigatran based on incremental risk of bleeding or stroke, the FDA conducted a subset analysis. The focus was on elderly patients, patients with impaired renal function, and patients with previous bleeding episodes.
7. Among the 40% of patients in the RE-LY trial who were 75 years of age or older, the rate of stroke or systemic embolism was lower with 150 mg of dabigatran (1.4 per 100 patient-years) than with 110 mg (1.9 per 100 patient-years), but the rate of major bleeding was higher (5.1 vs. 4.4 per 100 patient-years). A benefit–risk assessment in which strokes and systemic emboli are given more weight than nonfatal bleeding events would find the higher dose more favorable in the elderly.
8. In patients with moderate renal impairment, the rate of stroke or systemic embolism with 150 mg of dabigatran was approximately half that with 110 mg, and the rate of bleeding was no greater (5.3 vs. 5.7 major bleeding episodes per 100 patient-years).
9. To assess whether there is an incremental bleeding risk, they analyzed the risk of re-bleeding in the 57% of patients who had a major bleeding event during the study, who either resumed taking or had no interruption in their study medication at the same dose. The percentages of these patients who had an additional major hemorrhage were similar in both dabigatran groups and the warfarin group.
10. The Cardiovascular and Renal Drugs Advisory Committee considered each of the issues at length and slightly favored approval of only the higher strength. However, the FDA leadership's final decision was that using the low dose as a ‘play it safe’ option for patients and physicians represented an undesirable stimulus to use a less-effective regimen, and would lead to unnecessary strokes and disability.
While the FDA leadership explanation for its decision is clear, many would argue it is not adequate, and the decision should not be in their purview and the process sets an undesirable precedent.
Keywords: Stroke, Thrombin, United States Food and Drug Administration, Benzimidazoles, Warfarin, Pyridines, Embolism, Advisory Committees, United States
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