Dabigatran – The End of ‘Coumadin Clinics’?

Dear Readers,

Patients with atrial fibrillation (AF) can be at high risk of stroke. Warfarin therapy reduces that risk by about 70%. However, the limitations of anticoagulation therapy using warfarin are well known. There is also a major impact of warfarin therapy on the health care system itself. For example, although centralized anticoagulation clinics have been shown to improve the management and outcome of patients treated with warfarin, these clinics are often not profitable and require hospital subsidies. In the May 2009 issue of EP Lab Digest, my editorial focused on the WATCHMAN device (Atritech, Plymouth, MN), a percutaneous left atrial appendage (LAA) occluder designed to prevent stroke in patients with AF and risk factors for stroke. The device has been under development as a nonpharmacological alternative to warfarin and was the subject of an FDA advisory panel on April 23, 2009. Despite a conditional recommendation by the panel to approve the device (7 to 5 in favor), the device has yet to be approved and remains unavailable except at centers that are participating in the continued access protocol. In the interim, alternatives to warfarin besides LAA occlusion devices have gained ground. The results of the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial were published in the New England Journal of Medicine in August.¹ RE-LY was a noninferiority study comparing two different doses of dabigatran, a new oral direct thrombin inhibitor, given in a blinded fashion to open-label, dose-adjusted warfarin. In this trial, over 18,000 patients with AF and a risk of stroke were randomly assigned to receive fixed doses of dabigatran, 110 mg or 150 mg twice daily, or warfarin. The average duration of follow-up was 2.0 years. The annual rates of the primary outcome, which was stroke or systemic embolism, were 1.7% in the warfarin group, as compared with 1.5% in the group that received 110 mg of dabigatran (P<0.001 for noninferiority and 1.1% in the group that received 150 mg of dabigatran (P<0.001 for superiority). The annual rate of major bleeding was less common among the group receiving 110 mg of dabigatran (2.7%) compared to the group receiving warfarin (3.4%), but not less common among the group receiving the higher dose of 150 mg of dabigatran (3.1%). The rate of hemorrhagic stroke was lower in each dabigatran group compared to warfarin. The investigators concluded that in patients with AF, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. 

At either dose in the RE-LY study, dabigatran appears to be a better drug than warfarin. The other advantages of dabigatran over warfarin are that dabigatran does not require dose adjustments or anticoagulation monitoring. Dabigatran has the potential to provide benefits to both patients and the health care system. 

Many remember the failure of a different direct thrombin inhibitor, zimelagatran. Zimelagatran appeared to be a promising substitute for warfarin for stroke prevention, and patients with AF in the series of SPORTIF (Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation) trials, until it was found to have a high incidence of liver toxicity. Fortunately, dabigatran, on the other hand, appears to have no hepatotoxicity during 2 years of therapy. 

After a marathon of research and development to find an alternative to warfarin to prevent strokes in patients with AF, a device -- a percutaneous LAA occlude, and a drug, dabigatran, appears to be close to crossing the finish line. At the same time, if dabigatran becomes available, it could cause a sharp reduction in the enthusiasm for LAA occlusion devices.

Disclosure: Dr. Knight was a co-investigator for the RE-LY trial.

Reference

1.     Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.