Stroke is the most feared side effect in patients with atrial fibrillation, occurring in up to 35% of patients who have this arrhythmia. Coumadin can significantly reduce that risk of stroke. Unfortunately, Coumadin - an anticoagulant or "blood thinner" that reduces the blood's ability to clot - is a difficult drug to use. It requires frequent blood tests and dosage adjustments, a practice that both doctors and patients find impractical. Without these careful adjustments, however, Coumadin can cause problems. If you don't take enough Coumadin, the risk of stroke is not reduced. If you take too much, severe bleeding can result - including brain hemorrhage. Because of the difficulty in administering the drug properly, studies have documented that only about half the patients who should be getting Coumadin are receiving it appropriately. And for this reason, one of the "holy grails" for pharmaceutical companies for decades has been to develop a safe, effective, and convenient oral anticoagulant drug that can be used as a replacement for Coumadin.
Dabigatran is one of several drugs now being tested as such a replacement for Coumadin. Its major advantage is that it can be given as a standard, twice-daily dose, without the need of blood tests and constant dosage adjustment.
In a clinical trial called the RE-LY trial, more than 18,000 patients with atrial fibrillation in 44 countries were randomized to receive either one of two doses of dabigatran, or carefully administered Coumadin therapy. Investigators measured the strokes and other blood clotting events that occurred in these patients during drug treatment. They concluded that patients receiving higher-dose dabigatran did better than those on Coumadin, while those receiving lower-dose dabigatran did equally well as those on Coumadin. The incidence of major bleeding side effects were equal to (with higher dose dabigatran) or less than (with lower dose dabigatran) those seen in patients taking Coumadin.
The major non-bleeding-related side effect with dabigatran was heartburn, which was severe enough to require stopping the drug in a substantial minority of patents. The kind of liver toxicity that was seen a few years ago with a related drug (ximelagatran) was not seen in this study with dabigatran. However, there was a very small but statistically significant increase in the risk of heart attack (myocardial infarction) with dabigatran, which may temper some of the bubbling enthusiasm for the use of this drug.
At the moment, this very large randomized controlled clinical trial looks quite promising. However, it is not yet clear whether the higher dose or lower dose of dabigatran will be recommended. Furthermore, it seems likely that the FDA will want to look very closely at the (apparently tiny) heart attack risk that was identified in the RE-LY trial. But with these caveats, we may finally be very close to having a convenient, effective and safe substitute for Coumadin for patients with atrial fibrillation.
Dabigatran, marketed by Boehringer Ingelheim in Europe as Pradaxa and in Canada as Pradax, is not yet approved in the United States.
Sources:
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Medicine 2009; DOI:10.1056.NEJM0a0905561.
