Another strike against dabigatran

In addition to two new oral anticoagulants vying to take its place as the alternative to warfarin in patients with atrial fibrillation (AF), dabigatran (Pradaxa^®) took another hit last month when one of the proposed strategies for reversing its anticoagulant effects was shown to be ineffective in a small study of healthy volunteers.

Last year, dabigatran was shown to be more effective than warfarin in the prevention of stroke and systemic embolism in patients with AF, a result that came with comparable rates of overall bleeding and lower rates of intracranial bleeding. Improved efficacy in the absence of increased bleeding was certainly a welcomed change, but the question remained -- if you have one, how do you manage it?

A colleague and I worked with one of our hematologists to develop guidelines for the management of dabigatran at our institution and our proposed initial strategy for the management of severe to life-threatening bleeding events included the administration of prothrombin complex concentrate (PCC), a prohemostatic agent comprised of coagulation factors II, VII, IX, and X. This decision was based on several factors, including some evidence indicating efficacy in animal models, lower thrombogenic potential compared to other factor products, and truthfully, the absence of compelling data indicating that anything else would be more effective.

Well, it appears PCC is probably not the right answer either... at least not according to the study published in Circulation last month. Twelve healthy volunteers were randomized in a double-blind, placebo-controlled fashion to receive either rivaroxaban (Xarelto^®) 20 mg twice daily or dabigatran 150 mg twice daily for 2.5 days (i.e., enough time to allow each agent to achieve steady state concentrations) followed by 50 units/kg of PCC or placebo. After a washout period, patients crossed over and the process was repeated. Coagulation assays were performed at baseline, at steady state for each anticoagulant, and after administration of PCC. The anticoagulant effect of rivaroxaban was reversed following administration of PCC, whereas the effect of dabigatran remained unchanged.

While the study was small and conducted in a limited patient population (and uses parameters that have not yet been standardized for measuring the anticoagulant effects of new oral anticoagulants), it does provide some insightful human data where we once had none.

The question is... well, now what? For the time being, we are in the process of revising the dabigatran management guidelines at our institution to no longer recommend the routine use of PCC. We are considering recombinant factor VIIa (rFVIIa) as a potential strategy for the management of severe or life-threatening bleeding events, an agent that comes with some limited animal data but also an increased thrombotic risk compared to PCC. Lower doses of rFVIIa are becoming more commonplace in practice, so that may help swing the risk-benefit ratio in its favor.

While this was a small win for rivaroxaban, it may have inadvertently been a victory for apixiban (Eliquis^®) as well. With a similar molecular mechanism of action, one would expect PCC to have similar effects on reversing the anticoagulant effects of apixiban. Given that it was recently shown to be superior to warfarin in nearly every conceivable way, the results of this study only further add to the possible advantages of its use in clinical practice.