Factor Xa Inhibitor Antidotes: Evidence They Work May Be Untestable in Big Trials

July 08, 2013

AMSTERDAM, the Netherlands — Two different formulations of prothrombin complex concentrates (PCCs) showed promise as antidotes to rivaroxaban (Xarelto, Bayer/Johnson & Johnson), each in their own way, in a small study conducted in healthy volunteers.

PCCs are available nearly everywhere and widely used for reversing the effects of conventional anticoagulants in patients with uncontrolled bleeding or in the event of emergency surgery. Now their prospects as antidotes for the new generation of oral anticoagulants are looking better. But that's with at least two huge caveats.

Most research on PCCs and other agents for reversing the effects of the new oral factor Xa inhibitors like rivaroxaban and apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), and the direct thrombin inhibitor dabigatran etexilate (Pradaxa, Boehringer Ingelheim), have been limited, preliminary, and outside their intended clinical setting. And the kind of rigorous, placebo-controlled trials on which "class I, level of evidence A" guideline recommendations are generally based may not be possible.

In the recent study of two PCCs in healthy volunteers who had been given rivaroxaban, both promoted thrombin generation, the most meaningful end point for such comparisons, according to Dr Marcel Levi (University of Amsterdam, the Netherlands), who presented the analysis here at the 2013 Congress of the International Society on Thrombosis and Haemostasis. And they were about equally effective at promoting thrombin generation, "enough to overcome the effects of rivaroxaban," he told heartwire .

So the study, he said, provides no evidence to suggest that either PCC preparation, one containing factors II, IX, and X (Profilnine SD, Grifols Biologicals), and a four-factor preparation that also contains factor VII (Beriplex P/N, CSL Behring), should be preferred over the other for reversing the effects of a factor Xa inhibitor.

But Levi cautions that the study, which randomized 34 men and women to receive one of the two PCCs or placebo, was conducted under far from clinical conditions in healthy volunteers without indications for either PCC or factor Xa inhibition. Although the findings are helpful, he said, "at the end of the day we have to be careful not to extrapolate [them] to bleeding patients."

The subjects received rivaroxaban 20 mg twice daily for four days, followed by open-label randomization to 50 IU/kg bolus of either the three- or four-factor PCC, or to placebo.

Both PCCs reversed the anticoagulant effects of rivaroxaban, but did so with potential mechanistic differences. The four-factor PCC had a more pronounced effect on reversal of rivaroxaban-associated prolongations in prothrombin time, compared with the three-factor PCC. But, Levi reported, the three-factor PCC more strongly reversed rivaroxaban-related changes in endogenous thrombin generation.

Levi said that there was much discussion at the conference about prospects for randomized, controlled trials of reversal agents aimed at oral factor Xa inhibitors and antithrombins. "I think most people at the meeting came to the conclusion that the trials would be virtually impossible."

Taking rivaroxaban as an example, he said, "you would need patients who present with bleeding while on rivaroxaban, and the bleeding should be sufficiently severe to warrant reversal of the anticoagulant agent. Then rivaroxaban has a relatively short half-life, which means that many patients who took the pills a few hours ago are not eligible for a reversal agent anyway."

That leaves only a small and heterogeneous population of patients presenting with serious bleeding while on rivaroxaban who would be eligible, he said. "And also the end points--what are we going to measure?"

As an alternative, registry studies are "good for starters," Levi said. "That's not ultimately the type of research that will provide us with definitive answers, but I think at the moment that's the best we can do."

Levi disclosed being on scientific advisory boards for and receiving honoraria from Bayer and Janssen. Two of his coauthors are employees of Bayer, and two others are employees of Janssen.


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