Reversal Agent for Factor Xa Inhibitors Rapidly Reduces Anticoagulant Effects: ANNEXA-4

ROME, Italy—Andexanet alfa, which recently hit a road block on its path to approval by the US Food and Drug Administration (FDA), induces rapid reversal of the anticoagulant effects of factor Xa inhibitors in patients with acute major bleeding, a preliminary look at the ongoing ANNEXA-4 study shows.

Effective hemostasis was achieved in 79% of patients, who mostly had GI or intracranial bleeds, by 12 hours, Stuart Connolly, MD (McMaster University, Hamilton, Canada), reported here at the European Society of Cardiology Congress. The findings were published simultaneously online in the New England Journal of Medicine.

“I think that this medication does exactly what it is promising to do,” Paulus Kirchhof, MD (University of Birmingham, England), who was not involved in the study, commented to TCTMD. “We will have to define clear rules on how to use it, because it is a powerful tool and if used too early and too often then maybe there is a risk of provoking avoidable thrombotic events. But if used adequately, it may be lifesaving.”

Andexanet alfa is a recombinant modified human factor Xa protein that acts as a decoy, binding factor Xa inhibitors to remove them from the circulation. It has been shown to reverse the effects of rivaroxaban (Xarelto; Janssen Pharmaceuticals) and apixaban (Eliquis; Bristol-Myers Squibb) in healthy volunteers.

It was widely believed that it would be approved in the United States by August 17, the FDA’s deadline to make a decision, but the agency ultimately declined to approve it. Instead, the FDA asked for more information related to manufacturing and more data to support including all of the factor Xa inhibitors on the label.

Connolly said that the information will be provided and that he expects the FDA will eventually approve the reversal agent. He added that the agency did not raise any safety concerns.

The ANNEXA-4 Study

ANNEXA-4 is an ongoing prospective study of patients with acute major bleeding within 18 hours of their last dose of a factor Xa inhibitor. Connolly presented an interim analysis of the first 67 patients enrolled in the study, of whom 32 were taking rivaroxaban, 31 apixaban, and four enoxaparin. No patients were taking edoxaban (Savaysa; Daiichi Sankyo). Only the 47 patients who had baseline anti-factor Xa activity of at least 75 ng/mL (or 0.5 IU/mL for those taking enoxaparin) were included in the efficacy analyses, although all were included in the assessments of safety.

Most of the patients had substantial cardiovascular disease. Bleeding was mostly GI (49%) or intracranial (42%).

Andexanet alfa was administered as a bolus followed by a 2-hour infusion. After the bolus, median anti-factor Xa activity dropped by 89% for those receiving rivaroxaban and 93% for those receiving apixaban. Levels remained consistent for the duration of the infusion.

At 12 hours after the infusion, clinical hemostasis was classified as excellent or good in more than three-quarters of patients (79%).

In the safety analysis, 18% of patients had a thrombotic event within 30 days, including 6% who had one within 3 days of receiving andexanet alfa. The event rate is consistent with the severity of disease in the population and the fact that only 27% of patients reinitiated anticoagulation within 30 days, Connolly said. In fact, only one of the 12 patients who had an event had restarted anticoagulation.

Kirchhof agreed with that assessment and also said the number of deaths seen in the study (10) represents “a very good outcome for bleedings that were considered life-threatening in the majority of cases.”

Only for Life-Threatening Situations

Andexanet alfa “is an important addition to the tools that we have to manage patients with severe bleedings,” Kirchhof said, noting that 2% of anticoagulated patients with A-fib will have major bleeding events each year.

However, the vast majority of bleeds can and should be managed without reversal of the anticoagulant, he said. “Only in life-threatening situations should we probably use these direct reversal agents.”

As reversal agents are introduced, every center should have clear standard operating procedures for such situations, Kirchhof advised. Those protocols, he added, should involve a stepwise approach to managing bleeding that would include such agents as a last resort.

“We can safely say that should andexanet alfa be approved in Europe or in the US, it could easily be integrated,” he said.

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