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ORLANDO -- Patients on anticoagulants such as apixaban (Eliquis) who develop bleeding emergencies may be able to reverse the drug's impact with the investigational agent andexanet, researchers said here.
In the interim report of the ANNEXA-4 study, principal investigator Stuart Connolly, MD, professor of medicine at McMaster University in Canada, said that following a bolus injection of andexanet and a 2-hour infusion, the factor Xa inhibitor's activity was reduced by 91%.
He also reported at the annual scientific sessions of the American College of Cardiology that the impact of rivaroxaban was reduced by 88% when patients with serious bleeding complications used the reversal agent.
"Unlike for some other anticoagulants, there is currently no approved reversal agent for factor Xa inhibitors," said Connolly. "Factor Xa inhibitors are already widely used because of their excellent efficacy and safety profile. However, some physicians and patients may choose to use other anticoagulant drugs because they have a reversal agent rather than using one of the factor Xa inhibitors."
"We have shown that andexanet is both effective and safe and once it is approved and becomes available is a drug that will be very helpful to physicians who are treating the acutely bleeding patient," Connolly said.
About 100,000 people a year on factor Xa inhibitors are hospitalized each year for bleeding episodes, often the result of trauma, Connolly told ڴŮ. He estimated that about 20% of those cases are serious enough bleeds to require a reversal agent such as andexanet -- a drug now under review by regulatory agencies in the U.S. and Europe. The most common types of major bleeds include bleeding in the brain and gastrointestinal bleeding.
Connolly reported excellent or good clinical hemostasis was achieved in 83% of patients overall. "We believe this is a very good result and compares well with other reversal agents," he said.
Safety of andexanet was assessed in all 227 patients. At 30 days, 12% of patients had died and 11% experienced a thrombotic event such as a stroke, heart attack, or deep vein thrombosis. Connolly said these results are in line with what would be expected given the underlying medical condition of the patients in the trial and the fact that many had not resumed anticoagulant treatment during the 30 days after receiving andexanet.
"We don't believe these events are caused by the drug," he said. "These patients are at very high risk and we know they have an intrinsic risk of dying even if the bleeding is reversed." The incidents of stroke and heart attack are not unexpected events in this population, he said.
"This study is only focused on patients who are acutely bleeding, but there is also great interest in using a drug like andexanet for patients who come into a medical center on a factor Xa inhibitor and require urgent surgery," Connolly said. "We hope to study that patient population in the future."
In commenting on the study, Gregory Piazza, MD, instructor of medicine at Brigham and Women's Hospital and Harvard Medical School in Boston, told ڴŮ: "The frequency at which we are going to have to deal with the need for reversal is going to be much lower than with warfarin. That said, when you do have a bleeding patient on a direct oral anticoagulant you do want to have a way of reversing that anticoagulant effect."
Having a new reversal agent for these patients "will make a difference," Piazza said. He suggested that the drug is not likely to be needed every day, citing Connolly's estimate that the sites in the study tended to use andexanet every couple of months. "That is probably the frequency we would expect to have to use these drugs unless we are at a trauma center that will see a lot of anticoagulated patients. When patients present critically ill with bleeding, you want to have this on your shelf," Piazza said.
Approval of andexanet has been slow in coming, though. Its developer, Portola Pharmaceuticals, had hoped to win approval in 2016, but the FDA instead requested more data. A revised Biologics License Application is now under review with an , according to Portola.
Disclosures
The study was funded by Portola Pharmaceuticals.
Connolly disclosed relevant relationships with Sanofi-Aventis, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer, and Portola.
Piazza disclosed relevant relationships with Agile, BCRI, BIO2, Exithera, Optum, Bristol-Myers Squibb, Daiichi, EKOS, Janssen, and the Thrombosis Research Institute.
Primary Source
American College of Cardiology
Connolly S, et al "Report on the ANNEXA-4 study: Andexanet for reversal of anticoagulation in factor Xa-associated acute major bleeding" ACC 2018; Abstract 409-14.