ROME, ITALY — Andexanet alfa (AndexXa, Portola Pharmaceuticals), a factor Xa inhibitor antidote, worked quickly and was well tolerated in reversing acute anticoagulant-related, potentially life-threatening bleeding in patients in the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study, according to research reported at the European Society of Cardiology (ESC) 2016 Congress.
"Factor Xa inhibitors are safe and effective drugs, but occasionally patients have a case of severe bleeding. When they do, if the bleeding is severe, it can be difficult to manage because there is no specific drug currently available to reverse the effects of factor Xa inhibitors," Dr Stuart J Connolly (McMaster University, Hamilton, ON) said during a presentation at the ESC congress.
"Andexanet alpha has been specifically developed to reverse the effects of factor Xa inhibitors and to assist physicians in the management of acute severe bleeding," he said.
Connolly and colleagues are conducting the study, which continues to enroll participants. The interim results for 67 patients (mean age 77) were reported August 30, 2106 at the ESC congress and published simultaneously in the New England Journal of Medicine.
The patients required emergency reversal of acute bleeding after receiving the direct factor Xa inhibitors apixaban (Eliquis, Bristol-Myers Squibb), rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals), or edoxaban (Savaysa, Lixiana, Daiichi-Sankyo) or an indirect inhibitor (enoxaparin) within the past 18 hours. The primary bleeding sites were gastrointestinal (49%) and intracranial (42%). The patients had either atrial fibrillation or venous thromboembolism or both.
"It's important to note that this is an elderly, sick population . . . and there was a high burden of prior myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, and heart failure," Connolly said.
The patients received andexanet alfa in an immediate bolus over 15 to 30 minutes, then by infusion for 2 hours, with dosing based on which factor Xa inhibitor and when received.
Clinicians assessed patients at baseline, end of bolus, end of infusion, and at 4, 8, and 12 hours, then at 3 and 30 days postinfusion. Researchers included 47 patients in the efficacy assessment (patients whose factor Xa activity levels were high) and all 67 in the safety assessment.
Researchers observed an 89% decrease in anti–factor Xa activity from baseline to end of bolus (within a half hour) in patients exposed to rivaroxaban (n=26) and a 93% reduction for patients exposed to apixaban (n=20).
They rated clinical hemostatic efficacy as good to excellent in 79% of patients at 12 hours overall. Hemostatic efficacy came to 84% for gastrointestinal bleeders and to 80% for intracranial bleeders.
Thrombotic events occurred within 3 days of andexanet in four patients (6%) and by 30 days in 12 (18%). Eighteen patients (27%) restarted anticoagulation by 30 days. Ten deaths (15%) occurred within 30 days, six of them attributed to cardiovascular causes.
As for a potential mechanism, Connolly said, "This is actually a modified recombinant human protein. You might describe it as a decoy protein that goes around and scavenges up the factor Xa inhibitor molecules, pulling them out of the circulation, so that they're no longer available to inhibit coagulation."
Cardiologist Dr Kurt Huber (Wilhelminen Hospital, Vienna, Austria), ESC spokesperson, told heartwire from Medscape, "Everybody wants to connect the dots in cases of severe bleeding with factor Xa inhibitors. In clinical practice it will be necessary to use this only very rarely, but if you have it you can feel much safer.
"It's in the early stage of investigation. If the drug is safe it would reduce the anticoagulant effect of factor Xa inhibitors within a few minutes, it has been shown. It might help to stop bleeding complications earlier, and I think it would be extremely important to patients who need acute surgery and who are on a factor Xa inhibitor. Here you really can reach a lot of positive things," he said.
Earlier this month, Portola Pharmaceuticals (South San Francisco, California) announced that the US Food and Drug Administration had asked the company for additional information on manufacturing the drug prior to its potential approval.
The company's application for approval was based on two phase 3 studies involving rivaroxaban and apixaban. The FDA requested more information on edoxaban and enoxaparin, which are part of the current ongoing study.
"This information will be provided and I anticipate that once it's provided that they will eventually approve the drug," Connolly said at the ESC congress.
The request hasn't slowed down the study, according to Connolly.
"We have about 140 patients so far. It's changing from day to day. We're continuing to enroll patients and we will for certain enroll at least 250 patients," he told heartwire .
"There is some discussion now about increasing the enrollment to 350 patients. The main consideration will be to have more patients with intracranial hemorrhage, who are the patients whose bleeds are the most dangerous," he said.
Portola Pharmaceuticals funded this research. Connolly reports grant support from Boston Scientific and grant support and personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Sanofi, Bayer, and Portola outside the submitted work. Disclosures for the coauthors are listed on the journal website.
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Heartwire from Medscape © 2016
Cite this: Factor Xa Reversal Agent Shows Rapid Effectiveness in Preliminary Results - Medscape - Aug 30, 2016.