Patients who had acute major bleeding associated with factor Xa inhibitors experienced a significant reversal of anti-factor Xa activity when they received an andexanet bolus and infusion, according to a multicenter, open-label trial.
Lead researcher Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, Canada, and colleagues published their results online in the New England Journal of Medicine on Aug. 30.
The findings were also presented at the European Society of Cardiology (ESC) Congress in Rome.
In recent years, the FDA has approved several factor Xa inhibitors, including apixaban (Eliquis), rivaroxaban (Xarelto), edoxaban (Savaysa) and enoxaparin (Lovenox). Although the drugs are effective at treating and preventing venous thromboembolism and preventing strokes in patients with atrial fibrillation, the researchers noted that the medications have been associated with major and fatal bleeding.
In this study, known as ANNEXA-4, the researchers enrolled patients with acute major bleeding at 20 centers in the U.S., one center in the United Kingdom and one center in Canada beginning on April 20, 2015. The interim analysis of the ongoing study at the ESC Congress included 67 patients who had acute major bleeding within 18 hours after taking a factor Xa inhibitor.
The mean age of the patients was 77 years old, and each of them had a history of thrombotic events and cardiovascular disease.
All patients received andexanet alfa, an investigational agent designed by Portola Pharmaceuticals to reverse the effects of factor Xa inhibitors. The FDA granted andexanet a breakthrough therapy designation, but the agency has not yet approved the drug. Portola funded the study.
Patients received an andexanet bolus for 15 to 30 minutes and then had a two-hour infusion of the drug. Of the patients, 32 received rivaroxaban, 31 received apixaban and for received enoxaparin.
The primary site of bleeding was gastrointestinal in 49 percent of patients and intracranial in 42 percent of patients. The remaining 9 percent had other sites of primary bleeding.
After the bolus administration, the median anti-factor Xa activity decreased by 89 percent in patients who received rivaroxaban and by 93 percent in patients who received apixaban. The researchers said those levels were similar during the infusion period.
During the 12 hours after the infusion, 79 percent of patients had good or excellent clinical hemostasis. In addition, after 30 days, 18 percent of patients had a thrombotic event and 15 percent of patients died.
As of late August, the researchers had enrolled more than 130 patients in the study. They mentioned that they plan on enrolling patients until there were 162 available for the efficacy analysis and 230 available for the safety analysis.
“The hemostatic efficacy results are especially important because no FDA or EMA-approved antidote is available for these patients and no existing therapies, including plasma-derived products for warfarin reversal, have demonstrated reversal of Factor Xa inhibitor activity or clinical efficacy and safety,” Connolly said in a news release.