Investigational agent effective against anticoagulant-induced major bleeds

By Liz Meszaros, MDLinx
Published March 19, 2018

Key Takeaways

In patients who experience major bleeds while taking Factor Xa (FXa) inhibitor, the recombinant modified FXa molecule andexanet may be associated with a fast and significant decrease in anti-FXa activity and a high rate of clinically effective hemostasis, according to results from a study presented at the American College of Cardiology's 67th Annual Scientific Session, held March 10-12 in Orlando, FL.

"Unlike for some other anticoagulants, there is currently no approved reversal agent for FXa inhibitors," said lead author Stuart Connolly, MD, professor of medicine, McMaster University, Hamilton, Ontario, Canada. "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 FXa inhibitors. Having a safe and effective reversal agent available will benefit patients with acute bleeding."

Approximately 2.9 million people in the United States currently take FXa inhibitors. Most of these people are older, with comorbid conditions that put them at a higher risk for cardiovascular events. About 84,000 of these patients are hospitalized for major bleeds annually, according to a recent analysis of the MarketScan Commercial and Medicare databases.

Dr. Connolly and fellow researchers enrolled patients with acute major bleeding within 18 hours of their last treatment with an FXa inhibitor in the ongoing, prospective, open-label, single-arm ANNEXA-4 study.

They enrolled 228 patients from the United States, Canada, and Europe (mean age: 77 years) who presented with the bleeding event after taking one of four FXa inhibitors: apixaban, rivaroxaban, edoxaban, or enoxaparin.

Of these, 80% had atrial fibrillation, 27% coronary artery disease, and 20% venous thrombosis. One-hundred seventeen were treated with apixaban, 90 with rivaroxaban, 17 with enoxaparin, and 3 with edoxaban. In 61%, the bleeding site was intracranial; in 27%, gastrointestinal; and in 11%, other.

Patients were treated with a bolus (400 or 800 mg) of the investigational agent andexanet, followed by a 4- or 8-mg/min infusion for 2 hours. The primary endpoints were the change in anti-FXa activity and the achievement of good or excellent hemostasis. Safety endpoints were assessed in 227 patients and included thrombotic events and death at 30 days.

Researchers assessed drug efficacy in 137 patients and found a 92% reduction in median anti-FXa activity with andexanet. Adjudicated data were available for 132 patients, among whom 83% achieved good or excellent hemostasis at 12 hours (95% CI: 75%-89%). Median anti-FXa inhibitor activity was reduced by 88% of patients treated with rivaroxaban, by 91% in those treated with apixaban, and by 75% in those treated with enoxaparin.

In their safety assessment, researchers found that 11% of patients experienced a thrombotic event, and 12% died at 30 days. The incidence of adverse events was as expected.

One important limitation of the study was that it was not a randomized controlled trial. Because andexanet is for use during crisis situations, a randomized, controlled design was deemed to be ‘impractical,’ as researchers could not offer treatment with the speed deemed necessary.

"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," said Dr. Connolly. "We hope to study that patient population in the future."

This study was funded by Portola Pharmaceuticals Inc.

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