Andexanet was shown to reduce FXa inhibition activity by 91% for patients on apixaban, 88% for patients on rivaroxaban, and 75% for patients on enoxaparin.
Stuart Connolly, MD
Andexanet, an antidote for the Factor Xa (FXa) inhibitor class anticoagulants, has been associated with improved control of serious bleeding in patients taking FXa inhibitors.
In an interim analysis of ANNEXA-4, presented at the 67th American College of Cardiology Scientific Sessions in Orlando, Florida, the therapy was shown to reduce FXa inhibition activity by 91% for patients on apixaban, 88% for patients on rivaroxaban, and 75% for patients on enoxaparin.
“Unlike for some other anticoagulants, there is currently no approved reversal agent for Factor Xa inhibitors,” Stuart Connolly, MD, a professor of medicine at McMaster University in Canada and the study’s lead author, said. “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. Having a safe and effective reversal agent available will benefit patients with acute bleeding.”
FXa inhibitors, which greatly increase the risk of uncontrollable bleeding, are utilized by roughly 2.5 million US patients. Annually, 117,000 patients are hospitalized for major bleeding due to FXa inhibitors, with a mortality rate of 8%. For those that experience bleeding in the brain, the mortality rate is almost 25%.
The trial is observing safety outcomes in 227 patients and efficacy outcomes in 132 patients in centers in the US, Canada, and Europe. All participants presented with acute major bleeding within 18 hours of administration of apixaban, rivaroxaban, enoxaparin, or edoxaban.
For efficacy, there are 2 co-primary endpoints: the reduction in anti-FXa inhibitor activity and achievement of clinical hemostasis within 12 hours of administration. While there were large reductions for 3 FXa inhibitors, data on edoxaban could not be collected due to a low number of patients receiving it.
All told, 132 major bleeds were adjudicated, with 83% (n = 109) of patient achieving good or excellent hemostasis (95% CI, 0.75—0.89).
For safety, the main measurements were thrombotic events, the level of antibodies to Factor X, FXa, and andexanet, and 30-day mortality. By day 30, anticoagulation was resumed in 57% (n = 129) patients, with only 9 resuming anticoagulation prior to a thrombotic event. In total, a thrombotic event occurred in 2.6% (n = 6) of patients within 3 days of administration, and 11% (n = 24) within 30 days.
The mortality rate was 12% within 30 days (n = 27), with 11 deaths deemed as cardiovascular.
“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.”
Connelly and colleagues have thus far concluded that “in patients with acute major bleeding while taking an FXa inhibitor, reversal with andexanet was associated with a rapid and pronounced decrease in anti-fXa activity and a high rate of clinically effective hemostasis, with an acceptable rate of adverse events.”
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