Andexanet alfa cuts bleeding risk in patients taking factor Xa inhibitors
The experimental reversal agent andexanet alfa effectively reversed the anticoagulant effect of factor Xa (fXa) inhibitors by controlling serious bleeding events, according to interim results of the ANNEXA-4* trial presented at the American College of Cardiology Annual Scientific Session & Expo (ACC.18) in Orlando, Florida, US.
“Andexanet very rapidly reversed anti-fXa activity [in actively bleeding patients and] effective haemostasis was achieved in 83 percent of patients,” said lead author Professor Stuart Connolly from McMaster University in Hamilton, Ontario, Canada.
The study population comprised 227 participants (mean age 77 years) who had acute major bleeding within 18 hours of taking an fXa inhibitor (ie, apixaban, rivaroxaban, enoxaparin, or edoxaban). Of these, 61 percent had intracranial bleeding, 27 percent had gastrointestinal bleeding, and 12 percent had bleeding in other sites. Andexanet was administered initially as an intravenous bolus followed by a 2-hour infusion. All participants were included in the safety evaluation while 132 were included in the efficacy analysis. [ACC.18, abstract 409-14]
At baseline, anti-fXa activity median values were 169.75 ng/mL, 132.60 ng/mL, and 0.44 IU/mL for rivaroxaban, apixaban, and enoxaparin recipients, respectively. There were no results on edoxaban as patients were too few, said Connolly.
Upon introduction of andexanet, median anti-fXa inhibitor activity was substantially reduced to 11.30 ng/mL, 9.45 ng/mL, and 0.11 IU/mL, respectively, which was sustained towards the end of infusion (14.40 ng/mL, 10.10 ng/mL, and 0.11 IU/mL, respectively).
Despite the partial return to baseline levels when andexanet was stopped, the values eventually tapered off, resulting in the 12-hour median anti-fXa inhibitor activity values of 72.20 ng/mL, 80.90 ng/mL, and -0.18 IU/mL, respectively.
At 12 hours, 83 percent (109 out of 132 adjudicated major bleeds) achieved excellent or good clinical haemostasis.
These results were consistent with findings from previous studies [Eur Heart J 2015;36:1264-1272; Eur Heart J 2014;35:1873-1880] and support the preliminary results of ANNEXA-4 which revealed a rapid reversal of anti-fXa activity and a 79-percent efficacy rate with andexanet. [N Engl J Med 2016;375:1131-1141]
At 30 days, 12 percent of participants had died, 57 percent restarted anticoagulants, and 11 percent had a thrombotic event (ie, stroke, heart attack, or blood clot in the legs). These adverse event rates were expected due to the high-risk population with a substantial burden of comorbidities, Connolly said.
While the current findings were relatively comparable to those of REVERSE-AD** and Sarode 2013*** in terms of haemostatic efficacy (83 percent vs 68 percent and 72 percent) and thrombotic events (11 percent vs 5 percent and 8 percent), there was a higher incidence of intracranial bleeding compared with those respective trials (61 percent vs 33 percent and 12 percent), noted Connolly.
The use of fXa inhibitors has been widely practiced for high-risk stroke and venous thrombosis cases due to their excellent efficacy and safety profile, said Connolly. However, inhibiting blood clot formation may trigger uncontrolled bleeding events with a reported 15–20 percent fatality rate, [Eur Heart J 2015;36:1264-1272; Eur Heart J 2014;35:1873-1880] hence the partiality of some clinicians and patients to anticoagulant alternatives that have a reversal agent, said Connolly.
“[T]here is currently no approved reversal agent for [fXa] inhibitors … Having a safe and effective reversal agent [such as andexanet] will benefit patients with acute bleeding,” concluded Connolly, who highlighted the potential of evaluating andexanet efficacy in patients on fXa inhibitor therapy who require urgent surgery.