ANNEXA-4 confirms andexanet efficacy, safety for antithrombotic-related acute bleeding
Andexanet alfa effectively reduced anti-factor Xa activity in patients who experienced acute bleeding while on a factor Xa inhibitor*, results from the ANNEXA-4** study showed.
Participants in this multinational, open-label trial were 352 adults (mean age 77 years, 53 percent male) who were experiencing acute major bleeding within 18 hours of their last dose of factor Xa inhibitor (mean time between last factor Xa inhibitor dose and andexanet alfa administration, 12 hours). They were administered andexanet alfa at either low-dose (400 mg bolus plus 4 mg/min infusion for 2 hours) or high-dose (800 mg bolus plus 8 mg/min infusion for 2 hours). All patients who received andexanet alfa were included in the safety population, while the efficacy population comprised patients with baseline anti-factor Xa activity of ≥75 ng/mL (or ≥0.25 IU/mL for patients on enoxaparin) and confirmed major bleeding (n=254).
At baseline, 14 percent of patients had a history of myocardial infarction (MI), 20 percent had stroke, and 19 percent had deep vein thrombosis (DVT). Eighty percent of patients were receiving anticoagulants due to atrial fibrillation, with apixaban (55 percent, median daily dose 10 mg) and rivaroxaban (36 percent, median daily dose 20 mg) the main anticoagulants prescribed.
The main site of bleeding was intracranial (64 percent), primarily intraparenchymal (46 percent), subdural (28 percent), and subarachnoid (15 percent), followed by the gastrointestinal tract (26 percent).
Between baseline and the end of bolus administration, median anti-factor Xa activity decreased by 92 percent among patients on apixaban (from 149.7 to 11.1 ng/mL) and rivaroxaban (from 211.8 to 14.2 ng/mL), and by 75 percent among patients on enoxaparin (from 0.48 to 0.15 IU/mL). [ISC 2019, abstract LB7, N Engl J Med 2019;doi:10.1056/NEJMoa1814051]
Twelve hours after infusion of andexanet alfa, median anti-factor Xa activity had decreased by 38 and 62 percent from baseline, respectively, among patients on apixaban and rivaroxaban.
Eighty-two percent (n=204) of evaluable patients achieved excellent (n=171) or good (n=33) haemostatic efficacy 12 hours after end of infusion, 80, 83, and 87 percent of patients on rivaroxaban, apixaban, and enoxaparin, respectively, with haemostatic efficacy achieved by 80 and 85 percent of patients with intracranial and gastrointestinal bleeding, respectively.
“Rapid specific reversal of factor Xa inhibition to hasten haemostatic control should improve clinical outcomes,” said the researchers.
Discontinuation of anticoagulant therapy during episodes of acute bleeding can increase the risk of thrombotic events for which the anticoagulants are prescribed, they added.
Over the 30-day post-enrolment follow up, there were 49 deaths (14 percent; 35 due to cardiovascular causes), while 10 percent (n=34) experienced a thrombotic event (ie, MI [n=7], ischaemic stroke [n=14], DVT [n=13], and pulmonary embolus [n=5]).
Following cessation of factor Xa inhibitor therapy at enrolment, 220 patients received ≥1 dose of anticoagulant within 30 days of andexanet alfa treatment, of whom 28 percent restarted oral anticoagulation during follow up with no incidence of thrombotic events.
“Acute major bleeding that is associated with the use of factor Xa inhibitors can be a medical emergency with a poor prognosis [for which there are] limited treatment options,” said the researchers.
“The study supported the May 2018 FDA*** approval of andexanet alfa, now the only approved agent for patients taking rivaroxaban and apixaban when urgent reversal is needed for life-threatening or uncontrolled bleeding,” said senior author Associate Professor Truman J. Milling Jr. from the Seton Dell Medical School Stroke Institute in Austin, Texas, US, who presented the findings at ISC 2019.