Meeting NewsPerspective

ANNEXA-4: Andexanet alfa successfully reverses factor Xa inhibitor effects

Truman J. Milling Jr.
Truman J. Milling Jr.

Andexanet alfa reversed the anticoagulation effects of factor Xa inhibitors in most patients with acute major bleeding caused by a factor Xa inhibitor, according to the full data from the ANNEXA-4 study presented at the International Stroke Conference.

As Cardiology Today previously reported, interim data from ANNEXA-4 indicated that andexanet alfa (Andexxa, Portola) rapidly reversed anti-factor Xa activity in patients with acute major bleeding, and enabled most patients to achieve good to excellent hemostasis.

Truman J. Milling Jr., MD, research director of Ascension Seton Dell Medical School Stroke Institute in Austin, Texas, presented the full data at the International Stroke Conference, presented full data here.

The drug was approved by the FDA in May, though distribution has been limited to centers that participated in the trials. In January, the FDA approved a Prior Approval Supplement for the second generation of andexanet alfa, allowing for its broad commercial launch in the U.S.

The researchers analyzed 352 patients (mean age, 77 years; 53% men) who had an acute major bleeding event within 18 hours of taking a factor Xa inhibitor. Most patients had taken apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) or rivaroxaban (Xarelto, Janssen/Bayer), both of which are often used for stroke prevention in patients with atrial fibrillation. A small number of patients had taken an older factor Xa inhibitor, enoxaparin. All patients received a bolus of andexanet alfa followed by an infusion for 2 hours.

“Andexanet alfa is specifically designed to reverse the anticoagulant effects of factor Xa inhibitors,” Milling said during a presentation. “It acts as a factor Xa decoy to bind molecules that target and inhibit factor Xa.”

The primary outcomes were percent change in anti-factor Xa activity after administration of andexanet alfa and percentage of patients with good or excellent hemostatic efficacy at 12 hours after the end of the infusion. Hemostatic efficacy could be evaluated in 249 patients.

According to the researchers, 64% of patients had intracranial bleeding and 26% had gastrointestinal bleeding.

Among those who took apixaban, median anti-factor Xa activity dropped from 149.7 ng/mL at baseline to 11.1 ng/mL after the bolus (reduction, 92%; 95% CI, 91-93), whereas among those who took rivaroxaban, median anti-factor Xa activity dropped from 211.8 ng/mL at baseline to 14.2 ng/mL after the bolus (reduction, 92%; 95% CI, 88-94), Milling said.

Excellent or good hemostasis at 12 hours after the end of the infusion was observed in 82% of patients, he said, noting that among those who had excellent or good hemostasis, 84% had excellent status.

Efficacy rates were consistent regardless of specific factor Xa inhibitor taken, sex, bleeding site, age or dose of andexanet alfa, Milling said.

At 30 days, 13.9% of patients died and 9.7% had a thrombotic event, according to the researchers. Milling said there were no thrombotic events after oral anticoagulation was restarted.

“Thrombotic events at 30 days were in the expected range for the study population and were mitigated by restarting anticoagulation,” he said.

Although reduction in anti-factor Xa activity did not predict hemostatic efficacy in the overall cohort (area under the curve, 0.53; 95% CI, 0.44-0.62), it was a moderate predictor in the cohort of patients with intracranial hemorrhage (AUC, 0.64; 95% CI, 0.53-0.74), Milling said. – by Erik Swain

References:

Connolly SJ, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1814051.

Milling TJ, et al. LB7. Presented at: International Stroke Conference; Feb. 5-8, 2019; Honolulu.

Disclosure: The study was funded by Portola Pharmaceuticals. Milling reports he received an honorarium from the Public Health Research Institute at McMaster University for serving on the executive committee of the ANNEXA-4 trial, serves on the speakers bureau for Janssen, receives honoraria from CSL Behring and consults for Octapharma and Portola.

 

Truman J. Milling Jr.
Truman J. Milling Jr.

Andexanet alfa reversed the anticoagulation effects of factor Xa inhibitors in most patients with acute major bleeding caused by a factor Xa inhibitor, according to the full data from the ANNEXA-4 study presented at the International Stroke Conference.

As Cardiology Today previously reported, interim data from ANNEXA-4 indicated that andexanet alfa (Andexxa, Portola) rapidly reversed anti-factor Xa activity in patients with acute major bleeding, and enabled most patients to achieve good to excellent hemostasis.

Truman J. Milling Jr., MD, research director of Ascension Seton Dell Medical School Stroke Institute in Austin, Texas, presented the full data at the International Stroke Conference, presented full data here.

The drug was approved by the FDA in May, though distribution has been limited to centers that participated in the trials. In January, the FDA approved a Prior Approval Supplement for the second generation of andexanet alfa, allowing for its broad commercial launch in the U.S.

The researchers analyzed 352 patients (mean age, 77 years; 53% men) who had an acute major bleeding event within 18 hours of taking a factor Xa inhibitor. Most patients had taken apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) or rivaroxaban (Xarelto, Janssen/Bayer), both of which are often used for stroke prevention in patients with atrial fibrillation. A small number of patients had taken an older factor Xa inhibitor, enoxaparin. All patients received a bolus of andexanet alfa followed by an infusion for 2 hours.

“Andexanet alfa is specifically designed to reverse the anticoagulant effects of factor Xa inhibitors,” Milling said during a presentation. “It acts as a factor Xa decoy to bind molecules that target and inhibit factor Xa.”

The primary outcomes were percent change in anti-factor Xa activity after administration of andexanet alfa and percentage of patients with good or excellent hemostatic efficacy at 12 hours after the end of the infusion. Hemostatic efficacy could be evaluated in 249 patients.

According to the researchers, 64% of patients had intracranial bleeding and 26% had gastrointestinal bleeding.

Among those who took apixaban, median anti-factor Xa activity dropped from 149.7 ng/mL at baseline to 11.1 ng/mL after the bolus (reduction, 92%; 95% CI, 91-93), whereas among those who took rivaroxaban, median anti-factor Xa activity dropped from 211.8 ng/mL at baseline to 14.2 ng/mL after the bolus (reduction, 92%; 95% CI, 88-94), Milling said.

Excellent or good hemostasis at 12 hours after the end of the infusion was observed in 82% of patients, he said, noting that among those who had excellent or good hemostasis, 84% had excellent status.

Efficacy rates were consistent regardless of specific factor Xa inhibitor taken, sex, bleeding site, age or dose of andexanet alfa, Milling said.

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At 30 days, 13.9% of patients died and 9.7% had a thrombotic event, according to the researchers. Milling said there were no thrombotic events after oral anticoagulation was restarted.

“Thrombotic events at 30 days were in the expected range for the study population and were mitigated by restarting anticoagulation,” he said.

Although reduction in anti-factor Xa activity did not predict hemostatic efficacy in the overall cohort (area under the curve, 0.53; 95% CI, 0.44-0.62), it was a moderate predictor in the cohort of patients with intracranial hemorrhage (AUC, 0.64; 95% CI, 0.53-0.74), Milling said. – by Erik Swain

References:

Connolly SJ, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1814051.

Milling TJ, et al. LB7. Presented at: International Stroke Conference; Feb. 5-8, 2019; Honolulu.

Disclosure: The study was funded by Portola Pharmaceuticals. Milling reports he received an honorarium from the Public Health Research Institute at McMaster University for serving on the executive committee of the ANNEXA-4 trial, serves on the speakers bureau for Janssen, receives honoraria from CSL Behring and consults for Octapharma and Portola.

 

    Perspective
    Larry B. Goldstein

    Larry B. Goldstein

    The drug successfully reversed the anti-Xa effects of the anticoagulant. There was not a control group (ie, 4 factor concentrate) for comparison, so whether this leads to an improvement in clinical outcomes is not addressed in the study. Decisions will need to be made with this in mind and balancing the potential, unproven benefit in reducing negative outcomes against cost.

    • Larry B. Goldstein, MD, FAAN, FANA, FAHA
    • Cardiology Today Editorial Board Member
      University of Kentucky

    Disclosures: Goldstein reports no relevant financial disclosures.

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