Meeting NewsPerspective

ANNEXA-4: Andexanet alfa halts anticoagulation in most patients with severe bleeding events

Stuart J. Connolly

ORLANDO, Fla. — Andexanet alfa, a novel agent to reverse the effects of factor Xa inhibitors, demonstrated similar safety and efficacy outcomes to those seen with other reversal agents, according to an interim analysis of the ANNEXA-4 study.

Among 132 patients with adjudicated acute major bleeding assigned andexanet alfa (AndexXa, Portola Pharmaceuticals) who were included in an efficacy analysis, 83% achieved excellent or good hemostasis at 12 hours, Stuart J. Connolly, MD, FRCPC, from the Population Health Research Institute, McMaster University, Hamilton, Ontario, said during a presentation at the American College of Cardiology Scientific Session.

The efficacy results were consistent regardless of specific anticoagulant, sex, bleeding site, age and andexanet alfa dose, he said. The anticoagulants used by patients included apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), edoxaban (Savaysa, Daiichi Sankyo) and rivaroxaban (Xarelto, Janssen).

Of the 227 patients included in the safety analysis, anticoagulation was restarted in 57% at 30 days, thrombotic events occurred in 2.6% at 3 days and in 11% at 30 days, only nine patients had anticoagulation restarted before a thrombotic event occurred and 12% had died by 30 days, according to the researchers.

The rate of death at 30 days was also 12% in patients with intracerebral hemorrhage, he said.

“We saw a mortality rate of 12%, which seems really high, but it’s not as high as has been reported in several other studies. In intracerebral hemorrhage, for example, it’s measured in the range of 20% to 40% for mortality,” Connolly said during a press conference. 

He said the results were within range of those seen in trials of other anticoagulant inhibitors. In the REVERSE-AD study of idarucizumab (Praxbind, Boehringer Ingelheim), a reversal agent for dabigatran (Pradaxa, Boehringer Ingelheim), hemostatic efficacy was 68% and the thrombotic event rate was 5%. In two studies of reversal agents for warfarin, hemostatic efficacy was 72% and 65%, and the thrombotic event rates were 8% and 6%.

Factor Xa inhibitors are effective for the prevention of stroke in patients with nonvalvular atrial fibrillation and the prevention of venous thromboembolism, but are the cause of more than 100,000 annual hospitalizations in the United States, 15% to 20% of which are fatal, Connolly said.

The mean age of patients in the study was 77 years, and 52% were men.

“For both efficacy and thrombotic events, we are in the same range as the other agents,” Connolly said. 

Andexanet alfa is not yet approved for use in the United States. – by Erik Swain

Reference:

Connolly SJ, et al. Late-Breaking Clinical Trials: Interventional. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.

Disclosure: The study was funded by Portola Pharmaceuticals. Connolly reports he is a consultant for or receives honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Portola and Sanofi-Aventis.

Stuart J. Connolly

ORLANDO, Fla. — Andexanet alfa, a novel agent to reverse the effects of factor Xa inhibitors, demonstrated similar safety and efficacy outcomes to those seen with other reversal agents, according to an interim analysis of the ANNEXA-4 study.

Among 132 patients with adjudicated acute major bleeding assigned andexanet alfa (AndexXa, Portola Pharmaceuticals) who were included in an efficacy analysis, 83% achieved excellent or good hemostasis at 12 hours, Stuart J. Connolly, MD, FRCPC, from the Population Health Research Institute, McMaster University, Hamilton, Ontario, said during a presentation at the American College of Cardiology Scientific Session.

The efficacy results were consistent regardless of specific anticoagulant, sex, bleeding site, age and andexanet alfa dose, he said. The anticoagulants used by patients included apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), edoxaban (Savaysa, Daiichi Sankyo) and rivaroxaban (Xarelto, Janssen).

Of the 227 patients included in the safety analysis, anticoagulation was restarted in 57% at 30 days, thrombotic events occurred in 2.6% at 3 days and in 11% at 30 days, only nine patients had anticoagulation restarted before a thrombotic event occurred and 12% had died by 30 days, according to the researchers.

The rate of death at 30 days was also 12% in patients with intracerebral hemorrhage, he said.

“We saw a mortality rate of 12%, which seems really high, but it’s not as high as has been reported in several other studies. In intracerebral hemorrhage, for example, it’s measured in the range of 20% to 40% for mortality,” Connolly said during a press conference. 

He said the results were within range of those seen in trials of other anticoagulant inhibitors. In the REVERSE-AD study of idarucizumab (Praxbind, Boehringer Ingelheim), a reversal agent for dabigatran (Pradaxa, Boehringer Ingelheim), hemostatic efficacy was 68% and the thrombotic event rate was 5%. In two studies of reversal agents for warfarin, hemostatic efficacy was 72% and 65%, and the thrombotic event rates were 8% and 6%.

Factor Xa inhibitors are effective for the prevention of stroke in patients with nonvalvular atrial fibrillation and the prevention of venous thromboembolism, but are the cause of more than 100,000 annual hospitalizations in the United States, 15% to 20% of which are fatal, Connolly said.

The mean age of patients in the study was 77 years, and 52% were men.

“For both efficacy and thrombotic events, we are in the same range as the other agents,” Connolly said. 

Andexanet alfa is not yet approved for use in the United States. – by Erik Swain

Reference:

Connolly SJ, et al. Late-Breaking Clinical Trials: Interventional. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.

Disclosure: The study was funded by Portola Pharmaceuticals. Connolly reports he is a consultant for or receives honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Portola and Sanofi-Aventis.

    Perspective

    This ANNEXA-4 presentation contained more data and had more patients taking apixaban than previous presentations. I thought we might see more about patients taking low-molecular-weight heparin, but we did not. These data support the earlier work. We know the drug reverses anti-factor Xa activity rapidly. When the infusion is completed, that drug level starts to come back up. The efficacy data suggest the 2-hour infusion time may be enough to achieve hemostasis.

    I prescribe factor Xa inhibitors a lot, and some of my patients are concerned that there is no commercially available antidote. I believe this drug is safe and effective in the appropriate patients. Having the antidote will give a lot of people peace of mind. It won’t necessarily change my prescribing practices, but it’s important that it’s there.

    • Natalie S. Evans , MD, MS
    • Staff Physician
      Section of Vascular Medicine
      Cleveland Clinic

    Disclosures: Evans reports no relevant financial disclosures.

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