Andexanet controlled factor Xa inhibitor–related bleeding

The factor Xa antidote andexanet achieved effective hemostasis 12 hours after infusion in 79% of patients who had developed serious acute bleeding on factor Xa inhibitor therapy, according to a preliminary analysis of an ongoing study of how reducing anti–factor Xa activity affects clinical hemostatic outcomes.

“The site of bleeding was most often gastrointestinal or intracranial; anti–factor Xa activity was considerably elevated in most patients and, as such, was likely to be a major impediment to clinical hemostasis. The administration of an andexanet bolus and infusion resulted in rapid and substantial reversal of anti–factor Xa activity,” Stuart Connolly, MD, of McMaster University, Hamilton, Ont., and his associates reported at the ESC Congress and in a simultaneously published study (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607887).

Andexanet alfa is a recombinant modified human factor Xa decoy protein that “sharply” reduced plasma levels of unbound factor Xa inhibitors as well as anti-factor Xa activity in healthy older volunteers receiving apixaban or rivaroxaban, the researchers noted. Based on those findings, they designed a prospective, multicenter, single-group, open-label study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors; ANNEXA-4) of andexanet in patients with potentially life-threatening acute major bleeding related to anticoagulation with a factor Xa inhibitor.

This interim report from the ongoing study included 67 patients with data available by June 17, 2016. Participants averaged 77 years of age and were receiving a factor Xa inhibtor because of atrial fibrillation, venous thromboembolism, or both. All patients received a bolus of andexanet for 15 to 30 minutes followed by a 2-hour infusion. Based on previous studies, the researchers used a 400-mg bolus of andexanet followed by a 480-mg infusion when patients had last taken their factor Xa inhibitor more than 7 hours before, and a higher 800-mg bolus followed by a 960-mg infusion when patients had taken their anticoagulant more recently. Bleeding and hemostasis were evaluated based on serial CT or MRI scans of patients with intracranial hemorrhage and corrected hemoglobin and hematocrit levels at 12 hours for patients with gastrointestinal and other nonvisible bleeding.

Among 47 patients in the primary efficacy analysis, 37 (79%) achieved excellent or good hemostasis (95% confidence interval, 64% to 89%), including 81% of patients on rivaroxaban and 75% of patients on enoxaparin, the researchers reported. “The rates of excellent or good efficacy were 84% for gastrointestinal bleeding and 80% for intracranial bleeding, rates that were consistent for other subgroups that were examined,” they said. Among the five patients (10%) with the most residual anti–factor Xa activity, all had received the lower andexanet dose. Four had received rivaroxaban while one had received apixaban.

The safety population included all 67 patients, none of whom developed infusion reactions or antibodies to factors X, Xa, or andexanet. After 30 days of follow-up, 12 patients (18%) had experienced one or more thrombotic events, including deep vein thrombosis (seven patients), stroke (five patients), myocardial infarction (one patient), and pulmonary embolism (one patient). One-third of these events occurred within 3 days of receiving andexanet, while the rest occurred by day 30. A total of 10 patients (15%) died, and six deaths were from cardiovascular causes. “A controlled study would be required to assess whether the frequency of these events exceeded that expected in patients at increased risk for thrombotic events,” the researchers commented.

Portola Pharmaceuticals makes andexanet alfa and funded the study. Dr. Connolly disclosed ties to Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, CSL Behring, Octapharma, and Boehringer Ingelheim outside the submitted work.

The factor Xa antidote andexanet achieved effective hemostasis 12 hours after infusion in 79% of patients who had developed serious acute bleeding on factor Xa inhibitor therapy, according to a preliminary analysis of an ongoing study of how reducing anti–factor Xa activity affects clinical hemostatic outcomes.

“The site of bleeding was most often gastrointestinal or intracranial; anti–factor Xa activity was considerably elevated in most patients and, as such, was likely to be a major impediment to clinical hemostasis. The administration of an andexanet bolus and infusion resulted in rapid and substantial reversal of anti–factor Xa activity,” Stuart Connolly, MD, of McMaster University, Hamilton, Ont., and his associates reported at the ESC Congress and in a simultaneously published study (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607887).

Andexanet alfa is a recombinant modified human factor Xa decoy protein that “sharply” reduced plasma levels of unbound factor Xa inhibitors as well as anti-factor Xa activity in healthy older volunteers receiving apixaban or rivaroxaban, the researchers noted. Based on those findings, they designed a prospective, multicenter, single-group, open-label study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors; ANNEXA-4) of andexanet in patients with potentially life-threatening acute major bleeding related to anticoagulation with a factor Xa inhibitor.

This interim report from the ongoing study included 67 patients with data available by June 17, 2016. Participants averaged 77 years of age and were receiving a factor Xa inhibtor because of atrial fibrillation, venous thromboembolism, or both. All patients received a bolus of andexanet for 15 to 30 minutes followed by a 2-hour infusion. Based on previous studies, the researchers used a 400-mg bolus of andexanet followed by a 480-mg infusion when patients had last taken their factor Xa inhibitor more than 7 hours before, and a higher 800-mg bolus followed by a 960-mg infusion when patients had taken their anticoagulant more recently. Bleeding and hemostasis were evaluated based on serial CT or MRI scans of patients with intracranial hemorrhage and corrected hemoglobin and hematocrit levels at 12 hours for patients with gastrointestinal and other nonvisible bleeding.

Among 47 patients in the primary efficacy analysis, 37 (79%) achieved excellent or good hemostasis (95% confidence interval, 64% to 89%), including 81% of patients on rivaroxaban and 75% of patients on enoxaparin, the researchers reported. “The rates of excellent or good efficacy were 84% for gastrointestinal bleeding and 80% for intracranial bleeding, rates that were consistent for other subgroups that were examined,” they said. Among the five patients (10%) with the most residual anti–factor Xa activity, all had received the lower andexanet dose. Four had received rivaroxaban while one had received apixaban.

The safety population included all 67 patients, none of whom developed infusion reactions or antibodies to factors X, Xa, or andexanet. After 30 days of follow-up, 12 patients (18%) had experienced one or more thrombotic events, including deep vein thrombosis (seven patients), stroke (five patients), myocardial infarction (one patient), and pulmonary embolism (one patient). One-third of these events occurred within 3 days of receiving andexanet, while the rest occurred by day 30. A total of 10 patients (15%) died, and six deaths were from cardiovascular causes. “A controlled study would be required to assess whether the frequency of these events exceeded that expected in patients at increased risk for thrombotic events,” the researchers commented.

Portola Pharmaceuticals makes andexanet alfa and funded the study. Dr. Connolly disclosed ties to Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, CSL Behring, Octapharma, and Boehringer Ingelheim outside the submitted work.

The factor Xa antidote andexanet achieved effective hemostasis 12 hours after infusion in 79% of patients who had developed serious acute bleeding on factor Xa inhibitor therapy, according to a preliminary analysis of an ongoing study of how reducing anti–factor Xa activity affects clinical hemostatic outcomes.

“The site of bleeding was most often gastrointestinal or intracranial; anti–factor Xa activity was considerably elevated in most patients and, as such, was likely to be a major impediment to clinical hemostasis. The administration of an andexanet bolus and infusion resulted in rapid and substantial reversal of anti–factor Xa activity,” Stuart Connolly, MD, of McMaster University, Hamilton, Ont., and his associates reported at the ESC Congress and in a simultaneously published study (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607887).

Andexanet alfa is a recombinant modified human factor Xa decoy protein that “sharply” reduced plasma levels of unbound factor Xa inhibitors as well as anti-factor Xa activity in healthy older volunteers receiving apixaban or rivaroxaban, the researchers noted. Based on those findings, they designed a prospective, multicenter, single-group, open-label study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors; ANNEXA-4) of andexanet in patients with potentially life-threatening acute major bleeding related to anticoagulation with a factor Xa inhibitor.

This interim report from the ongoing study included 67 patients with data available by June 17, 2016. Participants averaged 77 years of age and were receiving a factor Xa inhibtor because of atrial fibrillation, venous thromboembolism, or both. All patients received a bolus of andexanet for 15 to 30 minutes followed by a 2-hour infusion. Based on previous studies, the researchers used a 400-mg bolus of andexanet followed by a 480-mg infusion when patients had last taken their factor Xa inhibitor more than 7 hours before, and a higher 800-mg bolus followed by a 960-mg infusion when patients had taken their anticoagulant more recently. Bleeding and hemostasis were evaluated based on serial CT or MRI scans of patients with intracranial hemorrhage and corrected hemoglobin and hematocrit levels at 12 hours for patients with gastrointestinal and other nonvisible bleeding.

Among 47 patients in the primary efficacy analysis, 37 (79%) achieved excellent or good hemostasis (95% confidence interval, 64% to 89%), including 81% of patients on rivaroxaban and 75% of patients on enoxaparin, the researchers reported. “The rates of excellent or good efficacy were 84% for gastrointestinal bleeding and 80% for intracranial bleeding, rates that were consistent for other subgroups that were examined,” they said. Among the five patients (10%) with the most residual anti–factor Xa activity, all had received the lower andexanet dose. Four had received rivaroxaban while one had received apixaban.

The safety population included all 67 patients, none of whom developed infusion reactions or antibodies to factors X, Xa, or andexanet. After 30 days of follow-up, 12 patients (18%) had experienced one or more thrombotic events, including deep vein thrombosis (seven patients), stroke (five patients), myocardial infarction (one patient), and pulmonary embolism (one patient). One-third of these events occurred within 3 days of receiving andexanet, while the rest occurred by day 30. A total of 10 patients (15%) died, and six deaths were from cardiovascular causes. “A controlled study would be required to assess whether the frequency of these events exceeded that expected in patients at increased risk for thrombotic events,” the researchers commented.

Portola Pharmaceuticals makes andexanet alfa and funded the study. Dr. Connolly disclosed ties to Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, CSL Behring, Octapharma, and Boehringer Ingelheim outside the submitted work.