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ROME—Preliminary results from the ANNEXA-4 study suggest that andexanet alfa, an investigational antidote to factor Xa inhibitors, can be effective in patients with acute major bleeding.
The drug reversed the anticoagulant effects of rivaroxaban, apixaban, and enoxaparin in this study, providing “excellent” or “good” hemostatic efficacy in 79% of patients over 12 hours.
Thrombotic events occurred in 18% of patients, and 15% died during the 30-day follow-up period.
According to investigators, these events occurred within the range expected in this patient population, given the severity of their bleeding, their underlying thrombotic risk, and the low percentage of patients who restarted anticoagulant therapy following their bleeding episode.
Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, Canada, presented results from ANNEXA-4 at ESC Congress 2016 (abstract 5718).
Results were also published in NEJM. The study was funded by Portola Pharmaceuticals Inc.
Patients and treatment
The preliminary analysis of the phase 3/4 ANNEXA-4 trial included 67 patients. All of these patients were evaluated for safety, and 47 were evaluated for efficacy. The mean age of both populations was 77.1, and slightly more than half of the patients were male.
All patients received andexanet alfa given as a bolus dose over 30 minutes, followed by a 2-hour infusion. Patients received a low or high dose depending on which factor Xa inhibitor they received and the time they received it. The patients were evaluated for 30 days following andexanet alfa administration.
The co-primary efficacy endpoints are the percent change in anti-factor Xa activity at 2 hours and the assessment of hemostasis over 12 hours following the infusion. Hemostatic efficacy is assessed by an independent endpoint adjudication committee as excellent, good, or poor/none.
Efficacy
“In this preliminary analysis, [andexanet alfa] was effective in rapidly reversing anti-factor Xa inhibitor activity and restoring normal blood clotting in real-world patients with factor Xa inhibitor-related bleeding,” Dr Connolly said.
Of the 47 patients evaluable for efficacy, 32 were receiving an anticoagulant due to atrial fibrillation, 12 had venous thromboembolism (VTE), and 3 had both atrial fibrillation and VTE.
Twenty-six patients were receiving rivaroxaban, 20 were receiving apixaban, and 1 was receiving enoxaparin. Twenty-five patients had gastrointestinal bleeding, 20 had intracranial bleeding, and 2 had bleeding at other sites.
Forty-two patients received a low dose of andexanet alfa, and 5 received a high dose. The mean time from presentation to the emergency department and the administration of the andexanet alfa bolus was 4.8 ± 1.8 hours.
After the bolus, the median anti-factor Xa activity decreased by 89% from baseline among patients receiving rivaroxaban and by 93% among those receiving apixaban. At the end of the 2-hour infusion, the decrease from baseline was 86% and 92%, respectively.
Twelve hours after the infusion ended, the median anti-factor Xa activity had decreased 64% from baseline among patients receiving rivaroxaban and 31% among those receiving apixaban.
Overall, at 12 hours, clinical hemostasis was rated excellent or good in 79% of patients. Hemostatic efficacy was rated as excellent or good in 81% of the patients on rivaroxaban, 75% of the patients on apixaban, and in the 1 patient on edoxaban.
Safety
Of the 67 patients in the safety population, 47 were receiving an anticoagulant due to atrial fibrillation, 15 had VTE, and 5 had both atrial fibrillation and VTE.
Thirty-two patients were receiving rivaroxaban, 31 were receiving apixaban, and 4 were receiving edoxaban. Thirty-eight patients had gastrointestinal bleeding, 28 had intracranial bleeding, and 6 had bleeding at other sites.
There were no infusion reactions, no antibodies to factors Xa or X, and no neutralizing antibodies to andexanet alfa.
Twelve patients (18%) experienced thrombotic events—1 with myocardial infarction, 5 with stroke, 7 with deep-vein thrombosis, and 1 with pulmonary embolism. (Some patients had more than 1 event.)
“This rate of events is not unexpected, considering the thrombotic potential of the patients and the fact that, in most of them, anticoagulation was discontinued at the time of bleeding and not restarted,” Dr Connolly said.
Four patients had a thrombotic event within 3 days of andexanet alfa treatment, and the rest occurred between 4 days and 30 days.
Eighteen patients (27%) resumed anticoagulant therapy within 30 days. One of the 12 patients with a thrombotic event restarted anticoagulation at a therapeutic dose before the event. One other patient received prophylactic doses of enoxaparin before developing a deep-vein thrombosis.
There were 10 deaths (15%), 6 due to cardiovascular events.
Andexanet alfa development
Andexanet alfa is being developed as a reversal agent for apixaban, rivaroxaban, edoxaban, and enoxaparin. Andexanet alfa is intended to be used when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
The drug is under review by the US Food and Drug Administration (FDA) and the European Medicines Agency. The FDA recently issued a complete response letter regarding the biologics license application for andexanet alfa.
Portola said it plans to meet with the FDA as soon as possible to resolve the outstanding questions in the letter and determine the appropriate next steps. 
ROME—Preliminary results from the ANNEXA-4 study suggest that andexanet alfa, an investigational antidote to factor Xa inhibitors, can be effective in patients with acute major bleeding.
The drug reversed the anticoagulant effects of rivaroxaban, apixaban, and enoxaparin in this study, providing “excellent” or “good” hemostatic efficacy in 79% of patients over 12 hours.
Thrombotic events occurred in 18% of patients, and 15% died during the 30-day follow-up period.
According to investigators, these events occurred within the range expected in this patient population, given the severity of their bleeding, their underlying thrombotic risk, and the low percentage of patients who restarted anticoagulant therapy following their bleeding episode.
Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, Canada, presented results from ANNEXA-4 at ESC Congress 2016 (abstract 5718).
Results were also published in NEJM. The study was funded by Portola Pharmaceuticals Inc.
Patients and treatment
The preliminary analysis of the phase 3/4 ANNEXA-4 trial included 67 patients. All of these patients were evaluated for safety, and 47 were evaluated for efficacy. The mean age of both populations was 77.1, and slightly more than half of the patients were male.
All patients received andexanet alfa given as a bolus dose over 30 minutes, followed by a 2-hour infusion. Patients received a low or high dose depending on which factor Xa inhibitor they received and the time they received it. The patients were evaluated for 30 days following andexanet alfa administration.
The co-primary efficacy endpoints are the percent change in anti-factor Xa activity at 2 hours and the assessment of hemostasis over 12 hours following the infusion. Hemostatic efficacy is assessed by an independent endpoint adjudication committee as excellent, good, or poor/none.
Efficacy
“In this preliminary analysis, [andexanet alfa] was effective in rapidly reversing anti-factor Xa inhibitor activity and restoring normal blood clotting in real-world patients with factor Xa inhibitor-related bleeding,” Dr Connolly said.
Of the 47 patients evaluable for efficacy, 32 were receiving an anticoagulant due to atrial fibrillation, 12 had venous thromboembolism (VTE), and 3 had both atrial fibrillation and VTE.
Twenty-six patients were receiving rivaroxaban, 20 were receiving apixaban, and 1 was receiving enoxaparin. Twenty-five patients had gastrointestinal bleeding, 20 had intracranial bleeding, and 2 had bleeding at other sites.
Forty-two patients received a low dose of andexanet alfa, and 5 received a high dose. The mean time from presentation to the emergency department and the administration of the andexanet alfa bolus was 4.8 ± 1.8 hours.
After the bolus, the median anti-factor Xa activity decreased by 89% from baseline among patients receiving rivaroxaban and by 93% among those receiving apixaban. At the end of the 2-hour infusion, the decrease from baseline was 86% and 92%, respectively.
Twelve hours after the infusion ended, the median anti-factor Xa activity had decreased 64% from baseline among patients receiving rivaroxaban and 31% among those receiving apixaban.
Overall, at 12 hours, clinical hemostasis was rated excellent or good in 79% of patients. Hemostatic efficacy was rated as excellent or good in 81% of the patients on rivaroxaban, 75% of the patients on apixaban, and in the 1 patient on edoxaban.
Safety
Of the 67 patients in the safety population, 47 were receiving an anticoagulant due to atrial fibrillation, 15 had VTE, and 5 had both atrial fibrillation and VTE.
Thirty-two patients were receiving rivaroxaban, 31 were receiving apixaban, and 4 were receiving edoxaban. Thirty-eight patients had gastrointestinal bleeding, 28 had intracranial bleeding, and 6 had bleeding at other sites.
There were no infusion reactions, no antibodies to factors Xa or X, and no neutralizing antibodies to andexanet alfa.
Twelve patients (18%) experienced thrombotic events—1 with myocardial infarction, 5 with stroke, 7 with deep-vein thrombosis, and 1 with pulmonary embolism. (Some patients had more than 1 event.)
“This rate of events is not unexpected, considering the thrombotic potential of the patients and the fact that, in most of them, anticoagulation was discontinued at the time of bleeding and not restarted,” Dr Connolly said.
Four patients had a thrombotic event within 3 days of andexanet alfa treatment, and the rest occurred between 4 days and 30 days.
Eighteen patients (27%) resumed anticoagulant therapy within 30 days. One of the 12 patients with a thrombotic event restarted anticoagulation at a therapeutic dose before the event. One other patient received prophylactic doses of enoxaparin before developing a deep-vein thrombosis.
There were 10 deaths (15%), 6 due to cardiovascular events.
Andexanet alfa development
Andexanet alfa is being developed as a reversal agent for apixaban, rivaroxaban, edoxaban, and enoxaparin. Andexanet alfa is intended to be used when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
The drug is under review by the US Food and Drug Administration (FDA) and the European Medicines Agency. The FDA recently issued a complete response letter regarding the biologics license application for andexanet alfa.
Portola said it plans to meet with the FDA as soon as possible to resolve the outstanding questions in the letter and determine the appropriate next steps.
ROME—Preliminary results from the ANNEXA-4 study suggest that andexanet alfa, an investigational antidote to factor Xa inhibitors, can be effective in patients with acute major bleeding.
The drug reversed the anticoagulant effects of rivaroxaban, apixaban, and enoxaparin in this study, providing “excellent” or “good” hemostatic efficacy in 79% of patients over 12 hours.
Thrombotic events occurred in 18% of patients, and 15% died during the 30-day follow-up period.
According to investigators, these events occurred within the range expected in this patient population, given the severity of their bleeding, their underlying thrombotic risk, and the low percentage of patients who restarted anticoagulant therapy following their bleeding episode.
Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, Canada, presented results from ANNEXA-4 at ESC Congress 2016 (abstract 5718).
Results were also published in NEJM. The study was funded by Portola Pharmaceuticals Inc.
Patients and treatment
The preliminary analysis of the phase 3/4 ANNEXA-4 trial included 67 patients. All of these patients were evaluated for safety, and 47 were evaluated for efficacy. The mean age of both populations was 77.1, and slightly more than half of the patients were male.
All patients received andexanet alfa given as a bolus dose over 30 minutes, followed by a 2-hour infusion. Patients received a low or high dose depending on which factor Xa inhibitor they received and the time they received it. The patients were evaluated for 30 days following andexanet alfa administration.
The co-primary efficacy endpoints are the percent change in anti-factor Xa activity at 2 hours and the assessment of hemostasis over 12 hours following the infusion. Hemostatic efficacy is assessed by an independent endpoint adjudication committee as excellent, good, or poor/none.
Efficacy
“In this preliminary analysis, [andexanet alfa] was effective in rapidly reversing anti-factor Xa inhibitor activity and restoring normal blood clotting in real-world patients with factor Xa inhibitor-related bleeding,” Dr Connolly said.
Of the 47 patients evaluable for efficacy, 32 were receiving an anticoagulant due to atrial fibrillation, 12 had venous thromboembolism (VTE), and 3 had both atrial fibrillation and VTE.
Twenty-six patients were receiving rivaroxaban, 20 were receiving apixaban, and 1 was receiving enoxaparin. Twenty-five patients had gastrointestinal bleeding, 20 had intracranial bleeding, and 2 had bleeding at other sites.
Forty-two patients received a low dose of andexanet alfa, and 5 received a high dose. The mean time from presentation to the emergency department and the administration of the andexanet alfa bolus was 4.8 ± 1.8 hours.
After the bolus, the median anti-factor Xa activity decreased by 89% from baseline among patients receiving rivaroxaban and by 93% among those receiving apixaban. At the end of the 2-hour infusion, the decrease from baseline was 86% and 92%, respectively.
Twelve hours after the infusion ended, the median anti-factor Xa activity had decreased 64% from baseline among patients receiving rivaroxaban and 31% among those receiving apixaban.
Overall, at 12 hours, clinical hemostasis was rated excellent or good in 79% of patients. Hemostatic efficacy was rated as excellent or good in 81% of the patients on rivaroxaban, 75% of the patients on apixaban, and in the 1 patient on edoxaban.
Safety
Of the 67 patients in the safety population, 47 were receiving an anticoagulant due to atrial fibrillation, 15 had VTE, and 5 had both atrial fibrillation and VTE.
Thirty-two patients were receiving rivaroxaban, 31 were receiving apixaban, and 4 were receiving edoxaban. Thirty-eight patients had gastrointestinal bleeding, 28 had intracranial bleeding, and 6 had bleeding at other sites.
There were no infusion reactions, no antibodies to factors Xa or X, and no neutralizing antibodies to andexanet alfa.
Twelve patients (18%) experienced thrombotic events—1 with myocardial infarction, 5 with stroke, 7 with deep-vein thrombosis, and 1 with pulmonary embolism. (Some patients had more than 1 event.)
“This rate of events is not unexpected, considering the thrombotic potential of the patients and the fact that, in most of them, anticoagulation was discontinued at the time of bleeding and not restarted,” Dr Connolly said.
Four patients had a thrombotic event within 3 days of andexanet alfa treatment, and the rest occurred between 4 days and 30 days.
Eighteen patients (27%) resumed anticoagulant therapy within 30 days. One of the 12 patients with a thrombotic event restarted anticoagulation at a therapeutic dose before the event. One other patient received prophylactic doses of enoxaparin before developing a deep-vein thrombosis.
There were 10 deaths (15%), 6 due to cardiovascular events.
Andexanet alfa development
Andexanet alfa is being developed as a reversal agent for apixaban, rivaroxaban, edoxaban, and enoxaparin. Andexanet alfa is intended to be used when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
The drug is under review by the US Food and Drug Administration (FDA) and the European Medicines Agency. The FDA recently issued a complete response letter regarding the biologics license application for andexanet alfa.
Portola said it plans to meet with the FDA as soon as possible to resolve the outstanding questions in the letter and determine the appropriate next steps.