Reversal agent exhibits efficacy in patients with major bleeding

Bristol Myers Squibb

ORLANDO—Interim trial results suggest andexanet alfa can reverse the activity of factor Xa inhibitors in patients with acute major bleeding.

Andexanet alfa reduced median anti-factor Xa inhibitor activity by 91% in patients taking apixaban, 88% in those taking rivaroxaban, and 75% in patients taking enoxaparin.

Eleven percent of patients experienced thrombotic events, and 12% of patients died.

Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, Canada, presented these results at the American College of Cardiology’s 67th Annual Scientific Session & Expo (ACC.18, abstract 409-14).

The trial, known as ANNEXA-4, was sponsored by Portola Pharmaceuticals, Inc.

“These data are particularly compelling when you consider the high-risk profile of the ANNEXA-4 population, which includes a substantial number of elderly patients presenting with intracranial hemorrhage and anticoagulated for venous thromboembolism, and the lack of any FDA- or EMA-approved reversal agent for these patients,” Dr Connolly said.

“The interim efficacy and safety data continue to support the promising role of AndexXa [the brand name for andexanet alfa] as an antidote to reverse anticoagulation in factor Xa-associated bleeding.”

Andexanet alfa is a recombinant modified factor Xa molecule designed to bind to and disable factor Xa inhibitors, thereby allowing factor Xa produced by the body to play its normal role in the formation of blood clots.

In earlier trials of healthy volunteers, andexanet alfa reversed the anticoagulant effect of factor Xa inhibitors without any significant safety problems.

ANNEXA-4 is an ongoing trial of andexanet alfa in patients experiencing major bleeding while taking factor Xa inhibitors.

Dr Connolly presented safety outcomes for 227 trial subjects and adjudicated efficacy outcomes for 132 subjects. All subjects presented with acute major bleeding within 18 hours of taking a factor Xa inhibitor, including apixaban, rivaroxaban, enoxaparin, and edoxaban.

The patients received andexanet alfa given as a bolus dose over 20 to 30 minutes, followed by a 2-hour (120 minute) infusion. The dosage was determined based on the specific factor Xa inhibitor the patients were taking and how long it had been since their last dose.

The patients were evaluated for 30 days after andexanet alfa administration.

Efficacy

The median age of the efficacy population (n=137) was 77, and 51% (n=70) were male. Indications for anticoagulation included atrial fibrillation (Afib, 76%, n=104), venous thromboembolism (VTE, 28%, n=38), and both Afib and VTE (4%, n=6).

Patients were receiving apixaban (n=68), rivaroxaban (n=54), or enoxaparin (n=10). None of these patients had received edoxaban.

Types of bleeding included intracranial hemorrhage (ICH, 57%, n=78), gastrointestinal (GI) bleeding (31%, n=43), and “other” bleeding (12%, n=16).

The researchers assessed andexanet alfa’s efficacy in terms of 2 co-primary endpoints—reduction in anti-factor Xa inhibitor activity and achievement of clinical hemostasis by 12 hours after administration. Hemostatic efficacy was assessed by an independent endpoint adjudication committee as “excellent,” “good,” or “poor/none.”

After the bolus dose of andexanet alfa, the median anti-factor Xa inhibitor activity was reduced by 91% for patients taking apixaban, 88% for those taking rivaroxaban, and 75% for those taking enoxaparin.

For patients taking rivaroxaban, the median anti-factor Xa inhibitor activity was reduced by 88% at the end of the bolus dose, 87% at the end of the infusion, 42% at 4 hours, 49% at 8 hours, and 60% at 12 hours.

For patients taking apixaban, the median anti-factor Xa inhibitor activity was reduced by 91% at the end of the bolus dose, 91% at the end of the infusion, 36% at 4 hours, 30% at 8 hours, and 35% at 12 hours.

Overall, 83% of patients had “excellent” or “good” clinical hemostasis, and 17% had “poor/none.”

Hemostasis was deemed excellent or good in 83% of patients on rivaroxaban, 82% of those on apixaban, and 80% of those on enoxaparin. It was excellent/good in 86% of patients with GI bleeding, 81% of patients with ICH, and 80% of patients with bleeding at other sites.

Safety

The median age of the safety population (n=227) was 77, and 52% (n=117) were male. Indications for anticoagulation included Afib (78%, n=178), VTE (23%, n=52), and both Afib and VTE (4%, n=8).

Patients were receiving apixaban (n=117), rivaroxaban (n=90), enoxaparin (n=17), and edoxaban (n=3). Types of bleeding included ICH (61%, n=139), GI (27%, n=62), and “other” (12%, n=26).

During the 30-day follow-up period, the rate of thrombotic events was 11% (n=24) for the entire population and 12% (n=17) among patients with ICH.

The mortality rate for all patients was 12% (n=27). Eleven deaths were due to cardiovascular causes.

According to Dr Connolly, these rates of adverse events are in line with what would be expected given the underlying medical condition of the patients in the trial and the fact that many (43%) had not resumed anticoagulant treatment in the 30-day follow-up period.

Two patients experienced an infusion reaction.

None of the patients developed antibodies to factor Xa or factor X, and there were no neutralizing antibodies to andexanet alfa.

Bristol Myers Squibb

ORLANDO—Interim trial results suggest andexanet alfa can reverse the activity of factor Xa inhibitors in patients with acute major bleeding.

Andexanet alfa reduced median anti-factor Xa inhibitor activity by 91% in patients taking apixaban, 88% in those taking rivaroxaban, and 75% in patients taking enoxaparin.

Eleven percent of patients experienced thrombotic events, and 12% of patients died.

Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, Canada, presented these results at the American College of Cardiology’s 67th Annual Scientific Session & Expo (ACC.18, abstract 409-14).

The trial, known as ANNEXA-4, was sponsored by Portola Pharmaceuticals, Inc.

“These data are particularly compelling when you consider the high-risk profile of the ANNEXA-4 population, which includes a substantial number of elderly patients presenting with intracranial hemorrhage and anticoagulated for venous thromboembolism, and the lack of any FDA- or EMA-approved reversal agent for these patients,” Dr Connolly said.

“The interim efficacy and safety data continue to support the promising role of AndexXa [the brand name for andexanet alfa] as an antidote to reverse anticoagulation in factor Xa-associated bleeding.”

Andexanet alfa is a recombinant modified factor Xa molecule designed to bind to and disable factor Xa inhibitors, thereby allowing factor Xa produced by the body to play its normal role in the formation of blood clots.

In earlier trials of healthy volunteers, andexanet alfa reversed the anticoagulant effect of factor Xa inhibitors without any significant safety problems.

ANNEXA-4 is an ongoing trial of andexanet alfa in patients experiencing major bleeding while taking factor Xa inhibitors.

Dr Connolly presented safety outcomes for 227 trial subjects and adjudicated efficacy outcomes for 132 subjects. All subjects presented with acute major bleeding within 18 hours of taking a factor Xa inhibitor, including apixaban, rivaroxaban, enoxaparin, and edoxaban.

The patients received andexanet alfa given as a bolus dose over 20 to 30 minutes, followed by a 2-hour (120 minute) infusion. The dosage was determined based on the specific factor Xa inhibitor the patients were taking and how long it had been since their last dose.

The patients were evaluated for 30 days after andexanet alfa administration.

Efficacy

The median age of the efficacy population (n=137) was 77, and 51% (n=70) were male. Indications for anticoagulation included atrial fibrillation (Afib, 76%, n=104), venous thromboembolism (VTE, 28%, n=38), and both Afib and VTE (4%, n=6).

Patients were receiving apixaban (n=68), rivaroxaban (n=54), or enoxaparin (n=10). None of these patients had received edoxaban.

Types of bleeding included intracranial hemorrhage (ICH, 57%, n=78), gastrointestinal (GI) bleeding (31%, n=43), and “other” bleeding (12%, n=16).

The researchers assessed andexanet alfa’s efficacy in terms of 2 co-primary endpoints—reduction in anti-factor Xa inhibitor activity and achievement of clinical hemostasis by 12 hours after administration. Hemostatic efficacy was assessed by an independent endpoint adjudication committee as “excellent,” “good,” or “poor/none.”

After the bolus dose of andexanet alfa, the median anti-factor Xa inhibitor activity was reduced by 91% for patients taking apixaban, 88% for those taking rivaroxaban, and 75% for those taking enoxaparin.

For patients taking rivaroxaban, the median anti-factor Xa inhibitor activity was reduced by 88% at the end of the bolus dose, 87% at the end of the infusion, 42% at 4 hours, 49% at 8 hours, and 60% at 12 hours.

For patients taking apixaban, the median anti-factor Xa inhibitor activity was reduced by 91% at the end of the bolus dose, 91% at the end of the infusion, 36% at 4 hours, 30% at 8 hours, and 35% at 12 hours.

Overall, 83% of patients had “excellent” or “good” clinical hemostasis, and 17% had “poor/none.”

Hemostasis was deemed excellent or good in 83% of patients on rivaroxaban, 82% of those on apixaban, and 80% of those on enoxaparin. It was excellent/good in 86% of patients with GI bleeding, 81% of patients with ICH, and 80% of patients with bleeding at other sites.

Safety

The median age of the safety population (n=227) was 77, and 52% (n=117) were male. Indications for anticoagulation included Afib (78%, n=178), VTE (23%, n=52), and both Afib and VTE (4%, n=8).

Patients were receiving apixaban (n=117), rivaroxaban (n=90), enoxaparin (n=17), and edoxaban (n=3). Types of bleeding included ICH (61%, n=139), GI (27%, n=62), and “other” (12%, n=26).

During the 30-day follow-up period, the rate of thrombotic events was 11% (n=24) for the entire population and 12% (n=17) among patients with ICH.

The mortality rate for all patients was 12% (n=27). Eleven deaths were due to cardiovascular causes.

According to Dr Connolly, these rates of adverse events are in line with what would be expected given the underlying medical condition of the patients in the trial and the fact that many (43%) had not resumed anticoagulant treatment in the 30-day follow-up period.

Two patients experienced an infusion reaction.

None of the patients developed antibodies to factor Xa or factor X, and there were no neutralizing antibodies to andexanet alfa.

Bristol Myers Squibb

ORLANDO—Interim trial results suggest andexanet alfa can reverse the activity of factor Xa inhibitors in patients with acute major bleeding.

Andexanet alfa reduced median anti-factor Xa inhibitor activity by 91% in patients taking apixaban, 88% in those taking rivaroxaban, and 75% in patients taking enoxaparin.

Eleven percent of patients experienced thrombotic events, and 12% of patients died.

Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, Canada, presented these results at the American College of Cardiology’s 67th Annual Scientific Session & Expo (ACC.18, abstract 409-14).

The trial, known as ANNEXA-4, was sponsored by Portola Pharmaceuticals, Inc.

“These data are particularly compelling when you consider the high-risk profile of the ANNEXA-4 population, which includes a substantial number of elderly patients presenting with intracranial hemorrhage and anticoagulated for venous thromboembolism, and the lack of any FDA- or EMA-approved reversal agent for these patients,” Dr Connolly said.

“The interim efficacy and safety data continue to support the promising role of AndexXa [the brand name for andexanet alfa] as an antidote to reverse anticoagulation in factor Xa-associated bleeding.”

Andexanet alfa is a recombinant modified factor Xa molecule designed to bind to and disable factor Xa inhibitors, thereby allowing factor Xa produced by the body to play its normal role in the formation of blood clots.

In earlier trials of healthy volunteers, andexanet alfa reversed the anticoagulant effect of factor Xa inhibitors without any significant safety problems.

ANNEXA-4 is an ongoing trial of andexanet alfa in patients experiencing major bleeding while taking factor Xa inhibitors.

Dr Connolly presented safety outcomes for 227 trial subjects and adjudicated efficacy outcomes for 132 subjects. All subjects presented with acute major bleeding within 18 hours of taking a factor Xa inhibitor, including apixaban, rivaroxaban, enoxaparin, and edoxaban.

The patients received andexanet alfa given as a bolus dose over 20 to 30 minutes, followed by a 2-hour (120 minute) infusion. The dosage was determined based on the specific factor Xa inhibitor the patients were taking and how long it had been since their last dose.

The patients were evaluated for 30 days after andexanet alfa administration.

Efficacy

The median age of the efficacy population (n=137) was 77, and 51% (n=70) were male. Indications for anticoagulation included atrial fibrillation (Afib, 76%, n=104), venous thromboembolism (VTE, 28%, n=38), and both Afib and VTE (4%, n=6).

Patients were receiving apixaban (n=68), rivaroxaban (n=54), or enoxaparin (n=10). None of these patients had received edoxaban.

Types of bleeding included intracranial hemorrhage (ICH, 57%, n=78), gastrointestinal (GI) bleeding (31%, n=43), and “other” bleeding (12%, n=16).

The researchers assessed andexanet alfa’s efficacy in terms of 2 co-primary endpoints—reduction in anti-factor Xa inhibitor activity and achievement of clinical hemostasis by 12 hours after administration. Hemostatic efficacy was assessed by an independent endpoint adjudication committee as “excellent,” “good,” or “poor/none.”

After the bolus dose of andexanet alfa, the median anti-factor Xa inhibitor activity was reduced by 91% for patients taking apixaban, 88% for those taking rivaroxaban, and 75% for those taking enoxaparin.

For patients taking rivaroxaban, the median anti-factor Xa inhibitor activity was reduced by 88% at the end of the bolus dose, 87% at the end of the infusion, 42% at 4 hours, 49% at 8 hours, and 60% at 12 hours.

For patients taking apixaban, the median anti-factor Xa inhibitor activity was reduced by 91% at the end of the bolus dose, 91% at the end of the infusion, 36% at 4 hours, 30% at 8 hours, and 35% at 12 hours.

Overall, 83% of patients had “excellent” or “good” clinical hemostasis, and 17% had “poor/none.”

Hemostasis was deemed excellent or good in 83% of patients on rivaroxaban, 82% of those on apixaban, and 80% of those on enoxaparin. It was excellent/good in 86% of patients with GI bleeding, 81% of patients with ICH, and 80% of patients with bleeding at other sites.

Safety

The median age of the safety population (n=227) was 77, and 52% (n=117) were male. Indications for anticoagulation included Afib (78%, n=178), VTE (23%, n=52), and both Afib and VTE (4%, n=8).

Patients were receiving apixaban (n=117), rivaroxaban (n=90), enoxaparin (n=17), and edoxaban (n=3). Types of bleeding included ICH (61%, n=139), GI (27%, n=62), and “other” (12%, n=26).

During the 30-day follow-up period, the rate of thrombotic events was 11% (n=24) for the entire population and 12% (n=17) among patients with ICH.

The mortality rate for all patients was 12% (n=27). Eleven deaths were due to cardiovascular causes.

According to Dr Connolly, these rates of adverse events are in line with what would be expected given the underlying medical condition of the patients in the trial and the fact that many (43%) had not resumed anticoagulant treatment in the 30-day follow-up period.

Two patients experienced an infusion reaction.

None of the patients developed antibodies to factor Xa or factor X, and there were no neutralizing antibodies to andexanet alfa.