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ORLANDO – Andexanet alfa, a new agent that reverses the anticoagulant effect of direct factor Xa inhibitors, showed an acceptable level of efficacy and safety in 227 patients who received the drug in the agent’s pivotal trial.
These results, which placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind), approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa), suggest that andexanet is likely on track for its own Food and Drug Administration marketing approval, Stuart Connolly, MD, said at the annual meeting of the American College of Cardiology.
Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa) previously announced that it expected Food and Drug Administration action on its marketing application by May 2018.
Andexanet reversal “has similar efficacy and safety as seen with other reversal agents” for other types of anticoagulants, said Dr. Connolly, a professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont. In the trial results he reported, andexanet treatment of patients who were bleeding while on treatment with a direct factor Xa inhibitor had an 83% rate of hemostatic efficacy and an 11% rate of thrombotic events. By comparison, idarucizumab, the FDA-approved reversal agent for the anticoagulant dabigatran, produced a 68% hemostatic efficacy and a 6% rate of thrombotic events in the idarucizumab pivotal trial, RE-VERSE AD (N Engl J Med. 2015 Aug 6;373[6]:511-20).
The Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4) enrolled 227 patients at any of 60 centers, with efficacy data available from 132 of the patients. About 60% of the patients had an intracranial bleed, and about 30% had a gastrointestinal bleed, and their average age was 77 years. Roughly three-quarters of patients were on an anticoagulant for atrial fibrillation, with the rest treated for venous thromboembolism, with 4% having both conditions. The most commonly used direct factor Xa inhbitors in these patients were apixaban (Eliquis) in 105 and rivaroxaban (Xarelto) in 75. The ANNEXA-4 study has not enrolled patients treated with a direct factor Xa inhibitor anticoagulant and undergoing surgery, a setting that will be the subject of a future study, Dr. Connolly said.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by about 75%-90% within minutes of starting the bolus and remained depressed at that level during the infusion but then began recovering by 2 hours after the stop of infusion. Andexanet is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops.
“There is no doubt that andexanet rapidly decreases anti–factor Xa activity,” he said.
Adjudicated efficacy results were available for 132 patients and showed good or excellent hemostasis achieved on andexanet in 109 patients (83%), Dr. Connolly reported. The effect on hemostasis was consistent regardless of patient age, sex, bleeding site, type of anticoagulant, and dosage tested.
Thrombotic events during the 30 days following treatment occurred in 24 of 227 patients (11%) who received andexanet and were evaluable for safety. Notably, no clustering of thrombotic events occurred early, even among the 129 patients who restarted on an anticoagulant during the 30 days after treatment. Among the 129 patients who restarted on an anticoagulant, 9 (7%) had a thrombotic event during the 30-day follow-up, compared with 15 events among 98 patients (15%) who did not restart on an anticoagulant.
Dr. Connolly acknowledged that a limitation of the ANNEXA-4 study is the absence of a control group, but he added that he and his associates believed randomizing patients with a serious bleed to placebo control would not have been “practical, feasible, or ethical.”
ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola, and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis. Dr. Kirtane has received research support from several device manufacturers.
SOURCE: Connolly S. ACC 2018.
Treatment with andexanet alfa produced good or excellent hemostasis in 83% of patients in the ANNEXA-4 study, which is what matters when patients are bleeding. Clinicians want to know that you can restore coagulation to a level where you can stop bleeding, and that’s what the results show.
The lack of a reversal agent until now for direct-acting factor Xa inhibitor drugs has probably been a modest but real obstacle to widespread adoption of these agents. We can look at the example of another new oral anticoagulant, dabigatran (Pradaxa), which works by a different mechanism, specifically by inhibiting thrombin. After a reversal agent for dabigatran, idarucizumab (Praxbind) received Food and Drug Administration approval and became available in late 2015, an uptick in dabigatran prescriptions occurred. That experience shows that patients and providers want the safety net of a reversal agent. They want to know that, if there is bleeding or need for urgent surgery, there is a way to facilitate restoration of hemostasis.
It’s the same with direct factor Xa inhibitors: Some patients are concerned about the lack of a reversal agent, and having such an agent may help increase access to these agents for such patients. I think that, once andexanet becomes available for routine U.S. practice, we’ll see an uptick in prescribing of direct factor Xa inhibitors. Also, some patients who have opted for treatment with warfarin will switch to a safer class of drugs, the direct factor X a inhibitors. A myth exists that reversal agents can easily negate the anticoagulant effect of warfarin. The reality is that, despite having treatments that reverse warfarin’s effect, this is often not an easy process in actual practice.
On the safety side, there was no indication in the ANNEXA-4 results of rebound thrombosis with andexanet alfa treatment. Patients receiving a direct factor Xa inhibitor are prothrombotic – that’s why they are on an anticoagulant – so their risk for a thrombotic event is always there, especially when they are not fully anticoagulated, such as when a reversal agent is administered. We need to look to restarting treatment with an anticoagulant because these patients have a high thrombotic risk.
Gregory Piazza, MD , is a cardiologist at Brigham and Women’s Hospital in Boston. He has been an advisor to Portola Pharmaceuticals, the company developing andexanet alfa, as well as to Bayer and Pfizer, and he has received research funding from Bristol-Myers Squibb, Janssen, and Daiichi Sankyo. He made these comments in an interview .
Treatment with andexanet alfa produced good or excellent hemostasis in 83% of patients in the ANNEXA-4 study, which is what matters when patients are bleeding. Clinicians want to know that you can restore coagulation to a level where you can stop bleeding, and that’s what the results show.
The lack of a reversal agent until now for direct-acting factor Xa inhibitor drugs has probably been a modest but real obstacle to widespread adoption of these agents. We can look at the example of another new oral anticoagulant, dabigatran (Pradaxa), which works by a different mechanism, specifically by inhibiting thrombin. After a reversal agent for dabigatran, idarucizumab (Praxbind) received Food and Drug Administration approval and became available in late 2015, an uptick in dabigatran prescriptions occurred. That experience shows that patients and providers want the safety net of a reversal agent. They want to know that, if there is bleeding or need for urgent surgery, there is a way to facilitate restoration of hemostasis.
It’s the same with direct factor Xa inhibitors: Some patients are concerned about the lack of a reversal agent, and having such an agent may help increase access to these agents for such patients. I think that, once andexanet becomes available for routine U.S. practice, we’ll see an uptick in prescribing of direct factor Xa inhibitors. Also, some patients who have opted for treatment with warfarin will switch to a safer class of drugs, the direct factor X a inhibitors. A myth exists that reversal agents can easily negate the anticoagulant effect of warfarin. The reality is that, despite having treatments that reverse warfarin’s effect, this is often not an easy process in actual practice.
On the safety side, there was no indication in the ANNEXA-4 results of rebound thrombosis with andexanet alfa treatment. Patients receiving a direct factor Xa inhibitor are prothrombotic – that’s why they are on an anticoagulant – so their risk for a thrombotic event is always there, especially when they are not fully anticoagulated, such as when a reversal agent is administered. We need to look to restarting treatment with an anticoagulant because these patients have a high thrombotic risk.
Gregory Piazza, MD , is a cardiologist at Brigham and Women’s Hospital in Boston. He has been an advisor to Portola Pharmaceuticals, the company developing andexanet alfa, as well as to Bayer and Pfizer, and he has received research funding from Bristol-Myers Squibb, Janssen, and Daiichi Sankyo. He made these comments in an interview .
Treatment with andexanet alfa produced good or excellent hemostasis in 83% of patients in the ANNEXA-4 study, which is what matters when patients are bleeding. Clinicians want to know that you can restore coagulation to a level where you can stop bleeding, and that’s what the results show.
The lack of a reversal agent until now for direct-acting factor Xa inhibitor drugs has probably been a modest but real obstacle to widespread adoption of these agents. We can look at the example of another new oral anticoagulant, dabigatran (Pradaxa), which works by a different mechanism, specifically by inhibiting thrombin. After a reversal agent for dabigatran, idarucizumab (Praxbind) received Food and Drug Administration approval and became available in late 2015, an uptick in dabigatran prescriptions occurred. That experience shows that patients and providers want the safety net of a reversal agent. They want to know that, if there is bleeding or need for urgent surgery, there is a way to facilitate restoration of hemostasis.
It’s the same with direct factor Xa inhibitors: Some patients are concerned about the lack of a reversal agent, and having such an agent may help increase access to these agents for such patients. I think that, once andexanet becomes available for routine U.S. practice, we’ll see an uptick in prescribing of direct factor Xa inhibitors. Also, some patients who have opted for treatment with warfarin will switch to a safer class of drugs, the direct factor X a inhibitors. A myth exists that reversal agents can easily negate the anticoagulant effect of warfarin. The reality is that, despite having treatments that reverse warfarin’s effect, this is often not an easy process in actual practice.
On the safety side, there was no indication in the ANNEXA-4 results of rebound thrombosis with andexanet alfa treatment. Patients receiving a direct factor Xa inhibitor are prothrombotic – that’s why they are on an anticoagulant – so their risk for a thrombotic event is always there, especially when they are not fully anticoagulated, such as when a reversal agent is administered. We need to look to restarting treatment with an anticoagulant because these patients have a high thrombotic risk.
Gregory Piazza, MD , is a cardiologist at Brigham and Women’s Hospital in Boston. He has been an advisor to Portola Pharmaceuticals, the company developing andexanet alfa, as well as to Bayer and Pfizer, and he has received research funding from Bristol-Myers Squibb, Janssen, and Daiichi Sankyo. He made these comments in an interview .
ORLANDO – Andexanet alfa, a new agent that reverses the anticoagulant effect of direct factor Xa inhibitors, showed an acceptable level of efficacy and safety in 227 patients who received the drug in the agent’s pivotal trial.
These results, which placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind), approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa), suggest that andexanet is likely on track for its own Food and Drug Administration marketing approval, Stuart Connolly, MD, said at the annual meeting of the American College of Cardiology.
Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa) previously announced that it expected Food and Drug Administration action on its marketing application by May 2018.
Andexanet reversal “has similar efficacy and safety as seen with other reversal agents” for other types of anticoagulants, said Dr. Connolly, a professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont. In the trial results he reported, andexanet treatment of patients who were bleeding while on treatment with a direct factor Xa inhibitor had an 83% rate of hemostatic efficacy and an 11% rate of thrombotic events. By comparison, idarucizumab, the FDA-approved reversal agent for the anticoagulant dabigatran, produced a 68% hemostatic efficacy and a 6% rate of thrombotic events in the idarucizumab pivotal trial, RE-VERSE AD (N Engl J Med. 2015 Aug 6;373[6]:511-20).
The Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4) enrolled 227 patients at any of 60 centers, with efficacy data available from 132 of the patients. About 60% of the patients had an intracranial bleed, and about 30% had a gastrointestinal bleed, and their average age was 77 years. Roughly three-quarters of patients were on an anticoagulant for atrial fibrillation, with the rest treated for venous thromboembolism, with 4% having both conditions. The most commonly used direct factor Xa inhbitors in these patients were apixaban (Eliquis) in 105 and rivaroxaban (Xarelto) in 75. The ANNEXA-4 study has not enrolled patients treated with a direct factor Xa inhibitor anticoagulant and undergoing surgery, a setting that will be the subject of a future study, Dr. Connolly said.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by about 75%-90% within minutes of starting the bolus and remained depressed at that level during the infusion but then began recovering by 2 hours after the stop of infusion. Andexanet is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops.
“There is no doubt that andexanet rapidly decreases anti–factor Xa activity,” he said.
Adjudicated efficacy results were available for 132 patients and showed good or excellent hemostasis achieved on andexanet in 109 patients (83%), Dr. Connolly reported. The effect on hemostasis was consistent regardless of patient age, sex, bleeding site, type of anticoagulant, and dosage tested.
Thrombotic events during the 30 days following treatment occurred in 24 of 227 patients (11%) who received andexanet and were evaluable for safety. Notably, no clustering of thrombotic events occurred early, even among the 129 patients who restarted on an anticoagulant during the 30 days after treatment. Among the 129 patients who restarted on an anticoagulant, 9 (7%) had a thrombotic event during the 30-day follow-up, compared with 15 events among 98 patients (15%) who did not restart on an anticoagulant.
Dr. Connolly acknowledged that a limitation of the ANNEXA-4 study is the absence of a control group, but he added that he and his associates believed randomizing patients with a serious bleed to placebo control would not have been “practical, feasible, or ethical.”
ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola, and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis. Dr. Kirtane has received research support from several device manufacturers.
SOURCE: Connolly S. ACC 2018.
ORLANDO – Andexanet alfa, a new agent that reverses the anticoagulant effect of direct factor Xa inhibitors, showed an acceptable level of efficacy and safety in 227 patients who received the drug in the agent’s pivotal trial.
These results, which placed andexanet in the same ballpark for efficacy and safety as idarucizumab (Praxbind), approved in 2015 for reversing the anticoagulant dabigatran (Pradaxa), suggest that andexanet is likely on track for its own Food and Drug Administration marketing approval, Stuart Connolly, MD, said at the annual meeting of the American College of Cardiology.
Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa) previously announced that it expected Food and Drug Administration action on its marketing application by May 2018.
Andexanet reversal “has similar efficacy and safety as seen with other reversal agents” for other types of anticoagulants, said Dr. Connolly, a professor of medicine and an electrophysiologist at McMaster University in Hamilton, Ont. In the trial results he reported, andexanet treatment of patients who were bleeding while on treatment with a direct factor Xa inhibitor had an 83% rate of hemostatic efficacy and an 11% rate of thrombotic events. By comparison, idarucizumab, the FDA-approved reversal agent for the anticoagulant dabigatran, produced a 68% hemostatic efficacy and a 6% rate of thrombotic events in the idarucizumab pivotal trial, RE-VERSE AD (N Engl J Med. 2015 Aug 6;373[6]:511-20).
The Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding (ANNEXA-4) enrolled 227 patients at any of 60 centers, with efficacy data available from 132 of the patients. About 60% of the patients had an intracranial bleed, and about 30% had a gastrointestinal bleed, and their average age was 77 years. Roughly three-quarters of patients were on an anticoagulant for atrial fibrillation, with the rest treated for venous thromboembolism, with 4% having both conditions. The most commonly used direct factor Xa inhbitors in these patients were apixaban (Eliquis) in 105 and rivaroxaban (Xarelto) in 75. The ANNEXA-4 study has not enrolled patients treated with a direct factor Xa inhibitor anticoagulant and undergoing surgery, a setting that will be the subject of a future study, Dr. Connolly said.
Clinicians administered andexanet alfa as a bolus followed by a 2-hour continuous infusion, with hemostatic efficacy assessed 12 hours after the start of treatment. The results showed that factor Xa inhibition fell by about 75%-90% within minutes of starting the bolus and remained depressed at that level during the infusion but then began recovering by 2 hours after the stop of infusion. Andexanet is a factor Xa “decoy” molecule that acts by latching onto the inhibitor molecules and thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops.
“There is no doubt that andexanet rapidly decreases anti–factor Xa activity,” he said.
Adjudicated efficacy results were available for 132 patients and showed good or excellent hemostasis achieved on andexanet in 109 patients (83%), Dr. Connolly reported. The effect on hemostasis was consistent regardless of patient age, sex, bleeding site, type of anticoagulant, and dosage tested.
Thrombotic events during the 30 days following treatment occurred in 24 of 227 patients (11%) who received andexanet and were evaluable for safety. Notably, no clustering of thrombotic events occurred early, even among the 129 patients who restarted on an anticoagulant during the 30 days after treatment. Among the 129 patients who restarted on an anticoagulant, 9 (7%) had a thrombotic event during the 30-day follow-up, compared with 15 events among 98 patients (15%) who did not restart on an anticoagulant.
Dr. Connolly acknowledged that a limitation of the ANNEXA-4 study is the absence of a control group, but he added that he and his associates believed randomizing patients with a serious bleed to placebo control would not have been “practical, feasible, or ethical.”
ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola, and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis. Dr. Kirtane has received research support from several device manufacturers.
SOURCE: Connolly S. ACC 2018.
REPORTING FROM ACC 18
Key clinical point:
Major finding: Hemostatic efficacy of andexanet alfa was 83%, and thrombotic events occurred in 11%.
Study details: ANNEXA-4, a single arm cohort study with 227 patients.
Disclosures: ANNEXA-4 is sponsored by Portola Pharmaceuticals, the company developing andexanet alfa (AndexXa). Dr. Connolly has been a consultant to Portola and also to Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis.
Source: Connolly S. ACC 2018.