ISAR-REACT 4 Trial Backs Bivalirudin for NSTEMI

ORLANDO – Bivalirudin had similar efficacy, and resulted in less major bleeding than did unfractionated heparin plus abciximab in patients undergoing percutaneous intervention for non–ST-elevation myocardial infarction in the ISAR-REACT 4 trial.

The primary composite end point of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding within 30 days occurred in 10.9% of patients treated with abciximab (ReoPro) plus heparin and in 11.0% of those treated with bivalirudin (Angiomax) plus heparin (P = .94; relative risk, 0.99).

Major bleeding occurred in 4.6% of the abciximab group and 2.6% of the bivalirudin group, with abciximab increasing the risk of major bleeding by 84% (RR, 1.84; P = .02), Dr. Adnan Kastrati said at the scientific sessions of the American Heart Association. The study used a strict definition of major bleeding as the presence of intracranial, intraocular, or retroperitoneal hemorrhage, or a decrease in hemoglobin of more than 40 g/L plus either overt bleeding or the need for transfusion of at least 2 or more units.

Bivalirudin also resulted in a lower rate of severe thrombocytopenia and has the added advantages of a shorter-duration infusion and likely lower cost, said invited discussant Dr. Deepak Bhatt, chief of cardiology at the Veterans Administration Boston Health Care System.

"Coupled with data from the HORIZONS-AMI trial, which showed a significantly lower mortality with bivalirudin than with heparin plus glycoprotein IIb/IIIa inhibitors, these data from ISAR-REACT 4 support the use of bivalirudin across the full spectrum of ACS [acute coronary syndromes], and at least in my opinion, will probably serve as the final chapter in what is the preferred anticoagulant during percutaneous coronary intervention," he said.

Dr. Robert Harrington, director of the Duke Clinical Research Institute in Durham, N.C., said the new data don’t close the chapter, but rather strengthen the recommendation to use bivalirudin in the broader spectrum of patients.

"Acute myocardial infarction remains an area where people might choose to use abciximab," he said in an interview. "Also, very complex angioplasty or thrombotic disease at the site of the angioplasty might cause you to want to have more potent platelet inhibitors on board, but in the broad spectrum of doing typical coronary intervention I think bivalirudin is a superb choice."

Bivalirudin is widely used during coronary interventions in the United States, particularly among stable elective patients, but its cost and lack of reimbursement have been obstacles in Europe, said Dr. Kastrati of the Deutsches Herzzentrum in Munich.

"More data like ISAR-REACT 4 will convince people to use bivalirudin," he said in an interview. "Insurance companies will have to look at this because on the one side you have costs that are higher with bivalirudin, but you also have to think about increased bleeding rates and rehospitalizations, and that financial burden has to be accounted for."

Bivalirudin was shown to be superior to heparin plus a glycoprotein IIb/IIIa inhibitor in acute ST-elevation myocardial infarction in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial (N. Engl. J. Med. 2006;355:2203-16), but that trial was open label and used a liberal definition of bleeding, and PCI was performed in less than 60%, Dr. Kastrati noted.

ISAR-REACT (Intracoronary Stenting and Anti-Thrombosis Research: Rapid Early Action for Coronary Treatment)-4 enrolled 1,721 patients with unstable angina, elevated levels of troponin or creatinine kinase MB isoenzyme, and coronary stenoses requiring PCI. All but two patients in each group underwent PCI.

All patients received clopidogrel 600 mg and 325-500 mg of aspirin before randomization.

A total of 861 patients were assigned to receive a bolus of abciximab 0.25 mg per kilogram body weight, followed by an infusion of 0.125 mcg/kg/min for 12 hours plus unfractionated heparin 70 units/kg bolus. Another 861 patients received bivalirudin 0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/hr for the duration of the procedure.

The secondary composite efficacy end point of death, any recurrent myocardial infarction, or urgent target-vessel revascularization occurred in 12.8% of the abciximab group and in 13.4% of the bivalirudin group (RR, 0.96; P = .76), Dr. Kastrati said.

"More data like ISAR-REACT 4 will convince people to use bivalirudin."

Bivalirudin also reduced the risk of minor bleeding based on TIMI (Thrombolysis in Myocardial Infarction) criteria (4.3% vs. 7.7%).

The bleeding advantage with bivalirudin would have been attenuated if more radial-access cases were done, but nevertheless bivalirudin still resulted in numerically lower pericardial, gastrointestinal, and genitourinary bleeds, with no apparent loss of efficacy, Dr. Bhatt said.

He noted that the newer antiplatelet agents prasugrel (Effient) and ticagrelor (Brilinta) were also not used, but added that it is difficult to see how this would change the results. Finally, he cautioned that the results of ISAR-REACT 4 may not be applicable to patients not treated with aspirin and clopidogrel.

The full results of the trial were simultaneously published online in the New England Journal of Medicine (2011 Nov. 13 [doi:10.1056/NEJMoa1109596]).

Nycomed Pharma sponsored the trial. Dr. Kastrati reported speaker fees or honoraria from Abbott, AstraZeneca, Bristol-Myers Squibb, Cordis, Daichii Sankyo/Lilly, and Medtronic. Dr. Bhatt reported research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, and The Medicines Company. Dr. Harrington is an adviser and/or consultant to AstraZeneca, Johnson & Johnson, Merck, Novartis, Pfizer, Portola, Regado, and Sanofi-Aventis.

ORLANDO – Bivalirudin had similar efficacy, and resulted in less major bleeding than did unfractionated heparin plus abciximab in patients undergoing percutaneous intervention for non–ST-elevation myocardial infarction in the ISAR-REACT 4 trial.

The primary composite end point of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding within 30 days occurred in 10.9% of patients treated with abciximab (ReoPro) plus heparin and in 11.0% of those treated with bivalirudin (Angiomax) plus heparin (P = .94; relative risk, 0.99).

Major bleeding occurred in 4.6% of the abciximab group and 2.6% of the bivalirudin group, with abciximab increasing the risk of major bleeding by 84% (RR, 1.84; P = .02), Dr. Adnan Kastrati said at the scientific sessions of the American Heart Association. The study used a strict definition of major bleeding as the presence of intracranial, intraocular, or retroperitoneal hemorrhage, or a decrease in hemoglobin of more than 40 g/L plus either overt bleeding or the need for transfusion of at least 2 or more units.

Bivalirudin also resulted in a lower rate of severe thrombocytopenia and has the added advantages of a shorter-duration infusion and likely lower cost, said invited discussant Dr. Deepak Bhatt, chief of cardiology at the Veterans Administration Boston Health Care System.

"Coupled with data from the HORIZONS-AMI trial, which showed a significantly lower mortality with bivalirudin than with heparin plus glycoprotein IIb/IIIa inhibitors, these data from ISAR-REACT 4 support the use of bivalirudin across the full spectrum of ACS [acute coronary syndromes], and at least in my opinion, will probably serve as the final chapter in what is the preferred anticoagulant during percutaneous coronary intervention," he said.

Dr. Robert Harrington, director of the Duke Clinical Research Institute in Durham, N.C., said the new data don’t close the chapter, but rather strengthen the recommendation to use bivalirudin in the broader spectrum of patients.

"Acute myocardial infarction remains an area where people might choose to use abciximab," he said in an interview. "Also, very complex angioplasty or thrombotic disease at the site of the angioplasty might cause you to want to have more potent platelet inhibitors on board, but in the broad spectrum of doing typical coronary intervention I think bivalirudin is a superb choice."

Bivalirudin is widely used during coronary interventions in the United States, particularly among stable elective patients, but its cost and lack of reimbursement have been obstacles in Europe, said Dr. Kastrati of the Deutsches Herzzentrum in Munich.

"More data like ISAR-REACT 4 will convince people to use bivalirudin," he said in an interview. "Insurance companies will have to look at this because on the one side you have costs that are higher with bivalirudin, but you also have to think about increased bleeding rates and rehospitalizations, and that financial burden has to be accounted for."

Bivalirudin was shown to be superior to heparin plus a glycoprotein IIb/IIIa inhibitor in acute ST-elevation myocardial infarction in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial (N. Engl. J. Med. 2006;355:2203-16), but that trial was open label and used a liberal definition of bleeding, and PCI was performed in less than 60%, Dr. Kastrati noted.

ISAR-REACT (Intracoronary Stenting and Anti-Thrombosis Research: Rapid Early Action for Coronary Treatment)-4 enrolled 1,721 patients with unstable angina, elevated levels of troponin or creatinine kinase MB isoenzyme, and coronary stenoses requiring PCI. All but two patients in each group underwent PCI.

All patients received clopidogrel 600 mg and 325-500 mg of aspirin before randomization.

A total of 861 patients were assigned to receive a bolus of abciximab 0.25 mg per kilogram body weight, followed by an infusion of 0.125 mcg/kg/min for 12 hours plus unfractionated heparin 70 units/kg bolus. Another 861 patients received bivalirudin 0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/hr for the duration of the procedure.

The secondary composite efficacy end point of death, any recurrent myocardial infarction, or urgent target-vessel revascularization occurred in 12.8% of the abciximab group and in 13.4% of the bivalirudin group (RR, 0.96; P = .76), Dr. Kastrati said.

"More data like ISAR-REACT 4 will convince people to use bivalirudin."

Bivalirudin also reduced the risk of minor bleeding based on TIMI (Thrombolysis in Myocardial Infarction) criteria (4.3% vs. 7.7%).

The bleeding advantage with bivalirudin would have been attenuated if more radial-access cases were done, but nevertheless bivalirudin still resulted in numerically lower pericardial, gastrointestinal, and genitourinary bleeds, with no apparent loss of efficacy, Dr. Bhatt said.

He noted that the newer antiplatelet agents prasugrel (Effient) and ticagrelor (Brilinta) were also not used, but added that it is difficult to see how this would change the results. Finally, he cautioned that the results of ISAR-REACT 4 may not be applicable to patients not treated with aspirin and clopidogrel.

The full results of the trial were simultaneously published online in the New England Journal of Medicine (2011 Nov. 13 [doi:10.1056/NEJMoa1109596]).

Nycomed Pharma sponsored the trial. Dr. Kastrati reported speaker fees or honoraria from Abbott, AstraZeneca, Bristol-Myers Squibb, Cordis, Daichii Sankyo/Lilly, and Medtronic. Dr. Bhatt reported research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, and The Medicines Company. Dr. Harrington is an adviser and/or consultant to AstraZeneca, Johnson & Johnson, Merck, Novartis, Pfizer, Portola, Regado, and Sanofi-Aventis.

ORLANDO – Bivalirudin had similar efficacy, and resulted in less major bleeding than did unfractionated heparin plus abciximab in patients undergoing percutaneous intervention for non–ST-elevation myocardial infarction in the ISAR-REACT 4 trial.

The primary composite end point of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding within 30 days occurred in 10.9% of patients treated with abciximab (ReoPro) plus heparin and in 11.0% of those treated with bivalirudin (Angiomax) plus heparin (P = .94; relative risk, 0.99).

Major bleeding occurred in 4.6% of the abciximab group and 2.6% of the bivalirudin group, with abciximab increasing the risk of major bleeding by 84% (RR, 1.84; P = .02), Dr. Adnan Kastrati said at the scientific sessions of the American Heart Association. The study used a strict definition of major bleeding as the presence of intracranial, intraocular, or retroperitoneal hemorrhage, or a decrease in hemoglobin of more than 40 g/L plus either overt bleeding or the need for transfusion of at least 2 or more units.

Bivalirudin also resulted in a lower rate of severe thrombocytopenia and has the added advantages of a shorter-duration infusion and likely lower cost, said invited discussant Dr. Deepak Bhatt, chief of cardiology at the Veterans Administration Boston Health Care System.

"Coupled with data from the HORIZONS-AMI trial, which showed a significantly lower mortality with bivalirudin than with heparin plus glycoprotein IIb/IIIa inhibitors, these data from ISAR-REACT 4 support the use of bivalirudin across the full spectrum of ACS [acute coronary syndromes], and at least in my opinion, will probably serve as the final chapter in what is the preferred anticoagulant during percutaneous coronary intervention," he said.

Dr. Robert Harrington, director of the Duke Clinical Research Institute in Durham, N.C., said the new data don’t close the chapter, but rather strengthen the recommendation to use bivalirudin in the broader spectrum of patients.

"Acute myocardial infarction remains an area where people might choose to use abciximab," he said in an interview. "Also, very complex angioplasty or thrombotic disease at the site of the angioplasty might cause you to want to have more potent platelet inhibitors on board, but in the broad spectrum of doing typical coronary intervention I think bivalirudin is a superb choice."

Bivalirudin is widely used during coronary interventions in the United States, particularly among stable elective patients, but its cost and lack of reimbursement have been obstacles in Europe, said Dr. Kastrati of the Deutsches Herzzentrum in Munich.

"More data like ISAR-REACT 4 will convince people to use bivalirudin," he said in an interview. "Insurance companies will have to look at this because on the one side you have costs that are higher with bivalirudin, but you also have to think about increased bleeding rates and rehospitalizations, and that financial burden has to be accounted for."

Bivalirudin was shown to be superior to heparin plus a glycoprotein IIb/IIIa inhibitor in acute ST-elevation myocardial infarction in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial (N. Engl. J. Med. 2006;355:2203-16), but that trial was open label and used a liberal definition of bleeding, and PCI was performed in less than 60%, Dr. Kastrati noted.

ISAR-REACT (Intracoronary Stenting and Anti-Thrombosis Research: Rapid Early Action for Coronary Treatment)-4 enrolled 1,721 patients with unstable angina, elevated levels of troponin or creatinine kinase MB isoenzyme, and coronary stenoses requiring PCI. All but two patients in each group underwent PCI.

All patients received clopidogrel 600 mg and 325-500 mg of aspirin before randomization.

A total of 861 patients were assigned to receive a bolus of abciximab 0.25 mg per kilogram body weight, followed by an infusion of 0.125 mcg/kg/min for 12 hours plus unfractionated heparin 70 units/kg bolus. Another 861 patients received bivalirudin 0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/hr for the duration of the procedure.

The secondary composite efficacy end point of death, any recurrent myocardial infarction, or urgent target-vessel revascularization occurred in 12.8% of the abciximab group and in 13.4% of the bivalirudin group (RR, 0.96; P = .76), Dr. Kastrati said.

"More data like ISAR-REACT 4 will convince people to use bivalirudin."

Bivalirudin also reduced the risk of minor bleeding based on TIMI (Thrombolysis in Myocardial Infarction) criteria (4.3% vs. 7.7%).

The bleeding advantage with bivalirudin would have been attenuated if more radial-access cases were done, but nevertheless bivalirudin still resulted in numerically lower pericardial, gastrointestinal, and genitourinary bleeds, with no apparent loss of efficacy, Dr. Bhatt said.

He noted that the newer antiplatelet agents prasugrel (Effient) and ticagrelor (Brilinta) were also not used, but added that it is difficult to see how this would change the results. Finally, he cautioned that the results of ISAR-REACT 4 may not be applicable to patients not treated with aspirin and clopidogrel.

The full results of the trial were simultaneously published online in the New England Journal of Medicine (2011 Nov. 13 [doi:10.1056/NEJMoa1109596]).

Nycomed Pharma sponsored the trial. Dr. Kastrati reported speaker fees or honoraria from Abbott, AstraZeneca, Bristol-Myers Squibb, Cordis, Daichii Sankyo/Lilly, and Medtronic. Dr. Bhatt reported research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, and The Medicines Company. Dr. Harrington is an adviser and/or consultant to AstraZeneca, Johnson & Johnson, Merck, Novartis, Pfizer, Portola, Regado, and Sanofi-Aventis.