CHICAGO — Bivalirudin was no better than unfractionated heparin for treating troponin-negative patients with angina who underwent percutaneous coronary intervention and received a full loading dose of clopidogrel before their procedure, in a randomized study with more than 4,500 patients.
Although treatment with bivalirudin led to significantly fewer major bleeding episodes, this benefit was balanced by a trend toward fewer ischemic events among the patients treated with unfractionated heparin. The net result was that for the study's primary end point—a composite of death, MI, need for urgent revascularization, and major bleeding events—the two drugs performed nearly identically, Dr. Adnan Kastrati reported at the Innovation in Intervention (i2) Summit.
The implications are that in this treatment situation, compared with bivalirudin, “unfractionated heparin may be a better choice [because of its lower] cost, but in certain patient subgroups one drug may be better than the other,” such as patients with an increased risk for bleeding, said Dr. Kastrati, director of interventional cardiology at the Heart Center in Munich.
But another expert disagreed and said that the results showed an outright advantage for bivalirudin because it caused fewer major bleeds. “The composite end point was numerically in favor of bivalirudin, there was no [significant] increase in ischemic events [with bivalirudin], and major bleeds were reduced. The results show that bivalirudin is the antithrombotic of choice” in the type of patients enrolled in the study, commented Dr. Harvey White, professor of cardiology at the University of New Zealand in Auckland.
But Dr. Kastrati warned against overinterpreting the bleeding result. “The main message should be based on the primary end point, not the individual end points,” he said.
The Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 trial enrolled patients at six centers in Germany and one U.S. center. Eligible patients had either stable or unstable angina, had no elevation of serum troponin, and were scheduled for PCI. Their average age was 67 years, and about three-quarters were men. All patients received a loading dose of 600 mg of clopidogrel (Plavix) 2 hours or more before their procedure began as well as at least 325 mg of aspirin, a regimen that has recently become the standard pretreatment for patients undergoing PCI.
Patients were randomized to either of two study treatments. A 0.75-mg/kg bolus of bivalirudin, followed by a 1.75-mg/kg per hour infusion, was administered to 2,289 patients. The control arm of 2,281 patients received a 140-U/kg bolus of unfractionated heparin, followed by placebo infusion. (This heparin dose is commonly used in Europe; a 100-U/kg bolus dose is more prevalent in the United States, Dr. Kastrati noted.) About 83% of the patients received a drug-eluting stent.
Following their procedure, all patients received 75–150 mg/day clopidogrel until they were discharged from the hospital, and then maintained on a 75-mg/day dosage for at least 6 months. All patients also received 80–325 mg/day aspirin indefinitely.
During the first 30 days after treatment, the incidence of the combined primary end point of death, MI, need for urgent revascularization, or a major bleeding event was 8.3% in the bivalirudin patients and 8.7% in the unfractionated heparin patients, a nonsignificant difference, reported Dr. Kastrati at the meeting, cosponsored by the American College of Cardiology and the Society for Cardiovascular Angiography and Intervention.
Major bleeds were defined by criteria first used in a 2003 study, the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial. Patients were considered to have a major bleed if they met any of four criteria: intracranial, intraocular, or retroperitoneal bleeding; clinically overt bleeding resulting in a drop in hemoglobin of at least 3 g/dL; a fall of hemoglobin by at least 4 g/dL due to any cause; or transfusion with at least two units of packed red blood cells or whole blood. The incidence of major bleeds was significantly less with bivalirudin, as was the rate of minor bleeds, and major bleeds by the criteria used in the Thrombolysis in Myocardial Infarction (TIMI) trials (see table).
ISAR-REACT 3 was funded in part by Nycomed Pharma, which markets bivalirudin (Angiomax) in Europe. Dr. Kastrati said that he and his coinvestigators had no other relevant financial relationships. Dr. White has served as a consultant to and has received speaker fees and research support from The Medicines Company, the U.S. marketer of bivalirudin.
In the primary end point of ISAR-REACT 3, bivalirudin and unfractionated heparin performed nearly identically. DR. KASTRATI
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