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Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion - BRAVO
Description:
The goal of the BRAVO trial was to evaluate the safety and efficacy of the oral glycoprotein (GP) IIb/IIIa antagonist lotrafiban in patients with coronary and cerebrovascular disease.
Study Design
Study Design:
Patients Enrolled: 9190
Mean Follow Up: median of 366 days
Mean Patient Age: mean age 62 years (range 20-96)
Female: 29%
Patient Populations:
Age ≥18 years and had: 1) prior MI or unstable angina within 14 days of baseline evaluation, 2) ischemic stroke from 5-30 days after the acute event, 3) a transient ischemic attack within 30 days, or 4) “double bed” vascular disease, defined as documented peripheral vascular disease combined with either coronary or cerebrovascular disease
Exclusions:
Predisposition to bleeding, suboptimal blood pressure control, intolerance or allergy to aspirin, recent use of an intravenous IIb/IIIa antagonist, or need for therapy with warfarin or a thienopyridine drug
Primary Endpoints:
Composite of death, MI, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization
Drug/Procedures Used:
Patients were randomized in a double-blind manner to lotrafiban (30 mg or 50 mg BID, depending on age and creatinine clearance; n=4,600) or matching placebo (n=4,590). Treatment was to be administered for two years. Patients were enrolled from 23 countries and 690 hospitals.
Concomitant Medications:
Aspirin 75-325 mg/d
Principal Findings:
The trial was discontinued early at the recommendation of the Data Safety and Monitoring Board, due to an increase in mortality in the lotrafiban arm (3.0% vs. 2.3%, hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.03-1.72, p=0.026). The cause of excess death was primarily vascular related. Cerebrovascular disease was present in 41% of patients at enrollment, while 59% had coronary artery disease.
The primary endpoint of death, myocardial infarction (MI), stroke, recurrent ischemia requiring hospitalization, or urgent revascularization did not differ significantly between the lotrafiban and placebo arms (16.4% vs. 17.5%, HR 0.94, 95% CI 0.85-1.03, p=0.19). Serious bleeding occurred more frequently in the lotrafiban arm (8.0% vs. 2.8%, p<0.001), and was more frequent in patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban.
Interpretation:
Among patients with coronary and cerebrovascular disease, treatment with the oral GP IIb/IIIa antagonist lotrafiban was not associated with a difference in the primary endpoint of death, MI, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization compared with placebo, but lotrafiban was associated with an increase in mortality, prompting the trial to be discontinued early.
While 41% of patients in the present trial had cerebrovascular disease, similar increases in mortality were observed in earlier trials of oral GP IIb/IIIa inhibitors in patients with acute coronary syndromes, such as TIMI 16-OPUS and SYMPHONY. Titrating the dose of lotrafiban according to patient age and creatinine clearance, as was done in the present trial, did not reduce this risk.
References:
Topol EJ, Easton D, Harrington RA, et al., for the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion Trial Investigators. Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease. Circulation 2003;108:399-406.
Keywords: Benzodiazepines, Coronary Artery Disease, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Creatinine, Peripheral Vascular Diseases, Platelet Membrane Glycoprotein IIb, Piperidines, Hospitalization, Platelet Glycoprotein GPIIb-IIIa Complex
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