BACKGROUND Despite current treatments, patients who have acute coronary syndromes without ST-segment elevation have high rates of major vascular events. We evaluated the efficacy and safety of the antiplatelet agent clopidogrel when given with aspirin in such patients. METHODS We randomly assigned 12,562 patients who had presented within 24 hours after the onset of symptoms to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) (6259 patients) or placebo (6303 patients) in addition to aspirin for 3 to 12 months. RESULTS The first primary outcome--a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke--occurred in 9.3 percent of the patients in the clopidogrel group and 11.4 percent of the patients in the placebo group (relative risk with clopidogrel as compared with placebo, 0.80; 95 percent confidence interval, 0.72 to 0.90; P<0.001). The second primary outcome--the first primary outcome or refractory ischemia--occurred in 16.5 percent of the patients in the clopidogrel group and 18.8 percent of the patients in the placebo group (relative risk, 0.86; 95 percent confidence interval, 0.79 to 0.94; P<0.001). The percentages of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures were also significantly lower with clopidogrel. There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7 percent vs. 2.7 percent; relative risk, 1.38; P=0.001), but there were not significantly more patients with episodes of life-threatening bleeding (2.2 percent [corrected] vs. 1.8 percent; P=0.13) or hemorrhagic strokes (0.1 percent vs. 0.1 percent). CONCLUSIONS The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation. However, the risk of major bleeding is increased among patients treated with clopidogrel.

BACKGROUND:Other than aspirin, there are few oral antithrombotic treatments with proven efficacy in patients with acute coronary syndrome. In this report, we present the rationale, design and baseline characteristics of the Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) trial, which includes a meta-analysis of the effects of thienopyridines in patients with vascular disease.METHODS AND RESULTS:Combined data from randomized trials of thienopyrindines in patients with atherosclerotic disease demonstrated a 29% reduction in vascular events when compared with placebo/control (n=2392) (OR 0.71, 95% CI 0.58-0.86, P=0.0006) and a 10% reduction in vascular events when compared with aspirin (n=22 254) (OR 0.91, 95% Cl 0.84-0.99, P=0.039). Similarly, randomized trials of aspirin plus thienopyridines in patients undergoing intracoronary stenting, demonstrated a marked benefit of aspirin plus ticlopidine in reducing death or myocardial infarction compared with aspirin alone (OR 0.23, 95% CI 0.11-0.49, P=0.0001) or aspirin plus warfarin (OR 0.51, 95% CI 0.33-0.78, P=0.002). Whether these benefits extend to the much larger population of patients with acute coronary syndrome is unknown. CURE is an international, randomized, double-blind trial, in which patients with acute coronary syndrome will be randomized to receive either a bolus dose of clopidogrel (300 mg) followed by 75 mg per day for 3-12 months, or matching placebo. Both groups will receive aspirin. The co-primary efficacy end-points of CURE are: (1) the composite of cardiovascular death, myocardial infarction or stroke; and (2) the composite of cardiovascular death, myocardial infarction, stroke or refractory ischaemia. CURE will recruit approximately 12 500 patients with acute coronary syndrome (from 28 countries) and its power to detect moderate treatment benefits will be in the region of 80-90%, while maintaining an overall type I error (alpha) of 0.05. The baseline characteristics of the study population are consistent with at least a moderate risk group of patients with acute coronary syndrome.CONCLUSIONS:Randomized trials of thienopyridines in patients with vascular disease demonstrate that thienopyridines are effective in reducing vascular events when compared with placebo/control or aspirin, as well as when used in combination with aspirin in patients undergoing intracoronary stent implantation. The CURE trial is a large international study to determine if acute and long-term treatment with the combination of clopidogrel and aspirin is superior to aspirin alone in patients with acute coronary syndrome.

LIPID is a multicenter, double-blind, randomized, placebo-controlled trial comparing the effects of pravastatin, 40 mg/day, with placebo, given for greater than or equal to 5 years, in patients aged 31 to 75 years with a total cholesterol level at baseline of 4.0 to 7.0 mmol/L (155 to 270 mg/dl), and with a history of acute myocardial infarction (AMI) or hospitalization for unstable; angina pectoris (UAP). Each group receives dietary advice according to National Heart Foundation guidelines. Individual care of each patient is otherwise left to the discretion of the patient's usual doctor, The study, has a primary outcome of coronary mortality, and is designed to detect an 18% reduction with 80% power. From April 1990 to September 1992, 11,106 patients were registered, and following the run-in phase, 9,014 were randomized: 5,754 (64%) after a qualifying event of AMI and 3,260 (36%) after hospitalization for UAP. The randomized population includes relatively large numbers in subgroups not assessed reliably in earlier trials: 1,511 women, 3,516 patients aged greater than or equal to 65 years, 777 diabetics, and 3,829 patients with serum cholesterol <5.5 mmol/L (213 mg/dl) at baseline. With a projected 700 fatal coronary events, the trial should be able to detect important reductions in coronary mortality and contribute substantially to prospective meta-analyses to detect effects on total mortality. The spectrum of patients being assessed will improve the reliability of evidence for the benefits and risks of cholesterol-lowering therapies in patients with lower cholesterol levels and in other important subgroups.