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. MethodsWe 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. ResultsThe 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, 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 (2.1 percent vs. 1.8 percent, P=0.13) or hemorrhagic strokes. ConclusionsThe 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 HROMBOSIS caused by a ruptured or eroded atherosclerotic plaque is the usual underlying mechanism of acute coronary syndromes. 1 Aspirin and heparin reduce the risk of death from cardiovascular causes, new myocardial infarction, and recurrent ischemia, 2,3 but there is still a substantial risk of such events in both the short term and the long term. Intravenous glycoprotein IIb/IIIa receptor blockers have been shown to reduce the incidence of early events, mainly among patients T who are treated according to an invasive strategy, 4,5 but long-term oral therapy with glycoprotein IIb/IIIa receptor blockers is not beneficial and may even increase mortality. 6 Similarly, continuing treatment with low-molecular-weight heparin beyond one week has not been shown to be effective. 7 Although the longterm use of oral anticoagulants may be useful, no convincing evidence of their benefit is yet available. 8 Therefore, there is a need to reduce further the risk of ischemic events in a broad spectrum of patients both when they first present with acute coronary syndromes and in the long term.The thienopyridine derivatives, ticlopidine and clopidogrel, are antiplatelet agents that inhibit the platelet aggregation induced by adenosin...

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Background-Heart rate reduction should benefit patients with chronic stable angina by improving myocardial perfusion and reducing myocardial oxygen demand. This study evaluated the antianginal and antiischemic effects of ivabradine, a new heart rate-lowering agent that acts specifically on the sinoatrial node. Methods and Results-In a double-blind, placebo-controlled trial, 360 patients with a Ն3-month history of chronic stable angina were randomly assigned to receive ivabradine (2.5, 5, or 10 mg BID) or placebo for 2 weeks, followed by an open-label 2-or 3-month extension on ivabradine (10 mg BID) and a 1-week randomized withdrawal to ivabradine (10 mg BID) or placebo. Primary efficacy criteria were changes in time to 1-mm ST-segment depression and time to limiting angina during bicycle exercise (exercise tolerance tests), performed at trough of drug activity. In the per-protocol population (nϭ257), time to 1-mm ST-segment depression increased in the 5 and 10 mg BID groups (PϽ0.005); time to limiting angina increased in the 10 mg BID group (PϽ0.05). Deterioration in all exercise tolerance test parameters occurred in patients who received placebo during randomized withdrawal (all PϽ0.02) but not in those still receiving ivabradine. No rebound phenomena were observed on treatment cessation. Conclusions-Ivabradine produces dose-dependent improvements in exercise tolerance and time to development of ischemia during exercise. These results suggest that ivabradine, representing a novel class of antianginal drugs, is effective and safe during 3 months of use; longer-term safety requires additional assessment.