Clopidogrel in Unstable angina to prevent Recurrent Events - CURE Timing of Events Substudy


The goal of this study was to compare the early and late effects of treatment with clopidogrel vs placebo in patients with ACS.

Study Design

Study Design:

Patients Enrolled: 12,562
Mean Follow Up: mean 9 months
Mean Patient Age: mean age 64.2 +/- 11.3
Female: 38

Patient Populations:

Hospitalized within 24 hours after the onset of symptoms, no ST-segment elevation, and either ECG changes or an elevation in the serum level of cardiac enzymes or markers at entry.


Contraindications to antithrombotic or antiplatelet therapy, high risk for bleeding or severe heart failure, use of oral anticoagulants, coronary revascularization in prior 3 months or IV glycoprotein IIb/IIIa receptor inhibitors in the prior 3 days.

Primary Endpoints:

Composite of cardiovascular death, MI, or stroke; the second primary outcome was the first primary composite plus refractory ischemia.

Drug/Procedures Used:

Patients were randomized to receive clopidogrel (300 mg initially, followed by 75 mg/d orally) (n=6259) or equivalent placebo (n=6303). Patients were treated for a minimum of 3 months and a maximum of 12 months (mean of 9 months). Approximately 5,000 patients were eligible to receive treatment for 1 year.

Concomitant Medications:

Aspirin (75 to 325 mg/d); all other treatments including use of PCI were at the discretion of the individual physicians.

Principal Findings:

At 30 days, the primary endpoint of cardiovascular death, MI, or stroke occurred 4.3% of patients in the clopidogrel arm vs 5.4% of patients in the placebo arm (relative risk 0.79, 95% CI 0.67-0.92, p<0.004). From day 31 to 1 year, the event rates were 5.2% vs 6.3%, respectively (RR 0.82, 95% CI 0.70-0.95, p<0.01). For the second primary endpoint of cardiovascular death, MI, stroke, or refractory ischemia, the event rates to day 30 were 7.7% vs 9.2%, respectively (RR 0.83, 95% CI 0.73-0.93, p<0.002) and from day 31 to 1 year were 9.6% vs 10.6%, respectively (RR 0.90, 95% CI 0.80-1.01, p=NS). The rate of life-threatening bleeds did not differ when broken down in each period (1.28% vs 0.97%, RR 1.32, 95% CI 0.95-1.84 for 0 to 30 days; 0.91% vs 0.83%, RR 1.09, 95% CI 0.75-1.59 for 31 days to 1 year), but was significantly higher in the clopidogrel arm when considered over the entire time (1.75% vs 1.18%, RR 1.48, 95% CI 1.1-2.0). Benefit in the primary endpoint in combination with refractory or severe ischemia was evident within 24 hours (1.4% vs 2.1%, RR 0.66, p<0.003) but not the primary endpoint of death, MI or stroke (0.4% vs 0.5%, p=NS).


Among patients with NSTEMI/UA, treatment with clopidogrel in addition to standard therapy was associated with a reduction in death, MI, or stroke at 30 days and from 31 days to 1 year. For the primary endpoint plus refractory or severe ischemia, benefit was seen by the first 24 hours. However, for the primary endpoint alone, benefit was not observed until after day 7. This substudy did not address how PCI use affected these outcomes and the timing of the events. Finally, approximately 21% of patients in CURE underwent PCI, a much lower rate of PCI than what is typically used in the US in NSTEMI/UA patients. It is therefore unclear how applicable the data would be in a population treated more aggressively with PCI.


Circulation. 2003;107:966-972.

Keywords: Risk, Myocardial Infarction, Stroke, Platelet Aggregation Inhibitors, Ticlopidine, Electrocardiography, Hemorrhage, Purinergic P2Y Receptor Antagonists

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