RATIONALE/DESIGN

The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme

Rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease.

CURE Study Investigators: Population Health Institute, the Canadian Cardiovascular Project Office and the Division of Cardiology, McMaster University, Hamilton, Canada

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 thienopyridines 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% CI 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 (α) 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. (Eur Heart J 2000;2033-2041, doi:10.1053/euhj.2000.2474)



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MAIN RESULTS

Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation

Abstract

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; 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 vs. 1.8 percent, P=0.13) or hemorrhagic strokes.

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. (N Engl J Med 2001; 345:494-502.)



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PCI-CURE

Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.


Summary

Background: Despite the use of aspirin, there is still a risk of ischaemic events after percutaneous coronary intervention (PCI). We aimed to find out whether, in addition to aspirin, pretreatment with clopidogrel followed by long-term therapy after PCI is superior to a strategy of no pretreatment and short-term therapy for only 4 weeks after PCI.

Methods : 2658 patients with non-ST-elevation acute coronary syndrome undergoing PCI in the CURE study had been randomly been assigned double-blind treatment with clopidogrel (n=1313) or placebo (n=1345). Patients were pretreated with aspirin and study drug for a median of 6 days before PCI during the initial hospital admission, and for a median of 10 days overall. After PCI, most patients (>80%) in both groups received open-label thienopyridine for about 4 weeks, after which study drug was restarted for a mean of 8 months. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or urgent target-vessel revascularisation within 30 days of PCI. The main analysis was by intention to treat.

Findings : There were no drop-outs. 59(4.5%) patients in the clopidogrel group had the primary endpoint, compared with 86 (6.4%) in the placebo group (relative risk 0.70 [95% CI 0.50-0.97], p=0.03). Long-term administration of clopidogrel after PCI was associated with a lower rate of cardiovascular death, myocardial infarction, or any revascularisation (p=0.03), and of cardiovascular death or myocardial infarction (p=0.047). Overall (including events before and after PCI) there was a 31% reduction cardiovascular death or myocardial infarction (p=0.002). There was less use of glycoprotein IIb/IIIa inhibitor in the clopidogrel group (p=0.001). At follow-up, there was no significant difference in major bleeding between the groups (p=0.64).

Interpretation: In patients with acute coronary syndrome receiving aspirin, a strategy of clopidogrel pretreatment followed by long-term therapy is beneficial in reducing major cardiovascular events, compared with placebo. (Lancet 2001;358:527-33)


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FUTURE PUBLICATIONS LISTING
  • COAG-CURE
  • Economic analysis
  • Bleeding
  • Effects of clopidogrel when combined with different ASA doses (75 mg, 160 mg, and 325 mg)
  • Effects of clopidogrel in low, medium and high risk patients
  • Temporal benefits of clopidogrel in ACS





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