Clopidogrel: Is it the Perfect CURE?

Source: Mehta SR, et al. Lancet. 2001;358:527-533.

The clopidogrel in unstable angina to prevent recurrent events study (CURE) was designed to be a trial of non-invasive medical management of unstable angina.1 A total of 12,562 patients without ST elevation on EKG and with symptoms suggestive of an acute coronary syndrome were randomly assigned to receive aspirin and either clopidogrel or placebo. Despite the emphasis on noninvasive management, 2658 of these patients required percutaneous coronary intervention (PCI) during their hospital stay (1730) or after discharge (928; median time to PCI = 49 days). Prior to the procedure, 1313 of these patients had been randomized to clopidogrel; 1345 of the patients had been randomized to placebo prior to the procedure. These patients were the subject of the retrospective PCI CURE study.

There was considerable overlap in treatment between the 2 groups. Twenty-five percent of each group was started on open-label thienopyridines (clopidogrel or ticlopidine) during the procedure. Eighty percent of both groups were continued on thienopyridines for a median of 30 days after the procedure. Thereafter, subjects were assigned to their study assignment, and followed for 6 months. The primary outcome was a composite score of cardiovascular death, myocardial infarction, or revascularization.

The risk of repeat myocardial infarction or ischemia prior to the procedure was lower in the clopidogrel group (relative risk [RR] = 0.76; confidence interval [CI] 0.62-0.93). Patients given clopidogrel also had a reduced risk of myocardial infarction at 30 days (RR = 0.56; CI 0.35-0.89) and at 8 months of follow-up (RR = 0.71; CI 0.51-0.99). There was not a significant difference in cardiovascular death or need for revascularization. The composite end point was lower in the clopidogrel group (RR = 0.69; CI 0.54-0.87). There was no difference in major bleeding.

Comment by Jeff Wiese, MD

This study supports prior studies suggesting that thienopyridines (clopidogrel or ticlopidine) have an additive benefit to aspirin in the medical management of acute coronary syndromes. Patients who received clopidogrel had a 30% reduction in the composite end point. This difference was almost completely due to a reduction in myocardial infarction. The absolute risk reduction was 3.8%; the number of patients needed to treat to prevent 1 myocardial infarction was 26. There was not a significant difference in mortality or need for revascularization.

The 2 groups were equal with respect to age, gender, diabetes, smoking status, prior MIs, EKG abnormalities, and stent placement. Nonetheless, the decision to perform the PCI was at the discretion of the individual physician, and not the study protocol. It is possible that the initial treatment assignment (clopidogrel or placebo) created a selection bias with respect to the need for revascularization.

The number of patients requiring revascularization was similar in both groups, but the time of revascularization was not. The clopidogrel group had a disproportionate number of PCIs occurring after discharge, while most of the interventions in the placebo group occurred during the initial hospitalization. It is possible that the interventions occurring after discharge were more likely to be elective, and may represent a different patient population.

It is impossible to determine the best time to administer clopidogrel from the results of this study. With the exception of the few days prior to the procedure, the 2 groups received essentially the same treatment (clopidogrel) for the first 30 days. Eighty percent of patients in both groups received thienopyridines between the intervention and the first 30 days. It is not clear if the initial assignment of clopidogrel at presentation, or the continuation of clopidogrel (from 30 days to 8 months) was responsible for the reduction in repeat myocardial infarction. A randomized trial would be required to determine this important question.

Eighty percent of all patients in this study received a coronary stent. The use of IIb/IIIa inhibitors, which is a common clinical practice in this clinical setting, was discouraged as part of the CURE protocol. This may limit this study’s generalizability to current clinical practice. Although there is evidence to support the additive benefit of clopidogrel and IIb/IIIa inhibitors, this study cannot provide insight into the additional benefit of clopidogrel on top of an aspirin and IIb/IIIa inhibitor.2,3 n

References

1. Yusuf S, et al. N Engl J Med. 2001;345:494-502.

2. Cannon CP, et al. N Engl J Med. 2001;344:1879-1887.

3. Steinhubl SR, et al. Circulation. 2001;103:1403-1409.

Dr. Wiese is Chief of Medicine, Charity, and University Hospitals, Associate Chairman of Medicine, Tulane Health Sciences Center, New Orleans, La.