Review of the CURE Trial

Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevations

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

Background The established medical treatments for acute coronary syndrome reviewed so far include aspirin and thrombolytics along with a smaller role for short-term anticoagulation.

Angiotensin converting enzymes inhibitors and, to a lesser extent, beta blockers were also found to reduce recurrent ischemic events and death as well as heart failure and ventricular remodeling. The EPHESUS trial, which studied Eplerenone in this patient population was not published until several years later.

Despite the benefits of the above therapies, patients who experienced an ACS event were still at a substantially higher risk for experiencing recurrent events compared to patients who never experienced an ACS event. Significant interest remained in finding additional agents to reduce “residual risk” (i.e., the risk of recurrent events that is left over after initiating effective therapies).

Imagine a heart attack survivor has a 20% risk of experiencing death, non-fatal MI or heart failure over the next 5 years. Now imagine that all known effective therapies cumulatively reduce that risk by 30% (a 6% absolute reduction in risk); the residual risk for events over 5 years would still be 14%, which is still high, and significantly higher than patients who never experienced an ACS event (e.g., primary prevention patients).

Thienopyridine derivatives, including clopidogrel, are antiplatelet agents with a different mechanism of action than aspirin. Up to this point in time they demonstrated efficacy in patients who had received a coronary stent for reducing myocardial infarction compared to either aspirin alone or warfarin. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial sought to test the hypothesis that 3 to 12 months of clopidogrel plus aspirin versus aspirin alone would reduce the rate of cardiovascular events (a composite endpoint) compared to aspirin alone in patients with ACS and no ST-segment elevation.

Patients Patients were eligible if they had been hospitalized within 24 hours after the onset of symptoms, who had either ECG changes or an elevation in cardiac enzymes at entry, and did not have ST-segment elevation. Exclusion criteria included a contraindication to antithrombotic or antiplatelet therapy, high bleeding risk or severe heart failure, those who were taking oral anticoagulants, and those who had undergone coronary revascularization in the previous 3 months or had received intravenous glycoprotein IIb/IIIa receptor inhibitors in the previous 3 days.

Baseline characteristics No information in the main manuscript is provided on the ratio of patients eligible to those enrolled, which limits our ability to make inferences about external validity. The average age of participants was 64 years of age and nearly 40% were woman, which is historically higher than the trials reviewed up to this point. The average time from pain onset to randomization was 14 hours. The diagnoses at study entry were unstable angina in 75% and MI in 25%. Many patients in the trial has a history of MI (32%) or revascularization (18%) in the past and the majority were either current or former smokers (61%). Most patients (94%) had some ECG abnormality; the most common being ST depression (42%) and T-wave inversion (36%).

Procedures Immediately following randomization patients were administered a 300 mg loading dose of clopidogrel or matching placebo followed by 75 mg per day of clopidogrel or matching placebo for 3 to 12 months (the mean duration of treatment was 9 months). Aspirin was started or continued simultaneously with the study drug or placebo. Follow-up assessments occurred at discharge, at 1 and 3 months, and then every 3 months until the end of the study (12 months).

Endpoints The first primary endpoint was the composite of death from cardiovascular causes (death for which there was no clearly documented nonvascular cause), nonfatal MI (which required at least 2 of 3 findings: ischemic chest pain, elevation of cardiac markers or ECG changes consistent with MI) or stroke (new focal neurological deficit of vascular origin lasting >24 hr and was subdivided into intracranial hemorrhage, ischemia, or uncertain cause) at 12 months. The second primary endpoint was the composite of the first primary endpoint or refractory ischemia. Secondary outcomes included severe ischemia, heart failure, and the need for revascularization. Safety related outcomes included life-threatening, major bleeding (requiring transfusion of ≥2 units of blood) or all other bleeding.

The study was initially designed to include 9000 patients, with an anticipated primary event rate of 12-14% in the placebo group; however, because the event rate was lower than anticipated, the size of the study was increased as the trial was ongoing, with an adjusted rate of 10% in the placebo group. A final sample size of 12,500 patients was based on an anticipated 17% risk reduction for the primary composite endpoint with 90% power and a two-sided alpha level of 0.045.

Results 12,562 patients were included in the final analysis; 6,303 in the placebo group and 6,259 in the clopidogrel group. During the initial hospital stay, 21% of patients in the clopidogrel group and 23% of patients in the placebo group underwent revascularization.

At 1-year clopidogrel significantly reduced the occurrence of the first primary composite endpoint (RR 0.80; 9.3% vs 11.4%; 95% CI 0.72-0.90) and second primary composite endpoint (RR 0.86; 16.5% vs 18.8%; 95% CI 0.79-0.94). These differences were driven primarily by reducing nonfatal MI (RR 0.77; 5.2% vs 6.7%; 95% CI 0.0.67-0.89). There were no significant differences in death from cardiovascular or non-cardiovascular causes, stroke or refractory ischemia.

Compared to placebo, clopidogrel significantly increased major bleeding (RR 1.38; 3.7% vs 2.7%; 95% CI 1.13-1.67). However, there was no significant excess of major bleeding in patients undergoing CABG surgery (RR 1.48; 1.3% vs 1.1%; 95% CI 0.93-1.71). The median time for clopidogrel discontinuation before CABG surgery was 5 days.

Results from various subgroups are presented for the first primary composite endpoint and suggest the possibility of important treatment effect heterogeneity. Patients with a history of revascularization represented a minority of patients in the study (18%) and experienced higher rates of events but derived a significantly greater benefit from clopidogrel compared to those not previously revascularized (RR 0.58 vs 0.89).

Patients >65 years of age made up about half of study participants, and experienced event rates >2x higher than those ≤65 years of age, but derived less benefit from clopidogrel (RR 0.87 vs 0.71). The same was true based on risk tertiles. Patients at low and intermediate risk of experiencing events based on risk scores, experienced similar risk reductions from clopidogrel of 76% and 69% respectively; however, those at the highest risk received less benefit (RR 91%). Finally, women appeared to benefit less than men (RR 89% vs 76%).

Notably, there was no evidence of treatment effect heterogeneity based on whether patients underwent revascularization or not following randomization.

During the trial, clopidogrel was discontinued temporarily (≥5 days) in 46% of patients mainly due to the need for a surgical procedure. A total of 21% of patients discontinued clopidogrel permanently compared to 18% in the placebo group.

Conclusions In patients admitted to the hospital for unstable angina or NSTEMI, clopidogrel for 3-12 months plus aspirin, reduced the rate of a composite primary endpoint compared to aspirin alone and was associated with a number needed to treat of approximately 50 patients. This benefit was driven almost entirely by reducing nonfatal MI. Clopidogrel increased major bleeding with an NNH of approximately 100 patients.

In our opinion, the benefit conferred by clopidogrel in this patient population is modest and the external validity is uncertain as no information is provided on patients enrolled compared to those who were eligible/screened. Patients with prior histories of revascularization derived the greatest benefit; however, several higher risk subgroups including older patients (>65 years of age) and the third of patients who were at the highest risk of experiencing events derived significantly less benefit. Women, also derived less benefit. In the groups less likely to benefit, we would expect them to experience higher rates of adverse events as well and thus, it is possible they derive no net benefit from clopidogrel or could even experience net harm.

While thienopyridines have come to be considered a foundational treatment for ACS, evidence of their benefit from the CURE trial is modest at best; based mainly on reduction of a nonfatal endpoint.

The CURE trial results should be translated cautiously, especially for patients who are older, frail and more susceptible to adverse events.