The CURE trial: Clopidogrel in ACS without ST-elevation [Classics Series]

1. The addition of clopidogrel significantly reduced the risk of death from cardiovascular causes, nonfatal myocardial infarction, or other ischemic events in patients with ACS without ST elevation.

2. Adding clopidogrel is associated with significantly higher risk of major and minor bleeding, but not life-threatening bleeding.

Original Date of Publication: August 16, 2001

Study Rundown: Acute coronary syndrome (ACS) refers to symptoms that may be attributed to the occlusion of coronary arteries. Common symptoms include chest pain radiating to the jaw or arms, shortness of breath, sweating, and a pressure-like sensation on the chest, resulting from myocardial ischemia or infarction. ST-segment changes are often used to classify ACS, with ST-elevation suggesting a transmural infarct – these are often treated with immediate revascularization. Patients suffering ACS without ST-elevation often do not undergo urgent revascularization. Prior to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, therapy for ACS without ST-elevation consisted mainly of aspirin and heparin. The purpose of the CURE trial, published in 2001, was to explore whether the addition of clopidogrel, a thienopyridine class antiplatelet agent, could further reduce the risk of recurrent ischemic events in patients suffering from ACS without ST-elevation.

This study demonstrated the benefit of adding clopidogrel to aspirin and other medications for the treatment of patients with acute coronary syndromes without ST-segment elevation. Treatment with clopidogrel resulted in a significantly lower risk of death from cardiovascular causes, nonfatal myocardial infarction, or stroke compared to placebo (RR 0.80; 95%CI 0.72-0.90). Of note, the addition of clopidogrel resulted in significantly higher rates of major (RR 0.80; 95%CI 0.72-0.90) and minor bleeding complications, though not life-threatening bleeds. Based on the findings of this study, clopidogrel is widely used, in addition to aspirin, heparin, and other medications, in managing patients with ACS.

Click to read the study in NEJM

In-Depth [randomized, controlled study]: This randomized, controlled trial compared clopidogrel with placebo in addition to aspirin in patients presenting with acute coronary syndromes without ST-segment elevation. Patients were eligible for the trial if they were hospitalized within 24 hours of symptom onset and did not have ST-segment elevation. Patients with contraindications to antithrombotic or antiplatelet therapy, at high risk of bleeding or severe heart failure, taking oral anticoagulants, and those who had revascularization in the past three months or glycoprotein IIb/IIIa inhibitors in the past 3 days were excluded. The first primary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke. The second primary outcome was the composite of the first primary outcome with refractory ischemia. Severe ischemia, heart failure and need for revascularization were secondary outcomes and other outcomes were bleeding complications categorized as life-threatening, major, or minor.

A total of 12,562 patients from 482 centres in 28 countries were enrolled in the trial. Patients in the clopidogrel group experienced significantly lower rates of the first primary outcome, when compared with patients receiving placebo (RR 0.80; 95%CI 0.72-0.90). The rate of the second primary outcome was also significantly lower in patients treated with clopidogrel (RR 0.86; 95%CI 0.79-0.94). Significantly fewer patients in the clopidogrel group experienced severe ischemia (RR 0.74; 95%CI 0.61-0.90) or recurrent angina (RR 0.91; 95%CI 0.85-0.98). Major bleeding, defined as bleeding requiring transfusion of two or more units of blood, was significantly more common in the clopidogrel group (RR 1.38; 95%CI 1.13-1.67).

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