Randomized, Placebo-Controlled Trial of Adding Clopidogrel to Aspirin in 46,000 Acute Myocardial Infarction Patients - COMMIT/CCS-2 – Clopidogrel

Description:

The goal of the trial was to evaluate treatment with clopidogrel compared with placebo among patients with ST elevation myocardial infarction (MI) also treated with aspirin.

Hypothesis:

Treatment with clopidogrel in addition to aspirin will be associated with a reduction in mortality compared with treatment with aspirin alone in patients with ST elevation MI.

Study Design

Study Design:

Patients Enrolled: 45,852
Mean Follow Up: Hospital discharge (or through four weeks if still hospitalized)
Female: 28

Patient Populations:

Suspected acute MI, presentation within 24 hours of symptom onset, and ST elevation or other ischemic ECG abnormalities with no clear indication for or contraindication to trial treatment

Exclusions:

Primary PCI, high risk of bleeding, shock, systolic blood pressure <100 mm Hg, heart rate <50 bpm, or II/III AV block

Primary Endpoints:

1) All-cause mortality by hospital discharge; and 2) all-cause mortality, nonfatal reinfarction, or stroke by hospital discharge

Drug/Procedures Used:

Patients were randomized to up to four weeks of treatment with clopidogrel (75 mg/day; n=22,961) or placebo (n=22,891). All patients were also given aspirin 162 mg/day. Patients were also randomized in a factorial design to treatment with metoprolol or placebo. The trial was conducted exclusively in China.

Principal Findings:

Baseline characteristics were well balanced between the treatment arms, with 67% presenting within 13 hours of symptom onset and 34% within six hours. Fibrinolytic therapy was used in 50% of patients and anticoagulants in 74%. Other concomitant medications included angiotensin-converting enzyme inhibitors (68%), nitrates (94%), antiarrhythmics (22%), diuretics (23%), and calcium antagonists (12%). MI or left bundle branch block was confirmed in 93% of patients.

The primary endpoint of all-cause mortality by hospital discharge was significantly lower in the clopidogrel group (7.5%, n=1,726 vs. 8.1%, n=1,845; p=0.03). Additionally, the co-primary composite endpoint of death, reinfarction, or stroke was lower in the clopidogrel group (9.2%, n=2,121 vs. 10.1%, n=2,310; p=0.002). Reinfarction was lower in the clopidogrel group (2.1% vs. 2.4%, p=0.02), but stroke did not differ by treatment group (0.9% vs 1.1%, p=NS). Any major bleed occurred in 0.58% of the clopidogrel group and 0.55% of the placebo group (p=NS).

Benefit of clopidogrel in primary composite endpoint was observed in all of the prespecified subgroups, including gender, age, time from symptom onset, and fibrinolytic use.

Interpretation:

Among patients with ST elevation MI, treatment with clopidogrel was associated with a reduction in mortality and in the composite of death, MI, or stroke compared with placebo.

In addition to the improvements associated with clopidogrel in ST elevation MI patients in the present trial, the CLARITY-TIMI 28 trial demonstrated a reduction in the composite of death, reinfarction, or TIMI flow grade 0/1 associated with clopidogrel compared with placebo, primarily driven by the reduction in infarct-artery occlusion. Prior clopidogrel studies such as CREDO and CURE have been conducted in patients with non-ST elevation acute coronary syndromes.

The present study, along with the CLARITY-TIMI 28 trial, are the first large-scale randomized trials to evaluate clopidogrel use in the setting of ST elevation MI. The COMMIT trial used a 75 mg/day dose with no loading dose, unlike CLARITY-TIMI 28, which treated patients with an initial 300 mg loading dose. Despite the lack of a loading dose in COMMIT, the endpoint curves began to diverge as early as day one.

While the findings of COMMIT demonstrate a clear advantage of clopidogrel plus aspirin over aspirin alone, it should be noted that patients in the study were treated with medical management strategy, with only 50% receiving fibrinolytic therapy and no patients undergoing primary percutaneous coronary intervention (PCI), an exclusion criteria. It is not known if similar results would be observed in patients treated with an early invasive strategy.

The risk of any major bleeding did not differ between the clopidogrel and placebo groups. However, minor bleeding was not reported, and it is unknown if the risk of bleeding would be higher had patients undergone revascularization.

References:

COMMITT Collaborative Group. Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607–21.

Presented by Dr. Zhengming Chen at the March 2005 ACC Annual Scientific Session, Orlando, FL.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Invasive Cardiovascular Angiography and Intervention, EP Basic Science, Interventions and ACS

Keywords: Thrombolytic Therapy, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Diuretics, Ticlopidine, Percutaneous Coronary Intervention, China, Nitrates, Bundle-Branch Block, Metoprolol, Hemorrhage


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