Clopidogrel as Adjunctive Reperfusion Therapy - CLARITY-TIMI 28

Description:

The goal of the trial was to evaluate treatment with clopidogrel compared with placebo among patients with ST elevation myocardial infarction (MI) treated with an initial medical management strategy.

Hypothesis:

Treatment with clopidogrel will be associated with a reduction in failure to reperfuse/reocclusion in patients with ST elevation MI treated with an initial medical management strategy.

Study Design

Study Design:

Patients Enrolled: 3,491
Mean Follow Up: 30 days
Mean Patient Age: Mean age 57 years
Female: 20

Patient Populations:

Age 18-75 years; ischemic discomfort within 12 hours and lasting at least 20 minutes; ST-segment elevation of ≥0.1 mV in ≥2 contiguous leads or new left bundle branch block; and scheduled to receive a fibrinolytic agent, an anticoagulant, and aspirin.

Exclusions:

Treatment with clopidogrel in prior seven days or planned treatment with clopidogrel or a glycoprotein IIb/IIIa inhibitor before angiography; contraindications to fibrinolytic therapy; plan to perform angiography within 48 hours in the absence of a new clinical indication; cardiogenic shock; prior coronary artery bypass grafting; and a weight of ≤67 kg and receipt of more than a 4000-U bolus of unfractionated heparin, a weight of ≥67 kg and receipt of more than a 5000-U bolus of unfractionated heparin, or receipt of more than a standard dose of low molecular weight heparin

Primary Endpoints:

Efficacy: Composite of death or recurrent MI by start of angiography or an occluded infarct-related artery (TIMI flow grade 0/1) on angiography

Safety: TIMI major bleeding

Drug/Procedures Used:

Patients were randomized to clopidogrel (300 mg load, 75 mg/day; n=1,752) or placebo (n=1,739). Choice of fibrinolytic agent and anticoagulant were at the discretion of the treating physician. Patients underwent angiography 48-192 hours after the start of study medication.

Concomitant Medications:

Aspirin

Principal Findings:

Baseline characteristics were well balanced between the treatment arms, with time from symptom onset to fibrinolytic of 2.7 hours and 69% treated with a fibrin-specific lytic. Low molecular weight heparin was used in 30% of patients and unfractionated heparin in 46%. Median time to angiography was 94 hours in each group.

The primary composite endpoint was significantly lower in the clopidogrel group (15.0% vs. 21.7%, odds ratio [OR] 0.64, p<0.001), driven primarily by a reduction in infarct-artery occlusion (11.7% vs. 18.4%, OR 0.59, p<0.001). Recurrent MI by time of angiography trended lower in the clopidogrel group (2.5% vs. 3.6%, OR 0.70, p=0.08) and there was no difference in mortality by time of angiography (2.6% vs. 2.2%, OR 1.17, p=0.49). TIMI myocardial perfusion grade 3 was present more often in the clopidogrel group (55.8% vs. 51.2%, OR 1.21, p=0.008), as was TIMI flow grade 3 (67.8% vs. 60.8%, OR 1.36, p<0.001). Mean percent ST-segment resolution at 180 minutes did not differ in the clopidogrel group compared with placebo (59% vs. 61%, p=0.22).

At 30 days, cardiovascular death, MI, or recurrent ischemia leading to urgent revascularization by 30 days was lower in the clopidogrel group (11.6% vs. 14.1%, p=0.03). Among the individual 30-day endpoints, recurrent MI (4.1% vs. 5.9%, p=0.02), recurrent ischemia leading to revascularization (3.5% vs. 4.5%, p=0.11), and stroke (0.9% vs. 1.7%, p=0.052) were lower in the clopidogrel group, but there was no difference in cardiovascular mortality (4.4% vs. 4.5%).

TIMI major bleed through the day after angiography occurred in 1.3% of the clopidogrel group and 1.1% of the placebo group (p=0.64), while minor bleed occurred in 1.0% and 0.5%, respectively (p=0.17). Among the 136 patients who underwent coronary artery bypass surgery, the bleeding rate did not significantly differ (7.5% for clopidogrel and 7.2% for placebo, p=1.0). Among patients who underwent surgery within five days, the rates were 9.1% and 7.9%, respectively.

Interpretation:

Among patients with ST-elevation MI treated with an early medical management strategy, use of clopidogrel was associated with a reduction in the primary composite endpoint compared with placebo, driven by the reduction in infarct-artery occlusion.

In addition to the improvements associated with clopidogrel in ST elevation MI patients in the present trial, the much larger COMMIT trial demonstrated a reduction in all-cause mortality associated with clopidogrel compared with placebo. 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 COMMIT trial, are the first large-scale randomized trials to evaluate clopidogrel use in the setting of ST elevation MI.

While the findings of CLARITY demonstrate a clear advantage of clopidogrel plus aspirin over aspirin alone, it should be noted that patients in the study were treated with an early medical management strategy and did not undergo coronary angiography for a median of 3.5 days. It is not known if similar results would be observed in patients treated with an early invasive strategy.

The risk of TIMI major bleeding did not differ between the clopidogrel and placebo groups, even among the 136 patients who underwent coronary bypass surgery. However, the overall number of patients is small and further evaluation is warranted.

References:

Sabatine MS, Cannon CP, Gibson CM, et al. Addition of Clopidogrel to Aspirin and Fibrinolytic Therapy for Myocardial Infarction with ST-Segment Elevation. N Engl J Med 2005 Mar 9; [Epub ahead of print].

Presented by Dr. Marc S. Sabatine at the March 2005 ACC Annual Scientific Session, Orlando, FL.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Anticoagulation Management and ACS, EP Basic Science, Cardiac Surgery and Arrhythmias, Interventions and ACS, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Thrombolytic Therapy, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Heparin, Low-Molecular-Weight, Heparin, Ticlopidine, Fibrinolytic Agents, Coronary Angiography, Bundle-Branch Block, Coronary Artery Bypass


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