Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization, Management, and Avoidance - CHARISMA


The goal of the trial was to evaluate antiplatelet treatment with aspirin alone compared with aspirin plus clopidogrel among high-risk patients with stable cardiovascular (CV) disease.


Dual antiplatelet therapy with aspirin plus clopidogrel will be superior to aspirin monotherapy for high-risk primary prevention and secondary prevention among patients with stable CV disease.

Study Design

Patients Enrolled: 15,603
Mean Follow Up: Median 2.3 years
Mean Patient Age: Median 64.9 years
Female: 30

Patient Populations:

Two major, three minor, or one major and two minor of the following risk factors:

Major: Diabetes, diabetic nephropathy, ankle brachial index <0.9, asymptomatic carotid stenosis ≥70%, ≥1 carotid plaque as evidenced by intima-media thickness

Minor: Systolic blood pressure ≥150 mm Hg despite therapy for at least 3 months, primary hypercholesterolemia, current smoking >15 cigarettes per day, male ≥65 years, female ≥70 years


Chronic oral antithrombotic medications likely to interfere with efficacy assessment by decreasing trial sensitivity and to increase the risk of bleeding

Primary Endpoints:

Composite of CV death, MI, or stroke

Secondary Endpoints:

Composite of CV death, MI, stroke, or hospitalization for unstable angina, transient ischemic attack, or a revascularization procedure

Drug/Procedures Used:

Patients were randomized to either clopidogrel (n = 7,802; 75 mg daily) or placebo (n = 7,801), on top of background therapy with aspirin (75-162 mg once daily).

Principal Findings:

As planned, patients in the trial were high risk, with 78% symptomatic, including 37.4% with coronary disease, 27.7% with cerebrovascular disease, and 18.2% with symptomatic peripheral arterial disease. Diabetes was present in 42% of patients and 33.4% were obese.

There was no difference in the primary endpoint of CV death, myocardial infarction (MI), or stroke between the clopidogrel plus aspirin group (6.8%) and the placebo plus aspirin group (7.3%; relative risk [RR], 0.93; p = 0.22). The secondary endpoint of death, MI, stroke, or hospitalization for ischemic event was lower in the clopidogrel plus aspirin group (16.7% vs. 17.9%; RR, 0.92; p = 0.04). There was no difference in the individual endpoints of CV death (3.1% for clopidogrel vs. 2.9% for placebo, p = 0.68) or nonfatal MI (1.9% vs. 2.0%, p = 0.48), but stroke was lower in the clopidogrel group (1.9% vs. 2.4%, p = 0.05).

Among the prespecified subgroups, some benefit of clopidogrel was evident in the symptomatic cohort (i.e., documented CV disease at enrollment) for the primary endpoint (6.9% for clopidogrel vs. 7.9% for placebo; RR, 0.88; p = 0.046), but not in the asymptomatic cohort (6.6% for clopidogrel vs. 5.5% for placebo; RR, 1.20; p = 0.20; interaction p = 0.045). In the asymptomatic cohort, both all-cause mortality (5.4% vs. 3.8%, p = 0.04) and CV mortality (3.9% vs. 2.2%, p = 0.01) was significantly higher in the clopidogrel group.

Severe bleeding trended higher in the clopidogrel group (1.7% vs. 1.3%; RR, 1.25; p = 0.09), while moderate bleeding was significantly higher in the clopidogrel group (2.1% vs. 1.3%, p < 0.001). There was no difference in intracranial hemorrhage (0.3% each).


Among high-risk patients with stable CV disease, dual antiplatelet therapy with aspirin plus clopidogrel was not associated with a difference in the primary composite endpoint of CV death, MI, or stroke compared to aspirin monotherapy.

While there was no significant benefit in the primary endpoint, the secondary endpoint, which also included rehospitalization for ischemic events, was marginally reduced in the clopidogrel group. The subgroup of patients with documented CV disease showed some benefit with clopidogrel, while patients without CV disease had no benefit in the primary endpoint and actually had higher mortality with clopidogrel. These divergent findings suggest that dual antiplatelet therapy may not be beneficial in all patients at risk for CV disease, but that in patients with established CV disease, dual therapy may be effective in reducing subsequent events. Several other large trials, including CLARITY-TIMI 28 and COMMIT, have established the efficacy of dual antiplatelet therapy in acute coronary syndromes as well as in the setting of percutaneous coronary intervention.


Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-17.

Post-hoc analysis: Bhatt DL, Paré G, Eikelboom JW, et al., on behalf of the CHARISMA Investigators. The Relationship Between CYP2C19 Polymorphisms and Ischemic and Bleeding Outcomes in Stable Outpatients: The CHARISMA Genetics Study. Eur Heart J 2012;Mar 26:[Epub ahead of print].

Presented by Dr. Deepak L. Bhatt at the March 2006 ACC Annual Scientific Session, Atlanta, GA.

Keywords: Risk, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Carotid Intima-Media Thickness, Ankle Brachial Index, Coronary Disease, Peripheral Arterial Disease, Ticlopidine, Blood Pressure, Diabetic Nephropathies, Hypercholesterolemia, Smoking, Percutaneous Coronary Intervention, Intracranial Hemorrhages, Carotid Stenosis, Hospitalization

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