Is the combination of clopidogrel and aspirin better than aspirin alone for patients with, or at high risk for, vascular disease?

The use of the combination of clopidogrel (Plavix) and aspirin should be limited to carefully defined groups of patients with acute coronary syndromes. It is not recommended for the broader group of patients with coronary disease, cerebrovascular disease, or multiple risk factors such as diabetes, hyperlipidemia, and hypertension. (LOE = 1b)

Bhatt DL, Fox KA, Hacke W, et al, for the CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-1717.  [PMID:16531616]

Randomized controlled trial (double-blinded)

Industry

Concealed

Outpatient (any)

The combination of aspirin and clopidogrel has been recommended for selected patients with acute coronary syndromes (ACS), such as those with non-ST elevation myocardial infarction (MI) or those with recurrent ACS. (Tran H, Anand SS. JAMA 2004;292:1867-74.) These investigators asked whether a broader group of patients would benefit from the combination. The authors enrolled patients 45 years or older who had documented coronary artery disease, cerebrovascular disease, or peripheral vascular disease, or if they had multiple risk factors for vascular disease. The most common risk factors in the latter group were diabetes (82%), hypertension (49%), hyperlipidemia (60%), or advanced age (51%). The patients' median age was 64 years and 30% were women. Participants were randomly assigned (allocation concealed) to either 75 mg clopidogrel plus 75 mg to 162 mg aspirin each given once daily or low-dose aspirin plus placebo. The primary outcome was a composite of MI, stroke, or death and was adjudicated by a panel blinded to treatment assignment. A total of 15,603 patients were enrolled and followed up for a median of 28 months. Analysis was by intention to treat. There was no difference between groups regarding the primary composite outcome and no difference for any of the individual elements (MI, stroke, or death). A predefined secondary composite end point added hospitalization for ischemic events, such as transient ischemic attack or revascularization, to the primary outcome. There was a very small benefit (16.7% vs 17.9%; P = .04; number needed to treat = 194 per year) of combination therapy for this secondary composite end point. However, there was also a trend toward more severe bleeding and a significant increase in moderate bleeding in the group given both clopidogrel and aspirin (2.1% vs 1.3%; P < .001; number needed to treat to harm = 291 per year). Severe bleeding was defined as intracranial hemorrhage, fatal bleeding, or bleeding that required significant clinical intervention, such as surgery, transfusion, or the use of intotropic agents.