CHARISMA

• CHARISMA (Clopidogrel for High Athero-thrombotic Risk and Ischemic Stabilization, Management, and Avoidance) study found that, in a broad population of patients at high risk of cardiovascular (CV) events, clopidogrel plus aspirin was no more effective than aspirin alone in preventing major CV events
  • a double-blind, randomised, placebo-controlled trial of 15,603 patients (median age 64, 30% women) with either clinically evident (78%), or multiple risk factors for, CV disease. Patients received low-dose aspirin (75 to 162mg daily) or low-dose aspirin plus clopidogrel (75mg daily) and were followed-up for a median of 28 months
  • the use of clopidogrel was associated with an increased the risk of moderate bleeding
    • no significant difference in severe bleeding between the groups (1.7% clopidogrel plus aspirin vs. 1.3% aspirin, P=0.09), the risk of moderate bleeding was significantly higher in the clopidogrel plus aspirin group (2.1% vs. 1.3%, P<0.001, number needed to harm [NNH] 125)
  • proportion of patients who suffered a primary outcome event (myocardial infarction [MI], stroke, or death from CV causes) was similar in both groups (clopidogrel plus aspirin 6.8% vs. aspirin 7.3%, P=0.22)
    • clopidogrel was associated with a small reduction in primary outcomes in patients who had existing CV disease (6.9% vs. 7.9%, P=0.046, number needed to treat 100). However, in asymptomatic patients it increased the risk of death from CV causes (3.9% vs. 2.2%, P=0.01, NNH 59) and from any cause (5.4% vs. 3.8%, P=0.04, NNH 63)
    • it has been stated that these subgroup analyses should only be regarded as a basis for future research and not as a reason to change practice
  • the study authors concluded (1) "...there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes.."
  • a MeReC Extra review states that "...Clopidogrel plus aspirin has shown benefit in the acute treatment of patients following an MI. However, the CHARISMA study does not support the general use of clopidogrel plus aspirin for subsequent prevention of CV events, or for primary prevention in high-risk patients.."
  • a further analysis of the CHARISMA data revealed (4):
    • findings do not support the use of dual-antiplatelet therapy with clopidogrel and aspirin in a primary prevention population. In this subgroup analysis, CV death occurred more frequently than anticipated
      • cause of this apparent harm is not elucidated, may represent play of chance, but requires further prospective evaluation

Reference:

• (1) Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. New Engl J Med 2006;354:1706?17
• (2) Pfeffer MA, Jarcho JA. The charisma of subgroups and the subgroups of CHARISMA. Editorial. New Engl J Med 2006;354:1744?6
• (3) MeReC Extra (May 2006);22.
• (4) Wang TH et al. An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial.Eur Heart J. 2007 Sep;28(18):2200-7.