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Primary prevention of atherothrombotic events: an excess of mortality with dual-antiplatelet therapy

Results from the CHARISMA ( Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance ) trial showed an excess mortality in patients randomized to Clopidogrel ( Plavix ) and Acetylsalicylic acid ( Aspirin ) vs Acetylsalicylic acid alone in the prespecified asymptomatic subgroup.

Researchers have investigated whether dual-antiplatelet therapy may be associated with adverse cardiovascular ( CV ) events in a primary prevention population.

Of 15 603 patients enrolled, 3284 were initially categorized as asymptomatic with CV risk factors, but 995 had a prior cardiovascular event, leaving 2289 patients to represent the primary prevention cohort.
This subset was compared with 13 148 symptomatic patients with established vascular disease and both were evaluated for cardiovascular death and bleeding.

Compared with Acetylsalicylic acid alone, a significant increase in cardiovascular death ( P = 0.01 ) was observed in patients receiving dual-antiplatelet therapy in the asymptomatic population.

Within the primary prevention cohort, this excess cardiovascular death was not significant ( P = 0.07 ).

Multivariate analysis of the primary prevention group showed a trend towards excess cardiovascular death ( P = 0.054; HR 1.72 ) with dual-antiplatelet therapy ( Acetylsalicylic acid plus Clopidogrel ).

Other independent predictors of cardiovascular death included increasing age, hypertension, atrial fibrillation, and a history of heart failure.

There was a non-significant increase in moderate or severe bleeding ( P = 0.218 ) with dual-antiplatelet therapy; thus, bleeding was an unlikely explanation for the excess event rate.

These findings do not support the use of dual-antiplatelet therapy with Clopidogrel and Acetylsalicylic acid in a primary prevention population. In this subgroup analysis, cardiovascular death occurred more frequently than anticipated. The cause of this apparent harm is not elucidated.

Source: European Heart Journal, 2007