In the case of clopidogrel pharmacogenomics, what went wrong? First, most initial studies that supported genetic testing were primarily based on analysis of surrogate markers, typically examining the association between CYP2C19 loss-of-function alleles and clopidogrel metabolites, platelet reactivity, or both. Over the last several decades, clinicians and researchers have learned painful lessons about the substitution of surrogate end points, such as relying on cholesterol or glucose levels as alternatives for clinically important cardiovascular events such as death, myocardial infarction, or stroke. Repeatedly, drugs that improve biochemical or physiological measures of disease have failed to favorably affect clinical outcomes. Examples include estrogen, rosiglitazone, torcetrapib, and nesiritide. Accordingly, when examining the pharmaco-genetic factors influencing the efficacy of a drug such as clopidogrel, the effects of CYP2C19 loss-of-function alleles on antiplatelet efficacy cannot be equated to increases in cardiovascular morbidity and mortality.
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