CYP2C19 Status Impact on Prasugrel vs. Clopidogrel Therapy

Study Questions:

What is the effect of CYP2C19 genotype on ischemic outcomes in patients with acute coronary syndrome (ACS) initially managed medically without revascularization who were randomized to either clopidogrel or prasugrel?

Methods:

A large genetic substudy within the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial was performed. The investigators classified patients as extensive metabolizers (EMs) or reduced metabolizers (RMs) based on CYP2C19 genotype, and evaluated ischemic outcomes and platelet reactivity. Among 9,326 patients enrolled from 2008 to 2011, 5,736 patients participated in the genetics cohort; of these, 2,236 had platelet function testing data. The relationship between CYP2C19 phenotype and clinical outcomes was assessed by fitting a Cox proportional hazards model for time to first event. To determine whether this relationship differed between treatment arms, an interaction term between CYP2C19 phenotype and treatment assignment was tested.

Results:

There was no association between CYP2C19 metabolizer status (EM vs. RM) and the primary composite endpoint of cardiovascular death, myocardial infarction (MI), or stroke (hazard ratio [HR], 0.86). EM and RM patients had similar rates of the primary endpoint whether treated with prasugrel (HR, 0.82) or clopidogrel (HR, 0.91; p for interaction = 0.495). After adjusting for clinical and treatment variables, EM patients had a lower risk of MI versus RM patients (HR, 0.80), but risks of other outcomes were similar. RM patients had significantly higher mean P2Y12 reaction units versus EM patients when treated with clopidogrel (39.93), but not with prasugrel (3.87).

Conclusions:

The authors concluded that CYP2C19 metabolizer status is not associated with the composite outcome of cardiovascular death, MI, or stroke in medically managed ACS patients treated with clopidogrel or prasugrel.

Perspective:

This study reports no significant association between CYP2C19 metabolizer status and the composite primary endpoint of cardiovascular death, MI, or stroke in medically managed ACS patients treated with clopidogrel or prasugrel. Clinical outcomes were similar for extensive metabolizers and reduced metabolizer patients whether treated with prasugrel or clopidogrel. These findings do not support the routine use of CYP2C19 genetic testing for selection of P2Y12 receptor inhibitor therapy for medically managed ACS patients.

Clinical Topics: Acute Coronary Syndromes

Keywords: Acute Coronary Syndrome, Blood Platelets, Genetic Testing, Genotype, Myocardial Infarction, Phenotype, Platelet Aggregation Inhibitors, Purinergic P2Y Receptor Antagonists, Stroke, Ticlopidine


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