Pharmacogenomics of anti-platelet therapy: how much evidence is enough for clinical implementation?

Abstract

Pharmacogenomics, the study of the genomics of drug response and adverse effects, holds great promise for more effective individualized (personalized) medicine. Recent evidence supports a role of loss-of-function (LOF) variants in the cytochrome P450 enzyme CYP2C19 as a determinant of clopidogrel response. Patients given clopidogrel after percutaneous coronary intervention who carry LOF variants do not metabolize clopidogrel, a prodrug, into its active form resulting in decreased inhibition of platelet function and a higher likelihood of recurrent cardiovascular events. Despite a large body of evidence supporting clinical utility, adoption of anti-platelet pharmacogenetics into clinical practice has been slow. In this review, we summarize the pharmacokinetic, pharmacodynamic and clinical evidence, identify gaps in knowledge and other barriers that appear to be slowing adoption, and describe CYP2C19 pharmacogenetics implementation projects currently underway. Only when we surmount these barriers will clinicians be able to use pharmacogenetic information in conjunction with the history, physical examination and other medical tests and information to choose the most efficacious anti-platelet therapy for each individual patient.

Figure 1

Summary of results from the Pharmacogenomics of Anti-platelet Intervention (PAPI) Study. Panel A. Distribution of ADP-stimulated platelet aggregation before (upper panel) and after (lower panel) 7-days of clopidogrel exposure in 420 PAPI Study participants. Panel B. Genome-wide association analysis of clopidogrel response in the PAPI Study (upper panel) revealing genome-wide significant associations in the region of the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster on chromosome 10 (lower panel). Panel C. Association of the loss of function CYP2C19*2 variant (rs4244285) with ADP-stimulated platelet aggregation post-clopidogrel (lower panel) but not pre-clopidogrel (upper panel) in PAPI Study participants. Figure adapted from Shuldiner