Transitioning genetic testing to tailoring patient care — pharmacogenomics — is evident in the recent example of CYP2C19, a drug-metabolizing enzyme that catalyzes the biotransformation of 5% to 10 % of drugs currently in clinical use. CYP2C19 has been shown to directly impact clopidogrel’s metabolism. The FDA’s black-box warning on clopidogrel’s package insert indicates it carries a significant risk of serious or life-threatening adverse effects, and informs doctors and patients of diminished response to the drug and increased risk of myocardial infarctions (MI) in patients with reduced CYP2C19 function.
Recent publications prove the importance of 2C19 genotyping in clopidogrel treatment. Mega, et al, concluded that subjects carrying at least one 2C19 reduced-function allele were at significantly higher risk (50% greater) for death from cardiovascular causes, MI, or stroke than non-carriers. The risk of stent thrombosis in carriers of a 2C19 reduced-function allele was three times that among non-carriers. More recently, a meta-analysis of 23 studies involving 9,685 patients showed, among those treated with clopidogrel, that carriage of even one reduced-function CYP2C19 allele shows a 30% increase in risk of death, MI, stroke, and particularly stent thrombosis. Pare, et al, concluded that among patients with acute coronary syndromes or atrial fibrillation, the effect of clopidogrel as compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status.
The GRAVITAS trial, the first multicenter placebo-controlled study to determine whether high-maintenance dose of clopidogrel therapy based on platelet-function testing would reduce ischemic events post-PCI, concluded there was no benefit on cardiovascular outcomes or stent thrombosis with a double dose of clopidogrel in patients receiving drug-eluting stents with high residual-platelet activity on the regular clopidogrel dose. (Genetic testing’s impact is being addressed by the GIFT Trial, a sub-study of GRAVITAS.) In light of this, Vanderbilt University launched a new genetic-screening program to prevent clopidogrel-therapy problems. As part of its PREDICT program, all its medical-center patients undergoing cardiac catheterization will be tested for CYP2C19 mutations. Routine commercially available FDA-approved tests include one that looks at CYP2C19 *2, *3 alleles and another CYP2C19 assay that detects 2C19 *2, *3, and *17 alleles.
Such testing is being reimbursed by Medicare and insurance companies that consider one genotyping for CYP2C19 polymorphisms medically necessary for persons who have been prescribed clopidogrel. Pharmacogenetic testing appears to be clearly beneficial and ready for prime time.
Anita Radhakrishnan, MD, is a cardiology fellow at Allegheny General Hospital in Pittsburgh, PA, and the two FDA-approved CYP2C19 tests she mentions are the Roche Amplichip and the AutoGenomics INFINITI, respectively.
