Pharmacogenomics of Clopidogrel: Clinical Implications

Deepak Voora, MD

Authors and Disclosures

Posted: 11/07/2011

Background

Clopidogrel, a second-generation thienopyridine, is used to inhibit platelet aggregation in patients with acute coronary syndromes (ACS) and in patients with recent myocardial infarction, recent stroke, or established peripheral arterial disease.
The current state of evidence reflects a strong and consistent association between the presence of a CYP2C19*2 allele and an increased risk for adverse cardiovascular outcomes such as myocardial infarction, stent thrombosis, and stroke in patients who are treated with clopidogrel in the setting of ACS and/or after percutaneous coronary intervention (PCI), although not in other settings.^[1-3] Individuals who carry the CYP2C19*2 allele, which results in loss of activity of the CYP2C19 enzyme, produce reduced levels of clopidogrel's active metabolite and experience reduced clopidogrel-induced platelet inhibition. It is estimated that at least 1 copy of the CYP2C19*2 allele is present in 25% of whites, 30% of blacks, and 40%-50% of Asians.^[2]

When Should Genetic Testing Be Considered?

CYP2C19 genotyping is commercially available, but whether genotype-guided therapy might improve outcomes remains unknown.
Consensus statements currently do not recommend routine testing.^[4] Nevertheless, there is sufficient evidence to support a physician’s decision to consider CYP2C19*2 testing on a selected basis in the following clinical scenarios:

• Patients who demonstrate complications of clopidogrel therapy, such as stent thrombosis, despite drug compliance;
• Selection of dual antiplatelet therapy in the ACS/PCI setting if the physician believes that additional information regarding the risk:benefit profile for clopidogrel will influence the choice of drug therapy.

Outside of these scenarios, in settings other than ACS/PCI, or in situations where there is already ample data to guide drug choice (eg, in patients with ST-elevation myocardial infarction,^[5] diabetes,^[6] age > 75 years, or prior stroke/transient ischemic attack), there is minimal rationale for the support of CYP2C19*2 testing.
On the basis of the available data, it is reasonable to conclude that if an individual is found to be a carrier of 2 CYP2C19*2 alleles and is considered a poor metabolizer of clopidogrel, an alternative to clopidogrel, such as the third-generation thienopyridine prasugrel or the nonthienopyridine ticagrelor, could be considered. This approach seems preferable to the use of increased clopidogrel doses, which has not shown benefit over standard-dose clopidogrel.^[7-9]
However, the therapeutic approach for patients with 1 loss-of-function allele who are considered to be intermediate metabolizers of clopidogrel is still unclear. In these patients, the integration of clinical risk factors such as diabetes, body mass index, and bleeding and thrombosis risk factors would need to be considered as well when determining the therapy with the optimal risk:benefit profile.

Pharmacogenomics of Clopidogrel: Clinical Implications