What is the role of genetic testing in determining responsiveness to Plavix (clopidogrel)?

From the Guidelines

Genetic testing for Plavix responsiveness is crucial in identifying patients who may not respond adequately to this antiplatelet medication, particularly those with CYP2C19 loss-of-function variants, and alternative medications like ticagrelor or prasugrel should be considered for these patients. The role of genetic testing in this context is supported by the most recent and highest quality study, which highlights the importance of testing for CYP2C19 gene variants in patients at high risk of poor outcomes from suboptimal antiplatelet therapy, such as those with acute coronary syndrome, history of stent thrombosis, or those undergoing percutaneous coronary intervention 1.

Key Points to Consider

• Approximately 30% of patients carry genetic variants that reduce their ability to convert clopidogrel to its active form, potentially leading to treatment failure and increased risk of cardiovascular events.
• CYP2C19 poor metabolizers (*2/*2, *2/*3, *3/*3) exhibit diminished platelet inhibition, enhanced platelet aggregation, and higher rates of coronary events when treated with clopidogrel after percutaneous intervention.
• A meta-analysis of 7 randomized controlled trials showed that ticagrelor and prasugrel compared with clopidogrel significantly reduced ischemic events in individuals who have CYP2C19 loss-of-function variants but not in individuals where no such variants have been identified 1.
• The US Food and Drug Administration approved labeling recommends avoiding the use of clopidogrel in patients with 2 no function alleles of the CYP2C19 gene.

Recommendations for Clinical Practice

• Genetic testing for CYP2C19 gene variants should be considered for patients at high risk of poor outcomes from suboptimal antiplatelet therapy.
• If testing reveals a patient is a poor metabolizer, alternative antiplatelet medications like ticagrelor or prasugrel should be considered.
• The standard dose of clopidogrel is 75mg daily after a loading dose of 300-600mg, but genetic poor metabolizers may not achieve adequate platelet inhibition even at these doses.
• Testing is typically done via blood sample or buccal swab, with results available within days to weeks depending on the laboratory.
• This personalized approach to antiplatelet therapy can significantly reduce the risk of recurrent cardiovascular events in genetically susceptible individuals, as supported by the technical standard of the American College of Medical Genetics and Genomics (ACMG) 1.

From the FDA Drug Label

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivoplatelet aggregation assays, differ according to CYP2C19 genotype Patients who are homozygous for nonfunctional alleles of the CYP2C19 gene are termed “CYP2C19 poor metabolizers.” Tests are available to identify patients who are CYP2C19 poor metabolizers.

The role of genetic testing for Plavix (clopidogrel) responsiveness is to identify patients who are CYP2C19 poor metabolizers, as they may have decreased active metabolite exposure and diminished inhibition of platelet aggregation.

• Genetic testing can help determine if a patient has a nonfunctional CYP2C19 allele, which can affect the efficacy of clopidogrel.
• CYP2C19 poor metabolizers may require alternative treatments or dose adjustments to ensure effective antiplatelet therapy.
• Genetic testing is available to identify patients who are at risk of reduced clopidogrel responsiveness due to their CYP2C19 genotype 2.

From the Research

Genetic Testing for Plavix Responsiveness

• Genetic testing can identify patients who may not respond adequately to Plavix (clopidogrel) due to genetic variations in the CYP2C19 isozyme 3, 4.
• Patients with certain genetic variants in CYP2C19 have been found to have lower levels of the active metabolite, less platelet inhibition, and greater risk of major adverse cardiovascular events such as heart attack, stroke, and death 4.
• The Food and Drug Administration has issued a boxed warning regarding the reduced efficacy of clopidogrel in patients with impaired CYP2C19 function, but specific recommendations on genetic testing and alternative therapeutic strategies are not currently available 3.

Role of Genetic Testing in Managing Clopidogrel Therapy

• Genetic testing may help identify patients who are at increased risk of adverse cardiovascular events due to impaired clopidogrel efficacy, and alternative treatments such as prasugrel or ticagrelor may be considered 5, 6.
• A meta-analysis found that patients with CYP2C19 loss-of-function alleles who were treated with prasugrel or ticagrelor had a significantly reduced risk of major adverse cardiovascular events compared to those treated with clopidogrel 6.
• However, the benefit of a management strategy that incorporates routine biomarker testing over standard of care without such testing remains unproven, and further studies are needed to determine the clinical utility of genetic testing in this context 5.

Limitations and Challenges

• There are many other factors that may contribute to the variability in antiplatelet effect seen with clopidogrel besides CYP2C19 genetic polymorphisms, and genetic testing is not a guarantee of optimal treatment outcomes 3, 7.
• The safety and efficacy of alternative treatments for patients with 'clopidogrel resistance' has not been demonstrated yet, and the routine use of platelet function measurements in the care of patients with cardiovascular disease cannot be recommended 7.
• Further studies are needed to determine the clinical utility of genetic testing and to develop personalized antiplatelet therapy strategies that take into account individual patient characteristics and genetic profiles 5, 6.