NUR 6410 Module 4 Pharmacogenomics Case: CYP2C19 and Clopidogrel After a Stent Example

A Drug His Liver Cannot Switch On: CYP2C19 Genotype, Clopidogrel and a Switch to Ticagrelor for a 58-Year-Old Filipino American Mechanic After a Stent

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Master of Science in Nursing, Thomas Edison State University

NUR-6410: Advanced Pharmacology

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Month Day, Year

A Drug His Liver Cannot Switch On: CYP2C19 Genotype, Clopidogrel and a Switch to Ticagrelor for a 58-Year-Old Filipino American Mechanic After a Stent

Introduction

Mr. B. is an invented patient, a 58-year-old Filipino American who repairs city buses in Jersey City. Three weeks ago chest pain stopped him under a bus; the diagnosis was unstable angina, and a coated stent now props open the main artery down the front of his heart. He was discharged on aspirin 81 milligrams and clopidogrel 75 milligrams daily, along with atorvastatin and metoprolol. His cardiology team ordered pharmacogenetic testing, and the report has reached his primary care nurse practitioner: he carries two no-function alleles of CYP2C19 and is classified as a poor metabolizer. This paper explains what that means for his clopidogrel and what should change.

A Prodrug That Needs Activation

Clopidogrel is a prodrug. Most of each dose is broken down by esterases into an inactive compound, and only a small fraction is converted by the liver, in two steps, into the active metabolite that binds the P2Y12 receptor on platelets and blocks them for the rest of their lifespan. CYP2C19 contributes to both steps. A person with no working CYP2C19 makes much less of the active metabolite, so the same 75-milligram dose leaves more of his platelets able to clump.

Mega et al. (2009) measured this in healthy volunteers and in patients from a large trial of acute coronary syndrome. People with even one weak copy of the gene made roughly a third less of the active compound, their platelets stayed stickier, and more of them died of heart disease or had a heart attack or stroke. The risk of stent thrombosis, the clot inside a new stent that can cause a sudden heart attack, was about three times higher. Mr. B. carries two such alleles, not one, so the effect in him is likely to be greater.

Ancestry and Allele Frequency

No-function CYP2C19 alleles are found in every population, but their frequency varies. The CPIC guideline (Lee et al., 2022) reports that they are considerably more common in people of East Asian and Oceanian ancestry than in people of European ancestry, so a larger share of patients from those groups are intermediate or poor metabolizers. Filipino Americans are a diverse group, and ancestry is a poor substitute for a test result. Mr. B.'s genotype answers the question for him directly. The population pattern matters mainly as a reason to test: in groups where poor metabolizers are common, a standard clopidogrel order fails more patients.

What the Guideline Recommends

The Clinical Pharmacogenetics Implementation Consortium publishes guidelines on how to act on a genotype that is already known. For patients with acute coronary syndrome or after a stent who are CYP2C19 poor metabolizers, Lee et al. (2022) recommend avoiding clopidogrel and using prasugrel or ticagrelor at standard doses if there is no contraindication. Both drugs are effective without CYP2C19. Prasugrel is also a prodrug, but its activation does not depend heavily on that enzyme, and ticagrelor is active as given.

Weighing the Evidence

Not every study has found a clear benefit to testing. Pereira et al. (2020), in the TAILOR-PCI trial, randomized more than 5,000 patients after a stent to genotype-guided therapy or standard clopidogrel. Among carriers of a weak allele, the group whose drug was chosen by genotype had fewer serious events over a year, yet the gap fell short of the trial's threshold for significance. Its authors and later readers pointed out that enrollment fell short of what a moderate benefit would need to show up clearly, and that the gap between groups looked widest in the first three months. The guideline's position reflects the whole body of evidence, including the mechanism and the cohort data, while recognizing this uncertainty. For a patient already known to be a poor metabolizer, continuing a drug his liver cannot activate is difficult to defend.

Choosing Between Prasugrel and Ticagrelor

Prasugrel is a poor fit for anyone who has had a stroke or a ministroke, and older or lighter patients (past 75, below 60 kilograms) get a smaller dose. Mr. B. has no history of stroke and weighs 82 kilograms, so prasugrel is possible. Ticagrelor is taken twice daily and can cause shortness of breath in some patients, usually mild. Because his cardiology team prefers ticagrelor for patients switched after a stent, and because twice-daily dosing fits his routine, ticagrelor is chosen. The switch is coordinated with cardiology, since dual antiplatelet therapy after a stent is their plan to manage.

Interactions and Safety

Aspirin doses above 100 milligrams a day reduce the benefit of ticagrelor, so his aspirin stays at 81 milligrams. Ticagrelor depends on CYP3A4 for clearance; clarithromycin or ketoconazole would pile it up in his blood, and rifampin would strip it away. His atorvastatin at a moderate dose is acceptable. Bleeding is the main risk of any potent antiplatelet drug, and he works with heavy equipment, so cuts and bruises need attention. Stopping the drug early, for cost, side effects or a dental procedure, is the most dangerous mistake, because stent thrombosis is most likely in the first months.

Teaching and Access

Mr. B. is taught to take ticagrelor morning and evening without missing doses, never to stop it without speaking to his cardiologist, to report black stools, blood in urine or prolonged bleeding, and to tell his dentist and any surgeon that he has a stent and takes two antiplatelet drugs. Mild breathlessness may occur and often fades, but he should report it rather than stopping the drug. Ticagrelor costs more than generic clopidogrel, so his insurance coverage is checked before he leaves the clinic, and a copay card or assistance program is arranged if needed. His genotype result goes into his permanent record, since it also affects other drugs metabolized by CYP2C19, including some antidepressants and proton pump inhibitors.

Conclusion

Mr. B. cannot activate clopidogrel, and the cohort data show what that means for patients after a stent. Following the 2022 CPIC guideline, and recognizing the uncertainty left by TAILOR-PCI, the plan replaces clopidogrel with ticagrelor, keeps aspirin at 81 milligrams and addresses interactions, bleeding, breathlessness and cost. His genotype will continue to guide his prescriptions for the rest of his life.

References

Lee, C. R., Luzum, J. A., Sangkuhl, K., Gammal, R. S., Sabatine, M. S., Stein, C. M., Kisor, D. F., Limdi, N. A., Lee, Y. M., Scott, S. A., Hulot, J.-S., Roden, D. M., Gaedigk, A., Caudle, K. E., Klein, T. E., Johnson, J. A., & Shuldiner, A. R. (2022). Clinical Pharmacogenetics Implementation Consortium guideline for CYP2C19 genotype and clopidogrel therapy: 2022 update. Clinical Pharmacology and Therapeutics, 112(5), 959-967. https://doi.org/10.1002/cpt.2526

Mega, J. L., Close, S. L., Wiviott, S. D., Shen, L., Hockett, R. D., Brandt, J. T., Walker, J. R., Antman, E. M., Macias, W., Braunwald, E., & Sabatine, M. S. (2009). Cytochrome P-450 polymorphisms and response to clopidogrel. New England Journal of Medicine, 360(4), 354-362. https://doi.org/10.1056/NEJMoa0809171

Pereira, N. L., Farkouh, M. E., So, D., Lennon, R., Geller, N., Mathew, V., Bell, M., Bae, J.-H., Jeong, M. H., Chavez, I., Gordon, P., Abbott, J. D., Cagin, C., Baudhuin, L., Fu, Y.-P., Goodman, S. G., Hasan, A., Iturriaga, E., Lerman, A., ... Rihal, C. S. (2020). Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: The TAILOR-PCI randomized clinical trial. JAMA, 324(8), 761-771. https://doi.org/10.1001/jama.2020.12443