Cited by 472Antiplatelet Therapy and Cardiovascular DiseasesPharmacogenetics and Drug MetabolismCoronary Interventions and Diagnostics

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CYP2C19 Genotype, Clopidogrel Metabolism, Platelet Function, and Cardiovascular Events: A Systematic Review and Meta-analysis

Holmes, Michael V., Perel, Pablo, Shah, Tina, Hingorani, Aroon D., Casas, Juan P.·2011·JAMA

DOI 10.1001/jama.2011.1880

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Abstract

CONTEXT: The US Food and Drug Administration recently recommended that CYP2C19 genotyping be considered prior to prescribing clopidogrel, but the American Heart Association and American College of Cardiologists have argued evidence is insufficient to support CYP2C19 genotype testing. OBJECTIVE: To appraise evidence on the association of CYP2C19 genotype and clopidogrel response through systematic review and meta-analysis. DATA SOURCES: PubMed and EMBASE from their inception to October 2011. STUDY SELECTION: Studies that reported clopidogrel metabolism, platelet reactivity or clinically relevant outcomes (cardiovascular disease [CVD] events and bleeding), and information on CYP2C19 genotype were included. DATA EXTRACTION: We extracted information on study design, genotyping, and disease outcomes and investigated sources of bias. RESULTS: We retrieved 32 studies of 42,016 patients reporting 3545 CVD events, 579 stent thromboses, and 1413 bleeding events. Six studies were randomized trials ("effect-modification" design) and the remaining 26 reported individuals exposed to clopidogrel ("treatment-only" design). In treatment-only analysis, individuals with 1 or more CYP2C19 alleles associated with lower enzyme activity had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding (relative risk [RR], 0.84; 95% CI, 0.75-0.94; absolute risk reduction of 5-8 events per 1000 individuals), and higher risk of CVD events (RR, 1.18; 95% CI, 1.09-1.28; absolute risk increase of 8-12 events per 1000 individuals). However, there was evidence of small-study bias (Harbord test P = .001). When analyses were restricted to studies with 200 or more events, the point estimate was attenuated (RR, 0.97; 95% CI, 0.86-1.09). In effect-modification studies, CYP2C19 genotype was not associated with modification of the effect of clopidogrel on CVD end points or bleeding (P > .05 for interaction for both). Other limitations included selective outcome reporting and potential for genotype misclassification due to problems with the * allele nomenclature for cytochrome enzymes. CONCLUSION: Although there was an association between the CYP2C19 genotype and clopidogrel responsiveness, overall there was no significant association of genotype with cardiovascular events.

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Claas, S. A., Aslibekyan, S. W., & Arnett, D. K. (2015) · Springer eBooks · doi:10.1007/978-3-319-22357-5_13 · Cited by 2
“Subsequent research on clopidogrel pharmacogenetics called into question the value of genotype-guided dosing: one meta-analysis found associations between clopidogrel CYP2C19 lossof-function alleles and responsiveness to the drug but found no signifi cant association between genotype and cardiovascular events [ 34 ].”
Background
Pharmacogenomics of Clopidogrel
Giusti, B., Saracini, C., Galora, S., & Marcucci, R. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-386882-4.00025-6 · Cited by 2
Pharmacogenetics in Cardiovascular Diseases
Cavallari, L. H., & Momary, K. M. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-391918-2.00005-6 · Cited by 2
Impact of CYP2C19 gene polymorphisms on clinical outcomes in patients with myocardial infarction during 60 months of follow-up
Grazhdankin, I. O., Prokhorikhin, A. A., Baystrukov, V. I., Kretov, E. I., Chernyavskiy, A. М., & Лукинов, В. Л. (2023) · Patologiya krovoobrashcheniya i kardiokhirurgiya · doi:10.21688/1681-3472-2023-4-64-76 · Cited by 2
The role of laboratory monitoring in antiplatelet therapy.
Cattaneo, M. (2012) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-642-29423-5_19 · Cited by 2
Clinical Implementation of Genomic Medicine in Primary Care
Cho, A. H., & Orlando, L. A. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-382227-7.00025-2 · Cited by 2
CYP2C19 in ACS Patients
Sibbing, D., Groß, L., & Maßberg, S. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.01.002 · Cited by 2
“However, in interpreting the data, some issues and important aspects merit mentioning: In the context of published data (7,8) on genetics and outcomes of ACS patients, present results highlight and confirm the need for a separate assessment of the role of genotyping in invasively versus noninvasively managed patients.”
Result
A Propensity-Matched Nested Case-Control Study of Acute Coronary Syndrome Patients Genotyped for CYP2C19
Kilpatrick, K., James, N., Smith, K., Mackay, J., Shepherd, P., Boyle, L., Thurier, Q., Ayar, Z., & Gladding, P. A. (2018) · Heart Lung and Circulation · doi:10.1016/j.hlc.2018.05.116 · Cited by 1
Racial differences in P2Y12 inhibitor responsiveness in patients undergoing neuro-endovascular procedures: A cohort from the Middle East
Jebrin, R., Nekidy, W. S. E., Abidi, E., John, T. L. S., Kesav, P., Hussain, S. I., Abdelsalam, M., Khaled, L., Raj, D., & John, S. (2024) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2024.108167 · Cited by 1
The Genetic Blueprint of Cardiovascular Therapy: Pharmacogenomics for Improved Efficacy and Safety
Andhi, N., & Darawadi, B. (2024) · Journal of Indian College of Cardiology · doi:10.4103/jicc.jicc_14_24 · Cited by 1
Antiplatelet dilemma: Clopidogrel or aspirin for long-term cardiovascular protection after dual antiplatelet therapy following PCI
Moawad, M. H. E. D., Elsayed, M., Serag, I., Wagih, R. M., Elgharabawi, A., Ahmed, Y., Elkholy, A., Abdel-Raouf, A., Alsolami, A. M., AlAttar, A., et al. (2026) · Medicine · doi:10.1097/md.0000000000047773 · Cited by 1
“[46,47] Incorporating genotype-guided antiplatelet strategies has been shown to reduce adverse cardiovascular events in post-PCI patients, particularly among those with LOS alleles.”
Molecular profiling of coronary stent testenosis: A systematic review and functional analysis of implicated genes
Elmansouri, R., Habbal, R., & Dehbi, H. (2026) · Medicine · doi:10.1097/md.0000000000049455 · Cited by 1
Controversies in the use & implementation of drug-eluting stent technology.
Itagaki, B. K., & Brar, S. S. (2012) · Europe PMC (PubMed Central) · Cited by 1
Multiple comparisons of drug efficacy between subgroups defined by genetic polymorphisms
Tu, Y., & Hsu, J. C. (2012) · Statistics in Medicine · doi:10.1002/sim.5421 · Cited by 1
Long-term antiplatelet therapy
Chew, D. P., & Lee, L. (2012) · Current Opinion in Cardiology · doi:10.1097/hco.0b013e328353fe5c · Cited by 1
“com analysis included 42 016 patients from 32 studies, representing the largest meta-analysis of these data to date [19].”
Method
Pharmacotherapy for the reduction of stent thrombosis
Yang, D. C.-S., Swaminathan, R. V., Kim, L. K., & Feldman, D. N. (2013) · Expert Review of Cardiovascular Therapy · doi:10.1586/erc.13.34 · Cited by 1
Almanac 2013: stable coronary artery disease
Islam, S., & Timmis, A. (2013) · Heart · doi:10.1136/heartjnl-2013-304593 · Cited by 1
Predictive or not predictive: understanding the mixed messages from the patient's DNA sequence
Janssens, A. C. J. W., Patch, C., & Skirton, H. (2015) · Journal of Clinical Nursing · doi:10.1111/jocn.13079 · Cited by 1
Pharmacogenetic testing for CYP2C19 gene polymorphism for optimization of using antiplatelet therapy in patients with ischemic heart disease
Карпенко, О. О. (2016) · ScienceRise Medical Science · doi:10.15587/2519-4798.2016.76377 · Cited by 1
Pharmacogenomics of Antiplatelet Drugs
Cerletti, C., Izzi, B., Iacoviello, L., & de Gaetano, G. (2017) · Springer eBooks · doi:10.1007/978-3-319-47462-5_89 · Cited by 1
Platelets and Polymorphisms
Geisler, T., Schaeffeler, E., & Schwab, M. G. (2017) · Cardiac and vascular biology · doi:10.1007/978-3-319-66224-4_17 · Cited by 1
Acute stent thrombosis: Should preventative measures start in the emergency department?
Hassen, G. W., Talebi, S., Al-Haddad, B., Azhir, A., Jennings, C. A., Zavaro, D., & Kalantari, H. (2018) · The American Journal of Emergency Medicine · doi:10.1016/j.ajem.2018.05.006 · Cited by 1
“prodrug conversion in vivo, which results in impaired platelet inhibitors [8-11].”
Background
Effect of polymorphism of platelet receptors genes P2RY12, ITGB3 and CYP2C19 cytochrome metabolizer enzyme on the platelet activity and efficiency of clopidogrel in patients with stable stenocardia in the Grodno region
Pronko, T. P., Snezhitskiy, V. А., Gorchakova, O. V., Степуро, Т. Л., & Гладкий, М. Л. (2021) · Proceedings of the National Academy of Sciences of Belarus Medical series · doi:10.29235/1814-6023-2021-18-2-147-159 · Cited by 1
Farmacogenómica cardiovascular
Scibona, P., Angriman, F., Simonovich, V., Heller, M. M., & Belloso, W. H. (2014) · Archivos de cardiología de México · doi:10.1016/j.acmx.2013.11.003 · Cited by 1
Role of Cytochrome p450 in Clopidogrel Resistance in Indonesian Stroke Patients
Hidayat, R., Rasyid, A., Harris, S., Harahap, A. R., Herqutanto, H., Louisa, M., Listiyaningsih, E., Rambe, A. S., & Loho, T. (2023) · Open Access Macedonian Journal of Medical Sciences · doi:10.3889/oamjms.2023.11557 · Cited by 1
“Damage or loss of function (LOF) in CYP2C19 alleles *2 and *3 is closely correlated with the effectiveness of clopidogrel [9], [10], [11].”
Background
The Importance of Ethnicity Definitions and Pharmacogenomics in Ethnobridging
Mohamed, E. H. M., Huei-xin, L., Poh, J. W. W., Toh, D., & Lee, E. J. D. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-391918-2.00010-x · Cited by 1
Early definite stent thrombosis with everolimus‐eluting stents
Naito, R., Miyauchi, K., Konishi, H., Tsuboi, S., Okazaki, S., & Daida, H. (2015) · Clinical Case Reports · doi:10.1002/ccr3.364 · Cited by 1
“Although there are conflicting data regarding definite effects of CYP2C19 polymorphisms on the incidence of cardiovascular events [8, 9], a recent report demonstrated that residual platelet activity was associated with cardiovascular mortality [10], which supported the observed relationship between our case and the in…”
Result
Efficient and Selective Alkane Hydroxylation Reactions Catalyzed by the Fungal Peroxygenase AaeAPO
Wang, X. (2015) · Springer theses · doi:10.1007/978-3-319-03236-8_2 · Cited by 1
A Knowledge-based System for Intelligent Support in Pharmacogenomics Evidence Assessment: Ontology-driven Evidence Representation and Retrieval.
Lee, C.-J., Devine, B., & Tarczy-Hornoch, P. Z. (2017) · PubMed Central · Cited by 1
Acute Coronary Syndromes
Eikelboom, J. W., & Weitz, J. I. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-35762-3.00146-3 · Cited by 1
CYP2C19 genotype-directed P2Y12 inhibitor antiplatelet therapy normalizes risk for major adverse cardiovascular events after percutaneous coronary intervention
Stys, T. P., Gedela, M., Gowda, S. N., Bares, V., Fanta, L. E., Petrasko, M. S., Hajek, C. A., Larson, E. A., & Stys, A. T. (2021) · Indian Heart Journal · doi:10.1016/j.ihj.2021.03.004 · Cited by 1
Impact of CYP2C19 gene polymorphisms on clinical outcomes in patients with myocardial infarction during 12-month follow-up
Grazhdankin, I. O., Baystrukov, V. I., Kretov, E. I., Prokhorikhin, A. A., & Chernyavsky, A. M. (2022) · Complex Issues of Cardiovascular Diseases · doi:10.17802/2306-1278-2022-11-3-17-28 · Cited by 1
ADVANCES IN PERSONALIZED MEDICINE
Ho, R. J. Y., & Gibaldi, M. (2013) · doi:10.1002/9781118660485.ch17 · Cited by 1
Publishing Genomic Studies: Walking the Fine Line
Feldman, A. M. (2012) · Clinical and Translational Science · doi:10.1111/j.1752-8062.2012.00395.x · Cited by 1
Farmakokinetyka kliniczna klopidogrelu i jego metabolitów z uwzględnieniem polimorfizmu genetycznego izoenzymu CYP2C19 i glikoproteiny P
Danielak, D. (2014)
Stable coronary artery disease
Henderson, R. A., & Timmis, A. (2011) · REMERI - Red Mexicana de Repositorios Institucionales
Genetic Considerations of Antiplatelet Therapy
Rollini, F., Tello-Montoliu, A., & Angiolillo, D. (2014) · doi:10.1002/9781118504499.ch6
Coordinated Regulation Of Hepatic And Renal Membrane Transporters In Experimental Nonalcoholic Steatohepatitis
Jimenez-Canet, M. (2014) · UA Campus Repository (The University of Arizona)

Authors: Holmes, M. V., Perel, P., Shah, T., Hingorani, A. D., & Casas, J. P.
Affiliations: University College London (GB)
Northwestern University (US)
ORCID: Holmes, Michael V.
Perel, Pablo
Shah, Tina
Hingorani, Aroon D.
Casas, Juan P.
Venue: JAMA
Publisher: American Medical Association (AMA)
Published: 2011-12-28
Volume: 306
Issue: 24
Pages: 2704
ISSN: 0002-9955 (ISSN-L)
0098-7484
DOI: 10.1001/jama.2011.1880
OpenAlex: W2119186881
Cited by: 472
References: 70
Citations by year: 2026: 10 · 2025: 10 · 2024: 7 · 2023: 13 · 2022: 18 · 2021: 22 · 2020: 19 · 2019: 27 · 2018: 23 · 2017: 25 · 2016: 36 · 2015: 46 · 2014: 53 · 2013: 89 · 2012: 70
FWCI: 47.48
Type: journal article
Language: en
Open access: closed
Locations: JAMA (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute for Health and Care Research (RP-PG-0407-10314)
British Heart Foundation (FS05/125)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Coronary Interventions and Diagnostics
Keywords: CYP2C19 genotype, clopidogrel, clopidogrel response, platelet function, platelet aggregation inhibition, cardiovascular events, bleeding risk, stent thrombosis, genotype testing, pharmacogenetics, small-study bias, effect modification, clopidogrel resistance, clopidogrel hypersensitivity, clopidogrel metabolite
MeSH terms: Clopidogrel, Aryl Hydrocarbon Hydroxylases, Cardiovascular Diseases, Genotype, Hemorrhage, Humans, Platelet Aggregation, Platelet Aggregation Inhibitors, Platelet Function Tests, Risk, Thrombosis, Ticlopidine, Angioplasty, Balloon, Coronary, Randomized Controlled Trials as Topic, Cytochrome P-450 CYP2C19

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CYP2C19 Genotype, Clopidogrel Metabolism, Platelet Function, and Cardiovascular Events: A Systematic Review and Meta-analysis

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