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CYP2C19 Genotype, Clopidogrel Metabolism, Platelet Function, and Cardiovascular Events: A Systematic Review and Meta-analysis
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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“Women and minorities have historically been under investigated and under-represented in clinical research 153 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [153]
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“However, another meta-analysis suggests that CYP2C19 may not be clinically relevant for all clopidogrel-treated patients [24], underscoring the importance of indication (i.”
CYP2D6 Genotype and Tamoxifen Response for Breast Cancer: A Systematic Review and Meta-Analysis
Lum, D. W. K., Perel, P., Hingorani, A. D., & Holmes, M. V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076648 · Cited by 50
“Statistical analysis The analysis was split into two main types depending on the design [16]: the treatment-only meta-analysis was limited to studies of individuals all receiving tamoxifen, and the effectmodification analysis was based on an evaluation of heterogeneity in the tamoxifen treatment effect size in groups…”
MethodSelf-citationStroke genetics: prospects for personalized medicine
Markus, H. S. (2012) · BMC Medicine · doi:10.1186/1741-7015-10-113 · Cited by 49
“A recent systematic review and meta-analysis identified 32 studies of 42,016 patients reporting 3,545 cardiovascular events and 1,413 bleeding events [53].”
BackgroundNiu, X., Mao, L., Huang, Y. J., Baral, S., Li, J., Gao, Y., Xia, Y., He, Q., Wang, M., Li, M., et al. (2015) · Journal of Huazhong University of Science and Technology [Medical Sciences] · doi:10.1007/s11596-015-1404-7 · Cited by 48
Musunuru, K., Hickey, K. T., Al‐Khatib, S. M., Delles, C., Fornage, M., Fox, C. S., Frazier, L. Q., Gelb, B. D., Herrington, D. M., Lanfear, D. E., et al. (2015) · Circulation Cardiovascular Genetics · doi:10.1161/hcg.0000000000000020 · Cited by 50
Genetic and non-genetic factors affecting the response to clopidogrel therapy
Karaźniewicz‐Łada, M., Danielak, D., & Główka, F. K. (2012) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2012.666524 · Cited by 47
“It is supported by recent metaanalyses, confirming that CYP2C19 LoF alleles cannot be credited as an independent factor influencing failure of CLP treatment [57,58].”
BackgroundResultSardella, G., Calcagno, S., Mancone, M., Palmirotta, R., Lucisano, L., Canali, E., Stio, R. E., Pennacchi, M., Roma, A. D., Benedetti, G., et al. (2012) · Circulation Cardiovascular Interventions · doi:10.1161/circinterventions.112.972463 · Cited by 47
Limdi, N. A., Cavallari, L. H., Lee, C. R., Hillegass, W. B., Holmes, A. M., Skaar, T. C., Pisu, M., Dillon, C., Beitelshees, A. L., Empey, P. E., et al. (2020) · The Pharmacogenomics Journal · doi:10.1038/s41397-020-0162-5 · Cited by 50
Personalised medicine: not just in our genes
Kitsios, G. D., & Kent, D. M. (2012) · BMJ · doi:10.1136/bmj.e2161 · Cited by 45
Osnabrugge, R. L. J., Head, S. J., Zijlstra, F., ten Berg, J. M., Hunink, M. G. M., Kappetein, A. P., & Janssens, A. C. J. W. (2014) · Genetics in Medicine · doi:10.1038/gim.2014.76 · Cited by 46
Wang, Y., Yan, B. P. Y., Liew, D., & Lee, V. W. Y. (2017) · The Pharmacogenomics Journal · doi:10.1038/tpj.2016.94 · Cited by 46
Lim, S. T., Coughlan, C. A., Murphy, S. J. X., Fernández‐Cadenas, I., Montaner, J., Thijs, V., Marquardt, L., & McCabe, D. J. H. (2015) · Platelets · doi:10.3109/09537104.2015.1049139 · Cited by 43
“Furthermore, when the overall metaanalysis was restricted to studies containing 4200 patients, the association with CYP2C19 polymorphisms and outcome events was not significant [90].”
Zhang, L., Yang, J., Zhu, X., Wang, X., Peng, L. H., Li, X., Cheng, P., & Yin, T. (2014) · Thrombosis Research · doi:10.1016/j.thromres.2014.12.007 · Cited by 44
“In the present meta-analysis, the association between CYP2C19*2 genotype and OTPR in the high-dose clopidogrel treated patients could still be found, which is similar to the previously reported metaanalysis in regular clopidogrel treated patients [7].”
ResultThe Metabolism of Clopidogrel: CYP2C19 Is a Minor Pathway
Ford, N. F. (2016) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.769 · Cited by 46
Lewis, J. P., Voora, D., & Beitelshees, A. L. (2015) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s52900 · Cited by 44
“However, others contest that the patients used in the analysis by Holmes et al, particularly those in the larger studies, in which no effect of CYP2C19*2 genotype was observed, were those who receive little-to-no benefit from clopidogrel therapy.”
Pharmacogenetics of Antiplatelet Therapy
Castrichini, M., Luzum, J. A., & Pereira, N. L. (2022) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-051921-092701 · Cited by 47
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Analysis of CYP2C19 Genetic Polymorphism in a Large Ethnic Hakka Population in Southern China
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Pharmacogenomics and pharmacogenetics for the intensive care unit: a narrative review
MacKenzie, M., & Hall, R. (2016) · Canadian Journal of Anesthesia/Journal canadien d anesthésie · doi:10.1007/s12630-016-0748-1 · Cited by 44
Pharmacogenomics and Clopidogrel
Nissen, S. E. (2011) · JAMA · doi:10.1001/jama.2011.1865 · Cited by 42
Genotype-based clinical trials in cardiovascular disease
Pereira, N. L., Sargent, D. J., Farkouh, M. E., & Rihal, C. S. (2015) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2015.64 · Cited by 43
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Wiśniewski, A., & Filipska, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176408 · Cited by 41
Data collection as a barrier to personalized medicine
Zakim, D., & Schwab, M. G. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.11.002 · Cited by 38
Expanding Role of Pharmacogenomics in the Management of Cardiovascular Disorders
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Lee, J. A., Lee, C. R., Reed, B. N., Plitt, D. C., Polasek, M. J., Howell, L. A., Cicci, J. D., Tasca, K. E., Weck, K. E., Rossi, J. S., et al. (2015) · Pharmacogenomics · doi:10.2217/pgs.14.180 · Cited by 39
Impact of CYP2C19 Metabolizer Status on Patients With ACS Treated With Prasugrel Versus Clopidogrel
Doll, J. A., Neely, M. L., Roe, M. T., Armstrong, P. W., White, H. D., Prabhakaran, D., Winters, K. J., Duvvuru, S., Sundseth, S. S., Jakubowski, J. A., et al. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.12.036 · Cited by 39
“Manuscript received July 30, 2015; revised manuscript received December 2 consideration of small-study bias (7).”
BackgroundImpact of an Interaction Between Clopidogrel and Selective Serotonin Reuptake Inhibitors
Bykov, K., Schneeweiß, S., Donneyong, M. M., Dong, Y., Choudhry, N. K., & Gagne, J. J. (2016) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2016.10.052 · Cited by 39
“Although this finding requires further investigation, recent studies reported a much higher increased risk of stent thrombosis than other cardiovascular events, including MI, among subjects carrying a CYP2C19 reduced function allele.(23,24) Given that the exposure groups were well balanced on cardiovascular risk facto…”
ResultGuided Antithrombotic Therapy: Current Status and Future Research Direction
Fuster, V., Bhatt, D. L., Califf, R. M., Michelson, A. D., Sabatine, M. S., Angiolillo, D. J., Bates, E., Cohen, D. J., Coller, B. S., Furie, B., et al. (2012) · Circulation · doi:10.1161/circulationaha.112.105908 · Cited by 38
Metadata
- Authors
- Holmes, M. V., Perel, P., Shah, T., Hingorani, A. D., & Casas, J. P.
- Affiliations
- University College London (GB)
- Northwestern University (US)
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2011-12-28
- Volume
- 306
- Issue
- 24
- Pages
- 2704
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- 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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