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.
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From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [153]
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Genomic Medicine: A Decade of Successes, Challenges, and Opportunities
McCarthy, J. J., McLeod, H. L., & Ginsburg, G. S. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005785 · Cited by 242 · see citing works
“Such is the case with the antiplatelet drug clopidogrel, where despite having an FDA “black box warning” for efficacy in individuals carrying the CYP2C19 genetic variant, there is no clear consensus among physicians on its use (69).”
BackgroundPereira, N. L., Rihal, C. S., So, D. Y. F., Rosenberg, Y., Lennon, R. J., Mathew, V., Goodman, S. G., Weinshilboum, R. M., Wang, L., Baudhuin, L. M., et al. (2019) · Circulation Cardiovascular Interventions · doi:10.1161/circinterventions.119.007811 · Cited by 228 · see citing works
Drug Resistance and Pseudoresistance
Großer, T., Fries, S., Lawson, J. A., Kapoor, S. C., Grant, G. R., & FitzGerald, G. A. (2012) · Circulation · doi:10.1161/circulationaha.112.117283 · Cited by 208 · see citing works
“The term aspirin resistance is often used to imply treatment failure, although clinical outcomes have rarely been assessed—not unlike studies of the pharmacogenomics of clopidogrel.(38) More commonly, a patient is classified as resistant to aspirin, if platelet aggregation, measured on a single occasion, is not depres…”
Holmes, M. V., Richardson, T. G., Ference, B. A., Davies, N. M., & Davey Smith, G. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-020-00493-1 · Cited by 184 · see citing works
Self-citationMagnesium and the Risk of Cardiovascular Events: A Meta-Analysis of Prospective Cohort Studies
Qu, X., Jin, F., Hao, Y., Li, H., Tang, T., Wang, H., Yan, W., & Dai, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057720 · Cited by 184 · see citing works
“Our main outcome was the association with total CVD events, comprising stroke, coronary heart disease (CHD), and CVD death [37,38,40].”
BackgroundCascorbi, I. (2012) · Deutsches Ärzteblatt international · doi:10.3238/arztebl.2012.0546 · Cited by 184 · see citing works
Understanding and preventing drug–drug and drug–gene interactions
Tannenbaum, C., & Sheehan, N. L. (2014) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2014.910111 · Cited by 165 · see citing works
“For instance, the risk of bleeding with clopidogrel is reduced in carriers of CYP2C19-deficient alleles, with the risk of cardiovascular events moderately increased [44].”
BackgroundElosúa, R., Sayols-Baixeras, S., Lluís-Ganella, C., & Lucas, G. (2014) · The Application of Clinical Genetics · doi:10.2147/tacg.s35301 · Cited by 163 · see citing works
“…question the validity of this warning based on the fact that the reported associations are mainly driven by studies with small sample sizes; 78,81,82 thus, they concluded that current evidence does not support the use of individualized clopidogrel regimens guided by the CYP2C19 genotype.”
Pharmacokinetic interactions of curcuminoids with conventional drugs: A review
Bahramsoltani, R., Rahimi, R., & Farzaei, M. H. (2017) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2017.07.022 · Cited by 156 · see citing works
The causal role of megakaryocyte–platelet hyperactivity in acute coronary syndromes
Martin, J. F., Kristensen, S. D., Mathur, A., Grove, E. L., & Choudry, F. (2012) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2012.131 · Cited by 152 · see citing works
Peat, G., Riley, R. D., Croft, P. R., Morley, K. I., Kyzas, P., Moons, K. G. M., Perel, P., Steyerberg, E. W., Schroter, S., Altman, D. G., et al. (2014) · PLoS Medicine · doi:10.1371/journal.pmed.1001671 · Cited by 152 · see citing works
“Holmes and colleagues [19], in their systematic review and meta-analysis of CYP2C19 genotype as a predictor of differential response to clopidogrel, found many ‘‘treatment only’’ studies ill-suited to evaluating differential treatment response, and evidence of publication bias in small studies.”
Self-citationFerri, N., Corsini, A., & Bellosta, S. (2013) · Drugs · doi:10.1007/s40265-013-0126-z · Cited by 145 · see citing works
“However, a recent meta-analysis did not demonstrate a direct association between CYP2C19 polymorphism and cardiovascular events [137], despite the association between CYP2C19 genotype, clopidogrel metabolism, and platelet aggregation [137].”
BackgroundPharmacogenetics to guide cardiovascular drug therapy
Duarte, J. D., & Cavallari, L. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00549-w · Cited by 119 · see citing works
Pharmacogenetics and Cardiovascular Disease—Implications for Personalized Medicine
Johnson, J. A., & Cavallari, L. H. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.007252 · Cited by 141 · see citing works
“Many of the metaanalyses report significant heterogeneity between the studies and/or suggest a small study bias whereby the smaller studies, mostly published earlier, revealed greater effect sizes than the larger studies (Hulot et al., 2010; Bauer et al., 2011; Holmes et al., 2011; Sofi et al., 2011; Zabalza et al., 2…”
MethodResultPereira, N. L., Cresci, S., Angiolillo, D. J., Batchelor, W., Capers, Q., Cavallari, L. H., Leifer, D., Luzum, J. A., Roden, D. M., Stellos, K., et al. (2024) · Circulation · doi:10.1161/cir.0000000000001257 · Cited by 132 · see citing works
Genetics and Genomics for the Prevention and Treatment of Cardiovascular Disease: Update
Ganesh, S. K., Arnett, D. K., Assimes, T. L., Basson, C. T., Chakravarti, A., Ellinor, P. T., Engler, M. B., Goldmuntz, E., Herrington, D. M., Hershberger, R. E., et al. (2013) · Circulation · doi:10.1161/01.cir.0000437913.98912.1d · Cited by 130 · see citing works
Sorich, M. J., Rowland, A., McKinnon, R. A., & Wiese, M. D. (2014) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.114.000669 · Cited by 127 · see citing works
“tently reported association between carriage of a CYP2C19 LoF allele and a clinical outcome is for stent thrombosis.(5,6) Conse-”
BackgroundBrown, S.-A. N., & Pereira, N. L. (2018) · Journal of Personalized Medicine · doi:10.3390/jpm8010008 · Cited by 123 · see citing works
“For example, reduced platelet inhibition by clopidogrel resulting from CYP2C19 loss-of-function genetic variants was observed in several studies on platelet aggregation [11,25,26,32,44,91], with a gene-dose effect [87].”
BackgroundZhu, Y., Swanson, K. M., Rojas, R. L., Wang, Z., Sauver, J. L. S., Visscher, S. L., Prokop, L. J., Bielinski, S. J., Wang, L., Weinshilboum, R. M., et al. (2019) · Genetics in Medicine · doi:10.1038/s41436-019-0667-y · Cited by 118 · see citing works
Hasan, M. S., Basri, H., Hin, L. P., & Stanslas, J. (2012) · International Journal of Neuroscience · doi:10.3109/00207454.2012.744308 · Cited by 110 · see citing works
Kang, H., Clare, R. M., Gao, R., Held, C., Himmelmänn, A., James, S. K., Lim, S. T., Santoso, A., Yu, C., Wallentin, L. C., et al. (2015) · American Heart Journal · doi:10.1016/j.ahj.2015.03.015 · Cited by 110 · see citing works
Benefit of Preemptive Pharmacogenetic Information on Clinical Outcome
Roden, D. M., Driest, S. L. V., Mosley, J. D., Wells, Q. S., Robinson, J. R., Denny, J. C., & Peterson, J. F. (2018) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1035 · Cited by 110 · see citing works
Kwok, C. S., Jeevanantham, V., Dawn, B., & Loke, Y. K. (2012) · International Journal of Cardiology · doi:10.1016/j.ijcard.2012.03.085 · Cited by 106 · see citing works
“arguing that the findings of existing studies are affected by selective outcome reporting and small study bias [38].”
ResultCost-Effectiveness of Genotype-Guided and Dual Antiplatelet Therapies in Acute Coronary Syndrome
Kazi, D. S., Garber, A. M., Shah, R. U., Dudley, R. A., Mell, M. W., Rhee, C., Moshkevich, S., Boothroyd, D. B., Owens, D. K., & Hlatky, M. A. (2014) · Annals of Internal Medicine · doi:10.7326/m13-1999 · Cited by 104 · see citing works
“In both cases, we assumed that carriers of loss-of-function alleles had a lower risk for bleeding than noncarriers (67).”
BackgroundMethodInfluentialPersonalizing health care: feasibility and future implications
Godman, B., Finlayson, A. E. T., Cheema, P. K., Zebedin-Brandl, E. M., Gutiérrez‐Ibarluzea, I., Jones, J., Malmström, R. E., Asola, E., Baumgärtel, C., Bennie, M., et al. (2013) · BMC Medicine · doi:10.1186/1741-7015-11-179 · Cited by 103 · see citing works
Medical Management After Coronary Stent Implantation
Brilakis, E. S., PATEL, V. G., & Banerjee, S. (2013) · JAMA · doi:10.1001/jama.2013.7086 · Cited by 90 · see citing works
The Importance of Patient-Specific Factors for Hepatic Drug Response and Toxicity
Lauschke, V. M., & Ingelman‐Sundberg, M. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17101714 · Cited by 90 · see citing works
Mital, S. R., Musunuru, K., Garg, V., Russell, M. W. W., Lanfear, D. E., Gupta, R. M., Hickey, K. T., Ackerman, M. J., Perez, M. V., Roden, D. M., et al. (2016) · Circulation Cardiovascular Genetics · doi:10.1161/hcg.0000000000000031 · Cited by 85 · see citing works
Modulation of CYP 450 Activities in Patients With Type 2 Diabetes
Gravel, S., Chiasson, J., Turgeon, J., Grangeon, A., & Michaud, V. (2019) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1496 · Cited by 84 · see citing works
Shaikh, A. S., Thomas, A. B., & Chitlange, S. S. (2020) · Phytotherapy Research · doi:10.1002/ptr.6585 · Cited by 90 · see citing works
Clopidogrel: A Case for Indication-Specific Pharmacogenetics
Johnson, J. A., Roden, D. M., Lesko, L. J., Ashley, E. A., Klein, T. E., & Shuldiner, A. R. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2012.21 · Cited by 82 · see citing works
Platelet function tests in clinical cardiology: unfulfilled expectations.
Gorog, D. A., & Fuster, V. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.11.080 · Cited by 83 · see citing works
“However, 2 recent meta-analyses (not confined to stented patients) showed that although there was an association between CYP2C19 genotype and clopidogrel responsiveness, genotype was not associated with cardiovascular events, with the possible exception of ST in the subgroup of patients undergoing PCI, where ST was as…”
ResultPhysician response to implementation of genotype‐tailored antiplatelet therapy
Peterson, J., Field, J., Unertl, K. M., Schildcrout, J. S., Johnson, D., Shi, Y., Danciu, I., Cleator, J. H., Pulley, J., McPherson, J., et al. (2015) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.331 · Cited by 72 · see citing works
Lala, A., Berger, J. S., Sharma, G. K., Hochman, J. S., Braithwaite, R. S., & Ladapo, J. A. (2012) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12059 · Cited by 70 · see citing works
Ross, S. A., Anand, S. S., Joseph, P. G., & Paré, G. (2012) · JRSM Cardiovascular Disease · doi:10.1258/cvd.2012.012001 · Cited by 70 · see citing works
Cresci, S., Depta, J. P., Lenzini, P. A., Li, A. Y., Lanfear, D. E., Province, M. A., Spertus, J. A., & Bach, R. G. (2014) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.113.000303 · Cited by 69 · see citing works
“In contrast, 2 other meta-analyses, one including 11 studies involving 16 360 patients and a second including 32 studies involving 42 016 patients exposed to clopidogrel concluded that CYP2C19*2 carriers had no increased risk of cardiovascular events, although a significantly increased risk of stent thrombosis after P…”
ResultSerbin, M., Guzauskas, G. F., & Veenstra, D. L. (2016) · Journal of Managed Care & Specialty Pharmacy · doi:10.18553/jmcp.2016.22.8.939 · Cited by 68 · see citing works
“2015;10(6):e0124653 Available at: http://www.”
Personalized medicine: is it a pharmacogenetic mirage?
Shah, R. R., & Shah, D. R. (2012) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2012.04328.x · Cited by 67 · see citing works
Reny, J., COMBESCURE, C., Daali, Y., & Fontana, P. (2012) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2012.04756.x · Cited by 65 · see citing works
Clinical implications of drug–drug interactions with P2Y12 receptor inhibitors
Siller-Matula, J. M., Trenk, D., Krähenbühl, S., Michelson, A. D., & Delle‐Karth, G. (2014) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12445 · Cited by 66 · see citing works
Shan, J., Zhang, B., Zhu, Y., Jiao, B., Zheng, W., Qi, X., Gong, Y., Yuan, F., Lv, F., & Sun, H. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300038c · Cited by 66 · see citing works
Role of genetic testing in patients undergoing percutaneous coronary intervention
Moon, J. Y., Franchi, F., Rollini, F., Rios, J. R. R., Kureti, M., Cavallari, L. H., & Angiolillo, D. J. (2017) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2017.1353909 · Cited by 67 · see citing works
Cattaneo, M. (2012) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2011.04602.x · Cited by 68 · see citing works
Würtz, M., & Grove, E. L. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212803251925 · Cited by 64 · see citing works
“A recent meta-analysis suggested that the CYP2C19 genotype does indeed influence on-clopidogrel platelet reactivity, while this influence yields only non-significant changes in clinical outcome [162].”
BackgroundPharmacogenomics for Primary Care: An Overview
Rollinson, V., Turner, R. M., & Pirmohamed, M. (2020) · Genes · doi:10.3390/genes11111337 · Cited by 64 · see citing works
“However, a second meta-analysis assessing CYP2C19 genotype and cardiovascular outcomes in 26, 251 individuals found no overall association with cardiovascular outcomes after exclusion of small studies, although an increased risk of stent thrombosis remained evident [115].”
MethodCardiovascular Pharmacogenomics: Expectations and Practical Benefits
Turner, R. M., & Pirmohamed, M. (2013) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2013.234 · Cited by 63 · see citing works
Amin, A. M., Chin, L. S., Noor, D. A. M., Kader, M. A. S. A., Yuen, K. H., & Ibrahim, B. (2017) · Cardiology Research and Practice · doi:10.1155/2017/8062796 · Cited by 64 · see citing works
Zheng, Y., Wu, T., Yang, Y., Hou, X., Gao, Y., Chen, Y., Yang, Y., Li, X., Ma, X., Ma, Y., et al. (2019) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvz059 · Cited by 62 · see citing works
Precision Cardiovascular Medicine: State of Genetic Testing
Giudicessi, J. R., Kullo, I. J., & Ackerman, M. J. (2017) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2017.01.015 · Cited by 60 · see citing works
TRAF3 Epigenetic Regulation Is Associated With Vascular Recurrence in Patients With Ischemic Stroke
Gallego-Fábrega, C., Carrera, C., Reny, J., Fontana, P., Słowik, A., Pera, J., Pezzini, A., Serrano‐Heras, G., Segura, T., Martí‐Fábregas, J., et al. (2016) · Stroke · doi:10.1161/strokeaha.115.012237 · Cited by 60 · see citing works
Genetic and Nongenetic Factors Affecting Clopidogrel Response in the Egyptian Population
Khalil, B., Mh, S., Solayman, M. H. M., Langaee, T. Y., Schaalan, M. F., Gong, Y., Hammad, L., El-Mesallamy, H., Hamdy, N. Μ., El‐Hammady, W., et al. (2016) · Clinical and Translational Science · doi:10.1111/cts.12383 · Cited by 58 · see citing works
Zhang, C., He, J., Zhang, Y., Chen, J., Zhao, Y., Niu, Y., & Yu, C. (2017) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2017.11.014 · Cited by 58 · see citing works
“In addition, accumulated evidence supports the relationship between CYP2C19 *2 gene and high ontreatment platelet reactivity (HTPR) and the risk of ischaemic cardiovascular event in clopidogrel-treated patient (Bauer et al., 2011; Holmes et al., 2011; Mega et al., 2010).”
BackgroundAdvances and challenges in treatment and prevention of ischemic stroke
Grossman, A. W., & Broderick, J. P. (2013) · Annals of Neurology · doi:10.1002/ana.23993 · Cited by 57 · see citing works
“Genetic testing in warfarin and clopidogrel therapy exemplifies the pharmacogenomic approach, yet it has not been widely accepted.(78,79) With additional research into genetics of stroke etiology, recovery, and therapeutics, these data will likely become incorporated into clinical decision making.”
BackgroundMaffrand, J. (2012) · Comptes Rendus Chimie · doi:10.1016/j.crci.2012.05.006 · Cited by 56 · see citing works
Genotype‐guided drug prescribing: a systematic review and meta‐analysis of randomized control trials
Goulding, R., Dawes, D., Price, M., Wilkie, S. S., & Dawes, M. G. (2014) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12475 · Cited by 55 · see citing works
Analysis of CYP2D6 genotype and response to tetrabenazine
Mehanna, R., Hunter, C., Davidson, A. L., Shahed, J. J., & Jankovic, J. J. (2012) · Movement Disorders · doi:10.1002/mds.25278 · Cited by 54 · see citing works
Antiplatelet drug interactions with proton pump inhibitors
Scott, S. A., Obeng, A. O., & Hulot, J. (2013) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2014.856883 · Cited by 53 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
Musunuru, K., Hickey, K., Al-Khatib, S., Delles, C., Fornage, M., Fox, C., Frazier, L. Q., Gelb, B., Herrington, D., Lanfear, D., et al. (2015) · Circulation: Cardiovascular Genetics · doi:10.1161/hcg.0000000000000020 · Cited by 49 · see citing works
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 · see citing works
“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 · see citing works
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 47 · see citing works
Personalised medicine: not just in our genes
Kitsios, G. D., & Kent, D. M. (2012) · BMJ · doi:10.1136/bmj.e2161 · Cited by 45 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 45 · see citing works
Lewis, J. P., Voora, D., & Beitelshees, A. L. (2015) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s52900 · Cited by 44 · see citing works
“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 46 · see citing works
Foti, R. (2024) · Drug Metabolism and Disposition · doi:10.1124/dmd.123.001384 · Cited by 43 · see citing works
Analysis of CYP2C19 Genetic Polymorphism in a Large Ethnic Hakka Population in Southern China
Zhong, Z., Hou, J., Li, B., Zhang, Q., Liu, S., Li, C., Liu, Z., Yang, M. H., Zhong, W. H., & Zhao, P. (2017) · Medical Science Monitor · doi:10.12659/msm.905337 · Cited by 43 · see citing works
So, D. Y. F., Wells, G. A., McPherson, R., Labinaz, M. X., May, M. R. L., Glover, C. A., DICK, A. J., Froeschl, M. P. V., Marquis, J., Gollob, M. H., et al. (2015) · The Pharmacogenomics Journal · doi:10.1038/tpj.2015.17 · Cited by 41 · see citing works
Liang, Z., Han, Y., Zhang, X., Li, Y., Yan, C., & Kang, J. (2013) · EuroIntervention · doi:10.4244/eijv9i3a53 · Cited by 42 · see citing works
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 42 · see citing works
Pharmacogenomics and Clopidogrel
Nissen, S. E. (2011) · JAMA · doi:10.1001/jama.2011.1865 · Cited by 42 · see citing works
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 41 · see citing works
Asai, T., Miyachi, S., Izumi, T., Matsubara, N., Haraguchi, K., Yamanouchi, T., Ota, K., Shintai, K., Tajima, H., & Wakabayashi, T. (2015) · Journal of NeuroInterventional Surgery · doi:10.1136/neurintsurg-2015-011727 · Cited by 41 · see citing works
Wiśniewski, A., & Filipska, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176408 · Cited by 41 · see citing works
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 40 · see citing works
Expanding Role of Pharmacogenomics in the Management of Cardiovascular Disorders
Yip, V. L. M., & Pirmohamed, M. (2013) · American Journal of Cardiovascular Drugs · doi:10.1007/s40256-013-0024-5 · Cited by 40 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
- 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 › Surgery › 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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