Is CYP2C Haplotype Relevant for Efficacy and Bleeding Risk in Clopidogrel-Treated Patients?
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Outline
2.2. Patients
2.3. Genotyping Procedures
2.4. Genotype-Predicted Phenotypes and CYP2C:TG Haplotype
2.5. Outcomes of Interest
2.6. Data Analysis
3. Results
3.1. Patient Characteristics
3.2. Outcomes across CYP2C19 Phenotypes—Raw Data
3.3. Outcomes across Phenotypes—Balanced Data
3.4. Outcomes Regarding the CYP2C:TG Haplotype
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Botton, M.R.; Whirl-Carrillo, M.; Del Tredici, A.L.; Sangkuhl, K.; Cavallari, L.H.; Agúndez, J.A.G.; Duconge, J.; Lee, M.T.M.; Woodahl, E.L.; Claudio-Campos, K.; et al. PharmVar GeneFocus: CYP2C19. Clin. Pharmacol. Ther. 2021, 109, 352–366. [Google Scholar] [CrossRef] [PubMed]
- PharmVar. PharmVar CYP2C19 Gene. Available online: https://www.pharmvar.org/gene/CYP2C19 (accessed on 13 April 2024).
- Pratt, V.M.; Del Tredici, A.L.; Hachad, H.; Ji, Y.; Kalman, L.V.; Scott, S.A.; Weck, K.E. Recommendations for Clinical CYP2C19 Genotyping Allele Selection. J. Mol. Diagn. 2018, 20, 269–276. [Google Scholar] [CrossRef] [PubMed]
- 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.; et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. Clin. Pharmacol. Ther. 2022, 112, 959–967. [Google Scholar] [CrossRef] [PubMed]
- PharmGKB. Gene-Specific Information Tables for CYP2C19. Available online: https://www.pharmgkb.org/page/cyp2c19RefMaterials (accessed on 13 April 2024).
- Johnston, S.C.; Easton, J.D.; Farrant, M.; Barsan, W.; Conwit, R.A.; Elm, J.J.; Kim, A.S.; Lindblad, A.S.; Palesch, Y.Y.; Neurological Emergencies Treatment Trials Network; et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N. Engl. J. Med. 2018, 379, 215–225. [Google Scholar] [CrossRef] [PubMed]
- Levine, G.N.; Bates, E.R.; Bittl, J.A.; Brindis, R.G.; Fihn, S.D.; Fleisher, L.A.; Granger, C.B.; Lange, R.A.; Mack, M.J.; Mauri, L.; et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2016, 68, 1082–1115. [Google Scholar] [CrossRef]
- Wang, Y.; Wang, Y.; Zhao, X.; Liu, L.; Wang, D.; Wang, C.; Wang, C.; Li, H.; Meng, X.; Cui, L.; et al. Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack. N. Engl. J. Med. 2013, 369, 11–19. [Google Scholar] [CrossRef] [PubMed]
- Kazui, M.; Nishiya, Y.; Ishizuka, T.; Hagihara, K.; Farid, N.A.; Okazaki, O.; Ikeda, T.; Kurihara, A. Identification of the Human Cytochrome P450 Enzymes Involved in the Two Oxidative Steps in the Bioactivation of Clopidogrel to Its Pharmacologically Active Metabolite. Drug Metab. Dispos. 2010, 38, 92–99. [Google Scholar] [CrossRef] [PubMed]
- Mega, J.L.; Simon, T.; Collet, J.-P.; Anderson, J.L.; Antman, E.M.; Bliden, K.; Cannon, C.P.; Danchin, N.; Giusti, B.; Gurbel, P.; et al. Reduced-Function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes among Patients Treated with Clopidogrel Predominantly for PCI: A Meta-Analysis. JAMA 2010, 304, 1821–1830. [Google Scholar] [CrossRef] [PubMed]
- Pan, Y.; Chen, W.; Xu, Y.; Yi, X.; Han, Y.; Yang, Q.; Li, X.; Huang, L.; Johnston, S.C.; Zhao, X.; et al. Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack. Circulation 2017, 135, 21–33. [Google Scholar] [CrossRef] [PubMed]
- Scott, S.A.; Sangkuhl, K.; Stein, C.M.; Hulot, J.-S.; Mega, J.L.; Roden, D.M.; Klein, T.E.; Sabatine, M.S.; Johnson, J.A.; Shuldiner, A.R. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update. Clin. Pharmacol. Ther. 2013, 94, 317–323. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Zhao, X.; Lin, J.; Li, H.; Johnston, S.C.; Lin, Y.; Pan, Y.; Liu, L.; Wang, D.; Wang, C.; et al. Association between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction among Patients with Minor Stroke or Transient Ischemic Attack. JAMA 2016, 316, 70–78. [Google Scholar] [CrossRef] [PubMed]
- Xie, H.-G.; Zou, J.-J.; Hu, Z.-Y.; Zhang, J.-J.; Ye, F.; Chen, S.-L. Individual Variability in the Disposition of and Response to Clopidogrel: Pharmacogenomics and Beyond. Pharmacol. Ther. 2011, 129, 267–289. [Google Scholar] [CrossRef]
- Zvyaga, T.; Chang, S.-Y.; Chen, C.; Yang, Z.; Vuppugalla, R.; Hurley, J.; Thorndike, D.; Wagner, A.; Chimalakonda, A.; Rodrigues, A.D. Evaluation of Six Proton Pump Inhibitors as Inhibitors of Various Human Cytochromes P450: Focus on Cytochrome P450 2C19. Drug Metab. Dispos. Biol. Fate Chem. 2012, 40, 1698–1711. [Google Scholar] [CrossRef] [PubMed]
- Mejin, M.; Tiong, W.N.; Lai, L.Y.H.; Tiong, L.L.; Bujang, A.M.; Hwang, S.S.; Ong, T.K.; Fong, A.Y.Y. CYP2C19 Genotypes and Their Impact on Clopidogrel Responsiveness in Percutaneous Coronary Intervention. Int. J. Clin. Pharm. 2013, 35, 621–628. [Google Scholar] [CrossRef] [PubMed]
- Yi, X.; Lin, J.; Zhou, Q.; Wu, L.; Cheng, W.; Wang, C. Clopidogrel Resistance Increases Rate of Recurrent Stroke and Other Vascular Events in Chinese Population. J. Stroke Cerebrovasc. Dis. 2016, 25, 1222–1228. [Google Scholar] [CrossRef]
- Gower, M.N.; Ratner, L.R.; Williams, A.K.; Rossi, J.S.; Stouffer, G.A.; Lee, C.R. Clinical Utility of CYP2C19 Genotype-Guided Antiplatelet Therapy in Patients at Risk of Adverse Cardiovascular and Cerebrovascular Events: A Review of Emerging Evidence. Pharmacogenomics Pers. Med. 2020, 13, 239–252. [Google Scholar] [CrossRef] [PubMed]
- Hu, C.-Y.; Wang, Y.-L.; Fan, Z.-X.; Sun, X.-P.; Wang, S.; Liu, Z. Effect of Cytochrome P450 2C19 (CYP2C19) Gene Polymorphism and Clopidogrel Reactivity on Long Term Prognosis of Patients with Coronary Heart Disease after PCI. J. Geriatr. Cardiol. JGC 2024, 21, 90–103. [Google Scholar] [CrossRef] [PubMed]
- Gross, L.; Trenk, D.; Jacobshagen, C.; Krieg, A.; Gawaz, M.; Massberg, S.; Baylacher, M.; Aradi, D.; Stimpfle, F.; Hromek, J.; et al. Genotype-Phenotype Association and Impact on Outcomes Following Guided De-Escalation of Anti-Platelet Treatment in Acute Coronary Syndrome Patients: The TROPICAL-ACS Genotyping Substudy. Thromb. Haemost. 2018, 118, 1656–1667. [Google Scholar] [CrossRef] [PubMed]
- Saiz-Rodríguez, M.; Romero-Palacián, D.; Villalobos-Vilda, C.; Caniego, J.L.; Belmonte, C.; Koller, D.; Bárcena, E.; Talegón, M.; Abad-Santos, F. Influence of CYP2C19 Phenotype on the Effect of Clopidogrel in Patients Undergoing a Percutaneous Neurointervention Procedure. Clin. Pharmacol. Ther. 2019, 105, 661–671. [Google Scholar] [CrossRef] [PubMed]
- Sibbing, D.; Koch, W.; Gebhard, D.; Schuster, T.; Braun, S.; Stegherr, J.; Morath, T.; Schömig, A.; von Beckerath, N.; Kastrati, A. Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients with Coronary Stent Placement. Circulation 2010, 121, 512–518. [Google Scholar] [CrossRef]
- Sibbing, D.; Gebhard, D.; Koch, W.; Braun, S.; Stegherr, J.; Morath, T.; Von Beckerath, N.; Mehilli, J.; Schömig, A.; Schuster, T.; et al. Isolated and Interactive Impact of Common CYP2C19 Genetic Variants on the Antiplatelet Effect of Chronic Clopidogrel Therapy. J. Thromb. Haemost. 2010, 8, 1685–1693. [Google Scholar] [CrossRef]
- Tiroch, K.A.; Sibbing, D.; Koch, W.; Roosen-Runge, T.; Mehilli, J.; Schömig, A.; Kastrati, A. Protective Effect of the CYP2C19 *17 Polymorphism with Increased Activation of Clopidogrel on Cardiovascular Events. Am. Heart J. 2010, 160, 506–512. [Google Scholar] [CrossRef] [PubMed]
- Danielak, D.; Karaźniewicz-Łada, M.; Komosa, A.; Burchardt, P.; Lesiak, M.; Kruszyna, Ł.; Graczyk-Szuster, A.; Główka, F. Influence of Genetic Co-Factors on the Population Pharmacokinetic Model for Clopidogrel and Its Active Thiol Metabolite. Eur. J. Clin. Pharmacol. 2017, 73, 1623–1632. [Google Scholar] [CrossRef] [PubMed]
- Lee, C.R.; Thomas, C.D.; Beitelshees, A.L.; Tuteja, S.; Empey, P.E.; Lee, J.C.; Limdi, N.A.; Duarte, J.D.; Skaar, T.C.; Chen, Y.; et al. Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype-Guided Antiplatelet Therapy after Percutaneous Coronary Intervention. Clin. Pharmacol. Ther. 2021, 109, 705–715. [Google Scholar] [CrossRef] [PubMed]
- Lewis, J.P.; Backman, J.D.; Reny, J.-L.; Bergmeijer, T.O.; Mitchell, B.D.; Ritchie, M.D.; Déry, J.-P.; Pakyz, R.E.; Gong, L.; Ryan, K.; et al. Pharmacogenomic Polygenic Response Score Predicts Ischaemic Events and Cardiovascular Mortality in Clopidogrel-Treated Patients. Eur. Heart J. Cardiovasc. Pharmacother. 2020, 6, 203–210. [Google Scholar] [CrossRef] [PubMed]
- Lewis, J.P.; Stephens, S.H.; Horenstein, R.B.; O’Connell, J.R.; Ryan, K.; Peer, C.J.; Figg, W.D.; Spencer, S.D.; Pacanowski, M.A.; Mitchell, B.D.; et al. The CYP2C19 *17 Variant Is Not Independently Associated with Clopidogrel Response. J. Thromb. Haemost. 2013, 11, 1640–1646. [Google Scholar] [CrossRef] [PubMed]
- Wallentin, L.; James, S.; Storey, R.F.; Armstrong, M.; Barratt, B.J.; Horrow, J.; Husted, S.; Katus, H.; Steg, P.G.; Shah, S.H.; et al. Effect of CYP2C19 and ABCB1 Single Nucleotide Polymorphisms on Outcomes of Treatment with Ticagrelor versus Clopidogrel for Acute Coronary Syndromes: A Genetic Substudy of the PLATO Trial. Lancet 2010, 376, 1320–1328. [Google Scholar] [CrossRef] [PubMed]
- Notarangelo, F.M.; Maglietta, G.; Bevilacqua, P.; Cereda, M.; Merlini, P.A.; Villani, G.Q.; Moruzzi, P.; Patrizi, G.; Malagoli Tagliazucchi, G.; Crocamo, A.; et al. Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients with Acute Coronary Syndromes: The PHARMCLO Trial. J. Am. Coll. Cardiol. 2018, 71, 1869–1877. [Google Scholar] [CrossRef] [PubMed]
- Claassens, D.M.F.; Vos, G.J.A.; Bergmeijer, T.O.; Hermanides, R.S.; van ‘t Hof, A.W.J.; van der Harst, P.; Barbato, E.; Morisco, C.; Tjon Joe Gin, R.M.; Asselbergs, F.W.; et al. A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI. N. Engl. J. Med. 2019, 381, 1621–1631. [Google Scholar] [CrossRef] [PubMed]
- Pereira, N.L.; Farkouh, M.E.; So, D.; Lennon, R.; Geller, N.; Mathew, V.; Bell, M.; Bae, J.-H.; Jeong, M.H.; Chavez, I.; et al. 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 2020, 324, 761–771. [Google Scholar] [CrossRef] [PubMed]
- Pereira, N.L.; Rihal, C.S.; So, D.; Rosenberg, Y.; Lennon, R.J.; Mathew, V.; Goodman, S.; Weinshilboum, R.M.; Wang, L.; Baudhuin, L.M.; et al. Clopidogrel Pharmacogenetics: State of the Art Review and the TAILOR-PCI Study. Circ. Cardiovasc. Interv. 2019, 12, e007811. [Google Scholar] [CrossRef] [PubMed]
- Massmann, A.; Christensen, K.D.; Van Heukelom, J.; Schultz, A.; Shaukat, M.H.S.; Hajek, C.; Weaver, M.; Green, R.C.; Wu, A.C.; Hickingbotham, M.R.; et al. Clinical Impact of Preemptive Pharmacogenomic Testing on Antiplatelet Therapy in a Real-World Setting. Eur. J. Hum. Genet. 2024; ahead of print. [Google Scholar] [CrossRef]
- Bråten, L.S.; Haslemo, T.; Jukic, M.M.; Ivanov, M.; Ingelman-Sundberg, M.; Molden, E.; Kringen, M.K. A Novel CYP2C-Haplotype Associated with Ultrarapid Metabolism of Escitalopram. Clin. Pharmacol. Ther. 2021, 110, 786–793. [Google Scholar] [CrossRef] [PubMed]
- Bråten, L.S.; Ingelman-Sundberg, M.; Jukic, M.M.; Molden, E.; Kringen, M.K. Impact of the Novel CYP2C:TG Haplotype and CYP2B6 Variants on Sertraline Exposure in a Large Patient Population. Clin. Transl. Sci. 2022, 15, 2135–2145. [Google Scholar] [CrossRef] [PubMed]
- Kee, P.S.; Maggo, S.D.S.; Kennedy, M.A.; Barclay, M.L.; Miller, A.L.; Lehnert, K.; Curtis, M.A.; Faull, R.L.M.; Parker, R.; Chin, P.K.L. Omeprazole Treatment Failure in Gastroesophageal Reflux Disease and Genetic Variation at the CYP2C Locus. Front. Genet. 2022, 13, 869160. [Google Scholar] [CrossRef] [PubMed]
- Patel, J.N.; Robinson, M.; Morris, S.A.; Jandrisevits, E.; Lopes, K.E.; Hamilton, A.; Steuerwald, N.; Druhan, L.J.; Avalos, B.; Copelan, E.; et al. Pharmacogenetic and Clinical Predictors of Voriconazole Concentration in Hematopoietic Stem Cell Transplant Recipients Receiving CYP2C19-Guided Dosing. Pharmacogenomics J. 2023, 23, 201–209. [Google Scholar] [CrossRef]
- Zubiaur, P.; Soria-Chacartegui, P.; Boone, E.C.; Prasad, B.; Dinh, J.; Wang, W.Y.; Zugbi, S.; Rodríguez-Lopez, A.; González-Iglesias, E.; Leeder, J.S.; et al. Impact of CYP2C:TG Haplotype on CYP2C19 Substrates Clearance In Vivo, Protein Content, and In Vitro Activity. Clin. Pharmacol. Ther. 2023, 114, 1033–1042. [Google Scholar] [CrossRef] [PubMed]
- von Kummer, R.; Broderick, J.P.; Campbell, B.C.V.; Demchuk, A.; Goyal, M.; Hill, M.D.; Treurniet, K.M.; Majoie, C.B.L.M.; Marquering, H.A.; Mazya, M.V.; et al. The Heidelberg Bleeding Classification. Stroke 2015, 46, 2981–2986. [Google Scholar] [CrossRef] [PubMed]
- Hainmueller, J. Entropy Balancing for Causal Effects: A Multivariate Reweighting Method to Produce Balanced Samples in Observational Studies. Polit. Anal. 2012, 20, 25–46. [Google Scholar] [CrossRef]
- Greifer, N. WeightIt: Weighting for Covariate Balance in Observational Studies. R Package Version 1.0.0. Available online: https://ngreifer.github.io/WeightIt/ (accessed on 11 April 2024).
- R Core Team. R: A Language and Environment for Statistical Computing; R Foundation for Statistical Computing: Vienna, Austria, 2024; Available online: https://www.r-project.org/ (accessed on 13 April 2024).
- Shuldiner, A.R.; O’Connell, J.R.; Bliden, K.P.; Gandhi, A.; Ryan, K.; Horenstein, R.B.; Damcott, C.M.; Pakyz, R.; Tantry, U.S.; Gibson, Q.; et al. Association of Cytochrome P450 2C19 Genotype with the Antiplatelet Effect and Clinical Efficacy of Clopidogrel Therapy. JAMA 2009, 302, 849–857. [Google Scholar] [CrossRef] [PubMed]
- Bouman, H.J.; Harmsze, A.M.; van Werkum, J.W.; Breet, N.J.; Bergmeijer, T.O.; ten Cate, H.; Hackeng, C.M.; Deneer, V.H.M.; ten Berg, J.M. Variability in On-Treatment Platelet Reactivity Explained by CYP2C19*2 Genotype Is Modest in Clopidogrel Pretreated Patients Undergoing Coronary Stenting. Heart 2011, 97, 1239–1244. [Google Scholar] [CrossRef] [PubMed]
- Fontana, P.; James, R.; Barazer, I.; Berdagué, P.; Schved, J.-F.; Rebsamen, M.; Vuilleumier, N.; Reny, J.-L. Relationship between Paraoxonase-1 Activity, Its Q192R Genetic Variant and Clopidogrel Responsiveness in the ADRIE Study. J. Thromb. Haemost. 2011, 9, 1664–1666. [Google Scholar] [CrossRef] [PubMed]
- Hochholzer, W.; Trenk, D.; Fromm, M.F.; Valina, C.M.; Stratz, C.; Bestehorn, H.-P.; Büttner, H.J.; Neumann, F.-J. Impact of Cytochrome P450 2C19 Loss-of-Function Polymorphism and of Major Demographic Characteristics on Residual Platelet Function After Loading and Maintenance Treatment with Clopidogrel in Patients Undergoing Elective Coronary Stent Placement. J. Am. Coll. Cardiol. 2010, 55, 2427–2434. [Google Scholar] [CrossRef] [PubMed]
- Scott, S.; Collet, J.-P.; Baber, U.; Yang, Y.; Peter, I.; Linderman, M.; Sload, J.; Qiao, W.; Kini, A.; Sharma, S.; et al. Exome Sequencing of Extreme Clopidogrel Response Phenotypes Identifies B4GALT2 as a Determinant of On-Treatment Platelet Reactivity. Clin. Pharmacol. Ther. 2016, 100, 287–294. [Google Scholar] [CrossRef] [PubMed]
- Verma, S.S.; Bergmeijer, T.O.; Gong, L.; Reny, J.-L.; Lewis, J.P.; Mitchell, B.D.; Alexopoulos, D.; Aradi, D.; Altman, R.B.; Bliden, K.; et al. Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated with Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium. Clin. Pharmacol. Ther. 2020, 108, 1067–1077. [Google Scholar] [CrossRef] [PubMed]
- Thomas, C.D.; Franchi, F.; Rossi, J.S.; Keeley, E.C.; Anderson, R.D.; Beitelshees, A.L.; Duarte, J.D.; Ortega-Paz, L.; Gong, Y.; Kerensky, R.A.; et al. Effectiveness of Clopidogrel vs Alternative P2Y12 Inhibitors Based on the ABCD-GENE Score. J. Am. Coll. Cardiol. 2024, 83, 1370–1381. [Google Scholar] [CrossRef]
- Ingelman-Sundberg, M.; Jukic, M.; Bråten, L.S.; Kringen, M.K.; Molden, E. What Is the Current Clinical Impact of the CYP2CTG Haplotype? Clin. Pharmacol. Ther. 2024, 115, 183. [Google Scholar] [CrossRef]
- Chang, C.-C.; Chou, Y.-C.; Chang, J.-Y.; Sun, C.-A. Effects of Treatment with Clopidogrel with or without Proton Pump Inhibitor Omeprazole on the Risk of Ischemic Stroke: A Nationwide Cohort Study. Sci. Rep. 2024, 14, 1686. [Google Scholar] [CrossRef] [PubMed]
- Lee, D.; Kim, J.S.; Kim, B.J.; Shin, S.Y.; Kim, D.B.; Ahn, H.S. Influence of Individual Proton Pump Inhibitors on Clinical Outcomes in Patients Receiving Clopidogrel Following Percutaneous Coronary Intervention. Medicine 2021, 100, e27411. [Google Scholar] [CrossRef] [PubMed]
- Tamargo, J.; Kaski, J.C.; Kimura, T.; Barton, J.C.; Yamamoto, K.; Komiyama, M.; Drexel, H.; Lewis, B.S.; Agewall, S.; Hasegawa, K. Racial and ethnic differences in pharmacotherapy to prevent coronary artery disease and thrombotic events. Eur. Heart J. Cardiovasc. Pharmacol. 2022, 8, 738–751. [Google Scholar] [CrossRef] [PubMed]
Characteristic | Value | Characteristic | Value |
---|---|---|---|
N | 283 | CYP2C19*2*17 phenotype | |
Age (years) | 60 ± 12 (22–85) | Normal (NM) | 88 (31.1) |
Female/male | 172 (60.8)/111 | Intermediate (IM) | 53 (18.7) |
Indication | Poor (PM) | 7 (2.5) | |
Percutaneous coronary intervention | 44 (15.6) | Rapid (RM) | 116 (41.0) |
Cerebral aneurism embolization | 160 (56.5) | Ultrarapid (UM) | 19 (6.7) |
Cerebrovascular stenting | 79 (27.9) | CYP2C rs11188059G>A | |
Medical history/comorbidity | GG | 209 (73.8) | |
Chronic kidney disease | 19 (6.7) | GA | 71 (25.1) |
Chronic heart failure | 16 (5.6) | AA | 3 (1.1) |
Chronic liver failure/cirrhosis/NAFLD | 5 (1.8) | CYP2C rs2860840C>T | |
Diabetes mellitus | 43 (15.2) | CC | 118 (41.7) |
Hypertension | 196 (69.3) | CT | 136 (48.1) |
History of ischemic stroke/TIA | 94 (33.2) | TT | 29 (10.2) |
Peripheral artery stenosis | 108 (38.2) | CYP2C cluster diplotype | |
Coronary artery disease | 25 (8.8) | CG/CG | 111 (39.2) |
Dyslipidemia | 118 (41.7) | CG/TG | 89 (31.5) |
Concomitant anticoagulant, total | 37 (13.1) | CA/TG | 46 (16.3) |
Direct oral anticoagulant | 33 (11.7) | TA/TG | 18 (6.4) |
Warfarin | 3 (1.1) | TG/TG | 9 (3.2) |
Enoxaparin | 1 (0.4) | CA/CG | 7 (2.5) |
Concomitant aspirin | 233 (82.3) | TA/TA | 2 (0.7) |
Gastroprotective treatment, total | 199 (70.3) | CA/TA | 1 (0.4) |
Pantoprazole | 168 (59.4) | CYP2C:TG carrier | 162 (57.2) |
Esomeprazole | 6 (2.1) | CYP2C19/2C phenotype | |
Ranitidine | 24 (8.5) | Normal (NM) | 23 (8.1) |
Rabeprazole | 1 (0.4) | Intermediate (IM) | 53 (18.7) |
CYP2C19*2 | Poor (PM) | 7 (2.5) | |
*1/*1 | 223 (78.8) | Rapid (RM) | 105 (37.1) |
*1/*2 | 53 (18.7) | Ultrarapid (UM) | 95 (33.6) |
*2/*2 | 7 (2.5) | Ischemic events total | 45 (15.9) |
CYP2C19*7 | CVI, retinal/opticus/stent | 40 (14.1) | |
*1/*1 | 131 (46.3) | TIA or amaurosis fugax | 5 (1.8) |
*1/*17 | 133 (47.0) | Bleeding events total | 49 (17.3) |
*17/*17 | 19 (6.7) | Cerebral | 6 (2.1) |
Extracerebral a | 44 (15.5) |
Phenotypes Based on CYP2C19*2*17 Genotype | Phenotypes Based on CYP2C19/CYP2C Cluster Genotype | |||||||
---|---|---|---|---|---|---|---|---|
PM/IM Phenotype | NM Phenotype | RM/UM Phenotype | Max d | PM/IM Phenotype | NM/RM Phenotype | UM Phenotype | Max d | |
N | 60 | 88 | 135 | --- | 60 | 128 | 95 | --- |
Age (years) | 61 ± 13 | 59 ± 12 | 61 ± 12 | 0.112 | 61 ± 13 | 60 ± 12 | 61 ± 13 | 0.116 |
Sex | ||||||||
Female | 26 (43.3) | 52 (59.1) | 94 (69.6) | 0.545 | 26 (43.3) | 81 (63.3) | 65 (68.4) | 0.522 |
Male | 34 (56.7) | 36 (40.9) | 41 (30.4) | 0.545 | 34 (56.7) | 47 (36.7) | 30 (31.6) | 0.522 |
Indication | ||||||||
PCI | 12 (20.0) | 14 (15.9) | 18 (13.3) | 0.181 | 12 (20.0) | 18 (14.1) | 14 (14.7) | 0.161 |
Brain AVM | 29 (48.3) | 47 (53.4) | 84 (62.2) | 0.281 | 29 (48.3) | 70 (54.7) | 61 (64.2) | 0.322 |
CV stenting | 19 (31.7) | 27 (30.7) | 33 (24.4) | 0.159 | 19 (31.7) | 40 (31.2) | 20 (21.1) | 0.238 |
CKD/CHF/CLD | 4 (6.7) | 16 (18.2) | 10 (7.4) | 0.377 | 4 (6.7) | 18 (14.1) | 8 (8.4) | 0.251 |
Hypertension | 40 (66.7) | 57 (64.8) | 99 (73.3) | 0.184 | 40 (66.7) | 85 (66.4) | 71 (74.7) | 0.181 |
DM/dyslipidemia | 30 (50.0) | 39 (44.3) | 67 (49.6) | 0.114 | 30 (50.0) | 58 (45.3) | 48 (50.5) | 0.104 |
CVI/PAD/CAD | 28 (46.7) | 44 (50.0) | 67 (49.6) | 0.067 | 28 (46.7) | 65 (50.8) | 46 (48.4) | 0.082 |
Gastroprotection | 40 (66.7) | 60 (68.2) | 99 (73.3) | 0.145 | 40 (66.7) | 91 (71.1) | 68 (71.6) | 0.107 |
Use PPI | 36 (60.0) | 49 (55.7) | 90 (66.7) | 0.226 | 36 (60.0) | 79 (61.7) | 60 (63.2) | 0.065 |
Use aspirin | 44 (73.3) | 79 (90.0) | 110 (81.5) | 0.430 | 44 (73.3) | 115 (89.8) | 74 (77.9) | 0.422 |
Use anticoagulants | 9 (15.0) | 8 (9.1) | 20 (14.8) | 0.177 | 9 (15.0) | 12 (9.4) | 16 (16.8) | 0.218 |
Phenotypes Based on CYP2C19*2*17 Genotype 1 | Phenotypes Based on CYP2C19/CYP2C Cluster Genotype 2 | |||||||
---|---|---|---|---|---|---|---|---|
PM/IM Phenotype | NM Phenotype | RM/UM Phenotype | Max d | PM/IM Phenotype | NM/RM Phenotype | UM Phenotype | Max d | |
N | 60 | 88 | 135 | --- | 60 | 128 | 95 | --- |
Age (years) | 60 ± 12 | 60 ± 12 | 60 ± 12 | 0.017 | 60 ± 12 | 60 ± 12 | 60 ± 12 | 0.016 |
Sex | ||||||||
Female | 58.2 | 61.7 | 61.4 | 0.072 | 57.9 | 61.2 | 61.7 | 0.078 |
Male | 41.8 | 38.3 | 38.6 | 0.072 | 42.1 | 38.8 | 38.3 | 0.078 |
Indication | ||||||||
PCI | 16.7 | 15.8 | 15.4 | 0.035 | 16.9 | 15.5 | 15.4 | 0.040 |
Brain AVM | 54.8 | 57.2 | 57.2 | 0.049 | 54.5 | 56.6 | 57.4 | 0.059 |
CV stenting | 28.5 | 27.0 | 27.4 | 0.034 | 28.6 | 27.9 | 27.2 | 0.032 |
CKD/CHF/CLD | 9.3 | 10.9 | 10.0 | 0.054 | 9.3 | 10.7 | 10.1 | 0.049 |
Hypertension | 67.9 | 68.6 | 69.3 | 0.031 | 68.0 | 69.3 | 69.6 | 0.035 |
DM/dyslipidemia | 47.0 | 47.2 | 47.7 | 0.012 | 47.1 | 48.0 | 47.6 | 0.017 |
CVI/PAD/CAD | 48.0 | 48.4 | 49.4 | 0.029 | 47.8 | 49.0 | 49.5 | 0.033 |
Gastroprotection | 69.5 | 69.9 | 70.9 | 0.033 | 69.4 | 70.3 | 71.0 | 0.035 |
Use PPI | 60.7 | 61.2 | 62.4 | 0.034 | 60.8 | 61.8 | 62.4 | 0.034 |
Use aspirin | 80.8 | 83.8 | 82.1 | 0.079 | 80.5 | 83.1 | 81.9 | 0.067 |
Use anticoagulants | 13.6 | 12.6 | 13.2 | 0.032 | 13.6 | 13.0 | 13.4 | 0.019 |
Before Entropy Balancing | After Entropy Balancing | |||||
---|---|---|---|---|---|---|
TG Carrier | TG Non-Carrier | d | TG Carrier | TG Non-Carrier | d | |
N | 162 | 121 | --- | --- | ||
Age (years) | 59 ± 13 | 62 ± 12 | −0.265 | 60 ± 12 | 60 ± 13 | −0.025 |
Sex | ||||||
Female | 100 (61.7) | 72 (59.5) | 0.045 | 61.0 | 60.7 | 0.005 |
Male | 62 (38.3) | 49 (40.5) | −0.045 | 39.0 | 39.3 | −0.005 |
Indication | ||||||
PCI | 23 (14.2) | 21 (17.4) | −0.087 | 15.4 | 16.0 | −0.015 |
Brain AVM | 97 (59.9) | 84 (52.1) | 0.158 | 56.8 | 56.1 | 0.015 |
CV stenting | 42 (25.9) | 121 (30.6) | −0.103 | 27.7 | 27.9 | −0.003 |
CKD/CHF/CLD | 19 (11.7) | 11 (9.1) | 0.086 | 10.7 | 10.4 | 0.010 |
Hypertension | 108 (66.7) | 88 (72.7) | −0.132 | 69.3 | 69.6 | −0.005 |
DM/dyslipidemia | 76 (46.9) | 60 (49.6) | −0.054 | 48.0 | 48.3 | −0.005 |
CVI/PAD/CAD | 79 (48.8) | 60 (49.6) | −0.016 | 49.2 | 49.1 | 0.002 |
Gastroprotection | 114 (70.4) | 85 (70.2) | 0.003 | 70.3 | 70.3 | −0.000 |
Use PPI | 99 (61.1) | 76 (62.8) | −0.035 | 61.8 | 61.9 | −0.003 |
Use aspirin | 132 (81.5) | 101 (83.5) | −0.052 | 82.2 | 82.5 | −0.007 |
Use anticoagulants | 23 (14.2) | 14 (11.6) | 0.078 | 13.2 | 12.8 | 0.012 |
Outcomes | ||||||
Ischemic events | 24 (14.8) | 21 (17.4) | −0.069 | 14.1 (9.7–20.7) | 16.1 (10.7–24.2) | −0.056 |
Bleeding events | 24 (14.8) | 25 (20.7) | −0.154 | 14.9 (10.2–21.7) | 20.1 (14.1–28.8) | −0.128 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Ganoci, L.; Palić, J.; Trkulja, V.; Starčević, K.; Šimičević, L.; Božina, N.; Lovrić-Benčić, M.; Poljaković, Z.; Božina, T. Is CYP2C Haplotype Relevant for Efficacy and Bleeding Risk in Clopidogrel-Treated Patients? Genes 2024, 15, 607. https://doi.org/10.3390/genes15050607
Ganoci L, Palić J, Trkulja V, Starčević K, Šimičević L, Božina N, Lovrić-Benčić M, Poljaković Z, Božina T. Is CYP2C Haplotype Relevant for Efficacy and Bleeding Risk in Clopidogrel-Treated Patients? Genes. 2024; 15(5):607. https://doi.org/10.3390/genes15050607
Chicago/Turabian StyleGanoci, Lana, Jozefina Palić, Vladimir Trkulja, Katarina Starčević, Livija Šimičević, Nada Božina, Martina Lovrić-Benčić, Zdravka Poljaković, and Tamara Božina. 2024. "Is CYP2C Haplotype Relevant for Efficacy and Bleeding Risk in Clopidogrel-Treated Patients?" Genes 15, no. 5: 607. https://doi.org/10.3390/genes15050607
APA StyleGanoci, L., Palić, J., Trkulja, V., Starčević, K., Šimičević, L., Božina, N., Lovrić-Benčić, M., Poljaković, Z., & Božina, T. (2024). Is CYP2C Haplotype Relevant for Efficacy and Bleeding Risk in Clopidogrel-Treated Patients? Genes, 15(5), 607. https://doi.org/10.3390/genes15050607