Clopidogrel utilization in patients with coronary artery disease and diabetes mellitus: should we determine CYP2C19*2 genotype?
- 90 Downloads
Clopidogrel non-responsiveness is multifactorial; several genetic and non-genetic factors may contribute to impaired platelet inhibition. The goal of this study is to determine the effect of the cytochrome P450 CYP2C19*2 polymorphism on the platelet response to clopidogrel in patients with and without diabetes mellitus (DM).
We conducted an observational study in patients with coronary artery disease and consequent exposure to clopidogrel therapy (75 mg/day for at least 7 consecutive days). We have analyzed two groups of patients: group I (DM patients) and group II (non-diabetes mellitus patients). Platelet reactivity was assessed by the VerifyNow P2Y12 assay and high on clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) ≥ 208. Genotyping for CYP2C19*2 polymorphism was performed by PCR-RFLP.
We have included 150 subjects (76 DM and 74 non-diabetes mellitus patients). The carriage of CYP2C19*2 allele, in DM patients, was significantly associated to HPR (odds ratio (OR) 4.437, 95% confidence interval (CI) 1.134 to 17.359; p = 0.032). Furthermore, 8.4% of the variability in percent inhibition by clopidogrel could be attributed to CYP2C19*2 carrier status. However, in non-diabetes mellitus patients, there was no significant difference in platelet response to clopidogrel according to the presence or absence of CYP2C19*2 allele carriage (OR 1.260, 95% CI 0.288 to 5.522; p = 0.759).
Our study suggests that the carriage of CYP2C19*2 polymorphism, in DM patients, might be a potential predictor of persisting HPR in these high-risk individuals.
Clinical Trials.gov NCT03373552 (Registered 13 December 2017)
KeywordsClopidogrel Cytochrome P-450 CYP2C19 Coronary artery disease Diabetes mellitus
The authors are very grateful to all patients who participated in this study.
Contributions of authors
SC designed the study, performed data analysis, and wrote the manuscript. HR, MG, and MR included the patients. RD and SHF performed genetic analysis and reviewed the manuscript. HA and AS conducted the statistical analysis. FA, FN, IH, MS, and LK supervised results. SN, KBH, FM, MFN, TM, and MH revised critically the intellectual content of the manuscript.
Compliance with ethical standards
The study protocol was approved by the Ethics Committee for Clinical Research at our center and all subjects gave informed consent for study participation.
Conflict of interest
The authors declare that they have no competing interests.
- 1.Levine GN, Bates ER, Bittl JA et al (2016) 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: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction, 2014 ACC/AHA guideline for the management of patients with non–ST-elevation acute coronary syndromes, and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation 134:e123–e155CrossRefGoogle Scholar
- 2.Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Jüni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN, ESC Scientific Document Group, ESC Committee for Practice Guidelines (CPG), ESC National Cardiac Societies (2018) 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 39(3):213–260CrossRefGoogle Scholar
- 3.Angiolillo DJ, Rollini F, Storey RF, Bhatt DL, James S, Schneider DJ, Sibbing D, So DYF, Trenk D, Alexopoulos D, Gurbel PA, Hochholzer W, de Luca L, Bonello L, Aradi D, Cuisset T, Tantry US, Wang TY, Valgimigli M, Waksman R, Mehran R, Montalescot G, Franchi F, Price MJ (2017) International expert consensus on switching platelet P2Y12 receptor-inhibiting therapies. Circulation 136(20):1955–1975CrossRefGoogle Scholar
- 5.Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS, COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group (2005) Addition of clopidogrel to aspirin in 45852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet 366:1607–1621CrossRefGoogle Scholar
- 6.Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe C, Braunwald E, CLARITY-TIMI 28 Investigators (2005) Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 352(12):1179–1189CrossRefGoogle Scholar
- 11.Stuckey TD, Kirtane AJ, Brodie BR, Witzenbichler B, Litherland C, Weisz G, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri el Jr, Gurbel PA, Mehran R, Généreux P, Ben-Yehuda O, Simonton CA, Stone GW, ADAPT-DES Investigators (2017) Impact of aspirin and clopidogrel hyporesponsiveness in patients treated with drug-eluting stents: 2-year results of a prospective, multicenter registry study. JACC Cardiovasc Interv 10(16):1607–1617CrossRefGoogle Scholar
- 12.Erathi HV, Durgaprasad R, Velam V, Pvgk S, Rodda M, C K, Kanavath SN (2018) Evaluation of On-Clopidogrel platelet reactivity overtime, SYNTAX SCORE, genetic polymorphisms and their relationship to one year clinical outcomes in STEMI patients undergoing PCI. Minerva Cardioangiol 66(1):16–25PubMedGoogle Scholar
- 13.Tang XF, Han YL, Zhang JH, Wang J, Yao Y, He C, Xu B, Gao Z, Qiao SB, Chen J, Wu Y, Chen JL, Gao RL, Yang YJ, Yuan JQ (2016) CYP2C19 genotyping combined with on-clopidogrel platelet reactivity in predicting major adverse cardiovascular events in Chinese patients with percutaneous coronary intervention. Thromb Res 147:108–114CrossRefGoogle Scholar
- 21.Price MJ, Angiolillo DJ, Teirstein PS, Lillie E, Manoukian SV, Berger PB, Tanguay JF, Cannon CP, Topol EJ (2011) Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the gauging responsiveness with a VerifyNow P2Y12 assay: impact on thrombosis and safety (GRAVITAS) trial. Circulation 124(10):1132–1137CrossRefGoogle Scholar
- 22.Aradi D, Kirtane A, Bonello L, Gurbel PA, Tantry US, Huber K, Freynhofer MK, ten Berg J, Janssen P, Angiolillo DJ, Siller-Matula JM, Marcucci R, Patti G, Mangiacapra F, Valgimigli M, Morel O, Palmerini T, Price MJ, Cuisset T, Kastrati A, Stone GW, Sibbing D (2015) Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 36(27):1762–1771CrossRefGoogle Scholar
- 23.Luo Y, Li J, Liu X, Xu J, Ye Z, Yao Y, Liu X, Lai Y (2016) Combination of P2Y12 reaction unit and percentage of platelet inhibition assessed by VerifyNowP2Y12 assay is a useful predictor of long-term clinical outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Thromb Res 139:114–120CrossRefGoogle Scholar
- 28.Verdoia M, Pergolini P, Rolla R, Nardin M, Schaffer A, Barbieri L, Marino P, Bellomo G, Suryapranata H, de Luca G (2016) Advanced age and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor. J Thromb Haemost 14(1):57–64CrossRefGoogle Scholar
- 31.Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R, Valente S, Antoniucci D, Abbate R, Gensini GF (2007) Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics 17(12):1057–1064CrossRefGoogle Scholar
- 33.Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, Valina CM, Stratz C, Schmiebusch P, Bestehorn HP, Büttner HJ, Neumann FJ (2008) Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 51(20):1925–1934CrossRefGoogle Scholar
- 34.Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS (2010) Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 376(9749):1312–1319CrossRefGoogle Scholar
- 36.Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR, Clinical Pharmacogenetics Implementation Consortium (2013) Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther 94(3):317–323CrossRefGoogle Scholar
- 37.Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC (2010) 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 376(9749):1320–1328CrossRefGoogle Scholar
- 40.Mangiacapra F, Patti G, Peace A, Gatto L, Vizzi V, Ricottini E, D'Ambrosio A, Muller O, Barbato E, di Sciascio G (2010) Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. Am J Cardiol 106(5):619–623CrossRefGoogle Scholar
- 43.Xie X, Ma YT, Yang YN, Li XM, Zheng YY, Ma X, Fu ZY, Ba·Bayinsilema, Li Y, Yu ZX, Chen Y, Chen BD, Liu F, Huang Y, Liu C, Baituola G (2013) Personalized antiplatelet therapy according to CYP2C19 genotype after percutaneous coronary intervention: a randomized control trial. Int J Cardiol 168(4):3736–3740CrossRefGoogle Scholar
- 44.Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff R, Duarte JD, Voora D, Kimmel SE, McDonough C, Gong Y, Dave CV, Pratt VM, Alestock TD, Anderson RD, Alsip J, Ardati AK, Brott BC, Brown L, Chumnumwat S, Clare-Salzler MJ, Coons JC, Denny JC, Dillon C, Elsey AR, Hamadeh IS, Harada S, Hillegass WB, Hines L, Horenstein RB, Howell LA, Jeng LJB, Kelemen MD, Lee YM, Magvanjav O, Montasser M, Nelson DR, Nutescu EA, Nwaba DC, Pakyz RE, Palmer K, Peterson JF, Pollin TI, Quinn AH, Robinson SW, Schub J, Skaar TC, Smith DM, Sriramoju VB, Starostik P, Stys TP, Stevenson JM, Varunok N, Vesely MR, Wake DT, Weck KE, Weitzel KW, Wilke RA, Willig J, Zhao RY, Kreutz RP, Stouffer GA, Empey PE, Limdi NA, Shuldiner AR, Winterstein AG, Johnson JA, IGNITE Network (2018) Multisite investigation of outcomes with implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention. JACC Cardiovasc Interv 11(2):181–191CrossRefGoogle Scholar
- 45.Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schomig A, von Beckerath N, Kastrati A (2010) Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 121(4):512–518CrossRefGoogle Scholar