Significance of CYP2C19 gene in guiding antiplatelet therapy after OPCAB

doi:10.3760/cma.j.issn.1007-1245.2022.04.004

Abstract

Abstract: Objective　To investigate whether dual antiplatelet therapy guided by CYP2C19 gene detection results can reduce the incidence of major adverse cardiovascular events (MACE) and its impact on bleeding complications after off-pump coronary artery bypass grafting (OPCAB). Methods　A total of 158 patients scheduled for OPCAB in The First Affiliated Hospital of Henan University of Science and Technology from January 2018 to September 2020 were divided into a gene guidance group and a traditional treatment group with the random number table. The gene guidance group was subdivided into a fast metabolizing subgroup and a non-fast metabolizing subgroup according to CYP2C19 gene. The patients in the fast metabolizing subgroup were given aspirin combined with clopidogrel antiplatelet therapy after OPCAB, and the patients in the non-fast metabolizing subgroup were given aspirin combined with ticagrelor. The traditional treatment group was randomly subdivided into a clopidogrel subgroup and a ticagrelor subgroup, and the patients were treated with aspirin combined with clopidogrel or ticagrelor respectively. The incidences of MACE and bleeding within 30 days and 6 months after surgery were compared. Independent sample t test was used for the measurement data, and χ² test was used for the count data. Results　Among 158 patients, 31 patients withdrew from the study because they did not meet the criteria, and 127 patients were eventually enrolled. There were 63 patients in the gene guidance group, including 42 males and 21 females, aged (62.65±7.88) years, and there were 20 patients in the fast metabolizing subgroup and 43 patients in the non-fast metabolizing subgroup according to CYP2C19 gene. There were 64 patients in the traditional treatment group, including 45 males and 19 females, aged (61.91±8.99) years, and they were randomly subdivided into a clopidogrel subgroup (32 cases) and a ticagrelor subgroup (32 cases). The incidence of MACE within 30 days after surgery was 1.6% (1/63) in the gene guidance group and 10.9% (7/64) in the traditional treatment group, respectively, with a statistically significant difference between the two groups (χ²=4.703, P=0.030); the incidence of MACE within 6 months after surgery was 3.2% (2/63) in the gene guidance group and 14.1% (9/64) in the traditional treatment group, respectively, with a statistically significant difference between the two groups (χ²=5.757, P=0.029). The incidence of bleeding within 30 days after surgery was 6.3% (4/63) in the gene guidance group and 10.9% (7/64) in the traditional treatment group, respectively, without statistically significant difference between the two groups (χ²=0.845, P=0.358); the incidence of bleeding within 6 months after surgery was 7.9% (5/63) in the gene guidance group and 12.5% (8/64) in the traditional treatment group, respectively, without statistically significant difference between the two groups (χ²=0.720, P=0.396). Conclusion　Precise dual antiplatelet therapy based on CYP2C19 gene detection can reduce the incidence of MACE after OPCAB without increasing the risk of bleeding.

Key words: CYP2C19 gene, OPCAB, Clopidogrel, Ticagrelor, Major adverse cardiovascular events

摘要： 目的　探讨根据CYP2C19基因检测结果指导非体外循环冠脉旁路移植术（OPCAB）后患者双联抗血小板治疗可否减少主要心血管不良事件（MACE）发生率及其对出血并发症的影响。方法　选择2018年1月至2020年9月入住河南科技大学第一附属医院拟行OPCAB患者158例为研究对象，按随机数字表法分为基因指导组和传统治疗组，基因指导组根据CYP2C19基因不同分为快代谢型亚组和非快代谢型亚组，快代谢型亚组患者OPCAB术后给予阿司匹林联合氯吡格雷抗血小板治疗，非快代谢型亚组予阿司匹林联合替格瑞洛；传统治疗组随机分为氯吡格雷亚组和替格瑞洛亚组，术后分别予阿司匹林联合氯吡格雷或替格瑞洛治疗。比较患者术后30 d及术后6个月MACE及出血发生率。计量资料采用独立样本t检验，计数资料采用χ²检验。结果　158例患者中，因不符合标准，31例患者先后退出本研究，最终入组127例患者。基因指导组患者63例，其中男42例、女21例，年龄（62.65±7.88）岁，根据CYP2C19基因不同分为快代谢型亚组20例、非快代谢型亚组43例；传统治疗组患者64例，其中男45例、女19例，年龄（61.91±8.99）岁，随机分为氯吡格雷亚组32例、替格瑞洛亚组32例。基因指导组和传统治疗组术后30 d的MACE发生率分别为1.6%（1/63）、10.9%（7/64），组间比较差异有统计学意义（χ²=4.703，P=0.030）；术后6个月MACE发生率分别为3.2%（2/63）、14.1%（9/64），组间比较差异有统计学意义（χ²=5.757，P=0.029）。基因指导组和传统治疗组患者术后30 d出血并发症发生率分别为6.3%（4/63）、10.9%（7/64），组间比较差异无统计学意义（χ²=0.845，P=0.358）；术后6个月出血并发症发生率分别为7.9%（5/63）、12.5%（8/64），组间比较差异无统计学意义（χ²=0.720，P=0.396）。结论　基于CYP2C19基因检测进行精准双联抗血小板治疗可减少OPCAB术后MACE发生率，且不增加出血风险。

关键词: CYP2C19基因, 非体外循环冠脉旁路移植术, 氯吡格雷, 替格瑞洛, 主要心血管不良事件

Zhang Xianfen, Zhang Dianbao, Han Wanqing, Wang Yongsheng. Significance of CYP2C19 gene in guiding antiplatelet therapy after OPCAB[J]. International Medicine and Health Guidance News, 2022, 28(4): 459-463.

张宪芬, 张殿宝, 韩婉青, 王永生. CYP2C19基因指导非体外循环冠脉旁路移植术后抗血小板治疗的意义[J]. 国际医药卫生导报, 2022, 28(4): 459-463.

References

[1] Halabi AR, Alexander JH, Shaw LK, et al. Relation of early saphenous vein graft failure to outcomes following coronary artery bypass surgery[J]. Am J Cardiol,2005,96(9):1254-1259. DOI:10.1016/j.amjcard.2005.06.067.

[2] Gaudino M, Antoniades C, Benedetto U, et al. Mechanisms, consequences, and prevention of coronary graft failure[J].Circulation,2017,136(18):1749-1764. DOI:10.1161/CIRCULATIONAHA.117.027597.

[3] Ferraris VA, Ferraris SP, Moliterno DJ, et al. The Society of Thoracic Surgeons practice guideline series: aspirin and other antiplatelet agents during operative coronary revascularization (executive summary) [J].Ann Thorac Surg,2005,79(4):1454-1461. DOI:10.1016/j.athoracsur. 2005.01.008.

[4] Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease[J].N Engl J Med,2009,360(10):961-972. DOI:10.1056/NEJMoa0804626.

[5] Gao G, Zheng Z, Pi Y, et al. Aspirin plus clopidogrel therapy increases early venous graft patency after coronary artery bypass surgery a single-center, randomized, controlled trial[J].J Am Coll Cardiol,2010,56(20):1639-1643. DOI:10.1016/j.jacc.2010.03.104.

[6] Mannacio VA, Di Tommaso L, Antignan A, et al. Aspirin plus clopidogrel for optimal platelet inhibition following off-pump coronary artery bypass surgery: results from the CRYSSA (prevention of Coronary arteRY bypaSS occlusion After off-pump procedures) randomised study[J].Heart,2012,98(23):1710-1715. DOI:10.1136/heartjnl-2012-302449.

[7] Gurbuz AT, Zia AA, Vuran AC, et al. Postoperative clopidogrel improves mid-term outcome after off-pump coronary artery bypass graft surgery: a prospective study[J].Eur J Cardiothorac Surg,2006,29(2):190-195. DOI:10.1016/j.ejcts.2005.11.033.

[8] Kulik A, Ruel M, Jneid H, et al. Secondary prevention after coronary artery bypass graft surgery: a scientific statement from the American Heart Association[J].Circulation,2015,131(10):927-964. DOI:10.1161/CIR.0000000000000182.

[9] Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes[J].N Engl J Med,2009,361(11):1045-1057. DOI: 10.1056/NEJMoa0904327.

[10] Wiviott SD, Antman EM. Clopidogrel resistance: a new chapter in a fast-moving story[J].Circulation,2004,109(25):3064-3067. DOI:10.1161/01.CIR.0000134701. 40946.30.

[11] van Werkum JW, Heestermans AA, Deneer VH, et al. Clopidogrel resistance: fact and fiction[J].Future Cardiol,2006,2(2):215-228. DOI:10.2217/14796678.2.2.215.

[12] Roberts DI, Nawarskas JJ. Treatment options for patients with poor clopidogrel response[J].Cardiol Rev,2013,21(6):309-317. DOI:10.1097/CRD.0b013e3182a72fab.

[13] Ford NF. Clopidogrel resistance: pharmacokinetic or pharmacogenetic?[J]. J Clin Pharmacol,2009,49(5):506-512. DOI:10.1177/0091270009332433.

[14] Hassani Idrissi H, Hmimech W, Khorb NE, et al. A synergic effect between CYP2C19*2, CYP2C19*3 loss-of-function and CYP2C19*17 gain-of-function alleles is associated with Clopidogrel resistance among Moroccan Acute Coronary Syndromes patients[J].BMC Res Notes,2018,11(1):46. DOI:10.1186/s13104-018-3132-0.

[15] Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel[J].N Engl J Med,2009,360(4):354-362. DOI:10.1056/NEJMoa0809171.

[16] Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy[J].JAMA,2009,302(8):849-857. DOI:10.1001/jama.2009.1232.

[17] Held C, Asenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial[J].J Am Coll Cardiol,2011,57(6):672-684. DOI:10.1016/j.jacc.2010.10.029.

[18] Toma N. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of Ticagrelor versus Clopidogrel in patients with stable coronary artery disease. The ONSET/OFFSET study[J].Maedica (Bucur),2010,5(1):75-76.

[19] Tang Y, Fan X, Zhang B, et al. Aspirin plus ticagrelor or clopidogrel on graft patency one year after coronary bypass grafting: a single-center, randomized, controlled trial[J].J Thorac Dis,2021,13(3):1697-1705. DOI:10.21037/jtd-20-3407.

[20] Hicks KA, Tcheng JE, Bozkurt B, et al. 2014 ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials: a report of the American College of Cardiology/American Heart Association task force on clinical data standards (writing committee to develop cardiovascular endpoints data standards)[J].J Am Coll Cardiol,2015,66(4):403-469. DOI:10.1016/j.jacc.2014. 12.018.

[21] Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium[J].Circulation,2011,123(23):2736-2747. DOI:10.1161/CIRCULATIONAHA.110.009449.

[22] Aldea GS, Bakaeen FG, Pal J, et al. The Society of Thoracic Surgeons clinical practice guidelines on arterial conduits for coronary artery bypass grafting[J].Ann Thorac Surg,2016,101(2):801-809. DOI:10.1016/j.athoracsur.2015. 09.100.

[23] Goldman S, Zadina K, Moritz T, et al. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study[J].J Am Coll Cardiol,2004,44(11):2149-2156. DOI:10.1016/j.jacc.2004.08.064.

[24] Parang P, Arora R. Coronary vein graft disease: pathogenesis and prevention[J].Can J Cardiol,2009,25(2):e57-e62. DOI:10.1016/s0828-282x(09)70486-6.

[25] Farooq V, Serruys PW, Bourantas C, et al. Incidence and multivariable correlates of long-term mortality in patients treated with surgical or percutaneous revascularization in the synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) trial[J].Eur Heart J,2012,33(24):3105-3113. DOI:10.1093/eurheartj/ehs367.

[26] Price MJ, Murray SS, Angiolillo DJ, et al. Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study[J].J Am Coll Cardiol,2012,59(22):1928-1937. DOI:10.1016/j.jacc.2011.11.068.