基于CYP2C19基因检测指导下的氯吡格雷和换用替格瑞洛个体化用药分析
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摘要
目的探讨CPY2C19基因多态性对氯吡格雷及换用替格瑞洛治疗急性冠脉综合征不良事件的影响,为临床个体化用药提供参考。方法选择2015年03月～2018年03月入住我院心血管内科的急性冠脉综合征患者1 086例为研究对象,根据患者是否同意做CPY2C19基因检测进行分组,A组为未进行基因检测,常规使用氯吡格雷+阿司匹林,B、C、D组患者采用实时荧光定量PCR方法进行CYP2C19基因型检测,B组(超快代谢型和快代谢型)同A组常规用药,C组(中间代谢型),采用双倍氯吡格雷+阿司匹林方案,D组(慢代谢型),采用双倍氯吡格雷+阿司匹林(D1组)或替格瑞洛+阿司匹林(D2组)方案,比较4组间患者主要不良事件和次要不良事件的发生情况。结果 A、B、C和D 4组间主要不良事件发生率及支架内血栓发生率有显著差异(P <0. 05),A组支架内血栓发生率显著高于B和C组(P <0. 05)。次要不良事件中靶血管重建和心源性再入院发生率在4组间存在显著差异(P均<0. 05),A组靶血管重建显著高于B和C组(P <0. 01),A组心源性再入院发生率显著高于B、C和D组(P <0. 01)。C组与D1组相比,D1组次要不良事件发生率、支架内血栓、靶血管重建和心源性再入院发生率均显著高于C组(P均<0. 05)。D2组与D1组相比,D1组心源性再入院发生率显著高于D2组(P <0. 05),但D2组出血事件偏高。结论经CPY2C19基因检测对急性冠脉综合征患者进行个体化给药,显著降低不良事件发生率,有极大的指导意义,同时要注意超快代谢型出血事件的发生。
OBJECTIVE To investigate the adverse events of CYP2 C19 gene polymorphism on clopidogrel and ticagrelor in the treatment of acute coronary syndrome and provide reference for clinical individualized medication. METHODS The total of 1 086 patients with acute coronary syndrome were selected as the subjects in the cardiovascular department of Zhengzhou Central Hospital Affiliated to Zhengzhou University from March 2015 to March 2018. The patients were grouped according to whether they agreed to do the CPY2 C19 gene test or not. The patients who didn't carry out CYP2 C19 gene testing were given routine dosage( Group A,75 mg clopidogrel and 100 mg aspirin). The CYP2 C19 genotype was detected by real-time fluorescence quantitative PCR for patients in group B,group C and group D. According to the genotype,patients were divided into three groups: group B( super fast metabolism and fast metabolism,75 mg clopidogrel and 100 mg aspirin),group C( intermediate metabolism,150 mg clopidogrel dosage and 100 mg aspirin),group D( slow metabolism,150 mg clopidogrel dosage and 100 mg aspirin or 180 mg ticagrelor and 100 mg aspirin). The incidence of major adverse events and minor adverse events were compared among the four groups. RESULTS There was significant differences in the incidence of major adverse events and stent thrombosis among group A,group B,group C and group D( P < 0. 05). The incidence of stent thrombosis in group A was significantly higher than that in group B and group C,respectively( all P < 0. 05). There were significant differences in the incidence of target vessel reconstruction and cardiogenic readmission among the four groups( all P < 0. 05).The target vessel reconstruction in group A was significantly higher than that in group B and group C( P < 0. 01). The cardiogenic readmission in group A was significantly higher than that in group B,group C and group D( all P < 0. 01). Compared with group D1,the incidence of secondary adverse events,stent thrombosis,target vessel reconstruction and cardiogenic readmission in group D1 were significantly higher than those in group C( all P < 0. 05). Compared with D1 group,the incidence of cardiogenic readmission in group D1 was significantly higher than that in group D2( P < 0. 05),but the incidence of bleeding was high in group D2. CONCLUSION The CPY2 C19 gene detection for individualized administration to patients with acute coronary syndrome can significantly reduce the incidence of adverse events,which is of great guiding significance. It is necessary to pay attention to the occurrence of bleeding events for patients with ultra-fast metabolic.
OBJECTIVE To investigate the adverse events of CYP2 C19 gene polymorphism on clopidogrel and ticagrelor in the treatment of acute coronary syndrome and provide reference for clinical individualized medication. METHODS The total of 1 086 patients with acute coronary syndrome were selected as the subjects in the cardiovascular department of Zhengzhou Central Hospital Affiliated to Zhengzhou University from March 2015 to March 2018. The patients were grouped according to whether they agreed to do the CPY2 C19 gene test or not. The patients who didn't carry out CYP2 C19 gene testing were given routine dosage( Group A,75 mg clopidogrel and 100 mg aspirin). The CYP2 C19 genotype was detected by real-time fluorescence quantitative PCR for patients in group B,group C and group D. According to the genotype,patients were divided into three groups: group B( super fast metabolism and fast metabolism,75 mg clopidogrel and 100 mg aspirin),group C( intermediate metabolism,150 mg clopidogrel dosage and 100 mg aspirin),group D( slow metabolism,150 mg clopidogrel dosage and 100 mg aspirin or 180 mg ticagrelor and 100 mg aspirin). The incidence of major adverse events and minor adverse events were compared among the four groups. RESULTS There was significant differences in the incidence of major adverse events and stent thrombosis among group A,group B,group C and group D( P < 0. 05). The incidence of stent thrombosis in group A was significantly higher than that in group B and group C,respectively( all P < 0. 05). There were significant differences in the incidence of target vessel reconstruction and cardiogenic readmission among the four groups( all P < 0. 05).The target vessel reconstruction in group A was significantly higher than that in group B and group C( P < 0. 01). The cardiogenic readmission in group A was significantly higher than that in group B,group C and group D( all P < 0. 01). Compared with group D1,the incidence of secondary adverse events,stent thrombosis,target vessel reconstruction and cardiogenic readmission in group D1 were significantly higher than those in group C( all P < 0. 05). Compared with D1 group,the incidence of cardiogenic readmission in group D1 was significantly higher than that in group D2( P < 0. 05),but the incidence of bleeding was high in group D2. CONCLUSION The CPY2 C19 gene detection for individualized administration to patients with acute coronary syndrome can significantly reduce the incidence of adverse events,which is of great guiding significance. It is necessary to pay attention to the occurrence of bleeding events for patients with ultra-fast metabolic.
引文
[1]KUSHNER F G,HAND M,SMITH S C,et al.2009 focused updates:ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction(updating the 2004guideline and2007focused update)and ACC/AHA/SCAI guidelines on percutaneous coronary intervention(updating the 2005guideline and 2007 focused update)a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines[J].J Am Coll Cardiol,2009,54(23):2205-2241.
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[3]SIMON T,VERSTUYFT C,MARY-KRAUSE M,et al.Genetic determinants of response to clopidogrel and cardiocascular events[J].N Engl J Med,2009,360(4):363-375.
[4]MEGA J L,CLOSE S L,WIVIOTT S D,et al.Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial:a pharmacogenetic analysis[J].Lancet,2010,376(9749):1312-1319.
[5]GONZALEZ A,MONICHE F,CAYUELA A,et al.Effect of CYP2C19 polymorphisms on the platelet response to clopidogrel and influence on the effect of high versus standard dose clopidogrel in carotid artery stenting[J].Eur J Vasc Endocasc Surg,2016,51(2):175-186.
[6]GAEDIGK A,INGELMAN-SUNDBERG M,MILLER N A,et al.The pharmacogene variation(Pharm Var)consortium:incorporation of the human cytochrome P450(CYP)allele nomenclature database[J].Clin Pharmacol Ther,2018,103(3):399-401.
[7]KIKKERT W J,GELOVEN N,LAAN M H,et al.The prognostic value of bleeding academic research consortium(BARC)-defined bleeding complications in ST-segment elevation myocardial infarction:a comparison with the TIMI(Thrombolysis In Myocardial Infarction),GUSTO(Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries),and ISTH(International Society on Thrombosis and Haemostasis)Bleeding Classifications[J].J Am Coll Cardiol,2014,63(18):1866-1875.
[8]SUN Y M,CUI M X,LI W B,et al.Research progress on clinical gene polymorphism of clopidogrel resistance[J].Chin Pharm J(中国药学杂志),2018,53(18):1529-1535.
[9]CHARFI R,MZOUGHI K,BOUGHALLEB M,et al.Response to clopidogrel and of the cytochrome CYP2C19 gene polymorphism[J].Tunis Med,2018,96(3):209-218.
[10]LIN J,HAN Z,WANG C,et al.Dual therapy with clopidogrel and aspirin prevents early neurological deterioration in ischemic stroke patients carrying CYP2C19*2 reduced-function alleles[J].Eur J Clin Pharmacol,2018,74(9):1131-1140.
[11]DONG J,SHI G H,HUANG S,et al.Correlation between CYP2C19,ABCB1,PON1 gene polymorphism and clopidogrel antiplatelet aggregation reactivity[J].Chin J Hosp Pharm(中国医院药学杂志),2018,11(1):1-7.
[12]JUPITER D C,FANG X,ADHIKARI D,et al.Safety of continued clopidogrel use in the preoperative course of gastrointestinal surgery:a retrospective cohort study[J].Ann Surg,2017,265(2):370-378.
[13]SAMANT S,JIANG X L,PELTIER L A,et al.Identifying clinically relevant sources of variability:the clopidogrel challengel[J].Clin Pharmacol Ther,2017,101(2):264-273.
[14]CLAVIJO L C,AL-ASADY N,DHILLON A,et al.Prevalence of high on-treatment(aspirin and clopidogrel)platelet reactivity in patients with critical limb ischemia[J].Cardiovasc Revasc Med,2018,19(5 Pt A):516-520.
[15]HULOT J S,COLLET J P,SILVAIN J,et al.Cardiovascular risk in clopidogrel-treated patients according to cytochrome P4502C19*2 loss-of-function allelte or proton pump inhibitor coadministration:a systematic meta-analysis[J].J Am Coll Cardiol,2010,56(2):134-143.
[16]CHEN S,ZHANG Y,WANG L,et al.Effects of dual-dose clopidogrel,clopidogrel combined with Tongxinluo capsule,and ticagrelor on patients with coronary heart disease and CYP2C19*2gene mutation after percutaneous coronary interventions(PCI)[J].Med Sci Monit,2017,23:3824-3830.
[17]AMSTERDAM E A,WENGER N K,BRINDIS R G,et al.2014 AHA/ACC guidline for the management of patients with non-ST-elevation acute coronary syndromes:a report of American College of Cardiology/American Heart Association Task Force on Practice Guidelines[J].J Am Coll Cardiol,2014,64(24):e139-e228.
[18]ARSLAN F,BONGARTZ L,TEN BERG J M,et al.2017 ESCguidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation:comments from the Dutch ACS working group[J].Neth Heart,2018,26(9):417-421.
[19]HU Y,REN W,MEI D,et al.Analysis on drug therapy in a patient with in-stent restenosis[J].Chin Pharm J(中国药学杂志),2017,52(22):2047-2050.
[20]HUANG L,WANG X Q,WU X P,et al.Antiplatelet and prognostic effects of ticagrelor and clopidogrel in diabetes patients with acute coronary syndrome after percutaneous coronary intervention[J].Chin J Mult Organ Dis Elderly(中华老年多器官疾病杂志),2017,11(16):846-849.
[21]LINDHOLM D,VARENHORST C,CANNON C P,et al.Ticagrelor vs.clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization:results from the PLATO trial[J].Eur Heart J,2014,35(31):2083-2093.
[22]LIN L J,TANG F K,HUA N,et al.Comparison study of the effects of ticagrelor and a double dose of clopidogrel on the incidence of cardiovascular ischemic events in patients with mutant CYP2C19 after percutaneous coronary intervention[J].Chin JMult Organ Dis Elderly(中华老年多器官疾病杂志),2018,17(9):647-651.
[2]ANTMAN E M,HAND M,ARMSTRONG P W,et al.2007 focused update of the ACC/AHA 2004guidelines for the management of patients with ST-elevation myocardial infarction:a report of the Ametican College of Cardiology/American Heart Association task force on practice guidelines[J].Circulation,2008,117(2):296-329.
[3]SIMON T,VERSTUYFT C,MARY-KRAUSE M,et al.Genetic determinants of response to clopidogrel and cardiocascular events[J].N Engl J Med,2009,360(4):363-375.
[4]MEGA J L,CLOSE S L,WIVIOTT S D,et al.Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial:a pharmacogenetic analysis[J].Lancet,2010,376(9749):1312-1319.
[5]GONZALEZ A,MONICHE F,CAYUELA A,et al.Effect of CYP2C19 polymorphisms on the platelet response to clopidogrel and influence on the effect of high versus standard dose clopidogrel in carotid artery stenting[J].Eur J Vasc Endocasc Surg,2016,51(2):175-186.
[6]GAEDIGK A,INGELMAN-SUNDBERG M,MILLER N A,et al.The pharmacogene variation(Pharm Var)consortium:incorporation of the human cytochrome P450(CYP)allele nomenclature database[J].Clin Pharmacol Ther,2018,103(3):399-401.
[7]KIKKERT W J,GELOVEN N,LAAN M H,et al.The prognostic value of bleeding academic research consortium(BARC)-defined bleeding complications in ST-segment elevation myocardial infarction:a comparison with the TIMI(Thrombolysis In Myocardial Infarction),GUSTO(Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries),and ISTH(International Society on Thrombosis and Haemostasis)Bleeding Classifications[J].J Am Coll Cardiol,2014,63(18):1866-1875.
[8]SUN Y M,CUI M X,LI W B,et al.Research progress on clinical gene polymorphism of clopidogrel resistance[J].Chin Pharm J(中国药学杂志),2018,53(18):1529-1535.
[9]CHARFI R,MZOUGHI K,BOUGHALLEB M,et al.Response to clopidogrel and of the cytochrome CYP2C19 gene polymorphism[J].Tunis Med,2018,96(3):209-218.
[10]LIN J,HAN Z,WANG C,et al.Dual therapy with clopidogrel and aspirin prevents early neurological deterioration in ischemic stroke patients carrying CYP2C19*2 reduced-function alleles[J].Eur J Clin Pharmacol,2018,74(9):1131-1140.
[11]DONG J,SHI G H,HUANG S,et al.Correlation between CYP2C19,ABCB1,PON1 gene polymorphism and clopidogrel antiplatelet aggregation reactivity[J].Chin J Hosp Pharm(中国医院药学杂志),2018,11(1):1-7.
[12]JUPITER D C,FANG X,ADHIKARI D,et al.Safety of continued clopidogrel use in the preoperative course of gastrointestinal surgery:a retrospective cohort study[J].Ann Surg,2017,265(2):370-378.
[13]SAMANT S,JIANG X L,PELTIER L A,et al.Identifying clinically relevant sources of variability:the clopidogrel challengel[J].Clin Pharmacol Ther,2017,101(2):264-273.
[14]CLAVIJO L C,AL-ASADY N,DHILLON A,et al.Prevalence of high on-treatment(aspirin and clopidogrel)platelet reactivity in patients with critical limb ischemia[J].Cardiovasc Revasc Med,2018,19(5 Pt A):516-520.
[15]HULOT J S,COLLET J P,SILVAIN J,et al.Cardiovascular risk in clopidogrel-treated patients according to cytochrome P4502C19*2 loss-of-function allelte or proton pump inhibitor coadministration:a systematic meta-analysis[J].J Am Coll Cardiol,2010,56(2):134-143.
[16]CHEN S,ZHANG Y,WANG L,et al.Effects of dual-dose clopidogrel,clopidogrel combined with Tongxinluo capsule,and ticagrelor on patients with coronary heart disease and CYP2C19*2gene mutation after percutaneous coronary interventions(PCI)[J].Med Sci Monit,2017,23:3824-3830.
[17]AMSTERDAM E A,WENGER N K,BRINDIS R G,et al.2014 AHA/ACC guidline for the management of patients with non-ST-elevation acute coronary syndromes:a report of American College of Cardiology/American Heart Association Task Force on Practice Guidelines[J].J Am Coll Cardiol,2014,64(24):e139-e228.
[18]ARSLAN F,BONGARTZ L,TEN BERG J M,et al.2017 ESCguidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation:comments from the Dutch ACS working group[J].Neth Heart,2018,26(9):417-421.
[19]HU Y,REN W,MEI D,et al.Analysis on drug therapy in a patient with in-stent restenosis[J].Chin Pharm J(中国药学杂志),2017,52(22):2047-2050.
[20]HUANG L,WANG X Q,WU X P,et al.Antiplatelet and prognostic effects of ticagrelor and clopidogrel in diabetes patients with acute coronary syndrome after percutaneous coronary intervention[J].Chin J Mult Organ Dis Elderly(中华老年多器官疾病杂志),2017,11(16):846-849.
[21]LINDHOLM D,VARENHORST C,CANNON C P,et al.Ticagrelor vs.clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization:results from the PLATO trial[J].Eur Heart J,2014,35(31):2083-2093.
[22]LIN L J,TANG F K,HUA N,et al.Comparison study of the effects of ticagrelor and a double dose of clopidogrel on the incidence of cardiovascular ischemic events in patients with mutant CYP2C19 after percutaneous coronary intervention[J].Chin JMult Organ Dis Elderly(中华老年多器官疾病杂志),2018,17(9):647-651.