Effects Of Individualized Antiplatelet Therapy Based On CYP2C19 Genotype And Platelet Function On The Prognosis Of Patients After PCI

Patients with acute coronary syndrome(ACS)are at risk of recurrent ische mic events.Percutaneous coronary intervention(PCI)is an important treatment for patients with ACS.However,even after coronary stent implantation,patient s with ACS still face the risk of cardiovascular adverse events such as in-stent thrombosis and myocardial infarction.Platelet activation and aggregation are i mportant mechanisms for the recurrence of ischemic events after PCI.Aspirin combined with a P2Yi2 receptor inhibitor(clopidogrel or ticagrelor)combined with antiplatelet therapy(dual anti platelet therapy,DAPT)is one of the standar d treatments to reduce the incidence of ischemic events in patients with corona ry heart disease after PCI.Clopidogrel is still widely used due to the adverse reactions of ticagrelor and other social and economic reasons.The antiplatelet effect of clopidogrel v aries widely among different individuals and races.Many patients still showed high on treatment platelet reactivity(HPR)after taking the conventional dose o f clopidogrel.HPR is an independent risk factor for ischemic events after PCI.CYP2C19 loss of function(LOF)allele was significantly correlated with H PR.The metabolic efficiency of clopidogrel and the effect of antiplatelet of clo pidogrel decreased in patients with CYP2C19 LOF allele.In patients treated wi th clopidogrel,the incidence of HPR and ischemic events in CYP2C19 LOF al lele carriers were significantly higher than those in non carriers.CYP2C19*2 allele is the most common CYP2C19 LOF mutation,which is not uncommon i n the population:about 15%in white and black people,29%～35%in yellow people.Therefore,it is of great significance to use individualized antiplatelet thera py for patients after PCI so that all patients,including CYP2C19 LOF allele c arriers,can get safe and sufficient antiplatelet therapy as much as possible,whi ch can effectively prevent ischemic events without increasing the risk of bleedi ng.It is getting more and more attention.However,it is not clear which indiv idual treatment is more safe and effective.In this study,the efficacy and safety of individualized antiplatelet therapy based on CYP2C19 genotype and platelet function were evaluated to explore a more safe and effective individualized antiplatelet therapy for ACS patients afte r PCI.This study mainly includes the following two parts:Part I:The effect of individualized antiplatelet therapy based on CYP2C19 genotype on platelet function in patients with acute coronary syndromeObjective:the purpose of this study was to evaluate the effect of individualized antiplatelet therapy based on CYP2C19 genotype on platelet function in patients with acute coronary syndrome(ACS)compared with conventional antiplatelet therapy.Research methods:1.Prospective research methods were used.This study included patients di agnosed as ACS in Shandong Provincial Qianfoshan Hospital from December 2014 to December 2017.2.Patients were randomly divided into conventional antiplatelet therapy group(CA)and individualized antiplatelet therapy group(IA)at 1:1.In CA Group,clopidogrel was administered once a day(QD).According to the CYP2C19 gene detection results,IA group was divided into three gene metabolic types,namely,extended metabolizers(EMs),intermediate metabolizers(IMs)and poor metabolizers(PMs).Clopidogrel 75 mg QD,Clopidogrel 75 mg twice a day(BID)and ticagrelor 90 mg BID were taken respectively.3.At least 6 hours after taking 300 mg loading dose of clopidogrel,at least 2 days after taking maintenance dose clopidogrel,at least 2 hours after taking 180 mg loading dose of ticagrelor,and at least 6 hours after taking maintenance of ticagrelor,platelet function was monitored by thromboelastograph(TEG)and MAADP values was recorded.MAADP is the platelet-fibrin blood clot strength induced by adenosine diphosphate(ADP),which can respond to the ADP induced platelet function that not inhibited by drugs.High platelet reactivity(HPR)was defined as MAADP>47mm,indicating a high risk of thrombus,and MAADP ≤ 31mm indicates a high risk of bleeding.Result:1.A total of 1063 patients with ACS were included in this study.There were 530 cases in CA Group and 533 cases in IA group.There was no statistical difference in the basic clinical data between the two groups.2.The number of EMs,IMs and PMs in IA group was 272(51.0%),194(36.4%)and 67(12.6%)respectively.The proportion of patients with CYP2C19 LOF gene was 49%,which was similar to the incidence of CYP2C19*2 and*3 allele mutations in Chinese Han population previously reported in the literature.3.The proportion of patients with MAADP>47mm in the IA group(158,29.6%)was significantly lower than that in the CA group(202,38.1%).The proportion of patients with MAADP≤31 mm in the IA group(165,31.0%)was significantly higher than that in the CA group(113,21.3)(P<0.001).4.1n the IA group,the number of patients with MAADP>47mm in IMs and EMs was 62(32.0%)and 90(33.1%)respectively,and the number of patients with MAADP≤31 mm was 51(26.3%)and 69(25.4%)respectively,and there was no significant difference between CA and IA group(P=0.959).Conclusion:1.The individualized antiplatelet therapy based on CYP2C19 genotyping enabled ACS patients to obtain stronger platelet inhibition than the conventional aspirin plus clopidogrel therapy and reduced the incidence of HPR.2.Patients with a CYP2C19 LOF gene who take double doses of clopidogrel overcome the decreased efficacy of clopidogrel which partly due to CYP2C19 LOF gene,without increasing the risk of bleeding.Part Ⅱ the effect of individualized antiplatelet therapy based on CYP2C19 genotype and platelet function on the prognosis of patients after PCIObjective:This study was designed to evaluate the effect of individualized antiplatelet therapy based on CYP2C19 genotype and platelet function on the prognosis of patients after percutaneous coronary intervention(PCI)compared with conventional antiplatelet therapy.Research methods:1.Prospective study method was used.This study included ACS patients who received PCI in Shandong Provincial Qianfoshan Hospital from December 2014 to December 2017.2.Patients were randomly divided into conventional antiplatelet therapy group(CA)and individualized antiplatelet therapy group(IA)at 1:1.In CA Group,clopidogrel was administered once a day(QD).According to the CYP2C19 gene detection results,IA group was divided into three gene metabolic types:extended metabolizers(EMs),intermediate metabolizers(IMs)and poor metabolizers(PMs).Clopidogrel 75 mg QD,Clopidogrel 75 mg twice a day(BID)and ticagrelor 90 mg BID were taken respectively.3.At least 6 hours after taking 300 mg loading dose of clopidogrel,at least 2 days after taking maintenance dose clopidogrel,at least 2 hours after taking 180 mg loading dose of ticagrelor,and at least 6 hours after taking maintenance of ticagrelor,platelet function was monitored by thromboelastograph(TEG)and MAADP values was recorded.MAADP is the platelet-fibrin blood clot strength induced by adenosine diphosphate(ADP),which can respond to the ADP induced platelet function that not inhibited by drugs.High platelet reactivity(HPR)was defined as MAADP>47mm,indicating a high risk of thrombus,and MAADP≤31mm indicates a high risk of bleeding.4.For EMs patients with HPR,the antiplatelet treatment will changed or unchanged decided by the clinician according to the patient’s conditions:changed the dosage of clopidogrel to 75mg bid,or changed clopidogrel to ticagrelor(90 mg BID),or maintained the original treatment.For IMs patients with HPR,the antiplatelet treatment will changed or unchanged decided by the clinician according to the patient’s conditions:changed clopidogrel to ticagrelor(90 mg BID),or maintained the original treatment.5.The main adverse cardiovascular events(MACE)and bleeding events were monitored after 1 year follow-up.Results:1.This study included 617 patients with ACS after PCI,306 patients in CA group and 311 patients in IA group.There was no significant difference in basic clinical data between the two groups.2.A total of 311 patients were included in the IA group.The EMs,IMs and PMs were 150(48.2%),117(37.6%)and 44(14.2%)respectively.The proportion of patients carrying CYP2C19 LOF gene was 51.9%.The incidence of*2 and*3 of CYP2C19 LOF alleles was 33.2%,which was similar to that of CYP2C19*2 and*3 alleles in Chinese Han population reported in previous literature.3.The patients with MAADP>47mm were 89(29.1%)in the CA group,89(28.6%)in the IA group,50(33.3%)in the EMs,36(30.8%)in the IMs and 3(6.8%)in the PMs.The patients with MAADP ≤31mm were 87(28.4%)in the CA group,97(31.2%)in the IA group,38(25.3%)in the EMs,28(23.9%)in the IMs and 31(70.5%)in the PMs.There was no significant difference in MAADP classification(≤ 31mm,31mm<MAADP≤47 mm,>47mm)between CA group and IA group(P=0.740).There was no significant difference between EMs and IMs(P=0.808).There were significant differences between PMs and EMs,PMs and IMs(P<0.001).There was no significant difference in the value of MAADP between CA group and IA group(P=0.341).There was no significant difference in the value of MAADP between CA group,IA group,EMs,IMs(all had P>0.05).There were significant differences between PMs and CA group,PMs and EMs,PMs and IMs(all had P<0.001).4.In the IA group,there were 50 EMs patients with MAADP>47mm(33.3%).Of which,there were 2 cases who changed the dosage of clopidogrel to 75mg BID,14 cases who changed clopidogrel to ticagrelor,1 case who changed clopidogrel to ticagrelor then changed back to clopidogrel because of the adverse effects of dyspnea of ticagrelor,and the other 33 cases maintained the original treatment.There were 36 IMs patients with MAADP>47mm(30.8%).Of which,there were 19 cases who changed clopidogrel to ticagrelor,1 case who changed clopidogrel to ticagrelor then changed back to clopidogrel because of outpatient health insurance medication restrictions,and the other 16 cases maintained the original treatment.5.Within 1 year after PCI,MACE occurred in 23 cases(7.5%)in CA group:non-fatal myocardial infarction in 16 cases(5.2%),in-stent thrombosis in 2 cases(0.7%),and all-cause death in 6 cases(2.0%).Among them,1 case of myocardial infarction were caused by in-stent thrombosis,a total of 1 cases were counted as MACE,and the number was not repeated.In the IA group,MACE occurred in 9 cases(2.9%),non-fatal myocardial infarction in 5 cases(1.6%),in-stent thrombosis in 1 case(0.3%),and all-cause death in 4 cases(1.3%).Among them,1 case died after in-stent thrombosis,1 case was counted as MACE,and the count was not repeated.The incidences of MACE,non-fatal myocardial infarction in the IA group were significantly lower than those in the CA group(P=0.010;P=0.013).There was no significant difference in the incidence of in-stent thrombosis and all-cause death between the CA group and the IA group(P=0.553;P=0.507).6.Within one year after PCI,moderate or severe bleeding events occurred in 7 cases in the CA group and 9 cases in the IA group.There was no significant difference between the two groups(P=0.636).7.Multiple Logiatic regression analysis showed that age(P=0.001)was the risk factor for MACE within 1 year after PCI in ACS patients,while history of diabetes mellitus(P=0.011)and MAADP value(P=0.015)were were risk factors for non-fatal myocardial infarction within 1 year after PCI in ACS patients.Conclusion:1.Patients with a CYP2C19 LOF gene who take double doses of clopidogrel overcome the decreased efficacy of clopidogrel which partly due to CYP2C19 LOF gene,without increasing the risk of bleeding.2.Individualized antiplatelet therapy based on CYP2C19 genotype and platelet function significantly reduced the incidence of MACE after PCI without increasing the risk of moderate or severe bleeding.