Investigation Of Relationship Between Genotype-Guided Oral Antiplatelet Therapy Selection And Clinical Outcomes After Percutaneous Coronary Intervention

Part Ⅰ.Implementation of CYP2C19 Genotyping and Clinical Outcomes Following Percutaneous Coronary Intervention in Patients Treated with Oral P2Y12 InhibitorsBackgroundDual antiplatelet therapy(DAPT)comprised of aspirin and a P2Y12 receptor inhibitor represents the standard care for patients undergoing percutaneous coronary intervention(PCI).Clopidogrel remains the most broadly used P2Y12 inhibitor,although novel P2Y12 inhibitors including ticagrelor and prasugrel have emerged as alternative treatment.The CYP2C19 loss-of-function(LOF)variants have significant impact on response to clopidogrel,which are quite common in East Asian populations.The efficacy and safety of tailored antiplatelet therapy under the guidance of CYP2C19 genetic polymorphisms remains elusive for patients undergoing PCI.ObjectiveThe aim of the present study was to investigate the selection of oral P2Y12 inhibitor therapy and outcomes following clinical implementation of CYP2C19 genotyping to guide antiplatelet therapy after PCI,providing information on applicability of CYP2C19 testing in clinical practice.MethodsData from a retrospective,all-comers,single-center real-world registry enrolling 41,090 consecutive PCI patients treated with dual antiplatelet therapy after procedure were analyzed.All eligible patients in the registry were followed up for 12 months.The association between CYP2C19 genotype and P2Y12 inhibitor selection was identified by multivariable Logistic regression models.We constructed time-to-event curves using the Kaplan-Meier method and compared survival curves with the log-rank test for major adverse cardiovascular events(MACE)and bleeding events within 12 months after PCI.Risks of MACEs and bleeding events were compared across CYP2C19 genotype and antiplatelet therapy groups using Cox proportional hazards models.ResultsCYP2C19 genotyping was successfully achieved for 9081 patients,of whom baseline characteristics including demographics,comorbidities and lesion features significantly differed from non-genotyped patients.A higher proportion of genotyped patients were prescribed ticagrelor compared with non-genotyped patients(27.0%vs.15.5%,P<0.001).CYP2C19 LOF alleles were present in 5832 patients(64.2%),of whom 4548 patients(50.1%)carrying one LOF allele(*1/*2,*1/*3)were intermediate metabolizers and 1284 patients(14.1%)carrying two LOF alleles(*2/*2,*2/*3,*3/*3)were poor metabolizers.CYP2C19 metabolic status was an independent predictor for use of ticagrelor(P<0.001).Ticagrelor was significantly associated with a lower risk of MACE in poor metabolizers(adjusted hazard ratio[HR]:0.62,95%confidence interval[CI]:0.42 to 0.92,P=0.017),but not in intermediate metabolizers or normal metabolizers.The interaction was not statistically significant(P for interaction=0.252).When CYP2C19 poor metabolizers treated with ticagrelor were identified as reference,poor metabolizers administered clopidogrel had a significantly increased risk of MACE(HR:1.60,95%CI:1.09 to 2.35,P=0.016)after adjustment for other confounders.Major bleeding event rates remained similar across the CYP2C19 phenotype and antiplatelet therapy groups.However,the multivariable analysis further detected significant differences in risk of minor bleeding between the two treatment groups in normal metabolizers(HR:2.06,95%CI:1.17 to 3.61,P=0.012)and intermediate metabolizers(HR:2.19,95%CI:1.41 to 3.41,P<0.001),but not in poor metabolizers.ConclusionsGenotype information on CYP2C19 metabolic status could increase the use of potent antiplatelet therapy in PCI patients.Clopidogrel use was associated with a higher risk of MACEs in poor metabolizers,which suggested the potential application of genotypeguided P2Y12 inhibitor selection for improving clinical outcomes.Part Ⅱ.Implementation of CYP2C19 Genotyping and Effect of Oral P2Y12 Inhibitors on Clinical Outcomes in Patients with Stable Coronary Artery Disease Undergoing Complex Percutaneous CoronaryInterventionBackgroundIn patients treated with stent implantation,current guidelines favor potent platelet inhibition with ticagrelor over clopidogrel in patients with acute coronary artery syndrome because of its superior net clinical benefits,while clopidogrel is indicated for the treatment of patients with stable coronary artery disease(SCAD).Patients undergoing complex percutaneous coronary intervention(PCI)have an increased risk of cardiovascular events.Whether potent antiplatelet therapy after complex PCI improves outcomes in patients with SCAD remains unclear.ObjectiveTo assess the efficacy and safety of ticagrelor versus clopidogrel in patients with SCAD undergoing complex PCI and effect of implementation of CYP2C19 genotyping to determine the optimal choice of P2Y12 inhibitor in this population.MethodsPatients with diagnosis of SCAD and undergoing PCI during January 2016 to December 2018 were selected from an institutional registry.The primary efficacy endpoint was major adverse cardiac events(MACE)within 12 months after PCI.The primary safety endpoint was major bleeding.The cumulative incidence of clinical outcomes up to 1 year was evaluated by Kaplan-Meier method and compared using the log-rank test.Cox proportional hazard models were used to calculate hazard ratio(HR)and 95%confidence intervals(CI)to compare the efficacy and safety outcomes of ticagrelor versus clopidogrel.ResultsAmong 15459 patients with SCAD included in this analysis,complex PCI was performed in 6335(41.0%)patients.Ticagrelor was prescribed in 17.7%(n=1123)and 10.4%(n=953)of patients with complex versus non-complex PCI,respectively.The primary efficacy outcome after complex PCI occurred in 8.6%of patients in the ticagrelor group and 11.2%in the clopidogrel group.Complex PCI was independently associated with increased risk of MACE(adjusted HR:3.51;95%CI:3.06 to 4.03,P<0.001).The primary efficacy endpoint occurred significantly less frequently in patients prescribed ticagrelor than clopidogrel in complex PCI group(8.6%vs.11.2%).Compared to clopidogrel,ticagrelor decreased the risk of MACE in patients undergoing complex PCI(HR:0.76;95%CI:0.62 to 0.95,P=0.015),but not in noncomplex PCI(P for interaction=0.001).There was no significant difference in incidence of major bleeding between patients treated with ticagrelor and clopidogrel(P=0.221),while ticagrelor was associated with an increased risk of minor bleeding(adjusted HR:3.10;95%CI:2.05 to 4.69,P<0.001).The benefit of treatment with ticagrelor versus clopidogrel on MACE was progressively greater in patients with more complexity characteristics(P for interaction=0.021).The use of ticagrelor was more common in patients carrying CYP2C19 loss-of-function(LOF)alleles and undergoing complex PCI.Ticagrelor tended to be associated with a lower risk of MACE following complex PCI in in patients carrying CYP2C19 LOF alleles.ConclusionsIn patients with SCAD and undergoing complex PCI,ticagrelor could substantially reduce the risk of adverse cardiovascular outcomes without increasing the risk of major bleeding compared with clopidogrel.Part Ⅲ.Implementation of CYP2C19 Genotyping and Effect of Oral P2Y12 Inhibitors on Clinical Outcomes After Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome Aged 75 Years or OlderBackgroundCurrent guidelines recommend ticagrelor over clopidogrel for patients with acute coronary syndrome(ACS).The benefits of potent antithrombotic therapy usually come at the expense of a higher risk of bleeding.There are no specific guidelines concerning the elderly,and data on optimal antiplatelet therapy in elderly are quite scarce.The efficacy and safety of ticagrelor in elderly East Asian populations remains debated due to the concerns about the imbalance of ischemic and bleeding risks.ObjectiveThis study aimed to compare the impact of clopidogrel with ticagrelor on clinical outcomes in East Asian patients aged≥75 years with ACS using data from an institutional registry and provide more information on the use of potent antiplatelet therapy in older patients from Asia.MethodsThe present study was a retrospective analysis using data from the efficacy and safety of an institutional registry.Among patients included in this registry,patients aged≥75 years and presenting with ACS at admission were eligible to constitute the present study population.The cumulative incidence of clinical outcomes was described using the Kaplan-Meier method and compared using the log-rank test.We assessed the treatment effect of ticagrelor versus clopidogrel based on multivariate Cox proportional hazards models and propensity scores to adjust for baseline differences and potential confounders between the ticagrelor and clopidogrel groups.ResultsA total of 2775 ACS patients were included,of whom 235(8.5%)were treated with ticagrelor.The primary efficacy outcome occurred in 11.9%of patients treated with ticagrelor versus 8.8%treated with clopidogrel.The cumulative rate of the combined primary outcome of all-cause death,MI and repeat target vessel revascularization over 1-year follow-up was 8.8%vs.11.9%in the clopidogrel and ticagrelor group,respectively.The net clinical benefit outcomes occurred in 9.6%of clopidogrel-treated patients and 12.3%of ticagrelor-treated patients.There was no significant association between treatment with ticagrelor and a lower risk of the primary efficacy outcome(P=0.156).However,the incidences of all-cause death(hazard ratio[HR]:1.69,95%confidence interval[CI]:1.02 to 2.79)and major bleeding(adjusted HR:2.20,95%CI:1.06 to 4.56)were significantly higher in patients treated with ticagrelor than clopidogrel.In the propensity score-matched cohort,the multivariate Cox models revealed that ticagrelor-treated patients were at a numerically but not statistically higher risk of MACEs(adjusted HR:1.62,95%CI:0.87 to 3.02,P=0.127)than clopidogreltreated patients,corresponding to a numerically increase in net clinical benefit outcomes(adjusted HR:1.71.95%CI:0.93 to 3.17,P=0.087).ConclusionsIn elderly patients with ACS from East Asia,the efficacy of clopidogrel was comparable to ticagrelor,while ticagrelor is associated with an increased risk of mortality and major bleeding.