The Study On The Clinical Benefit Of P2Y12 Inhibitor Pre-Treatment And The Influence Factors Of Optimal Timing Decisions In The STEMI Patients

Background and Objective:Upstream loading-dose P2Y12 inhibitor therapy before primary percutaneous coronary intervention(PCI)in the ST segment elevation myocardial infarction(STEMI)patients is recommended by current guidelines.The clinical benefit of the pre-treatment strategy,however,is debating.Besides the lacking of efficient clinical research evidences,many other factors involved in clinical practice are likely to interfere with the decision and optimal timing of the pre-loading of P2Y12 inhibitor agents.Based on the practice of local chest pain center(CPC)networks in dealing with STEMI patients,this study is aimed at the investigation into the influence factors of the clinical decision of P2Y12 inhibitor pre-loading therapy,and the potential benefit of different P2Y12 inhibitor pre-treatment strategies for the periprocedual reperfusion and clinical outcomes of the STEMI patients undergoing primary PCI.Methods:452 STEMI patients undergoing primary PCI at Jiading Central Hospital Chest Pain Center from May 2016 to October 2019 were enrolled as the study cohort.All the patients were treated with loading-dose aspirin and one P2Y12 inhibitor agent(ticagrelor 180mg,or clopidogrel 600mg,or clopidogrel 300mg)before PCI procedure.Section 1.The study population was devided into pre-treatment group and in-lab ticagrelor group due to their administration of P2Y12 inhibitors before or after entering the catheter laboratory.The pre-treatment group was further divided into ticagrelor pre-loading,high-dose(600mg)clopidogrel pre-loading,and low-dose(300mg)clopidogrel pre-loading group according to the definite type and loading-dose of the P2Y12 inhibitor agents they received.Baseline clinical characteristics,cardiovascular risk factors,mean in-hospital left ventricular ejection factors(LVEF)and the proportion of were compared between groups.Composite periprocedual reperfusion events included the proportion of significant ST segment elevation resolution(defined as 50%or above)within 24 hours after PCI,and the prevalence of self patency and no-reflow in the culprit artery.Logistic regression was performed to investigate the influence factors of the periprocedual reperfusion events.The composite clinical endpoints during hospitalization and within 28 days after primary PCI included major cardiovascular events(death,myocardial re-infarction,definite stent thrombosis,stroke),newly-onset heart failure,bleeding,ventricular aneurysm and regional wall motion abnormality.Cox regression was performed to investigate the risk factors and protective factors of the events duiring hospitalization and within 28 days after PCI.Compostie endpoints within 1 year after discharge included death,myocardial re-infarction,stent thrombosis,stroke,re-vascularization,re-hospitalization due to heart failure onset,and bleeding events.P<0.05 was defined as statistical difference.Section 2.The study population was divided into early pre-loading group,preprocedual loading group,and bail-out group according to the optimal timing of P2Y12 inhibitor administration.Baseline charateristics,major symptoms at first medical contact(FMC)and medical histories at emergency department,at elemantaty medical institutions,and on the ambulance were investigated retrospectively to determine the possible influence factors to the absence of early P2Y12 inhibitor pre-loading strategy.Logistic regression was performed to investigate the influence factors to the decision of preprocedual and bail-out administration of loading-dose P2Y12 inhibitors.Due to the time interval from first medical contact to the administration of P2Y12 inhibitor loading-dose was over 30 minutes or not,we divided the study population into delayed loading group and non-delayed loading group.Baseline characeristics,proportions of periprocedual reperfusion events,and proportions of composite cardiovascular events within 28 days after PCI were compared between the two groups.Logistic regression was peformed for the risk factors of delayed P2Y12 inhibitor administration.Finally,we divided the study population into preopration stage group,pre-certification stage group and post-certification stage group,according to their admission on which stage of the CPC construction.The optimal timing and insitiution of P2Y12 inhibitor administration,the time interval between first medical contact to the P2Y12 inhibitor loading,and the proportion of delayed P2Y12 inhibitor loading were compared between groups.P value of<0.05 was defined as staitstical difference.Results:1.Compared with the in-lab ticagrelor group,pre-loading of ticagrelor was associated with the significant increase of the prevalence of self patency in the culprit artery(25.71%vs.16.67%,P=0.046)and a non-significant increase of TIMI 3 flow at the initial of angiography(20.0%vs.12.37%,P=0.061).Clopidogrel pre-loading did not improve the rate of self patency and self TIMI 3 flow.No difference was found between groups in the case of no-reflow.Ticagrelor pre-loading treatment was associated with a significantly increased proportion of early ST segment elevation resolution of over 50%,in comparison with the high-dose clopidogrel pre-loading(45.87%vs.17.44%,P<0.001)and the in-lab ticagrelortreatment(45.87%vs.27.96%,P<0.001),while a non-significant increase was found when compared with the low-dose clopidogrel pre-loading(45.87%vs.35.0%,P=0.130).In the multivariate Logistic regression,ticagrelor pre-loading was found to be significantly related to the early resolution of ST segment elevation(OR=2.432,95%CI 1.322-4.475,P=0.002).High-dose clopidogrel pre-loading was non-significantly associated with the decrease of early ST segment elevation resolution(OR=0.498,95%CI 0.238-1.040,P=0.062).2.Both ticagrelor pre-loading(9.29%vs.17.20%,P=0.041)and high-dose clopidogrel pre-loading(8.14%vs.17.20%,P=0.048)were related to a significant reduction of in-hospital heart failurein comparison with the in-lab ticagrelor treatment.The proportion of major cardiovascular adverse events(MACEs)and all-cause mortality during hospitalization did not differ across the groups.Mean left ventricular ejection factors(LVEF)and the proportion of reduced LVEF of under 50%did not differ across the groups on admission.LVEF before discharge in the ticagrelor pre-loading group was significantly higher than the in-lab ticagrelor treatment group(62.65 ± 10.34%vs.59.28±10.44%,P=0.031).The proportion of in-hospital minor bleeding events was numerically increased in the ticagrelor pre-loading(5.71%)and low-dose clipidogel(5.00%)arms.Ticagrelor pre-loading was associated with significantly reduced rate of heart faliure onset at 28 days after PCI(9.29%vs.18.82%,P=0.016)and 1 year after discharge(2.48%vs.8.33%,P=0.032).High-dose clopidogrel pre-loading was asociated with non-significant reduction of heart failure onset within 28 days after PCI(10.46%vs.18.82%,P=0.083).No significant differences of MACEs and all-cause mortality during the follow up period were found across the groups.In the Cox regression,ticagrelor pre-loading was shown as aindependent factor ofreduced in-hospital heart failure events(HR=0.382,95%CI 0.193-0.755,P=0.006)and 28-day heart failure eventsafter PCI(HR=0.416,95%Cl 0.208-0.833,P=0.013).The rates of bleeding events within 28 days after PCI were non-significantly higher in the ticagrelor and low-dose clopidogrel pre-loanding groups.No statistical difference in bleeding events was found between groups during the 12-month follow up.3.In the multivariate Logistic regression,inadequate loading-dose of anti-platelet medication(OR=3.570,95%CI 1.241-10.268,P=0.018),insufficient P2Y12 inhibitor access at FMC institute or ambulance(OR=3.322,95%CI 1.794-6.149,P<0.001),time interval<10 minutes from the diagnosis of STEMI to entering the catheter lab(OR=21.376,95%CI 9.900-46.153,P<0.001),irregular electrocardiographic performance(OR=3.312,95%CI 1.765-6.215,P<0.001)and subjective decision of FMC physicians(OR=8.527,95%CI 4.254-17.093,P<0.001)were shown as the independent risk factors of pre-procedual loading of P2Y12 inhibitors in the catheter lab.Inadequate loading-dose of anti-plateletmedication(OR=11.981,95%CI 2.763-51.957,P=0.001),insufficient P2Y12 inhibitor access at FMC institute or ambulance(OR 2.767,95%CI 1.089-7.030,P=0.032),syncope(OR=4.816,95%Cl 1.461-15.872,P=0.010)and rapid transmission to the catheter lab within 10 minutes of STEMI diagnosis(OR 3.120,95%CI 1.013-9.615,P=0.048)were the independent risk factors of bail-out loading of P2Y12 inhibitors.First medical contact at an elementary CPC,on the other hand,was found as an independent protective facor of preventing the decision of preprocedual loading of P2Y12 inhibitors(OR=0.225,95%CI 0.103-0.492,P<0.001).4.Compared with the delayed loading group(defined as FMC to P2Y12 inhibitor loading>30 minutes),non-delayed group of STEMI patients was found to have a significant higher rate of early ST segment elevation resolution(40.19%vs.26.75%,P=0.002),and significant reductions in non-reflow(0.0%vs.2.05%,P=0.037).The proportion of heart failure within 28 days after PCI was lower in the non-delayed group,but the difference was not siatistically significant(11.00%vs.17.28%,P=0.058).No statistical difference was found between delayed and non-delayed group in the prevalence of MACEs and bleeding events.Multivariate Logistic regression indicated that remote consultation via instant-communication applications(OR 0.267,95%CI 0.109-0.657,P=0.004)and first medical contact at elementary CPCs(OR 0.130,95%CI 0.036-0.468,P=0.002)were independently protective to the delay of P2Y12 inhibitor loading,while insufficient drug access at FMC institute or ambulance(OR 4.813,95%CI 2.189-10.053,P<0.001),irregular ECG performance(OR 5.762,95%CI 2.073-16.018,P=0.001),respiratory or cardiac arrest(OR 16.387,95%CI 1.588-169.123,P=0.019),delayed elementary diagnosis(OR 23.366,95%CI 7.121-76.667,P<0.001),and subjective decision of FMC doctors(OR 43.794,95%CI 18.772-102.172,P<0.001)were independent risk factors of delayed P2Y12 inhibitor loading.5.The progress of CPC construction was associated with improved early administration of P2Y12 inhibitor loading-dose in STEMI patients.The rate of early pre-loading treatment was significantly increased in the post-certification stage than the preoperation(65.43%vs.43.90%,P=0.001)and pre-certification stage(65.43%vs.48.82%,P=0.002).The time interval from FMC to P2Y12 inhibitor loading was significantly reduced in the post-certification stage than in the preoperation stage(41.07±40.3 1 min vs.55.18±38.66 min,P=0.015)and the pre-certification stage(41.07±40.31 min vs.53.14±37.99 min,P=0.019).The proportion of delayed P2Y12 inhibitor loading was significantly reduced in the post-certification stage(42.79%vs.69.51%,P<0.001 with preoperation stage,and 42.79%vs.64.57%,P<0.001 with pre-certification stage).Conclusions 1.In the STEMI patients undergoing primary PCI,in comparison with in-lab ticagrelor loading-dose treatment,ticagrelor pre-loading treatment was associated with a significant increase in the early resolution of ST segment elevation and self patency in the culprit artery.The pre-treatment strategy was also related to the reduction of heart failure during hospitalization,28 days after PCI and 1 year after discharge,which indicated that the early pre-loading of ticagrelor was potentially benefit for the improvement of peri-procedual reperfusion and heart function,but with an excess to minor bleeding risks.Early pre-loading of 600mg clopidogrel was associated with decreased proportion of in-hospital heart failure,and did not increase the risk of bleeding events.These indicated that high-dose clopidogrel pre-loading might be beneficial to the improvement of periprocedual reperfusion and outcomes in STEMI patients,and was considerable when ticagrelor pre-treatment was unavailable.2.Delayed P2Y12 inhibitor loading was associated with increased risk of non-reflow and delayed ST segment elevation resolution in STEMI patients undergoing primary PCI.Subjective decisions of FMC clinicians,delayed elementary diagnosis and irregular electrocardiographic performance were proved as major risk factors of delayed P2Y12 inhibitor loading,while the development of elementary CPC and regional information sharing platforms could contribute to reduce the delay.3.By provoking the establishment and development of both in-hospital and pre-hospital cooperative STEMI treatment network,the construction of CPC significantly reduced the time interval from FMC to P2Y12 inhibitor loading and the proportion of delayed drug administration,resulted in a raised pre-treatment rate and better clinical benefits.