A Clinical Study On The Prediction For The Risk Of Bleeding In Acute Coronary Syndrome Patients Undergoing PCI

Background:Duel antiplatelet therapy(DAPT)with aspirin plus a P2Y12 inhibitor prevents ischemic events after percutaneous coronary intervention(PCI)in acute coronary syndrome(ACS)patients,but increases bleeding events.Moreover,major bleeding conveyed a risk of higher long-term mortality comparable to that of myocardial infarction.By far,there is still a lack of data on the evaluation of the long-term bleeding risk in Chinese ACS patients undergoing PCI in the real world,and the efficacy and safety of contemporary antithrombotic therapy strategies remain unclear.The impact of post-discharge bleeding(PDB)on post-discharge MACEs was unclear.Metrics to accurately predict the occurrence of PDB with Bleeding Academic Research Consortium type(BARC)?2 based on the real-world settings are lacking.In addition,novel plasma biomarkers or single nucleotide polymorphism(SNP)markers for the prediction of major bleeding risk are also lacking.Accordingly,we sought to identify the correlation between antithrombotic therapy and PDB,as well as the impact of PDB on post-discharge MACEs,then to develop a risk score for the prediction of the risk of PDB in Chinese ACS patients who underwent PCI.The novel plasma biomarkers or single nucleotide polymorphism(SNP)markers for predicting the risk of major bleeding were screened.Part 1:A non-interventional clinical study evaluating the risk of bleeding in Chinese ACS patients who underwent PCIObjectives:The aim was to evaluate the risk and the outcomes of PDB,and then to develop a risk score for predicting the risk of PDB in Chinese ACS patients after PCI.Methods:From May 2014 to January 2016,a real-world cohort of ACS patients undergoing PCI were recruited consecutively from 29 nationally representative Chinese tertiary hospitals.Clinical follow-up was scheduled at 1,3,6 and 12 months respectively.PDB was defined as post-discharge bleeding with BARC ?2(exclude BARC 4 type)during the follow-up of one year.Post-discharge MACEs were defined as the composite of all-cause deaths,non-fatal myocardial infarction,ischemic stroke,or urgent revascularization.The association between PDB and post-discharge MACEs,as well as the impact of DAPT with ticagrelor or clopidogrel on PDB was evaluated.With the identified predictors of PDB,a bleeding risk score was established and validated.Results:Among 2381 patients(95.4%,2381/2496)who finished 1-year follow-up,the cumulative incidence of PDB and post-discharge MACEs was 4.9%(n=117)and 3.3%(n= 79),respectively.PDB was significantly associated with the higher risk of post-discharge MACEs(7.7%vs.3.1%adjusted hazard ratio[HR]:2.59,95%confidence interval[CI]:1.17 to 5.74,p=0.02).In comparison to the patients with continuous clopidogrel treatment,the patients with continuous treatment with ticagrelor had a significantly higher risk for PDB(4.4%vs.8.0%,adjusted HR:2.05,95%CI:1.17-3.60,P =0.01),but no difference for the risk of MACEs(3.4%vs.2.0%,adjusted HR:1.14,95%CI:0.4-3.25,P =0.80).Based on the clinical environmental factors(include:sex,BMI,prior peptic ulcer,hypertension,multi-vessel lesion,hemoglobin,triglycerides;LDL-C at baseline,and continuous ticagrelor on top of aspirin),the established BRIC-ASC score showed a c-statistic for PDB of 0.67(95%CI 0.62-0.73)in the whole cohort.It showed good discriminatory ability for PDB in the subgroups of patients with NSTEMI,STEMI,diabetes and those implanted with more than two DESs(c-statistic,?0.70).Conclusions:PDB with BARC?2 is significantly associated with higher risk for MACEs in ACS patients who underwent PCI.The BRIC-ACS risk score showed a good discriminatory ability for PDB,especially in the patients with the high-risk ischemic events.Part 2:HDL-C as the novel biomarker for major bleeding in ACS patients who underwent PCIObjectives:The objective was to investigate whether plasma HDL-C levels are associated with major bleeding,and then to assess the predictive performance of adding HDL-C level to CRUSADE or PRECISE-DAPT risk score in term of major bleeding events in a cohort of ticagrelor treated ACS patients who underwent PCI.Methods:From September 2013 and August 2015,ACS patients who underwent PCI and treated with ticagrelor during hospitalization were recruited consecutively.Major bleeding event was defined as bleeding with BARC>3(exclude BARC 4 type).The association between HDL-C level and the major bleeding was assessed.The predictive performance of CRUSADE or PRECISE-DAPT risk score with the addition of HDL-C level for the major bleedings was evaluated.Results:Among 734 patients who finished the follow-up of one year,the overall rate of major bleeding was 3.1%.Elevated plasma HDL-C level(Ln HDL-C>0.207)was associated with an increased risk of major bleeding(5.9%vs.2.5%,HR:2.91,95%CI,1.07-7.87,P=0.036).Compared to CRUSADE risk score alone,the modified risk score with the addition of Ln HDL-C>0.207 offered an improved discriminative ability(AUC:0.69 vs.0.63).Compared to patients with CRUSADE score<40 and Ln HDL-C<0.207,those with CRUSADE>40 plus Ln HDL-C>0.207 had an almost sevenfold(1.7%vs.11.1%,HR:6.93,95%CI:1.50-32.07,P=0.01)greater risk of major bleeding.Meanwhile,the predictive performance also improved when combining Ln HDL-C>0.207 with the PRECISE-DAPT risk score(AUC:0.68 vs.0.64).Compared to patients with PRECISE-DAPT<25 and Ln HDL-C<0.207,those with PRECISE-DAPT>25 plus Ln HDL-C>0.207 appeared an almost six-fold(1.8%vs.10.5%,HR:6.23,95%CI:1.35-28.83,P=0.02)greater risk of major bleeding.Conclusions:Among ticagrleor treated ACS patients who underwent PCI,elevated level of HDL-C was independently associated with higher risk of major bleeding,and the discriminative ability definitely improved with the addition of HDL-C levels on top of the CRUSADE or PRCISE-D APT risk score.Part 3:Genetic markers screening for major bleeding in ACS patients who underwent PCIObjectives:This study aimed to screen and assess the impact of the genetic factors on the risk of maj or bleedings in ticagrelor treated ACS patients who underwent PCI.Methods:A retrospective analysis of 50 patients who experienced major bleedings during the follow-up of one year after PCI,and 53 patients without bleeding matched according to the proportion of 1:1.Major bleeding was defined as bleeding with BARC>3(exclude BARC 4 type).Single nucleotide poplymorphisms(SNPs)in the genes related with platelet activation and aggregation,and the metabolism of antiplatelet drugs were genotyped in the patients.Results:A total of 50 patients experienced the major bleedings,with gastrointestinal bleedings in 17 patients,the intracranial bleeding in 13 patients and others in 20 patients.Nine SNPs(including COX-1(rs10306114 and rs3842787),P2Y12(rs6809699),TBXA2R(rs2238631),CYP4F11(rs1060463),CYP2D6(rs28360521),GPIBA(rs2243100)and B4GALT2(rs1061781 and rsl859728))were candidate for the association analysis with the major bleeding events.Among the candidate SNPs,the CYP4F11 rs1060463 GG variant showed significant association with the major gastrointestinal bleedings(47.1%vs.18.9%,P=0.046),and the P2RY12 rs6809699-A variant associated with intracranial bleedings(30.8%vs.11.3%,P=0.03).Conclusions:In ticagrelor treated ACS patients underwent PCI,SNPs in CYP4F11(rs1060463)and P2RY12(rs6809699)could contribute to the risk of gastrointestinal or intracranial major bleedings.