Study On The Mechanism Of Clopidogrel - Induced Bleeding In Antiplatelet Drugs

BackgroundGene polymorphisms of ABCB1, CYP2C19, PON1 and P2RY12 may influence pharmacodynamics and clinical events of clopidogrel treatment.PurposeWe assessed the hypothesis that a genetic risk score based on identified high-risk single nucleotide polymorphisms (SNPs) would be associated with bleedings in clopidogrel-treated Chinese ST-elevation myocardial infarction (STEMI) patients after percutaneous coronary intervention (PCI).MethodsA total of 503 consecutive patients with STEMI who received an uneventful PCI and were exposed to clopidogrel treatment for 12 months, were enrolled in the single-center registry. There were 41 tag SNPs selected from ABCB1, CYP2C19, PON1 and P2RY12 genes, which were detected by the ligase detection reaction. The primary clinical safety endpoint was the incidence of major bleeding events. Major bleeding was quantified according to bleeding academic research consortium definition (BARC) criteria, including type 3 and 5 in the analysis. The follow-up period was 12 months.ResultsOverall,46 BARC≥3 bleeding events (9.1%) occurred, which included 11 (2.2%) cases of BARC 3b bleedings and 35 (7.0%) cases of BARC 3a bleedings. After adjustment for traditional clinical risk factors, multivariate logistic regression analysis identified SNPs significantly associated with bleedings were ABCB1 (rs1045642, rs7779562), P2RY12 (rs6809699) and PON1 (rs854560). A genetic risk score was constructed by summing the number of risk alleles. As a continuous variable, the risk score resulted in an OR of 1.412 per unit increase in score (95%CI=1.110-1.797, p=0.005). The addition of this genetic risk score significantly increased C-statistic from 0.79 to 0.83 (p=0.03), and significantly improved the predictive ability on bleeding risk by 22% using the NRI approach (p=0.01).ConclusionThis genetic risk score was significantly associated with bleedings after PCI in our study population.BackgroundAntiplatelet effect can be evaluated through clinical outcomes and laboratory platelet function tests. Although accumulating data from large studies underscore the importance of high on-treatment PR to ADP as a prognostic risk factor of ischemic events, the association between on-treatment PR and bleeding events is less clear.PurposeThis study sought to investigate the predictive value of thromboelastography (TEG) on bleeding risk in clopidogrel-treated patients with ST-elevation myocardial infarction (STEMI).MethodsBetween January 2011 and July 2012, a total of 449 consecutive patients with STEMI who received an uneventful PCI and were exposed to standard dual antiplatelet therapy, were enrolled in the single-center registry. Platelet reactivity was assessed by TEG. The primary clinical efficacy end point was a composite of cardiovascular death, non-fatal myocardial infarction, unplanned target vessel revascularization, and stent thrombosis. The primary clinical safety end point was the incidence of major bleedings defined according to the Bleeding Academic Research Consortium (BARC) criteria, including type 3 and 5 in the analysis. The follow-up period was 12 months.ResultsOverall,26 (5.8%) ischemic events occurred and 40 (8.9%) major bleedings occurred. By receiver operating characteristic curve analysis, the TEG platelet mapping assay value of ADP inhibition had the best predictive value of BARC≥3b bleedings, yielding an area under the curve (AUC) of 0.767 (95% CI 0.671-0.863; p=0.010; cut-off value≥93.5%). ADP inhibition can also predict BARC≥3 bleedings with an AUC of 0.652 (95% CI 0.574-0.730; p=0.002; cut-off value>92.65%). After adjustment for established risk factors of bleeding including age, female gender, renal function, the multivariable logistic regression model demonstrated that ADP inhibition>92.65%(OR=4.805, 95%CI=1.905-12.123, p=0.001) was independent predictor of BARC≥3 bleedings.ConclusionIn STEMI patients treated with clopidogrel after PCI, ADP inhibition in TEG has a predictive value of bleedings.BackgroundGrowth differentiation factor 15 (GDF-15), a stress-responsive member of the transforming growth factor beta cytokine superfamily, has emerged as a biomarker of recurrent cardiovascular events in coronary heart disease.PurposeThe aim of this study was to determine the predictive value of GDF-15 on bleeding events in ST-elevation myocardial infarction (STEMI) patients after percutaneous coronary intervention (PCI).MethodsBetween July 2012 and June 2013, a total of 322 consecutive patients with STEMI who received an uneventful PCI and were exposed to standard dual antiplatelet therapy, were enrolled in the single-center registry. All the enrolled patients received measurement of GDF-15 level on day 2 of PCI. The primary clinical efficacy end point was a composite of cardiovascular death, non-fatal myocardial infarction, unplanned target vessel revascularization, and stent thrombosis. The primary clinical safety end point was the incidence of major bleedings defined according to the Bleeding Academic Research Consortium (BARC) criteria, including type 3 and 5 in the analysis. The follow-up period was 12 months.ResultsOverall,12 (3.7%) ischemic events occurred and 28 (8.7%) major bleedings occurred. Plasma GDF-15 level was significantly higher in patients with major bleedings, compared to patients with ischemic events or no events [2094(253-5495)pg/mL vs 1241(594-3668) pg/mL vs 1173(232-5716) pg/mL, p=0.013]. By receiver operating characteristic curve analysis, plasma GDF-15>1896.0ng/L had a predictive value of major bleedings with an area under the curve= 0.682 (95%CI 0.570-0.795, p=0.001). Binary logistic regression analysis identified log GDF-15 (OR=4.805,95%CI=1.905-12.123, p=0.001) was a significant independent predictor of major bleedings after adjustment of traditional clinical bleeding risk factors.ConclusionGDF-15 is a strong predictor of major bleedings in patients with STEMI after PCI.