Yuan-Liang Ma

Association of PEAR1 genetic variants with platelet reactivity in response to dual antiplatelet therapy with aspirin and clopidogrel in the Chinese patient population after percutaneous coronary intervention

INTRODUCTION Platelet Endothelial Aggregation Receptor-1 (PEAR1) is a recently reported platelet transmembrane protein which plays an important role in platelet aggregation. The aim of this study was to investigate whether PEAR1 genetic variations were associated with platelet reactivity as assessed by adenosine diphosphate(ADP)-induced platelet aggregation in Chinese patients treated with aspirin and clopidogrel. METHODS Patients with coronary heart disease (CHD) who underwent percutaneous coronary intervention (PCI) were enrolled in the study. All patients were on dual antiplatelet therapy with aspirin and clopidogrel. ADP-induced platelet aggregation was measured by thromboelastography and defined as percent inhibition of platelet aggregation (IPA). Patients (n=204) with IPA <30% were identified as high on-treatment platelet reactivity (HPR). Patients (n=201) with IPA >70% were identified as low on-treatment platelet reactivity (LPR). Sixteen single nucleotide polymorphisms (SNPs) of PEAR1 were determined by a method of improved multiple ligase detection reaction. RESULTS Among the 16 SNPs examined by univariate analysis, 5 SNPs were significantly associated with ADP-induced platelet aggregation. Minor allele C at rs11264580 (p=0.033), minor allele G at rs2644592 (p=0.048), minor allele T at rs3737224 (p=0.033) and minor allele T at rs41273215 (p=0.025) were strongly associated with HPR, whereas homozygous TT genotype at rs57731889 (p=0.009) was associated with LPR. Multivariate logistic regression analysis further revealed that the minor allele T at rs41273215 (p=0.038) was an independent predictor of HPR and the homozygous TT genotype at rs57731889 (p=0.003) was an independent predictor of LPR. CONCLUSIONS PEAR1 genetic variations were strongly associated with ADP-induced platelet aggregation in Chinese patients with CHD treated with aspirin and clopidogrel. These genetic variations may contribute to the variability in platelet function. The utility of PEAR1 genetic variants in the assessment and prediction of cardiovascular risk warrants further investigation.

Relationship Between ABCB1 Polymorphisms, Thromboelastography and Risk of Bleeding Events in Clopidogrel-Treated Patients With ST-Elevation Myocardial Infarction

INTRODUCTION This study sought to investigate the relationship of polymorphisms in ABCB1 and the predictive value of thromboelastography (TEG) on bleeding risk in clopidogrel-treated patients with ST-elevation myocardial infarction (STEMI). METHODS 467 consecutive patients with STEMI undergoing percutaneous coronary intervention (PCI) were enrolled. Twenty tag single nucleotide polymorphisms (SNPs) selected from ABCB1 gene and CYP2C19*2, *3, *17 were detected by the ligase detection reaction. Platelet reactivity was assessed by TEG. The follow-up period was 12months. RESULTS By receiver operating characteristic curve analysis, the TEG platelet mapping assay value of ADP inhibition had the best predictive value of bleeding academic research consortium definition (BARC) ≥ 3b bleedings, yielding an area under the curve (AUC) of 0.707 (95% CI 0.662-0.749, p=0.009; cut-off value > 93.4%). ADP inhibition can also predict BARC ≥ 3 bleedings with an AUC of 0.594 (95% CI 0.546-0.640, p = 0.05; cut-off value > 92.5%). After adjustment for established risk factors of bleeding including the gain of function CYP2C19*17 allele, age, female gender, renal function, the multivariable logistic regression model demonstrated that ADP inhibition > 92.5% (OR 2.247, 95%CI 1.082-4.665, P=0.03), carriage of rs1045642 (OR 2.943, 95%CI 1.195-7.247, P = 0.019) and rs7779562 (OR 0.453, 95%CI 0.219-0.936, P = 0.032) were independent predictors of BARC ≥ 3 bleedings. These associations were validated in a second cohort of 504 STEMI patients. CONCLUSIONS In STEMI patients treated with clopidogrel after PCI, the ABCB1 tag SNP rs1045642 is associated with higher risk of bleedings while rs7779562 is associated with lower bleeding risk, and ADP inhibition in TEG has a predictive value of bleedings.

Effect of platelet receptor gene polymorphisms on outcomes in ST-elevation myocardial infarction patients after percutaneous coronary intervention

Abstract Polymorphisms in platelet receptor genes may influence platelet function. This study aimed to assess the impact of five polymorphisms of genes encoding platelet receptors on the risk of ischemic and bleeding events in ST-elevation myocardial infarction (STEMI) patients after percutaneous coronary intervention (PCI). 503 consecutive Chinese patients with STEMI after an uneventful PCI and exposed to standard dual antiplatelet therapy for 12 months were enrolled. Polymorphisms of platelet receptors, GPIa (ITGA2, 807C > T, rs1126643), GPVI (GP6, 13254T > C, rs1613662), PAR-1 (F2R, IVS-14A > T, rs168753) and P2Y12 (P2RY12, 34C > T, rs6785930 and H1/H2 haplotype, 52G > T, rs6809699) were detected by the ligase detection reaction. The follow-up period was 12 months. Overall, 34 (6.8%) ischemic events occurred and 46 (9.1%) major bleedings occurred. Multivariate Cox regression analysis showed the carriage of F2R rs168753 minor allele was an independent predictor of the composite ischemic events (HR 0.387, 95% CI 0.193–0.778, p = 0.008) after adjusted for established risk factors. Multivariate logistic regression model identified that carriage of P2RY12 rs6809699 minor allele (OR 2.71, 95% CI 1.298–5.659, p = 0.008) was an independent predictor of major bleedings. The associations were then validated in a second cohort of 483 STEMI patients. In STEMI patients after PCI, F2R rs168753 minor allele could significantly contribute to the risk of ischemic events, and P2RY12 rs6809699 minor allele could predict bleedings. The genetic testing of platelet receptors can be valuable in predicting adverse events in STEMI patients after PCI.

Long-term Outcomes of Primary Percutaneous Coronary Intervention with Second-generation Drug-eluting Stents in ST-elevation Myocardial Infarction Patients Caused by Very Late Stent Thrombosis

Background: The ST-segment elevation myocardial infarction (STEMI) patients due to stent thrombosis (ST) remain a therapeutic challenge for a clinician. Till date, very few researches have been conducted regarding the safety and effectiveness of primary percutaneous coronary intervention (PCI) with second-generation drug-eluting stents (DES) for STEMI caused by very late ST (VLST). This retrospective study evaluated the safety, efficacy, and outcomes of primary PCI with second-generation DES for STEMI due to VLST compared with primary PCI for STEMI due to de novo lesion. Methods: Between January 2007 and December 2013, STEMI patients with primary PCI in Fuwai Hospital had only second-generation DES implanted for de novo lesion (558 patients) and VLST (50 patients) were included in this retrospective study. The primary end points included cardiac death and reinfarction. The secondary end points included cardiac death, reinfarction, and target lesion revascularization. Continuous variables were expressed as mean (standard deviation) or median (interquartile range) and compared by Students t-test or Mann-Whitney U-test as appropriate. Categorical variables were expressed as counts and percentages, and comparison of these variables was performed with Chi-square or Fishers exact test. A two-tailed value of P < 0.05 was considered statistically significant for all comparisons. Statistical analyses were performed by SAS software (version 9.4, SAS Institute Inc., Cary, USA) for Windows. Results: In-hospital primary end point and the secondary end point were no significant differences between two groups (P = 1.000 and P = 1.000, respectively). No significant differences between two groups were observed according to the long-term primary end point and the secondary end point. Kaplan-Meier survival curves showed no significant difference between the two groups in the primary end point and the secondary end point at 2 years (P = 0.340 and P = 0.243, respectively). According to Cox analysis, female, intra-aortic balloon pump support, and postprocedural thrombolysis in myocardial infarction flow 3 were found to be independent predictors for long-term follow-up. Conclusion: Primary PCI with second-generation DES is a reasonable choice for STEMI patients caused by VLST.

Head to Head Comparison of Two Point-of-care Platelet Function Tests Used for Assessment of On-clopidogrel Platelet Reactivity in Chinese Acute Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention

Background: Platelet function tests are widely used in clinical practice to guide personalized antiplatelet therapy. In China, the thromboelastography (TEG) test has been well accepted in clinics, whereas VerifyNow, mainly used for scientific research, has not been used in routine clinical practice. The aim of the current study was to compare these two point-of-care platelet function tests and to analyze the consistency between the two tests for evaluating on-clopidogrel platelet reactivity in Chinese acute myocardial infarction patients undergoing percutaneous coronary intervention (PCI). Methods: A total of 184 patients admitted to Fuwai Hospital between August 2014 and May 2015 were enrolled in the study. On-clopidogrel platelet reactivity was assessed 3 days after PCI by TEG and VerifyNow using adenosine diphosphate as an agonist. Based on the previous reports, an inhibition of platelet aggregation (IPA) <30% for TEG or a P2Y12 reaction unit (PRU) >230 for VerifyNow was defined as high on-clopidogrel platelet reactivity (HPR). An IPA >70% or a PRU <178 was defined as low on-clopidogrel platelet reactivity (LPR). Correlation and agreement between the two methods were analyzed using the Spearman correlation coefficient (r) and kappa value (&kgr;), respectively. Results: Our results showed that VerifyNow and TEG had a moderate but significant correlation in evaluating platelet reactivity (r = −0.511). A significant although poor agreement (&kgr; = 0.225) in identifying HPR and a significantly moderate agreement in identifying LPR (&kgr; = 0.412) were observed between TEG and VerifyNow. By using TEG as the reference for comparison, the cutoff values of VerifyNow for the Chinese patients in this study were identified as PRU >205 for HPR and PRU <169 for LPR. Conclusions: By comparing VerifyNow to TEG which has been widely used in clinics, VerifyNow could be an attractive alternative to TEG for monitoring on-clopidogrel platelet reactivity in Chinese patients.

Effect of sex difference in clinical presentation (stable coronary artery disease vs unstable angina pectoris or non-ST-elevation myocardial infarction vs ST-elevation myocardial infarction) on 2-year outcomes in patients undergoing percutaneous coronary intervention

OBJECTIVE To determine whether there is a difference in 2-year prognosis among patients across the spectrum of coronary artery disease undergoing percutaneous coronary intervention (PCI). METHODS We analyzed all consecutive patients undergoing PCI at a single center from 1/1-12/31/2013. Clinical presentations were compared between sexes according to baseline clinical, angiographic, and procedural characteristics and 2-year (mean 730 ± 30-day) outcomes. RESULTS We grouped 10 724 consecutive patients based on sex and clinical presentation. Among patients with ST-elevation myocardial infarction (STEMI), rates of all-cause death (6.7% vs 1.4%) and cardiac death (3.8% vs 1.1%) were significantly higher in women than in men (P < 0.05), but these rates did not differ between men and women with stable coronary artery disease (SCAD) and non-ST-elevation acute coronary syndrome ((NSTE-ACS). Incidence of major bleeding was greater than in men only in those women presenting with ACS. After multivariable adjustment, female sex was not an independent predictor of outcomes in STEMI (hazard ratio [HR] for all-cause death: 1.33, 95% confidence interval [CI]:0.52-3.38; P = 0.55; HR for cardiac death: 0.69, 95%CI: 0.23-2.09, P = 0.51], but was still an independent predictor of bleeding in STEMI (HR: 3.53, 95%CI: 1.26-9.91, P = 0.017). CONCLUSION Among STEMI patients, women had worse 2-year mortality after PCI therapy, but female sex was not an independent predictor of mortality after adjustment for baseline characteristics. In STEMI patients, women were at higher bleeding risk than men after PCI, even after multivariable adjustment.

Comparison of Efficacy and Safety between First- and Second-Generation Drug-Eluting Stents in Patients with Acute Coronary Syndrome

Background: It remains undetermined whether second-generation drug-eluting stents (G2-DESs) outperform first-generation DESs (G1-DESs) in patients with acute coronary syndrome (ACS). We aimed to compare the efficacy and safety of G1-DES and G2-DES in ACS patients in a high-volume cardiovascular center. Methods: In 2013, 10,724 consecutive patients underwent percutaneous coronary intervention in our institution. We included 4037 patients with ACS who underwent exclusively G1-DES or G2-DES implantation (n = 364 and n = 3673, respectively). We used propensity score matching to minimize the imbalance between the G1-DES and G2-DES groups and followed patients for 2 years. The efficacy endpoints were major adverse cardiac events (MACEs) and its components including target vessel-related myocardial infarction (TV-MI), target vessel revascularization/target lesion revascularization (TVR/TLR), and cardiac death. The safety endpoint was stent thrombosis. Continuous variables were compared by Mann-Whitney U-test, and categorical variables were compared using Pearsons Chi-square or Fishers exact test. Kaplan-Meier curves were constructed to compare the event-free survival rates, and multivariate Cox proportional hazards regression analysis was used to assess whether stent type was an independent risk factor for the efficacy and safety endpoints. Results: At the 2-year follow-up, the results for MACE and it components, as well as stent thrombosis, were similar for G1-DES and G2-DES (MACE, 5.2% vs. 4.3%, &khgr;2 = 0.514, P = 0.474; TV-MI, 0.8% vs. 0.4%, P = 0.407; TVR, 4.9% vs. 3.7%, &khgr;2 = 0.939, P = 0.333; TLR, 3.8% vs. 2.5%, &khgr;2 = 1.610, P = 0.205; cardiac death, 0.3% vs. 0.5%, P = 0.670; and stent thrombosis, 0.5% vs. 0.4%, P > 0.999). Kaplan-Meier analysis indicated similar event-free survival rates between G1-DES and G2-DES after propensity score matching (all: log-rank P > 0.05). Multivariate analysis demonstrated that stent type was not an independent risk factor for the efficacy and safety endpoints (MACE, hazard ratio [HR] = 0.805, 95% confidence interval [CI]: 0.455–1.424, P = 0.456; TV-MI, HR = 0.500, 95% CI: 0.101–2.475, P = 0.395; TVR, HR = 0.732, 95% CI: 0.403–1.330, P = 0.306; TLR, HR = 0.629, 95% CI: 0.313–1.264, P = 0.193; cardiac death, HR = 1.991, 95% CI: 0.223–17.814, P = 0.538; and stent thrombosis, HR = 0.746, 95% CI: 0.125–4.467, P = 0.749). Conclusion: G1-DES and G2-DES have similar efficacy and safety profiles in ACS patients at the 2-year follow-up.

Comparison of Efficacy and Safety between First and Second Generation Drug-eluting Stents in Patients with Stable Coronary Artery Disease: A Single-center Retrospective Study.

Background: Lots of trials demonstrate that second-generation drug-eluting stents (G2-DES), with their improved properties, offer significantly superior efficacy and safety profiles compared to first generation DES (G1-DES) for patients with coronary artery disease (CAD) receiving percutaneous coronary intervention (PCI). This study aimed to verify the advantage of G2-DES over G1-DES in Chinese patients with stable CAD (SCAD). Methods: For this retrospective observational analysis, 2709 SCAD patients with either G1-DES (n = 863) or G2-DES (n = 1846) were enrolled consecutively throughout 2013. Propensity score matching (PSM) was applied to control differing baseline factors. Two-year outcomes, including major adverse coronary events as well as individual events, including target vessel-related myocardial infarction, target lesion revascularization (TLR), target vessel revascularization, and cardiogenic death were evaluated. Results: The incidence of revascularization between G1- and G2-DES showed a trend of significant difference with a threshold P - value (8.6% vs. 6.7%, &khgr;2 = 2.995, P = 0.084). G2-DES significantly improved TLR-free survival compared to G1-DES (96.6% vs. 97.9%, P = 0.049) and revascularization-free survival curve showed a trend of improvement of G2-DES (92.0% vs. 93.8%, P = 0.082). These differences diminished after PSM. Multivariate Cox proportional hazard regression analysis showed a trend for G1-associated increase in revascularization (hazard ratio: 1.28, 95% confidence interval: 0.95–1.72, P = 0.099) while no significance was found after PSM. Other endpoints showed no significant differences after multivariate adjustment regardless of PSM. Conclusions: G1-DES showed the same safety as G2-DES in this large Chinese cohort of real-world patients. However, G2-DES improved TLR-free survival of SCAD patients 2 years after PCI. The advantage was influenced by baseline clinical factors. G1-DES was associated with a trend of increase in revascularization risk and was not an independent predictor of worse medium-term prognosis compared with G2-DES.

Effect of coronary dominance on 2-year outcomes after percutaneous coronary intervention in patients with acute coronary syndrome

This retrospective, single‐center, observational analysis from prospectively collected database evaluated whether left dominance affected the long‐term outcomes of acute coronary syndrome patients undergoing percutaneous coronary intervention, and whether the effect was independent of SYNTAX score.