急性冠状动脉综合征患者替格瑞洛相关呼吸困难的危险因素分析

目的 探讨经皮冠状动脉介入（PCI）治疗的急性冠状动脉综合征（ACS）患者服用替格瑞洛后呼吸困难的发生率、临床特点及相关危险因素。方法 前瞻性纳入2018年12月至2019年6月我院283例PCI治疗后服用阿司匹林联合替格瑞洛治疗的ACS患者，排除既往肺部基础疾病和心功能不全（NYHA心功能分级Ⅲ级及以上或需药物干预治疗）的患者。采用Borg评分量表评估替格瑞洛相关呼吸困难的发生情况及严重程度，采用心肌梗死溶栓治疗出血分级评估患者出血情况，分析替格瑞洛相关呼吸困难的危险因素。绘制ROC曲线计算左心室射血分数（LVEF）对替格瑞洛相关呼吸困难发生的诊断效能。结果 替格瑞洛相关呼吸困难的发生率为16.3%（46/283），其中服药1周内发生呼吸困难者占60.9%（28/46）。替格瑞洛相关呼吸困难主要表现为轻度呼吸困难（56.5%，26/46），中度、重度呼吸困难分别占28.3%（13/46）和15.2%（7/46）。因药物不良反应停用替格瑞洛治疗的患者占8.5%（24/283），其中因为不能耐受呼吸困难而停药者占62.5%（15/24）。呼吸困难组患者出血事件、男性患者比例、吸烟史、左心房容积均高于非呼吸困难组（P均<0.05），而LVEF低于非呼吸困难组（P<0.01）。多因素logistic回归分析结果显示出血事件、低LVEF、男性、吸烟史是替格瑞洛相关呼吸困难发生的独立危险因素（P均<0.05）；其中发生出血事件的患者呼吸困难的风险是未发生出血事件患者的2.925倍（OR=2.925，95% CI：1.386~6.175，P=0.005）。ROC曲线分析结果显示LVEF的诊断界值为61%，即LVEF ≤ 61%的ACS患者更容易发生替格瑞洛相关呼吸困难。结论 呼吸困难在服用替格瑞洛的中国ACS人群中较常见，其程度多为轻度且大部分在服药后1周内出现。出血事件、低LVEF、吸烟史和男性是ACS患者发生替格瑞洛相关呼吸困难的危险因素。     

Effects of Methylnaltrexone on Ticagrelor-Induced Antiplatelet Effects in Coronary Artery Disease Patients Treated With Morphine

ObjectivesThe aim of this study was to assess if intravenous methylnaltrexone can counteract the effects of morphine on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ticagrelor.BackgroundMorphine delays the onset of action of oral P2Y₁₂ receptor inhibitors, including ticagrelor, by inhibiting gastric emptying and leading to delayed drug absorption. Methylnaltrexone is a peripheral opioid receptor antagonist that has the potential to prevent opioid-induced peripherally mediated side effects (e.g., gastric emptying inhibition) without affecting analgesia.MethodsIn this prospective, randomized, double-blind, placebo-controlled, crossover study, aspirin-treated patients with stable coronary artery disease (n = 30) were randomized to receive methylnaltrexone (0.3 mg/kg intravenous) or matching placebo. After methylnaltrexone or placebo administration, all patients received morphine (5 mg intravenous). This was followed 15 min later by a 180-mg loading dose of ticagrelor. Patients crossed over to the alternative study treatment after 7 ± 2 days of washout. PK and PD assessments were performed at 12 time points (6 pre- and 6 post-crossover). PK analysis included measurement of plasma levels of ticagrelor and its major active metabolite (AR-C124910XX). PD assessments included VerifyNow P2Y₁₂, light transmittance aggregometry, and vasodilator-stimulated phosphoprotein.ResultsOnly marginal changes in plasma levels of ticagrelor (and its major active metabolite) were observed with ticagrelor: maximum plasma concentration and area under the plasma concentration versus time curve from time 0 to the last measurable concentration were 38% and 30% higher, respectively, in patients receiving methylnaltrexone compared with those receiving placebo, but no differences in time to maximum plasma concentration were observed. There were no differences in P2Y₁₂ reaction units by VerifyNow P2Y₁₂ between groups at each time point, including 2 h (the primary endpoint; p = 0.261). Similarly, there were no differences in PD markers assessed by light transmittance aggregometry and vasodilator-stimulated phosphoprotein.ConclusionsIn patients with coronary artery disease receiving morphine, intravenous administration of the peripheral opioid receptor antagonist methylnaltrexone leads to only marginal changes in plasma levels of ticagrelor and its major metabolite, without affecting levels of platelet reactivity. (Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine; NCT02403830)     

The evolution of dual antiplatelet therapy in the setting of acute coronary syndrome: ticagrelor versus clopidogrel

Review of: Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Eng J Med 2009; 361(11): 1045–1057.

For acute coronary syndrome (ACS), a dual antiplatelet regimen comprised of treatment with aspirin and either P2Y12 adenosine diphosphate receptor antagonists, clopidogrel, prasugrel or ticagrelor is usually employed. This article compares clopidogrel with ticagrelor for the prevention of vascular events and death in broad population of ACS patients ranging from UA, NSTEMI to STEMI, utilizing planned strategies of medical or invasive treatment strategy.     

Effect of Ticagrelor on Left Ventricular Remodeling in Patients With ST-Segment Elevation Myocardial Infarction (HEALING-AMI)

ObjectivesThe aim of this study was to evaluate the effect of ticagrelor versus clopidogrel on left ventricular (LV) remodeling after reperfusion of ST-segment elevation myocardial infarction (STEMI) in humans.BackgroundAnimal studies have demonstrated that ticagrelor compared with clopidogrel better protects myocardium against reperfusion injury and improves remodeling after myocardial infarction.MethodsIn this investigator-initiated, randomized, open-label, assessor-blinded trial performed at 10 centers in Korea, patients were enrolled if they had naive STEMI successfully treated with primary percutaneous coronary intervention (PCI) and at least 6-month planned duration of dual-antiplatelet treatment. The coprimary endpoints were LV remodeling index (LVRI) (a relative change of LV end-diastolic volume) measured on 3-dimensional echocardiography and N-terminal pro–B-type natriuretic peptide level at 6 months.ResultsAmong initially enrolled patients with STEMI (n = 336), 139 in each group completed the study. LVRI at 6 months was numerically lower with ticagrelor versus clopidogrel (0.6 ± 18.6% vs. 4.5 ± 16.5%; p = 0.095). Ticagrelor significantly reduced the 6-month level of N-terminal pro–B-type natriuretic peptide (173 ± 141 pg/ml vs. 289 ± 585 pg/ml; p = 0.028). These differences were prominent in patients with pre-PCI TIMI (Thrombolysis In Myocardial Infarction) flow grade 0. By multivariate analysis, ticagrelor versus clopidogrel reduced the risk for positive LV remodeling (LVRI >0%) (odds ratio: 0.56; 95% confidence interval: 0.33 to 0.95; p = 0.030). The LV end-diastolic volume index remained unchanged during ticagrelor treatment (from 54.7 ± 12.2 to 54.2 ± 12.2 ml/m²; p = 0.629), but this value increased over time during clopidogrel treatment (from 54.6 ± 11.3 to 56.4 ± 13.9 ml/m²; p = 0.056) (difference −2.3 ml/m²; 95% confidence interval: −4.8 to 0.2 ml/m²; p = 0.073). Ticagrelor reduced LV end-systolic volume index (from 27.0 ± 8.5 to 24.7 ± 8.4 ml/m²; p < 0.001), whereas no reduction was seen with clopidogrel (from 26.2 ± 8.9 to 25.6 ± 11.0 ml/m²; p = 0.366) (difference −1.8 ml/m²; 95% confidence interval: −3.5 to −0.1 ml/m²; p = 0.040).ConclusionsTicagrelor was superior to clopidogrel for LV remodeling after reperfusion of STEMI with primary PCI. (High Platelet Inhibition With Ticagrelor to Improve Left Ventricular Remodeling in Patients With ST Segment Elevation Myocardial Infarction [HEALING-AMI]; NCT02224534)     

替格瑞洛抗血小板治疗致呼吸困难1例报告

1 临床资料 患者,男性,58岁,因“PCI术后3年余,再发胸痛3d”于2013年10月入院.既往曾于2010年4月因劳累后胸骨后疼痛在第二军医大学长海医院行冠脉造影.造影提示前降支中段闭塞,遂对闭塞处行支架植入术.2013年1月30日再次因情绪激动后感持续性心前区疼痛,呈压榨样并向左肩部放射再次入我院行造影提示:前降支近端支架内发出第一对角支处完全闭塞,回旋支中段狭窄75％,右冠近中段局限性狭窄85％.     

Safety and feasibility of low‐dose ticagrelor in patients with ST‐segment elevation myocardial infarction

BackgroundPrevious studies have confirmed the safety and feasibility of half‐dose ticagrelor in Chinese patients with acute coronary syndrome, but currently there is no plan for the use of ticagrelor for Chinese ST‐segment elevation myocardial infarction (STEMI) patients.HypothesisIt is safe and feasible of low‐dose ticagrelor in patients with STEMI.MethodsThe STEMI patients who were undergoing emergency intervention and taking ticagrelor were enrolled. Patients whose level of platelet aggregation rate (PAR) less than 30% after 7‐day treatment with standard‐dose ticagrelor were randomly divided into low‐dose group (LD group, 45 mg twice daily) and standard‐dose group (SD group, 90 mg twice daily). The changes of levels of platelet parameters were compared between the two groups. The incidence of major adverse cardiac events (MACE), bleeding events were compared between the two groups within 6 months of follow‐up.ResultsThe levels of PAR in the SD group decreased compared with baseline, and was lower than those of LD group at the same time point. The levels of platelet distribution width in both groups decreased from the baseline values (all p < .05) at 1, 3, and 6 months after grouping treatment, but there was no significant difference between the two groups. The incidence of MACE was similar between the two groups of patients. There were decreasing trends in the incidences of minimal bleeding event, minor bleeding event, dyspnea, and gout in the LD group.ConclusionIt is safe and feasible of low‐dose ticagrelor for patients with STEMI based on the monitoring of PAR.     

Review of pharmacoeconomic evaluation of genotype-guided antiplatelet therapy

Introduction: Clopidogrel is an antiplatelet agent widely prescribed for acute coronary syndrome (ACS), and it is activated by the CYP enzyme system to active metabolite. CYP2C19 loss-of-function (LOF) allele(s) affect the responsiveness of clopidogrel, but not the new antiplatelet agents (prasugrel and ticagrelor). We reviewed the pharmacoeconomic studies on genotype-guided use of new antiplatelet agents.

Areas covered: A literature search was conducted between the period of 2000 and 2014. Seven studies including cost-effectiveness and risk-benefit analyses of CYP2C19 genotype-guided antiplatelet therapy in ACS patients were reviewed. Genotype-guided prasugrel was found to be cost-effective when compared with universal antiplatelet therapy in four studies. Three studies showed genotype-guided ticagrelor to be cost-effective in ACS patients with percutaneous coronary intervention (PCI), and universal ticagrelor to be cost-effective in ACS patients. Drug cost of antiplatelet agents and relative risk of the new antiplatelet versus clopidogrel for clinical events were common influential factors of cost-effectiveness analyses.

Expert opinion: All studies in the present review focused on selecting antiplatelet agents for carriers of CYP2C19 LOF allele(s). Cost-effectiveness of genotype-guided use of antiplatelets was demonstrated in high-risk ACS patients.     

Mean platelet volume and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor

Objective: High on-treatment platelet reactivity (HRPR) is associated with a two- to ninefold increased risk of recurrent ischemic events among patients receiving dual antiplatelet therapy (DAPT) for coronary artery disease. However, its determinants are still poorly understood. The aim of the present study was to assess the impact of mean platelet volume (MPV) on platelet reactivity in patients receiving DAPT after an acute coronary syndrome or PCI.

Methods: Patients treated with DAPT (acetylsalicylic acid [ASA] and clopidogrel or ticagrelor) were scheduled for platelet function assessment at 30 – 90 days post-discharge. By whole blood impedance aggregometry, HRPR was considered for ASPI test > 862 aggregation units (AU)*min (for ASA) and ADP test values ≥ 417 AU*min (for ADP-antagonists).

Results: Our population is represented by a total of 487 patients on DAPT, divided according to MPV tertiles (< 10.4 fl; 10.4 – 11.29 fl; ≥ 11.3 fl). Larger-sized platelets were associated with use of statins (p < 0.001) and beta-blockers (p = 0.03), higher hemoglobin levels (p = 0.002) and lower platelets count (p < 0.001). Higher platelet reactivity was observed at ASPI test in patients with higher MPV (r = 0.12, p = 0.008), but not for ADP-mediated aggregation (r = -0.007, p = 0.88). However, a low prevalence of HRPR was observed with ASA, with no impact of MPV tertiles (1.2 vs 1.1 vs 1.6%, p = 0.70, adjusted OR [95% CI] = 1.05 [0.51 – 1.77], p = 0.87). MPV did not influence the prevalence of HRPR for ADP-antagonists (25.9 vs 1 vs 26.5%, p = 0.89; adjusted OR [95% CI] = 1.1 [0.84 – 1.45], p = 0.50) with similar results among the 259 patients receiving clopidogrel (adjusted OR [95% CI] = 1.15 [0.82 – 1.62], p = 0.43) and the 228 patients on ticagrelor (adjusted OR [95% CI] = 1.46 [0.84 – 2.55], p = 0.18).

Conclusion: In patients receiving DAPT, MPV does not affect the response to major antiplatelet therapies. In fact, MPV elevation does not influence the risk of HRPR with clopidogrel, ticagrelor or ASA.