替格瑞洛对冠心病心绞痛患者血小板功能抑制的研究

目的研究替格瑞洛对冠心病心绞痛患者血小板功能的抑制情况。方法选取2011年3月-2013年2月在中国医学科学院北京协和医学院阜外心血管病医院就诊的心绞痛患者88例,依据分层随机分组法将患者分为对照组和治疗组,每组44例。在常规治疗基础上,对照组给予口服负荷剂量氯吡格雷300 mg/d,1周后改为75 mg/d维持进行治疗;治疗组给予口服负荷剂量替格瑞洛180 mg/d,1周后改为90 mg/d维持进行治疗。观察比较两组患者用药前,用药1、2周后,停药6、12 h及1 d后的血小板聚集率（MPA）、血小板反应指数（PRI）,治疗1年内患者心血管意外事件发生情况和药物不良反应情况。结果治疗前两组患者的MPA和PRI比较差异无统计学意义（P〉0.05）。治疗1、2周后治疗组患者的MPA和PRI均明显低于对照组（P〈0.05）。停药12 h及1 d后治疗组患者的MPA和PRI均高于对照组患者（P〈0.05）。治疗1年内,治疗组患者的心绞痛发作及心肌梗死例数明显低于对照组（P〈0.05）。治疗组患者的挫伤、腹痛及皮疹例数明显低于对照组（P〈0.05）。治疗组患者的呼吸困难及出血例数与对照组比较差异无统计学意义。结论应用替格瑞洛代替氯吡格雷对心绞痛患者进行治疗可有效对抗血小板的凝血作用,并在停药后更快恢复,明显降低患者心绞痛及心肌梗死发作次数以及因心脑血管意外导致的死亡率。     

Circulating progenitor cells and their interaction with platelets in patients with an acute coronary syndrome

CD34⁺ cells expressing KDR (CD34⁺/KDR⁺) represent a small proportion of circulating progenitor cells that have the capacity to interact with platelets and to differentiate into mature endothelial cells, thus contributing to vascular homeostasis and regeneration as well as to re-endothelialization. We investigated the levels of CD34⁺ and CD34⁺/KDR⁺ progenitor cells as well as their interaction with platelets in acute coronary syndrome (ACS) patients before the initiation (baseline) of their treatment with a P2Y₁₂ receptor antagonist, and at 5-days post-treatment (follow-up). Sixty-seven consecutive ACS patients and thirty healthy subjects (controls) participated in the study. On admission, all patients received 325 mg aspirin, followed by 100 mg/day and then were loaded either with 600 mg clopidogrel or 180 mg ticagrelor, followed by 75 mg/day (n = 36) or 90 mg × 2/day (n = 31), respectively. The levels of circulating CD34⁺ and CD34⁺/KDR⁺ progenitor cells, as well as their interaction with platelets, were determined by flow cytometry, before and after activation with ADP, in vitro. The circulating levels of CD34⁺ and CD34⁺/KDR⁺ cells in both patient groups at baseline were lower compared with controls while they were significantly increased at 5-days of follow-up in both groups, this increase being more pronounced in the ticagrelor group. The platelet/CD34⁺ (CD61⁺/CD34⁺) conjugates were higher at baseline and reduced at follow-up while the platelet/KDR⁺ (CD61⁺/KDR⁺) conjugates were lower at baseline and increased at follow-up, both changes being more pronounced in the ticagrelor group. ADP activation of control samples significantly increased the KDR expression by CD34⁺ cells and the CD61⁺/KDR⁺ conjugates, these parameters being unaffected in patients at baseline but increased at follow-up. Short-term dual antiplatelet therapy in ACS patients restores the low platelet/KDR⁺ conjugates and CD34⁺ cell levels and improves the low membrane expression levels of KDR in these cells, an effect being more pronounced in ticagrelor-treated patients. This may represent a pleiotropic effect of antiplatelet therapy towards vascular endothelial regeneration.     

Ticagrelor Versus Clopidogrel in Patients With STEMI Treated With Fibrinolysis: TREAT Trial

BackgroundThe efficacy of ticagrelor in the long-term post–ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remains uncertain.ObjectivesThe purpose of this study was to evaluate the efficacy of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy.MethodsThis international, multicenter, randomized, open-label with blinded endpoint adjudication trial enrolled 3,799 patients (age <75 years) with STEMI receiving fibrinolytic therapy. Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). The key outcomes were cardiovascular mortality, myocardial infarction, or stroke, and the same composite outcome with the addition of severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events at 12 months.ResultsThe combined outcome of cardiovascular mortality, myocardial infarction, or stroke occurred in 129 of 1,913 patients (6.7%) receiving ticagrelor and in 137 of 1,886 patients (7.3%) receiving clopidogrel (hazard ratio: 0.93; 95% confidence interval: 0.73 to 1.18; p = 0.53). The composite of cardiovascular mortality, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events occurred in 153 of 1,913 patients (8.0%) treated with ticagrelor and in 171 of 1,886 patients (9.1%) receiving clopidogrel (hazard ratio: 0.88; 95% confidence interval: 0.71 to 1.09; p = 0.25). The rates of major, fatal, and intracranial bleeding were similar between the ticagrelor and clopidogrel groups.ConclusionAmong patients age <75 years with STEMI, administration of ticagrelor after fibrinolytic therapy did not significantly reduce the frequency of cardiovascular events when compared with clopidogrel. (Ticagrelor in Patients With ST Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis [TREAT]; NCT02298088)     

不同抗血小板治疗策略对非透析慢性肾功能不全患者冠状动脉搭桥术后胸廓内动脉及大隐静脉桥血管通畅率的影响

目的 比较阿司匹林联合替格瑞洛或者氯吡格雷的双联抗血小板药物治疗(DAPT)，对慢性肾功能不全患者冠脉搭桥手术（CABG）术后早期桥血管通畅率的影响。方法 我科接受CABG手术患者77例，随机纳入A组（阿司匹林+替格瑞洛）与B组（阿司匹林+氯吡格雷）。A组35例，B组42例。术后1年行计算机断层扫描血管造影（CTA）检查，评估桥血管通畅性。并随访主要心血管事件、出血事件发生情况。结果 随访期间7例失访。70例完成CTA检查，A组32例，B组38例。静脉桥血管通畅率A组显著高于B组（46/51 90.2% vs 42/56 75.0%，P=0.024）。小型出血事件发生率A组高于B组（P=0.022）。Logistic回归分析提示替格瑞洛+阿司匹林双联抗血小板治疗可以降低桥血管狭窄风险（OR=0.193, 95%CI=0.043 0.861，P=0.031）。结论 在CKD患者接受冠状动脉搭桥术后，DAPT替格瑞洛联合阿司匹林可能更好地维护静脉桥血管的通畅率，并未增加主要出血事件的风险。     

替格瑞洛及氯吡格雷对急性冠脉综合征介入治疗后的疗效比较

 目的 比较替格瑞洛和氯吡格雷对行经皮冠状动脉介入(percutaneous coronary intervention,PCI)治疗的急性冠脉综合征(acute coronary syndrome,ACS)的疗效。方法 选择2014-06至2015-06医院收取的68例采用PCI治疗的ACS患者,随机分为替格瑞洛组和氯吡格雷组。用药7 d后,复查血栓弹力图(TEG)比较两组血小板抑制率,随访2个月,对比两组的主要不良事件。结果 服药7 d后,替格瑞洛组ADP途径血小板抑制率较氯吡格雷组升高[(76.15±12.88)% vs(51.08±8.32)%],差异有统计学意义(P<0.01)。经2个月随访,氯吡格雷组出现急性心肌梗死、心血管死亡、消化道出血各1例,替格瑞洛组1例因明显呼吸困难导致停药。结论 在接受PCI的ACS患者中,替格瑞洛抗血小板聚集效果较氯吡格雷更强,且临床验证安全。     

替格瑞洛新盐型的制备、表征及溶解性能研究

为改善替格瑞洛溶解性差的问题,采用悬浮液法和加液研磨法制备得到替格瑞洛-3,5-二硝基苯甲酸、替格瑞洛-吡嗪酰胺、替格瑞洛-D-脯氨酸、替格瑞洛-L-脯氨酸4种新盐型物质。利用粉末X-射线衍射法、红外光谱法、差示扫描量热法、核磁共振波谱法和元素分析技术对盐进行表征,分析各分子间盐键等作用力。使用高效液相色谱法测定原料药和盐在pH 1.2和pH 6.8缓冲溶液中的平衡溶解度。替格瑞洛与3,5-二硝基苯甲酸、吡嗪酰胺、D-脯氨酸、L-脯氨酸均以1∶1比例成盐,除替格瑞洛-D-脯氨酸外,其余3种盐型物质在pH 1.2缓冲溶液中平衡溶解度均有所提高,其中,替格瑞洛-3,5-二硝基苯甲酸的溶解度与原料药相比提高了1.7倍。该成盐技术方法简单,能够有效提高替格瑞洛的溶解度。