抗血小板治疗平衡之道

平衡之道抗栓药物治疗临床获益和出血风险,抗血小板,抗凝,纤溶,血小板黏附激活、聚集,血细胞,凝血瀑布激活,血栓,纤维蛋白原,纤维蛋白,纤维蛋白交联,纤维蛋白降解,纤溶酶,动脉粥样硬化斑块破裂,抗血小板是抗栓治疗最重要的手段之一,16-20%,12-15%,8-12%,6-10%,4-8%,死亡 / 心梗,1988ASA,1992ASA+Heparin,1998 ASA+Heparin+Anti-GPIIB/IIIA,2003ASA+LMWH +Clopidogrel +Intervention,With permission from Christopher Cannon, 1988,抗栓药物治疗近20年的变化:疗效提高的同时出血问题随之增加,临床疗效提高同时，如何面对出血风险？,John W. Eikelboom, et al. Circulation 2006;114: 774 - 782,风险 5 倍P0.0001,出血患者 12.8%,未出血患者 2.5%,30天死亡率( % ),33676,33419,33157,32990,32879,32769,32710,470,459,440,430,420,410,408,(天),患者例数未出血出血,N=34146,出血事件显著增加30天死亡风险,(OASIS 注册/OASIS-2及CURE),Rao et al. JAMA 2004;292:1555-62,N=24,112 ACS患者 来自GUSTO IIb, PURSUIT 和 PARAGON研究,*Adjusted for baseline characteristics, bleeding and transfusion propensity and nadir hematocrit,UA/NSTEMI患者输血与30天死亡率相关,观察了1358例DES患者，出院后使用氯吡格雷+ASA12个月，平均随访32个月大出血导致抗血小板停药率增加，进而导致患者死亡、MACE和支架内血栓发生危险显著增高,P0.001,P=0.002,P0.001,大出血与ACS患者远期结局相关,Rao et al. Am J Cardiol 2005;96:1200-1206,N=26,452 ACS患者来自GUSTO IIb, PURSUIT 和PARAGON A&B研究,存在消化道出血（GIB）的ACS患者临床结局更差,GIB（+）的ACS患者1年死亡率显著高于GIB（-）患者,GIB(+)患者比GIB()患者30天时缺血性事件率显著增加,小出血与远期临床结局,小出血可导致抗血小板停药率增加 小出血可导致1年时MACE发生危险显著增高,P=0.001,P75岁、75岁、体重75岁 计划行CABG（手术前停药7天） 体重15个月（IIb C）拟PCI的STEMI患者，存在既往卒中和TIA病史者不推荐普拉格雷作为双联抗血小板治疗的方案。（III C）,2009年STEMI和PCI合并更新增加普拉格雷作为治疗选择，但鉴于高出血风险而对于其适应证和禁忌证均给出明确推荐,Ticagrelor （替格瑞洛）,口服、可逆性、ADP受体P2Y12的直接抑制剂体外试验显示，替格瑞洛及其活性代谢产物ARC126910是P2Y12的特异性抑制剂，即使浓度超过3molL以上时，对其它的P2受体也没有显著的亲和力。替格瑞洛对ADP诱导的血小板凝集反应有强效的抑制作用作用强：与氯吡格雷相比，起效更快，抑制血小板的作用更加强 可逆性：和氯吡格雷的作用方式不同。,替格瑞洛显著降低ACS患者心血管事件发生危险达16%,多中心、双盲、随机研究l, 18624例ACS( with or without ST-segment elevation)患者. 替格瑞洛（180-mg 负荷剂量, 90 mg bid ) and 氯吡格雷（300-to600-mg 负荷剂量, 75 mg qd. ) PLATO研究中替格瑞洛组平均用药时间277天,Days after randomisation,0,60,120,180,240,300,360,12,11,10,9,8,7,6,5,4,3,2,1,0,13,累积发生率 (%),9.8,11.7,HR 0.84 (95% CI 0.770.92), p=0.0003,Clopidogrel,Ticagrelor,MI: 5.8%vs 6.9% (p=0.005)CV死亡： 4.0% vs. 5.1%, (P=0.001)全因死亡： 4.5% vs. 5.9% ( P0.001). stroke： 1.5% vs. 1.3%, （P=0.22),CV 死亡、MI或卒中复合终点,大出血发生率无明显差异 (11.6% and 11.2%; P=0.43) 有增加颅内出血危险的趋势（P=0.06 )，其中致死性颅内出血发生率显著增高10倍 (P=0.02 ） Non-CABG 出血风险明显升高 (4.5% vs. 3.8%, P=0.03) 其他不良反应如呼吸困难（14.2%和 9.2%）、心动过缓发生率显著升高，血肌酐和尿酸水平显著升高因不良反应而致停药率显著增高（P0.001）一天2次给药降低治疗依从性,替格瑞洛：安全性终点,Non-CABG出血需要关注,替格瑞洛价值与探讨,研究中平均用药时间仅277天，缺乏长期维持治疗的证据Non-CABG出血风险明显升高 卒中获益不优于氯吡格雷，致死性颅内出血发生率明显升高，用于缺血性卒中患者是否获益尚待斟酌；存在呼吸困难等显著不良反应，且因给药次数较多降低治疗依从性。对于快速逆转的药物来说，直接停药对再发MI和卒中可能具有潜在的影响；PLATO排除溶栓治疗和口服抗凝治疗的患者，这些ACS患者联用替格瑞洛的疗效/安全性尚不明。,探讨,显著降低全因死亡和急性MI，而不增加严重出血的发生率适用于CABG患者，PLATO研究中CABG术前24-48小时停用并不增加出血风险降低复合终点发生危险达16%，如得到进一步研究证实，为平衡其不良反应所致风险留出了较多的空间,价值,2010年 7月 27日 04:34However, subgroup analysis found that ticagrelor apparently had no benefit for the studys 1,814 U.S. participants, and American patients taking ticagrelor actually had a 27% greater risk of having a clinical event than those taking clopidogrel (with a 95% confidence interval, ranging from 0.92 to 1.75).AstraZeneca has said that the difference in efficacy is because U.S. patients were taking higher doses of aspirin. Ticagrelors label states that it should be administered with low dose (75 to 100 mg) of aspirin.Play of chance, could be a possible explanation, they wrote, although that may be overstretching considering the U.S. population had a 27% greater risk for adverse events on ticagrelor while the rest of the world shows a clear benefit from it.Marciniak said that while efficacy is a bigger issue than safety for ticagrelor, there were a number of safety concerns.The most important safety issue for ticagrelor was bleeding, wrote another FDA reviewer.Major bleeds and less serious bleeds were substantially increased with ticagrelor. Some 14.5% of patients in the ticagrelor group experienced bleeding compared to 13.2% in the clopidogrel group (P=0.0083). However, life-threatening and fatal bleeds were not significantly increased in the ticagrelor group.The FDAs clinical safety reviewer commented that most major bleeds were CABG-related. The risk of CABG-bleeding was increased in ticagrelor patients who underwent CABG fewer than five days after stopping ticagrelor.Delaying major surgery for five or more after stopping ticagrelor is the most important management principle for dealing with the increased bleeding risk of ticagrelor, Marciniak wrote.In the PLATO trial, fewer patients died while taking ticagrelor compared with those taking clopidogrel (3.1% versus 3.7%). Most of the deaths were classified as vascular deaths, including MI and sudden heart failure.However, in the U.S. patients, there were more deaths in the ticagrelor group compared with clopidogrel (3.8% versus 3.2%).,2010年7月27日，FDA发布关于ticagrelor临床安全的意见 在PLATO研究亚组分析，1814例来自美国的研究对象中，服用ticagrelor组与clopidogrel组相比，临床事件的发生风险增加了27%（95%CI. 0.921.75)，死亡率亦有增加（3.8% vs. 3.2%） AstraZeneca对此解释说是由于美国患者同时使用了较大剂量的ASA所致，而ticagrelor的说明书要求给以较低剂量（75100mg）的ASA；是“随机性机遇”所致，在全世界其他地方ticagrelor是有效的 FDA认为对此尚需要更多的研究证实 同时，FDA对ticagrelor所导致的出血风险亦