阿司匹林抵抗的概念缺乏临床意义

阿司匹林抵抗的概念缺乏临床意义,301医院 陈韵岱,动脉粥样硬化-血栓形成： 进展性过程,正常,脂肪条纹,纤维斑块,粥样硬化斑块,斑块破裂 血栓形成,心肌梗死,缺血性卒中 / 短暂缺血发作,下肢缺血,无临床症状,心血管病死亡,年龄增长,稳定性心绞痛 间歇性跛行,不稳定心绞痛,血栓形成是心脑血管事件的发病基础,血小板激活通道,血小板激活,纤维蛋白原,血栓素A2,纤维蛋白结合位点,ADP,凝血酶,血小板,阿司匹林一级预防：汇总分析 （致死和非致死的心肌梗死）,* Silent MIs included. The relative risk, p-value and 95% CI are from Mantel-Haenszel method.,BMJ 2002, 324:71-86,阿司匹林二级预防的效益,ATC汇总分析,任何严重血管事件减少四分之一 非致死性心肌梗死减少三分之一 非致死性脑卒中减少四分之一 心脑血管病死亡率降低六分之一 对其他原因死亡无不良影响,BMJ 2002, 324:7186,CLARITY：Primary End-point 3491 patients with STEMI 12 hours,Placebo,Clopidogrel,P=0.00000036,Odds Ratio 0.64 (95% CI 0.530.76),1.0,0.4,0.6,0.8,1.2,1.6,Clopidogrel better,Placebo better,n=1752,n=1739,36% Odds Reduction,15.0,21.7,0,5,10,15,20,25,Occluded Artery or Death/MI (%),PCI-CURE: 30 Day Results CV death, MI, or urgent revascularization,0,5,10,15,20,25,30,Days of follow-up,0.0,0.02,0.04,0.06,0.08,30% RRR P = 0.03 N = 2658,Cumulative Hazard Rate,* Includes open label thienopyridine,6.4%,4.5%,Clopidogrel + ASA* (n=1313),Placebo + ASA* (n=1345),Mehta, Lancet 2001; 21: 2033,“抗血小板药物抵抗” 用语的出现,阿司匹林抵抗（Aspirin Resistance, 1994） 氯吡格雷抵抗（Clopidogrel Resistance, 2004） 肝素抵抗（Heparin Resistance, 2003）,“阿司匹林抵抗” 的定义,临床阿司匹林抵抗（Clinical Aspirin Resistance） 阿司匹林不能使患者免于缺血性心血管病事件，临床表现为在服用阿司匹林情况下仍然发生了心血管病事件 生化阿司匹林抵抗（Biochemical Aspirin Resistance） 服用阿司匹林后不能引起血小板功能试验的预期改变：延长出血时间；抑制血栓素A2（TXA2）的生物合成；或 在体外对血小板功能检测指标产生预期的影响,临床阿司匹林抵抗：与临床完全脱离,荒谬：按照这一定义，如果不发生阿司匹林抵抗，患者只要服用阿司匹林，就不会发生心血管病事件之虞 发生率：按照这一定义，阿司匹林抵抗发生率75%（汇总分析显示阿司匹林减少心血管病事件20%25%） 事实：心血管疾病的发生发展涉及诸多的因素，阿司匹林治疗只能减少、而不可能根绝心血管病事件 事实：根据被研究人群的临床特点、样本数量和随访时间长短，“临床阿司匹林抵抗” 的发生率可以从0%100%,“临床阿司匹林抵抗” 的可能原因,患者服药依从性差 阿司匹林剂量太小 同时服用与阿司匹林有不利相互作用的药物如布洛芬 血小板经其他途径激活 血小板加速更新 血小板组分或花生四烯酸代谢酶的基因多态性 非动脉粥样硬化因素引起心血管病事件,阿司匹林抗血小板效应的 实验室测定方法,Hankey GJ, et al. BMJ 2004, 328:477-479,Aspirin Resistance: Optical Aggregometry,AA, ADP, EPI, etc.,Platelet Function Analyzer (PFA)-100,Aspirin Resistance: History,In 1978, Mehta noted that 3 of 10 patients with coronary artery disease undergoing cardiac catheterization had normal platelet aggregation despite a 650 mg dose of aspirin prior to the procedure,Mehta J , et al. Atherosclerosis 1978; 31:169,Aspirin Resistance: An Example,Grotemeyers study Single 500 mg aspirin dose given to post-stroke patients 29 of 82 (36%) had normal platelet function* 12 hours after dose,Grotemeyer KH. Thromb Res 1991, 63: 587,* Platelet reactivity index (PR),Aspirin Resistance: Clinical Significance,Grotemeyers follow-up study Initially noted 36% of post stroke patients did not have expected antiplatelet response to aspirin These patients had an 89% increased risk of subsequent vascular events at 2 year follow-up (p 0.0001),Grotemeyer KH, et al. Thromb Res 1993; 71:397,HOPE Study: Case-Control Sub-Study,HOPE study Followed 9 541 high risk patients for 5 years This sub-study selected 488 pts who had events during 5 years of follow-up and 488 had no event Patients with elevated urinary thromboxane levels were 1.8 times more likely to suffer CV death, MI, or stroke,Eikelboom JW, et al. Circulation 2002, 105: 1650-1655,Clopidogrel Resistance by TEG PlateletMapping System vs. Clinical Outcomes,Bliden KP, et al. J Am Coll Cardiol 2007, 49:657-666,CAD patients (n = 100) undergoing PCI on chronic ASA 75 mg qd, clopidogrel 75 mg qd. Events = MACE over 1 year. HPR, high platelet reactivity; MA, clot strength.,生化阿司匹林抵抗：与临床若即若离,大多数试验缺乏特异性，未针对阿司匹林的作用机制 “生化阿司匹林抵抗” 发生率变化太大，令人无所适从 体外进行的试验其结果是否与体内实际发生的血小板聚集或抑制状态相关，目前并不清楚,Lordkipanidze M, et al. Pharmacol Ther 2006, 112:733-743,文献报道的阿司匹林抵抗发生率为0.4%83%定义不清楚测量方法不统一,非特异性试验 高估阿司匹林抵抗,7例PCI患者依从性差，住院给予阿司匹林治疗后全都显示敏感,223例患者中只有1例（0.4%）显示阿司匹林抵抗,生化阿司匹林抵抗：与临床若即若离,有临床使用价值的实验室指标必须具备以下特点： 有统一公认的检测方法和评价标准 前瞻性研究证实其与发生心血管病事件独立相关 随机试验显示逆转异常指标能显著改善临床转归 评价生化阿司匹林抵抗的现有血小板功能试验，无一具备上述任一特点，因此均无肯定临床实用价值,Aspirin Resistant Patient: Management,Educate patient on importance of compliance Eliminate interfering substances (ibuprofen) Increase aspirin dose (?) (.increasing the dose of aspirin does not enhance COX-1 inhibition) Switch to other anti-platelet medications (?) (.no evidence that switching to alternative treatment strategies improves outcomes),Clopidogrel Dose: 300 mg vs. 600 mg,Gurbel PA, et al. 2005,0,3,6,9,12,15,18,21,24,27,30,33,-30,(-30,-20,(-20,-10,(-10,0,(0,10,(10,20,(20,30,(30,40,(40,50,(50,60,(60,70, 70,300 mg Clopidogrel,600 mg Clopidogrel,D Aggregation (5 M ADP-induced Aggregation) at 24 Hours,Patients (%),Resistance = 28% (300 mg),Resistance = 8% (600 mg),-20,0,20,40,60,80,100,Inhibition of platelet aggregation (%),Prasugrel 60 mg LD,Clopidogrel 300 mg LD,Clopidogrel/Prasugrel Crossover Study,Brandt JT et al. Am Heart J 2007, 153:66.e9e16,IPA (%) to 20 M ADP 24 hr after LD,N=68,Michelson AD, et al. J Thromb Haemost 2005, 3:1309-1311,国际血栓与止血学会科学与标准化委员会血小板学组,除研究外，目前不宜在患者中检测阿司匹林“抵抗”，也不应根据这类试验来改变治疗方案。,建议阿司匹林用于抗血小板治疗获益/风险比良好的