课件：双重抗血小板治疗与消化道出血.ppt

双重抗血小板治疗与上消化道出血,Acute Coronary Syndromes,主要抗血小板治疗药物,GP IIb/IIIa,GP IIb/IIIa,血小板,5-羟色胺,肾上腺素,PAF,凝血酶,ADP,TXA2,胶原,纤维蛋白原,GP IIb/IIIa拮抗剂,氯吡格雷,阿司匹林,腺苷,ADP,AMP,前列环素,潘生丁,摄取,CURE研究设计,CURE Study Investigators Eur Heart J 2000;21:20332041,CURE 主要终点,下列一组事件中的任一事件首次发生: 心血管死亡 心肌梗死 中风 (缺血性，出血性，或类型不能确定) 顽固性缺血,CURE Study Investigators Eur Heart J 2000; 21:20332041,CURE - 主要疗效结果 主要终点 (1),The CURE Investigators. N Eng J Med August 2001 Data on file,The CURE Investigators. N Eng J Med August 2001 Data on file,CURE - 主要疗效结果 主要终点 (2),The CURE Investigators. N Eng J Med August 2001. Data on file,CURE - 主要疗效结果 主要终点 (3),从冠脉支架研发至今， PCI领域持续不断地飞速进展,PCI-CURE 研究设计,The CURE Investigators. N Eng J Med August 2001,PCI-CURE 30 天结果,The CURE Investigators. Lancet August 2001,心血管死亡、心肌梗死、或紧急血运重建的联合终点,PCI-CURE 总体长期 结果,The CURE Investigators. Lancet August 2001,从随机分组至随访结束时 ，心血管死亡或心肌梗死的联合终点,PCI-CURE 安全性出血并发症,The CURE Investigators. Lancet August 2001,The CURE Investigators. Lancet August 2001 M Sabatine, et al. 2005, In press.,波立维 + 标准治疗 标准治疗 % % PCI 至 30 天 严重出血 1.6 1.4 NS 危及生命的出血 0.7 0.7 其它严重出血 0.9 0.7 轻微出血 1.0 0.7 NS PCI 至随访结束时 严重出血 2.7 2.5 NS 危及生命的出血 1.2 1.3 其它严重出血 1.5 1.1 轻微 3.5 2.1 0.03,p 值,预先治疗，人数 (%) 氯吡格雷 安慰剂 安全性终点 (n=923) (n=918) p值 TIMI 严重或轻微出血 18 (2.0) 17 (1.9) NS -TIMI 严重出血 5 (0.5) 10 (1.1) NS -TIMI 轻微出血 13 (1.4) 7 (0.8) NS,PCI-,包括阿司匹林； NS = 无显著统计学差异,安全性： 波立维+ ASA不增加PCI患者严重出血风险,Importance rank of different medications or modalities of treatment,ASA Thienopyridins/clopidegrel blocker Low cholesterol diet Exercise Coronary revascularization Cholesteral-lowering drug,16-20%,12-15%,8-12%,6-10%,4-8%,死亡 / 心梗,1988 ASA,1992 ASA+ Heparin,1998 ASA+ Heparin+ Anti- GPIIB/IIIA,2003 ASA+ 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,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),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,P0.001,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,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,阿司匹林选择性地将COX多酞链第529位-单丝氨酸残基的羟基乙酰化, 不可逆性地使该酶失活。 由于血小板无细胞核, 它们再不能形成新的蛋白质, 因此阿司匹林对血小板的抑制作用将会在血小板的整个生命周期(大约7-10d)持续存在。因此, 虽然阿司匹林的半衰期只有2-3小时, 但它的抗血小板作用能持续5-7天。,阿司匹林胃肠不良反应的发生机制,PGE2合成,粘膜供血 粘液合成与分泌 碳酸氢盐合成,胃粘膜保护作用,胃粘膜受损,在胃粘膜堆积,直接毒性作用,阿司匹林缓慢释放,正常胃粘膜,双重抗血小板治疗 引起胃肠出血的病因因素,冠脉介入治疗后上消化道出血由多种原因共同引起。急性心肌梗死后4%12.5%的患者出现应激性溃疡而上消化道出血，多发生于心肌梗死后的72h以内，出血以呕血和黑便为主要临床表现。 阿司匹林因可以引起胃黏膜损伤而导致消化道出血； 氯吡格雷是否引起黏膜损伤不明确，可能由于影响止血功能而引起原黏膜缺损或瘢痕的再出血；,中国药物警戒 2010 07 (05): 280-280,Circulation.2003;108:1682-1687 Circulation 2006;113;e655-e658,Dr.Weil : all doses of aspirin are associated with an increased risk of GI bleeding. The risk of GI bleeding was dose related while examining the relationship between aspirin intake and hospitalizaion: Aspirin: 75 mg/d odds ratio 2.3 150 mg/d odds ratio 3.2 300 mg/d odds ratio 3.9 The risk of upper GI bleedingfor plain, enteric-coated, or buffered did not differ. Long-term aspirin therapy, even at a low dose (50 to 162.5 mg/d), may cause overt GI bleeding.,This dose-response relationship may reflect at least 2 cyclo-oxygenase (COX)-1dependent mechanisms, dose-dependent inhibition of COX-1 in the gastric mucosa and (relatively) dose-independent inhibition of COX-1 in platelets. 100mg asprin daily- platelet thromboxane synthesis is blocked completely higher doses - inhibit COXdependent thromboxane synthesis in vascular endothelium, monocytes, and macrophages. This could contribute to the impairment of hemostasis in patients using higher doses of aspirin.,Br J Clin Pharmacol. 1993; 35: 219226,阿司匹林剂量与血小板释放反应,100,mg 拜阿司匹灵/天,100mg,200mg,300mg,400mg,500mg,血小板释放反应（%）,100 mg,80,60,40,20,阿司匹灵（mg）,抑制血小板功能的最佳剂量,负荷剂量选择,Kleffer G et al. Thromb Haemost 1989;62(1):411 (Abstract),三种阿司匹林制剂和安慰剂的内镜比较 84例患者3个月研究，随机分4组，阿司匹林组剂量均为325mg/d,上海瑞金医院施仲伟,Risk of GI complications with Dual Anti-platelete Therapy,The risk of overt GI bleeding with dual antiplatelet therapy can be as high as 1.3% within the first 30 days of therapy. In the CURE study, it showed that the risk of bleeding increases with increasing dose of aspirin with or without clopidogrel. Placebo + aspirin 200 mg/d bleeding was higher (3.7%) Clopidogrel 75 mg/d+ aspirin100 mg/d Circulation.2003;108:1682-1687 Circulation 2006;113;e655-e658,Clopidogrel has no effect on the cyclooxygenase pathway and therefore acts independently of aspirin. In a retrospective analysis, the frequency of GI bleeding in a high-risk population with prior peptic ulcer disease was 12%.,Circulation.2003;108:1682-1687 Circulation 2006;113;e655-e658,N Engl J Med. 2005, 20:233 ACCF/ACG/AHA 2008专家共识,氯吡格雷组对照阿司匹林联合挨索美拉唑（20mg bid)组（8.6% vs 0.7%, 95% CI 3.4%13.4%),The analysis included data from 14,627 patients (12,001 receiving aspirin, 2626 receiving clopidogrel). aspirin users taking PPIs had a significantly lower adjusted risk of hospitalization for major GI complications than did non-PPI users (hazard ratio HR = 0.76; 95% CI, 0.64-0.91). Use of a PPI was not associated with a significant risk reduction among clopidogrel users (HR = 1.08; 95% CI, 0.89-1.33). CONCLUSIONS: In this analysis in patients at high GI risk who were receiving antiplatelet therapy for the secondary prevention of cardiovascular events, aspirin plus a PPI was associated with a reduced risk of recurrent hospitalization for major GI complications. This was not the case for clopidogrel plus a PPI.,Clin Ther. 2009 Sep;31(9):2038-47,对于 反复心肌缺血发作 心功能大于III级 应放宽应用PPI指征,ACCF/ACG/AHA 2008专家共识,Clopidogrel needs to be metabolized into its active metabolite, by cytochrome P450, especially by CYP2C19 isoenzyme. Various platelet function studies have shown that omeprazol can significantly decrease clopidogrel inhibitory effect on platelet P2Y12 receptor, leading to an increase in the number of patients who are “nonresponders“ to clopidogrel. Suggestion: 1) individual gastrointestinal risk assessment, with PPIs administration only to patients on dual anti-platelet therapy with additional GI risk factors; (2) preferential use of PPIs that have shown less interference with clopidogrel efficacy; (3) wide separation of PPI and clopidogrel dosing to minimize the risk of interaction (PPI may be given before breakfast and clopidogrel at bedtime); (4) or alternative use of histamine-2-receptor antagonist therapy, in patients at low GI risk,Rev Port Cardiol. 2010 Oct;29(10):1555-67,根据Rockall评分调整抗血小板治疗， 积分4，中断抗血小板治疗的死亡,风险大于UGH，继续行双重抗血小板治疗； 积分5，继续口服氯毗格雷，停用阿司匹林48 h再评估，2周内加用阿司匹林治疗；持续出血者应停用所有抗血小板。药物，每天评估出血状态，12周内加用氯吡,治疗策略总结,一、单纯便潜血阳性 二、血色素明显下降，但仍大于9g/dL，血压稳定 三、血色素迅速下降，6小时内下降大于3g/L,总 血色素小于7g/dL 四、经输血，停用抗凝药物，予抑酸等治疗3-5天后，血色素仍反复下降，需继续输血维持者 五、血色素迅速下降，进入心源性休克状态,主要抗血小板治疗药物,GP IIb/IIIa,GP IIb/IIIa,血小板,5-羟色胺,肾上腺素,PAF,凝血酶,ADP,TXA2,胶原,纤维蛋白原,GP IIb/IIIa拮抗剂,氯吡格雷,阿司匹林,腺苷,ADP,AMP,前列环素,昔洛他唑,摄取,临床获益最大化 出血风险最小化,谨慎的医疗决策改善抗栓治疗结果,Thank You!,胃肠道出血所致死亡1/3与服用NSAIDs相关,西班牙26所医院2001年资料，8010例严重胃肠道事件，死亡率为5.7% 尽管上消化道入院率是下消化道的6倍，但死亡率相似，分别为：5.7%和5.3%（下消化道损伤更加隐匿、危害更大） 由NSAID引起的死亡率占总体：36.3%,其中90%为60岁以上的老年人 在西班牙2001年由NSAID引起的消化道事件所致的死亡人数比AIDS所致死亡人数高50%,NSAIDs肠病并发症,NSAID肠病：70% 70%有小肠出血 70%有蛋白流失肠病 偶见 -狭窄,临床结果 贫 血 症 低蛋白血症 手 术,NSAIDs引起胃肠道损害的机制,花生四烯酸 传统的NSAIDs 环氧化酶,X,抗炎 镇痛 胃肠道损害 肾毒性,前列腺素,维护肾及 血小板功能,保护胃、 十二指肠粘膜,炎症、疼痛,联系方式: 毛懿 阜外心血管病医院ICU病房，邮编：100037 Email: alexanderM,一级预防指南：谁应该用阿司匹林,10年冠心病危险6者推荐长期使用阿司匹林75160mg/d 美国预防特别工作组（U.S. PSTF）,10年冠心病风险10者推荐长期使用阿司匹林75160mg/d 美国胸科医师协会（ACCP）,10年冠心病风险10者推荐长期使用阿司匹林75160mg/d 美国心脏协会（AHA）,Chest. 2004;126:609S-626S.,1000人用阿司匹林5年：得益与风险,注：70岁以上老人中，胃肠道大出血的发生率可能增加23倍。,X ,2008-2010年间，诊断冠心病人42105人次 消化道出血，159人次。,抗血小板治疗的出血并发症：汇总分析,Serebruany VL, et al. Am J Hematol 2004, 75:40-47,6.0 5.0 4.0 3.0 2.0 1.0 0.0,阿司匹林 100mg 13337,阿司匹林 100325mg 43489,阿司匹林 325mg 1409,双嘧达莫 3304,氯吡格雷 18574,IV IIb/IIIa 22501,口服 IIb/IIIa 20529,出血事件发生率,患者例数,51项临床试验、338 191例患者,上海瑞金医院施仲伟,普拉格雷安全性：显著增加严重出血,Wiviott SD, et al. NEJM 2007 Bhatt DL, et al. NEJM 2007,氯吡格雷 普拉格雷,对有脑血管疾病(卒中/TIA)的患者，普拉格雷显著有害（HR=1.54, p=0.04),列为禁忌症. 对年龄75岁、体重60kg的患者，普拉格雷治疗无净获益。 尽管普拉格雷所增加的致命性出血风险很小（大约每1000中增加3例），但在以往对阿司匹林氯吡格雷双抗治疗的任何研究或荟萃分析中都未发现致命性出血增加。 与氯吡格雷相比较, 普拉格雷每预防1例 CV死亡，同时增加1例致命性出血事件,Aspirin resistence 560% Clopidegrel resistence 1732%,阿司匹林大出血风险：每千人每年增加1.3例*,0.2 0.5 1 2 5,RR(95%CI) 1.71 (1.08-2.73) 0.73 (0.33-1.64) 2.25 (1.03-4.90) 1.40 (0.40-4.93) 1.84 (0.68-4.96) 2.83 (1.32-6.05) 1.74 (1.32-2.30) 1.56 (0.78-3.13) 1.71 (1.41-2.08),PHS Preliminary report of the Stroke Prevention in Atrial Fibrillation Study/Stroke Prevention in Atrial Fibrillation Study Swedish Aspirin Low-Dose Trial(SALT) EAFT (European Atrial Fibrillation Trial) Study Group Thrombosis prevention trial: randomised trial of low-intensity