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1、抗血小板治疗出血风险控制,抗血小板治疗出血风险控制抗血小板治疗出血风险控制,抗血小板治疗药物的演变,1988年FDA批准用于临床的抗血小板药物单用疗效有限，增加剂量会增加出血危险,第一个噻吩吡啶类 1991年FDA批准 严重不良反应：中性粒细胞减少、血栓性血小板减少性紫癜,1998年FDA批准 疗效、安全性被广泛证实,*普拉格雷*替格瑞洛,当代抗血小板药物治疗的发展：缺血与出血风险的平衡,抗血小板药物单药治疗,双联抗血小板药物,更强的血小板聚集抑制剂,Reduction inIschemic Events,Increase in Major Bleeds,Adapted from Gibson
2、,AHA 2007,氯吡格雷+ASA双联治疗12个月，显著降低NSTE-ACS患者缺血风险达20%,安全性：波立维组与安慰剂组危及生命的大出血无显著差异。,Yusuf S,Zhao F,Mehta SR,et al.N Engl J Med.2001;345(7):494-502.,NSTE-ACS患者应用氯吡格雷+ASA安全性良好,The CURE trial investigators.N Eng J Med.2001;345(7):494-502.,CURE研究表明，与安慰剂+ASA相比，氯吡格雷+ASA导致危及生命出血或出血导致死亡的发生率无明显增加,TRITON-TIMI 38研究：
3、普拉格雷的总体疗效与安全性,Wiviott SD,Braunwald E,McCabe CH,et al.N Engl J Med.2007;357:2001-15.,疗效：普拉格雷显著降低15个月CV死亡/MI/卒中风险(主要缺血终点)达19%；获益主要源于非致死性MI的降低。,出血：普拉格雷显著增加非CABG相关TIMI大出血风险(主要安全终点)达32%；包括危及生命、致命性出血等。,（非CABG相关出血）,替格瑞洛显著降低ACS患者心血管事件发生危险达16%,PLATO研究中替格瑞洛组平均用药时间277天，替格瑞洛显著降低CV 死亡、MI或卒中复合终点发生危险16%,Days after
4、 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,然而，代价是非CABG相关的大出血风险明显升高。,7,0,K-M estimated rate(%per year),9,8,6,5,4,3,2,1,Non-CABGPLATO majorbleeding,4.5,3.8,p=0.03,2.8,2.2,p=0.03,7.4,7.9,NS,5.3,5.8,NS
5、,Ticagrelor,Clopidogrel,Non-CABGTIMI majorbleeding,CABGPLATO major bleeding,CABGTIMI major bleeding,Wallentin L et al.New Engl J Med.2009;361:DOI:10.1056/NEJMoa0904327.,一旦出血，无论大小，都很麻烦,小出血临床常见，显著降低患者治疗依从性,ACS患者(n=396)成功置入支架，接受ASA+普拉格雷1个月,1个月内普拉格雷总停药率6%*,1个月内总体出血发生率13.6%,采用Roys出血分类及定义：令人惊恐的出血：颅内出血、危及生
6、命出血或需输血。内出血：血肿、鼻衄、口腔出血、阴道出血、黑便、眼睛出血、血尿及呕血。滋扰性出血：容易瘀伤、小切口出血、瘀点及瘀斑。小出血=滋扰性或内出血,因滋扰性出血或内出血停药,其他原因停药,15.3%,4%,P=0.03,*79%为患者自发停药,出血后过早停用抗血小板治疗是影响临床结局的重要因素,32.4%发生院内出血，其中近1/10出院后停用任何抗血小板药物：出院后停用抗血小板药物显著增加6个月死亡/MI/卒中风险(14.3%vs 用药者7.8%，P0.0001),N=26,451，入选自PURSUIT,PARAGON A&B，SYNERGY,PCI亚组分析：过早停用抗血小板治疗对院内P
7、CI患者长期预后更具危险性双联抗血小板治疗显著减少死亡等主要临床终点事件,Am Heart J.2010;160:1056-1064.e2.,log rank p-value for all four categories 0.0001log-rank p-value for no bleeding vs.mild bleeding=0.02log-rank p-value for mild vs.moderate bleeding 0.0001log-rank p-value for moderate vs.severe 0.001,出血风险与临床不良预后密切相关,Rao SV,et al.
8、Am J Cardiol.2005,按不同出血危险分层，30天的KaplanMeier生存分析 GUSTO IIb,PARAGON A,PARAGON B,和PURSUIT等研究，N=26,452 ACS患者,ACUITY研究中，对于ACS患者远期死亡的作用再发MI：随时间而减弱，30天已无显著性大出血和输血：存在持续影响，1年时仍具显著性,对ACS患者远期结局的持续影响大出血/输血的影响更甚于缺血,Eur Heart J.2009;30:1457-1466.,如何评估出血风险？,出血评估的有效工具出台 CRUSADE出血评分,CRUSADE出血评分计算器（可从 获得）,Circulation
9、 2009;119;1873-1882,缺血高危因素与出血高危因素大多一致,Hector Bueno,Francisco Fernandez-Aviles.Heart 2012;98:162-168,ACS缺血风险主要预测因素,ACS出血风险主要预测因素,老年患者和肾功能不全等特殊人群临床治疗尤其应重视出血与缺血平衡,抗血小板治疗时，如何减少出血风险？,其它抗血小板药物？(cilostazol,vorapaxar,cangrelor)调整DAPT持续时间？减少APT剂量？围PCI过程中，何种策略减少出血风险？消化道出血，加用PPI？,抗血小板治疗时，如何减少出血风险？,其它抗血小板药物？(ci
10、lostazol,vorapaxar,cangrelor)调整DAPT持续时间？减少APT剂量？围PCI过程中，何种策略减少出血风险？,Cilostazol vs Asaparin,Cochrane Database Syst Rev.2011 Jan 19;(1):CD008076.,Cochrane Database Syst Rev.2011 Jan 19;(1):CD008076.,CV EVENTS,Ischaemic stroke,Cochrane Database Syst Rev.2011 Jan 19;(1):CD008076.,Haemorrhagic stroke,Coc
11、hrane Database Syst Rev.2011 Jan 19;(1):CD008076.,MI,Cochrane Database Syst Rev.2011 Jan 19;(1):CD008076.,Vascular death,Cochrane Database Syst Rev.2011 Jan 19;(1):CD008076.,Extracranial haemorrhage,Cochrane Database Syst Rev.2011 Jan 19;(1):CD008076.,GI bleeding,Cochrane Database Syst Rev.2011 Jan
12、19;(1):CD008076.,Cilostazol+ASA vs ASA,American Heart JournalJune 2008,Revascularizatin,Restenosis,Conclusion for cilostazol,NO strong evidence for Cilostazol in CHDStronger than ASA,maybe equivalent to TICLIDDecrease bleedingNeed more date to support its use in CHD anti-platelet therapy,Vorapaxar,p
13、rotease-activatedreceptor 1 antagonistTwo large scale RCT results published,Original Article Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes(NSTEACS),Pierluigi Tricoci,M.D.,Ph.D.,Zhen Huang,M.S.,Claes Held,M.D.,Ph.D.,David J.Moliterno,M.D.,Paul W.Armstrong,M.D.,Frans Van de Werf,M
14、.D.,Harvey D.White,D.Sc.,Philip E.Aylward,M.D.,Lars Wallentin,M.D.,Ph.D.,Edmond Chen,M.D.,Yuliya Lokhnygina,Ph.D.,Jinglan Pei,M.S.,Sergio Leonardi,M.D.,Tyrus L.Rorick,R.N.,Ann M.Kilian,B.S.,Lisa H.K.Jennings,Ph.D.,Giuseppe Ambrosio,M.D.,Ph.D.,Christoph Bode,M.D.,Angel Cequier,M.D.,Jan H.Cornel,M.D.,
15、Rafael Diaz,M.D.,Aycan Erkan,M.D.,Ph.D.,Kurt Huber,M.D.,Michael P.Hudson,M.D.,Lixin Jiang,M.D.,J.Wouter Jukema,M.D.,Ph.D.,Basil S.Lewis,M.D.,A.Michael Lincoff,M.D.,Gilles Montalescot,M.D.,Jos Carlos Nicolau,M.D.,Ph.D.,Hisao Ogawa,M.D.,Matthias Pfisterer,M.D.,Juan Carlos Prieto,M.D.,Witold Ruzyllo,M.
16、D.,Peter R.Sinnaeve,M.D.,Ph.D.,Robert F.Storey,M.D.,D.M.,Marco Valgimigli,M.D.,Ph.D.,David J.Whellan,M.D.,Petr Widimsky,M.D.,Dr.Sc.,John Strony,M.D.,Robert A.Harrington,M.D.,Kenneth W.Mahaffey,M.D.,for the TRACER Investigators,N Engl J MedVolume 366(1):20-33January 5,2012,Study Overview,In this tria
17、l,vorapaxar,a protease-activatedreceptor 1 antagonist that inhibits thrombin-induced platelet activation,was not effective in reducing the primary cardiovascular efficacy end point,and it increased rates of bleeding,including serious bleeding and intracranial hemorrhage.,Study End Points.,Tricoci P
18、et al.N Engl J Med 2012;366:20-33,The primary efficacy end point was a composite of death from cardiovascular causes,myocardial infarction,stroke,recurrent ischemia with rehospitalization,or urgent coronary revascularization.,The prespecified key secondary end point was a composite of death from car
19、diovascular causes,myocardial infarction,or stroke.,Efficacy End Points.,Risk of Bleeding.,Tricoci P et al.N Engl J Med 2012;366:20-33,Bleeding End Points in the As-Treated Population.,Tricoci P et al.N Engl J Med 2012;366:20-33,Conclusions,In patients with acute coronary syndromes(NSTEACS),the addi
20、tion of vorapaxar to standard therapy(ASA+Thienopyridine)did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding,including intracranial hemorrhage.,Circulation.132(20):1871-1879,November 17,2015.DOI:10.1161/CIRCULATIONAHA.114.015042,backgro
21、und,26 449 patients over 3 years prior MI,stroke or peripheral vascular diseaserandomization to vorapaxar or placebo in addition to ASA or ASA+Thienopyridine,2,Baseline Characteristics,Characterization of Actual Thienopyridine Use From Randomization,Cardiovascular death,MI,or stroke stratified by pl
22、anned thienopyridine use,Efficacy end points stratified by planned thienopyridine use,Bleeding End Points Stratified by Planned Thienopyridine Use,Safety end point stratified by planned thienopyridine use,Net Clinical Outcome End Points Stratified by Planned Thienopyridine Use Among Patients With a
23、Previous MI and No History of TIA or Stroke,approved by the FDA and EMA for reducing ischaemic events in patients with a history of MIthe benefit of vorapaxar in addition to aspirin and clopidogrel is modest and must be carefully weighed against the increase in bleeding events Its use is contraindic
24、ated in patients with a history of cerebrovascular disease.,FDA&EMA recommendation,Cangrelor,Vol 382 December 14,2013,Included studies,Vol 382 December 14,2013,均联合应用氯吡格雷+ASA,Efficacy Results,Vol 382 December 14,2013,Vol 382 December 14,2013,Bleeding Events,Vol 382 December 14,2013,Cangrelor reduced
25、the odds of all-cause death,myocardial infarction,or ischaemia-driven revascularisation no difference in the primary safety outcome,in GUSTO moderate bleedingincreased GUSTO mild bleeding,Conclusion for Cangrelor,抗血小板治疗时，如何减少出血风险？,其它抗血小板药物？(cilostazol,vorapaxar,cangrelor)缩短DAPT持续时间？减少药物剂量？围PCI过程中，何种
26、策略减少出血风险？合并常规抗凝药物（房颤），如何处理？,3 months,出血事件没有差别！,！,！,！,6 months,Circulation January 24,2012,1 year follow-up，no difference in bleeding,Still no difference in bleeding for 1 year,1 month,Duration of DAPT for 1 month,JACC VOL.65,NO.8,2015,Conclusion for shortening DAPT Duration,Logically reasonableNo di
27、rect evidence yet,ESC 2015 NSTEACS guideline,Evidence？,Lowering APT dose？,50mg vs 75mg clopidogrel,50mg vs 75mg clopidogrel,Because of small sample size,no difference in bleeding,Ticagrelor 60mg bid VS 90mg bid,PEGASUS Study,60mg vs 90mg，略有减少？,仅有3年的数据结果，更短时间是否有差异呢？,Conclusion for lowering doses,Lowe
28、r doses may decrease bleedingNeed more data to support the efficacy and safety,抗血小板治疗时，如何减少出血风险？,其它抗血小板药物？调整DAPT持续时间？降低药物剂量？围PCI过程中，何种策略减少出血风险？(radial access,bivaludin，fondaparinux),MATRIXCo-primary compositeoutcomes at 30 days,N=8404 NSTE-ACS+STEMI Radial vs.femoral,Valgimigli M et al.Lancet.2015;3
29、85:2465-76,Radial vs femoral meta-analysis,Valgimigli M et al.Lancet.2015;385:2465-76,N19 000,Radial approach 2015 ESC NSTEACS Guideline,It is recommended that centres treating ACS patients implement a transition from transfemoral to transradial access.Proficiency in the femoral approach should be m
30、aintained(e.g.for IABP insertion and structural as well as peripheral procedures),比伐卢定的优势,20 个氨基酸的肽类药物，凝血酶的直接抑制剂与凝血酶的结合过程可控可逆 血浓度与 APTT、PT和 ACT 正相关（r分别为 0.77、0.73和 0.8）不需要抗凝血酶（AT-）作为辅助因子，量效关系更吻合对血栓中和循环中的凝血酶的抑制作用几乎相同不受激活血小板的影响不减少血小板,比伐卢定Vs肝素,ACUITY试验-JAMA2007REPLACE-2 试验-TCT 2008ISAR-REACT-4 试验-AHA20
31、11EUROMAX 试验-NEJM 2013HORIZONS AMI 试验-NEJM2006，TCT2008,Diff=0.0%-1.6,1.5 RR=0.99 0.76,1.30 Psup=0.95,Diff=-3.3%-5.0,-1.6 RR=0.60 0.46,0.77PNI 0.0001Psup 0.0001,Diff=-2.9%-4.9,-0.8RR=0.76 0.63,0.92 PNI 0.0001Psup=0.005,1 endpoint,1 endpoint,Major 2 endpoint,Stone GW et al.NEJM 2008;358:2218-30,HORIZO
32、NS AMI 试验,3,602 发病 12 小时的 STEMI 患者 3006 例作支架分组治疗，30天临床结果,HORIZONS AMI 试验,3,602 发病 12 小时的 STEMI 患者 3006 例作支架分组治疗，1年随访结果,1 年净临床不良事件,TCT 2008,HORIZONS AMI 试验,3,602 发病 12 小时的 STEMI 患者 3006 例作支架分组治疗，1年随访结果,TCT 2008,HORIZONS AMI 试验,3,602 发病 12 小时的 STEMI 患者 3006 例作支架分组治疗，3年随访结果,The Lancet,Volume 377,Issue
33、9784,2011,2193-2204,Major bleeding,Cardiac mortality,Reinfarction,Stent thrombosis,AHA 2013 STEMI guideline,Bivalirudin seems to be perfect!However,HEAT-PPCI研究掀起波澜,HEAT-PPCI(Unfractionated Heparin versus Bivalirudin in Primary PCI)研究-开放、单中心、随机对照,Adeel Shahzad，ACC 2014,英国利物浦心胸医院，14名介入医生参加，历时22个月1812
34、例STEMI患者随机分组比伐卢定组905例患者，751例(83%)造影后 行介入治疗；肝素组 907 例患者，740例(82%)行介入治疗两组 GP IIb/IIIa 抑制剂应用率相似，约 13%30天临床终点Lancet.2014 Jul 4.pii:S0140-6736(14)60924-7.,HEAT-PPCI 30天临床终点,Adeel Shahzad，ACC 2014,对HEAT-PPCI的批评,单中心入选速度（22个月近2000 例患者）肝素用量（70U/kg)ACT偏低（H-236，B-270)入选患者低危再梗的判断标准研究设计-知情签署晚-伦理？桡动脉途径比例高与出血低有关,N
35、APLES III 研究,Carlo Briguori(Clinica Mediterranea,Naples,Italy)，ACC 2014,830例高出血风险（危险积分10）择期股动脉途径PCI患者比伐卢定Vs UFH主要终点：院内出血主要结果：按不同出血标准，两组均无差异,TCT 2014,BRIGHT研究,Stent Thrombosis at 30 Days,TCT 2014,AHA 2014 NSTE-ACS guideline,ESC 2015 NSTE-ACS guideline,Fondaparinux,Comparison of Fondaparinux and Enoxa
36、parin in Acute Coronary Syndromes（NSTEACS）,The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators,N Engl J MedVolume 354;14:1464-1476April 6,2006,Cumulative Risks of Death,Myocardial Infarction,or Refractory Ischemia(Panel A)and of Major Bleeding(Panel B)through Day 9,
37、The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators N Engl J Med 2006;354:1464-1476,Main Efficacy and Safety Outcomes,The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators N Engl J Med 2006;354:1464-1476,Cumulative Risks of Death(Pane
38、l A)and of Death,Myocardial Infarction,or Stroke(Panel B)through Day 180,The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators N Engl J Med 2006;354:1464-1476,Results of Subgroup Analyses of Efficacy(the Composite of Death,Myocardial Infarction,or Refractory Ischemia)
39、(Panel A)and Safety(Major Bleeding)(Panel B)at Nine Days,The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators N Engl J Med 2006;354:1464-1476,Treatments,Complications,and Outcomes among Patients Undergoing Percutaneous Coronary Intervention(PCI)within the First Eight
40、 Days after Randomization,The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators N Engl J Med 2006;354:1464-1476,Conclusion,Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days,but it substantially reduces major bleeding and improv
41、es long term mortality and morbidity,ESC 2015 NSTE-ACS guideline,Effects of Fondaparinux on Mortality and Reinfarction in Patients With Acute ST-Segment Elevation Myocardial Infarction:The OASIS-6 Randomized Trial,JAMA.2006;295(13):1519-1530.doi:10.1001/jama.295.13.joc60038,JAMA.2006;295(13):1519-15
42、30.doi:10.1001/jama.295.13.joc60038,However,2012 ESC STEMI Guideline,Approach during peri-procedure,Bivaludin decreases bleedingRadial access is prefferedFondaparinux suitable in NSTEACS，not STEMI！,Bleeding risk evaluation！Radial access+bivaludin works！More data needed for new APT therapyShortening DAPT duration may works？Patient-centered individualized strategy！,Take-home messages,谢 谢,谢谢,
