抗血小板治疗的出血风险控制

1、冠心病抗血小板治疗的出血风险控制 抗血小板治疗药物的演变噻氯匹定噻氯匹定阿司匹林阿司匹林l 1988年FDA批准用于临床的抗血小板药物l单用疗效有限，增加剂量会增加出血危险l 第一个噻吩吡啶类 l 1991年FDA批准l 严重不良反应：中性粒细胞减少、血栓性血小板减少性紫癜l 1998 1998年年FDAFDA批准批准l 疗效、安全性被广泛证实疗效、安全性被广泛证实*普拉格雷普拉格雷*替格瑞洛替格瑞洛氯吡格雷氯吡格雷+ASA双联治疗双联治疗12个月，显著降低个月，显著降低NSTE-ACS患者缺血风险达患者缺血风险达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, Z

2、hao F, Mehta SR, et al. N Engl J Med. 2001;345(7):494-502. The CURE trial investigators. N Eng J Med. 2001;345(7):494-502.u 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：普拉格雷的总体疗效与安全性研究：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.事件率(

3、)CV死亡/MI/卒中CV死亡非致死性MI非致死性卒中(P0.001)(P=0.31)(P0.001)(P=0.93)RRR=19%RRR=24%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。TIMI大出血危及生命出血非致命性出血致命性出血颅内出血出血率()(P=0.002)(P=0.03)(P=0.01)(P=0.23)(P=0.74)RRI=319%RRI=32%RRI=52%氯吡格雷普拉格雷出血：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

4、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 randomisation060120180240300360121110987654321013累累积发生率积发生率 (%)9.811.7HR 0.84 (95% CI 0.770.92), p=0.0003ClopidogrelTicagrelor然而，代价是非CABG相关的大出血风险明显升高。70K-M estimated rate (% per year)98654321Non-CABGPLATO majorb

5、leeding4.53.8p=0.032.82.2p=0.037.47.9NS5.35.8NSTicagrelorClopidogrelNon-CABGTIMI majorbleedingCABGPLATO major bleedingCABGTIMI major bleedingWallentin 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Armero

6、 S, Bonello L, Berbis J, et al. Am J Cardiol. 2011;108(12):1710-3. 1个月内普拉格雷总停药率个月内普拉格雷总停药率6%*滋扰性出血滋扰性出血 63%内出血内出血 33.3%令人惊恐的出血 3.7%1个月内总体出血发生率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因滋扰性出血或内出血停药内出血停药 其他原因其他原因停

7、药停药 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，SYNERGYPCI亚组分析：过早停用抗血小板治疗对院内PCI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

8、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 31天0.5 1 2 4 8 16 32HR(95%CI)死亡P值0.0010.0010.0010.120.0010.0010.0010.0010.0010.0010.00131天输血 0-1天 2-7天 8-30天 31天HR(95%CI)ACUIT

9、Y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/index.html 获得）Circulation 2009;119;1873-1882缺血高危因素与出血高危因素大多一致缺血高危因素与出血高危因素大多一致Hector Bueno,Fr

10、ancisco Fernandez-Aviles. Heart 2012;98:162-168ACSACS缺血风险主要预测因素缺血风险主要预测因素ACSACS出血风险主要预测因素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？(c

11、ilostazol, 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 AsaparinCochrane Database Syst Rev. 2011 Jan 19;(1):CD008076.Cochrane Database Syst Rev. 2011 Jan 19;(1):CD008076.CV EVENTSIschaemic strokeCochrane Database Syst Rev. 2011 Jan 19;(1):CD008076.Haemorrhagic strokeCoch

12、rane Database Syst Rev. 2011 Jan 19;(1):CD008076.MICochrane Database Syst Rev. 2011 Jan 19;(1):CD008076.Vascular deathCochrane Database Syst Rev. 2011 Jan 19;(1):CD008076.Extracranial haemorrhageCochrane Database Syst Rev. 2011 Jan 19;(1):CD008076.GI bleedingCochrane Database Syst Rev. 2011 Jan 19;(

13、1):CD008076.Cilostazol+ASA vs ASAAmerican Heart JournalJune 2008RevascularizatinRestenosisConclusion for cilostazolNO strong evidence for Cilostazol in CHDStronger than ASA, maybe equivalent to TICLIDDecrease bleedingNeed more date to support its use in CHD anti-platelet therapy Vorapaxarprotease-ac

14、tivatedreceptor 1 antagonistTwo large scale RCT results publishedOriginal 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 Wer

15、f, M.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., A

16、ngel Cequier, M.D., Jan H. Cornel, M.D., 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

17、.D., Matthias Pfisterer, M.D., Juan Carlos Prieto, M.D., Witold Ruzyllo, M.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., f

18、or the TRACER InvestigatorsN Engl J MedVolume 366(1):20-33January 5, 2012Study OverviewIn this trial, 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

19、 rates of bleeding, including serious bleeding and intracranial hemorrhage.Study End Points.Tricoci P et al. N Engl J Med 2012;366:20-33The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urg

20、ent coronary revascularization. The prespecified key secondary end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. Efficacy End Points.Risk of Bleeding.Tricoci P et al. N Engl J Med 2012;366:20-33Bleeding End Points in the As-Treated Population.Tricoci P

21、et al. N Engl J Med 2012;366:20-33ConclusionsIn patients with acute coronary syndromes (NSTEACS), the addition 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 intracra

22、nial hemorrhage.Circulation. 132(20):1871-1879, November 17, 2015.DOI: 10.1161/CIRCULATIONAHA.114.015042background26 449 patients over 3 years prior MI, stroke or peripheral vascular diseaserandomization to vorapaxar or placebo in addition to ASA or ASA+Thienopyridine 2Baseline Characteristics Chara

23、cterization of Actual Thienopyridine Use From RandomizationCardiovascular death, MI, or stroke stratified by planned thienopyridine useEfficacy end points stratified by planned thienopyridine useBleeding End Points Stratified by Planned Thienopyridine Use Safety end point stratified by planned thien

24、opyridine useNet Clinical Outcome End Points Stratified by Planned Thienopyridine Use Among Patients With a Previous MI and No History of TIA or Strokeapproved by the FDA and EMA for reducing ischaemic events in patients with a history of MIthe benefit of vorapaxar in addition to aspirin and clopido

25、grel is modest and must be carefully weighed against the increase in bleeding events Its use is contraindicated in patients with a history of cerebrovascular disease. FDA & EMA recommendationC Vol 382 December 14, 2013 Included Vol 382 December 14, 2013 均联合应用氯吡格雷均联合应用氯吡格雷+ASAEfficacy R Vol 382 Decem

26、ber 14, 2013 Vol 382 December 14, 2013 Bleeding E Vol 382 December 14, 2013 Cangrelor reduced 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 bleedingConclusion for C

27、angrelor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 monthsCirculation January 24, 20121 year follow-up，no difference in bleeding Still no difference in bleeding for 1 year1 monthDuration of DAPT for 1 monthJAC

28、C VOL. 65, NO. 8, 2015Conclusion for shortening DAPT DurationLogically reasonableNo direct evidence yetESC 2015 NSTEACS guidelineEvidence？ Lowering APT dose？50mg vs 75mg clopidogrel50mg vs 75mg clopidogrelBecause of small sample size, no difference in bleedingTicagrelor 60mg bid VS 90mg bidPEGASUS S

29、tudy60mg vs 90mg，略有减少？，略有减少？仅有仅有3年的数据结果，更短时间是否有差异呢年的数据结果，更短时间是否有差异呢？Conclusion for lowering doses Lower doses may decrease bleeding Need 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)75MATRIXCo-prim

30、ary compositeoutcomes at 30 days Speaker N=8404 NSTE-ACS + STEMI Radial vs. femoralValgimigli M et al.Lancet. 2015;385:2465-76All-cause mortality, MI, strokeAll-cause mortality, MI, stroke, or BARC 3 or 5 bleedingRadial vs femoral meta-analysisNon-CABG major bleeedsDeath, MI, or strokeDeathMIStrokeP

31、RR (95% CI)Valgimigli M et al.Lancet. 2015;385:2465-76N19 000Radial approach 2015 ESC NSTEACS GuidelineIt is recommended that centres treating ACS patients implement a transition from transfemoral to transradial access.Proficiency in the femoral approach should be maintained (e.g. for IABP insertion

32、 and structural as well as peripheral procedures)77比伐卢定的优势比伐卢定的优势u20 个氨基酸的肽类药物，凝血酶的直接抑制剂个氨基酸的肽类药物，凝血酶的直接抑制剂u与凝血酶的结合过程可控可逆与凝血酶的结合过程可控可逆 u血浓度与血浓度与 APTT、PT和和 ACT 正相关正相关（ r分别为分别为 0.77、 0.73和和 0.8）u不需要抗凝血酶不需要抗凝血酶（AT-）作为辅助因子，量效关系更吻合）作为辅助因子，量效关系更吻合u对血栓中和循环中的凝血酶的抑制作用几乎相同对血栓中和循环中的凝血酶的抑制作用几乎相同u不受激活血小板的影响不受激活血

33、小板的影响u不减少血小板不减少血小板比伐卢定Vs肝素uACUITY试验-JAMA2007uREPLACE-2 试验- TCT 2008uISAR-REACT-4 试验-AHA2011uEUROMAX 试验-NEJM 2013uHORIZONS AMI 试验-NEJM2006，TCT20080.0% -1.6, 1.5 0.76, 1.30-3.3% -5.0, -1.60.60 0.46, 0.77-2.9% -4.9, -0.80.76 0.63, 0.921 endpoint1 endpointMajor 2 endpointStone GW et al. NEJM 2008;358:22

34、18-30HORIZONS AMI 试验试验3,602 发病发病 12 小时的小时的 STEMI 患者患者 3006 例作支架分组治疗，例作支架分组治疗，30天临床结果天临床结果HORIZONS AMI 试验试验3,602 发病发病 12 小时的小时的 STEMI 患者患者 3006 例作支架分组治疗，例作支架分组治疗，1年随访结果年随访结果1 年净临床不良事件年净临床不良事件HORIZONS AMI 试验试验3,602 发病发病 12 小时的小时的 STEMI 患者患者 3006 例作支架分组治疗，例作支架分组治疗，1年随访结果年随访结果HORIZONS AMI 试验试验3,602 发病发病

35、 12 小时的小时的 STEMI 患者患者 3006 例作支架分组治疗，例作支架分组治疗，3年随访结果年随访结果The Lancet, Volume 377, Issue 9784, 2011, 2193 - 2204Major bleedingCardiac mortalityReinfarctionStent thrombosisAHA 2013 STEMI guideline Bivalirudin seems to be perfect ! HoweverHEAT-PPCI研究掀起波澜研究掀起波澜 HEAT-PPCIHEAT-PPCI (Unfractionated Heparin v

36、ersus Bivalirudin in (Unfractionated Heparin versus Bivalirudin in Primary PCI)Primary PCI)研究研究-开放、单中心、随机对照开放、单中心、随机对照Adeel Shahzad Adeel Shahzad ，ACC 2014u英国利物浦心胸医院，英国利物浦心胸医院，1414名介入医生参加，历时名介入医生参加，历时2222个月个月u1812 1812 例例STEMISTEMI患者随机分组患者随机分组u比伐卢定组比伐卢定组905905例患者，例患者，751751例例(83%)(83%)造影后造影后 行介入治疗行介

37、入治疗；肝素组；肝素组 907 907 例患者，例患者，740740例例 (82%) (82%) 行介入治疗行介入治疗u两组两组 GP IIb/IIIa GP IIb/IIIa 抑制剂应用率相似，约抑制剂应用率相似，约 13% 13% u3030天临床终点天临床终点uLancet. 2014 Jul 4. pii: S0140-6736(14)60924-7.HEAT-PPCI 30天临床终点OutcomeBivalirudin (%)Heparin (%) RR (95% CI) pMACE2 (1.1 2.1)0.01Definite or probable stent

38、thrombosis1 (1.6 9.5)0.001Major bleeding3.53.1NSAdeel Shahzad Adeel Shahzad ，ACC 2014对HEAT-PPCI的批评u单中心u入选速度（22个月近2000 例患者）u肝素用量（70U/kg)uACT偏低（H-236，B-270)u入选患者低危u再梗的判断标准u研究设计-知情签署晚-伦理？u桡动脉途径比例高与出血低有关NAPLES III 研究Carlo BriguoriCarlo Briguori(Clinica Mediterranea, Naples, Italy) ， ACC 2014u83

39、0例高出血风险（危险积分例高出血风险（危险积分10）择期股动）择期股动脉途径脉途径PCI患者患者u比伐卢定比伐卢定Vs UFHu主要终点：院内出血主要终点：院内出血u主要结果：按不同出血标准，两组均无差异主要结果：按不同出血标准，两组均无差异TCT 2014 BRIGHT研究Stent Thrombosis at 30 DaysEventBivalirudin (n=735), n (%)Heparin (n=729), n (%)Heparin + tirofiban, n (%)pAll definite/probable stent thrombosis4 (0.6)6 (0.9)5 (

40、0.7)0.77Acute (24 h)2 (0.3)2 (0.3)2 (0.3)1.00Subacute (1 30 d)2 (0.3)4 (0.6)3 (0.4)0.66TCT 2014 AHA 2014 NSTE-ACS guideline Recommendations for anticoagulation in NSTE-ACSRecommendationsClassLOEParenteral anticoagulation is recommended at the time of diagnosis according to both ischaemic and bleedin

41、g risks.IBFondaparinux (2.5 mg s.c. daily) is recommended as having the most favourable efficacysafety profile regardless of the management strategy.IBBivalirudin (0.75 mg/kg i.v. bolus, followed by 1.75 mg/kg/hour for up to 4 hours after the procedure) is recommended as alternative to UFH plus GPII

42、b/IIIa inhibitors during PCI.IAUFH 70100 IU/kg i.v. (5070 IU/kg if concomitant with GPIIb/IIIa inhibitors) is recommended in patients undergoing PCI who did not receive any anticoagulant.IBIn patients on fondaparinux (2.5 mg s.c. daily.) undergoing PCI, a single i.v. bolus of UFH (7085 IU/kg, or 506

43、0 IU/kg in the case of concomitant use of GPIIb/IIIa inhibitors) is recommended during the procedure.IBEnoxaparin (1 mg/kg s.c. twice daily) or UFH are recommended when fondaparinux is not available.IBCrossover between UFH and LMWH is not recommended.IIIBIn NSTEMI patients with no prior stroke/TIA a

44、nd at high ischaemic risk as well as low bleeding risk receiving aspirin and clopidogrel, low-dose rivaroxaban (2.5 mg twice daily for approximately one year) may be considered after discontinuation of parenteral anticoagulation.IIbBESC 2015 NSTE-ACS guideline FondaparinuxComparison of Fondaparinux

45、and Enoxaparin in Acute Coronary Syndromes （NSTEACS）The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes InvestigatorsN Engl J MedVolume 354;14:1464-1476April 6, 2006Cumulative Risks of Death, Myocardial Infarction, or Refractory Ischemia (Panel A) and of Major Bleeding (Panel B)

46、through Day 9The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators N Engl J Med 2006;354:1464-1476Main Efficacy and Safety OutcomesThe Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators N Engl J Med 2006;354:1464-1476Cumulative Risks of

47、Death (Panel A) and of Death, Myocardial Infarction, or Stroke (Panel B) through Day 180The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators N Engl J Med 2006;354:1464-1476Results of Subgroup Analyses of Efficacy (the Composite of Death, Myocardial Infarction, or Ref

48、ractory Ischemia) (Panel A) and Safety (Major Bleeding) (Panel B) at Nine DaysThe Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators N Engl J Med 2006;354:1464-1476Treatments, Complications, and Outcomes among Patients Undergoing Percutaneous Coronary Intervention (PCI

49、) within the First Eight Days after RandomizationThe Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators N Engl J Med 2006;354:1464-1476Conclusion Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces ma

50、jor bleeding and improves long term mortality and morbidityRecommendations for anticoagulation in NSTE-ACSRecommendationsClassLOEParenteral anticoagulation is recommended at the time of diagnosis according to both ischaemic and bleeding risks.IBFondaparinux (2.5 mg s.c. daily) is recommended as having the most favourable efficacysafety profile regardless