新一代可吸收多聚体药物涂层支架(DES)最新进展_Thomas(1).ppt

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1、新一代可吸收多聚体药物涂层支架（DES）:最新进展?,Insights from the LEADERS trial 2 years FU BIOMATRIX(biabsorbable P)vs CYPHER(durable P)Thomas Ischinger MD PhD FACC FESCProfessor of Medicine/CardiologyHeart Center Bogenhausen,Munich,Germany,ESC 风暴:头号问题-死亡和心梗,“黑色星期二”,Isch 2008 nach Serruys,G.Guagliumi et al,Circulation20

2、03;107:1340,同一患者不同动脉Sirolimus洗脱支架 植入后病理改变：延迟内膜生长,BMS 24 月后内膜覆盖,Cypher 植入16月后:内膜尚未覆盖,重叠,overlapped,Cypher,Bx Velocity,Taxus,Express,BioLimus A9,S Stent,比较不同的BMS 和 DES植入兔髂动脉28天时病理改变,VIRMANI2006,支架表面内膜增生程度,Isch 2008,DES 动物研究,potential safety problems.,血栓形成 内皮化不全,严重炎症反应,持续纤维蛋白+炎症反应,动脉中层坏死支架贴壁不良,急性支架内血栓形

3、成的后果?,每年2,000,000 患者接受3,000,000 支架植入，平均每位患者1.3处病变,有效(TLR)1%26,000 TLRs2%52,000 TLRs5%130,000 TLRs,安全(ST)0.5%13,000 STs4,000 deaths10,000 MIs,Isch 2009,(DES)的优势？,支架特性输送能力支撑力再狭窄兼容性&致血栓性抗血小板治疗血栓形成风险血管舒缩功能,DES vs BMS BMS=BMS明显优于 BMS BMS明显比BMS差 BMS?BMS,如何改善?,有改善的空间!,Isch 2009,DES发展:PCI生物反应性的完善,月,强度,*Infl

4、ammation*Signaling*Proliferation,非药物非聚合物,*Healing*Endothelialization*Tissue contaction,6 月,非支架?,after Fitzgerald,Isch 2008,DES 改进可能提高安全性,药物,接触面,支架,NO DRUG:REPLACED BYPRO-HEALING CONCEPT:EPC Capture,无聚合物生物可降解聚合物,DEDICATED DRUG DELIVERY:RESERVOIRS(one/two way),BIODEGRADABLE PLATFORMwith/without drug e

5、lusion,Limuspaclitaxel.,聚合体,不锈钢,传统 DES,背景:1年LEADERS,BES（生物可降解多聚涂层支架）和 SES（不可降解多聚涂层支架）比较:植入9月后MACE发生率没有明显增加(主要终点事件 BES 9.2%vs.SES 10.5%,P=0.003)*植入后12月MACE发生率没有明显增加(BES 10.7%vs.SES 12.1%,P 0.001)OCT结果分析 显示，植入支架9月后，BES有较强的支撑力和较好的贴壁12月时支架内血栓形成率相似(ARC定义)2年临床随访结果尚未报道,*Windecker S et al.THE LANCET 2008;37

6、2 No 9644:1163-1173,BIOLIMUS A9 药物Biosensors proprietary rapamycin derivativeHighest lypophilicity of the common limus drugs,生物可降解 PLAPLA biodegradation along with BA9 elutionNo PLA/BA9 coating on the stent after 6 to 9 months*,血管内生物可降解涂层早期裸支架相似的内膜覆盖更多靶组织 释放更少的全身影响,The product is not available for s

7、ale in the USA,Biolimus A9 洗脱支架(BES)生物可降解多聚体血管内涂层支架DES,*Data on file-molecular weight10kDa1 Virmani R.,Are resorbable coatings better?,oral presentation,PCR 2008,*Data on file-molecular weight10kDa,Biolimus A9 洗脱支架 生物可降解血管内支架 DES,The product is not available for sale in the USA,Biolimus-A9 洗脱支架,Biol

8、imus 是半合成的西罗莫司类似物，和西罗莫司具有相似的效果，有10倍亲脂性Biolimus 渗透在生物可降解聚合物，聚乳酸中，浓度为15.6 g/mm，通过完美的自动的过程释放于支架表面聚乳酸和biolimus同时释放，6-9月后完全分解为二氧化碳和水不锈钢支架厚度112 m，距像结构,1o 终点:CV 死亡,MI,临床相关 TVR(9 month)2o 终点:死亡,CV 死亡,MI,TLR,TVR ARC 标准支架内血栓形成血管造影:支架内狭窄晚期丢失,多处狭窄,BESBioMatrix*Flex N=850,SESCypher Select N=850,实验设计,接受PCI治疗的稳定冠心

9、病或ACS 患者,N=1700 患者,1:3 Randomisation,Clinical F/UN=640,Angio F/UN=210,Clinical F/UN=640,Angio F/UN=210,评价-盲法 1:1 随机,*The product is not available for sale in the USA,患者入组,入选标准冠心病-稳定心绞痛-无症状心肌缺血 ACS包括心绞痛、NSTEMI、STEMI 最少有以下一种病变-狭窄直径 50%-RVD:2.25-3.5 mm-病变数量:不限制-病变血管支数:不限制 病变长度:不限制知情同意,排除标准对以下药物过敏 阿司匹林,

10、氯吡格雷,肝素,不锈钢,西罗莫司,biolimus,造影剂 6月内择期手术，除非双重能保证双重APT 治疗妊娠参加其他研究,BESSES857 人850人年龄 65 11 65 11男性 75%75%高血压74%73%糖尿病26%23%-胰岛素依赖10%9%高胆固醇65%68%家族史40%44%吸烟24%25%既往 MI32%33%既往 PCI36%37%-药物涂层支架12%14%既往 CABG11%13%稳定心绞痛45%44%,患者一般资料,BESSES 857 人850 人ACS55%56%-不稳定心绞痛22%21%-NSTEMI 17%18%-STEMI 16%17%EF56 11%55

11、 12%病变数量1.5 0.7 1.4 0.7平均每人病变数量-1 63%69%-2 29%22%-3 7%8%-4 1%2%De novo 病变92%91%长(20 mm)31%27%小血管(RVD 2.75 mm)68%69%Off label use81%78%,患者临床特征,流程图 临床,*F/U window 28 days,Lost to F/U=2Patient withdrawal=9Other=9,3=Lost to F/U6=Patient withdrawal12=Other,Lost to F/U=0Patient withdrawal=2Other=3,0=Lost

12、to F/U0=Patient withdrawal6=Other,0,5,10,15,0,1,2,3,4,5,6,7,8,9,Months of Follow-up,Cumulative Incidence(%),SES 10.5%,BES 9.2%,Pnon-inferiority=0.003,主要终点9月心源性死亡,MI 和 TVR,BES reached its primary endpoint,2Windecker S.et al.,The Lancet 2008;372 No.9644:1163-1173,长期结果有效、安全,好的支撑和贴壁3,至少5%未覆盖,至少5%贴壁不良,p=

13、0.005,10 x,N strut=6476,N strut=4592,p=0.04,20 x,N strut=6476,N strut=4592,植入9月时，BES 和SES 相比，覆盖及贴壁效果好10倍,3Di Mario C.,TCT 2008,%,%,MACE4,MACE=Cardiac Death,MI,or Clinically-Indicated TVR*P values for superiority4 Klauss V.,TCT 2009,Months,心源性死亡 or MI4,Months,*P values for superiority4 Klauss V.,TCT

14、2009,P=0.71*,%,P=0.35*,P=0.24*,P=0.59*,P=0.57*,P=0.42*,2年安全终点4,*P values for superiority4 Klauss V.,TCT 2009,临床相关的 TVR4,Months,*P values for superiority4 Klauss V.,TCT 2009,P=0.58*,%,P=0.25*,P=0.17*,P=0.37*,P=0.54*,2年安全终点,$,$,$Clinically Indicated*P values for superiority4 Klauss V.,TCT 2009,对复杂患者的益

15、处,复杂患者 分叉病变12 月 MACE5,Bifurcation Group BES vs.SESHR 0-2 days:1.62 0.77-3.40 p=0.20 3-360 days:0.46 0.24-0.88 p=0.02,SES Bifurcation BES BifurcationSES Non-bifurcationBES Non-bifurcation,对于分叉病变患者BES较 SES显著减少12月 MACE,5Garg,S.,PCR 2009,复杂患者 STEMI12月 MACE6,6Buszman,P.,PCR 2009,BES较SES有更好的12月临床结果,%,p=0.

16、04,p=0.22,p=0.07,p=0.02,复杂患者-STEMI12月 Def/Prob 支架内血栓6,p=0.05,Probable or Definite ST,BES ST 发生率显著降低,6Buszman,P.,PCR 2009,SES,BES,2年MACE分层分析 4,BES,SES,P Value,Risk Ratio(95%CI),P Int,MACE 8.1%for BES vs 19.3%for SES psup 0.01,*P values for superiority4 Klauss V.,TCT 2009,9月和2年MACE分层分析,2 Years4,9 Mont

17、hs2,2Windecker S.et al.,The Lancet 2008;372 No.9644:1163-11734 Klauss V.,TCT 2009,极晚期支架内血栓形成1年后安全性的指证,2 年 支架内血栓,%,2.0%,2.0%,2.2%,2.5%,Zoom at 1%scale,BES,SES,原发性及继发性 ST,BESN=857,SES$N=850,Definite Stent Thrombosis%According to ARC Definition,$Includes one secondary,definite ST occurring at 60 days i

18、n a patient who had early ST at 3 days*P values for superiority4Klauss V.,TCT 2009,抗血小板药物使用,*P values for superiority4Klauss V.,TCT 2009,DAPT 终止后结果4,%,N=0/154,N=2/163,N=3/479,N=0/484,总体,d/c DAPT,P=0.73*,*P values for superiority4Klauss V.,TCT 2009,结论,2 年随访所有进行2年随访的患者，BES 结果不比BES 差 在STEMI 人群，BES 有更好的

19、临床结果(MACE 发生率 BES 8.1%vs.SES19.3%p 0.01),9月随访 主要终点:MACE 发生率未见增高(BES9.2%vs.SES 10.5%p=0.003)OCT结果分析 BES 有更好的支撑和贴壁,结论,极晚期血栓形成 尽管是接受复查的患者的结果，BES极晚期血栓少见(BES 0.2%vs.SES 0.5%p=0.73)BES VLST 事件局限于 SVGs终止DAPT后，BES组没有发现 VLST 事件,结论,总体人群2年随访未发现BES比SES临床结果差在 LEADERS研究人群中 BES临床结果和 SES 相似：MACE-BES:13%vs SES:15.4%

20、(PSup=0.18)心源性死亡/MI-BES:8.3%vs SES:9.1%(PSup=0.59)临床相关TVR BES:7.7%vs SES:8.8%(PSup=0.37),结论,亚组分析 STEMI 患者BES 较SES MACE发生率降低(8.1%vs 19.3%Psup 0.01)极晚期血栓形成尽管是参加随访患者的资料，极晚期血栓形成少见(BES 0.2%vs SES 0.5%PSup=0.73)在终止DAPT 治疗后，BES 组未见极晚期血栓形成,LEADERS A Prospective,Randomised,Non-Inferiority Trial Comparing Bio

21、limus-Eluting Stent With Biodegradable Polymer Versus Sirolimus-Eluting Stent With Durable Polymer,Clinical Result Overview,LEADERS A Prospective,Randomised,Non-Inferiority Trial Comparing Biolimus-Eluting Stent With Biodegradable Polymer Versus Sirolimus-Eluting Stent With Durable Polymer,Patrick W

22、.Serruys,Simon Wandel,Pawel Buszman,Axel Linke,Thomas Ischinger,Franz Eberli,Roberto Corti,William Wijns,Marie-Claude Morice,Carlo di Mario,Robert-Jan van Geuns,Pedro Eerdmans,Gerrit-Anne van Es,Peter Jni,Stephan Windecker,New Insights from the LEADERS Trail&2-Year Clinical Follow-Up,LEADERS A Prosp

23、ective,Randomised,Non-Inferiority Trial Comparing Biolimus-Eluting Stent With Biodegradable Polymer Versus Sirolimus-Eluting Stent With Durable Polymer,First DES with biodegradable polymer:New Insights from the LEADERS Trial,The GW-ICC 2009Thomas Ischinger MD PhD FACC FESCHeart Center Bogenhausen,Mu

24、nich,Germany,Definite ST through 2 Years4,%,*P values for superiority4Klauss V.,TCT 2009,Stratified Analysis of MACE 2 Years,BES,SES,P Value,Risk Ratio(95%CI),P Int,NEW GENERATION DES WITH BIOABSORBABLE POLYMER:WHAT IS THE PROGRESS?,Insights from the LEADERS trial 2 years FU BIOMATRIX(biabsorbable P

25、)vs CYPHER(durable P)Thomas Ischinger MD PhD FACC FESCProfessor of Medicine/CardiologyHeart Center Bogenhausen,Munich,Germany,ESC firestorm:Issue#1 death and MI,“Our Black Tuesday”,Isch 2008 nach Serruys,G.Guagliumi et al,Circulation2003;107:1340,Mid Term Human Pathology Sirolimus Eluting Stents Fin

26、dings from Different Coronary Arteries in the Same Patient show delayed endothelial regrowth,BMS 24 Months after Deployment:endothelial coverage,Cypher 16 Months after Deployment:lack of endothelium,overlapped,overlapped,Cypher,Bx Velocity,Taxus,Express,BioLimus A9,S Stent,Comparison of Various BMS

27、and DES In Rabbit Iliac Arteries at 28-days,VIRMANI2006,Degree of endothelial regrowth over stentstruts,Isch 2008,DES-Animal Studies,potential safety problems.,Excessive thrombus Incomplete endothelialization,Severe inflammatory response,Persistent fibrin+inflammation,Medial necrosis Malapposition,H

28、ow relevant is the problem of acute stent thrombosis?,2,000,000 patients treated per year with 3,000,000 stents,1.3 lesions per patient,Efficacy(TLR)1%26,000 TLRs2%52,000 TLRs5%130,000 TLRs,Safety(ST)0.5%13,000 STs4,000 deaths10,000 MIs,Isch 2009,What have drug eluting stents(DES)provided?,Performan

29、ce characteristicsDeliverabilityScaffoldingRestenosisComponent compatibility&AthrombogenicityAntiplatelet therapythrombosis riskvasomotion,Todays Status vs BMS BMS BMStypically much worse than BMSdue to life long dependencyworse than BMS?Worse than BMS,Where and how to intervene for improvement?,Roo

30、m for improvement!,Isch 2009,Further R&D in DES:Adaptation of Technology to Biologic Response to PCI,Months,Intensity,*Inflammation*Signaling*Proliferation,NO DrugNO Polymer,*Healing*Endothelialization*Tissue contaction,6 months,NO STENT?,after Fitzgerald,Isch 2008,Potential DES alterations for impr

31、oved safety,DRUG,Interface,Platform,NO DRUG:REPLACED BYPRO-HEALING CONCEPT:EPC Capture,NO POLYMERBIODEGRADABLE POLYMER,DEDICATED DRUG DELIVERY:RESERVOIRS(one/two way),BIODEGRADABLE PLATFORMwith/without drug elusion,Limuspaclitaxel.,Polymer,Stainlesssteel,Conventional DES,Background:LEADERS at 1-Year

32、,Comparison of BES with biodegradable polymer to SES with durable polymer resulted in:Non-inferior MACE rate at 9 months(primary endpoint met:9.2%BES vs.10.5%SES,Pnon-inf=0.003)*Non-inferiority in MACE confirmed at 12 months(10.7%BES vs.12.1%SES,Pnon-inf 0.001)BES showed superior strut coverage and

33、stent apposition at 9 months in OCT sub-analysisSimilar rates of stent thrombosis(ARC definition)at 12 months Two year clinical outcomes have not yet been reported,*Windecker S et al.THE LANCET 2008;372 No 9644:1163-1173,BIOLIMUS A9 DRUGBiosensors proprietary rapamycin derivativeHighest lypophilicit

34、y of the common limus drugs,BIODEGRADABLE PLAPLA biodegradation along with BA9 elutionNo PLA/BA9 coating on the stent after 6 to 9 months*,ABLUMINAL BIODEGRADABLE COATINGEarly BMS-like endothelial coverage1More targeted tissue release Less systemic exposure,The product is not available for sale in t

35、he USA,Biolimus A9 Eluting Stent(BES)The abluminal biodegradable polymer DES,*Data on file-molecular weight10kDa1 Virmani R.,Are resorbable coatings better?,oral presentation,PCR 2008,*Data on file-molecular weight10kDa,Biolimus A9 Eluting Stent The abluminal biodegradable polymer DES,The product is

36、 not available for sale in the USA,Biolimus-A9 Eluting Stent,Biolimus is a semi-synthetic sirolimus analogue with 10 x higher lipophilicity and similar potency as sirolimus.Biolimus is immersed at a concentration of 15.6 g/mm into a biodegradable polymer,polylactic acid,and applied solely to the abl

37、uminal stent surface by a fully automated process.Polylactic acid is co-released with biolimus and completely desolves into carbon dioxide and water after 6-9 months.The stainless steel stent platform has a strut thickness of 112 m with a quadrature link design.,1o endpoint:CV death,MI,clinically-in

38、dicated TVR(9 month)2o endpoints:Death,CV death,MI,TLR,TVR Stent thrombosis according to ARC Angiographic study:In-stent%diameter stenosisLate loss,binary restenosisDAPT recommended for 12 months,BESBioMatrix*Flex N=850,SESCypher Select N=850,Trial Design,Stable and ACS Patients Undergoing PCI,N=170

39、0 Patients,1:3 Randomisation,Clinical F/UN=640,Angio F/UN=210,Clinical F/UN=640,Angio F/UN=210,Assessor-blind 1:1 Randomisation,*The product is not available for sale in the USA,Patient Eligibility,Inclusion CriteriaCoronary artery disease-Stable angina-Silent ischemia Acute coronary syndrome includ

40、ing UA,NSTEMI and STEMIAt least one lesion with-Diameter stenosis 50%-RVD:2.25-3.5 mm-Number of lesions:no limitation-Number of vessels:no limitation Lesion length:no limitationWritten informed consent,Exclusion CriteriaKnown allergy to aspirin,clopidogrel,heparin,stainless steel,sirolimus,biolimus,

41、contrast material Planned,elective surgery within 6 months of PCI unless dual APT could be maintainedPregnancyParticipation in another trial,BESSES857 Patients850 PatientsAge in years 65 11 65 11Male gender 75%75%Arterial hypertension74%73%Diabetes mellitus26%23%-insulin-dependent10%9%Hypercholester

42、olemia65%68%Family history40%44%Smoking24%25%Previous MI32%33%Previous PCI36%37%-with drug-eluting stent12%14%Previous CABG11%13%Chronic stable angina45%44%,Patient Demographics,BESSES 857 Patients850 PatientsAcute coronary syndrome55%56%-Unstable angina22%21%-Non-ST-elevation MI 17%18%-ST-elevation

43、 MI 16%17%Left ventricular ejection fraction56 11%55 12%Number of lesions per patient1.5 0.7 1.4 0.7Lesions per patient-1 lesion63%69%-2 lesions29%22%-3 lesions7%8%-4 lesions1%2%De novo lesions92%91%Long lesions(20 mm)31%27%Small vessels(RVD 2.75 mm)68%69%Off label use81%78%,Patient Characteristics,

44、Patient Flow-Clinical,*F/U window 28 days,Lost to F/U=2Patient withdrawal=9Other=9,3=Lost to F/U6=Patient withdrawal12=Other,Lost to F/U=0Patient withdrawal=2Other=3,0=Lost to F/U0=Patient withdrawal6=Other,0,5,10,15,0,1,2,3,4,5,6,7,8,9,Months of Follow-up,Cumulative Incidence(%),SES 10.5%,BES 9.2%,

45、Pnon-inferiority=0.003,Primary EndpointCardiac Death,MI and TVR 9 Months2,BES reached its primary endpoint,2Windecker S.et al.,The Lancet 2008;372 No.9644:1163-1173,Long Term ResultsProven Safety and Efficacy,Superior Strut Coverage and Stent Apposition3,Lesions with at least 5%uncovered struts,Lesi

46、ons with at least 5%malapposed struts,p=0.005,10 x,N strut=6476,N strut=4592,p=0.04,20 x,N strut=6476,N strut=4592,BES with an abluminal biodegradable polymer achieved a 10 x better strut coverage and a 20 x better stent apposition vs.SES with a symmetric durable polymer at 9 months,3Di Mario C.,TCT

47、 2008,%,%,MACE4,MACE=Cardiac Death,MI,or Clinically-Indicated TVR*P values for superiority4 Klauss V.,TCT 2009,Months,Cardiac Death or MI4,Months,*P values for superiority4 Klauss V.,TCT 2009,P=0.71*,%,P=0.35*,P=0.24*,P=0.59*,P=0.57*,P=0.42*,2-Year Safety Endpoints4,*P values for superiority4 Klauss

48、 V.,TCT 2009,Clinically-Indicated TVR4,Months,*P values for superiority4 Klauss V.,TCT 2009,P=0.58*,%,P=0.25*,P=0.17*,P=0.37*,P=0.54*,2-Year Efficacy Endpoints4,$,$,$Clinically Indicated*P values for superiority4 Klauss V.,TCT 2009,Advantage in Complex Patients,Complex Patients Bifurcation Lesions12

49、 Month MACE5,Bifurcation Group BES vs.SESHR 0-2 days:1.62 0.77-3.40 p=0.20 3-360 days:0.46 0.24-0.88 p=0.02,SES Bifurcation BES BifurcationSES Non-bifurcationBES Non-bifurcation,Significant reduction in MACE for BES vs.SES in bifurcation lesions up to 12 months,5Garg,S.,PCR 2009,Complex Patients STE

50、MI12 Month MACE6,6Buszman,P.,PCR 2009,Superior clinical outcomes for the BES vs.SES up to 12 months,%,p=0.04,p=0.22,p=0.07,p=0.02,Complex Patients-STEMI12 Month Def/Prob Stent Thrombosis6,p=0.05,Probable or Definite ST,BES has significant lower rates of ST vs.SES up to 12 months,6Buszman,P.,PCR 2009