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

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,Circulation2003;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,*Inflammation*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 elusion,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;372 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 sale 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,Biolimus 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,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 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 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=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 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,$,$,$Clinically Indicated*P values for superiority4 Klauss V.,TCT 2009,对复杂患者的益处,复杂患者 分叉病变12 月 MACE5,Bifurcation Group BES vs.SESHR 0-2 days:1.62 0.77-3.40 p=0.20 3-360 days:0.46 0.24-0.88 p=0.02,SES Bifurcation BES BifurcationSES Non-bifurcationBES Non-bifurcation,对于分叉病变患者BES较 SES显著减少12月 MACE,5Garg,S.,PCR 2009,复杂患者 STEMI12月 MACE6,6Buszman,P.,PCR 2009,BES较SES有更好的12月临床结果,%,p=0.04,p=0.22,p=0.07,p=0.02,复杂患者-STEMI12月 Def/Prob 支架内血栓6,p=0.05,Probable or Definite ST,BES ST 发生率显著降低,6Buszman,P.,PCR 2009,SES,BES,2年MACE分层分析 4,BES,SES,P Value,Risk Ratio(95%CI),P Int,MACE 8.1%for BES vs 19.3%for SES psup 0.01,*P values for superiority4 Klauss V.,TCT 2009,9月和2年MACE分层分析,2 Years4,9 Months2,2Windecker S.et al.,The Lancet 2008;372 No.9644:1163-11734 Klauss V.,TCT 2009,极晚期支架内血栓形成1年后安全性的指证,2 年 支架内血栓,%,2.0%,2.0%,2.2%,2.5%,Zoom at 1%scale,BES,SES,原发性及继发性 ST,BESN=857,SES$N=850,Definite Stent Thrombosis%According to ARC Definition,$Includes one secondary,definite ST occurring at 60 days in 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%(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 Biolimus-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.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 Prospective,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,Munich,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)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 Findings 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 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,How 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?,Performance 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?,Room 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 improved 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,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 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 lypophilicity 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 the 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 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 abluminal 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-indicated 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=1700 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 including 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,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%Hypercholesterolemia65%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 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,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%,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,Lesions 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 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 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 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 STEMI12 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