晚期血栓可降解聚合物是理想解决方法吗周斌全

晚期血栓:可降解聚合物是理想解决方法吗？,浙江大学医学院附属邵逸夫医院心内科 周 斌 全,与裸金属支架相比,药物洗脱支架 风险/获益的概况是什么?,心梗, 死亡, TLR,支架血栓,减少再狭窄,BMS = bare metal stent; DES = drug-eluting stent; MI = myocardial infarction; TLR = target lesion revascularization.,Time after Initial Procedure (years),Time after Initial Procedure (years),TAXUS I, II, IV, V, VI (n=3,513),RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS (n=1,748),Stone GW et al. NEJM 2007;356:998-1008,9 Prospective, Double-Blind, Randomized Trials Freedom From (Protocol) Stent Thrombosis,2003-2006年所有的瑞典冠脉介入的病人，包含了294，000 例手术操作，进行至少为期一年的随访才能进入观察组，结果年的期间，观察到2957例死亡和 4160 例MI发生。该研究录入13785 例病人至少使用一个药物支架，和 21477例病人仅使用BMS。结果，死亡和MI终点事件发生率没有差异（RR 1.01，95% CI：0.94-1.09) 。个月以内，DES组校正后的复合终点率较低，但个月后增加至与BMS组相当。年时DES组再狭窄率绝对数下降，支架血栓形成发生率每年为0.5 %。,瑞典冠脉造影和冠脉成形术注册研究（SCAAR）,Cypher 植入16月死亡患者尸检 （REVAL 研究）,分支血管口血栓,图1 DES表面内皮化80%,箭头所指为支架远端（侧面）未被内皮覆盖,图2 DES表面内皮细胞呈点状不愈合,图3 内皮细胞间连接不良, 箭头所指为血小板聚集,04PCR 报道: Cypher 重叠支架植入兔髂动脉28天修复及内皮愈合状况,Renu Virmani , 27th may , 2004 PCR,DES in Diseased Human Coronary Artery,16 Months After SES Implantation,Guagliumi, et al. Circulation 2003;107:1340-1,04PCR 报道: Cypher 支架植入猪冠脉28天和90天 有12.5%和35%的血管有肉芽肿反应(Granulomatous Reaction ),Renu Virmani , 27th may , 2004 PCR,药物释放支架与裸金属支架对比 更趋向与获益/风险的平衡,不会回到裸金属支架时代!,Chen MS et al. Am Heart J. 2006;151:1260.,1186 连续的裸金属支架再狭窄的临床事件,= 10 patients,心梗= 9.5% (112/1186),以不稳定心绞痛*和心梗就医 = 36% (425/1186),*Hospitalized before coronary angiography. Ellis et al. Am Heart J. 2006;151:1260.,“裸金属支架再狭窄不是一个良性的临床事实 ” Chen et al. Am Heart J 2006;151:12602 4,Adapted from Poster Presentation, ACC 2006,SIRIUS 4年MACE曲线图,P 0.001,270,360,720,1080,0,0,10,20,30,40,50,60,70,80,90,100,69.2%,83.2%,Freedom from MACE, %,Time after Initial Procedure, days,270,360,720,1080,0,0,10,20,30,40,50,60,70,80,90,100,69.2%,83.2%,p (log rank) 0.001,1440,为什么使用多聚物载体?,使用多聚物载体可能的益处:可预测性 控制剂量 均匀的药物分布 随意改变释放速率 持续释放 保护药物 在操作和植入时, 没有药物丢失 剂量一致,生物可降解Polymer,减少了亚急性血栓和血管瘤的发生率,提高患者的生存机率 100%的药物释放和聚合物降解 支架术后抗血小板药物治疗时间6个月,减少病人费用 不用担心像传统永久性的聚合物载体可能会引起的长期结构损坏和慢性炎症的影响。,PLA Polymer,Safe as biodegradable suture material Used in implanted controlled drug-release systems Orthopedic implants Degrades by hydrolysis to naturally occurring lactic acid Metabolized in the body to carbon dioxide and water or excreted in the kidneys In a porcine model the PLA coating is almost completely absorbed at 6 months.,Complete metabolisation of polymer can possible prevent persistent inflammation, late stent thrombosis, restenosis,传统的Polymer 的损伤,TCT 2004,thrombosis at cracking sites coronary microembolism of polymer pieces excessive chronic inflammatory neointimal reactions,EXCEL System,非对称涂层工艺 药物涂层只涂在支架外表面(组织一侧) 药物进入血流明显减少 有利于内皮愈合,EXCEL DES药物涂层的特点,Excel支架内雷帕霉素的释放特征,40的Sirolimus在24 h内释放，随后长时间缓慢释放，36月完全释放完毕,Long-Term Safety of DES: Future Directions,No Polymer No Drug,Asymmetric Biodegradable Polymer,Healing of Endothelium,SEM IMAGES OF PIG VESSELS 28 DAYS POST DES IMPLANT,BMS 3个月内皮,远离支架撑杆部位,支架撑杆部位,支架撑杆非直线走行部位,附表 两组犬支架术后3个月新生内膜的增生情况,Multi-Center Registry of Excel BiodegrAdable Polymer Drug EluTing StEnt,CREATE,Patients Recruitment (2006.6-2006.11),2077 Pts Enrolled,90 pts Excluded for Hybrid Stenting,Clinical Follow-up,Angio Follow-up,6-month Clopidogrel Aspirin Indefinitely,30 Days (2077 pts),6 Months (2068 pts),93 Months (653 pts),12 Months (2063 pts),Major Adverse Cardiac Events (Cardiac Death, MI, TLR),Late Lumen Loss Binary Restenosis,Thrombotic Events,Study Flowchart,Primary End Point: MACE at 12 months Secondary End Points: MACE at 1- and 6 months; Late Loss; Binary Restenosis; Thrombotic Events,Baseline Clinical Characteristics,Follow-up Clinical Outcomes,(%),12-month Clinical Follow-up Rate 99.3%,Thrombotic Events,days,3 thrombotic events developed after discontinuation of clopidogrel,9-month QCA Results,974 lesions(31.6%) analyzed,Two-year Follow-up of EXCEL First-In-Man Clinical Study:The Medistra Excel Drug-elutIng STent TRiAl (MEDISTRA),T. Santoso*, A. Wong+, T.H. Koh+ *Div. of Cardiology, Dept. of Internal Medicine, Univ. of Indonesia Medical School & the Medistra Hospital, Jakarta, Indonesia +National Heart Centre, Singapore,Medistra Excel Drug-ElutIng Stent TRiAl,Predilatation is encouraged, even though direct stenting is allowed in simple lesion Stent selection: Try to always use EXCEL If appropriate size / length not available, use other DES (Cypher or Taxus) If other DES is not available (logistic problem), use BMS Antiplatelet regimen: ASA 160 mg indefinitely (unless contraindicated) Clopidogrel 300 mg (loading), then 75 mg for 6 months,EXCEL in Real World Cases,%,Follow-up (6 months)(contd) Late loss, mm In-segment 0.20 0.27 0.02 0.53 In-stent 0.22 0.32 0.08 0.55 Restenosis (50%) In-segment 7/52 (13.5%) 3/42 (7.1%) 9/186 (4.8%) 2/19 (10.5%) In-stent 6/52 (11.5%) 2/42 (4.8%) 7/186 (3.8%) 2/19 (10.5%),CYPHER TAXUS EXCEL BMS,QCA analysis at 6 months*,* Biomatrix = 3 & Endeavour = 1 were not included in the analysis,Stents With Biodegradable Polymer,Biomatrix - Biosensor International Excel - JW Medical; Biosensor International Nobori - Terumo; Biosensor International Axxess - Devax; Biosensor Internati