晚期血栓可降解聚合物是理想解決方法嗎

1、晚期血栓:可降解聚合物是理想解決方法嗎？,浙江大學(xué)醫(yī)學(xué)院附屬邵逸夫醫(yī)院心內(nèi)科周 斌 全,與裸金屬支架相比,藥物洗脫支架風(fēng)險/獲益的概況是什么?,心梗, 死亡, TLR,支架血栓,減少再狹窄,,,BMS = bare metal stent; DES = drug-eluting stent; MI = myocardial infarction;TLR = target lesion revascularization.,,,

2、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-Bli

3、nd, Randomized TrialsFreedom From (Protocol) Stent Thrombosis,,,,,,2003-2006年所有的瑞典冠脈介入的病人，包含了294，000 例手術(shù)操作，進(jìn)行至少為期一年的隨訪才能進(jìn)入觀察組，結(jié)果４年的期間，觀察到2957例死亡和 4160 例MI發(fā)生。該研究錄入13785 例病人至少使用一個藥物支架，和 21477例病人僅使用BMS。結(jié)果，死亡和MI終點事件發(fā)生率沒有差異（

4、RR　1.01，95% CI：0.94-1.09) 。６個月以內(nèi)，DES組校正后的復(fù)合終點率較低，但６個月后增加至與BMS組相當(dāng)。３年時DES組再狹窄率絕對數(shù)下降４％，支架血栓形成發(fā)生率每年為0.5 %。,瑞典冠脈造影和冠脈成形術(shù)注冊研究（SCAAR）,,,,,,,,,Cypher 植入16月死亡患者尸檢（REVAL 研究）,分支血管口血栓,,,圖1 DES表面內(nèi)皮化>80%,箭頭所指為支架遠(yuǎn)端（側(cè)面）未被內(nèi)皮覆蓋,圖2 D

5、ES表面內(nèi)皮細(xì)胞呈點狀不愈合,圖3 內(nèi)皮細(xì)胞間連接不良, 箭頭所指為血小板聚集,04PCR 報道: Cypher 重疊支架植入兔髂動脈28天修復(fù)及內(nèi)皮愈合狀況,Renu Virmani , 27th may , 2004 PCR,DES in Diseased Human Coronary Artery,16 Months After SES Implantation,Guagliumi, et al. Circulation 200

6、3;107:1340-1,04PCR 報道: Cypher 支架植入豬冠脈28天和90天有12.5%和35%的血管有肉芽腫反應(yīng)(Granulomatous Reaction ),Renu Virmani , 27th may , 2004 PCR,藥物釋放支架與裸金屬支架對比更趨向與獲益/風(fēng)險的平衡,不會回到裸金屬支架時代!,,Chen MS et al. Am Heart J. 2006;151:1260.,1186 連續(xù)的裸金屬

7、支架再狹窄的臨床事件,= 10 patients,心梗= 9.5% (112/1186),以不穩(wěn)定心絞痛*和心梗就醫(yī) = 36% (425/1186),*Hospitalized before coronary angiography. Ellis et al. Am Heart J. 2006;151:1260.,“裸金屬支架再狹窄不是一個良性的臨床事實 ” Chen et al. Am Heart J 2006;151

8、:12602 4,Adapted from Poster Presentation, ACC 2006,SIRIUS 4年MACE曲線圖,,,,,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, %,,

9、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,,,為什么使用多聚物載體?,使用多聚物載體可能的益處:可預(yù)測性控制劑量均勻的藥物分

10、布隨意改變釋放速率持續(xù)釋放保護藥物在操作和植入時, 沒有藥物丟失劑量一致,,生物可降解Polymer,減少了亞急性血栓和血管瘤的發(fā)生率,提高患者的生存機率100%的藥物釋放和聚合物降解支架術(shù)后抗血小板藥物治療時間6個月,減少病人費用 不用擔(dān)心像傳統(tǒng)永久性的聚合物載體可能會引起的長期結(jié)構(gòu)損壞和慢性炎癥的影響。,PLA Polymer,Safe as biodegradable suture materialUsed

11、 in implanted controlled drug-release systems Orthopedic implantsDegrades by hydrolysis to naturally occurring lactic acidMetabolized in the body to carbon dioxide and water or excreted in the kidneysIn a porcine mod

12、el the PLA coating is almost completely absorbed at 6 months.,Complete metabolisation of polymer can possible prevent persistent inflammation, late stent thrombosis, restenosis,傳統(tǒng)的Polymer 的損傷,TCT 2004,thrombosis at cra

13、cking sitescoronary microembolism of polymer piecesexcessive chronic inflammatory neointimal reactions,,,,,,EXCEL System,,,,,非對稱涂層工藝藥物涂層只涂在支架外表面(組織一側(cè)) 藥物進(jìn)入血流明顯減少有利于內(nèi)皮愈合,EXCEL DES藥物涂層的特點,,Excel支架內(nèi)雷帕霉素的釋放特征,40％的Si

14、rolimus在24 h內(nèi)釋放，隨后長時間緩慢釋放，3~6月完全釋放完畢,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Long-Term Safety of DES: Future Directions,,No PolymerNo Drug,Asymmetric BiodegradablePolymer,Healing o

15、f Endothelium,SEM IMAGES OF PIG VESSELS @ 28 DAYS POST DES IMPLANT,BMS 3個月內(nèi)皮,遠(yuǎn)離支架撐桿部位,支架撐桿部位,支架撐桿非直線走行部位,附表 兩組犬支架術(shù)后3個月新生內(nèi)膜的增生情況,Multi-Center Registry of Excel BiodegrAdable Polymer Drug EluTing StEnt,CREATE,,Patients R

16、ecruitment(2006.6-2006.11),2077 Pts Enrolled,90 pts Excluded for Hybrid Stenting,Clinical Follow-up,Angio Follow-up,6-month ClopidogrelAspirin Indefinitely,30 Days (2077 pts),6 Months (2068 pts),9±3 Months(653 pt

17、s),12 Months (2063 pts),Major Adverse Cardiac Events(Cardiac Death, MI, TLR),Late Lumen LossBinary Restenosis,Thrombotic Events,Study Flowchart,Primary End Point: MACE at 12 monthsSecondary End Points: MAC

18、E 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.

19、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 Dru

20、g-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 Centr

21、e, 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

22、not available, use other DES (Cypher or Taxus) If other DES is not available (logistic problem), use BMSAntiplatelet regimen: ASA 160 mg indefinitely (unless contraindicated) Clopidogrel 300 mg (loading), t

23、hen 75 mg for 6 months,,EXCEL in Real World Cases,%,,,Follow-up (6 months)(cont’d)Late loss, mmIn-segment0.200.270.020.53 In-stent0.220.320.080.55Restenosis (>50%)In-segment7/5

24、2 (13.5%)3/42 (7.1%)9/186 (4.8%)2/19 (10.5%)In-stent6/52 (11.5%)2/42 (4.8%)7/186 (3.8%)2/19 (10.5%),CYPHERTAXUSEXCELBMS,QCA analysis at 6 months*,,,* Biomatrix = 3 & Endeavour = 1 were not included

25、in the analysis,,Stents With Biodegradable Polymer,Biomatrix --- Biosensor InternationalExcel --- JW Medical; Biosensor InternationalNobori --- Terumo; Biosensor InternationalAxxess --- Devax; Biosensor Internation

26、alCustom --- Xtent; Biosensor International,,,,,,,,,,,,SUMMARY,,DES with biodegradable polymer is safe and effective with:Very low rate of MACELow rate of restenosisNo or very low rate of LST with 6 months dual