晚期血栓:可降解聚合物是理想解決方法嗎？浙江大學醫學院附屬邵逸夫醫院心內科周斌全風險獲益與裸金屬支架相比,藥物洗脫支架

風險/獲益的概況是什么?心梗,死亡,TLR支架血栓減少再狹窄BMS=baremetalstent;DES=drug-elutingstent;MI=myocardialinfarction;TLR=targetlesionrevascularization.TimeafterInitialProcedure(years)01234TimeafterInitialProcedure(years)TAXUSI,II,IV,V,VI(n=3,513)RAVEL,SIRIUS,E-SIRIUS,andC-SIRIUS(n=1,748)CYPHERstent(n=870)Baremetalstent(n=878)StoneGWetal.NEJM2007;356:998-100801234TAXUSstent(n=1,755)Baremetalstent(n=1,758)9Prospective,Double-Blind,RandomizedTrials

FreedomFrom(Protocol)StentThrombosisP=0.2099.4%(5)98.8%(10)P=0.3099.1%(14)98.7%(20)5

vs.0,P=0.025After1year9

vs.2,P=0.028After1yearCypher植入16月死亡患者尸檢

（REVAL研究）分支血管口血栓1233圖1DES表面內皮化>80%,箭頭所指為支架遠端（側面）未被內皮覆蓋圖2DES表面內皮細胞呈點狀不愈合圖3

內皮細胞間連接不良,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天修復及內皮愈合狀況RenuVirmani,27thmay,2004PCRDESinDiseasedHumanCoronaryArtery16MonthsAfterSESImplantation

Guagliumi,etal.Circulation2003;107:1340-1Cypher支架后16個月，炎癥反應（F，71歲）TAXUS支架后18個月，炎癥反應（M，40歲）VirmaniR,etal.Circulation.2004;109:701-705.04PCR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(GranulomatousReaction)RenuVirmani,27thmay,2004PCR風險獲益TLR減少>50%可能減少

TLR-相關的死亡藥物釋放支架與裸金屬支架對比

更趨向與獲益/風險的平衡不會回到裸金屬支架時代!ChenMSetal.AmHeartJ.2006;151:1260.1186連續的裸金屬支架再狹窄的臨床事件=10patients心梗=9.5%

(112/1186)以不穩定心絞痛*和心梗就醫

=36%

(425/1186)*Hospitalizedbeforecoronaryangiography.Ellisetal.AmHeartJ.2006;151:1260.“裸金屬支架再狹窄不是一個良性的臨床事實”

Chenetal.AmHeartJ2006;151:126024

AdaptedfromPosterPresentation,ACC2006SIRIUS4年MACE曲線圖P<0.00127036072010800010203040506070809010069.2%83.2%FreedomfromMACE,%TimeafterInitialProcedure,days27036072010800010203040506070809010069.2%83.2%p(logrank)<0.001CYPHERBxVELOCITY?1440為什么使用多聚物載體?使用多聚物載體可能的益處:可預測性控制劑量均勻的藥物分布隨意改變釋放速率持續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PolymerPLAPolymerSafeasbiodegradablesuturematerialUsedinimplantedcontrolleddrug-releasesystemsOrthopedicimplantsDegradesbyhydrolysistonaturallyoccurringlacticacidMetabolizedinthebodytocarbondioxideandwaterorexcretedinthekidneysInaporcinemodelthePLAcoatingisalmostcompletelyabsorbedat6months.Completemetabolisationofpolymer

canpossiblepreventpersistentinflammation,latestentthrombosis,restenosis傳統的Polymer的損傷

TCT2004thrombosisatcrackingsitescoronarymicroembolismofpolymerpiecesexcessivechronicinflammatoryneointimalreactions單面涂層抗再狹窄避免內皮化延遲可降解聚合物避免血栓事件改變抗血小板策略避免聚合物永久殘留導致的血管壁炎癥反應或過敏反應EXCELSystemS-Stent(歐洲進口支架)Stent/DeliveryCatheter生物降解

聚合物載體Polymer雷帕霉素Drug生物降解

聚合物載體聚合物載體雷帕霉素藥物

非對稱涂層工藝藥物涂層只涂在支架外表面(組織一側)藥物進入血流明顯減少有利于內皮愈合EXCELDES藥物涂層的特點Excel支架內雷帕霉素的釋放特征40％的Sirolimus在24h內釋放，隨后長時間緩慢釋放，3~6月完全釋放完畢Long-TermSafetyofDES:FutureDirectionsNoPolymerNoDrugAsymmetricBiodegradablePolymerHealingofEndotheliumSEMIMAGESOFPIGVESSELS@28DAYSPOSTDESIMPLANTExcelTM3個月內皮細胞分布遠離支架撐桿部位支架撐桿部位支架撐桿非直線走行部位BMS3個月內皮遠離支架撐桿部位支架撐桿部位支架撐桿非直線走行部位0.03230.00260.0105P2.38±0.190.79±0.150.13±0.05BMS組2.63±0.120.42±0.120.05±0.02Excel組管腔面積(mm2)新生內膜面積(mm2)新生內膜厚度（mm）組別Multi-CenterRegistryofExcelBiodegrAdablePolymerDrugEluTingStEntCREATEPatientsRecruitment(2006.6-2006.11)2077PtsEnrolled90ptsExcludedforHybridStentingClinicalFollow-upAngioFollow-up6-monthClopidogrelAspirinIndefinitely30Days(2077pts)6Months(2068pts)9±3Months(653pts)12

Months(2063pts)MajorAdverseCardiacEvents(CardiacDeath,MI,TLR)LateLumenLossBinaryRestenosisThromboticEventsStudyFlowchartPrimaryEndPoint:

MACEat12monthsSecondaryEndPoints:

MACEat1-and6months;LateLoss;BinaryRestenosis;ThromboticEventsBaselineClinicalCharacteristicsFollow-upClinicalOutcomes(%)12-monthClinicalFollow-upRate99.3%ThromboticEventsdays3thromboticeventsdevelopedafterdiscontinuationofclopidogrel9-monthQCAResults974lesions(31.6%)analyzedTwo-yearFollow-upofEXCELFirst-In-ManClinicalStudy:TheMedistraExcelDrug-elutIngSTentTRiAl(MEDISTRA)T.Santoso*,A.Wong+,T.H.Koh+*Div.ofCardiology,Dept.ofInternalMedicine,Univ.ofIndonesiaMedicalSchool&theMedistraHospital,Jakarta,Indonesia+NationalHeartCentre,SingaporeMedistraExcel

Drug-ElutIngStentTRiAl

Predilatationisencouraged,eventhoughdirectstenting

isallowedinsimplelesion

Stentselection:TrytoalwaysuseEXCELIfappropriatesize/lengthnotavailable,useotherDES(CypherorTaxus)IfotherDESisnotavailable(logisticproblem),useBMSAntiplateletregimen:ASA160mgindefinitely(unlesscontraindicated)

Clopidogrel300mg(loading),then75mgfor6months

EXCEL

inRealWorldCases%In-hospital30-dayclinicaloutcome60-dayclinicaloutcome12monthclinicaloutcome24monthclinicaloutcomeN(%)357(100)357(100)357(100)288(100)159(100)Cardiacdeath(n,%)0(0)3(0.8)3(0.8)3(1.0)3(1.8)Non-cardiacdeath(n,%)0(0)0(0)0(0)2(0.7)2(1.3)Non-fatalQMI(n,%)0(0)0(0)0(0)0(0)0(0)NonfatalNQMI(n,%)0(0)0(0)0(0)0(0)0(0)AnynonfatalMI(n,%)0(0)0(0)0(0)0(0)0(0)TLR(n,%)0(0)1(0.3)12(3.4)12(4.2)10(7.5)Stentthrombosis(n,%)0(0)(acute)2(0.6)(subacute)0(0)(late)0(0)(late)0(0)(verylate)MACE(n,%)0(0)3(0.8)13(3.9)14(4.9)12(6.8)Follow-up(6months)(cont’d)Lateloss,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