晚期血栓可降解聚合物是理想解決方法嗎？-周斌全

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)科周斌全風(fēng)險(xiǎn)獲益與裸金屬支架相比,藥物洗脫支架

風(fēng)險(xiǎn)/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(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2DES表面內(nèi)皮細(xì)胞呈點(diǎn)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(bào)道:Cypher重疊支架植入兔髂動(dòng)脈28天修復(fù)及內(nèi)皮愈合狀況RenuVirmani,27thmay,2004PCRDESinDiseasedHumanCoronaryArtery16MonthsAfterSESImplantation

Guagliumi,etal.Circulation2003;107:1340-1Cypher支架后16個(gè)月，炎癥反應(yīng)（F，71歲）TAXUS支架后18個(gè)月，炎癥反應(yīng)（M，40歲）VirmaniR,etal.Circulation.2004;109:701-705.04PCR報(bào)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)(GranulomatousReaction)RenuVirmani,27thmay,2004PCR風(fēng)險(xiǎn)獲益TLR減少>50%可能減少

TLR-相關(guān)的死亡藥物釋放支架與裸金屬支架對(duì)比

更趨向與獲益/風(fēng)險(xiǎn)的平衡不會(huì)回到裸金屬支架時(shí)代!ChenMSetal.AmHeartJ.2006;151:1260.1186連續(xù)的裸金屬支架再狹窄的臨床事件=10patients心梗=9.5%

(112/1186)以不穩(wěn)定心絞痛*和心梗就醫(yī)

=36%

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

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(yù)測(cè)性控制劑量均勻的藥物分布隨意改變釋放速率持續(xù)釋放保護(hù)藥物在操作和植入時(shí),沒有藥物丟失劑量一致生物可降解PolymerPLAPolymerSafeasbiodegradablesuturematerialUsedinimplantedcontrolleddrug-releasesystemsOrthopedicimplantsDegradesbyhydrolysistonaturallyoccurringlacticacidMetabolizedinthebodytocarbondioxideandwaterorexcretedinthekidneysInaporcinemodelthePLAcoatingisalmostcompletelyabsorbedat6months.Completemetabolisationofpolymer

canpossiblepreventpersistentinflammation,latestentthrombosis,restenosis傳統(tǒng)的Polymer的損傷

TCT2004thrombosisatcrackingsitescoronarymicroembolismofpolymerpiecesexcessivechronicinflammatoryneointimalreactions單面涂層抗再狹窄避免內(nèi)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(dǎo)致的血管壁炎癥反應(yīng)或過敏反應(yīng)EXCELSystemS-Stent(歐洲進(jìn)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(duì)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EXCELDES藥物涂層的特點(diǎn)Excel支架內(nèi)雷帕霉素的釋放特征40％的Sirolimus在24h內(nèi)釋放，隨后長(zhǎng)時(shí)間緩慢釋放，3~6月完全釋放完畢Long-TermSafetyofDES:FutureDirectionsNoPolymerNoDrugAsymmetricBiodegradablePolymerHealingofEndotheliumSEMIMAGESOFPIGVESSELS@28DAYSPOSTDESIMPLANTExcelTM3個(gè)月內(nèi)皮細(xì)胞分布遠(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BMS3個(gè)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(nèi)膜面積(mm2)新生內(nèi)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