9/18/16

1

GreaterCincinna+AcuteStroke:AttheCu(ngEdge

PoojaKhatri,MD,MScProfessorofNeurology

DirectorofAcuteStrokeResearchUniversityofCincinnaD

RelevantIndustryDisclosure

•  TheUCDeptofNeurologyreceivesfundsfromGenentechformyeffortasLeadPIofthePRISMSTrial

TheLast50Years

•  1958:FirstIVthrombolysis

•  1974:ClinicalCTscans •  1983:Firstendovascularthrombolysis •  1995:IVrtPA •  1999:IApro-urokinase

•  2015:EndovascularTherapy

9/18/16

2

Pilot NINDS Trials

NINDSStudy

•  Double-blinded•  Placebocontrolled•  NIH-sponsored•  0.9mg/kgIVt-PA•  624paDents•  Treatmentwithin3hrs

–  1/2within90minutes–  1/2within91-180minutes

•  SubsequentIST3trialshowedefficacyoutto4.5hours

UCStrokeTeamCoverage•  16localhospitalsin-person

–  EMSbringsptstonearesthospital–  StrokeMDdrivestoalllocalhospitals–  Encouragepre-noDficaDon(priortoCT)–  Coordinatorgoesifpossibletrialcandidate–  StarDngtelemedicineatsomeofthese

•  8regionalhospitalstelemedicineonly–  Assessmentbytelemedicine–  Drip/shiptoUCMCforpost-tPAcare

•  Addi+onal~8regionalhospitals–  Assessmentbyphone–  Drip/shiptoUCMCforpost-tPAcare

•  ~3000consultaDoncallsin2015–  ~350treatmentsin2015–  ~100treatmentsin2004

9/18/16

3

IV Thrombolysis

Kleindorfer,Stroke2004,Adeoye,Stroke2011

IV Thrombolysis

JCAHOStrokeCtrs

IVrtPADRGbyCMS

Kleindorfer,Stroke2004,Adeoye,Stroke2011

ImprovedOutcomesbyIVrtPA

0:Nosymptomsatall1:Nosignificantdisabilitydespitesymptoms;abletocarryoutallusualduDesandacDviDes2:Slightdisability;unabletocarryoutallpreviousacDviDes,butabletolookacerownaffairswithoutassistance3:Moderatedisability;requiringsomehelp,butabletowalkwithoutassistance4:Moderatelyseveredisability;unabletowalkwithoutassistanceandunabletoadendtoownbodilyneedswithoutassistance5:Severedisability;bedridden,inconDnentandrequiringconstantnursingcareandadenDon6:Dead

NINDS,NEJM,1995

9/18/16

4

ImprovedOutcomesbyIVrtPA

0:Nosymptomsatall1:Nosignificantdisabilitydespitesymptoms;abletocarryoutallusualduDesandacDviDes2:Slightdisability;unabletocarryoutallpreviousacDviDes,butabletolookacerownaffairswithoutassistance3:Moderatedisability;requiringsomehelp,butabletowalkwithoutassistance4:Moderatelyseveredisability;unabletowalkwithoutassistanceandunabletoadendtoownbodilyneedswithoutassistance5:Severedisability;bedridden,inconDnentandrequiringconstantnursingcareandadenDon6:Dead

61%

NINDS,NEJM,1995

Intra-ArterialDrugDelivery

IllustraDonbyChristafordis,AJNR,2012

PROACTII(1996-1998)

•  SponsoredbyAbbodLaboratories,Inc.•  R-pro-urokinase+heparinvsheparinalone•  PosiDvetrial(n=180)

– mRS0-1of40%(ly+c)vs25%(p=0.04)•  FDAwanted2ndtrial;r-pro-UKnolongeravailable

Furlan,JAMA,1999

9/18/16

5

MERCIRetriever:FDA-ClearedonAugust11,2004

•  Single-armtrial(n=151)•  Treatmentstartedwithin8hours•  RecanalizaDonin46%(ITT)•  Devicescanalsoopenuparteries(FDAClearance)

Smith,Stroke,2005

MoreEffec+veDevices

2004

2007

2009

Revasculariza+onRatesImprove2004à2012

Fargen,JNIS,2012

9/18/16

6

Revasculariza+onRatesImprove2004à2012

Fargen,JNIS,2012

ButWereW

eMaking

Pa/entsB

e1er?

Endovascular Tx for IV-rtPA Treated Strokes: NIH-funded IMS III Trial (2006-2013)

IVtPAini+atedwithin3hoursNIHSS>/=10(or8-9withICA,M1,BAonCTA)Randomizedwithin40minofIVrtPAstart

Adjunc+veEndovascularTherapyStartby5hours,maxprocedureduraDonof2hours,

andcompleteby7hours

IVrtPAAlone

Broderick, NEJM, 2013

NIH-Funded IMS III Trial (2006-2012)

0

100

200

300

400

500

600

700

800

0 1 2 3 4 5 6

LastPa+entInApril17,2012

Year

FirstPa+entInSept26,2006

9/18/16

7

IMS III Trial Primary Result

� HaltedforfuDlityatn=656of900(4/18/12)

•  Nosafetyissues◦  sICH6.2%vs5.9%◦  Mortality19%vs22%

IV/Endovascular(n=434)

IVrtPAOnly(n=222)

mRS0-2(%) 177(40.8%) 86(38.7%)

CMHp-value0.70(adjustedforNIHSS8-19vs20+)

Broderick, NEJM, 2013

PhaseIIIItalianSYNTHESISandPhaseIININDSMRRESCUETrialswerealsonega?ve

Post-IMSIIIEra:TrialDesignConcepts

–  Bederdevices?•  MajorityMERCIdeviceorIAtPAonlyinIMSIII

–  Faster+mestoreperfusion?•  Faster=bederoutcomesinendovasculargroup

–  CTA+only?•  CTAnowmorewidespread,won’tlosemuchDme,concentratetreatmenteffect

– Worstclots?•  BylocaDonorlength

–  Imagingselec+on?•  BederprognosisiflessischemicchangeonCT

RandomizedEndovascularTrialsWorldwide

Khatri,Stroke,2015

9/18/16

8

DutchMRCLEAN–POSITIVERESULTS October22nd,2014

WorldStrokeCongressIstanbul,Turkey

CANADIANESCAPE&AUSTRALIANEXTEND-IATRIALSANNOUNCEDINTERIMANALYSESOFOVERWHELMINGEFFICACY

November7th,2014PICommunica+ons

HereWeAre:June,2015

TRIAL Enrolled Planned Results

MRCLEAN 500 500 NEJM12/17/14

ESCAPE 316 599 NEJM2/11/15

EXTENDIA 70 100 NEJM2/11/15

SWIFTPRIME 196 833 NEJM4/17/15

REVASCAT 206 690 NEJM4/17/15

THERAPY 108 692 ESOC4/2015

THRACE 412 480 ESOC4/2015

9/18/16

9

TimetoReperfusionMRCLEAN

ICAT,M1,andM2CaseswithoutReperfusion(10%;95%CI0.03-0.18)

ICAT,M1,andM2CaseswithReperfusionwith95%confidencebands(p=0.0045)

IMSIII

Fransen,ISC2015,abstract.Khatri,LancetNeurology,2014

MRCLEAN 332min

ESCAPE 241min

EXTEND-IA 248min

SWIFT-PRIME 252min

REVASCAT 355min

UCEndovascularProtocolTypicalEndovascularCandidate

•  Largevesselocclusion•  NIHSS≥6•  StartIAwithin6hoursofonset

– Andmoveasfastaspossible

•  Noupperagelimit–  If>80yrs,thenpaDentshouldbeindependentatbaseline

AccesstoEndoCareintheUS

Adeoye,Stroke,2014

9/18/16

10

AccesstoEndoCareintheUS

Adeoye,Stroke,2014

Byground,56%mayhaveaccesstoendovascular-capablehospitals(i.e.,performedsingleendocase).Byair,85%mayhaveaccesstoendovascularhospitals.LikelyanoveresDmate….

Regionaliza+onofAcuteStrokeCare

•  EMStriageofseverestrokestoComprehensiveStrokeCenters(CSCs)– How?

•  Needvalidateduserfriendlyscoringsystem•  Severalscoringsystemsatvariousstagesofdevelopment

–  RACE,LAMS,CSTAT,3ISS,PASS

– Tradeoffs?•  IVrtPADmetotreatmentvsendovascularDmetotreatment

FasterDTNTimes(<20minutes)

Meretoja,Neurology,2012

9/18/16

11

CURRENTANDUPCOMINGCLINICALTRIALSINCINCINNATI

TheCurrentCutngEdge

Selec+ngPa+entsforLaterTreatmentUsingPenumbralImaging?

Kidwell,Stroke,2013

DEFUSE3Trial

•  NIH-funded,Phase3trial//Thisisanewtrial!– NIHSS6+,largevesselocclusiononCTA– 6-16hoursfromlastknownwell– TesDngendovasculartxvsstandardmedmgmtinpaDentswithpenumbraonstudy-specificCTP

•  LocalPIsAchalaVagalandAndyRinger;Coordinator:CindyWerner

9/18/16

12

NIHStrokeNET•  UniversityofCincinnaDhousesthenaDonalclinicalcoordinatorcenter(NCC)forallmulDcentertrialsfundedbyNIH–  PI:Broderick,Co-PIs:Khatri,Chimowitz,Cramer;ProgramManagers:Spilker,Frasure

•  AlsoleadstheregionalcoordinaDoncenter(RCC)forbringingNIH-fundedtrialstothemetropolitanregion–  PIs:Khatri,Kleindorfer;ProgramMgr:EmilyGoodall

NINDSStudyBaselineNIHSSvsFavorableOutcome

0

20

40

60

80

100

0-5 6-10 11-15 16-20 >20

Percen

tfavorab

leoutcome

BaselineNIHSS

t-PA

Placebo

Ingall,Stroke,2004

NINDSStudyBaselineNIHSSvsFavorableOutcome

0

20

40

60

80

100

0-5 6-10 11-15 16-20 >20

Percen

tfavorab

leoutcome

BaselineNIHSS

t-PA

Placebo

n=5816placebo,81.3%goodoutcome(95%C.I.54-96%)42IVrtPA78.6%goodoutcome(95%C.I.63-90%)

Nointerac/onbystrokeseveritybutmildstrokeswerelargelyexcluded

Ingall,Stroke,2004

9/18/16

13

CurrentGuidelinesReflectCurrentStateofEvidence

IVrtPAforMildStroke?

Clinicaltrials.gov--NCT02072226

PRISMSTrial:PhaseIIIbStudyPopulaDon ≥18yearswithmildstroke(NIHSS≤5andnotclearly

disabling)abletoreceivetPAwithin3hours

ScheduleandDose tPA0.9mg/kgover60min(ASA325mgplaceboarm)

SponsorLeadPILocalPICoordinator

Genentech,Inc.(academic-industrypartnership)KhatriKleindorferWerner

Optimal Glucose Management?

� Hyperglycemia(>140mg/dL)duringthefirst24hoursacerstrokeisassociatedwithpooroutcomes

� CurrentAHAGuideline◦  Reasonabletotreathyperglycemiatogoalof140to180mg/dL)

ClassIIa,LevelofEvidenceC

� Tightercontrolofbenefit?SHINETrial

9/18/16

14

Optimal Antiplatelet Therapy?

� AllpaDentsshouldbestartedonaspirin(325mg)within48hours◦  Youwillprevent1recurrentstrokeoverthetwoweeksaceracuteischemicstrokeforevery100paDentsyoutreat(CAST,IST)

AHAClassI,LevelofEvidenceA

� EarlyASAandclopidogrelinTIA/mildstroke?

MoreEfficaciousIVThrombolysis?

•  PriorstudiescombiningeptafibaDdeandrtPA:– CLEAR– CLEAR-ER– CLEARFDR

•  Trialindevelopment– MOSTTrial(LeadPI:Adeoye)

EvenSafer,MoreEffec+veDevicesOntheWay?

FDA-CLEARED EXAMPLESOFPIPELINE….

MERCI RETRIEVER 2004

PENUMBRA ASPIRATION 2007

SOLITAIRE STENT RETRIEVER 2009

TREVO STENT RETRIEVER 2009

PENUMBRA 3D SEPARATOR

NEURAVI EMBO TRAP

MEDTRONIC LAZARUS COVER

9/18/16

15

Neuroprotec+on?

•  Canweprotectbrainfromischemicinjury?

EvenSafer,MoreEffec+veDevicesOntheWay?

FDA-CLEARED EXAMPLESOFPIPELINE….

MERCI RETRIEVER 2004

PENUMBRA ASPIRATION 2007

SOLITAIRE STENT RETRIEVER 2009

TREVO STENT RETRIEVER 2009

PENUMBRA 3D SEPARATOR

NEURAVI EMBO TRAP

MEDTRONIC LAZARUS COVER

EvenSafer,MoreEffec+veDevicesOntheWay?

FDA-CLEARED EXAMPLESOFPIPELINE….

MERCI RETRIEVER 2004

PENUMBRA ASPIRATION 2007

SOLITAIRE STENT RETRIEVER 2009

TREVO STENT RETRIEVER 2009

PENUMBRA 3D SEPARATOR

NEURAVI EMBO TRAP

MEDTRONIC LAZARUS COVER

9/18/16

16

PreventMalignantEdema?

Conclusions

•  TheCincinnaDregionhasplayedacriDcalroleinthedevelopmentofcurrentacutestroketherapies–  IVrtPAwithin4.5hoursoflastknownwell–  Endovasculartherapywithin6hoursoflastknownwell

•  TheregionconDnuestodevelopnewtherapiesthroughclinicaltrials– DEFUSE-3,StrokeNET,PRISMS,SHINE,POINT,RHAPSODYongoing

Reminder:WhentoCallStrokeTeam

•  Callstroketeamforallstrokes<12hoursfromDmethatpaDentwas“lastknownwell”

•  CallusforallTIAsandstrokes,nomaderhowmildthedeficitsmayseem

•  Preno+fyusbeforegetngtheCT/CTAscanresults

513-844-7686

9/18/16

17

ThankYou!