TheRESCUEBRAINstudy:AFrenchmulticenterrandomizedtrialonneuroprotectionwithlowerlimb
ischaemicper-conditioningintheacutephaseofcerebralinfarction(<H6)
F Pico, B Lapergue, M Ferrigno, ML Chadenat, F Bourdain, E Meseguer, M Obadia, C Hirel , DLDuong,SDeltour,CRosso,PAegerter,JLabreuche,ACattenoy,DSmadja,HHosseini,BGuillon,VWolff,YSamson,CCordonnier,PAmarenco,onbehalftheRESCUEBRAINinvestigators
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TheuniquesourceoffundingisagrantfromtheFrenchMinistryofHealth(PHRC).Therewasnoindustryfundingorinvolvementinanyaspectofthetrial
• Thereisaneedforneuroprotectiveagent.
• Ischemicconditioning:transientischemiawithoutnecrosis.Endogenousmechanism
• Ingoodqualitypreclinicalstudiesinbraininfarction(STAIRrecommendation):positiveresultsØ RIPerCeffectivealone.AdditiveeffectwithrTPainamurinemodelofembolicstroke(Hodaetal.Stroke2012)
• Promisingresultsincardiologyinmyocardialinfarction:Ø Botkeretal.Lancet2010,CONDI2Largeongoingtrial(n=5400).Nosafetyissue
BACKGROUND
ToevaluateifremoteischemicPer-Conditionning(RIPerC)intheunaffected
lowerlimb,performedinthefirst6hoursofcerebralinfarctionreducesthe
growthofthebraininfarction
OBJECTIVE
• RESCUEBrainisaninterventional,randomized,multicentertrialwithPROBEdesign
• (ProspectiveRandomizedOpen,BlindedEnd-point)
• Sourceoffunding:PHRCIR2014-A00104-43(MinistryofHealth)
• ApprovedbytheInstitutionalReviewBoard(IRB)(IledeFranceXI,approvalnumber14023).
• ClinicalTrials.govIdentifier:NCT02189928
• DesignpublishedinIntJStroke.2016Oct;11(8):938-943.
• RandomizationhasbeenstratifiedonthecenterandonIVthrombolysis.(Draftin2013)
• MechanicalthrombectomywasallowedfollowingIVthrombolysis(Draftin2013)
• Interimanalysisathalfrecruitment(n=102patients)
DESIGN
Patientsintheinterventiongroup:• Cuffisplacedinthethigh(unaffectedside)• TargetinflationBP=110mmHgabovesystBP• Electronictourniquetisprogramtodeliver• 4cyclesof5mininflation• With4cyclesofdeflationinbetween• Totalduration=40minutes
PrimaryEndpoint:• DWIvolume(cc)H24-Baseline(<H6)• CentrallabforlectureofbrainMRI,
blindedtoclinicaldata,dateofMRI.
Maininclusioncriteria:• patientswithcarotidBI• provenbybrainMRI<H6• NIHSSscore:5and25.
DESIGN
I:5’ D:5’ I:5’ D:5’ I:5’ D:5’ I:5’ D:5’
PatientsintheControlgroup:• Thecuffisplacedbutnoinflation
RDWI<H6 DWIH24
(H24-H36)
• H24NIHSS• D7:NIHSS• M3:Rankin
RESCUEBRAINNetwork11Frenchstrokecenters(7inParisarea)
BrainMRIDrRossoDrHirel
PrAmarenco DrMeseguer
DrPiotinDrObadia
PrSamsonDrDeltourPrHosseini
DrGuillon
PrWolff
PrCordonnier DrFerrigno
PrSmadja
PrPico DrChadenat
DrLapergue DrConsoli
DrRonzière
FLOWCHART
Baselinedemographics
andmedicalhistory
Overall
(N=188)
rIPerC
(N=93)
Control
(N=95)
Age,years,mean(SD) 67.2(15.7) 67.8(15.1) 66.7(16.4)
Men 98/188(52.1) 45/93(48.4) 53/95(55.8)
BMI,Kg/m2,mean(SD)1 26.3(5.4) 26.2(5.1) 26.5(5.8)
Medicalhistory
Hypertension 98/188(52.1) 48/93(51.6) 50/95(52.6)
Diabetes 30/188(16.0) 12/93(12.9) 18/95(19.0)
Hypercholesterolemia 72/188(38.3) 32/93(34.4) 40/95(42.1)
Currentsmoking 30/179(16.8) 14/88(15.9) 16/91(17.6)
Coronaryarterydisease 24/188(12.8) 12/93(12.9) 12/95(12.6)
PreviousstrokeorTIA 24/188(12.8) 11/93(11.8) 13/95(13.7)
Previousatrialfibrillation 32/188(17.0) 18/93(19.4) 14/95(14.7)
BASELINECHARACTERISTICS
CurrentstrokeeventOverall
(N=188)
rIPerC
(N=93)
Control
(N=95)
AdmissionNIHSSscore,median(IQR) 10(6to16) 9(6to15) 10(7to17)
OnsettobaselineMRItime,min,median(IQR) 104(82to145) 105(81to147) 103(83to142)
OcclusionatMRI
None 59/188(31.4) 30/93(32.3) 29/95(30.5)
MCA 94/188(50.0) 45/93(48.4) 49/95(51.6)
CervicalICA 6/188(3.2) 6/93(6.4) 0/95(0.0)
CarotidT 11/188(5.9) 6/93(6.4) 5/95(5.3)
Others 18/188(9.6) 6/93(6.4) 12/95(12.6)
Baselinebraininfarctvolume,cm3,median(IQR)3 11.4(3.6to35.8) 10.2(3.4to38.7) 12.2(3.7to32.3)
BASELINECHARACTERISTICS
TreatmentsofcurrentstrokeeventOverall
(N=188)
rIPerC
(N=93)
Control
(N=95)
IVthrombolysis 164/188(87.2) 82/93(88.2) 82/95(86.3)
OnsettoIVthrombolysistime,min,median(IQR) 149(111to179) 154(111to186) 145(112to175)
Endovasculartreatment 64/188(34.0) 30/93(32.3) 34/95(35.8)
Onsettogroinpuncturetime,min,median(IQR) 187(145to247) 187(130to250) 182(150to245)
OnsettorIPerCtime,min,median(IQR) - 222(176to275) -
BASELINECHARACTERISTICS
• 87%ofpatientshavebeentreatedbyI.V.thrombolysiswithamediantimeof2h30• 34%patientshavebeentreatedbyendovasculartreatmentwithamediantimeof3h10• ConcerningrIPerCthemediantimebetweenstrokeonsetandcuffinflationwas3h40.
BrainMRIVolume rIPerC(n=93) Control(n=95) P-Value
ITTanalysis
Baseline,median(IQR) 9.3(3.4to38.3) 12.2(3.7to32.3)
24-hours,median(IQR) 13.0(3.2to54.7) 18.8(4.9to66.7)
Mean(loge)change(95%CI) 0.30(0.11to0.48)2 0.37(0.19to0.55) 0.57
PPanalysis
Baseline,median(IQR) 9.1(3.3to37.9) 12.1(3.8to32.0)
24-hours,median(IQR) 13.0(3.6to45.4) 18.5(4.8to60.0)
Mean(loge)change(95%CI) 0.30(0.12to0.49)2 0.33(0.14to0.51) 0.86
PRIMARYENDPOINT
rIPerC(n=93) Control(n=95) P-Value
%changeinBIvolumeat24-hours,median(IQR)1 36.5(-7.3to98.1) 34.1(-11.0to106.4) 0.80
ChangeNIHSSscoreat24-hours
Baseline,median(IQR) 9(6to15) 10(7to17)
24-hours,median(IQR) 5(2to9) 7(2to12)
Mean(loge)change(95%CI) -0.59(-0.75to-0.43) -0.51(-0.67to-0.35) 0.48
SuccessfulrecanalizationinIV-treatedpatients 62(75.6) 65(79.5) 0.65
90-dayBathel≥95 61(67.2) 56(61.3) 0.41
90-daymRs0-1 44(48.6) 37(40.3) 0.26
90-daymRs,median(IQR) 2(1to3) 2(1to3) 0.35
SECONDARYENDPOINT
SAFETY Withatleastonecycleof
deflation/inflation
Yes(n=94) No(n=94) P-Value
SymptomaticIntracerebralhemorrhage 4/88(4.6) 4/88(4.6) 0.97
90-dayAll-causemortality,n(%) 14(15.8) 10(10.4) 0.45
Pain(VAS)duringper-conditioningischemicprocedure
>0 41/78(52.6) - -
Median(IQR)
(DatareportedforonlyforpatientswithVAS>0)6(3to7) - -
PerCIDrelatedevent:• Noacutelimbischemia• Nodeepvenousthrombosis
• PreviousRCTonrIPerCinacuteStroke(KDHougaardetal.Stroke2014)GAndersen,AarhusUniversityDenmark– Prehospitalsetting:64and57patientsanalyzedwithpostrIPerCMRI(DWIandPWI)
– LowNIHSS=4andsmallvolume1cc.
– NeutralbutposthocvoxelanalysessuggestrIPerCcanbebeneficial
DISCUSSION
Name Country(PI) n Patients Intervention Intervention Outcomes
RESIST Denmark(RABlauenfeldt)
1500 AISHIC
• PreHosp• NonpareticArm
• InHospH6• D1-D7=*2/d
mRS2022
REMOTE-CAT Spain,Catalonia(FPurroyGarcia)
575 AIS • PreHosp<H8• NonpareticArm
• Once mRS2022
RECAST-2 UnitedKingdom(TEngland)
120 AIS • InHosp• Nonpareticarm
• D1-D4*2/d Feasibility2018
TRIPCAIS China(AJiaqi)
120 AISrTPA • InHosp• Nonpareticarm
• OnceafterIVthrombolysis
2020
REPOST Netherlands(TLandman)
200 AIS • InHosp• Nonpareticarm
• Twiledaily Infarctsize
• 5ongoingtrialonrIPerCinAIS:2inPrehospitaland3withmultiplecycleofperCID
CONCLUSION
RESCUEBRAINisaneutralRCTevaluating
inhospitalremoteischemicperconditioningatlowerlimb
withinthe6firsthoursofprovenischemicstroke
ontoponIVthrombolysisandmechanicalthrombectomy
Acknowledgements
Center(numberofpatientsincluded)VERSAILLESHOSPITAL(n=48)PrPICO,DrCHADENAT,DrDUONGetal.FOCHHOSPITAL(n=42)DrLAPERGUE,DrBOURDAIN,DrCONSOLI,etal.LILLEHOSPITAL(n=28)PrCORDONNIER,DrFERRIGNOetal.BICHATAP-HP(n=18) PrAMARENCO,DrMESEGUERetal.SALPETRIEREAPHP(n=15)PrSAMSON,DrROSSO,DrDELTOURetal.CHSUDFRANCILIEN(n=15) PrSMADJA,DrCHAUSSON,DrAGHASARYANetal.ROTSCHILDHOSPITAL(n=11)DrOBADIA,DrPIOTIN,DrFISSELIERetal.MONDORAPHP(n=5) PrHOSSEINI,DrMAJHAIetal.NANTESHOSPITAL(n=3)DrGUILLON,DrSEVINetal.STRASBOURGHOSPITAL(n=3)PrWOLFFetal.RENNESHOSPITAL(n=0)DrRONZIEREetal.
VERSAILLESCLINICALRESEARCHUNIT:• MsMORISSET• MsCATTENOY,MsROUX• MsLEFEVRE,MrTURBE
PARISOUESTCLINICALRESEARCHUNIT• PrAEGERTER(Methodologist)• MsAZERAD(DataManager)• MsNKAM(Statistician)
DSMB:• PrALAMOWITCH(Paris)• PrOLIVOT(Toulouse)• MsCOZIC(Paris)
BRAINMRILecturegroup:• DrCROSSO(BRAINANDSPINEINSTITUTE)• DrCHIREL(VERSAILLESHOSPITAL)
Patientsandtheirfamilies
LILLEBIOSTATISTICDEPARTMENT• PrDUHAMEL• MrLABREUCHE(Statistician)