Highdiagnos+cperformanceofRb-PETascomparedto99mTc-MIBIwithCZTgammacamerasfordetec+onofCADinwomenand

overweightpeople

FabienHyafil;RenataChequer;EmmanuelSorbets;CandiceEstellat;FrançoisRouzet;ToniAlfaiate;HamzaRegaieg;MilanMilliner;SébasAenLeygnac;Pierre-YvesMarie;DominiqueLeGuludec

1.AP-HP,BichatUniversityHospital,DepartmentofNuclearMedicine,UniversityDiderot,Paris,France.2.INSERM,U-1148,DHUFIRE,UniversityDiderot,Paris,France.3.AP-HP,AvicenneUniversityHospital,DepartmentofCardiology,UniversityParis13,Bobigny,France.4.AP-HP,BichatUniversityHospital,DepartmentofCardiology,Paris,France5.AP-HP,HôpitalBichat,URCParisNord,Paris,France6.BramboisUniversityHospital,DepartmentofNuclearMedicine,LorraineUniversity,Vandœuvre-lès-Nancy,France

Disclosureslide

ü  Noconflictofinterest,norfinancialdisclosureinrelaAontothispresentaAon.

ü  ThisstudywasfullysupportedbyagrantfromtheFrenchMinistryofHealth(PHRC2011AOM11066).

ü  FHisadvisorforNaogen.

ü  WomenandobesepaAentsconsAtuteagrowingproporAonofpaAentsreferredforthedetecAonofCAD.

ü  Image quality is oden lower in women and obese paAents than in the generalpopulaAon.

ü  Clinical studies focusing on the diagnosAc performance of imaging test for thedetecAonofCADinthesegroupsofpaAentsare,however,scarce.

Detec+onofCADinwomenandobesepa+ents

TheGBD2015ObesityCollaborators.NEJM2017.

The2005-2010NaAonalHealthandExaminaAonSurvey.

ü  Inthepast10years,newgeneraAonsofSPECTandPETsystemshavebecomeavailableforcardiacscinAgraphy.

ü  CZTgammacamerasofferadramaAcincreaseinmyocardialcountratevs.Na/Icameras and could improve image quality in women and obese paAentssubjectedtoimportantsignalalenuaAon.

ü  82Rb-PETacquisiAons ina3DmodeprovideMPS imageswithhighsignalandaccuratealenuaAoncorrecAonandoffertoquanAfymyocardialbloodflow.

Background:CZTSPECTcamerasand3DPETsystems

Objec+vesoftheRUBIStrial

Primaryobjec+ve:tocompareinapopulaAonofwomenandoverweightindividualsthe diagnosAc performance for the detecAon of myocardial ischemia of Tc-MPS-SPECT inassociaAonwith thebeststress feasible (exercisewasprioriAzed)andRb-PET-MPSinassociaAonwithpharmacologicalstress.

Secondaryobjec+ves:

-thequalityandcertaintyofimageinterpretaAon

-  tocomparetheperformanceofTc-MPS-SPECTandRb-PET-MPSfor thedetecAonofbalancedmyocardialischemiainpaAentswiththree-vesselCAD

-  theradiaAonexposureassociatedwitheachimagingtechnique.

DesignofthestudyIRBapprovalnumber:2012-A00552-41Clinicaltrials.gov:NCT01679886

StressprotocolExerciseandcombinedtests(associaAonwithdipyridamole)wereprioriAzed.Pharmacologicalstressconsistedofastandardinfusionofdipyridamoleduring4minutes(0.7mg/kg).Radionuclideprotocol.ThechoiceofacquisiAonprotocol(onedayortwo-day)wasledatthephysician’sdiscreAon.Onedayprotocol:3MBq/kgofTc-sestamibiatstressand9MBq/kgofTc-sestamibi;Twodaysprotocol:7MBq/kgofTc-sestamibiIfstress-firstimagesdemonstratednormalstressECG,perfusionandLVEF,restimagingwasnotperformed.Imageacquisi6on.All acquisiAonswereperformedonaCZT cardiac-centered camera (D-SPECT; SpectrumDynamics).DuraAonofacquisiAonwasintherangebetween3and15minutes.Imagereconstruc6on.StaAcandgatedimagereconstrucAonswerereconstructedwithaspecificmethodofiteraAvereconstrucAontocompensateforcollimator-relatedlossinspaAalresoluAon.

Tc-SPECT-MPSacquisi+onprotocol

StressprotocolPharmacologicalstressconsistedofastandardinfusionofdipyridamoleduring4minutes(0.7mg/kg).RadionuclideprotocolForeachPETacquisiAon,paAentswereinjectedintravenouslywith10MBq/kg(minimaldose=740MBq;maximaldose=1480MBq)ofRb.Imageacquisi6onAll paAentswere studiedusing awhole-bodyPET-CT scanner. PET acquisiAonswere acquired in 3Dmodeand listmode;duraAonofacquisiAons :8minutes.AlenuaAoncorrecAonofPETacquisiAonswasperformedusinga low-doseCTbeforetherestandaderthestressacquisiAons.Imagereconstruc6onDynamicPETacquisiAonswerereconstructedusingFBPinto15Ameframes(9×10s,3×30s,1×60s,and2×120s;total,8min).StaAcandgatedPETimageswerereconstructedwithacquisiAonsbetween2and8minpostinjecAonusinganOSEMalgorithm(4iteraAons,24subsets).

Rb-PET-MPSacquisi+onprotocol

ü 311paAents(143women)wereincluded.

ü MeanBMIofpaAentswas31.8±6.5with41%ofpaAentswithBMI>30.

ü 31%paAentsweresymptomaAc;averagenumberofCVriskfactors:3;77%ofdiabeAcpaAents.

Results:popula+onofthestudy

82Rb-PET-CT

Abnormal Normal

99mTc-M

IBI-

SPEC

T Abnormal 37 16

Normal 19 236

Pa+entsincludedinthestudy(n=311)3paAentswithnoninterpretablePETwereexcludedfromtheanalysis.12pa&entswithabnormalSPECTorPETcouldnotbeevaluatedwithcoronaryangiography

Coronaryangiography(n=63)Abnormal(n=35)Normal(n=28)

NocoronaryangiographyFollow-upat1year(n=231)includingtwopaAentswithCVeventsLostatfollow-up(n=2)

Diagnos+cperformanceofTc-SPECT-MPSvs.Rb-PET-MPS

99mTc-MIBICZT 82Rb-PET-CT1stanalysis(n=296pa&ents)

Women(n=142pa&ents)

SensiAvitySpecificityAcccuracy

SensiAvitySpecificityAcccuracy

2ndanalysis(n=308pa&ents)

BMI>35(n=76pa&ents)

55.6 % 95.7%90.8%

83.3%93.4%92.2%

p=0.02p=0.22

59.5 % 94.4%89.6%

80.9%92.8%91.2%

p=0.04p=0.46

SensiAvitySpecificityAcccuracy

51.8 % 97.3%93.9%

77.1%94.7%93.4%

p=0.18-0.41p=0.21-0.37

SensiAvitySpecificityAcccuracy

68.0 % 97.6%93.9%

89.3%90.1%90.0%

p=0.32p=0.06

Comparisonofimagequalityanddiagnos+ccertainty

Imagequality Excellentorgood 80.4% 89.6% p<0.05

Diagnos+ccertainty Excellentorgood 80.4% 89.6% p<0.05

99mTc-MIBICZT 82Rb-PET-CT

99mTc-MIBICZT 82Rb-PET-CT

Results:detec+onof3-vesseldiseaseorequivalent99mTc-MIBI-SPECT-MPS

82Rb-PET-MPS

Stress

Rest

Stress

Rest

Stress

Rest

Stress

Rest

EDV:86mlESV:39mlLVEF:55%

Rest

StressMBF MFR

Stress

EDV:136mlESV:76mlLVEF:44%

EDV:90mlESV:37mlLVEF:59%

RestStressEDV:102mlESV:41mlLVEF:59%

Results:detec+onof3-vesseldiseaseorequivalentDiff.LVEDvol.stress/rest-Tc-SPECTvs.Rb-PETThreshold≥15mlvs.18mlAUC=0.68vs.0.75Se=44%vs.63%Sp=88%vs.81%

Diff.LVEFstress/rest-Tc-SPECTvs.Rb-PETThreshold≤-2vs.0%AUC=0.68vs.0.82Se=75vs.75%Sp=59%vs.83%

Rb-PET–globalstressMBFThreshold≤1.57ml/mn/gAUC=0.87Se=94%Sp=70%

Rb-PET–globalMFRThreshold≤2.0AUC=0.85Se=88%Sp=73%

GlobalstressMBF≤1.57ml/mn/g+Diff.LVEF≤0%Se=75%Sp=95%Acc.=93%

GlobalMFR≤2.0+Diff.LVEF≤0%Se=69%Sp=94%Acc.=93%

Quan6fica6onofmyocardialbloodflowwithRb-PET

Results:radia+onexposureofpa+entswithTc-SPECTvs.Rb-PET-CT

Conclusionsü  Rb-PET-MPS provided higher sensiAvity for the detecAon of myocardialischemiaincomparisontoTc-SPECT-MPSthanksto:

-  alenuaAon correcAon of PET acquisiAons in this populaAon of paAentswithimportantsignalalenuaAonofSPECT.

-  amoreaccuratedetecAonofpaAentswiththree-vesselCAD.

ü  RadiaAonexposureofpaAentswasca.50%lowerwithRb-PET-MPSthanwithTc-SPECT-MPS.

ü  The difference in diagnosAc performance between both imaging techniqueswere smaller than anAcipated because of the lower prevalence of CAD in thepopulaAonofthestudyandtheinterpretaAonofSPECTacquisiAonsbyexperts.

=>Rb-PET-MPSshowspromisefortheidenAficaAonofpaAentswith3V-CAD.

AcknowledgementsBichatUniversityHospital,ParisDepartmentofNuclearMedicineDominiqueLeGuludecRenataChequerSébasAenLeygnacMilanMillinerFrançoisRouzetAzizaTouaARanaBenAzzounaSouadBaniDepartmentofCardiologyEmmanuelSorbetsGrégoryDucrocqJérémyAbtan

DepartmentofDiabetologyMichelMarreRonanRousselDepartmentofClinicalResearchCandiceEstellatCarolineQuinAnToniAlafaiateBeaujonUniversityHospitalDepartmentofNuclearMedicineArnaudDieudonnéNidaaMikail

This studywas fully supported by the Programme de Recherche Clinique Hospitalier (PHRC) 2010 funded by theFrenchMinistry for Research and promoted by the Département de la Recherche Clinique et de Développement(DRCD)ofAssistancePublique–HôpitauxdeParis.PaAentswhoacceptedtoparAcipateinthisstudy.

Pi+é-SalpêtrièreUniversityHospitalDepartmentofCardiologyGillesMontalescotJohanneSilvainDepartmentofDiabetologyAgnèsHartemannNancyUniversityHospitalDepartmentofNuclearMedicinePierre-YvesMarieWassillaDjaballahLaeAAaImbertVéroniqueRoch

Imageanalysis

AnalysisofMPS.Experiencednuclear cardiologists analyzed Tc-MPS-SPECT andRb-MPS-PET studies separately andblindedtotheresultsofeachanother.EachTc-MPS-SPECTandRb-PET-PETwasclassifiedasposiAveornegaAveaderintegraAngallclinicalandimaginginformaAonavailable,includingmyocardialwallmoAonandglobalLVfuncAonforSPECTandPET,andflowquanAficaAononlyforPET.Stressand restmyocardialbloodflow (MBF)werequanAfiedondynamicPETacquisiAonsusingaone-compartmentmodelforRbuptakeinthemyocardiumintegratedintheFlowQuantsodware.ImagequalityanddegreeofdiagnosAccertaintyofinterpretaAonwereclassifiedasexcellent,good,fairorpoor.

StudyendpointcriteriaCoronaryangiography.Coronaryangiographywasperformedusingstandardtechniquewithin45daysaderpaAent inclusion.Thedegreeofcoronarystenosiswasevaluatedvisually.FFRwasmeasuredforeach coronary stenosis > 50%with a pressure guidewire duringmaximal hyperemia induced by anintravenousinfusionofadenosine.FFRvaluewasmeasuredforeachstenosisalongcoronaryarteriesattheexcepAonofcriAcalstenosis(>70%)thatdidnotallowformeasurementofFFRorocclusion.Attheend of the study, all coronary angiograms including FFR results were reviewed by two experiencedcardiologists blinded to the results of Tc-SPECT-MPS and Rb-PET-MPS. In case of discrepancy, theangiogram was reviewed with a third cardiologist to reach consensus. PaAents were classified asposiAve for myocardial ischemia in presence of coronary stenosis > 50% and FFR ≤ 0.8, coronarystenosis>50%fortheledmainartery,stenosis>70%orvesselocclusionforothervessels.Follow-up. PaAent outcome was determined one year ader inclusion by a pre-scripted telephoneinterview and, in case of clinical events, medical records were collected to idenAfy cardiovascularevents. Medical records were reviewed by a commilee formed of two cardiologists blinded to theresults of imaging. PaAentswere classified as posiAve formyocardial ischemia if theyhadpresentedduring the following year unexplained cardiovascular death, acute coronary syndrome or a coronaryangiogramshowingasignificantcoronarystenosisasdefinedperprotocol.

PaAentswererecruitedfromOctober2012toDecember2014intwocentresinFrance(BichatUniversityHospital,ParisandNancyUniversityHospital,Vandoeuvres-lès-Nancy).PaAentswereeligibleforinclusioninthestudyiftheymetthethreefollowingcondiAons:1.pa+entreferredforclinicallyindicatedSPECT-MPS.2.adultwoman,ormanwithbodymassindex(BMI)≥25.3.pre-testintermediateprevalenceofCAD(inpaAentswithchestpain,esAmatedprevalenceofCAD>30%withtheDiamondandForresterclinicalscore14or,inabsenceofchestpain,presenceof≥3cardiovascularriskfactors).PaAentswerenoteligibleinthestudyiftheyhadknownCADorcardiomyopathy,undergoneinvasivecoronaryangiography(CA)orcoronarycomputedtomographyangiographyinthepasttwoyearsbeforeinclusion,contra-indicaAontotheinjecAonofdipyridamole,severerenalinsufficiency(plasmaAccreaAnine>200µmole.l-1),lifeexpectancy<2years,anAcipatedpoorfollow-up,potenAalpregnancy.TheFrenchInsAtuAonalReviewBoardapprovedthestudyprotocol(IRBnumber:2012-A00552-41);allpaAentsprovidedsignedinformedconsent;thefulldescripAonofthestudydesignhasbeenregisteredonclinicaltrials.gov(NCT01679886).

Methods:pa+entselec+on

3-vesseldiseaseorequivalent

(n=13)

1-and2-vesseldisease(n=21)

Stenosis<50%orabsenceof

stenosis(n=29)

NormalSPECTandPET,noCVevent(n=295)

Tc-SPECT-MPS Diff.EDVstress/rest 11±14ml 2±12ml 3±15ml 0±11mlDiff.ESVstress/rest 10±13ml 2±9ml 4±8ml 0±8mlLVEFstress 52±11% 58±10% 56±12% 63±8%LVEFrest 56±11% 59±8% 58±12% 62±8%Diff.LVEFstress/rest -3±5% -1±8% -2±6% 1±7% Rb-PET-MPS Diff.EDVstress/rest 26±19ml 13±11ml 10±10ml 9±10mlDiff.ESVstress/rest 22±22ml 2±7ml 1±7ml -2±7mlLVEFstress 46±13% 59±8% 58±12% 64±8%LVEFrest 53±9% 54±9% 55±12% 57±9%Diff.LVEFstress/rest -7±10% 4±5% 3±6% 7±6%GlobalrestMBF(ml/mn/g)correctedforworkload

0.8±0.2 0.8±0.3 0.8±0.2 0.8±0.3

GlobalstressMBF(ml/mn/g) 1.1±0.3 1.5±0.7 1.9±0.6 2.1±0.7

GlobalMFRvalue 1.6±0.4 2.0±0.6 2.6±0.9 2.7±0.9

StudyendpointsCoronaryangiography.Coronaryangiographywasperformedusingstandardtechniquewithin45daysaderpaAent inclusion.Thedegreeofcoronarystenosiswasevaluatedvisually.FFRwasmeasuredforeach coronary stenosis > 50%with a pressure guidewire duringmaximal hyperemia induced by anintravenousinfusionofadenosine.AllcoronaryangiogramsincludingFFRresultswerereviewedbytwoexperiencedcardiologistsblindedtotheresultsofTc-SPECT-MPSandRb-PET-MPS. Incaseofdiscrepancy,theangiogramwasreviewedwithathirdcardiologisttoreachconsensus.PaAentswereclassifiedasposiAveformyocardialischemiainpresenceofcoronarystenosis>50%andFFR≤0.8,coronarystenosis>50%fortheledmainartery,stenosis>70%orvesselocclusionforothervessels.Follow-up. PaAent outcome was determined 1 year ader inclusion by a pre-scripted telephoneinterviewand,incaseofclinicalevents,medicalrecordswerecollectedtoidenAfyCVevents.Medicalrecordswerereviewedbyacommileeformedoftwocardiologistsblindedtotheresultsof imaging.PaAentswereclassifiedasposiAveformyocardialischemiaiftheyhadpresentedduringthefollowingyear unexplained CV death, ACS or a coronary angiogram showing a significant coronary stenosis asdefinedperprotocol.

Conclusionsü  In a populaAon of women and overweight paAents with high prevalence ofalenuaAon arAfacts, Tc-SPECT with CZT cameras was associated to an importantheterogeneityofperfusionimagesthatrequiredanon-automatedanalysisofMPS.

ü  Rb-PET-MPS inassociaAontoapharmacologicalstressprovidedhigherdiagnosAcperformanceforthedetecAonofmyocardial ischemiathanTc-SPECT-MPSwithCZTcamerainassociaAontoopAmizedstressprotocols.

ü Thepreciseroleandthemedico-economicimpactofRb-PET-MPSforthedetecAonofmyocardial ischemiainthisspecificpopulaAonwillneedtobeassessedinfuturestudiesincludingalargernumberofpaAents.

Limita+onsofthestudy

ü  PaAentswith both normal Tc-SPECT-MPS and Rb-PET-MPS did not undergo invasivecoronaryangiography.

⇒ Possibleunder-esAmaAonofthenumberoffalsenegaAvesandthusover-esAmaAonofsensiAvityvaluesforbothTc-SPECT-MPSandRb-PET-MPS.SensiAviAeswerefoundtobelowerthantheonespublishedinformersimilarstudies.

ü  Thelowerprevalenceofmyocardialischemiaobservedinthisstudythanexpecteddidnot provide adequate staAsAcal power for the comparison of the diagnosAcperformance of Rb-PET-MPS and Tc-SPECT-MPS in the pre-specified sub-groups ofwomenandoverweightindividuals.

ü  NoalenuaAoncorrecAonofSPECTimageswasperformedwithCZTcameras.