Comparison of the Captopril and the Saline Infusion Test for ...

Available confirmatory tests are composed of the oral sodium loading test, the saline infusion test (SAL), the captopril test (CAPT), or the fludrocortisone ... HomeHypertensionVol.50,No.2ComparisonoftheCaptoprilandtheSalineInfusionTestforExcludingAldosterone-ProducingAdenoma FreeAccessResearchArticlePDF/EPUBAboutViewPDFViewEPUBSections ToolsAddtofavoritesDownloadcitationsTrackcitationsPermissions ShareShareonFacebookTwitterLinkedInMendeleyRedditDiggEmail JumptoSupplementaryMaterialsFreeAccessResearchArticlePDF/EPUBComparisonoftheCaptoprilandtheSalineInfusionTestforExcludingAldosterone-ProducingAdenomaGianPaoloRossi,AnnaBelfiore,GiampaoloBernini,GiovambattistaDesideri,BrunoFabris,ClaudioFerri,GilbertaGiacchetti,ClaudioLetizia,MauroMaccario,FrancescaMallamaci,MassimoMannelli,GaetanaPalumbo,DamianoRizzoni,ErmannoRossi,EnricoAgabiti-Rosei,AchilleC.Pessina,FrancoManteroGianPaoloRossiGianPaoloRossiFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,AnnaBelfioreAnnaBelfioreFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,GiampaoloBerniniGiampaoloBerniniFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,GiovambattistaDesideriGiovambattistaDesideriFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,BrunoFabrisBrunoFabrisFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,ClaudioFerriClaudioFerriFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,GilbertaGiacchettiGilbertaGiacchettiFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,ClaudioLetiziaClaudioLetiziaFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,MauroMaccarioMauroMaccarioFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,FrancescaMallamaciFrancescaMallamaciFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,MassimoMannelliMassimoMannelliFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,GaetanaPalumboGaetanaPalumboFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,DamianoRizzoniDamianoRizzoniFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,ErmannoRossiErmannoRossiFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,EnricoAgabiti-RoseiEnricoAgabiti-RoseiFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,AchilleC.PessinaAchilleC.PessinaFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.Searchformorepapersbythisauthor,FrancoManteroFrancoManteroFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.SearchformorepapersbythisauthorFromtheDMCSInternalMedicine4(G.P.R.,A.C.P.),Padova,Italy;InternalMedicine(A.B.),Bari,Italy;InternalMedicine(G.B.),Pisa,Italy;DepartmentofInternalMedicineandPublicHealth(G.D.,C.F.),L’Aquila,Italy;InternalMedicine(B.F.),Trieste,Italy;Endocrinology(G.G.),Ancona,Italy;InternalMedicine(C.L.),Rome,Italy;Endocrinology(M.Maccario),Torino,Italy;Nephrology(F.M.),ReggioCalabria,Italy;Endocrinology(M.Mannelli),Firenze,Italy;InternalMedicine(G.P.),Legnano,Italy;InternalMedicine(D.R.,E.A.-R.),Brescia,Italy;AziendaOspedalieraASMNdiReggioEmilia,InternalMedicine(E.R.),ReggioEmilia,Italy;Endocrinology(F.M.),Padova,Italy.SearchformorepapersbythisauthorandforthePrimaryAldosteronismPrevalenceinItalyStudyInvestigatorsOriginallypublished25Jun2007https://doi.org/10.1161/HYPERTENSIONAHA.107.091827Hypertension.2007;50:424–431Otherversion(s)ofthisarticleYouareviewingthemostrecentversionofthisarticle.Previousversions: June25,2007:PreviousVersion1 AbstractWeperformedaprospectivehead-to-headcomparisonoftheaccuracyofthecaptopriltest(CAPT)andthesalineinfusiontest(SAL)forconfirmingprimaryaldosteronismduetoanaldosterone-producingadenoma(APA)inpatientswithdifferentsodiumintake.Atotalof317(26.9%)ofthe1125patientsscreenedinthePrimaryAldosteronismPrevalenceinItalyStudyunderwentbothCAPTandSAL.Theywerecomposedofthepatientswithahighaldosterone/reninratiobaselineand1every4patientswithoutsuchcriterion.Theaccuracyofpost-CAPTorpost-SALplasmaaldosteronevaluesfordiagnosingAPAwasestimatedwiththeareaunderthereceiveroperatorcharacteristicscurves.Primaryaldosteronismwasfoundin120patients,ofwhich46hadanAPA.Nountowardeffectoccurredwitheithertest.Theareaunderthereceiveroperatorcharacteristicscurveofplasmaaldosteroneforbothtestswashigher(P<0.0001)thanthatunderthediagonal,butthebetween-testdifferencewasborderlinesignificant(P=0.054).TheoptimalaldosteronecutoffvalueforidentifyingAPAwas13.9and6.75ng/dLfortheCAPTandSAL,respectively.Evenatthesecutoffs,sensitivityandspecificityweremoderatebecauseofoverlapofvaluesbetweenpatientswithandwithoutAPA.Whenexaminedinrelationtosodiumintake,theaccuracyoftheSALsurpassedthatoftheCAPTinthepatientswithasodiumintake≤130mEqperday;thisdifferencewanedatahigherNa+intake.Thus,boththeCAPTandtheSALaresafeandmoderatelyaccurateforexcludingAPA;atasodiumintake>7.6gperday,theSALoffersnoadvantageovertheeasier-to-performCAPT.ThePrimaryAldosteronismPrevalenceinItaly(PAPY)Studyshowedthatprimaryaldosteronism(PA)isfarmorecommonthanusuallyperceived:11.2%of1125newlydiagnosedhypertensivepatientsreferredtohypertension(HT)centershadPA,whichwasbecauseofanaldosterone-producingadenoma(APA)in4.8%ofthesubjects.1Thepotentialcurabilityandpreventionofexcesscardiovasculardamage(reviewedinReference2)andevents3alsounderscorestheimportanceofdevelopingaccuratestrategiesfortimelydiagnosingofAPA.Thealdosterone/reninratio(ARR)andthemultivariableapproachesproposedtothisendaresensitivebutmoderatelyaccurate,4–6becausetheydonotcompletelydifferentiatepatientswithPAandthosewithprimary(essential)HT(PH),asinitiallybelieved.7TheARRallowsdiscriminationofpatientswithPAfromthosewithlow-reninPHonlyifaldosteroneisovertlyincreaseddespiteahighsodium(Na+)intake,providedthatloworverylowplasmareninactivitycanbeaccuratelymeasured,whichisrarelyfeasibleincurrentlaboratorypractice.8–12Moreover,calculationoftheARRundersomeantihypertensivemedications,13likeβ-adrenergicblockers,14,15whichbluntreninbuthavelittleeffectonaldosteronesecretion,cangeneratefalse-positiveARR,thusfurtherloweringitsspecificity.9,16IdentificationofAPAandunilateralhyperplasia,thesurgicallycurableformsofPA,requiresadrenalveinsampling(AVS),whichisinvasiveandminimallyrisky.17,18Hence,aconfirmatorytestisnecessaryinthepatientswithapositivescreeningtesttoselectcandidatesforAVS.19Availableconfirmatorytestsarecomposedoftheoralsodiumloadingtest,20thesalineinfusiontest(SAL),21,22thecaptopriltest(CAPT),4,23,24orthefludrocortisonesuppressiontest.21,25–28TheirvalidationstandsonstudiesonfewpatientswithAPA,mostlyperformedretrospectively,andwithanothertestasreferent.10,13,22,26Todate,onlyonestudyhascomparedtheperformanceoftheCAPTtestwiththeoralNa+loading,20andalthoughinoneofthestudiesthatintroducedtheCAPTtheSALwasusedasreferent,24therewasnohead-to-headcomparisonoftheCAPTandtheSAL.Moreover,notwithstandingthewell-knowninverserelationshipbetweenreninandaldosteronesecretionononehandandNa+intakeontheother,thereisnoinformationontheimpactofNa+balanceoneithertestperformance.Thediagnosticperformanceofatestcanbeevaluatedwithaconclusivediagnosisasreferent,whichisfeasibleonlyinAPA,becausetherearenocriteriaforreliablydiagnosingidiopathichyperaldosteronism(IHA).Therefore,thePAPYStudySteeringCommitteeplannedtoprospectivelycomparetheperformanceoftheCAPTandSALforexcludingAPAandtoevaluatetheeffectofNa+intakeonthisperformance.SubjectsandMethodsThePAPYStudyprotocolfollowedtheStatementforReportingStudiesofDiagnosticAccuracyrecommendations,29asdetailed.1Theproceduresfollowedwereinaccordancewithinstitutionalguidelines;theprotocolwasapprovedbytheinstitutionalreviewcommitteeoftheUniversityofPaduaandadheredtotheprinciplesoftheDeclarationofHelsinki.Aninformedwrittenconsentwasobtainedfromeachparticipant.Briefly,consecutive,newlydiagnosedhypertensivepatients,referredtospecializedHTcentersnationwideinItaly,wereenrolledafteraninformedconsentwasobtained.1ApreviousdiagnosisofasecondaryformofHTandthepatient’srefusaltoparticipateinthestudyweretheexclusioncriteria.TheCAPTandtheSALTheflowchartshowninFigure1summarizesthestudyprotocol.Allofthepatientsunderwentmeasurementofthe24-hourNa+urineexcretion.TheCAPTwasperformedinthesittingpositionwith50mgofPOcaptopril.1Forthehead-to-headcomparisonofthe2tests,thosewhohadanARR≥40baseline,and/or≥30aftercaptopril,and/oralogisticdiscriminantfunctionscore≥0.50(pleaseseesupplementaldataavailableathttp://hyper.ahajournals.org)and1ofevery4consecutivepatientsnotfulfillingsuchcriteriaunderwenttheSAL. DownloadfigureDownloadPowerPointFigure1.Theflowchartshowsthestudydesign.Afterenrollment,55patientswerediscardedfromfurtheranalysisbecauseofincompletedata,protocolviolations,orunwillingnesstoundergofurthertesting.Theremaining1125patientsundergoingmeasurementoftheARRbaselinealsohadtheCAPT.ThosewithanARR≥40baseline,and/or≥30aftercaptopril,and/oralogisticdiscriminantfunctionscore≥0.50(seethedatasupplement)and1every4consecutivepatientsnotfulfillingthiscriterionweresubmittedtotheSAL.TheconclusivediagnosisofAPA,asdefinedinDiagnosticCriteria,(andthepresumeddiagnosisofIHA)wasthenusedforthepurposeofassessingthediagnosticperformanceoftheCAPTandSALinthe317patientswhounderwentbothtests.ForcalculationoftheARR,thelowestvalueofthedenominator,eg,plasmareninactivity(PRA),wassetto0.2ng/mLperhourtoavoidoverinflatingtheARR.Forbothtests,patientswerepreparedfromthepharmacologicalstandpointasdescribed(datasupplement).1Treatmentwithalong-actingcalciumchannelblockerand/ordoxazosinwasallowedifnecessaryforminimizingtherisksofuncontrolledHT.TheSALwasperformedonlywhenserumK+levelswere≥3.0mEq/L,becausehypokalemiabluntsaldosteronesecretionand,therefore,mightprecludethedetectionofsuppressibilityofaldosteronewithvolumeexpansion.Thus,oralpotassiumsupplementationwasallowedduringthedaysbeforetheSAL.TheSALinvolvedinfusionof2Lof0.9%salineIVover4hours.21Beforeand4hoursaftertheinfusion,PRA,plasmaaldosterone,cortisol,andserumK+weremeasured(seethedatasupplement).FurtherTestsToavoidbiasingthetestperformanceevaluation,thefurtherdiagnosticworkup(Figure1)wasbasedonlyontheresultsofARRbaseline,and/oraftertheCAPT,and/orthelogisticdiscriminantfunctiontest4(seethedatasupplement).1Thepatientspositiveatsuchtestsweresubmittedtoanimagingtestforidentificationofadrenocorticalnodules,1buttheywerealsosubmittedtoAVS17ortodexamethasone-suppressedadrenocorticalscintigraphytoidentifyalateralizedaldosteroneexcessproduction,regardlessoftheimagingtestresults.1AVSwasdeemedtoprovidealateralizationdiagnosisonlyifbilaterallyselective17;corticotropinstimulationwasnotsystematicallyusedduringAVS,becausealthoughitimprovesassessmentofselectivityofcatheterization,itdoesnotimprovethediagnosticaccuracy.30,31BiochemicalMeasurementsSerumcreatinine,serumandurineNa+andK+levels,PRA,aldosterone,cortisol,andglomerularfiltrationrateweremeasuredasdescribed1;hypokalemiawasdefinedasserumK+≤3.5mEq/L.Normalranges,intra-assayandinterassaycoefficientsofvariation,andantibodycross-reactivityforthehormonalmeasurementshavealreadybeenreported.1DiagnosticCriteriaIdentificationofAPArequiredallofthefollowingcriteria:(1)evidenceofPAatthescreeningtestasdefinedabove;(2)lateralizationofaldosteronesecretionatAVSorat131I-norcholesteroldexamethasone–suppressedadrenocorticalscintigraphy;(3)evidenceofadenomaatcomputedtomography,and/ormagneticresonance,and/orsurgery,and/orpathology;and(4)demonstrationofnormokalemiaandHTcure,orimprovement,atfollow-upafteradrenalectomybythecriteria(seethedatasupplement)alreadydescribed.1PatientswithPAbutwithoutconclusiveevidenceforalateralizedaldosteroneexcesswerepresumedtohaveIHA.StatisticalAnalysisAnormaldistributionwasattainedbyappropriatetransformationsofskewedvariablesasPRA,aldosterone,andcortisol.One-wayANOVAfollowedbyBonferroni’stestposthocwasusedtocomparequantitativevariablesbetweengroups.Categoricalvariablesdistributionwasinvestigatedbyχ2analysis;correlationwasassessedbynonparametricSpearmantest.SignificancewassetatP<0.05.Thecutoffvaluesthatgavethehighestaccuracy,eg,thebestcombinationofsensitivityandfalse-positiverate,weredeterminedbytheplotofsensitivity/specificityversuscriterionvalue.WeassessedtheaccuracyoftheCAPTandSALforidentifyingAPA,IHA,andPAatlargebytheareaunderthereceiveroperatorcharacteristics(ROC)curve(AUC).TheAUCcanbeinterpretedastheaveragevalueofsensitivityforallofthepossiblevaluesofspecificityortheaveragevalueofspecificityforallofthepossiblevaluesofsensitivity.WhentheROCcurvecoincideswiththediagonalline,theAUCisequalto0.50,and,therefore,thetestcannotdiscriminatebetweengroups;whenthereisnovalueoverlappingbetweenthegroups,theAUCequals1,andtheROCcurvereachestheupperleftcorneroftheplot.TheROCcurvescomparisonwasperformedwiththeMedCalcsoftware8.1.1.0(MedCalcSoftware).PoweroftheStudyWith197patientswithPHand46withAPA,andwiththispairwisewithin-patientdesign,thestudyhadapower>95%toinvestigatetheaccuracyoftheCAPTandtheSALfordiagnosingAPA.Fordetailsonpowercalculation,pleaseseethedatasupplement.ResultsBaselineCharacteristicsThebaselinefeaturesofthepatients,dividedbydiagnosis,areshowninTable1.TheAPApatientswereolder,hadhighersystolicbloodpressure(BP),andalsohadbaselineplasmaaldosteroneandARR,whereasreninandK+levelswerelowerthaninthePHpatients.The74patientspresumedtohaveIHAdidnotdifferfromtheAPApatientsforbaselineplasmaaldosterone,PRA,andcortisollevels,althoughserumK+washigherandARRlowerthanintheAPApatients.TheSALwasperformed,onaverage,4weeksafterthescreening;however,therewerenosignificantdifferencesamongthePRA,aldosterone,cortisol,andARRbaselinevaluesmeasuredatthescreeningtestandattheSAL. TABLE1.AnthropometricandBiochemicalCharacteristicsofthePatientsWithPHandWithPACausedbyanAPAandanIHAVariablePHPAPAPIHAP(IHAvsPH)Dataaremean±SDor95%CI,inparentheses,forvariablesnotnormallydistributed.BMIindicatesbodymassindex;Na+uV,sodiumurinaryexcretion;ARR,aldosterone(ngdL−1)/PRA(ngmL−1h−1)ratio;NS,notsignificant.Age,y46±110.03151±13NS48±11NSBMI,kgm−227.4±4.7NS27.4±4.1NS26.9±4.1NSSystolicBP,mmHg147±180.002158±23NS153±160.066DiastolicBP,mmHg97±11NS97±10NS100±100.035SerumK+,mEqL−14.1±0.4<0.00013.4±0.5<0.00013.9±0.40.028Na+uV,mEqday−1145(135to155)NS131(110to153)NS136(122to151)NSGFR,mLmin−190±20NS84±16NS90±20NSPRA,ngmL−1h−11.31(1.00to1.63)0.0020.64(0.31to0.98)NS0.52(0.37to0.68)<0.001Plasmaaldosterone,ngdL−117.9(16.3to19.6)<0.000132.1(26.0to38.2)NS25.6(22.4to28.8)<0.0001ARR,(ngdL−1)/(ngmL−1h−1)−113.7(12.2to16.3)<0.000150.2(26.5to123.2)NS49.2(32.9to77.8)<0.0001Plasmacortisol,nmolL−1146(137to154)NS131(120to143)NS143(130to156)NSAtthetimeoftheCAPTandSAL,41%ofthepatientswereuntreated,35%wereonacalciumchannelblockerordoxazosin,and24%wereonbothagents.TheAPApatientsrequiredmoreoftenthantheothergroups(42%)acombinationofcalciumchannelblockerordoxazosintoachieveBPcontrol.BaselinePRA,aldosterone,andcortisol,eitherwithintheentirecohortorineachdiagnosisgroup,didnotdifferacrosstreatmentgroups.CAPTCaptoprilloweredBPbutcausednosymptomatichypotensionandadverseeffects.ItincreasedPRAinallofthegroups(Table2);post-CAPTPRAwashigherinthePHthanintheAPAandIHAgroups(P<0.05)butdidnotdifferbetweenAPAandIHA.Aldosteroneandcortisolconcentrationsfellinallofthegroups.AldosteronewashigherinAPAandIHAthaninthePHgroup(bothP<0.0001),albeitwithavaluesoverlap. TABLE2.ChangesofPRA,Aldosterone,andCortisolObservedAftertheSalineInfusioninPatientsWithPHandPACausedbyanAPAandanIHAVariableAPAIHAPHBeforeAfterBeforeAfterBeforeAfter*P<0.05;†P<0.01;‡P=0.003;§P<0.001vsbeforeeachtest.Captopril    PRA,ngmL−1h−10.64(0.31to0.98)1.15(0.54to1.76)†0.52(0.36to0.68)0.82(0.55to1.09)‡1.31(0.99to1.63)3.32(2.39to4.26)§    Plasmaaldosterone,ngdL−132.4(26.7to39.1)22.7(18.4to27.0)§24.2(20.7to27.6)20.9(18.4to23.4)§15.2(13.5to16.9)11.4(10.4to12.4)§    Plasmacortisol,nmolL−1131(120to143)97(87to106)§143(130to156)120(107to133)§146(137to154)125(116to133)§Saline    PRA,ngmL−1h−10.76(0.42to1.09)0.39(0.21to0.56)*0.65(0.44to0.87)0.34(0.22to0.46)§1.39(1.03to1.76)0.81(0.55to1.07)§    Plasmaaldosterone,ngdL−132.4(25.6to39.1)17.6(13.4to21.9)§24.1(20.7to27.6)11.1(8.6to13.6)§15.2(13.5to16.9)5.5(4.9to6.1)§    Plasmacortisol,nmolL−193(68to117)52(35to70)§88(63to112)51(36to67)§101(91to111)63(56to70)§ThefallofaldosteroneafterCAPTshowednocorrelationwiththeincreaseofPRAinanydiagnosisgroup.Itcorrelatedwiththefallofcortisolintheallcohort(ρ=0.240;P<0.001)andinthePHgroup(ρ=0.181;P=0.05)butnotintheAPAandIHAgroups.SALAraiseofBPwasoccasionallyseenwithSAL,butnoadverseeffectsandnochangeofserumK+occurred(Table2).TheSALloweredPRA,aldosterone,andcortisolconcentrationssignificantlywithoutdifferencesacrossdiagnosisandtreatmentgroups.Thepost-SALaldosteronewashigherintheAPAandtheIHAthaninthePHgroup(bothP<0.0001),albeitwithavaluesoverlap.Bycontrast,therewerenosignificantdifferencesofPRAandcortisol.Thefallofaldosteronepost-SALcorrelatedwiththatofPRAintheallcohort(ρ=0.177;P<0.001),thePH(ρ=0.304;P=0.001),andAPA(ρ=0.396;P=0.030)groupsbutnotintheIHAgroup(ρ=0.253;Pnotsignificant).Thefallofaldosteronecorrelatedwiththatofcortisolintheallcohort(ρ=0.450;P<0.001),thePH(ρ=0.522;P<0.001),theAPA(ρ=0.485;P=0.003),andtheIHA(ρ=0.372;P=0.005)groups.DiagnosticAccuracyoftheCAPTandSALTable3showstheAUCofplasmaaldosteroneaftertheCAPTandSALandtheoptimalcutoffvaluesfordiagnosingAPA,IHA,andPAintheallcohort.BecausetheAUCundertheROCcurvewashigher(P<0.0001)thanthatunderthediagonal,bothtestswereusefultomakeall3ofthediagnoses.ForboththeCAPT(0.769±0.042)andtheSAL(0.854±0.030),theaccuracywashighestforidentificationofAPAandlowestforidentificationofIHAintheallcohort. TABLE3.ResultsoftheROCCurveAnalysisforPost-CAPTandPost-SALPAConcentrationDiagnosisPatientsAUC(95%CI)POptimalCutoff,ng/dLAllAUCsdifferedsignificantly(<0.0001)fromtheAUCunderthediagonal(identity)line.TheoptimalcutoffwasthevalueofPAaftertheSALthatprovidedthehighestaccuracy,eg,thebesttradeoffbetweensensitivityandspecificity.ThePvaluesinthetablerelatetocomparisonoftheCAPTandSAL.NSindicatesnotsignificantdifferencebetweentests.PASalinen=3170.811(0.764to0.859)NS6.80Captopril0.785(0.734to0.836)13.40APASalinen=2430.853(0.794to0.912)0.0546.75Captopril0.765(0.680to0.849)13.90IHASalinen=2710.786(0.727to0.844)NS6.91Captopril0.798(0.743to0.852)13.40Theoptimalcutoffvaluesofaldosteronewerehigherforpost-CAPTthanforpost-SAL,suggestingthatwithinthe(different)timecoursesofthesetests,thelatterprovidesamorepotentsuppressionofaldosteronesecretion.However,forbothtests,theygenerallyfellinanarrowrange.Post-CAPTplasmaaldosteronevalueof13.9ng/dL,whichcorrespondedwiththehighestaccuracyforidentificationofAPA,furnishedonlymoderatesensitivity(69.6;95%CI:54.2to82.2)andspecificity(74.0;95%CI:67.2to80.0).Thesensitivity(82.6;95%CI:68.6to92.2)andthespecificity(75.1;95%CI:68.5to81.0)wereslightlyhigherforthepost-SALattheplasmaaldosteronevalueof6.75ng/dLthatrepresentsthehighestpointestimateofaccuracyforidentificationofAPA.Thebetween-testsdifferenceofaccuracywasonlyborderlinesignificant(P=0.054;Figure2).PracticallyidenticalconclusionswerereachedwhentheanalysiswasconfinedtothecentersthatcouldperformAVS.1DownloadfigureDownloadPowerPointFigure2.TheplotshowstheROCofPAaftertheCAPTandtheSALfortheidentificationofAPA.TheAUCundertheSALwashigherthanthatundertheCAPT,butthedifferencewasborderlinesignificant(inset).TheCAPTandSALEndPointsToinvestigatewhetherthePRA-orcortisol-correctedaldosteronevaluescouldimprovethediagnosticaccuracyovertherawplasmaaldosteronevalues,wemeasuredtheAUCundertheROCcurveforidentificationofAPAofthePRA-andcortisol-correctedaldosteronevaluesafterCAPTandSAL.WefoundnosignificantincreaseoftheAUCbetweentherawandthePRA-orcortisol-adjustedaldosteronevalues(datanotshown)foreithertest.EffectofSodiumIntakeontheCAPTandSALPerformancesWefoundthattheaccuracyoftheCAPTforthediagnosisofAPAwashigheratanNa+intakeaboveratherthanbelowthepopulationmedian(Table4andFigureS2online).Bycontrast,theSALaccuracywasunaffectedbyNa+intake.Hence,theborderlinesignificantdifferencefavoringtheSALovertheCAPTbecamesignificantinthelowsodiumandwanedintheNa+halfofthepatients.TheNa+intakenotonlyaffectedthealdosteroneoptimalcutoffvaluesforboththeCAPTandtheSALbutalsotheoperativefeaturesofbothtests(Table4). TABLE4.OperativeFeatures(DefinitionAvailableintheOnlineDataSupplement)oftheCAPTandtheSALfortheIdentificationofAPAAccordingtoanNa+IntakeBeloworAbovethePopulationMedianNa+IntakeROCCurveAUC(95%CI)PA,ng/dLSensitivity(95%CI)Specificity(95%CI)PositiveLikelihoodRatioNegativeLikelihoodRatioPositivePredictiveValueNegativePredictiveValueThesensitivity,specificity,positiveandnegativelikelihoodratio,andpositiveandnegativepredictivevalueswerecalculatedattheAPAprevalenceratefoundinourpatientcohortbelowandabovemedianNa+intake,whichwere20.8%and17.2%,respectively.*Thiscutoffvaluecorrespondedwiththehighestaccuracy,eg,thebestcombinationofsensitivityandspecificity.CAPT    Belowmedian0.691(0.601to0.772)>15.9*56.0(34.9to75.6)81.0(71.7to88.4)2.960.5443.787.5    Abovemedian0.847(0.771to0.906)>13.4*85.7(63.6to96.8)70.3(60.4to79.0)2.890.2037.595.9SAL    Belowmedian0.849(0.772to0.907)>6.61*84.0(63.9to95.4)75.8(65.9to84.0)3.470.2147.794.    Abovemedian0.856>11.3*61.996.115.790.4076.592.5PredictiveValueoftheCAPTandSALThepositivepredictivevalueandthenegativepredictivevaluefortheCAPTandSALasfunctionsoftheAPAprevalenceinthepatientsdividedbyNa+intakeareshowninFigure3.Inthepatientsscreenedatmostreferralcenters,theAPAprevalenceislikelytobe<50%;hence,bothtestsperformbetteratexcludingthanatconfirmingAPA.Na+intakehadanimpactonthepredictivevalues:atalowNa+intake,theSALhadahighernegativepredictivevaluethantheCAPT;atahighNa+intake,theSALhadahigherpositivepredictivevaluebutalowernegativepredictivethantheCAPT. DownloadfigureDownloadPowerPointFigure3.Theplotsshowthepositiveandnegativepredictivevaluesasafunctionoftheprevalence(pretestorprevious,probability)ofAPAinthepatientsdividedintothoseabove(top)andthosebelow(bottom)themedian(130mEqperday)ofNa+intake.PredictivevalueswerecalculatedatthesensitivityandspecificitycorrespondingwiththevaluesofplasmaaldosteroneaftertheCAPT(15.9and13.4ng/dL,respectively)andtheSAL(6.61and11.3ng/dL,respectively)thatfurnishedthehighestaccuracyfortheidentificationofAPAinthelow-andhigh-Na+intakecohort.Theplotshowsthat,underthemostcommonratesofprevalenceencounteredinpractice,asthoseseeninourlow-(20.8%)andhigh-(17.2%)Na+intakecohort(dashedverticallines),theSALperformsbetteratrulingoutratherthanatconfirmingthepresenceofAPA.DiscussionBecausethescreeningtestsforPAhavealowspecificity,theselectionofthePApatientsforAVSrequiresdemonstrationofnonsuppressibilityofaldosteroneafterdynamictesting.Tothisend,boththeCAPTandSALcanfeatureidealconfirmatorytests,21,32butwhichtesttopreferremainscontentious,becausetheydidnotundergoahead-to-headcomparison.Moreover,theirperformanceswereexaminedinfewselectedpatients,mostlyincomparisonwithanothertestthatwasusedasthe“golddiagnostic”standard.4–6,14,33–40Instead,theyshouldbetestedforaccuracyatidentifyingAPA,theonlycausesofPAthatcanbeunequivocallydiagnosed.8Thus,inthePAPYStudy,asaconclusivediagnosisofAPAwasestablishedwithrigorouscriteria,1wecouldevaluateofthediagnosticperformanceofCAPTandSALinthelargest-seriesofAPAeverreported.TreatmentEffectsandAccuracyofEndPointsoftheCAPTandSALforConfirmingAPATherewasnosignificanttreatmenteffectonhormonevalueseitheratbaselineoraftertheCAPTandSAL,indicatingthatalong-actingcalciumchannelblockerand/ordoxazosindoesnotmarkedlyinfluencethealdosteroneresponsetoacuteangiotensin-convertingenzymeinhibitionandvolumeloading.Fromthepracticalstandpoint,thisimpliesthattheseagentscanbeallowedduringtheCAPTandSALtoavoidtherisksofuncontrolledHT.AldosteronedecreasedaftertheCAPTandSAL,butintheAPAandIHAgroups,itremainedhigherthaninthePHpatients,indicatingthataldosteroneafterbothtestscarriesadiagnosticgainoverbaselinedata.ThesignificantdifferencesofAUC(fromthediagonalAUC)foridentificationofAPA,IHA,andPAforbothtests(Table3)confirmtheirdiagnosticusefulness.However,attheplasmaaldosteronevalueprovidingthehighestaccuracyforidentificationofAPA,thesensitivityandspecificityoftheCAPTandtheSALweremoderate.Overall,theaccuracyoftheSALwasborderlinesignificantly(P=0.054)higherthanthatoftheCAPT.TheoptimalplasmaaldosteronecutoffvalueaftertheCAPT(13.9ng/dL)was≈2-foldhigherthanthat(6.75ng/dL)aftertheSAL,indicatingthatthelattertestinducesamuchgreaterdegreeofsuppressionofaldosteronesecretionthantheformer,atleastwithinthetimecoursesofthe2tests.WecannotexcludethatagreateraldosteronesuppressioncouldoccuratalatertimepointafterCAPT;however,thispotentialadvantagehastobeweighedagainstthecostsandinconvenienceofdoublingthetimeofthistest.Moreover,ithastobeconsideredthattheseoptimalcutoffscandifferslightlyatothercentersdependingonseveralfactors,includingthealdosteroneassay,thetestconditions,thesodiumintake,etc.Witheithertest,therewasnoincreaseoftheAUCwhenthePRA-orcortisol-adjustedaldosteronevalueswereusedinsteadoftherawaldosteronevalues.Thus,ourresultsdonotconfirmthecontentionthatthemeasurementsofPRAandcortisolimprovethediagnosticaccuracyoftheSAL.32AconclusivediagnosisofAPAwaslargelyunavailableinpreviousstudies,becauseAVSand/orfollow-up–baseddiagnosticcriteriawerenotsystematicallyused.Moreover,thediagnosisofPAwasbasedontheSALresultsitself,whichintroducedatautologybias,41orthepatientswithsevereHT,whocomposeasubstantialproportionoftheAPApatients,wereexcluded.Recentstudieswithothertestsasreferents22,26,42didnotconfirmthehighaccuracyoftheSALoriginallyreported41;studiesevaluatingtheSALversusthefludrocortisonetestasareferentalsoconcludedthattheSALwasmoderatelyaccurate.10,26,42TheARRafter25mgofcaptopril,ie,halfthedoseusedinourstudy,allowedidentificationof6PApatientswithnormalARRbaselines.43Thesamelowdosewasusedinahead-to-headcomparisonoftheCAPTwiththeoralNa+loadingwhereapost-CAPTaldosteronevalueof8.5ng/dLprovidedahighsensitivity(97%)closetothat(100%)oftheNa+loading.20However,specificityandaccuracycouldnotbedetermined,becausetherewereonly5patientswithPHinthatstudy;moreover,Na+intakewasnotcontrolledduringtheCAPT.20Thus,ourresults,consistentwithpreviousstudies,indicateoverallthatboththeCAPTandtheSALaremoderatelyaccurateforidentifyingAPA.AccuracyoftheCAPTandSALAccordingtoNa+IntakeAlowNa+intakeactivatestherenin-angiotensin-aldosteronesystemand,therefore,mightaltertheresultsoftheCAPTandSAL;however,Na+intakewasnottakenintoconsiderationinstudiessupportinguseofthesetests.22,32BysplittingourpatientsaccordingtothemedianofdailyurinaryNa+excretion,wefoundthattheSALperformedsimilarlyinbothcohorts.Bycontrast,theCAPTperformancewasmarkedlyaffectedbyNa+intake:a<130mEqperdayNa+intakeresultedintoasignificant(P=0.023)decreaseoftheAUC(FigureS2).Thus,thefallofaldosteroneafteracutevolumeexpansionisinsensitivetodietaryNa+intake,whereasthatinresponsetoacuteangiotensin-convertingenzymeinhibitionisaffectedbyNa+intake.Fromthepracticalstandpoint,thisimpliesthatanNa+intake>130mEqperdayshouldberecommendedduringthedaysbeforethetest,becauseanNa+-restricteddietmightimpairthediagnosticaccuracyoftheCAPT.PositiveandNegativePredictiveValuesoftheCAPTandSALThepositivepredictivevalue,eg,theprobabilitythatthediseaseispresentwhenthetestispositive,andthenegativepredictivevalue,eg,theprobabilitythatthediseaseisabsentwhenthetestisnegative,canbemostinterestingforclinicians,becausetheyallowdeterminationoftheperformanceofbothtestsintheirownpatientpopulation.Figure3showsaplotofthesepredictivevaluesfortheCAPTandSALasafunctionofAPAprevalence.Itshowsthat,attheprevalenceofAPA(<50%)seenatmostreferralcenters,bothtestsperformbetteratexcludingthanatconfirmingthediagnosis,and,thus,theyshouldbeviewedas“exclusion”ratherthanconfirmatorytests.Notunexpectedly,theNa+intakehadaffectedthepredictivevalues:atalowNa+intake,thepositivepredictivevalueoftheCAPTandSALweresimilar,butthenegativepredictivevalueoftheSALexceededthatoftheCAPT.AtahighNa+intake,thepositivepredictivevalueoftheSALwashigherthanthatoftheCAPT,butthenegativepredictivevalueoftheCAPTexceededthatoftheSAL.SafetyoftheCAPTandSALAlthoughweusedacaptoprildosethatwastwicethatusedpreviously,20,24,43,44theCAPTwaswelltolerated,20andcausedneithersignificanthypotensionnorchangesofserumK+(Table2).Likewise,noadverseeffectsorchangesofserumK+wereseenwiththeSAL,althougharaiseofBPwasoccasionallyseen.LimitationsoftheStudyAlbeitdoneprospectivelyinnewlydiagnosedhypertensivepatientsreferredtospecializedHTcenters,mostpatientsinvestigatedinthePAPYStudyhad,infact,mildHT.Thus,howrelevantthecurrentfindingsaretoapopulationwithmoresevereHTremainsunknown.Moreover,theprespecifiedARRof40usedinthePAPYStudyforthescreeningofPAisquiteconservative.Hence,wecannottotallyexcludethatwithsuchhighARRsomeAPAcouldbeoverlooked.ItmightalsobethatfewweremisdiagnosedasIHAbecauseofthetightcriteriaforidentifyingAPA,thelackofavailabilityofAVSatsomecenters,andtheintrinsicinsensitivityofdexamethasone-suppressedadrenocorticalscintigraphyfordiagnosingAPA,asdiscussed.1Despitetheselimitations,becauseofthelackofacceptedcriteriatodiagnoseIHA,which,therefore,canonlybepresumed,thereisnooptionotherthantobaseinvestigationofdiagnostictestsonthe“firmground”oftheAPAdiagnosis.Thus,itisworthmentioningthatourconclusionsontheCAPTandSALperformancesremainedunchangedafterrestrictingouranalysistothecentersthatperformedAVS.Thus,thetightdiagnosticcriteriausedforAPAarestrengthsratherthanweaknessesofthisstudy.ItmightalsobearguedthattheCAPTandSALperformanceswereoverestimated,becausemorethanhalfofthepatientswerepreselectedforthesetestsbasedontheARRresultsatbaselineandaftercaptopril.However,ourprotocolreflectscommoncurrentpractice,becausethesetestsaremostlyregardedasconfirmatory.Moreover,therelativelylargecohortofpatientswithoutPAinvestigatedinthisstudyrepresentsasafeguardfromthispotentialbias.Finally,becauseweexcludedpatientswithheartand/orrenalfailurefromthisstudy,thesafetyofthesetestsunderthoseconditionsneedstobeinvestigated.ConclusionsThisstudyallowsthefollowingconclusions:(1)evenwhenappliedtopopulationswithenrichedprevalencesofPA,theaccuracyoftheCAPTandSALismoderate,andfalse-positiveandfalse-negativeresultsaretobeexpected;(2)bothtestsaresensitivefortheidentificationofAPA,andtheiraccuracydidnotdiffersignificantlyatanadequateNa+intake;and(3)underthemostcommonconditionsofprevalenceofAPA,boththeCAPTandSALaremorehelpfulatexcludingratherthanatconfirmingthepresenceofAPA.BecausecaptoprillowersBP,whereasthesalineinfusionmightincreaseit,andbecausetheCAPTismoresimpleandcheaper,itshouldbepreferredtotheSAL,providedthatthepatientsareonNa+intakeof≥130mEqperday(7.6gofNaClperday).PerspectivesBecauseitislikelythattheeventhehighprevalencerateofPAfoundinthePAPYStudyunderestimatedtherealprevalenceofthisdisease,1futureworkshouldbeaimedatdeterminingtheSALandCAPTperformancesinpatientsselectedbasedonlowercutoffvaluesoftheARRversusthosedeterminedinthePAPYStudy.AppendixAlistofallPrimaryAldosteronismPrevalenceinItalyStudyinvestigatorsisgiveninTable5. TABLE5.ListofParticipatingCentersandPAPYStudyInvestigatorsCenterInvestigators1.Padova,Italy,DMCSInternalMedicine4GianPaoloRossi,AndreaSemplicini,ChiaraGanzaroli,AchilleCesarePessina2.Padova,Italy,EndocrinologyFrancoMantero,DecioArmanini,GiuseppeOpocher,PaoloSartorato3.Ancona,Italy,EndocrinologyGilbertaGiacchetti,VanessaRonconi,MarcoBoscaro4.ReggioEmilia,Italy,AziendaOspedalieraASMNdiReggioEmiliaInternalMedicineErmannoRossi5.Pisa,Italy,InternalMedicineGiampaoloBernini,AngelicaMoretti6.L’Aquila,Italy,DepartmentofInternalMedicineandPublicHealthClaudioFerri,GiovambattistaDesideri7.Palermo,Italy,InternalMedicineGiuseppeAndronico,GiovanniCerasola8.Brescia,Italy,InternalMedicineDamianoRizzoni,EnzoPorteri,EnricoAgabiti-Rosei9.Legnano,Italy,InternalMedicineGaetanaPalumbo,CarloCostantini,MariaTeresaLavazza10.Rome,Italy,InternalMedicineClaudioLetizia,ChiaraCaliumi11.Trieste,Italy,InternalMedicineBrunoFabris14.Firenze,Italy,EndocrinologyMassimoMannelli,GabrieleParenti15.Torino,Italy,EndocrinologyMauroMaccario,EzioGhigo17.ReggioCalabria,Italy,NephrologyFrancescaMallamaci,GraziellaCaridi,CarmineZoccali18.Bari,Italy,InternalMedicineAnnaBelfioreSourcesofFundingThisstudywassupportedbyresearchgrantsfromTheFoundationforAdvancedResearchinHypertensionandCardiovascularDiseases(FORICA)andtheSocietàItalianadell’IpertensioneArteriosa.DisclosuresNone.FootnotesCorrespondencetoGianPaoloRossi,InternalMedicine4,UniversityHospital,viaGiustiniani,2,35126Padova,Italy.E-mail[email protected] 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FiguresReferencesRelatedDetailsCitedByChangY,TsaiC,PengS,ChenZ,ChangC,LeeB,LiaoC,PanC,ChenY,LinL,ChangY,PengK,ChouC,WuV,HungCandLinY(2020)KCNJ5SomaticMutationsinAldosterone-ProducingAdenomaAreAssociatedWithaWorseBaselineStatusandBetterRecoveryofLeftVentricularRemodelingandDiastolicFunction,Hypertension,77:1,(114-125),Onlinepublicationdate:1-Jan-2021.ChangY,LiaoC,TsaiC,ChenC,PanC,ChenZ,ChenY,LinL,ChangY,WuV,WuK,HungC,LinY,WuC,ChangH,MDL,HuF,LiuK,WangS,HuangK,ChenY,ChangC,LiaoSandYenR(2019)LeftVentricularDysfunctioninPatientsWithPrimaryAldosteronism:APropensityScore–MatchingFollow‐UpStudyWithTissueDopplerImaging,JournaloftheAmericanHeartAssociation,8:22,Onlinepublicationdate:19-Nov-2019.MaiolinoG,RossittoG,BisogniV,CesariM,SecciaT,PlebaniM,RossiG,SempliciniA,GanzaroliC,PessinaA,ManteroF,ArmaniniD,OpocherG,MattarelloM,GiacchettiG,RonconiV,BoscaroM,RossiE,BerniniG,MorettiA,FerriC,DesideriG,AndronicoG,RizzoniD,PorteriE,PalumboG,LetiziaC,CaliumiC,FabrisB,MannelliM,ParentiG,MaccarioM,GhigoE,MallamaciF,ZoccaliCandBelfioreA(2017)QuantitativeValueofAldosterone‐ReninRatioforDetectionofAldosterone‐ProducingAdenoma:TheAldosterone‐ReninRatioforPrimaryAldosteronism(AQUARR)Study,JournaloftheAmericanHeartAssociation,6:5,Onlinepublicationdate:5-May-2017.UmakoshiH,NaruseM,WadaN,IchijoT,KamemuraK,MatsudaY,FujiiY,KaiT,FukuokaT,SakamotoR,OgoA,SuzukiT,NanbaKandTsuikiM(2016)AdrenalVenousSamplinginPatientsWithPositiveScreeningbutNegativeConfirmatoryTestingforPrimaryAldosteronism,Hypertension,67:5,(1014-1019),Onlinepublicationdate:1-May-2016.ManieroC,FassinaA,GuzzardoV,LenziniL,AmadoriG,PelizzoM,Gomez-SanchezCandRossiG(2011)PrimaryHyperparathyroidismWithConcurrentPrimaryAldosteronism,Hypertension,58:3,(341-346),Onlinepublicationdate:1-Sep-2011.RossiG,SecciaT,PalumboG,BelfioreA,BerniniG,CaridiG,DesideriG,FabrisB,FerriC,GiacchettiG,LetiziaC,MaccarioM,MallamaciF,MannelliM,PatalanoA,RizzoniD,RossiE,PessinaAandManteroF(2009)Within-PatientReproducibilityoftheAldosterone:ReninRatioinPrimaryAldosteronism,Hypertension,55:1,(83-89),Onlinepublicationdate:1-Jan-2010.MatrozovaJ,SteichenO,deMédecineFandPlouinP(2009)ResponsetoMetabolicDysfunctioninPrimaryAldosteronism,Hypertension,53:6,(e38-e38),Onlinepublicationdate:1-Jun-2009.RossiG,PessinaAandManteroF(2007)MoreFueltotheDebateonthe“EpidemicsofPrimaryAldosteronism”,Hypertension,51:1,(e1-e2),Onlinepublicationdate:1-Jan-2008.KaplanN(2007)ResponsetoMoreFueltotheDebateonthe“EpidemicofPrimaryAldosteronism”,Hypertension,51:1,(e3-e3),Onlinepublicationdate:1-Jan-2008.RossiG,BolognesiM,RizzoniD,SecciaT,PivaA,PorteriE,TiberioG,GiuliniS,Agabiti-RoseiEandPessinaA(2008)VascularRemodelingandDurationofHypertensionPredictOutcomeofAdrenalectomyinPrimaryAldosteronismPatients,Hypertension,51:5,(1366-1371),Onlinepublicationdate:1-May-2008.KaplanN(2007)IsThereanUnrecognizedEpidemicofPrimaryAldosteronism?(Con),Hypertension,50:3,(454-458),Onlinepublicationdate:1-Sep-2007. August2007Vol50,Issue2ArticleInformationMetrics Download:753 https://doi.org/10.1161/HYPERTENSIONAHA.107.091827PMID: 17592070 ManuscriptreceivedApril3,2007ManuscriptacceptedMay21,2007OriginallypublishedJune25,2007 KeywordsaldosteroneclinicalsciencesecondaryaldosteronismsecondaryhypertensionPDFdownload SubjectsClinicalStudiesHypertensionDiagnosticTesting TitleCaptionTitleCaptionTitleCaptionTitleCaption