A Decade of Reversal An Analysis of Contradicted Medical Practices Vinay Prasad MD Andrae - PDF document

ADecadeofReversal:AnAnalysisof146ContradictedMedicalPracticesVinayPrasad,MD;AndraeVandross,MD;CaitlinToomey,MD;MichaelCheung,MD;JasonRho,MD;StevenQuinn,MD;SatishJacobChacko,MD;DurgaBorkar,MD;VictorGall,MD;SenthilSelvaraj,MD;NancyHo,MD;andAdamCifu,MDObjective:ToidentifymedicalpracticesthatoffernonetbeneMethods:Wereviewedalloriginalarticlespublishedin10years(2001-2010)inonehigh-impactjournal.Articleswereclassiedonthebasisofwhethertheyaddressedamedicalpractice,whethertheytestedaneworexistingtherapy,andwhetherresultswerepositiveornegative.Articleswerethenclassiedas1of4types:replacement,whenanewpracticesurpassesstandardofcare;backtothedrawingboard,whenanewpracticeisnobetterthancurrentpractice;reafrmation,whenanexistingpracticeisfoundtobebetterthanalesserstandard;andreversal,whenanexistingpracticeisfoundtobenobetterthanalessertherapy.ThisstudywasconductedfromAugust1,2011,throughOctober31,2012.Wereviewed2044originalarticles,1344ofwhichconcernedamedicalpractice.Ofthese,981articles(73.0%)examinedanewmedicalpractice,whereas363(27.0%)testedanestablishedpractice.Atotalof947studies(70.5%)hadpositivendings,whereas397(29.5%)reachedanegativeconclusion.Atotalof756articlesaddressingamedicalpracticeconstitutedreplacement,165werebacktothedrawingboard,146weremedicalreversals,138werereafrmations,and139wereinconclusive.Ofthe363articlestestingstandardofcare,146(40.2%)reversedthatpractice,whereas138(38.0%)reafrmedit.Conclusion: Foreditorialcomment,seepage779FromtheNationalCancerInstitute,NationalInstitutesofHealth,Bethesda,MD(V.P.);DepartmentofMedicine,YaleUniversity,NewHaven,CT(A.V.);DepartmentofMedicine(C.T.,J.R.,S.J.C.)andFeinbergSchoolofMedicine(D.B.,S.S.),NorthwesternUni-versity,Chicago,IL;Depart-mentofMedicine,LankenauMedicalCenter,Philadelphia,PA(M.C.);DepartmentofMedicine(S.Q.)andDepart-mentofSurgery(V.G.),GeorgeWashingtonUniver-sity,Washington,DC;Depart-mentofMedicine,UniversityofMaryland,Baltimore,MD(N.H.);andDepartmentofMedicine,UniversityofChi-cago,Chicago,IL(A.C.).MayoClinProc. ORIGINALARTICLE generatemorethan150low-valuepractices.Medicaljournalshavespecicallyfocusedonin-stancesinwhichmorehealthcareisnotneces-sarilybetter.TheArchivesofInternalMedicinecreatedanewfeatureseriesin2010entitledLessisMore.Givenongoingandvigorouseffortstoiden-tifymedicalpracticesthatofferlittlebenetandminimalempiricalstudiesdocumentingtherateatwhichcurrentpracticesarecontradicted,weperformedareviewof10yearsoforiginalpublicationsinonehigh-impactjournal.METHODSWeusedmethodssimilartoourpriorsurveyof1yearofpublicationsinahigh-impactjour-WereviewedallarticlesundertheheadingOriginalArticlesintheNewEnglandJournalofMedicinefrom2001to2010.Theseyearswerethelastcomplete10yearswhenwebeganourinvestigation.Ourchoiceofjournalwasmadeonthebasisofthe5-yearHirschindexformed-icaljournals.Tworeviewers(C.T.,A.V.,M.C.,J.R.,S.Q.,S.J.C.,D.B.,V.G.,orS.S.)andV.P.independentlyextractedinformationforeachcalendaryear.Thisstudywasconduct-edfromAugust1,2011,throughOctober31,2012.Onthebasisofpublishedabstracts,articleswereclassiedastowhethertheyaddressedaclinicalpractice.Articlesaddressingamedicalpracticeweredenedasanyinvestigationthatassessesascreening,stratifying,ordiagnostictest,amedication,aprocedureorsurgery,oranychangeinhealthcareprovisionsystems.Manyresearcharticlesconcernthenovelmo-lecularbasisofdiseaseornovelinsightsinpathophysiology.Thesearticleswereexcluded.Whenpracticeinformationcouldnotbeascertainedbyabstractalone,fullarticleswereread.Tworeviewers(C.T.,A.V.,M.C.,J.R.,S.Q.,S.J.C.,D.B.,V.G.,orS.S.)andV.P.readarticlesaddressingamedicalpracticeinfull.Ontheba-sisoftheabstract,introduction,anddiscussion,articleswereclassiedastowhetherthepracticeinquestionwasneworexisting.Methodswereedasoneofthefollowing:randomizedcontrolledtrial,prospectivecontrolled(butnonrandomized)interventionstudy,observa-tionalstudy(prospectiveorretrospective),case-controlstudy,orothermethods.Endpointsforarticleswereclassiedintothosethatreachedpositiveconclusionsandthosethatfoundnegativeornodifferenceinendpoints.Lastly,articlesweregiven1of4designa-wasdenedasanewpracticesurpassinganolderstandardofcare.Backtothedrawingboardwasdenedasanewpracticefailingtosurpassanolderstandard.wasdesignatedwhenacurrentmedicalpracticewasfoundtobeinferiortoalesserorpriorstan-wasdenedasanexistingmedicalpracticebeingfoundtobesuperiortoalesserorpriorstandard.Finally,articlesinwhichnormconclusioncouldbereachedweretermed.Thedesignationofanarticlewasalsoperformedinduplicate.Whenthereweredifferencesinopinionbe-tweenthe2reviewers,adjudicationinvolveddiscussionbetweenthe2readerstoseewhetheragreementcouldbereached.Ifdisagreementpersisted,athirdreviewer(A.C.)adjudicatedthediscrepancy.Lessthan3%ofarticlesrequireddiscussion,andlessthan1%requiredadjudication.Atablede-tailingeachmedicalreversalwasconstructedSupplementalAppendix;availableonlineat),andthethirdreviewer(A.C.)reviewedallreversals.Dataaresummarizedusingcountsandper-centages.Alinearregressionwasperformedtodeterminetherelationshipbetweenpercentageofreversalsandtime,andthePearsonwasusedwhenappropriate.AnalyseswereconductedusingStatastatisticalsoftware,ver-sion12(StataCorpLP).RESULTSFrom2001through2010,2044originalarticlesappearedinonehigh-impactjournal.Mostarti-cles(1344[65.8%])addressedamedicalprac-tice.Atotalof981studies(73.0%)examinedanewmedicalpractice,whereas363(27.0%)addressedanexistingpractice.Duringthese10years,therewere911(67.7%)randomizedcontrolledtrials,220(16.4%)prospectivecontrolledbutnonrandomizedstudies,117(8.7%)observationalstudies,43(3.2%)case-controlstudies,and53(3.9%)studiesusingothermethods.Concerningthestudyresults,947(70.5%)reachedpositiveconclusions,whereas397(29.5%)reachednegativeconclusionsorfoundnodifferencebetweencomparators.Assuch,756articles(56.3%)foundanewpractice DECADEOFREVERSALMayoClinProc.August2013;88(8):790-798http://dx.doi.org/10.1016/j.mayocp.2013.05.012www.mayoclinicproceedings.org surpassingcurrentstandardofcare(replace-ment),165(12.3%)foundanewpracticefailingtoimproveonthecurrentpractice(backtothedrawingboard),146(10.9%)werereversals,and138(10.3%)upheldstan-dardofcareoveralesserorpriorstandardrmation).Atotalof139(10.3%)weredeemedinconclusive.Figure1showsabreak-downofarticles.Thesinglemostcommonstudytypewasarandomizedtrialexamininganewpracticeandndingbenetforthatprac-tice;530(39.4%)ofall1345articleswereclas-edassuch.Ofthe363articlesthattestedanexistingmed-icalpractice,146(40.2%)founditineffectivecomparedwithapreviousstandardoritsomission(reversals),whereas138(38.0%)upheldtheprac-tice,and79(27.3%)wereinconclusive.Table1andFigure2provide,forarticlestestingexistingstandardofcare,abreakdownofreversal,reafmation,andinconclusivearticlesbyyear.Ofthe146reversalarticles,mostwererandomizedcontrolledtrials(111[76.0%]);13(8.9%)wereprospective,nonrandomizedstudies;20(13.7%)wereretrospectivestudies;1wasacase-controlstudy;and1usedanalternativestudydesign.Articlesthattestednewpracticesweremorelikelytondthembenecialthanarticlesthattestedexistingones(77.1%vs.001).Conversely,articlesthattestedexistingstandardsweremorelikelytondthosepracticesineffectivethanarticlestestingnewpractices(40.2%vs17.0%;Severalofthereversalarticlesconcernedthesametopic.Fourarticlescalledintoques-tionthedrugaprotinin,whichwaswidelyusedincardiacsurgerybutfoundtoincreasemortality.Threearticlesaddresseduseofapri-maryrhythmcontrolstrategyforpatientswithatrialbrillation.Threearticlesinasingle 60 (6.1%) Are inconclusive79 (21.8%) Are inconclusive FIGURE1.Abreakdownofarticlesconcerningamedicalpractice. TABLE1.Number(Percentage)ofReversal,Reafrmation,andInconclusiveArticlesbyYearReversalReafrmationInconclusive2001(n14(29.2)2002(n12(46.2)2003(n12(38.7)2004(n12(36.4)2005(n19(46.3)2006(n12(60.0)2007(n18(33.3)2008(n15(46.9)2009(n16(45.7)2010(n16(37.2)Total(N363)146(40.2)138(38.0)79(21.7) MAYOCLINICPROCEEDINGSMayoClinProc.August2013;88(8):790-798http://dx.doi.org/10.1016/j.mayocp.2013.05.012www.mayoclinicproceedings.org issuefoundincreasedrisksofcardiovasculareventsfromusingthecyclooxygenase2inhib-itors,includingrofecoxib.Threearticlesprovidedextendedfollow-upforatrialofchil-drenrandomlyassignedtoearlymyringotomywiththeinsertionoftympanostomytubesoradelayedprocedure.Althoughtheprocedurewasthemostcommonoperationperformedonchildrenbeyondthenewbornperiodandbolsteredbyexpertguidelines,nodiffer-encewasfoundinanearlyvsdelayedstrategyonoutcomesat3,or9to11yearsofage.Threearticlesfurthercontradictedroutinehormonetherapyinpostmenopausalwomen.Twoarticlescontradictedroutineuseofthepul-monaryarterycatheter,and2articlesfoundworseoutcomeswithrecommendedglycemictargets(asopposedtomorepermissivestandards)forpatientswithdiabetes.ThebenetofstentinginpatientswithstablecoronaryarterydiseasewasunderminedbytheOccludedArteryClinicalOutcomesUtilizingRevasculari-zationandAggressiveDrugEvaluationandafollow-upquality-of-lifestudyfromtheOccludedArteryTrial.Twostudiessuggestedthatalthoughezetimibeimproveslow-densityli-poproteinvalues,itdoesnotimprovecarotidar-teryintimamediathickness.surgeryofthekneeforosteoarthritiswascalledintoquestionby2studies5yearsapart,whereasvertebroplastyforosteoporoticfracturewascontradictedby2pairedarticles.ingforthefactthatseveralreversalsconcernedthesamepractice,128medicalpracticeswerecontra-dictedduringthese10years.Eightofthereversalsweidentiedover-lappedwithanAustralianstudyof156low-valuepracticesSupplementalFigure;availableonlineathttp://www.mayoclinicproceedings.org).Thesereversalsincludearthroscopicsur-geryforkneeosteoarthritis,vertebroplastyforosteoporoticfractures,endovascularrepairofinfrarenalabdominalaorticaneurysms,stentinginpatientswithstablecoronaryarterydisease,amnioinfusionforwomenwithmeco-niumstaining,C-reactiveproteintesting,screeningmenwiththeprostatespecicantigentest,androutinerevascularizationorstresstestingbeforesurgery.Thus,weprovideatleast138uniquelow-valuepractices.Table2liststhe10selectedreversalsinthedecadeandhoweacharticlecontradictedcurrentstandardofcare.TheSupplementalAppendixdetailsall146reversals.Figure2showsthepercentageofarticlesthattestedstan-dardofcareand,ofthose,thepercentageofre-versalsandreafrmations.Thepercentageofreversalsamongarticlesthattestedstandardofcarewereconstantduringthedecade(DISCUSSIONOurreviewof10yearsofpublicationsinahigh-impactjournalinvolvedexamining2044articlesinduplicatetoidentify146medicalre-versals.Reversalsincludedmedications,proce-dures,diagnostictests,screeningtests,andevenmonitoringandtreatmentguidingdevices.Wewereunabletoidentifyanyclassofmedicalpracticethatdidnothavesomereversalofstan-dardofcare(SupplementalAppendixThebispectralindexmonitor(BIS)illus-tratesmanyoftheprinciplesofmedicalreversal.Althoughrare,anesthesiaawareness(orintraoperativeawareness)isdebilitatingandisassociatedwithposttraumaticstressdis-orderandanxiety.TheBISmonitorwasdevelopedtoensurethatpatientswerereceivingadequateanesthesiabyusingasingleelectroencephalographicleadtocalculatea 2001200220032004200520062007200820092010 FIGURE2.Percentageofreversal,reafrmation,andallarticlestestingstandardofcare. 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TABLE2.KeyReversals,2001-2010Reference,yearDescriptionAntimicrobialtreatmentindiabeticwomenwithasymptomaticbacteriuria(Hardingetal,IncontrasttoEuropeansocieties,severalgroupsintheUnitedStatesrecommendedscreeningandtreatingforasymptomaticbacteriuriainwomenwithdiabetes.Thisrandomizedtrialfoundthatalthoughthispracticeleadstomoreantibioticuse,itdidnotreducecomplicationsorimprovethetimetosymptomaticinfectionConventionaladjuvantchemotherapywithorwithouthigh-dosechemotherapyandautologousstem-celltransplantationinhigh-riskbreastcancer(Tallmanetal,Multiplestudieshaveclaimedthathigh-dosechemotherapywithstemcelltransplantationimprovesdisease-freesurvivalat3yearsto65%-70%,animprovementof20%-30%beyondstandardadjuvantchemotherapy.High-dosechemotherapyandautologousstemcelltransplantationbecameacommon,costly,andcontroversialpracticeformorethanadecade.Thistrialrandomizedpatientswithprimarybreastcancerwithinvolvementofatleast10ipsilateralaxillarylymphnodestostandardadjuvantchemotherapyvsadjuvantchemotherapyfollowedbyhigh-dosechemotherapyandstemcelltransplant.Thestudyarmwasfoundtoreduceriskofrelapse,butnoimprovementinsurvivalwasfoundControlofexposuretomiteallergenandallergen-impermeablebedcoversforadultswithasthma(Woodcocketal,Thecostofimpermeablebedcoversisinthemillionsofdollarsannually,whereasthecostofallpreventiveinterventionsforasthmaandallergicrhinitisisinthebillions.andEuropeanguidelinesrecommendthesecoversbeusedamongmanypatientswithasthma.Thisdouble-blind,randomized,placebo-controlledtrialof1100patientsfoundnobenetonanyclinicalorphysiologicoutcomeforthispracticeMethylprednisolone,valacyclovir,orthecombinationforvestibularneuritis(Struppetal,Thecauseofvestibularneuritisispresumedtobeaviralinfection,andyetitisunknownwhethercorticosteroids,anantiviralmedication,oracombinationofbothhaveanybenetintreatingthisdisease.Atthetimeofthispublication,physiciansprescribedeitherorboth.Aprospective,randomized,double-blind,2-by-2factorialtrialwasperformedassessingwhetherplacebo,methylprednisolone,valacyclovir,oracombinationofthe2wouldimprovesymptoms.Onlythecorticosteroids,andnottheantiviral,improvedtherecoveryofpatientswithvestibularneuritisMildintraoperativehypothermiaduringsurgeryforintracranialaneurysm(Toddetal,Hypothermiawasfoundtobehelpfulasaneurosurgicaladjunctin1955,especiallyforischemicandtraumaticinsults.Atthetimeofthispublication,thepracticewasusedinnearly50%ofaneurysmsurgeries.Thislargerandomizedstudy,theIntraoperativeHypothermiaforAneurysmSurgeryTrial(IHAST),foundnoimprovementinneurologicoutcomeswithhypothermia,whilenotinganincreaseinbacterialinfectionswiththeinterventionOptimalmedicaltherapywithorwithoutPCIforstablecoronarydisease(Bodenetal,Althoughtreatmentguidelinesrecommendedaninitialapproachofintensivemedicaltherapy,reductionofriskfactors,andlifestylemodication(optimalmedicaltherapy)forpatientswithstablecoronaryarterydisease,percutaneouscoronaryintervention(PCI)wasstillacommoninitialtreatmentstrategyforpatientswithstablecoronaryarterydiseaseatthetimethisstudywasperformed.TheauthorsfoundthatPCIaddedtooptimalmedicaltherapydidnotreducetheriskofdeath,myocardialinfarction,orothermajorcardiovasculareventsInvitrofertilizationwithpreimplantationgeneticscreening(Mastenbroeketal,Becauselowpregnancyratesinwomenofadvancedmaternalageundergoinginvitrofertilization(IVF)mayresultfromchromosomalabnormalities,theuseofpreimplanationgeneticscreeninghadbecomeincreasinglymorecommonatthetimeofthisstudy.However,thismulticenter,double-blindrandomizedcontrolledtrialcomparingIVFwithandwithoutpreimplantationgeneticscreeningfoundthatscreeningsignicantlyreducedratesofongoingpregnanciesandlivebirthsafterIVFinwomenofadvancedmaternalageEffectsofintensiveglucoseloweringintype2diabetes(ActiontoControlCardiovascularRiskinDiabetesStudyGroupetal,AtargethemoglobinAof7.0%orlessasrecommendedformostpatientswithdiabetes.TheActiontoControlCardiovascularRiskinDiabetes(ACCORD)trialfoundthattargetof7.0%sustainedfor3.5yearsincreasedmortalityanddidnotsignicantlyreducemajorcardiovasculareventscomparedwithamorepermissivegoalRevascularizationversusmedicaltherapyforrenal-arterystenosis(ASTRALInvestigatorsetal,Renalarterystenosisisassociatedwithhypertensionandkidneydisease,butitisuncleariftherelationshipiscausal.Despitethisuncertainty,datafromstudiesintheUnitedStatesindicatethatrevascularizationisperformedin16%ofpatientswithnewlydiagnosedatheroscleroticrenovasculardiseaseandhypertension.ThislargerandomizedtrialofrevascularizationwithmedicalmanagementvsmedicalmanagementalonefoundsubstantialrisksbutnoevidenceofbenetfromrevascularizationinthispopulationGentamicin-collagenspongeforinfectionprophylaxisincolorectalsurgery(Bennett-Guerreroetal,Thegentamicin-collagenspongehasbeenapprovedforuseinnumerouscountriesandusedinmillionsofpatientsworldwidesince1985.Asingle-center,randomizedtrialfounda70%decreaseinsurgicalsiteinfectionwithimplantationofthesponge.However,thislarge,multicenter,phase3trialfoundthatthegentamicin-collagenspongeparadoxicallyresultedinsignicantlymoresurgicalsiteinfections,wasassociatedwithmorevisitstotheemergencydepartmentorsurgicalofce,andmorefrequentlyprecipitatedsubsequenthospitalizationfortheinfection MAYOCLINICPROCEEDINGSMayoClinProc.August2013;88(8):790-798http://dx.doi.org/10.1016/j.mayocp.2013.05.012www.mayoclinicproceedings.org dimensionlessmeasureofconsciousness.Intheory,anesthesiacouldbetitratedtotheBISreading.In1997,theUSFoodandDrugAdministrationapprovedthedevice.Only2trialsexistedbeforethereversalstudy.One,anindustry-sponsoredtrial,didnotuseastandard-izedprotocolforthecomparatorarmandfoundthedevicereducedawareness.Theotherwasunderpoweredtomakeanyconclusions.Nevertheless,themonitorsuseincreased.ByJuly2007,halfofalloperatingroomsintheUnitedStateshadaBISmonitor.Thenin2008,alarge,randomizedtrialcomparingtheBISmonitorwithastandardizedsedationmoni-toringstrategyfoundnobenetforthedeviceonanesthesiaawareness.Manyreversalshavesimilarnarratives.Althoughthereisaweakev-idencebaseforsomepractice,itgainsacceptancelargelythroughvocalsupportfromprominentadvocatesandfaiththatthemechanismofactionissound.Later,futuretrialsunderminethether-apy,butremovingthecontradictedpracticeoftenproveschallenging.79,80AlthoughtheBISmonitorwasdesignedtopreventarareevent(anesthesiaawareness),manyreversalsconcerncommonendpoints,suchasmortality.Recently,aprojectof,entitledClinicalEvidence,completedareviewof3000med-icalpractices.Theprojectfoundthatslightlymorethanathirdofmedicalpracticesareeffectiveorlikelytobeeffective;15%areharmful,unlikelytobebenecial,oratrade-offbetweenbenetsandharms;and50%areofunknowneffectiveness.OurinvestigationcomplementsthesedataandsuggeststhatahighpercentageofallpracticesmayultimatelybefoundtohavenonetbeneToourknowledge,thisisthelargestandmostcomprehensivestudyofmedicalreversal.Previously,wehaveconsideredthecausesandconsequencesofreversal.4-6,82Whenmedicalpracticesareinstitutedinerror,mostoftenonthebasisofpremature,inadequate,biased,andconictedevidence,thecoststosocietyandthemedicalsystemareimmense.such,wefavorpoliciesthatminimizereversal.Nearlyallsuchmeasuresinvolveraisingthebarfortheapprovalofnewtherapies6,83,84andaskingforevidencebeforethewidespreadadoptionofnoveltechniques.Inallbuttherarestcases,large,robust,pragmaticrandom-izedtrialsmeasuringhardendpoints(withshamcontrolsforstudiesofsubjectiveendpoints)shouldberequiredbeforeapprovaloracceptance.Ourpositionisincontrasttoeffortstolowerstandardsfordeviceanddrugapproval,whichfurthererodesthevalueoftheregulatoryprocess.Onesurprisingtypeofreversalweobservedwaspotentiallybenecialtherapiesbeingwith-heldbecauseofunfoundedconcernsabouttheirpotentialtocauseharm.Long-standingcon-cernsthatvaccinationsprecipitateareofmulti-plesclerosisledmanyphysicianstoomitthisintervention,buttheconcernswerelargelyunderminedbytheresultsof2studiesin2001.86,87Concernsthatoralcontraceptivesin-creaselupusarescreatedreluctancetopre-scribethisclassofmedicationstowomen.Thispracticemaycontributetoahigherrateofelectiveabortionsamongpatientswithlupus.In2005,2trialsreportedthatoralcon-traceptivesdonotincreaselupusares.89,90AlthoughtheAmericanCollegeofObstetricsrecommendedthatepiduralanesthesiabedelayeduntilcervicaldilationhasreached4cmoutofconcernthatearlieradminis-trationincreasesratesofcesareansectionrandomizedtrialsreportedthatthisfearwasunfounded.Warningsthatturnedouttobewrongrepresentauniqueformofreversalandraisequestionsaboutotherdubiousre-strictionstakenatfacevalue,forinstance,thatpatientswithClostridiumdifshouldnotbetreatedwithantimotilityagentsforfearofincreasingratesoftoxicmegaco-Discerningreadersmayyetidentifyothernovelpatternsofcontradiction.Thecurrentstudyhasseverallimitations.Ourchoiceofjournalwasmadeonthebasisofimpactfactorrankings;thus,weareunsurewhetherourresultsapplytoalljournals.Asinanystudyofpublishedresearchndings,onemaywonderwhetherthereexistsapublicationbiasfavoringcertainstudies,inthiscase,thosethatcontradictstandardofcare.However,thetestingofstandardofcareisrarelydoneaccordinglyisinitselfnoteworthy.Itseemsunlikelythatthereexistsaselectionagainstreafrmationarticles.Ourclassicationschemewasbasedonpriorwork,butothersmayhavealterna-tivepreferencesforgroupingmedicalarticles.Whetheramedicalpracticewasconsideredneworexistingwasdecidedonthebasisofthearticlesabstract,introduction,anddiscussion. 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Wedidnotperformanindependentsearchtoverifythatexistingpracticeswereindeedinuseandnewpracticeswerenot.Assuch,wemayhavemadeerrorsbothofinclusionandexclu-sion.Someauthorsmayhavechosentodown-playatherapysreal-worlduse,whereasothersmayhavechosentooveremphasizeit.Aninde-pendentevaluationofpracticepatternswouldhavestrengthenedourinvestigationbutwouldhavebeenoverlytime-consumingbecauseitwouldhaverequiredinvestigationofhundredsoftopics,manyofwhicharecommonmedica-tionsthatlackuniquecodingfortheirvaryingindications.Thereversalswehaveidentiedbynomeansrepresentthenalwordforanyofthesepractices.Simplybecausenewer,larger,bettercontrolledordesignedstudiescontradictstan-dardofcaredoesnotnecessarilymeanthatolderpracticesarewrongandnewonesareright.Onaverage,however,betterdesigned,controlled,andpoweredstudiesreachmorevalidconclusions.Nevertheless,thereversalswehaveidentiedattheveryleastcallthesepracticesintoquestion.Somepracticesoughttobeabandoned,whereasotherswarrantretest-inginmorepowerfulinvestigations.Oneofthegreatestvirtuesofmedicalresearchisourcontinualquesttoreassessit.ItislikelythatothersmayfeeldifferentlyaboutsomeofthereversalswehaveidentiSupplementalAppendix).Althoughweper-formedouranalysisinduplicate,withlittledisagreement,othersmayneverthelessdrawdifferentconclusions.Weinterpretedarticlesingoodfaith,astheauthorspresentedthere-sults.Inaddition,thepurposeofourinvestiga-tionwastooutlinebroadtrendsinmedicalpracticeandidentifyalargenumberofpoten-tiallow-valuepractices.Wedonotseektoissueanaldeterminationregardinganyparticularpractice.Changingadozenclassicationswouldmakelittledifferenceintheinterpretationofourresults.CONCLUSIONWepresent146medicalpracticesthatwerereversedin10yearsofpublicationsinalejournal.Ourresultsmaybeofin-teresttopractitionersandpolicymakerswhoseektoidentifylow-valuepracticesandmeth-odologistsandscientistswhoareinterestedinthepatternsofmedicalresearch.ACKNOWLEDGMENTSTheviewsandopinionsofDrPrasaddonotnecessarilyreectthoseoftheNationalCancerInstituteorNationalInstitutesofHealth.SUPPLEMENTALONLINEMATERIALSupplementalonlinematerialcanbefoundon-lineathttp://www.mayoclinicproceedings.orgCorrespondence:AddresstoVinayPrasad,MD,MedicalOncologyBranch,NationalCancerInstitute,NationalInsti-tutesofHealth,10CenterDr10/12N226,Bethesda,MD20892(vinayak.prasad@nih.gov).REFERENCESBodenWE,ORourkeRA,TeoKK,etal.Optimalmedicalther-apywithorwithoutPCIforstablecoronarydisease.NEnglJ.2007;356(15):1503-1516.RossouwJE,AndersonGL,PrenticeRL,etal;WritingGroupfortheWomensHealthInitiativeInvestigators.Risksandbenetsofestrogenplusprogestininhealthypostmeno-pausalwomen:principalresultsfromtheWomensHealthInitiativerandomizedcontrolledtrial.JAMA.2002;288(3):321-333.SandhamJD,HullRD,BrantRF,etal;CanadianCriticalCareClinicalTrialsGroup.Arandomized,controlledtrialoftheuseofpulmonary-arterycathetersinhigh-risksurgicalpatients.NEnglJMed.2003;348(1):5-14.PrasadV,GallV,CifuA.Thefrequencyofmedicalreversal.InternMed.2011;171(18):1675.PrasadV,CifuA,IoannidisJPA.Reversalsofestablishedmedicalpractices:evidencetoabandonship..2012;307(1):37-38.PrasadV,CifuA.Medicalreversal:whywemustraisethebarbeforeadoptingnewtechnologies.YaleJBiolMed.2011;84(4):471-478.IoannidisJA.Contradictedandinitiallystrongereffectsinhighlycitedclinicalresearch..2005;294(2):218-228.CasselCK,GuestJA.Choosingwisely:helpingphysiciansandpatientsmakesmartdecisionsabouttheircare.JAMA.2012;307(17):1801-1802.BrodyH.Medicinesethicalresponsibilityforhealthcarethetopvelist.NEnglJMed.2010;362(4):283-285.GarnerS,LittlejohnsP.Disinvestmentfromlowvalueclinicalinterventions:NICElydone?.2011;343:d4519.ElshaugAG,WattAM,MundyL,WillisCD.Over150poten-tiallylow-valuehealthcarepractices:anAustralianstudy.MedJ.2012;197(10):556-560.GradyD,RedbergRF.Lessismore:howlesshealthcarecanresultinbetterhealth.ArchInternMed.2010;170(9):749-750.TopPublicationsHealth&MedicalSciences.google.com/citations?view_optop_venues&hlen&vqAccessedJune30,2011.ManganoDT,TudorIC,DietzelC.Theriskassociatedwithapro-tininincardiacsurgery.NEnglJMed.2006;354(4):353-365.SchneeweissS,SeegerJD,LandonJ,WalkerAM.Aprotinindur-ingcoronary-arterybypassgraftingandriskofdeath.NEnglJ2008;358(8):771-783.ShawAD,Stafford-SmithM,WhiteWD,etal.Theeffectofaprotininonoutcomeaftercoronary-arterybypassgrafting.NEnglJMed.2008;358(8):784-793.FergussonDA,HébertPC,MazerCD,etal.Acomparisonofaprotininandlysineanaloguesinhigh-riskcardiacsurgery.NEnglJMed.2008;358(22):2319-2331.RoyD,TalajicM,NattelS,etal;AtrialFibrillationandConges-tiveHeartFailureInvestigators.Rhythmcontrolversusrate 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