Elliott M. Antman
Evidence and Education
Brigham and Women's Hospital|Harvard University
homecirculationvol 123 6evidence education free accessbrief reportpdfepubaboutview pdfview epubsections toolsadd favoritesdownload citationstrack citationspermissions shareshare onfacebooktwitterlinked inmendeleyreddit jump tofree accessbrief reportpdfepubevidence education elliott antman md elliott antmanelliott antman brigham womens hospital harvard medical school boston search papers author originally published15 feb 2011httpsdoiorg101161circulationaha110015255circulation 2011123681685given illustrious list prior awardees feel deeply honored james b herrick lecturer 20101 planning herrick lecture thought would instructive use legacy dr herrick lens assess evolution acquire evidence organize educational mission article based 2010 herrick lecture also includes additional material derived experience clinical research writing guidelines documentsninetyeight years ago dr herrick published classic article sudden obstruction coronary artery emphasizing event uniformly fatal2 hypothesized coronary occluded left ventricular function could preserved enhancing collateral flow2 herrick clearly master clinician keen observer patients would argue nascent clinical investigator however unlike todays clinical investigators herrick able test hypotheses one improving collateral flow conspicuously absent black bag modern day methods acquiring evidence make informed therapeutic decisionmethods acquiring evidence clinical trialsour evidence toolbox grew watershed event 1948 doll darcy hart avery jones working united kingdom introduced concept randomization individual subjects3 early randomized controlled trials rcts cardiology involved pertussis vaccine streptomycin tuberculosis major research concepts influence contemporary research strategies including informed consent ethics rcts blinding grew early experienceanother major advance clinical trial methodology came 10 years later 1958 mathematician working bell labs wondered long vacuum tubes would last repeaters undersea cables replaced time biostatistician johns hopkins working way describe long person cancer would expected live without treatment common problem 2 investigators faced individual variation followup resulting incomplete observations moment time edward kaplan mathematician teamed paul meier biostatistician describe method calculating time probability surviving free event thereby permitting comparison treatment versus treatment b kaplanmeier curves4now cardiovascular investigators running rich array clinical trials performed robust evidence base developed clinical practice guidelines generated starting 19845 derivative products performance measures produced facilitate translation recommendations guidelines routine practice6the writing committees american college cardiologyamerican heart association aha guidelines turn rcts registries many cases expert consensus however despite high degree precision clinical trials limited scope evidence rcts often insufficient inform general clinical practice future also need include information gleaned comparative effectiveness research cer patient preferences despite economic challenges facing contemporary healthcare systems remains dispute whether cost drive recommendations well important task learn incorporate data cer patient preferences larger evidence base formulating future practice recommendationslet us first reflect current state clinical trials cardiovascular medicine prototypical structure randomized doubleblind controlled trial today questions ask quite complex whereas surrogate end points may helpful earlyphase proofofconcept research misleading designing largescale rcts7 valid surrogate end points must tightly linked relevant clinical outcome changes surrogate predictive outcomes surrogate end point must also causal pathway disease reliably capture impact treatment tested clinical outcomes thus investigators increasingly focusing clinical outcomes primary end point rct however event rates dropping see greater use composite clinical end point greater availability effective treatments makes harder show superiority important clinically meaningful advantages may still exist new treatment leads noninferiority designbecause blinding treatment arms rct challenging investigators may use prospective randomized openlabel blinded end point probe design8 probe design may still introduce bias therefore blinding investigators patients remains preferable given public health impact application evidence rcts9 increase efficiency clinical trials periodic review blinded aggregate data investigators may use adaptive design could lead modification enrollment criteria treatments tested sample sizeheightened attention safety marketed drugs led us food drug administration consider postapproval clinical trials new drug applications based rcts may required include risk evaluation management strategy rems agency believes plan important ensure benefits drug outweigh risks10 effort accelerate development new medical products food drug administration introduced critical path initiative promotes tools acquiring evidence include new assays standards computer modeling techniques biomarkers end points clinical trials11 goal reduce time delivering promising new treatments patients identifying products hold clinical promise earlier development pathway facilitating testing products likely improve health patientsthe final point consider direct outgrowth information delivery hightechnology age often filtered sound bite findings study headline blog reaches busy clinician patient simplistic summary fails capture rich array information contained clinical trial need think much comprehensively set issues interpreting evidence 6step process figure 112download figuredownload powerpointfigure 1 6step process interpreting evidence randomized controlled trial process begins bottom left continues counterclockwise fashion around top left see text discussion modified information hulley et al12what scientific hypothesis appropriately framedhow effectively study plan test hypothesishow well study implementedwe examine actual findings study typically treatment effectfrom report treatment effect confidence intervals measures statistical significance make inference truth studyimportantly clinical practice draw inference applicability findings population patients target disease investigationthese last 2 inferences allow us make judgments internal external validity clinical trial welldesigned implemented clinical trials get high marks internal validity may still questions generalizability external validity findingsmethods acquiring evidence comparative effectivenessenter world cer new method obtaining evidence1316 need type research gaps variations quality care delivered clinical outcomes need know return investment healthcare dollars need know works real world toolbox cer consists ofclinical trials usually simpler design referred pragmatic trials examples include antihypertensive lipidlowering treatment prevent heart attack trial allhat trial acute study clinical effectiveness nesiritide decompensated heart failure trial ascendhf1718systematic overviews metaanalysesdecision modelsobservational studies often problematiccomparative effectiveness studies hold great promise need much experience methodology statistical tools used cer order apply evidence investigations appropriately formulating recommendations clinical care point aptly illustrated 2 studies investigating personalized medicine using genotypeguided warfarin therapy consider ongoing clarification optimal anticoagulation genetics coag study sponsored national institutes health httpwwwclinicaltrialsgov unique identifier 00839657 patients indication warfarin randomized doubleblind fashion anticoagulation managed either standard clinically guided warfarin regimen genotyping added standard approach experts area felt benefits genotyping would seen early would influence late events primary end point therefore time therapeutic range warfarin first 4 weekscontrast warfarin effectiveness study reported march 20101920 investigators used quasiexperimental approach offered genotyping participants 29 prescription drug benefit plans eight hundred ninetysix patients accepted offer genotype results supplied physician median 32 days starting warfarin primary end point rate allcause hospitalization 6 months genotyping group compared nonrandomized matched historical control group year earlier prescription drug plans using claims data investigators observed 31lower hospitalization rate genotyping group despite propensity score adjustment need concerned selection bias potentially healthconscious individuals agreed genotyped health behaviors lifestyles may rate hospitalization knowledge genotype warfarin unmeasured confounders might also impacted hospitalization ratesthe warfarin effectiveness study also raised classic epidemiological concerns reduced rate hospitalization genotype group appears statistical association causal relationship using 9 criteria introduced 1965 bradfordhill21 example reduction hospitalizations inconsistent studies temporal relationship unsupported evidence date scientific plausibility supporting observation although evidence coag rct likely considered guidelineswriting committee members perhaps thirdparty payors doubt warfarin effectiveness study would convincing either groupin november 2010 new oral anticoagulant dabigatran became available pharmacies around country alternative warfarin preventing stroke systemic embolic events patients atrial fibrillation approval dabigatran based phase3 trial randomized evaluation longterm anticoagulation therapy rely8 results rely trial analyzed subgroups according percentage time international normalized ratio inr therapeutic range centers randomizing patients around world22 inr poorly controlled highdose dabigatran appeared show superiority warfarin inr wellcontrolled high lowdose dabigatran appeared show noninferiority warfarin imagine comparative effectiveness study degree inr control would represent real world answer clearly complex onewe must also avoid silo thinking simplistic blind cost containment coverage decisions withhold payment new anticoagulant dabigatran arguing instead using warfarin better 60 years warfarin experience still problems achieving high rates inr control uniformly one needs factor cost inr monitoring warfarin healthcare system savings associated earlier discharge prevention events also give weight voices patients clinicians seeking treatment option free anticoagulation monitoring fooddrug interactions many considerations taken account investigators estimated incremental costeffectiveness ratio qualityadjusted life years saved found dabigatran appeared cost effective23how might one strengthen cer toolbox improve clinical trials cer investigators shouldembed randomization increasingly available electronic medical records imagine differently might view warfarin effectiveness study use genotyping randomized using electronic medical record also case report form inr resultsuse cluster randomization practices hospitals defined better accountable care organizations24study patient preferences health literacy social determinants health impact understanding compliance prescribed regimento improve observational studies investigators use propensity scores adjustments instrumental variable analyses sensitivity analyses multiple control groups data sources25 efforts help increase degree confidence accuracy observation emphasized aha position paper cer must alert issues association versus causation15some important steps bring structure organization field cer occurred last 2 years 2009 11 billion dollars american recovery reinvestment act grant funds allocated cer distributed us department health human services national institutes health agency healthcare research quality federal coordinating council comparative effectiveness submitted report defined cer comparison benefit harm different interventions real world26 council described strategic framework involves support cer investment training individuals conduct research data infrastructure collate research findings platform disseminating information also set priorities cer cardiovascular disease including stroke hypertension high listthe affordable care act 2010 established independent patientcentered outcomes research institute pcori27 september 23 2010 government accountability office announced membership pcori charging refining methodologies cer setting research agenda overseeing dissemination research findings28 remains seen impact change balance power congress midterm elections 2010 ability move forward proposals cer29another major development bearing discussion formation clinical translational science centers30 designed accelerate transformation basic biomedical discoveries improved global health overcoming series translational blocks t1translation humans firstinhuman proofofconcept studies t2translation patients disease rcts establish efficacy t3translation practice cer plays important role t4translation research findings population scale skill sets collaborations biostatistical expertise educational needs vary considerably along t1t4 spectrum31our educational missionhow incorporate information clinical trials cer explosion data clinical translational science thinking educational efforts annual scientific meetings suggested educational psychologist benjamin bloom must acquire core set information constitutes knowledge base figure 232 date many cases acquisition core set knowledge focus cardiovascular training programs designed pass board examination cardiovascular diseasesdownload figuredownload powerpointfigure 2 perspective formulation educational mission pyramid cognitive domain conceived benjamin bloom shown left30 objective arrive state critical thinking ascending pyramid cognitive domain integrating clinical experiences taxonomy equip clinicians investigators patients must process increasing number facts healthcare decision making see text discussionhowever given number facts involved per decision anticipated exponential increase future need move beyond simple information acquisition must emphasize trainees faculty importance striving comprehend learn apply analyze synthesize evaluate evidence integrating iterative clinical experiences figure 233 arrive state critical thinking moved beyond recitation facts knowledge base taxonomy useful construct training cardiovascular investigators future clinicians caring patients also framing communicate educate patients healthcare choicesa contemporary view evidence educationhow put together figure 3 axis represents strength evidence x axis proximity patient roughly translates generalizability routine practice rcts highest strength evidence enrollment criteria farthest patient routine practice cer design provides generalizable information based evidence strong mentioned ways cer increase strength evidence providesdownload figuredownload powerpointfigure 3 contemporary view evidence education strength evidence depicted vertical axis generalizability information routine practice depicted along horizontal axis relative positions evidence provided rcts cer shown interface clinicians investigators patients rcts cer educational mission illustrated toward top left ideal healthcare system shown top right call action clinicians protect patients consequences blind costcontainment coverage decisions shown bottom right see text discussionthe primary driver clinical trials scientific advance tested primary driver cer consumer based focusing interface patient healthcare system patients move research subjects research partners going forward need view rcts cer complementary methods obtaining data need inform practice guidelines clinical decisions well educate investigators clinicians patientssurely difficult work get right fair evidencebased efficient healthcare system importantly obligation safeguard patients draconian interpretation evidence blind cost containment coverage decisions example denial coverage particular statin angiotensinconverting enzyme inhibitor angiotensin ii receptor blocker basis flimsiest evidence dominated business decision critical point pathway actual delivery care patientas members council clinical cardiology largest 16 councils aha position take leadership role maintaining legacy dr herrick reviewers manuscripts editorialists 1 11 aha journals discussant latebreaking clinical trial one meetings need exhibit critical thinking keep focus patientby attending responsibility evaluate act evidence help aha reach bold 2020 impact goal improve cardiovascular health americans 20 reducing deaths cardiovascular disease stroke 2034disclosuresnonefootnotespresented herrick award lecture council clinical cardiology american heart association chicago il november 13 2010correspondence elliott antman md brigham womens hospital harvard medical school 75 francis st boston 02115 email email protectedorgreferences1 american heart associationthe james b herrick award outstanding achievement clinical cardiology2010available httpwwwamericanheartorgpresenterjhtmlidentifier3028995accessed november 30 2010google scholar2 herrick jb clinical features sudden obstruction coronary arteries jama 1912 5920152022crossrefgoogle scholar3 doll r controlled trials 1948 watershed bmj1998 31712171220crossrefmedlinegoogle scholar4 kaplan el meier p nonparametric estimation incomplete observations j stat assoc 1958 53457481crossrefgoogle scholar5 gibbons rj smith antman e american college cardiologyamerican heart association clinical practice guidelines part come circulation 2003 10729792986linkgoogle scholar6 antman em peterson ed tools guiding clinical practice american heart association american college cardiology clinicians use circulation 2009 11911801185linkgoogle scholar7 demets dl califf rm lessons learned recent cardiovascular clinical trials part circulation 2002 106746751linkgoogle scholar8 connolly sj ezekowitz md yusuf eikelboom j oldgren j parekh pogue j reilly pa themeles e varrone j wang alings xavier zhu j diaz r lewis bs darius h diener hc joyner cd wallentin lrely steering committee investigatorsdabigatran versus warfarin patients atrial fibrillation n engl j med 2009 36111391151crossrefmedlinegoogle scholar9 psaty bm prentice rl minimizing bias randomized trials importance blinding jama 2010 304793794crossrefmedlinegoogle scholar10 office extramural research national institutes healthwhat nih grantees need know clinicaltrialsgov fdaaaavailable httpgrantsnihgovclinicaltrialsfdaaaaccessed december 2 2010google scholar11 us food drug administrationcritical path initiativeavailable httpwwwfdagovscienceresearchspecialtopicscriticalpathinitiativedefaulthtmaccessed december 2 2010google scholar12 hulley sb cummings sr browner ws grady dg newman tb eds designing clinical research3d edphiladelphia lippincott williams wilkins 2007google scholar13 nellesen birnbaum hg greenberg pe perspectives comparative effectiveness research views diverse constituencies pharmacoeconomics 2010 28789798crossrefmedlinegoogle scholar14 committee comparative effectiveness research prioritization institute medicineinitial national priorities comparative effectiveness researchwashington dc national academies press 2009google scholar15 gibbons rj gardner tj anderson jl goldstein lb meltzer n weintraub ws yancy cwamerican heart association advocacy coordinating committeethe american heart associations principles comparative effectiveness research policy statement american heart association circulation 2009 11929552962linkgoogle scholar16 sox hc comparative effectiveness research progress report ann intern med 2010 153469472crossrefmedlinegoogle scholar17 major outcomes highrisk hypertensive patients randomized angiotensinconverting enzyme inhibitor calcium channel blocker vs diuretic antihypertensive lipidlowering treatment prevent heart attack trial allhat jamadec2002 28829812997crossrefmedlinegoogle scholar18 hernandez af oconnor cm starling rc reist cj armstrong pw dickstein k lorenz tj gibler wb hasselblad v komajda massie b mcmurray jj nieminen rouleau jl swedberg k califf rm rationale design acute study clinical effectiveness nesiritide decompensated heart failure trial ascendhf heart j 2009 157271277crossrefmedlinegoogle scholar19 epstein rs moyer tp aubert kane dj xia f verbrugge rr gage bf teagarden jr warfarin genotyping reduces hospitalization rates results mmwes medcomayo warfarin effectiveness study j coll cardiol 2010 5528042812crossrefmedlinegoogle scholar20 epstein rs teagarden jr comparative effectiveness research personalized medicine catalyzing colliding pharmacoeconomics 2010 28905913crossrefmedlinegoogle scholar21 hill ab environment disease association causation proc r soc med 1965 58295300crossrefmedlinegoogle scholar22 wallentin l yusuf ezekowitz md alings flather franzosi mg pais p dans eikelboom j oldgren j pogue j reilly pa yang connolly sjrely investigatorsefficacy safety dabigatran compared warfarin different levels international normalised ratio control stroke prevention atrial fibrillation analysis rely triallancet 2010 376 9745 975983crossrefmedlinegoogle scholar23 freeman jv zhu rp owens dk garber hutton dw go wang pj turakhia mp costeffectiveness dabigatran compared warfarin stroke prevention atrial fibrillation ann intern med 2011 154111crossrefmedlinegoogle scholar24 mcclellan mckethan lewis jl roski j fisher es national strategy put accountable care practice health aff millwood 2010 29982990crossrefmedlinegoogle scholar25 normand sl old new statistical tools outcomes research circulation 2008 118872884linkgoogle scholar26 federal coordinating council comparative effectiveness researchreport president congress2009available httpwwwhhsgovrecoveryprogramscercerannualrptpdfaccessed november 30 2010google scholar27 clancy c collins fs patientcentered outcomes research institute intersection science health care sci transl med2010 237cm18crossrefmedlinegoogle scholar28 us government accountability officegao announces appointments new patientcentered outcomes research institute pcori board governors2010available httpwwwgaogovpresspcori2010sep23htmlaccessed november 30 2010google scholar29 mitka us government kicks program comparative effectiveness research jama 2010 30422302231crossrefmedlinegoogle scholar30 clinical translational science awardsavailable httpwwwctsaweborgaccessed november 30 2010google scholar31 harvard catalystthe harvard clinical translational science centeravailable httpcatalystharvardeduaccessed november 30 2010google scholar32 bloom bstaxonomy educational objectives classification educational goalshandbook cognitive domainnew york mckay 1956google scholar33 stead ww recalibrating informatics true northavailable httpwwwscribdcomdoc32904101closingplenarybillsteadaccessed november 30 2010google scholar34 lloydjones dm hong labarthe mozaffarian appel lj van horn l greenlund k daniels nichol g tomaselli gf arnett dk fonarow gc ho pm lauer ms masoudi fa robertson rm roger v schwamm lh sorlie p yancy cw rosamond wdamerican heart association strategic planning task force statistics committeedefining setting national goals cardiovascular health promotion disease reduction american heart associations strategic impact goal 2020 beyond circulation 2010 121586613linkgoogle scholar previous back top next figuresreferencesrelateddetailscited pocock clayton stone g 2015 design major randomized trials journal american college cardiology 101016jjacc201510036 6624 27572766 online publication date 1dec2015 antman e califf r choudhry n 2013 tools assessment cardiovascular tests therapies cardiovascular therapeutics companion braunwalds heart disease 101016b9781455701018000011 132 braunwald e 2012 rise cardiovascular medicine european heart journal 101093eurheartjehr452 337 838845 online publication date 1apr2012 schwann n hillel z hoeft barash p mhnle p miao mangano 2011 lack effectiveness pulmonary artery catheter cardiac surgery anesthesia analgesia 101213ane0b013e31822c94a8 1135 9941002 online publication date 1nov2011 february 15 2011vol 123 issue 6 advertisement article informationmetrics 2011 american heart association inchttpsdoiorg101161circulationaha110015255pmid 21321184 originally publishedfebruary 15 2011 pdf download advertisement subjectsanticoagulantscomplianceadherencecosteffectivenessethics policygenetics