AHA Scientic Statement1Depression and elevated depressive
symptoms are com-mon among the estimated 15.4 million US adults
with coronaryheartdisease(CHD).1Approximately20%of patients
hospitalized for an acute coronary syndrome (ACS;
myocardialinfarction[MI]orunstableangina[UA])meet
theAmericanPsychiatricAssociationsDiagnosticand BackgroundAlthough
prospective studies, systematic reviews, and meta-analyses have
documented an association between
depressionandincreasedmorbidityandmortalityinavarietyofcardiacpopulations,depressionhasnotyetachieved
formal recognition as a risk factor for poor prognosis in patients
with acute coronary syndrome by the American Heart Association and
other health organizations. The purpose of this scientic statement
is to review available evidence and recommend whether depression
should be elevated to the status of a risk factor for patients with
acute coronary syndrome.Methods and ResultsWriting group members
were approved by the American Heart Associations Scientic Statement
and Manuscript Oversight Committees. A systematic literature review
on depression and adverse medical outcomes after
acutecoronarysyndromewasconductedthatincludedall-causemortality,cardiacmortality,andcompositeoutcomes
for mortality and nonfatal events. The review assessed the
strength, consistency, independence, and generalizability of the
published studies. A total of 53 individual studies (32 reported on
associations with all-cause mortality, 12 on cardiac mortality, and
22 on composite outcomes) and 4 meta-analyses met inclusion
criteria. There was heterogeneity across studies in terms of the
demographic composition of study samples, denition and measurement
of depression, length of follow-up, and covariates included in the
multivariable models. Despite limitations in some individual
studies, our review identied generally consistent associations
between depression and adverse
outcomes.ConclusionsDespitetheheterogeneityofpublishedstudiesincludedinthisreview,thepreponderanceofevidence
supports the recommendation that the American Heart Association
should elevate depression to the status of a risk factor for
adverse medical outcomes in patients with acute coronary
syndrome.KeyWords:AHAScienticStatementsacutecoronarysyndromecoronaryheartdiseasedepression
riskfactors Depression as a RiskFactor for Poor Prognosis Among
Patients With Acute Coronary Syndrome: Systematic Reviewand
RecommendationsA Scientic Statement Fromthe AmericanHeart
AssociationJudithH.Lichtman,PhD,MPH,Co-Chair;ErikaS.Froelicher,RN,MA,MPH,PhD,FAHA,Co-Chair;
James A.Blumenthal,PhD, ABPP;RobertM.Carney,PhD;Lynn
V.Doering,RN,DNSc,FAHA;
NancyFrasure-Smith,PhD;KennethE.Freedland,PhD; AllanS.Jaffe,MD;
EricaC.Leifheit-Limson,PhD;DavidS.Sheps,MD,MSPH,FAHA; Viola
Vaccarino,MD,PhD,FAHA; Lawson Wulsin,MD;onbehalfofthe AmericanHeart
AssociationStatisticsCommitteeoftheCouncil
onEpidemiologyandPreventionandtheCouncilonCardiovascularandStrokeNursingThe
American Heart Association makes every effort to avoid any actual
or potential conicts of interest that may arise as a result of an
outside relationship or a personal, professional, or business
interest of a member of the writing panel. Specically, all members
of the writing group are required to complete and submit a
Disclosure Questionnaire showing all such relationships that might
be perceived as real or potential conicts of interest.This
statement was approved by the American Heart Association Science
Advisory and Coordinating Committee on January 24, 2014. A copy of
the
documentisavailableathttp://my.americanheart.org/statementsbyselectingeithertheBy
TopiclinkortheByPublicationDatelink. Topurchase additional
reprints, call 843-216-2533 or e-mail
[email protected] American Heart Association
requests that this document be cited as follows: Lichtman JH,
Froelicher ES, Blumenthal JA, Carney RM, Doering LV, Frasure-Smith
N, Freedland KE, Jaffe AS, Leifheit-Limson EC, Sheps DS, Vaccarino
V, Wulsin L; on behalf of the American Heart Association Statistics
Committee of the Council on Epidemiology and Prevention and the
Council on Cardiovascular and Stroke Nursing. Depression as a risk
factor for poor prognosis among patients with acute coronary
syndrome: systematic review and recommendations: a scientic
statement from the American Heart Association. Circulation.
2014;129:.Expert peer review of AHA Scientic Statements is
conducted by the AHA Ofce of Science Operations. For more on AHA
statements and guidelines development, visit
http://my.americanheart.org/statements and select the Policies and
Development
link.Permissions:Multiplecopies,modication,alteration,enhancement,and/ordistributionofthisdocumentarenotpermittedwithouttheexpress
permission of the American Heart Association. Instructions for
obtaining permission are located
athttp://www.heart.org/HEARTORG/General/Copyright-Permission-Guidelines_UCM_300404_Article.jsp.
A link to the Copyright Permissions Request Form appears on the
right side of the page.(Circulation. 2014;129:00-00.) 2014 American
Heart Association, Inc.Circulation is available at
http://circ.ahajournals.orgDOI: 10.1161/CIR.0000000000000019 by
guest on August 14, 2015 http://circ.ahajournals.org/ Downloaded
from 2CirculationMarch25,
2014StatisticalManualofMentalDisorders(DSM)criteriafor major
depression, and an even larger percentage show
sub-clinicallevelsofdepressivesymptoms.24Bycomparison, 4% of the
general US adult population meets the criteria for major depression
at any given time.5 Numerous prospective studies, systematic
reviews, and meta-analyses have shown
arobustassociationbetweendepression(majordepression
orelevateddepressivesymptoms)andincreasedmorbidity and mortality
after ACS.3,4,611 However, depression has not
yetachievedformalrecognitionasariskfactorforpoor prognosis after
ACS by national health organizations.The goal of this scientic
statement is to review current
evi-denceontheroleofdepressionasariskfactorforadverse medical
outcomes among adults recovering from ACS in order
tomakearecommendationastowhetherdepressionshould be elevated to the
status of a risk factor among patients with ACSbythe AmericanHeart
Association(AHA).Guidelines for assessing a risk factor include the
presence of an objective outcome measure; prospective designs;
evidence of a strong,
consistentassociationbetweentheriskfactorandoutcome; evidence that
the risk factor is not explained by other variables or covariates
linked to both the risk factor and outcomes; and the existence of a
plausible biological mechanism to account
fortheobservedrelationship.1214Toformulateourrecom-mendations, we
examined the strength, consistency, indepen-dence, and
generalizability of the ndings in a set of carefully
selectedstudiesof3outcomes:(1)all-causemortality,(2)
cardiacmortality,and(3)compositeoutcomesthatincluded mortality and
nonfatal events. In addition, this Writing Group sought to identify
important areas for future research that may further our
understanding of the relationship between depres-sion and
ACS.Writing Group members were nominated by the committee co-chairs
on the basis of their previous work in relevant topic
areasandwereapprovedbytheAHAScienticStatement
OversightCommitteeandtheAHAManuscriptOversight Committee. All
members of the Writing Group had the
oppor-tunitytocommentonandapprovethenalversionofthis
document.Thedocumentsubsequentlyunderwentextensive
AHAinternalpeerreview,includingCouncilLeadership
reviewandScienticStatementOversightCommittee
review,beforeapprovalbytheAHAScienceAdvisoryand Coordinating
Committee.Literature Search StrategyTo identify relevant
peer-reviewed studies, we updated
previ-oussystematicreviews10,1417toincludepublicationsthrough July
24, 2011. We searched the MEDLINE, Current Contents,
andPsycINFOdatabasesforcombinationsofthefollowing terms:1.
Coronaryheartdisease,coronaryarterydisease,isch-emicheartdisease,myocardialinfarction,unstable
angina, acute coronary syndrome, coronary bypass
sur-gery,atherosclerosis,suddendeath,ventricularbrilla-tion,
ventricular tachycardia, or heart failure2. Mortality, survival, or
prognosis3. Depression, depressive symptoms, dysthymia, mood, or
depressive
disorderThearticleswerelimitedtoEnglishlanguagepubli-cations.Thesearchyielded1559uniquecitations.We
restricted our review to studies of patients recovering from
ACSandthosemeetingthefollowingadditionalinclu-sion criteria adapted
from Kuper et al17 and Frasure-Smith
andLesprance10,14,15:(1)Theyusedaprospectivedesign,
(2)included100patients,(3)usedestablishedassess-ment instruments to
dene major depression or depressive
symptoms(studiesthatidentieddepressiononthebasis
ofantidepressanttreatment,self-reportedtreatmentof depression,
single-item measures, study-specic measures,
ornonspecicdistressscreeningindiceswereexcluded),
and(4)reportedall-causemortality,cardiacmortality,or
acombinationofeitherofthesemortalityoutcomesand
nonfatalevents.Weexcludedstudiesthatdidnothavea
nondepressedcomparisonsampleorthatfocusedonthe comparison of
particular subtypes of depression or patterns of depressive
symptoms.Aminimumof2 WritingGroupmembersindependently
reviewedthetitlesandabstractsofeachofthe1559cita-tionsidentiedbythesearchandthe92studiesreviewed
previouslybyKuperetal17andFrasure-Smithand
Lesprance10,14,15;atotalof1509citationswereexcluded
onthebasisofthepredenedinclusioncriteria(Figure).
Thefull-textpublicationsoftheremaining142potentially
eligiblestudieswerereviewedindetail,whichresultedin the exclusion
of 89 additional studies. Data were abstracted from the nal 53
studies by use of a standardized form that
includedstudyobjective,design,datasource,geographic
location,andtimeperiod;samplesize,denitionofpopu-lation/cohort,andpatientcharacteristics;depressionmea-surement
instrument and denition, timing of the
interview/questionnaire,anddepressionprevalence;outcomedeni-tion,lengthoffollow-up,andnumberofevents;covariates
includedinrisk-adjustedmodels;andresultsandconclu-sions.Foreachoftheincluded53publications,1Writing
Groupmemberabstractedthedataandasecondreviewed the data for
completeness and accuracy. Disagreements were resolved by
consensus.Wealsoconductedasystematicreviewtoidentifypub-lishedmeta-analysesoftherelationshipbetweendepression
and outcomes among patients with ACS or other CHD diag-noses.
Wefollowedthesamesearchstrategyasabove,add-ingthefollowingsetofsearchterms:quantitativereview
or meta-analy*(using*fortruncation).Thissearchyielded
65uniquecitations,including4meta-analysesrelevantto our
review.FindingsA total of 53 studies met the criteria for inclusion
in the pres-entreview;32studiesreportedonassociationswithall-cause
mortality, 12 on associations with cardiac mortality, and 22 on
associations with a composite outcome that included mortality and
nonfatal events. These outcome groupings are not mutually
exclusive. Details of the 53 studies are presented by study
char-acteristics and by outcome type. Methodological
characteristics
variedacrossstudiesintermsoftheselectionofdepression measures,
outcome denitions, and covariates included in
mod-els(Table1).Themajorityofstudies,regardlessofoutcome, by guest
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Lichtman et alDepression Among Patients With ACS3included 25
depressed patients in their sample, had no more
than20%ofparticipantslosttofollow-up,andadjustedfor potential
confounding factors. Self-report measures of
depres-sionweremorecommonthanstructuredorsemistructured
interviews,withtheBeckDepressionInventory-I(BDI-I) being the most
commonly used measure. Most studies assessed
depressionasaprimarypredictorofoutcomesratherthan merely including
it as a covariate, although some of the cohorts
werenotspecicallydevelopedforthepurposeofassessing
therelationshipofdepressiontoACSoutcomes.Depression
wasassessedonacontinuousscaleinapproximatelyhalfof
thestudiesthatexamined all-causeandcardiacmortalityout-comes; this
was somewhat less common in studies that assessed a composite
outcome. Few studies used troponin levels in their denition of ACS,
most likely because data collection occurred
beforetheadoptionoftroponinasacriterionfordiagnosis. Outcome events
were adjudicated independently, and adequate denitions of outcomes
were provided in most analyses of all-cause mortality or cardiac
mortality; the quality of the outcome
denitionswasmorevariedforcompositeoutcomes. Amore
detaileddiscussionofselectedstudiesandresultsisprovided below
according to the specic outcome category.Depression and All-Cause
MortalityThe32studiesthatincludedall-causemortalityasanout-come
(Tables 1 and 2)1849 reported on 22 unique ACS patient cohorts.
Thesestudiesincludedpatientsfrom9countrieson 3 continents (North
America, Europe, and Asia), with sample sizesrangingfrom10025to21
74518patients.Twenty-four
studiesincludedonlypatientswhopresentedwithMI,*6 included patients
with any form of ACS,24,26,29,38,46,49 1 included
onlypatientspresentingwithUA,34and1includedpatients presenting with
MI complicated by congestive heart failure.47
Fifteenmeasuresofdepressionwereevaluatedaspotential
predictorsofall-causemortality.Self-reportquestionnaires were used
to assess depressive symptoms in nearly all of these
studies,withtheBDI-Iusedin20studies.Lessthanhalfof
thestudiesincludedstructuredorsemistructureddiagnostic
interviewsfordepression.Inmoststudies,theassessment
ofdepressionoccurredduringorwithinafewweeksafter
theindexhospitaladmission.However,3studiesmeasured depression
before the ACS event,18,19,47 and 2 included a
mea-sureofdepression1yearaftertheevent.33,35Themaximum Figure.
Selection of publications for abstraction. ACS indicates acute
coronary syndrome; CHD, coronary heart disease. *Previous reviews
included the following: Frasure-Smith and Lesprance,10,14,15 Kuper
et al,17 and Hemingway and Marmot.16 Outcome categories are not
mutually exclusive.References 18, 2023, 25, 28, 29, 33, 34, 36, 39,
49.*References 1823, 25, 27, 28, 3033, 3537, 3945, 48. by guest on
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4CirculationMarch25, 2014Table 1.Comparison of Study
Characteristics by OutcomesAll-Cause Mortality(n=32)Cardiac
Mortality(n=12)Composite Outcome(n=22)Study sample Total sample
size 100299 12 (38) 5 (42) 8 (36) 300599 7 (22) 1 (8) 8 (36) 600999
9 (28) 5 (42) 4 (18) 1000 4 (13) 1 (8) 2 (9) Sample included 25
depressed patients 30 (94) 11 (92) 19 (86) Inclusion/exclusion
criteria clearly described 26 (81) 12 (100) 19 (86) No more than
20% lost to follow-up 29 (91) 11 (92) 20 (91)Denition of acute
coronary syndrome Troponin levels 11 (34) 0 (0) 6 (27) Enzyme
levels other than troponins 24 (75) 11 (92) 9 (41) ECG changes 25
(78) 12 (100) 12 (55) Chest pain 22 (69) 12 (100) 10 (45)Depression
measure Self-report measure Beck Depression Inventory-I 20 (63) 9
(75) 11 (50) Beck Depression Inventory-II 1 (3) 0 (0) 2 (9) Center
for Epidemiologic Studies Depression Scale 1 (3) 0 (0) 0 (0)
Hospital Anxiety and Depression Scale, Depression Subscale 2 (6) 0
(0) 1 (5) Zung Self-Rating Depression Scale 2 (6) 2 (17) 2 (9)
Other 5 (16) 0 (0) 5 (23) Structured interview Diagnostic Interview
Schedule 3 (9) 3 (25) 3 (14) Depression Interview and Structured
Hamilton 5 (16) 0 (0) 1 (5) Structured Clinical Interview for DSM
Disorders 3 (9) 0 (0) 4 (18) Composite International Diagnostic
Interview 0 (0) 0 (0) 2 (9) Other 2 (6) 0 (0) 0 (0) Depression is a
primary predictor of outcomes (vs covariate) 26 (81) 11 (92) 19
(86) Depression measured by use of a continuous scale 14 (44) 7
(58) 8 (36)Outcome Outcomes were within 1 y (early recovery) 18
(56) 5 (42) 8 (36) Outcomes were assessed beyond 1 y 17 (53) 7 (58)
14 (64) At least 25 end points, with 10 events for every model
variable 10 (31) 1 (8) 10 (45) Outcome events dened adequately 30
(94) 11 (92) 12 (54) Outcome events adjudicated independently (vs
self-report, billing codes, etc)N/A 9 (75) 14 (64)Covariates
Adjusted for potential confounding factors recognized at the time
the study was conducted22 (69) 8 (67) 18 (82) Adjusted for systolic
function (eg, LVEF, Killip class) 18 (56) 7 (58) 17
(77)Risk-adjusted results Statistically signicant relationship
observed (depression associated with poorer outcome)21 (65) 8 (67)
17 (77)Data are presented as n (%) and represent columnwise
percentages. The number of unique cohorts represented for the 3
outcomes is as follows: 22 cohorts for all-cause mortality, 8
cohorts for cardiac mortality, and 18 cohorts for the composite
outcome.DSM indicates Diagnostic and Statistical Manual of Mental
Disorders; LVEF, left ventricular ejection fraction; and N/A, not
applicable. by guest on August 14, 2015
http://circ.ahajournals.org/ Downloaded from Lichtman et
alDepression Among Patients With ACS5Table 2.Summary of Included
Studies That Examined All-Cause MortalityStudyNo. of Sites;
Setting; CohortEnrollment Period NMeanAge, yWomen, %Instrument,
PrevalenceAssessment Timing Follow-UpNo. ofEvents
AssociationsAbrams et al, 200918144; United States; VHA
Administrative Data20032006 21 745 69 2 ICD-9-CM 296.20- 36/311/
300.4: inpatient diagnosis, 5%; outpatient diagnosis,
15%In-hospital; prior 12 mo1 mo; 12 mo 8100* Adj inpatient:NS (1
mo;unadj, S),NS (12 mo; unadj,S); adj outpatient:S (1 mo; unadj,
NS), S (12 mo; unadj, NS)Berkman et al, 1992192; United States;
EPESE- New Haven, CT19821988 194 6574, 40%; 7584, 44%; 85, 16%48
CES-D-20 16, 17% 0-3 y pre-MI 6 mo 76 Unadj: NSBush et al, 2001201;
United States 19951996 271 65 42 SCID MD/ dysthymia, 17%; BDI 10,
20%25 d 4 mo 18 Adj BDI 10/SCID MD/dysthymia: S;adj BDI linear
trend: SCarney et al, 2003214; United States; ENRICHD +
ancillary19972000 766 59* 40* DISH MD, 21%; DISH mD/dysthymia, 25%;
BDI 10, 47%28 d 30 mo 47 Adj DISH MD/ mD: S; adj DISH MD: S; adj
DISH mD: SCarney et al, 2007224; United States; ENRICHD +
ancillary19972000 498 61* 39* DISH MD/mD/ dysthymia, 47%; BDI 10,
47%28 d 30 mo(median 24)43 Adj DISH MD/ mD: NS (13 y);adj DISH
MD/mD:NS (1 y); adj DISH MD/mD: S (23 y)Carney et al, 2008234;
United States; ENRICHD + ancillary19972000 766 59* 40* DISH MD,
21%; DISH mD/dysthymia, 25%; BDI 10, 47%28 d Median 60 mo 106 Adj
DISH MD/ mD: S; adj DISH MD: S; adj DISH mD: SDoyle et al,
20062438; Ireland 2003 598 63* 24 HADS-D >7/ BDI-FS >3, 18%;
HADS-D >7, 15%; BDI-FS >3, 22%25 d 12 mo 24 Adj HADS-D >7/
BDI-FS >3: S; adj HADS-D >7: S; adj BDI-FS >3: NSDrago et
al, 2007251; Italy 1999 100 62 23 DSM-IV interview MD, 15%; BDI 10,
35%714 d Mean 60 mo 6 Adj DSM-IV MD: S; adj BDI 10: SGrace et al,
20052612; Canada 19971999 750 62 35 BDI 10, 31% 25 d 5 y 115 Adj
BDI 10: SIrvine et al, 19992731; Canada; CAMIAT19901995 671 64 17
BDI 10, NR 14 d after randomization2 y 63 Adj BDI 10: NSKaufmann et
al, 1999281; United States 1995 331 65 34 DIS MD, 27% 315 d 12 mo
33 Adj DIS MD: NS (unadj: S)Kronish et al, 2009293; United States;
COPES20032005 457 61 41 BDI 10, 47%; DISH MD, 11%7 d 12 mo 18 Adj
DISH MD: S; adj BDI continuous (excluding BDI 59): SLane et al,
2001302; United Kingdom19971998 288 63 25 BDI 10, 31% 215 d 12 mo
31 Unadj BDI 10: NSLane et al, 2002312; United Kingdom19971998 288
63 25 BDI 10, 31% 215 d 3 y 38 Unadj BDI 10: NSLauzon et al,
20033210; Canada 19961998 550 60* 21 BDI 10, 35% (baseline)23 d 12
mo 28 Adj BDI 10: NSLesprance et al, 1996331; Canada; EPPI 19911992
222 60 22 DIS history of MD, 27%; DIS current MD, 16%; DIS
postdischarge MD, 16% (86% of these by 6 mo);
DIScurrent/postdischarge MD, 32%515 d; 6 mo; 12 mo18 mo 21 Unadj
current MD: S; unadj 6 mo MD: NS(Continued ) by guest on August 14,
2015 http://circ.ahajournals.org/ Downloaded from
6CirculationMarch25, 2014Lesprance et al, 2000341; Canada 19941996
430 62 29 BDI 10, 41% Mean 5 d 12 mo 16 Unadj BDI 10: S; unadj DIS
MD: NS (among BDI 10)Lesprance et al, 20023510; Canada; EPPI and
M-HART19911994 896 59 32 BDI
