No benefits of statins for sudden cardiac death prevention in patients with heart failure and reduced

24 Pages·2017·2.7 MB·English

RESEARCHARTICLE
No benefits of statins for sudden cardiac
death prevention in patients with heart failure
and reduced ejection fraction: A meta-analysis
of randomized controlled trials
MuaamarAl-Gobari1*,Hai-HaLe2,MorFall2,3,Franc¸oisGueyffier2,BernardBurnand1
1 Instituteofsocial&preventivemedicine(IUMSP)andCochraneSwitzerland,LausanneUniversityHospital
(CHUV),Lausanne,Switzerland,2 LaboratoiredeBiologieetBiome´trieEvolutive–Servicedepharmacologie
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clinique,EquipeMode´lisationdesEffetsThe´rapeutiques(EMET),UMR,Universite´ClaudeBernardLyon1,
a1111111111
Lyon,France,3 LaboratoiredePharmacologie&dePharmacodynamie,Universite´CheikhAntaDiop,Dakar,
a1111111111
Se´ne´gal
a1111111111
a1111111111 *[email protected]
Abstract
OPENACCESS
Citation:Al-GobariM,LeH-H,FallM,GueyffierF, Backgroundandobjectives
BurnandB(2017)Nobenefitsofstatinsforsudden
Statinsshowedmixedresultsinheartfailure(HF)patients.ThebenefitsinmajorHFout-
cardiacdeathpreventioninpatientswithheart
failureandreducedejectionfraction:Ameta- comes,includingall-causemortalityandsuddencardiacdeath(SCD),havealwaysbeen
analysisofrandomizedcontrolledtrials.PLoSONE discordantacrosssystematicreviewsandmeta-analyses.Weintendedtosystematically
12(2):e0171168.doi:10.1371/journal.
identifyandappraisetheavailableevidencethatevaluatedtheeffectivenessofstatinsin
pone.0171168
clinicaloutcomesforHFpatients.
Editor:PasqualeAbete,UniversitadegliStudidi
NapoliFedericoII,ITALY
Design
Received:October21,2016
Systematicreviewandmeta-analysis
Accepted:January16,2017
Published:February6,2017 Datasources
Copyright:©2017Al-Gobarietal.Thisisanopen Wesearched,untilApril28,2016:Medline,Embase,ISIWebofScienceandEBMreviews
accessarticledistributedunderthetermsofthe
(CochraneDSR,ACPjournalclub,DARE,CCTR,CMR,HTA,andNHSEED),checkedclini-
CreativeCommonsAttributionLicense,which
caltrials.govforongoingtrialsandmanuallysearchedreferencesofincludedstudies.
permitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginal
authorandsourcearecredited. Eligibilitycriteriaforselectingstudies
DataAvailabilityStatement:Allrelevantdataare Weidentified24randomizedclinicaltrialsthatevaluatedtheefficacyofstatinsforHFpatients.
withinthepaperanditsSupportingInformation
Allrandomizedclinicaltrialswereassessedforriskofbiasandpooledtogetherinameta-anal-
files.
ysis.Pre-specifiedoutcomesweresuddencardiacdeath,all-causemortality,andhospitaliza-
Funding:MA,thecorrespondingauthor,receiveda
tionforworseningheartfailure.
financialgrant(2014.0193)fromTheFederal
DepartmentofEconomicAffairs,Educationand
Research(EAER),Switzerland.HHLreceiveda Results
financialgrantfromUniversityClaudeBernard
Statinsdidnotreducesuddencardiacdeath(SCD)eventsinHFpatients[relativerisk(RR)
Lyon1(scholarshipofFrenchMinistryofHigher
Education&Research)forathree-yearPhD 0.92,95%confidenceinterval(CI)0.70to1.21],all-causemortality[RR0.88,95%CI0.75
PLOSONE|DOI:10.1371/journal.pone.0171168 February6,2017 1/24
Statinsforsuddencardiacdeathpreventioninheartfailure
contract(10/2014-09/2017)attheUMR5558 to1.02]butsignificantlyreducedhospitalizationforworseningheartfailure(HWHF)although
CNRS.Allfundingisindependentfromthestudy modestly[RR0.79,95%CI0.66to0.94].Nevertheless,estimatedpredictiveintervalswere
design,datainterpretation,writingorthedecision
insignificantinSCD,all-causemortalityandHWHF[RR,0.54to1.63,0.64to1.19,and0.54
tosubmitthearticleforpublication.
to1.15],respectively.Animportantfindingwasthepossiblepresenceofpublicationbias,
CompetingInterests:Allauthorshavedeclared
small-studyeffectsandheterogeneityofthetrialsconductedinHFpatients.
thatnocompetinginterestsexist.
Abbreviations:AMI,AcuteMyocardialInfarction;
CHF,ChronicHeartFailure;DC,Dilated Conclusions
Cardiomyopathy;DCM,DilatedCardiomyopathy;
Statinsdonotreducesuddencardiacdeath,all-causemortality,butmayslightlydecrease
GRADE,GradingofRecommendationAssessment,
hospitalizationforworseningheartfailureinHFpatients.Theevaluationoftheriskofbiases
DevelopmentandEvaluation;HF,HeartFailure;
HFpEF,HeartFailurewithpreservedEjection suggestedmoderatequalityofthepublishedresults.Untilnewevidenceisavailable,this
Fraction;HWHF,HospitalizationforWorsening studysupportsthe2013ACCF/AHAguidelinestonotsystematicallyprescribestatinsin
HeartFailure;IDCM,IdiopathicDilated
“only”HFpatients,whichshouldhelpavoidunnecessarypolypharmacy.
Cardiomyopathy;LVEF,LeftVentricularEjection
Fraction;NA,NotAvailable;NICM,Non-Ischaemic
Cardiomyopathy;NR,NotReported;NYHA,New
YorkHeartAssociation;PCI,Percutaneous
CoronaryIntervention;RCTs,RandomizedClinical
Trials;SCD,SuddenCardiacDeath;WHO,World
Introduction
HealthOrganization;ACCF,AmericanCollegeof
CardiologyFoundation;AHA,AmericanHeart
Heartfailure(HF)patientsarelikelytotakemorethanonedrugandtendtowardpolypharmacy.
Association.
Guideline-directedmedicaltherapyincludesangiotensinconvertingenzymeinhibitors,beta-
blockers,aldosteroneantagonistsaswellasimplantablecardioverterdefibrillators,whichallhave
reportedareductioninmortalityandmorbidityinheartfailurepatients[1–4].Though,such
benefitsarestillinsufficienttothecurrentmanagementneedasalmosthalfofHFpatientsdie
within5yearsafterinitialdiagnosisandhalfofthemortalityisattributedtosuddencardiacdeath
(SCD)[5,6].MorepotentialbenefitsarehypothesizedwithstatintreatmentbutcurrentACCF/
AHAguidelinesdonotrecommendstatinsforonlyHFdiagnosis[7].However,3-hydroxy-
3-methylglutarylcoenzymeA(HMG-CoA)reductaseinhibitorsorsimplystatinsarestillwidely
prescribedforHFpatients[8].
Severalstudies[9–11]evaluatedtheeffectsofstatinonsuddencardiacdeathpreventionbut
withavarietyofpopulationcharacteristicswhichmadetheresultdifficulttoapplyforHFpatients.
Oppositely,twolargerandomizedclinicaltrials(RCTs)[12,13]inheartfailurereportednoreduc-
tionofall-causemortalityandSCDeventsbystatins.Moreover,studiesoftenevaluatedsurrogate
endpointsorbiomarkersotherthanimportantclinicalendpointssuchasmortalityandthatmight
haveexaggeratedtheexpectedbenefitsofstatins[14].
Asystematicreview[15],publishedin2006,stressedontheimportanceofthisresearch
questionandpointedouttheconflictingandunclearevidence.CORONA[13]andGISSI-HF
[12](unpublishedatthattime)wasexpectedtoresolvetheissue.Inthecontrary,bothstudies,
afterpublication,raisedcontroversialstatementsanddebates.Themorbidityandmortality
rateamongHFpatientsisconsiderablyhighandanemphasisoneffectivepreventionstrategies
wouldleadtoasignificantreductionofsuchevents.Similarly,HFpatientshaveareducedlon-
gevitythustheneedforprovidingcliniciansandhealthcareactorsanoptimalevidence-based
strategyisofvitalimportance.
Nevertheless,currenttrials,systematicreviewsandmeta-analyses[16–24]forstatinshave
shownmixedresultsformajorHFoutcomes.Positivestudieswerenotimmunetobias,serious
limitationsorindirectness.Therefore,weintendedtoevaluateandupdatethequalityofevi-
denceofstatinsefficacytoreduceSCD,mortalityorhospitalizationforworseningheartfailure
(HWHF)bymeansofasystematicreviewandameta-analysiswithacarefulconsiderationof
potentialbiasesinpublishedstudies.
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Statinsforsuddencardiacdeathpreventioninheartfailure
Methods
Studysearchstrategy
WesearchedMedline(1946toApril28,2016),Embase(1974toApril28,2016),EBMreviews
(CochraneDSR,ACPjournalclub,DARE,CCTR,CMR,HTA,andNHSEED)(toApril28,
2016),andISIwebofscience(‘‘Allyears”toApril28,2016)viaanOvidonlineinterfaceandiden-
tifiedsystematicreviewsandmeta-analysesviaasearchstrategyaccessibleonS1File.Inafirst
step,weusedafilter[25,26]tosearchforsystematicreviewsandmeta-analysesandinitially
excludedindividualclinicaltrialsforthepurposeofourstudy.Inasecondstep,wesearchedfor
primarystudiesandincludedrandomizedclinicaltrialsevaluatingstatinsinheartfailurepatients.
InMedlineandEmbase,wecombinedmedicalsubjectheadingterms(MeSHandEMTREE
respectively),textwordsaswellasatruncationwhenappropriate.Themethodincludedacombi-
nationofadisease(i.e.,heartfailure),anintervention(i.e.,statins)aswellastheaforementioned
filter.Also,weaddedanoutcome(i.e.,suddencardiacdeathand/ormortality)tolimittheresearch
output.Nolanguagerestrictionswereappliedandabimonthlyalertwassetupforanautomatic
updateduringthestudy.Wealsocheckedthereferencesofincludedstudiesforpotentialaddi-
tionalstudies,searchedclinicaltrials.govandtriedtocontactauthorsforadditionalormissing
data.Fig1showsthesearchstrategyresultsaccordingtothePRISMAguidelines(seealsoS2File).
Selectioncriteriaanddataabstraction
Weincludedrandomizedclinicaltrials(RCTs)thatevaluatedstatinsefficacyinheartfailure
patientsandcontainedatleastoneoutcomeofinterest.Noexclusionwasbasedontreatment
durationorfollow-upperiod,languageorintention-to-treat analysis.Riskofbiaswasdeter-
minedbytheCochraneriskbiasassessmenttool[27].Tworeviewers(MA&HHL)indepen-
dentlycollecteddataandwerecheckedbyathirdreviewer(MF)whilediscrepancieswere
resolvedviadiscussionandconsensus.Abstracteddataincludedeligibilitycriteria,baseline
characteristics,studydesign(includingtreatmentandcontrolarms),follow-upduration,and
Fig1.Flowchartforsearchresult.
doi:10.1371/journal.pone.0171168.g001
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Statinsforsuddencardiacdeathpreventioninheartfailure
outcomes.Pre-specifiedoutcomesofinterestincludedsuddencardiacdeath(SCD),all-cause
mortalityandhospitalizationforworseningheartfailure(HWHF)andwereanalyzedaccord-
ingtoanintention-to-treat principlewhenpossible.
Statisticalanalysis
Wepooledthedatainameta-analysis,usingrandom-effectsandfixed-effectsmodelwithMan-
tel-Haenszelmethodsthatarepreferabletoinversevariancemethodsincaseoffewevents[27].
Sensitivityandsubgroupanalysesweredonetoverifytheextenttowhichdifferenthypotheses
mightchangeourconfidenceintheresult.Theeffectsizewasrelativeriskorriskratio(RR),
confidenceintervals(CIs)of95%wasgivenwhenapplicableandasignificancelevelwasdeter-
minedattwo-sidedalphalessthan5%.Wereportedbothfixed-effectandrandom-effectsmod-
elsforthemeta-analysisandusedriskratios(RR)asthesummaryeffectestimatethatmaygive
betterinterpretationastheoutcomeishospitalizationordeathevents,termedbadoutcome.
Wecalculatedtheabsoluteeffectortheabsoluteriskreduction(ARR)forSCD,all-causemor-
talityandHWHFwithanassumedcontrolrisk(ACR)of0.11,0.27and0.38respectively.To
checkthevalidityofchoosingthesummarystatistic,oddsratio(OR)wasusedinsteadofRRin
asensitivityanalysis.The95%predictioninterval,anintervalthatestimateatreatmenteffectof
aneworfuturetrialwithinwhichweareconfidentitlies,wasgivenwhenarandom-effects
modelisused.Also,weratedthequalityoftheevidenceusingasummaryoffindingstablefrom
theGRADEapproach[28].Wecomputedthesamplesizerequiredtoreachastatisticalsignifi-
canceaccordingtotheobserveddifferencesbetweenthegroupsofstatinandplaceboorcontrol
foralloutcomes[α=5%andpower(1-β)=0.80]andintendedtostratifythestudiesaccording
tofollow-upandsamplesizeinsubgroupandsensitivityanalyses.Heterogeneitywasmeasured
byI-squared(I2,variationinRR/ORattributabletoheterogeneity)andTau-squared(Tau2,esti-
mateofbetween-studyvariance).Wenoticedthatthefollow-upperioddifferedlargelyfrom
onestudytoanotherfromonemonth[29,30]tomorethan30months[12,13,31].Therefore,
studiesweregroupedaccordingtofollow-upasapotentialdeterminantofanyheterogeneity
amongstudies.DatawasanalyzedwithSTATAversion14.1(StataCorpLP,Texas),RevMan
(version5.3)andGradePro(version3.6.1).
Results
Studyselection
Electronicdatabasesandmanualsearchesresultedin1335studiesafterremovalofduplicates.
Afterscreeningoftitlesandabstractsandexaminationofselectedfull-texts,weendedupwith
17systematicreviews/meta-analyses[9,11,18–24,32–39]and24randomizedcontrolledtrials
(RCTs)[12,13,40–51][29,31,52][30,53–58](Fig1).
Studyandbaselinepatientcharacteristics
AsshowninTables1and2,weidentified24RCTsofstatinsinheartfailure(HF)patientsfor
inclusioninthismeta-analysis,whichenrolledatotalof11,463patients.Themeanandthe
medianoffollow-updurationwere11.5and6monthsrespectively.Thestudiesincludedin
majoritymaleparticipants(ratiorangedfrom54%to100%)withanaverageageof60years.
Themeanageofthethreebiggeststudies(CORONA[13],GISSI-HF[12]andTakanoH.etal.
(PEARL)[31])was68years.AllstudiesincludedHFpatientswithNewYorkHeartAssociation
classification(NYHA)rangingfromI-IVandatleast9studiesincludedstableHFpatients.
Sevenstudiesincludednon-ischaemicHFpatients,4studiesexclusivelyischaemic,12included
bothtypesandoneunknown.Allpatientsinincludedstudieshadanejectionfractionlessthan
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Statinsforsuddencardiacdeathpreventioninheartfailure
Table1. Randomizedtrialsofstatinsinheartfailurepatients.
Trial[Reference] Publication Numberofpatients Nameof Comparator Meanbaseline PrimaryEndpoint Dosage(mg/ Follow-up
Year (statin/comparator) drug Lipids day) (months)
AbdulHulE.etal. 2012 56(28/28) Atorvastatin Nostatin LDL-c=2.73 Biomarkers,BNP 40 6
[40] mmol/L
Bielecka-D.etal. 2009 68(41/27) Atorvastatin Nostatin LDL-c=3.15 Factorsaffect 10–40 6
[41] mmol/L HWHF/mortality
BleskeBE.etal. 2006 18(9/9)* Atorvastatin Placebo LDL-c=2.84 Surrogatemarkersin 80 3
[42] mmol/L NICM
CORONA[13] 2007 5011(2514/2497) Rosuvastatin Placebo LDL-c=3.55 HWHF/SCD/mortality 10 32.8
mmol/L
ErbsS.etal.[43] 2011 42(22/20) Rosuvastatin Placebo LDL-c(cid:21)3.78 Pleiotropiceffects 40 24
mmol/L
Gissi-HF 2008 4574(2285/2289) Rosuvastatin Placebo NR HWHF/SCD/mortality 10 46.8
Investigators[12]
HammadA.etal. 2005 23(13/10) Atorvastatin Placebo TC(cid:25)3.5 Autonomicnervous 40 3
[44] mmol/L system
Hongetal.[58] 2005 202(106/96) Simvastatin Nostatin LDL-c(cid:25)3.62 PCIrate,restenosis, 40 12
mmol/L mortality
HorwichTB.etal. 2011 26(14/12) Atorvastatin Placebo LDL-c(cid:25)2.79 Sympatheticnervous 10 3
[45] mmol/L system
Krumetal.[46] 2007 86(40/45) Rosuvastatin Placebo NR Ventricular 10–40 6
remodeling
LaufsU.etal.[47] 2004 15(8/7) Cerivastatin Placebo LDL-c(cid:25)3.46 Pleiotropiceffects 0.4 5
mmol/L
LiuM.etal.[48] 2009 64(32/32) Atorvastatin Placebo LDL-c(cid:25) Inflammation 10 3
3.03mmol/L
MozaffarianD.etal. 2005 22(12/10) Atorvastain Placebo LDL-c=3.33 Inflammation 10 2
[49] mmol/L
NodeK.etal.[50] 2003 51(23/25) Simvastatin Placebo LDL-c(cid:25)3.85 Cardiacfunction 5–10 3.5
mmol/L
SolaS.etal.[51] 2006 108(46/43) Atorvastatin Placebo LDL-c(cid:25)3.12 Inflammation 20 12
mmol/L
StreyCH.etal.[52] 2006 23(11/12)* Atorvastatin Placebo LDL-c(cid:25)3.56 Endothelialfunction 40 1.5
mmol/L
TakanoH.etal.[31] 2013 577(288/286) Pitavastatin Nostatin LDL-c(cid:25)3.24 Mortality/HWHF/ 2 35.5
mmol/L stroke
TousoulisD.etal. 2005 38(19/19) Atorvastatin Nostatin TC(cid:25)4.83 Inflammation 10 1
[29] mmol/L
TousoulisD.etal. 2004 38(14/12) Atorvastatin Nostatin TC(cid:25)5.04 Inflammation 10 1
[30] mmol/L
VrtovecB.etal. 2005 80(40/40) Atorvastatin Nostatin TC(cid:25)5.07 HRV/QTV/QTc 10 3
[53] mmol/L
VrtovecB.etal. 2008 110(55/55) Atorvastatin Nostatin LDL-c=2.45 SCD 10 12
[54] mmol/L
WojniczR.etal. 2006 74(36/38) Atorvastatin Nostatin LDL-c(cid:25)4.18 Inflammation 40 6
[55] mmol/L
XieRQ.etal.[56] 2008 119(78/41) Atorvastatin Statin/no LDL-c(cid:25)3.64 Cardiacfunction 10–20 12
statin mmol/L
YamadaT.etal. 2007 38(19/19) Atorvastatin Nostatin LDL-c(cid:25)3.02 Cardiacfunction 10 31
[57] mmol/L
BNP:B-typenatriureticpeptide;HRV:heartratevariability;QTV:QTvariability;QTc:QTcinterval;HWHF:Hospitalizationforworseningheartfailure;LDL-
c:lowdensitylipoproteincholesterol;NICM:Non-IschaemicCardiomyopathy;PCI:percutaneouscoronaryintervention;SCD:suddencardiacdeath;TC:
totalcholesterol;NR:notreported;(cid:25):approximately.
*Estimatedvalues
doi:10.1371/journal.pone.0171168.t001
45%andnooneincludedHFwithapreservedejectionfraction(HFpEF).Baselinemeanlipid
levelswererelativelysimilarfromonestudytoanotherwithmeanlow-densitylipoprotein
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Statinsforsuddencardiacdeathpreventioninheartfailure
Table2. Patientcharacteristicsinrandomizedtrialsofstatinsinheartfailurepatients.
Trial[Reference] Meanage Male Inclusioncriteria Population(Ischaemicornon- MeanLVEF NYHA
(Years) (%) ischaemic,%) (%)
AbdulHulE.etal.[40] 72 68 Mild-moderateHF,LVEF(cid:20)45% Ischaemic,64 35 II-III
Bielecka-D.etal.[41] 57 85 StableHFwithDC NR 29 I-III
BleskeBE.etal.[42] 56 60 CHFduetoNICM,LVEF<40% Non-ischaemic 25 I-III
CORONA[13] 73 76 IschaemicHF,age(cid:21)60, Ischaemic,100 31 II-IV
LVEF<40%
ErbsS.etal.[43] 62 76 CHF—IschaemicHForDC Ischaemic,28 30 II-III
Gissi-HFInvestigators 68 77 CHF,NoLVEFrestriction Ischaemic,40 33 II-IV
[12]
HammadA.etal.[44] 67 86 StablesystolicHF Ischaemic,57 31 II-III
Hongetal.[58] 61 72 PatientsunderwentPCIforAMI Ischaemic,100 31 II-IV
HorwichTB.etal.[45] 48 62 SymptomaticHF,LVEF(cid:20)35% Non-ischaemic 26 I-III
Krumetal.[46] 62 80 NYHAII-IV,LVEF(cid:20)35% Ischaemic,12 29 II-IV
or(cid:20)40%
LaufsU.etal.[47] 51 NR CHFwithNICM Non-ischaemic 42 II-III
LiuM.etal.[48] 67 94 NYHAII-III,CHFwithIDCM Ischaemic/Non-ischaemic 20 II-IV
MozaffarianD.etal.[49] 51 86 AmbulatoryHF,LVEF<40% Ischaemic,9 31 II-III
NodeK.etal.[50] 54 69 HFwithIDCM Non-ischaemic 33 II-III
SolaS.etal.[51] 54 63 Stablenon-ischaemicHF Non-ischaemic 33 II-IV
StreyCH.etal.[52] 61 70 SymptomaticHF,LVEF<40% Non-ischaemic 30 II-III
TakanoH.etal.[31] 63 81 CHF,LVEF(cid:20)45% Ischaemic,27 34 II-III
TousoulisD.etal.[29] 69 100 IschaemicHF,LVEF(cid:20)35% Ischaemic 25 III-IV
TousoulisD.etal.[30] 58 NR StableHF.LVEF(cid:20)35% Ischaemic,65.7 25 II-IV
VrtovecB.etal.[53] 67 54 StableHF,LVEF<30% Ischaemic,62 25 III
VrtovecB.etal.[54] 62 61 StableHF,LVEF<30% Ischaemic,59 25 III
WojniczR.etal.[55] 38 81 StableHFwithDC Non-Ischaemic 28 II-III
XieRQ.etal.[56] NR NR IschaemicHF,LVEF<45% Ischaemic,100 38 II-IV
YamadaT.etal.[57] 64 79 StableHF,NYHAI-III Ischaemic,53 34 I-III
AMI:acutemyocardialinfarction;CHF:ChronicHeartFailure;DC:dilatedcardiomyopathy;DCM:dilatedcardiomyopathy;HF:heartfailure;IDCM:
idiopathicdilatedcardiomyopathy;LVEF:LeftVentricularEjectionFraction;NICM:Non-IschaemicCardiomyopathy;NR:notreported;NYHA:NewYork
HeartAssociation;PCI:percutaneouscoronaryintervention.
doi:10.1371/journal.pone.0171168.t002
cholesterol(LDL-c)of3.3for19studiesandmeantotalcholesterol(TC)of5.19for3studies
andunknownfor2studies.Only5studies[13][12][31][58][54]hadamortalityendpoint
whileothersevaluatedsurrogateendpointsandbiomarkers.Statinswerecomparedtoplacebo
in13studiesandtonostatinin10studies;onestudycomparedtwodifferentdosesofstatinsto
anostatingroup[56].
Riskofbiasandqualityofstudies
Weassessedstudies’riskofbiasbymeansoftheCochranebiastool[27].Wenoticedthatthe
intention-to-treat principlewasnotfollowedinalltrials,amongwhich10hadeitherhighor
unclearrisk(Fig2(B)).Mostoftheincludedtrialshadunclearrisktowardsblindingofinvestiga-
torsoroutcomeassessors.Overall,thestudiesfluctuatedfromhightomoderate/lowlevelofqual-
ity.Fig2(A)showsthesummaryofbiasriskassessmentinpercentagesandforeachincluded
trial.Wealsoratedeachoutcome(SCD,All-causemortalityandhospitalizationforworsening
heartfailure(HWHF))accordingtotheGRADEapproach(Fig3).Studieswereevaluatedper
outcomeforanybias,inconsistency,indirectness,imprecisionorpublicationbias.Thelatterwas
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Statinsforsuddencardiacdeathpreventioninheartfailure
Fig2.Riskofbiasforincludedstudies.A)Riskofbiasgraphforstatintrialsinheartfailurepatients:review
authors’judgmentsabouteachriskofbiasitempresentedaspercentagesacrossallincludedstudies.B)Risk
ofbiassummaryforstatinsinheartfailurepatients:reviewauthors’judgmentsabouteachriskofbiasitemfor
eachincludedstudy.
doi:10.1371/journal.pone.0171168.g002
aconcernforalloutcomesandthisresultedinmoderateevidence.Duetomissingdataor
absenceofevents,only8studiesforSCD,13studiesforall-causemortalityand12studiesfor
HWHFwereanalyzed.
Efficacyofstatinsandsynthesisofresults
Wepooledthestudiestoevaluateeffectsofstatinsonthereductionofsuddencardiacdeath
(SCD),all-causemortality,andhospitalizationduetoworseningheartfailure(HWHF).The
forestplotsinFig4showsinsignificantreductioninSCD[RiskRatio(RR)0.92;95%CI,0.70
to1.21,P=0.554]andall-causemortality[RR0.88;95%CI,0.75to1.02,P=0.092]andasta-
tisticallysignificantdifferenceinHWHF[RR0.79;95%CI,0.66to0.84,P=0.008].Random-
effectsandfixed-effectmodelswereusedtoquantifythesummarystatisticbyRR.Theeffect
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Fig3.GRADEsummaryoffindingstable.
doi:10.1371/journal.pone.0171168.g003
sizeoffixed-effectsmodelswasquitesimilartoCORONA[13]whichweighted59.9%,50.8%,
and63.7%fortherespectiveoutcomesofthestudypopulation.
InGradeoutput(Fig3),theSCDratewas10.7%(n=540/5057)inthosetreatedwithstatins
comparedwith10.8%(n=544/5020)inthosetreatedwithplacebo/controlwithanabsoluteeffect
of9fewerper1000(from33fewerto23more).All-causemortalityratewas25.9%(n=1436/
5549)inthosetreatedwithstatinscomparedwith27.3%(n=1494/5475)inthosetreatedwith
placebo/controlwithanabsoluteeffectof33fewerper1000(from68fewerto5more).Also,hos-
pitalizationratewas33.33%(n=1804/5412)inthosetreatedwithstatinscomparedwith38%
(n=2033/5349)inthosetreatedwithanabsoluteeffectof80fewerper1000(from23fewerto
129fewer)(seealsoS1Table).Theestimatedsamplesizeneededtodetectastatisticallysignificant
difference,giventheeffectsizefound,were599506,15394and1642respectivelyforSCD,all-
causemortalityandHWHF[59].Moreover,theestimatedpredictiveintervals(PIs)werestatisti-
callyinsignificant[0.52to1.63,0.54to1.15,and0.64to1.19]inSCD,all-causemortalityand
HWHF,respectively,asshowninFig4.
Theretrievedpublishedsystematicreviewsandmeta-analyseswereevaluatedagainst
potentialbiasesandarecomparedwiththeresultsofoursystematicreviewinthediscussion
section.
Meta-regressionandheterogeneityofcombinedstudies
ForSCD,all-causemortalityandHWHF,heterogeneityestimatorswere,respectively:I2=
(42.8%,37.9%,and58%)andTau2=(0.0353,0.0135,and0.0215).Weintendedtoexplainthe
heterogeneitybyameta-regressionanalysisforcholesterollevelschangesforeachoutcome
butthiswasnotstatisticallyfeasiblebecauseofzeroeventsintheinterventionorcontrolgroup
insometrials[log(OR)orlog(RR)becameundefined].Also,atleastbecausethenumberof
studiesleftforanyoutcomeassessmentdecreasedandtheriskoftype errormayhaveproba-
blyincreased.
However,wetriedtoexplaintheheterogeneityobservedforassessedoutcomesbystratifica-
tionaccordingtofollow-upduration.AsshowninFig5,studieswereclassifiedintothreecate-
gories:6monthsorless,morethan6monthsandlessthan12,andmorethan12months.
Negativeresultwasmaintainedinthisanalysisexceptforstudiesoflessthan12monthsoffol-
low-upwhichwaslikelyduetosmall-studyeffects,revealedbyinsignificantreductionfor
studiesmorethan12monthswhichrepresentedbetween85–92%ofthestudiedpopulation.
PLOSONE|DOI:10.1371/journal.pone.0171168 February6,2017 8/24
Statinsforsuddencardiacdeathpreventioninheartfailure
Fig4. Efficacyofstatinscomparedwithcontrolinheartfailureforthepreventionof(A)sudden
cardiacdeath(SCD)(B)all-causemortality,and(C)hospitalizationforworseningheartfailure(HWHF).
doi:10.1371/journal.pone.0171168.g004
Sensitivityandsubgroupanalyses
BothCORONA[13]andGISSI-HF[12]comprisedatleast70%ofthestudypopulationirrespec-
tiveoftheoutcomeorthemodelused.Therefore,weconductedasensitivityanalysistoassess
theimpactofthesetrialsontheresultsbyexcludingthemfromtherandom-effectestimate.This
resultedintosignificantdifference:RRforSCD[0.27(95%CI,0.11to0.66),P=0.004],RRfor
all-causemortality[0.55(95%CI,0.40to0.77),P=0.0001],andRRforHWHF[0.54(95%CI,
0.39to0.76),P=0.0001](seeFig6).
PLOSONE|DOI:10.1371/journal.pone.0171168 February6,2017 9/24
Statinsforsuddencardiacdeathpreventioninheartfailure
Fig5. Efficacyofstatinscomparedwithcontrolinheartfailurestratifiedbyfollow-updurationforthe
preventionof(A)suddencardiacdeath(SCD)(B)all-causemortality,and(C)hospitalizationforworsening
heartfailure(HWHF).
doi:10.1371/journal.pone.0171168.g005
Ontheotherhand,afterdeletinglesspoweredstudies,i.e.,thosewithlessthan100patients
ineachgroup,thisresultedintoinsignificantincreaseinSCD[RR1.03(95%CI,0.88to1.20),
P=0.725],RRforall-causemortality[0.98(95%CI,0.90to1.06),P=0.566],andRRfor
HWHF[0.90(95%CI,0.79to1.04),P=0.149].Theremainingstudieswere(CORONA[13],
GISSI-HF[12]forSCDplusTakanoH.etal.(PEARL)[31]forall-causemortalityandHWHF
outcomes)(seeFigs7and8).
PLOSONE|DOI:10.1371/journal.pone.0171168 February6,2017 10/24