Antioxidant supplements for prevention of mortality in healthy participants and patients with various

238 Pages·2017·9.08 MB·English

Antioxidant supplements for prevention of mortality in
healthy participants and patients with various diseases
(Review)
Bjelakovic G, NikolovaD, Gluud LL, Simonetti RG, Gluud C
ThisisareprintofaCochranereview,preparedandmaintainedbyTheCochraneCollaborationandpublishedinTheCochraneLibrary
2008,Issue2
http://www.thecochranelibrary.com
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review)
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Analysis1.1.Comparison1Antioxidantsversusplacebo/nointervention,Outcome1Mortalityintrialswithaloworhigh
riskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Analysis1.2.Comparison1Antioxidantsversusplacebo/nointervention,Outcome2Mortalityinprimaryandsecondary
preventiontrialswithaloworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . 173
Analysis1.3.Comparison1Antioxidantsversusplacebo/nointervention,Outcome3Mortalityafterexcludingtrials
administratingextrasupplementsintheantioxidantgroup. . . . . . . . . . . . . . . . . . . 176
Analysis1.4.Comparison1Antioxidantsversusplacebo/nointervention,Outcome4Mortalityafterexcludingtrialswith
extrasupplementsforbothinterventiongroups. . . . . . . . . . . . . . . . . . . . . . . 179
Analysis1.5.Comparison1Antioxidantsversusplacebo/nointervention,Outcome5Mortalityafterexcludingfactorial
trialswithpotentialconfounding. . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Analysis1.6.Comparison1Antioxidantsversusplacebo/nointervention,Outcome6Mortalityafterexcludingfactorial
trialswithpotentialconfoundingandtrialswithextrasupplements. . . . . . . . . . . . . . . . 184
Analysis1.7.Comparison1Antioxidantsversusplacebo/nointervention,Outcome7Mortalityafterexcludingtrialswith
anypotentialconfounding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Analysis1.8.Comparison1Antioxidantsversusplacebo/nointervention,Outcome8Mortalityinbeta-carotenetrialswith
aloworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
Analysis1.9.Comparison1Antioxidantsversusplacebo/nointervention,Outcome9MortalityinvitaminAtrialswitha
loworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Analysis1.10.Comparison1Antioxidantsversusplacebo/nointervention,Outcome10MortalityinvitaminCtrialswith
aloworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
Analysis1.11.Comparison1Antioxidantsversusplacebo/nointervention,Outcome11MortalityinvitaminEtrialswith
aloworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Analysis1.12.Comparison1Antioxidantsversusplacebo/nointervention,Outcome12Mortalityinseleniumtrialswitha
loworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
Analysis1.13.Comparison1Antioxidantsversusplacebo/nointervention,Outcome13Mortalityinlow-biasriskbeta-
carotenetrialswithoutselenium. . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
Analysis1.14.Comparison1Antioxidantsversusplacebo/nointervention,Outcome14Mortalityinlow-biasriskvitamin
Atrialswithoutselenium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Analysis1.15.Comparison1Antioxidantsversusplacebo/nointervention,Outcome15Mortalityinlow-biasriskvitamin
Ctrialswithoutselenium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
Analysis1.16.Comparison1Antioxidantsversusplacebo/nointervention,Outcome16Mortalityinlow-biasriskvitamin
Etrialswithoutselenium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) i
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) ii
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Antioxidant supplements for prevention of mortality in
healthy participants and patients with various diseases
GoranBjelakovic1,DimitrinkaNikolova2,LiseLotteGluud2,RosaGSimonetti3,ChristianGluud2
1Departmentof Internal Medicine -GastroenterologyandHepatology, MedicalFaculty, University of Nis,Nis, Serbia.2Cochrane
Hepato-BiliaryGroup,CopenhagenTrialUnit,CentreforClinicalInterventionResearch,Department3344,Rigshospitalet,Copen-
hagenUniversityHospital,Copenhagen,Denmark.3DivisionediMedicina,OspedaleV.Cervello,Palermo,Italy
Contactaddress:GoranBjelakovic,DepartmentofInternalMedicine-GastroenterologyandHepatology,MedicalFaculty,University
ofNis,BoulevardDrZoranaDjindjica81,Nis,18000,[email protected].
Editorialgroup:CochraneHepato-BiliaryGroup.
Publicationstatusanddate:Edited(nochangetoconclusions),commentaddedtoreview,publishedinIssue1,2010.
Reviewcontentassessedasup-to-date: 19February2008.
Citation: BjelakovicG,NikolovaD,GluudLL,SimonettiRG,GluudC.Antioxidantsupplementsforpreventionofmortalityin
healthyparticipantsandpatientswithvariousdiseases.CochraneDatabaseofSystematicReviews2008,Issue2.Art.No.:CD007176.
DOI:10.1002/14651858.CD007176.
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Animalandphysiologicalresearchaswellasobservationalstudiessuggestthatantioxidantsupplementsmayimprovesurvival.
Objectives
Toassesstheeffectofantioxidantsupplementsonmortalityinprimaryorsecondarypreventionrandomisedclinicaltrials.
Searchmethods
WesearchedTheCochraneLibrary(Issue3,2005),MEDLINE(1966toOctober2005),EMBASE(1985toOctober2005),andthe
ScienceCitationIndexExpanded(1945toOctober2005).Wescannedbibliographiesofrelevantpublicationsandwrotetopharmaceutical
companiesforadditionaltrials.
Selectioncriteria
Weincludedallprimaryandsecondarypreventionrandomisedclinicaltrialsonantioxidantsupplements(beta-carotene,vitaminA,
vitaminC,vitaminE,andselenium)versusplaceboornointervention.Includedparticipantswereeitherhealthy(primaryprevention
trials)orhadanydisease(secondarypreventiontrials).
Datacollectionandanalysis
Threeauthorsextracteddata.Trialswithadequaterandomisation,blinding,andfollow-upwereclassifiedashavingalowriskofbias.
Random-effects and fixed-effect meta-analyses were performed. Random-effects meta-regression analyses were performed to assess
sourcesofintertrialheterogeneity.
Mainresults
Sixty-sevenrandomisedtrialswith232,550participantswereincluded.Forty-seventrialsincluding180,938participantshadlowrisk
of bias. Twenty-one trialsincluded 164,439 healthyparticipants. Forty-six trials included 68111 participants with various diseases
(gastrointestinal, cardiovascular, neurological, ocular, dermatological, rheumatoid, renal, endocrinological, or unspecified). Overall,
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 1
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
theantioxidant supplementshadnosignificant effectonmortalityinarandom-effectsmeta-analysis(relativerisk[RR]1.02, 95%
confidenceinterval[CI]0.99to1.06),butsignificantlyincreasedmortalityinafixed-effectmodel(RR1.04,95%CI1.02to1.06).
In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial
heterogeneity.Inthetrialswithalowriskofbias, theantioxidant supplementssignificantly increasedmortality(RR1.05, 95%CI
1.02to1.08).Whenthedifferentantioxidantswereassessedseparately,analysesincludingtrialswithalowriskofbiasandexcluding
seleniumtrialsfoundsignificantlyincreasedmortalitybyvitaminA(RR1.16,95%CI1.10to1.24),beta-carotene(RR1.07,95%
CI1.02to1.11),andvitaminE(RR1.04,95%CI1.01to1.07),butnosignificantdetrimentaleffectofvitaminC(RR1.06,95%
CI0.94to1.20).Low-biasrisktrialsonseleniumfoundnosignificanteffectonmortality(RR0.90,95%CI0.80to1.01).
Authors’conclusions
Wefoundnoevidencetosupportantioxidantsupplementsforprimaryorsecondaryprevention.VitaminA,beta-carotene,andvitamin
Emay increase mortality.Future randomised trialscouldevaluatethepotential effectsof vitamin Candseleniumforprimary and
secondary prevention. Such trials should be closely monitored for potential harmful effects. Antioxidant supplements need to be
consideredmedicinalproductsandshouldundergosufficientevaluationbeforemarketing.
PLAIN LANGUAGE SUMMARY
Noevidencetosupportantioxidantsupplementstopreventmortalityinhealthypeopleorpatientswithvariousdiseases
Previousresearchonanimalandphysiologicalmodelssuggestthatantioxidantsupplementshavebeneficialeffectsthatmayprolonglife.
Someobservationalstudiesalsosuggestthatantioxidantsupplementsmayprolonglife,whereasotherobservationalstudiesdemonstrate
neutralorharmfuleffects.Randomisedtrialshavelargelybeenneutral.Weneedevidencefromrandomisedtrialstodecideifantioxidant
supplementsshouldbeusedforprevention.
BACKGROUND tioxidants may play dual roles, acting as double-edged swords
(Bjelakovic 2007b). Excessive antioxidants can adversely affect
Oxidativestressmayplayroleinthepathogenesisofcancerand
key physiological processes. The results of our recent system-
cardiovasculardisease,theleadingcausesofdeathinmiddle-and
atic review and meta-analyses of the role of antioxidant sup-
high-incomecountries(Sies1985;Halliwell1999).Dietprovides
plementsforpreventionofgastrointestinal cancerswereunfore-
numerousvitaminsandtraceelementsthatareessentialforgood
seen(Bjelakovic2004).Wefoundthatantioxidant supplements
health.Severalobservationalstudieshaveshownasignificantpos-
significantly increased mortality in the antioxidant group with
itiveassociationbetweenhigherintakeoffruitsandvegetablesand
the fixed-effect model meta-analysis but not with the random-
reducedriskofchronicdiseases(Block1992;Ames1993;Willcox
effects meta-analysis (Bjelakovic 2004). The effect of antioxi-
2004). However, exactly which specific dietary constituents of
dant supplements on mortality has also been assessed in sev-
fruitsandvegetablesmightbebeneficialisnotclear.Furthermore,
erallargetrialsonprimaryandsecondarypreventionofdiseases
causal inferences are hard to establish from observational stud-
(HPS2002Low;ATBC2003Low;CARET2004Low;SUVIMAX
ies.Antioxidantshaveattractedmostattentionaspromisingpre-
2004Low;HOPETOO2005Low;WHS2005Low).Theresults
ventiveagents.Fruitsandvegetablesaresourcesofnumerousmi-
oftheindividualtrialsareequivocal.Furthermore,noneofthetri-
cronutrientsandsomeofthese,includingbeta-carotene,vitamin
alshadsufficientstatisticalpowertoidentifytheeffectofantioxi-
A,vitaminC,vitaminE,andseleniumhaveantioxidantpotential.
dantsonmortality.Accordingly,weperformedasystematicreview
Manypeopletakeantioxidantsupplementsbelievingtoimprove
ofrandomisedtrialsonantioxidantsupplementsforprimaryand
theirhealth(Balluz2000;Millen2004;Radimer2004;Nichter
secondaryprevention.
2006).
Whetherantioxidantsupplementsarebeneficialorharmfulisun-
certain(Herbert1997;Caraballoso2003;Vivekananthan2003;
Bjelakovic2004;Stanner2004;Miller2005;Berger2005).An- OBJECTIVES
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 2
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Ouraimwastoassesstheeffectofantioxidantsupplements(beta- Searchmethodsforidentificationofstudies
carotene,vitaminA,vitaminC,vitaminE,andselenium)onover-
We searched the Cochrane Central Register of Controlled Trials
allmortalityinprimaryorsecondarypreventionrandomisedclin-
(CENTRAL)inTheCochraneLibrary(Issue3,2005),MEDLINE
icaltrials.
(1966 to October 2005), EMBASE (Excerpta MedicaDatabase)
(1985toOctober2005),andtheScienceCitationIndexExpanded
(1945toOctober2005)(Royle2003).Wescannedbibliographies
METHODS ofrelevantpublicationsforadditionaltrials.Allsearchstrategies
aregiveninAppendix1.
Wesentlettersbypostore-mailtomajormanufacturersofan-
tioxidantsupplements,ie,CBHinChina,DSMinSwitzerland,
Criteriaforconsideringstudiesforthisreview
CVC4healthinUSA,andBASFinGermany,askingforunpub-
lishedrandomisedtrials.Noreplywasreceivedfromanyof the
contactedmanufacturers.
Typesofstudies
Allprimaryandsecondarypreventionrandomisedclinicaltrials,
irrespectiveoftrialdesign,blinding, publicationstatus,publica-
Datacollectionandanalysis
tion year,or language. Fromcross-overtrials, onlythefirsttrial
periodwasconsidered. Thepresentreviewisbasedonourprotocolonantioxidantsup-
plementsforpreventinggastrointestinalcancers(Bjelakovic2003)
adoptedtoassessoverallmortality.Anabbreviatedversionofthe
Typesofparticipants reviewhaspreviouslybeenpublished(Bjelakovic2007a).
Adultparticipants(age18yearsorover)whowere Inclusioncriteriaapplication
• healthyparticipantsorwererecruitedamongthegeneral Two of thethreeauthors (GBand DN or RGS) independently
population(primaryprevention); assessedtrialeligibilitywithoutblindingofthestudyauthors.We
• diagnosedwithaspecificdiseaseinastablephase listedexcludedtrialswiththereasonsforexclusion.Disagreement
(secondaryprevention). wasresolvedbydiscussion orinconsultation with LLGorCG.
Wecontactedauthorsofthetrialsformissinginformation.
We excluded tertiary prevention trials, ie, randomised trials in Dataextraction
whichantioxidantsupplementswereusedtotreataspecificdisease
Participantcharacteristics,diagnosis,andinterventions
or nutritional defects,liketrialswith patientswith acute, infec-
Fromeachtrialwerecordedfirstauthor;countryoforigin;country
tious,ormalignantdiseases(exceptnon-melanomaskincancer).
incomecategory(low,middle,high)(WorldBank2006);number
Weexcludedtrialsincludingchildrenandpregnantwomensince
ofparticipants;characteristicsofparticipants:agerange(meanor
theymaybeinneedofcertainantioxidantsupplements. median)andsexratio;participationrate;dropoutrate;trialdesign
(parallel,factorial,orcrossover);typeofantioxidant;dose;dura-
tion of supplementation; duration of follow-up (ie, duration of
Typesofinterventions
interventionpluspost-interventionfollow-up);andco-interven-
Weconsideredforinclusiontrialsthatcomparedantioxidantsup- tions.
plements(ie,beta-carotene,vitaminA,vitaminC,vitaminE,and
selenium)atanydose,duration,androuteofadministrationver- Trialcharacteristics
susplaceboornointervention. We recorded the date, location, sponsor of the trial (known or
Theantioxidantscouldhavebeenadministered unknownandtypeofsponsor)aswellaspublicationstatus.
• separatelyorinanycombinationamongthemselves;or Assessmentofmethodologicalquality
• incombinationwithothervitamins;or Wedefinedthemethodologicalqualityastheconfidencethatthe
• incombinationwithtraceelementswithoutantioxidant design and report restrict bias in the intervention comparison
function. (Schulz1995;Moher1998;Kjaergard2001).Duetotheriskof
overestimation of intervention effects in randomised trials with
Concomitantinterventionswereallowedifusedequallyinboth
inadequate methodological quality (Schulz 1995; Moher 1998;
interventionarmsofthetrial.
Kjaergard2001),weassessedtheinfluenceofmethodologicalqual-
ityofthefourcomponentsbelowasreportedinthetrials.When
this information was not available, we asked the authors of the
Typesofoutcomemeasures
trialpublicationstoprovideit.
Oursoleoutcomemeasurewasall-causemortality.
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 3
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Generationoftheallocationsequence Analyses(RevMan2003),STATA8.2(STATACorp,CollegeSta-
• Adequate,iftheallocationsequencewasgeneratedbya tion,Tex),SigmaStat3.0(SPSSInc,Chicago,Ill),andStats-Di-
computerorrandomnumbertable.Drawingoflots,tossingofa rect(StatsDirectLtd,Altrincham,England).
coin,shufflingofcards,orthrowingdicewasconsideredas We analysed the data with both random-effects (DerSimonian
adequateifapersonwhowasnototherwiseinvolvedinthe 1986)andfixed-effect(DeMets1987)modelmeta-analyses.We
recruitmentofparticipantsperformedtheprocedure. presentedtheresultsofrandom-effectsmodelanalyses.Whensta-
• Unclear,ifthetrialwasdescribedasrandomised,butthe tisticallysignificantresultsareobtainedineithertherandom-or
methodusedfortheallocationsequencegenerationwasnot fixed-effectmodel,wepresentbothanalyses.Resultsarepresented
described. astherelativerisk(RR)with95%confidenceintervals(CI).Weas-
• Inadequate,ifasysteminvolvingdates,names,or sessedheterogeneitywithI2,whichdescribesthepercentageofto-
admittancenumberswereusedfortheallocationofpatients. talvariationacrossstudiesduetoheterogeneityratherthanchance
(Higgins2002).
Allocationconcealment
Random-effectsmeta-regressionanalyseswereperformedtoassess
• Adequate,iftheallocationofpatientsinvolvedacentral
potentialcovariatesthatcouldpredictintertrialheterogeneity,ie,
independentunit,on-sitelockedcomputer,identicallyappearing
whichcovariatesthatwerestatisticallyassociatedwithestimated
numbereddrugbottlesorcontainerspreparedbyan
interventioneffects.Theincludedcovariateswerebiasrisk(lowor
independentpharmacistorinvestigator,orsealedenvelopes.
high),typeanddoseofsupplement,singleorcombinedantiox-
• Unclear,ifthetrialwasdescribedasrandomised,butthe
idant experimental supplement regimen, duration of treatment,
methodusedtoconcealtheallocationwasnotdescribed.
andtypeofprevention(primaryorsecondary).Wealsoperformed
• Inadequate,iftheallocationsequencewasknowntothe
subgroupanalysescomparingtheprimaryandsecondarypreven-
investigatorswhoassignedparticipantsorifthestudywasquasi-
tiontrials.Furthermore,weperformedsensitivityanalysesexclud-
randomised.
ing trials using small dose antioxidant supplements in both the
experimentalandcontrolstudygroups.Theexclusionoftrialsus-
Blinding(ormasking)
• Adequate,ifthetrialwasdescribedasdoubleblindandthe ingsmalldoseantioxidantsupplementsinboththeexperimental
andcontrolstudygroupswasbasedonthefactthatadditionof,
methodofblindinginvolvedidenticalplacebooractivedrugs.
• Unclear,ifthetrialwasdescribedasdoubleblind,butthe eg,avitaminpillcouldbeaconfounder.Weobservedthatsele-
niumseemedtohaveabeneficialeffectongastrointestinalcancer
methodofblindingwasnotdescribed.
• Notperformed,ifthetrialwasnotdoubleblind. development(Bjelakovic2004).Thesensitivityanalysisremoving
seleniumtrialsfromouranalysistoevaluatetheirinfluenceonour
Follow-up conclusionswasthereforenotaposthocdecision.
• Adequate,ifthenumbersandreasonsfordropoutsand Theinfluenceoftrialswithzeroeventsinthetreatmentorcontrol
withdrawalsinallinterventiongroupsweredescribedorifitwas groupwasassessedbyre-calculatingtherandom-effectsmeta-anal-
specifiedthattherewerenodropoutsorwithdrawals. yseswith 0.5, 0.05, and0.005 continuity corrections (Sweeting
• Unclear,ifthereportgavetheimpressionthattherehad 2004;Bradburn2007).Wealsoperformedadditionalmeta-anal-
beennodropoutsorwithdrawals,butthiswasnotspecifically ysesincludingonelargehypotheticaltrialwithoneeventinthe
stated. treatmentandcontrolgroupandasamplesizecorrespondingto
• Inadequate,ifthenumberorreasonsfordropoutsand thetotalnumberofparticipantsinthezeroeventstrials.
withdrawalswerenotdescribed. Allouranalysesfollowedtheintention-to-treatprinciple.Weac-
counted all of the participants for each trial and performedthe
Trialswith adequate generation oftheallocationsequence, ade-
analysesirrespectiveofhowtheoriginaltrialistshadanalysedthe
quate allocation concealment, adequate blinding, and adequate
data.Participantslosttofollow-upwereconsideredsurvivors.For
follow-upwereconsideredlow-biasrisktrials(highmethodologi-
trialswithafactorialdesign,webasedourresultson’atthemargins’
calquality)(Kjaergard2001;Gluud2006a).Weappended’Low’
analysis, comparing allgroups thatreceivedantioxidant supple-
tothereferencesofthesetrials.Trialswithoneormoreunclearor
mentswithgroupsthatdidnotreceiveantioxidantsupplements
inadequatequalitycomponentswereclassifiedashigh-biasrisktri-
(McAlister 2003).Thisentailsarisk of interaction betweenthe
als(lowmethodologicalquality)(Kjaergard2001;Gluud2006a).
antioxidantandtheotherintervention(s)assessed,whethersignif-
We also reported on whether the investigators had performed
icantornotintheindividualtrial.Duetotheriskofconfounding
a sample-size calculation and used intention-to-treat analysis
infactorialtrialsassessingotherinterventions,weconductedpost-
(Gluud2001).
hocsensitivity analysis including onlyfactorial trialdata, which
Statisticalanalyses
couldnotbeaffectedofsuchconfounding (ie,’inside thetable’
Weperformedthemeta-analysesaccordingtotherecommenda-
analysis)(McAlister2003).Todeterminetheeffectofasinglean-
tionsofTheCochraneHandbookforSystematicReviewsofInterven-
tioxidantwealsoperformed’insidethetable’analysis(McAlister
tions(Higgins2006).Forthestatisticalanalyses,weusedRevMan
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 4
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
2003)inwhichwecomparedthesingleantioxidantintervention RESULTS
with the placebo or no intervention. In the trials with parallel
group design with more than two arms and additional therapy,
we compared only antioxidant intervention with placebo or no Descriptionofstudies
intervention.Forcross-overtrialsweincludedonlydatafromthe
See:Characteristicsofincludedstudies;Characteristicsofexcluded
firstperiod(Higgins2006).
studies;Characteristicsofongoingstudies.
Comparison of intervention effects was conducted with test of
Searchresults
interaction(Altman2003).
Databasesearchesyielded16111references(Figure1).Exclusion
Weperformedadjustedrankcorrelation(Begg1994)andregres-
ofduplicatesandirrelevantreferencesleft1201referencesdescrib-
sionasymmetrytest(Egger1997)fordetectionofbias.AP<0.10
ing815trials.Toobtainadditionalinformationwewrotetoau-
wasconsideredsignificant.
thorsofabout500eligibletrials.Morethanonehundredauthors
responded.
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 5
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Figure1. FlowdiagramofidentificationofrandomisedtrialsforInclusion
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 6
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Weexcluded815referencesdealingwith748studies.Afterfur-
ther evaluation we excluded 339 studies because they were not withantioxidants,minerals,orotherinterventions(Table1;Table
randomisedtrialsordidnotfulfilourinclusioncriteria.There- 2).Allantioxidantsupplementswereadministeredorally.Thedose
maining409wererandomisedtrialsexaminingantioxidantsup- andregimenoftheantioxidantsupplementswere:beta-carotene
plements. Four of these were still ongoing. The authors of the 1.2 to50.0 mg(mean 18 mg), vitamin A 1333 to 200,000 IU
405trialsdidnotreportdataonmortality(thesetrialsareshown (mean 20219 IU), vitamin C 60 to 2000 mg (mean 497 mg),
athttp://ctu.rh.dk).ThemajorityoftheseweresmallphaseIor vitaminE10to5000IU(mean570IU),andselenium20to200
phaseIItrialswithshortdurationoffollow-upwithoutassessment µg(mean99µg)dailyoronalternatedaysfor28daysto12years
ofclinicaloutcomemeasures.Wecontactedtheauthorsandabout (mean2.8years).Inonetrial(Murphy 1992Low),antioxidants
onefifthofthemconfirmedthatmortalitywasindeedzero. wereappliedinasingle dose andparticipants werefollowedup
Weincluded386referencesdescribing67randomisedtrialsful- forthreemonthsthereafter.Themeandurationoffollow-upinall
fillingourinclusioncriteriaandabletoprovidedataforouranal- trialswas3.4years(range,28daysto14.1years)(Table2;Table
yses(Table1;Table2)(http://ctu.rh.dk).Thiscorresponds toa 1).
medianof6referencesperincludedtrial(range1to44references Beta-carotenewastestedin25trials,vitaminAin15,vitaminCin
pertrial). 33,vitaminEin54,andseleniumin21trials.Beta-carotenewas
Includedtrials testedsinglyin6trials,vitaminAin2,vitaminEin24,vitamin
TheincludedtrialsaredescribedindetailintheTableofincluded Candseleniumin3trialseach.
studiesandinTable1toTable3. Theantioxidantsupplementsweregiveninthefollowingcombi-
Trialcharacteristics nations:
Outofthe67includedtrials,39trialsusedparallel-groupdesign, • beta-caroteneandvitaminA
26trialsusedfactorialdesign(22trials2x2;3trials2x2x2; • beta-caroteneandvitaminC
1trialhalfreplicateof2x2x2x2),and2trialsusedcross-over • beta-caroteneandvitaminE
design(Pocock2004). • vitaminAandvitaminC
In54trials(81%),theantioxidantswereprovidedatnocostfrom • vitaminCandvitaminE
pharmaceuticalcompanies.Intherestofthetrials,fundingwas • vitaminEandselenium
notreported. • seleniumandzinc
ThetrialswereconductedinEurope,NorthandSouthAmerica, • beta-carotene,vitaminC,andvitaminE
Asia,andAustralia.Sixty-onetrialscamefromhigh-incomecoun- • beta-carotene,vitaminC,vitaminE,andselenium
triesand6trialscamefromlower-middle-incomecountries(NIT1 • beta-carotene,vitaminC,vitaminE,selenium,andzinc
1993;NIT21993Low;delaMaza1995;Correa2000Low;Stevic • vitaminA,vitaminC,vitaminE
2001;SIT2001). • vitaminA,vitaminC,vitaminE,selenium,andzinc
Participants • vitaminA,vitaminC,vitaminE,selenium,methionine,
Atotalof232,550participantswererandomlyassignedinthe67 andubiquinone.
trials.Thenumberofparticipantsineachtrialrangedfrom24to
Controlinterventions
39876(Table1;Table2).Themeanagewas62years(range,18 Sixty-threetrialsusedplaceboandfourtrialsusednointervention
to103years).Themeanproportionofwomenwas45%inthe63 inthecontrolgroup(terRiet1995;GISSI1999;PPP2001;Takagi
trialsreportingsex.
2003).
Twenty-one trials were primary prevention trials including
Concomitantinterventions
164,439healthyparticipants;46trialsweresecondaryprevention
In11trials,participantsweresupplementedwithdifferentmix-
trialsincluding68111 participantswithgastrointestinal (n=10
turesofantioxidantsaswellaswithvitaminsandmineralswith-
trials), cardiovascular (n = 9), neurological (n = 6), ocular (n =
out antioxidant properties (Chandra 1992; NIT1 1993; NIT2
5),dermatological(n=5),rheumatoid(n=2),renalandcardio-
1993Low;Pike1995Low;Hogarth1996;AMDS1996Low;Graat
vascular(n=1),endocrinological(n=1),orunspecified(n=7)
2002Low;Allsup2004Low;LAST2004Low;MAVIS2005Low;
diseases.Mainoutcomemeasuresintheprimarypreventiontrials
Witte2005Low).
werecancerandmortality(cause-specificandall-causemortality),
In nine trials, the experimental and control groups were sup-
andinthesecondarypreventiontrialstheywereprogressionofdis-
plementedwithvitamins andminerals(withorwithout antiox-
easeandmortality(cause-specificandall-causemortality)(Table idant properties)(Gillilan1977; Murphy 1992Low; Takamatsu
4;Table3). 1995;terRiet1995;HATS2001Low;Sasazuki 2003;Meydani
Experimentalinterventions 2004Low; DATATOP 2005Low; ADCS 2 2005). In six of the
Antioxidants wereadministeredeitheralone,orincombination
trials,thesupplementationwaswithvitaminE4IU(Takamatsu
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 7
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