Antioxidant supplements for prevention of mortality in healthy - Rima

240 Pages·2009·2.16 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
2009,Issue3
http://www.thecochranelibrary.com
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review)
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Figure4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Analysis1.1.Comparison1Antioxidantsversusplacebo/nointervention,Outcome1Mortalityintrialswithaloworhigh
riskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
Analysis1.2.Comparison1Antioxidantsversusplacebo/nointervention,Outcome2Mortalityinprimaryandsecondary
preventiontrialswithaloworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . 197
Analysis1.3.Comparison1Antioxidantsversusplacebo/nointervention,Outcome3Mortalityafterexcludingtrials
administratingextrasupplementsintheantioxidantgroup. . . . . . . . . . . . . . . . . . . 200
Analysis1.4.Comparison1Antioxidantsversusplacebo/nointervention,Outcome4Mortalityafterexcludingtrialswith
extrasupplementsforbothinterventiongroups. . . . . . . . . . . . . . . . . . . . . . . 202
Analysis1.5.Comparison1Antioxidantsversusplacebo/nointervention,Outcome5Mortalityafterexcludingfactorial
trialswithpotentialconfounding. . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Analysis1.6.Comparison1Antioxidantsversusplacebo/nointervention,Outcome6Mortalityafterexcludingfactorial
trialswithpotentialconfoundingandtrialswithextrasupplements. . . . . . . . . . . . . . . . 207
Analysis1.7.Comparison1Antioxidantsversusplacebo/nointervention,Outcome7Mortalityafterexcludingtrialswith
anypotentialconfounding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Analysis1.8.Comparison1Antioxidantsversusplacebo/nointervention,Outcome8Mortalityinbeta-carotenetrialswith
aloworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
Analysis1.9.Comparison1Antioxidantsversusplacebo/nointervention,Outcome9MortalityinvitaminAtrialswitha
loworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Analysis1.10.Comparison1Antioxidantsversusplacebo/nointervention,Outcome10MortalityinvitaminCtrialswith
aloworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Analysis1.11.Comparison1Antioxidantsversusplacebo/nointervention,Outcome11MortalityinvitaminEtrialswith
aloworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Analysis1.12.Comparison1Antioxidantsversusplacebo/nointervention,Outcome12Mortalityinseleniumtrialswitha
loworhighriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Analysis1.13.Comparison1Antioxidantsversusplacebo/nointervention,Outcome13Mortalityinlow-biasriskbeta-
carotenetrialswithoutselenium. . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Analysis1.14.Comparison1Antioxidantsversusplacebo/nointervention,Outcome14Mortalityinlow-biasriskvitamin
Atrialswithoutselenium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Analysis1.15.Comparison1Antioxidantsversusplacebo/nointervention,Outcome15Mortalityinlow-biasriskvitamin
Ctrialswithoutselenium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Analysis1.16.Comparison1Antioxidantsversusplacebo/nointervention,Outcome16Mortalityinlow-biasriskvitamin
Etrialswithoutselenium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) i
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) ii
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Antioxidant supplements for prevention of mortality in
healthy participants and patients with various diseases
GoranBjelakovic1,DimitrinkaNikolova1,LiseLotteGluud1,RosaGSimonetti2,ChristianGluud1
1CochraneHepato-BiliaryGroup,CopenhagenTrialUnit,CentreforClinicalInterventionResearch,Department3344,Rigshospitalet,
CopenhagenUniversityHospital,Copenhagen,Denmark.2DivisionediMedicina,OspedaleV.Cervello,Palermo,Italy
Contact address: Goran Bjelakovic, Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention
Research, Department 3344, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, DK-2100, Denmark.
[email protected].(Editorialgroup:CochraneHepato-BiliaryGroup.)
CochraneDatabaseofSystematicReviews,Issue3,2009(Statusinthisissue:Edited,commented)
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
DOI:10.1002/14651858.CD007176
Thisversionfirstpublishedonline:23April2008inIssue2,2008.Re-publishedonlinewithedits:8July2009inIssue3,2009.
Lastassessedasup-to-date: 19February2008.(Helpdocument- DatesandStatusesexplained)
This record should be cited as: Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for
preventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases.CochraneDatabaseofSystematicReviews2008,Issue
2.Art.No.:CD007176.DOI:10.1002/14651858.CD007176.
ABSTRACT
Background
Animalandphysiologicalresearchaswellasobservationalstudiessuggestthatantioxidantsupplementsmayimprovesurvival.
Objectives
Toassesstheeffectofantioxidantsupplementsonmortalityinprimaryorsecondarypreventionrandomisedclinicaltrials.
Searchstrategy
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©2009TheCochraneCollaboration.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
key physiological processes. The results of our recent system-
Oxidativestressmayplayroleinthepathogenesisofcancerand atic review and meta-analyses of the role of antioxidant sup-
cardiovasculardisease,theleadingcausesofdeathinmiddle-and plementsforpreventionofgastrointestinal cancerswereunfore-
high-incomecountries(Sies1985;Halliwell1999).Dietprovides seen(Bjelakovic2004).Wefoundthatantioxidant supplements
numerousvitaminsandtraceelementsthatareessentialforgood significantly increased mortality in the antioxidant group with
health.Severalobservationalstudieshaveshownasignificantpos- the fixed-effect model meta-analysis but not with the random-
itiveassociationbetweenhigherintakeoffruitsandvegetablesand effects meta-analysis (Bjelakovic 2004). The effect of antioxi-
reducedriskofchronicdiseases(Block1992;Ames1993;Willcox dant supplementson mortality hasalsobeen assessed in several
2004). However, exactly which specific dietary constituents of large trials on primary and secondary prevention of diseases (
fruitsandvegetablesmightbebeneficialisnotclear.Furthermore, HPS2002Low;ATBC2003Low;CARET2004Low;SUVIMAX
causal inferences are hard to establish from observational stud- 2004Low;HOPETOO2005Low;WHS2005Low).Theresults
ies.Antioxidantshaveattractedmostattentionaspromisingpre- oftheindividualtrialsareequivocal.Furthermore,noneofthetri-
ventiveagents.Fruitsandvegetablesaresourcesofnumerousmi- alshadsufficientstatisticalpowertoidentifytheeffectofantioxi-
cronutrientsandsomeofthese,includingbeta-carotene,vitamin dantsonmortality.Accordingly,weperformedasystematicreview
A,vitaminC,vitaminE,andseleniumhaveantioxidantpotential. ofrandomisedtrialsonantioxidantsupplementsforprimaryand
Manypeopletakeantioxidantsupplementsbelievingtoimprove secondaryprevention.
theirhealth(Balluz2000;Millen2004;Radimer2004;Nichter
2006).
OBJECTIVES
Whetherantioxidantsupplementsarebeneficialorharmfulisun-
certain(Herbert1997;Caraballoso2003;Vivekananthan2003; Ouraimwastoassesstheeffectofantioxidantsupplements(beta-
Bjelakovic2004;Stanner2004;Miller2005;Berger2005).An- carotene,vitaminA,vitaminC,vitaminE,andselenium)onover-
tioxidants may play dual roles, acting as double-edged swords allmortalityinprimaryorsecondarypreventionrandomisedclin-
(Bjelakovic 2007b). Excessive antioxidants can adversely affect icaltrials.
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 2
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
METHODS ofrelevantpublicationsforadditionaltrials.Allsearchstrategies
aregiveninAppendix1.
Wesentlettersbypostore-mailtomajormanufacturersofan-
Criteriaforconsideringstudiesforthisreview tioxidantsupplements,ie,CBHinChina,DSMinSwitzerland,
CVC4healthinUSA,andBASFinGermany,askingforunpub-
lishedrandomisedtrials.Noreplywasreceivedfromanyof the
Typesofstudies contactedmanufacturers.
Allprimaryandsecondarypreventionrandomisedclinicaltrials,
irrespectiveoftrialdesign,blinding, publicationstatus,publica-
tion year,or language. Fromcross-overtrials, onlythefirsttrial
periodwasconsidered. Datacollectionandanalysis
Thepresentreviewisbasedonourprotocolonantioxidantsup-
Typesofparticipants plementsforpreventinggastrointestinalcancers(Bjelakovic2003)
Adultparticipants(age18yearsorover)whowere adoptedtoassessoverallmortality.Anabbreviatedversionofthe
reviewhaspreviouslybeenpublished(Bjelakovic2007a).
• healthyparticipantsorwererecruitedamongthegeneral Inclusioncriteriaapplication
population(primaryprevention); Two of thethreeauthors (GBand DN or RGS) independently
• diagnosedwithaspecificdiseaseinastablephase(sec- assessedtrialeligibilitywithoutblindingofthestudyauthors.We
ondaryprevention). listedexcludedtrialswiththereasonsforexclusion.Disagreement
wasresolvedbydiscussion orinconsultation with LLGorCG.
We excluded tertiary prevention trials, ie, randomised trials in
Wecontactedauthorsofthetrialsformissinginformation.
whichantioxidantsupplementswereusedtotreataspecificdisease
Dataextraction
or nutritional defects,liketrialswith patientswith acute, infec-
Participantcharacteristics,diagnosis,andinterventions
tious,ormalignantdiseases(exceptnon-melanomaskincancer).
Fromeachtrialwerecordedfirstauthor;countryoforigin;country
Weexcludedtrialsincludingchildrenandpregnantwomensince
incomecategory(low,middle,high)(WorldBank2006);number
theymaybeinneedofcertainantioxidantsupplements.
ofparticipants;characteristicsofparticipants:agerange(meanor
median)andsexratio;participationrate;dropoutrate;trialdesign
Typesofinterventions
(parallel,factorial,orcrossover);typeofantioxidant;dose;dura-
Weconsideredforinclusiontrialsthatcomparedantioxidantsup- tion of supplementation; duration of follow-up (ie, duration of
plements(ie,beta-carotene,vitaminA,vitaminC,vitaminE,and interventionpluspost-interventionfollow-up);andco-interven-
selenium)atanydose,duration,androuteofadministrationver- tions.
susplaceboornointervention.
Theantioxidantscouldhavebeenadministered Trialcharacteristics
• separatelyorinanycombinationamongthemselves;or We recorded the date, location, sponsor of the trial (known or
• incombinationwithothervitamins;or unknownandtypeofsponsor)aswellaspublicationstatus.
• incombinationwithtraceelementswithoutantioxidant Assessmentofmethodologicalquality
Wedefinedthemethodologicalqualityastheconfidencethatthe
function.
design and reportrestrictbias in the intervention comparison (
Concomitantinterventionswereallowedifusedequallyinboth Schulz1995;Moher1998;Kjaergard2001).Due totheriskof
interventionarmsofthetrial. overestimation of intervention effects in randomised trials with
inadequate methodological quality (Schulz 1995; Moher 1998;
Typesofoutcomemeasures Kjaergard2001),weassessedtheinfluenceofmethodologicalqual-
ityofthefourcomponentsbelowasreportedinthetrials.When
Oursoleoutcomemeasurewasall-causemortality.
this information was not available, we asked the authors of the
trialpublicationstoprovideit.
Searchmethodsforidentificationofstudies
Generationoftheallocationsequence
We searched the Cochrane Central Register of Controlled Trials
(CENTRAL)inTheCochraneLibrary(Issue3,2005),MEDLINE • Adequate,iftheallocationsequencewasgeneratedby
(1966 to October 2005), EMBASE (Excerpta MedicaDatabase) acomputerorrandomnumbertable.Drawingoflots,
(1985toOctober2005),andtheScienceCitationIndexExpanded tossing of a coin, shuffling of cards, or throwing dice
(1945toOctober2005)(Royle2003).Wescannedbibliographies was considered as adequate if a person who was not
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 3
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
otherwise involved in the recruitment of participants Weperformedthemeta-analysesaccordingtotherecommenda-
performedtheprocedure. tionsofTheCochraneHandbookforSystematicReviewsofInterven-
• Unclear, if thetrial was described asrandomised, but tions(Higgins2006).Forthestatisticalanalyses,weusedRevMan
themethodusedfortheallocationsequencegeneration Analyses(RevMan2003),STATA8.2(STATACorp,CollegeSta-
wasnotdescribed. tion,Tex),SigmaStat3.0(SPSSInc,Chicago,Ill),andStats-Di-
• Inadequate, ifasysteminvolvingdates,names,orad- rect(StatsDirectLtd,Altrincham,England).
mittance numbers wereused for theallocation of pa- We analysed the data with both random-effects (DerSimonian
tients. 1986)andfixed-effect(DeMets1987)modelmeta-analyses.We
presentedtheresultsofrandom-effectsmodelanalyses.Whensta-
Allocationconcealment
tisticallysignificantresultsareobtainedineithertherandom-or
• Adequate,iftheallocationofpatientsinvolvedacen- fixed-effectmodel,wepresentbothanalyses.Resultsarepresented
astherelativerisk(RR)with95%confidenceintervals(CI).Weas-
tral independentunit, on-site lockedcomputer,iden-
sessedheterogeneitywithI2,whichdescribesthepercentageofto-
ticallyappearingnumbereddrugbottlesorcontainers
talvariationacrossstudiesduetoheterogeneityratherthanchance
preparedbyanindependentpharmacistorinvestigator,
(Higgins2002).
orsealedenvelopes.
• Unclear, if thetrial was described asrandomised, but Random-effectsmeta-regressionanalyseswereperformedtoassess
potentialcovariatesthatcouldpredictintertrialheterogeneity,ie,
themethodusedtoconcealtheallocationwasnotde-
whichcovariatesthatwerestatisticallyassociatedwithestimated
scribed.
• Inadequate,iftheallocationsequencewasknowntothe interventioneffects.Theincludedcovariateswerebiasrisk(lowor
high),typeanddoseofsupplement,singleorcombinedantiox-
investigators whoassignedparticipantsorifthestudy
idant experimental supplement regimen, duration of treatment,
wasquasi-randomised.
andtypeofprevention(primaryorsecondary).Wealsoperformed
Blinding(ormasking) subgroupanalysescomparingtheprimaryandsecondarypreven-
tiontrials.Furthermore,weperformedsensitivityanalysesexclud-
• Adequate,ifthetrialwasdescribedasdoubleblindand
ing trials using small dose antioxidant supplements in both the
the method of blinding involved identical placebo or
experimentalandcontrolstudygroups.Theexclusionoftrialsus-
activedrugs.
ingsmalldoseantioxidantsupplementsinboththeexperimental
• Unclear,ifthetrialwasdescribedasdoubleblind,but
andcontrolstudygroupswasbasedonthefactthatadditionof,
themethodofblindingwasnotdescribed.
eg,avitaminpillcouldbeaconfounder.Weobservedthatsele-
• Notperformed,ifthetrialwasnotdoubleblind.
niumseemedtohaveabeneficialeffectongastrointestinalcancer
Follow-up development(Bjelakovic2004).Thesensitivityanalysisremoving
seleniumtrialsfromouranalysistoevaluatetheirinfluenceonour
• Adequate,ifthenumbersandreasonsfordropoutsand conclusionswasthereforenotaposthocdecision.
withdrawals in allintervention groups weredescribed Theinfluenceoftrialswithzeroeventsinthetreatmentorcontrol
or if it was specified that there were no dropouts or groupwasassessedbyre-calculatingtherandom-effectsmeta-anal-
withdrawals. yseswith 0.5, 0.05, and0.005 continuity corrections (Sweeting
• Unclear, if the report gave the impression that there 2004;Bradburn2007).Wealsoperformedadditionalmeta-anal-
hadbeennodropoutsorwithdrawals,butthiswasnot ysesincludingonelargehypotheticaltrialwithoneeventinthe
specificallystated. 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
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 4
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
couldnotbeaffectedofsuchconfounding (ie,’inside thetable’
analysis)(McAlister2003).Todeterminetheeffectofasinglean-
tioxidantwealsoperformed’insidethetable’analysis(McAlister
2003)inwhichwecomparedthesingleantioxidantintervention
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
intervention.Forcross-overtrialsweincludedonlydatafromthe
firstperiod(Higgins2006).
Comparison of intervention effects was conducted with test of
interaction(Altman2003).
Weperformedadjustedrankcorrelation(Begg1994)andregres-
sionasymmetrytest(Egger1997)fordetectionofbias.AP<0.10
wasconsideredsignificant.
RESULTS
Descriptionofstudies
See:Characteristicsofincludedstudies;Characteristicsofexcluded
studies;Characteristicsofongoingstudies.
Searchresults
Databasesearchesyielded16111references(Figure1).Exclusion
ofduplicatesandirrelevantreferencesleft1201referencesdescrib-
ing815trials.Toobtainadditionalinformationwewrotetoau-
thorsofabout500eligibletrials.Morethanonehundredauthors
responded.
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 5
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Figure1. FlowdiagramofidentificationofrandomisedtrialsforInclusion
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 6
Copyright©2009TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Weexcluded815referencesdealingwith748studies.Afterfur-
ther evaluation we excluded 339 studies because they were not
randomisedtrialsordidnotfulfilourinclusioncriteria.There-
maining409wererandomisedtrialsexaminingantioxidantsup-
plements. Four of these were still ongoing. The authors of the
405trialsdidnotreportdataonmortality(thesetrialsareshown
athttp://ctu.rh.dk).ThemajorityoftheseweresmallphaseIor
phaseIItrialswithshortdurationoffollow-upwithoutassessment
ofclinicaloutcomemeasures.Wecontactedtheauthorsandabout
onefifthofthemconfirmedthatmortalitywasindeedzero.
Weincluded386referencesdescribing67randomisedtrialsful-
fillingourinclusioncriteriaandabletoprovidedataforouranal-
yses(Table1;Table2)(http://ctu.rh.dk).Thiscorresponds toa
medianof6referencesperincludedtrial(range1to44references
pertrial).
Table1. Characteristicsofincludedtrialswithlowriskofbias
Trial Design Num- Meanage Suppl Beta- Vitamin A VitaminC Vitamin E Selenium
berpartic- (Follow- carotene (IU) (mg) (IU) (µg)
ipants up)-y (mg)
SCPS Parallel 1805 NA 5(5) 50
1990
Murphy Parallel 109 NA 0.003 200000
1992 (0.25)
NIT2 Parallel 3318 54 6(6) 15 10000 180 60 50
1993
PPS1994 2x2 864 61 4(4) 25 1000 440
Pike1995 Parallel 47 69 1(1) 2666 90 45
AMDS Parallel 71 72 1.5(1.5) 12 750 200 50
1996
CHAOS Parallel 2002 62 1.4(1.4) 600
1996
NPCT Parallel 1312 63 4.5(7.4) 200
1996
PHS1996 2x2 22071 53 12(12.9) 25
Antioxidantsupplementsforpreventionofmortalityinhealthyparticipantsandpatientswithvariousdiseases(Review) 7
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