《医学论文写作-全英语》
Forstudentsinthe8-yearprogramofWestChinaSchoolofMedicine,Sichuan
University
四川大学华西医院/华西临床医学院
Officelocation:Room2-22,8thBuilding
Springsemester
NOTE:Thiscoursebookiscopyrightedmaterial.Donotreproduceitwithoutwrittenpermissionofthe
authorsofthecourse,whocanbereachedattheemailaddressesabove.
MedicalResearchCommunicationpage2of29Tableofcontents
Chapter12345678910111213DescriptionIntroductiontothecourseIntroductiontoconceptsofbiomedicalresearchPrimaryandsecondaryliteratureEthicalresearchandPublishingethicsInstructionstoAuthorsIntroductiontothePaperWritingAssignmentGuidelineforOralpresentationsExamplesofgoodFiguresandTablesGuidelinesandcommonerrorswhenwritingscientificandmedicalEnglishExercisesAppendixMaternalcaffeineintakeduringpregnancyandfetalgrowthrestrictionIrbesartaninPatientswithAtrialFibrillationMedicalResearchCommunicationpage3of29A.CourseDescription
Manyofyouwillcarryoutsomekindofbiomedicalresearchduringyourcareers,perhapsintheclinicorperhapsinthelaboratory.Thiscourseaimstohelpprepareyouforcarryingoutresearch,bypresentingfundamentalconceptsinresearchdesignandpublishingofresearcharticles.
Thiscoursewillrequireyoutoworkalot,bothinclassandathome.Learningtowriteislikelearningalanguage:youcanadvanceonlyifyoupractice.Themoreyouworkduringthecourse,thebetteryouwillbecomeattheend.
Forseveralofyourassignments,youwillworkingroupswithyourclassmates.Thisisgoodpracticeforyourcareeratahospitalorinacompany:youwillconstantlyneedtocollaboratewithothers,shareduties,andtakeresponsibilityforyourpartofaproject.Doyourbesttofulfillyourcontributiontothegroup'sactivities,anddonotbea\"freeloader\".Duringaproject,keepincontactwiththerestofyourgroupanddon't\"disappear\"ifyourealizeyouarerunninglateorwillnotbeabletocompleteatask--itisbettertotellthegroupandaskthemtohelpyou.
Belowarethethingsthatwehopeyouwilllearninthiscourse(Objectives),thetypesofworkwewilldointhecourse(Format),andthescheduleofduedatesforassignments(DueDates).
CourseObjectivesA.Understandingmedicalresearch
--Understandbasicaspectsofresearchstudydesignanddifferenttypesofresearchstudy--Encounterdifferenttypesofresearchwriting
--Understandtheadvantagesanddifficultiesofdifferenttypesofresearchstudy--Defineaspecificresearchquestion(SRQ)
--Followethicalbehaviorwhenconductingmedicalresearch
B.Readingmedicalresearcharticles
--Knowthestructureandfunctionofthedifferentpartsofaresearcharticle
--Readaresearcharticleeffectively:quicklyfindtheSRQ,results,andconclusionsC.Writingmedicalresearcharticles
--TakeanSRQandrawdataandcreateashortresearcharticle--UsestandardEnglishphrasescommonlyusedinresearcharticles--AvoidcommonmistakesinscientificEnglish--Properlycitesourcesofinformation
--Chooseajournaltosubmitthemanuscript,andformatthemanuscripttothatjournal’s
AuthorGuidelines
--FollowethicalbehaviorwhenwritingmedicalresearchD.Researchbehavior
--Learntocollaboratewithothersindesigningastudy,writingamanuscript,andpreparing
anoralpresentation
--Followethicalbehaviorwhendesigningresearchstudies
--Learnhowtocarryoutpeer-reviewonothers'workandhaveyourownworkpeer-reviewedCourseFormatLectures
In-classexercisesinsmallgroups
PaperWritingAssignmentingroupsoutsideclass(lasting6weeks)
Exam(60min)onfundamentalaspectsofbiomedicalresearchandscientificEnglishOralpresentation(onepergroup)onPaperWritingAssignment
MedicalResearchCommunicationpage4of29B.Introductiontoconceptsofbiomedicalresearch1.GeneralresearchtopicandSpecificresearchquestion
Todogoodbiomedicalresearch,youmustgeneratenewknowledge,i.e.somethingthatwedon'talreadyknow.Todoexcellentbiomedicalresearch,youmustgeneratenewknowledgethatis
importantandusefultothelargercommunity,whomightberesearchers,physicians,orpolicymakers.Twokeyconceptsinbiomedicalresearchthatwewilluseofteninthiscoursearethefollowing:
Generalresearchtopic(GRT,宽泛的科研课题):theareaofyourresearch.
Sometopicsaretoobroad/generaltomakeamanageablepaper.Beginbydoingsomegeneralreadingaboutsomethingyouareinterestedinandthentrytofindafocus.
Specificresearchquestion(SRQ,具体的科研课题):thespecific'knowledgegap'(知识上的缺失)thatyouwanttofulfillwithintheGRT.
BasedonyourSRQ,youshoulddesignthemostrigorousstudypossible.
MedicalResearchCommunicationpage5of292.Typesofclinicalstudy
Thereareseveralpossibledesignsforaclinicalstudy.Thelistbelowisincomplete,butismeanttogiveyouanidea.Notetheadvantagesanddisadvantagesofthedifferenttypesofstudy.TypeofstudyDefinitionCommentsAdvantage.SinceyouknowyourSRQwhenyoudesignthestudy,youareinabetterpositiontocollectalldatathatmightberelevant.Disadvantage.Prospectivestudiestakemoretime,money,andeffortthanretrospectiveones.Advantage.Certainstudiesareeasier(andmuchcheaper!)todoretrospectivelythanprospectively,suchasverylong-termstudiesorstudieswithlargeamountsofpeople.Disadvantage.Thedatamaybeincomplete,becausetheSRQwasnotknownwhenthedatawerecollected.Forexample,imagineyouwanttodoastudytodeterminewhatfactorsaffectlong-termrecoveryfrompancreatitis.Yourelyonmedicalrecords,whicharedetailedaboutseveralfactors(e.g.age,smokingstatus,weight,clinicalhistory)butnotaboutothers(sizeofhousehold,educationlevel,incomelevel).Yourstudywillbelimitedtothefactorsforwhichyouhavedata;thus,youwillnotbeabletoincludesizeofhousehold,educationlevel,orincomelevelaspossiblefactorsinyourstudy.Advantage.Thesestudiesareeasierandcheapertodothanlongitudinalones.DataarecollectedduringasinglepointintimeDisadvantage.Itisimpossibletotrackresultsovertime,soyoumaynotbesurethatyourresultsarerepresentativeofthenormalsituation.Inaddition,cross-sectionalstudiesgiveyoulessinformationthanlongitudinalones.Advantage.Thesestudiesallowyoutotrackresultsovertimeandgainmuchmoreinformationaboutclinicalreality.ProspectiveDataarecollectedaftertheSRQisformulatedRetrospectiveDataarecollectedbeforetheSRQisformulatedCross-sectionalLongitudinalDataarecollectedoveraperiodoftime(usuallymonthsoryears);thisallowsforfollow-upafterdiseaseonsetortherapeuticintervention.MedicalResearchCommunicationpage6of29TypeofstudyDefinitionCommentsDisadvantage.Thesestudiestakemoretime,moneyandeffortthancross-sectionalones.Advantage.Thesestudiesgiveyoumoreinformationthanobservationalones.Disadvantage.Thesestudiesrequiremoretime,moneyandeffortthanobservationalones.Note:Longitudinal,observationalstudiesareoftenreferredtoascohortstudies.Cohortstudiescanberetrospectiveorprospective.Advantage.Thesestudiesareeasierandcheapertodothancontrolledones.Forexample,controlledstudiesrequireatreatmentgroupandacontrolgroup,whichmeans~50%moresubjectsthaninanuncontrolledstudywithoutacontrolgroup.Disadvantage.Itcanbedifficulttodeterminewhethertheresultsare'real',sincethereisno'pointofreference'(basisofcomparison)Advantage.Controlledstudiesalwaysgivemoreinformationthanuncontrolledones.Seebelowandonpage8formorediscussionaboutthis.Disadvantage.Thesestudiestakemoretime,effort,andmoneythanuncontrolledones.Note:Controlledstudiesareoftenreferredtoas\"case-controlstudies\".InterventionalPatientsorsubjects,ortheirenvironment,aremanipulatedinordertoanswertheSRQObservationalResearchersonlyobservewhathappens;theydonotmanipulatethetreatmentorpatientenvironmentUncontrolledAgroupofpatientsorsubjectsismanipulatedorobserved,andno\"referencegroup\"isincludedforcomparisonControlledPatientsorsubjectsaredividedintotwosimilar(comparable)groups:onegroupismanipulated,andtheotherisnot.Thesecondgroupservesasacomparisonforthefirst.Exercise1TypesofStudies
Indicatewhatkindofstudythefollowingexamplesis.
StudyA:Researchersreviewtherecordsof176peopleadmittedtoERdepartmentsbetween2010and
2014duetoinjuriessustainedduringcarcrashes.TheinvestigatorswishtounderstandwhetherthereisanassociationbetweentimespentintheERandclinicaloutcome.
MedicalResearchCommunicationpage7of29StudyB:SameasStudyA,exceptthattheauthorsalsoexamineoutcomesfornon-carcrashpatients
whoweretreatedintheERbetween2010and2014.Theresearchersthencomparetheoutcomesforthecarcrashandnon-carcrashvictims.StudyC:ThecancerwardofamajorChinesecancerhospitalwantstodeterminewhetheranew
chemotherapyisaseffectiveasitscurrentmethod.Researchersrecruitcancerpatientstoundergothenewchemotherapy,andtheyexaminetheoutcomesofthesepatients.StudyD:SameasStudyC,exceptthattheauthorsalsoanalyzetheoutcomesforcancerpatientswho
undergotheconventionaltherapyintheirward.Thentheycomparetheoutcomesforthetwodifferentgroups.StudyE:TheBeijingInstituteofInfectiousDiseasessurveys2350Beijingresidentstodeterminethe
prevalenceofcancerriskfactors,includingdiet,smokingstatus,exposuretocarcinogens.Atthesametime,theyanalyzetheresultsofsimilarsurveysconducted5and10yearsagotodeterminehowtheseprevalenceshavechangedovertime.3.Patientassignment
\"Patientassignment\"referstowhenyouplace(divide,categorize)patientsintodifferentgroupsinyourstudy.Forexample,youmighthaveacontrolgroupandatreatmentgroup;youmighthavemultipletreatmentgroups,eachreceivingadifferentdoseofmedicine.
Whenyouhavetreatmentandcontrolgroups,itisbesttoassignpatientsrandomlytothetwogroups.Thishelpstoensurethatanydifferencesinoutcomesareduetotheintervention,nottootherfactors(age,weight,smokingstatus).Pleasenotethedifferencebetweenrandomandarbitrarily.Ifyou
assignpatientstogroupAorgroupBinformally(e.g.byflippingacoin),thisisarbitraryassignment.Tobeatrulyrandomassignment,youmustuserandomnumbertables(随机数表)orrandomnumbergenerators(RNGs,随机数发生器)thathavebeenverifiedtogiverandomresults.ExamplesofRNGsincludeprogramsthatyoucanaddtoMicrosoftExcel('plug-ins')andwebsitessuchaswww.random.org
Remember:tobeabletosay\"subjectswererandomlyassigned\"intheMethodssectionofyourarticle,youmusthaveusedarandomnumbertableoranRNG.Otherwise,youmustwrite\"subjectswerearbitrarily(武断地)assigned\".4.Blindingandbiasinclinicalstudies
PartyInvestigatorsIfthepartyknowsthepatientassignment......theymayassignthepatientsinawaythatfulfillstheirexpectationsorsatisfiesthestudyhypothesis.Forexample,ifyouthinkthatfatpatientsaremorelikelytogetsick,youmaytendtoputtheminthetreatmentinsteadofthecontrolgroup....theymayrespondbetter(placeboeffect)orworsetotheassignedtreatment,comparedtohowtheywouldrespondiftheydidn'tknow....theymayanalyzethedatainawaythatfulfillstheirexpectationsorsatisfiesthestudyhypothesis.Forexample,iftheyknowthatpatientAwasinthetreatmentgroup,theymay\"see\"animprovementinthebiopsyresults,eveniftheresultisthesameasthecontrol!Patients/subjectsDatacollectors,dataanalystsMedicalResearchCommunicationpage8of29C.Primaryandsecondaryliterature
Themedicalliteratureiswrittenworkthatseekstodisseminateknowledgeaboutmedicineandmedicalpractice.Whatdoesitinclude?
Primaryliterature(一次文献)--describesresultsforthefirsttime
Peer-reviewedjournals(同行评估期刊):publishedatregularintervals,suchaseverymonth
oreveryweek,inprintoron-line
Conferenceproceedingsandabstracts(会议录或会议论文集)
•Technicalreportsfromagovernmentagency(e.g.theChineseCenterforDiseaseControl,
中国疾病预防控制中心)orfromacompanySecondaryliterature(二次文献)--drawsnewconclusionsfromresultsalreadypublished
Monographs(专论，specificbookaboutasingletopic,e.g.abookaboutHIVTreatmentsin
Women)
Textbooks(generalbookaboutmultipletopics,e.g.atextbookcalledHumanAnatomyor
ClinicalBiochemistry)
•Dictionaries
•Encyclopedias(百科全书)Boththeprimaryliteratureandsecondaryliteratureare\"peer-reviewed\meaningthatthecontentisreviewedandcheckedbyexpertsinthefieldbeforeitispublished.Nevertheless,thesecondaryliteratureisoftenamorereliablesourceofinformationthantheprimaryliterature.Thisisbecausearesultusuallyentersthesecondaryliteratureonlywhenitisconsideredtruebyarelativelylargenumberofpeopleforatleastayearortwo.Differenttypesofprimarybiomedicalliterature
TypeofpublicationLettertotheEditorEditorialCaseReportReview,ReviewarticleMeta-analysisDescriptionShortcommunicationthatexpressesanopinionaboutaresearchtopicMid-lengthcommunication(shorterthanArticle,longerthanLettertotheEditor)thatexpressesanopinionaboutaresearchtopicDescriptionofthediseaseandtreatmentofoneorafewpatientsSummary,analysis,andsynthesisofpreviouslypublishedresearcharticlesReanalyzesdatafrompublishedarticles,combinestheminappropriateways,andreportsthenewresultsandnewconclusionsSimilartoameta-analysisbutmorerigorous;theauthorsmustfollowwidelyusedstandardswhenselectingpublishedarticlesandanalyzingthedata,andtheyareupdatedregularlyTowriteasystematicreview,youmustfirstjoinaReviewGrouponthetopicofyourexpertiseandyoushouldfollowcertainrigorousprocedures.Learnmoreathttp://www.cochrane.org/about-us/get-involvedThewebsitefortheChineseCochraneCenter(basedat华西!)isfoundathttp://www.hxyx.com/cochrane_new/.OriginalreportdescribingtheresultsofaresearchstudySystematicReview**Article,Researcharticle**MedicalResearchCommunicationpage9of29D.EthicalresearchandPublishingethics
Anygoodbiomedicalresearchprojectalsotriestobeethical:ittriesnottoexposepatientsorsubjectstoriskfornoreason.Thus,itisunethicaltoperformastudythatisbadlydoneordonewithsofewpatientsthatnoonewillwanttousetheresultslater.Forthatreason,youshouldusecorrect,rigorousprocedureswhenyoudobiomedicalresearch,andyoushouldensurethatyourstudywillhavestatisticalpower(统计功效).Thismeansthatyoushouldrecruitasufficientnumberofpatients/subjectssothatyourmeasurementswillbestatisticallyconvincing.
Inadditiontoensuringanethicalstudydesign,youwillneedtoobtaintwotypesofapprovalwheneveryoucarryoutresearchwithhumans:
ApprovalDescriptionInvestigatorsmustexplaintopatients/subjectswhatwillhappentotheminthestudyandwhattherisksare.Patients/subjectsshouldhavetherighttorefusetoparticipate,ortowithdrawfromthestudylaterInvestigatorsmustjustifytheirstudytocolleaguesandleadersattheirowninstitutionbeforetheycanrecruitpatients/subjectsReasonTopreventpeoplefrombeingforcedtoparticipateinresearchagainsttheirwill.Thishasoccurredseveraltimesinhistory:•whentheNazisconductedresearchonJewsduringWorldWarII•whentheU.S.carriedoutsyphilisexperimentsinGuatemalaandintheU.S.(Tuskegeeexperiments)•whenPfizertestedanewdruginNigeriaTopreventpatients/subjectsfrombeingexposedtoriskfornoreason,e.g.whenthestudyissopoorlydesignedthatresultscannotbeusedorpublishedinthefutureInformedconsent(知情同意)ApprovalfromtheInstitutionalReviewBoard(EthicsCommittee,伦理委员会)JournalswillrequireyoutoobtainbothinformedconsentandapprovalfromyourInstitutionalReviewBoard,andyoumustmentionbothintheMethodssectionofyourarticle.Inaddition,journalsmayrequireyoutosendtheactualapprovalletterstothembeforetheywillpublishyourarticle.Publishingethics
Justasthereareethicalissueswhendoingresearch,thereareethicalissueswhenpublishingit.EthicalissueDescriptionJournalswanttopublishresultsthatarecompletelynew,sotheyassumethatthetextandresultsinyourmanuscripthavenotbeenpublishedbefore.Theyaskyoutoconfirmthisinyourcoverletterandwhenyousubmityourmanuscripton-line.Journalsdonotwantyoutosubmitthesamemanuscripttomorethanonejournalatthesametime.JournalswanttoseeevidenceHowtodealwiththeissueSomejournalswillpublishresultsthathavealreadybeenpublishedelsewhere.Forexample,ifyouhavealreadypublishedsomeresultsinChinese,andyouwishtorepublishtheminanAmericanorEuropeanjournal,perhapsyoucandoso.Readyourtargetjournal'sInstructionstoAuthorstoseewhetherthejournalprohibitsthis.Ifnot,sendthemanuscriptandexplainthesituationtotheminthecoverletter.Neverdothis.Ifajournalfindsoutthatyouhavedonethis,theymayrefusetoconsideryourmanuscript--andanyfuturemanuscriptsyouwanttosend!BesuretogetapprovalbeforeyoubeginthePreviouspublicationSimultaneoussubmissionEthicalapprovalMedicalResearchCommunicationpage10of29EthicalissueforanimalresearchDescriptionthatyoureceivedapprovaltocarryoutyourresearch.Howtodealwiththeissueresearch.ReadtheInstructionstoAuthorsabouttherequirementsforauthorship.ManyjournalsfollowthedefinitionoftheInternationalCommitteeofMedicalJournalEditors(ICMJE):\"Authorshipcreditshouldbebasedon1)substantialcontributionstoconceptionanddesign,acquisitionofdata,oranalysisandinterpretationofdata;2)draftingthearticleorrevisingitcriticallyforimportantintellectualcontent;and3)finalapprovaloftheversiontobepublished.Authorsshouldmeetconditions1,2,and3.\"*Manyjournalsalsowantyoutobrieflydescribethecontributionsofeachauthortothestudy.Youcanborrowshortphrases(<5-6words)frompublishedworks,butnotlongerphrases.Donotcopyentiresentencesorparagraphsfromothersources--evenifyouwrotetheearlierwork!Thiswillgetyouintotroublewiththejournal.AuthorshipJournalswanttheauthorlisttocontainonlypeoplewhohavecontributedalottothethinkingandexperimentsinthepaper.PlagiarismJournalsdonotwantyoutowriteinyourmanuscriptlongphrasesandsentencesthathavealreadybeenpublishedbefore.Thiscancausecopyright(版权)problems.*中文版：
MedicalResearchCommunicationpage11of29E.InstructionstoAuthors
Whenpreparingamanuscripttosubmittoajournal,youmustformatitaccordingtotheirInstructionstoAuthors(alsocalledGuidelinestoAuthors).Theearlieryoucanidentifyyour\"targetjournal\whichisthejournalwhereyouplantosendyourmanuscript,theearlieryoucanreadtheInstructionstoAuthorsandmakesureyoucanprepareyourfinalmanuscriptthewaytheywantit.
Infact,sometimestheInstructorstoAuthorstellyouhowthejournalwantsyoutodefinethestudy,soyoumaywanttothinkabouttargetjournalsatthebeginningofanyresearchproject!Inthatway,youcanreadtheirInstructionstoAuthorstohelpyoudesignyourstudy.CommonTermsusedinInstructionstoAuthors
EnglishtermChinesetermDefinitionandcommentsFullprofessionaladdress.Listthesmallestunitfirstandthelargestunitlast,e.g.\"SectionofGeneticDisorders,DepartmentofCardiology,WestChinaHospital,Chengdu610041,SichuanProvince,P.R.China\".Theconditionsthatmustbesatisfiedinorderforsomeonetobelistedasanauthoronanarticle.ManyjournalsusethecriteriaoftheInternationalCommitteeofMedicalJournalEditors(ICMJE):\"Authorshipcreditshouldbebasedon1)substantialcontributionstoconceptionanddesign,acquisitionofdata,oranalysisandinterpretationofdata;2)draftingthearticleorrevisingitcriticallyforimportantintellectualcontent;and3)finalapprovaloftheversiontobepublished.Authorsshouldmeetconditions1,2,and3.\"(中文版在22页里。)Formthatallauthorsmustsubmitbeforeamanuscriptcanbepublishedbythejournal.Usuallytheformaskstheauthorstoconfirmthattheysatisfytheauthorshipcriteria(seeabove),explainanyconflictsofinterest(seeConflictofinterestform),andtransferthecopyrightofthemanuscripttothejournal(seeCopyrighttransfer).Feesthatsomejournalschargeforprintingyourfiguresincolor.Mostjournalschargemoneytoprint4-colorfigures(often~2100RMBperfigure!),sothinkcarefullywhenyoumakefiguresincolor.Itisusuallybettertoredesignthefigureinblack-and-white.Somejournalswillallowyouonefreecolorfigure,andthenyoumustpayforthesecond,third,etc.Manyjournalswillallowyouunlimitedfreecolorfortheon-lineAffiliation作者的单位名称AuthorshipcriteriaAuthorshipformColorcharges彩色图片版面费MedicalResearchCommunicationpage12of29EnglishtermChinesetermConflictofinterestform(alsocalled\"disclosureform\\"declarationofcompetinginterests\")Copyrighttransfer(alsocalled\"copyrightagreement\")Definitionandcommentsversionofyourpaper,buttheywillchargeyouforcolorintheprintedversion.ChecktheInstructionstoAuthors!Aform,whichmaybeseparateorpartoftheAuthorshipForm,inwhichallauthorsofthemanuscriptmustdeclareanyfinancial,personal,professionalorotherrelationshipsthatmayhaveaffectedtheirobjectivitywhentheywrotethearticle.Form,whichmaybeseparateorpartoftheAuthorshipForm,inwhichallauthorsofthemanuscriptagreetotransferownershipofthearticletothejournal.Youmustsignthisifyouwantthejournaltopublishyourarticle.Note:whenyoupublishanarticle,thejournalbecomestheownerofthepublishedtextandfigures/tables.Thus,ifyoulaterwriteanarticleandwanttousesomeofthattextordata,youmustgetwrittenpermissionfromtheearlierjournal(seePlagiarism).Authortowhomthejournalsendsallcommunications,suchasevaluationsbyreferees,thefinaleditorialdecision,revisionsofthearticlebeforepublication,etc.Thecorrespondingauthorisoftenconsideredthepersonwhohasthegreatest\"authority\"ontheproject,i.e.who\"managed\"theproject.Mostjournalswillallowmorethanoneauthortobecorrespondingauthor,butprobablynevermorethantwo.Ashortletterthattheauthorssendtogetherwiththemanuscript.Intheletter,theauthorsexplain•whatcategoryofsubmission(ResearchArticle,CaseReport,somethingelse--seethecategoriesintheInstructionstoAuthors)•whytheirmanuscriptisnew,important,andlikelytobecitedbyreadersofthatjournal•whetheranypartofthemanuscripthasalreadybeenpublished,andwhetherallauthorsagreetothesubmissionYoumayneedtowriteotherthings,soreadtheInstructionstoAuthors!Mostjournalswantyoutouse1.5-ordoublespacingwhenyouformatyour版权转让协议Correspondingauthor通讯作者Coverletter投稿信Double-spaced,doublespacing双倍行距MedicalResearchCommunicationpage13of29EnglishtermChinesetermDuplicate/previouspublication重复发表Definitionandcommentsmanuscript.Whenallorpartofyourmanuscripthasalreadybeenpublishedinajournal.Ifthisisyourcase,youmustexplaininyourcoverletterwhichpartshavealreadybeenpublished.Ifthejournalapprovesthis,youwillneedtogetwrittenpermissionfromthefirstjournal,andyouwillneedtosendthatpermissiontothesecondjournal.Forexample,thisisthesituationofauthorswhohavepublisheddatainChineseandwishtorepublishitinEnglish.Somejournalsallowthis,othersdonot.ChecktheInstructionsforAuthorsandexplaineverythinginyourcoverletter.Whenyousubmitthesamemanuscripttomorethanonejournalatthesametime.Thisisneveracceptable,sodon'tdoit!Alljournalswillaskyoutopromisethatyouhavenotdonethiswhenyousubmitamanuscripttothem.Approvalfromyourresearchinstitutiontocarryoutresearchinvolvinghumans.Manyjournalswillrequireyoutosendthemacopyofthisethicalapproval.Typeface.MostjournalswantsimpletypefacessuchasHelvetica,Arial,TimesNewRoman.Publicationfeethatdependsonthenumberofpagesinthepublishedarticle.Manyjournalschargethisfee,butmanydonot.AlwayschecktheInstructionstoAuthors.Aprintedcopyofyourpublishedarticle.Authorsoftenorderreprintstosendtocolleagues,friends,oranyonewhoasksforthem.Youcanorderthesefromthejournal,butyoumustpayforthem.AcheaperoptionistodownloadyourpublishedarticleasaPDFanddistributeittoyourcolleagues.TheInternationalSystemofUnits(SystèmeInternational),themostwidespreadmeasurementsystemintheworld.JournalswantyoutousetheSIsystem,whichincludesthefollowingunits:•meter(m)•kilogram(kg)•second(s)•ampere(A)•mole(mol)Inaddition,journalswantyoutousetwonon-SIunits:Duplicatesubmission重复投稿Ethicalapproval伦理委员会的同意Font字体Pagecharges版面费ReprintSIunits国际单位MedicalResearchCommunicationpage14of29EnglishtermChinesetermTrialregistration临床实验注册Definitionandcomments•Celsiusdegrees(°C)•liter(L)Ifyouwanttopublishresultsfromaclinicaltrial,journalswillrequireyoutoregisterthetrialinaninternationaldatabase.AlwayschecktheInstructionstoAuthors.Examplesofthesedatabasesinclude•U.S.RegistryofClinicalTrials(http://clinicaltrials.gov/)--althoughtheregistryismaintainedintheU.S.,thetrialscancomefromallovertheworld(currentlytherearetrialsfrom174countriesinthedatabase)•WHOInternationalClinicalTrailsSearchPortal(http://apps.who.int/trialsearch/)ChecktheInstructionstoAuthorstoseewhetherthejournalwantsyourtextjustifiedorunjustified.Unjustified(e.g.\"rightmarginsunjustified\\"rightmarginsragged\")不齐行（如文稿的右侧缘不用对齐）（注：中文常见两侧对齐，英语文稿常见的格式是左对齐）MedicalResearchCommunicationpage15of29F.IntroductiontoPaperWritingAssignment
Objectives:
•Topracticewritingallthepartsofashortmanuscript,aswellasanethicsapplication•Toobtainpeerreviewonthemanuscriptfromclassmatesandtorevisethemanuscript
accordingly
•TolearntocollaboratewithothersonmanuscriptwritingGuidelines:
Usea12-pointsansseriffont(Arial,Helvetica)with2.54-cmmarginsonallsidesofthepaper.Usedoublespacing.
Title:Donotuseabbreviations.Useasfewwordsaspossibletoexpressthemainmessageofyourstudy(thewhoandwhat,perhapsthehowifitisspecial/new/unique).
AuthorPage:Writethefirstnamesandlastnamesofallauthors.Writetheaffiliationsofeachauthor.Indicatewhoisthecorrespondingauthorusinganasterisk(*).
Abstract:Writeastructuredabstractwiththesectionsbelow.Themaximumlengthoftheabstractis150words.Defineallabbreviationsanddonotuseliteraturereferences.
ObjectivesMethodsResultsConclusionsIntroduction:Shouldbe250-350words.Besuretosupportimportantstatementswithreferences.Defineallabbreviations,evenifyoualreadyusedthemintheAbstract.
Discussion:Shouldbe250-350words.MinimizewhatyourepeatfromtheResultssection;only
summarizetheresults.Besuretocompareyourresultswiththoseofotherstudiesandcommentonthecomparisons.Ifyourresultsaresimilar,drawaconclusion;ifyourresultsaredifferent,drawaconclusion.
References:Usethereferencestylebelow:
Journalarticle:CarratF,SimpsonH,LiaoGS.2002.Nonrandomizedtrialcomparingice
creamandchocolatefortreatingsadness.J.Am.Med.Assoc.292:2389-48.Book:DicksonM,ShouldersR.1999.Humanpathology(2nded.).London:Routledge,
page239.Chapterinabook:DicksonM,ShouldersR.InHumanpathology(2nded.).London:
Routledge,p.239.Internetsite:\"ResearchobjectivesoftheCONSORTprogram\www.consort.hr.Accessed
5January2005.ConflictsofInterest:Indicatewhetheranyoftheauthorshasanyfinancial,personal,orother
professionallinksthatmayconstituteconflictsofinterest.Ifnone,pleasewrite\"Theauthorsreportnoconflictsofinterest.\"
MedicalResearchCommunicationpage16of29G.GuidelineforOralpresentations
Youshouldprepareatalkforatotalof7minutes.Donotexceedthistime,oryouwilllosepoints.Onecommonmistakeistogivetoomuchintroduction--discussonlythethingsthattheaudienceneedstoknowinordertounderstandtheimportanceofyourSRQ.ClearlystateyourSRQassoonaspossibleinthefirsttwominutesoftheoralpresentation.
Eventhoughyourtimeisshort,youmustpresentallthesectionsofyourtalk.Thefollowingtablemayhelpyoubudgetyourtimeeffectively:
SectionIntroduction(keepitfocusedontheSRQ!)MethodsResultsConclusionsApproximatetime(min)<3121Inplanninganddeliveringyourpresentation,trytoavoidthesecommonmistakes:
CommonmistakeSolutionMakesuretobreathewellbeforeandduringyourpresentation.Forexample,toprepareforyourtalk,breathedeeplyafewtimes.Countasyouinhale(吸气)slowly,andcountasyouexhale(呼气)slowly.Theexhalationshouldtaketwiceaslongastheinhalation.Breathingwellduringyourpresentationwillforceyoutoslowdown,putpausesbetweenideas,andgivemoretimetobothyouandtheaudiencetoprocessyourideas.Ifyoumaketheintroductiontoolong,theaudiencewillstarttolosefocus;theywon'tknowhowtomakesenseofalltheinformationyou'regiving,becausetheydon'tknowyourSRQ.Thus,giveonlythebackgroundnecessarytounderstandtheSRQandmentiontheSRQasearlyaspossibleinapresentation.AgoodrulewouldbetomentiontheSRQ40%ofthewaythroughthetalk.Forexample,iftheentiretalkis5minuteslong,mentiontheSRQwithinthefirst2minutes.Don'tspendtheentirepresentationtalkingtotheslides,thecomputer,orthewall!Theaudiencewillpaymoreattentiontoyouifyoumakeeyecontactwiththemand\"connect\"withthemby•facingthemwheneveryouwantthemtolistentoyou(turnyourwholebodytowardthem)•usinghandgesturestoemphasizekeyideasChangeyourtoneandvolume,justasyouwouldwhentalkingtofriendsinyourdorm.Ifyoudothis,youwillnotsoundlikearobotduringyourpresentation,andtheaudiencewillpaymoreattentiontoyou.•MakeyoursentencesshortSpeakingtoofast,nopausesduringthetalk,theaudiencegets\"nervous\"listeningtoyouToomuchintroductionatthebeginningNocontactwiththeaudienceSpeakingina(boring)monotoneTheideasinthepresentationaredifficulttoMedicalResearchCommunicationpage17of29CommonmistakeprocessSolution•Putpausesbetweenimportantideas•Speakslowly!Preparetheaudienceforthenextslidebeforeyoushowit.Helptheaudienceseehowthenextslidefollowslogicallyfromthecurrentone.Example1:ifyou'removingfromoneResultsslidetoanother,youmightsay\"Hereweseetheeffectoftemperature,nowwhatabouttheeffectofpressure? 1.Thepatientpopulationflowchart(Bloometal.NEJM355:2195) 2.The‘Table1’ofbaselinecharacteristics(Marchbanksetal.NEJM346:2025) Petersonetal.BMCCardiovascularDisorders6:41(2006) MedicalResearchCommunicationpage19of293.Barchart(Petersonetal.) Lauetal.NEJM356:1631 MedicalResearchCommunicationpage20of294.Afigure(Gosmanetal.RespiratoryResearch9:64) 5.Kaplan-Meierplottoestimatesurvival/lifetimedata(Uemuraetal.NEJM345:784) MedicalResearchCommunicationpage21of296.Plotsshowingstatisticaldetails(Wassmeretal.PLoSMedicine,issue9,e245) MedicalResearchCommunicationpage22of29Johnsonetal.Am.J.Cardiol.102:1312 7.Linechart(Nashetal.Am.J.Transp.8:162) MedicalResearchCommunicationpage23of29H.GuidelinesandcommonerrorswhenwritingscientificandmedicalEnglishBelowareseveralcommonproblemswhenChinesespeakerswritescientificEnglish(1)Avoidsubjectiveterms/judgmentalterms.Speakasobjectivelyaspossible. LessgoodoptionProblemIftheresultsarereally\"obvious\"or\"clearhenyoushouldnotneedtosay\"obvious\"or\"clear\".Letthedataspeakforthemselves!Youwanttoavoidasituationinwhichyousay\"theincreaseinprevalencewasobvious\andtherefereethinksthatitisnotobvious!Inthatcase,thereviewermaythinkyouareincompetent.最好去掉这个词！BetteroptionObvious(ly),clear(ly)(2)Usethepasttensewhendiscussingresults(whichoccurredinthepast),andthepresenttensewhendiscussingconclusions(whichyouhopearetrueinthefuture!).Herearesomeexamples:Results-pasttenseIntheirexperiments,Smithetal.(1995)usedamoresimplifiedmodelthanwedid.Intheexperimentsinvolvinglivercancerpatients,weobservedthatrecoverywassignificantlybetterafterTCMtreatmentthanafterresection.Wetestedsamplesfromseveralcities,andweobtainedsimilarresultsinallcases.Conclusions-presenttenseIntheirexperiments,Smithetal.(1995)usedamoresimplifiedmodelthanwedid,whichmayexplainthedifferencesinresults.Interferoniseffectiveatreducingviralload(Smith1995).Inthispaper,weprovideevidencethatresectiondoesnotaffectqualityoflife.(3)Whenmakingcomparisons,makeabsolutelyclearwhatthingsarebeingcompared.Avoidusing\"increase\"and\"decrease\"ifyouwanttocomparedifferentsamples/groups.LessgoodoptionThehormonelevelsweremeasuredindiabeticpatientsandcontrolsat0and3months.Anincreasewasobservedindiabeticpatients.Weobservedandecreaseincorticotropininsmokerscomparedtonon-smokers.ProblemDoyoumeanthatthehormonelevelsincreasedindiabeticpatientsfrom0to3months?Orareyoucomparinglevelsbetweendiabeticpatientsandcontrols?Didyoumeasurethecorticotropinovertime,ordidyoudoasingledetermination?BetteroptionThehormonelevelsweremeasuredindiabeticpatientsandcontrolsat0and3months.Thelevelswerehigherindiabeticpatientsthanincontrolsatbothtimepoints.Thecorticotropinlevelwaslowerinsmokersthaninnon-smokers.(4)Ifyou'remakingacomparison,usecomparativeterms.InmostcasesinEnglish,comparativetermsendwith\"er\"or\"est\".Forexample,thecomparativeformsof\"low\"arelowerandlowest.LessgoodoptionProblemBetteroptionMedicalResearchCommunicationpage24of29Thelowmortalityofthetreatmentgroupcomparedtothecontrolgroupsuggests… Doyoumeanthatthemortalitywaslowerinthetreatmentgroup,ordoyoumeanthatthemortalitywaslowinboththetreatmentgroupandcontrolgroup? Ourfindingthatthemortalityofthetreatmentgroupwaslowerthanthatofthecontrolgroupsuggests… Ourobservationthatthe mortalityofthetreatmentgroupwaslowerthanthatofthecontrolgroupsuggests... (5)Trynot\"sendthereaderbackwards\".Writeina\"forwarddirection\". LessgoodoptionProblemWhenthereaderarrivesatthedata(145,70)andthe\"respectivelyheymayhavetorereadthefirstpartofthesentencetorememberwhatthingsarebeingcompared.Ifyouhaveaphrasethatappliestotheentiresentence(e.g.\"inthemultiplexarrayconfiguration\"),itisoftenbettertoputitatthebeginningofthesentenceratherthantheend.BetteroptionTheenergyreleaseinthepresenceofPMA(145AU)was2-foldhigherthaninitsabsence(70AU)inthemultiplexarrayconfiguration.Inthemultiplexarrayconfiguration,theenergyreleaseinthepresenceofPMA(145AU)was2-foldhigherthaninitsabsence(70AU).TheenergyreleaseinthepresenceofPMAwas2-foldhigherthaninitsabsenceinthemultiplexarrayconfiguration(145vs.70AU,respectively).Whenyou'rewritinginEnglish,tryasmuchaspossibletowriteinthesequence:subject-->verb(动词)-->object.Thismeansusingactivevoice(主动语态)insteadofpassivevoice(被动语态)asmuchaspossible.Thiswillmakeyourtextas\"forward-moving\"aspossibleandeasierforthereadertoprocess. LessgoodThelevelsofBAR1andMAPKK-3inGroupBweresignificantlyelevatedbyPMAadministration(p=0.013).ThemodelwiththehighestcorrelationcoefficientandaBayesianlikelihoodp<0.05wasaccepted.Problem\"wereelevated\"(被动语态)BetterPMAadministrationsignificantlyelevatedthelevelsofBAR1andMAPKK-3inGroupB(p=0.013).Thesolutionistoswitchtoactivevoiceandputthesubjectnexttotheverb:WeacceptedthemodelwiththehighestcorrelationcoefficientandaBayesianlikelihoodp<0.05.Longdistancebetweenthesubject(\"model\")andverb(\"wasaccepted\"):whenthereaderarrivesat\"wasacceptedheymayhavetorereadthefirstpartofthesentencetorememberwhatwasaccepted!(6)Trynottoputtoomanyideasinthesamesentence;youwilltireandconfusethereader. LessgoodoptionProblemBetteroptionMedicalResearchCommunicationpage25of29Wefoundthatthemortalitywassignificantlyhigheratadoseof30mg/kgthanat15mg/kg,whichmayreflecttoxicityofthedrug,althoughsimilar studies(Lynch1999)suggestedthatthedrugwassafeatdosesabove35mg/kg. Thebestsolutionistoturnonesentenceinto2or3: Toomanyideasinonesentence;thereaderwill probablyneedtoreadittwiceorthreetimestounderstandalltheideasand\"organizethem\"inhisorherhead. Wefoundthatthemortalitywassignificantlyhigheratadoseof30mg/kgthanat15mg/kg.Thismayreflecttoxicityofthedrug,althoughsimilarstudies(Lynch1999)suggestedthatthedrugwassafeatdosesabove35mg/kg. (7)Trytoeliminatenominalizations(名词化) Anominalizationisaverbthathasbeenchangedintoanoun.Often,thisverbisthemost importantoneinthesentence.Whenitisbecomesanoun,anotherweakerverbhastobeintroducedtomakethesentencecompleteagain.Thus,nominalizationsmakeyouwritelongersentences.Inaddition,peoplelikeaction,soverbsaregenerallymoreattractivetoreadersthannouns. LessgoodoptionThisstudygivesananalysisofhearinglossinChineseworkersandoffersrecommendationstodecreaseitsprevalence.[18words]ProblemThenominalizations“analysis,”and“recommendations,”makethesentencelonger,andmorecomplex.Inaddition,youneedtoaddtwoverbs--“give”and“offer”--tomakethesentencecomplete.BetteroptionThisstudyanalyzeshearinglossinChineseworkersandrecommendsstepstodecreaseitsprevalence.[15words](8)Trynottoswitchbackandforthbetweensynonyms(同义词)becauseitcanconfusethereaders. keepusingthesamewordforthesamething.Donotbeafraidtorepeatyourself;repetitionisgoodinsciencewriting. LessgoodoptionSeveralstudieshaveproposedtreatments,includingsurgicalresectionandHendersonablation.Thelaserprocedureismorepopular.ProblemThreetermsarementioned:surgicalresection,Hendersonablation,andlaserprocedure.Dotheyreferto2or3procedures?BetteroptionSeveralstudieshaveproposedtreatments,includingsurgicalresectionandHendersonlaserablation.Thelaserprocedureismorepopular.(9)Usesimplerwordstomakeyourideascleartoyourreaders. MedicalResearchCommunicationpage26of29PracticewithscientificEnglish Exercise1.Rewritethefollowingtextsinactivevoice. (A)Inourexperiment,ahigherlevelwasobservedinthetreatmentgroup comparedtothecontrolgroup. (B)Basedonourresults,itissuggestedthatADL-125isamoreefficientdrug thanlamivudineforolderHCVpatients. (C)Itisshowninthebloodanalysisthatleukocytelevelswerelow. Exercise2.Rewritethefollowingsentenceswithoutthenominalizations. (A) Thereisaneedforfurtherstudytoclarifywhetherlong-termexposuretomobilephonesincreasestherisk. (B)Itisourbeliefthatoptimizationofdosesshouldbecarriedoutbeforechangesintreatment aremade. (C)Ourexpectationwastheestablishmentofabetterprocedureforpancreaticsurgery. Wedidstatisticalanalysiswiththedatawecollectedfromthequestionnaire. Exercise3.Simplifythefollowingphrases (A)Attheterminationoftheexperiment...→(B)Thisendoscopehasthecapabilityto...→(C)Weleftpriortothesurgery...→(D)Approximately3mlwasremoved.→(E)Injectionsweregivenonaregularbasis.→(F)Intheearlypost-operativeperiod,→ MedicalResearchCommunicationpage27of29Exercise4.Improvethefollowingtexts. (A)AsshowninFigure1,wemeasuretheinsulinlevelsandwefindthatthe levelsinthepatients(mean:145±14g/dl)aresignificantlyhigherthaninthecontrols(102±10g/dl). (B)Comparedtolamivudine,AntivirolTMwas38%effective. . (C)Thecontrol,low-doseandhigh-dosetreatmentgroupsshowedsignificantdifferencesin hepatitisincidenceandageofonset(43vs.19vs.25%,p<0.001;23vs.41vs.63years,p=0.002). (D)Inordertoconsiderallpossibleriskfactors,wedevelopedamodelthat includedBMI,bloodpressure,smokingstatus,etc. (E)Theresultsfromthisstudysuggestthatearlydiagnosisisessentialforeffectivetreatment, thoughthisworkhasimportantlimitations,suchassmallsamplesizeand retrospectivedesign,whichmakefutureinvestigationsessentialtoimprovediagnosisofveryyoungchildren. Exercise5:Useoftransitionalwords Recentchangesinthepracticeofmechanicalventilationhaveimprovedsurvivalinpatientswiththeacuterespiratorydistresssyndrome(ARDS),_______mortalityremainsunacceptablyhigh.__________lowtidalvolumesareclearlybeneficialinpatientswithARDS,howtochooseapositiveend-expiratorypressure(PEEP)isuncertain.4Ideally,mechanicalventilationshouldprovidesufficienttranspulmonarypressuretomaintainoxygenationwhileminimizingrepeatedalveolarcollapseoroverdistentionleadingtolunginjury.5Incriticalillness,__________,thereismarkedvariabilityamongpatientsinabdominalandpleuralpressures6;_____,foragivenlevelofPEEP,transpulmonarypressuresmayvaryunpredictablyfrompatienttopatient.7 MedicalResearchCommunicationpage28of29Appendices（附录） Appendix1:WritingclearandsimpleEnglish (takeninpartfromPeatetal.2002andDumontetal.)Lessclearduetothefactthat,onaccountof,owingtothefactthat,onthebasisthattakenintoconsiderationdosagemethodologyincloseproximitytoatthepresenttime,atthispointintimethemajorityofdyadssymptomatology,complaints,clinicalpictureutilizeMakeanexaminationof...Presentacomparisonof...Beinagreement...Performananalysisof...Produceanimprovementin...Moreclearbecause,sinceconsidereddosemethod,approachnearnow,currentlymostpairssymptomsuseexaminecompareagreeanalyzeimproveAppendix2:OptionsforEnglishverbs(fromDumontetal.) Thelistbelowprovidesexamplesofverbsthatexpressresearchactions:VerbapplyassesscalculatecomparecomputederivedesigndeterminedevelopevaluateexploreimplementinvestigatemeasuremodelExampleWeappliedLaklöter'sprincipleto...Weassessedtheeffectsoflargerdosesof...Wecalculatedthephotoluminescencespectrumof...Wecomparedtheeffectsof...tothoseof...Wecomputedthevelocitypredictedby...Wederivedanewsetofrulesfor...Wedesignedaseriesofexperimentsto...Wedeterminedthecompletenucleotidesequenceof...Wedevelopedanewalgorithmto...Weevaluatedtheefficacyandbiocompatibilityof...Weexploredtherelationshipbetween...Weimplementedageneticalgorithmfor...Weinvestigatedthebehaviorof...Wemeasuredtheconcentrationofcadmiumin...WemodeledtheinteractionbetweenproteinAandproteinB...Thelistbelowprovidesexamplesofverbsthatexpresscommunicationactions: VerbclarifydescribeExampleThispaperclarifiestheroleofsoilsin...Thispaperdescribesthemechanismbywhich...MedicalResearchCommunicationpage29of29detaildiscussexplainofferpresentproposesprovidereportsummarizeThispaperdetailsthealgorithmusedfor... Thispaperdiscussestheinfluenceofacidityon...Thispaperexplainshowthenewencodingscheme...Thispaperoffersfourrecommendationsfor...Thispaperpresentstheresultsof... Thispaperproposesasetofguidelinesfor... Thispaperprovidesthecompleteframeworkand...Thispaperreportsonourprogresssofar... Thispapersummarizesourresultsfor27patientswith... Downloaded from bmj.com on 6 November 2008 Maternal caffeine intake during pregnancy andrisk of fetal growth restriction: a large prospective observational study CARE Study Group BMJ 2008;337;a2332 doi:10.1136/bmj.a2332 Updated information and services can be found at: http://bmj.com/cgi/content/full/337/nov03_2/a2332 These include: References This article cites 36 articles, 13 of which can be accessed free at: http://bmj.com/cgi/content/full/337/nov03_2/a2332#BIBL 1 online articles that cite this article can be accessed at: http://bmj.com/cgi/content/full/337/nov03_2/a2332#otherarticles 3 rapid responses have been posted to this article, which you can access forfree at: http://bmj.com/cgi/content/full/337/nov03_2/a2332#responses You can respond to this article at: http://bmj.com/cgi/eletter-submit/337/nov03_2/a2332 Receive free email alerts when new articles cite this article - sign up in thebox at the top left of the article Rapid responses Email alerting service Topic collections Articles on similar topics can be found in the following collections Smoking and tobacco (2423 articles) Pregnancy (3058 articles) Reproductive medicine (4812 articles) Health education (4560 articles) Health promotion (5573 articles) Smoking (2448 articles) Notes To order reprints follow the \"Request Permissions\" link in the navigation box To subscribe to BMJ go to: http://resources.bmj.com/bmj/subscribers Downloaded from bmj.com on 6 November 2008 RESEARCH Maternalcaffeineintakeduringpregnancyandriskoffetalgrowthrestriction:alargeprospectiveobservationalstudy Correspondenceto:JustinCKonje,DepartmentofCancerStudiesandMolecularMedicine,UniversityofLeicester,LeicesterLE27LX,jck4@le.ac.uk.Alternativecorrespondence:JanetECade,CentreforEpidemiologyandBiostatistics,UniversityofLeeds,LeedsLS29JT, j.e.cade@leeds.ac.uk Citethisas:BMJ2008;337:a2332doi:10.1136/bmj.a2332 BMJ|ONLINEFIRST|bmj.com CAREStudyGroup ABSTRACT ObjectiveToexaminetheassociationofmaternalcaffeineintakewithfetalgrowthrestriction.DesignProspectivelongitudinalobservationalstudy.SettingTwolargeUKhospitalmaternityunits.Participants2635lowriskpregnantwomenrecruitedbetween8-12weeksofpregnancy.InvestigationsQuantificationoftotalcaffeineintakefrom4weeksbeforeconceptionandthroughoutpregnancywasundertakenwithavalidatedcaffeineassessmenttool.Caffeinehalflife(proxyforclearance)wasdeterminedbymeasuringcaffeineinsalivaafteracaffeinechallenge.Smokingandalcoholwereassessedbyselfreportedstatusandbymeasuringsalivarycotinineconcentrations.MainoutcomemeasuresFetalgrowthrestriction,asdefinedbycustomisedbirthweightcentile,adjustedforalcoholintakeandsalivarycotinineconcentrations.ResultsCaffeineconsumptionthroughoutpregnancywasassociatedwithanincreasedriskoffetalgrowthrestriction(oddsratios1.2(95%CI0.9to1.6)for100-199mg/day,1.5(1.1to2.1)for200-299mg/day,and1.4(1.0to2.0)for>300mg/daycomparedwith<100mg/day;testfortrendP<0.001).Meancaffeineconsumptiondecreasedinthefirsttrimesterandincreasedinthethird.Theassociationbetweencaffeineandfetalgrowthrestrictionwasstrongerinwomenwithafastercomparedtoaslowercaffeineclearance(testforinteraction,P=0.06).ConclusionsCaffeineconsumptionduringpregnancywasassociatedwithanincreasedriskoffetalgrowthrestrictionandthisassociationcontinuedthroughoutpregnancy.Sensibleadvicewouldbetoreducecaffeineintakebeforeconceptionandthroughoutpregnancy.INTRODUCTIONCaffeineisthemostwidelyconsumedxenobioticinpregnancy,withthepotentialtoadverselyaffectthedevelopingfetoplacentalunit.Maternalcaffeineintakehasbeenreportedtobeassociatedwithareductioninbirthweight,1-5butthepreciselevelofintakeabovewhichtheriskisincreasedremainsunknown.Caffeineintakeof≥300mg/dayhasbeenassociatedwithfetalgrowthrestriction,6-8butVlajinacetalfoundasignificantreductionininfantbirthweightof114gwithmaternalcaffeineconsumptionofaslittleas141mg/day.9Morecontroversially,othershaveshownthatmaternalcaffeineconcentrationhasaninverseassociationwithbirthweightwhenconfounderssuchassmokingweretakenintoaccount.21011In2001theCommitteeonToxicityofChemicalsinFood,UK,afterathoroughreviewoftheliterature,concludedthat,althoughcaffeineintake>300mg/daymightbeassociatedwithlowbirthweightandspontaneousmiscarriage,theevidencewasinconclusive.12Possiblereasonsfortheseinconsistentoutcomesincludeinaccurateestimationofcaffeineconsumption,includinganassumptionthatteaandcoffeearetheonlysourcesofcaffeine,3910retrospectiveassessmentofcaffeineintake,21013-15assessmentofassociationbasedonconsumptioninindividualtrimestersratherthanthroughoutpregnancy,491013failuretoallowforindividualvariationsincaffeinemetabolism,416inade-quatecontrolforconfoundingfactorssuchassmokingandalcoholconsumption,1718andnon-uniformityindefiningtheprimaryoutcomemeasures.12469101516Caffeineisrapidlyabsorbedandcrossestheplacentafreely.19Afteringestionof200mgcaffeine,intervillousbloodflowintheplacentawasfoundtobereducedby25%.20CytochromeP4501A2,theprincipalenzymeinvolvedincaffeinemetabolism,isabsentintheplacentaandthefetus.21Theamountofcaffeineandmetabolitesavailabletothefetoplacentalunitthereforedependsonthematernalcaffeinemetabolism,whichshowsmarkedvariationbetweenindividualsbecauseofgeneticandenvironmentalfactorssuchasnicotine.22-24Variationsincaffeinemetabolicactivityhavebeenfoundtobemorecloselyassociatedwithfetalgrowthrestrictionthanhavebloodcaffeineconcentrations.25Therefore,anycompre-hensivestudyoftheeffectsofcaffeineonfetalgrowthmustincludeanassessmentofcaffeinemetabolism.Inordertoexaminetheassociationofmaternalcaffeineintakeonfetalgrowth,weusedavalidated,robustcaffeineassessmenttooltoquantifytotalcaffeineintake,fromallpossiblesources,throughoutpregnancy.26Usingthesedata,andtakingintoaccountindividualvariationincaffeinemetabolism,weaimedtoestablishthesafeupperlimitofcaffeineconsumptionwithrespecttoadversepregnancyoutcome(specificallyfetalgrowthrestriction).METHODSParticipants WeprospectivelyrecruitedlowriskpregnantwomenfromtwolargeUKteachinghospitalmaternityunits(LeedsandLeicester)fromSeptember2003toJunepage1of8 Downloaded from bmj.com on 6 November 2008 2006.Theinclusioncriteriaincludedage18-45yearsandsingletonpregnanciesaccuratelydatedbyultra-sound.Womenwithconcurrentmedicaldisorders,psychiatricillness,HIVinfection,orhepatitisBinfectionwereexcluded.Weidentifiedeligiblewomenbyscreeningtheirpre-bookingmaternitynotes,thensentthemdetailedinformationaboutthestudyandaskedthemtoreturnareplyslipabouttheirwillingnesstotakepartinthestudy.Personalcontactswerethenmadewiththosewhoagreedtoparticipate.Thisinitialvisitwasconductedatthehospitaloratthevolunteer’sgeneralpracticeorhomebyaclinicalresearchfellow(Leicester)oramidwife(LeicesterandLeeds)at8-12weeksgestation.Volunteers’demo-graphicdetails(age,parity,maternalheight,weight,socioeconomicstatus,andgestationalage)wererecordedbymeansofaquestionnaire.Quantificationofcaffeineintake Caffeineintakewasestimatedwithavalidatedcaffeineassessmenttool,aquestionnairedesignedattheUniversityofLeeds,torecordhabitualcaffeineintakebeforeandduringpregnancy.26Informationinthequestionnaireincludedestimatesofcaffeinecontentfromallpotentialdietarysourcesandoverthecounterdrugsanddetailsofpotentialconfounderssuchassmoking,alcoholintake,andnausea.Werecordedspecificbrandnames,portionsizes,methodsofpreparation,andquantityandfrequencyofintakefordifferentgestationalperiods.Wealsoobtaineddetailsofcaffeinecontentforeachitemfrompublishedreports,27manufacturers,andcoffeehouses,and,fromthese,weestimatedprecisecaffeineintakesusinganSPSSv14programdevelopedin-house.26Threecaffeineassessmenttoolswereadministeredbytheclinicalresearchfellowandresearchmidwivestodeterminecaffeineintakeinpregnancy—thefirst,administeredatrecruitmentbytheresearcher,Table1|Demographicandclinicalcharacteristicsof2635pregnantwomenandtheirbabies,accordingtopregnancyoutcome.Valuesarenumbers(percentages)unlessstatedotherwise PregnancyoutcomeFetalgrowthAppropriatefetalTotalrestriction(n=343)growth(n=2292)(n=2635)MaternalcharacteristicsMean(SD)age(years)30.0(6.6)29.8(6.5)30(6.6)Mean(SD)weightbeforepregnancy(kg)66.7(13.2)66.8(12.6)66.8(13.1)Mean(SD)bodymassindexbefore24.5(4.5)24.5(4.6)24.5(4.5)pregnancy(kg/m2)Primiparous186(55)1042(46)1228(47)Pretermlabour29(8)77(3)106(4)Gestationalhypertensionorpre-25(7)42(2)67(3)eclampsiaStillbirth3(0.9)6(0.3)9(0.3)Latemiscarriage3(0.9)16(0.7)19(0.7)NeonatalcharacteristicsMean(SD)gestationalageatdelivery40(3)40(2)40(2)(weeks)Mean(SD)birthweight(g)2750(520)3560(470)3450(550)Male172(50)1152(52)1324(51)page2of8 no0.20itcirtser0.15 htworg 0.10latef fo k0.05sir deta0m0100200300400500itsECaffeine intake (mg/day) Fig1|Relationbetweenriskoffetalgrowthrestrictionandcaffeineintake(mg/day)duringpregnancy.Therelationismodelledbythebest-fittingsecond-orderfractionalpolynomial,with95%confidenceintervals.Thegraphisrestrictedto<500mg/dayforclarity.Horizontaldottedlinesmarknationalaverageriskoffetalgrowthrestriction(10%)andaverageriskinstudycohort(13%)includedaspectsofrecallofcaffeineintakefromfourweeksbeforepregnancyuntilrecruitmentintothestudyat8-12weeksofpregnancy;thesecondcoveredtheperiod13-28weeks;andthethirdincludedtheperiod29-40weeksofpregnancy.Salivasamplecollection,storage,andtransport Salivasamplesfordeterminingnicotineexposure(definedasbaselinevaluesbeforethecaffeinechal-lenge)werecollectedfromwomenatrecruitment,usingaSalivette(Sarstedt,Aktiengesellschaft,Lough-borough,UK)keptinthemouthfor5-10minutes.Additionally,weassessedcaffeinehalflifefromacaffeinechallengetest(adaptedfromButleretal28)performedwithintwoweeksofrecruitment.Weprovidedparticipantswithappropriatematerialsandinstructionstoperformthetestathome,andthesampleswerethenreturnedinaprepaidenvelope.Thetestinvolvedovernightfasting,followedbythechallenge(adrinkof500mldietcolacontaining63.5mgcaffeineingestedoveraperiodof20minutes)withnoothercaffeineconsumedduringthechallenge.Participantsthencollectedsalivasamplesaboutoneandfivehoursafterthechallenge.Precisesamplecollectiontimesanddetailsofdrinksorfoodconsumedduringthetestperiodwererecordedonaquestion-naire.Whensamplesarrivedatthelaboratory,salivawasisolatedfromtheSalivettesbycentrifugationandstoredat−80°C.Biochemicalanalyses AllsampleswereanalysedintheMolecularEpide-miologyUnit(UniversityofLeeds).Salivarycaffeine—Salivarycaffeinewasextractedandquantifiedusingliquid:liquidextractionandreversedphasehighperformanceliquidchromatography(HPLC)withultravioletdetection.26Wecalculatedthehalflifeforcaffeinefromsalivarycaffeineconcentrationsrecordedatoneandfivehoursafterthecaffeinechallenge.BMJ|ONLINEFIRST|bmj.com Downloaded from bmj.com on 6 November 2008 Salivarycotinine—Salivarycotinineconcentrationsinsamplestakenatrecruitmentwerequantifiedbymeansofenzymelinkedimmunosorbentassay(ELISA)(CozartBioscience,Oxfordshire,UK)accordingtothemanufacturer’sinstructions.Wethenclassifiedparticipantsonthebasisofthesecotinineconcentra-tionsasactivesmokers(>5ng/ml),passivesmokers(1-5ng/ml),ornon-smokers(<1ng/ml).29Pregnancyoutcomes Weobtainedinformationonantenatalpregnancycomplicationsanddeliverydetails(gestationalageatdelivery,birthweight,andsexofthebaby)fromtheelectronicmaternitydatabases.Theprimaryoutcomemeasurewasfetalgrowthrestrictiondefinedasbirthweight<10thcentileonacustomisedcentilechartwhichtakesintoaccountmaternalheight,weight,ethnicity,andparityandneonatalbirthweightandsex(www.gestation.net).30Wechosethisdefinitionasitisthemostcommonlyusedandbecause,althoughnotallthosecasesclassifiedasfetalgrowthrestrictionwouldbepathological,itislikelytoincludemostpathologicalfetalgrowthrestrictions.Inaddition,weassessedtheassociationofmaternalcaffeineintakewithbirthweight.Otherpregnancyoutcomesstudiedwerelatemiscarriage(spontaneouspregnancylossbetween12and24weeks),pretermdelivery(deliveryat<37completedweeks),gestationalhypertension(bloodpressure≥140/90mmHgonmorethanoneoccasion4hoursapartafter>20weeksofpregnancy),Table2|Meancaffeineandalcoholintakeandsmokingstatusamong2635pregnantwomenaccordingtopregnancyoutcome.Valuesarenumbers(percentages)unlessstatedotherwise PregnancyoutcomeFetalgrowthAppropriatefetalTotalCharacteristicrestriction(n=343)growth(n=2292)(n=2635)Mean(SD)caffeineintake(mg/day):Throughoutpregnancy200(202)153(145)159(154)Firsttrimester201(206)157(160)163(167)Secondtrimester184(207)141(144)147(156)Thirdtrimester197(222)143(146)153(164)Caffeineintakeduringpregnancy:<100mg/day122(36)1000(46)1122(44)100-199mg/day90(27)601(27)691(27)200-299mg/day63(19)313(14)376(15)≥300mg/day63(19)284(13)347(14)Mean(SD)alcoholintake(units/day):Throughoutpregnancy0.4(0.7)0.4(0.5)0.4(0.6)Firsttrimester0.6(0.9)0.4(0.7)0.5(0.8)Secondtrimester0.2(0.4)0.2(0.5)0.2(0.5)Thirdtrimester0.3(0.4)0.2(0.5)0.3(0.5)Smokingstatus(n=2509)*:Non-smoker213(64)1622(75)1835(73)Passivesmoker39(12)268(12)307(12)Currentsmoker79(24)288(13)367(15)*Smokingstatusbasedonsalivarycotinineconcentrations:non-smoker<1ng/ml,passivesmoker1-5ng/ml,currentsmoker>5ng/ml. BMJ|ONLINEFIRST|bmj.com proteinurichypertension(gestationalhypertensionandproteinuriaof≥300mgproteinin24hours,basedontheInternationalSocietyfortheStudyofHypertensioninPregnancy31),andstillbirth(delivery≥24weekswithnosignsoflifeatbirth).Statisticalmethods Weexpressedparticipants’caffeineconsumptioninmg/dayaveragedoverthewholepregnancyandfortheindividualtrimesters.Toestimatethesamplesizerequired,weassumedthatthemeancaffeineintakeduringpregnancywas206mg/day,4andthatcaffeinefollowedalognormaldistribution,withacoefficientofvariationof1.Assumingthat10%ofbirthsshowedfetalgrowthrestriction,then3000birthswouldgive80%powertodetectadifferenceof30mg/dayincaffeineintakesbetweenmothersofbabieswithrestrictedfetalgrowthandmothersofbabiesofappropriateweightforgestationalagewithtypeIerrorsetat0.05.Thisalsogave80%powertodetectanoddsratioforfetalgrowthrestrictionof1.4betweenhighandlowcaffeineconsumers(definedasbeingaboveorbelowthemediancaffeineintake).Weperformedunconditionallogisticregressionmodellingforfetalgrowthrestrictionandgenerallinearmodellingforbirthweight,withstratificationforthetwomaternityunits,usingStataversion10surveyfacilities.32Maternalheight,weight,ethnicity,andparityatbookingandneonatalgestationatdeliveryandsexweretakenintoaccountinthedefinitionforfetalgrowthrestriction,andwereadjustedforinthemodelforbirthweight.Wealsomadestatisticaladjustmentforsalivarycotininelevelsandselfreportedalcoholconsumptioninallmodels.Weconductedsensitivityanalysestoassesstherobustnessoftheresultstoadjustmentfornausea,exclusionofhighriskpregnancies,multiparity,extremelyhighorlowcaffeineintakes,andthematernityunit.Wealsoassessedtherelationbetweentheriskoffetalgrowthrestrictionandmaternalcaffeineintakeduringpregnancybyconsideringcaffeineintakeasacontin-uousvariable:afteradjustingforthefactorsmentionedabove,weperformedmodellingusingthebestfitting,secondorder,fractionalpolynomialwith95%confidenceintervals.Caffeinehalflifeasassessedbythecaffeinechallengetestwasnotnormallydistributed.Wethereforecategorisedwomeninrelationtothemedianvalueashavingashorterhalflife(fastercaffeineclearancefromthecirculation)orlongerhalflife(slowerclearance).Westratifiedtheoddsratioforfetalgrowthrestrictionbycaffeinehalflife(asaproxyforclearance)andintakeaftertakingaccountofmaternalage,weight,height,ethnicity,andparityandneonatalgestationandsexandadjustingforsmokingstatus,amountsmoked(cotinineconcentration),andalcoholintake.RESULTSOveraperiodofthreeyears,13071eligiblewomenwereinvitedtoparticipatefromthetwomaternitypage3of8 Downloaded from bmj.com on 6 November 2008 page4of8 Table3|Riskoffetalgrowthrestrictionamongoffspringof2635pregnantwomenaccordingtocaffeineintakeduringpregnancy Unadjustedrisk*Adjustedrisk†Caffeineintake(mg/day)Oddsratio(95%CI)TestfortrendOddsratio(95%CI)TestfortrendAverageoverpregnancy:<10011100-1991.2(0.9to1.6)1.2(0.9to1.6)200-2991.6(1.2to2.3)P<0.0011.5(1.1to2.1)P=0.02≥3001.8(1.3to2.5)1.4(1.0to2.0)Inweeks5-12:<10011100-1991.2(0.9to1.6)1.1(0.8to1.5)200-2991.4(1.0to2.0)P<0.0011.3(0.9to1.9)P=0.05≥3001.8(1.3to2.5)1.4(1.0to1.9)Inweeks13-28:<10011100-1991.5(1.1to2.0)1.4(1.0to2.0)200-2991.8(1.3to2.6)P=0.0011.7(1.2to2.4)P=0.02≥3001.6(1.1to2.4)1.3(0.9to2.0)Inweeks29-40:<10011100-1991.4(1.0to1.9)1.4(1.0to2.0)200-2991.9(1.3to2.8)P<0.0011.8(1.2to2.7)P=0.004≥3001.9(1.3to2.8)1.6(1.0to2.4)*Unadjustedoddsratiostakeaccountofmaternalage,weight,height,ethnicity,andparityandneonatalgestationalageatdeliveryandsex.†Adjustedoddsratiosarealsoadjustedforsmokingstatus(salivarycotinineconcentration)andalcoholintake. units,and2635(20%)consented.Table1showstheof200-299mg/day,andto1.4(1.0to2.0)forintakesofdemographicandclinicalcharacteristicsofthestudy≥300mg/day.Thisrelationwasconsistentacrossallpopulation.Theprevalenceoffetalgrowthrestrictionthreetrimesters.inthecohortwas343/2635(13%).Themeanalcoholintakeduringpregnancywas0.4(95%confidenceCaffeineconsumptionof>200mg/dayduringinterval0to9)units/day,withthehighestconsumptionpregnancywasassociatedwithareductioninbirthoccurring,asmightbeexpected,beforeconceptionweightofabout60-70g,withasignificanttrendforandduringthefirstfourweeksofpregnancy.greaterreductioninbirthweightwithhighercaffeineintake(P=0.004).ThisrelationwasconsistentacrossallCaffeineintakeduringpregnancy threetrimesters(table4).Thewomen’smeancaffeineintakeduringpregnancyInasmallcohortofwomen(n=109)whohadwas159mg/day(table2).Itdecreasedfromreducedtheircaffeineintakefrom300mg/daybefore238mg/daybeforepregnancyto139mg/daybetweenpregnancyto<50mg/daybyweeks5-12ofpregnancyweeks5and12ofpregnancyandremainedatabouttheiroffspring’smeanbirthweightwashigherthanthatthisleveluntilthethirdtrimester,whenitgraduallyofthosewhomaintainedtheircaffeineintakeatincreasedto153mg/day.About62%ofthecaffeine>300mg/day(n=193)(differenceinbirthweightingestedbythewomenduringpregnancywasfromtea.161g(95%confidenceinterval24to297g),P=0.02).Otherimportantsourceswerecoffee(14%),coladrinksToexaminepossiblethresholdeffects,weanalysed(12%),chocolate(8%),andsoftdrinks(2%).Hottherelationbetweentheestimatedriskofdeliveringachocolate,energydrinks,andalcoholicdrinkscon-growthrestrictedfetusandmaternalcaffeineintaketributed2%,1%,and<1%respectively.Overtheduringpregnancymeasuredasacontinuousvariablecounterdrugsmadeanegligiblecontributiontothe(fig1).Therewasarapidincreaseinassociatedrisktotalcaffeineintake.fromincreasingcaffeineintakeuptoabout30mg/day.Thereafter,estimatedriskcontinuedtoriseroughlyRelationbetweencaffeineintakeinpregnancyandfetallinearlyinadose-responserelation.Atnopointdidthegrowth estimatedriskceasetoincreasewithincreasingcaffeineTherelationbetweentotalcaffeineintakeinpregnancyintake.Therewasnoobservedplateaueffect.andfetalgrowthrestrictionshowedasignificanttrendwithincreasingcaffeineintake(testfortrendP=0.02,Relationbetweencaffeineclearanceandfetalgrowth table3).Comparedwithcaffeineintakeof<100mg/Usingmaternalcaffeinehalflifeasaproxyforday,theoddsratioofhavingagrowthrestrictedbabyclearancerate,wefoundsomeevidencethattheincreasedto1.2(95%confidenceinterval0.9to1.6)forassociationbetweencaffeineintakeandfetalgrowthintakesof100-199mg/day,to1.5(1.1to2.1)forintakesrestrictionwasstrongerinwomenwithafastercaffeineBMJ|ONLINEFIRST|bmj.com Downloaded from bmj.com on 6 November 2008 BMJ|ONLINEFIRST|bmj.comclearancethaninthosewithslowerclearance(testforStrengthsandweaknessesofthestudy interaction,P=0.06)(table5).Althoughonly20%ofthewomenweinvitedtookpartinthestudy,thislowresponseratedoesnotlessentheRelationbetweensmokinginpregnancyandfetalgrowth validityofourdata,astheassociationofcaffeinewithWomenclassifiedasactivesmokers(basedontheirbirthweightshouldnotbedifferentfromthatinthesalivarycotinineconcentrations)hadnearlytwicethegeneralpopulation,especiallyasvariousconfoundersriskoffetalgrowthrestrictioncomparedwithwomenweretakenintoconsideration.Inaddition,examina-classifiedasnon-smokers(adjustedoddsratio1.9(95%tionofourmaternitydatabasesindicatedthattheconfidenceinterval1.4to2.6),P<0.001).Thebirthpopulationwestudiedwassimilartothatoftheweightsofbabiesborntoactivesmokerswere178gmaternityunitsasawhole.lighter(95%confidenceinterval127to230g)thanAmajorstrengthofourstudyisthatwehavethoseborntonon-smokers(P<0.001).Adjustingforobjectivelyquantifiedcaffeinefromallknownsources.nausea(reportedby81%ofthepopulationinthefirstCaffeineintakewasvalidatedbycomparisonwithatrimester)didnotaltertheseresults.fooddiaryandrepeatedmeasuresofexposurefromsalivasamples,27andwebelievethat,forthefirsttime,DISCUSSIONthisreflectsatruepictureoftotalcaffeineintakebyThisisoneofthelargestprospectivestudiesinvestigat-womenduringpregnancy.Morethan60%oftheingtheassociationofmaternalcaffeineintakewithfetalcaffeineconsumedwasfromtea,andonly14%fromgrowth.Maternalcaffeineintakewasassociatedwithcoffee.Ourfindingsemphasisetheweaknessesofanincreasedriskoffetalgrowthrestrictionevenafterstudieswherecaffeineintakewasequatedtothatofadjustmentforsmokingandalcoholintake.Wecouldcoffeealone.Wengetalreportedthatcoffeewasthefindnolevelofintakeatwhichtherewasnoassociationsolesourceofcaffeinein19%oftheirpregnantcohort,withincreasedriskoffetalgrowthrestriction.Thesizeand44%consumedcaffeinefromcombinedcaffeineoftheassociationforcaffeinewasofasimilarsizetothatandnon-caffeinesources.33Since26%ofcaffeineintakeforalcoholintakeinpregnantwomeninthisstudy(datainourcohortwasfromneithercoffeenortea,studiesnotshown).thatconcentratedoncoffeeandteaalonewouldhavegrosslyunderestimatedcaffeineintake.Thestrongassociationbetweencaffeineintakeandbirthweightwasmaintainedacrossallofthetrimesters.Studyresultsincomparisonwithotherstudies However,fromtheseresultswecannotdefineacriticalCaffeineconsumptionalmosthalvedinearlytimewindowforanymaximaleffect.Thisclearlypregnancy(from250mg/daybeforepregnancytowarrantsfurtherinvestigation.150mg/dayinthefirsttrimester),ashasbeenreportedTable4|Unadjustedandadjustedlinearregressionforbirthweightamongoffspringof2635pregnantwomenaccordingtocaffeineintakeduringpregnancy Unadjustedchangeinbirthweight(g)Adjustedchangeinbirthweight(g)*Caffeineintake(mg/day)Change(95%CI)TestfortrendChange(95%CI)TestfortrendAverageoverpregnancy:<10000100-199−1(−51to50)−21(−62to20)200-299−63(−129to4)P<0.001−70(−123to−18)P=0.004≥300−144(−221to−66)−63(−119to−6)Inweeks5-12:<10000100-199−6(−58to45)−34(−76to8)200-299−66(−134to2)P<0.001−61(−112to−9)P=0.009≥300−144(−220to−69)−59(−114to−4)Inweeks13-28:<10000100-199−15(−74to44)−24(−72to24)200-299−44(−119to30)P=0.003−65(−124to−6)P=0.006≥300−129(−212to46)−74(−138to−10)Inweeks29-40:<10000100-199−25(−98to48)−66(−125to−7)200-299−61(−154to31)P=0.009−69(−141to3)P=0.004≥300−119(−211to−27)−89(−158to−21)*Adjustedestimatestakeaccountofmaternalage,weight,height,ethnicity,parity,smokingstatus(salivarycotinineconcentration),andalcoholintakeandneonatalgestationalageatdeliveryandsex. page5of8 Downloaded from bmj.com on 6 November 2008 Table5|Stratificationofriskoffetalgrowthrestrictionamongoffspringof2635pregnantwomenaccordingtocaffeineintakeduringpregnancyandcaffeinehalflife(proxyforclearance) Riskoffetalgrowthrestriction*Caffeineintake(mg/day)Oddsratio(95%CI)TestfortrendShortercaffeinehalflife(n=774)†<1001100-1991.6(0.9to3.0)200-2992.4(1.3to4.4)P=0.02≥3001.7(0.9to3.3)Longercaffeinehalflife(n=764)†<1001100-1991.1(0.6to1.7)200-2990.6(0.3to1.3)P=0.8≥3001.5(0.7to2.9)TestforinteractionofhalflifeP=0.06*Adjustedformaternalage,weight,height,ethnicity,parity,smokingstatus(salivarycotinineconcentration),andalcoholintakeandneonatalgestationalageatdeliveryandsex. †Shortercaffeinehalflife(≤medianvalue)=fasterclearance;longerhalflife(>medianvalue)=slowerclearance). elsewhere.34Themeancaffeineintakethroughoutpregnancywasmuchlowerthanthelimitof300mg/dayrecommendedbytheUKgovernment’sFoodStandardsAgency12andintheUSA.35Severalstudieshaveconcludedthatcaffeineintakeof>300mg/dayisassociatedwithlowbirthweightorfetalgrowthrestriction.6-8Ourstudyconfirmsthesefindingsandfurtherdefinesthenatureoftheassocia-tion.Wecouldfindnolevelofintakeatwhichtherewasnoassociationwithincreasedriskoffetalgrowthrestriction,andthisriskwasmaintainedthroughoutpregnancy.Althoughtheoverallsizeofthereductioninbirthweightmaybeseenassmall,anextra60-70ginweightcouldreduceperinatalmorbidityandmortalityinanalreadycompromisedfetus.Thesteepdeclineinriskassociatedwithcaffeineintakesof<30mg/daymaybeattributabletounmeasuredconfounding.Furthermore,womenwhoconsumelittleornocaffeinemaybegenerallymorehealthconsciousthanthosewhoconsumemore,andtheeffectmaybeoneforwhichwehavebeenunabletoadjust.Wefoundthataveragecaffeineconsumptionof>100mg/daywasassociatedwithareductioninbirthweightof34-59ginthefirsttrimester,24-74ginthesecond,and66-89ginthethird(afteradjustmentforsmokingstatusandalcoholintake).SimilarresultswereseenbyBrackenetalinaprospectivestudyof2291pregnantwomenintheUS,wheremeanbirthweightwasreducedby28gforevery100mg/dayofcaffeineconsumed(P=0.0001),buttheriskforfetalgrowthrestrictionwasunchanged(oddsratio0.96).36Thisdifferencecouldbeexplainedbymethodologicaldifferencesinthestudies.ADanishcohortof1207womendrinkingatleastthreecupsofcoffeeadaybefore20weeksofpregnancywererandomisedtoreceiveeithercaffeinatedordecaffeinatedinstantcoffee:therewasnosignificantdifferenceinbirthweightbetweenthetwogroupsafteradjustmentforparity,gestationalageatbirth,andsmoking.37However,thesewomenwererecruitedinpage6of8 thesecondhalfofpregnancy,sotheeffectoffirsttrimestercaffeineintakewasnotassessed,andtherewasnobiochemicalconfirmationofparticipants’compliancewithcaffeinatedordecaffeinatedcoffeeconsumption.Inaddition,BicalhoandFilhoreportednoassocia-tionbetweenmaternalcaffeineconsumptionandlowbirthweightafteradjustingforconfoundingvariablesinacase-controlstudyinBrazil.38Caffeinemetabolism Someofthevariationinpreviouslyreportedassocia-tionsbetweencaffeineintakeandpregnancyoutcomesmayreflecttheeffectofdifferencesincaffeinemeta-bolism.Thedegreetowhichafetusisexposedtocaffeineanditsmetabolites,whichpassfreelyacrosstheplacenta,dependsonmaternalcytochromeP4501A2(CYP1A2)activitybecausethisenzymeisabsentinthefetus.Wecomplementedourassessmentofcaffeineintakewithameasureofcaffeinemeta-bolismandobservedthattheassociationofcaffeineintakewithfetalgrowthrestrictionwasgreateramongwomenwithfastercaffeineclearance.Caffeineisprimarilymetabolisedinthehumanlivertoparaxanthine,39butthereislittledataaboutmeta-bolisminpregnantwomen.Inourstudycaffeinewasmetabolisedtoparaxanthine,theobromine,andtheo-phylline,withtheobrominepresentinhighestconcen-trationinmostofthewomen.Aswewereunabletomeasuretherateofformationorsubsequentmeta-bolismoftheseprimarymetabolites,wecannotattributetheassociationwithfetalgrowthtoanysinglemetabolite.Theassociationweobservedmaybeduetocaffeineitselforoneofitsmetabolites,ortoanycombinationofthem.Inastudyofpregnantwomenwhosmoked,KlebanoffetalreportedapositiveassociationbetweenmaternalparaxanthineconcentrationinthethirdWHATISALREADYKNOWNONTHISTOPIC Caffeineisthemostcommonxenobioticconsumedinpregnancy,andthereareconflictingresultsregardingtheassociationofincreasedcaffeineintakeinpregnancywithfetalgrowthrestrictionandlowbirthweightThesedifferencescouldbeexplainedbyinconsistenciesinaccuratequantificationofcaffeineandinthedefinitionoffetalgrowthrestrictionWHATTHISSTUDYADDS MaternalcaffeineintakeisassociatedwithanincreasedriskoffetalgrowthrestrictionafteradjustmentforsmokingandalcoholintakeThesizeoftheassociationforcaffeineintakewithfetalgrowthrestrictionissimilartothatforalcoholintakeTheassociationofcaffeinewithfetalgrowthrestrictionseemstobestrongerinwomenwithfastercaffeineclearanceSensibleadvicetopregnantwomenwouldbetoreducecaffeineintakebeforeconceptionandduringpregnancyBMJ|ONLINEFIRST|bmj.com Downloaded from bmj.com on 6 November 2008 BMJ|ONLINEFIRST|bmj.com trimesterandhavinganinfantthatwassmallforitsgestationalage.40Inanotherstudy,thehighestcon-centrationsofparaxanthinewereassociatedwithanincreasedriskofspontaneousabortion.41Recently,highercordbloodparaxanthineconcentrationshavebeenshowntobeassociatedwithanincreasedriskofintrauterinegrowthrestrictionafteradjustmentforcaffeinelevels,implyinganeffectofCYP1A2activityratherthanabsolutelevelsofparaxanthine.25FurtherconsiderationoftheroleofCYP1A2activityandcaffeinemetabolitesisclearlywarranted.Conclusion Thislargeprospectivecohortstudyhasdemonstratedthatmaternalcaffeineintakeisassociatedwithanincreasedriskoffetalgrowthrestriction.Thethresholdatwhichthisriskissignificantlyhigherisnotwellcharacterised,butourdataconfirmthattheassociationoffetalgrowthrestrictionwithcaffeineisreducedforthoseconsuming<100mg/day.Wesuggestthatsensibleadviceforwomencontemplatingpregnancyistoreducetheircaffeineintakefromallsourcesbeforeconception.Oncepregnancyisconfirmed,theyshouldmakeeveryefforttostopormarkedlyreducecaffeineconsumption.WethankGordonGibson,FredKadlubar,andMarkKlebanofffortheirusefulcommentsduringthestudy.TheLeicesterteamoftheCAREStudyGroupthankVilasMisty,ClareLawrence,BhavinDaudia,andtheDepartmentofChemicalPathology,UniversityHospitalsofLeicesterNHSTrust,forsamplehandlingandprocessing.MembersoftheCAREStudyGroup:Leedsteam:SineadBoylan,JanetECade,VivienADolby,DarrenCGreenwood,AlastairWMHay,SaraFLKirk,SusanShires,NigelSimpson,JamesDThomas,JamesWalker,KayLMWhite,ChristopherPWild,CentreforEpidemiologyandBiostatistics,UniversityofLeeds,LeedsLS29JTLeicesterteam:NeelamPotdar,JustinCKonje,NicholasTaub,JimCharvill,KarenCChipps,ShabiraKassam,ChetanGhandi,,MarcusSCooke,DepartmentsofCancerStudiesandMolecularMedicineandHealthSciences,UniversityofLeicester,LeicesterLE27LXSteeringgroup:JustinCKonje(chair),MarcusCooke(principalinvestigator),Leicester;JanetCade(principalinvestigator),Leeds;DavidGott,NatalieThatcher,StuartCreton,CarolineTahourdin,FoodStandardsAgency,London;GordonGibson,UniversityofSurreyStatisticians:DarrenGreenwood,Leeds;NicholasTaub,Leicester;CliftonGay,FoodStandardsAgencyClinicians:NeelamPotdar,JustinCKonje,Leicester;NigelSimpson,JamesWalker,LeedsResearchmidwives:VivDolby,HeatherOng,Leeds;ShabiraKassam,KarenChipps,LeicesterNutritionalmethods:SineadBoyland,SaraKirk,JanetCade,LeedsLaboratorymethods:KayWhite,SusanShires,AlastairHay,ChristopherWild,Leeds;MarcusCooke,LeicesterDatabasemanagement:JamesThomas,EllenHill,nutritioniststudents,Leeds;JimCharvill,ChetanGhandi,Leicester.Funding:FoodStandardsAgency,UnitedKingdom,GrantcontractNoT01032/33.Competinginterests:Nonedeclared.Ethicalapproval:Obtainedfromthelocalethicscommittees,DirectorateofResearchandDevelopment,LeicesterandLeeds,LRECRef7260.Participantsgavesignedinformedconsentbeforeenrolmentintothestudy.1 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19GoldsteinA,WarrenR.Passageofcaffeineintohumangonadalandfetaltissue.BiochemPharmacol1962;11:166-8. 20KirkinenP,JouppilaP,KoivulaA,VuoriJ,PuukkaM.Theeffectofcaffeineonplacentalandfetalbloodflowinhumanpregnancy.AmJObstetGynecol1983;147:939-42. 21AldridgeA,ArandaJV,NeimsAH.Caffeinemetabolisminthenewborn.ClinPharmacolTher1979;25:447-53. 22 RasmussenBB,BrixTH,KyvikKO,BrøsenK.Theinterindividualdifferencesinthe3-demethylationofcaffeinealiasCYP1A2isdeterminedbybothgeneticandenvironmentalfactors.Pharmacogenetics2002;12:473-8. 23 KotakeAN,SchoellerDA,LambertGH,BakerAL,SchafferDD, JosephsH.ThecaffeineCO2breathtest:doseresponseandrouteofN-demethylationinsmokersandnonsmokers.ClinPharmacolTher1982;32:261-9. 24KalowW,TangBK.UseofcaffeinemetaboliteratiostoexploreCYP1A2andxanthineoxidaseactivities.ClinPharmacolTher1991;50:508-19. 25 GrossoLM,TricheEW,BelangerK,BenowitzNL,HolfordTR,BrackenMB.Caffeinemetabolitesinumbilicalcordblood, cytochromeP-4501A2activity,andintrauterinegrowthrestriction.AmJEpidemiol2006;163:1035-41. 26BoylanSM,CadeJE,KirkSFL,GreenwoodDC,WhiteKLM,ShiresS,etal.Assessingcaffeineexposureinpregnantwomen.BrJNutr2008,Onlinepublicationdoi:10.1017/S0007114508939842.27DirectorateMFS.Surveyofcaffeineandothermethylxanthinesinenergydrinksandothercaffeine-containingproducts(updated).FoodSurveillanceInformationSheet1998:144. 28 ButlerMA,LangNP,YoungJF,CaporasoNE,VineisP,HayesRB,etal.DeterminationofCyp1a2andNat2phenotypesinhuman-populationsbyanalysisofcaffeineurinarymetabolites.Pharmacogenetics1992;2:116-27. 29 BinnieV,McHughS,MacphersonL,BorlandB,MoirK,MalikK.Thevalidationofself-reportedsmokingstatusbyanalysingcotininelevels page7of8 Downloaded from bmj.com on 6 November 2008 page8of8instimulatedandunstimulatedsaliva,serumandurine.OralDiseases2004;10:287-93. 30GardosiJ.Customisedfetalgrowthstandards:rationaleandclinicalapplication.SeminPerinatol2004;28:33-40. 31 BrownMA,LindheimerMD,deSwietM,VanAsscheA,MoutquinJM.Theclassificationanddiagnosisofthehypertensivedisordersofpregnancy:StatementfromtheInternationalSocietyfortheStudyofHypertensioninPregnancy(ISSHP).HypertensioninPregnancy2001;20:IX-XIV. 32Statastatisticalsoftware:Release10.Collegestation,TX:StataCorporation,2007. 33 WengX,OdouliR,LiDK.Maternalcaffeineconsumptionduring pregnancyandtheriskofmiscarriage:aprospectivecohortstudy.AmJObstetGynecol2008;198:279e1-8. 34RosenbergL,MitchellAA,ShapiroS,SloneD.Selectedbirthdefectsinrelationtocaffeine-containingbeverages.JAMA1982;247:1429-32.35 OrganisationofTeratologyInformationSpecialists.Caffeineandpregnancy.December,2006.www.otispregnancy.org 36BrackenMB,TricheE,GrossoL,HellenbrandK,BelangerK,Leaderer, etal.Heterogeneityinassessingself-reportsofcaffeineexposure:implicationsforstudiesofhealtheffects.Epidemiology2002;13:165-71. 37BechBH,ObelC,HenriksenTB,OlsenJ.Effectofreducingcaffeine intakeonbirthweightandlengthofgestation:randomisedcontrolledtrial.BMJ2007;334:409-12. 38BicalhoGG,BarrosFilhoAdeA.[Birthweightandcaffeine consumption].RevistadeSaudePublica2002;36:180-7. 39KlebanoffMA,LevineRJ,DersimonianR,ClemensJD,WilkinsDG. Serumcaffeineandparaxanthineasmarkersforreportedcaffeineintakeinpregnancy.AnnEpidemiol1998;8:107-11. 40KlebanoffMA,LevineRJ,ClemensJD,WilkinsDG.Maternalserum caffeinemetabolitesandsmall-for-gestationalagebirth.AmJEpidemiol2002;155:32-7. 41KlebanoffMA,LevineRJ,DerSimonianR,ClemensJD,WilkinsDG. Maternalserumparaxanthine,acaffeinemetabolite,andtheriskofspontaneousabortion.NEnglJMed1999;341:1639-44. Accepted:24October2008 BMJ|ONLINEFIRST|bmj.com The new england journal of medicineoriginal articleIrbesartan in Patients with Atrial FibrillationThe ACTIVE I Investigators*AbstractBackgroundThe members of the writing group (Salim Yusuf, M.B., B.S., D.Phil., Jeff S. Healey, M.D., Janice Pogue, M.Sc., Susan Chro-lavicius, R.N., Marcus Flather, M.B., B.Ch., Robert G. Hart, M.D., Stefan H. Hohn-loser, M.D., Campbell D. Joyner, M.D., Marc A. Pfeffer, M.D., and Stuart J. Con-nolly, M.D.), assume responsibility for the overall content and integrity of the arti-cle. Address reprint requests to Dr. Yusuf at the Population Health Research Insti-tute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton Health Sciences and McMaster University, 237 Barton St. East, Hamilton, ON L8L 2X2, Canada, or at yusufs@mcmaster.ca.* The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascu-lar Events (ACTIVE I) investigators are listed in the Supplementary Appendix, available at NEJM.org. The affiliations of the writing group are listed in the Appendix.N Engl J Med 2011;364:928-38.Copyright © 2011 Massachusetts Medical Society.The risk of cardiovascular events among patients with atrial fibrillation is high. We evaluated whether irbesartan, an angiotensin-receptor blocker, would reduce this risk.MethodsWe randomly assigned patients with a history of risk factors for stroke and a systolic blood pressure of at least 110 mm Hg to receive either irbesartan at a target dose of 300 mg once daily or double-blind placebo. These patients were already enrolled in one of two trials (of clopidogrel plus aspirin versus aspirin alone or versus oral anti-coagulants). The first coprimary outcome was stroke, myocardial infarction, or death from vascular causes; the second was this composite outcome plus hospitalization for heart failure.ResultsA total of 9016 patients were enrolled and followed for a mean of 4.1 years. The mean reduction in systolic blood pressure was 2.9 mm Hg greater in the irbesartan group than in the placebo group, and the mean reduction in diastolic blood pressure was 1.9 mm Hg greater. The first coprimary outcome occurred at a rate of 5.4% per 100 person-years in both groups (hazard ratio with irbesartan, 0.99; 95% confi-dence interval [CI], 0.91 to 1.08; P = 0.85). The second coprimary outcome occurred at a rate of 7.3% per 100 person-years among patients receiving irbesartan and 7.7% per 100 person-years among patients receiving placebo (hazard ratio, 0.94; 95% CI, 0.87 to 1.02; P = 0.12). The rates of first hospitalization for heart failure (a pre-specified secondary outcome) were 2.7% per 100 person-years among patients re-ceiving irbesartan and 3.2% per 100 person-years among patients receiving placebo (hazard ratio, 0.86; 95% CI, 0.76 to 0.98). Among patients who were in sinus rhythm at baseline, there was no benefit of irbesartan in preventing hospitalization for atrial fibrillation or atrial fibrillation recorded on 12-lead electrocardiography, nor was there a benefit in a subgroup that underwent transtelephonic monitoring. More patients in the irbesartan group than in the placebo group had symptomatic hypo-tension (127 vs. 64) and renal dysfunction (43 vs. 24).ConclusionsIrbesartan did not reduce cardiovascular events in patients with atrial fibrillation. (Funded by Bristol-Myers Squibb and Sanofi-Aventis; ClinicalTrials.gov number, NCT00249795.)928n engl j med 364;10 nejm.org march 10, 2011 The New England Journal of Medicine Downloaded from nejm.org on February 28, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. Irbesartan in Atrial FibrillationThe most common risk factor for the development of atrial fibrillation is hyper-data or in the writing of the manuscript. The tension,1 and two common complications members of the writing group had full access to in atrial fibrillation are stroke and heart failure, all data and had final responsibility for publica-both of which are related to elevated blood pres-tion decisions. The protocol was approved by the sure.2 Randomized trials of blood-pressure reduc-appropriate regulatory authorities and the ethics tion have shown a reduced risk of stroke and heart committee at each site. The protocol, including failure in populations without atrial fibrillation.3-6 the statistical analysis plan, is available with the However, a similar relationship has yet to be full text of this article at NEJM.org. All authors shown in patients with atrial fibrillation, and data attest that the study was performed in accordance from trials of blood-pressure reduction in patients with the protocol and vouch for the accuracy and with atrial fibrillation are lacking. Blockers of completeness of the reported data. All patients the renin–angiotensin–aldosterone system are provided written informed consent.hypothesized to have specific properties that Patient Selection and Study Drugsbeneficially alter atrial mechanical and electrical remodeling.7-9 Secondary analyses of data from Patients were eligible to enroll in the trial if they trials of angiotensin-converting–enzyme (ACE) in-had permanent atrial fibrillation or had at least hibitors or angiotensin-receptor blockers (ARBs) two episodes of intermittent atrial fibrillation in in patients with heart failure or left ventricular the previous 6 months. In addition, patients were dysfunction suggest that these agents prevent required to have one of the following risk factors: atrial fibrillation.10an age of 75 years or older; treatment for hyper-We hypothesized that an ARB may prevent car-tension; a history of stroke, transient ischemic diovascular events and enhance the maintenance attack, or non-central nervous system systemic of sinus rhythm in patients with intermittent embolism; a left ventricular ejection fraction of atrial fibrillation by reducing blood pressure and less than 45%; peripheral vascular disease; or an by specific effects related to blockade of the renin–age of 55 to 74 years plus either diabetes mellitus angiotensin–aldosterone system.7-9 In the Atrial or coronary artery disease. Patients were excluded Fibrillation Clopidogrel Trial with Irbesartan for if they required clopidogrel or oral anticoagulants, Prevention of Vascular Events (ACTIVE I), patients had received a diagnosis of peptic ulcer disease with atrial fibrillation who were already enrolled within the previous 6 months, had a history of into two large parallel trials evaluating clopido-intracerebral hemorrhage, or had thrombocyto-grel plus aspirin11,12 underwent a second ran-penia or mitral stenosis.domization, to irbesartan or placebo. The study In one of the parallel trials, ACTIVE W, pa-involved the use of a partial factorial design to tients were randomly assigned to receive clopi-determine the effects of irbesartan on the risk of dogrel plus aspirin or oral anticoagulation. In the death from vascular causes, myocardial infarc-other parallel trial, ACTIVE A, patients received tion, or stroke; on this composite outcome plus aspirin (75 to 100 mg per day) and were ran-hospitalization for heart failure; and on recurrent domly assigned to either clopidogrel at a dose of atrial fibrillation in patients who were in sinus 75 mg or placebo. Eligible patients from these rhythm at study entry.two trials (who had a systolic systemic arterial pressure of at least 110 mm Hg and who were not receiving an ARB) were also eligible to be Methodsenrolled in this trial, ACTIVE I, and patients who provided consent were randomly assigned to re-Study Design and ProtocolA steering committee was responsible for the de-ceive irbesartan once daily (at a dose of 150 mg sign, conduct, and reporting of the study. The per day for 2 weeks, and 300 mg per day there-Population Health Research Institute designed the after) or placebo. Assignment was performed study, collected all data, adjudicated outcomes, with the use of a central randomization system, and performed the analysis. Representatives of stratified according to center and enrollment Bristol-Myers Squibb and Sanofi-Aventis, the study into ACTIVE A or ACTIVE W.sponsors, were members of the steering commit-Study Outcomestee, but the sponsors had no direct role in the collection, analysis, or interpretation of study The first coprimary outcome was the composite of stroke, myocardial infarction, or death from n engl j med 364;10 nejm.org march 10, 2011 The New England Journal of Medicine Downloaded from nejm.org on February 28, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. 929The new england journal of medicinevascular causes, and the second coprimary out-come was this composite outcome plus hospital-ization for heart failure. (For definitions, see Ap-pendix A in the Supplementary Appendix, available at NEJM.org). All components of the coprimary outcomes were reviewed by an adjudication com-mittee; members of the committee were unaware of the study-drug assignments. Other outcomes were recurrence of atrial fibrillation on 12-lead elec-trocardiography performed at 2 years and at the Table 1. Baseline Characteristics of the Patients.*VariableAge — yrBlood pressure — mm HgSystolicDiastolicHeart rate — beats/minBody-mass indexCHADS2 score†Creatinine clearance — ml/minLeft ventricular ejection fraction — %Male sex — no. (%)Type of atrial fibrillation — no. (%)PermanentParoxysmalPersistentMissing dataMarkers of high risk — no. (%)Age ≥75 yrHypertensionStroke, transient ischemic attack, or systemic embolismLeft ventricular dysfunctionPeripheral artery diseaseAge 55–74 yr plus diabetes or coronary artery diseaseHeart failureDiabetes mellitusPrevious cardioversion — no. (%)Ethnic group — no. (%)EuropeanNon-EuropeanECG findings at randomization — no. (%)Sinus rhythmAtrial fibrillationAtrial flutterOther rhythmECG evidence of left ventricular hypertrophyIntraventricular conduction delayend of the study, the rate of rehospitalization for atrial fibrillation, and recurrence of atrial fibrilla-tion with the use of transtelephonic monitoring.Transtelephonic Monitoring SubstudyPatients from selected centers who were in sinus rhythm at the time of randomization participated in the substudy on the recurrence of atrial fibril-lation. The patients were instructed how to use transtelephonic event monitors (ER300, Braemar) Irbesartan (N = 4518)69.5±9.7138.3±17.682.6±11.575.3±14.428.9±4.902.0±1.175.5±31.655±132745 (60.8)2982 (66.0)886 (19.6)644 (14.3)6 (0.1)1551 (34.3)3982 (88.1)613 (13.6)568 (12.6)103 (2.3)1008 (22.3)1460 (32.3)906 (20.1)1669 (36.9)3394 (75.1)1124 (24.9)847 (18.7)3457 (76.5)37 (0.8)177 (3.8)765 (16.9)622 (13.8)Placebo (N = 4498)69.6±9.7138.2±17.282.2±11.174.9±14.428.7±4.92.0±1.0774.5±31.455±132730 (60.7)2898 (64.4)921 (20.5)668 (14.9)11 (0.2)1576 (35.0)3947 (87.8)599 (13.3)561 (12.5)133 (3.0)970 (21.6)1421 (31.6)881 (19.6)1704 (37.9)3375 (75.0)1123 (25.0)883 (19.6)3390 (75.4)42 (0.9)183 (4.1)749 (16.7)597 (13.3)930n engl j med 364;10 nejm.org march 10, 2011 The New England Journal of Medicine Downloaded from nejm.org on February 28, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. Irbesartan in Atrial FibrillationTable 1. (Continued.)VariableIrbesartan (N = 4518)Placebo (N = 4498)Smoking status — no. (%)Current smoker331 (7.3)367 (8.2)Former smoker1910 (42.3)1897 (42.2)Alcohol consumption >1 drink/day — no. (%)362 (8.0)374 (8.3)Use of medication at baseline — no. (%)Aspirin2652 (58.7)2666 (59.3)Thienopyridine146 (3.2)144 (3.2)Oral anticoagulant1721 (38.1)1692 (37.6)Angiotensin-converting–enzyme inhibitor2720 (60.2)2724 (60.6)Angiotensin-receptor blocker232 (5.1)211 (4.7)Beta-blocker2458 (54.4)2455 (54.6)Digoxin1586 (35.1)1562 (34.7)Calcium-channel blocker‡1220 (27.0)1225 (27.2)Diuretic2453 (54.3)2432 (54.1)Vasodilator537 (11.9)498 (11.1)Lipid-lowering drug1405 (31.1)1459 (32.4)Antiarrhythmic drug1025 (22.7)1041 (23.1)* Plus–minus values are means ±SD. The body-mass index is the weight in kilograms divided by the square of the height in meters. ECG denotes electrocardiographic.† The CHADSindicating an increased risk of stroke.2 score, an index of the risk of stroke in patients with atrial fibrillation, ranges from 1 to 6, with higher scores ‡ A total of 910 patients (10.1%) — 454 (10.0%) in the irbesartan group and 456 (10.1%) in the placebo group — were receiving drugs to slow the heart rate (verapamil or diltiazem).for two monitoring periods (between randomiza-was extended by 1.1 years (mean, 4.1 years), with a tion and 4 months and between 18 and 20 months). power of 80% to detect risk reductions of 15.5% Patients were asked to transmit a recording and and 15.8% in the two coprimary outcomes, re-to complete a questionnaire if they had symptoms spectively.of atrial fibrillation. They were also asked to trans-mit weekly recordings taken while they were board monitored the accumulating data during An independent data and safety monitoring asymptomatic to detect asymptomatic atrial fibril-the trial according to prespecified guidelines.11,12 lation. All transtelephonic monitoring transmis-Analyses were based on the intention-to-treat sions were analyzed at a core laboratory in Ham-principle, and the time to a first occurrence of ilton by investigators who were unaware of the an outcome in the two study groups was com-study-drug assignments.pared with the use of Cox proportional-hazards regression models, stratified according to enroll-Statistical AnalysisWe originally anticipated that enrollment of 9000 ment in either ACTIVE A or ACTIVE W. Subgroup patients and follow-up for a mean of 3 years analyses used tests of interactions in the same would result in 89% statistical power to detect a models. Modeling of proportional rate and mean reduction of 15% in the risk of the first coprimary functions was used to compare the time to re-outcome (at an alpha level of 0.045) if the event current outcomes in the two groups.13 The total number of hospital admissions in the two study rate per year in the control group was 7%, and groups was compared with the use of Poisson 92% power to detect a 15% risk reduction in the regression.14 Differences in blood pressure were second coprimary outcome (at an alpha level of compared with the use of analysis of variance.0.01), assuming an event rate of 11% per year. The prevalence of atrial fibrillation on follow-Because overall event rates were lower than ex-up electrocardiography was compared between pected (5.4% and 7.7%, respectively), follow-up study groups with the use of Fisher’s exact test, n engl j med 364;10 nejm.org march 10, 2011 The New England Journal of Medicine Downloaded from nejm.org on February 28, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. 931The new england journal of medicineand the treatment effect was expressed as relative risks. The time to outcomes such as cardiover-sion or hospitalization for atrial fibrillation was assessed with the use of the Kaplan-Meier meth-od, and differences between the study groups were compared with the use of the log-rank test. In the transtelephonic monitoring substudy, the time to a first episode of recurrent atrial fibril-lation in each group was examined with the use of a plot of conditional probability. A second analysis was conducted with the use of the recur-rent-events (proportional-means) model13 in order to include each individual episode of recurrent atrial fibrillation.for discontinuation of the study medication was withdrawal of consent (accounting for about half the cases of discontinuation), and the incidence of symptomatic hypotension was higher among patients who received irbesartan than among pa-tients who received placebo (2.8% [127 patients] vs. 1.4% [64 patients], P<0.001).Blood Pressure and Antihypertensive TherapyResultsStudy PopulationTable 1 lists the baseline characteristics of the patients. The mean age was 69.6 years, 60.7% of the patients were men, and the mean CHADS2 score was 2.0 (the CHADS2 score, an index of the risk of stroke in patients with atrial fibrillation, ranges from 1 to 6, with higher scores indicating an increased risk of stroke). Among patients who were enrolled in both ACTIVE W and ACTIVE I, a total of 2048 (51.0%) were randomly assigned to receive an oral anticoagulant, and 1970 (49.0%) were randomly assigned to receive clopidogrel plus aspirin. (After termination of ACTIVE W, 16.7% of patients received aspirin, and 86.6% of pa-tients were treated with nonstudy oral anticoagu-lants.) Among patients enrolled in both ACTIVE A and ACTIVE I, a total of 2494 patients (49.9%) were randomly assigned to receive clopidogrel plus aspirin and 2504 patients (50.1%) were assigned to aspirin alone. A total of 19.2% of patients were in sinus rhythm at enrollment. Commonly used medications included rate-control drugs (beta-blockers in 54.5% of patients, digoxin in 34.9%, and calcium-channel blockers that slow heart rate in 10.1%) and antiarrhythmic drugs (in 22.9%).Follow-up and Adherence to the Study-Drug RegimensAt study entry, the mean blood pressure was 138.3 mg Hg systolic and 82.6 mm Hg diastolic in the irbesartan group and 138.2 mm Hg sys-tolic and 82.2 mm Hg diastolic in the placebo group. The mean reduction in blood pressure was 6.8 mm Hg systolic and 4.5 mm Hg diastolic in patients who received irbesartan, as compared with 3.9 mm Hg systolic and 2.6 mm Hg diastolic in patients who received placebo (mean differ-ence during the trial, 2.9 mm Hg systolic and 1.9 mm Hg diastolic). At 2 years, 10.7% of pa-tients receiving irbesartan and 7.7% of patients receiving placebo were not receiving any blood-pressure–lowering agent; 55.3% of patients receiv-ing irbesartan and 53.3% of patients receiving placebo were receiving one or two nonstudy drugs to reduce blood pressure, and 34.1% and 39.1%, respectively, were receiving three or more non-study drugs to reduce blood pressure. At 2 years, the mean number of such drugs per patient was 2.00 among patients who received irbesartan as compared with 2.15 among patients who received placebo (P<0.001).Coprimary OutcomesThe mean follow-up was 4.1 years (median, 4.5 years) and was complete for vital status in 8976 of 9016 patients (99.6%). The rates of permanent discontinuation of study drugs were 14.8% with irbesartan and 13.7% with placebo at 1 year, 20.6% and 19.4% at 2 years, and 30.3% and 30.3% at 4 years, respectively. The most common reason 932As shown in Table 2, the first coprimary outcome occurred in 5.4% of patients per 100 patient-years in both study groups (hazard ratio with irbesar-tan, 0.99; 95% confidence interval [CI], 0.91 to 1.08; P = 0.85) (Fig. 1A), with no significant dif-ference in the second coprimary outcome (7.3% per 100 patient-years with irbesartan and 7.7% per 100 patient-years with placebo; hazard ratio, 0.94; 95% CI, 0.87 to 1.02; P = 0.12) (Fig. 1B). Analysis of recurrent events, which accounts for multiple events in the same patient, showed little differ-ence in the first coprimary outcome (1100 vs. 1123 events; hazard ratio, 0.97; 95% CI, 0.89 to 1.07; P = 0.58) but a significant reduction in the second coprimary outcome (1791 vs. 1993; hazard ratio, 0.89; 95% CI, 0.82 to 0.98; P = 0.02). The only component of the coprimary outcome that showed a nominally significant reduction with n engl j med 364;10 nejm.org march 10, 2011 The New England Journal of Medicine Downloaded from nejm.org on February 28, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. Irbesartan in Atrial FibrillationTable 2. Relative Risks of Primary and Key Secondary Outcomes.OutcomeIrbesartan(N = 4518)Placebo(N = 4498)Relative Risk(95% CI)P Valueno. of patients with first events (%/100 patient-yr of follow-up)Coprimary outcomesStroke, myocardial infarction, or death from vascular causesStroke, myocardial infarction, hospitalization for heart failure, or death from vascular causesRecurrent eventsStroke, myocardial infarction, or death from vascular causesStroke, myocardial infarction, hospitalization for heart failure, or death from vascular causesCerebrovascular and systemic embolic eventsStrokeTransient ischemic attackNon–central nervous system systemic embolismStroke, transient ischemic attack, or non–central nervous system embolism Types of strokeIschemicPrimary hemorrhagicHemorrhagic transformation of ischemic strokePrimary hemorrhagic or secondary transformationStroke type uncertainMyocardial infarctionHospitalization for heart failureDeath from vascular causesDeath from any cause308 (1.7)33 (0.2)6 (<0.1)39 (0.2)46 (0.2)143 (0.8)482 (2.7)666 (3.6)949 (5.1)329 (1.8)46 (0.2)19 (0.1)65 (0.4)55 (0.3)135 (0.7)551 (3.2)646 (3.5)929 (5.0)0.93 (0.79–1.08)0.71 (0.46–1.11)0.31 (0.13–0.78)0.60 (0.40–0.89)0.83 (0.56–1.23)1.05 (0.83–1.33)0.86 (0.76–0.98)1.02 (0.92–1.14)1.01 (0.93–1.11)0.350.140.010.010.350.670.020.670.75379 (2.1)130 (0.7)47 (0.3)515 (2.9)411 (2.3)150 (0.8)64 (0.3)584 (3.3)0.91 (0.79–1.05)0.86 (0.68–1.09)0.72 (0.50–1.05)0.87 (0.77–0.98)0.200.210.090.021100 (24.3)1791 (39.6)1123 (25.0)1993 (44.3)0.97 (0.89–1.07)0.89 (0.82–0.98)0.580.02963 (5.4)1236 (7.3)963 (5.4)1291 (7.7)0.99 (0.91–1.08)0.94 (0.87–1.02)0.850.12irbesartan was a first hospitalization for heart failure (482 patients with events in the irbesartan group vs. 551 in the placebo group; hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P = 0.02).Cerebrovascular Events and Systemic EmbolismRecurrence of Atrial FibrillationThere were trends toward fewer strokes with ir-besartan than with placebo (379 vs. 411), fewer transient ischemic attacks (130 vs. 150), and fewer cases of systemic emboli (47 vs. 64). Thus, a post hoc analysis of the composite of any of these cerebrovascular and embolic events was nomi-nally significant (515 vs. 584; hazard ratio, 0.87; 95% CI, 0.77 to 0.98; P = 0.02).Of the 9005 patients who underwent a baseline electrocardiographic examination, 6926 (76.8%) were in atrial fibrillation, 1730 (19.2%) were in sinus rhythm, and 349 (3.9%) had a paced or other rhythm at baseline. Among patients who were in atrial fibrillation at baseline, sinus rhythm was present on one follow-up electrocardiographic examination in 10.6% of patients who received irbesartan as compared with 9.7% of patients who received placebo (relative risk, 1.10; 95% CI, 0.94 to 1.28; P = 0.26). In patients with sinus rhythm at baseline, atrial fibrillation was present at one follow-up electrocardiographic examina-tion in 36.8% of patients who received irbesartan 933n engl j med 364;10 nejm.org march 10, 2011 The New England Journal of Medicine Downloaded from nejm.org on February 28, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. The new england journal of medicineAStroke, Myocardial Infarction, or Death from Vascular Causes0.40.3Placebo0.2Irbesartan0.1Hazard ratio, 0.99 (95% CI, 0.91–1.08)P=0.85012344.50.0common symptoms were: palpitations (in 86.8% of the patients), fatigue (in 43.8%), breathlessness (in 31.9%), dizziness (in 18.4%), chest pain (in 13.9%), and sweating (in 13.1%). In all, 56.7% of symptomatic transmissions and 9.0% of asymp-tomatic transmissions showed atrial fibrillation. Atrial fibrillation recurred at least once in 68.6% of patients randomly assigned to irbesartan and in 62.6% of patients randomly assigned to placebo (hazard ratio, 1.14; 95% CI, 0.80 to 1.64; P = 0.46) (Fig. 2B). A recurrent-events analysis did not show an effect of irbesartan (hazard ratio, 1.21; 95% CI, 0.72 to 2.04; P = 0.46).HospitalizationsCumulative Hazard RateYears since RandomizationNo. at RiskPlaceboIrbesartan 449845184195422039123926364736692737216027812170BStroke, Myocardial Infarction, Death from Vascular Causes, or Hospitalizationfor Heart Failure0.4Cumulative Hazard Rate0.3PlaceboIrbesartan0.20.1Hazard ratio, 0.94 (95% CI, 0.87–1.02)P=0.12012344.50.0Years since RandomizationNo. at RiskPlaceboIrbesartan449845184035408436903741340234662523197925982019Figure 1. Kaplan–Meier Curves for the Coprimary Study Outcomes.as compared with 38.1% of patients who received placebo (relative risk, 0.97; 95% CI, 0.85 to 1.10; P = 0.61). Irbesartan did not significantly reduce the risk of hospitalization for atrial fibrillation (hazard ratio, 0.95; 95% CI, 0.85 to 1.07; P = 0.41) (Fig. 2A) or the risk of cardioversion (hazard ra-tio, 0.97; 95% CI, 0.86 to 1.10; P = 0.67).Transtelephonic Monitoring SubstudyThe number of patients with a first hospitaliza-tion for cardiovascular events was 1846 (40.9%) in the irbesartan group as compared with 1900 (42.2%) in the placebo group (relative risk, 0.97; 95% CI, 0.92 to 1.02). As shown in Table 3, there were fewer hospital admissions for cardiovascu-lar events in the irbesartan group than in the placebo group (3817 vs. 4060; difference, −243; P = 0.003). There were also fewer hospitalizations for noncardiovascular events with irbesartan (dif-ference, −60), so that the total number of hospi-talizations was significantly reduced (6519, vs. 6822 with placebo; difference, −303; P = 0.004). The mean duration of a hospital stay for cardio-vascular events was 9.55 days in the irbesartan group as compared with 9.84 in the placebo group (P = 0.28). Thus, there was a significant reduction in the total hospital days for cardiovascular events among patients who received irbesartan (36,447 vs. 39,960; difference, −3513; P<0.001). Data on the duration of hospitalizations for noncardio-vascular events were not collected.Prespecified Subgroup AnalysesA total of 185 patients who were in sinus rhythm at randomization participated in the substudy of recurrence of atrial fibrillation (86 patients who received irbesartan and 99 patients who received placebo). Of 1202 episodes of atrial fibrillation captured during transtelephonic monitoring, only 665 were symptomatic (55.3%). The most 934There was no significant interaction for the ef-fects of irbesartan on either coprimary outcome according to whether patients were enrolled in ACTIVE A or ACTIVE W or according to baseline use or nonuse of ACE inhibitors and baseline blood pressure (Fig. 3). The reductions in hospital-izations for heart failure in the irbesartan group were consistent whether patients had a history of heart failure at baseline (hazard ratio, 0.90; 95% CI, 0.75 to 1.08) or did not have a history of heart failure (hazard ratio, 0.81; 95% CI, 0.69 to 0.96; P = 0.40 for interaction). A measure of left ven-tricular dysfunction was available in 4810 patients, among whom 1296 (26.9%) had a normal ejection n engl j med 364;10 nejm.org march 10, 2011 The New England Journal of Medicine Downloaded from nejm.org on February 28, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. Irbesartan in Atrial FibrillationCumulative Hazard Ratefraction. In this subgroup, 122 patients were hos-pitalized for heart failure in the irbesartan group as compared with 150 in the placebo group (rela-tive risk, 0.81; 95% CI, 0.63 to 1.02).Adverse EventsAHospitalization for Atrial Fibrillation0.200.15PlaceboIrbesartanConditional Probability of RecurrenceMore patients in the irbesartan group than in the placebo group discontinued the study medication because of symptomatic hypotension (127 vs. 64, P<0.001). Irbesartan did not significantly increase the number of patients with either a doubling of the serum creatinine level or an increase in the potassium level to 6.0 mmol per liter or more (37 patients who received irbesartan vs. 34 patients who received placebo). However, any renal dys-function leading to drug discontinuation was more frequent in the irbesartan group than in the placebo group (43 patients vs. 24 patients, P = 0.02). Four patients in the irbesartan group required dialysis; three of whom were also re-ceiving an ACE inhibitor; none of the patients in the placebo group required dialysis.0.100.05Hazard ratio, 0.95 (95% CI, 0.84–1.07)P=0.410.00012344.5Years since RandomizationNo. at RiskPlaceboIrbesartan 449845184047406237273756346434922598206826802088BFirst Episode of Recurrent Atrial Fibrillation in the Substudy, as Assessedwith the Use of Transtelephonic Monitoring1.00.8Irbesartan0.60.40.2Hazard ratio, 1.14 (95% CI, 0.80–1.64)P=0.46090180270365455545630730DiscussionAmong patients with atrial fibrillation, most of whom had well-controlled hypertension and 60% of whom were receiving an ACE inhibitor, the addition of irbesartan did not reduce the risk of death from cardiovascular causes, stroke, or myo-cardial infarction or this composite outcome plus hospitalization for heart failure. Among patients in sinus rhythm at randomization, there was also no effect on recurrence of atrial fibrillation. How-ever, there was a significant reduction in hospital-izations for heart failure (a secondary outcome), total hospitalizations, and the number of days of hospitalization for cardiovascular reasons. The results of the latter two outcomes were not pre-specified and therefore should be cautiously inter-preted.We hypothesized that the key mechanisms of benefit would be due to renin–angiotensin block-ade, as well as lowering of blood pressure. The lack of a significant reduction in the coprimary outcomes weakens these hypotheses but may be attributable to several other factors. Although irbesartan reduced systolic blood pressure by 6.8 mm Hg, more patients in the placebo group received multiple antihypertensive drugs, and their systolic blood pressure was also reduced by 3.9 mm Hg, so that the difference between the groups was modest (2.9 mm Hg). In fact, the ob-Placebo0.0Days since Follow-upNo. at RiskPlaceboIrbesartan99865850464245384437413439333728Figure 2. Kaplan–Meier Curves for Hospitalization Due to Atrial Fibrillation and for Recurrent Atrial Fibrillation.served 9% reduction in stroke among patients who received irbesartan is consistent with the modest reduction in blood pressure observed. An observational analysis from the Ongoing Telmisartan Alone and in Combination with Ramipril Global End-point Trial (ONTARGET; ClinicalTrials.gov number, NCT00153101) indi-cates a particularly strong relationship between systolic blood pressure and stroke at levels above 115 mm Hg,15 and two recent trials16,17 showed that lowering of blood pressure in high-risk populations with initial blood pressure similar to that in ACTIVE I reduced stroke.ACE inhibitors may reduce cardiovascular events despite modest reductions in blood pres-935n engl j med 364;10 nejm.org march 10, 2011 The New England Journal of Medicine Downloaded from nejm.org on February 28, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. The new england journal of medicineTable 3. Effect of Irbesartan on Hospital Admissions.Reason for HospitalizationCardiovascular diseaseAtrial fibrillationCondition other than atrial fibrillationMyocardial infarctionStrokeNon–central nervous system embolismHeart failureTransient ischemic attackNoncardiovascular diseaseOverall (cardiovascular plus noncardiovascular events)Irbesartan (N = 4518)38179412876151383518788527026519Placebo (N = 4498)no. of admissions406097630841394266010679627626822−243−35−20812−43−9−189−11−60−3030.0030.370.0040.510.120.38<0.0010.400.330.004DifferenceP Valuesure in patients with previous vascular disease. In a meta-analysis of three of the largest trials of ACE inhibitors in patients with vascular dis-ease,3,5,18 these agents reduced major vascular events by 23%,19 with the same modest lowering of blood pressure that was seen in ACTIVE I, suggesting that mechanisms that are independent of blood-pressure lowering may also play a role. However, in those studies, the majority of pa-tients had previous vascular disease (as compared with only 40% in ACTIVE I), and few were re-ceiving concomitant ARBs.The possibility that cerebrovascular and pe-ripheral thromboembolic events may be reduced by irbesartan is suggested by parallel nonsig-nificant reductions in transient ischemic attacks and systemic embolic events, and the reduction in the composite of these outcomes plus stroke which was nominally significant. A subgroup analysis of the Perindopril Protection against Re-current Stroke Study (PROGRESS) involving pa-tients with atrial fibrillation who had a nonfatal stroke also suggests that lowering of blood pressure reduces the risk of stroke and tran-sient ischemic attack among patients with atrial fibrillation.20 The observation of reduced hem-orrhagic stroke and hemorrhagic transforma-tion of ischemic stroke among patients who received irbesartan is intriguing, since similar results were also observed among patients who received telmisartan in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS, NCT00153062) study, in which patients also re-ceived an antiplatelet agent.21 Moreover, a sub-group analysis of the PROGRESS data indicates 936that lowering of blood pressure reduces the risk of intracerebral hemorrhage more rapidly and to a greater extent than it reduces the risk of ischem-ic stroke.22 This finding suggests that aggressive lowering of blood pressure may prevent intrace-rebral bleeding in patients with atrial fibrillation receiving concomitant antithrombotic drugs; this hypothesis warrants prospective evaluation.Small trials and post hoc analyses indicate that blockers of the renin–angiotensin–aldoste-rone system may prevent recurrent atrial fibrilla-tion in patients with heart failure or left ven-tricular hypertrophy. However, we observed no benefits in this regard, which is consistent with the Gruppo Italiano per lo Studio della Soprav-vivenza nell’Infarto Miocardico-Atrial Fibrillation (GISSI-AF) study of valsartan.23 Collectively, these two trials conclusively indicate that an ARB has no effect in preventing atrial fibrillation in pa-tients with intermittent atrial fibrillation.In ACTIVE I, we observed a reduction in hos-pitalizations for heart failure among patients who received irbesartan as compared with those who received placebo, even though 60% of all the patients were receiving an ACE inhibitor. These findings are consistent with the results of a trial of ARBs in patients with a low ejection fraction24 and with the results of the Candesar-tan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Preserved trial (NCT00634712), involving patients with a normal ejection fraction and heart failure,25 but not with the results of the Telmisartan Randomized Assess-ment Study in ACE Intolerant Subjects with Cardio-vascular Disease (TRANSCEND, NCT00153101)26 n engl j med 364;10 nejm.org march 10, 2011 The New England Journal of Medicine Downloaded from nejm.org on February 28, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. Irbesartan in Atrial FibrillationAStroke, Myocardial Infarction, or Death from Vascular CausesTotal No.P Value forSubgroupof PatientsIrbesartanPlaceboHazard Ratio (95% CI)Interaction%/100 patient-yr of follow-upOverall90165.405.40ACE inhibitor use0.91Yes54445.865.92No35704.714.73Age0.24<65 yr28403.353.06≥65 yr 61766.456.64Baseline systolic blood pressure0.15<126 mm Hg22785.065.81126–140 mm Hg32665.344.84>140 mm Hg34675.705.76Previous coronary heart disease0.49Yes32627.237.10No57544.434.540.70.91.11.3IrbesartanPlaceboBetterBetterBHospitalization Due to Heart Failure, Stroke, Myocardial Infarction, or Death from Vascular CausesTotal No.P Value forSubgroupof PatientsIrbesartanPlaceboHazard Ratio (95% CI)Interaction%/100 patient-yr of follow-upOverall90167.307.70ACE inhibitor use0.58Yes54448.178.81No35705.946.12Age0.14<65 yr28404.924.71≥65 yr 61768.469.25Baseline systolic blood pressure0.36<126 mm Hg22787.288.45126–140 mm Hg32667.006.99>140 mm Hg34677.507.90Previous coronary heart disease0.77Yes32629.6010.12No57546.046.430.70.91.11.3IrbesartanPlaceboBetterBetterFigure 3. Hazard Ratios for Study Outcomes According to Subgroup.The size of squares is proportional to the number of patients in the subgroup. ACE denotes angiotensin-converting enzyme. or Nateglinide and Valsartan in Impaired Glu-tion Fraction (I-PRESERVE, NCT00095238) study, cose Tolerance Outcomes Research (NAVIGATOR, in which no benefit with respect to heart failure NCT00097786). The reduction in hospitalizations was observed among patients who received irbe-for heart failure among patients who received sartan.27 ACTIVE I included twice as many pa-irbesartan in ACTIVE I is supported by a reduc-tients as did I-PRESERVE, so it had a higher tion in recurrent events and episodes of heart power to detect moderate reductions in hospital-failure that did not require hospitalization. How-izations for heart failure. An important observa-ever, ACTIVE I results differ from those of the tion in ACTIVE I was that hospitalizations for Irbesartan in Heart Failure with Preserved Ejec-heart failure were more common than stroke in n engl j med 364;10 nejm.org march 10, 2011 The New England Journal of Medicine Downloaded from nejm.org on February 28, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. 937Irbesartan in Atrial Fibrillationthis population of patients with atrial fibrilla-tion, and both increased the risk of death by a factor of 4. This finding suggests that preventing heart failure is as important as preventing strokes in this population.In summary, in patients with atrial fibrilla-tion, irbesartan was associated with a modest reduction in blood pressure but did not signifi-cantly reduce cardiovascular events. It was associ-ated with a reduction in heart failure and hospi-talizations for cardiovascular causes. It is not known whether more aggressive lowering of blood pressure would be effective in patients with atrial fibrillation.Supported by Bristol-Myers Squibb and Sanofi-Aventis.Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.appendixThe affiliations of the writing group of the ACTIVE Investigators are as follows: Population Health Research Institute, McMaster Uni-versity, Hamilton, ON, Canada (S.Y., J.S.H., J.P., S.C., S.J.C.); the Royal Brompton and Harefield NHS Foundation Trust, London (M.F.); Department of Neurology, University of Texas Health Science Center, San Antonio (R.G.H.); J.W. Goethe University, Frankfurt, Ger-many (S.H.H.); Division of Cardiology, Sunnybrook Health Sciences Centre, Toronto (C.D.J.); and Department of Medicine, Brigham and Women’s Hospital, Boston (M.A.P.).References1. Kannel WB, Abbott RD, Savage DD, 10. Healey JS, Baranchuk A, Crystal E, et al. function or heart failure: a combined McNamara PM. 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Ef-fects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angioten-sin-converting enzyme inhibitors: a ran-domised controlled trial. Lancet 2008;372: 1174-83.27. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456-67.Copyright © 2011 Massachusetts Medical Society.938n engl j med 364;10 nejm.org march 10, 2011 The New England Journal of Medicine Downloaded from nejm.org on February 28, 2016. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. 因篇幅问题不能全部显示，请点此查看更多更全内容