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15/4/2016

Controlofventricularrateinatrialfibrillation:Pharmacologictherapy

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Controlofventricularrateinatrialfibrillation:Pharmacologictherapy
Author
SectionEditor
LeonardIGanz,MD,FHRS,FACC BradleyPKnight,MD,FACC

DeputyEditor
GordonMSaperia,MD,FACC

Contributordisclosures
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Mar2016.|Thistopiclastupdated:Apr13,2016.
INTRODUCTIONInpatientswithatrialfibrillation(AF),theventricularrateiscontrolledbytheconduction
propertiesoftheatrioventricular(AV)node.InthetypicalpatientwithuntreatedAF,theventricularratecanreach
150beats/minorhigher.
TheuseofpharmacologictherapiestoachieveratecontrolinAFwillbereviewedhere.Nonpharmacologic
therapiesforratecontrolinAFarediscussedseparately.(See"Controlofventricularrateinatrialfibrillation:
Nonpharmacologictherapy".)
RATIONALETherearetwoestablishedreasonstopreventarapidventricularresponseinpatientswithatrial
fibrillation:
Avoidanceofhemodynamicinstabilityand/orsymptoms.(See"Hemodynamicconsequencesofatrial
fibrillationandcardioversiontosinusrhythm".)
Avoidanceofatachycardiamediatedcardiomyopathy.(See"Arrhythmiainducedcardiomyopathy".)
Inaddition,thereissomeevidencetosuggestamortalitybenefitfromratecontrol.Inalarge,populationbased
cohortstudyinTaiwan,mortalityinindividualsreceivingbetablockers(43,879),nondihydropyridinecalcium
channelblockers(18,466),anddigoxin(38,898)wascomparedwithmortalityinindividualsnottakingaratecontrol
drug.Patientswereexcludediftheyweretakingmorethanonerateslowingdrug.Afteradjustmentforbaseline
differences,theriskofdeathwaslowerinpatientsreceivingbetablockers(adjustedhazardratio[HR]0.76,95%
CI0.740.78)andcalciumchannelblockers(adjustedHR0.93,95%CI0.900.96).However,theriskofdeathwas
higherinthegroupreceivingdigoxin(adjustedHR1.12,95%CI1.101.14).Werecommendcautioninapplyingto
clinicalpracticethefindingsinthisnonrandomizedstudy.
GENERALPRINCIPLESTheinitialmanagementofpatientswithatrialfibrillation(AF)andarapidventricular
responseinvolvestwodecisions:
Determiningtheurgencyofinitialtherapy(eg,intravenousversusoralratecontroltherapy,and/orimmediate
versuselectivecardioversion).
Choosingbetweenaratecontrolandarhythmcontrolstrategy.(See"Rhythmcontrolversusratecontrolin
atrialfibrillation".)
Thesedecisionsarenotindependent,andtheoptionsarenotmutuallyexclusive.Asanexample,apatientfor
whomratecontrolmaybetheappropriatelongtermstrategymayrequireurgentcardioversionintheacutesetting
duetohemodynamicinstability.Ontheotherhand,apatientforwhomachronicrhythmcontrolstrategyischosen
mayrequireinitialratecontrolforthreetofourweekstopermitappropriateanticoagulationpriortocardioversion.
(See"Overviewofatrialfibrillation",sectionon'Treatmentissues'.)
Whenaratecontrolstrategyischosen,mostpatientscanbesuccessfullymanagedwithpharmacologictherapy.
SelectionofanappropriateregimenisguidedbyanunderstandingofthedeterminantsoftheventricularrateinAF
andastructuredmethodforassessingtheadequacyofratecontrol.
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DeterminantsofventricularrateDuringAF,electricalactivityintheatriacanexceed400beats/min.The
majorityoftheseimpulsesdonotconducttotheventriclesbecauseoftheelectricalpropertiesofthe
atrioventricular(AV)node.(See"Mechanismsofatrialfibrillation",sectionon'Roleoftheatrioventricularnode'.)
AVnodaltissueconsistsofsocalled"slowresponse"fibers.Inmostmyocardialtissue,theinitialdepolarizing
phaseoftheactionpotential(phase0)ismediatedbyrapidsodiumchannels.Incontrast,intheslowresponse
fibersoftheAVnode,phase0ismediatedbyaninwardcalciumcurrent,whichusesakineticallyslowchannel.
(See"Myocardialactionpotentialandactionofantiarrhythmicdrugs".)
TherelativelyslowkineticsoftheinwardcalciumcurrentlimitsconductionvelocitythroughtheAVnode,and
thereforetheventricularrateduringAF.Inadditiontotheseintrinsicproperties,theAVnodeisalsorichlysupplied
andaffectedbybothcomponentsoftheautonomicnervoussystem.AVconductionisenhancedbysympathetic
fibersandslowedbyparasympatheticfibers(figure1).
InthetypicalpatientwithuntreatedAF,theventricularrateduringthedayvariesbetween90and170beats/min.
Theventricularratemaybeslower(eg,lessthan60beats/min)inthefollowingsettings:
Increasedvagaltone.
DrugsthataffectAVnodalconduction.
AVnodaldisease,whichshouldbesuspectediftheventricularrateisbelow60beats/minintheabsenceof
adrugthatslowsAVconduction.
Aventricularrateabove200beats/minsuggestsoneofthefollowing:

Catecholamineexcess
Parasympatheticwithdrawal
Hyperthyroidism
Anaccessorypathwayasoccursinthepreexcitationsyndrome.(See"Atrioventricularreentranttachycardia
(AVRT)associatedwithanaccessorypathway".)

RatecontrolgoalsTheoptimalrategoalforpatientswithAFhasnotbeendetermined[1].Achievingrates
similartothoserecommendedforpatientsinsinusrhythmwithheartdiseasehasbeenadvocated:restingheart
rate80beats/minand110beats/minduringmoderateexercisesuchaswiththesixminutewalk.Goalssimilar
tothesewereusedinmanyofthetrialsofrateversusrhythmcontrol,suchasAFFIRM[2].(See"Rhythmcontrol
versusratecontrolinatrialfibrillation".)
ThisissuewasdirectlyaddressedintheRACEIItrial,whichrandomlyassigned614physicallyactivepatients
withpermanentAFtoeitheralenientratecontrolstrategy(restingheartrate<110beatsperminute)orastrictrate
controlstrategy(restingheartrate<80beatsperminuteandheartrateduringmoderateexercise<110beatsper
minute)[3].Theprimaryoutcomewasacompositeofcardiovasculardeath,hospitalizationforheartfailure,and
stroke,systemicembolism,bleeding,andlifethreateningarrhythmicevents.Thefollowingfindingswerenoted:
Withregardtothethreeyearestimatedcumulativeincidenceoftheprimaryoutcome,lenientcontrolwas
noninferiortostrictratecontrol(12.9versus14.9percent,respectivelyhazardratio0.8490%CI0.581.21).
Inthelenientandstrictratecontrolgroups,98and75percentofpatients,respectively,mettheirrestingheart
ratetarget.Thistargetrequireduseofmorethanonerateslowingagent(AVblocking)in30and69percentof
patients,respectively.Whenthedatawereanalyzedfromtheendofthedoseadjustmentphaseuntiltheend
offollowup(median2.9years),theaverageheartratesinthelenientcontrolgroup,strictcontrolgroup
patientswhometthetarget,andstrictcontrolgrouppatientswhofailedtomeetthetargetweresignificantly
differentat93,72,and86beatsperminute,respectively[4].However,therewasnosignificantdifferencein
theprimaryoutcome(12.1versus14.2versus15percent).
Therewerenearlyninetimesasmanyvisits(684versus75)toachieveratethecontroltarget(s)inthose
assignedtostrictcontrol.Ratecontrolwasstricterthananticipatedinthelenientcontrolgroup.Thoughthe
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targetratewaslessthan110beatsperminuteatrest,meanrestingratesinthisgroupattheafteroneyear,
twoyears,andattheendoffollowupwere86+15,84+14,and85+14beatsperminute,respectively.By
comparison,meanrestingratesinthestrictcontrolgroupwere75+12,75+12,and76+14beatsperminute,
respectively.
TheresultsoftheRACEIItrialmustbetemperedgiventhatthelenientcontrolgroupwasinfacttreatedmore
aggressivelythantheprotocolrequired.Inaddition,RACEIIincludedonlypatientswithpermanentAF,so
extrapolationtopatientswithparoxysmalAFisdifficult.
BasedupontheresultsoftheRACEIItrial,webelievethatachievingstrictheartratecontrolmaynotbe
necessaryinmanyphysicallyactivepatientswithAFwhoareminimallysymptomatic.Amorelenientratecontrol
strategyofferstheadvantagesoflessmedication(fewerdrugsideeffects,lowercost)andfeweroutpatientvisits
toachieveheartratecontrol.Forpatientsinwhomalenientstrategyischosen,wesuggestagoaloflessthan85
beatsperminute(85beatsperminutewasthemeaninthelenientgroupinRACEII).
Thepreventionofsymptomsduringnormalactivitiesorexerciseisaprimarygoaloftherapy.Itisimportantto
considerthatsymptomsmaybeduetoeitherinadequateratecontrolorrelativebradycardia(eg,inpatientswith
tachybradysyndrome).(See"Sicksinussyndrome:Epidemiology,etiology,andnaturalhistory".)
Thus,forthosepatientsinwhomalenientstrategyischosenbutwhoremainsymptomatic,anattemptshouldbe
madetodecreasesymptomsbysettingalowerrategoal.
DocumentingratecontrolInpractice,theefficacyofheartratecontroltherapycanbeassessedby
measurementofboththerestingheartrateanduseofeitherasixminutewalktest(atmoderateexercise)or
submaximalormaximalexerciseelectrocardiogram(ECG)testing.A24hourambulatorymonitorcanalsobeused
toevaluateefficacy.Foryoungactivepatients,werecommendeitheranexerciseECGtestoraHolterduring
exercise.Forolderorsedentarypatients,measuringheartrateafterwalkingbrisklyaroundtheofficeorupstairs
mayprovidesufficientinformation.
TachycardiamediatedcardiomyopathyPersistentlyincreasedventricularratesinAFhavebeen
associatedwithaleftventricularcardiomyopathy.(See"Arrhythmiainducedcardiomyopathy".)
Whilethisissuehasnotbeenwellstudied,webelievethatthisphenomenonisunlikelytooccuriftheventricular
rateiskeptbelow110beats/min,whichistherecommendedheartrategoal.Someexpertsperforman
echocardiogrameverytwotothreeyearsinasymptomaticpatientswithhigheraverageventricularrateswhile
othersdonot.
UrgencyoftherapyInapatientwithneworrecurrentAFwitharapidventricularresponse,theintensityof
initialtherapydependsupontheclinicalscenario:
EmergenttherapyInpatientswhoareclinicallyorhemodynamicallyunstable(eg,myocardialischemia,
pulmonaryedema,hypotension)duetoAFandarapidventricularresponse,treatmentoptionsinclude
intravenousratecontrolmedicationsand/orimmediatecardioversion.Inpatientswithanadequateblood
pressure,pharmacologicratecontrolwithintravenouscalciumchannelblockersorbetablockersmaybe
attempted,whilearrangementsaremadeforcardioversion.Ifthepatientrespondstoratecontroltherapybut
remainsunstable,anexplanationotherthanAFwitharapidventricularresponseshouldbesought.(See
"Atrialfibrillation:Cardioversiontosinusrhythm".)
UrgenttherapyInpatientswithAFandarapidventricularresponsewhoaresymptomaticbutnotunstable,
initialtherapyusuallyinvolvesintravenousratecontrolmedications.Patientswhoarechronicallymanaged
witharhythmcontrolstrategycanundergocardioversioniftheyhavebeenadequatelyanticoagulatedorare
consideredtohavealowthromboembolicrisk.
ElectivetherapyPatientswhohavemildornosymptoms,andwhoseventricularrateismildlyto
moderatelyelevated(eg,120beats/min)canbemanagedwiththeadditionorincreaseoforalratecontrol
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medications.
RhythmversusratecontrolThetwomaintherapeuticstrategiesinpatientswithAFare:
Rhythmcontrol,whichconsistsofcardioversion,oftenfollowedbymaintenanceofsinusrhythmwith
arrhythmicdrugs.
Ratecontrol,usuallywithdrugsthatslowconductionthroughtheAVnode.
Inthepast,manyphysicianspreferredarhythmcontrolstrategybecauseofpresumedimprovementsin
symptoms,hemodynamics,andembolicrisk.However,theexpectedadvantagesofrhythmcontrolwerenot
confirmedinAFFIRM,RACE,andotherrandomizedtrials[2,5].Asaresult,aratecontrolstrategyisnow
preferredinmostasymptomaticpatients[6,7].Thedatasupportingthisconclusionarediscussedindetail
separately.(See"Rhythmcontrolversusratecontrolinatrialfibrillation".)
CautioninpreexcitationsyndromeAmongpatientswithAFandpreexcitation,initialtherapyisaimedat
reversiontosinusrhythm.Intravenousprocainamideoributilideshouldbegivenifhemodynamicsarestable,and
directcurrentcardioversionshouldbeperformedifthepatientisunstable.
TheAVnodalblockingdrugs(calciumchannelblockers,betablockers,anddigoxin)canparadoxicallyincrease
theventricularresponseinpatientswithAFandpreexcitationbyimpairingconductionviathenormalAVnodeHis
Purkinjesystem.Thisdecreasesretrogradeconcealedconductionintheaccessorypathway,therebyimproving
antegradeconductionoverthepathway.Intravenousadenosine,amiodarone,digoxin,verapamil,anddiltiazemare
thereforecontraindicatedwithpreexcitedAFdataarelimitedwithintravenousbetablockersbuttheoreticallypose
thesamerisk.(See"TreatmentofsymptomaticarrhythmiasassociatedwiththeWolffParkinsonWhite
syndrome",sectionon'AvoidanceofAVnodalblockers'.)
LongtermtherapyinpreexcitedAFincludesablationoftheaccessorypathway.(See"Treatmentofsymptomatic
arrhythmiasassociatedwiththeWolffParkinsonWhitesyndrome",sectionon'Catheterablation'.)
PHARMACOLOGICTREATMENTTheventricularrateinatrialfibrillation(AF)isslowedusingbetablockersor
calciumchannelblockers,andtoalesserextentdigoxinoramiodarone.Theseagentsslowatrioventricular(AV)
nodalconductionbaseduponthefollowingphysiologicmechanisms(figure2)[8,9]:
Blockadeofthecalciumchannelwiththenondihydropyridinecalciumchannelblockersverapamiland
diltiazem.
Decreasedsympathetictoneresultingfrombetablockers.
Enhancementofparasympathetictonewithvagotonicdrugs,themostimportantofwhichisdigoxin.
BetablockersBetablockersarecommonlyusedforboththeacuteandchroniccontrolofventricularratesin
patientswithAF.
AcutecontrolwithbetablockersFortheacutecontrolofventricularrate,intravenousbetablockadewith
metoprolol,propranolol,oresmololcanbeeffective.Betablockersmaybeparticularlyusefulinstatesofhigh
adrenergictone(eg,postoperativeAF).
Metoprololisgivenasanintravenousbolusof2.5to5.0mgovertwominutes.Thedosemayberepeatedatfive
minuteintervalsuptoatotalof15mgasneeded.Whilesubsequentdosescanbegivenintravenously,theoptimal
regimenisnotwelldefined,andoraladministrationispreferable.
Esmololisarapidlyactingintravenousbetablockerthatismetabolizedbyredbloodcellesterase,resultingina
shortdurationofaction(10to20minutes)[1012].Esmololmaybeparticularlyusefulifitisuncertainthatabeta
blockerwillbetolerated,sinceitsshorthalflifepermitsatherapeutictrialtobeperformedatreducedrisk.If
esmololistolerated,thenalongactingbetablockercanbegiven.
Thefollowingesmololregimenisrecommendedforacuteratecontrol:
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Abolusof0.5mg/kgisinfusedoveroneminute,followedby50g/kgpermin.
If,afterfourminutes,theresponseisinadequate,anotherbolusisgivenfollowedbyaninfusionof100g/kg
permin.
If,afterfourminutes,theresponseisstillinadequate,athirdandfinalboluscanbegivenfollowedbyan
infusionof150g/kgpermin.
Ifnecessary,theinfusioncanbeincreasedtoamaximumof200g/kgperminafteranotherfourminutes.
Alternatively,aninfusioncanbestartedat50g/kgperminwithoutabolus,andtherateofadministrationcanbe
increasedby50g/kgperminevery30minutes.
Intravenouspropranolol,1mgoveroneminute,canbegivenandrepeateduptothreedosesattwominute
intervals.
ChronicbetablockertherapyOralbetablockersarewidelyusedasprimarytherapyforratecontrolin
chronicAF(table1).Betablockersdecreasetherestingheartrateandblunttheheartrateresponsetoexercise.
Mostbetablockersappeartohavesimilarefficacy,althoughatenolol,metoprolol,timolol,pindolol,andnadolol
havethemostsupportingevidence.Therearesomedatathatlabetalolislesseffectivethanotherbetablockers
forreducingheartrateatrest[7].Bisoprololandcarvedilolarealsoused.
Atenololandnadololhavetheadvantagesofalonghalflifeandaretypicallygivenoncedaily.Inourexperience,
atenololhastheadditionaladvantageofproducinglesscentralnervoussystemsideeffectsthanotherbeta
blockers.Longactingpropranololandmetoprololpreparationsarealsoeffectiveiftolerated.Wegenerallybegin
with25mgofatenololperdayandgraduallyincreasethedailydoseto100mg,andsometimes200mg,if
necessary.
BetablockershaveadditionalpropertiesthatmaymakethempreferredtootherratecontroldrugsinsomeAF
patients:
PatientswithchronicheartfailureduetosystolicdysfunctionAretrospectiveanalysisfromtheUnited
StatesCarvedilolTrialsProgramevaluated1094heartfailurepatientswithAF[13].Inthispopulation,
carvediloltherapyledtoastatisticallysignificantimprovementinleftventricularejectionfraction.Inaddition,
therewasatrendtowardadecreaseinthecombinedendpointofdeathorhospitalizationforheartfailure.
(See"Themanagementofatrialfibrillationinpatientswithheartfailure"and"Useofbetablockersand
ivabradineinheartfailurewithreducedejectionfraction".)
BetablockersmayreducetheincidenceofAFrecurrenceinpatientswithepisodesofAFthataretriggered
bysurgesinsympatheticactivity[14].
Betablockersalsohaveavarietyofadverseeffects.Someofthesecomplicationsthatmaybeimportantin
patientswithAFinclude(see"Majorsideeffectsofbetablockers"):

Worseningheartfailure
Hypotension
Bronchospasm
Reducedexercisetolerance[15,16]
HighdegreeAVblock
Bradycardia

SomepatientswithparoxysmalAFalsohavesinusnodedysfunction,withthetachycardiabradycardiasyndrome.
Insuchpatients,betablockerswithintrinsicsympathomimeticactivitymaybeusefulsincetheyarelesslikelyto
worsenbradycardiathanstandardbetablockers(table1).(See"Sicksinussyndrome:Epidemiology,etiology,and
naturalhistory".)
CalciumchannelblockersThenondihydropyridinecalciumchannelblockersverapamilanddiltiazemare
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usefulinthemanagementofAFintheabsenceofpreexcitation.Thesedrugscanbeusedintravenouslyforacute
ratecontrolandcanproducelongtermrateslowingwhenusedorally.(See"Calciumchannelblockersinthe
treatmentofcardiacarrhythmias".)
VerapamilincreasesrefractorinessanddecreasesconductionvelocityintheAVnode[1724].Althoughitis
oftenusedincombinationwithdigoxin,monotherapywithoralverapamilisoftenpossible[2224].
Diltiazemmayhavealesspronouncednegativeinotropiceffectthanverapamil[25].Theintravenous
preparationiseffectiveforacutecontroloftheventricularrateinAF[2628],whileoraltherapyiseffectivefor
chronicratecontrol[29,30].
AcutecontrolwithcalciumchannelblockersWepreferintravenousdiltiazemtointravenousverapamil.
However,intravenousverapamilcanbegivenacutelyinadoseof5to10mgovertwotothreeminutesthisdose
canberepeatedevery15to30minutes,asnecessary.Onceratecontrolisachievedwithintravenousbolus(often
oneortwoarenecessary),westartamaintenanceinfusionatarateof5mg/hourhigherinfusionrates,perhaps
upto20mgperhour,maybenecessaryforratecontrol[31,32].Theonsetofactioniswithintwominutesandthe
peakeffectoccursin10to15minutes.Controloftheventricularresponseislostinapproximately90minutesif
repeatedbolusesoramaintenanceinfusionarenotgiven.
ThesuggestedregimenforintravenousdiltiazemisderivedfromtheDiltiazemAtrialFibrillation/AtrialFlutterStudy
Group[2628].Diltiazemisgivenasanintravenousbolusof0.25mg/kg(averageadultdose20mg)overtwo
minutesin15minutes,ifthefirstdoseistoleratedbutdoesnotproducethedesiredresponse(20percent
reductioninheartratefromthebaselineoraheartratelessthanorequalto100beats/min)asecondbolusof0.35
mg/kg(averageadultdose25mg)isgivenovertwominutesinthosewhorespondtothefirstorsecondbolus,a
continuousinfusionatarateof5to15mg/hisinitiated.Thisregimenusuallycontrolstheventricularratewithin
fourtofiveminutes.
Theefficacyofthisregimenwasevaluatedinareportof84consecutivepatientswithAF,atrialflutter,orboth
[28].Thefollowingfindingswerenoted:
Theoverallresponseratewas94percent.
Thecontinuousinfusionmaintainedadequateratecontrolfor10hoursorlongerinadosedependentfashion
47percentat5mg/h68percentaftertitrationto10mg/hand76percentaftertitrationto15mg/h(figure
3).
Hypotensionoccurredin13percentandwassymptomaticinalmost4percent.Allsuchpatientsresponded
toisotonicsaline.
ChroniccalciumchannelblockertherapyTheinitialdoseoforalverapamilis40mgthreeorfourtimes
perdayincreasedtoamaximumof360mg/dayindivideddoses.Theequivalentdoseofsustainedrelease
verapamilcanbeusedonceperday,butadivideddoseoftenmustbeusedtomaintainratecontrol.
Oraldiltiazemisstartedat30mgfourtimesdaily.Theusualmaximumdoseisatotalof360to480mgdaily(ie,
90to120mgfourtimesperday).Forconversiontothesustainedreleaseformofdiltiazem,thesametotaldaily
doseisgiveninasingletabletordividedintotwodoses.
ClinicalcautionsCalciumchannelblockershaveanumberofcharacteristicsthatneedtobeconsidered
whentheyareadministeredtopatientswithAF:
Theeffectonsinoatrial(SA)nodalfunctionisvariable.Althoughbothverapamilanddiltiazemhavean
inhibitoryeffectonthesinusnode,theirvasodilatoreffectscauseareflexreleaseofcatecholaminesthat
usuallymaintainsorslightlyacceleratestheSAnodalrate.However,patientswiththesicksinussyndrome
maybeparticularlysensitivetotheeffectsofcalciumchannelblockers.(See"Sicksinussyndrome:
Epidemiology,etiology,andnaturalhistory".)
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Bothverapamilanddiltiazemhavenegativeinotropiceffects,althoughthisislesspronouncedwithdiltiazem.
Asaresult,thesedrugsshouldbeusedwithcautioninpatientswithheartfailureandinpatientstakingother
negativeinotropes,suchasbetablockers.Theyshouldnotbegivenifthepatientishypotensive.
Verapamilinteractswithdigoxin,resultinginanincreaseinserumdigoxin.Thisinteractionisdoserelated
(oftenoccurringwhenverapamildosesareover240mg/day)andgenerallyoccursaftersevendaysof
therapywithbothagents.Similartothedigoxinquinidineinteraction,verapamilreducestherenalclearance
ofdigoxinitmayalsointerferewithitshepaticmetabolism[3335].
Witheitherverapamilordiltiazem,itshouldberememberedthatolderpatientsaremorelikelytodevelopside
effects,especiallycardiac.Althoughthesamemaximumdosesmaybetolerated,itisusuallyappropriateto
titratemoreslowly.
Insummary,diltiazemandverapamilshouldnotbegiventopatientswithsevereheartfailure(NewYorkHeart
FailureclassIIIorIV),thepreexcitationsyndrome,orsignificanthypotension.Inaddition,thesedrugsshouldbe
givenwithcautiontopatientswithsinusnodedysfunction,significantliverdisease,mildhypotension,marked
firstdegreeheartblock,ortheconcurrentintakeofotherdrugsthatinhibitSAnodalfunctionorslowAVnodal
conduction.
DigoxinWegenerallyreservedigoxinforpatientswhoseratehasnotadequatelybeencontrolledwiththeuse
ofabetablockerand/oracalciumchannelblocker.Itisnotaseffectiveasthesetwocategoriesofdrugandthere
issomeconcernaboutitsusebeingassociatedwithhighermortality.Itmaynotbeappropriateforuseinolder
patients.
Older,smallobservationalstudiesandposthocanalysesofclinicaltrialshavereacheddifferingconclusions,with
someshowinganincreaseinmortality[3638]andothersnot[39,40].Similarly,morecontemporarylarge
observationalstudieshavereacheddifferingconclusions,withatleasttwofindinganincreaseinallcause
mortalityofabout20percent[41,42]andonefindingnoincrease[43].
Althoughthemechanismbywhichdigoxincouldincreasemortality,ifreal,isnotknown,thereisaconcernit
mightbelinkedtohigherserumconcentrations.Ourrecommendationsfordosingarediscussedbelow.(See
'Dosingandmonitoring'below.)
Thereareadditionalreasonsthatdigoxinshouldnotbeusedasafirstlinedrugforratecontrolinmostsettings
[44,45].DigoxinslowstheventricularrateduringAFprimarilybyvagotonicinhibitionofAVnodalconduction.
Digoxinisgenerallylesseffectiveforratecontrolthanbetablockersorcalciumchannelblockers,particularly
duringexercisewhenvagaltoneislowandsympathetictoneishigh[10,17,18,4651].(See'Comparativeefficacy'
below.)Furthermore,digoxinhasnoabilitytoterminateAF.
TheuseofdigoxininpatientswithAFandheartfailureisdiscussedseparately.(See"Themanagementofatrial
fibrillationinpatientswithheartfailure",sectionon'Ratecontrol'.)
LeftventriculardysfunctionInpatientswithheartfailureduetosystolicdysfunctionandAF,digoxinhas
twopotentialbenefits:reductionintheventricularrateandimprovementincontractility.Forthesereasons,digoxin
wasinthepastconsideredareasonablefirstlinetherapyforratecontrolinsuchpatients[48,52].However,beta
blockers,iftolerated,arenowastandardcomponentoftherapyforallpatientswithheartfailureduetosystolic
dysfunction.(See"Pharmacologictherapyofheartfailurewithreducedejectionfraction",sectionon'Beta
blocker'.)
Thus,inpatientswithleftventriculardysfunction,theuseofdigoxinislimitedtothefollowingsettings(see"The
managementofatrialfibrillationinpatientswithheartfailure"):
Patientswhodonotachieveratecontroltargetsonbetablockersalone.
Patientswhocannottoleratetheadditionoforincreaseddosesofabetablockerduetoacute
decompensatedheartfailure.
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PatientsinwhomdigoxinwouldbeaddedforimprovedcontrolofheartfailuresymptomsindependentofAF.
Manysuchpatientswillalreadybetreatedwithabetablocker,andcaremustbetakentoavoidexcessive
bradycardia.(See"Useofdigoxininheartfailureduetosystolicdysfunction",sectionon'Summaryand
recommendations'.)
DosingandmonitoringDigoxincanbeadministeredorally,intravenously,orintramuscularly,althoughwe
donotusetheintramuscularroutebecauseabsorptioniserratic.Intravenousdigoxinbeginstoactwithin15to30
minutes,withapeakeffectattainedinonetofivehours.(See"Treatmentwithdigoxin:Initialdosing,monitoring,
anddosemodification".)
Ifdigoxinisused,levelsshouldbeobtainedperiodically.Althoughthecorrelationbetweendrugconcentrationand
ventricularratecontrolispoor,thepresenceofalowserumdigoxinconcentrationisusefulinthatitallowsa
higherdosetobeadministered.However,becauseofconcernsaboutanincreaseinmortalityinpatientstaking
thedrug,weattempttokeepthelevelbelow1.0ng/mL(1.28nmol/L).(See'Digoxin'above.)
Junctionalescapebeats(detectedbytheequalityofallofthelongestobservedRRintervalsonthe
electrocardiogram)arecommonwhendigitalishassuccessfullyslowedtheventricularrate.Givingmoredigoxinin
thissettingwillincreasethedegreeofAVnodalblockandproduceperiodsofaregularjunctionalescaperhythm.
Thechangefromsinglejunctionalescapestoperiodicjunctionalrhythmusuallysignifiesthedevelopmentof
digoxintoxicity.AFwithaslow,regularventricularresponsegenerallyreflectscompleteAVblock,whichmaybe
duetodigoxinexcess.(See"Theelectrocardiograminatrialfibrillation",sectionon'EffectofhighdegreesofAV
nodalblockandexitblockonventricularresponse'.)
AmiodaroneAmiodaroneiscommonlyusedtomaintainsinusrhythminAFpatientsinwhomarhythmcontrol
strategyischosen.However,amiodaronecanalsoslowtheventricularrateinpatientswhoremaininAF.Inone
study,forexample,intravenousamiodarone(7mg/kg),flecainide,orplacebowasgivento98patientswithrecent
onsetAF(0.5to72hours)[53].EvenwhenAFdidnotreverttosinusrhythm,amiodaronepromptlyslowedthe
ventricularrateduringtheeighthourobservationperiod(figure4).Inaddition,incriticallyillpatients,amiodarone
maybelesslikelytocausesystemichypotensionthanintravenousdiltiazem[54].
Becauseofthelongtermriskofsideeffects,the2014AmericanHeartAssociation/AmericanCollegeof
Cardiology/HeartRhythmSocietyAFguidelinestatesthatamiodaronecanbeusedassecondlinetherapyfor
chronicratecontrolonlywhenothertherapiesareunsuccessfulorcontraindicated[44,45].Weagreewiththisvery
limitedroleforamiodaroneasachronicratecontrolagentandrecommendthatpatientstreatedwithamiodarone
receivecarefulfollowup,includingmonitoringforknownsideeffects.(See"Majorsideeffectsofamiodarone".)
MagnesiumsulfateMagnesiumhasphysiologicpropertiessuggestingthatitmighthaveefficacyforrate
controlinAF.Initialsmallstudiesprovidedtherationaleforaclinicaltrialinwhich199patientspresentingwith
rapidAF(meanbaselineventricularrate142beatspermin)weretreatedwithusualtherapyforratecontrol,most
oftendigoxin,andrandomlyassignedtointravenousmagnesiumsulfate(2.5gover20minutesfollowedby2.5g
overtwohours)orplacebo[55].Magnesiumtherapyincreasedthelikelihoodofachievingaventricularrate<100
beats/min(65versus34percentwithplacebo)andconversiontosinusrhythm(27versus12percentwith
placebo).However,thedifferenceinmeanventricularrateneverexceeded12beats/min.
Importantlimitationstotheresultsofthestudyincludethefollowing:
Thebenefitofmagnesiumwasmodest.
Preferredprimarytherapies(calciumchannelblocker,betablocker)wereusedinonly12to13percentofthe
patients.
Magnesiumwasassociatedwithsideeffectssuchasflushingandhypotension.
COMPARATIVEEFFICACYTherearefewstudiesdirectlycomparingtheefficacyofthesedrugs.Ingeneral,
calciumchannelblockersareeffectiveatrestandduringexercise,betablockersaresimilarlyeffectiveatrest,but
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moreeffectiveduringexercise,anddigitalisisreasonablyeffectiveatrestbutlesseffectivethantheotherdrugs
duringexercise.Thus,itisparticularlyimportanttoassessheartratewithexertioninpatientstreatedwithdigoxin
alone.
Inasmallcrossoverstudyof12patientswithchronicAF,patientsweretreatedfortwoweekintervalswithfive
differentdrugregimens:digoxin0.25mgdaily,diltiazemCD240mgdaily,atenolol50mgdaily,digoxinplus
diltiazem,anddigoxinplusatenolol[46].Digoxinplusatenololwasthemosteffectiveregimenforcontrollingthe
meanventricularrateandreducingthepeakheartrateduringexercisedigoxinanddiltiazemassingleagentswere
theleasteffective(figure5).
AFFIRMtrialAmongevaluationsofratecontroldrugs,thestudywiththelargestsamplesizeandlongest
followupisaposthocanalysisfromtheAFFIRMtrial[56].InAFFIRM,whichcomparedratecontrolandrhythm
controlstrategies,2027patientswererandomlyassignedtotheratecontrolarm.Adequateratecontrolatrestand
exercisewasdefinedaccordingtopredeterminedcriteria.(See'Ratecontrolgoals'above.)
Theoveralleffectiveness(meetingbothrestandexertiongoals)ofinitialtherapywasasfollows:

Betablockeralone59percent
Calciumchannelblockeralone38percent
Digoxinalone58percent
Betablockerplusdigoxin68percent
Calciumchannelblockerplusdigoxin60percent
Betablockerpluscalciumchannelblocker59percent
Betablockerpluscalciumchannelblockerplusdigoxin76percent

Atfiveyearfollowup,adequateratecontrolincreasedfromapproximately60to80percentofpatients.Only58
percentofpatientshadadequateratecontrolwiththefirstdrugorcombinationused.Patientsinitiallytreatedwith
abetablockerweresignificantlylesslikelythanthosetreatedwithcalciumchannelblockersordigoxintohave
theirdrugregimenchanged.
Severalimportantlimitationstothisstudyneedtobeconsidered:
Oncerandomizedtotheratecontrolarmofthetrial,drugselectionwasnotrandomized.Therewere
significantdifferencesbetweenpatientstreatedwithdifferentregimensbetablockersweremorecommonly
usedinpatientswithcoronarydisease,calciumchannelblockersweremoreoftengiventopatientswith
pulmonarydiseaseandtowomen,whiledigoxinwasusedmoreofteninpatientswithcardiomyopathyandin
nonwhitepatients.Whetherthesebaselinedifferenceshadanimpactontheadequacyofratecontrolisnot
known.
Only361(18percent)ofthepatientsassignedtotheratecontrolstrategyhadaninitialassessmentofthe
adequacyofratecontrolatrestandwithexertion.Thisisbecausemanypatientsspontaneouslyrevertedto
sinusrhythm(andtherefore,ratecontrolcouldnotbeassessed),andalsobecauseofthelimitednumberof
patientsinatrialfibrillation(AF)whohadheartrateassessedwithexertion.
SystematicreviewAsystematicreviewoftheoverallmanagementofAFincludedadiscussionof54trialsthat
evaluated17differentagentsusedforratecontrol[7].Thestudieswereallrelativelysmall(6to239patients),and
hadfollowupperiodsofeightweeksorless.Mostcomparedsingleagentstoplacebo.Duetoextensivevariability
inmethodsandoutcomeassessments,asummaryanalysisofthetrialscouldnotbeperformed.However,the
followingobservationswerenoted:
Diltiazem,verapamil,andmostbetablockers(atenolol,metoprolol,timolol,pindolol,andnadolol)wereall
effectiveinreducingtheventricularrateduringrestandexercise.Thebetablockerslabetalol,xamoterol,and
celiprololwerelesseffectiveatrest,butdidreduceventricularratesduringexercise.
Trialscomparingdigoxintoplaceboreportedinconsistentresults,particularlywhenheartduringexercisewas
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assessed.

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