14/7/2015

Reninangiotensinsysteminhibitioninthetreatmentofhypertension

OfficialreprintfromUpToDate
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Reninangiotensinsysteminhibitioninthetreatmentofhypertension
Authors
JohannesFEMann,MD
KarlFHilgers,MD

SectionEditors
GeorgeLBakris,MD
NormanMKaplan,MD

DeputyEditor
JohnPForman,MD,MSc

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jun2015.|Thistopiclastupdated:Oct08,2014.
INTRODUCTIONInhibitorsofthereninangiotensinsystem(RAS),includingangiotensinconvertingenzyme
(ACE)inhibitors,angiotensinIIreceptorblockers(ARBs),anddirectrenininhibitorsarecommonlyusedinthe
treatmentofhypertension.TheroleoftheRASinhypertensionandtheuseofspecificinhibitorsofthissystemto
treathypertensionwillbereviewedhere.
TheuseofRASinhibitorsinpatientswithkidneydiseaseanddiabetesarediscussedseparately.(See"Choiceof
drugtherapyinprimary(essential)hypertension:Recommendations"and"Antihypertensivetherapyand
progressionofnondiabeticchronickidneydiseaseinadults"and"Treatmentofhypertensioninpatientswith
diabetesmellitus"and"Treatmentofdiabeticnephropathy".)
Theimportanceoflocal(ie,tissue)RASactivityinlowreninhypertensionandtheeffectsofangiotensinIIonthe
heartarepresentedelsewhere.(See"Lowreninprimary(essential)hypertension"and"ActionsofangiotensinIIon
theheart".)
ANGIOTENSINCONVERTINGENZYMEINHIBITORSSincetheintroductionofcaptoprilin1977[1],
angiotensinconvertingenzyme(ACE)inhibitorshavebecomewidelyusedforthetreatmentofhypertensionand
threeofitsmajorcomplications:acutemyocardialinfarction[2],congestiveheartfailure[3],andchronickidney
disease.Fiftyto60percentofCaucasianpatientshaveagoodresponsetomonotherapywithACEinhibitors,a
responseratesimilartootherfirstlineantihypertensivedrugs[4].ACEinhibitorshavetheadditionaladvantagesof
havingamorefavorablesideeffectprofilethansympatheticblockers,betablockers,anddiuretics[5],andof
producingmoreregressionofleftventricularhypertrophythanbetablockers[6].(See"Clinicalimplicationsand
treatmentofleftventricularhypertrophyinhypertension",sectionon'Choiceofdrugs'.)
Guidelinesissuedin2009bytheEuropeanSocietyofHypertension[7],andin2011byNICE(NationalInstitute
forHealthandClinicalExcellenceofGreatBritain)[8],recommendtheuseofanACEinhibitororangiotensinII
receptorblocker(ARB)inyoungerandnonblackpatients[9].However,thisrecommendationisbasedupon
relativelysmallcrossovertrials[10].
SpecificindicationsforuseThereareanumberofsettingsinwhichACEinhibitorsaretheantihypertensive
drugsofchoicebecauseofpossiblebenefitsinadditiontoloweringthebloodpressure.(See"Choiceofdrug
therapyinprimary(essential)hypertension:Recommendations",sectionon'Indicationsforspecificdrugs'.)
Theseinclude:
Heartfailurewithreducedejectionfraction(HFrEF)[3].(See"ACEinhibitorsinheartfailureduetosystolic
dysfunction:Therapeuticuse"and"Useofbetablockersandivabradineinheartfailurewithreducedejection
fraction"and"Useofdiureticsinpatientswithheartfailure"and"Useofmineralocorticoidreceptor
antagonistsinsystolicheartfailure".)
Proteinuricchronickidneydisease,bothdiabeticandnondiabetic[11].(See"Antihypertensivetherapyand
progressionofnondiabeticchronickidneydiseaseinadults"and"Moderatelyincreasedalbuminuria
(microalbuminuria)intype1diabetesmellitus"and"Moderatelyincreasedalbuminuria(microalbuminuria)in
type2diabetesmellitus"and"Treatmentofhypertensioninpatientswithdiabetesmellitus".)
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Afteramyocardialinfarctioninmostpatients,particularlythosewithheartfailureorreducedsystolicfunction
[2].(See"Angiotensinconvertingenzymeinhibitorsandreceptorblockersinacutemyocardialinfarction:
Recommendationsforuse".)
AntihypertensiveresponseThedeclineinbloodpressureseenwithACEinhibitorsappearstobeprimarilydue
todecreasedformationofangiotensinII,butdecreaseddegradationofkininscouldcontributebybothdirect
vasodilationandincreasingtheproductionofvasodilatorprostaglandins[12].
BlackpatientsmaybelesssensitivethanwhitepatientstoACEinhibitorsasmonotherapyforhypertension(figure
1)[13].AlthoughACEinhibitorsarerelativelyineffectiveasmonotherapyinblacks,theadditionofevenalow
doseofathiazidediuretictoanACEinhibitorleadstoafallinbloodpressurethatiscomparabletothatseenin
whitepatients[14].(See"Treatmentofhypertensioninblacks".)
TheutilityofACEinhibitorswithdiureticsisnotlimitedtoblackpatientssincethesedrugshaveasynergistic
effect,attaininggoalbloodpressureinupto85percentofpatientswithmildhypertension[14].The
antihypertensiveresponsetodiureticsisoftenlimitedbythehypovolemiainducedincreaseinreninreleaseand
subsequentangiotensinIIproduction[15]thiseffectispreventedbyconvertingenzymeinhibition,leadingtoa
moreprominentreductioninbloodpressure.(See"Useofthiazidediureticsinpatientswithprimary(essential)
hypertension".)Forsimilarreasons,dietarysodiumrestrictioncanalsoenhancetheresponsetoanACEinhibitor
[16].(See"Saltintake,saltrestriction,andprimary(essential)hypertension",sectionon'Responseto
antihypertensivedrugs'.)
ACEinhibitorsminimizesomeofthemetabolicchangesinducedbydiuretictherapy.Hypokalemia,forexample,is
lessprominentbecausethereductioninangiotensinIIformationinducedbytheACEinhibitorleadstodecreased
secretionofaldosterone.ACEinhibitorsalsodonotinduceglucoseintolerance,hyperlipidemia,orhyperuricemia,
mayincreaseinsulinsensitivity,andmayminimizeorpreventdiureticinducedelevationsinserumglucose,
cholesterolanduricacidlevels[17].
Apartfromdiuretics,calciumchannelblockerscanbeusedeffectivelywithACEinhibitors,and,asshowninthe
ACCOMPLISHtrial,mayhaveclinicaladvantagesoverdiureticswhenachievedbloodpressureissimilar.
CombinationofanACEinhibitorwithabetablockermaybelessusefulbecauseofinferiorantihypertensive
activitycomparedwithotherACEinhibitorcombinations[18].Thisrelativelackofefficacymaybedueinpartto
similarmechanismsofaction,asangiotensinIIformationandreninsecretionarerespectivelyreduced.(See
"Choiceofdrugtherapyinprimary(essential)hypertension:Recommendations",sectionon'ACCOMPLISHtrial'.)
DoseAswithotherantihypertensiveagents,properdosecanminimizetheincidenceofsideeffects(table1).
TominimizetheriskoffirstdosehypotensionduetoanabruptdeclineinangiotensinIIlevels,thepatientshould
notbevolumedepleted.Theinitialdosecanbereducedbyonehalfinelderlypatientsorthosewithheartfailure
whoareathigherriskforhypotension.SideeffectsotherthanthoserelatedtohypotensioncanoccurwithACE
inhibitors,themostcommonbeingcough[19],lesscommonlyhyperkalemia,andrarelyangioedema[20].ACE
inhibitorsarecontraindicatedduringpregnancy[21].(See"Majorsideeffectsofangiotensinconvertingenzyme
inhibitorsandangiotensinIIreceptorblockers".)
ThedurationofactionvarieswithdifferentACEinhibitors.SomeACEinhibitorscanbegivenoncedaily(eg,
trandolapril,lisinopril,andbenazepril).Theuseoflongeractingagentsoncedailyshouldimprovepatient
compliance,reducecosts,maintainsmoothercontrol,andensurethattheabruptriseinpressureuponawakening
intheearlymorningisblunted,hopefullytherebyreducingtheincidenceofseriouscardiovasculareventsatthis
time.
Aftertheinitiationoftherapy,thepatientshouldbereexaminedinafewweekstoallowthefullantihypertensive
effecttooccur.Ifthereisnoorlittlefallinbloodpressurewithanadequatedose,thedrugcanbestoppedand
differentclassofdrugstarted,aconceptcalled"sequentialmonotherapy."Alternatively,anotherdrugmaybe
added,suchasacalciumchannelblocker.(See"Choiceofdrugtherapyinprimary(essential)hypertension:
Recommendations",sectionon'Sequentialmonotherapy'.)
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Ifthepatient'sbloodpressureisreducedbytheACEinhibitorbutthegoalpressureisnotachieved,thedosecan
begraduallyincreasedtothemaximumlevelsnotedinthetable(table1).However,theadditionofaseconddrug
fromadifferentclasswillprovidemuchgreaterantihypertensiveeffect[22].
Inpatientswithextensiveatherosclerosisorrenalinsufficiencywhoaremorelikelytohaverenovascular
stenoses,arepeatplasmacreatinineconcentrationshouldbeobtainedwithinonetotwoweekstoensurethat
renalperfusionhasbeenmaintained.However,amodestandnonprogressiveincreaseintheplasmacreatininein
suchpatientsshouldnotpromptdiscontinuationoftherapy.(See"RenaleffectsofACEinhibitorsin
hypertension",sectionon'Renovascularhypertension'.)
ANGIOTENSINIIRECEPTORBLOCKERSAngiotensinIIreceptorblockers(ARBs)interferewiththerenin
angiotensinsystembyimpairingthebindingofangiotensinIItotheAT1receptoronthecellmembrane,thereby
inhibitingtheactionofangiotensinII[23].BlockadeoftheactionofangiotensinIIleadstoelevationsinplasma
levelsofrenin,angiotensinI,andangiotensinII.However,thisbuildupofprecursorsdoesnotoverwhelmthe
receptorblockade,asevidencedbyapersistentfallinbothbloodpressureandplasmaaldosteronelevels[24].
DifferencesbetweenACEinhibitorsandARBsTherearesubstantialpharmacologicaldifferencesinthe
actionsofangiotensinconvertingenzyme(ACE)inhibitorsandARBs,butfewclinicaldifferenceshavebeen
documented.Atleastthreefactorsmaycontributetothepharmacologicaldifferences(figure2):
Angiotensinconvertingenzymeisakininase.Thus,inhibitingthisenzyme,whichnormallydegrades
bradykinin,withanACEinhibitorleadstoincreasedkininlevels,aneffectnotseenwithanARB.Thisis
likelyresponsibleforthecoughthatmaybeseenwithACEinhibitors(butnotwithARBs),althoughhigh
bradykininlevelsmayalsoprovideadditionalvasodilationandotherbenefitsnotobservedwithARBs.
BydecreasingangiotensinIIproduction,ACEinhibitorsreducetheeffectofbothAT1andAT2receptors
onlytheformerareinhibitedbytheARBs.
Intheheart,kidney,andperhapsthebloodvessels,theproductionofangiotensinIImaybecatalyzedby
enzymesotherthanangiotensinconvertingenzyme,suchaschymase[25].TheeffectoftheangiotensinII
producedbythisreactioncanbeinhibitedbytheARBsbutnotbyACEinhibitors.However,theroleofthese
nonACEenzymesforthegenerationofangiotensinIIinvivo,ifany,isuncertain.
EfficacyanddoseTheARBshaveaneffectsimilartothatseenwithmonotherapywithotherantihypertensive
drugs(table1)[26].However,severalstudieshaveshownthatlosartan,whengivenoncedaily,doesnotcontrol
bloodpressuretothesamemagnitudeasotherARBs(irbesartan,telmisartan,candesartan,andvalsartan)[2730].
Ontheotherhand,losartanproducesaslightfallinplasmauricacidthatdoesnotoccurwiththeotherARBs,an
effectthatisduetoenhanceduricacidexcretion[31].Thisappearstobemediatedatleastinpartbydirect
inhibitionoftheproximalurateanionexchangerthatisresponsibleforuratereabsorption[32].
TheantihypertensiveefficacyofARBsappearstoberoughlyequivalenttothatoftheACEinhibitors.Ameta
analysisof61studiesthatdirectlycomparedangiotensinIIreceptorblockersandACEinhibitorsreportedno
differenceintheantihypertensiveeffectsoftheseagents[26].
Inaddition,theeffectsofARBsandACEinhibitorsoncardiovasculareventsappearsimilar.TheONTARGETtrial
comparedtelmisartan(80mg/day),ramipril(10mg/day),andcombinationtherapy(80+10mg/day)withboth
agentsin25,620patientswithvasculardiseaseordiabetes[33].Theprimaryoutcomewasdeathfrom
cardiovascularcauses,myocardialinfarction,stroke,orhospitalizationforheartfailure.Achievedmeanblood
pressurewaslowerinpatientswhoreceivedtelmisartancomparedwithramipril(by0.9/0.6mmHg)andinpatients
whoreceivedbothagentscomparedwithramipril(2.4/1.4mmHg).Thecardiovascularoutcomesweresimilarinall
threegroups,whilecoughwasmorecommonwithramiprilandbothhyperkalemiaandacutekidneyinjurywere
morecommonwithcombinedtherapy.(See"Majorsideeffectsofangiotensinconvertingenzymeinhibitorsand
angiotensinIIreceptorblockers".)
Inaddition,ametaanalysisofninetrialsand11,007patientsthatdirectlycomparedACEinhibitorswithARBsin
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hypertensivepatientsfoundsimilarratesofallcausemortalityandcardiovascularmortality[34].Incontrast,drug
withdrawalduetoadverseeventswassignificantlymorefrequentwithACEinhibitors(oneadditionalwithdrawal
fromtherapyforevery55patientstreatedwithACEinhibitorsoverfouryears),mostlyduetodrycough.Thus,
ARBsareareasonablealternativetoACEinhibitortherapyinhypertensivepatients.
Aswithotheragentsthatinhibitthereninangiotensinsystem,theefficacyofARBsisenhancedbyconcomitant
administrationoflowdosesofadiuretic[35],andbyareductionindietarysodiumintake.AswithACEinhibitors,
ARBsappeartominimizethehypokalemiaandhyperuricemiainducedbydiuretictherapy[35].(See"Saltintake,
saltrestriction,andprimary(essential)hypertension",sectionon'Responsetoantihypertensivedrugs'.)
SIDEEFFECTSBothangiotensinconvertingenzyme(ACE)inhibitorsandangiotensinIIreceptorblockers
(ARBs)aregenerallywelltolerated.CoughandangioedemaarelesscommonwithARBs[33].BothACE
inhibitorsandARBsarecontraindicatedinpregnancy.Theseissuesarediscussedindetailseparately.(See
"MajorsideeffectsofangiotensinconvertingenzymeinhibitorsandangiotensinIIreceptorblockers"and
"Angiotensinconvertingenzymeinhibitorsandreceptorblockersinpregnancy".)
ACEinhibitorsplusARBsAseparateissueisthesideeffectsassociatedwithcombinedACEinhibitor/ARB
therapycomparedwitheitherdrugalone.TheONTARGETtrialcitedaboveofhighriskpatients[33,36]founda
significantincreaseinadverseeffects(includingapossibleincreaseinmortality)withcombinedtherapycompared
withanACEinhibitoralone.Asaresult,combinedtherapyisnotrecommendedforthetreatmentofhypertension.
Thedatasupportingadverseeffectsandthepossibleroleofcombinedtherapytoslowprogressioninpatientswith
proteinuricchronickidneydiseasearediscussedelsewhere.(See"Majorsideeffectsofangiotensinconverting
enzymeinhibitorsandangiotensinIIreceptorblockers",sectionon'CombinationofACEinhibitorsandARBs'and
"Antihypertensivetherapyandprogressionofnondiabeticchronickidneydiseaseinadults",sectionon
'CombinationofACEinhibitorsandARBs'.)
DIRECTRENININHIBITORSThefirsteffectiveoraldirectrenininhibitor,aliskiren,becameavailableinthe
UnitedStatesinMarch2007.Aliskirenlowersbloodpressuretoadegreecomparabletomostotheragents[37].A
numberofstudieshaveevaluatedthebloodpressureloweringeffectofaliskirenincombinationwithother
antihypertensivedrugs[3740].Inonereport,thecombinationofmaximumdosesofaliskirenandvalsartan
decreasedbloodpressuremorethanmaximumdosesofeitheragentalonebutnotmorethanwouldbeexpected
withdualtherapyusingdrugsfromdifferentclasses[41].Aliskiren,aswithotherinhibitorsofthereninangiotensin
system,shouldnotbeusedinpregnancy.
IntheAVOIDtrial,aliskirenpluslosartanwasassociatedwithasignificant20percentgreaterreductionin
proteinuriacomparedwithlosartanaloneinpatientswithtype2diabetesandnephropathy,intheabsenceofa
significantlygreatereffectonbloodpressure[42].However,thiseffectonproteinuriadidnottranslateintoa
clinicalbenefit.IntheALTITUDEtrial,8600patientswithtype2diabetesandkidneydiseasealreadytakingeither
anangiotensinconvertingenzyme(ACE)inhibitororangiotensinIIreceptorblocker(ARB)wererandomlyassigned
toadditionaltherapywithaliskirenorplacebo[43].TheALTITUDEtrialwasstoppedearlybecauseoffutility(no
benefitontheprimarycardiovascularandrenaloutcomes)andbecausealiskirentherapyproduceda
nonsignificantlyhigherrateofadverseevents(ie,nonfatalstroke,hypotension).TheALTITUDEtrialisdiscussed
indetailelsewhere.(See"Treatmentofdiabeticnephropathy",sectionon'Aliskirenplusangiotensininhibition'.)
Theeffectofaliskirenonprogressionofatheroscleroticcoronaryarterydiseaseinpatientswithcontrolled
hypertensionwasexaminedintheAliskirenQuantitativeAtherosclerosisRegressionIntravascularUltrasound
Study(AQUARIUS)[44].Inthistrial,613patientswithasystolicbloodpressurebetween125and139mmHg
(mostofwhomweretreatedwithantihypertensivemedications)andtwoothercardiovascularriskfactorswere
randomlyassignedtoaliskiren(300mg/day)orplacebo.After18months,theatheroscleroticburdenand
progressionofatherosclerosis(measuredbycoronaryintravascularultrasound)wassimilarbetweenthegroups.In
asecondaryanalysisbaseduponasmallnumberofevents,aliskirenappearedtoreducetherateof
cardiovascularevents.However,thisanalysisexcludeddiabeticpatientswhoweretreatedwithangiotensin
inhibitors(approximately15percentofthestudypopulation),assuchpatientswereremovedfromthestudyafter
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publicationoftheALTITUDEtrial[45].Inaddition,adverseeventsweremorecommonwithaliskiren.
AnincreasedriskofhyperkalemiawhenaliskireniscombinedwithACEinhibitorsorARBshasbeendescribedin
theALTITUDEtrialandinotherstudies[43,46].Thus,aliskirenshouldnotbecombinedwithACEinhibitorsor
ARBs[47].
SUMMARYANDRECOMMENDATIONS
Inhibitorsofthereninangiotensinsystem,includingangiotensinconvertingenzyme(ACE)inhibitors,
angiotensinIIreceptorblockers(ARBs),anddirectrenininhibitorsarecommonlyusedinthetreatmentof
hypertension.(See'Introduction'above.)
ThereareanumberofsettingsinwhichACEinhibitorsaretheantihypertensivedrugsofchoicebecauseof
possiblebenefitsinadditiontoloweringthebloodpressure(see'Specificindicationsforuse'above):
Heartfailurewithreducedejectionfraction(HFrEF)
Proteinuricchronickidneydisease,bothdiabeticandnondiabetic
Afteramyocardialinfarctioninmostpatients,particularlythosewithheartfailureorreducedsystolic
function
ProperdoseofACEinhibitorscanminimizetheincidenceofsideeffects(table1).Thedurationofaction
varieswithdifferentACEinhibitors.SomeACEinhibitorscanbegivenoncedaily(eg,trandolapril,lisinopril,
andbenazepril).(See'Dose'above.)
TherearepharmacologicaldifferencesintheactionsofACEinhibitorsandARBs.Exceptforthecough
associatedwithACEinhibitors,thesepharmacologicaldifferencesarenotassociatedwithclinically
meaningfuldifferencesintherapeuticeffects.Atleastthreefactorsmaycontributetothepharmacological
differences(figure2)(see'DifferencesbetweenACEinhibitorsandARBs'above):
Angiotensinconvertingenzymeisakininase.Thus,inhibitingthisenzyme,whichnormallydegrades
bradykinin,withanACEinhibitorleadstoincreasedkininlevels,aneffectnotseenwithanARB.This
islikelyresponsibleforthecoughthatmaybeseenwithACEinhibitors(butnotwithARBs),although
highbradykininlevelsmayalsoprovideadditionalvasodilationandotherbenefitsnotobservedwith
ARBs.
BydecreasingangiotensinIIproduction,ACEinhibitorsreducetheeffectofbothAT1andAT2
receptorsonlytheformerareinhibitedbytheARBs.
Intheheart,kidney,andperhapsthebloodvessels,theproductionofangiotensinIImaybecatalyzed
byenzymesotherthanangiotensinconvertingenzyme,suchaschymase.Theeffectoftheangiotensin
IIproducedbythisreactioncanbeinhibitedbytheARBsbutnotbyACEinhibitors.
TheARBshaveaneffectsimilartothatseenwithmonotherapywithotherantihypertensivedrugs,including
ACEinhibitors(table1).
TheantihypertensiveeffectofbothACEinhibitorsandARBsisenhancedbyconcomitantadministrationof
lowdosesofadiuretic,andbyareductionindietarysodiumintake.Bothdrugsalsoappeartominimizethe
hypokalemiaandhyperuricemiainducedbydiuretictherapy.(See'Dose'aboveand'Efficacyanddose'
aboveand"Saltintake,saltrestriction,andprimary(essential)hypertension",sectionon'Responseto
antihypertensivedrugs'.)
BothACEinhibitorsandARBsaregenerallywelltolerated.Sideeffectsotherthanthoserelatedto
hypotensioncanoccurwithbothdrugs,includinghyperkalemiaandrarelyangioedema,aswellasacute
kidneyinjuryinpatientswithloweffectivearterialbloodvolume(eg,diarrhea,vomiting,andheartfailure).
CoughisacommonsideeffectofACEinhibitors.ACEinhibitorsandARBsarecontraindicatedduring
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pregnancy.(See'Sideeffects'aboveand"Majorsideeffectsofangiotensinconvertingenzymeinhibitorsand
angiotensinIIreceptorblockers".)
CombinedtherapywithbothanACEinhibitorandARBisnotrecommendedforthetreatmentof
hypertension.(See'ACEinhibitorsplusARBs'above.)
Thefirsteffectiveoraldirectrenininhibitor,aliskiren,lowersbloodpressuretoadegreecomparabletomost
otheragents.IncombinationwithanACEinhibitororARB,aliskirenincreasestheriskofadverseeffects
anddoesnotlowertheriskofcardiovascularevent.Thus,aliskirenshouldnotbecombinedwithACE
inhibitorsorARBs.(See'Directrenininhibitors'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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33. ONTARGETInvestigators,YusufS,TeoKK,etal.Telmisartan,ramipril,orbothinpatientsathighriskfor
vascularevents.NEnglJMed2008358:1547.
34. LiEC,HeranBS,WrightJM.Angiotensinconvertingenzyme(ACE)inhibitorsversusangiotensinreceptor
blockersforprimaryhypertension.CochraneDatabaseSystRev20148:CD009096.
35. SofferBA,WrightJTJr,PrattJH,etal.Effectsoflosartanonabackgroundofhydrochlorothiazidein
patientswithhypertension.Hypertension199526:112.
36. MannJF,SchmiederRE,McQueenM,etal.Renaloutcomeswithtelmisartan,ramipril,orboth,inpeopleat
highvascularrisk(theONTARGETstudy):amulticentre,randomised,doubleblind,controlledtrial.Lancet
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37. OhBH,MitchellJ,HerronJR,etal.Aliskiren,anoralrenininhibitor,providesdosedependentefficacyand
sustained24hourbloodpressurecontrolinpatientswithhypertension.JAmCollCardiol200749:1157.
38. PoolJL,SchmiederRE,AziziM,etal.Aliskiren,anorallyeffectiverenininhibitor,providesantihypertensive
efficacyaloneandincombinationwithvalsartan.AmJHypertens200720:11.
39. VillamilA,ChrysantSG,CalhounD,etal.Renininhibitionwithaliskirenprovidesadditiveantihypertensive
efficacywhenusedincombinationwithhydrochlorothiazide.JHypertens200725:217.
40. ShafiqMM,MenonDV,VictorRG.Oraldirectrenininhibition:premise,promise,andpotentiallimitationsof
anewantihypertensivedrug.AmJMed2008121:265.
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41. OparilS,YarowsSA,PatelS,etal.Efficacyandsafetyofcombineduseofaliskirenandvalsartanin
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43. ParvingHH,BrennerBM,McMurrayJJ,etal.Cardiorenalendpointsinatrialofaliskirenfortype2
diabetes.NEnglJMed2012367:2204.
44. NichollsSJ,BakrisGL,KasteleinJJ,etal.Effectofaliskirenonprogressionofcoronarydiseaseinpatients
withprehypertension:theAQUARIUSrandomizedclinicaltrial.JAMA2013310:1135.
45. TardifJC,GrgoireJ.Reninangiotensinsysteminhibitionandsecondarycardiovascularprevention.JAMA
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46. HarelZ,GilbertC,WaldR,etal.Theeffectofcombinationtreatmentwithaliskirenandblockersofthe
reninangiotensinsystemonhyperkalaemiaandacutekidneyinjury:systematicreviewandmetaanalysis.
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47. RajagopalanS,BakrisGL,AbrahamWT,etal.Completereninangiotensinaldosteronesystem(RAAS)
blockadeinhighriskpatients:recentinsightsfromreninblockadestudies.Hypertension201362:444.
Topic3815Version11.0

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GRAPHICS
Antihypertensiveresponsetodifferentdrugsinblacks

Responseratestosingledrugtherapyforhypertensioninblacksoverthe
ageof60years.Thehighestresponsewasseenwithdiltiazemand
hydrochlorothiazide(HCTZ)andthelowestwithcaptopril.Aresponsewas
definedasadiastolicpressurebelow90mmHgattheendofthetitration
phaseandbelow95mmHgatoneyear.Thepatternofresponsewas
similarbutthesuccessrateforeachdrugwasreducedby5to15percent
ifgoaldiastolicpressurewerelessthan90mmHgatoneyear.There
werebetween42and53patientsineachgroup.
Datafrom:MatersonBJ,RedaDJ,CushmanWC.DepartmentofveteransAffairs
singledrugtherapyofhypertensionstudy.Revisedfiguresandnewdata.
DepartmentofVeteransAffairsCooperativeStudyGrouponAntihypertensive
Agents.AmJHypertens19958:189.
Graphic65117Version5.0

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Angiotensinconvertingenzyme(ACE)inhibitorsandreceptor
antagonistsfortreatmentofadultswithhypertension

Drug

UStradename

Generic
preparation
availableinUS

Usualoraldaily
doserange
(adult)mg*

ACEinhibitors
Benazepril

Lotensin

Yes

20to80

Captopril

Capoten

Yes

25to150intwoor

(onlyavailableinUS
asgenericpreparation)
Cilazapril

Inhibace
(Canadiantrade

threedivideddoses
No

2.5to5

name)
Enalapril

Vasotec

Yes

10to40

Fosinopril

Monopril
(onlyavailableinUS
asgenericpreparation)

Yes

20to80

Lisinopril

Prinivil ,Zestril

Yes

10to40

Moexipril

Univasc

Yes

7.5to30

Perindopril

Aceon

Yes

4to8

Quinapril

Accupril

Yes

10to40

Ramipril

Altace

Yes

2.5to20

Trandolapril

Mavik

Yes

2to4

AngiotensinIIreceptorantagonists
Azilsartan

Edarbi

No

80

Candesartan

Atacand

No

16to32

Eprosartan

Teveten

Yes

600to800

Ibresartan

Avapro

Yes

150to300

Losartan

Cozaar

Yes

50to100

Olmesartan

Benicar

No

20to40

Telmisartan

Micardis

No

40to80

Valsartan

Diovan

No

80to320

*Thedoserangereferstothetreatmentofpatientswithhypertension.Dosesaslowasonehalforone
quarterthelowerdoseshownmaybeusedinitiallyinhighriskpatientssuchasthosewithheartfailure,
significantrenalinsufficiency,hyponatremia,intravascularvolumedepletion,orreceivingconcurrent
treatmentwithadiuretic.
Thedrugmaybegivenindivideddosesatthehigherdoselevels.Adjustaccordingtobloodpressure
responseatpeakandtroughbloodlevels.
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NotavailableinUS.
Datafrom:LexicompOnline.Copyright19782015Lexicomp,Inc.AllRightsReserved.
Graphic64770Version8.0

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Comparisonoftheactionsofangiotensinconverting
enzymeinhibitorsandangiotensinIIreceptor
blockers

ACE:angiotensinconvertingenzymeACEI:angiotensinconvertingenzyme
inhibitorARB:angiotensinIIreceptorblocker.
Graphic55726Version3.0

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Disclosures
Disclosures:JohannesFEMann,MDGrant/Research/ClinicalTrialSupport:NovoNordisk[Diabetes(Liraglutide)]Vifor[Dialysis(Iron
hydroxide)]Clegene[Dialysis(Sotatercept)].Speaker'sBureau:Amgen[Anemia(Darbepoetin)Roche[Anemia(Methoxypolyethylene
glycolepoetinbeta)Novartis[Hypertension(Valsartan)]Bruan[Dialysis(dialysisdevices)]Fresenius[Dialysis(dialysisdevices)].
Consultant/AdvisoryBoards:NovoNordisk[Diabetes(Liraglutide)]Relypsa[Kbinder(Patiromer)]Abbvie[CKD(Paricalcitol)]Bayer
[Hypertension(Diuretics)].KarlFHilgers,MDGrant/Research/ClinicalTrialSupport:AstellasNovartis[Kidneytransplantation
(Tacrolimus,cyclosporine,everolimus)].GeorgeLBakris,MDGrant/Research/ClinicalTrialSupport:MedtronicRelypsa[Hypertension,
hyperkalemia].Consultant/AdvisoryBoards:MedtronicRelypsaBayerNovartisDSIBoehringerIngelheimLexiconJanssenAstra
ZenecaKona[Diabetes,hyperkalemia,resistanthypertension(Canagliflozin,dapagliflozin,empagliflozin)].NormanMKaplan,MD
Nothingtodisclose.JohnPForman,MD,MScNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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