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OPIE’S CARDIOVASCULAR DRUGS
ACOMPANIONTO BRAUNWALD’S HEARTDISEASE
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OPIE’S CARDIOVASCULAR DRUGS
ACOMPANIONTO BRAUNWALD’S HEARTDISEASE
NINTHEDITION
DEEPAKL. BHATT,MD,MPH
ExecutiveDirectorofInterventionalCardiovascularPrograms
BrighamandWomen’sHospital ProfessorofMedicine
HarvardMedicalSchool
Boston,Massachusetts
Elsevier
1600JohnF.KennedyBlvd. Ste1800 Philadelphia,PA19103-2899
OPIE’SCARDIOVASCULARDRUGS:ACOMPANION TOBRAUNWALD’SHEARTDISEASE,NINTHEDITION
Copyright©2021byElsevierInc.Allrightsreserved. NewillustrationsbyDrBernardBulwer,Boston,MA.
ISBN:978-0-323673617
Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans, electronicormechanical,includingphotocopying,recording,oranyinformationstorageand retrievalsystem,withoutpermissioninwritingfromthepublisher.Detailsonhowtoseek permission,furtherinformationaboutthePublisher’spermissionspoliciesandourarrangements withorganizationssuchastheCopyrightClearanceCenterandtheCopyrightLicensingAgency, canbefoundatourwebsite: www.elsevier.com/permissions.
Thisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythe Publisher(otherthanasmaybenotedherein).
Notice
Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledge inevaluatingandusinganyinformation,methods,compoundsorexperimentsdescribed herein.Becauseofrapidadvancesinthemedicalsciences,inparticular,independent verificationofdiagnosesanddrugdosagesshouldbemade.Tothefullestextentofthelaw, noresponsibilityisassumedbyElsevier,authors,editorsorcontributorsforanyinjuryand/or damagetopersonsorpropertyasamatterofproductsliability,negligenceorotherwise,or fromanyuseoroperationofanymethods,products,instructions,orideascontainedinthe materialherein.
Previouseditionscopyrighted2013,2009,2005,2001,1995,1991,1987,1984.
LibraryofCongressControlNumber:2020944971
PublishingDirector: DoloresMeloni
ContentStrategist: RobinR.Carter
ContentDevelopmentSpecialist: SaraWatkins
PublishingServicesManager: DeepthiUnni
ProjectManager: BeulaChristopher
DesignDirection: RyanCook PrintedinIndia
Lastdigitistheprintnumber:987654321
Tomywife, Shanthala, andourfoursons: Vinayak,Arjun,Ram,andRaj.
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Contributors
GeorgeL.Bakris,MD ProfessorandDirector
AHAComprehensiveHypertensionCenter DepartmentofMedicine
TheUniversityofChicagoMedicine Chicago,Illinois
Chapter2.AntihypertensiveTherapies
ChristieM.Ballantyne,MD ProfessorofMedicineandGenetics Chief,SectionofCardiovascularResearch Chief,SectionofCardiology DepartmentofMedicine Director,CenterforCardiometabolicDiseasePrevention BaylorCollegeofMedicine Houston,Texas
Chapter6.Lipid-ModifyingDrugs
RichardC.Becker,MD,FAHA ProfessorofMedicine Director,Heart,Lung,andVascularInstitute UniversityofCincinnatiCollegeofMedicine Cincinnati,Ohio
Chapter8.AntithromboticDrugs
MichaelJ.Blaha,MD,MPH DirectorofClinicalResearch DepartmentofCardiology
JohnsHopkinsCiccaroneCenterforthePreventionofHeartDisease Baltimore,Maryland
Chapter4.DrugsforDiabetes
WilliamE.Boden,MD ScientificDirector,ClinicalTrialsNetwork DepartmentofMedicine VABostonHealthcareSystem; PhysicianResearchLead VISN1 VANewEnglandHealthcareSystem VANewEnglandHealthcareSystem; ProfessorofMedicine
BostonUniversitySchoolofMedicine; LecturerinMedicine
HarvardMedicalSchool Boston,Massachusetts
Chapter1.DrugsforIschemicHeartDisease
MarcP.Bonaca,MD,MPH ProfessorofMedicine CardiologyandVascularMedicine DirectorofVascularResearch UniversityofColoradoSchoolofMedicine Aurora,Colorado
Chapter10.VascularMedicineDrugs
StephenY.Chan,MD,PhD ProfessorofMedicine Director,VascularMedicineInstitute Director,CenterforPulmonaryVascularBiologyandMedicine DivisionofCardiology,DepartmentofMedicine UniversityofPittsburghSchoolofMedicineandUPMC Pittsburgh,Pennsylvania
Chapter11.DrugsforPulmonaryHypertension
VladCotarlan,MD DivisionofCardiovascularHealthandDisease Heart,Lung,andVascularInstitute UniversityofCincinnatiCollegeofMedicine Cincinnati,Ohio
Chapter8.AntithromboticDrugs
OmarDzaye,MD,PhD ResearchFellow CicarroneCenterforthePreventionofCardiovascularDisease JohnsHopkinsUniversity Baltimore,Maryland
Chapter4.DrugsforDiabetes
RobertH.Eckel,MD ProfessorofMedicine DepartmentofMedicine UniversityofColoradoAnschutzMedicalCampus Aurora,Colorado
Chapter4.DrugsforDiabetes
MohammedA.Effat,MD DivisionofCardiovascularHealthandDisease Heart,Lung,andVascularInstitute UniversityofCincinnatiCollegeofMedicine Cincinnati,Ohio
Chapter8.AntithromboticDrugs
MichaelV.Genuardi,MD,MS AssistantProfessorofClinicalMedicine DivisionofCardiology PerelmanSchoolofMedicine UniversityofPennsylvania Pittsburgh,Pennsylvania
Chapter11.DrugsforPulmonaryHypertension
AhmedA.K.Hasan,MD,PhD,FACC,FAHA ProgramDirectorandMedicalOfficer
NationalHeart,Lung,andBloodInstitute NationalInstitutesofHealth
Bethesda,Maryland; ProfessorofMedicineandCardiology(adjunct) UniversityofMarylandSchoolofMedicine Baltimore,Maryland
Chapter7.DrugsTargetingInflammation
AlizaHussain,MD FellowPhysician DepartmentofMedicine BaylorCollegeofMedicine Houston,Texas
Chapter6.Lipid-ModifyingDrugs
LukeJ.Laffin,MD StaffPhysician MedicalDirectorofCardiacRehabilitation DepartmentofCardiovascularMedicine ClevelandClinicFoundation
Cleveland,Ohio
Chapter2.AntihypertensiveTherapies
PeterLibby,MD DivisionofCardiovascularMedicine DepartmentofMedicine
BrighamandWomen’sHospital
HarvardMedicalSchool
Boston,Massachusetts
Chapter7.DrugsTargetingInflammation
MandeepR.Mehra,MD MedicalDirector HeartandVascularCenter BrighamandWomen’sHospital
Boston,Massachusetts
Chapter3.HeartFailure
AnjuNohria,MD AssistantProfessorinInternalMedicine DivisionofCardiovascularMedicine DepartmentofMedicine BrighamandWomen’sHospital
HarvardMedicalSchool
Boston,Massachusetts
Chapter7.DrugsTargetingInflammation
CaraReiter-Brennan CiccaroneCenterforthePreventionofHeartDisease JohnsHopkinsSchoolofMedicine Baltimore,Maryland; DepartmentofRadiologyandNeuroradiology Charite Berlin,Germany
Chapter4.DrugsforDiabetes
BenjaminM.Scirica,MD,MPH SeniorInvestigator TIMIStudyGroup; Director,Innovation CardiovascularDivision BrighamandWomen’sHospital Boston,Massachusetts; AssociateProfessorofMedicine HarvardMedicalSchool Cambridge,Massachusetts
Chapter5.DrugsforObesity
SreekanthVemulapalli,MD DivisionofCardiology DukeUniversityMedicalCenter Durham,NorthCarolina
Chapter8.AntithromboticDrugs
AtulVerma,MD,FRCPC,FHRS AssociateProfessor UniversityofToronto SouthlakeRegionalHealthCentre Ontario,Canada
Chapter9.AntiarrhythmicDrugs
JeffersonL.Vieira,MD,PhD Post-DoctoralResearchFellow HeartandVascularCenter BrighamandWomen’sHospital Boston,Massachusetts Chapter3.HeartFailure
Foreword
LionelOpiewasatrueRenaissanceman.Hewasabrilliant,creativescientist,whoseinvestigationsoncardiacmetabolism,onthe roleofthesympatheticnervoussysteminheartfailureandinmyocardialischemiawererespectedbyphysiologistsandadmired bycardiologists.Dr.OpiewasaleaderwhoseCardiovascular ResearchInstituteinCapeTown,SouthAfricagainedworldwide attentionandpraise.Aspowerfulashisresearchwas,hisabilities totransmitinformation atthebedsideoronthelectureplatform wereevenmoremasterful.Hiswrittenwordwasespecially important.Ofhis31booksnonehadagreaterworldwideimpact thantheeighteditionsof DrugsfortheHeart.Opieexplained,in relativelysimpleterms,aidedbyhisexcellentdiagrams,themechanismsofactionofcardiovasculardrugs.Thisbookprovidedclinicianswithasolidunderstandingofthisever-expandingand progressivelymoreimportantaspectofcardiology.
Whilehismanyfriendsandliterallyhundredsofthousandsof hisstudentsmournLionel’spassing,theeditorsof Braunwald’ s HeartDisease wishedtocontinuehisverysuccessfulapproach totheeducationofcardiologistsandtheirtrainees.Fortunately, bothbookshavethesamepublisher,Elsevier,andthesame excellentPublishingDirector,DoloresMeloni.Tobringaboutthis marriage,theeditorsof HeartDisease selectedoneoftheirown, Dr.DeepakL.Bhatt,toassumeeditorialresponsibilityforthisninth editionof DrugsfortheHeart,nowcalled Opie’sCardiovascular Drugs.Dr.Bhatt,likeDr.Opie,hasmadeenormouscontributions totheunderstandinganduseofavarietyofcontemporarypharmacologictreatmentsofcardiovasculardisorders.Whilethisbook certainlybuildsonthestrengthsofitspredecessor,ithasbeen rewrittenbyagroupoftalentedspecialistsnotonlyincardiology, butalsoinendocrinology,hematology,nephrology,andvascular medicine,carefullyselectedbyDr.Bhatt,whosestrongguiding handisevidentthroughoutthisbook.Hehasretainedtheuseof explanatorydiagramsandhasbeenaidedbyDr.BernardBulwer, asuperbmedicalillustrator,whichhelpstomakeeventhemost complexconceptsunderstandable.
Wewelcomewithgreatenthusiasm Opie’sCardiovascular Drugs asanewcompanionto HeartDisease.
EugeneBraunwald,MD
PeterLibby,MD
RobertO.Bonow,MD
DouglasL.Mann,MD
GordonF.Tomaselli,MD
ScottSolomon,MD
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Preface
Asamedicalstudent,Iusedtocarryaroundthesecondeditionof Dr.Opie’snowclassictextoncardiacdrugs.ItwasthereforeadistincthonorformewhenDr.Braunwaldaskedmetotakeoveras editorofthisnintheditionasitjoinsthefamilyofcompanionsto Braunwald’sHeartDisease.
Withthisedition,thetitleischangingfrom DrugsfortheHeart to Opie’sCardiovascularDrugs,simultaneouslyacknowledgingthe richlegacypasseddownbyDr.Opieandanevolutionfromafocus ononlythehearttotheentirecardiovascularsystem.Certainly,coverageoftopicssuchasdrugsforangina,heartfailure,hypertension, arrhythmia,thrombosis,anddyslipidemiacontinueunabated. However,expansionintoobesity,vascularmedicine,pulmonary hypertension,inflammation,andthefullspectrumofcardiometabolicdiseasemirrorsthetransformationofcardiologyintermsof bothclinicalpurviewandalsowithrespecttotheconductofinvestigativetrials.
Thehighlyexpertauthorsspandisciplinesthatincludenot onlycardiologyanditssubspecialties,butalsovascularmedicine, nephrology,endocrinology,andhematology.Thismultidisciplinaryapproachillustratestheinterconnectednessofmedicine. Indeed,itisthislineofthinkingthatledtothelargecardiovascular outcometrialsindiabetesthathavecatapultedthefieldbeyonda fixationwithmereglucoseloweringtoexaminecardiovascular endpoints – andnotjustischemicendpoints,butheartfailureas well,whichwehavelearnedisatleastasvexingaproblemasmyocardialinfarctioninthosewithdiabetes.Itisonlywiththistypeof crossfertilizationofknowledgethatafieldcantrulyadvance,and thisbookattemptstoemulatethatphilosophy.
Inadditiontopresentingandinterpretingthedata,thesedistinguishedauthorshavemaderichuseofgraphics,modelledafter the “Opiegrams” thatmadeprioreditionssopopularamongnot onlytraineesbutalsoexperiencedpractitionersoftheartofmedicine.Thesefigureswillbeofgreatvaluetotheprintversion,of course,butwillplayanimportantroleinthegrowingonlinepresenceof Braunwald’sHeartDisease.Tothereaders,Ihopeyoufind thisbookeducational,funtoread,clinicallyuseful,andavaluable companionasyounavigatetheincreasinglycomplex,rapidly changingworldofcardiovasculardrugs.
DeepakL.Bhatt,MD,MPH
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Acknowledgments
First,ImustacknowledgeDr.LionelH.Opie,posthumously,for creatinganenduringbookthathasbeenusefultosomanypeople intheworldofmedicine.Aswell,creditgoestoDr.BernardGersh forhiscontributionsasaco-editoroftheprioredition.Iwould liketoexpressmydeepgratitudetoDr.EugeneBraunwaldfor bringingmeintothe Braunwald’sHeartDisease family,aswellas forseveralyearsofmentorshipandfriendship.Iwouldalsolike tothankDr.PeterLibbyforhismentorshipandfriendship,and tothanktheothereditorsof Braunwald’sHeartDisease: Dr.Robert O.Bonow,Dr.DouglasL.Mann,Dr.GordonF.Tomaselli,and Dr.ScottSolomon.Thepublisher,Elsevier,deservespraisefor thehigh-qualityprintandonlineproduction.PublishingDirector, DoloresMeloni,waskeyinbringingthisbookintothe Braunwald’sHeartDisease fold.RobinCarter,SaraWatkins,and BeulaChristopherfromElsevieralsomeritimmensecreditfor carryingthiseditiontofruition.Dr.BernardBulwerservedas theexceptionallytalentedmedicalillustrator,whichwascritical tocontinuethelegacyofexcellenceofDr.Opie’sbook.Finally, Imustthankmyfamilyforallowingmetopursueavarietyof clinicalandacademicinterests,includingthetimenecessaryto serveaseditorofthisclassicbook.
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Braunwald’sHeartDisease FamilyofBooks
DrugsforIschemicHeart Disease
WILLIAME.BODEN Introduction
Thecontemporarymanagementofpatientswithischemicheart diseasedemandsasoundunderstandingofthepathophysiologic precipitantsofbothanginapectorisandmyocardialischemiafrom whichtheprinciplesofpharmacotherapycanbeappliedandtailoredtothespecificcausesunderlyingtheseperturbationsof myocardialoxygensupplyanddemand.Thischapterdetailsseveralbroadclassesofdrugtherapiesdirectedatbothsymptom reliefandamelioratingtheconsequencesofreducedcoronary bloodflowandmyocardialsupply-demandimbalancesforwhich specifictreatmentsaretargeted,includingthetraditionalagents (β-blockers,nitrates,calciumchannelblockers)aswellasnewer, non-traditionalantianginalagentssuchasranolazineaswellas agents(ivabradine,nicorandil,andtrimetazidine)thatarenot availableforuseintheUS,butareinuseinternationally.These drugsarediscussedcomprehensivelyforbothacuteandchronic coronarysyndromes,withparticularattentiontodrugselection, dosingconsiderations,druginteractions,andcommonsideeffects thatmayinfluencetreatmentconsiderations.
β-Blockers Introduction
β-adrenergicreceptorantagonistagentsremainatherapeuticmainstayinthemanagementofischemicheartdiseasewiththeexceptionofvariantanginaormyocardialischemiaduetocoronary vasospasm. β-blockadeisstillwidelyregardedasstandardtherapy incardiologyprofessionalsocietyguidelinesforexertionalangina, unstableangina,andforvariablethresholdangina(ormixed
angina),particularlywhereincreasesinheartrateand/orblood pressure(BP)(includingtherate-pressureproductrisethatoccurs duringexerciseorstress)resultsinanincreaseinmyocardialoxygenconsumption. β-blockershaveanimportantroleinreducing mortalitywhenusedassecondarypreventionafteracutemyocardialinfarction(MI),thoughoutcomesdataarelackingtosupport abeneficialroleof β-blockersinischemicheartdiseasepatients withoutpriorMI.Andwhile β-blockersexertamarkedlybeneficial effectonoutcomesinpatientswithheartfailure,particularlyin thosewithreducedEF,andhaveanimportantroleasantiarrhythmicagentsandtocontroltheventricularrateinchronicatrialfibrillation,aswellastoadjunctivelytreathypertension,thetherapeutic applicationsof β-blockersintheseotherdiseasestateswillnotbe discussedinthischapter.Establishedandapprovedindications for β-blockersintheUnitedStatesareshownin Table1.1.
Theextraordinarycomplexityofthe β-adrenergicsignalingsystemprobablyevolvedmillionsofyearsagowhenrapidactivation wasrequiredforhuntingandresistinganimals,withtheneedfor rapidinactivationduringtheperiodofrestandrecovery.These mechanismsarenowanalyzed.1
Table1.1
Indicationsfor β-blockadeandUSFDA-approveddrugs
Indicationsfor β-blockadeFDA-approveddrugs
1.Ischemicheartdisease
AnginapectorisAtenolol,metoprolol,nadolol, propranolol
SilentischemiaNone
AMI,earlyphaseAtenolol,metoprolol
AMI,follow-upPropranolol,timolol,metoprolol, carvedilol
PerioperativeischemiaBisoprolola,atenolola
2.Hypertension
Hypertension,systemicAcebutolol,atenolol,bisoprolol, labetalol,metoprolol,nadolol, nebivolol,pindolol,propranolol, timolol
Hypertension,severe,urgentLabetalol
HypertensionwithLVHPreferARB
Hypertension,isolatedsystolicNooutcomestudies,prefer diuretic,CCB
Pheochromocytoma(already receivingalpha-blockade) Propranolol
Hypertension,severe perioperative Esmolol
Table1.1
Indicationsfor β-blockadeandUSFDA-approveddrugs (Continued)
Indicationsfor β-blockadeFDA-approveddrugs
3.Arrhythmias
ExcessurgentsinustachycardiaEsmolol
Tachycardias(sinus,SVT, andVT)
Propranolol
Supraventricular,perioperativeEsmolol
RecurrencesofAfib,AflSotalol
Controlofventricularrate inAfib,Afl
Digitalis-induced tachyarrhythmias
Propranolol
Propranolol
AnestheticarrhythmiasPropranolol
PVCcontrolAcebutolol,propranolol
SeriousventriculartachycardiaSotalol
4.CongestiveheartfailureCarvedilol,metoprolol,bisoprolola
5.Cardiomyopathy
Hypertrophicobstructive cardiomyopathy
6.Othercardiovascularindications
Propranolol
POTSPropranolollowdosea
Aorticdissection,Marfan syndrome,mitralvalve prolapse,congenitalQT prolongation,tetralogyof Fallot,fetaltachycardia
7.Centralindications
All?a Onlysometesteda
AnxietyPropranolol a
EssentialtremorPropranolol
MigraineprophylaxisPropranolol,nadolol,timolol
AlcoholwithdrawalPropranolol,a atenolola
8.Endocrine
Thyrotoxicosis(arrhythmias)Propranolol
9.Gastrointestinal
Esophagealvarices? (datanotgood)
Propranolol?a Timololnegative studya
10.Glaucoma(localuse)Timolol,betoxalol,carteolol, levobunolol,metipranolol
aWelltestedbutnotFDAapproved. Afib, Atrialfibrillation; Afl, atrialflutter; AMI, acutemyocardialinfarction; ARB, angiotensinreceptorblocker; CCB, calciumchannelblocker; FDA, FoodandDrug Administration; LVH, leftventricularhypertrophy; POTS, posturaltachycardia syndrome; PVC, prematureventricularcontraction; SVT, supraventricular tachycardia; VT, ventriculartachycardia.
MechanismofAction
The β1-adrenoceptorandsignaltransduction. Situatedonthe cardiacsarcolemma,the β1-receptorispartoftheadenylyl(¼ adenyl)cyclasesystem(Fig.1.1)andisoneofthegroupofGprotein–coupledreceptors.TheGproteinsystemlinksthereceptortoadenylylcyclase(AC)whentheGproteinisinthestimulatoryconfiguration(Gs,alsocalledGαs).Thelinkisinterruptedbythe inhibitoryform(Gi orGαi),theformationofwhichresultsfrommuscarinicstimulationfollowingvagalactivation.Whenactivated,AC producescyclicadenosinemonophosphate(cAMP)fromadenosinetriphosphate(ATP).Theintracellularsecondmessengerof β1-stimulationiscAMP;amongitsactionsisthe “opening” ofcalciumchannelstoincreasetherateandforceofmyocardialcontraction(thepositiveinotropiceffect)andincreasedreuptakeof cytosoliccalciumintothesarcoplasmicreticulum(SR;relaxing orlusitropiceffect,see Fig.1.1).Inthesinusnodethepacemaker currentisincreased(positivechronotropiceffect),andtherateof conductionisaccelerated(positivedromotropiceffect).Theeffect ofagiven β-blockingagentdependsonthewayitisabsorbed,the bindingtoplasmaproteins,thegenerationofmetabolites,andthe extenttowhichitinhibitsthe β-receptor(lock-and-keyfit).
β2-receptors. The β-receptorsclassicallyaredividedintothe β1-receptorsfoundinheartmuscleandthe β2-receptorsofbronchial andvascularsmoothmuscle.Ifthe β-blockingdrugselectivelyinteractsbetterwiththe β1-thanthe β2-receptors,thensucha β 1-selective blocker islesslikelytointeractwiththe β2-receptorsinthebronchial tree,therebygivingadegreeofprotectionfromthetendencyofnonselective β-blockerstocausepulmonarycomplications.
β3-receptors. Endothelial β3-receptorsmediatethevasodilation inducedbynitricoxideinresponsetothevasodilating β-blocker nebivolol(see Fig.1.2).2,3
Secondaryeffectsof β-receptorblockade. Duringphysiologic β-adrenergicstimulation,theincreasedcontractileactivityresulting fromthegreaterandfasterriseofcytosoliccalcium(Fig.1.3)is coupledtoincreasedbreakdownofATPbythemyosinadenosine triphosphatase(ATPase).Theincreasedrateofrelaxationislinked toincreasedactivityofthesarcoplasmic/endoplasmicreticulum calciumuptakepump.Thus,theuptakeofcalciumisenhanced withamorerapidrateoffallofcytosoliccalcium,therebyacceleratingrelaxation.IncreasedcAMPalsoincreasesthephosphorylationoftroponin-I,sothattheinteractionbetweenthemyosin headsandactinendsmorerapidly.Therefore,the β-blockedheart notonlybeatsmoreslowlybyinhibitionofthedepolarizingcurrents
