New Inotropic Drugs for Heart Failure JAMA 1987

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New Inotropic Drugs for Heart FailureIrvin F. Goldenberg, MD, Jay N. Cohn, MD

DEPRESSION of myocardial contrac-tility along with abnormalities in the

peripheral circulation and the neuroen-

docrine system lead to the syndrome ofcongestive heart failure. Patients withheart failure have limited exercise toler-ance because of breathlessness and/or

fatigue. These symptoms are likely tobe related to an exercise-induced rise in

pulmonary capillary pressure and inad-equate blood flow to exercising skeletalmuscle. Optimal treatment of heart fail-ure is based on manipulation of thethree principal determinants of cardiacperformance: preload, impedance, and

contractility. Vasodilator therapy mayreduce preload and/or impedance and

improve cardiac function. This reportwill not deal with vasodilator treat-ment, which has been the subject of a

recent review,1 but will focus on newer

inotropic agents aimed at increasingmyocardial contractility.

RATIONALE

The rationale for inotropic therapy isbased on the observation that contrac-

tility of failing myocardium can be aug-mented.2 Studies in animal models with

myocardial dysfunction and in the fail-

ing human heart have suggested theexistence of this residual myocardialcontractile reserve. The only oral in¬

otropic drugs presently approved forclinical use in this country are the car¬diac glycosides. Because of their limitedinotropic potential and low therapeutic/ toxic ratio and because of renewed inter¬est in the pharmacologie managementof heart failure, the search for new

inotropic drugs has accelerated.The ideal inotropic agent for the

treatment of congestive heart failureshould improve cardiac contractility, in¬crease oxygen delivery to the tissues,optimize regional blood flow, and relievepulmonary congestion without causingunacceptable increases in heart rate,

arrhythmias, or

myocardial oxygenconsumption. The drug should be activein both intravenous and oral forms andhave both short- and long-term effectsand minimal noncardiac side effects.

Perhaps most importantly, i t should re¬lieve symptoms of heart failure and

ideally would inhibit progression of the

syndrome and prolong life.

MECHANISMSMost available inotropic agents ap¬

pear to work at least in part by increas¬ing the amount of intracellular calciumavailable to react with contractile pro¬

teins to generate a greater force of myo¬cardial contraction.3 Some drugs (eg,pimobendan, DPI 201-206, sulmazole)may also increase contractile proteinsensitivity to intracellular calcium.3"5

Cardiac glycosides inhibit Na+, K+-ATPase activity. The resultant cyto-plasmic accumulation of Na+ probablyraises intracellular Ca++ by means of aNa+-Ca++ exchange mechanism. Thecatecholamines produce their inotropicaction by stimulation of ß,-receptors,leading to an increase in activity ofthe membrane-bound adenylate cyclaseand in intracellular cyclic AMP. This

increase in cyclic AMP stimulates pro¬tein kinases that phosphorylate sub¬stances on both the cell membrane andthe intracellular sarcoplasmic reticu-lum.6 These changes lead to enhancedCa++ flux that increases cytoplasmicCa++ and the intensity of actin and

myosin interaction and thus the forceof myocardial contraction. More recentevidence suggests that catecholaminesalso may increase myocardial contrac¬tion by ß2- and a,-receptor stimula¬tion.7,8 These mechanisms could becomemore important in a heart in whichB,-receptors are down-regulated.8

Many ofthe newer noncatecholamine,nonglycoside inotropic agents probablycause at least part of their inotropiceffect by increasing intracellular cyclicAMP. Although other mechanisms forthe increased contractility may exist,4amrinone, milrinone, sulmazole, enox-

imone, and piroximone all are phos-phodiesterase (PDE) inhibitors andincrease cyclic AMP levels by this mech¬anism.9,10 By raising cyclic AMP levels,these drugs enhance slow Ca++ inwardcurrent and increase the force of myo-

cardial contraction. However, because

the maximum increase in contractilitywith some of these agents occurs priorto maximum increases in cyclic AMPlevels, other mechanisms for their in¬

otropic effect m ay be involved."Sulmazole, pimobendan, and DPI

201-106 are unique agents that appear toexert some of their inotropic effect byincreasing the contractile protein sensi¬

tivity to calcium.4,5 The extent to whichthis increased sensitivity to Ca++ con¬tributes to improved myocardial per¬formance is unknown.

Some agents (eg, DPI 201-106) appear

to cause an increase in contractility byactivation of Na+ channels.12 The in¬crease in intracellular Na+ competeswith calcium for extrusion via the Na+-Ca++ exchange system. The net resultis an increase in intracellular Ca+ +

.

Because patients with congestiveheart failure have been found to bedeficient in some compounds associatedwith myocardial energy metabolism(eg, coenzyme Q10), an attempt has beenmade to increase contractility by re¬placement of these compounds. Re¬

placement therapy of coenzyme Q10 isnow being evaluated in this manner.13

Many of the new inotropic agents alsohave direct vasodilator effects14 thatmay also improve ventricular perform¬ance. It often is difficult to determinewhether the inotropic or vasodilatoreffect predominates in improving myo¬cardial function. The Table lists the

proposed mechanism of action of some ofthe new inotropic drugs.

INOTROPIC AGENTS

[VAdrenoceptor AgonistsIsoproterenol is the classic ß,-ago-

nist, but its potent ß2-dilator effect, theprominent direct and reflex tachycardiain response to its administration, and itsunsuitability for oral administrationmake it unattractive for treatment ofheart failure. Dopamine hydrochlorideand dobutamine hydrochloride have

partially solved the vasodilator and

chronotropic problems of isoproterenolhydrochloride, but these ßragonistsare still not orally absorbed.

One direction for drug developmenthas been the synthesis of compoundsthat interact with ß,-receptors to blockthe receptor but at the same time pro-

This article is one of a series sponsored by theAmerican Heart Association.

From the Minneapolis Heart Institute (Dr Golden-berg) and the Cardiovascular Division, Department ofMedicine, University of Minnesota Medical School,Minneapolis (Dr Cohn).

Reprint requests to the Minneapolis Heart Institute,Suite 160, 920 E 28th St, Minneapolis, MN 55407 (DrGoldenberg).

ownloaded From: http://jama.jamanetwork.com/ by a UNIV OF MINN LIBRARIES User on 02/18/2014



Positive Inotropic Effects and Main Mechanisms of Action

CardlotonlcAgent_Main Mechanisms o f Inotropic Effect*

Digitalis glycosides Na-K ATPase inhibition

CatecholaminesEpinephrineNorepinephrineIsoproterenol hydrochlorideDobutamine hydrochlorideDopamine hydrochlorideLevodopaIbopamine hydrochlorideButopamine

ß,-Adrenergic partial agonistPrenalterol hydrochloride ß,-Stimulation—increased cyclic A MP

Xamoterol fumerate

Bipyridine derivativesAmrinone Phosphodiesterase inhibition—increased cyclic AMP, vasodilationMilrinone

Imldazollne derivativesEnoximone Phosphodiesterase inhibition—increased cyclic AMP, vasodilator effect

Piroximone

Benzimidazole derivativesSulmazole Phosphodiesterase inhibition—increased cyclic AMP, increased sensitivity of

Pimobendan_contractile proteins tocalcium_ Methylxanthines

Caffeine Phosphodiesterase inhibition—increased cyclic AMP

Theophylline ethylenediamineGlucagon hydrochloride Increased cyclic AMP, effect independent of ß,-adrenergic receptors and n ot

Histamine phosphate_due to phosphodiesterase inhibition_ OPC-8212_Increased cyclic AMP, mechanismunknown_

DPI 201 -106 Prolongs Na +

channel activity, increased sensitivity of contractile protein to

_Ca++_ Coenzyme Q10 Possible replacement therapy of deficient compound

Bay K 8644 Calcium agonist, increases Ca+ influx by prolonging mean time Ca+ +

slow channel gates open

ß,-Stimulation—increases cyclic AMP, increase in slow calcium inward

current, increase in calcium uptake by sarcoplasmic reticulum, some exertvasodilation secondary to ß2 or dopamine receptor stimulation

*AMP indicates adenosine monophosphate.

duce a partial agonistic effect. Prenal-terol hydrochloride, a ß,-agonist with amaximum effect of 80% of that achiev¬

able with isoproterenol, is orally ab¬sorbed and has been studied in patientswith heart failure.15 Despite short-termimprovement in indices of left ventricu¬lar function and reports of symptomatic

improvement in some uncontrolledstudies,16 long-term treatment in dou¬

ble-blind, placebo-controlled studieshas shown lack of sustained improve¬ment.15,17 Furthermore, some authorshave reported hemodynamic deteriora¬

tion, ventricular arrhythmias, and sud¬den death soon after administering the

drug.16 The drug has been withdrawnfrom further clinical testing.

Another partial ß,-agonist, xamo-

terol fumarate (Corwin), is less potentthan prenalterol (40% of isoproterenol'sagonistic activity) and may be bettertolerated. Early clinical trials suggestsome possible short- and long-termben¬efits in at least a subset of patients withcongestive heart failure.18,19 The ration¬ale behind therapy with these partialagonists—which also can be viewed as

ßrblockers with intrinsic ß,-sympatho-mimetic activity—is that producing a

titratable ß-agonist effect while simul¬taneously blocking the endogenous car¬diac sympathomimetic activity will fa¬

vorably affect cardiac performance and/ or prevent the adverse effect of en¬hanced sympathetic discharge. Further

controlled trials will be needed to provethis thesis.

The failure to market a ßragonist for

long-term oral use has encouraged some

to seek the solution with long-term am¬

bulatory intravenous administration ofdobutamine.20 Reports have suggestedoccasionally dramatic responses to in¬

termittent infusion of dobutamine.20Controlled trials have not yet provedefficacy of this form of therapy nor hasan appropriate adm inistration schedulebeen selected to mount a pivotal study.If such therapy proves successful, itwould be necessary to accept the con¬

cept that intermittent inotropic supportcan have a sustained beneficial effect.

ß2-Adrenergic AgonistsAlbuterol sulfate, terbutaline sulfate,

fenoterol hydrobromide, and pirbuterolhydrochloride are ß2-adrenergic drugsthat probably possess both inotropic(possibly due to ß2 stimulation and/or ß,stimulation of the heart vs reflex releaseof catecholamines) and vasodilator prop¬erties. It is not clear which of thesemechanisms for improving cardiac per¬formance predominate. Of the ß2-ago-nists, pirbuterol has undergone themost thorough investigation. Despiteimprovement in acute hemodynamics,21long-term studies with pirbuterol have

given variable results.21,22 Some havedemonstrated sustained benefits21whereas others have suggested loss of

efficacy during long-term administra¬

tion, possibly related to down-regula¬tion of ß-receptors.22 Ventricular ar¬rhythmias, tremors, and muscle crampshave been the most frequently reportedside effects.

Dopaminergic AgonistsDopamine exerts an inotropic effect

through a direction action on ßrrecep-tors

and/or through induction of

localnorepinephrine release.23 Dopaminealso has vasodilator effects on the renaland mesenteric vascular beds as well asregional vasoconstrictor effects and

presynaptic effects to inhibit norepi¬nephrine release. The multiple actionsof dopamine are critically dose depen¬dent. Because of the favorable hemody-namic effects of dopamine infusion inheart failure, a search has been madefor an orally effective dopaminergicagent. There are at present several

drugs undergoing investigation that ei¬ther convert to dopamine (levodopa)

and/or have dopaminergic properties(ibopamine hydrochloride, fenoldopammesylate) on oral administration.

Levodopa is an oral drug that is con¬verted by the enzyme dopa-decarboxy-lase to dopamine. Rajfer et al24 showedacute hemodynamic improvement in tenpatients given this drug. Furthermore,they found a significant correlation be¬tween plasma dopamine levels and im¬

provement in cardiac index, suggestinga link between dopamine productionand hemodynamic effects. They reportthat five patients given long-term (6.8months) therapy with levodopa had per¬

sistent hemodynamic and clinical im¬provement. Shah et al,25 however, have

reported acute deterioration in patientssoon after starting therapy with thisdrug. This acute deterioration has been

postulated to be due to the vasoconstric¬tor effects of dopamine. This variable

response could relate to the amount of

dopamine generated. Lower dopamineblood levels may produce an inotropicand vasodilator response, but higherlevels may result in vasoconstriction and

hemodynamic deterioration.Ibopamine is the diisobutyric ester of

N-methyldopamine. It has both ino¬

tropic and vasodilator properties. Thepredominant mechanism by which this

drug improves cardiac function still re¬

quires further clarification; however, it

probably acts on ß,-, ß2-, DAr, and DA2-receptors. Early uncontrolled studieshave demonstrated a favorable clinicalresponse to this drug.26,27

Phosphodiesterase Inhibitors

Blocking the normal rapid breakdownof cyclic nucleotides by phosphodiester-ases (PDEs) should increase intracellu-




lar cyclic AMP levels and increase con¬

tractility. Although the traditional PDE

inhibitors, such as theophylline ethyl-enediamine, exert this effect, this ac¬

tion is nonselective and not potent. Incontrast, a ne w series of PDE inhibitorsthat appear to be selective for the myo¬cardial cyclic AMP PDE (PDE III) hasbeen synthesized. These agents appearto produce a prominent hemodynamic

effect when given to man.10Certain features of the inotropic ef¬fect of PD E inhibitors are predictable.A vasodilator effect accompanies thecardiac stimulation and a tendencytoward tachycardia and possible aggra¬vation of arrhythmias would be antici¬

pated. Since the drugs exert this effectdirectly on cyclic AMP concentrationand not on a receptor mechanism, toler¬ance due to receptor down-regulationwould not be anticipated.

Furthermore, the inotropic effect ofthe drugs would be expected to be most

prominent when cyclic AMP levels are

high due to adenylate cyclase stimula¬tion, such as by sympathetic discharge.The bipyridine and imidazole deriva¬tives are the two groups of PD E inhib¬itors most studied as inotropes in pa¬tients with congestive heart failure.

Bipyridine Derivatives.—Amrinoneand milrinone are bipyridine derivativeswith both inotropic and vasodilator

properties. Their inotropic effects are

independent of ß-receptors and Na-KATPase and a re probably at least partlydue to PDE inhibition.10 Controversyexists as to whether their predominantaction is an inotropic or a vasodilator

effect.While amrinone exerts short-term

hemodynamic effects similar to dobu¬

tamine,28 milrinone causes a greaterdecrease in left ventricular diastolicpressure and mean arterial pressureprobably secondary to its vasodilatoryproperties.29 Patients who have failed torespond to catecholamines may respondto these drugs.30

While the short-term hemodynamicresponse to amrinone has been favor¬

able,28 long-term studies have given var¬

iable results.3134 Amrinone in one study

improved exercise tolerance and caused

a deterioration of the clinical state withwithdrawal of drug therapy.32 This hadbeen taken as evidence for efficacy;however, prospectively randomizeddouble-blind studies have failed to con¬firm a favorable clinical response.33,34Unfortunately, the evaluation of theclinical response to oral amrinone hasbeen complicated by the high drop-outrate from side effects.34 Because of thelack of efficacy with oral amrinone, onlythe intravenous form has been approved.

Milrinone appears to have fewer side

effects and early uncontrolled trialshave revealed both short- and long-termimprovement in ventricular functionand in exercise tolerance.3638 Controlledtrials are currently under way to con¬firm this beneficial effect. Of particularconcern, however, has been the highmortality rate in patients treated withmilrinone.35 Although this experiencemay merely reflect the short life expec¬

tancy in the severely ill patients enteredinto these trials, controlled studies willbe necessary to exclude the possibilityof an adverse effect of the drug.

Imidazolone Derivatives.—Enoximone (MDL 17,043) and pirox-imone (MDL 19,205) are the two im-idazoline derivatives with known PDE

inhibitory properties that have under¬

gone the most study. Enoximone, pirox-imone, and dobutamine cause similarincreases in cardiac index but enox¬

imone and piroximone cause a greaterdecrease in pulmonary arterial wedgepressure.39 While acute hemodynamicsimprove with enoximone, long-termstudies evaluating clinical improvementhave given variable results.40"42 Of greatconcern is the reported high morbidityand mortality.42 While piroximone alsocauses short-term hemodynamic im¬

provement,39 long-term studies have notconfirmed a favorable response to this

drug.43Benzimidazole Derivative.—Sul¬

mazole (AR-L 115-BS) is a noncatechol-amine, nonglycoside agent with ino¬tropic and vasodilator properties shownto produce short-term hemodynamicimprovement in patients with severe

heart failure.44 The main mechanism bywhich this drug increases contractilityis unclear. Although sulmazole is a phos¬phodiesterase inhibitor and increasescyclic AMP, the increase in cyclic AM Pbecomes significant only after this drugproduces its positive inotropic effect.45The drug appears to increase the cal¬cium sensitivity of the contractile pro¬tein.4 When compared with dobu¬

tamine, both drugs increased ejectionfraction by similar amounts. El Allafet al46 have reported sustained clinicalbenefit in patients receiving this drug.

Recently this

drughas been

reported to

cause hepatocarcinogenic effects in therat and this has led to sulmazole's re¬moval from further clinical investiga¬tion. However, pimobendan, a sulma¬zole analogue, is now undergoingclinical trials.

Future AgentsIn addition to the glycosides, cate¬

cholamines, and PDE inhibitors, newer

inotropic drugs with additional andsometimes unknown mechanisms of ac¬tion are being investigated.

DPI 201-106 is an interesting new

agent with both inotropic and vasodila¬tor properties. In isolated cardiac mus¬

cle, two possible modes of action havebeen found. DPI 201-106 has been shownto prolong Na+ channel activity and alsoto sensitize the contractile apparatus toCa+ + .6,12 Which of these mechanisms ismost important to the development ofthe inotropic response is unclear. In

isolated vascular smooth muscle, it ap¬pears that vasodilation may result fromCa++ channel inhibition. In the intactanimal, there is evidence that it mayalso limit the inotropic response to

isoproterenol, but the mechanism ofthis effect is unclear. Uretsky et al47have demonstrated that this agentimproves hemodynamics in patientswith heart failure. A major concern

is that prolongation of the QT inter¬val by DPI 201-106 may be arrhythmo-genic.

OPC-8212 is a quinoline derivativethat has positive inotropic propertieswith little positive chronotropic or vaso¬dilator effects. Its mechanism of actionis poorly understood. The positive ino¬

tropic effects of OPC-8212 are effectiveeven after ß-blockade.48 OPC-8212 in¬creases the duration of the action poten¬tial and is a weak inhibitor of cardiacPDE. This drug is now being tested inclinical trials.

The calcium agonist Bay K 8644 has

undergone study as an inotropicagent.49 It is a dihydropyridine deriva¬tive that causes an increase in myocar¬dial contractility by increasing calciuminflux. Unfortunately, this drug alsocauses significant increase in total pe¬ripheral resistance. Further search fora cardioselective calcium agonist is in

progress.Coenzyme Q10 (ubiquinone) is a mito-

chondrial respiratory chain redox com¬

ponent that is important in myocardialenergy metabolism. Patients with con¬

gestive heart failure have been shownto be deficient in this compound, whichmay be associated with decreased en¬ergy production. Replacement of thiscompound has been reported to be ofbenefit to patients with congestiveheart failure in a

double-blind, double-

crossover study.13 Further evaluation ofthis drug appears warranted.

CLINICAL APPLICATIONS

Initial treatment of patients with con¬gestive heart failure now consists ofsodium restriction, diuretics, digitalisglycosides, and vasodilators, includingangiotensin-converting enzyme inhib¬itors. The order in which these drugsare introduced in clinical practice issomewhat controversial. Some physi¬cians now favor early interventions with




vasodilator drugs rather than with di-

goxin, whereas others prefer to restrictvasodilator use to patients who remain

symptomatic despite digoxin and diu¬retic therapy. Patients refractory tothese measures have few therapeuticoptions. Experimental drug therapy isstarted for some patients and some

proceed to orthotopic cardiac transplan¬tation. At present, most of the new

inotropic agents discussed in this re¬view are not available for widespreadclinical use. They should be considered

investigational and should be used in

patients unresponsive to conventionaltherapy and willing to participate indouble-blind, placebo-controlled trialsto test their efficacy and safety.

Although new inotropic drugs can

stimulate the failing ventricle and im¬

prove hemodynamics, their influence on

the natural history of heart failure isless clear. Can they delay progression ofleft ventricular dysfunction? Do they in¬crease or decrease ventricular arrhyth¬mias and the risk of sudden death? Dothey improve symptoms and quality oflife? Can we identify subsets of patientswho would be responsive? These andother issues can be answered only withcarefully designed studies using well-tolerated drugs in appropriate doses.

The authors would like to thank Gary Shank,MD, president of The Corporation, for his thought¬ful review of this article. We would also like to thank

Wendy Markuson, Annette Dear, and the networkfor their excellent secretarial assistance.

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New Inotropic Drugs for Heart Failure JAMA 1987

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