ICC Inh Peptido Natriuretico IndianJPharmacol353139-6497827_180258

NEUTRAL PEPTIDASE INHIBITORS

Indian Journal of Pharmacology 2003; 35: 139-145 EDUCATIONAL FORUM

NEUTRAL PEPTIDASE INHIBITORS: NEW DRUGS FOR HEART FAILURE

I. BASURAY

Interventional Electrophysiology & Device Therapy, Arrhythmia Service; Division of Cardiology,St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Manuscript Received: 29.7.2002 Revised: 23.10.2002 Accepted: 26.1.2003

Once it sets in, the left ventricular dysfunction is a continuous process ultimately leading to end stageheart disease. End stage heart disease has a high mortality despite the presence of a number of treatmentmodalities, as most of them are sub optimal. Thus despite considerable advancement in therapy, theoverall prognosis remains dismal. This has spurred the search for newer agents that can effectivelyattenuate the aberrant physiological changes evident in heart failure. Early research in heart failuretreatment had made it evident that unloading the heart should be a primary consideration if the progressof the aberrant physiology is to be attenuated. Subsequently it became evident that opposing the aberrantneurohormonal stimulation, to achieve unloading is associated with a better outcome. Thus ACE(angiotensin converting enzyme) inhibitors, which unload the heart by reducing the formation ofangiotensin II; have a better effect on mortality & morbidity, than the combination of nitrates andhydralazine. This is despite the fact that both the latter mentioned drugs are very potent venous andarteriolar dilator, respectively. Certain recent studies, albeit small ones, conducted in the last few yearshave shown natriuretic agents which promote diuresis by augmenting body's defense against the abnormalneurohormonal milieu evident in heart failure might have a better effect on long term prognosis than thesymptomatically more effective diuretics. These studies have lead to the development of novel agentsthat not only block the over stimulated renin-angiotensin system but also augment the natriuretic peptidesystem, the body's defence against the abnormal neurohormonal milieu that is evident in heart failure.This article reviews the clinical pharmacology of novel agents that augments the natriuretic peptidesystem in the body and their potential as new agents in the armamentarium of drugs for heart failure.

Cardiac failure natriuretic peptides neutral endopeptidase inhibitors

Introduction

Treatment of heart failure till date has at best beensymptomatic, with very little effort being made toreverse the pathology. The introduction of the ACEinhibitors in the treatment of heart failure was thefirst successful attempt to achieve symptomatic wellbeing along with attenuation of aberrant biochemicalchanges that accompany failure. It has beenappreciated that certain commonly used anti-failuremedications which induce symptomatic relief quiteeffectively may either do not change (e.g. digitalis1)or even worsen the biochemical anomalies of heartfailure (e.g. loop diuretics) and thus provide thepatient with little or even adverse mortality benefits.

An illustration in this context is the use of frusemide,a loop diuretic, in heart failure. Although it causesdiuresis and reduces the pulmonary capillary wedgepressure, it does so at the cost of producing amanifold increase in renin. This chemical releasedfrom the kidney amongst other places, is an adversebiochemical marker in heart failure2. It has nowbecome evident that an increase in such adversemarkers correlate with a poor mortal i ty andmorbidi ty. Thus, in the hope of producing asymptomatic benefit and reversing the pathology,there is a determined effort world over, to generatedrugs that effectively alter the aberrations ofneurohormonal milieu that accompany ventricularfailure. A group of drugs presently undergoing

ABSTRACT

KEY WORDS

Correspondence: I. Basuraye-mail: [email protected]

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I. BASURAY

clinical trials that effectively fit in such criteria are theneutral peptidase inhibitors. These are a group ofchemicals that inhibit the degradation of atrialnatriuretic peptide (ANP) and related neuro-hormones which are released by the body as acompensatory mechanism to reverse thepathophysiological state present in heart failure thereby causing an increase in the levels and activities ofthese hormones. This article intends to review therecent evidences gathered from clinical trials thatpoint to the possible role of these agents, as a groupwill play as future drugs for heart failure. This reviewwill also discuss the role of novel designer drugs;that combine ACE inhibition with peptide inhibition,all as one molecule to treat heart failure.

Physiological role of natriuretic peptides in heartfai lure: A review of the physiological role of thenatriuretic peptides would be in order to understandthe pharmacodynamics of the neutral peptidaseinhibitors. Three natriuretic peptides, the atrial (ANP),the brain (BNP) and the C type natriuretic peptide (CNP)have been identified in humans3. ANP is a 28 aminoacid peptide stored predominantly in the right atriumand is believed to be coupled to mechanoreceptors,and released upon atrial distension, as observed incardiac failure. Accumulated evidence from the pastone decade points to the crucial role played by thispeptide in inducing vasodilatation, promoting natriuresisand miscellaneous other functions including counter-acting the pathological role played by catecholamines,the arginine-vasopressin, renin-angiotensin-aldosterone system [RAAS]4. RAAS is known to besignificantly augmented as part of body's mechanismto counter fall in cardiac output in heart failure. Thisbecomes counter productive as water & sodiumretention occurs, causing an overt increase in theafterload to the failing ventricle. BNP is structurallysimilar to ANP and is stored mainly in the ventricles5.The ventricular filling pressure coordinates its releaseand is functionally similar to ANP. CNP is a potentvasodilator and is postulated to have a regulatory roleon the RAAS. The natriuretic peptides are degraded inthe body by a ubiquitous enzyme called neutralendopeptidase (NEP)6, found in many organs andtissues. These include the kidneys, brain and lungs7.Experimental evidence in lower mammals, initially8 andlater in humans, have corroborated the finding thatinhibition of these enzymes produce a sustainedincrease in plasma ANP level9.

A large body of accumulated data supports the factthat ANP therapy in heart failure is accompanied byfavourable hemodynamic responses. Prolongedinfusion of ANP in heart failure patients belonging toclass III or IV is associated with a two fold increasein urine flow rate and an almost four fold increase insodium excretion10. In severe heart failure patients,similar infusions have produced an increase incardiac output with a concomitant decrease inpulmonary capillary wedge pressure (PCWP),plasma renin levels and pulmonary vascularresistance11. BNP has similar effects as ANP12; itreduces the pulmonary capillary wedge pressure andsystemic vascular resistance and also initiates asustained natriuresis producing up to a 10 foldincrease in sodium excretion. Interestingly, thisbiochemical also fosters favourable changes in theneurohormonal milieu. While suppressing plasmaaldosterone levels, it increases ANP secretions.These profiles of diuresis, vasodilatation andneurohormonal suppression make the natriureticpeptides, a potentially attractive treatment modalityfor heart failure patients.

However, it is obviously ostensible that the therapeuticpotential of natriuretic peptides are considerablyattenuated in chronic heart failure patients becauseof the need to give them, as intravenous infusions.Thus, treatment of chronic LV failure necessitates thedevelopment of orally active long acting analoguesor agents that block the metabolism of endogenouslygenerated natriuretic peptides. The development ofNEP inhibitors, is thereby a step to meet the latterend.

Oral ly act ive natr iuret ic pept idase inhibi tors:Candoxatril and ecadotril are the two highly specificinhibitors of NEP presently undergoing trials as futuredrugs for heart failure. Both these agents areprodrugs metabol ised in the body to act ivecongeners. Candoxatril is activated in the liver tocandoxatrilat, the active metabolite, while ecadotrilis converted to its active congener, S-thiorphan.

While candoxatril has undergone the largest numberof trials amongst drugs in this group, experience withecadotril is limited to a few trials till date. Patientswith mild heart failure infused with candoxatrilat, theactive molecule of candoxatril, have both diuresisand natriuresis13. However, in severe heart failurepatients these actions are considerably lessened,

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probably due to decreased renal perfusion1 4 .Northridge et al., in a recent trial1 5 comparedcandoxatril in oral doses of 200-400 mg as mono-therapy in mild heart failure patients in a double-blindclinical trial, with 20 mg frusemide. Severe heartfailure patients could not be included in the trial sincea diuretic free period of two weeks, as required inthe study design, could not be enforced in them.Monotherapy with candoxatril induced diuresis,natriuresis and kaluresis compared to frusemide.While a greater decrease in systolic blood pressurewas documented with NEP inhibitors, the heart rate,diastolic blood pressure and the functional class ofthe patients remained similar to baseline studies.Plasma renin activity, a negative prognostic factor inchronic heart failure, showed a two fold increasefollowing the first dose of frusemide, with a four-foldrise later on. Therapy with candoxatril was notassociated at any stage with any discernableincrements in plasma renin activity. Treadmillexercise capacity, an important prognostic markerin heart failure, registered an increase of 12+3.5 secafter 200 mg candoxatril twice a day and a rise of35+3.1 sec after 400 mg of the drug twice daily for9 days. However, frusemide treated patients in thesame period, recorded a decreased exercisecapacity by 30+2.6 sec. The same group in an earlierstudy also documented a 40% decrease inpulmonary capil lary wedge pressure usingcandoxatril compared to a 15% reduction withfrusemide2.

Experience with ecadotril as stated before is limited.In a recent pilot safety study, though the drugcompared favorably with placebo, as far as short-term safety and tolerance is concerned, its clinicaleff icacy was shown to be disappointinglynegative 16,17 . Though this has been attributedprimarily to the study design, which was not gearedto observe this parameter, other factors l ikeinadequate dosing could have also played a role.However, in earlier studies reported by Kahn et al.18

ecadotril administration to heart failure patientsresulted in a rise in plasma ANP, decrease in bothplasma renin activity and pulmonary capillary wedgepressure.

Role of NEP inhibitors in heart fai lure: The firstline treatment for mild heart failure has been adiuretic, which is usually combined with an ACEinhibitor. While ACE inhibitor use is associated with

decreased hospitalization and death19, the long termeffects of diuretics in heart failure, as far as mortalityand morbidity statistics go, are yet ill-defined. Therehave been contradictory findings with diuretic trialsin mild and severe heart failure. Cowley et al.2 0

showed that moderately severe cardiac failurepatients put on frusemide at high doses (120 mg),exhibited improved quality of life and better exercisecapacity. Few other uncontrolled studies too havecome to the same conclusion21. However, Northridgeand colleagues, using low doses to treat mild heartfailure, have shown a decrease rather than anincrease in exercise capacity. These adverse effectsof diuretics on mild heart failure, with no evidence offluid retention, can be explained by detrimentalchanges they induce including stimulation of theRAAS mechanism, and a decrease in cardiac outputby ventricular unloading15. Though both these factorsexist even in severe heart failure patients treatedwith diuretics, the decrease in congestion andreduction of fluid overload achieved, producessymptomatic benefits. Thus the pathophysiologicalaberrations instead of getting attenuated; actuallyworsens over a time period, leading to more severeforms of heart failure. The end point of this vortex ofincreasing failure ultimately makes the disease drug-refractory. Accumulated evidence for the past onedecade has confirmed the early elevation of NEP inthe progression of left ventricular dysfunction, evenbefore the onset of symptoms. There is considerableevidence that indicate the fact that this increase isbeneficial; by preventing the activation of RAAS andconsequent salt and water retention, thus delayingthe initiation of pathological changes that continueunabated leading to end stage cardiac failure22. Thusit is hypothesized, but not actually proved thatinitiation of diuretics at this stage, as is commonlydone nowadays, produces double harm; it not onlyreduces the natriuretic peptide concentration but alsounleashes the RAAS from the inhibitory effect ofthe endogenous NEP.

NEP inhibitors have a number of potential advantagesover conventional diuretics in the treatment of patientswith chronic heart failure since they do not activateRAAS system. Ample evidence also suggests thathemodynamic changes attained using these drugsare decidedly better at least in cases of mild heartfailure when compared to diuretics. Extrapolation ofthese results to more severe cases of cardiac failure

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I. BASURAY

is not undesirable; as presently we have some, thoughnot extensive data advocating their efficacy in suchstates. More extensive studies are warranted withsubjects in New York Heart Association class III orIV to collect supporting data. It is also important torealise that these group of patients are really in needof more effective pharmacological agents to controlheart failure. Failure of appropriate pharmacologicalmeasures to treat such patients makes it inevitablein clinical practice to go for invasive alternatives likebiventricular pacing.

An additional unique property present in these drugscould be of clinical importance. The effects of NEPinhibitors are caused by potentiation of endogenousnatriuretic peptides, so their action depends on thesecretion of such peptides. It has thus beenhypothesised but not proved that NEP inhibitors wouldbe most effective in patients with high peptidesecretion. As the peptide secretion is related to high

left ventricular preload, such patients are in most needof diuresis. Thus there is a built-in self regulation; anyevent like dehydration or diuresis that decreasespreload would automatically decrease natriureticpeptide secretion and their diuretic effect, so that thedehydration is not exacerbated. Dehydration is animportant adverse effect of diuretics that restrict theiruse in heart failure patients. However there is a flipside to this phenomenon; this may be also the causeof the rather nonsustained action of these drugs, whengiven to heart failure patients.

To summarise, the use of NEP inhibitors at variousstages of heart failure, results in an equitable or evenbetter hemodynamic changes but not at the cost ofadverse neurohormonal stimulation. The role of thesedrugs in more severe form of heart failure alone orin combination, though appears to be promising, isyet to be tested by clinical trials.

Figure 1. Pathways showing the sites of drug action in heart failure.

Angiotensinogen Kininogen

Natriuretic peptidase

Kininogenase

ACE

Angiotensinogen I

Angiotensinogen II Bradykinin

Inactivemetabolite

NEP

Inactivemetabolite

ACE inhibitors

Vasoactivepeptidase inhibitors

Facilitates:

Renin

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NEP inhibitors

Inhibits:



Future directions: While the salutary effect of ACEinhibitors in heart failure, in general, and NEPinhibitors in particular, in changing adverseneurohormonal milieu per se remains unquestioned,efforts are in progress to develop a chimericmolecule; called vasopeptidase inhibitors, combiningboth these properties23. Figure 1 depicts the site ofaction of such drugs. Such molecules (Table 1),would have both the advantage of antagonising theRAAS and added natriuresis and diuresis of NEPinhibitors. In principle it is also expected to haveboth the tremendous mortality and morbidity benefitsas ACE inhibitors with potent anticongestive powersof loop diuretics, but devoid of their adverse effects.

Clinical trials with omapatrilat, the combined ACE andNEP inhibitor has indeed shown it to have betternatriuretic and humoral (decrease in renin) effectsthan the ACE inhibitor lisinopril24. If the mortalityamong two recently concluded trials are comparedomapatrilat exhibited a significant decrease inmortality when compared to 20 mg/d of lisinopril25.In the just concluded joint International Society andEuropean Society of Hypertension meet; the resultsof the massive OCTAVE trial, that comparedOmapatrilat to Enalapril, another ACE inhibitor wasannounced. This trial tested; omapatrilat Vs enalaprilin25-27 hypertensive patients recruited from 3298 sitesin 12 countries26. Though the trial did not have any

Table 1. Combined NEP and ACE inhibitors (vasoactivepeptidase inhibitors) and their inhibitory activity in various phases of studies.

Agent Study phase ACE Ki (nmol/L) NEP Ki (nmol/L)

Omapatrilat (BMS186716) III 6 9

Sampatrilat (UK81252) II 1.2 8

Fasidotril (BP1.137) II 9.8 5.1

MDL 100,240 (active metabolite MDL 100,173) I 0.08 0.11

Z13752A I 3.2 1.8

BMS189921 II 12 63

Mixanpril (active metabolite RB105) Preclinical 4.2 1.7

ACE = angiotensin-converting enzyme; Ki = inhibitory constant; NEP = neutral endopeptidase.

Table 2. Clinical trials showing efficacy of omapatrilat in varying severity of heart failure.

Heart failure No of patients Treatment Findings(NYHA Class)

II-IV27 369 Omapatrilat 2.5, 5, 10, 20, Dose-dependent reduction in PCWP,and 40 mg/day SBP/DBP, and SVR, and improvement in

NYHA class

II and III2 8 48 Omapatrilat 2.5, 5-10, 20-40 Dose-dependent improvement in functionalmg/day status and LVEF

Dose-dependent reduction in SBP/DBPSignificant reduction in predose serum BNP,epinephrine, and aldosterone.

II-IV29 573 Omapatrilat 10 mg/day Significant benefit of composite end pointstitrated to 40 mg/day Vs of death, hospitalization, discontinuation oflisinopril 5 mg/day titrated study treatment for worsening heart failureto 20 mg/day

SBP=systolic blood pressure; DBP=diastolic blood pressure; SVR=systemic vascular resistance; LVEF-left ventricular ejection fraction

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I. BASURAY

heart failure patient as such but the fact thatomapatrilat was a more effective antihypertensivethan enalapril clearly positions the drugs to be moreeffective in attenuating changes that lead to frankheart failure than enalapril. Omapatrilat was foundto have the same side effect profile as Enalapril,other than the incidence of Angioedema wasdecidedly more (3.1 times more). This has raisedsome concern, with FDA withholding its approval forthis particular agent. There has however been anumber of other trials that has compared the efficacyof omapatrilat in heart failure. These are summarizedin Table 2 27-29.

Conclusion

With the elucidation of the neurohumoral mechanismof heart failure, the realization has dawned thateffective therapy, against these hormonal changesappropriately modifies the course of heart failure withapparent decrease in both mortality and morbidity.The RAAS has been decidedly one of the mostimportant culprits, in the progressive down hill courseof an untreated heart failure. Similarly secretion ofNEP is one of the few positive responses of the bodyagainst the self destructive neurohormonalstimulation that is active in heart failure. Thus atreatment modality that effectively attenuates theformer and potentiates the latter would indeed be amajor pharmacological progress. Preliminary resultswith such drugs like NEP inhibitors and Omapatrilatconform to the above expectation. However, giventhe fact that medical practice at the present time isexclusively evidence based, larger studies with thesedrugs are warranted to confirm or negate our positiveexperience with these agents30.

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14. Munzel T, Kurz S, Holtz J, Busse R, Just H, Drexler H, etal. Neurohormonal inhibition and hemodynamic unloadingduring prolonged inhibition of ANF degradation in patientswith severe chronic heart failure. Circulation 1992;86:1089-98.

15. Northridge DB, Newby DE, Rooney E, Norrie J, Dargie HJ.Comparison of the short-term effects of candoxatril, anorally active neutral endopeptidase inhibitor, and frusemide

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in the treatment of patients with chronic heart failure. AmHeart J 1999;138:1149-57.

16. Christopher MO, Wendy AG, Christopher BG. A randomizedtrial of ecadotril versus placebo in patients with mild tomoderate heart failure: The U.S. Ecadotril Pilot SafetyStudy. Am Heart J 1999;138:1140-8.

17. Francis GS. Is there still a future for neutral endopeptidaseinhibitors? Am Heart J 1999;138:1007-8.

18. Kahn JC, Patey M, Dubois-Rande JL, Merlet P, CastaigneA, Lim-Alexandre C, et al. Effect of sinorphan on plasmaatrial natriuretic factor in congestive heart failure. Lancet1990;335:118-9.

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20. Cowley AJ, Stainer K, Wynne RD, Rowly JM. Symptomaticassessment of patients with heart failure: Double-blindcomparison of increasing doses of diuretics and captoprilin moderate heart failure. Lancet 1986;2:770-2.

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22. Francis GS, Benedict C, Johnstone DE, Kirlin PC, NicklasJ, Liang CS, et al. Related articles, links comparison ofneuroendocrine activation in patients with left ventriculardysfunction with and without congestive heart failure. Asubstudy of the studies of left ventricular dysfunction(SOLVD). Circulation 1990;82:1724-9.

23. Gros C, Noel N, Souque A. Mixed inhibitors of angiotensin-converting enzyme (EC 3.4.15.1) and enkephalinase(E.C.3.4.24.22): Rational design, properties, and potential

cardiovascular applications of glycopril and alatriopril. ProcNatl Acad Sci USA 1991;88:4210-4.

24. Kostis JB, Rouleau JL, Pfeffer MA. Beneficial effects ofvasopeptidase inhibition on mortality and morbidity in heartfailure: Evidence from the omapatrilat heart failure program.J Am Coll Cardiol 2000;35:240.

25. Chen HH, Lainchbury JG, Harty G, Burnett JC. Thesuperior, renal and humoral actions of acute dual NEP/ACE inhibition by vasopeptidase inhibitor versus ACEinhibition alone in experimental mild heart failure: Propertiesmediated via potentiation of endogenous cardiac natriureticpeptides. J Am Coll Cardiol 2000;35:270.

26. Kostis JB. Omapatrilat Cardiovascular TreatmentAssessment Versus Enalapril (OCTAVE). Abstracts ofHypertension Prague 2002 - Joint 19th Scientific Meetingof the International Society of Hypertension and 12thEuropean Meeting on Hypertension, June 23-27, 2002,Prague, Czech Republic. Abstract O018a.

27. Ikram H, McClean DR, Mehta S. Long-term beneficialhemodynamic and neurohormonal effects of vasopeptidaseinhibition with omapatrilat in heart failure [abstract]. J AmColl Cardiol 1999;33:A185.

28. McClean DR, Ikram H, Garlick AH, Richards AM, NichollsMG, Crozier IG. The clinical, cardiac, renal, arterial andneurohormonal effects of omapatrilat, a vasopeptidaseinhibitor, in patients with chronic heart failure. J Am CollCardiol 2000;36:479-86.

29. Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier F,Kerut EK, et al. Comparison of vasopeptidase inhibitor,omapatrilat and lisinopril on exercise tolerance andmorbidity in patients with heart failure: IMPRESSrandomised trial.Lancet. 2000;356:615-20.

30. Basu Ray I, Reddy KN. Neutral peptidase inhibitors. HeartDrug 2001;1:236-40.

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ICC Inh Peptido Natriuretico IndianJPharmacol353139-6497827_180258