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Ibopamine in heart failure. Efficacy and safety in clinical and experimental studies. Veldhuisen, Dirk Jan van

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Publication date: 1993

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SUMMARY AND CONCLUSIONS

The aim of this thesiswas to assessthe role of ibopamine, in the treatment of patients with heart failure. Ibopamine is an orally active agonist which has beneficial hemodynamicand neurohumoral effects.In the 10 Appendices both clinical and experimentalstudies are reported that were designedto examine the efficacy and safety of ibopamine. The clinical studies, which constitute Appendices 1-7, were conductedin patientswith mild, moderateand.severe heart failure. In thesestudies, we evaluated the influence of ibopamine on hemodynamics(Appendices 3,4,6), renal function (Appendices5,6), neurohumoral parameters (Appendices 1,2,3), arrhythmias and electrophysiology(Appendices 1,3), exercise tolerance (Appendices 1,2), signs and symptomsof heart failure and side-effects(Appendices 1,5,7). The experimentalstudies, which constituteAppendices 8-L0, were performedin rats who underwentcoronary ligation, therebycreating a model of myocardialinfarction and heart failure. We first studiedthe effectsof ibopaminewhen administeredlate (6 weeks)after myocardialinfarction (Appendix 8). Subsequentstudies were undertaken to investigate the effect of the drug when given early after myocardial infarction. Accordingly,we evaluatedthe effectsof ibopamineon ventricularremodeling (Appendix 9) and B-adrenoceptordensity (Appendix 10). The studiescan be summarizedas follows:

In Appendix1, The Dutch IbopamineMulticenter Trial (DIMT) is reported.T'his double-blind,placebo-controlled trial was performed in 161 patients with mild to moderateheart failure (80o/o of patientsin NYHA classII and20ohin classIII), who had backgroundtreatment of low dosediuretics or no medication.Patients were randomized to treatmentwith ibopamine(n=53), digoxin(n=55) or placebo(n=53) and follow-up was 6 months. Of the 161 patients, 128 (80Vo)completed the study. Compared to placebo,digoxin preventeda decreasein exercisetime after 6 months (p=0.008 on intention-to-treatanalysis), but ibopaminedid not. In a subgroupof patientswith a relatively preservedleft ventricular function, ibopamine significantlyincreased exercise time. However,in patientswith more advanceddisease, more patientsdropped out of the studyfor progressionof heartfailure on ibopaminethan on digoxin,but the design of the study (patientswere allowed to have 0-80mg furosemideat entry to the study,but if more than 80 mg was required,they were considereda treatmentfailure), did not allow definite conclusionsto be drawn from this finding. On the neurohumorallevel, ibopamineand digoxinfavorably affected plasma and plasmarenin, but did not influence plasma aldosteroneconcentrations. With regard to safety, no proarrhythmiarvas observed with ibopamineand total mortalitywas similar between the treatmentgroups. Ibopamine was well toleratedand causedless side-effects than digoxin

r81 Summary and Conclusions In some in this study. unchanged thereafter. increase in filling Pressures\ il In Appendices 2 and 3, the effects of ibopamine in patients with moderate to decrease.It is concluded that b1 severeheart failure are reported. In these2 studies,ibopamine was given as adjunct to Its main effects are caused to maximal, conventionaltreatment, including ACE-inhibitors. In Appendix2, the effect of arterial blood flow appears ibopamine on peak oxygenconsumption (peak VO2) and plasmacatecholamines (at rest cl and during exercise)was studied in 11 patients with moderately severe heart failure. t In APPendix 5, the agents (intrav After 6 weeks,peak VO2 was not significantlyincreased, but plasmanorepinephrine was I I n significantlyreduced, both at rest (-23Vo)and during exercise(aVo). This blunting of fenoldoPamand iboPamine) wert sympathetic drive confirmed results from previous studies.As it has been suggestedthat patients with heart failure \ neurohumoralinhibition implies a beneficial long-term effect,it might therefore also be in the intensive care setting' true for ibopamine. ) its additive value. IrvodoPa tolerance. Becauseof the higl hea In Appendix 3, the electrophysiologicalprofile of ibopamine was analyzed,both required for Patientswith is a invasively(programmed electrical stimulation) and noninvasively(Holter monitoring) in clinicaluse. effi 12 patients with heart failure and documentedventricular tachycardia,who were also which limits its long-term may treated with amiodarone.Invasive electrophysiologic measurements were performed at failure. PerhaPsthe drug have t baseline and after 1 tablet of 100 mg ibopamine. Ambulatory arrhythmias on 24 hour Ibopamine appears to long Holter recordings were compared before and after 1 weeks ibopamine (3x 100 mg) least with resPectto the treatment. Electrophysiologic effects of ibopamine were related to changes in hemodynamicsand plasma catecholamines.Ibopamine did not significantly affect the The effects of iboParn APPet induction of ventricular tachyarrhythmiasand the effective refractory period during profile are rePorted in on programmed electrical stimulation. Ambulatory arrhythmias on 24 hour Holter who were clinicallY stable 1 ta monitoring were also unchanged.It is suggestedthat the favorable effect of ibopamine studies before and after on hemodynamics and plasma norepinephrine concentrations counteracts possible were monitored simultaneou ínc' adverse electrophysiologic effects of the drug, or that ibopamine lacks such plasma flow and a 10Vo electrophysiologiceffects. filtration fraction and sodium increase,without an effect on elici Effects on invasivehemodynamics are often the first parametersstudied, when a that although iboPamine I new drug like ibopamine is introduced. This was indeed the first work which we to be secondary to systemic conducted in patients with heart failure (Appendix ). The hemodynamic effects of effect. ibopaminewere studiedagain later in relation to the electrophysiologic(Appendix 3) and clin renal effects (Appendix 6). The effects of one tablet of 100 mg ibopamine were In APPendix7 the In t investigated both in the presence and in the absence of concomitant medication term efficacY and safetY' (including ACE-inhibitors) in 27 patients with moderate to severe heart failure. A of patients were studied, w significantincrease in cardiac index was observed,which was mainly attributed to a fall ibopamine' One studYthat he: in vascularresistance. Heart rate was not affected,and blood pressureslightly increased 25 patients with severe The after 30 minutes, only in patients in whom other medication was continued, and was ibopamine 100 mg tid'

188 SummaryandConclusions

unchangedthereafter. In some patients a slight and transient,clinically asymptomatic, increase in filling pressureswas observed,which was followed by a longer lasting )to decrease.It is concludedthat ibopamine has an overall beneficial hemodynamicprofile. tto Its main effects are causedby peripheral vasodilation,of which the influence on the tof arterial blood flow appearsto be more pronouncedthan the effectson venous capacity. 'est lre. In Appendix 5, the cardiac and renal effects of the most commonly used VAS dopaminergic agents (intravenous: dopamine and , oral: levodopa, of fenoldopam and ibopamine) were compared,and data of studiesin normal men, and in hat patientswith heart failure were reviewed.Intravenous dopamine is a valuable compound be in the intensive care setting.With regard to dopexamine,questions remain concerning its additive value. Irvodopa has a beneficial hemodynamic profile and induces no tolerance. Becauseof the high incidence of side-effectsthat are observedin the doses )th required for patientswith heart failure, the drug can however,not be recommendedfor in clinical use. Fenoldopam is a potent vasodilator,but it increasesneurohumoral activity, lso which limits its long-term efficacy.As a result, it is not being used anymore for heart at failure. Perhapsthe drug may earn a place in the treatment of acute hypertensivecrises. ur Ibopamine appearsto have the most favorable profile of the dopaminergic agents,at :g) least with respectto the long-term treatment of patientswith heart failure. in he The effects of ibopamine on renal parametersin relation to its cardiovascular ng profile are reported in Appendix 6. Ten patients with mild to moderate heart failure, er who were clinically stable on digoxin and low-dosediuretics, underwent renal function 1e studies before and after 1 tablet of 100 mg ibopamine, while invasive hemodynamics le were monitored simultaneously.Ibopamine caused a 10Voincrease in effective renal :h plasma flow and a 1,0Voincrease in glomerular filtration rate (both p< 0.05), while filtration fraction and sodiumexcretion were unaffected.Cardiac output showeda similar increase,without an effect on heart rate and blood pressure.The data therefore suggest, a that although ibopamine elicitsfavorable effects on renal function, this influence appears 'e to be secondaryto systemichemodynamic changes, but not becauseof a selectiverenal rf effect. d e In Appendix 7 the clinical data on ibopaminewere reviewed,particularly the long- n term efficacyand safety.In most of the long-term trials that are discussed,large groups \ of patients were studied, who were using open label (=not placebo-controlled) I ibopamine.One studythat was performed earlier in our institution,is discussed,in which

J 25 patients with severe heart failure (NYHA class IV) were treated long-term with S ibopamine 100 mg tid. The one-yearmortality that was found in this study (387a) is in

189 Summary and Conclusions relatedto agreement with data from other groups. Not included in this review are subsequent receptor activationis were col studies of which the resultswere not yet available at that time, particularly the DIMT used. These regimens =no gI study (Appendix 1). A1so,our animal experimentshad not yet been concludedat that control ( drug treatment) infarct t time. Finally,some indications for the useof ibopaminein patientswith heartfailure are to significantlYreduce provided. infarcted rats. In the chrontcP higher blood Pressurethan untl noreP The experimental work with ibopamine (Appendices 8-10), conducted at the of the elevated Plasma to untret Department of Pharmacologyand Clinical Pharmacology,was initiated to evaluatethe captoPril, comPared found effects of ibopamine in a rat model of myocardial infarction and heart failure. This infarcteclrats were again that ibc model is currently the most widely used experimentalheart failure model. Our aim was than controls,and also 9 (a to study the neurohumoral and hemodynamiceffects of ibopamine when given in the values found in APPendix b early and late phase after myocardial infarction. At the time we started these studies difference maYbe exPlained both (1990),it had becomeclear, that earlyintervention after myocardial infarction with ACE- of APPendix 9 is, that mYocardial inhibitorswas beneficial.Since the rat myocardiumis endowedwith predominantlya- remodeling after vasodilating adrenoceptors(in contrastto man), there was initially some concern,however, whether ibopaminehas no maY or not this model might be suitableto evaluatethe effectsof ibopamine. norepinePhrinelevels Pli these findings confirmedthe f We startedtherefore by giving ibopaminein the chronicphase (6 weeks)after 10, the I myocardial infarction (Appendix 8). The principal findings of this studywere, that after In APPendix investi 3 weekstreatment, ibopamine significantly reduced the elevatedplasma norepinephrine distribution(8,:8,) was we co levels and cardiac (tissue) ACE-activity in rats with myocardial infarction. In contrast, le function.In thisstudY ( other plasmaneurohumoral parameters and hemodynamicswere not differentbetween captoPril, and no treatment infar infarcted and normal rats, and were also not affected by ibopamine. These findings treatment), untreated to suggested,that ibopamineacted as a selectivesympathetic antagonist in ratswith heart hemodYnamics,comPared as wel failure after myocardial infarction. (Bn,u")was unaffected, though' High levelsof circulatingcatecholamines have been associatedwith: myocardialinfarction to u 1): ventricular hypertrophy and remodeling after myocardial infarction, becauseof plus captoprilcomPared l growth-stimulatingeffects on the cardiac myocyte,and inducea significantincrease' ls 2): down-regulationof myocardialB-adrenoceptor density, with loss of contractile and heart failr.rre,there force and hemodynamicimpairment. ventricular function' Further r'rntret Sinceibopamine was shownto lower plasmanorepinephrine levels in the first (pilot-) ( = down-regulation)in witt study (and also to reducecardiac ACE), we hypothesized,Ihat ibopamine a) might have in infarcted rats treated a beneficialeffect on ventricularremodeling and b) as a result,myocardial B-adreno- fully confirmthe secondPart ceptor density might increase. to be Present,and these Pron model. In Appendix 9, the effects of ibopamine on ventricular remodeling was studied, and compared to the effects of captopril. Drug treatment was started within 24 hours after myocardial infarction and the measurementswere made 8 weeks later. Since

190 Summary and Conchuioru

)nt receptoractivation is relatedto the doseof ibopamine,both a high and a low dosewas IT used. These regimens were compared with a standard dose of captopril and with a lat control (=no drug treatment)group. Ibopamine, particularly the higherdose, was found tre to significantly reduce infarct size and ventricular dilatation, compared to untreated infarcted rats. In the chronic phase,both ibopamine and captopril treated rats had a higherblood pressurethan untreatedinfarcted rats. In addition,a significantreduction he of the elevated plasma norepinephrinelevels was causedby both ibopamine and he captopril, compared to untreated infarcted rats. It should be noted, that although ris infarcted rats were againfound to have significantlyhigher plasmanorepinephrine levels AS than controls, and also that ibopamine treatment significantlyreduced these levels,the :le valuesfound in Appendix 9 (and 10) were markedlyhigher than in Appendix 8. This es difference may be explained by a different method of blood sampling.The conclusion )-l of Appendix 9 is, that both ibopamine and captopril favorably affect ventricular 7- remodeling after myocardial infarction. Since previous studies have indicated that 3r ibopaminehas no vasodilatingeffects in the rat, it seemsthat the reductionin plasma norepinephrineIevels may play an important role in this beneficialeffect. Moreover, thesefindings confirmed the first part of our (aforementioned)hypothesis. )r )r In Appendix 10, the influence of ibopamine on B-adrenoceptordensity and re distribution(8,:Br) was investigated and thiswas related to possiblechanges in contracti-

L, le function.In this studywe compared3 treatmentregimens: ibopamine, ibopamine plus n captopril,and no treatment(=control group).At the end of the study (after 8 weeks is treatment), untreated infarcted rats had a significant impairment of baseline :t hemodynamics,compared to untreated normal rats. However, B-adrenoceptordensity (8n,"*)was unaffected,as well as the distributionof B, vs B, adrenoceptors.In ratswith myocardialinfarction though,a significantincrease in Bn,u"was observedwith ibopamine plus captoprilcompared to untreatedanimals (p=0.03), while ibopaminealone did not inducea significantincrease. It wasconcluded, that in thismodel of myocardialinfarction and heart failure, there is a dissociationbetween B-adrenoceptordensity and left ventricularfunction. Further, it was found that althoughthere was no decreasein B.u* (=down-regulation)in untreatedinfarcted rats, an increaseinB-adrenoceptorswas found in infarctedrats treatedwith ibopamineplus captopril.Although thesefindings do not fully confirm the secondpart of our hypothesis,a treatment effect of ibopamine appears to be present,and thesepromising results support further research with ibopaminein this model.

191 Summary and Conclusions

CONCLUSIONS THE PLACE OF IBOPAMIN

The following conclusions can be drawn from these studies: The results of these st summarized in ChaPter 3. Dr The hemodynamic effect of ibopamine, an increase in cardiac output, is mainly treatment of heart failure h causedby peripheral vasodilation,although a mild positive inotropic effect could pathophysiolory' as well as re possiblybe present.Heart rate and blood pressureare not affected. drugs.This is discussedin Chr drawn with regard to the rok The renal effects of ibopamine are a (mild) increase in renal blood flow and done in ChaPter 4. glomerular filtration rate, and are mainly secondaryto the systemichemodynamic effect of the drug. The degreein which ibopamineexerts this renal effect depends At the Presenttime, tht on the clinical situation in which these parametersare studied. This holds also who have chronic manifest t true for its stimulating effect on sodium excretion. diuretics. or as an alternative agents,with the Primary aim Ibopamine inhibits neurohumoralactivation in patientswith heart failure. Plasma with mild heart failure, iboPat t norepinephrinelevels are reduced,both at rest and during exercise.Although the with diuretics' Furthermore, drug does not directly affect the renin-angiotensinsystem, plasma aldosterone, absence of ProarrhYthmia' ot plasma renin and in experimental studies also cardiac (tissue) ACE may be events that will lead to m lowered under specialcircumstances, depending on the degreeof neurohumoral intervention at a stage wh( activation. symptoms of heart failure' R' following mYocardialinfarcti The electrophysiologic effects of ibopamine are mild and neither invasive nor drawn on this issue.Neverthe noninvasive studies indicate clinically significant proarrhythmic effects. patientswith heart failurewi

Small, but significant increasesin exercisetolerance have been reported when given alone or in combinationwith low-dosediuretics in mild heart failure. When ibopamine is given as adjunct to maximal medication in more advanceddisease, this effect appearsto be also present.

The effects of ibopamine on signs and symptoms of heart failure were also beneficial when the drug was administeredto the same patients groups.

Ibopamine is well tolerated and in general a low incidence of side-effectsis reported; gastrointestinalcomplaints are the most common.

t92 Summan andConclusioru

THE PLACE OF IBOPAMINE IN HEART FAILURE

The results of these studies are supported by other studies,which have been summarized in Chapter 3. During the time when these studies were performed, the ly treatment of heart failure has changed fundamentally due to new insights in its td pathophysiology,as well as results of recently published major trials with old and new drugs.This is discussedin Chapter 2. When this is all put together,conclusions can be drawn with regard to the role of ibopamine in the treatment of heart failure. This is Ld done in Chapter 4. ic ls At the presenttime, the useof ibopaminecan alreadybe prescribedto all patients o who have chronic manifest heart failure, despite treatment with ACE-inhibitors and diuretics,or as an alternativefor ACE-inhibitors in patientswho are intolerant for these agents,with the primary aim to improve symptomatologyand quality of life. In patients a with mild heart failure, ibopamine may be consideredas monotherapyor in combination with diuretics.Furthermore, because of its neurohumoralmodulating properties and the absenceof proarrhythmia, one may even postulate a beneficial effect on the chain of events that will lead to manifest heart failure. This means, early pharmacologic l intervention at a stage when only left ventricular dysfunction is present, without symptomsof heart failure. Resultsof impending studieson survival and on remodeling following myocardial infarction have to be awaited before definite conclusionscan be drawn on this issue.Nevertheless, ibopamine offers a new approachto the treatment of patients with heart failure with promising perspectives.

193