University of Groningen Ibopamine in heart failure. Efficacy and safety in clinical and experimental studies. Veldhuisen, Dirk Jan van IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 1993 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Veldhuisen, D. J. V. (1993). Ibopamine in heart failure. Efficacy and safety in clinical and experimental studies. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 30-09-2021 I 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 dopamine 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 norepinephrine 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 dopaminergic 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. FenoldoPam 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 dopexamine, 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