How to Select a Drug for the Long-Term Treatment of Chronic Heart Failure

December 1QQD Brodde American Heart Journal

heart failure: concomitant reduction in betar- and betaz- Veld AJ, Schlieper P, Michel MC. Agonist-induced desensiti- adrenoceptor function related to the degree of heart failure in zation of P-adrenoceptor function in man. Subtype-selective patients with mitral valve disease. J Am Co11 Cardiol reduction in &- or @s-adrenoceptor-mediated physiological i989;14:323-31. effects by xamoterol or procaterol. Circulation 1990;81:914-21. 50. Bijhm M, Diet F, Feiler G, Kemkes B, Erdmann E. a-Adreno- 54. Motomura S, Khamssi M, Zerkowski H-R, Brodde O-E. Is ceptors and a-adrenoceptor-mediated positive inotropic ef- there a receptor reserve for isoprenaline in the human heart? fects in failing human myocardium. J Cardiovasc Pharmacol [Abstract]. Eur Heart J 1989;1O(suppl):427. 1988;12:357-64. 55. Levevre-Borg F, Lorrain J, Lechaire J, Thiry C, Hicks PE, 51. Bristow MR, Minobe W, Rasmussen R, Hershberger RE, Cavero I. Studies on the mechanisms of the development of Hoffman BB. Alpha-l adrenergic receptors in the nonfailing tolerance to the hypotensive effects of fenoldopam in rats. J and failing human heart. J Pharmacol Exp Ther 1988247: Cardiovasc Pharmacol 1988;11:444-55. 1039-45. 56. Eden RJ, Harvey CA, Hutchinson M, Owen DAA, Parker SG. 52. Schmitz W, Kohl C, Neumann J, Scholz H, Scholz J. On the Characterisation of the tolerance to the cardiovascular effects mechanism of positive inotropic effects of alpha-adrenoceptor of SK&F 101468-A in spontaneously hypertensive rats [Ab- agonists. Basic Res Cardiol 1989;84(suppl 1):23-33. stract]. Br J Pharmacol 1989;97(suppl):39OP. 53. Brodde O-E, Daul A, Michel-Reher M, Boomsma F, Man in’t

How to select a drug for the long-term treatment of chronic heart failure

First-line drugs for the treatment of chronic congestive heart failure should produce immediate symptomatic benefit, improve exercise tolerance, and thereby improve the quality of life. They should preferentially be active as monotherapy or at least reduce the need for comedication. The drugs must be safe and well tolerated by patients and change, in the end, the natural history of the disease, so that sudden death will be prevented and life expectancy improves. None of the currently available drugs satisfies all these criteria. Diuretics, digitalis, converting-enzyme inhibitors, and ibopamine come close to the described ideal. (Au HEART J 1990;120:1572-8.)

Arie J. Man in ‘t Veld, MD, PhD Rotterdam, The Netherlands

The question addressed in the title of this article is who are in sinus rhythm has been disputed for almost certainly not new and has, in fact, been discussed re- 200 years.l However, some recently reported, care- peatedly in several leading editorials in recent fully controlled, randomized, double-blind trials have years.lm6 Apparently the subject is still surrounded by now shown beyond any doubt that digoxin relieves controversies or new developments, particularly in disability and improves exercise tolerance in CHF, the field of innovations in drug treatment of the dis- thereby ending, to some extent, this long-lasting ease that are required for frequent reorientation. For discussion.8-‘2 many years digoxin and diuretics were the only It should be clearly noted that most of the infor- choices for the treatment of chronic congestive heart mation in this article as well as several considerations failure (CHF). However, even the combination of the for answering the question of how to choose a drug for two drugs fails to help patients with advanced disease the treatment of CHF, are from reviews by Packer.5y 6 and those who have the most debilitating forms of These criteria13 for choosing a drug for the treatment CHF. The efficacy of digoxin for patients with CHF of CHF will also be applied to the novel, orally active inodilator ibopamine in this article.

DRUGSFORCHFTREATMENT From the Department of Internal Medicine I, University Hospital Dijkzigt, Erasmus University Rotterdam. During the past 5 years, more new drugs have been Reprint requests: Arie J. Man in’t Veld, MD, Department of Internal Med- synthesized and evaluated for the treatment of CHF icine I, University Hospital Dijkzigt, Erasmus University Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. than during the previous 200 years.5 More than 80 4/o/23941 different orally active compounds have been admin-

1572 Volume 120 Number 6, Part 2 Drug treatment of CHF 1573

Table I. Oral drugsfor the treatment of CHF: Vasodilators Table II. 0ra.l drugs for the treatment of CHF: Neurohu- moral modulators Venodilators Isosorbide dinitrate ACE inhibitors Erythrityl tetranitrate Captopril Pentaerythritol tetranitrate Enalapril Isosorbide 5-mononitrate Lisinopril Molsidomine Quinapril Arterial dilators Ramipril Hydralazine Cilazapril Dihydralazine Perindopril Endralszine Zofenopril Cadralazine Spirapril Dipyridamole Benazapril Minoxidil Sympathetic inhibitors Ro 12-4713 Clonidine Fenoldopam Methyldopa Pinacidil Guanabenz L-Dopa Bromocriptine Ibopamine Lu-Methyl-p-tyrosine Calcium antagonists Guanethidine Verapamil Ibopamine Nifedipine a-Adrenoreceptor blockers Diltiazem Phenoxybenzamine Nicardipine Prazosin Nisoldipine Trimazosin Isradipine Terazosin Felodipine Doxazosin Amlodipine Bunazosin Nitrendipine Indoramin Mixed Urapidil Flosequinan &Adrenergic blockers More than 30 *(3-Adrenergic partial agonista Xamoterol istered to patients with CHF, and more than 30 ad- Prenalterol ditional drugs have been tested by the intravenous Serotonin antagonist Ketanserin route. Although some of these new drugs have either directly or indirectly multiple actions on the complex ACE, Angiotensin-converting enzyme. hemodynamic and neurohumoral derangements in heart failure, on the basis of their pharmacodynamic actions, they can be classified as follows: (1) vasodi- CLASSIFICATION OF CHF PATIENTS lators (arterial-venous, mixed, including a-adrenore- The clinical syndrome of CHF represents an enor- ceptor antagonists and calcium antagonists), (2) mous heterogenous entity. The patient with symp- inotropic agents, (3) o-adrenoreceptor antagonists toms may present in an early or relatively late stage (including @-adrenoreceptor “buffers” or “modula- of the disease. However, early and late are certainly tors”), (4) angiotensin-converting enzyme inhibitors, not synonymous with mild as opposed to severe, since and (5) diuretics. different causes of heart failure (ischemic vs nonis- Some drugs with a combined vasodilator and ino- chemic) and different stages of neurohumoral adap- tropic action are classified as “inodilators” according tion and cardiac remodeling complicate the picture. to the concept postulated by Opie.14 Ibopamine, a Furthermore, heart failure with left ventricular hy- prodrug, which is converted into epinine, is one of pertrophy as opposed to left ventricular dilatation these inodilators with a combined action on adrener- requires a different approach. Also, abnormalities in gic and dopaminergic receptors, through which ino- systolic and diastolic cardiac function should be tropic and vasodilator effects are mediated.15 Beyond taken into account. Still in most trials, patients are this inodilator effect, the drug also has a diuretic and classified according to the New York Heart Associa- natriuretic effect, which is mediated through renal tion (NYHA) classification despite the fact that its dopamine receptors. l6 Most of the different com- limitations are widely recognized: (1) The classifica- pounds that have been tested in patients with CHF tion does not take into account the cause of heart are listed in Tables I through IV. failure or the drugs used at the time of assessment; December 1990 1574 Man in ‘t Veld American Heart Journal

Table III. Oral drugs for the treatment of CHF: Inotropics Table IV. Oral drugs for the treatment of CHF: Diuretics c-AMP independent Direct Digoxin Thiazides DPI 201-106 Loop of Henle Taurine Ibopamine Carnitine Indirect Co-enzyme QlO Aldosterone antagonists (3-adrenoreceptor stimulants Ephedrine Denopamine Pirbuterol Salbutamol Table V. Requirements for first-line drugs for the treat- Terbutaline ment of CHF, according to Packer Ibopamine Dopamine agonists Rapid relief of symptoms Improve exercise tolerance Fenoldopam Improve quality of life Dopa Reduce mortality Prevent sudden death Ibopamine (arrhythmias) Phosphodiesterase inhibitors Change natural history of Amrinone the disease (reduced Milrinone medication requirement, Enoximone hospitalizations, decline in Imazodan left ventricular function) Piroximone Effective as monotherapy CI-930 Safe, well tolerated Compliance with Ro-13-6438 prescription OPC-8212 Theophylline Calcium sensitizers Sulmazol Pimobendan GOALS IN CHF TREATMENT c-AMP, Cyclic adenosine monophosphate. CHF is a chronic, disabling, and killing disease. In modern Western society, the admission rate to hos- pitals because of the disease has increased more than (2) the lifestyle of the patient is one of the major de- threefold within 15 years.20 It is the most common terminants of the severity of symptoms; (3) the stage disease in subjects over the age of 65 years. Further- and success of compensatory mechanisms are not more, the disease carries a prognosis often worse than taken into account, and (4) above all, the classifica- cancer: &year survival rates of only 50% for even tion is notoriously subjective.4s”7 Nevertheless, since mild cases and l-year survival rates of 40 % to 60 % the classification judges the functional status of the in heart failure after a myocardial infarction under- patient, by definition it correlates well with the line the malignant character of the disease.20 Given symptoms of the patient and exercise tolerance. the prevalence of CHF-more than 15 million people Consequently, the patient’s quality of life is fairly worldwide-the disease also represents a major bur- well related to NYHA status, but it is unrelated to the den on health care economics. Because the incidence hemodynamic status and is also a poor predictor of of the disease is also expected to rise in the future as therapeutic response to drugs or a predictor of a result of the aging of the population and better sur- survival after drug treatment.4y I89 ig Consequently, vival is expected after myocardial infarction as a the questions, “who should be treated, how should consequence of intervention with thrombolytic one be treated and when should treatment start?,” agents, angioplasty, and surgery, the ultimate goal are still not easy to answer from a pathophysiologic will be the prevention of the disease.lg Studies to ex- point of view. Aside from difficulties in predicting the plore this option are currently underway. In the in- therapeutic outcome in patients with CHF, a low left terim, our goals will be to improve the quality of life ventricular ejection fraction, high concentrations of in our patients by offering therapeutic regimens that plasma norepinephrine and vasopressin, low plasma primarily provide symptomatic relief and improve sodium concentrations, and recurrent ventricular exercise tolerance and that secondarily prolong life tachycardia indicate a bad prognosis. Obviously by preventing sudden death caused by arrhythmias, rapid clinical deterioration is also an alarming which are still the major cause of death in CHF (Ta- signala 17-20 ble V). Volume 120 Number 6, Part 2 Drug treatment of CHF 1575

Table VI. Choosing drug therapy for CHF Hydralazine Calcium Phosphodiesterase &Blockers Diuretics Digorin Enalapril + nitrates antagonists inhibitors buffers (5Prazosin Ibopamine

Symptoms + + + ? ? ? ? + + (short term) Exercise ? + + ? ? ? + ? + (medium/long term) Mortality ? ? + + ? ? ? ? ? (long-term) Monotherapy ? ? ? ? ? ? + ? +

Safe ? ? ? ? ? ? ? + + Well tolerated + + + ? ? ? ? + +

References are reviewed in Packer.6 +, Positive effect; ?, questionable or negative effect.

CHOOSING CHF DRUG THERAPY tomatic benefit is negligible. Although the initial en- Before a drug is chosen for the treatment of CHF, thusiasm for the hemodyamic profile of the calcium an adequate diagnostic workup should be performed antagonists in CHF has provoked widespread re- for the detection of reversible forms of heart failure search activities, the negative inotropic actions of the such as alcohol abuse, the use of cardiodepressant drugs, particularly in subjects with the most com- drugs in subjects with preexisting symptomless left promised left ventricular function, have mitigated ventricular dysfunction (@blockers, calcium antago- this interest. Finding the right patient for the right nists, and antiarrhythmic agents), reversible (silent) drug is still one of the problems to be solved. ischemia, valvular disease, arterial hypertension, ane- Reasoning along similar lines also situates the phos- mia, myxedema, and thyrotoxicosis. phodiesterase inhibitors for the moment not in the When considering the requirements for successful position of first-line agents. Selection of the right pa- drug therapy for CHF as formulated by Packer6 few tient is also still a major problem for prescribing @- drugs fullfill all criteria (Table V and VI). Diuretics blockers or P-buffers, drugs with partial agonist not invariably improve exercise tolerance, although activity. Here again, in subjects with severe left ven- they do provide short-term relief of symptoms. Their tricular dysfunction, the negative inotropic effects of effect on mortality is unknown. In the long-run they these drugs can easily cause rapid deterioration of the are seldom effective when given as monotherapy, and clinical status of the patient. Of the a-blockers, pra- because of metabolic derangements, particularly hy- zosin has been investigated extensively. This drug pokalemia, their safety is questionable, although the reduces preload and afterload, ensures rapid relief of drugs are generally well tolerated by patients. Digoxin symptoms, and has no negative inotropic activity, but is effective in controlling short-term symptoms: it positive effects on survival could not be demon- increases exercise capacity, and in strictly controlled strated. This is possibly related to the rapid develop- trial situations, the drug appears to be surprisingly ment of tolerance for this drug, which has been well tolerated. However, the effects on mortality are reported frequently. not known and long-term efficacy as monotherapy in patients who are in sinus rhythm is still much IS THERE A PLACE FOR IBOPAMINE IN CHF disputed as is its safety because of the proarrhythmic TREATMENT? activity of the drug. Enalapril was the first drug for Chemistry and receptor pharmacology. Ibopamine is which there was a positive effect on survival in the 3,4-diisobutyrylester of N-methyldopamine or patients with endstage CHF. However, the efficacy of epinine. Esterase activity in the blood rapidly con- the drug as monotherapy in patients with symptoms verts ibopamine into epinine, which is the active has not been demonstrated. Furthermore, the effects moiety of the molecule, so that ibopamine can be of angiotensin-converting enzyme inhibitors on renal considered a prodrug. Animal studies have shown function are still a cause for concern. Combined that epinine has dopaminergic and (II- and P-adren- treatment with hydralazine and nitrates prolongs ergic activities in cardiac and vascular tissue. These survival in CHF. However, the effects on exercise activities result in positive inotropic, vasodilating, tolerance are disappointing, and short-time symp- natriuretic, and diuretic effects, which led the origi- December 1990 1576 Man in ‘t Veld Amerkan Heart Journal

nal investigators to study this drug in humans, par- lack of the development of tolerance was recently re- ticularly in patients with CHF.21 ported in two studies. 2gp3o Dei Cas et al.2g followed The activities of epinine on a host of cardiovascu- the hemodynamic response to ibopamine when given lar postsynaptic, presynaptic, and ganglionic recep- on a short-term basis at the beginning of treatment tors do not create an easy understanding of its mech- and after long-term therapy in 15 patients. Hemody- anism of action. Positive inotropic effects can be me- namic responses to ibopamine at 0, 1, 2, 3, 8, and 12 diated by @I- and cu-adrenoreceptors, although the months of therapy were similar. Reffo et aL30 evalu- latter are unlikely to play a role in this respect in hu- ated ibopamine after 3 months of treatment in 15 mans. Vasodilatation may be achieved directly by patients compared with placebo under double-blind stimulation of postsynaptic DAl- and /?2-adrenore- conditions by means of invasive hemodynamic mon- ceptors and indirectly by stimulation of presynaptic itoring. In both evaluations, ibopamine improved a2-receptors and DAZ-receptors, which are located on hemodynamic response to the same extent before and ganglionic cells and presynaptically, resulting in a after 3 months of treatment, so that the development reduction in sympathetic vasoconstrictor nerve ac- of tolerance could also not be demonstrated in this tivity. Natriuresis may result directly from a DAl- study. receptor-mediated mechanism on renal tubular cells The clinical efficacy of ibopamine has been dem- controlling sodium reabsorption or more indirectly onstrated for as long as 1 and 2 years. Both in short- by way of a DAs-receptor-mediated mechanism that and long-term comparative studies, ibopamine, 100 inhibits aldosterone release from the adrenal glands. mg, three times daily, improves disability scores, ex- Postsynapticcul- or as-adrenoreceptor activities could ercise tolerance, and left ventricular function during potentially lead to vasoconstriction, which can, how- exercise. These initially encouraging data have been ever, be offset by the net sum of the above-mentioned confirmed in double-blind, placebo-controlled vasodilator mechanisms. Consequently, ibopamine studies and in comparative studies with digoxin and can be listed under several headings in Tables I diuretics. In a relatively short-term study (4 weeks) through IV. in 58 patients with mild-to-moderate CHF stabilized Hemodynamic effects. The acute hemodynamic ef- on digoxin and diuretics, in half the patients ibo- fects of ibopamine have been reviewed recently.22> 23 pamine was substituted for digoxin in a double-blind, In essence flow increases, afterload decreases, and randomized way. Ibopamine appeared to be as effec- arterial pressure and heart rate do not change. Tran- tive as digoxin in this study as judged by clinical sient elevations of cardiac filling pressure have been symptom and disability scores, echocardiographic observed at higher dosages of ibopamine (>200 mg). parameters, left ventricular function, and exercise The mechanism of this phenomenon is not fully un- tolerance as measured by bicycle ergometry.31 derstood. Although the initial idea was that it could Three large, well-controlled, randomized, and dou- be explained by a-adrenoreceptor-mediated vaso- ble-blind trials have been reported only in abstract constriction, this hypothesis is not very likely, since form to date.32-34 In a 4-week study, ibopamine, 200 pretreatment with the cw-adrenoreceptor antagonist mg, two times daily, was compared with digoxin and praxosin does not prevent this response.24 placebo in 60 untreated patients with NYHA classes The neurohumoral counterregulations after an in- I and II. Changes in body weight, peripheral edema, sult to the myocardium lead to elevated concentra- fatigue, and dyspnea ratings and patients’ question- tions of plasma renin, aldosterone, and norepineph- naire scores were evaluated.32 Body weight decreased rine. After treatment with ibopamine, the elevated by 3.5,1.7, and 0.9 kg in the ibopamine, digoxin, and levels of these neurohumoral parameters de- placebo groups, respectively. Mean edema scores de- crease.25-28 Thus if one pieces together the profile of creased from 1.9 to 0.1, 1.5 to 0.3, and 1.5 to to 1.0, hemodynamic, renal, and neurohumoral abnormali- respectively. Total mean patient questionnaire scores ties in CHF and the actions of ibopamine on these decreased from 6.2 to 1.1,5.3 to 2.7, and 4.7 to 4.6 in parameters, a mirror image emerges. However, this the three groups, respectively. In another study of 80 does not necessarily imply long-term clinical efficacy patients in NYHA classes II and III treated with of the drug in the areas of improved quality of life or digoxin and diuretics, the subjects were randomly al- survival. located to receive placebo or ibopamine, 200 mg, Efficacy. A review of several noncomparative and three times daily.33 Sixty of these patients were fol- comparative studies of ibopamine shows that the lowed up for 4 months and 21 were followed for 6 drug maintains its hemodynamic improvements es- months. The last group was also included in an ana- tablished in single-dose studies without significant lyis of exercise tolerance. The mean exercise time was alteration in blood pressure and heart rate.‘O The greater for the ibopamine-treated group than for the Volume 120 Number 6, Part 2 Drug treatment of CHF 1577 placebo-treated group at 1, 2, and 6 months (place- pamine and 22 after placebo (JJ < 0.05). The com- bo, minus 0.35 minute, and ibopamine, plus 1.02 plexity of ectopic supraventricular beats did not minute, p < 0.05). After 6 months of treatment, 70 % change with the treatment regimen. The mean num- of ibopamine-treated patients improved compared ber of ectopic ventricular beats was 31 after ibopam- with baseline versus 40% of the patients receiving ine and 30 after placebo (p < 0.05). The distribution placebo. Improvement in symptom score was greater of the patients among the Lown classification in the for the ibopamine-treated patients than for placebo- 48 hours of ibopamine and placebo was also not dif- treated patients at 1, 2, and 6 months (p < 0.05). In ferent. None of the patients experienced sustained a double-blind study of 247 patients in NYHA classes ventricular tachycardia. Ventricular repolarization I and II, placebo (n = 63), hydrochlorothiaside, 25 behavior was also not affected. Thus apparently in mg, two times daily (n = 60), ibopamine, 200 mg, two this group of patients, ibopamine appeared to be free times daily (n = 61), or ibopamine plus hydrochlo- of proarrhythmogenic activity despite its positive in- rothiazide (n = 63) were compared for 8 weeks.34*43 otropic action. In another study 25 patients (NYHA All active treatments were more effective than pla- classes II and III) were studied during 7 days of placebo in the reduction of body weight and edema. Pa- cebo, 7 days of ibopamine (100 mg, three times daily) tients withdrawn from treatment because of insuffi- and ibopamine (200 mg, three times daily) sequen- cient therapeutic response included 15 on placebo, 3 tially by means of 48 hours of Holter monitoring.41 on ibopamine, 2 on ibopamine plus hydrocholothiaz- No significant differences between the data collected ide, and 2 on hydrochlorothiazide alone. All treat- under the three conditions were found. Although ment groups had a similar incidence of adverse statistically not significant, the number of supraven- events, although there was a greater incidence of hy- tricular beats and ventricular premature contrac- pokalemia in hydrochlorothiazide-treated patients. tions was lower for ibopamine than for placebo. Thus Although further double-blind, controlled studies it appears that ibopamine is well tolerated by pa- are required to verify the long-term (more than 12 tients and is free of proarrhythmic activity. Side ef- months) beneficial effects of ibopamine, it already ap- fects do not limit its prescription in patients with pears that this inodilator is potentially an attractive symptoms of CHF. addition to the treatment of CHF as a substi- Survival. Although data from a formal survival trial tute for digoxin or diuretics or as an adjunct to these with ibopamine are unavailable today, given that its remedies either alone or in combination. This sup- efficacy is comparable with digitalis and diuretics in position was confirmed recently in several larger patients with CHF, and considering its excellent tol- trials.35-38 erability and safety, it is quite likely that there is a Safety and side effects. Noncardiovascular adverse place for ibopamine as a first-line agent in the treat- effects are mainly from gastrointestinal origin, as ment of CHF. Ibopamine could serve as a substitute judged from a large postmarketing survey in Italy in for digitalis or diuretics as monotherapy in NYHA 515 patients, who were treated for a mean period of classes I and II or as an adjunct to diuretics or dig- 71/2 months.3g Gastrointestinal symptoms occurred italis in NYHA classes II and III as a step before in 3.1% of patients, and complaints ranging from vasodilator therapy is started. Examination of the anxiety to headache, rash, or tremor were between available published and unpublished reports in which 0.2% and 0.6%. Because positive inotropic drugs survival was a coincidental observation and not the may exert arrhythmogenic properties, special atten- primary end point suggests that ibopamine may also tion was paid to arrhythmias in patients treated with have a beneficial effect on lifespan in patients with digoxin or ibopamine. Arrhythmia was reported in moderate or severe heart failure.42 5.6 % of patients receiving ibopamine versus 9.4 % of patients receiving digoxin. The issue of potential REFERENCES proarrhythmogenic action of ibopamine was further 1. Lipkin DP, Poole-Wilson PA. Treatment of chronic heart addressed in a double-blind, multicenter study of 97 failure: a review of recent drug trials. Br Med J 1985;291:993- 6. patients (NYHA classes II and III), who were treated Braunwald E. Newer positive inotropic agents. Circulation with ibopamine, 100 mg, three times daily, for 7 days 1986;73:1111-1113. in a random, crossover design with placebo. Any Timmis A. Modern treatment of heart failure; diuretics are often enough, but do not overuse. Br Med J 1988;297:83-4. complex ventricular arrhythmias under basal condi- Cohn JN. Current therapy of the failing heart. Circulation tions were not present at baseline. While on placebo 1988:78:1009-107. and ibopamine, all patients were subject to 48 hours Packer M. Vasodilator and inotropic drugs for the treatment of chronic heart failure: distinguishine hwe from hone. J Am of Holter monitoring. 4o The mean number per hour Co11 Cardiol 1988;12:1299-317‘: - ” - * of ectopic supraventricular beats was 26 after ibo- 6. Packer M. Therapeutic options in the management of chronic December 1990 1578 Man in ‘t Veld American Heart Journal

heart failure. Is there a drug of first choice? Circulation 28. Rajfer SI, Rossen JD, Douglas FL, Goldberg LI, Karrison T. 1979;1:198-204. Effects of long-term therapy with oral ibopamine on resting 7. Anonymous. Enoximone. Lancet 1988;1:1085-6. hemodynamics and exercise capacity in patients with heart 8. The Cantonril-Dieoxin Multicenter Research Groun. Com- failure: relationship to the generation of N-methyldopamine parative effects ofiaptopril and digoxin in patients with mild and to plasma norepinephrine levels. Circulation 1986;73:740- to moderate heart failure. JAMA 1988;259:539-44. 8. 9. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant R, 29. Dei Gas L, Metra M, Nodari S, Diva S, Manta C, Visioli 0. Wright R, for the Milrinone Multicenter Trial Group. A com- Lack of tolerance development during chronic ibopamine ad- parison of oral milrinone, digoxin and their combination in the ministration to patients with congestive heart failure. Cardio- treatment of patients with chronic heart failure. N Engl J Med vast Drug Ther 19882:221-g. 1989;320:677-83. 30. Reffo GC, Gabelline A, Forattini C, et al. Double-blind acute 10. Lee DCS, Johnson RA, Bingham JB, et al. Heart failure in haemodynamic invasive evaluation in congestive heart failure out-patients: a randomized trial of digoxine versus placebo. N before and after sustained treatment with ibopamine. Curr Engl J Med 1982;306:699-705. Ther Res 1988;44:723-30. 11. Guyatt GH, Sullivan MJJ, Fallon EL, et al. A controlled trial 31. Cavalli A, Riva E, Schleman M, Abbondati G, Euccella LM, of digoxine in congestive heart failure. Am J Cardiol Smith-Kline and French Ibopamine Group. Ibopamine as a 1983;61:371-5. substitute for digitalis in patients with congestive heart fail- 12. The German and Austrian Xamoterol Study Group. Double- ure on chronic digitalis therapy. Int J Cardiol 1989;22:381-7. blind placebo controlled comparison of digoxin and xamoterol 32. Clowdus B, Greither A, Tiggeman R, Moore A, Wilta B. Com- in chronic heart failure. Lancet 1988;i:489-93. parison of ibopamine with placebo and digoxin in chronic mild 13. Man in ‘t Veld AJ. Is there a place for ibopamine in the treat- congestive heart failure. [Abstract 10711 Tenth World Con- ment of congestive heart failure? Cardiovasc Drug Ther gress of Cardioloev. Washington D.C.. 1986. 198$3:1065-g. 33. Kayanakis JG, Sihbath J, Sihlaman MM, Moore AL, Hosutt 14. Opie LH. Inodilators. Lancet 1986;1:1336. JA. Comparison of ibopamine and placebo in the treatment of 15. Casagrande C, Santangelo F, Saini C. Synthesis and chemical chronic congestive heart failure NYHA class II-III. Second properties of ibopamine and of related esters of N-substituted Cardiovascular Pharmacotherapy International Symposium, dopamines. Arzneim-Forsch 1986;36:291-303. San Francisco, Calif., 1987. 16. Casagrande C, Merlo L, Ferrini R, Miragoli G, Semeraro C. 34. Clowdus B, Schaeffer J, Tiggeman R, Schleman M, Moore A, Cardiovascular and renal action of dopaminergic prodrugs. J Hosutt J, Nagle B. Effects of ibopamine, hydrochlorothiazide Cardiovasc Pharmacol 1989;14:S40-S60. or placebo on signs and symptoms of mild chronic congestive 17. Gorlin R. Treatment of congestive heart failure: where are we heart failure. Fifth Joint Meeting of the Working Groups of going. Circulation 1987;75:IV108-IVlll. the European Societv of Cardioloev and Svmnosium on Ten 18. Packer M. Neurohumoral interactions and adaptations in Years Bailoon Dilatation in Cardiovascular Disease Santiago congestive heart failure. Circulation 1988;77:721-30. de Compostela, Spain, 1987. 19. Cohn JN. Plasma norepinephrine as a guide to prognosis in 35. Alicandri C, Fariello R, Boni E, Zaninelli A, Muiesan G. Ibo- patients with chronic congestive heart failure. N Eng J Med pamine vs. digoxin in chronic heart failure: a double-blind, 1984;311:819-823. cross-over study. J Cardiovasc Pharmacol1989;14-8S77S83. 20. Packer M. Prolonging life in patients with congestive heart 36. Condorelli M, Mattioli G, Caponetto S, et al. The long-term failure: the next frontier. Circulation 1987;75:IVl-IV3. efficacy of ibopamine in treating patients with severe heart 21. Casagrande C, Castelnovo P, Cerri 0, Ferrini R, Merlo L, et failure: a multicentre investigation. J Cardiovasc Pharmacol al. Ibopamine: investigation of metabolism and pharmacoki- 1989;14-8:S83-S93. netics in relationship to pharmacodynamics. Proceedings of 37. Rolandi E, Sabino F, Cantoni V, Ghirardi P, Marchetti GV, the 8th International Symposium on Medical Chemistry, Cicchetti V. Long-term therapy of chronic congestive heart Uppsala, 1984. Stockholm: Swedish Pharmaceutical Press, failure with ibopamine: a multicenter trial. J Cardiovasc 1985:481-91. Pharmacol 1989;14-8:S93-S104. 22. Henwood J, Todd PA. Ibopamine, a preliminary review of its 38. Dei Cas L, Metra M, Nodari S Visioli 0. Efficacy of ibopam- pharmacodynamic and pharmacokinetic properties and ther- ine treatment in patients with advanced heart failure: purpose apeutic efficacy. Drugs 1988;36:11-31. of a new therapeutic scheme with multiple daily administra- 23. Lopez-Sendon J. Hemodynamic effects of ibopamine in con- tions. J Cardiovasc Pharmacol 198914~8:Slll-S8. gestive heart failure. Cardiovasc Drug Ther 1989;3:1029-41. 39. Sher D, Ferrari V. Ibopamine post-marketting surveillance. 24. Rocke DA, Naidoo DP, Mahomedy AE, Chetty S, Mitha AS. First report from a parallel-cohorts survey ongoing since April Hemodynamic effects of ibopamine with prazosin in conges- lst, 1985. Arzneim-Forsch 1987;37:873-99. tive heart failure [Abstract]. 61st American Association, 40. Furlanello et al. Influence of dopamine on heart rate and ar- Washington, DC., 1988. rhythomogenic pattern in patients with congestive heart fail- 25. Incerti PL, Badalmenti S, Lorenzano E, et al. Humoral and ure. Giornale Italian0 di Cardiologia 1990 [in press]. renal effects of ibopamine in normal subjects. Arzneim-Forsch 41. Caponetto S, Terrachini Canale C, Bruzzone F, Licciardello L, 1986;36:405-7. Marchetti GV. Absence of proarrhythmic effects of ibopamine 26. Rolandi E, Marchetti G, Franceschini R, et al. Inhibition of in patients with congestive heart failure. J Cardiovasc Phar- prolactin and aldosterone secretion by the dopamine deriva- macol 1989;14-8:S104-Sll. - . tive ibopamine. Eur J Clin Pharmacol 1986;29:629-30. 42. Taylor SH. Ibopamine and lifespan in heart failure. Cardio- 27. Nakano T, Morimoto Y, Katuta Y, et al. Acute effects of ibo- vast Drugs Ther 1989;3:1059-65. pamine hydrochloride on hemodynamic plasma catechola- 43. Kleber F,X, Thyroff Friesinger U, Treatment of mild chronic mine levels, renin activity, aldosterone, metabolism and blood congestive heart failure with Ibopamine, Hydrochlorthiazide, gasses in patients with severe congestive heart failure. Ibopamine plus Hydrochlorthiazide or Placebo. Cardiology Arzneim-Forsch 1986;36:1829-33. 1990;77(suppl 5).