A double-blind dose response comparison of oral enoximone and placebo for congestive heart failure

Enoximone (MDL 17,043), a newly synthesized imidazole derivate, has been shown to possess both positive inotropic and vasodilating properties. Sixteen patients with congestive heart failure were allocated to receive either enoximone, 50, 100 or 150 mg, or placebo, each given 3 times daily for 4 weeks, to investigate the dose-related efficacy and tolerability of oral enoximone. Symptom-limited exercise capacity improved in 5 of 10 patients in the enoximone group. The ejection fraction increased from 28% to 36% after 4 weeks, to 36% after 8 weeks and to 35% after 12 weeks in the enoximone group. Exercise duration and ejection fraction did not change in the patients in the placebo group. With enoximone, heart rate, blood pressure, Holter monitoring and laboratory tests showed no significant drug-related changes. The addition of oral enoximone to existing therapy with digitalis and diuretics may improve the clinical condition and left ventricular function in patients with congestive heart failure. Enoximone shows clinical efficacy at dosages of 50 mg and 100 mg 3 times daily. With the higher dosage, unwanted side effects increased but efficacy did not. Enoximone did not increase ventricular ectopy in the doses given.     

Double-blind crossover comparison of enoximone and placebo in patients with congestive heart failure

The efficacy of oral enoximone, a new positive inotropic and vasodilator agent, was assessed in 12 patients with chronic congestive heart failure (New York Heart Association [NYHA] class II or III) in a double-blind randomized crossover comparison with placebo. Duration of each treatment was 6 weeks and the dose of enoximone was 150 mg tid. Efficacy was assessed by exercise tolerance, symptoms, radionuclide angiography for ejection fraction at rest and during exercise, and Holter monitoring. Two patients were withdrawn before completion of the study, one with pulmonary edema after 1 week on placebo and the other for noncompliance with enoximone therapy. Symptom-limited exercise capacity improved with enoximone by 30% and 43% (p less than .01) compared with baseline after 2 and 6 weeks treatment, respectively. Ejection fraction improved at rest (p less than .02) with enoximone but not with placebo. No change was found during exercise. Heart rate and blood pressure remained unaltered. During treatment with enoximone symptoms of exertional dyspnea and fatigue were improved and NYHA class decreased by at least one class for every patient. Holter monitoring revealed an overall increase (NS) in ectopic activity during enoximone therapy. There were no serious adverse effects and laboratory values did not change significantly. The addition of enoximone to the existing therapy of patients with moderately severe congestive heart failure provided clear and sustained subjective and objective benefit when compared with placebo.     

Low-dose enoximone improves exercise capacity in chronic heart failure. Enoximone Study Group

OBJECTIVES: This study was designed to evaluate the effects of low-dose enoximone on exercise capacity. BACKGROUND: At higher doses the phosphodiesterase inhibitor, enoximone, has been shown to increase exercise capacity and decrease symptoms in heart failure patients but also to increase mortality. The effects of lower doses of enoximone on exercise capacity and adverse events have not been evaluated. METHODS: This is a prospective, double-blind, placebo-controlled, multicenter trial (nine U.S. centers) conducted in 105 patients with New York Heart Association class II to III, ischemic or nonischemic chronic heart failure (CHF). Patients were randomized to placebo or enoximone at 25 or 50 mg orally three times a day. Treadmill maximal exercise testing was done at baseline and after 4, 8 and 12 weeks of treatment, using a modified Naughton protocol. Patients were also evaluated for changes in quality of life and for increased arrhythmias by Holter monitoring. RESULTS: By the protocol-specified method of statistical analysis (the last observation carried-forward method), enoximone at 50 mg three times a day improved exercise capacity by 117 s at 12 weeks (p = 0.003). Enoximone at 25 mg three times a day also improved exercise capacity at 12 weeks by 115 s (p = 0.013). No increases in ventricular arrhythmias were noted. There were four deaths in the placebo group and 2 and 0 deaths in the enoximone 25 mg three times a day and enoximone 50 mg three times a day groups, respectively. Effects on degree of dyspnea and patient and physician assessments of clinical status favored the enoximone groups. CONCLUSIONS: Twelve weeks of treatment with low-dose enoximone improves exercise capacity in patients with CHF, without increasing adverse events.     

Rationale and design of the enoximone clinical trials program

BACKGROUND: Chronic heart failure is a disease syndrome characterized in its advanced stages by a poor quality of life, frequent hospitalizations, and a high risk of mortality. In advanced and ultra-advanced chronic heart failure, many treatment options, such as cardiac transplantation and mechanical devices, are severely limited by availability and cost. Short-term Phase II clinical trials suggest that low-dose oral inotropic therapy with enoximone may improve hemodynamics and exercise capacity, without adversely affecting mortality, in selected subjects with advanced chronic heart failure. Based on these data, the ability of enoximone to deliver safe and efficacious palliative treatment of advanced/ultra-advanced chronic heart failure is being evaluated in Phase III clinical trials. METHODS AND RESULTS: The Enoximone Clinical Trials Program is a series of 4 clinical trials designed to evaluate the safety and efficacy of oral enoximone in advanced chronic heart failure. ESSENTIAL I and II (The Studies of Oral Enoximone Therapy in Advanced Heart Failure) will investigate the effects of oral enoximone on all-cause mortality and cardiovascular hospitalization, submaximal exercise capacity, and quality of life in subjects with New York Heart Association Class III/IV chronic heart failure. EMOTE (Oral Enoximone in Intravenous Inotrope-Dependent Subjects) will evaluate the potential of oral enoximone to wean subjects with ultra-advanced chronic heart failure from chronic intravenous inotropic therapy to which they have been shown to be dependent. EMPOWER (Enoximone Plus Extended-Release Metoprolol Succinate in Subjects with Advanced Chronic Heart Failure) will explore the potential of enoximone to increase the tolerability of continuous release metoprolol in subjects shown previously to be hemodynamically intolerant to beta-blocker treatment. CONCLUSION: These studies are Phase III, multicenter, randomized, double-blinded, placebo-controlled trials designed to test the general hypothesis that chronic oral administration of low doses of enoximone can produce beneficial effects in subjects with advanced or ultra-advanced chronic heart failure.     

Disparity between improvement in left ventricular function and changes in clinical status and exercise capacity during chronic enoximone therapy

Twenty patients with moderately severe congestive heart failure were randomized to chronic enoximone (n = 10) or placebo (n = 10) therapy in a double-blind manner and serially evaluated over a 16-week-period. The purpose of the study was to determine if the addition of standard doses (1 and 2 mg/kg) of this new phosphodiesterase inhibitor to conventional therapy (digitalis and diuretics) would alter the clinical and laboratory course of this patient population. Except for a transient improvement in the quality of life score, none of the symptomatology indicators were significantly affected by enoximone. Similarly, maximal exercise capacity was not altered. Enoximone did elicit a statistically significant augmentation of echocardiographic, radionuclide angiographic, and systolic time interval parameters of left ventricular function. These enoximone-induced effects were accompanied by a significant increase (7% to 11%) in resting heart rate. Enoximone is capable of improving ventricular function when added to digitalis-diuretic therapy in moderately severe congestive heart failure. While individual patients may benefit from enoximone, the ability of standard doses of this agent to improve symptoms and exercise capacity over a 16-week period appears somewhat limited in a moderately severe heart failure population as a whole. Furthermore, a disparity between improvement in ventricular function parameters and changes in clinical status and exercise performance is apparent in this heart failure population.     

A preliminary report of the effects of orally administered enoximone on regional hemodynamics in congestive heart failure

Twelve patients with moderately severe congestive heart failure underwent the simultaneous determination of central and regional hemodynamics after administration of placebo and enoximone. The regions examined hemodynamically included renal, hepatic-splanchnic and upper limb. Enoximone was studied in 2 doses, 1 and 2 mg/kg, and administered in a double-blind, placebo-controlled, crossover design. At these doses enoximone elicited a significantly greater increase in cardiac output and a greater decrease in systemic vascular resistance than placebo. Systemic blood pressure was not significantly altered. Enoximone did not significantly change the flow or resistance of renal or hepatic-splanchnic vascular beds. Limb vascular resistance decreased modestly after enoximone with a significant augmentation (+12% to 17%) of limb blood flow compared with placebo. The initial oral administration of the 1 and 2 mg/kg doses of enoximone improved central hemodynamic parameters with apparent preferential reduction of limb vascular resistance and augmentation of blood flow to the limb region (peripheral musculoskeletal system).     

A dose-response study of intravenous enoximone in congestive heart failure

Previous clinical studies with intravenous enoximone have used cumulative dosing to quantify enoximone's hemodynamic effects. The magnitude and duration of the hemodynamic effects of single intravenous doses of enoximone were evaluated in patients with congestive heart failure. Sixty patients, who were in New York Heart Association functional classes III and IV, received single intravenous doses of enoximone, either 0.25 (12 patients), 0.5 (13 patients), 1 (14 patients), 1.5 (10 patients) or 2 mg/kg (11 patients). Cardiac index was increased by 20% with the 0.25 mg/kg dose and by 48% and 42% with the 1.5 and 2 mg/kg doses, respectively. These increases were statistically significant (Student's paired t test with Bonferroni's correction, p less than 0.007) for 1 hour after 0.25 and 0.5 mg/kg, for 2 hours after 1 mg/kg and for 4 hours after 1.5 and 2 mg/kg. Enoximone also reduced pulmonary artery diastolic pressure by 19% with 0.25 mg/kg and by 29% with 2 mg/kg. The duration of effect varied from 1 hour with 0.25 mg/kg to 4 hours with 2 mg/kg. Enoximone produced no consistent or dose-related effects on heart rate or blood pressure. Eighteen adverse reactions were reported by 15 patients, of which 11 were minor and transient (vein pain, flushes, nausea). In 5 patients ventricular or supraventricular arrhythmias were observed, including nonsustained ventricular tachycardia and extrasystoles; 3 of these patients had evidence of arrhythmias before enoximone. Laboratory studies before and after treatment showed no drug-related effects. Dose-related effects on the magnitude and duration of hemodynamic responses to intravenous enoximone were evident within the dose range of 0.25 to 2 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term treatment with oral enoximone for chronic congestive heart failure: the European experience

The long-term safety and efficacy of the inotropic/vasodilatory agent enoximone (50 to 100 mg 3 times daily) were evaluated in 30 patients with chronic congestive heart failure (New York Heart Association classes II to IV). Nineteen patients had idiopathic dilated cardiomyopathy and 11 had ischemic heart disease. Patients were receiving maintenance therapy of digitalis and diuretics. Cardiac function was assessed at 12 week intervals (physical examination, exercise testing, chest x ray, echocardiography, radionuclide angiography, 24-hour Holter monitoring and blood chemistry). During a mean follow-up of 40 weeks, 6 patients died, due to noncardiac (n = 1) and sudden death (n = 1) and to cardiac failure (n = 4) within 36 weeks of drug treatment. In the remaining patients New York Heart Association class improved in 18, was stationary in 5 and deteriorated in 1. Exercise capacity increased during the first 26 weeks and was maintained improved thereafter. Clinical improvement appeared not to wane with time. No change in heart rate, blood pressure and cardiothoracic ratio was observed. Echocardiographic left ventricular dimensions did not change significantly; however, the fractional shortening increased from baseline (14%) to 19% after 12 weeks, 17% after 26 weeks and 21% after 52 weeks (p less than 0.05). The preejection period/left ventricular ejection time ratio decreased from 0.74 to 0.35, 0.44 and 0.43 (p less than 0.05), respectively. There was an increase in radionuclide ejection fraction from 23% to 27% (difference not significant).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of xamoterol, a beta 1 adrenoceptor partial agonist, in patients with ischaemic dysfunction of the left ventricle.

The effects of xamoterol (200 mg twice a day) in 21 patients with left ventricular dysfunction were studied in a double blind, randomised, crossover, placebo controlled trial with treatment periods of four weeks. Most patients had moderate heart failure (New York Heart Association class II), all had ischaemic heart disease, a history of a myocardial infarction, and symptoms of dyspnoea on exertion. Patients were assessed in terms of exercise duration (bicycle ergometer), clinical signs of heart failure, symptoms and activities, and ejection fraction. Xamoterol increased exercise duration (mean (SD] (from 445 (8) seconds to 484 (8) seconds) and ejection fraction (from 41.9 (1.3)% to 46.6 (1.3)%) and reduced the signs and symptoms of heart failure. The results of this study show that xamoterol is a safe and effective treatment for left ventricular dysfunction resulting from ischaemic heart disease.     

Effects of xamoterol, a beta 1 adrenoceptor partial agonist, in patients with ischaemic dysfunction of the left ventricle

The effects of xamoterol (200 mg twice a day) in 21 patients with left ventricular dysfunction were studied in a double blind, randomised, crossover, placebo controlled trial with treatment periods of four weeks. Most patients had moderate heart failure (New York Heart Association class II), all had ischaemic heart disease, a history of a myocardial infarction, and symptoms of dyspnoea on exertion. Patients were assessed in terms of exercise duration (bicycle ergometer), clinical signs of heart failure, symptoms and activities, and ejection fraction. Xamoterol increased exercise duration (mean (SD] (from 445 (8) seconds to 484 (8) seconds) and ejection fraction (from 41.9 (1.3)% to 46.6 (1.3)%) and reduced the signs and symptoms of heart failure. The results of this study show that xamoterol is a safe and effective treatment for left ventricular dysfunction resulting from ischaemic heart disease.     

Comparison of the effects of captopril and enoximone in patients with severe heart failure: a placebo controlled double-blind study

The effects of enoximone, a new cyclic adenosine monophosphate phosphodiesterase inhibitor, were compared with those of captopril in a double-blind study in a group of 10 patients with severe heart failure. Four weeks treatment with enoximone improved symptom-limited exercise tolerance from a mean value of 11.33 to 13.36 minutes (P less than 0.05) and 4 weeks of captopril treatment from 11.01 to 13.92 minutes (P less than 0.05). Four of the patients had a greater exercise tolerance taking enoximone, the remaining 6 while taking captopril. Both drugs reduced perceived exertion during submaximal exercise. Minute ventilation measured at rest and during submaximal exercise was also reduced by both drugs. Resting and post exercise calf blood flow was increased to a similar extent with captopril (P less than 0.03) and enoximone (P less than 0.005). There was no difference in calf blood flow and calf vascular resistance between the drugs suggesting that the peripheral haemodynamic effects of enoximone are due to peripheral vasodilatation. Enoximone is a useful drug for the treatment of patients with severe heart failure.     

The electrophysiologic effects of enoximone in patients with preexisting ventricular tachyarrhythmias

Electrophysiologic and hemodynamic effects of intravenous enoximone were studied in 15 male patients, mean age 62.2 years, with New York Heart Association classes II to IV congestive heart failure (coronary artery disease in 10 and idiopathic dilated cardiomyopathy in five patients; mean ejection fraction, 0.19). All patients had spontaneous ventricular tachyarrhythmias; eight had sustained ventricular tachycardia (VT), one had ventricular fibrillation, and six had nonsustained VT. Hemodynamic and electrophysiologic parameters including VT induction were determined before and during an intravenous infusion of enoximone. The cardiac index increased (2.49 +/- 0.89 to 2.96 +/- 0.78), and the pulmonary capillary wedge pressure decreased (22.4 +/- 13.2 to 10.0 +/- 9.0) after enoximone per predefined protocol endpoints. There was a significant decrease in spontaneous sinus cycle length, corrected sinus nodal recovery time, AH interval during atrial pacing, shortest cycle length at which 1:1 atrioventricular nodal conduction occurred, and refractory periods of the atrium, ventricle, and atrioventricular node. Enoximone did not alter the cycle length of induced VT, and there was no consistent change in the number of extrastimuli required for VT induction. A baseline 24-hour ECG recording was obtained on 14 patients (while receiving a long-term antiarrhythmic drug regimen, if needed) and repeated after 1 week and 1 month of oral enoximone therapy. There was no significant increase in the number of premature ventricular complexes per hour or VT episodes per 24 hours after 1 week or 1 month of therapy with enoximone. However, if four patients who received amiodarone and may not yet have reached steady state were excluded from analysis, there was a significant increase in the frequency of premature ventricular complexes per hour 1 month after initiation of enoximone. We conclude that intravenous enoximone reduces pulmonary capillary wedge pressure and increases cardiac output in most patients. Intravenous enoximone in doses sufficient to have hemodynamic effects shortens atrial, ventricular, and atrioventricular nodal refractoriness and decreases AV nodal conduction time but has no consistent effect on VT induction or VT cycle length. The frequency of spontaneous ventricular ectopy may increase in some patients after oral enoximone, but its clinical significance is undefined. Enoximone may be administered cautiously to patients with congestive heart failure and preexisting ventricular tachyarrhythmias.     

Placebo-controlled study of oral enoximone in congestive heart failure with initial and final intravenous hemodynamic evaluation

Seventeen patients with stable congestive heart failure (class II and III New York Heart Association) received intravenous and oral enoximone in a 2-part study. Hemodynamic data were first obtained after intravenous administration of 0.75 mg/kg of enoximone; data were again obtained after 12 weeks of therapy with either oral enoximone (150 mg 3 times daily) or placebo. The efficacy and safety of oral enoximone were also studied in a 12-week, double-blind randomized format. In the intravenous study, enoximone was delivered over 5 minutes and hemodynamic data were measured for up to 12 hours after. Cardiac index increased 2.76 +/- 0.63 to 3.42 +/- 0.72 liters/min/m2), pulmonary wedge pressure decreased (19.5 +/- 8.8 to 14.6 +/- 8.0 mm Hg) as did mean arterial blood pressure (101 +/- 14.8 to 85 +/- 13.7 mm Hg) and systemic vascular resistance (1,880 +/- 573 to 1,254 +/- 383 dynes s cm-5). Heart rate increased slightly (82 +/- 17 to 86 +/- 14 beats/min). All these changes were maximal 1 to 2 hours after infusion and lasted 8 hours at least. Patients were then randomized double-blind to oral treatment. Baseline values showed that the 7 patients who received placebo had more severe CHF. Therefore, comparison might be biased. Patient overall assessment showed a continuous benefit in both groups. Ejection fraction improved from 30.1 +/- 6.8% to 33.9 +/- 9.9% in the enoximone group while it remained unchanged with placebo (23.4 +/- 6.5% to 23.4 +/- 1.5%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Double-blind placebo-controlled comparison of enoximone and dobutamine infusions in patients with moderate to severe chronic heart failure

Few data exist on the safety of transferring patients to standard oral therapy for chronic heart failure (CHF) after acute management with inotropic agents. This study compares hemodynamic responses and cardiac dysrhythmic effects of continuous infusion of enoximone, dobutamine, or placebo in patients with moderate to severe CHF. The authors enrolled 136 patients who were randomly assigned to either open-label dobutamine or double-blind enoximone vs placebo. After 24 hours of treatment, the study was unblinded. Patients receiving placebo completed the study. Patients receiving enoximone or dobutamine received the infusion for an additional 24 hours and were then switched to standard oral therapy for 72 hours. Compared with placebo, both enoximone and dobutamine increased cardiac index and decreased pulmonary capillary wedge pressure (PCWP). Compared with dobutamine, enoximone significantly increased cardiac index after the first 24 hours of infusion and significantly decreased PCWP throughout the infusion period. There was no difference in the incidence of arrhythmias between enoximone and dobutamine. More patients (65%) tolerated the switch to oral therapy in the enoximone group compared with dobutamine (49%; P =.12). Enoximone is effective in improving the hemodynamics in patients with moderate to severe CHF and is tolerated at least as well as dobutamine.     

Central and regional hemodynamic effects of oral enoximone in congestive heart failure: a double-blind, placebo-controlled study

Twelve patients with congestive heart failure underwent a double-blind, placebo-controlled study for the purpose of examining the central and regional hemodynamic effects of first-dose (1 and 2 mg/kg) oral enoximone, a new phosphodiesterase III inhibitor. Enoximone augmented cardiac output, generally through a positive chronotropic response. Indices of left ventricular contractility, specifically stroke volume, delta P/delta t, fractional shortening rate, and the duration of the preejection period, were only modestly enhanced by enoximone. At 2 mg/kg, systemic vascular resistance fell below baseline values without affecting systemic blood pressure; these parameters were not altered by the 1 mg/kg dose. Both pulmonary artery pressure and pulmonary vascular resistance dropped below baseline and below placebo control for the 2 mg/kg dose. Enoximone at 2 mg/kg lowered right and left heart filling pressures below baseline. Examination of regional hemodynamic responses to both doses demonstrated a reduction in limb vascular resistance and an increase in limb blood flow proportional to the concomitant increase in cardiac output. Renal and hepatic-splanchnic blood flow and vascular resistances were not altered by enoximone. First-dose oral enoximone (1 and 2 mg/kg) alters hemodynamics in heart failure by predominant vasodilatation, particularly of limb-musculoskeletal and pulmonary vascular beds, some positive chronotropism, and modest positive inotropism.     

Placebo controlled trial of felodipine in patients with mild to moderate heart failure. UK Study Group.

OBJECTIVE--To compare the effects of felodipine and placebo in patients with New York Heart Association functional class II or III and stable congestive heart failure despite treatment with an angiotensin converting enzyme inhibitor, diuretic, or digoxin, or any combination of these three drugs. PATIENTS AND DESIGN--252 patients were randomised in a double blind, parallel group study after a 2-4 week placebo run-in to oral treatment with either felodipine extended release formulation or placebo 2.5-10 mg twice daily given in addition to existing background medication for a further 12 weeks. METHODS--Patients aged 18-75 years of either sex with chronic congestive heart failure due to ischaemic heart disease, hypertensive heart disease, or dilated cardiomyopathy with or without secondary mitral insufficiency that was stable during the preceding two months were included in the study. Treadmill exercise tests according to the modified Naughton protocol were performed at baseline, and after six, 11, and 12 weeks of treatment. Signs and symptoms of heart failure were assessed at every visit. Physical examination was performed and left ventricular ejection fraction measured at baseline and after 12 weeks. RESULTS--Mean (SD) baseline exercise test times increased from 434 (162) s and 480 (157) s for felodipine and placebo groups respectively to 541 (217) s and 591 (218) s at 12 weeks or the last visit. The change in exercise from baseline to last visit was 107 (141) s for patients given felodipine and 112 (128) s for those given placebo (P > 0.20). There was also no difference between treatments with respect to the other efficacy variables. There were few deaths in the study (felodipine n = 3, placebo n = 2). More patients who received felodipine were withdrawn from treatment (n = 29) than those who received placebo (n = 17). The most common adverse events of the 54 and 28 cited as reasons for withdrawal in the felodipine and placebo groups respectively were increased need for non-study heart failure treatment (n = 10; 8%)--that is, starting new medication or changes in the dosage of existing treatment for patients given felodipine, and nausea (n = 4; 3%) for those given placebo. Patients withdrawn from the study due to increased need for non-study heart failure treatment rapidly stabilised and recovered. CONCLUSION--Felodipine has not been shown to be of benefit in patients with mild to moderate heart failure.     

Effects of enoximone on exercise tolerance in patients with mild to moderate heart failure.

To evaluate the efficacy of enoximone on exercise tolerance in patients with mild to moderate heart failure, 33 patients underwent cardiopulmonary exercise tests before and 3 hours after placebo or after receiving 25 or 100 mg of enoximone administered randomly in a double-blind manner. The electrocardiogram was monitored and blood pressure measured every minute throughout cycle ergometer exercise testing with a ramp protocol in which the work rate increased 1 W every 6 seconds after a 4-minute 20-W warm-up. Minute ventilation, oxygen uptake (VO2), and carbon dioxide output were measured every 10 seconds in order to determine anaerobic threshold (AT) and peak VO2. Five patients were excluded from evaluation before breaking the double-blind key because of insufficient data. Heart rate increased and systolic blood pressure decreased throughout the testing only in the group taking 100 mg (n = 10). Significant increases in AT (14.4 to 16.2 ml/min/kg) and peak VO2 (20.8 to 22.9 ml/min/kg) were observed in the group taking 100 mg. The increases in AT showed a dose response, namely +0.7% in the placebo (n = 9), +6.9% in the 25-mg (n = 9) and 12.5% in the 100-mg group. The work rates at the AT point increased in the 25- and 100-mg groups. These results indicate that a single oral administration of enoximone improves exercise tolerance in patients with mild to moderate heart failure.     

Comparison of treatment with lisinopril versus enalapril for congestive heart failure.

The effect of lisinopril 5-20 mg once daily or enalapril 5-20 mg once daily on exercise capacity, ventricular ectopic activity, and signs and symptoms of heart failure have been studied in 278 patients with mild-to-moderate (New York Heart Association [NYHA] classes II and III) heart failure in a randomized, double-blind, parallel-group study of 12 weeks' duration. Exercise duration was significantly increased by both angiotensin-converting enzyme (ACE) inhibitors after 6 and 12 weeks of treatment compared with their respective baseline values. There was a trend toward a greater increase in exercise duration on lisinopril after 12 weeks, although this did not reach statistical significance (p = 0.0748). There were no significant treatment differences with respect to the effect of the 2 drugs on ventricular ectopic counts, couplets, or nonsustained ventricular tachycardia. Both drugs were equally effective in improving NYHA grading and symptoms. Neither treatment had any significant effect on mean heart rate or mean blood pressures. Both treatments were equally well tolerated. The most commonly reported adverse events on both drugs were cough, dizziness, fall in blood pressure, vertigo, and myocardial infarction. The results of this study indicate that lisinopril 5-20 mg once daily is at least as effective and well tolerated as enalapril 5-20 mg once daily.     

Comparative effects on hemodynamics of enoximone (MDL 17,043), dobutamine and nitroprusside in severe congestive heart failure

To assess their comparative effects on hemodynamics, nitroprusside, dobutamine and enoximone were sequentially administered to 10 patients with severe congestive heart failure. Nitroprusside, dobutamine (at 10 micrograms/kg/min) and enoximone (at 2 mg/kg) increased stroke volume index to a similar extent (31%, 34% and 36%, respectively). Enoximone produced less tachycardia than dobutamine and, consequently, a smaller improvement in cardiac index. Mean arterial pressure was not altered by dobutamine but was reduced 9% by enoximone, 2 mg/kg. This finding accounts for the larger (although not significant) increase in left ventricular stroke work index observed with dobutamine compared with enoximone. Ventricular filling pressures and vascular resistances were significantly decreased by all 3 drugs (p = 0.001). All 3 drugs improved cardiac pump function when assessed by the increase in stroke index to a similar extent; however, enoximone (2 mg/kg) resulted in less hypotension than nitroprusside (mean arterial pressure -9% vs -22%, p = 0.0001) and in less tachycardia than dobutamine 10 micrograms/kg/min. Those differences in mode of action account for the variations observed in the heart rate-blood pressure product (dobutamine 10 micrograms/kg/min, +18%, enoximone 2 mg/kg, -5%, p = 0.003). Enoximone thus appears to be of great value in the management of severe congestive heart failure by its combination of vasodilatory and inotropic properties. Enoximone (2 mg/kg) provides a clinically significant increase in cardiac index, a clear reduction of ventricular filling pressures, a moderate reduction of mean arterial pressure and only minor changes of heart rate and of rate pressure product.     

Metabolic and cardiovascular benefits deriving from beta-adrenergic blockade in chronic congestive heart failure.

Ten patients with congestive heart failure were given metoprolol (50 mg/day) or placebo during a double-blind, crossover, randomized study. After a run-in period of 4 weeks, metoprolol and placebo were administered over a period of 3 months, which was separated by a washout period of 4 weeks. At the end of the run-in, metoprolol, and placebo periods, all patients underwent metabolic (oral glucose tolerance and hyperinsulinemic glucose clamp tests) and noninvasive cardiologic (New York Heart Association classification, bimodal echocardiographic left ventricular end-diastolic determination, maximal oxygen consumption, left ventricular radionuclide ejection fraction) tests. Our results show that beta-adrenergic blockade significantly enhances insulin-mediated suppression of hepatic glucose output (p less than 0.005) and increase in glucose uptake (p less than 0.01) with a concurrent improvement in New York Heart Association functional class (p less than 0.05) and the multistage exercise treadmill test score (p less than 0.05). After administration of metoprolol all changes in glucose turnover parameters were found to correlate with the decrease in basal plasma free fatty acid levels. In conclusion, our findings confirm the beneficial cardiologic effects of beta-adrenergic blockade in congestive heart failure and demonstrate that metoprolol is also useful for reversing the metabolic damage caused by exaggerated plasma norepinephrine levels.