OPC-8212 in the treatment of congestive heart failure: Results of a pilot study

Summary To characterize the effects of OPC-8212, a quinolone inotropic agent, in patients with heart failure, we utilized invesive homodynamics, exercise testing, 24-hour ambulatory electrocardiograms, and two patient self-assessment questionnaires, before and after 1 month of treatment with OPC-8212, in 17 patients with moderate to severe congestive heart failure. There were no significant changes from baseline in heart rate (83±8 beats/min), mean arterial pressure (70±15 mmHg), pulmonary wedge pressure (18±7 mmHg), or cardiac index (2.3±0.4 L/min/m²) following treatment with OPC-8212. Both exercise duration (5.3±1.6 min) and peak oxygen consumption (12.0±2.9 mL/kg/min) were unchanged by OPC-8212. Two independent patient self-assessment scores, the Sickness Impact Profile and the Minnesota Living with Heart Failure Questionnaire, showed improvements from 6.8 to 5.4 and 49 to 38, respectively (both p<.05), suggesting that the patients reported an improvement in daily functioning. The median ventricular premature contraction count and frequency were reduced from 1,118 beats to 243 beats (p<0.05) and 11/1,000 beats to 2,4/1,000 beats (0.05<p<0.10), respectively. Two patients developed agranulocytosis during longer-term treatment following this 1-month study. These data demonstrate that OPC-8212 did not have significant effects on hemodynamics or exercise tolerance. However, the improvement in patient self-assessment scores and the trend for improvement in ventricular arrhythmia profiles suggest that OPC-8212 may have some benefit for patients with congestive heart failure, but additional placebo-controlled, double-blind studies are necessary.     

Oral OPC-8212 for the treatment of congestive heart failure: Hemodynamic improvement and increased exercise capacity

Summary The chronic effects of the oral administration of OPC-8212 (3,4-DIHYDRO-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone) on resting hemodynamics and exercise capacity were assessed in 15 patients with congestive heart failure (NYHA II–IV). Doses of 30 or 60 mg per day were given per os over 3.0 weeks on average (range 2–6 weeks). Multigated radionuclide ventriculography and multistage exercise testing were performed before and during OPC-8212 therapy to assess the changes in left ventricular volume and exercise capacity respectively. Systolic blood pressure showed a slight increase (from 123±3 to 129±4 mmHg) during OPC-8212 therapy, while heart rate was unchanged (69±3 vs 67±3 beats/min). The left ventricular end-diastolic volume index decreased from 127±9 to 107±7 ml/m², and ejection fraction and the P/V index (the ratio of peak systolic pressure to left ventricular end-systolic volume index) increased during OPC-8212 therapy (from 27%±3% to 30%±4% and from 1.5±0.2 to 2.0±0.3 mmHg/ml/m² respectively). NYHA functional class was improved in 9 of 15 patients, and the average peak work load achieved during exercise testing increased from 27±6 to 47±7 W. No significant adverse effect was observed in any patient. These results indicate that OPC-8212 enhances the inotropic state and, hence, reduces heart size with no change in heart rate. Moreover, it increases exercise capacity. Thus, OPC-8212 is an inotropic agent with promise for application in the long-term treatment of congestive heart failure.     

Acute hemodynamic effects of a new inotropic agent,OPC-8212, on severe congestive heart failure

Summary The hemodynamic and clinical effects of OPC-8212, a newly synthesized, orally effective inotropic agent, were assessed for the first time in ten patients with severe congestive heart failure by means of right heart catheterization with a Swan-Ganz catheter. Cardiac output was determined by the thermodilution technique. Patients received a single oral dose of 6 mg/kg. To determine the magnitude and time-course of the effects of OPC-8212, measurements were made during an observation period before and 2, 4, 8, and 12 h after administration. Blood was also taken at these times for measurement of the concentration of plasma OPC-8212. No large meals were allowed during the first 4 h. After the single oral dose of OPC-8212, plasma concentrations increased rapidly, reaching an effective level after 8 h and peaking at 12 h. Hemodynamic performance improved as the mean OPC-8212 plasma level increased, with the maximum effect being observed between 8 and 12 h after acute administration of the drug. At 8 h, the cardiac index was increased from the baseline value of 2.4±0.2 (SEM) to 2.8±0.3 l/min/m² (P<0.01). The stroke work index rose from 26.2±5.1 to 31.7±60 g · m/m². The excessive pulmonary artery diastolic pressure fell from 22±2 to 17±3 mmHg at 8 h (P<0.001) and to 16±2 mmHg (P<0.001) at 12 h. The incidence of ventricular premature beats was not increased and no other side effects were observed. These changes were not associated with significant changes in heart rate or systolic blood pressure. Thus, this drug appears to be very promising for the long-term treatment of congestive heart failure.     

Usefulness of OPC-8212, a quinolinone derivative, for chronic congestive heart failure in patients with ischemic heart disease or idiopathic dilated cardiomyopathy

To evaluate the safety and efficacy of the inotropic agent OPC-8212 in patients with chronic congestive heart failure, 76 patients with impaired cardiac function and diminished exercise tolerance were studied. They were randomized to 12 weeks of double-blind therapy with either 60 mg/day of OPC-8212 or placebo. The study drug was added to their baseline medical regimen. The primary study outcome was the combined outcome of the time to either mortality (of all cause) or substantial worsening of heart failure (major morbidity), whichever occurred first. Treatment with OPC-8212 significantly (p less than 0.01) decreased the combination of major morbidity/mortality over 12 weeks of therapy. Quality of life, assessed by the Sickness Impact Profile questionnaire, was significantly improved in patients receiving OPC-8212 (p less than 0.01). Furthermore, ventricular premature contractions as assessed by 24-hour Holter monitoring were not increased with OPC-8212 treatment. Although patients treated with OPC-8212 were able to reach a significantly higher peak oxygen uptake and exercise longer during symptom-limited exercise, when data were analyzed as percent change from baseline, the absolute increases were small. These results suggest that OPC-8212 is beneficial in treating patients with congestive heart failure and that further evaluation of this new inotropic agent is warranted.     

Sustained inotropic effects of a new cardiotonic agent. OPC-8212 in patients with chronic heart failure

OPC-8212, a newly synthesized noncatecholamine, nonglycosidic, orally effective inotropic agent, has been shown to exert a potent cardiotonic action in acute administration to patients with heart failure. However, its long-term effect has not yet been established. Eight patients with dilated cardiomyopathy (New York Heart Association functional class II-III) were given a single dose of 60 mg of OPC-8212 daily for 4 to 8 weeks. OPC-8212 produced symptomatic improvement in four patients. Though there were no detectable changes in arterial pressure and left ventricular end-diastolic dimension, heart rate and end-systolic dimension significantly decreased after administration of OPC-8212. Baseline fractional shortening rose significantly and depression of shortening in response to acute pressor stress (afterload mismatch) was corrected after OPC-8212. The end-systolic pressure-dimension relation was shifted to the left with a steeper slope. These findings indicate that the inotropic state was substantially enhanced by the drug. No adverse effects were observed in any patient. Thus, the drug appears to hold promise for the chronic treatment of patients with moderate congestive heart failure who are essentially asymptomatic at rest, but develop severe impairment of cardiac function in a stressed state.     

Acute and chronic effects of a diuretic monotherapy with piretanide in congestive heart failure—A placebo-controlled trial

Summary To evaluate the acute and chronic effects of diuretic monotherapy with 3 mg piretanide bid, 46 patients (pts) with congestive heart failure (NYHA II-III) secondary to coronary artery disease were studied. Within 3 weeks of therapy, the patients lost 1.6 kg body weight. Forty-four patients reported a subjective feeling of improvement. Echocardiographically, a highly significant (p<0.001) reduction of diastolic and systolic diameters was found, as well as an increase of fraction shortening. Chest x-ray indicated a reduction of heart volume from 1012±263 ml to 936±233 ml (p<0.001). The serum potassium level remained unchanged. A subgroup of 26 pts underwent invasive hemodynamic examinations. IV injection of 6 mg piretanide resulted in an acute reduction of pulmonary wedge pressure (pc) from 20.2±5.3 mmHg to 11.9±5.0 mmHg (p<0.001); simultaneously a slight decrease of cardiac index from 3.2±0.6 l/min/m² to 3.0±0.4 l/min/m² was observed. Invasive control after 3 weeks of oral therapy showed no decline of the piretanide effect. The exercise tolerance increased clearly from 135±161 Wmin to 249±268 Wmin (p<0.05). A control group of further 14 pts was treated with placebo only and did not show any significant changes of pc (20.0±6.4 mmHg vs. 22.8±19.2 mmHg), exercise tolerance, or other clinical parameters. Thus, the diuretic monotherapy of congestive heart failure with piretanide is highly effective and shows a significant improvement in all clinical and hemodynamic parameters in the absence of any remarkable side effects.     

Evaluation of a new inotropic agent, OPC-8212, in patients with dilated cardiomyopathy and heart failure

OPC-8212 is a new positive inotrope with a unique mechanism of action. To assess its clinical utility we administered 60 mg/day for 30 days to 10 patients with overt congestive heart failure, who had substantial limitations in exercise performance despite treatment with conventional therapy. Patients were evaluated by simultaneous respiratory gas exchange and radionuclide ventriculography measurements during graded maximal exercise testing. Improvement was demonstrated in both peak oxygen uptake and radionuclide-determined cardiac index after 30 days of treatment with OPC-8212. These changes were not associated with alterations in heart rate at rest or during peak exercise. Furthermore OPC-8212 significantly decreased ventricular ectopy in our patients. However, two patients had possible hematologic toxicity with prolonged use. The results of the present phase II study suggest that a larger randomized double-blind placebo study to evaluate the safety and clinical efficacy of this drug is warranted.     

Enalapril in patients with chronic heart failure: a placebo-controlled, randomized, double-blind study

A number of studies have shown short-term hemodynamic and symptomatic improvement in patients with congestive heart failure treated with angiotensin converting-enzyme inhibitors. The long-term efficacy of the oral long-acting converting-enzyme inhibitor enalapril remains to be established in controlled studies. We evaluated this drug in 36 patients with New York Heart Association functional class II to III heart failure who were clinically stable on digoxin and diuretic therapy. After baseline assessment of symptoms, exercise capacity, and results of echocardiographic examination and right heart catheterization, patients were randomly assigned to treatment with 5 mg enalapril twice daily (n = 18) or placebo (n = 18) in a double-blind fashion. The two groups had similar clinical, echocardiographic, and hemodynamic characteristics before treatment. After 3 months of treatment, the enalapril group showed a significant improvement as judged by subjective patient impression, functional class, and exercise duration (9.3 +/- 5.7 vs 17.6 +/- 5.6 min; p less than .001). Diuretic dosage was reduced in six patients and increased in one patient, one patient had died and another had been withdrawn from the study. In the placebo group there was no significant change with respect to patient impression, functional class, or exercise duration; diuretic dosage was increased in seven patients and four patients had died. Echocardiographic left ventricular dimensions were significantly reduced and left ventricular shortening fraction significantly increased in the enalapril group but were unchanged in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Safety and efficacy of angiotensin-converting enzyme inhibitors in symptomatic severe aortic stenosis: Symptomatic Cardiac Obstruction-Pilot Study of Enalapril in Aortic Stenosis (SCOPE-AS)

Background

Animal models have demonstrated a benefit of angiotensin-converting enzyme inhibitors (ACEI) in experimental aortic stenosis (AS), and intravenous nitroprusside has shown hemodynamic improvements in AS with left ventricular (LV) dysfunction. Although routinely used in most heart failure situations, ACEI are avoided in AS because of the risk of hypotension. We aimed to determine the clinical tolerance and efficacy of the ACEI enalapril in the setting of symptomatic severe AS.

Methods

Patients with symptomatic severe AS were enrolled in a randomized, double-blinded, controlled trial to enalapril or placebo arms after initial stabilization. Standard antifailure medications were continued. Enalapril was started at 2.5 mg bid and increased to 10 mg bid. The primary end points were development of hypotension and improvements in Borg dyspnea index and 6-minute walk distance at 1 month. Secondary end points were minor ACEI intolerance, cough, presyncope, improvement in New York Heart Association class, and echocardiographic parameters.

Results

Fifty-six patients were enrolled (37 in the enalapril arm and 19 in the placebo arm). Enalapril was tolerated without hypotension or syncope when LV systolic function was preserved. Three of 5 patients with LV dysfunction and congestive heart failure had hypotension and were withdrawn. Patients who tolerated enalapril (n = 34) demonstrated significant improvement in NYHA class, Borg index (5.4 ± 1.2 vs 5.6 ± 1.7, P = .03), and 6-minute walk distance (402 ± 150 vs 376 ± 174, P = .003) compared with control subjects. Within the enalapril group, patients with associated regurgitant lesions improved the most.

Conclusions

ACEI are well tolerated in symptomatic patients with severe AS. Patients with congestive heart failure with LV dysfunction and low normal blood pressure are prone to have hypotension. Enalapril significantly improves effort tolerance and reduces dyspnea in symptomatic AS.     

Effects of acute and chronic ibopamine administration on resting and exercise hemodynamics, plasma catecholamines and functional capacity of patients with chronic congestive heart failure.

The effects of acute and chronic ibopamine treatment on resting and exercise hemodynamics, exercise capacity and plasma catecholamines were evaluated in 25 patients with chronic heart failure, using a double-blind, parallel, placebo-controlled design. During 2 months of therapy with either placebo or ibopamine (100 mg, 3 times daily), 1 patient was withdrawn from each group for worsening heart failure, New York Heart Association functional class improved in 4 patients on ibopamine and in 1 on placebo, and furosemide dose could be decreased in 4 on ibopamine and in no patient on placebo. Acute ibopamine administration induced, in comparison with placebo, a significant increase of cardiac and stroke volume indexes both at rest and peak exercise, with a reduction of systemic vascular resistance. These hemodynamic changes were maintained also after chronic therapy, with no evidence of tolerance development. Exercise capacity (evaluated as peak exercise duration and oxygen consumption, and ventilatory threshold) did not significantly change. Resting and peak exercise norepinephrine plasma levels were significantly reduced after both acute and chronic ibopamine administration. Thus, the hemodynamic and neurohumoral effects of ibopamine make this drug potentially useful for the chronic treatment of congestive heart failure.     

Acute hemodynamic effects of a new inotropic agent (OPC-8212) in patients with congestive heart failure

The acute effects of OPC-8212, a newly synthesized orally effective inotropic agent, were assessed clinically. Eleven patients with moderate congestive heart failure received a single mean dose of 6.5 mg/kg body weight of the drug. Eight hours after administration, the cardiac and stroke work indexes increased by 11% (p less than 0.01) and 20% (p less than 0.005), respectively, with concomitant decreases in the diastolic pulmonary artery (25%, p less than 0.005) and right atrial pressures (33%, p less than 0.01). There were no significant changes in blood pressure or heart rate. The contractile state of the left ventricle was also assessed by the shift of the Starling curve. To construct the function curve, lower body negative pressure was used to regulate the venous return to the heart. An inotropic effect of the agent was confirmed by the shift of this function curve upward and to the left, even when an augmentation of the cardiac output was masked by the marked reduction in preload. The hemodynamic and clinical effects of OPC-8212 were encouraging and the drug appears to be promising for the treatment of congestive heart failure.     

Clinical effects of long-term administration of pimobendan in patients with moderate congestive heart failure

Summary The long-term efficacy of the positive inotropic and vasodilator drug, pimobendan, was assessed in 21 patients suffering from symptomatic heart failure. Patients were randomized to 16 weeks of double-blind therapy with either 2.5 or 5.0mg/day of pimobendan (n = 10), or a matching placebo (n = 11). Patients were blinded on the study drug if their clinical status had not substantially worsened during the study. Of the placebo-treated patients, 5 patients were withdrawn from the study because of a deterioration of their heart failure, while none of the active treated group was withdrawn because of increased symptoms. Quality of life, assessed by the specific activity scale derived from the metabolic costs of individual physical activity, was 3.45 ± 0.90 (SD) mets in the baseline state and increased significantly after week 16, averaging 5.07 ± 1.40 and 4.67 ± 1.47 mets at weeks 16 and 24, respectively. In the placebo-treated group, the specific activity scale was 3.27 ± 1.21 mets at the baseline and remained unchanged throughout the study period. Patients treated with pimobendan were able to significantly increase their exercise duration. The accompanying increase in peak oxygen uptake was statistically insignificant, due to the limited number of patients enrolled in the study. These results suggest that in contrast to the recent pessimistic view of the long-term efficacy of cardiotonic drugs, pimobendan is beneficial in treating patients with congestive heart failure and may favorably modify their prognosis. Further largescale evaluation of this agent is warranted.     

A multicenter study of a new inotropic agent,piperanometozine (opc-8212) in congestive heart failure: Clinical improvement during short-term treatment

Summary Piperanometozine (OPC-8212) is a new, orally effective inotropic agent. To evaluate the efficacy of this agent on systemic hemodynamics and clinical symptoms in patients with congestive heart failure, a multicenter study was performed. Thirty four patients with New York Heart Association (NYHA) functional classes II to IV and initially treated with digitalis were enrolled from ten centers. After a washout period of one or two weeks (placebo period), digitalis was replaced by piperanometozine (30 or 60 mg/day) for four weeks, while other drugs were continued. Clinical symptoms, routine physical findings, electrocardiogram, chest roentgenogram, echocardiogram, exercise tolerance time, and routine laboratory data were obtained in 34 patients. Four patients were withdrawn from the study before completion. After the withdrawal of digitalis, heart rate was increased and ejection fraction was decreased. Exercise tolerance time was increased while other parameters were unchanged. At the end of the treatment period with piperanometozine, ejection fraction significantly (p<0.05) increased with a decrease in LV end-systolic volume (p<0.05), whereas heart rate and blood pressure remained unchanged. Systolic blood pressure/LV end-systolic volume (P/V index) tended to decrease after the withdrawal of digitalis and increase during piperanometozine therapy. Exercise tolerance time was further increased (p<0.01) and NYHA functional class was improved in 11 patients, whereas it worsened in only one patient. No major adverse effects were observed. These results indicate that a short-term therapy of oral piperanometozine restored the depressed cardiac performance of the heart and improved clinical symptoms in patients with congestive heart failure. Thus, this promising agent deserves further clinical study in long-term trials.     

The use of digitalis for the treatment of congestive heart failure: A tale of its decline and resurrection

Summary The decline of the use of digitalis for the treatment of congestive heart failure was due to the introduction of oral diuretic therapy, the recognition of the frequency of digitalis induced arrhythmias and the uncontrolled observations that digitalis could frequently be withdrawn from patients with a history of heart failure without recurrence of heart failure. Subsequently, it has been well documented that digitalis has chronic beneficial hemodynamic effects in patients with chronic congestive heart failure. Moreover, digitalis has been shown to improve hemodynamics when added to other drugs including diuretics, ACE inhibitors and vasodilators. It is concluded that digitalis is a mild inotropic agent that is still a primary drug for the treatment of mild to moderate acute or chronic left ventricular failure.     

The acute effects of transvenous biventricular pacing in a patient with congestive heart failure

The management of congestive heart failure remains an issue of great interest. Encouraging data emerged over the last 2 years supporting the use of multisite pacing in patients with severe congestive heart failure and intraventricular conduction delay. We present a case of acute biventricular pacing in a 81-year old man with dilated cardiomyopathy and symptomatic congestive heart failure. This novel form of pacemaker treatment resulted in a rapid hemodynamic and clinical improvement.     

Acute and chronic oral magnesium supplementation: effects on endothelial function, exercise capacity, and quality of life in patients with symptomatic heart failure

Endothelial dysfunction is an important pathophysiologic mechanism in the progression of heart failure. The objective of the present study was to determine the effects of acute and chronic oral magnesium supplementation on endothelial function in patients with symptomatic heart failure. Twenty-two symptomatic chronic heart failure patients were randomized to receive 800 mg oral magnesium oxide daily or placebo for 3 months. Data collected included large and small arterial elasticity/compliance, hemodynamic parameters, exercise capacity, and quality-of-life score at baseline, 1 week, and 3 months. Patients who received magnesium had improved small arterial compliance at 3 months from baseline compared with placebo. This study suggests that chronic supplementation with oral magnesium is well tolerated and could improve endothelial function in symptomatic heart failure patients.     

Quinapril in chronic heart failure

Angiotensin converting enzyme inhibitors are now firmly established in the treatment of patients with chronic heart failure (CHF). Their beneficial acute and chronic hemodynamic effects are not associated with reflex tachycardia or drug tolerance. Angiotensin converting enzyme inhibitors produce symptomatic improvement and improve exercise capacity in all grades of heart failure. They also improve the prognosis of patients with severe heart failure. Quinapril is a recently introduced, nonsulfhydryl ACE inhibitor, whose intermediate half-life makes it well-suited for the treatment of patients with CHF. The acute and chronic hemodynamic effects of quinapril are similar to those of other ACE inhibitors. In a large, multicenter, randomized, placebo-controlled study of 225 patients with mild to moderate CHF, 10 to 40 mg/day quinapril significantly improved clinical status and exercise capacity in a dose-related manner. The incidence of side effects did not differ significantly from that of placebo. The initial studies with quinapril are promising and warrant further clinical investigation of this compound.     

Intravenous dopexamine in the treatment of acute congestive heart failure: Results of a multicenter,double-blind,placebo-controlled withdrawal study

Summary Acute hemodynamic effects of intravenous infusion of dopexamine were evaluated by a placebo-controlled withdrawal study in patients with acute congestive heart failure. Twenty patients were enrolled at 10 centers in Japan. All patients had a pulmonary capillary or diastolic pressure of 15 mmHg or greater and a cardiac index of 2.5 l/min/m² or less.Phase I: Intravenous dopexamine was introduced in a single-blind, uncontrolled fashion at the rate of 0.5 µg/kg/min and was titrated up to achieve a 30% or more increase in the cardiac index. Two patients withdrew from the study due to sinus tachycardia and ventricular ectopy or exacerbation of heart failure.Phase II: The remaining 18 responders who were free of limiting side effects were randomized in double-blind fashion to continue dopexamine or to switch to placebo for an additional 60 minutes. At the end of phase II, the hemodynamic improvement obtained in phase I of the study disappeared completely after substitution of placebo but was maintained in dopexamine-treated patients. Our findings suggest that dopexamine, when given in appropriate doses to selected patients, shows balanced vasodilator action suitable for the treatment of acute congestive heart failure.See Appendix 1 for complete list of participating centers and principal investigators     

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.     

Chronic therapy for congestive heart failure with benazepril HCl, a new angiotensin converting enzyme inhibitor

Benazepril HCl is an orally effective angiotensin converting enzyme (ACE) inhibitor previously shown to have significant acute hemodynamic benefits in patients with congestive heart failure. In this study, 21 patients with New York Heart Association Class III or IV congestive heart failure were treated with 2 to 15 mg of benazepril HCl as a single daily oral dose for 28 days to determine the clinical and hemodynamic value of chronic therapy. Each patient underwent clinical evaluation during the 28-day period, as well as invasive hemodynamic studies on the first two and last two days of the trial. Plasma ACE activity and aldosterone levels fell significantly and renin levels rose after therapy. Benazepril HCl produced significant (p less than 0.01) reductions in arterial pressure and systemic vascular resistance, with corresponding increases in cardiac output and decreases in pulmonary artery wedge pressure. Responses after 28 days of therapy were equivalent to those after the initial doses. Clinical effects included reduced rest, exertional and paroxysmal nocturnal dyspnea, as well as reduced peripheral edema. Only one patient developed symptomatic orthostatic hypotension. Thus, benazepril HCl, given once daily, is an effective and well tolerated oral agent for the chronic treatment of advanced congestive heart failure.