Controlled trial of enalapril in congestive cardiac failure.

Twenty five patients with chronic congestive cardiac failure had enalapril (n = 13) or placebo (n = 12) added to their existing regimen of digoxin and frusemide in a randomised double blind trial. Four hours after the first 5 mg dose, the enalapril group showed significant falls in blood pressure, heart rate, and concentrations of plasma angiotensin II, angiotensin converting enzyme, and noradrenaline. During the 12 week trial heart failure became worse in one enalapril treated patient (8%) and in seven placebo treated patients (58%). There were no significant changes in cardiac ejection fraction or exercise duration in either group. Plasma noradrenaline response to graded exercise and maximum exercise rate-pressure product were significantly reduced after four and 12 weeks of active treatment but unchanged with placebo treatment. There was a sustained increase in plasma potassium and a slight rise in plasma creatinine in the enalapril group. Plasma concentrations of the active drug, enalaprilate, were dose related and log enalaprilate correlated significantly with percentage of plasma angiotensin converting enzyme activity (r = -0.66). Enalapril was well tolerated and produced no adverse effects. The drug appears to be superior to placebo and offers considerable promise for the treatment of this condition.     

Effects of enalapril in heart failure: a double blind study of effects on exercise performance,renal function,hormones, and metabolic state.

Several studies have shown symptomatic and haemodynamic improvement after the introduction of angiotensin converting enzyme inhibitors in patients with heart failure treated with diuretics. The concomitant long term effects of the new orally effective long acting angiotensin converting enzyme inhibitor, enalapril, on symptoms, exercise performance, cardiac function, arrhythmias, hormones, electrolytes, body composition, and renal function have been further assessed in a placebo controlled double blind cross over trial with treatment periods of eight weeks. Twenty patients with New York Heart Association functional class II to IV heart failure who were clinically stable on digoxin and diuretic therapy were studied. Apart from the introduction of enalapril, regular treatment was not changed over the study period; no order or period effects were noted. Enalapril treatment significantly improved functional class, symptom score for breathlessness, and exercise tolerance. Systolic blood pressure was significantly lower on enalapril treatment. Echocardiographic assessment indicated a reduction in left ventricular dimensions and an improvement in systolic time intervals. In response to enalapril, the plasma concentration of angiotensin II was reduced and that of active renin rose; plasma concentrations of aldosterone, vasopressin, and noradrenaline fell. There were significant increases in serum potassium and serum magnesium on enalapril. Glomerular filtration rate measured both by isotopic techniques and by creatinine clearance declined on enalapril while serum urea and creatinine rose and effective renal plasma flow increased. Body weight and total body sodium were unchanged indicating that there was no overall diuresis. There was a statistically insignificant rise in total body potassium, though the increase was related directly to pretreatment plasma renin (r = 0.5). On enalapril the improvement in symptoms, exercise performance, fall in plasma noradrenaline, and rise in serum potassium coincided with a decline in the frequency of ventricular extrasystoles recorded during ambulatory monitoring. Adverse effects were few. In patients with heart failure, enalapril had a beneficial effect on symptoms and functional capacity. The decline in glomerular filtration rate on enalapril may not be beneficial in early heart failure.     

Effects of enalapril in heart failure: a double blind study of effects on exercise performance, renal function, hormones, and metabolic state

Several studies have shown symptomatic and haemodynamic improvement after the introduction of angiotensin converting enzyme inhibitors in patients with heart failure treated with diuretics. The concomitant long term effects of the new orally effective long acting angiotensin converting enzyme inhibitor, enalapril, on symptoms, exercise performance, cardiac function, arrhythmias, hormones, electrolytes, body composition, and renal function have been further assessed in a placebo controlled double blind cross over trial with treatment periods of eight weeks. Twenty patients with New York Heart Association functional class II to IV heart failure who were clinically stable on digoxin and diuretic therapy were studied. Apart from the introduction of enalapril, regular treatment was not changed over the study period; no order or period effects were noted. Enalapril treatment significantly improved functional class, symptom score for breathlessness, and exercise tolerance. Systolic blood pressure was significantly lower on enalapril treatment. Echocardiographic assessment indicated a reduction in left ventricular dimensions and an improvement in systolic time intervals. In response to enalapril, the plasma concentration of angiotensin II was reduced and that of active renin rose; plasma concentrations of aldosterone, vasopressin, and noradrenaline fell. There were significant increases in serum potassium and serum magnesium on enalapril. Glomerular filtration rate measured both by isotopic techniques and by creatinine clearance declined on enalapril while serum urea and creatinine rose and effective renal plasma flow increased. Body weight and total body sodium were unchanged indicating that there was no overall diuresis. There was a statistically insignificant rise in total body potassium, though the increase was related directly to pretreatment plasma renin (r = 0.5). On enalapril the improvement in symptoms, exercise performance, fall in plasma noradrenaline, and rise in serum potassium coincided with a decline in the frequency of ventricular extrasystoles recorded during ambulatory monitoring. Adverse effects were few. In patients with heart failure, enalapril had a beneficial effect on symptoms and functional capacity. The decline in glomerular filtration rate on enalapril may not be beneficial in early heart failure.     

Effects of enalapril on myocardial noradrenaline overflow during exercise in patients with chronic heart failure

The effects of the angiotensin converting enzyme inhibitor enalapril on myocardial sympathetic tone, as represented by noradrenaline overflow, were studied in 14 men with congestive heart failure (mean ejection fraction 20%) in a double blind crossover comparison with placebo. Arterial and coronary sinus catecholamine concentrations and oxygen content, and coronary sinus blood flow, were measured at rest and during peak symptom limited upright exercise on a bicycle ergometer. There were no significant changes four hours after the first dose of enalapril, but after six weeks of treatment (10-20 mg/day) enalapril reduced myocardial overflow of noradrenaline at peak exercise. The external workload (exercise duration) increased from baseline values after both placebo and enalapril, and there was no difference between placebo and enalapril at six weeks. Heart work, however, was lower after enalapril: stroke work index was reduced at rest and the double product was lower at peak exercise. The reduction in maximal myocardial oxygen consumption after enalapril did not reach statistical significance. Coronary sinus adrenaline concentrations after enalapril and after placebo were not significantly different. The long term reduction of myocardial sympathetic activity on exercise may represent a significant benefit from angiotensin converting enzyme inhibition in heart failure and may reflect a reduced cardiac workload.     

Effects of enalapril on myocardial noradrenaline overflow during exercise in patients with chronic heart failure.

The effects of the angiotensin converting enzyme inhibitor enalapril on myocardial sympathetic tone, as represented by noradrenaline overflow, were studied in 14 men with congestive heart failure (mean ejection fraction 20%) in a double blind crossover comparison with placebo. Arterial and coronary sinus catecholamine concentrations and oxygen content, and coronary sinus blood flow, were measured at rest and during peak symptom limited upright exercise on a bicycle ergometer. There were no significant changes four hours after the first dose of enalapril, but after six weeks of treatment (10-20 mg/day) enalapril reduced myocardial overflow of noradrenaline at peak exercise. The external workload (exercise duration) increased from baseline values after both placebo and enalapril, and there was no difference between placebo and enalapril at six weeks. Heart work, however, was lower after enalapril: stroke work index was reduced at rest and the double product was lower at peak exercise. The reduction in maximal myocardial oxygen consumption after enalapril did not reach statistical significance. Coronary sinus adrenaline concentrations after enalapril and after placebo were not significantly different. The long term reduction of myocardial sympathetic activity on exercise may represent a significant benefit from angiotensin converting enzyme inhibition in heart failure and may reflect a reduced cardiac workload.     

The variable effects of angiotensin converting enzyme inhibition on myocardial ischaemia in chronic stable angina.

The effect of angiotensin converting enzyme inhibition on myocardial ischaemia was studied in 12 normotensive patients with chronic stable angina and exercise induced ST segment depression. The study was randomised, double blind, placebo controlled, and crossover with treatment periods of two weeks. Enalapril was used to inhibit angiotensin converting enzyme. Assessment was by angina diaries and maximum symptom limited treadmill exercise tests. The results for the whole group showed a significant reduction in systolic blood pressure at rest and at peak exercise. Mean total exercise duration was 466 s (95% confidence interval 406 to 525) when the patients were taking placebo and 509 s (436 to 583) when they were taking enalapril. Four patients prolonged their total exercise time (mean 450 to mean 591 s) by more than 20%. Two patients, however, developed ischaemia earlier on exercise and reduced their total exercise duration (mean 490 to mean 390 s). Although angiotensin converting enzyme inhibition tended to reduce myocardial ischaemia in the group as a whole, some patients improved while others deteriorated. Thus the effects of enalapril are variable and this may have important implications when enalapril is used to treat heart failure in patients with underlying severe ischaemic heart disease.     

The variable effects of angiotensin converting enzyme inhibition on myocardial ischaemia in chronic stable angina

The effect of angiotensin converting enzyme inhibition on myocardial ischaemia was studied in 12 normotensive patients with chronic stable angina and exercise induced ST segment depression. The study was randomised, double blind, placebo controlled, and crossover with treatment periods of two weeks. Enalapril was used to inhibit angiotensin converting enzyme. Assessment was by angina diaries and maximum symptom limited treadmill exercise tests. The results for the whole group showed a significant reduction in systolic blood pressure at rest and at peak exercise. Mean total exercise duration was 466 s (95% confidence interval 406 to 525) when the patients were taking placebo and 509 s (436 to 583) when they were taking enalapril. Four patients prolonged their total exercise time (mean 450 to mean 591 s) by more than 20%. Two patients, however, developed ischaemia earlier on exercise and reduced their total exercise duration (mean 490 to mean 390 s). Although angiotensin converting enzyme inhibition tended to reduce myocardial ischaemia in the group as a whole, some patients improved while others deteriorated. Thus the effects of enalapril are variable and this may have important implications when enalapril is used to treat heart failure in patients with underlying severe ischaemic heart disease.     

Haemodynamic, hormonal, and electrolyte effects of enalapril in heart failure.

Enalapril, the new converting enzyme inhibitor, was administered to eight patients with heart failure (NYHA Functional Class II to IV) during standardised and intensive haemodynamic, hormone, and electrolyte monitoring. The first dose (5 mg) of enalapril induced a fall in plasma angiotensin II and noradrenaline levels, and prolonged decrements in systemic vascular resistance, arterial pressure, heart rate, and right heart pressures. Maximum haemodynamic effects were evident four to eight hours after the first dose, with return to baseline by 24 hours. Plasma angiotensin II levels, however, were still suppressed at 24 hours. The magnitude of haemodynamic response was related closely to baseline (pre-enalapril) activity of the renin-angiotensin system and the sympathetic system. Enalapril treatment over three days induced a positive cumulative balance of sodium and potassium, and a small increase in plasma potassium. Urine aldosterone excretion decreased in a stepwise fashion. Continued enalapril administration for four to eight weeks resulted in improved clinical status (NYHA Functional Class) and exercise tolerance in patients who initially were most severely incapacitated, but little change was observed in healthier subjects. We conclude that in heart failure, enalapril is a long acting converting enzyme inhibitor with clear cut beneficial haemodynamic effects in the short term. Long term controlled studies of enalapril in heart failure are warranted.     

Neurohormonal activation in patients with mild or moderately severe congestive heart failure and effects of ramipril. The Ramipril Trial Study Group.

OBJECTIVES--To describe neurohormonal activation in patients with mild or moderate heart failure and how it may be modified by treatment with ramipril. SETTING--Cardiology departments at 24 hospitals in Denmark, Finland, Norway, and Sweden. PATIENTS--223 patients with mild or moderately severe congestive heart failure who were taking diuretics with or without digitalis. DESIGN--Randomised, double bind, multicentre, placebo controlled comparison of ramipril and placebo. Venous blood samples were drawn at rest, before blind treatment, and after 12 weeks of treatment with the study drug. A probability prediction score for mortality derived by stepwise linear discriminant from neurohormone data in the first cooperative north Scandinavian enalapril survival study (CONSENSUS I) was used to assess combined activity of the different neurohormonal systems. RESULTS--Plasma concentrations of atrial natriuretic peptide were raised at baseline but angiotensin II, aldosterone, and noradrenaline concentrations were within normal limits. There was, however, a wide interindividual variation. Plasma noradrenaline concentration and prediction score were higher among patients with class III congestive heart failure according to the New York Heart Association's classification than among patients with class II congestive heart failure (P < 0.05). There was a modest but significant inverse correlation between exercise duration at baseline and plasma noradrenaline concentration (r = -0.21, P = 0.0023), aldosterone concentration (r = -0.14, P = 0.04), and prediction score (r = -0.24, P = 0.0004). Prediction score at baseline was significantly higher among those who died (n = 10) than among survivors (P = 0.03). Angiotensin converting enzyme activity was suppressed and plasma concentrations of aldosterone and atrial natriuretic peptide were reduced after 12 weeks of treatment with ramipril compared with placebo. In patients with the most pronounced neurohormonal activation at baseline (highest third of noradrenaline concentration or prediction score), noradrenaline concentration and prediction score were significantly lower after 12 weeks of taking ramipril compared with placebo. Patients with a prediction score in the highest third at baseline had a higher heart rate than to those in the lowest third (P = 0.003). CONCLUSIONS--Neurohormonal activation is associated with the degree of symptoms and the severity of disease in mild or moderately severe congestive heart failure. Treatment with ramipril attenuates neurohormonal activation. This effect is most pronounced among patients with the highest circulating concentrations of neurohormones before the start of treatment.     

Effect of beta 1 blockade with atenolol on progression of heart failure in patients pretreated with high-dose enalapril

BACKGROUND: The survival benefit of beta-blocker treatment in patients with heart failure has been established in recent trials. Yet, the impact of beta-blockers added on high dose angiotensin converting enzyme inhibitors has not been reported. AIMS: To investigate the effect of atenolol, a hydrophilic, selective beta1-adrenergic antagonist, added on enalapril 40 mg/day in patients with advanced left ventricular dysfunction in a double-blind placebo-controlled trial. METHODS: One hundred and nineteen patients with class II or III heart failure, left ventricular ejection fraction < or = 25% and treatment with 40 mg enalapril daily were given an initial challenge dose of atenolol 12. 5 mg. One hundred patients (54 with idiopathic, 28 with ischemic, 18 with other dilated cardiomyopathy) tolerated challenge and were randomized to atenolol (maintenance dose 89+/-11 mg/day, range 50-100 mg/day) or placebo. The primary endpoint was combined worsening heart failure or death within 2 years, the secondary endpoint was hospitalization for cardiac events. RESULTS: After 395+/-266 days interim analysis revealed a significant difference between the atenolol and placebo group (log rank P<0.01) and the trial was concluded. Twenty-seven patients had developed worsening heart failure (8 in the atenolol group vs. 19 in the placebo group) and 13 patients had died (5 in the atenolol vs. 8 in the placebo group). Overall there were 23 hospitalizations for cardiac events (6 in the atenolol group vs. 21 in the placebo group, P=0.07); 17 hospitalizations were due to worsening heart failure (5 in the atenolol group, 12 in the placebo-group, P=0.05) and 10 due to arrhythmias (1 in the atenolol group vs. 9 in the placebo group, P<0.01) CONCLUSIONS: The data suggest that in patients with advanced left ventricular dysfunction, beta-blockers can provide substantial benefits supplementary to that already achieved with high dose enalapril treatment.     

Effectiveness of converting enzyme inhibition (enalapril) for mild congestive heart failure

The present study investigates the effectiveness of converting enzyme inhibition (CEI) on cardiac performance of patients with congestive heart failure (New York Heart Association functional class II). Outpatients (n = 12) were treated with enalapril, 5 to 10 mg twice daily, in addition to stable doses of digitalis and diuretic drugs. Before and after 4 and 12 weeks of treatment a treadmill exercise test and echocardiography were performed. Maximal oxygen uptake and exercise tolerance increased significantly and mean arterial pressure at rest and on exertion decreased significantly. Heart rate did not change. Left ventricular end-diastolic diameter decreased significantly. Serum angiotensin converting enzyme activity was reduced to nearly 0; plasma renin concentration, which was already elevated, increased further. Plasma norepinephrine levels did not change significantly. Treatment was tolerated well by all patients. CEI decreased preload and afterload, suggesting that they might have had an inappropriately elevated arteriolar and venous tone owing to a moderately stimulated renin angiotensin system and sympathetic nervous system. These conditions may lead to further deterioration of cardiac performance. By means of CEI one may be able to interrupt these pathogenetic mechanisms, relieving the already damaged heart from inappropriate elevations of preload and afterload and delaying or even preventing further deterioration of cardiac performance.     

Sustained beneficial effects of enalapril in Africans with congestive heart failure

A single blind, placebo controlled, dose-ranging 3 month study of the effects of enalapril on cardiovascular parameters, clinical status and self-paced exercise capacity was undertaken in 12 Nigerians with chronic heart failure. Enalapril exerted only a modest reduction in blood pressure and heart rate but significantly improved functional capacity (P less than 0.01), and prolonged self-paced exercise time (P less than 0.05) compared to the placebo baseline. The pressure rate product and the double product corrected for exercise time, an index of myocardial oxygen demand, exhibited a significant and sustained reduction on enalapril treatment (P less than 0.01). Concentration of sodium in the serum was significantly increased (P less than 0.05) but concentrations of potassium and creatinine were unaltered. These results demonstrate the sustained efficacy of enalapril in black Africans with heart failure and indicate no important racial difference in the response to inhibition of angiotensin converting enzyme in congestive heart failure.     

Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure: a placebo controlled study.

OBJECTIVE--To compare the first dose responses to low dose angiotensin converting enzyme inhibitors (captopril, enalapril, and perindopril) in elderly patients with stable chronic heart failure. DESIGN--Double blind, randomised, placebo controlled, parallel, group prospective study of elderly patients with stable chronic heart failure. SETTING--General hospital in-patient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of angiotensin converting enzyme inhibitor therapy. PATIENTS--48 unselected elderly (58-85 years) patients with symptomatic but stable chronic heart failure (New York Heart Association grades II-IV) confirmed by clinical history, examination, and cardiological investigations. Patients gave their written and informed consent to receive their initial treatment under double blind conditions; blood pressure was monitored and blood samples taken to measure the pharmacokinetic and neurohormonal responses. INTERVENTION--Patients were randomised to receive a daily oral dose of placebo, captopril (6.25 mg), enalapril (2.5 mg), or perindopril (2 mg). MAIN OUTCOME MEASURES--Blood pressure and heart rate responses, drug concentration, and plasma renin and ACE activities. Differences between treatment groups were analysed by analysis of variance. RESULTS--The four randomised groups of patients had similar age, severity of heart failure (NYHA class), pretreatment diuretic dosage, plasma renin activity, and serum electrolyte state. Placebo treatment caused a modest but significant diurnal fall in blood pressure. Captopril produced a significant early (1.5 hours) and brief fall in blood pressure. The blood pressure fall with enalapril was later (4-10 hours), longer lasting, and was associated with significant slowing of supine heart rate. Though perindopril produced a similar plasma ACE inhibition to that produced by enalapril, it only caused changes in blood pressure that were similar to those caused by placebo. CONCLUSIONS--This controlled study is the first to indicate a qualitative difference in the acute response to angiotensin converting enzyme inhibitors with similar structure and metabolism (that is, enalapril and perindopril). Low dose perindopril seems to be less likely to cause hypotension in patients with heart failure. The explanation for the differences is unclear but may reflect differential effects on local tissue angiotensin generation.     

Comparison of the effects of losartan and enalapril on clinical status and exercise performance in patients with moderate or severe chronic heart failure

Objectives. This study assessed the feasibility of an efficacy trial comparing angiotensin-converting enzyme inhibition and angiotensin II receptor antagonism in heart failure. Patients with moderate or severe heart failure whose condition had previously been stabilized by treatment with a converting enzyme inhibitor were randomly assigned to receive enalapril or losartan. The study was designed to detect any signs of clinical deterioration during double-blind treatment.Background. Losartan is a specific, nonpeptide angiotensin II receptor-1 antagonist with a vasodilator hemodynamic profile similar to that of converting enzyme inhibitors. Although therapy with specific receptor blockade has certain theoretic advantages over nonspecific converting enzyme inhibition, demonstration of a comparable therapeutic effect in patients with congestive heart failure will require a major effort comparing two active agents.Methods. One hundred sixty-six patients with stable heart failure in New York Heart Association functional class III or IV and an ejection fraction ≤35% were included in a multicenter, double-blind, parallel, enalapril-controlled trial. After a 3-week stabilization period with optimal therapy, including digitalis, diuretic drugs and a converting enzyme inhibitor, patients were randomly assigned to 8 weeks of therapy with losartan, 25 mg/day (n = 52); losartan, 50 mg/day (n = 56); or enalapril, 20 mg/day (n = 58). Patients were assessed with frequent clinical and laboratory evaluation and exercise testing.Results. No significant differences between groups in terms of changes in exercise capacity (6-min walk test), clinical status (dyspnea-fatigue index), neurohumoral activation (norepinephrine, N-terminal atrial natriuretic factor), laboratory evaluation or incidence of adverse experience were observed.Conclusions. The results suggest that losartan and enalapril are of comparable efficacy and tolerability in the short-term treatment of moderate or severe congestive heart failure. A trial designed to compare the efficacy, tolerability and effect on mortality of long-term angiotensin II receptor blockade with converting enzyme inhibition is both feasible and ethically responsible.     

Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure: a placebo controlled study.

OBJECTIVE--To compare the first dose responses to low dose angiotensin converting enzyme inhibitors (captopril, enalapril, and perindopril) in elderly patients with stable chronic heart failure. DESIGN--Double blind, randomised, placebo controlled, parallel, group prospective study of elderly patients with stable chronic heart failure. SETTING--General hospital in-patient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of angiotensin converting enzyme inhibitor therapy. PATIENTS--48 unselected elderly (58-85 years) patients with symptomatic but stable chronic heart failure (New York Heart Association grades II-IV) confirmed by clinical history, examination, and cardiological investigations. Patients gave their written and informed consent to receive their initial treatment under double blind conditions; blood pressure was monitored and blood samples taken to measure the pharmacokinetic and neurohormonal responses. INTERVENTION--Patients were randomised to receive a daily oral dose of placebo, captopril (6.25 mg), enalapril (2.5 mg), or perindopril (2 mg). MAIN OUTCOME MEASURES--Blood pressure and heart rate responses, drug concentration, and plasma renin and ACE activities. Differences between treatment groups were analysed by analysis of variance. RESULTS--The four randomised groups of patients had similar age, severity of heart failure (NYHA class), pretreatment diuretic dosage, plasma renin activity, and serum electrolyte state. Placebo treatment caused a modest but significant diurnal fall in blood pressure. Captopril produced a significant early (1.5 hours) and brief fall in blood pressure. The blood pressure fall with enalapril was later (4-10 hours), longer lasting, and was associated with significant slowing of supine heart rate. Though perindopril produced a similar plasma ACE inhibition to that produced by enalapril, it only caused changes in blood pressure that were similar to those caused by placebo. CONCLUSIONS--This controlled study is the first to indicate a qualitative difference in the acute response to angiotensin converting enzyme inhibitors with similar structure and metabolism (that is, enalapril and perindopril). Low dose perindopril seems to be less likely to cause hypotension in patients with heart failure. The explanation for the differences is unclear but may reflect differential effects on local tissue angiotensin generation.     

Acute and long-term effects of enalapril on the cardiovascular response to exercise and exercise tolerance in patients with congestive heart failure

Enalapril is a recently developed angiotensin-converting enzyme inhibitor that improves cardiac function at rest in patients with congestive heart failure. This study investigated the acute effects of enalapril on the cardiovascular response to exercise, and then evaluated the long-term effects of enalapril on exercise capacity and functional status during a 12 week placebo-controlled trial in patients with heart failure. Ten patients underwent hemodynamic monitoring while at rest and during incremental bicycle exercise before and after 5 to 10 mg of enalapril orally. At rest, enalapril decreased mean blood pressure 13% (p less than 0.01) and systemic vascular resistance 20% (p less than 0.05) and increased stroke volume index 21% (p less than 0.01). During maximal exercise, enalapril decreased systemic vascular resistance and increased both cardiac and stroke volume indexes. Enalapril acutely increased exercise duration (p less than 0.05) and maximal oxygen consumption (p less than 0.001). These 10 patients and an additional 13 patients were then randomized to either placebo or enalapril treatment and followed up for 12 weeks. Of the 11 patients assigned to active treatment, 73% considered themselves improved compared with 25% of the patients assigned to placebo treatment (p less than 0.02). During long-term treatment, exercise capacity increased in patients receiving enalapril (p less than 0.001) but was unchanged in patients receiving placebo (intergroup difference, p less than 0.05). During long-term treatment, no adverse effects of enalapril occurred. Thus, enalapril improves cardiac function at rest and during exercise. Compared with placebo, maintenance therapy with enalapril results in symptomatic improvement and increased exercise capacity.     

Effects of lacidipine on peak oxygen consumption, neurohormones and invasive haemodynamics in patients with mild to moderate chronic heart failure.

OBJECTIVE: To evaluate the efficacy and safety of the second generation dihydropyridine calcium channel blocker lacidipine in patients with heart failure. DESIGN: Placebo controlled, parallel group, double blind study over 8 weeks. SETTING: General community hospital in Breda, The Netherlands. PATIENTS: A random sample was studied of 25 outpatients with symptoms of mild to moderate heart failure, despite treatment with diuretics, digoxin, and angiotensin converting enzyme inhibitors. Their mean age was 65 years, with mean left ventricular ejection fraction of 0.24 and a peak oxygen consumption of 14.4 ml/min/kg. Two patients dropped out on lacidipine, one patient on placebo. INTERVENTION: Treatment with lacidipine 4 mg once daily or placebo for eight weeks. MAIN OUTCOME MEASURE: Cardiopulmonary exercise testing, invasive haemodynamics, and plasma neurohormones. RESULTS: Treatment with lacidipine 4 mg once daily, as compared to placebo treatment, significantly improved peak oxygen consumption (P < 0.02), cardiac index (P < 0.01), and stroke volume (P < 0.03) paralleled by a decrease in systemic vascular resistance (P < 0.03) and arteriovenous oxygen content difference (P < 0.01). Plasma noradrenaline, plasma renin activity, and aldosterone values did not differ between lacidipine and placebo. CONCLUSIONS: This second generation dihydropyridine may be of value as an adjunct to standard treatment in congestive heart failure patients.     

The Clinical Application of Converting Enzyme Inhibitors

Chronic blockade of the renin angiotensin system became possible when orally active inhibitors of angiotensin converting enzyme, the enzyme which catalyzes the transformation of angiotensin I into angiotensin II, were synthetized. Two compounds, captopril and enalapril, have been investigated in clinical studies. The decrease of the pressor response to exogenous angiotensin I and of the circulating levels of angiotensin II following administration of these inhibitors has been demonstrated to be directly related to the degree of suppression of plasma angiotensin converting enzyme activity. These inhibitors have been shown to normalize blood pressure alone in some hypertensive patients whereas in many others, satisfactory blood pressure control can be achieved only after the addition of a diuretic. Captopril and enalapril also markedly improve cardiac function of patients with chronic congestive heart failure. Chronic blockade of the renin angiotensin system has therefore provided an interesting new approach to the treatment of clinical hypertension and heart failure.     

Increased myocardial [123I]-metaiodobenzylguanidine uptake after enalapril treatment in patients with chronic heart failure.

OBJECTIVE: To assess non-invasively the effect of enalapril on cardiac sympathetic neuronal uptake function in patients with congestive heart failure, by using [123I]-metaiodobenzylguanidine (MIBG), which is a noradrenaline analogue. Cardiac MIBG uptake was visualised by single photon emission tomography (SPET). In addition, plasma noradrenaline concentration, indicating systemic sympathetic activity, was measured to see whether it was related to cardiac MIBG uptake. DESIGN: Consecutive patients were treated with enalapril and served as their own controls. SETTING: Cardiac unit of a tertiary care centre. PATIENTS: 23 Patients with chronic, mild to moderate, stable congestive heart failure, and a left ventricular ejection fraction less than 40%. Heart failure was caused by ischaemic heart disease or was idiopathic. INTERVENTIONS: Cardiac MIBG SPET was performed and plasma noradrenaline concentration was measured before and after 6 weeks treatment with enalapril. MAIN OUTCOME MEASURES: Cardiac uptake of MIBG was measured by using the left ventricular cavity and a venous blood sample as a reference. RESULTS: Cardiac uptake of MIBG increased significantly after enalapril treatment, indicating improved cardiac neuronal uptake function. Plasma noradrenaline concentration did not decrease significantly. Cardiac MIBG uptake was not related to plasma noradrenaline concentration. CONCLUSIONS: Cardiac MIBG SPET can be used to assess changes in cardiac sympathetic neuronal uptake function caused by pharmacological intervention. Enalapril seemed to improve cardiac sympathetic neuronal uptake function but did not significantly affect plasma noradrenaline concentrations in a group of patients with predominantly moderate heart failure. These results accord with the hypothesis that restoration of cardiac neuronal uptake of noradrenaline is one of the beneficial effects of enalapril in such patients.     

Neurohormonal effects of early treatment with enalapril after acute myocardial infarction and the impact on left ventricular remodelling

Plasma neurohormones were sequentially analysed in 98 patientswith acute myocardial infarction randomized to treatment withenalapril or placebo for 4–6 months. Plasma angiotensinconverting enzyme activity was rapidly suppressed by enalapril,but unaffected by placebo (P = 0.0001). No significant differenceswere found in the plasma levels of angiotensin II, aldosterone,atrial natriuretic peptide, noradrenaline, adrenaline or dopaminebetween the two treatment groups. Among patients with infarctsize above median, plasma angiotensin II increased during head-uptilt at one month in the placebo group, but not in the enalaprilgroup. Left ventricular end-diastolic volume (LVEDV) and leftventricular endsystolic volume (LVESV) were evaluated by echocardiographyin 28 patients (placebo 15, enalapril 13) and changes in leftventricular volumes between baseline and 4–6 months werecalculated. Only in the placebo group was a positive correlationfound between plasma levels of noradrenaline at day 5–7and the subsequent increase in LVEDV (r = 0.78, P = 0.005) andLVESV (r = 0.75, P = 0.008). The same trend was found for angiotensinII, adrenaline and dopamine levels at days 5–7 and thesubsequent increase in left ventricular volumes. In the placebogroup a negative correlation was found between plasma aldosteroneat days 5–7 and the subsequent increase in left ventricularejection fraction (r = –0.77, P = 0.006) during the studyperiod. Although circulating neurohormones were not significantlyinfluenced by enalapril treatment, it is concluded that enalaprilmay influence the relationship found between sustained neurohormonalactivation and left ventricular remodelling after acute myocardialinfarction.