Cooperative North Scandinavian Enalapril Survival Research Articles

Angiotensin-converting enzyme inhibitors after myocardial infarction: Indications and timing

A number of major studies have examined the impact of angiotensin-converting enzyme inhibitors on mortality in patients with ischemic heart disease. However, in these studies, selection of patients, choice of agent and timing of treatment after myocardial infarction have differed. In the Second Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS II), all patients, unless hypotensive, were treated immediately after thrombolysis with placebo or intravenous enalaprilat followed by oral therapy. In contrast, in the Survival and Ventricular Enlargement (SAVE) study, patients were selected with a reduced radionuclide ejection fraction and without overt ongoing ischemia. Despite these different approaches, both studies were based on the rationale that angiotensin-converting enzyme inhibition would beneficially affect infarct expansion and subsequent remodeling. The SAVE study reported a significant reduction in mortality rate (19% risk reduction, 95% confidence interval [CI] 3% to 32%) over an average follow-up period of 42 months, but with no observable impact on mortality rate until almost 1 year into treatment. The CONSENSUS II trial closed prematurely, with no benefit (a 10% increase in risk, 95% CI 7% reduction to 29% increase) apparent from enalapril after 6 months of follow-up. The recently reported but unpublished findings of Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) and the Fourth International Study of Infarct Survival (ISIS-4) indicate a small benefit from early (within 24 h) short-term (4 to 6 weeks) treatment of all patients, unless hypotensive, after a myocardial infarction. In contrast, the Acute Infarction Ramipril Efficacy (AIRE) study demonstrated a marked reduction in mortality rate (27% risk reduction, 95% CI 11% to 40%) when the angiotensin-converting enzyme inhibitor ramipril was given to patients manifesting some clinical evidence of heart failure, even if transient, 3 to 10 days after myocardial infarction for an average period of 15 months. Extrapolation from the findings of the AIRE study and from subgroup analyses of GISSI-3 and ISIS-4 indicate that patients manifesting clinical evidence of heart failure after myocardial infarction derive most of the benefit to be gained from the use of angiotensin-converting enzyme inhibitors. Appropriate selection of patients and careful timing of treatment after myocardial infarction to allow patients to achieve clinical stability will maximize potential benefit against potential harm from these effective agents.

Atrial natriuretic peptide ANP(1–98) and ANP(99–126) in patients with severe chronic congestive heart failure: Relation to echocardiographic measurements

Studies in patients with moderate heart failure have shown a positive relation between atrial size and plasma atrial natriuretic peptide (ANP)(99–126) concentrations; however, the relation of the hormone level and left atrial size and left ventricular function in patients with severe chronic heart failure has not been determined. Fifty-three patients from the Cooperative North Scandinavian Enalapril Survival Study with severe chronic heart failure were evaluated with M-mode echocardiography and determination of plasma concentrations of ANP(99–126). In 35 patients, the plasma level of N-terminal ANP(1–98) was also measured. A significant negative relation was found between ANP(1–98), ANP(99–126), and left atrial diameter ( r = −.28, P = .05 and r = −.41, P < .005, respectively). Plasma concentrations of both ANP(1–98) and ANP (99–126) were related to left ventricular systolic function as determined by the systolic time interval index ( r = .4, P < .05 and r = .29, P < .05, respectively). A significant improvement of left ventricular systolic function was found in the enalapril group but not in the placebo group. After 6 weeks of therapy, no correlation was found between changes in left atrial size or systolic function or changes in either the ANP(1–98) or ANP(99–126) concentration. The results indicate that high ANP(1–98) or ANP(99–126) plasma concentration is determined by the depressed left ventricular function rather than increased left atrial size in patients with chronic severe heart failure. The findings suggest that the ANP release relation to atrial pressure/atrial size is distorted in severe heart failure.

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

To describe neurohormonal activation in patients with mild or moderate heart failure and how it may be modified by treatment with ramipril. Cardiology departments at 24 hospitals in Denmark, Finland, Norway, and Sweden. 223 patients with mild or moderately severe congestive heart failure who were taking diuretics with or without digitalis. 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. 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). 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.

Neuroendocrine activation in relation to left ventricular function in chronic severe congestive heart failure: A subgroup analysis from the cooperative north scandinavian enalapril survival study (CONSENSUS)

Left ventricular (LV) function and plasma levels of cardiovascular hormones were examined in patients with severe chronic congestive heart failure (CHF), randomized to placebo or enalapril, in addition to conventional therapy. M-mode echocardiography and plasma hormone concentrations were available at baseline and after 6 weeks of treatment. There was a significant relationship between LV systolic function and levels of angiotensin-II and norepinephrine. Enalapril increased LV fractional shortening (FS%) (13.3 +/- 5.6 to 15.4 +/- 5.8, p < 0.05) and decreased the systolic time interval index (0.58 +/- 0.14 to 0.48 +/- 0.15, p < 0.05) concurrent with a significant decrease in angiotensin-converting enzyme activity and in aldosterone, angiotensin-II, and norepinephrine concentrations after 6 weeks. No changes were found in the placebo group. However, there was no direct relationship between the amount of change in neurohormones and improvement in LV function after 6 weeks. These findings indicate that in patients with severe chronic CHF, severe LV systolic dysfunction is associated with high plasma levels of angiotensin-II and norepinephrine, which can be favorably modified by enalapril. This may be of importance for prolonging life in severe heart failure. The lack of relationship between changes in individual hormones and systolic function suggests complex dynamic interaction. It is, therefore, not sufficient to predict changes in LV function by measuring changes in only one hormone.

Neurohormonal mechanisms and the role of angiotensin-converting enzyme (ACE) inhibitors in heart failure

Clinical evidence accumulated over the past decade suggests that neurohormonal mechanisms significantly influence the pathogenesis and eventual outcome of congestive heart failure (CHF). Pharmacologic modulation of this neuroendocrine activity can, consequently, be expected to improve patient prognosis. Results of several recent clinical trials--the Studies of Left Ventricular Dysfunction (SOLVD), the second Veterans Administration Cooperative Vasodilator Heart Failure Trial (VH eFT-II), and the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)--provide substantial evidence that addition of the angiotensin-converting enzyme (ACE) inhibitor enalapril to conventional therapeutic regimens can significantly reduce mortality and improve prognosis in patients with all grades of heart failure. Moreover, data from all three trials confirm the involvement of neurohormonal systems in the development and progression of CHF and suggest that the beneficial effects of enalapril in heart failure may in part be due to the suppression of this neurohormonal activity. It is now apparent that some form of neurohormonal activation is present early in the course of the disease before the emergence of overt heart failure symptoms. On the basis of such findings, it would seem that early introduction of therapy targeted at neurohormonal influences may well become a central component of any future CHF treatment program.

Optimizing the treatment of heart failure

The introduction of new drugs, and a re-evaluation of older drugs, have radically changed the pharmacological management of heart failure. Angiotensin converting enzyme (ACE) inhibitors, digitalis, diuretics and the combination of nitrates and hydralazine are now used. The first Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS I) and the second Vasodilator therapy in Heart Failure Trial (V-HeFT II) have demonstrated that patients with severe or advanced heart failure should be treated with ACE inhibitors, digitalis and diuretics (other vasodilators can be used if ACE inhibitors are contraindicated) to improve symptoms and duration of life. The Studies Of Left Ventricular Dysfunction (SOLVD) and the Munich Heart Failure trial have shown that patients with mild heart failure should be treated with ACE inhibitors. However, data from several large clinical registries suggest that only 40% of patients with heart failure are being given ACE inhibitors perhaps through fear of serious renal damage or hypotension; these fears are unfounded. Patients with anterior myocardial infarcts and reduced left ventricular function also benefit from ACE inhibitors. The fourth International Study of Infarct Survival (ISIS 4) and results from the Gruppo Italiano per Io Studio della Sopravvivenza nell'Infarto miocardico 3 (GISSI 3) have indicated that patients with acute myocardial infarction benefit from early ACE inhibitor therapy and that survival is increased. Heart failure treatment can be optimized by establishing a disease etiology and stressing the need to restrict dietary sodium. ACE inhibitors should be used for depressed left systolic ventricular function, including patients in New York Heart Association class I heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-converting enzyme inhibitors in heart failure: new strategies justified by recent clinical trials

New information suggests that heart failure treatment strategies should change. Indeed, angiotensin-converting enzyme (ACE) inhibitors now should be considered first-line therapy in some instances. It is important, therefore, to review results of recently completed mortality end-point trials of ACE inhibitors in patients with congestive heart failure and asymptomatic left ventricular dysfunction. In the Treatment Trial of Studies of Left Ventricular Dysfunction (SOLVD), addition of enalapril to baseline therapy significantly improved prognosis in patients with mild to moderate heart failure. These results extend the findings of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), and indicate that ACE inhibition is beneficial to patients with all grades of overt congestive heart failure. In the Prevention Trial of SOLVD, and the Survival and Ventricular Enlargement Study (SAVE), therapy with enalapril or captopril improved prognosis among patients with, generally, asymptomatic left ventricular dysfunction. In particular, the risk of development of overt heart failure was reduced. Importantly, a marked anti-ischaemic effect of ACE inhibition was identified in both the SOLVD and SAVE trials. Clinical data amassed in nearly 9000 patients identify a substantial role for ACE inhibition in patients with all grades of symptomatic heart failure as well as in those with asymptomatic left ventricular dysfunction (such as often follows a myocardial infarction). Data support early intervention with ACE inhibitor therapy alone in asymptomatic cardiac failure and triple combination therapy (ACE inhibitor, diuretic, digoxin) in patients with symptomatic congestive heart failure.

Lessons from recent randomized controlled trials for the management of congestive heart failure

In 1987 the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) was published, which was a milestone for the treatment of patients with heart failure. The study showed a highly significant reduction in mortality in patients with severe heart failure treated with enalapril in comparison to placebo in combination with conventional treatment for heart failure, including the use of other vasodilators. The improvement in survival was exclusively due to a reduction of progression of pump failure. The incidence of sudden cardiac death was not affected. In 1991 2 studies were published in which patients with mild and moderate heart failure were included. The Second Vasodilator-Heart Failure Trial (V-HeFT II) compared the efficacy of enalapril with the effects of a vasodilator therapy consisting of the combination of hydralazine and isosorbide dinitrate. The study showed a highly significant reduction in mortality in the group of patients on the angiotensin-converting enzyme (ACE) inhibitor. In contrast to CONSENSUS, the benefit on survival was due to a reduction of sudden cardiac death. The second study was the Studies of Left Ventricular Dysfunction (SOLVD) treatment arm trial, which compared enalapril and placebo in combination with standard therapy in symptomatic patients with mild-to-moderate heart failure. The SOLVD treatment trial showed a highly significant improvement in survival on enalapril in comparison with placebo. ACE inhibition resulted in a borderline significant reduction of fatal myocardial infarctions, suggesting an impact of ACE inhibition on the pathogenesis of coronary artery disease. The data available show a clear indication for the treatment of symptomatic patients with mild and moderate-to-severe heart failure with ACE inhibitors as a first-line therapy.

Renal function in severe congestive heart failure during treatment with enalapril (the Cooperative North Scandinavian Enalapril Survival Study [CONSENSUS] Trial)

The effect on renal function of long-term treatment with either enalapril (n = 123) or placebo (n = 120) in addition to conventional therapy was studied in a randomized trial in patients with severe congestive heart failure (New York Heart Association functional class IV; the Cooperative North Scandinavian Enalapril Survival Study). Enalapril was administered in a dose of 2.5 to 40 mg/day. The analysis was restricted to the first 6 months of treatment. There was an average initial increase of 10 to 15% (10 to 20 μmol/liter) irrespective of baseline serum creatinine within the first 3 weeks of enalapril treatment, whereafter mean serum creatinine remained on a similar level during the first 6 months. Enalapril was well-tolerated by most patients, and serum creatinine was reduced in 24%. Serum creatinine increased by >100% in 13 patients (11%) in the enalapril group (mainly as a consequence of intercurrent disease or severe hypotension, and usually transiently) and in 4 (3%) in the placebo group. The maximal increase in serum creatinine in the enalapril group was inversely correlated to the diastolic blood pressure (p = 0.008) at baseline and to the mean diastolic and systolic blood pressures measured at the time of the maximal increase in serum creatinine (p = 0.0001). According to multivariate regression analysis, the maximal increase in serum creatinine was also slightly influenced by the dose of furosemide taken. The development of hypotension emerged as the strongest factor explaining an abnormal increase in serum creatinine. Patients with marked reduction of baseline glomerular filtration rate had an increased risk of developing hypotension. Therefore, low beginning doses of enalapril and monitoring of blood pressure and serum creatinine are recommended in patients with severe heart failure, especially in those with marked reduction of glomerular filtration rate and in those expected to have an excessive stimulation of the renin-angiotensin system.

Left ventricular hypertrophy: An initial response to myocardial injury

The prevailing wisdom generally has been that the failing heart hypertrophies in response to increased wall stress. The increase in myocardial mass observed in heart failure is therefore a relatively late compensatory event geared to normalize wall stress. Although this is undoubtedly true, especially for heart failure resulting from a large anterior myocardial infarction accompanied by rapid left ventricular expansion, it is possible that an important form of hypertrophy occurs much earlier as an initial response to myocardial injury. One can hypothesize that the initial response to injury is a nonspecific phenotypic alteration of the cardiac myocyte to one of growth and development. Such changes may be driven by both trophic and mechanical forces and may be important in altering the architecture of the myocardial cell and surrounding cardiac interstitium. Preliminary data from a variety of models support the concept that neuroendocrine activity is an important component in the ventricular remodeling process, and that pharmacologic interventions designed to block systemic and tissue neuroendocrine activity may prevent excessive cardiac enlargement and its ultimate consequences. Because this concept has important implications for preventive cardiology, the results of several prevention trials, including the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), Studies of Left Ventricular Dysfunction (SOLVD), and Survival and Ventricular Enlargement (SAVE) are awaited eagerly. ∗ ∗ Editor's note: The results of these studies have been presented but have not yet been published.

Tolerability of enalapril in congestive heart failure

This report reviews the tolerability profile of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, in the treatment of patients with congestive heart failure. Data have been collected from 546 patients treated with enalapril for up to 9 months in clinical trials other than the Cooperative North Scandinavian Enalapril Survival Study. Results in patients treated with enalapril (n = 193) or placebo (n = 195) in double-blind, controlled clinical trials show that the incidences of death, serious adverse experiences, and adverse experiences requiring discontinuation of double-blind therapy, as well as the overall incidence of such experiences, were similar in the 2 groups. However, certain adverse experiences that are related to the mechanism of action of ACE inhibitors were seen more often after enalapril than after placebo treatment. Dizziness and hypotension were the most frequent adverse experiences reported in patients with heart failure treated with enalapril. The most frequent laboratory adverse experiences were increases in blood urea nitrogen and serum creatinine levels. Hyperkalemia was also seen in patients receiving enalapril. It is possible to identify patients at risk of these experiences before initiating treatment with enalapril and to take certain measures (such as withholding or reducing the dose of diuretic drugs and discontinuing potassium supplements or potassium-sparing diuretic drugs) to reduce the likelihood that hypotension, increases in blood urea nitrogen and serum creatinine levels, or hyperkalemia will occur. Angioedema, a recognized adverse effect of ACE inhibitors, was not seen in the clinical trials reviewed here. Cough, another recognized adverse effect of these agents, was seen infrequently and rarely resulted in the discontinuation of enalapril. The data from the clinical trials of enalapril in patients with heart failure show that this drug is well tolerated.

Appendix: Monitoring methods, considerations, and statement of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) Ethical Review Committee

The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) was terminated prematurely when an independent Ethical Review Committee concluded, on the basis of interim analyses, that continuation would not be advisable on either ethical or scientific grounds. Among 124 patients treated with enalapril and 120 randomized to placebo, 6-month mortality rates were 27 and 48%, respectively. The 2 groups were found to be well balanced with regard to baseline clinical characteristics, and a consistent treatment effect was evident among subgroups. Furthermore, the difference favoring enalapril was found to have been present since the beginning of the study and was consistent over time. Based on these findings, the study was halted on December 14, 1986.

Effect of drug therapy on survival in chronic congestive heart failure

A review of the current evidence on the effects of various agents on survival among patients with congestive heart failure (CHF) suggests that angiotensin-converting enzyme inhibitors probably offer the greatest potential for benefit. Trials undertaken before the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) revealed favorable trends among patients in New York Heart Association functional classes II to IV who received angiotensin-converting enzyme inhibitors. Data from CONSENSUS clearly demonstrate that enalapril reduces mortality rates among patients in New York Heart Association class IV, but conclusions regarding effects in patients with mild or moderate CHF must await the results of future studies. In contrast, the large data base on alpha-adrenergic blockers suggests that these drugs are not likely to improve survival. Information on inotropic agents is sparse, but it is possible that these drugs may not improve survival and, in fact, may have a harmful effect. Mortality data on CHF patients treated with beta blockers and calcium channel blockers are likewise limited; conclusions concerning effects on survival must be postponed until further studies are conducted. Many of the investigations undertaken thus far to examine survival in patients with CHF have been small and of short duration, so any comparisons of the effects of various drugs must be interpreted with caution.

When and how to use angiotensin-converting enzyme inhibition in congestive heart failure

Angiotensin-converting enzyme (ACE) inhibitors have been found effective in the treatment of congestive heart failure (CHF) and have been recommended as the first choice of vasodilator therapy by some observers. Favorable hemodynamic responses, apparent both at rest and during exercise, result from a considerable reduction in both systemic and pulmonary vascular resistance, apparently due to both the arterial and venodilating effects of these agents. In addition, the recently reported results of the Cooperative North Scandinavian Enalapril Survival Study demonstrate that ACE inhibitors reduce mortality rates in patients with CHF. The etiology of heart failure does not seem to predict clinical response to ACE inhibitors, nor do acute resting and exercise hemodynamic responses. A weak relation has been found between plasma renin activity and short-term hemodynamic and clinical responses, but this association is not evident over the long term. Therefore, a trial of therapy with ACE inhibitors is necessary to judge efficacy in an individual patient with advanced CHF symptoms. Two such agents--captopril and enalapril--are available. The former has a more rapid onset and shorter duration of action, whereas the latter may be given on a twice-daily basis, simplifying chronic therapy.