[Use of angiotensin II receptor blockaders in heart failure]. / Bruk av angiotensin II-reseptorblokkere ved hjertesvikt.

Angiotensin converting enzyme (ACE) inhibitors and diuretics represent the first line of therapy in patients with symptomatic heart failure. Inhibition of angiotensin II production is, however, incomplete with ACE inhibitors, due to non-ACE dependent conversion pathways. Moreover, some patients are intolerant to ACE inhibitors due to side effects or renal insufficiency. Angiotensin II receptor blockers may be an alternative to, or an additional treatment in heart failure. Preliminary studies comparing the angiotensin II receptor blocker losartan with placebo have demonstrated improved haemodynamic parameters, reduced hospitalisation and mortality in patients with heart failure. Reduced morbidity and mortality have also been found with losartan treatment, as compared to the ACE inhibitor captopril. This paper discusses the role of angiotensin II receptor blockers in the treatment of heart failure. Some results from published studies and a short description of ongoing trials are presented.

Long-term effects on cardiac output and peripheral resistance in patients treated with enalapril after acute myocardial infarction. CONSENSUS II Multi-Echo Study Group. Cooperative New Scandinavian Enalapril Survival Study.

In the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS II), in which enalapril treatment was initiated intravenously within 24 h after acute myocardial infarction, there was a neutral effect on 6-month mortality, whereas a beneficial effect on the progression of congestive heart failure was noted. We studied the effect of enalapril on left ventricular systolic function in terms of cardiac output and mean acceleration time measured by pulsed-wave Doppler in the left ventricular outflow tract and peripheral resistance. Early angiotensin-converting enzyme inhibition after acute myocardial infarction did not result in a general improvement of cardiac output. However, a small increase in cardiac output was observed in a subgroup of enalapril-treated patients with ejection fraction > or = 45%, probably due to a reduction in peripheral resistance in these patients.

Benefit of converting enzyme inhibition on left ventricular volumes and ejection fraction in patients receiving beta-blockade after myocardial infarction. CONSENSUS II multiecho study group.

Beta-blockers reduce infarct size and improve survival after acute myocardial infarction (MI). Post-MI angiotensin-converting enzyme inhibition also improves survival and may attenuate left ventricular (LV) dilatation. We evaluated the effect of early enalapril treatment on LV volumes and ejection fraction (EF) in patients on concomitant beta-blockade after MI. Intravenous enalaprilat or placebo was administered <24 hours after MI and was continued orally for 6 months. LV volumes were assessed by echocardiography 3 +/- 2 days, 1 and 6 months after MI. Change in LV diastolic volume during the first month was attenuated with enalapril (2.7 vs placebo 6.5 ml/m2 change; p < 0.05), and significantly lower LV diastolic and systolic volumes were observed with enalapril treatment compared with placebo at 1 month (enalapril 47.21 23.9 vs placebo 53.1/29.2 ml/m2; p < 0.05) and at 6 months (enalapril 47.9/24.8 vs placebo 53.8/29.6 ml/m2; p < 0.05). EF was also significantly higher 1 month after MI in these patients (enalapril 50.4% vs placebo 46.4%; p < 0.05). Our date demonstrate that early enalapril treatment attenuates LV volume expansion and maintains lower LV volumes and higher EF in patients receiving concurrent beta-blockade after MI. A possible additive effect of combined therapy should be evaluated prospectively.

Effect of enalapril initiated early after acute myocardial infarction on heart failure parameters, with reference to clinical class and echocardiographic determinants. CONSENSUS II Multi-Echo Study Group.

BACKGROUND AND HYPOTHESIS: Although the angiotensin-converting enzyme inhibitor enalapril has recently been shown to reduce mortality and the need for hospitalization in patients with left ventricular dysfunction and congestive heart failure, this drug was found to have no significant impact on short-term mortality after acute myocardial infarction (AMI) in the CONSENSUS II trial. The effect of enalapril initiated early after AMI on clinical and echocardiographic determinants of left ventricular (LV) function was studied in a subset of patients from CONSENSUS II. METHODS: Symptoms and signs of heart failure were classified as NYHA and dyspnea classes. Echocardiography included LV end-systolic volumes (ESV) and end-diastolic volumes (EDV), as well as ejection fraction (EF), wall motion index (WMI), and mitral flow indices. In all, 428 patients were included and followed for an average of 5.1 months by serial examinations, starting 2-5 days after myocardial infarction (MI) and repeated after 1 month and at the completion of the study. RESULTS: There was no beneficial effect of enalapril on clinically determined function. Changes (i.e., changes in NYHA class) in the functional status remained correlated with changes in echocardiographic determinants throughout the study in patients belonging to the placebo group: EDV index (r = 0.36, p = 0.002, ESV index (r = 0.49, p < 0.001), EF (r = -0.41, p < 0.001), and WMI (r = 0.29, p = 0.008). In a stepwise logistic regression model, the best baseline parameters to predict NYHA class at final visit in all patients were age (p = 0.014) and ESV index (p = 0.001). CONCLUSION: Enalapril treatment for an average period of 5.1 months following MI resulted in no clinically significant beneficial effects on NYHA and dyspnea class. Changes in clinical function class were correlated with changes in echocardiographic determinants in placebo-treated patients, but not in patients given enalapril.

Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide.

BACKGROUND: Elevated plasma levels of atrial natriuretic peptide (ANP) and the N-terminal fragment of the ANP prohormone (N-ANP) are associated with decreased left ventricular function and decreased long-term survival after acute myocardial infarction (AMI). Previous data suggest that plasma brain natriuretic peptide (BNP) may increase proportionally more than plasma ANP after AMI and in chronic heart failure. The diagnostic and prognostic value of plasma BNP as an indicator of left ventricular dysfunction and long-term survival after AMI, relative to that of ANP and N-ANP, remain to be established. METHODS AND RESULTS: Venous blood samples for analysis of ANP, N-ANP, and BNP were obtained on day 3 after symptom onset from 131 patients with documented AMI. Left ventricular ejection fraction was determined by echocardiography in a subsample of 79 patients. Twenty-eight cardiovascular and 3 noncardiovascular deaths occurred during the follow-up period (median, 1293 days). All three peptides proved to be powerful predictors of cardiovascular mortality by univariate Cox proportional hazards regression analyses (ANP: P < .0001; N-ANP: P = .0002; BNP: P < .0001). In a multivariate model, plasma BNP (P = .021) but not ANP (P = .638) or N-ANP (P = .782) provided additional prognostic information beyond left ventricular ejection fraction. Logistic regression analysis showed that ANP (P = .003) and N-ANP (P = .027) but not BNP (P = .14) were significantly associated with a left ventricular ejection fraction < or = 45%. CONCLUSIONS: These results suggest that plasma BNP determination provides important, independent prognostic information after AMI. Although plasma ANP appears to be a better predictor of left ventricular dysfunction, plasma BNP may have greater potential to complement standard prognostic indicators used in risk stratification after AMI because of its strong, independent association with long-term survival, enhanced in vitro stability, and simplicity of analysis.

Novel drugs and current therapeutic approaches in the treatment of heart failure.

Treatment of heart failure attempts to reduce symptoms, increase functional capacity and prolong survival. Optimal therapy usually requires a combination of several drugs. At present, ACE inhibitors are the drugs of first choice, but must be combined with diuretics in symptomatic patients. Digitalis glycosides are still an important supplement to diuretics and ACE inhibitors. Specific angiotensin receptor antagonists such as losartan have an effect comparable with that of ACE inhibitors and may possess certain advantages because of their direct effect at the receptor level. Extensive research has been conducted in the treatment of heart failure. Newer direct acting vasodilators such as flosequinan and epoprostenol have demonstrated improved exercise tolerance but have an adverse effect on mortality. Positive inotropic agents consisting of a heterogeneous group of drugs have been evaluated. Although novel agents such as xamoterol, milrinone, pimobendan and vesnarinone have demonstrated improved haemodynamics and improved symptoms, they are not advisable at present due to increased mortality related to treatment or a high incidence of adverse events. beta-Blockers, used judiciously, may improve functional capacity as well as mortality and may be an important supplement to current conventional treatment. The new generation of beta-blockers with vasodilating properties such as carvedilol and bucindolol appear promising.

Neurohumoral measurements as indicators of long-term prognosis after acute myocardial infarction.

The objective of this study was to evaluate the prognostic accuracy and usefulness of neurohumoral determination as a risk stratification tool after acute myocardial infarction (AMI) by comparing the long-term prognostic value of subacute neurohumoral measurements with other established indicators of adverse outcome. The study included 145 patients with documented AMI. During a median follow-up of 3.7 years, 30 cardiovascular and 6 noncardiovascular deaths occurred. By univariate analysis, plasma atrial natriuretic factor (ANF) and endothelin levels were strongly related to long-term cardiovascular mortality. In multivariate models, both peptides added prognostic information to that obtained from clinical evaluation, but not to that obtained from left ventricular ejection fraction (LVEF). Estimation of the area under the receiver-operating characteristic curve showed comparable prognostic accuracy for LVEF (0.7788), plasma ANF (0.7795), plasma endothelin (0.7493), and Killip classification (0.8203), meaning that for all these prognostic indicators, a randomly selected patient from the group of patients dying will have a test value larger than that of a randomly selected patient from the group of surviving patients 75% to 82% of the time. The clinical usefulness of neurohumoral determination in routine risk stratification after AMI appears to be limited since no additional prognostic information to that provided by objective evaluation of LV systolic function is obtained. However, in patients for whom objective assessment of LV performance is not readily available, measurement of plasma ANF and endothelin may be helpful in identifying asymptomatic patients at risk for cardiac death.

Effects of early enalapril treatment on global and regional wall motion in acute myocardial infarction. CONSENSUS II Multi Echo Study Group.

Angiotensin-converting-enzyme inhibitor therapy can preserve left ventricular (LV) function and geometric features and improve survival in subsets of patients with acute myocardial infarction (AMI). We investigated the effect of enalapril treatment initiated < 24 hours after AMI on global and regional echocardiographic wall motion indexes obtained at 2 to 5 days and at 1 and 6 months in 428 consecutive patients enrolled in the randomized, placebo-controlled Cooperative New Scandinavian Enalapril Survival Study II. In anterior AMIs, the non-infarct-zone index deteriorated in the placebo group but remained unchanged in the enalapril-treated group (0.18 vs 0.02; p < or = 0.05), an effect related to attenuated LV volume expansion. No treatment effects were observed in nonanterior AMIs or in the entire unselected population. Thus in an unselected population with AMI, early enalapril treatment had no effect on LV function; yet in patients with anterior infarcts, LV function was maintained through preservation of function in the noninfarcted myocardium.

Left ventricular volumes, ejection fraction, and plasma proatrial natriuretic factor (1-98) after withdrawal of enalapril treatment initiated early after myocardial infarction. CONSENSUS II Multi-Echo Study Group.

OBJECTIVES: To assess whether the reduction in left ventricular dilatation after acute myocardial infarction obtained by early administration of angiotensin converting enzyme inhibitors depends on continuous treatment. DESIGN: Prospective observational and cross sectional study of withdrawal of randomised treatment with enalapril or placebo. PATIENTS: 106 patients on 6 months trial treatment after an acute myocardial infarction. MAIN OUTCOME MEASURES: Left ventricular volumes and ejection fraction as assessed by echocardiography and circulating proatrial natriuretic factor (1-98) before and 4-6 weeks after withdrawal of treatment. RESULTS: There were no significant changes (mean (SD)) in left ventricular systolic (0.7 (4.7) ml/m2) and diastolic (0.4 (6.6) ml/m2) volume indices, ejection fraction (-0.9 (6)%), and proatrial natriuretic factor (172 (992) pmol/l) after withdrawal of enalapril. The significantly lower left ventricular volumes observed with 6 months of enalapril therapy after acute myocardial infarction, as compared with placebo, were maintained 6 weeks after drug withdrawal. CONCLUSION: The results show that the benefit of 6 months of enalapril treatment initiated early after myocardial infarction is maintained for at least 6 weeks after drug withdrawal, suggesting that the treatment effect on left ventricular structure is not reversed by changes in loading conditions caused by subsequent drug withdrawal.

Plasma proatrial natriuretic factor (1-98) concentration after myocardial infarction: relation to indices of cardiac and renal function.

OBJECTIVES: (a) To assess the relation between plasma concentrations of proatrial natriuretic factor (1-98) and non-invasively derived indices of left ventricular systolic and diastolic performance and (b) to assess the potential confounding effect of renal function and age on this relation in patients with acute myocardial infarction. DESIGN: Cross sectional comparison of biochemical and echocardiographic indices of cardiac function. SETTING: Norwegian central hospital. PATIENTS: Sixty four patients with acute myocardial infarction. MAIN OUTCOME MEASURES: Relation between plasma proatrial natriuretic factor (1-98) concentrations and echocardiographic indices of left ventricular systolic function as assessed by univariate and multivariate linear regression analysis. Sensitivity and specificity of plasma proatrial natriuretic factor (1-98) concentration as a measure of left ventricular systolic and diastolic dysfunction. RESULTS: Plasma proatrial natriuretic factor (1-98) concentrations were significantly related to left ventricular ejection fraction (r = -0.33; P = 0.008), age (r = 0.43; P < 0.001), and creatinine clearance (r = - 0.53; P < 0.001). In a multivariate model left ventricular ejection fraction and creatinine clearance were both independently related to plasma values. The mean concentration of proatrial natriuretic factor (1-98) was significantly higher in patients with an ejection fraction of < 40% than in those with an ejection fraction of > or = 40% (1876 (1151) v 1174 (530) pmol/l; P = 0.03) and in patients with an abnormal transmitral E/A ratio ( < 0.65 or > 1.65, where E/A is ratio of peak early filling velocity to peak atrial component) compared with those with a normal ratio (1572 (895) v 1137 (523) pmol/l, respectively; P = 0.02). When patients were subdivided according to the median concentration of proatrial natriuretic factor (1192 pmol/l) the sensitivity and specificity were 89% and 56% respectively for detecting a left ventricular ejection fraction of < 40% and 75% and 61% respectively for detecting an abnormal E/A ratio. Concentrations below the median had a negative predictive value of 97% in excluding an ejection fraction of < 40% and of 84% in excluding an abnormal E/A ratio. CONCLUSION: These results suggest that soon after myocardial infarction left ventricular ejection fraction and indices of renal function are independently related to plasma concentrations of proatrial natriuretic factor (1-98). Plasma concentrations of proatrial natriuretic factor (1-98) seem to reflect renal and cardiac performance rather than specific haemodynamic variables assessed by noninvasive methods. Plasma proatrial natriuretic factor (1-98) measurements may be a useful screening tool to identify patients with normal cardiac function soon after myocardial infarction.

Prognostic significance of N-terminal pro-atrial natriuretic factor (1-98) in acute myocardial infarction: comparison with atrial natriuretic factor (99-126) and clinical evaluation.

OBJECTIVE: To evaluate the prognostic significance of plasma N-terminal pro-atrial natriuretic factor (1-98) concentrations measured in the subacute phase after acute myocardial infarction, and to compare the predictive value of measurement of N-terminal pro-atrial natriuretic factor (1-98) with the measurement of atrial natriuretic factor (99-126) and with clinical assessment of the degree of heart failure. DESIGN: Prospective observational. SETTING: Norwegian central hospital. PATIENTS: 139 patients (mean (SD) age 66.9 (11.1) years, 71.2% males) with acute myocardial infarction. Patients in cardiogenic shock or with severe heart failure (New York Heart Association class IV) were excluded. MAIN OUTCOME MEASURE: Cardiovascular death within 12 months. RESULTS: During the follow up period 15 patients died. In a univariate Cox proportional hazards model N-terminal pro-atrial natriuretic factor (1-98) was significantly related to mortality (p = 0.0003). In a multivariate model the prognostic value of N-terminal pro-atrial natriuretic factor (1-98) was better than that of atrial natriuretic factor (99-126) and clinical assessment of heart failure (N-terminal pro-atrial natriuretic factor (1-98), p = 0.0003; atrial natriuretic factor (99-126), p = 0.4513; heart failure, p = 0.0719). The odds ratio estimate of patients in whom plasma concentrations of N-terminal pro-atrial natriuretic factor (1-98) were greater than 2000 pmol/l was 25 (95% confidence interval 2.8-225.0) compared with patients with plasma concentrations less than 1000 pmol/l. CONCLUSIONS: These results suggest that determination of plasma N-terminal pro-atrial natriuretic factor (1-98) in the subacute phase of myocardial infarction may provide clinically relevant prognostic information that is superior to that obtained from atrial natriuretic factor (99-126) measurements and clinical evaluation.

Attenuation of left ventricular dilatation after acute myocardial infarction by early initiation of enalapril therapy. CONSENSUS II Multi-Echo Study Group.

This trial investigated the effect of enalapril, administered early, on left ventricular (LV) volumes after myocardial infarction. Four hundred twenty-eight patients included in the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS II) were examined with echocardiography within 5 days, at 1 month and at 6 months after myocardial infarction. Enalaprilat (1 mg) or placebo infusion was initiated within 24 hours after infarction, followed by oral treatment to a target dose of 20 mg/day. A significant attenuation of LV dilatation was noted at 1 month in patients treated with enalapril compared with those receiving placebo. Changes in LV end-diastolic volume indexes during the first month were (mean +/- SEM) 5.7 +/- 1.0 ml/m2 for the placebo group and 1.9 +/- 0.8 ml/m2 for the enalapril group (p < 0.02). Changes in LV end-systolic volume indexes were 3.1 +/- 0.8 and 0.5 +/- 0.6 ml/m2, respectively (p < 0.02). The between-group difference was most marked in patients with anterior wall infarction (p < 0.005). Volume changes beyond the first month were similar in both groups but the differences observed at 1 month were maintained. The larger volumes in the placebo versus enalapril group were significant or borderline significant at 1 and 6 months. Thus, enalapril treatment initiated early after myocardial infarction and continued for 6 months can attenuate LV dilatation during the first month resulting in smaller LV volumes after 1 and 6 months.

The relationship between early plasma atrial natriuretic factor levels and exercise performance after myocardial infarction.

We tested the hypothesis that early plasma atrial natriuretic factor (ANF) values are related to subsequent functional capacity in patients with acute myocardial infarction (MI). Blood for ANF determination was sampled from 90 male patients (age 66.5 +/- 9.5 (mean +/- SD) years) day 3 post MI. Exercise testing on an upright bicycle ergometer to symptomatic end-points was performed 1 and 6 months after MI in 83 and 78 patients, respectively. A weak, but significant inverse relationship between day 3 plasma ANF levels and exercise duration after MI (1 month: r = -0.27, P = 0.012; 6 months: r = -0.36, P = 0.001) was observed. In the subgroup of patients without effort-associated ischaemia, the relationship was closer (1 month; n = 38, r = -0.57, P < 0.001; t months: n = 33, r = -0.65, P < 0.001). In multivariate analysis, with ANF, patient age and peak creatine kinase MB values as covariates, the relationship remained significant. These findings suggest that in male patients subacute plasma ANF measurements are predictive of exercise capacity following acute MI. The relationship appears to be especially prominent in patients without effort-related ischaemia during exercise.