Asian Cardiovasc Thorac Ann 2001;9:302-307
© 2001 Asia Publishing EXchange Pte Ltd
Losartan in the Therapy of Heart Failure Patients
Alexander E Berezin, MD
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Department of Hospital Therapy State Medical University Zaporozhye, Ukraine
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For reprint information contact: Alexander E Berezin, MD Tel: 380 612 72 9607 Fax: 380 612 12 3777 email: megacat{at}mail.ru Department of Hospital Therapy, State Medical University, Chujkow Street, Box 6323, Zaporozhye UA-69121, Ukraine.
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ABSTRACT
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The effects of losartan on myocardial remodeling and neurohumoral status were studied in 240 patients with congestive heart failure. The patients were randomized into 3 groups of 80 subjects. Each group continued to receive conventional therapy including the angiotensin-converting enzyme inhibitor enalapril. Group 1 was also given a placebo, groups 2 and 3 had losartan in doses of 25 mg and 50 mg daily, respectively. The course of treatment was 48 weeks. Cardiac function was assessed by B-mode and Doppler echocardiography. Plasma neurohormone levels were determined by radioimmunoassay. Losartan in a dose of 50 mg daily gave the best improvement in cardiac function and the most marked reduction in plasma levels of renin, angiotensin II, aldosterone, atrial natriuretic peptide, endothelin-1, and norepinephrine levels than the lower dose of losartan or placebo. The fall in cortisol and serotonin levels was similar in each group. These data demonstrate the dose-dependent effects of losartan and clarify its role in the treatment of congestive heart failure.
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INTRODUCTION
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Heart failure is an invariably fatal stage in the majority of cardiovascular diseases. Improving the prognosis for patients with congestive heart failure (CHF) is a major aim of modern medication. Currently, excessive activation of the renin-angiotensin and sympathoadrenal systems are considered to be independent risk factors for sudden death and acute coronary syndromes, as well as the initiation and progression of CHF.1 Neurohumoral activation in patients with left ventricular (LV) dysfunction is associated with elevated circulating and local levels of catecholamines, vasopressin, endothelin, atrial natriuretic peptide, renin, and angiotensin II.2 Recent research has indicated that remodeling of the heart and blood vessels in CHF involves neurohumoral activation and is associated with an expansion of the collagen matrix, hypertrophy of cardiac myocytes, cytoarchitectonic disturbances of the myocardium and vessels, and a decline in cardiac wall kinetic parameters.3 Agents that limit the influence of circulating and locally active components of the renin-angiotensin and sympathoadrenal systems, such as angiotensin-II receptor antagonists, are considered to prevent remodeling and improve the quality of life and survival in CHF patients.4 On the other hand, AT1 antagonists were found to have no substantial influence on survival in CHF, and no superiority over angiotensin-converting enzyme (ACE) inhibitors.5 However, the role of AT1 antagonists in clinical practice has not been completely defined.6 The aim of this study was to examine the influence of the AT1 receptor antagonist losartan on myocardial remodeling and neurohumoral status in patients with CHF.
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PATIENTS AND METHODS
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Informed consent was obtained from 240 patients with CHF in New York Heart Association functional classes II to IV due to ischemic heart disease. Ages ranged from 41 to 68 years. Inclusion criteria were LV end-diastolic volume > 160 mL, left ventricular ejection fraction (LVEF) < 35%, and sinus rhythm. Exclusion criteria were atrial fibrillation, sick sinus syndrome, second or third-degree atrioventricular block, stroke, uncontrolled arterial hypertension, hepatic dysfunction, renal dysfunction with plasma creatinine > 140 µmol•L-1, a change in basic CHF therapy during the 3 weeks before randomization, myocardial infarction within 6 weeks of the study, prior treatment with an AT1 antagonist, or contraindications to an AT1 antagonist.
All patients were stabilized by conventional oral therapy comprising furosemide 280–740 mg weekly, and daily doses of isosorbide dinitrate (40–80 mg), aspirin (125–250 mg), digoxin (0.25–0.5 mg), and the ACE inhibitor enalapril 10 mg. Enalapril dosage was increased by 2.5 mg per day during the run-up to the study (1–3 weeks) to assess tolerance to the drug. Enalapril-intolerant patients were not included in the study. Three weeks after the start of the run-up period, the patients were randomized into 3 groups of 80 subjects each. A placebo was added to the CHF therapy in group 1. Group 2 patients received CHF therapy plus losartan 25 mg daily, orally (low dose). Group 3 patients received CHF therapy and losartan 50 mg (high dose). The course of treatment was 48 weeks. Losartan was donated by Merck Sharp and Dohme, Inc. (Whitehouse Station, NJ, USA), aspirin was supplied by Bayer Diagnostic GmbH (Munich, Germany), and isosorbide dinitrate was the gift of Schwarz Pharma (Monheim, Germany).
All patients underwent a physical examination, blood pressure and body mass measurements, echocardiography, electrocardiograms, and blood sampling within 6 hours before randomization. After resting for 10 minutes in the sitting position, blood pressure (BP) was measured in the nondominant arm using a mercury sphygmomanometer. The mean of 3 BP measurements taken at 2-minute intervals was recorded (diastolic BP = fifth Korotkoff sound). Systolic, diastolic, and mean BP, and body mass were measured every 3 weeks. Electrocardiograms were carried out at baseline and at every admission of patients to the clinic and/or every 3 weeks. M-mode and B-mode echocardiography was performed according to the recommendations of the American Society of Echo-cardiography, in apical 4-chamber and parasternal views, every 3 weeks.7 Echocardiographic studies were carried out with a Sonoline Versa Plus (Siemens AG, Munich, Germany) using a transducer with a frequency of 5 MHz. LV wall thickness and short-axis dimensions in diastole and systole were measured serially by M-mode echo-cardiography. LV long-axis dimensions in diastole and systole were determined by B-mode echocardiography. LV end-diastolic and end-systolic volumes were obtained using a two-dimensional reference sector in Simpson's method.8 Two-dimensional echo and Doppler tracings were recorded over 8 cardiac cycles and stored on video-tape for later playback and analysis. LV stroke volume and ejection fraction were determined. Peripheral vascular resistance (PVR) was calculated (in PVR units) by:
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where BM = body mass, HR = heart rate, MBP = mean blood pressure, SV = stroke volume. Myocardial stress index (MSI) was derived from:
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where Ls = end-systolic left ventricular long-axis dimension, LVPWs = systolic left ventricular posterior wall thickness, SBP = systolic blood pressure, and Rs = end-systolic left ventricular short-axis dimension. Diastolic left ventricular sphere index was defined as the ratio of LV end-diastolic short-axis dimension to LV end-diastolic long-axis dimension. Pulsed-wave Doppler was used to assess LV diastolic filling.9 To record transmitral filling velocity, the sample volume of the pulsed-wave Doppler was placed between the tips of the mitral leaflets in apical 4-chamber view. Three consecutive cardiac cycles were used to obtain a mean for each parameter. Isovolumic relaxation time, early diastolic filling velocity, and late diastolic filling velocity were recorded. The Doppler index was calculated as the ratio of early to late diastolic filling velocity.
Blood samples (15 mL) were taken between 6 pm and 9 pm on the first and last days of the study period. The samples were collected in heparin-coated tubes (Vacutainer; Becton, Dickinson and Company, Franklin Lakes, NJ, USA) and immediately centrifuged (1,500 g, 10 minutes, 4°C). The plasma was removed and stored at –80°C until tested. After ethanol extraction and vacuum lyophilization, the plasma samples were analyzed with radioimmunoassay kits (Amersham Pharmacia Biotech, Piscataway, NJ, USA) for renin, angiotensin II, aldosterone, atrial natriuretic peptide (ANP), endothelin-1, norepinephrine, cortisol, and serotonin. Aldosterone was measured with an Immunotech (Marseille, France) test kit.
Data are presented as mean ± standard deviation. The paired Student t test was used to compare cardiac hemodynamic parameters and neurohormone levels at baseline with those measured after 48 weeks. Differences between values with nonparametric dispersion were evaluated by analysis of variance; if this revealed signifi-cant differences, the Tukey test for multiple comparisons was employed. Values were considered significantly different when p < 0.05. Correlations were determined by linear regression analysis. These statistical comparisons were performed with NCSS software (Unisoft; Athens, Greece).
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RESULTS
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The clinical characteristics of the study population are given in Table 1
. The majority of patients were in New York Heart Association functional class III, and Canadian Cardiology Society angina class III, with LVEFs of 25% to 29%. Although 49% of patients had a history of myocardial infarction, local contractility disturbances (LV akinetic and dyskinetic zones) were found in 65%, and mitral regurgitation in 89%. Hemodynamic data are presented in Table 2. LV end-diastolic volume pro-gressively increased during the 48-week study in all 3 groups, but the increase was not statistically significant in group 3. LV end-systolic volume increased in groups 1 and 2; it decreased in group 3 but not significantly (p > 0.5). Stroke volume increased in all groups (p > 0.5). The high dose of losartan was associated with an increase in LVEF after 48 weeks, although it was not significantly higher than baseline. Peripheral vascular resistance tended to the decrease, especially in group 3 (p > 0.5). Diastolic LV sphere index values were unchanged. There were significant decreases in myocardial stress index in all groups (p < 0.5), and this was most marked in group 3. Isovolumic relaxation time and Doppler index tended to fall, particularly in group 3 (p > 0.5).
Changes in plasma neurohormones and peptides are shown in Table 3. There were no significant differences among the 3 groups. However, plasma angiotensin II, aldosterone, endothelin-1, cortisol, and norepinephrine were signifi-cantly decreased in group 3 patients at the end of the study. Cortisol levels were also reduced in groups 1 and 2. The results of multivariate regression analysis are presented in Table 4. The dose of losartan correlated best with peripheral vascular resistance, endothelin-1, norepinephrine, aldosterone, and LVEF.
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DISCUSSION
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Previous studies showing favorable hemodynamic effects of losartan make it rather attractive in the treatment of patients with CHF.10,11 Initially, it was postulated that losartan might be useful in patients who could not tolerate ACE inhibitors.12 On the other hand, the recently completed ELITE-II trial did not demonstrate improved survival due to losartan compared with the ACE inhibitor captopril in elderly CHF patients.5 It has been speculated that the combination of an AT1 antagonist and an ACE inhibitor might favorably influence the course of CHF.13 However, the RESOLVD study failed to demonstrate a significant advantage of combined therapy compared to AT1 antagonist or ACE inhibitor alone, in terms of long-term prognosis in patients with CHF. However, the AT1 antagonist candesartan and the ACE inhibitor enalapril in combination improved LVEF more effectively than either drug alone after 48 weeks, and enalapril plus candesartan slightly decreased LV end-diastolic volume compared to control groups.14 In spite of the enhanced hemodynamic status, long-term prognosis was not improved by the combined therapy. Nevertheless, the possibility of improving the outcome of CHF by ACE inhibition and AT1 antagonism continues to interest many investigators.15,16
This study demonstrated the dose-dependent nature of the effects of an AT1 antagonist in CHF patients. The low dose of losartan did not increase the efficacy of conventional therapy, whereas the high dose had a significant favorable influence on hemodynamics and LV remodeling. An experimental study suggested that AT1 antagonists could improve survival rates in CHF and limit LV remodeling.17 It is also known that the hemodynamic effects of losartan are partially abolished by the administration of captopril.18 The data obtained in this study demonstrate that while the standard combination ACE inhibitor + diuretic + vasodilator did not prevent the gradual increase in LV end-diastolic volume and decrease in ejection fraction over 48 weeks, addition of losartan in a high dose (50 mg per day) modified the progress of cardiac failure and significantly decreased plasma levels of angiotensin II, aldosterone, endothelin-l, and norepinephrine. The correlation between New York Heart Association functional class, hemodynamic performance, neurohumoral activation, and losartan dosage corroborates the greater efficacy of the higher dose regimen.
Plasma renin, atrial natriuretic peptide, cortisol and serotonin were reduced by both the high and low doses of losartan in CHF patients receiving conventional therapy with enalapril. Neurohumoral activation is an independent risk factor of unfavorable prognosis in CHF.19 However, ACE inhibition does not always result in substantial changes in the neurohumoral profile, which may be due to low plasma renin and angiotensin II levels, DD genotype of ACE, or genetic variations in beta-receptor affinity.20,21 Therefore, it is reasonable to add an AT1 antagonist to the treatment of patients with CHF. The findings in this study clarify the neurohumoral effects of losartan in CHF, which is dose-dependent and more pronounced than those of the ACE inhibitor enalapril. It is postulated that losartan, in addition to ACE inhibitor therapy, may influence the long-term outcome of CHF, and further clinical investigations and longer follow-up are warranted.
Presented at the 3rd International Congress on Coronary Artery Disease — From Prevention to Intervention, Lyon, France, October 2–5, 2000.
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Acknowledgments
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This study was supported by the Ministry Board of Ukraine, the Ukraine Cardiology Association, and Merck Sharp and Dohme, Inc. (USA). I am grateful to Professor A. D. Vizir, MD, rector of Zaporozhye Medical University, Academician of National Ukrainian Academy of Sciences and Ukrainian Academy of Medical Sciences, and Professor V. A. Vizir, MD, Chief of the Hospital Therapy Department of Zaporozhye Medical University.
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ABSTRACT
INTRODUCTION
