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European Journal of Heart Failure 2003 5(1):47-53; doi:10.1016/S1388-9842(02)00205-2
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© 2002 European Society of Cardiology

Neurohormonal effects of furosemide withdrawal in elderly heart failure patients with normal systolic function

Dave J.W. van Kraaija,*, René W.M.M. Jansenb, Fred C.G.J. Sweepc and Willibrord H.L. Hoefnagelsb

a Department of Cardiology, Academic Hospital Maastricht Maastricht, The Netherlands
b Department of Geriatric Medicine, University Medical Center St. Radboud Nijmegen, The Netherlands
c Department of Chemical Endocrinology, University Medical Center St. Radboud Nijmegen, The Netherlands

* Corresponding author. Department of Cardiology, University Hospital Maastricht, P.O. Box 5800, 6200 AZ Maastricht, The Netherlands. Tel.: +31-43-387-5106; fax: +31-43-387-5104 E-mail address: dvankraaij{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: In heart failure patients, diuretics cause renin–angiotensin–aldosterone system (RAS) activation, which may lead to increased morbidity and mortality despite short-term symptomatic improvement.

Aim: To determine changes in RAS activation and clinical correlates following furosemide withdrawal in elderly heart failure patients without left ventricular systolic dysfunction.

Methods and results: We performed clinical assessments and laboratory determinations of aldosterone, plasma renin activity (PRA), atrial natriuretic peptide (ANP), norepinephrine, and endothelin in 29 heart failure patients [aged 75.1±0.7 (mean±S.E.M.) years], before, 1 and 3 months after placebo-controlled furosemide withdrawal. Recurrent congestion occurred in 2 of 19 patients withdrawn, and in 1 of 10 patients continuing on furosemide. Three months after withdrawal, PRA had decreased –1.61±0.71 nmol/l/h (P<0.05). Decreases in aldosterone levels did not reach significance (–0.17±0.38 nmol/l). The decreases in PRA after withdrawal correlated with decreases in systolic (rs=0.61, P=0.020) and diastolic blood pressure (rs=0.80, P=0.01). Successful withdrawal was associated with increases in norepinephrine (+0.58±0.22 nmol/l) and ANP (+3.5±1.3 pmol/l) (P<0.05) after 1 month, but these changes did not persist after 3 months. Endothelin levels did not change in both groups.

Conclusion: Successful furosemide withdrawal in elderly heart failure patients causes persistent decreases in RAS activation.

Key Words: Aged-80-and-over • Diuretic withdrawal • Diastolic heart failure • Renin–angiotensin system • Neurohormones

Received June 29, 2001; Revised July 6, 2002; Accepted July 12, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
In elderly heart failure patients, several (neuro-)hormonal systems are activated as a result of a complex interplay of both aging itself, the type, and severity of the heart failure, as well as the medications in use [1–3]. In particular, activation of the renin–angiotensin-system (RAS) is of pivotal importance in the pathophysiology, progression and prognosis of congestive heart failure [3–7]. Blocking of the RAS by angiotensin-converting-enzyme (ACE) inhibitors produces substantial improvement of the failing heart [8,9]. Furthermore, additional blocking of aldosterone receptors is associated with significant reductions in morbidity and mortality, as recently demonstrated [10]. In contrast, diuretics, which are most frequently prescribed in elderly heart failure patients, enhance activation of the RAS [11,12], and might thus increase morbidity and mortality despite short-term symptomatic improvement [5].

The role of chronic diuretic therapy in elderly heart failure patients may also be questioned for other reasons. In approximately 30–40% of elderly patients, heart failure is caused by impaired diastolic ventricular filling [13]. In these patients, preload reduction by diuretics might further impair diastolic filling of the left ventricle and lower cardiac output, thus provoking exercise intolerance, fatigue, and hypotension [14]. Nagano et al. reported up to 10% reductions in cardiac output after preload reducing therapy in hypertensive heart failure patients with intact left ventricular systolic function [15]. We recently demonstrated significant improvements in orthostatic and postprandial blood pressure homeostasis after diuretic withdrawal in elderly heart failure patients with intact left ventricular ejection fraction [16,17]. Elderly heart failure patients with intact systolic function appear critically dependent on adequate intravascular volume. Diuretics that reduce intravascular volume might thus be expected to cause disproportional activation of the RAS in these patients.

There is little experimental data on the neuroendocrine effects of diuretic therapy in older patients with diastolic heart failure. As part of a randomized placebo-controlled trial of furosemide withdrawal in elderly heart failure patients without current congestion and without left ventricular systolic dysfunction [17], we aimed a first pilot-study at determining the neuroendocrine changes, in particular with regard to RAS activation, following loop diuretic withdrawal. We hypothesized that successful furosemide withdrawal might cause significant reductions in RAS activation in these patients. We also explored whether hormonal changes were related to alterations in clinical parameters, such as heart failure symptoms, blood pressure, or heart rate.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients and protocol
Physicians from the departments of Internal Medicine and Cardiology of a local 700-bed non-academic teaching hospital, recruited patients via advertisements in newspapers, requesting participation in an investigation of furosemide withdrawal. For responders, a questionnaire was sent to the primary care physician to assess the current indication for furosemide and to obtain the physician's consent for withdrawal. Subsequent screening included echocardiography and bicycle ergometry and occurred according to the criteria listed in Table 1. These criteria have been described in detail elsewhere [16]. Ultimately, 32 elderly heart failure patients without left ventricular systolic dysfunction and without current clinically manifest congestion entered the trial. For logistic reasons, no blood samples could be taken in 3 of these 32 patients, leaving 29 patients included in the study. All patients gave their written informed consent to the study, which had received prior approval by the committee for experiments with human subjects of the University Hospital Nijmegen and the medical ethics committee of the Canisius-Wilhelmina Hospital. The investigations conformed with the principles outlined in the Declaration of Helsinki.


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  		Table 1 Inclusion and exclusion criteria

 
The study was designed as a randomized, placebo-controlled, double-blind trial of furosemide withdrawal [17]. After a 2-week run-in, patients were randomly assigned in a 2:1 ratio to withdrawal or continuation of furosemide, both groups were balanced for age, gender, cardiovascular comedications, and daily furosemide dose. Study medication consisted of a 1-week dose-halving regimen followed by placebo in the withdrawal group, and of matching daily furosemide in the continuation group. Drug compliance was assessed by means of tablet counts. No other medication was administered during the study as a substitute for loop diuretic therapy. At baseline, 24-h urine samples were collected for estimation of creatinine clearance and measurement of sodium content. Six follow-up visits took place over 3 months after randomization. History and physical examination were performed to determine the patients heart failure score [17,18]. Body weight to the nearest 0.1 kg (SECA electronic scale, Hamburg, Germany) and blood pressure (sphygmo-manometrically) were also measured. Chest X-rays were made to verify pulmonary congestion. The primary end point of the study was the requirement to restart or augment furosemide therapy during the 3-month follow-up period. Predefined criteria for unsuccessful withdrawal of furosemide were a heart failure score >7 points with verified pulmonary congestion on chest X-ray, and/or twice repeated systolic or diastolic blood pressure measurements >180 mmHg or >100 mmHg, respectively.

2.2. Blood collection and handling
Laboratory determinations were performed at baseline, and 1 and 3 months after start of furosemide withdrawal or continuation. An intravenous canula (short 18- or 20-gauge plastic catheter connected to a three-way valve) was inserted. The catheter was filled with diluted heparinized saline, and blood samples were obtained after 30 min of supine rest. After aspiration and discarding the catheter dead space, blood was collected for measurement of atrial natriuretic peptide (ANP), plasma renin activity (PRA), endothelin and aldosterone in pre-chilled K3-EDTA tubes and centrifuged for 10 min at 1500xg (4 °C) within 1 h. For ANP, PRA, and endothelin the plasma obtained was aliquoted in polystyrene tubes containing 250 KIU/ml plasma Trasylol (aprotonin, Bayer, Leverkusen, Germany), frozen and stored at –20 °C (PRA, endothelin) or –80 °C (ANP), respectively, until assayed. For aldosterone the plasma obtained was aliquoted in polystyrene tubes, frozen and stored at –20 °C. Blood samples for norepinephrine analysis were collected in precooled tubes containing 0.25 mol/l EDTA and 0.2 mol/l glutathione in distilled water. The blood samples were placed in melting ice, plasma was separated by refrigerated centrifugation (10 min at 1500xg), and frozen until assayed within 4 months of collection.

2.3. Hormonal measurements
Plasma ANP was measured by radioimmunoassay as described previously [19]. PRA was measured with the Phadebas Angiotensin-1 test (Pharmacia Diagnostics, Uppsala, Sweden). Plasma endothelin levels were quantitated after C18 extraction using a radioimmunoassay kit (Nichols Institute Diagnostics B.V., Wijchen, The Netherlands). Plasma aldosterone concentration was measured after extraction and paper chromatography as described by De Man et al. [20]. Plasma samples were analysed for norepinephrine using high performance liquid chromatography with fluorometric detection after selective precolumn derivatization of the catecholamines with the fluorescent agent 1,2 diphenylethylenediamine [21].

2.4. Statistical analysis
Data are presented as means±S.E.M. or means with 95% confidence intervals. Appropriate independent randomization was tested with {chi}2 and Fisher's exact tests for proportions and t-tests for continuous variables. Changes in laboratory parameters were compared to baseline values using Wilcoxon's rank-sum test, as were differences between the patients withdrawn and the patients continuing on furosemide. A two-sided P-value <0.05 was considered significant. Analysis was carried out using the SPSS for Windows 6.1 package (SPSS Inc., 1994).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Patients (13 male, 16 female) had a mean age of 75.1±0.7 years. They were using furosemide in an average dose of 34±3 mg. The average baseline heart failure classification score was 1.6±0.3 points, and the left ventricular ejection fraction was 60±2%. Ejection fraction was 57±18% in the 10 patients with a history of previous myocardial infarction. Baseline creatinine clearance was 68±5 ml/min, 24 h natriuresis was 124±60 mmol/l. Of the 29 patients, 19 were randomized to withdrawal (=placebo) and 10 to continuation of furosemide. Baseline clinical and echocardiographic characteristics were not significantly different between the 2 groups (Table 2). Compliance was computed at 98% in the withdrawal group and 96% in the continuation group. During the 3 month follow-up, 2 patients from the withdrawal group and 1 from the continuation group experienced an episode of recurrent congestive heart failure necessitating restart or augmentation of furosemide, respectively. Three other patients from the withdrawal group restarted because of ankle edema (n=2) and hypertension (n=1).


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  		Table 2 Baseline characteristics of 29 heart failure patients

 
Table 3 shows that there were no significant baseline differences in neurohormone levels between the patients successfully withdrawn (n=15), and the patients that continued on a constant dose of furosemide (n=9), although adrenergic and reninergic activation appeared somewhat higher in the withdrawal group. Baseline hormone levels were also not correlated to initial furosemide dose. At baseline, epinephrine levels were higher in men compared to women (0.32±0.05 nmol/l vs. 0.18±0.02 nmol/l, P<0.05) and PRA was higher in patients using ACE inhibitors compared to patients not using these medications (5.74±1.80 vs. 2.08±0.51 nmol/l/h, P<0.05). There were no mutual correlations between baseline hormone levels, with the exception of PRA and norepinephrine levels, which demonstrated a weak correlation (rs=0.53, P=0.01). Baseline plasma hormone levels did not differ for the 6 patients who restarted on furosemide.


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  		Table 3 Baseline neuroendocrine levels in patients successfully withdrawn from furosemide (n=15) and patients continuing on furosemide (n=9)

 
Figs. 1 and 2 show heart failure scores, weight, blood pressure, heart rate and plasma neurohormone concentrations, at baseline and 1 and 3 months after successful furosemide withdrawal. There were no significant changes in heart failure score, body weight, blood pressure, or heart rate after successful withdrawal. After 3 months, PRA had decreased significantly in 11 of 15 patients successfully withdrawn from furosemide, on average from 3.21±0.80 to 1.60±0.30 nmol/l/h (P<0.05). Aldosterone levels decreased in 10 of 15 patients, but the average decrease was not significant (from 0.40±0.11 to 0.22±0.03, P=0.10). The decline in PRA levels after withdrawal was correlated to decreases in systolic (rs=0.61, P=0.02) and diastolic blood pressure (rs=0.80, P=0.01). Successful withdrawal was accompanied by temporary increases in body weight (+0.6±0.2 kg, P<0.05), and plasma concentrations of norepinephrine (+0.58±0.22 nmol/l) and ANP (+3.5±1.3 pmol/l) (P<0.05) after 1 month. However, 3 months after withdrawal, body weight had returned to baseline values (+0.3±0.3 kg), and norepinephrine levels (–0.30±0.14 nmol/l, P=0.11) and ANP levels (+2.6±1.5 pmol/l, P=0.07) were not significantly different compared to baseline levels. During this trial, no changes in plasma endothelin levels occurred after successful withdrawal. In the continuation group, PRA and aldosterone levels tended to increase during the 3 months (from 2.39±1.10 to 3.88±2.44 nmol/l/h and from 0.27±0.04 to 0.42±0.26 nmol/l, respectively), whereas norepinephrine levels appeared to show a temporary increase after 1 month (from 2.11±0.34 to 3.23±0.54 nmol/l). However, we did not observe significant changes in neurohormonal levels in this group.


Figure 1
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  		Fig. 1 Heart failure symptom score (panel A), body weight (panel B), systolic blood pressure (panel C), diastolic blood pressure (panel D), and heart rate (panel E) for patients successfully withdrawn from furosemide (circles, n=15), and patients continuing on furosemide (triangles, n=9), at baseline, and 1 month and 3 months after withdrawal. Bars represent means±standard error. *P<0.05 compared to baseline.

 


Figure 2
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  		Fig. 2 Plasma levels of atrial natriuretic peptide (ANP, panel A), endothelin (panel B), plasma renin activity (PRA, panel C), aldosterone (panel D), and norepinephrine (panel E) for patients successfully withdrawn from furosemide (circles, n=15), and patients continuing on furosemide (triangles, n=9), at baseline, and 1 month and 3 months after withdrawal. Bars represent mean±standard error. *P<0.05 compared to baseline.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In this placebo-controlled pilot study of furosemide withdrawal in elderly heart failure patients with normal systolic function and without manifest congestion, successful withdrawal was achieved in 16 of 19 patients without changes in heart failure score, body weight, blood pressure or heart rate. Successful withdrawal was associated with a decreases in PRA and aldosterone levels in most patients, and the decline in PRA was correlated to decrements in systolic and diastolic blood pressure. After withdrawal, temporary increases occurred in body weight, norepinephrine and ANP levels. Withdrawal did not appear to influence plasma endothelin levels.

Activation of the RAS is of pathophysiologic and prognostic importance in heart failure [4,22]. ACE inhibitors improve symptoms and survival in heart failure patients, in part by inhibiting endocrine activation [8,9]. Blockade of aldosterone receptors by spironolactone in addition to standard therapy also substantially reduces morbidity and mortality in heart failure patients [10]. In contrast, diuretics enhance RAS stimulation [11,23], both in asymptomatic [12] as well as in elderly heart failure patients [3]. By activating the RAS, diuretics may reinforce fluid retention and peripheral vasoconstriction, as well as complicating attempts at subsequent introduction of ACE-inhibitor therapy. In the patients continuing on furosemide in our study, PRA and aldosterone levels tended to increase, possibly because of improved compliance with their diuretic. The present study demonstrates that successful withdrawal of furosemide in heart failure patients without overt congestion may reduce PRA and aldosterone levels. Therefore, in our opinion, reducing or withdrawing diuretic therapy is a fundamental and elegant way of reducing the risk of morbidity and mortality in heart failure patients, and should not be overlooked in heart failure treatment.

Elevated levels of plasma ANP have been related to both aging itself [2] as well as increased left atrial pressures in patients with congestive heart failure [24,25]. We found temporary increases in body weight and plasma ANP levels, occurring 1 month after furosemide withdrawal. After 3 months, ANP levels were no longer significantly different from baseline. A possible explanation might be a physiologic increase in intravascular volume after stopping diuretics [25], which might also signify improved left ventricular filling in these patients. An additional explanation could be the occurrence of temporary rebound fluid retention as previously documented [26,27].

Norepinephrine levels increased 1 month after furosemide withdrawal, but not after 3 months, when levels tended to be lower than baseline. The latter might signify a decline in sympathetic nervous system arousal after withdrawal, which would be in line with the decreases observed in PRA and aldosterone levels. We do not have a clear explanation for the apparent temporary increase in norepinephrine levels in both the withdrawal and continuation groups after 1 month. Endothelin-1 is an endothelium-derived peptide with important vasoconstrictor and inotropic properties, and may be an important predictor of clinical outcome in heart failure patients [28,29]. Early clinical studies with endothelin receptor antagonists suggest beneficial hemodynamic effects, and these medications even seem capable of blunting the diuretic-induced activation of RAS [30]. However, data on endothelin levels in elderly patients with heart failure and intact left ventricular function are lacking. We did not find any effects of withdrawing diuretic therapy on endothelin-1 levels. Therefore, the role of endothelin-1 among the other compensatory neurohormonal systems in this particular patient population remains to be established.

An important limitation to the present study was the small number of patients involved. Neurohormone levels may show considerable within-patient variability [31], and correlations of neurohormonal levels and clinical parameters could not be analysed sufficiently. For the same reasons, we were unable to correct for possible effects of the medications used by the patients, nor for possible differences in heart failure etiology. Investigation of the long-term neuroendocine effects of diuretic withdrawal and its consequences for morbidity and mortality also fell beyond the scope of the present study. We were unable to obtain data on angiotensin-II levels, although the interpretation of these levels might be complicated because of the use of various types and doses of ACE-inhibitors in our patients. Our results may also not apply to chronic very low-dosed diuretic therapy. Nevertheless, the results of this randomized pilot study may apply to a very large group of elderly heart failure patients without left ventricular systolic dysfunction using diuretics long-term, and they must be cautiously substantiated in future studies.

In conclusion, the present study demonstrates that diuretic withdrawal is frequently possible in non-congested elderly heart failure patients with a preserved left ventricular systolic function. Successful withdrawal is associated with decreases in PRA and possibly aldosterone and norepinephrine levels that appear to reflect reductions in neurohormonal activation. As reduced neurohormonal compensatory activity has been associated with improved morbidity and mortality risks in heart failure patient populations, these preliminary data therefore suggest that reducing diuretic therapy may be an important way of attenuating these risks. Heart failure patients should not automatically receive long-term furosemide therapy, unless this is proven necessary to treat or prevent congestive heart failure. Attempts at withdrawing diuretic therapy should be integrated in heart failure treatment of elderly patients with normal systolic function.


   Acknowledgements
 
This study was supported by the Netherlands Program for Research on Aging, NESTOR, funded by the Ministry of Education, Culture and Science, and the Ministry of Health, Welfare and Sports. The authors thank Henk J.J. van Lier, M.Sc., Department of Medical Statistics and Epidemiology, University of Nijmegen, The Netherlands, for his help with the statistical analyses, and the staff of the Laboratory of Chemical Endocrinology, University Medical Center St. Radboud, Nijmegen, The Netherlands, for their help in performing this study.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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