© 2004 European Society of Cardiology
Clinical and neurohumoral consequences of diuretic withdrawal in patients with chronic, stabilized heart failure and systolic dysfunction
a Servei de Cardiologia, Hospital General Universitari Vall d'Hebron Pg Vall d'Hebron 119-129, 08035 Barcelona, Spain
b Servei de Bioquímica Hospital General Universitari Vall d'Hebron, Barcelona, Spain
* Corresponding author. Tel.: +34 93 274 6134; fax: +34 93 274 6063. E-mial address: egalve{at}vhebron.net
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Abstract |
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 Top Abstract 1. Introduction and study...2. Methods3. Results4. DiscussionReferences |
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Background: Loop diuretics are beneficial in heart failure in the short term because they eliminate fluid retention, but in the long-term, they could adversely influence prognosis due to activation of neurohumoral mechanisms.
Aims: To explore the changes induced by diuretic withdrawal in chronic nonadvanced heart failure.
Methods: Diuretics were withdrawn in 26 stabilized heart failure patients with systolic dysfunction (ejection fraction [EF]<45%). Clinical status was evaluated by physical exam, exercise capacity (corridor test) and New York Heart Association (NYHA) class. Biochemical and neurohumoral determinations were performed at baseline and at 3 months.
Results: At 3 months, 17 out of 26 patients (65%) were able to tolerate diuretic interruption without a deterioration in exercise capacity or New York Heart Association functional class. Renal function parameters improved (baseline urea 46.2±10.8 to 39.2±10.1 mg/dl at 3 months, p=0.014; creatinine 1.1±0.23 to 0.98±0.2 mg/dl, p=0.013). Glucose metabolism also improved (fasting glucose 151±91 to 122±14 mg/dl, p=0.035). Heart rate and systolic blood pressure did not significantly change, while diastolic blood pressure increased (from 80±10 to 87±13 mm Hg, p=0.006). Neurohumoral determinations showed a decrease in plasma renin activity (4.19±5.96 to 2.88±4.98 ng/ml, p=0.026), with no changes in aldosterone, arginine-vasopressin, endothelin-1 and norepinephrine. In contrast, atrial natriuretic peptide significantly increased (115±87 to 168±155 pg/ml, p=0.004).
Conclusion: Diuretic withdrawal in stabilized heart failure with systolic dysfunction is associated with an improvement in renal function parameters, glucose metabolism and some neurohumoral parameters, such as plasma renin activity; however, atrial natriuretic peptide levels increased.
Key Words: Heart failure • Diuretics • Neurohumoral activation
Received April 19, 2004; Revised September 14, 2004; Accepted September 20, 2004
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1. Introduction and study rationale |
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TopAbstract1. Introduction and study...2. Methods3. Results4. DiscussionReferences |
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Heart failure is a chronic disease with increasing prevalence and poor midterm prognosis [1]. Patients with heart failure receive a large number of drugs, and diuretics are considered first choice [2]. Diuretics are useful in avoiding the natural tendency of these patients to retain liquids and salt. Nevertheless, it has been suggested that loop diuretics increase the neurohumoral activation (renin–angiotensin–aldosterone, sympathoadrenal and other systems) in heart failure [3,4]. Considering that neurohumoral hyperactivation has been associated with an adverse prognosis [5], it could be speculated that diuretics are beneficial in the short term because of their ability to eliminate fluid retention, but in the mid or long-term, they could adversely influence prognosis due to neurohumoral mechanisms.
Although diuretics are necessary in decompensated heart failure with signs of congestion, to ameliorate symptoms such as dyspnea, orthopnea or edema, it may be possible in some cases, after proper stabilization, that diuretics could be withdrawn for a certain period of time. This study focuses on this particular clinical scenario. The aim of this study was to determine the clinical changes and neurohumoral modifications that occur after withdrawing loop diuretics in patients with stabilized mild heart failure (New York Heart Association (NYHA) class II). Specifically, the study was performed in patients with systolic heart failure, which has not been done previously.
The objectives are (1) to determine the clinical changes induced by withdrawing loop diuretics in patients with chronic stabilized systolic heart failure and 2) to examine the modifications in biochemical and neurohumoral parameters associated with the withdrawal.
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2. Methods |
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The study was conducted in our heart failure clinic, was approved by the Institutional Review Board, and all patients provided written informed consent.
2.1. Patient selection
Twenty-six consecutive patients aged 61±13 years old (range 32–80) with a history of heart failure were recruited. Inclusion criteria were as follows: (1) patients of both genders aged >18 years old; (2) evidence of symptomatic heart failure with past history of NYHA class III or IV; (3) patients had to be stable NYHA class II over the previous 3 months; (4) left ventricular ejection fraction <45% (based on contrast ventriculography, radionuclide scan or echocardiography) within the last 3 months; (5) no symptoms or signs of congestion at the time of inclusion (absence of edema, liver stasis, orthopnea, paroxysmal nocturnal dyspnea, rales, pleural effusion or Kerley B lines on chest X-ray); and (6) in addition, at the time of inclusion, patients were required to be on loop diuretics (maximal dosage 80 mg of furosemide or equivalent) and angiotensin converting inhibitors, digitalis or other vasodilators being optional. Doses should have been unchanged during the last 3 months. Exclusion criteria were as follows: (1) renal disease defined as serum creatinine concentration above 2.0 mg/dl or BUN above 100 mg/dl; (2) intrinsic liver disease; (3) chronic, clinically significant pulmonary airway disease; (4) acute coronary syndrome within the last 3 months; (5) any extracardiac disease that could modify clinical status or prognosis in the short–midterm; (6) treatment with any diuretic other than that under investigation; (7) treatment with drugs that could modify neurohumoral status, such as dopamine agonists or antagonists, beta blockers, spironolactone or calcium antagonists; and (8) alcohol or drug addiction. During the course of the study and in view of the expanding use and benefits of beta blockers in heart failure, the prohibition of these drugs was reconsidered, and they were permitted in the follow-up after the 3-month determinations.
2.2. Study design
To assess clinical stability, patients were assessed in our outpatient clinic 1 week before the baseline visit. Informed consent, medical history, physical exam, weight and blood pressure, NYHA class and ECG were obtained. An exercise test (6-min corridor test) was also performed. One week after the screening visit, all the procedures were repeated, the neurohumoral determinations were performed, and the corridor test repeated (the data obtained at this visit were taken as the baseline for comparison with the follow-up data). At this baseline visit, the diuretics were discontinued. Fifteen days after this baseline visit, patients were reevaluated (only physical exam, weight, NYHA class and ECG) to rule out any decompensation after the diuretic withdrawal. Afterwards, patients were assessed again at 3 months (physical exam, weight, blood pressure, NYHA class, corridor test and neurohumoral analysis). Intermediate visits were done if necessary for clinical purposes. No drug changes to optimize heart failure therapy were permitted during the first 3 months (with the exception of diuretic reinitiation). At 12 months, a final follow-up visit was performed to evaluate clinical status. Special care was taken in maintaining a low and stable salt intake throughout the study.
2.3. Neurohumoral study
Venous blood samples were obtained by venipuncture in the morning between 8 and 9 a.m. in fasting state and before taking any medication. Patients had to rest in the supine position during 30 min in a quiet environment before blood collection. For plasma renin activity, vasopressin, endothelin-1, atrial natriuretic peptide and norepinephrine measurements, venous blood was collected in EDTA at 4 °C and immediately transferred to precooled plastic tubes containing trasylol (500 KIU/ml) to prevent proteolysis. For aldosterone determinations, venous blood was collected in vacutainer tubes. Samples were centrifuged at 3.000 rpm at 4 °C for 20 min to separate the plasma. Plasma was stored at –70 °C until analysis.
All samples for each patient were analyzed in one assay in a blinded manner without knowledge of the patient's characteristics. Aldosterone and plasma renin activity were determined from nonextracted samples by iodine-125 radioimmunoassay reagent kits (DiaSorin, Saluggia, Vercelli, Italy). Minimum detectable concentrations were 0.05 nmol/l and 0.20 ng/ml, respectively (95% CI). Intra- and interassay coefficients of variation were 8.2% and 10.4% for aldosterone, and 7.7% and 10.4% for plasma renin activity, respectively. Vasopressin was determined with an iodine-125 radioimmunoassay kit (Buhlman Laboratories, Basel, Switzerland) after solid-phase extraction of the plasma samples with reversed-phase columns C 18 (Sep-Pak Waters, Milford, CT). The minimum detectable dose was 0.35 pg/ml. Intra- and interassay coefficients of variation were 7.2% and 11.2%, respectively. Norepinephrine was analyzed by a competitive iodine-125 radioimmunoassay reagent kit (IBL, Hamburg, Germany) with a previous extraction procedure in macrotiter plates. The minimum detectable dose was 0.15 ng/ml. Intra- and interassay coefficients of variation were 9.3% and 10.8%, respectively. Atrial natriuretic peptide was measured in plasma by an iodine-125 competitive radioimmunoassay kit (DiaSorin, Saluggia, Vercelli, Italy) after a sample extraction with octadecasilyl silica columns (C 18 Sep-Pak). The assay detection limit was 32 pg/ml. Intra- and interassay coefficients of variation were 9.1% and 10.2%, respectively. Plasma immunoreactive endothelin-1 was determined by an iodine-125 radioimmunoassay method (Peninsula Laboratories, Belmont, CA) after and extraction–concentration procedure with C 18 columns using 60% acetonitrile in 0.1% trifluoroacetic acid for the peptide elution. The detection limit of the assay was 2 pg/tube. Intra- and interassay variations were 8.7% and 11.8%, respectively.
All neurohumoral determinations were performed in plasma except for aldosterone, which was performed in serum.
2.4. Reinitiation of diuretic therapy
Diuretic therapy was restarted if the patient described worsening congestive heart failure symptoms (progressive dyspnea on exertion or at rest, orthopnea, paroxysmal nocturnal dyspnea, abdominal swelling or peripheral edema), and the investigator confirmed objectives findings of deterioration (weight gain, jugular venous distension, ventricular gallop, rales, hepatomegaly, ascites or edema). Otherwise, patients were continued without diuretics (last visit included).
2.5. Statistical analysis
Statistical analysis was done using STATA 6.0. Nonparametric tests were used due to the small sample size. For comparisons between groups, the U Mann-Whitney test was used to compare independent groups, and the Friedman test was used to compare different observations across time. Statistical significance was defined as p<0.05.
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3. Results |
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3.1. Baseline characteristics
Twenty-six patients were enrolled, mean age was 61±13 years old (range 32–80), and 20 were males. Eleven patients had ischaemic cardiomyopathy, nine idiopathic cardiomyopathy and six miscellaneous (hypertensive, hypertrophic, postchemotherapy). Six patients had diabetes mellitus. Mean ejection fraction was 34±10 (range 16–43). Eight patients had never been admitted to hospital for heart failure, while 14 had been admitted once, three patients twice and one patient on three occasions. All patients were on oral furosemide; 23 were receiving 40 mg daily, one patient was receiving 20 mg, and two patients were receiving 80 mg. Other drugs that they were receiving were angiotensin converting enzyme inhibitors in all cases, digoxin in 12 cases, nitrates in 5 cases, antiagregants in 10 cases, coumadin in 11 cases, lipid lowering agents in 3 cases and amiodarone in 6 cases. There were no patients on beta blockers, angiotensin II antagonists or other drugs with neurohormonal properties. All patients were in NYHA class II. The clinical, echocardiographic and neurohumoral parameters are shown in Table 1.
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3.2. Patients that tolerated diuretic withdrawal
Seventeen out of 26 (65%) patients tolerated diuretic withdrawal throughout the 3 months of study follow-up. These patients had a modest body weight increase (from 70.2 to 71.0 kg at 3 months). There was no deterioration in clinical status (no admissions, no relevant clinical events, no deaths, none lost to follow-up). At baseline, all patients were in NYHA class II; at the 15-day and 3-month visits, two patients were in class I, and the rest remained in class II. Diuretic withdrawal was not associated with distance reduction in the 6-min walk test (baseline 376±84 m, 3 months 375±89 m, p=ns).
Table 2 summarizes the clinical and neurohumoral data. After 3 months without diuretics, renal function significantly improved (urea 46.2±10.8 to 39.2±10.1 mg/dl, p=0.014; creatinine 1.10±0.23 to 0.98±0.20 mg/dl, p=0.013), glucose metabolism improved as well (fasting glucose 151±91 to 122±41 mg/dl, p=0.035). Heart rate and systolic blood pressure did not significantly change, while diastolic blood pressure increased (from 80±10 to 87±13 mm Hg, p=0.006). With respect to the neurohumoral determinations, the discontinuation of diuretic therapy was associated at 3 months with a decrease in plasma renin activity (from 4.19±5.96 to 2.88±4.98 ng/ml, p=0.026), and no changes in aldosterone, vasopressin, endothelin-1 and norepinephrine. In contrast, atrial natriuretic peptide significantly increased during the same period (from baseline 115±87 to 168±155 pg/ml at 3 months, p=0.004).
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3.3. Patients requiring diuretic reinitiation
Nine patients (35%) required diuretic reinitiation at some time during the initial 3 months of follow-up. The median time to reinitiation was 33 days (range 2–83). None of these patients needed hospital readmission for diuretic reinitiation. In five cases, the reinitiation was performed during an outpatient visit to our clinic, two patients reinitiated diuretics on their own for symptoms of dyspnea or edema, and in two cases, reinitiation occurred after a transient admission to the emergency ward (that is, the patient was discharged in less that 12 h and without other drug interventions, such as inotropic support).
Evaluation of neurohumoral changes in this group of patients showed that plasma renin activity did not change (baseline 3.4±4.0 to 3.2±2.9 ng/ml at 3 months), and there was a global tendency to an increase in other neurohumoral parameters, but this was not statistically significant: aldosterone baseline 0.3±0.2 to 0.5±0.3 nmol/l at 3 months, vasopressin 2.0±0.9 to 2.4±1.3 pg/ml, endothelin –1 9.3±2.4 to 10.8±4.1 pg/ml, norepinephrine 298±67 to 353±92 pg/ml, atrial natriuretic peptide 159±94 to 168±119 pg/ml.
3.4. Comparison of patients that tolerated discontinuation of diuretics versus those that did not
Table 3 shows comparative baseline data for patients that needed reinitiation versus patients that did not need reinitiation of diuretic therapy. There were no differences with regard to all baseline variables examined: age, sex, ventricular function, clinical status, exercise capacity and neurohumoral determinations.
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3.5. One-year follow-up
The 17 patients that tolerated diuretic withdrawal were followed-up at 1 year to determine the midterm tolerance of diuretic discontinuation. Only two patients required diuretic reintroduction during this period of time. The clinical status at the final 12-month visit with respect to New York Heart Association functional classification was the following: one patient was in class I, one in class III, and the rest were in class II. In the corridor test, patients without diuretics walked 411±106 m (p=ns with respect to baseline and 3-month control).
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4. Discussion |
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TopAbstract1. Introduction and study...2. Methods3. Results4. DiscussionReferences |
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This study was designed to evaluate the possibilities and changes induced by diuretic discontinuation in patients with stabilized but not far advanced chronic heart failure. Loop diuretics are considered the cornerstone in congestive heart failure therapy. However, no controlled studies have been done to demonstrate the benefit of diuretic therapy due to the difficulties of randomizing this type of patient to placebo. However, there have been a number of concerns expressed about the chronic use of loop diuretics in heart failure [5–8], as they may further impair left ventricular diastolic filling and lower cardiac output, causing fatigue, decreased exercise capacity and hypotension [9]. In addition, diuretics can cause adverse effects, including hypokalemia [10], hypomagnesemia [11] and renal dysfunction [12]. Finally, diuretic use in heart failure has been related to neuroendocrine hyperactivation [8], an issue that we will address in more detail. All these harmful effects have led to the recommendation to aim for the lowest dose of diuretics in chronic heart failure.
4.1. Previous studies on diuretic withdrawal
Discontinuation of diuretics has been reported in several studies in the literature. Three trials have been performed in geriatric populations without manifest HF or uncontrolled hypertension [13–15], the proportion of patients from whom diuretics could successfully be withdrawn in these studies ranged from 50% to 92%. With respect to heart failure, one study performed in elderly subjects with intact left ventricular function (mean ejection fraction 60%) showed a 90% tolerance of diuretic withdrawal in a 3-month follow-up [16]. Finally, only one study [7] has been performed in heart failure with left ventricular dysfunction (ejection fraction below 37%) and revealed, as expected, the highest proportion of diuretic reinitiation (71% in a 12-week follow-up). In comparison with the previous literature, our study was performed in heart failure patients with systolic dysfunction and addressed not only the need for diuretic reintroduction (which can change from one study to another because of differences in the population included) but also the clinical and neurohumoral consequences of diuretic withdrawal.
4.2. Feasibility and predictors of successful diuretic withdrawal
Diuretic withdrawal is possible in a proportion of compensated heart failure patients, as our results have demonstrated. Patients who tolerated diuretic interruption had smaller ventricles, higher left ventricular ejection fraction and less atrial fibrillation than those who did not (Table 3), but all these comparisons were statistically not significant. It has to be emphasized that this study did not have enough power to detect potential predictors of successful diuretic withdrawal.
4.3. Diuretics and neurohumoral activation
The influence of diuretics on neuroendocrine variables, although of vital importance, has not been studied on a large scale. It is probably complex, especially in heart failure patients who are treated simultaneously with other drugs, such as angiotensin converting enzyme inhibitors or beta blockers. With respect to the renin–angiotensin–aldosterone system, diuretics cause stimulation of the whole system, with increased plasma renin activity, angiotensin II and aldosterone concentrations [3]. These effects are counteracted by angiotensin converting enzyme inhibitors, which reduce the rise in plasma angiotensin II. With respect to the sympathetic nervous system, loop diuretics reduce the heart failure increase in plasma norepinephrine concentration [4,17–19]. In relation to atrial natriuretic peptide, this neurohormone is released by the atria, atrial stretch being the most direct trigger mechanism. It has been demonstrated [20,21] that any successful heart failure intervention (such as treatment with diuretics) is followed by a decrease in atrial natriuretic peptide concentration because when atrial pressures decrease, atrial natriuretic peptide release diminishes in direct proportion.
4.4. Changes induced by diuretic discontinuation
In our study, the discontinuation of diuretics was associated with some beneficial changes; renal function improved, as demonstrated by such simple renal function parameters as urea and creatinine. Glucose metabolism also improved. With respect to the neurohumoral state, it has to be recognized that it is not easy to test the neuroendocrine changes associated with diuretic discontinuation in heart failure patients because there is a considerable fluctuation in neuroendocrine levels. Another issue is that drugs interfere with determinations, as is the case of angiotensin converting inhibitors, which decrease angiotensin II levels and aldosterone, although there are well-known ways of escape. We avoided other confounding effects of drugs, such as beta blockers (our study started before the wide implementation of these drugs in heart failure), calcium antagonists or dopamine agonists. We found some expected and some unexpected results. Plasma renin activity improved, and this can be considered the logical variation, considering the results of Bayliss et al. [3], which showed that diuretics may increase plasma renin activity. We did not find any variation in the other neurohormones (norepinephrine, endothelin-1, vasopressin, aldosterone), but atrial natriuretic peptide levels were significantly augmented after diuretic discontinuation. Interestingly, these neurohormonal findings are nearly identical to those found in heart failure patients with normal systolic function: van Kraaij et al. [22] also found that diuretic interruption caused a decrease in plasma renin activity and an increase in atrial natriuretic peptide. Atrial natriuretic peptide is a neurohormone that promotes diuresis; why diuretic interruption was associated with atrial natriuretic peptide increase is a matter of speculation. However, if we accept that atrial natriuretic peptide decreases when diuretics are introduced in heart failure, our finding would be expected to result in the opposite effect; that is to say, diuretic withdrawal leads to fluid retention that is associated with increased atrial pressures, thus inducing atrial stretching and, as a consequence, atrial natriuretic peptide release.
4.5. Study limitations
Firstly, the number of patients in our study was small, therefore, we have to consider it as a pilot study. Secondly, it has to be noted that the study was not blinded. Thirdly, we did not use either beta blockers or spironolactone; thus, the results may not apply to patients treated with these drugs. Finally, the follow-up period was short although it has been demonstrated that reinstitution of diuretics generally occurs in the early weeks after discontinuation [13]. In addition, it has to be emphasized that our results are probably not applicable to more severe heart failure patients, those that are receiving more elevated doses of loop diuretics or those with advanced heart failure (New York Heart Association classes III or IV).
4.6. Conclusions
This study shows that loop diuretics can be withdrawn in a proportion of stabilized heart failure patients but not in advanced stage heart failure despite the presence of systolic dysfunction. Patients that tolerate diuretic interruption maintain their clinical functional status and exercise capacity and have a better biochemical profile as well as interesting changes in neuroendocrine activation. Considering that heart failure is a progressive disease, it is likely that the majority of patients will require diuretics in the future. The open question is whether patients should avoid diuretics during certain periods of compensation and whether this is clinically beneficial.
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Acknowledgements |
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We acknowledge Irene Moral for her contribution in the statistical study.
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References |
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