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European Journal of Heart Failure 2003 5(6):793-801; doi:10.1016/S1388-9842(03)00150-8
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© 2003 European Society of Cardiology

Torasemide vs. furosemide in primary care patients with chronic heart failure NYHA II to IV—efficacy and quality of life

Karin Müllera, Giancesare Gambab, Françoise Jaquetc and Bernhard Hessd,*

a Roche Pharmaceuticals Switzerland CH-4153 Reinach, Switzerland
b Biometrix S.A. CH-1196 Gland, Switzerland
c Five Office Ltd., Study Coordinating Agency CH-8620 Wetzikon, Switzerland
d Department of Medicine Spital Zimmerberg, CH-8820 Waedenswil, Switzerland

* Corresponding author. Tel.: +41-1-728-15-02; fax: +41-1-728-15-05 E-mail address: b.hess{at}spital-zimmerberg.ch


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Background: The hypothesis was that torasemide, due to more predictable pharmacokinetics/pharmacodynamics, induces greater improvements in functional and social limitation than furosemide and reduces the frequency of hospitalisations in primary care patients with chronic heart failure (CHF).

Patients and Methods: Prospective, randomized, unblinded study in primary care, 237 patients with CHF (NYHA II–IV), all on ACE inhibitors. Randomisation: torasemide (n=122) or furosemide (n=115), treated for 9 months. Endpoints: Clinical efficacy, quality of life, safety, tolerability, hospitalisations.

Results: Clinical improvement was observed in both groups, but the trend to improve by at least one NYHA class was significant only in torasemide- (P=0.014), but not in furosemide-treated patients. There were no differences with regard to adverse events and hospitalisation due to CHF. Overall, tolerability (P=0.0001) and improvement in daily restrictions (P=0.0002) were significantly higher, number of mictions at 3, 6 and 12 h after diuretic intake (P<0.001 at all time points) and urgency to urinate (P<0.0001) significantly lower in torasemide- vs. furosemide-treated patients.

Conclusion: CHF patients treated with torasemide gain a higher benefit in quality of life than furosemide treated patients, due to torasemide's dual effect on both clinical status and social function.

Key Words: Chronic heart failure • Diuretics • Torasemide • Furosemide • Efficacy • Quality of life

Received February 12, 2003; Revised April 23, 2003; Accepted July 17, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
The prevalence of chronic heart failure (CHF) steadily rises. In Europe, it is estimated that between 0.4 and 2.0% of the general population presently suffer from CHF [1]. The prevalence of CHF rapidly increases with age: in the Echocardiographic Heart of England Screening (ECHOES) study, definite diagnosis of CHF was made in 0.2% of patients aged 45–54 years, but in 15.2% of those aged 85 years and older [2]. In persons 65 years of age or older, heart failure—also named the ‘new epidemic of cardiovascular disease’ [3]—has become the single most frequent cause of hospitalisation [3]. Mortality is high: death rates of patients with a principal diagnosis of CHF reach 44.5%, 76.5% and 87.6% after 1, 5 and 10 years, respectively [4].

As a complex syndrome, CHF results in dyspnea, orthopnea and fatigue, which may limit exercise capacity, and in salt and water retention, which may induce pulmonary and peripheral edema [1,5,6]. These clinical symptoms basically reflect the major pathophysiologic features of CHF, i.e. decreased effective circulating volume with subsequent sodium and water retention [6]. The latter is clinically of utmost importance, which appears to be mirrored by the way patients with CHF are treated in clinical practice. As demonstrated by a recent survey among primary care physicians in 15 European countries, diuretics are the drugs primarily used to treat CHF, followed by ACE inhibitors/angiotensin receptor blockers, digitalis and betablockers [7].

Treatment with loop diuretics reduces pulmonary pressure, which is followed by a rapid and significant improvement of CHF symptoms and exercise tolerance. Furosemide and torasemide are the most frequently used loop diuretics. They differ in several aspects: while the bioavailability of torasemide varies between 76 and 96%, furosemide exhibits extremely wide inter- and intraindividual variation with bioavailabilities between 10 and 90% [8,9]. Futhermore, intestinal absorption of furosemide is greatly influenced by simultaneous food intake, which is not the case with torasemide [10,11]. Moreover, torasemide has a longer elimination half-life and, therefore, a longer duration of action than furosemide [9].

Several studies have analysed whether these superior pharmacokinetic properties of torasemide have an impact on clinical outcome. It was found that torasemide, in comparison with furosemide, reduced both the frequency and the duration of CHF-related hospitalisations [12,13]. Most recently, the TORIC (Torasemide in Congestive Heart Failure) study not only demonstrated that torasemide was more efficacious in improving NYHA class, but also was associated with a 51.5% reduction in mortality in comparison with furosemide/other diuretics [14]. Yet, information on improvement of the patients’ QoL parameters on account of treatment remains inconclusive [15]. In patients with CHF, all aspects of QoL are significantly affected [16], mainly due to functional limitation, psychological problems, adverse effects of treatment and social limitation [17]. In clinical practice, improvement of QoL is mostly assessed by ‘physician-driven’ questions regarding only functional limitation and by clinical tests for quantifying surrogate endpoints such as dyspnea, nycturia and edema [18]. Yet, little is known about the impact of adverse treatment effects on other factors such as number of mictions and urgency to urinate which may greatly affect social contacts of CHF patients. Indeed, a recent study on understanding symptoms and drug therapy of CHF confirmed that patients deliberately postpone or leave out diuretic intake in order to better be able to leave home without the need for frequent trips to the lavatory [19].

In the present study, we wanted to investigate whether the more predictable bioavailability and pharmacokinetics of torasemide could not only improve clinical outcome and possibly reduce the rate of hospitalisations, but may also result in greater improvement of various aspects of QoL of CHF patients in comparison to furosemide.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Patients with CHF were eligible if they were at least 18 years old, were treated with an ACE inhibitor and needed diuretic therapy because their CHF had reached New York Heart Association (NYHA) functional class II–IV [20]. Enrolment in the study was done by participating physicians in practice who were provided with the written definitions of NYHA functional classes by the study coordinating centre after they had agreed to recruit patients. After NYHA classification and enrolment in the study (baseline visit), patients returned for scheduled visits after 1, 3, 6 and 9 months. At each visit, clinical status including body weight, systolic/diastolic blood pressure and heart rate was assessed, and NYHA class was determined. The five major CHF symptoms, i.e. dyspnea, pulmonary rales, oedema, nycturia and orthopnea, were rated 0 (absent), 1 (minor), 2 (moderate) or 3 (severe). The cumulated symptom score (CSS) was then calculated as the sum of the five values, thus the maximum value that possibly could be reached was 15. Treating physicians also rated the overall efficacy of the prescribed diuretic as bad (0), moderate (1), good (2), or very good (3). Similarly, overall tolerability was rated as bad (0), moderate (1), good (2) or very good (3). Quality of life (QoL) of patients was assessed monthly by phone calls, using a simple QoL questionnaire (Table 1). Venous blood for measurements of serum potassium (K), magnesium (Mg), creatinine and urea was taken on a voluntary basis at the discretion of the treating physician.


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  		Table 1 Questionnaire for the assessment of the influence of treatment with loop diuretics on quality of life

 
2.2. Study design
The study was a prospective, multicenter, randomised, unblinded trial, comparing the effects of single-dose regimens of the loop diuretics torasemide and furosemide on top of ACE inhibitors in patients with congestive heart failure (CHF). The study involved 57 centres throughout Switzerland and was carried out from May 1998 to May 2001 under everyday life conditions by generalists, internists and cardiologists, either in their private practice or in specialized clinics or in retirement homes. The protocol followed the ethical principles of the Declaration of Helsinki and the ICH Guidelines for good clinical practice. Informed consent was obtained from all patients, and all local ethics committees gave their approval after the protocol had first been approved by the Ethical Committee of the Faculty of Medicine of the University of Berne.

After patients had been found eligible for study and signed the informed consent, investigating physicians received treatment allocation from the study coordination centre, based on a predetermined randomisation scheme. The study was then conducted under unblinded conditions. The dosage of the assigned study drug was chosen by the physician on an individual basis. Since physicians were not yet very familiar with the use of torasemide when the study was begun, they were advised by the protocol to start with a daily dose of 10 mg of torasemide in all patients in whom they would have given 40 mg of furosemide. At each study visit or between the scheduled visits if urgently needed, the investigating physician adapted the dose of the study medication and/or of concomitant drugs. Study drugs were purchased by the patients and, therefore, packed commercially. No specific measures except monthly phone calls by the study coordinating centre were taken to monitor treatment compliance.

2.3. Statistics
The determination of the sample size was based on the total number of hospitalisations and the mean duration of hospital stay regarding studies on pharmacoeconomic aspects of diuretic therapy [12]. The statistical significance was set for an {alpha} risk at 0.05 for an inferiority of torasemide vs. furosemide (unilateral instead of bilateral), and for a β of 0.2 (power of the test=80%). A two-proportions method was used for the calculations based on an optimistic (less patients required to find a significant difference) or pessimistic (more patients required to obtain a significant difference between groups) point of view. Finally, the realistic point of view was used for sample size determination, which is the average of the optimistic and pessimistic point of view. For a two group {chi}2 test with a 0.005 one-sided significance level with 80% power to detect the difference between a group-1 proportion, {pi}1, of 0.02 (four hospitalisations in 200 patients) and a group-2 proportion, {pi}2, of 0.005 (11 hospitalisations in 200 patients), a sample size of 120 in each group was needed.

At baseline, study groups were compared according to the nature of the variables, i.e. Chi-square or Fisher's Exact test were applied for dichotomous and nominal variables, respectively. For the follow-up period, the repeated measure ANOVA method could not be applied since the drastic assumptions of this method (e.g. no missing data) were not completely met in this clinical study. Therefore, comparisons between groups were based on the analysis of single variables, which summarize the whole treatment period (global variables) and were built up similarly to an area-under-the-curve (AUC) calculation. Analysis of global variables was then performed by paired t-tests for parametric or by Wilcoxon Rank test for non-parametric variables. All values are means ±S.D.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
3.1. Baseline data
As depicted in Fig. 1, a total of 295 patients of both sexes were screened for CHF with NYHA class II–IV. After discarding 15 patients for non-compliance with the entry criteria, 280 patients were selected for the study and then randomised to the study medication. Out of these, 43 patients could not enter the study due to protocol violation or withdrawn consent. Most frequent reasons for exclusion after enrolment were: treatment with angiotensin II receptor blocker (n=14), no ACE inhibitor (n=6), patient withdrawal (n=5), NYHA class I at entry (n=4), and investigator withdrawal (n=2). Of the 237 remaining patients, 122 were randomly assigned to torasemide and 115 to furosemide and treated according to their individual needs for 9 months.


Figure 1
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  		Fig. 1 Study profile.

 
A total of 194 patients completed the trial. Reasons for early termination (n=43) were: occurrence of an adverse event (n=15), death (n=14), lost to follow up (n=6), investigator withdrawal (n=4) and protocol violation (n=4) (Fig. 1). All early terminators entered the final analysis.

Table 2 summarizes baseline characteristics of torasemide- and furosemide-treated patients. There were no significant differences in demographics, important concomitant diseases and NYHA class, except that patients in the furosemide group exhibited more frequently renal insufficiency, defined as a serum creatinine value above 120 µmol/l (P=0.007). The majority of patients from both groups were suffering from valvular insufficiency, cardiac arrhythmias, diabetes and renal insufficiency. Regarding baseline symptoms of heart failure, similar patterns were recorded at baseline in the two treatment groups. The mean scores of torasemide and furosemide patients were 1.65±0.79 and 1.44±0.85 for dyspnea (P=0.048), 0.64±0.74 and 0.62±0.72 for pulmonary rales (NS), 0.98±0.76 and 1.06±0.78 for oedema (NS), 1.18±0.75 and 1.10±0.72 for nycturia (NS), and 0.53±0.76 and 0.53±0.77 for orthopnea (NS), respectively. With respect to the cumulative symptom score (CSS), there was a statistically non-significant trend for a higher value in the torasemide group (4.98±2.59 vs. 4.74±2.84). Regarding previous treatment for CHF, 87.7% of patients in the torasemide and 90.5% in the furosemide group had received ACE inhibitors (NS); respective values for diuretics were 64.8% and 65.2% in the torasemide and furosemide group, respectively (NS). Potassium supplements had been required in 6.6% and 5.2% of patients in the torasemide and furosemide group, respectively (NS).


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  		Table 2 Baseline characteristics of study patients

 
3.2. Follow-up throughout the study
A total of 194 patients completed the trial. Forty-three patients terminated the study prematurely for the following reasons: adverse events (n=15), death (n=14), lost to follow up (n=6), investigator withdrawal (n=4) and protocol violation (n=4) (Fig. 1). All early terminators entered the final analysis. Mean duration of the trial was 239.0±83.9 (range 23–333) days in torasemide- and 250.6±77.7 days (range 27–387) days in furosemide-treated patients. The scheduled visits at 1, 3, 6 and 9 months of treatment occurred at 31.6±7.3, 90.0±13.5, 182.6±18.2 and 275.7±22.3 days in the torasemide and at 32.0±8.1, 93.1±16.4, 183.8±20.0 and 282.1±29.0 days in the furosemide group.

Over the entire study period, mean doses for torasemide and furosemide were 11.36±11.79 mg and 40.04±21.78 mg, respectively. During follow-up, average doses of torasemide and furosemide remained relatively stable, with overall tendencies to decrease for furosemide and increase for torasemide; the latter was only significant after 1 month of treatment (from 10.8±10.4 mg at baseline to 11.2±10.4 mg, P=0.019).

Use of ACE inhibitors remained stable during the study in both treatment groups. The most frequently prescribed ACE inhibitors were enalapril (27.7% of all patients), captopril (18.8%), fosinopril (17.9%) and lisinopril (11.2%). A number of patients were treated with ACE inhibitors combined with a second diuretic: in 9.1% of the patients, a combination with hydrochlorothiazide was used, whereas 5.2% of the patients received indapamide in combination with an ACE inhibitor. The mean dose of these additional diuretics also remained stable during the study in both treatment groups (data not shown).

3.3. Treatment efficacy
NYHA class improved in both treatment groups throughout the study. As shown in Fig. 2, percentages of patients classified as NYHA I and NYHA II increased in both treatment groups, while those classified as NYHA III and NYHA IV decreased. In the torasemide group, mean NYHA class decreased by 0.48±0.73 (from 2.47±0.54 to 1.99±0.58; in the furosemide group, the respective value was 0.39±0.68 (from 2.37±0.49 to 2.01±0.61, NS vs. torasemide). However, when considering individual changes in NYHA classes, 40.2% of torasemide-treated patients improved by at least one NYHA class, 38.5% were unchanged and 21.3% worsened. Respective figures in furosemide-treated patients were 30.7% improved, 46.5% unchanged and 22.8% worsened. The overall trend for improvement was only significant in torasemide- (P=0.014), but not in furosemide-treated patients (P=0.269).


Figure 2
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  		Fig. 2 Frequency distribution of NYHA classes (in percent) at baseline and at study termination in torasemide- and furosemide-treated patients.

 
Mean severity scores of dyspnea, pulmonary rales, oedema, nycturia and orthopnea improved in a similar fashion in both treatment groups throughout the study, without significant differences between groups. The overall efficacy of diuretic therapy, scored by the treating physicians, was equal for torasemide (2.40±0.62) and furosemide (2.39±0.61). Between baseline and end of the study, mean body weight decreased from 77.9±17.1 to 76.5±16.9 kg in the torasemide and from 76.3±18.7 to 75.6±16.3 kg in the furosemide group (P=0.267). Mean systolic (SBP) and diastolic (DBP) blood pressures fell in both groups, from 142±21/82±11 to 137±20/80±12 mmHg in the torasemide and from 143±24/84±12 to 138±19/80±10 mmHg in the furosemide group (P=0.431 for SBP and P=0.187 for DBP, torasemide vs. furosemide). No significant changes were found in mean heart rate during the study in both treatment groups (data not shown).

3.4. Quality of life and tolerability
As assessed by the treating physicians, overall tolerability of torasemide was rated significantly superior (global score 2.56±0.64) to that of furosemide (2.22±0.79, P=0.0004 vs. torasemide). Assessed monthly by means of the QoL questionnaire (Table 1), a persistently higher number of mictions at various time points after diuretic intake was recorded in the furosemide than in the torasemide group throughout the whole study period (Table 3). Fig. 3 depicts the number of mictions during the first 6 h following diuretic intake; the pattern at 3 and 12 h following drug intake was very similar (data not shown). As can be seen from Fig. 3, the number of mictions tended to decrease in furosemide-treated patients throughout the 9 months of study.


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  		Table 3 Average cumulated number of mictions after diuretic intake (global value over 9 months)

 


Figure 3
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  		Fig. 3 Mean number of mictions within 6 h after diuretic intake. {circ} Torasemide, {blacktriangleup} Furosemide. P<0.000001 (global value over 9 months).

 
Upon the question ‘How was your urgency to urinate?’ with scores from 3(=highly urgent) to 1(=not urgent), patients treated with furosemide indicated stronger urgency (global score 2.00±0.66) than those treated with torasemide (1.66±0.60, P<0.0001). This was valid for the whole study period. As shown in Fig. 4, patients on torasemide also felt significantly less restricted in their daily life than patients on furosemide throughout the whole study period (P=0.0005). Moreover, when asked ‘If you have previously taken a diuretic, have the restrictions in your daily life been improved by the change in diuretic?’ torasemide patients indicated a greater improvement (0.88±0.74 for global score) in their quality of daily life than furosemide patients (0.43±0.47, P=0.0002 vs. torasemide).


Figure 4
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  		Fig. 4 Evolution of the restriction of daily life due to diuretic treatment over the trial period as rated by the patients (0: no, 1: little, 2: moderate, 3: severe restriction). {circ} Torasemide, {blacktriangleup} Furosemide. P<0.001 (global value over 9 months).

 
3.5. Safety
As depicted in Table 4, 31 adverse events were reported in 30 patients in the torasemide group, whereas 23 events were noted in 22 patients in the furosemide group. Treating physicians considered adverse events serious, e.g. leading to death, life-threatening or requiring prolonged hospitalisation, in 24 patients in the torasemide and 14 patients in the furosemide group. Adverse events were mostly attributed to CHF itself, other underlying diseases or concomitant medication. Only three adverse events were attributed to the study drug, all three in the furosemide group.


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  		Table 4 Causes of adverse events (judged by treating physicians)

 
Neither treatment with torasemide nor with furosemide-induced relevant changes in serum potassium, magnesium or urea over the observation period in patients in whom such data were available (72 in the torasemide and 67 in the furosemide group, data not shown). For serum creatinine, a significant increase from baseline (93±28 µmol/l) within the normal range was observed at 3 (104±44 µmol/l, P=0.007), 6 (104±42 µmol/l, P=0.012), and 9 months (102±43 µmol/l, P=0.011) of treatment with torasemide; no such changes were observed with furosemide (data not shown).

3.6. Hospitalisations and deaths
A total of five hospitalisations were considered by the investigators as due to decompensated heart failure, two in the torasemide and three in the furosemide group (P=0.678). Total numbers of hospital days for decompensated heart failure amounted to 31 in torasemide- and 35 in furosemide-treated patients (NS). Sixteen patients (eight patients in each group) were hospitalised for cardiovascular disease. When combining heart failure and cardiovascular disease, patients in the torasemide group had fewer in-hospital days than in the furosemide group over the whole study period (95 vs. 146 days, P=0.0006); however, this difference was mainly due to one furosemide patient who required an unusually long hospitalisation.

Fourteen patients died during the study for various reasons, eight in the torasemide group and six in the furosemide group.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
The present prospective, randomised, unblinded trial confirms previous work which already had suggested that torasemide was superior to furosemide regarding the improvement in NYHA class in patients with congestive chronic heart failure [12–14]. The most important new information of this study, however, is that diuretic therapy with torasemide instead of furosemide optimises the quality of daily life of patients with CHF.

As suggested by a recent systematic review [15], data on quality of life in the management of patients with chronic heart failure disease are still not conclusive. The present data again emphasise the importance of diuretic therapy in managing the major pathophysiologic features of CHF, i.e. sodium and water retention [6], which go along with reduced functional limitation—one important aspect of quality of life in CHF patients [17]. Not much is known, however, about the impact of diuretic treatment on other factors possibly interfering with quality of life, such as psychological problems and social limitation [17]. In their prospective open-label randomised trial, Murray et al. [13] found that fatigue scores at certain intermediate time-points, but not at the end of the study, had improved more in torasemide- than in furosemide-treated patients, whereas emotional function was unaffected by diuretic treatment. Appropriate diuretic treatment, however, may also affect number of mictions and urgency to urinate and thus directly interfere with the capability of leaving home and cultivate social contacts—so far rather neglected aspects of quality of life [17].

Our unblinded study clearly suggests that the pharmacologic differences between furosemide and torasemide have indeed a direct impact on two important aspects of quality of life of CHF patients, namely functional and social limitation [17]. Due to its superior and more constant bioavailability as well a its prolonged duration of action, torasemide theoretically may be expected to exert a clinically ‘smoother’, longer lasting and more powerful diuretic action than furosemide [10]. This appears to be confirmed by the present study in that weight loss and serum creatinine increases—indicators of diuretic action—in torasemide patients tended to be higher than in furosemide patients. Moreover, the clinical efficacy of torasemide was greater, because a higher percentage of torasemide than furosemide patients improved their NYHA status by at least one functional class.

Nevertheless, torasemide patients counted less trips to the lavatory and had fewer complaints about great urgency than furosemide patients and, therefore, indicated fewer restrictions in daily life, i.e. less social limitation. Thus, in comparison with furosemide, CHF patients on torasemide exhibit a dual improvement of quality of life aspects, because functional as well as social limitation are reduced. This may result in an overall better quality of life and become an important driver of patient compliance. Indeed, it is known that patients with CHF often disregard dosing schedules if their quality of life is adversely affected by their prescribed drugs [19]. Therefore, better patient compliance may be an additional factor contributing to the greater reductions in decompensations and hospitalisations, which have been observed in torasemide-treated patients with CHF [12–14].

Important limitations of the present study are the lack of blinding and the fact that it did not find significant differences between torasemide and furosemide treatment with regard to rates of hospitalisation for heart failure or mortality, as two other recent trials have demonstrated [13,14]. This is entirely explained by the study design. First of all, our study lasted only 9 months, whereas the duration of the two other trials was 12 months [13,14]. Moreover, our study included a rather small number of patients and was, therefore, not statistically powered to detect differences in mortality rates, as did the TORIC investigators in their non-randomised post-marketing surveillance trial with 1377 patients [14]. However, a significant reduction in readmissions for heart failure in torasemide- vs. furosemide-treated patients was found by Murray et al. [13] who included 234 patients, a number almost identical to the one in the present study. However, Murray et al. [13] selected patients with more advanced heart failure, as judged by mean NYHA class at baseline (2.8 vs. 2.5 for torasemide- and 2.6 vs. 2.4 for furosemide-treated patients) and mean doses of diuretics used throughout the trial (72 vs. 11 mg of torasemide, 136 vs. 40 mg of furosemide). Consequently, this patient selection resulted in a much higher rate of readmissions for CHF than in our study (17 vs. 2% for torasemide- and 32 vs. 3% for furosemide-treated patients). Last but not least, all patients in our study had to be on ACE inhibitors, a mainstay of CHF treatment [2]. In the study of Murray et al. [13], 81% of torasemide- and 77% of furosemide-treated patients were on ACE inhibitors; respective values in the TORIC study were only 32 and 29% [14]. This additional important difference in study design most likely explains why our study differed from the other two trials with regard to hospital readmissions [13] and mortality [14].

In conclusion, the present unblinded study which was carried out in a typical everyday primary care setting confirms that torasemide, when administered on top of ACE inhibitors, exhibits greater efficacy in reducing functional limitation than furosemide in patients with CHF of NYHA classes II–IV. Important new information emerges from the fact that this improved clinical efficacy occurs at reduced social limitation, because numbers of mictions and urgency to urinate are significantly lower on torasemide. Altogether, torasemide appears to improve quality of life more than furosemide in patients with CHF of NYHA classes II–IV, due to a more pronounced and dual impact on functional as well as social limitation.


   Acknowledgements
 
We would like to acknowledge the collaboration and commitment of all local investigating physicians and their staff. Without their great help, the study would not have been possible.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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K. A Wargo and W. M Banta
A Comprehensive Review of the Loop Diuretics: Should Furosemide Be First Line?
Ann. Pharmacother., November 1, 2009; 43(11): 1836 - 1847.
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