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European Journal of Heart Failure 2002 4(4):507-513; doi:10.1016/S1388-9842(02)00122-8
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© 2002 European Society of Cardiology

Torasemide in chronic heart failure: results of the TORIC study

Juan Cosína, Javier Díezb,* on behalf of the TORIC investigators

a Cardiocirculatory Research Unit, Research Center University Hospital La Fe, Valencia, Spain
b Division of Cardiovascular Pathophysiology School of Medicine and Department of Cardiology and Cardiovascular Surgery, University Clinic University of Navarra, Pamplona, Spain

* Corresponding author. Tel.: +34-948-42-56-00; fax: +34-948-42-56-49. E-mail address: jadimar{at}unav.es


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background: Diuretics such as torasemide are commonly used to treat chronic heart failure (CHF).

Aims: The objective of the TOrasemide In Congestive Heart Failure (TORIC) Study was to investigate the safety, tolerability and efficacy of torasemide in CHF patients compared to furosemide or other diuretics in an open-label, non-randomised, post-marketing surveillance trial.

Methods: The present analysis shows the findings of 1377 patients with New York Heart Association (NYHA) class II–III CHF who received diuretic therapy with torasemide 10 mg/day orally (n=778) vs. patients who received furosemide 40 mg/day orally (n=527) or other diuretics (n=72) on top of their existing standard CHF therapy for 12 months. Besides safety and tolerability, efficacy was assessed by documentation of mortality, morbidity, functional class and serum potassium levels every 3 months.

Results: TORIC confirmed the safety and tolerability of torasemide in CHF patients. Mortality was significantly lower in the torasemide (n=17, 2.2%) than in the furosemide/other diuretics group (n=27, 4.5%) (P<0.05). Functional improvement as assessed by NYHA class was observed in more patients who received furosemide torasemide (n=356, 45.8%) than those who received furosemide/other diuretics (n=223, 37.2%) (P=0.00017). At the end of the study abnormally low serum potassium levels were observed in fewer torasemide (n=95, 12.9%) than furosemide/other diuretics patients (n=102, 17.9%) (P=0.013).

Conclusion: Torasemide is safe and well tolerated in CHF patients. Although not designed as a mortality study, TORIC suggests a lower mortality amongst CHF patients treated with torasemide compared to furosemide/other diuretics. A functional improvement and a lower incidence of abnormal serum potassium levels were also observed in patients receiving torasemide as compared to those receiving furosemide/other diuretics.

Key Words: Chronic heart failure • Mortality • Diuretics • Torasemide • Furosemide

Received May 30, 2002; Revised July 4, 2002; Accepted July 6, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Chronic Heart Failure (CHF) is a clinical syndrome caused by heart disease that is characterised by abnormal sodium and water retention resulting in oedema [1]. In CHF patients, diminished cardiac output activates the sympathetic nervous and renin-angiotensin-aldosterone systems and the non-osmotic release of vasopressin. This causes a decrease in renal blood flow and an increase in the filtration fraction resulting in an increase in water and sodium retention and consequently oedema [2,3].

Loop diuretics such as furosemide and torasemide are important for the symptomatic treatment of CHF [4] and are currently recommended by the European Society of Cardiology (ESC) [5], the American College of Cardiology (ACC) and the American Heart Association (AHA) guidelines on the treatment of heart failure [6,7].

Torasemide acts on the thick ascending limb of the loop of Henle to promote rapid and marked excretion of water, sodium and chloride [8,9]. It has a high bioavailability (>80%), and an elimination half-life of 3–4 h [10]. The efficacy of torasemide in reducing salt and water retention in CHF has been established in double-blind studies in comparison with furosemide, another loop diuretic of the same therapeutic class [8,9,11,12]. CHF patients receiving torasemide for up to 1 year have shown reduced body weight, improved pulmonary haemodynamics, diuresis and decreased CHF severity [10].

Known adverse effects of torasemide include hypokalemia [13], symptoms of electrolyte and volume depletion (headache, dizziness, hypotension, drowsiness and cramps), gastrointestinal disturbances, urine retention and allergic reactions such as rash [12,14].

Traditionally, diuretics were thought to only have a symptomatic effect in CHF patients by inducing diuresis. However, the Randomised Aldactone Evaluation Study (RALES) clearly showed that spironolactone, a diuretic with aldosterone-receptor antagonist activity, significantly reduced the incidence of mortality in CHF patients. It is possible that this anti-aldosterone effect may account for the reduction in mortality rate in CHF patients. Torasemide has recently been shown to inhibit aldosterone secretion from rat, cow and guinea pig adrenal cells in vitro [15]. Another study has shown that torasemide inhibits the binding of aldosterone to its receptor in the cytoplasmic fraction of rat kidney [16,17].

Given the extensive use of torasemide, it is important to determine the risk and benefit associated with torasemide treatment. This study, TOrasemide In Congestive Heart Failure (TORIC), was designed as a post-marketing surveillance study to investigate the safety and tolerability of torasemide vs. furosemide/other diuretics in patients with NYHA class ≥II CHF. However, given the results obtained in the RALES trial, the incidence of mortality and hospitalisation rate as well as the treatment effects of diuretic therapy on exercise capacity, assessed by New York Heart Association (NYHA) functional class [18], were also investigated.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Patients
The original TORIC protocol was a post-marketing surveillance study with wide inclusion criteria and few exclusion criteria, which allowed the concomitant use of other diuretics as well as torasemide or furosemide. The study enrolled 2303 patients. The original primary analysis of the TORIC data showed an unexpected morbidity and mortality benefit [19]. In the total population of 2303 patients, 1287 patients were receiving torasemide and 1016 patients were receiving furosemide and/or other diuretics. During the observation period, 26/1287 patients in the torasemide group died (2.02%) and 35/1016 patients receiving furosemide and/or other diuretics died (3.44.%). This difference was statistically significant (relative risk reduction 41.4%, P=0.035). In light of these findings the TORIC data underwent further post-hoc analysis to investigate these results more closely.

The present analysis of 1377 patients compares the results of patients who received torasemide (n=778) with patients who received furosemide and/or other diuretics (n=599) in addition to individualised standard CHF therapy. In order to be included in the analysis, all patients were required to have at least one follow-up visit with sufficient clinical documentation. Eligible patients had to be over 18 years of age, with CHF NYHA class II–III [18] as established by the Goldman questionnaire [18,20]. Protocol violators (patients who did not meet the inclusion criteria, had a major exclusion criterion or for whom insufficient follow-up data could be obtained) were excluded from this analysis. Main exclusion criteria were hypersensitivity to torasemide, significant electrolyte disturbances, severe ventricular arrhythmia, complete atrioventricular block and dyspnoea due to lung disease.

Patients were informed orally and in writing that they were participating in an observational clinical trial and gave their informed consent. The protocol was approved by the Department of Health and the investigation conformed with the guidelines of the Spanish Direción General de Farmacia y Productos Sanitarios and the principles outlined in the Declaration of Helsinki.

2.2. Study design
This was an open-label, post-marketing surveillance study [21] conducted in 231 centres in Spain. Patients were to receive either torasemide 10 mg/day orally, furosemide 40 mg/day orally or other diuretics (spironolactone, amiloride, hydrochlorothiazide, indapamide, triamterene, altizide, mubutizide, chlorthalidone, xipamide and piretanide) at the recommended respective dosages for 12 months, in addition to their existing CHF therapy.

Patients visited the clinic at baseline and thereafter every 3 months for the following 12 months. Demographic data, medical history, concomitant medication, NYHA class [18], Framingham diagnosis [22], Ross radiologic pattern [23], blood chemistry and ECG according to standard procedures were recorded at baseline and at all follow-up visits. Existing concomitant CHF medication was continued and documented during the study (Table 1). Potassium supplements were recommended for patients treated with furosemide.


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  		Table 1 Patient demographics at baseline

 
2.3. Statistical methodology
Each investigator enrolled a pre-determined number of patients, who were recruited in matched pairs with the same age, sex and NYHA class. The patients had to fulfil the inclusion criteria and agree to participate in the study. In each pair, one patient received torasemide and the other was allowed any other diuretic or diuretic combination therapy. The present analysis compares the results of all patients receiving torasemide vs. the group of patients receiving furosemide or other diuretics.

Independent sample t-tests were used to compare continuous basal characteristics between the treatment groups, while the {chi}2-test was applied for categorical data. Logistic regression was used to compare the incidence of mortality between treatment groups adjusting for NYHA class at baseline, and ordinal regression was used to test the differences in NYHA evolution also adjusting for NYHA class at baseline. Analysis of variance was used to compare mean serum potassium levels during the study. A logistic regression model was used to calculate the proportion of patients with abnormal serum potassium levels.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Patients, diuretic treatment, NYHA class and radiologic pattern
Patient baseline characteristics including, age, gender, height, weight, radiologic pattern and NYHA class were similar between all treatment groups. Despite a significant difference in existing diuretic treatment at baseline (0.9 vs. 7.4%, P<0.001), there were no significant differences in the pre-existing CHF therapy between the study groups (Table 1).

Of the 1377 patients included in this analysis, 778 patients received torasemide at a dosage of 10 mg/day orally, seven of these patients (0.9%) were receiving an additional diuretic at baseline. 527 patients received furosemide at a dosage of 40 mg/day and 72 patients received other diuretics. Of the 72 patients taking other diuretics, 46 patients received spironolactone in combination with thiazides or other diuretics and 26 patients received either thiazides alone or in combination with other potassium sparing diuretics.

The average dose of torasemide used in the study was 8.2±2.4 mg, and the average dose of furosemide was 35±7.2 mg.

3.2. Mortality results
The average follow-up time was 9.2 months. Torasemide treatment was associated with a 51.5% reduction in the risk of death compared to furosemide or other diuretics (P<0.05) (Fig. 1). A total of 17 (2.2%) patients in the torasemide group and 27 (4.5%) patients in the furosemide/other diuretics group died during the study.


Figure 1
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  		Fig. 1 Incidence of mortality in patients who received torasemide or furosemide/other diuretics.

 
A significantly lower incidence of cardiac mortality was reported in the torasemide group (n=11, 1.4%) compared to the furosemide/other diuretics group (n=27, 3.5%) (P<0.05), representing a 59.7% decrease in the risk of cardiac mortality (Fig. 1). No significant difference was observed in the frequency of non-cardiac death between the treatment groups.

3.3. Change in NYHA class
The change in NYHA class is depicted in Fig. 2. Torasemide was significantly more efficacious than furosemide/other diuretics in improving NYHA class. The proportion of patients showing a functional improvement of at least 1 grade in NYHA class was significantly greater in the torasemide group (n=356, 45.8%) than in the furosemide/other diuretics group (n=223, 37.2%) (P=0.00017). As shown in Table 2, torasemide was also more efficacious than furosemide alone, in improving NYHA class.


Figure 2
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  		Fig. 2 Changes in NYHA class from baseline to the end of treatment in patients who received torasemide or furosemide/other diuretics.

 


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  		Table 2 NYHA class at baseline and at the end of the study

 
3.4. Serum potassium levels
Data on serum electrolytes were available in 620 of the 1377 patients included in the analysis. Abnormal potassium levels (<3.5 mEq/l or >5 mEq/l) were reported in a significantly lower proportion of torasemide patients (n=95, 12.9%) than patients receiving furosemide/other diuretics (n=102, 17.9%) (P=0.013) (normal serum potassium levels 3.5–5.5 mEq/l). Throughout treatment the mean serum potassium levels were higher in the torasemide group than in the furosemide/other diuretics group (Fig. 3). However, at the end of treatment both the torasemide and the furosemide/other diuretics group showed a significant decrease in the mean serum potassium levels from baseline. Taking into account that only 3% of patients treated with torasemide received potassium supplements vs. 30% of patients treated with furosemide/other diuretic these results suggest that torasemide is associated with a lower incidence of hypokalemia.


Figure 3
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  		Fig. 3 Mean serum potassium levels throughout treatment.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
The results of this open-label, cohort study showed that torasemide is a safe, well tolerated and efficacious diuretic treatment in CHF patients, thus confirming the results of previous studies [24,25]. Although not designed as a mortality study, torasemide treatment was associated with a significantly lower total mortality and cardiac mortality. In addition, a significantly greater proportion of patients in the torasemide group showed improvement in NYHA class compared to patients treated with furosemide or other diuretics. Thus, the presented data suggest that torasemide offers additional benefits regarding mortality, morbidity and functional improvement over furosemide or other diuretics. A reduction in hospitalisation rates by torasemide as compared to furosemide has also been reported by Murray et al. [26] who conducted a randomised, open-label trial in 234 patients with CHF. Compared with furosemide/other diuretics-treated patients, torasemide-treated patients were less likely to need readmission for heart failure (32% vs. 17%, P<0.01) or for all cardiovascular causes (59% vs. 44%, P=0.03).

Until recently diuretics have been considered to have a positive effect on CHF symptoms only, and not mortality. However, data from the RALES study have shown that the aldosterone antagonist spironolactone, originally thought to act only as a potassium sparing diuretic, can significantly improve survival, reduce hospitalisation rates and improve symptoms in CHF patients, by its interference with the neurohumoral system [27]. These data from the TORIC study support these findings and provide further support for the concept that some diuretics, by their specific pharmacologic profile, might provide additional benefits in CHF which are beyond their pure diuretic effect.

Torasemide differs from other loop diuretics such as furosemide in that it has a longer half-life and longer duration of action [8,9,28,29]. In vitro studies in which pharmacological concentrations of torasemide and furosemide were used, showed that torasemide but not furosemide inhibits angiotensin II-induced vasoconstriction [30] and vascular growth-promoting activity [30]. On a milligram-to-milligram basis the diuretic, natriuretic and chloruretic effects of torasemide are approximately eight times greater than for furosemide [28,29]. Torasemide has also been shown to promote potassium excretion to a lesser extent than furosemide [28,29], possibly because torasemide but not furosemide, can inhibit aldosterone binding to its receptor in the rat kidney [16,17]. Aldosterone activity has been shown to promote myocardial fibrosis, potassium and magnesium depletion, sympathetic activation, parasympathetic inhibition and baroreceptor dysfunction [31,32]. Anti-aldosterone treatment is recommended for the treatment of advanced heart failure (NYHA class III–IV) [5]. The reported anti-aldosterone effect of torasemide may account for its ability to reduce mortality rate in CHF patients.

4.1. Limitations
Although the presented data are derived from an open-label cohort study, the population analysed was large and had well defined inclusion and exclusion criteria. The baseline radiologic pattern between treatment groups were slightly different but not considered to be clinically important, as there was no significant difference in the functional NYHA class distribution between groups.

Overall, mortality rate was relatively low in both treatment groups, which was not surprising since approximately half of the patients in both study groups were in NYHA class I or II. In this rural, non-hospital based setting of a cohort study, the percentage of patients receiving standard therapy with ACE inhibitors and beta blockers was relatively low and shows that physicians are still reluctant to prescribe recommended standard therapies in patients who seem to be only mildly symptomatic.

The interesting findings of torasemide treatment in this study regarding the prognostic and functional effects of torasemide in CHF should be confirmed in further randomised trials.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
We would like to acknowledge the collaboration and commitment of all the local investigators and their staff, without whom the present study would not have been possible. In particular, we would like to acknowledge the collaboration given by Dr A. Scherhag, Dr M. Vera and T. De Agustin.


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

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