Torasemide in chronic heart failure: results of the TORIC study

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1 The European Journal of Heart Failure 4 (2002) Torasemide in chronic heart failure: results of the TORIC study a b, Juan Cosın, Javier Dıez *, 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 Received 30 May 2002; received in revised form4 July 2002; accepted 6 July 2002 Abstract 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 mgyday orally (ns778) vs. patients who received furosemide 40 mgyday orally (ns527) or other diuretics (ns72) 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 (ns17, 2.2%) than in the furosemideyother diuretics group (ns27, 4.5%) (P-0.05). Functional improvement as assessed by NYHA class was observed in more patients who received furosemide torasemide (ns356, 45.8%) than those who received furosemideyother diuretics (ns223, 37.2%) (Ps ). At the end of the study abnormally low serum potassium levels were observed in fewer torasemide (ns95, 12.9%) than furosemideyother diuretics patients (ns102, 17.9%) (Ps0.013). 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 furosemideyother 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 furosemideyother diuretics European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved. Keywords: Chronic heart failure; Mortality; Diuretics; Torasemide; Furosemide 1. Introduction Chronic Heart Failure (CHF) is a clinical syndrome caused by heart disease that is characterised by abnormal sodiumand water retention resulting in oedema w1x. 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 sodiumretention and consequently oedema w2,3x. *Corresponding author. Tel.: q ; fax: q address: jadimar@unav.es (J. Dıez). Loop diuretics such as furosemide and torasemide are important for the symptomatic treatment of CHF w4x and are currently recommended by the European Society of Cardiology (ESC) w5x, the American College of Cardiology (ACC) and the American Heart Association (AHA) guidelines on the treatment of heart failure w6,7x. Torasemide acts on the thick ascending limb of the loop of Henle to promote rapid and marked excretion of water, sodiumand chloride w8,9x. It has a high bioavailability ()80%), and an elimination half-life of 3 4 h w10x. 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 w8,9,11,12x. CHF patients receiving torasemide for up to 1 year have shown reduced body weight, improved /02/$ - see front matter 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved. PII: S Ž

2 508 J. Cosın et al. / The European Journal of Heart Failure 4 (2002) pulmonary haemodynamics, diuresis and decreased CHF severity w10x. Known adverse effects of torasemide include hypokalemia w13x, symptoms of electrolyte and volume depletion (headache, dizziness, hypotension, drowsiness and cramps), gastrointestinal disturbances, urine retention and allergic reactions such as rash w12,14x. 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 fromrat, cow and guinea pig adrenal cells in vitro w15x. Another study has shown that torasemide inhibits the binding of aldosterone to its receptor in the cytoplasmic fraction of rat kidney w16,17x. 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. furosemideyother diuretics in patients with NYHA class GII 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 w18x, were also investigated. 2. Methods 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 w19x. In the total population of 2303 patients, 1287 patients were receiving torasemide and 1016 patients were receiving furosemide andyor other diuretics. During the observation period, 26y1287 patients in the torasemide group died (2.02%) and 35y1016 patients receiving furosemide andyor other diuretics died (3.44.%). This difference was statistically significant (relative risk reduction 41.4%, Ps0.035). 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 (ns778) with patients who received furosemide andyor other diuretics (ns599) 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 w18x as established by the Goldman questionnaire w18,20x. Protocol violators (patients who did not meet the inclusion criteria, had a major exclusion criterion or for whominsufficient follow-up data could be obtained) were excluded fromthis 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 Direcion General de Farmacia y Productos Sanitarios and the principles outlined in the Declaration of Helsinki Study design This was an open-label, post-marketing surveillance study w21x conducted in 231 centres in Spain. Patients were to receive either torasemide 10 mgyday orally, furosemide 40 mgyday 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 w18x, Framingham diagnosis w22x, Ross radiologic pattern w23x, 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). Potassiumsupplements were recommended for patients treated with furosemide 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

3 J. Cosın et al. / The European Journal of Heart Failure 4 (2002) Table 1 Patient demographics at baseline Torasemide (ns778) Furosemide (ns527)y Other diuretics (ns72) Gender, male 383 (49.2%) 305 (50.9%) Age (years) 68.6" "10.9 Weight (kg) 71.9" "11.8 Height (cm) 163.3" "8.5 NYHA class (n,%) I II 11 (1.4%) 15 (2.5%) II 361 (46.4%) 273 (45.6%) II III 3 (0.4%) 3 (0.5%) III 384 (49.4%) 294 (49.1%) IV 19 (2.4%) 14 (2.3%) Radiologic pattern 0 20 (2.7%) 7 (1.2%) I 161 (21.6%) 116 (20.0%) I II 0 (0%) 1 (0.17%) II 411 (55.2%) 292 (50.3%) II III 2 (0.27%) 5 (0.86%) III 135 (18.1%) 147 (25.3%) IV 16 (2.1%) 13 (2.2%) Concomitant CHF therapy Diuretics a 0.9% 7.4% Digoxin 52.6% 53.3% Beta-blockers 9.5% 9.4% ACE inhibitors 32.3% 28.9% a Chi-square P No significant difference in the patient demographics and baseline measurements was found between treatment groups. Radiologic pattern ns745 for torasemide and ns581 for furosemideyother diuretics group as the radiologic pattern was not assessed in all patients. 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 2 groups, while the x -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 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 mgyday orally, seven of these patients (0.9%) were receiving an additional diuretic at baseline. 527 patients received furosemide at a dosage of 40 mgyday 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 potassiumsparing 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 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 furosemideyother diuretics group died during the study. A significantly lower incidence of cardiac mortality was reported in the torasemide group (ns11, 1.4%) compared to the furosemideyother diuretics group (ns 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. Table 2 NYHA class at baseline and at the end of the study Baseline End of the study Torasemide Furosemide Torasemide Furosemide (ns778) (ns527) (ns778) (ns527) I or I II 0 (0%) 0 (0%) 194 (24.9%) 100 (19.0%) II or II III 372 (47.8%) 248 (47.1%) 471 (60.5%) 317 (60.2%) III or III IV 387 (49.7%) 267 (50.7%) 109 (14.0%) 102 (19.4%) IV 19 (2.4%) 12 (2.3%) 4 (0.5%) 8 (1.5%)

4 510 J. Cosın et al. / The European Journal of Heart Failure 4 (2002) Fig. 1. Incidence of mortality in patients who received torasemide or furosemideyother diuretics Change in NYHA class The change in NYHA class is depicted in Fig. 2. Torasemide was significantly more efficacious than furosemideyother 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 (ns356, 45.8%) than in the furosemideyother diuretics group (ns223, 37.2%) (Ps ). As shown in Table 2, torasemide was also more efficacious than furosemide alone, in improving NYHA class Serum potassium levels Data on serumelectrolytes were available in 620 of the 1377 patients included in the analysis. Abnormal potassiumlevels (-3.5 meqyl or )5 m Eqyl) were reported in a significantly lower proportion of torasemide patients (ns95, 12.9%) than patients receiving furosemideyother diuretics (ns102, 17.9%) (Ps0.013) (normal serum potassium levels meqyl). Throughout treatment the mean serum potassium levels were higher in the torasemide group than in the furosemideyother diuretics group (Fig. 3). However, at the end of treatment both the torasemide and the furosemideyother 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 furosemideyother diuretic these results suggest that torasemide is associated with a lower incidence of hypokalemia. 4. Discussion 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 w24,25x. 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. w26x who conducted a randomised, open-label trial in 234 patients with CHF. Compared with furosemidey other diuretics-treated patients, torasemide-treated

5 J. Cosın et al. / The European Journal of Heart Failure 4 (2002) Fig. 2. Changes in NYHA class from baseline to the end of treatment in patients who received torasemide or furosemideyother diuretics. Fig. 3. Mean serumpotassiumlevels throughout treatment.

6 512 J. Cosın et al. / The European Journal of Heart Failure 4 (2002) patients were less likely to need readmission for heart failure (32% vs. 17%, P-0.01) or for all cardiovascular causes (59% vs. 44%, Ps0.03). 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 potassiumsparing diuretic, can significantly improve survival, reduce hospitalisation rates and improve symptoms in CHF patients, by its interference with the neurohumoral system w27x. These data fromthe 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 w8,9,28,29x. In vitro studies in which pharmacological concentrations of torasemide and furosemide were used, showed that torasemide but not furosemide inhibits angiotensin II-induced vasoconstriction w30x and vascular growth-promoting activity w30x. On a milligram-to-milligram basis the diuretic, natriuretic and chloruretic effects of torasemide are approximately eight times greater than for furosemide w28,29x. Torasemide has also been shown to promote potassium excretion to a lesser extent than furosemide w28,29x, possibly because torasemide but not furosemide, can inhibit aldosterone binding to its receptor in the rat kidney w16,17x. Aldosterone activity has been shown to promote myocardial fibrosis, potassium and magnesium depletion, sympathetic activation, parasympathetic inhibition and baroreceptor dysfunction w31,32x. Anti-aldosterone treatment is recommended for the treatment of advanced heart failure (NYHA class III IV) w5x. The reported anti-aldosterone effect of torasemide may account for its ability to reduce mortality rate in CHF patients Limitations Although the presented data are derived froman 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 seemto 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 We would like to acknowledge the collaboration and commitment of all the local investigators and their staff, without whomthe 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 w1x Haslett C, Chilvers ER, Hunter JAA, Boon NA. Davidson s principles and practice of medicine, 18th ed. London: Churchill Livingstone, w2x AbrahamWT. 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