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CLINICAL THERAPEUTICS 14. Domic JA, Miller RE, Anderson J, McAllister RC. Pharmacology of verapamil. II. Impairment of glucose toler ance by verapamil in the conscious dog. Pharmacology 1980; 20:196-202. 15. Donelly T, Harrower ADB. Effect of nifedipine on glucose tolerance and insu lin secretion in diabetic and non-diabetic patients. Curr Med Res Opin 1980; 6:690-693. 16. Fujii S, Matsumura S, Nakayama H, et al. Effect of long-term treatment with slow-release nifedipine on glucose homeostasis in hypertensive-diabetic pa tients. Jpn Pharmacol Ther 1990; 18: 2127-2133. 17. Trost N, Eeidmann P, Beretta-Piccoli C. Antihypertensive therapy in diabetic pa tients. Hypertension 1985; 7(Suppl 2): 102-108. 18. Struthers AD, Murphy MB, Dollery CT. Glucose tolerance during antihypertensive therapy in patients with diabetes mellitus. Hypertension 1985; 7(Suppl 2): 95-101. 19. Black HR. The coronary artery disease paradox: The role of hyperinsulinemia and insulin resistance and implications for therapy. J Cardiovasc Pharmacol 1990; 15(Suppl 5):S26-S38. 20. Gerber A, Weidman P, Bianchetti MG, et al. Serum lipoproteins during treat ment with the antihypertensive agent indapamide. Hypertension 1985; 7:70-72. CLINICAL THERAPEUTICS/VOL, 15, NO. 6,1993 Six-Week Study of Torsemide in Patients with Congestive Heart Failure Klaus-Michael Goebel, M.D. Medical University Clinics, Center for Internal Medicine, Philipps University, Marburg, Germany 21. Meyer-Sabellek W, Gotzen R, Heitz J, Schulte K. Serum lipoprotein levels dur ing long-term treatment of hypertension with indapamide. Hypertension 1985; 7(Suppl):170-174. 22. Scalabrino A, Galenone F, Giuntoli F, et al. Clinical investigation on longterm effects of indapamide in patients with essential hypertension. Curr Ther Res 1984; 35:17-22. : 23. Tuck M. Treatment of hypertensive diabetic patients. Diabetes Care 1988; 11: 828-832. ABSTRACT A double-blind, randomized, multicenter study compared treatment with 10 mg torsemide, 20 mg torsemide, and 40 mg furosemide, once daily, in 70 patients with congestive heart failure who had been maintained on 40 mg furosemide daily for at least 2 weeks. All three treatment groups showed statistically significant decreases in body weight, ranging from 1 to 3 kg at week 6. The decreases in body weight were significantly greater in the 20-mg torsemide group than in the furosemide group at weeks 4 and 6 and in the 10-mg torsemide group than in the furosemide group at week 4. The 20-mg torsemide group showed a statistically significant reduction in edema. Both the 10-mg and 20-mg torsemide groups showed statistically significant improvement in heart size. Pulmonary congestion decreased with treatment in each group. At week 6, both edema and pulmonary congestion were significantly less in the 20-mg torsemide group than in the 10-mg torsemide or 40-mg furosemide groups. Torsemide was well tolerated. Small, clinically insignificant de- 0149-2918/93/$3.50 creases in serum potassium and increases in creatinine and uric acid were observed with both torsemide and furosemide. In conclusion, 20 mg torsemide was more effective than 40 mg furosemide in reducing body weight and improving symptoms of congestive heart failure. INTRODUCTION Torsemide (USAN; INN, torasemide), the first loop diuretic of the pyridine sulfonylurea class, has been studied in patients with edema due to congestive heart failure, renal insufficiency, and cirrhosis. Its use in the treatment of hypertension has also been studied. Torsemide differs from furosemide in that it has a longer half-life and greater oral bioavailability (approximately 80% in healthy subjects), 1-3 which allows patients to be switched to and from the intravenous form with no change in dose. Torsemide is eliminated by the liver (hepatic metabolism, 80%) as well as by the kidneys (renal excretion, 20%), whereas furosemide is eliminated primarily by the kidneys. Thus the half-life of torsemide 1051 CLINICAL THERAPEUTICS is relatively unaffected by renal function, and there is little risk that the drug will accumulate.4-7 In patients with congestive heart failure, the serum and urinary halflives of torsemide are to some extent, but not significantly, prolonged when compared with half-lives in healthy subjects.8 The hemodynamic effects of torsemide in patients with congestive heart failure are similar to those of furosemide.9-12 In clinical studies in patients with congestive heart failure, torsemide treatment was associated with decreases in body weight and edema13-15 and improvement in functional class according to the New York Heart Association classification system.15.16 Torsemide was well tolerated. The purpose of the present study was to evaluate the clinical effectiveness of torsemide at doses of 10 mg and 20 mg in comparison with 40 mg furosemide in patients with chronic heart failure treated for 6 weeks. A brief report of this study has been published. 17 PATIENTS AND METHODS Patients Four centers participated in this study. Male and female patients having heart failure requiring long-term therapy with furosemide to prevent edema were entered into the study if they had been successfully treated with 40 mg oral furosemide daily for at least 2 weeks immediately preceding their entry into the study. Patients with hypokalemia, hyponatremia, hypovolemia, or anemia were excluded. Informed consent was obtained from each patient before entry into the study. Seventy patients were enrolled (24 patients received 10 mg torsemide, 23 re- ceived 20 mg torsemide, and 23 received 40 mg furosemide). The three treatment groups were similar in baseline demographic and clinical characteristics (Table I). Overall, 61% of the patients (57% to 71% in each group) received cardiac glycosides concomitantly. Procedures Patients were randomly assigned to the three treatment groups. A medical history was recorded and a physical examination was performed, including measurements of body weight, sitting blood pressure, pulse rate, and respiration rate. The degree of edema was rated. A chest roentgenogram was obtained, from which heart size and pulmonary congestion were rated. A blood sample was obtained, for clinical laboratory tests. Study medication was dispensed in double-blind fashion, and patients were instructed to take one tablet daily in the morning. Patients returned to the clinic after 2, 4, and 6 weeks of therapy. At each visit, body weight and vital signs were measured, edema severity was rated, and a blood sample was obtained for clinical laboratory tests. Adverse events and concomitant medications were recorded at each visit. At the last visit, a chest roentgenogram was again obtained for the rating of heart size and pulmonary congestion. Body weight was measured to the nearest 0.1 kg using a standard calibrated scale before administrating the daily dose of study medication and after an overnight fast. Ratings of edema severity were made using a three-point scale: 1, severe; 2, moderate; 3, none. Heart size was rated as 1, normal; 2, moderately enlarged; or 3, severely enlarged. Pulmonary congestive as rated as 1, none; 2, K.-M. GOEBEL Table I. Demographic and clinical characteristics of congestive heart failure patients, by randomized group. Treatment Group Characteristic Sex 10 mg Torsemide 20 mg Torsemide 40 mg Furosemide 13(54%) 1 1 (46%) 9 (39%) 14(61%) 12(52%) 1 1 (48%) Male Female Age (yr) Mean Range Height (cm) Mean Range 62.9 45-76 62.8 43-77 62.0 42-81 168 153-183 169 158-185 170 156-184 Weight (kg) Mean Range 76.5 57-98 74.9 55-101 Duration of congestive heart failure (mo) Mean Range 33 7-72 24 3-60 29 2-72 Duration of edema (mo) Mean Range 10 1-48 7 1-24 1-60 26 14-60 23 14-41 24 14-62 Duration of prior furosemide treatment (day) Mean Range 73.1 49-93 13 slight; or 3, marked. The following clini- group were analyzed by analysis of variance. cal laboratory tests were performed: Whenever the overall treatment group effect hemoglobin, hematocrit, erythrocyte was significant at the 5% level, the three count, white blood cell count, sodium, pairwise comparisons among the treatment potassium, uric acid, creatinine, and groups were also examined at the 5% level. glucose. Within-group analyses of the change in Statistical Analysis congestive heart failure symptom ratings from baseline to the final visit were performed as Changes in body weight from baseline follows: For each symptom and treatment to the final visit within each treatment group, the number of pa1053 CLINICAL THERAPEUTICS tients rated as improved was contrasted with the number rated as worsened; this was done by a binomial test of the null hypothesis that the proportion is 0.5, including only patients who had a change in rating at the final visit. Comparisons among treatment groups with respect to edema severity, heart size, and pulmonary congestion were made by the Cocbran-Mantel-Haenszel procedure.18 Whenever the overall treatment-group effect was significant at the 5% level, the three pairwise comparisons among the treatment groups were also examined at the 5% level. All means for effectiveness variables are least square means, which give equal weight to each study center regardless of differences in sample size between centers. RESULTS None of the patients withdrew from the study prematurely. For each of the three treatment groups, the mean duration of therapy was 43 days. Change in Body Weight As shown in Table II, all three treatment groups showed statistically significant decreases in body weight at each evaluation (2 weeks, 4 weeks, and 6 weeks). In comparisons between treatment groups, mean weight loss in the 10mg torsemide group was significantly greater than in the 40-mg furosemide group at week 4 (P = 0.04), Weight loss in the 20-mg torsemide group was significantly greater than in the 40-mg furosemide group at weeks 4 and 6 (P = 0.01). Symptoms of Congestive Heart Failure Edema severity decreased in each group during treatment. However, torsemide was more effective than furosemide in reducing edema. The percentages of patients with severe edema were 33%, 22%, and 39% at baseline and 4%, 0%, and 17% at week 6 in the 10-mg torse- Table II. Mean baseline body weight and change from baseline during treatment of congestive heart failure patients with torsemide or furosemide. Mean Cl lange from line (kg), Base; by Study Week Treatment Group l0mg torsemide n 24 Mean Baseline Body Weight (kg) 77.4 Week 2 -1.06‡ Week 4* -2.20§ Week6† -2.08§ 20 mg torsemide 40 mg furosemide 23 23 75.7 72.9 -1.56§ -0.93‡ -2.47§ -1.07‡ -2.96§ -1.29‡ *10mg torsemide versus 40 mg furosemide, P = 0.04; 20 mg torsemide versus 40 mg furosemide, p = 0.01. †20 mg torsemide versus 40 mg furosemide, P = 0.01, ‡ P<0.01 versus baseline. §P<O.OOI versus baseline. K.-M. GOEBEL mide, 20-mg torsemide, and 40-mg furosemide groups, respectively. The figure correlates the baseline edema severity with the severity after 6 weeks of treatment. All the patients who had severe edema at baseline had no edema or moderate edema after treatment. A 77-year-old man in the 40-mg furosemide group had no edema at baseline, moderate edema at weeks 2 and 4, and severe edema at week 6. None of the patients in the 20-mg torsemide group showed a worsening of their edema at week 6 relative to baseline. The improvement in edema at week 6 was marginally significant for the 10-mg torsemide group (P = 0.057) and clearly significant for the 20-mg torsemide group (P<0.001) (Table III). Improvement in heart size at week 6 was statistically significant for the 10-mg and 20-mg torsemide groups but not for the 40-mg furosemide group (Table III). All three treatment groups showed statistically significant improvement in pulmonary congestion. In comparisons among treatment groups at 6 weeks, there was significantly less edema and pulmonary congestion in the 20-mg torsemide group than in the 10mg torsemide group (edema, P = 0.003; pulmonary congestion, P = 0.03) or the 40-mg furosemide group (edema, P = 0.001; pulmonary congestion, P = 0.02). The overall treatment-group effect was not statistically significant for heart size; therefore no pairwise comparisons of the treatment groups were performed. Safety No patient withdrew from the study because of an adverse event. A 54-yearold man in the 20-mg torsemide group experienced orthopnea as well as mild leg cramps and nausea for a period of 2 weeks, beginning after 4 weeks of treatment. All three treatment groups showed small decreases in serum potassium and increases in creatinine and uric acid (Table IV). Two patients in the 10-mg torsemide group and three in the 20-mg torsemide group received potassium supplementation during the study. Statistically significant decreases in blood pressure were observed during treatment in the 20-mg torsemide and 40mg furosemide groups. The effects on systolic blood pressure were more marked than those on diastolic blood pressure. Hypotension was not reported as an adverse event; the lower recorded blood pressures were 90 mmHg systolic and 60 mmHg diastolic. There were no observable effects on pulse rate or respiratory rate. DISCUSSION AND CONCLUSION In the present study, all treatment groups showed decreases in body weight and symptomatic improvement relative to baseline. However, 20 mg torsemide was statistically significantly more effective than 40 mg of furosemide in decreasing body weight, edema, and pulmonary congestion. These findings indicate the therapeutic effectiveness of torsemide in congestive heart failure. Other studies have compared orally administered torsemide and furosemide with regard to diuretic effects in healthy subjects' and clinical efficacy in patients with congestive heart failure. 13,15,16 As in the present study, on a milligram-formilligram basis, torsemide was consistently more effective than furosemide in 1055 CLINICAL THERAPEUTICS K.-M. GOEBEL Table III. Changes in ratings of congestive heart failure symptoms from baseline to week 6 of treatment with torsemide or furosemide. Parameter/ Treatment Group Edema 10 mg torsemide 20 mg torsemide 40 mg furosemide Heart size 10 mg torsemide 20 mg torsemide 40 mg furosemide Pulmonary congestion 10 mg torsemide 20 mg torsemide 40 mg furosemide n Worsened No Change 24 23 23 3 0 4 l0† 6 8 Improved 11 17 11 P Value* 0.057 <0.001 0.1 18 24 0 16 8 0.008 23 23 0 1 12 15 11 0.001 0.070 24 23 23 3 0 3 7 8 8 14 13 7 12 0.013 <0.001 0.035 *P value from a binomial test comparing the number improved with the number worsened within a given treatment group. † Includes one patient who had no record of edema severity at week 6 but had moderate edema at baseline and at weeks 2 and 4. Figure. Distribution of edema severity after 6 weeks of treatment with torsemide (TOR) or furosemide (FUR) versus baseline edema severity. 1056 increasing urinary sodium and volume and sium were small and not dose related. Slight, clinically insignificant decreases in reducing body weight. 14 Torsemide was well tolerated when ad- in serum potassium and increases in 15 ministered over a period of 6 weeks. One uric acid were observed in previous patient experienced mild leg cramps and nausea studies of torsemide in congestive heart that may have been related to the study failure. After 4 weeks of treatment with medication. Cramps and gastrointestinal 10 mg torsemide daily, mean serum uric 15 complaints were reported in a few patients acid rose by 0.43 mg/dl, compared with treated with torsemide in other studies.14-16 0.29 mg/dl in the present study. Hypotensionl3,15 and decreases in blood In conclusion, torsemide was found to pressure13,16 were also reported in previous be an effective and well-tolerated diuretic for the treatment of edema in pastudies of torsemide. The effects on clinical laboratory tests were tients with congestive heart failure. consistent with the pharmacology of loop diuretics and included decreases in serum potassium and increases in cre-atinine and uric ACKNOWLEDGMENT acid. As observed for urinary potassium excretion in pharmacody-namic studies of This study was supported in part by torsemide in healthy subjects,3,19 the decreases Boehringer Mannheim GmbH, Mannheim, Germany. in serum potas- CLINICAL THERAPEUTICS Table IV. Baseline clinical laboratory values and changes from baseline in congestive heart failure patients treated with torsemide or furosemide. Laboratory Testy Treatment Group Sodium (mEq/L) 10 mg torsemide 20 mg torsemide 40 mg furosemide Potassium (mEq/L) n Baseline 24 23 23 140 141 142 Change from Baseline -1.8* -0.4 24 23 23 4.6 4.8 4.5 -0.4† -0.2* Creatinine (mg/dl) 10 mg torsemide 20 mg torsemide 40 mg furosemide 24 23 23 0.87 0.87 0.85 0.10* 0.22† 0.27† 24 23 23 5.4 5.1 5.2 0.29 0.90† 0.60* 20 mg torsemide 40 mg furosemide -O.4t *P<0.05 versus baseline. †P<0.001 versus baseline. REFERENCES 1. Lesne M. Comparison of the pharmaco- 4. Barr WH, Smith HL, Karnes HT, et al. kinetics and pharmacodynamics of tora- Comparison of bioavailability, pharma-cokinetics semide and furosemide in healthy volun- and pharmacodynamics of torasemide in young and teers. Arzneim-Forsch 1988; 38:160-163. elderly healthy volunteers. Prog Pharmacol Clin Phar-macol 1990; 8:15-28. 2. Neugebauer G, Besenfelder E, Von Moellendorff E. Pharmacokinetics and 5. Dodion L, Willems JL. 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