4-O-Demethylyatein from the branch wood ofThuja occidentalis

CURRENT THERAPEUTIC RESEARCH” VOL. 59, NO. 10, OCTOBER

1998

EFFICACY AND SAFETY OF TORSEMIDE IN PATIENTS MODERATE CONGESTIVE HEART FAILURE

WITH

LUIGI ARGENZIANO,’ CARMINE MORISC0,2 BRUNO TRIMARCO,’ CARMINE MARIN0,2 DIEGO BEDOSCHI,3 AND PAOLO FEDERICO BOSCAN13

‘Clinica Medica I, “Federico II” University, Naples, “‘Neuron&” Institute, Pozzilli (IS), and 3Boehringer Mannheim Italia S.p.A., Monza, Italy

ABSTRACT

A multicenter open-label study was conducted to evaluate the efficacy and safety of torsemide in 170 patients with New York Heart Association (NYHA) Class II to Class III congestive heart failure (CIIF). Patients were assigned to receive torsemide for 2 months starting at 10 mg/d, to be adjusted after 14 or 30 days according to the diuretic effect and overall clinical condition of the individual. NYIIA class, body weight, ankle circumference, blood pressure, heart rate, degree of dyspnea, and signs and symptoms of CHF were recorded monthly. Safety was evaluated by recording adverse events during the study and by monitoring electrocardiographic tracings and laboratory test results. All 170 study patients were eligible for the safety anslysis, 160 of whom were included in the efficacy (perprotocol) analysis. Statistically significant changes in fluid mobilization with a progressive decrease in body weight and marked reduction of peripheral edema were observed. Functional status (NYIIA class) improved in 66 patients (44%), and a lower degree of dyspnea, based on the World Health Organization classification, was detected in 98 patients (65.3%), with nocturnal coughing and pulmonary rales resolving in 30 of 34 and 81 of 87 patients, respectively. Torsemide did not significantly affect carbohydrate or lipid metabolism or serum electrolyte levels. Fourteen adverse events were reported for 9 patients (6.3%). Two of the 9 patients discontinued treatment, 1 because of persistent left ventricular failure and multiple episodes of dizziness and 1 because of hospitsIization for suspected hepatoma. One patient with persistent dizziness, increased sweating, and asthenia required a dose change; the symptoms resolved after the dose was reduced. Results of this study suggest that torsemide was well tolerated and effective in the treatment of moderate CIIF. Key words: left ventricular dysfunction, loop diuretics, tomemide, congestive heart failure. Ih’TRODUCTION

Although several drugs, such as digitalis, angiotensin-converting enzyme (ACE) inhibitors, and vasodilators, are currently used in the management Address correspondence to: Luigi Argenziano, MD, Clinica Medica I, “Federiw Pansini, 5-80131 Naples, Italy. Received for publication on June 1, 1998. Printed in the USA. Reproduction in whole or part is not permitted.

697

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TORSEMIDE

IN CONGESTWE

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of congestive heart failure (CHF), diuretics are considered first-line 1-6 The diuretics most commonly used for treating CHF are the therapy. loop diuretics. These compounds reduce excess intravascular and extracellular fluid by increasing salt and water excretion. This relieves symptoms and reduces stress on the heart wall, in turn decreasing oxygen consumption by the ventricle and increasing pumping efficacy. However, the chronic administration of diuretics can induce metabolic and electrolyte abnormalities; potassium depletion commonly occurs in patients treated chronically with loop diuretics,7,8 and is often associated with the appearance of malignant ventricular arrhythmias.g Recent studies”,” have indicated that torsemide, a high ceiling loop diuretic, has diuretic and natriuretic activity comparable to that of furosemide but with less kaliuretic effect than furosemide. Several studies12-18 have demonstrated the clinical efficacy and safety of torsemide in the treatment of CHF; however, most studies have a short observational period (4 weeks). Thus it is still unclear whether a longer period of torsemide therapy would be effective in relieving symptoms of CHF while preserving potassium serum levels.12-18 Therefore, we planned the present study to evaluate the efficacy and tolerability of 8 weeks of torsemide therapy in patients with New York Heart Association (NYHA) Class II (slight limitation of activity; comfortable at rest or with mild exertion) to Class III (marked limitation of activity; comfortable only at rest) CHF whose condition had been stabilized with digitalis or ACE inhibitor treatment.

PATIENTS AND METHODS

Patients Men and women aged 35 to 35 years with NYHA Class II to III CHF stabilized with digitalis or ACE inhibitors were eligible to enter the study. Patients with evidence of active ischemic cardiomyopathy, arrhythmias, bradycardia, valvular heart diease, severe kidney or liver dysfunction, severe pulmonary disease, electrolyte imbalance (serum potassium levels ~3.5 mEq/L or serum sodium levels ~135 mEq/L), uncontrolled diabetes mellitus, or alcoholism were excluded from the study. Patients receiving concomitant neurotoxic or nephrotoxic therapy (eg, aminoglycosides, antidepressant drugs, anticonvulsants, lithium, amphetamines, barbiturates), those treated with corticosteroids or spasmolytic and anticholinergic agents, and patients not adhering to a low sodium diet were also excluded. Finally, women with childbearing potential and those who were breastfeeding were not eligible to participate in the study. Concomitant therapy with other diuretics or drugs that could affect ventricular function, except established therapy with digoxin or ACE in-

L. ARGENZIANO

ET AL

hibitors, was not permitted during the trial. The protocol was conducted according to the Declaration of Helsinki and its modifications and was approved by the ethics committees of the participating institutions. Study Design

Eligible patients, after giving oral witnessed consent, were assigned to receive torsemide for 2 months at an initial dose of 10 mg/d, to be taken in the morning. After 14 or 30 days, the dose was decreased to 5 mgld or increased to 20 mg/d if necessary based on the diuretic effect achieved and the observed pattern of fluid retention. At the baseline visit and monthly thereafter, NYHA class was determined; systolic and diastolic blood pressures, heart rate, and body weight were measured; and blood was collected for determination of serum electrolyte and glucose levels. Patients also underwent a complete physical examination, including evaluation of peripheral edema by left and right ankle circumference measurements; by signs such as jugular venous distention, pulmonary rales, cyanosis, hepatomegaly, or cardiomegaly; and by symptoms such as nocturnal coughing, nocturia, and dyspnea, the latter assessed by the World Health Organization (WHO) classification (0 = dyspnea absent; 1 = breathlessness caused by running or walking up an incline; 2 = breathlessness caused by walking on a level road; 3 = the need to stop walking on a level road because of breathlessness; 4 = breathlessness when washing or dressing). At baseline and at the end of treatment, routine laboratory tests (complete blood count with differential cell count, hemoglobin, hematocrit, platelet count, total and fractioned cholesterol, triglycerides) and 12-lead electrocardiography were performed. All adverse events experienced during the study were recorded, with date of onset, severity, duration, and any countermeasures specified. Statistical Analysis

All variables assessed‘on entry and at succeeding visits (demographic data, history, concomitant diseases and treatments, NYHA classification, severity of signs and symptoms) were submitted to a descriptive analysis, with the number of observations, means, standard deviations, and the minimum and maximum of frequencies reported as appropriate. Descriptive statistics were also computed for all variables at each visit. For signs and symptoms, frequencies of change compared with baseline values were assessed, with patients classified as recovered, same, or worsened. For NYHA class and dyspnea, patients were classified as improved, unchanged, or worsened. All assessable patients who completed 2 months of treatment were included in the efficacy (per-protocol) analysis.

TORSEMIDE

IN CONGESTIt%

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For quantitative variables (body weight, ankle circumference, blood pressure, and heart rate), statistical analysis was performed by repeatedmeasure analysis of variance (within patients). If significant differences occurred among times lie, baseline, day 15, 30, or 60), multiple comparisons by Student’s t test were performed to compare each time versus baseline. For ordered categoric or nominal variables (signs and symptoms, NYHA class, dyspnea), differences between baseline and final distribution were tested by the paired &i-square test. The level of significance was CY= 0.05. Safety analysis included all patients who entered the study and took at least one dose of the study drug. Descriptive statistics were also used for safety variables. Because normal ranges for laboratory values varied among centers, absolute and relative frequencies of patients with values below, within, or above these ranges were computed. Furthermore, patients were classified according to the final change of each variable compared with baseline value (increase, no change, decrease). Absolute and relative frequencies of adverse events were also recorded. RESULTS

A total of 170 patients (114 men and 56 women> with a mean age of 61.8 * 8.6 years (range, 35 to 85 years) were enrolled in 14 centers. Of these patients, 20 were excluded from the efficacy analysis, 17 having violated protocol (use of prohibited concomitant treatments, poor compliance, NYHA Class IV [any physical activity brings on discomfort, and symptoms also occur at rest; confined to bed or chair]) and 3 having dropped out before the a-month treatment period ended (lost to follow-up [ll, adverse events [2]) (Table I). Thus the per-protocol sample comprised 150 patients, while 170 patients entered the safety analysis. Baseline characteristics of the two patient populations are shown in Table II.

After 14 days of treatment, the dose of torsemide was reduced to 5 mgfd in 27 patients and increased to 20 mgld in 16 patients; 107 patients Table I. Protocol violations

and withdrawals

from study population

No. of patients in safety analysis Protocol violations Use of prohibited concomitant treatment Poor compliance Use of rohibited concomitant treatment and poor compliance NYHA Elass IV Withdrawals Lost to follow-up Adverse events No. of patients in efficacy analysis NYHA = New York Heart Association. 700

(N = 170). 170 17

; z 3 : 150

L. ARGENiXANO

Table II. Baseline characteristics

ET AL

of patients assessable

for safety and efficacy analyses.

Efficacy Analysis (N I 150)

Characteristics

Seb;eW) Female Age (Y)* Body weight (kg)* Height (cm)* Sm;rrs, n (%)

61 .a f 8.6 74.2 * 10.4 166.4 f 7.3

74.5 f I 0.8 166.9 i 7.2

Yes Medical history, n (%) Essential hypertensron Myocardial infarction Chronic ischemic heart disease Atrial fibrillation Cardiomyopathy Cardiomegaly Congenital heart disease Renal and ureteral disease Respiratory abnormality Concomitant drugs, n (%) Analgesic Antiarrhythmic, class Ill Antiasthmatic Antihypertensive Antithrombotic Beta-blocker Calcium channel blocker Converting enzyme blocker Digitalis Diuretic Dopaminergic ;II;;ec mtrate NY;tislayification,

n (%)

Class Ill Class IVt NYHA = New York Heart Association. * Mean f SD. t Protocol violations,

continued to receive 10 mg/d. After the first month, only 1 patient required further reduction, from 20 mg/d to 10 mg/d. Body weight (Figure 1) and ankle circumference (Figure 2) decreased throughout the study period, with statistically significant differences compared with baseline values for both parameters (P c 0.001). Table III shows the changes in heart rate and systolic and diastolic blood pressures recorded in the supine and standing positions. Most signs and symptoms improved progressively throughout the study period (Table IV). Cardiac enlargement was present at baseline in 113 patients (75.3%) and at the end of treatment in 110 patients (73.3%), with 5 patients classified as recovered, 2 as worsened, and 143 as un701

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Day 60

Figure 1. Mean body weight of patients included in the efficacy analysis (n = 150) from baseline to day 60 (end of treatment). *P < 0.001.

changed. Jugular vein distention was present at baseline in 54 patients (36.0%); 51 patients had recovered by the end of treatment (P < O.OOl), while the condition had not worsened in any patient. Congestive hepatomegaly was present at baseline in 54 patients (36.0%) and at the end of the

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Day 15

Figure 2. Mean left and right ankle circumference treatment). *P < 0.001.

702

Day 60

changes from baseline to day 60 (end of

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ET AL.

Table III. Changes in heart rate and systolic and diastolic blood pressures cluded in the efficacy analysis (n = 150). Baseline He;er;;t~ .&ps/min) 77.9 * 10.8 Range FL?-105 Sys$$ood pressure (mm Hg) 14;‘t7&3Ol Mean + SD Ranae Standing 139;ii2;5 Mean f SD Range Diesmiieblood pressure (mm Hg) R1ean f SD Range Standing Mean * SD Range

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Day 60


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’ Baseline versus day 14. t Baseline versus day 30. $ Baseline versus day 60.

study in 30 patients (20.0%); 25 patients were classified as recovered (P c O.OOl), 1 as worsened, and 124 as unchanged. Of the 87 patients with pulmonary rales at baseline, 81 recovered after treatment with torsemide (P < O.OOl), while 1 of the 63 patients without initial symptoms worsened. Nocturnal coughing improved in 30 of the 34 patients with symptoms at baseline (P c 0.001). Of the 66 patients with nocturia at baseline, 35 improved (P < O.OOl), while 4 of the 84 patients who were not initially symptomatic had worsened by the end of treatment. After 2 months of treatment with torsemide, peripheral edema resolved in 56 of the 78 patients who were edematous at baseline (P c 0.001). Edema did not develop in any of the patients during the study. The percentage of patients with different degrees of dyspnea, according to the WHO classification, before and after treatment with torsemide is

Table Iv.

Number (%) of patients included in the efficacy analysis (n = 150) who had signs and symptoms during the study period.

Baseline

Day14

Cardiac enlargement Congestive hepatomegaly Cyanosis Jugular vein distention Pulmonary rales Nocturnal coughing Nocturia Peripheral edema

703

Day 30

Day 60

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shown in Figure 3. Decreased severity of dyspnea and overall improvement of symptoms were noted in 98 patients (65.3%) after 2 months of torsemide therapy (P c 0.001). Furthermore, overall NYHA functional class improved significantly during the study: 37 patients (24.7%) changed from Class III to II, 5 (3.3%) from Class III to I, and 24 (16.0%) from Class II to I, with an overall improvement in 66 patients (44%) (P c 0.001) (Figure 4). NYHA class did not worsen in any patient during the treatment period.

All patients who received torsemide were included in the safety analysis. Torsemide therapy did not have a negative effect on laboratory findings. In particular, torsemide 5 to 20 mg/d for 2 months did not significantly affect serum electrolyte levels (Figure 5) or carbohydrate or lipid metabolism (Figure 6). The percentage of patients with normal (5.4%) electrocardiographic tracings at the end of treatment was similar to that determined at baseline (4.7%). Overall, 14 adverse events were reported for 9 patients (5.3%). Details of these adverse events, most of which resolved spontaneously or after dose

0

1

2

3

4

WHO Class Figure 3. Percentage of patients included in the efficacy analysis (n = 150) with different degrees of dyspnea, according to World Health Organization (WHO) classification (0 = dyspnea absent; 1 = breathlessness caused by running or walking up an incline; 2 = breathlessness caused by walking on a level road, 3 = the need to stop walking on a level road because of breathlessness; 4 = breathlessness when washing or dressing) before and aher 60 days of treatment with torsemide. 704

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NYHA Classification

Baseline

ET AL.

No. (%) of patients who improved

60 Days

Figure 4. Number and percentage of the patients whose New York Heart Association (NYHA) functional class improved after 2 months of torsemide treatment.

reduction, are summarized in Table V. Two patients discontinued treatment because of adverse events: 1 due to persistent left ventricular failure and multiple episodes of dizziness not responsive to torsemide dose reduction, and 1 because of hospitalization for suspected hepatoma. DISCUSSION

In the present study, in patients with NYHA Class II to Class III CHF whose condition had been stabilized with digitalis or ACE inhibitors, torsemide 5 to 20 mg/d had a beneficial effect on the clinical symptoms of CHF without affecting potassium serum levels. Eight weeks of torsemide treatment improved NYHA functional class in 44% of patients, especially those with more severe CHF. Our results are partially consistent with previous reports14,15that demonstrated the efficacy of 4 weeks of treatment with torsemide 5 or 10 mg/d in improving mean NYHA functional class. However, these studies also describe slight decreases in serum potassium concentration of 0.11 mmol/L and 0.27 mmol/L after administration of 5 or 10 mg of torsemide, respectively; in contrast, we found no such decrease in serum potassium concentration after 8 weeks of torsemide therapy. This latter observation is noteworthy, because it is well known that excessive potassium loss can trigger life-threatening arrhythmias, especially in patients with CHF who are receiving concomitant digitalis therapy. 705

TORSEMIDE

IN CONGESTIVE

Glucose

HEART

FAILURE

Potassium

Sodium 1OOI

100 90 80 70 60 50 $9

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z n

20 10 0 Baseline

Baseline

60 Days

Baseline

60 Days

b

Magnesium

Calcium 1OOT

Baseline

n

Below normal range

60 Days H Within normal range

0

Above normal range

Figure 5. Percentage of the patients included in the safety analysis (N = 170) with serum glucose, potassium, sodium, calcium, and magnesium levels below, within, and above the normal ranges before and after 2 months of torsemide treatment.

We detected a decrease in pulmonary congestion accompanied by a reduction in pulmonary rales. Body weight and peripheral edema showed statistically significant decreases during the study period, confirming the positive action of torsemide on fluid mobilization. These effects on the signs of CHF also occurred in the 84 patients who did not experience improvement in NYHA class. Most patients (71%) were responsive to 10 mg/d; 20 mg/d was required to achieve an adequate response in ll%, and the initial dose of 10 mg/d was reduced to 5 mg/d in the remaining 18%. Our data support the use of torsemide 5 mgld as a starting dose in patients with CHF, with the dose increased to 10 mg/d or even 20 mg/d if symptoms do not improve. Overall, as reported in other studies,lP17 the incidence of adverse events with torsemide treatment was low. Only nine patients (5.3%) reported adverse events; the relationship of these events with the study drug could not be determined definitively in the presence of concomitant therapies. Two patients withdrew from treatment; one required hospitalization for suspected hepatoma, and the other had persistent left ventricular failure and multiple episodes of dizziness.

706

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Total Cholesterol

Triglycerides 100

100

90

SO

80

80 70 60

6

Baseline

$ B

60 Days

HDL

5

100

r a p

90 30 70

100 SO 30 70 60

60

!iO 40 30 20 10 01 Baseline

n

Below -al

range

SO Days

n Within

-I

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0 Above mmml range

Figure 6. Percentage of the patients included in the safety analysis (n = 170) with serum triglyceride, total cholesterol, high-density lipoprotein (I-CDL), and low-density lipoprotein (LDL) levels below, within, and above the normal ranges before and after 2 months of treatment with torsemide.

Table V. Adverse events (AEs) reported in patients included in the safety analysis (N = 170) during 2 months of treatment with torsemide.

No. of Patients Adverse event Hyperglycemia Dizziness Increased sweating Asthenia Left ventricular failure Atrial fibrillation Dyspepsia Flatulence H peruricemia Az normal liver function test Hepatoma Hypotension Total number of AEs No. % of patients reporting AEs No. I% 1 of patients withdrawn because of AEs

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CONCLUSION

The present study demonstrates that torsemide is well tolerated, effective in treating moderate CHF, and useful when administered with digoxin or ACE inhibitors to reduce the signs and symptoms of CHF. Acknowledgment The study was supported by a grant from Boehringer Mannheim Italia S.p.A., Monza, Italy. The following are the participating investigators: C. Vecchio and G. Derchi, Ospedali Galliera, Genova; U. Guiducci and M. Pantaleoni, Arcispedale S. Maria Nuova, Reggio Emilia; G. B. Ambrosio, C. Leprotti, and G. Vescovo, Ospedale SS. Giovanni e Paolo, Venezia; E. Bartoli and A. Sechi, Policlinico Universitario, Udine; P. I. Porciello and P. Borgheresi, Ospedale Civile, Arezzo; V. Ceci and R. Ricci, Ospedale S. Spirito, Roma; A. Purcaro and C. Costantini, Ospedale G. M. Lancisi, Ancona; P. Marsili and E. Marsili, Ospedale S. Salvatore, L’Aquila; 0. De Divitiis, S. Di Somma, A. Carotenuto, Cattedra di Metodologia Clinica S.A.D. Universita Federico II, Napoli; R. Fanelli, R. Massaro, and N. Cianfrone, Casa Sollievo della Sofferenza IRCCS, S. Giovanni Rotondo (FG); B. Ravera and F. Rufolo, Ospedali Riuniti S. Giovanni di Dio e Ruggi D’Aragona, Salerno; L. Cavallaro and S. Mangano, Ospedale Papardo, Messina; A. Castello, A. Taormina, and S. Andolina, Ospedale Buccheri La Ferla, Palermo. References: 1. Cohn JN. Physiological rationale Heart J. 1994;72(Suppl):S63-S67. 2. Taylor SH. Refocus on diuretics 1995;16(Suppl F):7-15. 3. Burkart F. Rationale

for co-treatment

with diuretics

in the treatment

for current drug treatment.

of heart

changes

failure.

Eur Heart J.

Eur Heart J. 1995;16(Suppl

4. Cody RJ, Pickworth KK. Approaches to diuretic therapy congestive heart failure. Cardiol Clin. 1994;12:37-50. 5. Silke B. Diuretic induced 1994;72(Suppl):S57-S62.

in heart failure. Br

in symptoms

and electrolyte

and quality

of loop diuretics. Drugs. 1991;41(Suppl

7. Kruck F. Acute and long-term 1991;41(Suppl 3k60-68.

effects

diuretics

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in

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6. Brater DC. Clinical pharmacology

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F):2-3.

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8. Reyes JA. Loop diuretics versus others in the treatment of congestive heart failure after myocardial infarction. Cardiovasc Drugs Ther. 1993;7:869-876. 9. Nordrehaug JA, Johannessen KA, von der Lippe G. Serum potassium concentration as a risk factor of ventricular arrhythmias early in acute myocardial infarction. Circulation. 1985;71:645-649. 10. Scheen AJ, Vancrombreucq

JC, Delarge J, Luyckx AS. Diuretic activity of torsemide and

708

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furosemide in chronic heart failure: A comparative double-blind cross-over study. EUF J Clin Pharmacol. 1986;31(Supp 1):35-42. 11. Dunn CJ, Fitton A, Brogden RN. Torsemide. An update of its pharmacological properties and therapeutic efficacy. Drugs. 1995;49(Suppl 1):121-142. 12. Podszus T, Piesche L. Effect of torsemide on pulmonary and cardiac haemodynamics after oral treatment of chronic heart failure. In: Rruck F, Mutschler E, Knauf H, eds. Torsemide: Clinical Pharmacology and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology. Stuttgart: Gustav-Fischer-Verlag; 1990:158-166. 13. Fiehring H, A&hammer I. Influence of 10 mg torsemide iv. and 20 mg furosemide i.v. on the intracardiac pressures in patients with heart failure at rest and during exercise. In: Eruck F, Mutschler E, Knauf H, eds. Torsemide: Clinical Pharmacology and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology. Stuttgart: GustavFischer-Verlag; 1990:97-104. 14. Dusing R, Piesche L. Second line therapy of congestive heart failure with torsemide. In: Kruck F, Mutschler E, &auf H, eds. Torsemide: Clinical Pharmacology and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology. Stuttgart: GustavFischer-Verlag; 1990:105-120. 15. Stauch M, Stiehl L. Controlled, double-blind clinical trial on the efficacy and tolerance of torsemide in comparison with furosemide in patients with congestive heart failure-a multicenter study. In: Eruck F, Mutschler E, Enauf H, eds. Torsemide: Clinical Pharmacology and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology. Stuttgart: Gustav-Fischer-Verlag; 1990:121-126. 16. Goebel EM. Six week study of torsemide in patients with congestive heart failure. Clin The?-. 1993;15:1051-1059. 17. Achhammer I. Long term efficacy and tolerance of torsemide in congestive heart failure. In: Rruck F, Mutschler E, Enauf H, eds. Torsemide: Clinical Pharmacology and Therapeutic Applications. Progress in Pharmacology and Clinical Pharmacology. Stuttgart: Gustav-Fischer-Verlag; 1990:127-136. 18. Hariman RJ, Bremner S, Louie EE, et al. Dose-response study of intravenous torsemide in congestive heart failure. Am Heart J. 1994;128:352-357.

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