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CLINICAL THERAPEUTICS
14. Domic JA, Miller RE, Anderson J,
McAllister RC. Pharmacology of verapamil. II. Impairment of glucose toler
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15. Donelly T, Harrower ADB. Effect of
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16. Fujii S, Matsumura S, Nakayama H, et
al. Effect of long-term treatment with
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2127-2133.
17. Trost N, Eeidmann P, Beretta-Piccoli C.
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102-108.
18. Struthers AD, Murphy MB, Dollery CT.
Glucose tolerance during antihypertensive therapy in patients with diabetes
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95-101.
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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.
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