Download Study protocol

Comparison of the angiotensin II antagonist losartan
with the angiotensin converting enzyme inhibitor enalapril
in patients with essential hypertension
Ilkka Tikkanen, Per Omvik* and Henrik Æ. Jensen† for
the Scandinavian Study Group‡
Objective: To evaluate the blood pressure lowering efficacy as well as tolerability and safety
of the angiotensin II antagonist losartan compared with that of the angiotensin converting
enzyme inhibitor enalapril in patients with rnild-to-moderiate essential hypertension.
Design and methods: The study was a multicentre, double-blind, double-dummy,
randomized, parallel study. Patients (n = 407) with diastolic blood pressure >95
and < 120 mmHg at the end of a 2-week baseline placebo period were randomly
allocated to receive either 50 mg losartan once a day or 20 mg enalapril once a day for
12 weeks. Blood pressure, clinical and laboratory safety, specific symptoms including
coughing determined using a symptoms questionnaire and metabolic variables were
examined at baseline and at weeks 6 and 12.
Results: Both losartan and enalapril decreased systolic and diastolic blood pressure
from baseline at weeks 6 and 12. Blood pressure changes from baseline at trough
(22-26 h after the dose) did not differ between the two groups in the per-protocol
analysis. Response to treatment at trough was excellent or good (diastolic blood
pressure < 90 mmHg or reduction in diastolic blood pressure of 10 mmHg) in 51
and 53% of the patients in the losartan and enalapril groups, respectively. Enalapril
administration increased dry coughing symptoms whereas losartan did not. The
incidence of dry coughing was 1.0 and 1 2.2% as a spontaneously reported discomfort
at week 12 and 3.0 and 15.1% as a clinical adverse experience in the losartan
and enalapril groups, respectively. The difference from baseline at week 12 in the
incidence of dry coughing between the two groups was 1 4.9% as a specific symptom in
the symptoms questionnaire, Losartan reduced serum uric acid concentration,
whereas effects on other metabolic parameters did not differ between the groups.
Conclusions: Losartan is an effective and well-tolerated antihypertensive drug
showing similar blood-pressure-lowering efficacy to that of enalapril at trough.
However, in contrast to enalapril, losartan does not increase the incidence of dry
coughing. Thus, the angiotensin lI antagonist losartan provides a promising new
approach to treatment of hypertension.
Journal of Hypertension 1995, 13:1343 -1351
Keywords: angiotensin II antagonist, losartan,
angiotensin converting enzyme inhibitor, enalapril, blood
pressure, cough, side effects, essential hypertension
Introduction
Inhibition of the renin-angiotensin system by means of
angiotensin converting enzyme inhibitors has proved
efficacious in the treatment of hypertension and other
cardiovascular diseases. The development of specific
type 1 angiotensin II receptor (AT 1 ) antagonists [1,2]
has recently provided a new tool to inhibit the
renin—angiotensin system. Experimental data and preliminary clinical experience suggest that the efficacy
From the Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland, the *Medical Department A,
Haukeland Hospital, Bergen, Norway, and the †Hvidovre University Hospital, Denmark. ‡See Appendix.
Requests for reprints to Dr I. Tikkanen, Department of Medicine, Helsinki Universjty Central Hospital, Unioninkatu 38,
FIN-00170 Helsinki, Finland.
Date of receipt: 6 March 1995; revised: 7 August 1995; accepted: 9 August 1995.
© Rapid Science Publishers ISSN 0263-6352
1343
1344
Journal of Hypetension 1995, Vol 13 No. 11
of angiotensin II antagonists in the treatment of
hypertension is similar to that of angiotensin converting enzyme inhibitors [3,4]. However, those two
drug categories also have potential differences because of
different mechanisms of action. The anigiotensin
converting enzyme inhibitors may have actions that are
not related to inhibition of the renin-angiotensin system
by preventing the breakdown of bradykinin and other
biologically active peptides [5,6]. However, a more
complete blockade of the renin-angiotensin system may
be achieved by treatment with angiotensin II antagonists,
compared with angiotensin converting enzyme inhibitors,
because it has been suggested that significant amounts of
angiotensin II are also generated by non-angiotensin
converting enzymes not affected by angiotensin converting
enzyme inhibitors [7].
In clinical practice, the possible differences between angiotensin converting enzyme inhibitors and angiotensin II
antagonists may concern not only antihypertensive
efficacy but also tolerability and side effects. In particular,
dry coughing, which is a typical class-specific side effect of
angiotensin converting enzyme inhibitors associated with
accumulation ofbradykinin and substance P [8—10], is not
expected
during
treatment
with
angiotensin II
antagonists. Thus, whereas angiotensin converting
enzyme inhibitors in general have proved to be well
tolerated, treatment with angiotensin II antagonists
could provide an additional advantage over angiotensin
converting enzyme inhibitors. The objective of the
present multicentre trial was to evaluate the efficacy of
the first angiotensin II antagonist losartan compared with
the
angiotensin
converting
cnzymje
inhibitor
enalapril in lowering of blood pressure in patients with
mild-to-moderate essential hypertension. In addition,
special attention was paid to evaluating the tolcrability
and safety with particular reference to coughing and
effects on metabolic variables.
Methods
Patients
Male or female patients aged 20-75 years with mild-tomoderate essential hypertension (sitting diastolic blood
pressure > 95 and < 120 mmHg after 2 weeks of
placebo) were included in the study. Patients were
either not treated previously or had been treated
with the concomitant use of up to two different
antihypertensive drugs. Patients with secondary hypertension of any aetiology, significant renal impairment
[serum creatinine level >150 mol/l and proteinuria
>1+ by Albustix (Bayer Diagnostics, Puteaux, France)],
cerebrovascular accidents, transient ischaemic attacks or
hypertensive encephalopathy during the past year,
myocardial infarction during the last 6 months, or angina
pectoris were excluded from the study. Pregnant or
nursing women and women of child-bearing potential
were also excluded. Other reasons for exclusion were
present
use
ot
non-steroidal
anti-inflammatory
corticosteroids, or drugs known to affect blood pressure,
uncontrolled diabetes mellitus (fasting blood glucose level
>11 mmol/1), obesity (arm circumference > 41 cm serum
potassium level < 3.5 or > 5.5 mmol/l, abnormal liver
function tests (serum glutamate oxaloacetate transaminase/serum glutamate pyruvate transaminase twice
the upper limit of normal), blood haemoglobin level <
100 g/dl, or any other clinically important disease or
condition that might interfere with participation in the
study, confound the results of the study, or produce a
significant risk to the patient. In addition, patients who
had previously been treated with angiotensin converting
enzyme inhibitors were excluded if that treatment
had been stopped because of adverse reactions or an
unsatisfactory effect on blood pressure, or both.
Study protocol
The study was a multicentre, double-blind, doubledummy randomized, parallel study. The study protocol
was approved by the local ethics committees. All of
the patients gave their written informed consent to
participate. Those who were currently being treated
for hypertension were withdrawn from antihypertensive
drugs for at least a 2-week washout period. Patients who
satisfied the eligibility criteria received placebo during a
single-blind 2-week baseline
period. Patients with
sitting diastolic blood pressure 95-120 mmHg at the
end of the baseline period were randomly allocated to
receive either 50 mg losartan once a day or 20 mg
enalapril once a day for a period, of 12 weeks. Five
clinical visits were scheduled during the study: one at
screening, two at baseline, one at week 6 and one at
week 12. The patients were asked to take their daily dose of
the study drug in the morning. However, in order to
ensure trough blood pressure values (i.e. after 24 h) the
patients were instructed not to take their study drug on
the days of clinical visits until after the blood pressure
measurement. Blood pressure, clinical safety and specific
symptoms including a cough were monitored at each
clinical visit (Table 1). Patients maintained their usual
diet throughout the baseline and treatment periods.
Clinical and laboratory evaluations
At each visit, sitting systolic (Korotkoff phase I) and
diastolic (Korotkoff phase V) blood pressures were
measured from the non-dominant arm using a standard
mercury sphygmomanometer and an appropriate cuff
size. Blood pressure values recorded were the means of
three measurements taken at 1 min intervals atter 10 min
of supine rest. The pulse rate was recorded at the same
times. Physical examination, complete blood counts, a
blood chemistry profile and urine analysis were
performed at the screening visit, and abbreviated laboratory
evaluations at visits shown in Table 1.
Evaluation of side effects and safety
Evaluation of side effects and safety was approached in
three different ways. First, the incidence of cough ana
other symptoms was evaluated at baseline and at weeks
Losartan versus enalapril in essential hypertension Tikkanen et. al.
Table 1. Study design.
Trough blood pressure (22-26 h after last dose)
Physical examination
Laboratory examinationa
Lipidsb
Adverse experience
Questionnaire for specific symptoms (i.e. coughing)
-4
X
X
-2
X
X
x
X
X
Weekc
0
X
X
X
X
X
X
6
X
X
X
X
X
12
X
X
X
X
X
X
a
Haemoglobin, white blood cells, serum glutamate pyruvate transaminase (aspartate transaminase), serum glutamate oxaloacetate transaminase (alanine transaminase), serum potassium, creatinine and uric acid levels, fasting blood glucose level, urinanalysi s [pH, protein,
glucose by Albustix (Bayer Diagnostics, Puteaux, France)]. bSerum total cholesterol, triglycerides and high-density lipoprotein cholesterol
levels. cScreening/washout period = weeks -4 to -2; placebo = weeks -2 to 0; therapy = weeks 0 to 12: losartan 50 mg once daily (n=202),
enalapril 20 mg once daily (n = 205).
6 and 12 (Table 1) using a symptoms questionnaire
[11]. The patients had to respond 'Yes' or 'No' to the
general question: 'Have you felt any kind of discomfort
during the past week?', and if 'Yes', describe 'what kind of
discomfort' they felt (spontaneously reported discomfort).
Second, information concerning the occurrence of the
following specific symptoms during the previous week
was requested separately (specific symptoms questionnaire):
headache, dizziness/vertigo, dizziness on standing,
weakness on exercising, muscle pain, swollen ankles, cold
hands/feet, flushing, rash/itching, breathing disturbances,
nasal stuffiness, dry coughing, dry mouth, taste
disturbance, nausea, diarrhoea, constipation, palpitations/tachycardia, nervousness/restlessness, reduced
sexual activity and other possible symptoms. Finally,
clinical and laboratory adverse experiences were monitored and reported by the investigators with respect to
intensity, seriousness and estimated relationship to the
treatment, at timepoints (Table 1).
Data analysis
Primary end-points were change from baseline in the
incidence of coughing as assessed by the appropriate
question of the symptoms questionnaire and change from
baseline in sitting diastolic blood pressure. Secondary
outcome variables were change from baseline in sitting
systolic blood pressure, change from baseline in the
incidence of symptoms from the questionnaire, response to
antihypertensive treatment in diastolic blood pressure
(excellent: 90 mmHg; good: > 9.0 mmHg and reduction
l0 mmHg; fair: > 90 mmHg and reduction SmmHg
but < 10 nimHg; poor: > 90 mmHg and reduction <
5 mmHg) and change from baseline in metabolic
parameters.
Within-group changes in blood pressure variables (effi-.
cacy) were reported by the use of mean change from
baseline and its associated 95% confidence interval on
the basis of the one-sample t-test. Between-group changes
in efficacy variables were analysed by an analysis of
variance model with treatment, country and study centre
within country as factors. Consistency
of the itreatment effect among countries was tested
at the level 0.10 in an analysis of variance model
with treatment  country interaction in addition to the
main factors. The normality of the residuals and the
homogeneity of variance assumption for analysis of
variance were examined graphically and tested by the
Shapiro—Wilk test and Levene's test.
For analysis of blood pressure variables, an additional 'perprotocol' approach was used excluding protocol violators.
The exclusion criteria applied for the per-protocol
analysis were violation of baseline blood pressure entry
criteria, violation of the trough (22-26 h after the
dose window) blood pressure measurement (data
excluded at that timepoint), concomitant antihypertensive therapy during the study, not having taken the
drug 2 or more days before blood pressure measurement
(data excluded at that timepoint) and rounding of blood
pressure measurements (data excluded at that timepoint).
The analysis of symptoms (coughing) was based on
the change from baseline in the percentage of patients
who responded to the specific symptom question in
the symptoms questionnaire, A generalized linear model
(SAS/CATFMOD) was used with time, treatment and
time  treatment interaction. The latter term tested for
between-treatment differences in the proportion of
positive answers. The within-group test was based on
McNernar’s test.
For analysis of safety, the treatment groups were
compared with regard to the incidence of clinical and
laboratory adverse events by using Fishers exact test.
Primarily, changes outside predefined limits in the
laboratory; safety test were compared between groups
using Fisher’s exact test. Secondarily, mean changes from
baseline were compared between groups with an analysis of
variance model and within-group comparisons were made
by the use of confidence intervals on the basis of Students
redistribution.
All of the statistical tests are two-tailed and P-values are
rounded to two decimal places. P<0.05 was considered
statistically significant.
1345
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Journal of Hypertension 1995, Vol 13 No 11
Results
Patient characteristics
Four hundred and seven patients were randomly allocated
in 32 centres in four countries (Denmark, Finland, Iceland
and Norway) to treatment with losartan (n=202) or
enalapril (n=205). The distribution of patients among
centres was similar in the two treatment arms. All of
the patients were white. The treatment groups were
similar with respect to sex, age, secondary diagnoses and
previous antihypertensive treatment (Table 2). The most
common secondary diagnoses were a headache (5%) and
eczema (4.5%) in the losartan group and a headache
(5.9%) and menopausal disorder (4.4%) in the enalapril
group. There were no significant differences between
the two treatment groups with regard to the baseline
mean blood pressures and pulse, or the incidence of dry
coughing.
Nine patients discontinued in the losartan group (six for
adverse clinical experiences) and 16 in the enalapril
group (14 for adverse clinical experiences during
treatment). Two hundred patients were, evaluated for
efficacy in the losartan group and 199 patients in th
enalapril group in the 'all-patients-treated' approach
(corresponding to the 'intention-to-treat' approach), an
142 and 133 patients in the 'per-protocol' approach
respectively. The majority (95% at week 6 and 96%:
week 12) of exclusions from the 'per-protocol' approach
was due to measurements taken outside the trough
(22-26 h after the dose) blood pressure measurement
window.
Efficacy (blood pressure)
Change in diastolic blood pressure
Both losartan and enalapril treatments decreased the si
ting diastolic blood pressure of the patients from baseline
at week 6 (P<0.01) and week 12 (P<0.01, Tab
3). The mean decrease (all-patients-treated approach)
at week 12 was 8.4 mmHg in the losartan group an
10.6 mmHg in the enalapril group (P<0.01, Fig. 1)
In the per-protocol approach (see data analysis), the
corresponding mean changes in diastolic blood pressure
at week 12 were 8.4 and 9.7 mmHg (between-group
difference NS) in the losartan and the enalapril group
respectively (Fig. 1).
Table 2. Summary of patient characteristics.
Losartan
Enalapril
n
%
80
122
%
n
%
n
39.6
60.4
71
• 134
34.6
65.4
151
256
37.1
62.9
8
43
75
48
28
4.0
21.3
37.1
23.8
13.9
11
27
77
62
28
5.4
13.2
37.6
30.2
13.7
1.9
70
152
110
56
4.7
17.2
37.3
27.0
13.8
130
32
13
11
2
3
11
64.4
15.8
6.4
5.5
1.0
1.5
5.5
143
25
15
7
0
2
13
69.8
12.2
7.3
3.4
0.0
1.0
6.3
273
57
28
18
2
5
24
67.1
14.0
6.9
4.4
0.5
1.2
5.9
123
79
60.9
39.1
126
79
61.5
38.5
249
158
61.2
38.8
Sex
Female
Male
Age (years)
< 35
35-44
45-54
55-64
> 64
Previous antihypertensive treatment
None
ACEI
-Blocker
Calcium antagonist
Central antihypertensive
Diuretic
More than one
Secondary diagnoses
Yes
No
Total
-
ACEI, angiotensin converting enzyme inh ibitor.
Table 3. Mean change from baseline in diastolic blood pressure at week 12 in patients treated with either losartan (50 mg once a day)
enalapril (20 mg once a day).
Approach
Treatment
n
Baseline
Week 12
Change from baseline
All patients treated
Losartan
200
103.1 ± 6.0
94.7 + 9.0
-6.4 ± 7.1(-94; -7.5)**
Per protocol
Enalapril
Losartan
Enalapril
199
142
133
103. 7 ± 6.1
102. 9 ± 6.0
103. 4 ± 5. 9
93.0 ± 17.9
94,4- ± 8,7
93.7 ± 7.8
-10.6 ± 7.2(-11.6;"9.6)** ††
-6.4 ± 6.6 (-9.5; -7.3)**
-9.7 ± 7.2 (-10.9; -6.5)**
Values are expressed as means  SD (95% confidence limits).**P<0.01, versus baseline;
††P<0.01,
versus losartan treatment.
Losartan versus enalapril in essential hypertension Tikkanen et al.
1347
Table 4. Mean choree from baseline in systolic blood pressure at week 12 in patients treated with either losartan or enalapril.
Approach
Treatment
n
Baseline
Week 12
Change from baseline
All patients treated
Per protocol
Losartan
Enalapril
Losartan
Enalapril
200
199
142
133
157.5 ± 17.1
158.8 ± 16.5
156.5 ± 16. 4
158.3 + 16.7
Values are expressed as means  SD (95% confidence limits).**P<0.01, versus baseline;
Change in Diastolic Blood Pressure at 12 weeks
Fig. 1. The mean change in sitting diastolic blood pressure from
baseline at week 1 2 in patients treated with either losartan (50 mg once a
day) or enalapril (20 mg once a clay). Results based on the 'all-patientstreated' approach and the 'per-protocol' approach are shown.
146.9 ± 18.3
146.0 ± 16.9
145.6 ± 17.1
145.5 ± 16. 6
††P<0.01,
-10.6 ± 13.0 (-12.4; -8.8)**
-12.9 ± 12.9 (-14.7; -11.1)**†
-10.9 ± 12.0 (--12. 9; -8.9)**
-12.8 ±1 2.1 (-14.8; -10.7)**
versus losartan treatment.
Change in Systolic Blood Pressure at 12 weeks
Fig. 2. The mean change in sitting systolic blood pressure from baseline
at week 1 2 in patients receiving either losartan (50 mg once a day) or
enalapril (20mg once a day). Results based on the 'all-patients-treated'
approach and the 'per-protocol' approach are shown.
When the actual time of. after-dose blood pressure
measurements was taken into account, it was found that,
the diastolic blood pressure lowering effect of enalapril
was more pronounced if measured before 22 h after the
dose (mean time 8.3 h after the last dose) compared with
losartan (P<0.05). However, at trough (22-26 h after the
dose, mean 24.6 h), the two treatments did not differ
with respect to change in diastolic blood pressure from
baseline.
Response to treatment
In the all-patients-treated analysis, the distribution of
patients among the three categories of. response
(excellent or good, fair, poor) was significantly different
in favour of enalapril (P<0.05). In the per-protocol
analysis, the treatment groups were similar with respect
to the distribution of patients in the three categories
of response. The efficacy in lowering diastolic blood
pressure (response to treatment) at trough was excellent
or good in 51% of the patients in the losartan group and
in 53% of the patients in the enalapril group (Table 5).
Change in systolic blood pressure
The mean decrease in sitting systolic blood pressure
from baseline was also statistically significant both in the
losartan and in the enalapril groups at weeks 6 (P<0.01)
and 12 (P<0.01, Table 4). The mean decrease in systolic
blood pressure (all-patients-treated approach) at week 12
was 10.6 mmHg in the losartan group and 12.9 mmHg
in the enalapril group (P<-0.05 for between-groups
difference; Fig. 2). In the per-protocol approach at
week 12, the change in mean systolic blood pressure was
10.9 mmHg in the losartan group and 12.8 mmHg in the
enalapril group (P—0.08 for between-groups difference;
Fig. 2).
Incidence of symptoms
Coughing
The incidence of a dry cough given as a spontaneous
symptom was 2.0% at baseline, 2.0% at week 6 and
1.0% at week 12 in the losartan group, whereas it
was 3.9% at baseline, 9.3% at week 6 and 12.2% ,
ac week 12 in the enalapril group (P <0.01, versus
losartan treatment at weeks 6 and 12). The incidence of
dry coughing reported as a specific symptom in the
symptoms questionnaire increased from baseline by 11.4%
(P<0.01) at week 12 in the enalapril group whereas no
change (-3.5%, NS) occurred in the losartan group (Fig.
3). The two groups were significantly
1348
Journal of Hypertension 1995, Vol 13 No. 11
Table 5. Response to treatment with either losartan (50 mg once a day) or enalapril (20 mg once a clay) with respect to diastolic blood pressure
(DBP) lowering efficacy at week 12.
Excellent/good
Normalized DBP (< 90 mmHg)
Reduction in DBP  10 mmHg)
Fair
Reduction in DBP 5  DBP  10 mmHg
Poor or no response
Reduction in DBP < 5 mmHg
Comparison between groups
(excellent or good/fair/poor)
All patients tested
Losartan
Enalapril
(n = 200)
(n = 199)
51
59
34
37
17
22
Per protocol
Losartan
Enalapril
(n = 142)
(n = 133)
51
53
34
29
17
24
20
23
21
25
29
18
28
22
P  0.05
NS
Values are expressed as percentages. NS, not significant.
Fig. 3. The incidence of coughing reported as a specific symptom in
the symptoms questionnaire at baseline and at week 12 in the
losartan and enalapril groups. The change from baseline in the
incidence of coughing (-3.5% in the losartan group, NS, and +11.4%
in the enalapril group, P<0.01) was significantly different (14.9%,
P<0.01) between the groups.
different with respect to the change from baseline in the
incidence of dry coughing at week 6 (between-groups
difference 13.8%, P<0.01) and at week 12 (14.9%,
P<0.01) in favour of losartan. The incidence of dry
coughing as a clinical adverse experience reported as
possibly, probably or definitely related to treatment was
higher in the enalapril group (15.1%), P<0.01) than in the
losartan group (3.0%)).
Fig. 4. The incidence of any kind of symptoms reported at baseline
and at week 12 in the losartan and enalapril groups.
Table 6. Clinical adverse experiences (AE) reported by the investigators in patients treated with either losartan or enalapril.
Losartan
Enalapril
(n = 202)
(n-205)
At least one AE
65
93**
AE related to treatment
Withdrawals caused by AE
Withdrawals caused by AE
related to treatment
23
6
52**
14
3
12*
*P<0.05, **P<0.001, versus losartan treatment.
Any symptom reported
The incidence of any kind of symptom decreased from
43.3% at baseline to 29.8% at week 12 (P<0.01) in the
losartan group, and from 42.8 to 35.5% (NS) in the
enalapril group, respectively (Fig. 4). The difference hi the
change from baseline between the two groups was not
statistically significant.
Symptoms other than a cough
The incidence of headaches decreased significantly from
baseline during treatment in both groups; the difference
between the groups was not significant. No change in the
incidence of other specific symptoms as reported in the
symptoms questionnaire was found. However, the change
from baseline in the incidence of swollen ankles at week 12
(2.5% increase in the losartan group and
Losartan versus enalapril in essential hypertension Tikkanen et al.
1349
Table 7. Mean changes (%) in metallic parameters at the end or the study in patients treated with either losartan ( 50 mg once a day) or enalapril
(20mg once a day) for 12 weeks.
Losartan
Enalapril
Before
After
A%
Glucose level
Cholesterol level
High-density lipoprotein cholesterol level
Triglycen'des level
Uric acid level
Creatinine level
5,11
6,02
1.10
1.68
333
88.7
5.07
5,91
1.37
1 ,63
322
88.6
-0.8
1.8**
2.1
-3.0
-3.5** † †
-0.1
ϯϯ <0.01
between groups.
*P<0.05, **P<0.01, within group;
2.5% decrease in the enalapril group) differed (P<0.05)
between the two groups. A marginal difference between
the groups was found with respect to the incidence
of a rash/itching at week 6 (P=0.07, NS) in favour
of losartan. However, the absolute numbers were small
and no support for such difference was found in previous
publications.
Safety
Sixty-five patients (32.2%) in the losartan group
and 93 (45.4%) in the enalapril group (P<0.01,
versus losartan) had at least one clinical adverse
experience during the treatment phase. Twenty-three
(11.4%) adverse experiences in the losartan group and
52 (25.4%) in the enalapril group (P<0.01, versus
losartan) were considered possibly, probably or
definitely related to treatment. When those treatmentrelated
adverse experiences were further analysed
according to the body system, the two treatment
groups were significantly different with respect to
respiratory adverse experiences (P<0.01), and with
respect to coughing in particular (P<0.01). Six
patients (3.0%) were withdrawn from the therapy in
the losartan group and 14 (6.8%) in the enalapril
group because of clinical adverse experiences; of them
three (1.5%) in the losartan group and 12 (5.9%) in the
enalapril group (P<0.05, versus losartan) were
considered to be drug-related (Table 6). One serious
adverse experience (lipothymia considered probably
not to be related to treatment) was reported in the
losartan group and one (a dry cough considered
definitely to be related to treatment) in the
enalapril group. No serious laboratory adverse
experiences were reported and treatment of no
patient was discontinued because of adverse
laboratory experiences.
Metabolic parameters
Losartan reduced the serum uric acid concentration at
the end of the study compared with baseline (P<0.01)
whereas enalapril did not (P<0.01 for between-groups
difference). The two groups did not differ concerning
the other metabolic parameters studied (Table 7). A
small but significant decrease in serum total cholesterol
level was observed in the losartan group (P<0.01). A
slight increase in serum creatinine level was found in
the enalapril group (P<0.05) whereas no change was
observed in the losartan group.
Before
5.09
6.06
1.37
1.77
347
90.3
After
5.09
6.05
1.35
1.73
354
91.8
A%
0
-0.2
1.5
2.3
2.2
1.7*
Discussion
The present study is the largest double-blind, randomized multicentre trial so far to have compared an
angiotensin II antagonist and an angiotensin converting
enzyme inhibitor in patients with essential hypertension. It
shows that the blood pressure-lowering efficacy of
losartan, a specific AT1-type angiotensin II receptor
antagonist, is similar to that of enalapril, a previously well
documented angiotensin converting enzyme inhibitor
[12,13], It was also found that treatment with losartan is
associated with a significantly lower incidence of
adverse experiences, notably coughing, than is treatment
with enalapril. Thus, although angiotensin converting
enzyme inhibitors in general are considered to be
tolerated well [13,14], treatment with the angiotensin II
antagonist losartan appears to provide additional benefits.
The comparison of angiotensin II antagonists and angiotensin converting enzyme inhibitors in the treatment of
hypertension is of special interest because both drugs act
by inhibiting the renin-angiotensin system [3], which is
the key system involved in the regulation of blood
pressure and sodium and water balance [15]. However,
there are also potential differences between those two
types of drugs because of their different mechanisms of
action. Being inhibitors of kininase II, angiotensin
converting enzyme inhibitors have been shown to
potentiate bradykinin-mediated effects, which may
contribute both to the efficacy and to the side effects
of angiotensin converting enzyme inhibitors [3-6].
However, specific angiotensin II antagonists, unlike
angiotensin converting enzyme inhibitors, are able to
antagonize the effects of angiotensin II regardless of the
enzymatic pathway by which angiotensin II is
generated [3-6]. According to a recent theory that has
not been demonstrated to be valid in hypertensive
patients, significant amounts of angiotensin II may also be
generated by enzymes other than angiotensin
converting enzyme, such as chymase [7]. It should be
added that the majority of the effects of angiotensin II
are mediated by AT 1 receptors whereas the biological
significance of AT 2 receptors remains largely unknown
At the doses used in the present study namely 50 mg
losartan once a day versus 20 mg enalapril once a day,
1350 Journal of Hypertension 1995, Vol 1 3 No 11
enalapril was marginally more effective in reducing
diastolic blood pressure than was losartan as judged
by blood pressure changes in all of the treated
patients. However, at trough, the two drugs were
equally effective, in accord with earlier observations
[16-18]. According to the present data, enalapril
seemed to be more effective approximately 3 h after the
close compared with blood pressure values obtained at
trough. A similar trend was not found in the losartantreated patients. That is compatible with ambulatory
blood pressure measurements showing a smooth blood
pressure lowering profile over 24 h with losartan
[18,19], and the documented long duration of action of
losartan resulting in peak: trough ratios consistently
above 50% [16,18]. The present study
design
compared 20 mg enalapril once a day with 50 mg
losartan once a day. It should be noted that the
enalapril dose used was relatively high, exceeding
the average dose of enalapril used in the treatment of
hypertension. In previous studies comparing
losartan with other antihypertensive drugs, losartan
has been reported to be as effective as atenolol [20],
hydrochlorothiazide [21] and felodipine
(Merck
Sharpe & Dohme Ltd, Whitehouse Station, New Jersey,
USA, data on file, 1994).
An important finding in the present, study was that
enalapril increases the incidence of dry coughing
whereas losartan does not. The higher incidence of
coughing in the enalapril-treated patients compared with
losartan was demonstrated by three different methods
used to evaluate cough symptoms: coughing as a
spontaneously reported discomfort, dry coughing as a
specific symptom in the symptoms questionnaire, and
dry coughing reported as a clinical adverse experience.
Dry coughing is now considered to be a class-specific
side effect of angiotensin converting enzyme inhibitors
depending on their ability to potentiate bradykininmediated responses [5,8—10]. The present data prove that
inhibition of the renin—angiotensin system by a specific
angiotensin II antagonist is not associated with increased
incidence of dry coughing.
Previous studies have shown that the incidence of
dry coughing in hypertension treatment trials varies
considerably according to the methodology applied for
evaluation of that adverse effect [9]. In accord with
that, the occurrence of coughing at baseline varied
from 2.0% as a spontaneously mentioned discomfort
to 17.9% when patients were asked specifically in a
symptoms questionnaire in the present study. However,
the difference in incidence of dry cough between the
enalapril group and the losartan group was found to be
remarkably constant ranging from 11.2 to 14.9% at week
12 irrespective of the method used to estimate that side
effect. Thus, those drugs with different mechanisms of
action to inhibit the renin-angiotensin system are clearly
different with respect to specific side effects in patients
with essential hypertension.
It was interesting to find that losartan treatment
decreased even the total proportion of symptoms
compared with the baseline placebo period. Thus, the
present data support the view [16,17,22] that losartan could
be an exceptionally well tolerated antihypertensive drug.
Further studies exploring the effects of losartan on side
eflects and other aspects of the quality of life in
comparison with other antihypertensive drugs are warranted.
Losartan induced fewer clinical adverse experiences than did
enalapril and the treatment was discontinued less often,
because of drug-related side effects in the losartan group than
in the enalapril group. Neither drug had clinically
significant effects on plasma glucose levels or lipid
parameters. The present data also confirmed the previous
findings that losartan lowers the serum uric acid
concentration [17,19]. That effect appears to be a
consequence of a uricosuric action of losartan [17], which
is not shared by all angiotensin II antagonists [23].
Neither the exact mechanism nor the possible clinical
significance of that finding arc clear.
In summary, losartan, a novel angiotensin II antagonist, is
an effective and safe antihypertensive drug and appears
to be tolerated especially well. Compared with the
angiotensin converting enzyme inhibitor enalapril, losartan
showed similar blood pressure-lowering efficacy evaluated at
trough , whereas it was marginally less effective when all of
the treated patients were analysed. However, in contrast to
enalapril, losartan did not increase the incidence of dry
coughing. Thus, losartan provides a promising new approach
to treatment of hypertension. In the future, studies exploring
effects of losartan on morbidity and mortality are needed to
assess the long-term benefits of that angiotensin II
antagonist as an antihypertensive agent.
Acknowledgements
We thank F. Mercier, statistician, for excellent assistance in
statistical work.
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Appendix
The Scandinavian Study Group investigators are:
Finland: T. Forslund, F. Fyhrquist, A. Halonen, J. Hämäläinen, P. Kivi, R.
Lampen, A. Lehtniemi, I. Nikkari, H. Noronen, P. Saarinen, H.
Säynäjoki, T. Silvennoinen, J. Silvo, T, Tikkanen, H. Ty Ö lahti, P.
Vuojolahti.
Denmark: P. Aarslev, J. Andersen, H.G. Bertelsen, M. Brahm, N. Borrild,
R. Christensen, P. Duedal, T. Fredcriksen, O. Hansen, P.E. Heldgaard,
T.E. Kristensen, T. Lassen, H.A. Lenler-Eriksen, O. Lindegaard, K.
Moeller-Soerensen, S. Oegaard, J.E. Oestergaard, O. Oestergaard, J.
Praest, O. Runesten, T. Sandager, H, Schmdt, P. Schultz-Larsen, F.
Sorensen, P. Toft-Christensen, P. Vittrup, C. Voetmann, E. WendelEriksen.
Iceland: A. Knstinsson.
Norway: P.M. Chritensen, N. Espeland, R. Gundersen, G. Haugeberg,
B.Helland, G. Hjorth, H Holmboc, H. Istad, K.L. Jacobsen, C. Lundbo,
B. Ravlo, T Risanger, K. Sveen, T. Smedsrud, T. Thomassen, S. Vabo,
P. Walvik.