Original article 795
The ef®cacy and tolerability of losartan versus atenolol in
patients with isolated systolic hypertension
Csaba Farsanga , Juan Garcia-Puigb , Joanna Niegowskac ,
Adalberto Quintero Baizd , France Vrijense and Guillermo Bortmanf for the
Losartan ISH Investigators Group
Objective To compare the ef®cacy and tolerability of
angiotensin II (Ang II) antagonist losartan and the âblocker atenolol in the treatment of patients with isolated
systolic hypertension (ISH) after 16 weeks of treatment.
Methods A double-blind, randomized, multi-country study
was carried out in 273 patients with ISH. Patients with a
sitting systolic blood pressure (SiSBP) of 160±205 mmHg,
and a sitting diastolic blood pressure (SiDBP) < 90 mmHg
at screening and at placebo baseline were subjected to a
4-week placebo period and then randomly grouped to
receive 50 mg losartan or 50 mg atenolol once daily for 16
weeks. At 8 and 12 weeks, patients not controlled (SiDBP
> 160 mmHg) were given additional treatment of 12.5 mg
hydrochlorothiazide (HCTZ) once daily.
Results Similar signi®cant reductions in SiSBPs
(mean 6 SD) were obtained with 50 mg losartan and
50 mg atenolol, from 173.7 6 10.3 and 173.5 6 10.7 mmHg
at baseline to 149.0 6 15.5 and 148.2 6 15.3 mmHg after
16 weeks of losartan or atenolol treatment, respectively.
Sixty-seven percent of the losartan-treated and 64% of the
atenolol-treated patients remained on monotherapy
throughout the study. Only 1.5% of the losartan-treated
patients withdrew because of a clinical adverse event
(CAE) compared with 7.2% in the atenolol-treatment group
Introduction
Isolated systolic hypertension (ISH) is the most common type of untreated hypertension among adults [1,2],
and even patients with borderline ISH are at increased
risk of de®nite hypertension and the development of
cardiovascular disease [2] as systolic blood pressure is a
stronger risk indicator than diastolic blood pressure
[3,4]. ISH at least doubles all-cause mortality, cardiovascular mortality and cardiovascular morbidity [2,5].
The increased systolic blood pressure has many causes,
including a decrease in the content of elastin and an
increase in the collagen content (types I and III) of the
arterial wall, a thickening and ®brotic remodelling of
the vascular intima, and an increase in arterial wall
thickness and stiffness caused by proliferation of vascular smooth muscle with partial loss of contractility. Such
0263-6352 & 2000 Lippincott Williams & Wilkins
(P = 0.035). Drug-related CAEs were observed signi®cantly
more frequently with atenolol than with losartan treatment
(20.3 versus 10.4%; P = 0.029).
Conclusion It is concluded that 50 mg losartan and 50 mg
atenolol produced comparable reductions in SiSBP in
patients with ISH but losartan was better tolerated. This is
the ®rst demonstration of the therapeutic value of selective
Ang II receptor blockade with losartan in the treatment of
ISH. J Hypertens 2000, 18:795±801 & Lippincott Williams &
Wilkins.
Journal of Hypertension 2000, 18:795±801
Keywords: losartan, atenolol, isolated systolic hypertension, angiotensin II
antagonists, beta adrenoceptor antagonist
a
Szent Imre Hospit, Budapest, Hungary, b Hospital La Paz, Madrid, Spain,
Instytut Kardiologii, Warszawa, Poland, d Unidad Medica del Norte, Barranquilla,
Colombia, e International Institute for Drug Development, Brussels, Belgium and
f
Hospital Espanol, Moreno 2956 Capital Federal, Argentina.
c
Sponsorship: This study was sponsored by Merck & Co Inc, Whitehouse Station,
New Jersey, USA.
Correspondence and requests for reprints to Csaba Farsang, 1st Department of
Internal Medicine, St. Imre Teaching Hospital, TeÂteÂnyi ut 12-16, 1115 Budapest,
Hungary.
Tel: ‡36 1 20 33 613; fax: ‡36 1 20 33 588; e-mail: [email protected]
Received 12 July 1999 Revised 23 February 2000
Accepted 25 February 2000
factors may contribute to the development of ISH by
decreasing arterial compliance, the arterial wall : lumen
ratio and the lumenal cross-sectional area. Consequently, the systolic blood pressure increases with no
change or a decrease in diastolic blood pressure. The
resultant widening of the pulse pressure has been
implicated in the increased risk of cardiovascular and
stroke morbidity [6,7]. Additional mechanisms that may
be involved in the aetiology of ISH include changes in
baroreceptor sensitivity, sympathetic nervous system
activity and left ventricular hypertrophy [8,9].
ISH is a disease of the elderly and only recently have
outcome trials shown that drug treatment increases
survival [8,10]. The landmark SHEP trial [11] in older
patients showed that the incidence of stroke was
signi®cantly reduced (36%). The Medical Research
796 Journal of Hypertension 2000, Vol 18 No 6
Council trial [12] con®rmed the bene®cial effects of
diuretic treatment in older adults, although these patients had combined systolic ‡ diastolic hypertension.
Similar ®ndings were reported with calcium channel
blocker-based regimens in the Syst-Eur and Syst-China
trials [13,14]. Treatment trials have shown that angiotensin converting enzyme (ACE) inhibitors have a
similar blood-pressure-lowering effect to diuretics and
â-blockers in patients with ISH [15,16].
The effects of angiotensin II (Ang II) on vascular
smooth muscle and interstitial cells in causing vascular
hypertrophy and remodelling, in increasing sympathetic
nerve activity and in altering baroreceptor sensitivity
could be involved in the development and maintenance
of ISH. These actions of Ang II have been shown to be
inhibited by ACE inhibitors and by Ang II antagonists
such as losartan [17,18].
Losartan is an Ang II antagonist that has been shown to
have signi®cant antihypertensive effects in patients
with all severities of hypertension, alone or in combination with hydrochlorothiazide (HCTZ) [19,20]. Losartan also has similar blood-pressure-lowering effects to
enalapril or atenolol, but is better tolerated [20].
The present study was undertaken to evaluate the
antihypertensive effects of losartan and atenolol in
patients with ISH. Although the primary objective was
to evaluate the antihypertensive effects of Ang II
antagonism it was important to provide optional titration with losartan plus low dose HCTZ for those
patients who did not respond to monotherapy. For
comparison, atenolol was chosen because of its extensive usage worldwide and its common use in combination with HCTZ. We report here the results of the ®rst
clinical trial of an Ang II antagonist in ISH. We show
that both losartan and atenolol effectively decreased
systolic blood pressure but losartan produced signi®cantly fewer drug-related side effects and withdrawals
as a result of adverse drug reactions.
Patients and methods
Study population
The study population consisted of 273 patients (96
male and 177 female; mean age 66.3 years) with ISH
[sitting systolic blood pressure (SiSBP) between 160
and 205 mmHg and sitting diastolic blood pressure
(SiDBP) , 90 mmHg at the end of the placebo run-in
period]. Patients were excluded from the study if they
had secondary hypertension, any contraindications for
â-blockers (i.e. atrial-ventricular conduction disturbances, bronchial asthma) or Ang II antagonists, congestive heart disease, aortic insuf®ciency, mitral
regurgitation, gastrointestinal absorption disturbances or
known hypersensitivity to losartan or atenolol.
Study design
This multicentre, randomized, parallel-group, 20-week
study included a 4-week single-blind placebo run-in
followed by a 16-week double-blind treatment period.
During the treatment period patients were randomly
grouped (see procedure below) to receive either 50 mg
losartan once daily or 50 mg atenolol once daily (Fig.
1). In both treatment groups, 12.5 mg HCTZ was
added at weeks 8 and/or 12 if SiSBP was > 160 mmHg.
Patients were instructed to take the drug(s) at the same
time each day (between 0800 and 1100 h) except for
the days of the scheduled clinical visits so that blood
pressure measurements of trough effect could be
obtained.
Randomization procedures
The investigators, the study statistician and the local
Merck Sharpe and Dohme study monitors were blinded
(triple-blind). The treatment allocation schedule was
prepared in accordance with standard operating procedures established by Merck Research Laboratories
(MRL) whereby unique schedule numbers were electronically assigned. Only after all of the data had been
received and validated by the MRL data coordination
group were the data unblinded for statistical analysis.
Measurements
Clinic blood pressures were measured by a standard
mercury sphygmomanometer on the same arm of patients after they had been in the sitting position for at
least 5 min and in the standing position for at least
2 min. Korotkoff phase V was used for diastolic blood
pressure. The mean of three consecutive measurements
at 1±3 min intervals (if within 10 mmHg of the three
individual measurements) was recorded. Heart rate was
read from the radial pulse before blood pressure was
measured. Seven clinical visits were planned for each
patient: three during the placebo period and four
during the double-blind treatment phase. A complete
medical history, physical examination, electrocardiogram and body weight was recorded and routine
laboratory testing was performed at visits 3, 5 and 7.
Adverse experiences were monitored throughout the
study and recorded at each examination.
Data analysis
This study was designed for detecting a difference of
8 mmHg between the two groups in the change from
baseline in SiSBP, assuming a standard deviation of the
change in SiSBP of 18 mmHg. In order to detect this
difference with 90% power (two-sided test, signi®cance
level of 5%), 109 patients were required in each
treatment group. To allow for a drop-out rate of 15%, a
total of approximately 260 patients had to be randomized in a 1 : 1 ratio.
The primary endpoint of the study was the change
Losartan versus atenolol in ISH Farsang et al. 797
Fig. 1
50 mg Losartan 1 12.5 mg HCTZ od
50 mg Losartan od
50 mg Atenolol 1 12.5 mg HCTZ od
Placebo period
50 mg Atenolol od
Patients NOT on antihypertensive therapy
Visit
Week
Visit
1
2
3
4
5
6
7
25a
24
22
0b
4
8c
12c
16
1
Uns
2
3
4
5
6
7
Patients on antihypertensive therapy
a If the current antihypertensive therapy can be terminated at Visit 1, there is only a 7-day washout period until the unscheduled visit (Uns)
If the patient needs tapering off the current antihypertensive therapy, Visit 1 occurs in fact prior to Week 25, depending on the duration of tapering (plus the 7-day washout period
until the unscheduled visit exactly at Week 24).
b If SiSBP 160–205 mmHg and SiDBP ,90 mmHg.
c Titration with HCTZ if SiSBP $160 mmHg.
The patient visit and titration schedule. od, once daily; HCTZ, hydrochlorothiazide; SiSBP, sitting systolic blood pressure.
from baseline to week 16 in mean SiSBP. Other
endpoints included the change from baseline to week
16 in mean SiDBP, the response to treatment (category
I was de®ned as SiSBP at week 16 , 160 mmHg,
category II as SiSBP at week 16 > 160 mmHg but with
a reduction of > 20 mmHg and category III was
de®ned as neither I or II), the change from baseline to
week 16 in mean sitting pulse rate and adverse
experiences.
The changes in blood pressures and the response to
treatment were analysed twice; ®rst, following the
intention-to-treat (ITT) principle using the last value
carry-forward approach and, second, following the perprotocol approach. This paper contains results of the
ITT analysis. The changes from baseline within a
group were assessed by the one-sample t test. The
between-groups comparisons were assessed using an
analysis of variance (ANOVA). The ANOVA model
included treatment, investigator and the interaction
between the treatment and the investigator as main
effects. If the interaction was not signi®cant (at level
0.10) then this term was removed and the model
included treatment and investigator as main effects.
The difference between the two treatment groups was
estimated by the difference in adjusted means in the
model with its associated 95% con®dence interval. The
categories of antihypertensive response with respect to
the SiSBP were compared between the two groups
using the McCullagh's method (proportional odds) for
ordered categorical data, including treatment as the
main effect. All patients were included in the assessment of the clinical adverse experiences (CAEs). The
proportion of clinical and laboratory adverse experiences in the two groups was compared using the Fisher
Exact Test. The change from baseline to week 16 in
sitting heart rate was analysed using the same methodology as for the analysis of the primary endpoint.
Results
Patient characteristics
The patient characteristics at entry (distribution by sex,
age, severity of hypertension) were similar for the
losartan and atenolol treatment groups (Table 1). The
study was entered by 273 patients and completed by
247 (90.5%) of them; 126 losartan-treated (93.3%) and
121 atenolol-treated (87.7%) patients completed the
study. The main reason for withdrawal from the study
was a CAE (1.7% in the losartan group and 7.2% in the
atenolol group).
798 Journal of Hypertension 2000, Vol 18 No 6
Patient characteristics at entry
Entered
Completed
Sex
Women
Men
Mean age (years)
Severity of hypertension
Systolic BP > 175 mmHg
Systolic BP 175±190 mmHg
Systolic BP . 190 mmHg
SiSBP (mmHg)
Mean SD
Fig. 2
50 mg
losartan
50 mg
atenolol
135
126 (93%)
138
121 (88%)
87 (64%)
48 (36%)
67.3 (20±88)
90 (65%)
48 (35%)
65.3 (31±91)
87 (64%)
37 (27%)
11 (8%)
89 (64%)
39 (28%)
10 (7%)
173.6 10.3
173.5 11.7
50 mg Losartan (n 5 133)
50 mg Atenolol (n 5 138)
0
Change from baseline (mmHg)
Table 1
25
210
215
*
*
220
*
*
225
*
*
*
*
230
BP, blood pressure; SiSBP, sitting systolic blood pressure.
0
4
8
Week
12
16
Clinical blood pressures
The baseline SiSBPs were similar in the two treatment
groups (mean SD; 173.6 10.3 and 173.5 11.7 mmHg for losartan and atenolol, respectively;
Table 2). The SiSBPs were signi®cantly reduced by
the losartan or atenolol treatments after 4 weeks and
the blood pressure continued to decrease in both
groups throughout the study (Fig. 2). The trough SiSBP
after 16 weeks of treatment was 149.0 15.5 versus
148.2 15.3 mmHg for the losartan and atenolol treatment groups, respectively. The two treatments had a
similar effect on the mean change from baseline in
SiSBP (P ˆ 0.750): the mean changes in SiSBP (end of
placebo run-in baseline in SiSBP (P ˆ 0.750): the mean
changes in SiSBP (end of placebo run-in baseline
versus 16-week value) were ÿ24.7 15.5 and
ÿ25.3 14.7 for the losartan and atenolol treatment
groups, respectively. Analysis of standing systolic blood
pressures showed similar results (data not shown).
The baseline SiDBPs were similar in the two treatment
groups (mean SD; 81.0 6.1 and 81.4 5.7 mmHg
for losartan and atenolol, respectively) and were also
signi®cantly reduced in both treatments, but the magnitude of the reduction was less than with the SiSBP
(ÿ3.26 6.9 and ÿ4.31 7.1 mmHg for losartan and
atenolol, respectively). Likewise, analysis of standing
The changes in sitting systolic blood pressures in ISH patients in
response to 50 mg losartan or 50 mg atenolol, alone or in combination
with HCTZ for 16 weeks. Values are means CI. P , 0.001.
diastolic blood pressure showed similar results (data not
shown).
The sitting pulse pressure was signi®cantly decreased
(P ˆ 0.001) by both losartan and atenolol treatments
(ÿ21.5 14.9 and ÿ20.9 13.7 mmHg, respectively);
however, the two treatments elicited a similar change
from baseline in sitting pulse pressure (P ˆ 0.818).
The baseline sitting pulse rates were comparable in the
losartan and atenolol treatment groups (74.0 9.2 and
73.5 9.0 bpm, respectively). The two treatments signi®cantly reduced the sitting pulse rate [ÿ1.7
8.5 bpm for the losartan treatment (P ˆ 0.023) and
ÿ9.2 8.6 bpm (P , 0.001) for atenolol]. Atenolol induced a greater reduction of sitting pulse rate than
losartan (P , 0.001).
Patient response rate
The two treatment groups were similar (P ˆ 0.593) in
the distribution of patients in the three antihyperten-
Table 2 Summary of changes in sitting SBP, DBP, pulse pressure and pulse rate after 16 weeks of
treatment with 50 mg losartan or 50 mg atenolol
Parameter
Sitting SBP (mmHg)
Sitting DBP (mmHg)
Sitting pulse pressure (mmHg)
Sitting pulse rate (beats/min)
Treatment group
Baseliney
Week 16y
Change from baseline
50 mg losartan
50 mg atenolol
50 mg losartan
50 mg atenolol
50 mg losartan
50 mg atenolol
50 mg losartan
50 mg atenolol
173.7 10.3
173.5 10.7
81.0 6.1
81.4 5.7
92.8 10.7
92.1 10.0
74.0 9.2
73.5 9.0
149.0 15.5
148.2 15.3
77.6 7.7
77.1 7.9
71.4 14.0
71.1 14.1
72.3 10.3
64.3 8.8
ÿ24.7 15.5
ÿ25.3 14.7
ÿ3.26 6.9
ÿ4.31 7.1
ÿ21.5 14.9
ÿ20.9 13.7
ÿ1.7 8.5
ÿ9.2 8.6
y
means SD; n ˆ 133 for losartan treatment and n ˆ 138 for atenolol treatment. DBP, diastolic blood pressure; SBP,
systolic blood pressure. P ˆ 0.023; P , 0.001.
Losartan versus atenolol in ISH Farsang et al. 799
sive response categories (de®ned in Methods section).
One hundred and sixteen patients (87%) in the losartan
group and 116 (84%) in the atenolol group `responded'
to the treatment (SiSBP , 160 mmHg or change from
baseline > 20 mmHg).
Although the treatment goal of this study was
SiSBP , 160 mmHg, it was of interest to determine the
proportion of patients with SiSBP , 140 mmHg. After
8 and 16 weeks of treatment, SiSBP was , 140 mmHg
in 32 (24.1%) and 34 (25.6%) patients in the losartan
group, respectively, and in 30 (21.7%) and 38 (27.5%)
in the atenolol group, respectively (P . 0.05 between
treatment groups).
HCTZ optional titration
If the SiSBP was . 160 mmHg after 8 or 12 weeks of
treatment with either 50 mg losartan or 50 mg atenolol,
the patients were titrated with the addition of 12.5 mg
HCTZ once daily. A similar proportion of patients from
each group needed titration: 44 patients (33%) in the
losartan and 50 patients (36%) in the atenolol treatment
groups were titrated. After 16 weeks, the titrated patients showed a similar reduction in SiSBP as the
patients who had remained on monotherapy (Table 3).
Safety
All patients were weighed, vital signs checked and a
physical examination performed (including head and
neck, heart and lungs, abdomen and liver, skin and
extremities). No signi®cant change in body weight was
Table 3
noted in either treatment group. The effects of both
treatments on blood pressure and heart rate are described above. If the physical examination was not
`normal' then CAEs were recorded. There were signi®cantly (P ˆ 0.019) more patients who experienced at
least one CAE during the active treatment period in
the atenolol group (65 patients; 47.1%) than in the
losartan group (44 patients; 32.6%). The CAEs that
were considered by the investigators as being possibly,
probably or de®nitely drug-related were also signi®cantly (P ˆ 0.029) more frequent in the atenolol group
(28 patients; 20.3%) than in the losartan group (14
patients; 10.4%). The occurrence of serious CAEs was
similar in the two treatment groups: a serious CAE
occurred in three patients (two of which were drug
related) in the atenolol and none in the losartan group.
Signi®cantly (P ˆ 0.035) more patients had to be discontinued from the study because of CAEs in the
atenolol group (10 patients; 7.2%) than in the losartan
group (two patients; 1.5%). The most common CAEs
(incidence > 5% in any one treatment group) were
asthenia/fatigue, bradycardia, dizziness, headache and
upper respiratory infections (Table 4).
Laboratory adverse experiences
The two groups displayed a similar incidence of
laboratory adverse experiences (LAEs) (23 patients;
17.9% for losartan and 20 patients; 15.0% for atenolol).
Out of these 12 (9.3%) in the losartan group and eight
(6.0%) in the atenolol group were considered by the
Subgroup analysis by titration group at week 16
Not titrated to HCTZ
Patients (n)
SiSBP ± baseline (mmHg)
SiSBP ± treatment (mmHg)
Change from baseline (mmHg)
P value
Titrated to HCTZ at week 8 or 12
50 mg
losartan
50 mg
atenolol
50 mg
losartan/HCTZ
50 mg
atenolol/HCTZ
89
171.2 8.60
146.2 13.12
ÿ25.0 14.83
, 0.001
88
171.3 9.36
145.9 13.91
ÿ25.4 14.94
, 0.001
44
178.8 11.67
154.6 18.30
ÿ24.2 17.06
, 0.001
50
177.4 11.81
152.4 16.84
ÿ25.0 14.29
, 0.001
Values are means SD. HCTZ, 12.5 mg hydrochlorothiazide; SiSBP, sitting systolic blood pressure.
Table 4
Most common clinical adverse events (CAEs), incidence > 5% in any one treatment group
50 mg losartan (n ˆ 135)
Total CAEs
Asthenia/fatigue
Bradycardia
Dizziness
Headache
Upper respiratory infection
3 (2%)
0 (0%)
7 (5%)
11 (8%)
6 (4%)
Any CAE
Any serious CAE
Any CAE leading to discontinuation
44 (33%)
0 (0%)
2 (1.5%)
50 mg atenolol (n ˆ 138)
DDR CAEsy
Total CAEs
DDR CAEsy
2 (1.5%)
0 (0%)
0 (0%)
4 (3%)
0 (0%)
9 (7%)
8 (6%)
8 (6%)
11 (8%)
11 (8%)
6 (4%)
6 (4%)
4 (3%)
2 (1%)
0 (0%)
65 (47%)
3 (2%)
10 (7%)
28 (20%)
2 (1.5%)
10 (7%)
14 (10%)
0 (0%)
1 (1%)
Values represent number of patients (%). y DDR, possibly, probably or de®nitely drug-related CAE.
800 Journal of Hypertension 2000, Vol 18 No 6
investigators as being possibly, probably or de®nitely
drug-related.
Discussion and conclusions
The present study provided the ®rst direct evidence of
the involvement of Ang II in the maintenance of ISH.
The ef®cacy of Ang II receptor blockade with losartan
in lowering systolic blood pressure signi®cantly is consistent with previous studies with ACE inhibitors,
which block Ang II synthesis and signi®cantly reduce
blood pressure in patients with ISH [16,21]. The
magnitude of the blood pressure reduction with losartan
in patients with ISH in the present study was similar to
that observed with long-term treatment using a diuretic-based treatment regimen in the SHEP trial [11]
(ÿ26 mmHg versus ÿ15 mmHg in the placebo group)
and nitrendipine-based regimens in the Syst-Eur study
[13] (ÿ23 mmHg versus ÿ13 mmHg). Diuretics and
calcium channel blockers are currently recommended
for the initial treatment of ISH according to the
recently released WHO/ISH guidelines [22]. Atenolol
treatment produced a very signi®cant reduction in
SiSBP in the current study. The magnitude of this
SiSBP effect after 16 weeks of treatment with atenolol
(ÿ25 mmHg) is larger than that reported previously,
e.g. ÿ11 mmHg after 6 weeks [16] or ÿ15 mmHg after
6 months [23].
Losartan and atenolol both signi®cantly lowered sitting
and standing systolic blood pressure in patients with
ISH in the present study. This effect was more
pronounced than the decrease in diastolic blood pressure, resulting in a decrease in pulse pressure. Decreasing pulse pressure may reduce the risk associated with
elevated pulse pressure [6]. The antihypertensive
effects of losartan in ISH are consistent with many
previous studies in patients with mild to moderate and
severe hypertension [19,20]. The present signi®cant
reductions in systolic blood pressure in older patients
(mean age 66.3 years) are consistent with earlier studies
that showed that losartan alone or in combination with
HCTZ had signi®cant antihypertensive effects in elderly patients [24±26].
The majority of the ISH patients in the present study
(66%) responded to losartan monotherapy, with a single
oral dose of 50 mg/day throughout the study. The
SiSBP of those patients who did not respond remained
above 160 mmHg and these patients were titrated to
50 mg losartan plus 12.5 mg HCTZ. Eighty-seven percent of patients in the losartan group reached a goal
SiSBP of , 160 mmHg or a reduction of . 20 mmHg.
The ef®cacy of adding low dose HCTZ to losartan has
been well documented in several earlier studies [26±
28]. This appears to be a particularly useful combination therapy to achieve long-term blood pressure control and may be needed to achieve the lower target
blood pressures suggested by HOT results [29]. Losartan has also been used in combination with other
antihypertensive agents such as â-blockers and calcium
channel blockers as needed to control blood pressure in
resistant patients [30].
Although losartan and atenolol produced similar signi®cant reductions in systolic blood pressure in patients
with ISH, losartan was better tolerated as evidenced by
fewer drug-related adverse effects and drug-related
withdrawals. The excellent tolerability of losartan compared with atenolol is also well documented, consistent
with earlier comparative studies in patients with mild
to moderate hypertension [31]. In addition to clinical
trial experience, the open market use of losartan in six
million patients has not identi®ed any Ang II antagonism-related side effects. This has also been con®rmed
by clinical studies with other Ang II antagonists [32,33].
The present data suggest that additional studies are
needed to explore the effects of losartan or Ang II
antagonist-based treatment on cardiovascular mortality
in patients with ISH. The current study set a target
SiSBP/SiDBP at , 160/90 mmHg. The new guidelines
suggest that the de®nition of ISH is systolic blood
pressure ˆ 140 mmHg and diastolic blood pressure
, 90 mmHg [22]. Additional studies are therefore
needed to evaluate losartan-based therapies designed to
reach this new goal. Currently, losartan is being evaluated in a large mortality trial in hypertensive patients
with left ventricular hypertrophy (LIFE Trial) [34] in
which losartan is being compared with atenolol. The
blood pressure goal in this trial is 140/90 mmHg.
Approximately 27% of the 9100 patients in this trial
have ISH (de®ned as S/D 160/95 mmHg) [35], therefore the LIFE Trial should provide important mortality
data for Ang II antagonism in ISH.
ISH is the most common type of untreated hypertension among adults [1,2] particularly because of the
side effects of currently used drugs. The Ang II
antagonist losartan has been demonstrated to be very
well tolerated in short-term and long-term studies
[31,36]. The present study provides important new
evidence for the effectiveness and excellent tolerability
of losartan in patients with ISH.
Acknowledgements
We thank Mr Steve Justice and Ms Kristin Nuyen, who
served as clinical and data coordinators for this study,
and Dr Ronald D. Smith who assisted in the preparation of the manuscript.
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Appendix
Listed below are the Losartan ISH principle investigators: C. Crespo, M. Bendersky (Argentina); D. Aristizabal, G. Gamarra (Colombia); K. Siamopoulos, A.
Manolis (Greece); W.-K. Chan (Hong Kong); A. Atilano, A. Dans (Phillippines); T.H. Koh (Singapore); A.
Puras-Tellaeche, C. Suarez-Fernandez, E. MahiquesVicedo, B. Gil-Extremera (Spain); and W.L. Lee (Taiwan).