Full text of DOI:10.1111/j.1524-6175.2001.01481.x

The Effect of a Losartan-Based Treatment
Regimen on Isolated Systolic Hypertension
William C. Cushman, MD;1 William E. Brady, MS;2
Lisa P. Gazdick, BA;2 Robert K. Zeldin, MD2
This study was conducted to compare the antihyper-
tensive efficacy and tolerability, over 12 weeks, of a
losartan-based treatment regimen and placebo in pa-
tients with isolated systolic hypertension. Three hun-
dred eight patients ≥35 years of age with isolated
systolic hypertension, defined as trough sitting blood
pressure between 140 and 200 mm Hg systolic and
between 70 and 89 mm Hg diastolic, were random-
ized to losartan 50 mg (n=157) or placebo (n=151)
once daily, with titration as necessary to achieve a goal
trough sitting systolic blood pressure (SBP) <140 mm
Hg. At baseline, mean trough sitting SBP was
140–159 mm Hg in 20.5% of patients, 160–179 mm
Hg in 62.7%, and 180–200 mm Hg in 16.9%, and
was similar in the two groups (losartan, 165.3 mm
Hg; placebo, 166.1 mm Hg). At 12 weeks, mean
trough sitting SBP decreased significantly (p<0.001) in
both the losartan-based treatment group (by 19.2 mm
Hg) and in the placebo group (by 7.6 mm Hg). The
reduction in sitting SBP was significantly greater for
losartan than placebo (–11.6 mm Hg; 95% confidence
interval, –14.8 to –8.4). In patients with isolated sys-
tolic hypertension, a once-daily losartan-based treat-
ment regimen significantly lowered SBP. The
ypertension is one of the most common adult
diseases in the United States, and is a well estab-
H
lished risk factor for fatal and nonfatal cardiovascular
and cerebrovascular events, including stroke, coronary
heart disease, heart failure, and renal disease.1 Histori-
cally, isolated systolic hypertension (ISH), defined in
the sixth report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of
Hypertension as systolic blood pressure (SBP) ≥140
mm Hg with diastolic blood pressure (DBP) <90 mm
Hg,2 has been considered a less important gauge of
cardiovascular health, and therefore has not been ag-
gressively treated.3 However, data from the Framing-
ham Heart Study and other sources show that SBP is a
better predictor of cardiovascular disease risk than
DBP, especially for those over 60 years of age.4–7
ISH accounts for approximately two thirds of
cases of hypertension among individuals greater than
60 years of age.8 In Western countries, the preva-
lence of ISH increases precipitously, from 5% of 60-
year-olds to 20% of octogenarians.9 Therefore,
improving outcomes in patients with hypertension
requires the successful control of SBP, especially
among elderly patients, in whom ISH is prevalent.
Several studies demonstrate that ISH is a modifi-
able cardiovascular risk factor.10–12 In the Systolic
Hypertension in the Elderly Program (SHEP),11
4736 patients with ISH were randomized to diuret-
ic-based antihypertensive therapy or placebo for a
mean of 4.5 years. Antihypertensive therapy reduced
SBP as well as total mortality (–13%), fatal and
nonfatal stroke (–36%), total cardiovascular events
(–32%), and coronary heart disease events (–25%),
compared with placebo.10,11 Similarly, in the Sys-
tolic Hypertension in Europe Trial (Syst-Eur),12
among 4695 patients with ISH followed for a medi-
losartan-based regimen exhibited antihypertensive effi-
cacy that was superior to that of placebo, with a simi-
lar tolerability profile. (J Clin Hypertens.
©
2002;4:101–107) 2002 Le Jacq Communications, Inc.
From the Preventive Medicine Section, Veterans Affairs
Medical Center, Memhis, TN;1 Merck & Co.,
West Point, PA2
Address for correspondence:
William C. Cushman, MD, Veterans Affairs Medical Center
Preventive Medicine Section (111Q), 1030 Jefferson Av-
enue, Memphis, TN 38104
Manuscript received December 20, 2001;
accepted February 6, 2002
VOL. IV NO. II MARCH/APRIL 2002
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101

an of 2 years, calcium channel blocker-based antihy-
pertensive therapy reduced SBP as well as total mor-
tality (–14%), fatal and nonfatal stroke (–42%),
total cardiovascular events (–31%), and all cardiac
events, including sudden death (–26%), compared
with placebo.
fested by serum creatinine >1.5 mg/dL and creatinine
clearance <40 mL/min (calculated by the Cockroft and
Gault formula); proteinuria >2+ by urine dipstick;
anuria; serum potassium <3.5 or >5.5 mEq/L; hema-
turia (more than 20 red blood cells/high-power field or
of unknown etiology); arm circumference >41 cm; or
who were pregnant or breast-feeding. All patients pro-
vided written informed consent.
ISH is thought to arise primarily from stiffening
of the large arteries, with a resultant reduction in
distensibility and elasticity.13 The renin-angiotensin
system-modulating medications, such as an-
giotensin II receptor antagonists (AIIAs, sometimes
referred to as angiotensin II receptor blockers, or
ARBs), can reduce arterial stiffness via several
mechanisms.14 Losartan has been shown to inhibit
angiotensin II-mediated adverse vascular remodel-
ing of the arterial wall and to normalize endothelial
function of small arteries in patients with essential
hypertension, effects that may render them useful in
the treatment of ISH.15 Losartan has been shown to
be as effective as atenolol, amlodipine, nifedipine
gastrointestinal therapeutic system, or enalapril in
the reduction of SBP and DBP.16–18 Its effects in
ISH have not been extensively studied. In an open
label, community-based trial, another AIIA was
usually given in combination with hydrochloroth-
iazide (HCTZ) and was shown to reduce SBP in pa-
tients with ISH.23 This paper reports the results of a
multicenter, randomized, double-blind, placebo-
controlled trial conducted to assess the efficacy and
tolerability of a losartan-based regimen in the treat-
ment of ISH. The primary hypothesis was that a
once-daily losartan-based regimen is superior in an-
tihypertensive efficacy to placebo in the treatment
of patients with ISH after 12 weeks of therapy, as
measured by the change from baseline in mean
trough sitting SBP (SiSBP).
Procedures
The protocol for this multicenter, randomized, dou-
ble-blind, parallel-group, placebo-controlled clinical
trial was approved by institutional review boards
for the study sites. The study included a screening
visit, a 2–4-week placebo run-in phase before which
prestudy antihypertensive medications were discon-
tinued if necessary, and a 12-week double-blind
phase during which patients received a once-daily
losartan-based treatment regimen or placebo.
Blood pressure was measured according to the
American Heart Association recommendations,19
using standard mercury sphygmomanometers.
Patients rested quietly in the sitting position for 5
minutes before the first measurement of blood
pressure and pulse rate. Mean readings were ob-
tained by taking three consecutive sitting blood
pressure readings separated by at least 1 minute,
all of which had to be within 5 mm Hg.
Screening. During the screening clinic visit, medical
histories were obtained and a physical examination
and 12-lead electrocardiography were performed. All
clinical laboratory tests (complete blood cell count
with differential, chem 7, alanine transaminase, aspar-
tate transaminase, serum uric acid, and urinalysis)
were performed in a central laboratory. After provid-
ing written informed consent, patients who were cur-
rently taking antihypertensive medications were
instructed on procedures for discontinuing them be-
fore the 2–4-week placebo run-in phase.
METHODS
Patients
Adults ≥35 years of age with ISH, defined as a mean
trough SiSBP of 140–200 mm Hg and a mean trough
sitting DBP (SiDBP) of 70–89 mm Hg were eligible for
randomization into the study. Patients were excluded
if they were taking more than two antihypertensive
medications, their SiSBP varied by more than 15 mm
Hg between the prerandomization and randomization
visits, or if they had known or suspected secondary
hypertension, a history of malignant hypertension, or
clinically significant cardiovascular disease. Also ex-
cluded were patients with known sensitivity to an
AIIA, hydrochlorothiazide, or any other sulfonamide-
derived drugs; a history of angioedema, cerebrovascu-
lar disease, or syncopal disorder; unstable diabetes
mellitus; severe hepatic impairment; a single functional
kidney; moderate or severe renal impairment, as mani-
Placebo Run-in Phase. Mean trough SiSBP and
SiDBP were assessed at 2 and 4 weeks into the
placebo run-in phase and at additional study visits
scheduled at the investigator’s discretion. Patients
with a mean trough SiSBP <140 mm Hg or >200
mm Hg or a mean trough SiDBP ≥90 mm Hg were
discontinued from the study. Patients with a mean
trough SiSBP of 140–200 mm Hg and a mean
trough SiDBP of 70–89 mm Hg could enter the
double-blind phase of the study at the end of
the 4-week washout period, or earlier if the inves-
tigator judged it appropriate and mean trough
SiSBP was between 180 and 200 mm Hg on two
study visits.
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Double-Blind Treatment. For the 12-week double-
blind treatment phase, patients were stratified by
stage of ISH (stage 1, SiSBP 140–159 mm Hg;
stage 2, 160–179 mm Hg; modified stage 3,
180–200 mm Hg) based on mean trough SiSBP at
randomization. They were randomized to receive
either a losartan-based regimen or placebo, to be
taken once daily between 6 a.m. and 10 a.m.
Study visits occurred after 4, 8, and 12 weeks of
treatment. During study visits, blood pressure and
pulse measurements were obtained and adverse expe-
riences (defined as any untoward medical occurrence
regardless of its suspected cause) occurring since the
last study visit were recorded. Blood pressure mea-
surements were to be performed 22–26 hours after the
last dose of study medication.
Concomitant therapy with any antihypertensive
medication was prohibited. Additionally, concomitant
therapy with lithium or other major psychotropic
agents, oral steroids, or adrenocorticotropic hormone,
or daily use of nonsteroidal anti-inflammatory drugs
(NSAIDs) or high-dose aspirin was prohibited. Inter-
mittent use of ephedrine, sildenafil, or NSAIDs was
permitted, except within 72 hours of study visits.
If the SBP goal (<140 mm Hg) was not met at the
week 4 study visit, losartan 50 mg was titrated to
losartan 50 mg/HCTZ 12.5 mg once daily, with
sham titration in the placebo group. If the SBP goal
was not met at the week 8 study visit, patients who
were taking losartan 50 mg received losartan 50
mg/HCTZ 12.5 mg once daily, while patients taking
losartan 50 mg/HCTZ 12.5 mg received losartan
100 mg/HCTZ 25 mg once daily for the remaining 4
weeks of the study. The dose in the placebo group
was sham titrated.
Patients whose mean trough SiSBP was
180–200 mm Hg at the time of the second titra-
tion received an additional blinded once-daily res-
cue treatment for the remainder of the study.
Patients in the placebo group received blinded res-
cue treatment of losartan 50 mg, while those in
the losartan-based treatment group received blind-
ed placebo as rescue treatment. This approach
was taken in order to provide rescue therapy for
patients in the placebo group without unblinding
patients in the losartan-based treatment group.
Patients with a mean trough SiSBP of 200–220
mm Hg returned for repeat blood pressure mea-
surements within 24 hours. At follow-up, if the
mean trough SiSBP was >200 mm Hg, the patient
was discontinued from the study. Patients with a
mean trough SiSBP >220 mm Hg followed within
1 hour by a repeat measurement >200 mm Hg,
and those with a mean trough SiDBP <60 or >100
mm Hg, were also discontinued.
Data Analysis
All patients taking study medication and having a
valid mean SiSBP measurement at baseline and at least
one valid measurement after baseline were included in
the efficacy analyses. The primary efficacy measure
was the mean change from baseline in trough SiSBP at
week 12. Statistical analyses of the changes from base-
line in SiSBP were conducted using the last-observa-
tion-carried-forward (LOCF) approach. Values
obtained after initiation of rescue therapy in the place-
bo group were not used in the analysis but instead
were imputed using LOCF of pre-rescue values. An
analysis of covariance (ANCOVA) model was used to
compare treatment groups; the model included terms
for treatment and study site and baseline mean trough
SiSBP as a covariate. Mean values presented in this re-
port are least squares means, which are adjusted for
the terms in the model. Mean changes in SiSBP from
baseline to weeks 4 and 8, mean changes in SiDBP
and pulse from baseline to weeks 4, 8, and 12, as well
as post hoc analyses of mean changes in pulse pressure
from baseline to weeks 4, 8, and 12 were also ana-
lyzed in this manner.
The percentages of patients who responded to
treatment (i.e., reached the SBP goal of mean
trough SiSBP of <140 mm Hg or at least a 20-mm
Hg reduction from baseline in mean trough SiSBP)
were compared between treatment groups using a
logistic regression model, including terms for
treatment and baseline SiSBP.
To assess the effect of the severity of hypertension
at baseline on response to losartan, post hoc analyses
of mean changes from baseline in mean trough SiSBP
at week 12 were conducted by stage of ISH at ran-
domization. Analysis of variance (ANOVA) models
with terms for treatment, study site, stage of ISH, and
treatment by stage interaction were used to compare
treatments with respect to mean changes from base-
line to week 12 in mean trough SiSBP. The study was
not designed to detect differences between treatment
groups within stages of ISH.
The safety of the treatment regimens was com-
pared through Kaplan-Meier estimates of the cumula-
tive incidences at week 12 of all adverse experiences
(AEs) and drug-related AEs. The times to the first AE
that occurred during the double-blind treatment peri-
od, but before the administration of rescue medication
in the placebo group were used for these analyses.
Power calculations assumed a minimum de-
tectable difference in SiSBP between the losartan-
based treatment group and the placebo group of 8
mm Hg, with a standard deviation of 18 mm Hg.
With 135 patients per treatment group, the study
had 95% power to detect, at the 0.05 level with a
two-sided test, an 8-mm Hg difference between
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103

Table. Demographics, Clinical Characteristics, and Patient Disposition
LOSARTAN
(N=157)
PLACEBO
(N=151)
Age in years, mean (SD)
Sex, no. (%)
Male
Female
Race, no. (%)
66.9 (9.7)
66.7 (9.5)
71 (45.2)
86 (54.8)
72 (47.7)
79 (52.3)
White
Black
Asian
138 (87.9)
7 (4.5)
2 (1.3)
124 (82.1)
17 (11.3)
1 (0.7)
Other
10 (6.4)
9 (6.0)
Baseline SiSBP (mm Hg), mean (SD)
Baseline SiDBP (mm Hg), mean (SD)
Baseline pulse pressure (mm Hg), mean (SD)
Baseline pulse rate (beats/min), mean (SD)
Stage of ISH*, no. (%)
Stage 1: 140–160 mm Hg
Stage 2: 160–180 mm Hg
Modified stage 3: >180 mm Hg
Completed study, no. (%)
Discontinued study, no. (%)
Clinical adverse event
Withdrawn consent
Protocol deviation
165.3 (12.1)
83.6 (5.4)
81.7 (12.7)
73.5 (8.7)
166.1 (12.1)
84.4 (5.6)
81.7 (12.8)
73.7 (8.3)
32 (20.4)
98 (62.4)
27 (17.2)
136 (86.6)
21 (13.4)
9 (5.7)
31 (20.5)
95 (62.9)
25 (16.6)
119 (78.8)
32 (21.2)
11 (7.3)
7 (4.6)
1 (0.6)
3 (1.9)
2 (1.3)
Lost to follow-up
Lack of efficacy of study drug
Relocation
2 (1.3)
2 (1.3)
1 (0.6)
3 (2.0)
3 (2.0)
1 (0.7)
Laboratory adverse event
Other
1 (0.6)
2 (1.3)
1 (0.7)
4 (2.6)
SiSBP/DBP=sitting systolic/diastolic blood pressure; ISH=isolated systolichypertension; *SiSBP values
for stage 1, stage2, and modified stage 3 are 140–159 mm Hg, 160–179 mm Hg, and 180–200 mm
Hg, respectively.
losartan and placebo in the change from baseline
in mean trough SiSBP.
placebo group prematurely discontinued, for rea-
sons listed in the Table.
RESULTS
Use and Titration of Study Medication
Patients
At the week 4 visit, 25.2% (38/151) of patients in the
losartan-based treatment group continued on losartan
50 mg and 14.3% (19/133) of patients in the placebo
group continued on losartan 50 mg placebo. At this
visit, 74.2% (112/151) of patients in the losartan-
based treatment group were titrated to losartan 50
mg/HCTZ 12.5 mg and 0.7% (1/151) were titrated to
losartan 100 mg/HCTZ 25 mg. Eighty-five percent
(113/133) of patients in the placebo group were titrat-
ed to losartan 50 mg/HCTZ 12.5 mg placebo, and
0.8% (1/133) were titrated to losartan 100 mg/HCTZ
25 mg placebo. At the week 8 visit, 17.5% (25/143) of
patients in the losartan-based treatment group contin-
ued on losartan 50 mg and 7.1% (9/126) of patients in
the placebo group continued on losartan 50 mg place-
bo. At this visit, 34.3% (49/143) of patients in the
The number of patients randomized to treatment
was 308: 157 to the losartan-based treatment
group and 151 to the placebo group. Demograph-
ic characteristics were similar between groups
(Table). The majority of patients were white
(85%) with a mean age of 66.8 years (range,
36–90 years). Approximately one half of patients
(53.6%) were female.
Baseline clinical characteristics were compara-
ble between groups (Table). The mean duration of
ISH was 5.1 years (SD, 6.4). The majority of pa-
tients (62.7%) had stage 2 ISH, while 20.5% had
stage 1 and 16.9% had modified stage 3. Twenty-
one (13.4%) of the patients in the losartan-based
treatment group and 32 (21.2%) of those in the
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SiSBP
SiDBP Pulse Pressure
0
-2
Stage 1
Stage 2
Modified Stage 3
0
-5
-0.4
-4
-3.8
*
-4.6
-6
-10
-15
-20
-25
-30
-35
-8.3
-8.2
-8
-10.6
-7.2
-7.6
-10
-12
-14
-16
-18
-20
-22
-19.2
*
-15.4
*
Losartan
Placebo
-28.4
*
Losartan
Placebo
-19.2
*
Figure 2. Mean change from baseline in sitting systolic
blood pressure after 12 weeks of treatment with a
losartan-based regimen or placebo by baseline severity
of isolated systolic hypertension (stage 1=140–159 mm
Hg; stage 2=160–179 mm Hg; modified stage
3=180–200 mm Hg)
Figure 1. Mean change from baseline in sitting systolic
blood pressure (SiSBP), sitting diastolic blood pressure
(SiDBP), and pulse pressure after 12 weeks of treatment
with a losartan-based treatment regimen or placebo
*p<0.001 vs. placebo
*p<0.001 vs. placebo
losartan-based treatment group received losartan 50
mg/HCTZ 12.5 mg, and 18.3% (23/126) of patients
in the placebo group received losartan 50 mg/HCTZ
12.5 mg placebo. At the week 8 visit, 43.4% (62/143)
of patients in the losartan-based treatment group were
titrated to losartan 100 mg/HCTZ 25 mg, and 61.9%
(78/126) of patients in the placebo group were titrated
to losartan 100 mg/HCTZ 25 mg placebo. At this
visit, 4.9% (7/143) of patients in the losartan-based
treatment group were given rescue medication, as
were 12.7% (16/126) of patients in the placebo group.
More than 95% of patients in both groups took at
least 95% of their study medications.
cally significant (p<0.001) at each week. For the pri-
mary efficacy end point (week 12), the mean change
from baseline systolic pressure was –19.2 mm Hg in
the losartan-based treatment group, compared with
–7.6 mm Hg in the placebo group (p<0.001) (Figure
1). Mean changes at week 4 and week 8 were –12.9
mm Hg and –19.2 mm Hg in the losartan-based treat-
ment group and –5.8 mm Hg and –7.5 mm Hg in the
placebo group. The differences between the groups
were –7.1 mm Hg (95% confidential interval [CI],
–10.0 to –4.2) at week 4 (losartan as monotherapy
minus placebo); –11.7 mm Hg (95% CI, –15.1 to
–8.3) at week 8 (losartan with or without HCTZ
minus placebo); and –11.6 mm Hg (95% CI, –14.8 to
–8.4) at week 12 (losartan with or without HCTZ
minus placebo).
The frequency of titration to higher doses of
blinded study medication increased with the stage
of ISH in both the losartan-based treatment group
and the placebo group.
Trough SiSBP
Percentage of Patients Responding to Therapy
The percentage of patients responding to treat-
ment (i.e., trough SiSBP <140 mm Hg or at least a
20-mm Hg decrease from baseline if mean trough
value was >140 mm Hg) was significantly higher
in the losartan-based treatment group than in the
placebo group at the end of the study (p<0.001).
At study end (week 12), 54% (85/156) of patients
in the losartan-based treatment group, compared
with 28% (42/148) of placebo patients, had re-
sponded. The odds (and 95% CI) of responding to
treatment were 3.02 (1.87–4.86) times greater
with losartan than with placebo (p<0.001).
As shown in the Table, mean baseline SiSBP was simi-
lar in the losartan-based treatment group (165.3 mm
Hg) and the placebo group (166.1 mm Hg). For the
LOCF analyses, there were 156, 155, 156, and 156
patients in the losartan-based treatment group at base-
line and at weeks 4, 8, and 12, respectively, and 148
patients at baseline and at weeks 4, 8, and 12 in the
placebo group. At weeks 4, 8, and 12, mean trough
SiSBP decreased significantly (p<0.001) in both the
losartan-based treatment and placebo groups. The dif-
ferences between the treatment groups in mean
changes from baseline systolic pressure were statisti-
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Effect of Baseline Hypertension Stage on Antihy-
pertensive Efficacy
in each treatment group who experienced at least one
clinical AE by study end were 50.5% (95% CI,
42.5%, 58.5%) for patients in the losartan-based
treatment group and 55.2% (95% CI, 46.8%,
63.6%) for patients in the placebo group. Drug-relat-
ed clinical AEs were reported by 10.4% of patients,
12.7% (20/157) of those in the losartan-based treat-
ment group and 7.9% (12/151) of those in the place-
bo group. Kaplan-Meier estimates of the percentage of
patients in each treatment group who experienced at
least one drug-related clinical AE by study end were
13.4% (95% CI, 7.9%, 18.8%) for patients in the
losartan-based treatment group and 9.0% (95% CI,
3.8%, 14.2%) for patients in the placebo group.
Similar proportions of patients in both the
losartan-based treatment group and placebo group
reported the most common AEs, which included
upper respiratory infection (7.6% losartan; 8.6%
placebo), headache (5.1% losartan; 7.3% place-
bo), dizziness (5.7% losartan; 2.6% placebo), si-
nusitis (4.5% losartan; 2.0% placebo), lower
extremity edema (1.9% losartan; 3.3% placebo),
urinary tract infection (3.2% losartan; 0.7%
placebo), and diarrhea (3.2% losartan; 0% place-
bo). No other AEs were reported by >3% of pa-
tients in either group. No clinically significant
changes in laboratory tests were observed.
For all stages of baseline hypertension, after 12
weeks of treatment, a losartan-based regimen was
more effective than placebo at lowering mean
SiSBP. Statistical significance (p<0.001) was
achieved for stage 2 and modified stage 3 hyper-
tension (Figure 2).
Trough SiDBP
As shown in the Table, mean baseline SiDBP was
similar in the losartan-based treatment group
(83.6 mm Hg) and the placebo group (84.4 mm
Hg). Mean trough SiDBP decreased significantly
(p<0.001) in the losartan-based treatment group,
by 2.5, 4.4, and 3.8 mm Hg at weeks 4, 8, and 12,
respectively, but not in the placebo group (Figure
1). The differences between the treatment groups
with respect to changes from baseline were signifi-
cant at each week. The difference (losartan minus
placebo) was –2.4 mm Hg (95% CI, –3.8 to –1.1)
at week 4; –3.6 mm Hg (95% CI, –5.1 to –2.0) at
week 8; and –3.4 mm Hg (95% CI, –5.0 to –1.9)
at week 12.
Pulse Pressure
Mean baseline pulse pressure was 81.7 mm Hg in
both treatment groups. Mean trough pulse pres-
sure decreased significantly (p<0.001) in the losar-
tan-based treatment group by 10.4, 14.8, and 15.4
mm Hg at weeks 4, 8, and 12, respectively, and
decreased significantly (p<0.001) in the placebo
group by 5.8, 6.6, and 7.2 mm Hg at weeks 4, 8,
and 12 (Figure 1). The differences between the
treatment groups with respect to changes from
baseline were significant (p≤0.001) at each week.
The difference (losartan minus placebo) was –4.6
mm Hg (95% CI, –7.3 to –1.9) at week 4, –8.1
mm Hg (95% CI, –11.0 to –5.2) at week 8, and
–8.1 mm Hg (95% CI, –11.0 to –5.3) at week 12.
DISCUSSION
In this study, the first large, prospective, placebo-con-
trolled trial of an AIIA in the treatment of ISH, a
once-daily losartan-based treatment regimen was
consistently more effective than placebo at reducing
SBP in patients with ISH. The effect of the losartan-
based treatment regimen was observed beginning
with the first blood pressure measurement at week 4
and was maintained throughout the 12-week treat-
ment period. At week 12, the placebo-adjusted mean
change from baseline in trough SiSBP was –11.6 mm
Hg. Comparable placebo-adjusted reductions in
SiSBP were observed in the SHEP and Syst-Eur stud-
ies. In SHEP11 and Syst-Eur,12 the mean differences
in SiSBP reduction between the active and placebo
groups were 10–11 mm Hg, with achieved mean
SiSBP of 144 mm Hg and 151 mm Hg, respectively,
in the actively treated groups. The current study was
not designed to determine the impact of treatment of
ISH with a losartan-based regimen on cardiovascular
morbidity and mortality.
Pulse Rate
Baseline sitting pulse rate was 73.5 beats/min in
the losartan-based treatment group and 73.7
beats/min in the placebo group. No significant
changes from baseline were observed for either
group at any time point, nor were the mean
changes from baseline significantly different be-
tween the two groups at any week.
The data from this study extend those of a random-
ized, double-blind comparison of losartan and
atenolol in the treatment of ISH.20 In that study, pa-
tients received losartan 50 mg or atenolol 50 mg once
daily over a 16-week treatment period with HCTZ
added at weeks 8 and 12 if necessary. Both the losar-
Clinical and Laboratory AEs
Similar proportions of patients in both groups report-
ed at least one AE: 49.7% (78/157) of losartan pa-
tients and 53.0% (80/151) of placebo patients.
Kaplan-Meier estimates of the percentage of patients
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2000;14:83–90.
tan and atenolol-based regimens effectively reduced
baseline SiSBP in patients with ISH (173.7 mm Hg re-
duced to 149.0 mm Hg with losartan and 173.5 mm
Hg reduced to 148.2 mm Hg with atenolol).
8
9
Franklin SS, Jacobs MJ, Wong ND, et al. Predominance of
isolated systolic hypertension among middle-aged and el-
derly US hypertensives: analysis based on the National
Health and Nutrition Examination Survey (NHANES) III.
Hypertension. 2001;37:869–874.
Staessen JA, Wang JG, Thijs L, et al. Overview of the out-
come trials in older patients with isolated systolic hyper-
tension. J Hum Hypertens. 1999;13:859–863.
In the current study, as expected, patients with ad-
vanced stages of ISH required higher doses of study
therapy to attain blood pressure control. This finding
is consistent with the experience of other large clinical
trials attempting to achieve an SBP of <140 mm Hg,
such as the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT)21
and the Controlled Onset Verapamil Investigation of
Cardiovascular Endpoints (CONVINCE) study.22 In
the current study, the tolerability profile of the losar-
tan-based regimen in the treatment of ISH was similar
to that of placebo, as indicated by the incidence of any
AEs and of drug-related AEs.
10 The Systolic Hypertension in the Elderly Program Cooper-
ative Research Group. Implications of the Systolic Hyper-
tension in the Elderly Program (SHEP). Hypertension.
1993;21:335–343.
11 SHEP Cooperative Research Group. Prevention of stroke
by antihypertensive drug treatment in older persons with
isolated systolic hypertension. Final results of the Systolic
Hypertension in the Elderly Program (SHEP). JAMA.
1991;265:3255–3264.
12 Staessen JA, Fagard R, Thijs L, et al., for the Systolic Hy-
pertension in Europe (Syst-Eur) Trial Investigators. Ran-
domized double-blind comparison of placebo and active
treatment for older patients isolated systolic hypertension.
Lancet. 1997;350:757–764.
13 Rigaud AS, Forette B. Hypertension in older adults. J
Gerontol. 2000;56A:M217–M225.
CONCLUSION
14 Franklin SS. Is there a preferred antihypertensive therapy
for isolated systolic hypertension and reduced arterial
compliance? Curr Hypertens Rep. 2000;2:253–259.
15 Schiffrin EL, Park JB, Intengan HD, et al. Correction of
arterial structure and endothelial dysfunction in human es-
sential hypertension by the angiotensin receptor antagonist
losartan. Circulation. 2000;101:1653–1659.
In patients with ISH, a once-daily losartan-based
treatment regimen significantly lowered SBP. The
losartan-based regimen exhibited antihypertensive
efficacy that was superior to that of placebo, with
a similar tolerability profile.
16 Goa KL, Wagstaff AJ. Losartan potassium: a review of its
pharmacology, clinical efficacy, and tolerability in the
management of hypertension. Drugs. 1996;51:820–845.
17 Oparil S, Barr E, Elkins M, et al. Efficacy, tolerability, and
effects on quality of life of losartan, alone or with hy-
drochlorothiazide, versus amlodipine, alone or with hy-
drochlorothiazide, in patients with essential hypertension.
Clin Ther. 1996;18:608–625.
18 Weir MR, Elkins M, Liss C, et al. Efficacy, tolerability,
and quality of life of losartan, alone or with hy-
drochlorothiazide, versus nifedipine GITS in patients with
essential hypertension. Clin Ther. 1996;18:411–428.
19 Perloff D, Grim C, Flack J, et al. Human blood pressure
determination by sphygmomanometry. Circulation.
1993;88:2460–2470.
Acknowledgments: This study was funded by Merck & Co.,
Inc., Whitehouse Station, New Jersey. A list of investigators
and study coordinators is available upon request. We would
like to acknowledge the assistance of Colleen M. Valenzuela in
the preparation of the manuscript.
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