Original Research

A randomized, comparative
study evaluating the efficacy
and tolerability of losartan-low
1. Introduction dose chlorthalidone (6.25 mg)
2. Materials and methods
3. Results combination with losartan-
4. Discussion
5. Expert opinion and conclusions
hydrochlorothiazide (12.5 mg)
combination in Indian patients
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by McGill University on 12/16/12

with mild-to-moderate essential

hypertension
Anil Pareek†, Hathur Basavanagowdappa, Shyamsundar Zawar, Anil Kumar &
Nitin Chandurkar
†Medical Affairs and Clinical Research, Ipca Laboratories Ltd, Mumbai, India

Objective: The relationship of blood pressure (BP) to cardiovascular risk is linear,

positive, and continuous. Lowering elevated BP reduces the risk of cardiovascu-
For personal use only.

lar events. The primary objective of this randomized, multicenter, comparative,

3-month, open-label study was to evaluate the antihypertensive efficacy of
losartan/chlorthalidone versus losartan/hydrochlorothiazide in mild-to-moderate
essential hypertension. Methods: A total of 137 eligible patients underwent a
2-week placebo washout period, following which 131  patients were random-
ized to losartan (L) 25mg/chlorthalidone (C) 6.25 mg (66/131) or to losartan
25 mg/hydrochlorothiazide (H) 12.5 mg (65/131) at three centers. Patients not
responding after 4 weeks of therapy were escalated to losartan 25 mg/chlortha-
lidone 12.5 mg and losartan 50 mg/hydrochlorothiazide 12.5 mg, respectively.
Results: Both treatment groups were similar with respect to demography and
baseline characteristics. Altogether, 120  patients completed the study. After
4 weeks of therapy, both treatments showed a significant fall from baseline in
systolic BP (SBP) and diastolic BP (DBP) (L/C: -20.17/-10.30; L/H: -17.63/-10.20).
Both treatments were similar with respect to mean fall in SBP (p = 0.258), DBP
(p = 0.934) and response rate (p = 0.769). Both step-up therapies were similar
with respect to mean fall in SBP (p = 0.418), DBP (p = 0.389) from baseline and
response rate (p = 0.769). All reported adverse events were of mild-to-moderate
intensity, except for two serious AEs that occurred in patients who received L/H.
Conclusions: The losartan/low-dose chlorthalidone (6.25 mg) combination is as
effective as the widely used losartan/hydrochlorothiazide combination in lower-
ing BP and is well tolerated, thus providing a useful therapeutic option for
treating mild-to-moderate hypertension.

Keywords: angiotensin receptor blockers (ARBs), chlorthalidone, essential hypertension,

hydrochlorothiazide, losartan

Expert Opin. Pharmacother. (2009) 10(10):1529-1536

10.1517/14656560902991514 © 2009 Informa UK Ltd ISSN 1465-6566 1529

All rights reserved: reproduction in whole or in part not permitted
 losartan-low dose chlorthalidone in essential hypertension
1.  Introduction
Hypertension is an important and independent risk factor for
cardiovascular disease, is best managed by maintaining blood
pressure (BP) below 140/90 mmHg  [1]. According to the
Framingham Heart Study, even a 2 mmHg incremental
reduction in diastolic BP (DBP) may be associated with a
9% reduction in the risk of coronary heart disease and a
15% reduction in the risk of stroke  [2]. Therefore, the major
hypertension guidelines  [3-6] establish strict goals for target
BP. It is frequently difficult to achieve these goals using a
single antihypertensive agent  [7]. A combination therapy
with different antihypertensive drugs is more successful than
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by McGill University on 12/16/12
monotherapy in most hypertensive patients, with the added
advantage of a better safety profile  [8].
JNC 7 recommends that thiazide-type diuretics should
be used as initial therapy for most patients, either alone or
in combination with other antihypertensives  [4]. The com-
bination of an angiotensin receptor blocker (ARB) and
thiazide diuretic provides additive efficacy through their
different actions on the renin–angiotensin–aldosterone sys-
tem (RAAS) and sympathetic nervous system  [2]. Thiazide
and thiazide-like diuretics affect the renal tubular mecha-
nisms of electrolyte reabsorption, directly increasing the
For personal use only.
excretion of sodium and chloride  [8]. ARBs are known to
counteract many of the adverse effects associated with the
use of thiazide diuretics, including a reduction in the occur-
rence of new-onset diabetes mellitus  [9]. In a recent clinical
study, chlorthalidone at a dose of 6.25 mg/day, alone and
in combination, was found to be effective in lowering BP
without any metabolic adverse effects  [10]. Chlorthalidone is
reported to be more than twice as potent as hydrochloro-
thiazide (HCTZ)  [11]. Chlorthalidone possesses a distinct
pharmacokinetic profile from that of HCTZ, and it
has been suggested that its longer duration of action
might provide greater antihypertensive effects, particularly
through the night  [12]. Several landmark studies that
primarily used chlorthalidone as initial therapy showed a
more consistent reduction in cardiovascular events than
studies that primarily used HCTZ  [11].
With this in mind, we hypothesized that the combination
of 6.25 mg chlorthalidone is as effective as hydrochloro-thi-
azide 12.5 mg in combination with losartan for the treatment
of hypertension. The primary objective of this study was to com-
pare the mean fall in systolic BP (SBP) and DBP between losartan/
chlorthalidone and losartan/hydrochlorothiazide combinations
in patients with mild-to-moderate essential hypertension. The
secondary objective was to compare the number of responders
and to evaluate the tolerability of study treatments.
2.  Materials and methods
2.1  Study design
This was a randomized, comparative, multicenter, open-label
study, conducted at Indira Gandhi Government Medical
1530 Expert Opin. Pharmacother. (2009) 10(10)
College and Mayo Hospital, Nagpur; JSS Medical College
and Hospital, Mysore; and MS Ramaiah Medical College
and Hospital, Bangalore. Ethics committee approval was
obtained prior to initiating the study at each centre. All
the patients gave their written informed consent to partici-
pate in the study, in accordance with the declaration of
Helsinki. The execution and monitoring of the study was
done in accordance with the requirements of good
clinical  practice.
2.2  Subject selection criteria
Male and female patients aged 18 – 75 years were eligible if
they were diagnosed with mild-to-moderate essential hyper-
tension, were willing to sign informed consent form, and
were ready for regular follow-up. Patients currently receiving
antihypertensive therapy with DBP > 109 mmHg were
excluded from the  study.
Exclusion criteria were: patients with known history of
hypersensitivity to study medication; patients with severe
hypertension; significant medical illness; patients with electro-
lyte imbalance or abnormal hepatic/renal functions. Pregnant
and lactating women, or females of childbearing potential
not practising contraception, were also excluded from
the  study.
2.3  Treatment procedures
This was a multicenter, randomized, comparative, parallel-
group study. During the screening visit, the patient’s demog-
raphy and medical history was recorded and patients
were screened for the eligibility criteria. Eligible patients
underwent a 2-week placebo washout period. After this,
baseline BP measurements were reconfirmed and eligible
patients entered the 3-month active treatment phase,
randomized to either losartan 25 mg/chlorthalidone
6.25 mg or losartan 25 mg/hydrochlorothiazide 12.5 mg
for 4  weeks. Randomization charts were provided to each
center by the sponsor. Study medications were provided as a
single tablet to be taken in the morning. After the baseline
visit, patients were examined for tolerability and efficacy
outcomes on days 7, 15, 30, 60 and 90.
At each visit, the patient’s BP was measured in the morn-
ing prior to taking medication. During the treatment phase,
after 4  weeks of therapy, nonresponders from the losartan
25 mg/chlorthalidone 6.25 mg group were shifted to losar-
tan 25 mg/chlorthalidone 12.5 mg for a further 8  weeks;
similarly, nonresponders from the losartan 25 mg/hydro-
chlorothiazide 12.5 mg group were shifted to receive losartan
50 mg/hydrochlorothiazide 12.5 mg for a further 8  weeks.
The responders from each group continued on the same
therapy for a total duration of 3 months.
2.4  Efficacy
Efficacy was evaluated by change in SBP and DBP at each
study visit during the study period. Blood pressure was
measured by the auscultatory method. Measurements were
 Pareek, Basavanagowdappa, Zawar, Kumar & Chandurkar

Table 1. Baseline characteristics of patients.

Characteristics L + C (n = 66) L + H (n = 65) p-value

Males 30 32 0.665
Females 36 33
Average age (SD) (years) 48.86 ± 10.30 51.88 ± 9.96 0.091
Average weight (SD) (kg) 62.30 ± 10.52 59.24 ± 10.76 0.102
Body mass index (kg/m2) 25.32 ± 4.03 24.21 ± 3.83 0.107
Stage I essential hypertension 44 48 0.369
Stage II essential hypertension 22 17
Diabetics 10 09 0.832
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Mean SBP (mmHg) (SD) 154.03 ± 8.03 153.32 ± 8.01 0.615

Mean DBP (mmHg) (SD) 94.87 ± 3.79 95.04 ± 4.50 0.819
Mean pulse rate (beats/min) (SD) 80.48 ± 5.78 80.44 ± 6.05 0.970
Triglyceride (mg/dl) (SD) 139.0 ± 41.2 133.5 ± 45.5 0.506
Total cholesterol (mg/dl) (SD) 177.6 ± 33 182.4 ± 29.6 0.419
LDL (mg/dl) (SD) 97.0 ± 27.5 99.8 ± 28.7 0.554
HDL (mg/dl) (SD) 49.7 ± 11.7 51.1 ± 12.9 0.568

C: Chlorthalidone; H: Hydrochlorothiazide; HDL: High-density lipoprotein; L: Losartan; LDL: Low-density lipoprotein; SD: Standard deviation.
For personal use only.

performed after 10 min rest in duplicate, separated by 2 min,
and the average calculated. If the first two readings of DBP
differed by > 5 mmHg, an additional reading was obtained
and the average of the two closest readings was used.
2.5  Tolerability
Patients who received at least one dose of study medication
were evaluable for safety assessment. Blood samples were
obtained at baseline and at the end of 3 months’ therapy to
perform hematology and biochemistry tests including com-
plete blood count, routine urine, electrocardiogram, serum
electrolytes (Na+, Cl-, K+), fasting blood sugar, and lipid
profile (triglycerides, total cholesterol, high-density lipoprotein,
low-density lipoprotein).
Tolerability was evaluated based on the adverse events
(AEs) reported during the study. AEs were categorized by
the investigator according to their intensity as mild, moder-
ate or severe and the relationship to the study drug as none,
probably not, possible, probable or definite. At every visit
during the study period, the reported AEs, clinical state of
the patients and details of concomitant medication, if any,
were  captured.
2.6  Statistical plan
Descriptive statistics, including mean ± standard deviation
(SD) and median for continuous variables, and frequency
counts and percentage for categorical variables, were used to
compare treatment groups at baseline with respect to demo-
graphic characteristics. The two treatment groups were
compared for homogeneity at baseline by using tests such
as the two-sample t-test, chi-square test and Mann–Whitney
U-test, as appropriate.
The efficacy parameter (fall in SBP and DBP) was
measured from baseline to day 90. Changes in SBP and
DBP after 4 and 12 weeks of therapy for study groups were
compared using Student’s t-test or Mann–Whitney U-test,
as appropriate. Response rates in each group were compared
using chi-square  test.
Tolerability was evaluated by reporting AEs and changes
in laboratory parameters. Changes in laboratory parameters
were analyzed using paired t-test or Wilcoxon signed rank
test as appropriate. Statistical analysis was performed using
statistical software MINITAB 14 (Minitab Inc., USA).
3.  Results
A total of 131/137 enrolled patients completed the 2-week
placebo washout period. Out of 131 eligible patients,
66  patients were randomized to receive the losartan/
chlorthalidone combination and 65 received the losartan/
HCTZ combination.
From the losartan/chlorthalidone combination group,
60/66 patients completed the study; four were lost to fol-
low-up after visit 1; one was withdrawn due to protocol
violation; and one patient refused further participation in
the study, as he reported itching. Similarly, 60/65 patients
from the losartan/HCTZ group completed the study. Two
patients refused further study treatment after visit 1; two
patients were withdrawn from the study; one each due to
serious AE and protocol violation and one patient was lost

Expert Opin. Pharmacother. (2009) 10(10) 1531

 losartan-low dose chlorthalidone in essential hypertension

Table 2. Comparison of mean fall in BP measurements and response rates across the study treatments at the
end of 4 weeks of therapy.

Efficacy L 25 mg + C 6.25 L 25 mg + H 12.5 p-value 95% CI

parameters mg (n = 60) mg (n = 60)

Mean SBP (mmHg) 154.10 ± 8.10 152.90 ± 8.04 – –

(at baseline)
Mean SBP (mmHg) 133.93 ± 8.94 135.27 ± 10.34 – –
(at 4 weeks)
Mean DBP (mmHg) 95.06 ± 3.78 94.80 ± 4.49 – –
(at baseline)
Mean DBP (mmHg) 84.76 ± 5.19 84.60 ± 6.03 – –
(at 4 weeks)
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Mean fall in SBP -20.17 ± 12.65 -17.63 ± 11.73 0.258 -1.8763, 6.9429
(mmHg)
Mean fall in DBP -10.30 ± 6.11 -10.20 ± 7.12 0.934 -2.3016, 2.5016
(mmHg)
Responders 54 53
0.769 –
Nonresponders 06 07
Control rate (%) 40 (66.67) 39 (65) 0.847 –

C: Chlorthalidone; DBP: Diastolic blood pressure; H: Hydrochlorothiazide; L: Losartan; SBP: Systolic blood pressure.
For personal use only.

Table 3. Comparison of mean fall in BP measurements and response rates across the study treatments for
nonresponders at the end of 12 weeks of therapy.

Efficacy L 25 mg + C 12.5 L 50 mg + H 12.5 p-value 95% CI

parameters mg (n = 06) mg (n = 07)

Mean SBP (mmHg) 145.33 ± 5.88 150.28 ± 8.28 0.23 –

(at 4 weeks)
Mean SBP (mmHg) 131.33 ± 7.76 137.71 ± 7.34 0.161 –
(at 12 weeks)
Mean DBP (mmHg) 92.00 ± 3.09 92.85 ± 5.27 0.72 –
(at 4 weeks)
Mean DBP (mmHg) 83.00 ± 3.03 85.42 ± 6.70 0.414 –
(at 12 weeks)
Mean fall in SBP -14.00 ± 12.00 -12.57 ± 6.39 0.418 -6.1061, 13.4394
(mmHg)
Mean fall in DBP -9.00 ± 4.14 -7.42 ± 2.50 0.389 -3.4982, 8.0696
(mmHg)
Responders 06 06
0.769 –
Nonresponders 00 01

C: Chlorthalidone; DBP: Diastolic blood pressure; H: Hydrochlorothiazide; L: Losartan; SBP: Systolic blood pressure.

to follow-up. The two study groups were similar with
respect to demographic and baseline disease characteristics
(p > 0.05) (Table  1).
Efficacy was evaluated in 120 patients. At the end of 4 weeks
of therapy, two starting treatments showed a significant
fall in mean SBP and DBP (p < 0.05) (Table  2). There was
no significant difference with respect to mean fall in SBP
and DBP across the study treatment groups (p > 0.05).
Similarly, two treatment groups were not significantly different
in terms of response rates (Table  2). At the end of 4  weeks’
therapy, 65% of patients from the losartan/HCTZ group
and 66.67% of patients from the losartan/chlorthalidone
group achieved goal BP (SBP < 140 mmHg and DBP < 90
mmHg). Altogether, there were 13 nonresponders at the
end of 4  weeks’ therapy. Nonresponders from the chlor-
thalidone 6.25 mg combination group were shifted to

1532 Expert Opin. Pharmacother. (2009) 10(10)

 Pareek, Basavanagowdappa, Zawar, Kumar & Chandurkar

Table 4. Blood pressure responses to therapy for stage II hypertensive patients.

Efficacy L 25 mg + C 6.25 L 25 mg + H 12.5 p-value

parameters mg (n = 20) mg (n = 15)

Mean SBP (mmHg) 160.40 ± 9.48 162.67 ± 7.39 0.433

(at baseline)
Mean SBP (mmHg) 132.70 ± 8.83 134.30 ± 12.8 0.689
(at 4 weeks)
Mean DBP (mmHg) 97.0 ± 4.75 97.60 ± 6.68 0.770
(at baseline)
Mean DBP (mmHg) 83.80 ± 6.39 82.93 ± 7.52 0.722
(at 4 weeks)
Mean fall in SBP (mmHg) -27.7 ± 13.4 -28.4 ± 12.4 0.874
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(at 4 weeks)
Mean fall in DBP (mmHg) -13.20 ± 7.44 -14.67 ± 9.67 0.629
(at 4 weeks)
Responders 12 11
0.411
Nonresponders 08 04
Nonresponders
Efficacy L 25 mg + C 12.5 L 50 mg + H 12.5 p-value
parameters mg (n = 8) mg (n = 4)
Mean SBP (mmHg) 140.50 ± 5.53 152.0 ± 9.93 0.120
(at 4 weeks)
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Mean SBP (mmHg) 134.0 ± 4.14 145.0 ± 7.39 0.070

(at 12 weeks)
Mean DBP (mmHg) 88.75 ± 3.01 90.5 ± 10.2 0.760
(at 4 weeks)
Mean DBP (mmHg) 83.25 ± 2.82 88.50 ± 8.39 0.310
(at 12 weeks)
Mean fall in SBP (mmHg) -6.50 ± 3.66 -7.0 ± 3.46 0.825
(at 12 weeks)
Mean fall in DBP (mmHg) -5.50 ± 5.10 -2.0 ± 2.31 0.137
(at 12 weeks)

C: Chlorthalidone; DBP: Diastolic blood pressure; H: Hydrochlorothiazide; L: Losartan; SBP: Systolic blood pressure.

losartan 25 mg/chlorthalidone 12.5 mg and nonresponders
from the HCTZ 12.5 mg combination group were shifted
to losartan 50 mg/HCTZ 12.5 mg. Both step-up therapies
showed a significant fall in mean SBP and DBP (p < 0.05)
(Table  3). After a total 12  weeks of treatment, out of
13 nonresponders, 12 responded to the respective step-up
therapies. There was one nonresponder to the step-up therapy
in the losartan/HCTZ group. All responders after 4  weeks of
therapy remained respondent until the end of therapy except
for one patient from the chlorthalidone group, who earlier
had responded to starting treatment but did not respond
to the study treatment at the end of therapy due to poor
compliance with study medication. Both treatment groups
were similar with respect to response rates and mean fall
in SBP and DBP (p > 0.05). In both treatment groups, the
mean fall in SBP and DBP was maximum after the
first 4 weeks, and subsequently the fall was maintained until
the end of 3 months. At the end of therapy, amongst
responders, 88.88% of patients from the losartan 25 mg/
chlorthalidone 6.25 mg group and 92.45% patients from
the losartan 25 mg/HCTZ 12.5 mg group achieved goal
BP (SBP < 140 mmHg and DBP < 90 mmHg). Similarly,
out of 13 nonresponders, 100% patients from the losartan
25 mg/chlorthalidone 12.5 mg group and 85.71% of patients
from the losartan 50 mg/hydrochlorothiazide 12.5 mg
group achieved goal BP. Altogether, there were 35 (losartan/
chlorthalidone: 20; losartan/HCTZ: 15) stage II hypertensive
patients. Table 4 shows the BP responses for stage II hypertensive
patients. After 4  weeks of therapy, the mean fall in SBP
(p = 0.874) and DBP (p = 0.629) was comparable for the t
reatment groups in stage II hypertensive patients. At the end
of therapy, both step-up therapies were comparable with respect
to mean fall in SBP (p = 0.825) and DBP (p = 0.137)
for nonresponders.

Expert Opin. Pharmacother. (2009) 10(10) 1533

 losartan-low dose chlorthalidone in essential hypertension

Table 5. Mean changes in serum electrolytes and blood sugar from baseline to end of study for all patients.

Laboratory Visit L + C (n = 66) L + H (n = 65) p-value L + C vs L + H

parameters

Sodium Baseline 139.27 ± 3.68 139.42 ± 3.75

(mEq/l)
End 138.70 ± 2.40 139.32 ± 3.66 0.633
p-value 0.727 0.269
Potassium Baseline 4.24 ± 0.40 4.05 ± 0.37
(mEq/l)
End 4.12 ± 0.34 4.07 ± 0.38 0.143
p-value 0.917 0.057
Chloride Baseline 100.54 ± 2.50 100.53 ± 2.14
(mEq/l)
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End 100.32 ± 2.48 100.50 ± 2.13 0.902

p-value 0.830 0.754
Fasting blood sugar Baseline 114.67 ± 33.43 118.8 ± 53.5
(mg/dl)
End 108.95 ± 28.49 116.31 ± 39.29 0.971
p-value 0.524 0.076
Triglycerides Baseline 139.03 ± 41.17 133.53 ± 45.53
(mg/dl)
End 140.78 ± 58.53 130.09 ± 49.65 0.702
p-value 0.857 0.719
Total cholesterol Baseline 177.61 ± 33.02 182.44 ± 29.61
(mg/dl)
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End 186.05 ± 45.69 182.42 ± 31.34 0.387

p-value 0.306 0.997
LDL (mg/dl) Baseline 95.49 ± 29.51 99.79 ± 28.65
End 103.35 ± 36.13 99.22 ± 30.66 0.270
p-value 0.208 0.898
HDL (mg/dl) Baseline 49.69 ± 11.68 51.05 ± 12.94
End 49.47 ± 11.85 49.00 ± 20.47 0.618
p-value 0.902 0.518

C: Chlorthalidone; H: Hydrochlorothiazide; HDL: High-density lipoprotein; L: Losartan; LDL: Low-density lipoprotein; SD: Standard deviation.

Tolerability was evaluated in patients who received at least
one dose of the study medication. The percentage of patients
reporting AEs was generally similar in both treatment
groups. The commonly reported adverse events were
dizziness (L/C: 3.03%; L/H: 4.61%), diarrhea (L/C: 4.54%;
L/H: 3.07%) and fatigue (L/C: 3.03%; L/H: 3.07%).
The less common adverse events were fever (L/C: 3.03%),
itching (L/C: 3.03%), headache (L/H: 3.07%), rash (L/C: 1.51%)
and back ache (L/H: 1%). In the investigator’s judgment,
the reported adverse events were of mild-to-moderate
intensity, and possibly related to the study drugs. These
adverse events subsided on their own and did not require
any treatment.
The laboratory evaluations were done at baseline and at
the end of therapy. Mean changes from baseline for various
laboratory parameters were evaluated at the end of 3 months
for all the patients. There were no clinically significant
trends evident across the treatment groups (Table  5) at the
end of study evaluation. The six nonresponders from the
losartan 25 mg/chlorthalidone 6.25 mg starting therapy,
who were stepped up to a higher dose (chlorthalidone
12.5 mg/losartan 25 mg), did not report any clinically sig-
nificant changes in serum electrolytes, fasting blood sugar,
triglycerides and total cholesterol. The similar effect was
observed in six patients who were stepped up to losartan
50 mg/HCTZ 12.5 mg. Changes in serum electrolytes and
blood sugar levels were clinically unremarkable across the
therapy groups. There was no serious laboratory abnormality
reported in any patient in this  study.
4.  Discussion
This study examined the antihypertensive efficacy of
12  weeks’ treatment with fixed-dose combinations of

1534 Expert Opin. Pharmacother. (2009) 10(10)


losartan/chlorthalidone in Indian patients with essential
hypertension. This is probably the first study to compare
tolerability and efficacy of a losartan/low-dose chlorthalidone
combination with losartan/HCTZ. The advantage of using
an ARB/HCTZ fixed-dose combination for lowering BP is
well documented: indeed, it was because of the well-
recognized higher potency, longer duration of action and
long-term cardiovascular benefits that we chose to combine
chlorthalidone with an ARB like  losartan.
Thiazide and thiazide-like diuretics have shown good efficacy
as well as long-term benefits in terms of morbidity and mortality
in hypertensive patients. One of the major reasons for low
usage of diuretics in clinical practice is concern regarding
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adverse metabolic effects such as hypokalemia, hypona-
tremia, hyperuricemia and impaired glucose tolerance  [11].
The available literature indicates that chlorthalidone is twice
as potent as hydrochlorothiazide  [11]. Keeping in view the
potency of chlorthalidone, we used chlorthalidone at a dose
of 6.25 mg instead of 12.5 mg, which may further reduce
the risk of metabolic adverse  effects.
Both the treatments reported significant reduction in BP
from baseline and were similar with respect to magnitude
of reduction in BP after 4, 8, and 12  weeks of therapy
(p > 0.05).
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As reported in the literature, there was a fall of -18.0 ±
14.3 mmHg in SBP and -12.7 ± 8.2 mmHg in DBP after
8  weeks of treatment with losartan 50 mg/HCTZ 12.5
mg  [8], whereas our study reported a fall of -12.57 ± 6.39
mmHg in SBP and -7.42 ± 2.50 mmHg in DBP with losartan
50 mg/HCTZ 12.5 mg after 4 weeks of  treatment.
The probable reasons for the greater fall in BP in our
study may be the baseline disease condition, ethnicity, diet
and lifestyle of the studied patient population. Since this
was a randomized, comparative study, the variable factors
were similar for both  groups.
Moreover, this study included both pretreated as well as
newly diagnosed patients; hence a longer placebo washout
period of 4 weeks instead of 2 weeks, for these patients
would have resulted in lower mean BP values at baseline,
ultimately the fall in BP would have been in line with that
reported in the literature.
All six nonresponders from the losartan 25 mg/chlorthalidone
6.25 mg group responded to losartan 25 mg/chlorthalidone
12.5 mg that is, without increasing the dose of losartan,
escalation of chlorthalidone resulted in 100% response; thus
again proving the effectiveness of chlorthalidone 12.5 mg.
The incidence of AEs was generally similar in both
treatment  groups.
There were no clinically significant changes in serum
electrolytes and blood sugar levels at the end of the therapy.
Expert Opin. Pharmacother. (2009) 10(10) 1535
Pareek, Basavanagowdappa, Zawar, Kumar & Chandurkar
Those patients who received a higher dose of chlorthalidone
in this study did not show any significant changes in serum
electrolytes. The goal of antihypertensive treatment is to
reduce cardiovascular events associated with high BP. The
combination of antihypertensive drugs with complementary
actions represents a logical approach that is likely to achieve
target BP control, and may minimize AEs and improve
clinical outcomes by enhancing BP control and organ pro-
tection. Current trends in hypertension management emphasize
multidrug regimens rather than monotherapy  [8].
Due to the short-term nature of the study, we were unable to
examine the influence of BP reductions on cardiovascular mor-
bidity and mortality. However, the results of the present study
confirmed the efficacy and tolerability of low-dose chlorthalidone
in patients diagnosed with mild-to-moderate hypertension.
The strong record of evidence, low cost and favorable
tolerability profile makes low-dose chlorthalidone and its
combinations a useful therapeutic option for treatment
of hypertension.
5.  Expert opinion and conclusions
Losartan in combination with low-dose chlorthalidone
(6.25 mg) is as effective as the widely used combination of
losartan/HCTZ in lowering BP, and was well tolerated, with no
significant metabolic AEs. Thus, the losartan/chlorthalidone
combination could be an useful therapeutic option for treating
patients with mild-to-moderate essential hypertension.
Acknowledgements
The authors would like to thank Shruti Kulkarni for technical
assistance right from the inception of the study and Mitesh
Sharma, biostatistician, for statistical analysis and data
management for this  study.
The abstract of this article has been accepted for poster
presentation and was presented in Jackson Cardiovascular-
Renal Meeting 2008 organized by the Center for Excellence
in Cardiovascular-Renal Research, University of Mississippi
Medical Center, Jackson,  Mississippi.
Declaration of interest
This study was sponsored by Ipca Laboratories Ltd, Mumbai,
India. A Pareek and N Chandurkar, who are associated with
Ipca Laboratories Ltd, were involved in the conceptualization,
coordination and execution of the study, at all centers.
H Basavanagowdappa, SD Zawar and A Kumar, who were
study investigators, did not receive any financial benefits and
declare that they have no conflicts of interest to declare.
 losartan-low dose chlorthalidone in essential hypertension

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Affiliation
Anil Pareek†1, Hathur Basavanagowdappa2,
Shyamsundar Zawar3, Anil Kumar4 &
Nitin Chandurkar5
†Author for correspondence
1President
Medical Affairs and Clinical Research,
Ipca Laboratories Ltd,

142 AB, Kandivli Industrial Estate,

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1536 Expert Opin. Pharmacother. (2009) 10(10)