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Clinical and Experimental Hypertension, 4:331341, 2005

Copyright D Taylor & Francis, Inc.

ISSN: 1064-1963 print / 1525-6006 online
DOI: 10.1081/CEH-200057421

Efficacy of Combination Antihypertensive

Therapy with Low-Dose Indapamide:
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Assessment by Blood Pressure

Self-Monitoring at Home
For personal use only.

Department of Planning for Drug Development and Clinical Evaluation,
Tohoku University Graduate School of Pharmaceutical Science and Medicine,
Sendai, Japan
Tohoku University 21st Century COE Program Comprehensive Research and
Education Center for Planning of Drug Development and Clinical Evaluation,
Sendai, Japan
Department of Clinical Pharmacology and Therapeutics, Tohoku University
Graduate School of Pharmaceutical Science and Medicine, Sendai, Japan

We examined the effects of the addition of low-dose indapamide to antihypertensive

drugs of other classes, as well as its duration of action, using blood pressure (BP) self-
monitoring at home. Seventy-six patients undergoing monotherapy with a calcium
channel blocker (CCB), angiotensin converting-enzyme inhibitor (ACEI), or angio-
tensin AT1-receptor blocker (ARB), but had an average morning home systolic BP
(SBP)  135 mmHg or diastolic BP (DBP)  85 mmHg, were studied. Indapamide
(1 mg) was added to their existing treatment once daily for 4 weeks. The additional
hypotensive effects of indapamide were evaluated by casual and home BPs, and the
results were compared among the three groups of subjects classified according to
their initial drug treatment classes. The morning/evening (M/E) ratio of BP reduction
was calculated to assess the duration of the effect. Overall, indapamide significantly
( P < 0.001) lowered morning home BP (147 12/87 9 mmHg to 135 12/81
9 mmHg), evening home BP (138 15/79 10 mmHg to 126 12/73 9 mmHg),
and casual BP (145 21/86 14 mmHg to 136 17/81 13 mmHg). All groups

Received 20 August 2004; accepted 16 November 2004.

Address correspondence to Junichiro Hashimoto, M.D., Ph.D., Department of Planning
for Drug Development and Clinical Evaluation, Tohoku University Graduate School of
Pharmaceutical Science and Medicine, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan;
Fax: +81-22-795-6839; E-mail:


Order reprints of this article at

332 J. Hashimoto et al.

showed significant indapamide-induced home SBP/DBP decreases, whereas only the

ACEI and ARB groups, but not the CCB group, showed a home pulse pressure (PP)
reduction. Evening SBP and PP decreases were significantly greater in the ARB
group than in the CCB group. The mean M/E ratio with indapamide was 0.95 for SBP
and 0.85 for DBP. Low-dose indapamide used in combination can provide additional
anti-hypertensive efficacy lasting for 24 h. The added effect of indapamide may be
more prominent on ARBs than on CCBs.
Keywords indapamide, combination therapy, home blood pressure, self-monitoring,

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Combination therapy is required for most hypertensive patients to attain adequate blood
pressure (BP) control (1, 2). Use of a diuretic in combination with other anti-hypertensive
drugs has been considered beneficial, because it can enhance the effects of the other
drugs. The U.S. Joint National Committee recommends that diuretics be preferentially
used for combination therapy (1).
Indapamide is an indoline, thiazide-like diuretic with additional direct vasodilatory
properties (3). Some previous studies have reported that lower doses of indapamide can
provide anti-hypertensive efficacy comparable to the usual higher doses, along with
fewer adverse effects (4, 5). The effectiveness of low-dose indapamide in combination
with an angiotensin converting-enzyme inhibitor (ACEI), perindopril, has been noted (6).
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By contrast, little is known about the efficacy of indapamide combined with other anti-
hypertensive drug classes.
In most previous studies of indapamide, the anti-hypertensive effect has been
evaluated solely by conventional office BP measurement. Recent evidence suggests that
home BP self-monitoring can provide more reliable information about drug effects
(7 11). Home BP measurements are also useful in assessing the time-effect profile of
anti-hypertensive drugs and so can document their 24-hour efficacy (11 14).
The objectives of the present study with low-dose indapamide were threefold:
1. to clarify to what extent the addition of indapamide can reduce home BP in patients
not responding adequately to monotherapy with an ACEI, an angiotensin II receptor
blocker (ARB) or a calcium channel blocker (CCB);
2. to compare the effects of adding indapamide to the three drug classes;
3. to evaluate its suitability for once-daily administration.

Consecutive outpatients with essential hypertension, who were undergoing medical
monotherapy with a CCB, an ACEI, or an ARB, but whose BP remained uncontrolled,
were enrolled in this study. Uncontrolled BP was defined as an average morning home
systolic BP (SBP)  135 mmHg or average diastolic BP (DBP)  85 mmHg (1). None
of the patients had accelerated or malignant hypertension, renal impairment (serum
creatinine >1.5 mg/dl), or any contraindications to the study drug or study procedure.
Informed consent was obtained from all subjects.
Subjects were classified into three groups (the CCB, ACEI, and ARB groups)
according to the drug classes used for initial treatment. The three groups were matched
for baseline BP. Thus, the distribution of the initial drugs was as follows: 26 patients
Indapamide in Combination Therapy 333

in the CCB group taking amlodipine (5 mg, n = 12), benidipine (4 8 mg, n = 7),
valnidipine (10 15 mg, n = 5), nisoldipine (5 mg, n = 1), or nifedipine CR (40 mg,
n = 1); 25 patients in the ACEI group taking imidapril (5 10 mg, n = 12), perindopril
(4 8 mg, n = 6), quinapril (10 20 mg, n = 3), enalapril (10 mg, n = 3) or lisinopril (10
mg, n = 1); 25 patients in the ARB group taking candesartan (4 12 mg, n = 14),
valsartan (80 120 mg, n = 10), or losartan (50 mg, n = 1). The drugs in all three groups
were administered once daily in the morning. The duration of these anti-hypertensive
medications was 9 8 weeks.

Study Procedure
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The study period consisted of a 2-week observation period and a subsequent 4-week
treatment period. Indapamide was prescribed in an add-on manner at a dose of 1 mg once
daily in the morning (after breakfast) for each day of the treatment period. The initial
treatment drug (a CCB, an ACEI, or an ARB) was given continuously during this study
without any dosage change.
The subjects were instructed to measure their own BP at home everyday during the
study period, by using an automatic device based on the cuff-oscillometric method (HEM
701C, 703C, 747IC, or 747IC-N; Omron Life Science, Kyoto, Japan). The measurements
were performed in a sitting position after a 2-minute rest, twice a day (once in the
morning within 1 hour of awakening, after micturition, but before drug ingestion or
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breakfast; and once in the evening just before going to bed) (10). Casual BP was also
determined in the office by a physician or a trained nurse during the final days of the
observation and treatment periods.

Evaluation of Drug Effects

Home SBP, DBP, and pulse pressure (PP) were averaged in each subject separately for
the final 5 days of the observation period (days  4 0), for the final 5 days of the second
week of the treatment period (days 10 14), and for the final 5 days of the fourth week of
the treatment period (days 24 28). As there was missing data for some patients, the 5-day
average was calculated using at least three data points.
Following processing of the data, we first evaluated the overall effects of
indapamide in all 76 subjects. The therapeutic effects on morning and evening BP
were assessed by analyzing the differences in the 5-day mean values between the
observation period and the second or fourth week of the treatment period. The effects
on casual BP were also assessed by using the BP values obtained on the final days of
the observation and treatment periods. The subsequent subanalysis was performed on
separate data obtained from the subjects classified into the three groups (namely, the
CCB, ACEI, and ARB groups), and the effects of indapamide were compared among
the three groups.
To assess the duration of the anti-hypertensive action of indapamide, we calculated
the morning/evening (M/E) ratio of the home BP decrease in response to the
administration of indapamide. Details of the concept of the M/E ratio have been
described previously (12 14). Briefly, the M/E ratio is obtained by dividing the drug-
induced home BP reduction in the morning (M) by that in the evening (E). For an anti-
hypertensive drug administered once daily in the morning, M represents the minimal
BP-lowering effect at the end of the between-dose interval (the trough effect), and E
represents the plateau effect. Hence, the M/E ratio has been proposed as an alternative to
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Table 1
Baseline characteristics of subjects

Total ( n = 76) CCB group ( n = 26) ACEI group ( n = 25) ARB group ( n = 25) P
Age (years) 61.6 10.2 61.5 11.8 60.9 8.6 62.3 10.5 NS
Male/Female (n) 42/35 16/10 13/12 13/12 NS
Body height (cm) 155.9 8.7 160.4 9.0 160.4 8.0 158.8 9.2 NS
Body weight (kg/m2) 64.1 11.2 64.4 12.5 64.2 10.7 63.7 10.5 NS
Morning SBP (mmHg) 146.6 12.0 146.1 10.1 146.8 13.6 146.8 12.7 NS
Morning DBP (mmHg) 86.7 9.4 88.0 10.6 85.8 9.2 86.1 8.3 NS
Morning PP (mmHg) 59.9 12.9 58.0 11.6 61.0 14.0 60.7 13.4 NS
Morning HR (bpm) 68.1 9.8 69.0 12.3 68.9 7.0 66.4 9.4 NS
Evening SBP (mmHg) 137.7 14.6 135.9 14.7 138.7 13.1 138.6 16.1 NS
Evening DBP (mmHg) 78.5 9.9 79.6 11.8 77.8 9.4 78.2 8.5 NS
Evening PP (mmHg) 59.2 12.3 56.4 12.1 60.9 11.6 60.4 13.1 NS
Evening HR (mmHg) 73.3 11.2 74.2 12.1 73.7 10.0 71.9 11.8 NS
Casual SBP (mmHg) 146.1 19.3 146.6 18.1 143.5 21.4 148.3 18.7 NS
Casual DBP (mmHg) 85.9 13.6 86.1 16.1 85.2 12.6 86.3 12.2 NS
Casual PP (mmHg) 60.3 15.0 60.5 13.4 58.3 17.2 62.0 14.8 NS
Casual HR (bpm) 77.5 13.9 78.9 14.4 77.9 12.8 75.4 14.6 NS
Serum creatinine (mg/dl) 0.83 0.19 0.86 0.24 0.82 0.16 0.80 0.16 NS
Fasting blood glucose (mg/dl) 105.7 22.4 107.7 28.3 104.6 19.1 104.7 18.9 NS
CTR on chest X-ray 48.7 4.6 48.5 4.8 48.4 4.7 49.2 4.3 NS
RV5 + SV1 on ECG 2.4 0.7 2.4 0.8 2.4 0.8 2.3 0.6 NS
CCB, calcium channel blocker; ACEI, angiotensin converting-enzyme inhibitor; ARB, angiotensin II receptor antagonist; SBP, systolic blood pressure; DBP,
diastolic blood pressure; HR, heart rate; CTR, cardio-thoracic ratio; ECG, electrocardiogram; NS, not significant.
Indapamide in Combination Therapy 335

the trough/peak (T/P) ratio. In the present study, the individual M/E ratio was calculated
only in patients who responded significantly to anti-hypertensive therapy (responders),
because the resulting M/E ratio becomes irrelevant when the E is either close to zero or
negative. To choose responders, we arbitrarily defined a cut-off point in the home evening
SBP or DBP to be a reduction of  4 mmHg. This cut-off value fulfilled the requirements
for demonstrating a statistically significant anti-hypertensive effect for the number of
subjects in this study (10).
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Figure 1. Effects of indapamide on home blood pressure in all subjects ( n = 76). Data are
represented as the mean SE. SBP, systolic blood pressure; DBP, diastolic blood pressure; PP,
pulse pressure; ., morning; 6, evening. *P < 0.05, versus the observation period.
336 J. Hashimoto et al.

Statistical Analysis
Data are expressed as the mean SD unless stated otherwise. The treatment effects of
indapamide on home BP and PR values were evaluated using one-way analysis of
variance (ANOVA) with repeated measures, followed by Bonferronis post hoc test.
Comparisons among the CCB, ACEI, and ARB groups were made using factorial one-
way ANOVA or the w2-test. When appropriate, the least significant difference test was
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Figure 2. Home blood pressure changes in response to the addition of indapamide in the calcium
channel blocker (CCB) group, the angiotensin converting enzyme inhibitor (ACEI) group, and the
angiotensin II receptor blocker (ARB) group. Data are represented as the mean SE. SBP, systolic
blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; Week 2, the second week of the
treatment period; Week 4, the fourth week of the treatment period; open columns, the CCB group
( n = 26); hatched columns, the ACEI group ( n = 25); closed columns, the ARB group ( n = 25).
*P < 0.05, versus the observation period; yP < 0.05, versus the CCB group.
Indapamide in Combination Therapy 337

successively used for the comparisons between the CCB and ARB groups. Multivariate
comparisons of the indapamide-induced BP decline among the three groups were
performed by analysis of covariance (ANCOVA) using age, gender, and baseline BP
values as covariates. The effects of indapamide on casual BP were analyzed using
paired t-tests. Differences with a P < 0.05 were considered statistically significant.
Statistical analyses were performed using SPSS version 11.0 for Windows (SPSS Inc.,
Chicago, Illinois, USA).

The baseline characteristics for the study population are shown in Table 1. There were no
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significant differences in the baseline characteristics among the CCB, ACEI, and ARB
groups, including age, gender, anthropometric parameters, BP profile, serum creatinine,
fasting blood glucose, the cardiothoracic ratio on the chest X-ray, and electrocardio-
graphic left ventricular hypertrophy.
All 76 subjects tolerated indapamide well, and none had major adverse symptoms
during the 4-week treatment course. Overall, indapamide significantly lowered casual
SBP/DBP from 145 21/86 14 mmHg to 136 17/81 13 mmHg ( P < 0.001).
Morning home SBP/DBP also significantly decreased by 10 9/5 4 mmHg in the
second week of the treatment period and by 12 10/6 6 mmHg in the fourth week of
the treatment period (Figure 1). Morning PP was reduced by indapamide in treatment
week 2 and week 4. Similarly, evening SBP, DBP, and PP were significantly decreased
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with the administration of indapamide.

In each of the three groups, morning SBP and DBP were significantly lowered by the
addition of indapamide in both the second and fourth weeks of the treatment period
(Figure 2). In treatment week 2, morning SBP and DBP decreases were greater in the
ARB group than in the CCB group. Similar results were observed in the evening SBP
changes; the evening SBP decline seen in week 2 and week 4 was greater for the ARB
group than for the CCB group. Morning and evening PP was significantly reduced with
indapamide in the ARB and ACEI groups, but not in the CCB group. Compared with the
CCB group, the ARB group showed greater PP reductions in the morning (week 2) and
evening (week 2 and 4). These differences in BP response to indapamide between the
ARB and the CCB groups were still observed even after controlling for age, gender, and
baseline BP values ( P < 0.05).
The M/E ratios for indapamide are shown in Table 2. Since the M/E ratios were
comparable among the three groups, the data of all the groups were combined. The mean
individual SBP M/E ratio was 0.94 for week 2 and 0.95 for week 4. Similar results were
obtained for the DBP M/E ratios.

Table 2
The morning/evening (M/E) ratios for indapamide at 2 and 4 weeks
of treatment
2 Weeks 4 Weeks
SBP 0.94 0.15 (54) 0.95 0.08 (53)
DBP 0.92 0.12 (33) 0.85 0.10 (45)
Data are represented as mean SE. The numbers in parentheses show the
number of responders.
338 J. Hashimoto et al.

In the present study using home BP self-monitoring, the addition of indapamide to
patients whose BP remained uncontrolled on monotherapy was shown to result in a
notable hypotensive effect. Of note, the effect of indapamide was greater in patients
pretreated with an ARB than with a CCB. Moreover, since we found that the ap-
proximate M/E ratio for indapamide was as high as 1, this suggests that it is suitable for
once-daily administration.
We used home as well as casual BP measurement in the current study because the
recent literature suggests a superiority of home over casual measurement in evaluating
responses to anti-hypertensive drug treatments (7 11). Home measurement is a sensitive
method for detecting even small BP changes and has a high reproducibility and minimal
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placebo and regression to the mean effects, and thus it allows one to minimize the
number of subjects necessary for clinical drug assessment (10, 11, 15). Furthermore, the
results obtained by an automatic BP measuring device are consistent and not affected by
the white-coat effect, terminal digit preference, or observer bias (11).
The daily dose of indapamide used in this study was less than the dose commonly
used. Nevertheless, the add-on therapy with indapamide resulted in an overall significant
home BP reduction of up to 12/6 mmHg. This finding clearly indicates the effectiveness
of low-dose indapamide used in combination with other drug classes.
The subanalysis of the present study revealed a more pronounced combined effect of
indapamide with ARBs than with CCBs, particularly in the early treatment period. This
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observed greater efficacy of the combination of indapamide and ARBs may be explained
by the following hypothesis: a blocker of the renin-angiotensin system would counteract
the reactive hyperreninemia caused by diuretic-induced salt depletion, thereby resulting
in a synergistic hypotensive effect (16). This hypothesis is also compatible with the
present finding that the combination of indapamide with an ARB was as effective as that
of indapamide combined with an ACEI. On the other hand, the lesser effect of
indapamide in combination with CCBs might have been due to some intrinsic natriuretic
activity of CCBs (17, 18).
Recent clinical studies on drug effects have focused not only on SBP or DBP but also
on PP (19). The PP (particularly home PP) may be an independent predictor of
cardiovascular risk in treated hypertensive patients (20, 21). However, drug effects on PP
do not necessarily parallel those on SBP or DBP, and the PP effect differs among the
various anti-hypertensive drug classes (22). The results of the current study indicate that
the combination of indapamide with an ARB or ACEI may be particularly effective in
reducing PP, and hence in potentiating these drugs cardiovascular-protective effects.
In the present study, we calculated the M/E ratio of home BP reduction as an index of
the 24-hour efficacy of indapamide. The mean individual M/E ratio for indapamide was
0.85 0.95, indicating that it has a long-acting effect lasting to the next morning (23). To
date, the T/P ratio calculated from ambulatory BP monitoring data has been considered a
standard index for the duration of anti-hypertensive drug action (24). However, as a
number of methodological problems have been recognized in the calculation of the T/P
ratio (25, 26), the M/E ratio has become increasingly used as a substitute (11 14). It is
possible that the observed M/E ratio might be an overestimation of the true T/P ratio,
because it is generally thought that M corresponds to the trough effect and that E is
somewhat smaller than the peak effect (13). Nevertheless, the M/E ratio observed in the
present study indicates that indapamide lowers BP equally in the morning and in the
evening, which confirms its suitability for once-daily administration.
Indapamide in Combination Therapy 339

In a recently published Valsartan Antihypertensive Long-Term Used Evaluation

(VALUE) trial (27), BP-lowering effects of amlodipine-based regimen were more
pronounced than those of valsartan-based regimen, although a considerable number of
subjects in these two groups received combination therapy with a diuretic. The result
might be somewhat different from our result, but it is likely due to the following
differences in study design. First, the previous study used hydrochlorothiazide as a
combined diuretic, whereas our study used indapamide. Second, casual BP reduction was
evaluated in the previous study, whereas home BP reduction in our study. Third, the
previous study was designed to compare overall effects between amlodipine- and
valsartan-based regimens irrespectively of monotherapy or combined therapy, whereas
the current study was to focus specifically on comparing the added effects of indapamide
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on different drug classes and therefore the three treatment groups were matched for the
baseline BP prior to indapamide treatment.
In order to prevent cardiovascular complications, the current target BP values for
anti-hypertensive therapy have been set lower than previously (1, 2). To attain these
target BP levels, most patients with hypertension actually require two or more anti-
hypertensive drugs (28), and therefore, combination therapy is of great importance in any
therapeutic strategy (1, 2). The present observations indicate that the use of indapamide in
combination therapy would appear to be a rational choice, because it enhances the effects
of the other anti-hypertensive drugs. In this connection, a recent study has shown that
combination therapy with indapamide and perindopril produced a greater risk reduction
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for stroke than single drug therapy with perindopril alone (29). Further studies will be
necessary to clarify whether the combination of indapamide with drugs other than
perindopril has similar beneficial effects on cardiovascular outcomes.

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