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ISSN: 1064-1963 (print), 1525-6006 (electronic)

Clin Exp Hypertens, 2015; 37(3): 260–266

! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10641963.2014.954712

Efficacy and safety of fixed-dose losartan/hydrochlorothiazide/

amlodipine combination versus losartan/hydrochlorothiazide
combination in Japanese patients with essential hypertension
Hiromi Rakugi1, Takuya Tsuchihashi2, Kazuyuki Shimada3, Hirotaka Numaguchi4, Chisato Nishida4,
Hiroya Yamaguchi4, Masayoshi Shirakawa4, Kyoichi Azuma4, and Kenji P. Fujita5
1
Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan, 2Hypertension Center, Steel
Memorial Yawata Hospital, Kitakyushu, Japan, 3Department of Internal Medicine, Shin-Oyama City Hospital, Tochigi, Japan, 4MSD K.K., Japan,
Tokyo, Japan, and 5Merck & Co., Inc., Whitehouse Station, NJ, USA

Abstract Keywords
Japanese patients with uncontrolled essential hypertension received single-blind losartan Amlodipine, hydrochlorothiazide, Japanese,
50 mg/hydrochlorothiazide 12.5 mg (L50/H12.5) for 8 weeks. Patients whose blood pressure losartan
(BP) remained uncontrolled were randomized double-blind to fixed-dose losartan 50 mg/
hydrochlorothiazide 12.5 mg/amlodipine 5 mg (L50/H12.5/A5) or L50/H12.5 for 8 weeks History
followed by open-label L50/H12.5/A5 for 44 weeks. Adverse events were assessed. After
8 weeks, diastolic and systolic BP were reduced significantly more with L50/H12.5/A5 versus Received 28 May 2014
L50/H12.5 (both p50.001). Mean changes in diastolic and systolic BP were sustained for Revised 1 July 2014
44 weeks. L50/H12.5/A5 was well-tolerated and improved BP significantly versus L50/H12.5 in Accepted 15 July 2014
Japanese patients with uncontrolled essential hypertension. Published online 30 September 2014

Introduction (an angiotensin II receptor blocker), hydrochlorothiazide

The most commonly used antihypertensive agents in Japan
are calcium channel blockers and angiotensin II receptor
blockers (ARBs) (1). Various treatment guidelines recom-
mend that, to effectively control blood pressure, the majority
of hypertensive patients will require a combination of two or
more antihypertensive agents (2–4). Although combining
antihypertensive agents with complementary mechanisms of
action may improve disease control, many patients consider it
burdensome to take multiple dosage forms on a daily basis (5)
and increasing the number of medications may result in
reduced adherence to treatment (6,7). Fixed-dose combin-
ations of antihypertensive agents are now widely available.
The advent of such medications has resulted in not only an
improvement in patients’ adherence to treatment (8,9), but
also an improvement in clinical outcomes (8).
A combination of losartan 50 mg and hydrochlorothiazide
12.5 mg (L50/H12.5) administered in a single tablet
(PreminentÕ ; Merck & Co., Inc., Whitehouse Station, NJ)
has been shown to be an effective and generally well-tolerated
treatment in Japanese hypertensive patients (10,11). However,
a proportion of hypertensive patients will require three
antihypertensive agents to achieve adequate blood pressure
control. A fixed-dose combination comprising losartan 50 mg
Correspondence: Dr. Hiromi Rakugi, Department of Geriatric Medicine
and Nephrology, Osaka University Graduate School of Medicine, 2-2
Yamadaoka, B6, Suita 565-0871, Osaka, Japan. E-mail: rakugi@
geriat.med.osaka-u.ac.jp
12.5 mg (a diuretic) and amlodipine 5 mg (a calcium channel
blocker) is currently being investigated in clinical trials. The
objective of the present study was to assess the antihyperten-
sive efficacy, safety, and tolerability of this fixed-dose
triple combination therapy in Japanese patients with essen-
tial hypertension who were inadequately controlled with
L50/H12.5.
Methods
This was a Phase III, randomized, active-controlled trial
(protocol number: PN356; ClinicalTrials.gov identifier
NCT01299376) carried out in 20 centers in Japan between
January 2011 and September 2012. The study was conducted
in accordance with principles of Good Clinical Practice and
the protocol was approved by the appropriate institutional
review boards. All patients provided written, informed
consent prior to entering the study.
Patients
Japanese male and female patients aged 20–80 years were
considered eligible if they remained hypertensive despite
treatment with one or two agents, and had a mean trough
sitting diastolic blood pressure (DBP)  90 mmHg but
5110 mmHg, and a mean trough sitting systolic blood
pressure (SBP)  140 mmHg but 5200 mmHg. Patients
were excluded from the study if they were taking more than
two anti-hypertensive medications or had suspected second-
ary hypertension, any history/current evidence of malignant
DOI: 10.3109/10641963.2014.954712
hypertension, or hypertensive encephalopathy. Patients were
also excluded if they had significant multiple and/or severe
allergies to losartan potassium, amlodipine (or dihydropyr-
idine drugs), and/or hydrochlorothiazide (or thiazide/related
drugs). Female patients of child-bearing potential were
required to agree to remain abstinent or use suitable
contraception for the duration of the study.
Study design
The study consisted of a screening period of up to 4 weeks, an
8-week single-blind filter period, and an 8-week double-blind
treatment period, followed by a 44-week open-label extension
period. The primary investigator enrolled and assigned
participants in a sequential manner into the study. Patients
were randomized 1:1 to double-blind treatment using a
computer-generated allocation schedule created by the
permuted block method (with a block size of four) by the
clinical biostatistics department of the study sponsor.
Randomization was stratified by study center.
Treatments
All treatments were taken orally once daily. During the
8-week filter period, all patients received L50/H12.5 under
single-blind conditions. Subsequently, patients whose blood
pressure remained uncontrolled despite treatment with L50/
H12.5 were randomized in a 1:1 ratio to receive losartan
50 mg/hydrochlorothiazide 12.5 mg/amlodipine 5 mg (L50/
H12.5/A5) or L50/H12.5 in an 8-week double-blind treatment
period. During the 44-week extension period, all patients
received L50/H12.5/A5 on an open-label basis.
Study endpoints
The primary objectives of the study were to compare the
efficacy, safety, and tolerability of L50/H12.5/A5 and L50/
H12.5 over the 8-week double-blind period and to evaluate
the long-term safety and tolerability of L50/H12.5/A5 for up
to 52 weeks of treatment.
The primary efficacy endpoint was the change from
baseline in mean trough sitting DBP at week 8 (i.e. the end
of the double-blind treatment period). The secondary efficacy
endpoint was the change from baseline in mean trough sitting
SBP at week 8. Exploratory endpoints included the proportion
of responders at week 8 (defined as percentage of patients
with a sitting DBP 590 mmHg or a sitting DBP 90 mmHg
with a  10 mmHg reduction from baseline), the change in
mean trough sitting DBP and sitting SBP after 4 weeks of
double-blind treatment with L50/H12.5/A5 and L50/H12.5,
and the change in mean trough sitting blood pressure after 52
weeks of treatment with L50/H12.5/A5.
Safety was assessed by adverse event (AE) monitoring
throughout the treatment period. In addition, blood biochem-
istry, hematology, and urinalysis were performed at regular
intervals throughout the study. Pre-specified safety events of
special interest were: any hypotension reported as an AE; an
asymptomatic decrease in blood pressure (sitting DBP
reduced by 415 mmHg or SBP by 430 mmHg from previous
measurement); orthostatic hypotension (change from sitting to
standing blood pressure measurement 420 mmHg systolic or
410 mmHg diastolic with symptoms); dizziness; syncope;
Losartan triple therapy vs. losartan/hydrochlorothiazide 261
edema; change in renal function (increase in serum creatinine
40.5 mg/dL from baseline); serum potassium 45.5 mEq/L
and an increase in serum potassium 40.5 mEq/L from
baseline; serum potassium 53.5 mEq/L and a decrease in
serum potassium from baseline of40.5 mEq/L; serum sodium
5125 mEq/L; consecutive elevations in aspartate aminotrans-
ferase or alanine transaminase43 x upper limit of normal; and
blood uric acid 48.4 mg/dL and elevation by 420% from
baseline. Vital signs were monitored throughout the study.
Statistical analysis
The primary population for the efficacy evaluation was the
full analysis set (FAS) population, defined as all randomized
patients who received at least one dose of the study
medication and had at least one post-randomization observa-
tion after at least one dose of the study medication. The
primary and secondary efficacy endpoints were analyzed
using a constrained longitudinal data analysis (cLDA) model
(12) with terms for treatment, time, and treatment-by-time
interaction. Missing data were not explicitly imputed. The
week 4 results were also obtained from the same model.
For the analysis of the proportion of responders at week 8,
five sets of imputations were made with missing data imputed
based on the cLDA model above. Each of the imputed
datasets were analyzed using a logistic regression with a term
for treatment and baseline mean trough sitting DBP as a
covariate. Parameter estimates on log odds ratio were
combined using the asymptotic theory of Robins and Wang
(13) with Kenward and Roger (14) degrees of freedom used to
construct the confidence interval (CI) and calculate the
p value. Data from the double-blind period were analyzed
after all patients completed the period. Descriptive statistics
for the change from baseline in trough sitting blood pressure
during the extension period were provided by double-blind
treatment group. The data obtained after the patient received
antihypertensives other than L50/H12.5/A5 were excluded
from the analysis.
The safety analysis was performed in the all-patients-
as-treated (APaT) population, which was defined as all
randomized patients who received at least one dose of study
treatment. In the double-blind period, p values and 95% CIs
for between-treatment differences in the percentage of
patients with pre-specified safety events of interest were
calculated using the method of Miettinen and Nurminen (15).
All other AEs and safety events were assessed via point
estimates with 95% CIs for between-group comparisons or
point estimates by treatment group. All statistical tests were
two-sided with a significance level of 5%. In the 44-week
extension phase, 95% CIs for the percentage of patients with
events, according to the double-blind treatment group as well
as pooling of the two treatment groups, were calculated using
the exact binomial method by Clopper and Pearson (16).
It was planned that 272 patients would be equally
randomized to treatment with L50/12.5/A5 or L50/H12.5 to
ensure 122 completers per treatment arm during the double-
blind treatment period. This sample size was designed to
detect a between-treatment difference of 3.2 mmHg (stand-
ard deviation [SD] estimate 7.6) and 5.1 mmHg (SD 12.2) in
mean trough sitting DBP and SBP, respectively, with 90%
262 H. Rakugi et al. Clin Exp Hypertens, 2015; 37(3): 260–266

power, all at a two-sided significance level of 0.05. The power 7.5, 4.2]; P50.001; Figure 2a and Table 2). Similarly, the
calculation was based on the inverse probability weighted decrease in mean trough sitting SBP during the 8-week
complete cases approach described by Lu et al. (17), double-blind treatment period was significantly greater in
assuming a rate of discontinuation of 10% during the patients treated with L50/H12.5/A5 than in patients treated
8-week double-blind treatment period. The number of with L50/H12.5 (treatment difference: 10.3 mmHg [95%
patients was also chosen to ensure that at least 100 patients CI 12.8, 7.7]; P50.001; Figure 2b and Table 2).
would complete 52 weeks of treatment with L50/H12.5/A5,
based on a projected discontinuation rate of 20%. All Table 1. Patient demographics and baseline characteristics (FAS
statistical analyses were performed by the Clinical population, n ¼ 285).
Biostatistics Department of MSD K.K.
L50/H12.5 L50/H12.5/A5 Total
(n ¼ 144) (n ¼ 141) (n ¼ 285)
Results
Gender
Patients Male, n (%) 110 (76.4) 108 (76.6) 218 (76.5)
Female, n (%) 34 (23.6) 33 (23.4) 67 (23.5)
Patient flow through the study is shown in Figure 1. Overall, Age (years)
286 patients were randomized to receive L50/H12.5/A5 Mean 56.3 ± 9.8 53.9 ± 9.1 55.1 ± 9.5
(n ¼ 141) or L50/H12.5 (n ¼ 145). Because one patient in Age group
565 years, n (%) 115 (79.9) 127 (90.1) 242 (84.9)
L50/H12.5 had no endpoint data, this patient was excluded 65 years, n (%) 29 (20.1) 14 (9.9) 43 (15.1)
from FAS (n ¼ 285). A total of 267 patients completed the Body mass index (kg/m2)
8-week double-blind treatment period and entered the Mean 26.3 ± 3.6 26.1 ± 4.4 26.2 ± 4.0
44-week open-label extension period. Of these, 242 patients Baseline SiDBP
5100 mmHg, n (%) 103 (71.5) 103 (73.0) 206 (72.3)
completed 52 weeks of treatment, with 124 and 118 patients 100 mmHg, n (%) 41 (28.5) 38 (27.0) 79 (27.7)
treated with L50/H12.5/A5 and L50/H12.5, respectively, in Type 2 diabetes mellitus
the double-blind period. The demographic and baseline Yes, n (%) 23 (16.0) 22 (15.6) 45 (15.8)
characteristics of patients were generally similar for the two No, n (%) 121 (84.0) 119 (84.4) 240 (84.2)
Dyslipidemia
double-blind treatment groups (Table 1). Yes, n (%) 49 (34.0) 46 (32.6) 95 (33.3)
No, n (%) 95 (66.0) 95 (67.4) 190 (66.7)
Efficacy Years of hypertension
Mean 7.6 ± 7.6 6.7 ± 6.6 7.2 ± 7.1
Over the 8-week double-blind treatment period, the decrease Number of prior anti-hypertensive medications
1, n (%) 28 (19.4) 34 (24.1) 62 (21.8)
in mean trough sitting DBP was significantly greater in
2, n (%) 116 (80.6) 107 (75.9) 223 (78.2)
patients treated with L50/H12.5/A5 than in patients treated
with L50/H12.5 (treatment difference: 5.9 mmHg [95% CI Values are mean ± SD unless otherwise stated.

Figure 1. Flow of patients through the study.

DOI: 10.3109/10641963.2014.954712 Losartan triple therapy vs. losartan/hydrochlorothiazide 263

The difference in blood pressure-lowering efficacy between
L50/H12.5/A5 and L50/H12.5 was evident within 2 weeks of
treatment (Figure 2). After 4 weeks of double-blind treatment,
the least squares mean (± standard error) change in trough
sitting DBP with L50/H12.5/A5 was 11.3 ± 0.6 mmHg and
with L50/H12.5 was 4.9 ± 0.6 mmHg (Figure 2a; treatment
difference: 6.3 mmHg [95% CI 8.0, 4.7]; p50.001).
The corresponding values for trough sitting SBP were
16.9 ± 0.9 mmHg and 6.2 ± 0.9 mmHg, respectively
(treatment difference: 10.8 mmHg [95% CI 13.1, 8.4];
p50.001).
The proportion of patients responding to therapy at week 8
was significantly higher with L50/H12.5/A5 (79.7%) versus
L50/H12.5 (52.4%) (odds ratio 3.97, [95% CI 2.31, 6.82],
p50.001).
The mean changes from baseline in trough sitting DBP and
SBP were sustained during the open-label phase of treatment
(Supplementary Figure 1). At the end of the open-label phase
Figure 2. Least-squares mean change from baseline in trough sitting (a)
DBP and (b) SBP over 8 weeks of double-blind treatment with L50/
H12.5/A5 (n ¼ 141) or L50/H12.5 (n ¼ 144; FAS population).
after 52 weeks of treatment in the group randomized to double-
blind treatment with L50/H12.5/A5, the mean (± SD) change
from baseline in trough sitting DBP was 13.09 ± 7.41 mmHg.
The mean (± SD) change in trough sitting SBP over the same
time period was 20.01 ± 11.23 mmHg. Similar changes from
baseline were observed at the end of the open-label phase in
patients originally randomized to L50/H12.5 (Supplementary
Figure 1).
Safety
The percentages of patients with AEs, drug-related AEs, and
those who discontinued treatment because of AEs at 8 weeks
and 52 weeks are shown in Table 3. There were no deaths
during the course of the study. Over the 52-week study, six
patients (2.2%) discontinued because of an AE. Four of
six patients experienced decreased blood potassium. Two
patients in the L50/H12.5 group experienced 3.3 mEq/L at
baseline (on the start day of the double-blind period), one
patient in the L50/H12.5/A5 group (screening ¼ 3.5 mEq/L)
had 3.1 mEq/L on day 29, and the other in the L50/H12.5/
A5 group (baseline ¼ 3.9 mEq/L) had 3.5 mEq/L on day 85.
Other events were dizziness (L50/H12.5) and eczema
(L50/H12.5/A5).
During the 8-week double-blind treatment period, the
overall incidence of AEs was similar between the two
treatment groups (Table 3). In addition, there were no
statistically significant differences between the treatment
groups in terms of the proportion of patients experiencing
prespecified safety events of interest, with the exception of
blood pressure decrease (defined as a decrease in sitting DBP
by 415 mmHg or sitting SBP by 430 mmHg from previous
measurement) which occurred more frequently with L50/
H12.5/A5 (Table 4). The drug-related AEs with an incidence
2% during the double-blind period were increase in blood
uric acid (L50/H12.5: 5.5% [8/145 patients], L50/H12.5/A5:
4.3% [6/141 patients]), hyperuricaemia (L50/H12.5:2.8%
[4/145 patients], L50/H12.5/A5:3.5% [5/141 patients]) and
increase in alanine aminotransferase (ALT; L50/H12. 5: 0.0%,
L50/H12.5/A5: 2.1% [3/141 patients; Supplementary
Table 1]).
During the 52 weeks of treatment, the overall incidence of
drug-related AEs for the two treatment groups combined was
21.2% (58/274 patients). The drug-related AEs with an
incidence 2% during the entire study were increase in blood

Table 2. Change from baseline in mean trough sitting DBP and SBP (mmHg) at week 8 (FAS population).

Change from baseline at week 8

Baseline Week 8 Pairwise comparison for difference
mean (SD) mean (SD) Mean (SD) LS mean (SE) 95% CI in LS means* (95% CI) p Value
DBP
L50/H12.5/A5 (n ¼ 141) 96.5 (5.5) 84.4 (9.6) 12.1 (7.0) 12.1 (0.6) 13.3, 10.9 5.9 (7.5, 4.2) 50.001
L50/H12.5 (n ¼ 144) 96.5 (5.4) 90.1 (8.0) 6.2 (7.0) 6.2 (0.6) 7.4, 5.0
SBP
L50/H12.5/A5 (n ¼ 141) 152.0 (10.2) 134.1 (12.7) 17.8 (11.3) 17.7 (0.9) 19.6, 15.9 10.3 (–12.8, 7.7) 50.001
L50/H12.5 (n ¼ 144) 151.5 (9.9) 143.7 (12.9) 7.2 (10.6) 7.5 (0.9) 9.3, 5.7

*L50/H12.5/A5 versus L50/H12.5.

CI, confidence interval; DBP, diastolic blood pressure; L50/H12.5, losartan 50 mg/hydrochlorothiazide 12.5 mg; SBP, systolic blood pressure; L50/
H12.5/A5, losartan 50 mg/hydrochlorothiazide 12.5 mg/amlodipine 5 mg; LS, least squares; SD, standard deviation; SE, standard error.
264 H. Rakugi et al. Clin Exp Hypertens, 2015; 37(3): 260–266

Table 3. Number (%) of patients experiencing AEs (APaT population).

8-Week double-blind period Week 52 analysis

L50/H12.5/A5 L50/H12.5/A5
L50/H12.5/A5 L50/H12.5 Difference (95% CI) in % (L50/H12.5/A5) (L50/H12.5)
(n ¼ 141) (n ¼ 145) between treatment groups (n ¼ 141)a (n ¼ 133)b
At least one AE 38 (27.0) 43 (29.7) 2.7 (13.1, 7.8) 100 (70.9) 88 (66.2)
Drug-related AE 17 (12.1) 21 (14.5) 2.4 (10.5, 5.6) 39 (27.7) 19 (14.3)
Serious AE 1 (0.7) 2 (1.4) 0.7 (4.3, 2.7) 3 (2.1) 4 (3.0)
Serious drug-related AE 0 0 0.0 (2.6, 2.7) 0 1 (0.8)
Discontinued due to AE 1 (0.7) 2 (1.4) 0.7 (4.3, 2.7) 3 (2.1) 3 (2.3)
Discontinued due to drug-related AE 1 (0.7) 2 (1.4) 0.7 (4.3, 2.7) 3 (2.1) 1 (0.8)
Discontinued due to serious AE 0 0 0.0 (2.6, 2.7) 0 2 (1.5)
Discontinued due to serious drug-related AE 0 0 0.0 (2.6, 2.7) 0 1 (0.8)

AE, adverse event; CI, confidence interval; L50/H12.5, losartan 50 mg/hydrochlorothiazide 12.5 mg; L50/H12.5/A5, losartan 50 mg/
hydrochlorothiazide 12.5 mg/amlodipine 5 mg.
a
Patients received L50/H12.5/A5 for 8 weeks on a double-blind basis followed by L50/H12.5/A5 for 44 weeks on an open-label basis (data relate to
the entire 52 weeks of treatment with L50/H12.5/A5).
b
Patients received L50/H12.5 for 8 weeks on a double-blind basis followed by L50/H12.5/A5 for 44 weeks on an open-label basis (data relate to the
44 weeks of open-label treatment with L50/H12.5/A5 only).

Table 4. Number (%) of pre-specified safety events and estimated difference between treatment groups occurring during the 8-week double-blind
treatment period (APaT population).

Difference in % between
treatment groups
L50/H12.5/A5 L50/H12.5 Estimate
(n ¼ 141) (n ¼ 145)a (95% CI) p Value
Hypotension 1 (0.7) 1 (0.7) 0.0 (3.2, 3.3) 0.984
Decreased blood pressureb 33 (23.4) 10 (6.9) 16.5 (8.4, 24.9) 50.001
Orthostatic hypotensionc 0 0 0.0 (2.6, 2.7) 1.000
Dizziness 0 1 (0.7) 0.7 (3.8, 2.0) 0.324
Syncope 0 0 0.0 (2.6, 2.7) 1.000
Edema 0 0 0.0 (2.6, 2.7) 1.000
Worsening renal functiond 1 (0.7) 0 0.7 (1.9, 3.9) 0.312
Serum potassium 45.5 mEq/L and an increase of 40.5 mEq/L from baseline 0 0 0.0 (2.6, 2.7) 1.000
Serum potassium 53.5 mEq/L and a decrease of 40.5 mEq/L from baseline 1 (0.7) 0 0.7 (1.9, 3.9) 0.312
Serum sodium 5125 mEq/L 0 0 0.0 (2.6, 2.7) 1.000
Consecutive elevations in AST 43 x ULN 0 0 0.0 (2.6, 2.7) 1.000
Consecutive elevations in ALT 43 x ULN 1 (0.7) 0 0.7 (1.9, 3.9) 0.312
Blood uric acid 48.4 mg/dL and elevation of 420% from baseline 3 (2.1) 4 (2.8) 0.7 (5.1, 3.6) 0.723

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; L50/H12.5, losartan 50 mg/hydrochlorothiazide 12.5 mg;
L50/H12.5/A5, losartan 50 mg/hydrochlorothiazide 12.5 mg/amlodipine 5 mg; ULN, upper limit of normal.
a
Outcomes relating to blood pressure decreased, orthostatic hypotension, worsening renal function, serum potassium, serum sodium, AST, ALT, and
blood uric acid were only assessed in 144 patients.
b
Sitting diastolic blood pressure decrease by 415 mmHg or sitting systolic blood pressure decrease by 430 mmHg from previous measurement.
c
Change in sitting blood pressure to standing blood pressure measurement 420 mmHg systolic or 410 mmHg diastolic with symptoms
d
Increase in serum creatinine 40.5 mg/dl from baseline.

uric acid (4.7% [13/274 patients]), increase in ALT (4.0%
[11/274 patients]), increase in aspartate aminotransferase
(AST; 2.6% [7/274 patients]) and hyperuricaemia (2.6%
[7/274 patients; Supplementary Table 2]). One patient
reported a serious drug-related AE of altered state of
consciousness in the L50/H12.5/A5 (L50/H12.5) group,
which resolved after discontinuation of the study drug.
Discussion
L50/H12.5/A5 is a fixed-dose combination of three estab-
lished antihypertensive agents that act in a complementary
manner. Losartan and hydrochlorothiazide address the renin-
dependent and -independent components of blood pressure
lowering, respectively, while amlodipine is a potent calcium
channel blocker. The aim of the current study was to assess
the tolerability and blood pressure-lowering efficacy of this
triple combination therapy in Japanese patients not adequately
controlled with L50/H12.5.
The results of the current study indicated that a fixed-dose
combination of L50/H12.5/A5 was significantly more effect-
ive than L50/H12.5 at lowering mean trough sitting DBP and
SBP in Japanese patients who have elevated blood pressure
despite treatment with L50/H12.5. Furthermore, L50/H12.5/
A5 was found to be as well tolerated as L50/H12.5, with an
acceptable safety and tolerability profile when administered
for up to 1 year.
To date, this was the first study to assess the efficacy and
safety of this triple combination therapy exclusively in
Japanese patients. However, the advantages of a triple
DOI: 10.3109/10641963.2014.954712
combination therapy compared with dual therapy have also
been observed in other studies of mainly Western patients.
Those studies investigated the efficacy and tolerability of
triple combination regimens incorporating ARBs other than
losartan (i.e. valsartan or olmesartan) with hydrochlorothia-
zide and amlodipine (18,19). For example, in the TRINITY
study of adult patients with moderate-to-severe hypertension,
treatment with olmesartan 40 mg, amlodipine 10 mg, and
hydrochlorothiazide 25 mg was associated with significantly
(P50.001) greater blood pressure reductions and resulted in
more patients reaching blood pressure targets than dual
combinations of the individual components (18). In another
study, treatment with a triple combination of valsartan
320 mg, hydrochlorothiazide 25 mg, and amlodipine 10 mg
resulted in significantly greater reductions in mean sitting
DBP and SBP in patients with moderate-to-severe hyperten-
sion compared with valsartan 320 mg and hydrochlorothiazide
25 mg, as well as dual combinations with the other individual
components (19). The current study further confirms the
efficacy results of the previous studies, demonstrating the
advantages of triple combination therapy in patients not
adequately controlled on dual antihypertensive therapy.
The improved disease control observed with L50/H12.5/
A5 versus L50/H12.5 has important implications in the
management of hypertension. As hypertension is a major
contributor to cardiovascular morbidity and mortality, con-
trolling blood pressure is an important therapeutic goal in
preventing or slowing the progression of cardiovascular
disease. It is estimated that one-quarter of all hypertensive
patients will require three antihypertensive agents to achieve
adequate control of blood pressure (20). Fixed-dose combin-
ations of three antihypertensive drugs are becoming increas-
ingly available, and their availability is likely to improve ease
of use, resulting in improved adherence. Data show that
medication adherence in non-treatment-naı̈ve patients pre-
scribed a fixed-dose combination therapy was 14% higher
than that in patients prescribed the individual components (9).
The current study indicated that L50/H12.5/A5 had a
comparable safety and tolerability profile compared with dual
L50/H12.5. Over the 8-week double-blind phase of the study,
the overall safety profile of the two treatment regimens was
generally similar. Furthermore, long-term treatment with L50/
H12.5/A5 for up to 1 year was generally well tolerated.
Limitations of the current study were the short duration of
the comparative treatment period (8 weeks) and that the
extension phase was open-label. Nevertheless, the level of
blood pressure control was sustained throughout the 44-week
extension period in patients randomized to L50/H12.5/A5,
with patients initially receiving dual therapy rapidly achieving
a similar mean reduction in both DBP and SBP over their first
2 weeks of triple combination therapy, which was maintained
for the remainder of the trial.
In conclusion, in Japanese patients with uncontrolled
essential hypertension, treatment with triple combination
therapy L50/H12.5/A5 resulted in a significantly greater
improvement in blood pressure control compared with
treatment with dual combination L50/H12.5. Triple combin-
ation therapy was generally well tolerated when administered
for a period of up to 1 year. As seen in previous studies of
mainly Western patients, the current study confirms the
Losartan triple therapy vs. losartan/hydrochlorothiazide 265
benefits of using drugs with complementary mechanisms of
action to treat hypertension in Japanese patients.
Acknowledgements
MK-0954E L50/H12.5 Filter Study Investigators: S. Kaneta
(ONO CLINIC), H. Makino(Makino Clinic), H.
Okumura(Okumura Clinic), H. Ishii(Shin Nihonbashi Ishii
Clinic), Y. Noguchi (Noguchi Clinic), I. Morii (Hokusetsu
General Hospital), K. Izumino (Fujikoshi Hospital), S. Sawai
(Sawai Medical Clinic), K. Fujimoto (Fujimoto internal
medicine Clinic), K. Sato (Itsukikai Heart Clinic), D. Fujii
(Fujii Clinic), M. Ikebuchi (Ikebuchi Clinic), M. Iiyama
(Hirakata Kohsai Hospital), T. Yamato (Kowa Clinic), H.
Nakamura (Mille Dix Clinic for internal diseases), D.
Kasahara (Kasahara Clinic), Y. Ueyama (Medical
Corporation Nijyunnkai Ueyama Clinic), K. Harada
(Kasaoka Daiichi Hospital), M. Takeda (Takeda Hospital),
S. Hayashi (Social Insurance Ritsurin Hospital).
Medical writing and editorial assistance was provided by
Melanie Jones of Prime Healthcare, Knutsford, Cheshire, UK.
This assistance was funded by Merck & Co., Inc., Whitehouse
Station, NJ, USA. The authors would like to thank: William
Malbecq, Kristel Vandormael, and Rachid Massaad of MSD
Belgium for providing statistical expertise; Emanuela Santoro
of Merck & Co., Inc., Whitehouse Station, NJ, USA for
assistance with conduct of the study; Hiroomi Iwata and Inoue
Yoichi, MD, of MSD K.K. for assistance with conduct of the
study; Sachiko Yoshimoto, MD, of MSD K.K. for assistance
with study design and conduct; Mary E Hanson, PhD, of
Merck & Co., Inc. for scientific input and editorial assistance;
and the primary investigators for conduct of the study.
Declaration of interest
This study was designed and funded by Merck Sharp &
Dohme (MSD) K.K., Tokyo, Japan.
HR has received honoraria and/or fees for promotional
materials from Astellas Pharma, Daiichi Sankyo, Kyowa
Hakko Kirin, Nippon Boehringer Ingelheim, Novartis
Pharma, and Takeda Pharmaceutical, and has received
research funding from Astellas Pharma, Daiichi Sankyo,
Kyowa Hakko Kirin, Mitsubishi Tanabe Pharma, MSD KK,
Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer
Japan, and Takeda Pharmaceutical. TT has received honoraria
and/or fees for promotional materials from Dainippon-
Sumitomo Co. and MSD KK, and has received research
funding from MSD KK. KS has received honoraria and/or
fees for promotional materials from Daiichi Sankyo,
Dainippon-Sumitomo Co., MSD KK, Novartis, and Takeda
Pharmaceutical. HN, CN, HY, MS, and KA are employees of
MSD K.K, and may own stock or hold stock options in the
company. KPF was an employee of Merck & Co., Inc,
Whitehouse Station, NJ, at the time the study was conducted.
Analysis of the study data and opinions, conclusions, and
interpretation of the data are the responsibility of the authors.
References
1. Fukui T, Rahman M, Hayashi K, et al. Candesartan
Antihypertensive Survival Evaluation in Japan (CASE-J) trial of
266 H. Rakugi et al.
cardiovascular events in high-risk hypertensive patients: rationale,
design, and methods. Hypertens Res 2003;26:979–90.
2. Gradman AH, Basile JN, Carter BL, Bakris GL. Combination
therapy in hypertension. J Am Soc Hypertens 2010;4:42–50.
3. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC
Guidelines for the management of arterial hypertension: the Task
Force for the management of arterial hypertension of the European
Society of Hypertension (ESH) and of the European Society of
Cardiology (ESC). J Hypertens 2013;31:1281–357.
4. Shimamoto K, Ando K, Fujita T, et al. The Japanese Society of
Hypertension Guidelines for the Management of Hypertension
(JSH 2014). Hypertens Res 2014;37:253–87.
5. Hagendorff A, Freytag S, Muller A, Klebs S. Pill burden in
hypertensive patients treated with single-pill combination therapy –
an observational study. Adv Ther 2013;30:406–19.
6. Chowdhury EK, Owen A, Krum H, et al. Barriers to achieving
blood pressure treatment targets in elderly hypertensive individuals.
J Hum Hypertens 2013;27:545–51.
7. Ingersoll KS, Cohen J. The impact of medication regimen factors
on adherence to chronic treatment: a review of literature. J Behav
Med 2008;31:213–24.
8. Sakima A, Ohshiro K, Nakada S, et al. Switching therapy from
variable-dose multiple pill to fixed-dose single-pill combinations of
angiotensin II receptor blockers and thiazides for hypertension. Clin
Exp Hypertens 2011;33:309–15.
9. Sherrill B, Halpern M, Khan S, et al. Single-pill vs free-equivalent
combination therapies for hypertension: a meta-analysis of health
care costs and adherence. J Clin Hypertens (Greenwich) 2011;13:
898–909.
10. Hosoya T, Kuriyama S, Ohno I, et al. Antihypertensive effect of a
fixed-dose combination of losartan/hydrochlorothiazide in patients
Supplementary material available online
Supplementary Tables 1 and 2
Clin Exp Hypertens, 2015; 37(3): 260–266
with uncontrolled hypertension: a multicenter study. Clin Exp
Nephrol 2012;16:269–78.
11. Saruta T, Ogihara T, Matsuoka H, et al. Antihypertensive efficacy
and safety of fixed-dose combination therapy with losartan plus
hydrochlorothiazide in Japanese patients with essential hyperten-
sion. Hypertens Res 2007;30:729–39.
12. Liang K, Zeger S. Longitudinal data analysis of continuous and
discrete responses for pre-post designs. Sankyâ. Indian J Stat 2000;
62:134–48.
13. Robins JM, Wang N. Inference for imputation estimators.
Biometrika 2000;87:113–24.
14. Kenward MG, Roger JH. Small sample inference for fixed effects
from restricted maximum likelihood. Biometrics 1997;53:983–97.
15. Miettinen O, Nurminen M. Comparative analysis of two rates. Stat
Med 1985;4:213–26.
16. Clopper C, Pearson E. The use of confidence or fiducial limits
illustrated in the case of the binomial. Biometrika 1934;26:404–13.
17. Lu K, Mehrotra DV, Liu G. Sample size determination for
constrained longitudinal data analysis. Stat Med 2009;28:679–99.
18. Oparil S, Melino M, Lee J, et al. Triple therapy with olmesartan
medoxomil, amlodipine besylate, and hydrochlorothiazide in adult
patients with hypertension: the TRINITY multicenter, randomized,
double-blind, 12-week, parallel-group study. Clin Ther 2010;32:
1252–69.
19. Calhoun DA, Lacourciere Y, Chiang YT, Glazer RD. Triple
antihypertensive therapy with amlodipine, valsartan, and hydro-
chlorothiazide: a randomized clinical trial. Hypertension 2009;54:
32–9.
20. Neutel JM, Smith DH. Hypertension management: rationale for
triple therapy based on mechanisms of action. Cardiovasc Ther
2013;31:251–8.
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