Journal of Human Hypertension (2010) 24, 823 830

& 2010 Macmillan Publishers Limited All rights reserved 0950-9240/10

ORIGINAL ARTICLE

www.nature.com/jhh

Achieving blood pressure goal: initial

therapy with valsartan/hydrochlorothiazide
combination compared with monotherapy
MH Weinberger1, RD Glazer2, NA Crikelair2 and YT Chiang2
Department of Medicine, Hypertension Research Center, Indiana University School of Medicine,
Indianapolis, IN, USA and 2Cardiovascular/Metabolism Clinical Research and Development, Novartis
Pharmaceuticals Corporation, East Hanover, NJ, USA
1

The benefits of valsartan (Val)/hydrochlorothiazide

(HCTZ)
combination
as
initial
treatment
for
hypertension were evaluated in a post hoc analysis of
an 8-week, double- blind, placebo-controlled, parallelgroup trial. The highest dose of Val/HCTZ combination
(320/25 mg), component
monotherapies (Val 320 mg, HCTZ 25 mg) and placebo
were selected for this analysis (N 675, 52.1% men,
68.6% Caucasians, mean age 52.9 years, baseline
blood pressure (BP) 150.6/99.1 mm Hg). As soon as 2 weeks
after initiation of active therapy, greater BP control rates
were observed with Val/HCTZ (320/25 mg) compared
with Val (320 mg), HCTZ (25 mg) and placebo. Similar
results were observed in subgroups of patients with
stage 1 and stage 2 hypertension, as well as in diabetic
patients. As baseline

BP increased, the probability of achieving mean sitting

systolic BP (o140 and o130 mm Hg) and mean sitting
diastolic BP control (o90 and o80 mm Hg), determined
using a logistic regression model, decreased with all
treatments. However, at all levels of baseline BP, the
probability of achieving BP control was greater with
Val/HCTZ combination. The Val/HCTZ combination was
well tolerated with overall incidence of adverse events
similar to that observed with monotherapy and placebo.
These results support the use of Val/HCTZ combination
as initial therapy in hypertensive patients unlikely to
achieve BP control with a single agent.
Journal of Human Hypertension (2010) 24, 823830;
doi:10.1038/jhh.2010.17; published online 25 February 2010

Keywords: valsartan; HCTZ; initial therapy

Introduction
Inadequate control of blood pressure
(BP) is a major predisposing factor
for cardiovascular (CV) disease. With
the number of adults suffering from
elevated BP anticipated to increase to
1.56
billion
worldwide
by
2025,
hypertension poses
a major challenge
1
to public health.
Current guidelines are in agreement
that aggres- sive therapy is required
to reduce CV morbidity and mortality
in
patients
with
significantly
elevated BP.26 It is recommended that
consideration be given to initiating
therapy with two drugs for patients
with systolic/diastolic BP (SBP/DBP)
420/10
mm
Hg
above
target
goal,
thereby increasing the likelihood of
achieving
goal
BP
in
a
timely
manner.2,5
This
recommendation
is
supported by the fact that there is a
o5% chance of decreasing DBP 412 mm Hg7
with a single antihypertensive agent.
Even if patients BP are initially
controlled
by
a
single
agent,
additional agents may need to be added
to
Correspondence: Dr MH Weinberger, Hypertension
Research Center, Indiana University School of
Medicine,
541
Clinical
Drive,
Room
380G,
Indianapolis, IN 46202, USA.
E-mail: mweinbe@iupui.edu
Received 12 January 2010; accepted 25 January
2010; published
online 25 February 2010

maintain control over time. In the

ALLHAT (Anti- hypertensive and LipidLowering Treatment to Prevent Heart
Attack Trial), B63% of patients were
treated
with
two
or
more
antihypertensive agents
at the end of
5 years of follow-up.8
Not only is adequate BP control
critical, the time taken to achieve
this goal is also important. The longer
a patient experiences higher levels of
BP,
the
greater
the
risk
for
restructuring
and
remodelling
of
vascular
beds
with
subsequent
stiffening and loss of compliance.9,10
These pathophysiological
changes can
ultimately
interfere
with
normal
vasorelaxation processes, which may be
important in the reduction of11,12 BP,
particularly over the long term.
In
addition, rapid BP reduction also leads
to a reduction in the associated CV
events.1315
Finally,
one
must
consider
the
potential
impact
of
initial
combination therapy in a clinical
practice setting. There is a strong
relationship between the number of
medication changes during the first 6
months of antihypertensive treatment
and compli- ance rates during the
subsequent 6 months of therapy. The
longer it takes to reach BP control,
the lower the compliance with time. 16
Therefore, initial combination therapy
may improve long-term compliance in
clinical
practice
with
potentially
improved outcomes.

Rapid BP control with Val/HCTZ initial therapy

MH Weinberger et
al

Understanding the relationship

between baseline
BP and the probability of achieving BP
control with either monotherapy or
combination
therapy
would
enable
physicians
to
better
evaluate
the
benefit
and
risk
of
initiating
treatment with combination ther- apy.
Recent studies have shown that the
combination
of
an
angiotensin
receptor blocker, such as valsartan
(Val),
with
the
diuretic
hydrochlorothiazide
(HCTZ),
has
enhanced
efficacy
compared
with
component monotherapies and is well
tolerated in hypertensive patients. 1720
This report describes the results of
post hoc analyses designed to evaluate
the benefit:risk profile of initial
combination
therapy
with
Val/HCTZ
compared with monotherapy with Val or
HCTZ and placebo by assessing efficacy
as a function of baseline BP.

Methods
Study design

This was a post hoc analysis of an 8week,

randomized,
double-blind,
placebo-controlled, mul- tifactorial,
parallel-group trial. Complete details
of
the
study
have
been
published
previously.17 A total of 1652 patients
were enrolled into the single-blind
period of the study, and 1346 patients
with a mean sitting DBP (MSDBP) X95 and
o110 mm Hg were randomly allocated into
the double-blind treatment phase. The
study
assessed
the
antihypertensive
efficacy and tolerability of once-daily
dosing of Val/HCTZ combination therapy
(160/12.5, 320/12.5 and
320/25 mg)
compared with Val (160 and 320 mg),
HCTZ (12.5 and 25 mg) and placebo.
Patients randomized to Val/HCTZ
were
initiated
on
combination
therapy.
During
the
first
week
after
randomization, patients in the Val/HCTZ
320/12.5 and 320/25 mg treatment groups
received Val/HCTZ 160/12.5 mg, whereas
patients randomized to the remaining
six treatment groups received their
respective final doses. From the second
postrandomization
week
(week
1)
through the end of the trial (week 8),
all treatment groups received their
final dose. These analyses included the
safety information of all available
doses. The efficacy analyses focused
strictly on the highest dose of the
Val/HCTZ combination (320/25 mg) along
with the respective highest doses of
component monothera- pies (Val 320 mg
or HCTZ 25 mg), as the efficacy and
safety profile of the maximum doses of
monotherapy
would
influence
the
decision-making process of initiating
therapy with the combination.

BP control rates o130/80 mm Hg were also

assessed
in the overall population and in the
subgroup of patients with diabetes. The
percentage of patients achieving SBP
(o140 and o130 mm Hg) and DBP (o90 and
o80 mm Hg) control at end point was
predicted as a function of baseline
BP.
Safety

Safety was assessed by evaluating the

incidence of adverse events (AEs),
serious
AEs
and
AEs
leading
to
discontinuation
in
the
safety
population, defined as all randomized
patients who had received at least one
dose of the study drug.
Statistical analysis

All efficacy analyses were performed

post
hoc
on
the
intent-to-treat
population, defined as all rando- mized
patients
who
had
a
baseline
BP
measurement and at least one postbaseline efficacy measurement. SBP and
DBP control rates were analyzed in the
intent-to-treat
population
at
end
point, using a logistic regression
model with treatment as a factor and
baseline BP as a covariate. End point
was defined as measurement at week 8,
or the last post- baseline observation
was carried forward as the end point
measurement. Summary statistics were
per- formed for control rates at each
biweekly visit for the intent-to-treat
population and also for the subgroups
of
patients
with
diabetes
and
stage 1 and stage
2 hypertension. Two-dimensional line
plots and predicted values of SBP and
DBP control rates relative to baseline
were generated for the Val/HCTZ 320/25
mg combination, component monotherapies
(Val 320 mg; HCTZ 25 mg) and placebo. To
keep a single curve for each treatment
across all centres, the region factor
was excluded from the logistic regression model for the plots and predicted
control
rates. Patients with baseline
MSSBP o140 mm Hg, MSSBP o130 mm Hg,
MSDBP o90 mm Hg and MSDBP o80 mm Hg
were excluded from the respec- tive
control rate analyses using the same
criteria.

Results
Patient population

The complete details of the patient

disposition for the entire17 study have
been published previously. Of the 675
patients included in the Val/HCTZ
320/25 mg, Val 320 mg, HCTZ 25 mg and
placebo groups, 568 (84.2%) completed
the study. Study discontinuation rates
in the Val/HCTZ 320/25 mg, Val 320 mg,
Efficacy
HCTZ 25 mg and placebo groups were
The overall BP control rates o140/90 mm
10.1,
19.4,
15.0
and
18.9%,
Hg were assessed every 2 weeks in the
respectively. Disconti- nuations due
intent-to-treat popula- tion and in
to unsatisfactory therapeutic effect
subgroups of patients with stage 1
were
1.2,
2.9,
6.6
and
10.7%,
(mean sitting SBP (MSSBP) X140 and o160
respectively.
mm Hg and/or MSDBP X90 and o100 mm Hg)
Treatment groups were well balanced
and stage 2 (MSSBP X160 and/or MSDBP
for
baseline
demographics,
disease
X100 mm Hg)
hypertension.
characteristics
and
number
of
17
patients. Of the patients in this post
hoc data set, a total of 352 (52.1%)
patients were men,
463
(68.6%) were Caucasian and 62 (9.2%)
betic. The mean age of the study population
were
diawas
Journal of Human
Hypertension

Rapid BP control with Val/HCTZ initial therapy

MH Weinberger et al

in the subgroup of diabetic patients in whom a

goal of
o130/80 mm Hg is recommended, with
control rates of 31.6, 5.6, 12.5 and
11.1%, respectively.

52.9 years with 102 (15.1%) patients

X65 years of age.
MSSBP
and
MSDBP
were
150.6 and
99.1 mm Hg, respectively.
BP control in overall population by week

BP control in patients with stage 1 and stage 2

hypertension by week

Val/HCTZ combination therapy resulted in

greater BP control rates compared with
both HCTZ and Val monotherapies and
placebo, as early as 2 weeks after
starting
therapy
and
continuing
through the final week (Figures 1a and
b). At the study end point, BP control
rates (o140/90 mm Hg) for Val/HCTZ,
Val, HCTZ and placebo were 74.9%
(Po0.05,
vs
monotherapies
and
placebo),
48.8,
51.8
and
30.9%,
respectively. For the more aggressive
goal of o130/ 80 mm Hg, the control
rates at the study end point were
30.5% (Po0.05, vs monotherapies and
placebo),
10.8,
9.2
and
3.0%,
respectively. Results were similar

70

% Patients with BP control (<140/90 mmHg)

80
70

Placebo
Val 320 mg
HCTZ 25 mg
Val/HCTZ 320/25 mg

60

79.1
69.4

60

62.6

50
40

70.9

51.3

50.0
46.9

44.4

44.3
41.7

30
20

55.9
51.1

33.6
28.9
23.4

10

17.8

0
2 wks

4 wks

wks
Weeks of treatment

35
30

6 wks

Placebo Val 320 mg

HCTZ 25 mg
Val/HCTZ 320/25 mg

32.7

25

26.3
24.7
22.7

20
15

12.8
11.8
10.5

10

10.8
9.7

10.3

7.6
5.8

5
3.2

2.6

4.2

3.6

2 wks

4 wks
6 wks
Weeks of treatment

Placebo Val 320 mg

HCTZ 25 mg
Val/HCTZ 320/25 mg

65.8
60.5

50

54.9

47.6

40

39.3

30

30.9

31.1

30.0

26.0

24.2

20
10

33.3

21.1

20.7

19.7

11.3

10.4

0
2 wks

4 wks

6 wks

8 wks

Weeks of treatment

100

Placebo Val 320 mg

HCTZ 25 mg
Val/HCTZ 320/25 mg

93.2

90
% Patients with BP control (<140/90 mmHg)

a
90

%Patients with BP control (<130/80 mmHg)

% Patients with BP control (<140/90 mmHg)

Higher BP control (o140/90 mm Hg) rates

were also observed in the subgroup of
stage 2 hypertensive patients receiving
Val/HCTZ combination therapy compared
with each of the monotherapies (HCTZ or
Val) and placebo, as early as 2 weeks
(Figure
2a).
These
results
were
observed consistently through- out the
study period, including study end point
(Val/HCTZ 62.1%; Val 31.7%; HCTZ 33.8%;
placebo
21.1%). A similar pattern was observed
in stage 1 patients (Figure 2b), but
the relative differences between the
Val/HCTZ combination and the monotherapies were greater for stage 2
patients than for stage 1 patients.

84.6

81.8

78.5

80

73.3

62.5

60

67.9
59.8

58.3

54.4

50
40

72.5

68.8

70

42.5
34.5

33.3

30

23.5

20
10
0
2 wks

4 wks
6 wks
Weeks of treatment

8 wks

8 wks

Journal of Human
Hypertension

Rapid BP control with Val/HCTZ initial therapy

MH Weinberger et
al

Figure 1 Overall BP control rates at weeks 2, 4, 6

and
8
by
treatment
groups
(intent-to-treat
population).
(a)
BP
o140/
90 mm Hg and (b)
BP
o130/80
mm
Hg;
N

158163
for
the
Val/ 145158
HCTZ group, 148156 for Val monotherapy,
for HCTZ
monotherapy and 142158 for placebo.

Prediction of systolic and diastolic control rates

as a function of baseline BP

Figure 2 Overall BP control (o140/90 mm Hg) rates

at weeks 2, 4,
6
and
8
by
treatment
groups
(intent-to-treat population).
(a)
Patients
withgroup,
stage 7376
2 hypertension;
N 8184
for the
Val/HCTZ
for Val monotherapy,
6168
for
HCTZ monotherapy
and 5871 for placebo. (b) Patients with stage
1 hypertension;
N
7779
for the Val/HCTZ group, 7580 for
Val
monotherapy,
8487
for placebo.8490 for HCTZ monotherapy and

Results of logistic regression models

generated
to
predict
SBP
and
DBP
control rates at end point as
a
function of baseline BP are shown in
Figure 3.
As expected, as baseline BP
increased, the probability of achieving
MSSBP
and
MSDBP
control
decreased
regardless of therapy. Irrespective of
the
baseline
BP,
however,
the
probability of achieving an MSSBP o140
mm Hg and MSDBP o90 mm Hg was greater
with
combination
therapy
than
with
monotherapies and placebo (Figures 3a
and b). For example, the probability of
achieving an
MSSBP
o140 mm Hg for a
patient with a baseline MSSBP between
160
and 170 mm Hg was
77.1%
with
Val/HCTZ 320/25 mg, 32.4% with Val 320
mg and 39.6% with HCTZ 25 mg.
As expected, with more aggressive
criteria of MSSBP o130 mm Hg and MSDBP
o80 mm Hg, the probability of achieving
control was less with each therapy
compared
with
the
less
stringent
criteria of o140 and o90 mm Hg,
respectively. Nevertheless, even with
the more aggressive criteria of MSSBP
o130 mm Hg and MSDBP o80 mm Hg, the
prob- ability of attaining BP control
was greater with combination therapy
compared with monotherapy regardless of
baseline BP (Figures 3c and d). For

Journal of Human
Hypertension

example,
the
probability
of
achieving an MSSBP
o130 mm Hg for a patient with a
baseline MSSBP between 160 and 170 mm
Hg was 38.8% with Val/ HCTZ 320/25 mg,
10.4% with Val 320 mg and 9.7% with
HCTZ 25 mg.

Tolerability of initial therapy

The
overall
incidence
of
AEs
regardless of study drug relationship
in patients initiated on combina- tion
therapy was generally similar to that
observed
in
those
treated
with
monotherapy and placebo (Table 1). The
frequency
of
dizziness
was
dose
dependent within the monotherapy and
combina- tion groups; however, the
incidence with Val/HCTZ 160/12.5 mg
was similar to that observed with Val
320
mg
and
HCTZ
25
mg.
Discontinuations due to AEs ranged
from 3.0 to 4.2% in the Val/HCTZ
combination treatment groups compared
with 2.4% in the placebo group. Six
(1.2%) patients receiving Val/HCTZ and
one (0.6%) patient receiving Val 320
mg
discontinued
therapy
owing to
hypotension
or
orthostatic
hypotension.
Three
(0.6%)
patients
receiving
Val/HCTZ,
one
(0.6%)
receiving Val 320 mg and one (0.6%)
receiving placebo discontinued therapy
because of

Rapid BP control with Val/HCTZ initial therapy

MH Weinberger et al

Figure 3 Probability of achieving MSSBP and MSDBP control at end point (week 8 or LOCF) as a function of
baseline BP by treatment
groups
(intent-to-treat
population).
(a) 136
MSSBP o140
mm Hg;
143o90
for Val/HCTZ
126 Val/HCTZ
for Val
monotherapy,
133
for
monotherapy 164
and
placebo.
(b) Nand
MSDBP
Hg; N(c)
group,
167 for
group,
165
for
ValHCTZ
monotherapy,
for for
HCTZ
monotherapy
for mm
placebo.
o130 mm (d)
Hg;
N 164
for
Val/HCTZ
group,
160
for Val
monotherapy,
157 monotherapy,
for HCTZ 165
monotherapy
and monotherapy
156 MSSBP
for placebo.
MSDBP
o80
mm
Hg;
N

167
for
Val/HCTZ
group,
166
for
Val
164
for
HCTZ
and
165
for placebo.

Journal of Human
Hypertension

Table 1 Incidence of the most frequent adverse events regardless of relationship to study drug (X4% for
Val/HCTZ 320/25 mg group)

SAEs
D/C due to AEs
AEs
Dizziness
Cough
URTI
Arthralgia
Fatigue
Headache
Nasopharyngiti
s

in

the

Val/HCT
Z 320/25
mg (N
167)

Val/HCTZ
320/12.5 mg
(N 168)

0 (0.0)
5 (3.0)
97
(58.1)
16
(9.6)
10 (6.0)
9 (5.4)
8 (4.8)
7 (4.2)
7 (4.2)
7 (4.2)

1 (0.6)
5 (3.0)
103
(61.3)
12
(7.1)
1 (0.6)
9 (5.4)
1 (0.6)
4 (2.4)
10 (6.0)
15 (8.9)

safety populationa
Val/HCTZ
160/12.5 mg
(N 168)

Val 320 mg

Val 160 mg

HCTZ 25 mg

(N 169)

(N 166)

(N 166)

1
7
99
10
3
7
3
5
11
11

2 (1.2)
12 (7.1)
105
(62.1)
8
(4.7)
6 (3.6)
11 (6.5)
5 (3.0)
6 (3.6)
12 (7.1)
5 (3.0)

(0.6)
(4.2)
(58.9)
(6.0)
(1.8)
(4.2)
(1.8)
(3.0)
(6.5)
(6.5)

2 (1.2)
2 (1.2)
94
6(56.6)
(3.6)
3 (1.8)
7 (4.2)
4 (2.4)
2 (1.2)
12 (7.2)
14 (8.4)

1
3
86
9
2
9
0
6
13
4

HCTZ
12.5 mg
(N
169)

(0.6)
2 (1.2)
(1.8)
4 (2.4)
(51.8)
91
(5.4)
4(53.8)
(2.4)
(1.2)
4 (2.4)
(5.4)
7 (4.1)
(0.0)
4 (2.4)
(3.6)
5 (3.0)
(7.8) 14 (8.3)
(2.4)
8 (4.7)

Placebo
(N
169)
0 (0.0)
4 (2.4)
89
4(52.7)
(2.4)
2 (1.2)
7 (4.1)
3 (1.8)
3 (1.8)
22
4(13.0)
(2.4)

Abbreviations: AE, adverse event; D/C, discontinuations, HCTZ, hydrochlorothiazide; SAE, serious adverse event; URTI,
upper respiratory tract infections; Val, valsartan.
Values are no. (%) of patients.
a
All randomized patients who had received at least one dose of study drug.

dizziness. The incidence of serious

AEs was low in the Val/HCTZ groups (0
0.6%).

Discussion
This post hoc analysis of a randomized,
doubleblind,
placebo-controlled,
multifactorial, parallel- group study
showed that initial therapy with the
dual combination of Val/HCTZ produced
an
B1.5fold
greater
number
of
patients (74.9% vs 48.8 and 51.8%)
achieving a target BP of o140/90 mm Hg
and a three-fold greater number of
patients (30.5% vs
10.8
and
9.2%)
achieving
a
more
aggressive target BP of o130/80 mm Hg
compared
with
Val
or
HCTZ
monotherapies. This enhanced efficacy
with initial combination therapy was
observed as early as 2 weeks after
starting therapy and the combination
was
well
tolerated
compared
with
monotherapy.
Furthermore,
the
probability of achieving BP goal was
greater
with
combination
therapy
irrespective of baseline BP.
These
results
provide
important
comparative
data
for
practicing
physicians
in
determining
whether
initial therapy is appropriate for a
given patient. For patients with lower
baseline
BP,
both
Val
and
HCTZ
monotherapy provided good BP control
in the majority of patients. For
patients with higher base- line BP,
reaching goal with monotherapy was
less
likely
and
the
benefit
of
Val/HCTZ
combination
relative
to
monotherapy was even more evident with
greater treatment differences in BP
goal rates and BP reductions. These
data are consistent with the current
Seventh Report of the Joint National
Com- mittee on Prevention, Detection,
Evaluation, and Treatment of high BP,
as well as the updated ESH/ ESC
(European
Society
of
Hypertension/European
Society
of
Cardiology)
hypertension
treatment
guidelines, which recommend initial
therapy with two drugs in patients
with SBP levels 420 mm Hg
cerebrovascular
complications
death.1315

above goal or DBP level 410 mm Hg above

goal or in patients at high CV risk
because of the presence of target organ
damage, diabetes, renal disease
or a
history
of
CV
disease.2,21
As
hypertension
is
a
multifactorial
disease, disruption of a single physiological
mechanism
is
often
insufficient to control BP. Indeed, only
4050%
of
patients
treated
with
monotherapy, which target a single
physiological
pathway,
have
been
reported to achieve goal BP. Therefore,
a combination of two drugs with different, but complementary, modes of action
is
supported
by
hypertension
guidelines
to achieve effective BP
2,5,22,23
control.
In fact, our data suggest
that
select
patients
with
higher
baseline BP may require the addition of
a third agent. Indeed, the need for
three agents in combination to reach
target goals has been demonstrated
by
several
large-scale
trials.8,2426
In
moderate
and
severe
hypertensive
patients,
triple
therapy
with
the
combination of amlodipine/Val/HCTZ has
been shown to produce significantly
greater BP reductions than dual therapy with amlodipine/Val,
Val/HCTZ or
amlodipine/ HCTZ.27
In a previously reported study by
Calhoun et al.,28 the primary objective
was to compare initial therapy with
Val/HCTZ combination therapy with Val
monotherapy in patients with severe
hypertension.
Patients
initiated
therapy with either Val 160 mg or
Val/HCTZ 160/12.5 mg and were forcetitrated to Val 320 mg and Val/HCTZ
320/25 mg, respectively. At the end of
the 6-week study, significantly more
patients achieved BP control and had
greater BP reductions with combination
therapy
than
with
monotherapy.
BP
control rates were also greater with
the combination regimen as early as 2
weeks after initiating therapy. This
prompt
reduction
in
BP
with
the
combination of Val/HCTZ was observed
in our current post hoc analyses. Several
large clinical studies have shown that
prompt BP reduc- tion is associated
with a reduced risk of CV and

and

In
addition,
the
aggressive reduction

prompt
and
of BP may

have an important role in the subsequent

antihypertensive
response
to
the
addition of other agents. For example,
in
SCOPE
(Study
on
Cognition
and
Prognosis in the Elderly) and the ASCOTBPLA
(Anglo-Scandinavian
Cardiac
Outcomes Trial-Blood Pressure Lowering
Arm) trial, the treatment group that had
a smaller initial BP reduction failed to
achieve BP reduction compared with the
other treatment group in the long term,
despite
the
addition
of
other
antihypertensive
agents
to
achieve
14,29
target BP.
Despite the need to achieve a prompt
reduction in BP in patients with higher
baseline BP, physicians are reluctant to
prescribe higher doses of mono- therapy
or
combination
therapy
because
of
potential
adverse
effects.
This
hesitancy
by
physicians
to
change
and/or intensify treatment is often
referred30,31to as therapeutic or clinical
inertia.
Initiating
therapy
with
monotherapy
with
subsequent
dose
escalations that require multiple office
visits
may
result
in
a
loss
of
compliance as well as a patients
confidence in the treatment plan. The
updated ESH/ ESC guidelines favour the
use
of
combination
of
two
antihypertensive agents in a single
pill, as reducing the number of pills
results in improved compli- ance. 21,32
Thus, using a single pill combination
of Val/HCTZ would be a valuable first
treatment step in patients with either
high initial BP or those at high CV
risk requiring a lower BP target. The
availability
of
different
dose
combinations of the same two drugs
further facilitates and simplifies the
approach of a single pill combination
therapy for management of hypertension.
Initial therapy with Val/HCTZ was
well
tolerated
in
the
overall
population in the current study. The
combination did not present
any
additional
safety concerns compared
with monotherapy and the risks were
manageable. Hypokalaemia asso- ciated
with
higher
doses
of
HCTZ
was
attenuated with the co-administration
of Val and HCTZ
as

therapy and the individual patients

goal BP that is
based on their CV risk profile. Data
from our analyses support the favourable
benefit:risk profile of Val/HCTZ as
initial therapy in patients likely to
need multiple drugs to achieve BP goal.
The subsequent addition of a third agent
may be required in select patients.

Conclusions
Initial
therapy
with
the
dual
combination of Val/ HCTZ allowed a
greater number of patients to achieve
goal BP compared with both Val and HCTZ
monotherapies. Greater efficacy with the
dual combination was observed as early
as 2 weeks after starting therapy.
Initiating therapy with Val/HCTZ was
well
tolerated
compared
with
monotherapy.
Furthermore,
the
probability of achieving BP goal was
greater
with
combination
therapy
irrespective of baseline BP or target BP
goal.
Initiating
antihypertensive
therapy with Val/HCTZ is an appropriate
therapeutic option in patients likely to
need multi- ple drugs to achieve BP
goal.
What is known about this topic
K Current guidelines are in agreement that
aggressive therapy, using two or more
antihypertensive agents, is required to
reduce CV morbidity and mortality in 26
patients with significantly elevated BP.
K Studies have shown that the combination of an
angiotensin receptor blocker, such as
valsartan (Val), with the diuretic
hydrochlorothiazide (HCTZ), has enhanced
efficacy compared with component
monotherapies and is well
tolerated in
hypertensive patients;1720 and, the singlepill combination has been recently approved
in the United States as initial therapy.
What this study adds
K To enable clinicians to make better
informed decisions for the treatment of
individual patients, this current report
evaluates the benefit:risk profile of
starting antihypertensive therapy with the
dual combination treatment Val/HCTZ based
on post hoc analyses assessing BP goals as a
function of baseline BP.

reported previously.17
A limitation to this report is the fact
that the efficacy analyses were not
pre-specified and the
Conflict of interest
clinical trial was not specifically
designed to
address the objectives of
MH Weinberger has received research
this report. The probability estimates
support as a study investigator from
of reaching goal are less reliable at
Novartis Pharmaceuticals Corporation. RD
higher baseline BPs because of the small
Glazer, NA Crikelair and YT Chiang are
numbers of patients in this range. The
employed by Novartis Pharmaceuticals
8-week double-blind period of the trial
Corpora- tion, East Hanover, NJ, USA.
limits the predictive value on longerterm therapy. Another limitation was the
lack of a formal analysis of compliance
or adherence to the treatment regimen.
In summary, patients with higher
levels of BP, for example, stage 2
Acknowledgements
hypertension, are at greater risk for
adverse clinical outcomes. Practicing
This study was funded by Novartis
physicians
must
evaluate
whether
Pharmaceuticals
Corporation,
East
initiating dual combination therapy is
Hanover, NJ, USA. The sponsor was
warranted on an individual patient
involved in the design of the study and
basis
based
on
baseline
BP,
the
collection
of
data;
and
Novartis
likelihood of achieving goal with
monotherapy compared with combination
statisticians per- formed the post hoc
analysis of the data. We
had
access to all study data and were
paper. We thank Ramya Rajagopal, PhD and
responsible for the
Ashish Agarwal, PhD (Novartis, India) for
editorial and writing assistance on this
interpretation of data, the reporting
paper.
of the study and the decision to
approve submission of the finished

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