AJH 2007; 20:807– 815
Time to Achieve Blood-Pressure Goal:
Influence of Dose of Valsartan Monotherapy
and Valsartan and Hydrochlorothiazide
Combination Therapy
Matthew R. Weir, Drew Levy, Nora Crikelair, Ricardo Rocha, Xiangyi Meng,
and Robert Glazer
Background: Our objective was to assess time to
achieve blood-pressure (BP) goal with incremental doses
of valsartan alone, and together with hydrochlorothiazide
(HCTZ), in patients with uncomplicated hypertension.
Methods: This analysis pooled patient-level data from
nine randomized, double-blind, fixed-dose, placebo-con-
trolled trials (N ⫽ 4278) of once-daily valsartan 80 mg,
160 mg, and 320 mg, and valsartan/hydrochlorothiazide
(HCTZ) 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5
mg, and 320/25 mg. Kaplan-Meier methods estimated the
cumulative proportion of patients achieving BP ⬍140/90
mm Hg over 8 weeks and the median time to BP goal. The
HCTZ 12.5-mg and 25-mg doses were pooled for the
time-to-goal analysis in patients receiving combinations
with valsartan 160 mg or 320 mg.
Results: Overall, the median time-to-goal was 8.1 weeks
with valsartan 160 mg, 6.1 weeks with valsartan 320 mg, 2.6
weeks with valsartan 160 mg/HCTZ, and 2.1 weeks with
valsartan 320 mg/HCTZ. In patients with stage 2 hyperten-
sion, the median time-to-goal was 4.3 weeks with valsartan
he use of antihypertensive agents to lower blood
T pressure (BP) decreases the risk of cardiovascular
events,1 and greater BP reductions result in im-
proved clinical outcomes.2,3 Traditionally, a cautious
(“start low, go slow”) approach to dose titration of anti-
hypertensive agents was advocated to avoid hypotension
and other dose-related adverse events. However, the re-
sults of recent clinical trials suggest that time-to-treatment
effect may significantly influence cardiovascular out-
comes.4 –7 Current guidelines support aggressive BP tar-
gets for patients at high risk and the use of aggressive
therapy to attain these goals in a timely manner.1
Received November 14, 2006. First decision December 24, 2006. Ac-
cepted February 23, 2007.
From the Division of Nephrology (MRW), Department of Medicine,
University of Maryland School of Medicine, Baltimore, Maryland; and
Novartis Pharmaceuticals Corporation (DL, NC, RR, XM, RG), East
© 2007 by the American Journal of Hypertension, Ltd.
Published by Elsevier Inc.
160 mg/HCTZ and 2.4 weeks with valsartan 320 mg/HCTZ.
Goal rates by Week 4 for valsartan/HCTZ exceeded rates by
Week 8 with the same doses of valsartan alone. Overall, the
proportion that achieved BP goal by Week 8 was 32.6% with
valsartan 80 mg, 48.4% with valsartan 160 mg, 54.2% with
valsartan 320 mg, 74.6% with valsartan 160 mg/HCTZ, and
84.8% with valsartan 320 mg/HCTZ, versus 24.2% with
placebo. With valsartan 320 mg/HCTZ, 75.8% of stage 2
patients and 94% of stage 1 patients reached BP goal by
Week 8. Discontinuation rates due to adverse events were
generally low across doses.
Conclusions: In both stage 1 and stage 2 hypertension,
BP control is achieved more frequently and promptly when
patients receive higher doses of valsartan monotherapy or
valsartan combination therapy, with a favorable benefit-risk
profile. Am J Hypertens 2007;20:807– 815 © 2007 Amer-
ican Journal of Hypertension, Ltd.
Key Words: Blood-pressure control, combination ther-
apy, hydrochlorothiazide, hypertension, valsartan.
The Seventh Report of the Joint National Committee on
the Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure (JNC 7) recommends considering
the initiation of antihypertensive therapy with more than
one agent among patients requiring BP reductions ⬎20/10
mm Hg.1 Most patients at high risk will require ⱖ2 anti-
hypertensive agents to achieve their BP goal, and the use
of combination therapy may allow goal achievement in a
shorter time than monotherapy.1 In addition, earlier treat-
ment efficacy may contribute to improving patient adher-
ence, which is essential for the reduction of cardiovascular
risk.8
Hanover, New Jersey.
Address correspondence and reprint requests to Dr. Matthew R. Weir,
Division of Nephrology, Department of Medicine, University of Mary-
land School of Medicine, 22 South Greene street, Room N3W143,
Baltimore, MD 21201; e-mail: mweir@medicine.umaryland.edu
0895-7061/07/$32.00
doi:10.1016/j.amjhyper.2007.02.017
808 TIME TO BLOOD PRESSURE GOAL WITH VALSARTAN AND VALSARTAN/HCTZ AJH–July 2007–VOL. 20, NO. 7

Angiotensin II Type 1 receptor blockers (ARBs) effec-
tively lower BP with a low incidence of adverse events.9
The accumulated evidence from large clinical-outcome
trials suggests that higher doses of ARBs are associated
with greater reductions in cardiovascular risk,10 and that
selecting the appropriate dose may be as important as the
choice of antihypertensive agent.11 Studies demonstrated
that the addition of hydrochlorothiazide (HCTZ) augments
the BP-lowering efficacy of ARBs, without a substantial
increase in adverse events.12–15 Few analyses, however,
aggregated data from multiple trials to evaluate the dose
response of an ARB alone and in combination with HCTZ
for lowering BP in large numbers of patients across the
full range of available doses.16,17 Furthermore, few studies
evaluated the relationship between the dosing of ARBs
and the time to achieve BP goal.7 The degree of BP
reduction that clinicians may expect with increasing doses
of ARB monotherapy and ARB/HCTZ combination ther-
apy and the time to achieve such reductions are not well
defined.
The purpose of the current analysis was to estimate the
time to achieve target BP levels with fixed doses of the
ARB valsartan alone and combined with HCTZ, based on
patient-level data pooled from nine randomized, double-
blind, placebo-controlled, fixed-dose trials. The studies
included in this analysis were designed to evaluate fixed
doses of valsartan monotherapy and combination therapy
and therefore did not permit forced or optional dose titra-
tion. Analyses of patient-level data pooled from clinical
trials allow for integration of the totality of relevant data,
improvements in the reliability of data, and the ability to
explore the relationship between patient characteristics
and response.18 Finally, pooled data from multiple trials
provide sufficient observations over the duration of the
treatment period to use survival analysis methods to esti-
mate time to BP goal.
Methods
Design of Analysis
The selection of studies for inclusion in this analysis was
based on the following criteria: randomized, parallel-
group, placebo-controlled design; placebo run-in phase;
administration of daily doses of valsartan or valsartan/
HCTZ; a duration of at least 4 weeks and a maximum
of 8 weeks with no dose titration; and no administration of
supplemental antihypertensive medication. A total of nine
of 17 available trials met the inclusion criteria, and all had
similar eligibility criteria (Table 1). All trials had a 2- to
4-week placebo run-in period before randomization, fol-
lowed by a double-blind treatment period of 4 weeks in
one trial, 6 weeks in one trial, and 8 weeks in the remain-
ing seven trials. In all nine trials, the primary end point for
the original analyses was mean diastolic BP (DBP) at the
end of the study (measured with patients seated in eight
trials, and supine in one trial). The results of seven of these
trials were published.19 –25
The current analysis included patients who received
daily doses of valsartan (80, 160, or 320 mg) or valsartan/
HCTZ (80/12.5, 160/12.5, 160/25, 320/12.5, or 320/25
mg) that are currently marketed for the treatment of hy-
pertension. Patients received a fixed dose of valsartan or
valsartan/HCTZ, with the exception of the valsartan/
HCTZ 320/12.5-mg and 320/25-mg arms, in which pa-
tients received valsartan/HCTZ 160/12.5 mg for the first
week after randomization and were then force-titrated to
higher doses. Although four studies evaluated other anti-
hypertensive agents, only patients receiving valsartan in

Table 1. Multicenter, randomized, double-blind, placebo-controlled, parallel-group trials included in the

meta-analysis

Duration of No. randomized

treatment
(wk) Doses (mg)* Eligibility Val ⴞ HCTZ Placebo
4 Val: 80, 160 DBP ⱖ95 and ⱕ115 mm Hg, 18 to 70 y 46 25
6 Val: 80 DBP ⱖ95 and ⱕ115 mm Hg, 18 to 80 y 112 111
8 Val: 80, 160 DBP ⬎95 and ⬍115 mm Hg, ⱖ65 y 283 144
8 Val: 80, 160, 320 DBP ⱖ95 and ⱕ115 mm Hg, 21 to 80 y 445 145
8 Val: 80 DBP ⱖ95 and ⱕ115 mm Hg, 20 to 79 y 136 142
8 Val: 80, 160 DBP ⱖ95 and ⱕ115 mm Hg, 18 to 80 y 482 93
Val/HCTZ: 80/12.5,
160/12.5, 160/25
8 Val: 80, 160, 320 DBP ⱖ95 and ⬍110 mm Hg, ⱖ18 y 378 127
8 Val: 160, 320 DBP ⱖ95 and ⬍110 mm Hg, ⱖ18 y 833 165
Val/HCTZ: 160/12.5,
320/12.5, 320/25
8 Val: 160, 320 DBP ⱖ95 and ⬍110 mm Hg, ⱖ18 y 406 205
Total 3121 1157

DBP ⫽ diastolic blood pressure; HCTZ ⫽ hydrochlorothiazide; SBP ⫽ systolic blood pressure; Val ⫽ valsartan.
* Indicates only those doses evaluated in the original studies that are included in the analysis.
AJH–July 2007–VOL. 20, NO. 7 TIME TO BLOOD PRESSURE GOAL WITH VALSARTAN AND VALSARTAN/HCTZ
doses of ⱖ80 mg alone or in combination with HCTZ
were included in this analysis.
This secondary analysis of data pooled from multiple
trials was intended to evaluate time-to-goal for various
approaches to treatment involving valsartan, but was not
designed, as in a single, sufficiently powered, randomized
trial, to make definitive dose-versus-dose comparisons.
Imbalances in the contribution of various trials to the
combination-therapy arms confounded the comparison of
the valsartan/HCTZ 320/12.5-mg versus 320/25-mg doses
and the valsartan/HCTZ 160/12.5-mg versus 160/25-mg
doses. Whereas the higher dose of the diuretic produced a
greater response than the lower dose in the primary effi-
cacy analyses in the two original trials that evaluated the
valsartan 160-mg and 320-mg combination doses,22,25 a
dose response was not observed in the current analysis.
Therefore, to simplify the presentation of the results of the
time-to-goal analysis, the valsartan/HCTZ 160/12.5-mg
and 160/25-mg doses were combined, as were the valsar-
tan/HCTZ 320/12.5-mg and 320/25-mg doses.
In all studies, systolic BP (SBP) and DBP were mea-
sured at trough (24 h postdose) at 2-week or 4-week
intervals using a sphygmomanometer. Three of the nine
studies did not have measurements available at 2 weeks
after randomization. The efficacy variable for this analysis
was the first time to achieve the JNC 7 goal for patients
with uncomplicated hypertension,1 defined as BP ⬍140/90
mm Hg. The efficacy variable was analyzed for the overall
population and by hypertension stage according to JNC 7
classification. Stage 1 hypertension was defined as SBP
140 to ⬍160 and DBP 90 to ⬍100 mm Hg. Stage 2 hyper-
tension was defined as SBP ⱖ160 or DBP ⱖ100 mm Hg.1
Statistical Methods
The analysis comprised descriptive summaries of patient-
level data pooled from the nine eligible trials. The efficacy
analysis was based on the intent-to-treat (ITT) population
(N ⫽ 4278), which included patients who received at least
one dose of the randomized trial drug (valsartan, valsartan/
HCTZ, or placebo) and had baseline and at least one
postbaseline BP measurements. The Kaplan-Meier prod-
uct-limit estimator26 –28 method was used to estimate the
cumulative proportion of patients achieving their BP goal
at each week (from weeks 2 to 8), with 95% confidence
intervals (CIs), for the ITT population overall and for the
hypertension stage subgroups. Kaplan-Meier curves were
constructed to illustrate the cumulative proportion of pa-
tients achieving their BP goal as a function of time over 8
weeks of treatment. The time point at which 50% of
patients reach end point (median time-to-goal) is the esti-
mate conventionally used to compare groups with Kaplan-
Meier methodology. The median time-to-goal and 95%
CIs were calculated as the time at which 50% of patients
achieved their BP goal. Because Kaplan-Meier analysis
was based on the actual number of days from time of
809
randomization, two patients without a recorded visit date
were not included in the efficacy calculations.
Adverse events were summarized, regardless of rela-
tionship to treatment, for all patients randomized to the
doses of interest who received at least one dose of study
drug in the nine trials included in this analysis. If a patient
experienced more than one episode of an adverse event,
that patient was counted only once for each type of event.
Results
Patients
Baseline characteristics for the ITT population are shown
in Table 2. The mean age ranged from 51.7 years in the
valsartan/HCTZ 80/12.5-mg group to 57.1 years in the
valsartan 80-mg group. Percentages of men and women
were comparable across dose groups. For other baseline
characteristics, there was some variation across doses.
Because patients were selected for baseline DBP levels in
all trials, there appeared to be somewhat greater variation
in baseline SBP than in DBP values across dose groups.
Time to JNC 7 Goal
The cumulative proportion of patients achieving their JNC
7 goal of ⬍140/90 mm Hg by specific time points (2, 4,
and 8 weeks) for the overall ITT population is shown in
Fig. 1. Within each dose group, including placebo, goal
rates increased over time for the three time points ana-
lyzed. Rates of achieving BP goal generally increased
across dose groups with incremental valsartan mono-
therapy and valsartan/HCTZ doses at each of the three
time points analyzed. By Week 8, the proportion of pa-
tients achieving their JNC 7 goal was 48.4% with valsartan
160 mg and 54.2% with valsartan 320 mg, versus 32.6%
with valsartan 80 mg and 24.2% with placebo. With com-
bination therapy, 74.6% achieved their JNC 7 goal with
valsartan 160 mg/HCTZ, and 84.8% with valsartan 320
mg/HCTZ, by Week 8.
Increasing doses of valsartan and valsartan/HCTZ con-
sistently facilitated achieving JNC 7 goals at earlier time
points. In the overall population, the JNC 7 goal rate with
valsartan 160 mg by 4 weeks was comparable to that with
80 mg by 8 weeks (approximately 33%). At every dose
level and for each time point, combination therapy facili-
tated earlier goal achievement compared with mono-
therapy. Goal rates by Week 4 for the 80-mg, 160-mg, and
320-mg combination doses exceeded rates by Week 8 with
the same monotherapy doses. For example, 56.4% of
patients achieved their JNC 7 goal with valsartan 160
mg/HCTZ by 4 weeks versus 48.4% with valsartan 160
mg by 8 weeks.
Kaplan-Meier estimates of the proportion of patients
achieving their JNC 7 goal over the study period in the
ITT population overall and by hypertension stage are
shown in Figs. 2, 3, and 4. The general pattern of earlier
achievement of JNC 7 goal with incrementally higher
810 TIME TO BLOOD PRESSURE GOAL WITH VALSARTAN AND VALSARTAN/HCTZ AJH–July 2007–VOL. 20, NO. 7

doses of valsartan and valsartan/HCTZ, and of increasing

53.6 ⫾ 11.1

11.7

10.5
320/25 mg

3.6
8.6
1.4

3.8
20 (12.0)

78 (46.7)
89 (53.3)

(68.9)
(19.8)
(11.4)
(55.1)
(47.9)
(52.1)
(n ⴝ 167)
Val/HCTZ

BMI ⫽ body mass index (kg/m2); DBP ⫽ diastolic blood pressure; HCTZ ⫽ hydrochlorothiazide; ITT ⫽ intent-to-treat; SBP ⫽ systolic blood pressure; SD ⫽ standard deviation; Val ⫽ valsartan.
BP control within dose groups over time, was observed

⫾
⫾
⫾
⫾
⫾
⫾
overall and in patients with stage 1 or stage 2 hyperten-

152.5
99.2
145.6
97.0
158.8
101.3
115
33
19
92
80
87
sion. Across the 8-week study period, the 320-mg combi-
nation doses resulted in a greater proportion of patients
reaching their goal at earlier time points than all other
320/12.5 mg

52.1 ⫾ 11.4

12.7

11.0
3.7
9.1
1.6

3.6
21 (12.5)

87 (51.8)
81 (48.2)

(68.5)
(20.8)
(10.7)
(54.8)
(51.8)
(48.2)
(n ⴝ 168)
Val/HCTZ

doses. In the stage 1 subgroup, similar goal rates were

⫾
⫾
⫾
⫾
⫾
⫾
observed at end of the study with the 160-mg and 320-mg

101.7
150.7
99.2
143.2
96.8
158.7
115
35
18
92
87
81
combination doses.
In terms of time-specific prevalence of goal achieve-
ment, the magnitude of effect was greater in the stage 1
55.0 ⫾ 11.3

12.8

11.3
than in the stage 2 subgroup, which, by definition, had

4.1
8.7
1.8

3.9
129 (20.0)

360 (55.7)
286 (44.3)

(76.9)
(10.7)
(12.4)
(44.9)
(42.0)
(58.0)
(n ⴝ 646)
320 mg

higher mean BP at baseline. Among stage 1 patients,

Val

⫾
⫾
⫾
⫾
⫾
⫾
72.0% and 74.7% achieved their JNC 7 goal by Week 8
153.4
99.6
144.5
96.6
159.8
101.8
497
69
80
290
271
375

with valsartan 160 mg and 320 mg, respectively, versus

56.8% with valsartan 80 mg and 45.7% with placebo. With
valsartan/HCTZ, 92% to 94% of stage 1 patients reached
52.6 ⫾ 11.1

14.8

12.1
160/25 mg

4.8
8.4
1.3

4.7
Val/HCTZ

17 (18.1)

51 (54.3)
43 (45.7)

(72.3)
(16.0)
(11.7)
(50.0)
(37.2)
(62.8)
(n ⴝ 94)

their goal with the 160-mg and 320-mg combination

⫾
⫾
⫾
⫾
⫾
⫾

doses, respectively. In the stage 2 subgroup, 60.6% of

155.9
101.4
142.9
97.5
163.6
103.7
68
15
11
47
35
59

patients achieved their goal with valsartan 160 mg/HCTZ

and 75.8% with valsartan 320 mg/HCTZ by Week 8,
compared with 12.2% of patients receiving placebo. A
160/12.5 mg

53.0 ⫾ 10.6

13.5

12.5
4.0
9.4
1.5

4.1
41 (15.7)

153 (58.6)
108 (41.4)

(73.6)
(17.6)

(55.9)
(47.1)
(52.9)
(n ⴝ 261)
Val/HCTZ

substantially higher percentage of patients in this subgroup

(8.8)

⫾
⫾
⫾
⫾
⫾
⫾

achieved their BP goal by 4 weeks with the 320-mg

151.6
99.8
143.5
97.2
158.9
102.1
192
46
23
146
123
138

combination doses (52.7%) than by 8 weeks with 320-mg

monotherapy (39.4%).
The median time to achieve JNC 7 goal (ie, the time
56.5 ⫾ 12.9

15.6

14.2

point at which 50% of patients reached their goal) is

4.3
9.5
1.4

4.3
284 (31.3)

467 (51.5)
440 (48.5)

(79.5)

(11.4)
(42.8)
(39.3)
(60.7)
(n ⴝ 907)
160 mg

(9.2)

shown in Table 3. Overall, the median time-to-goal was

Val

⫾
⫾
⫾
⫾
⫾
⫾

approximately 8 weeks with valsartan 160 mg and valsar-

155.5
100.1
144.0
97.0
162.9
102.1
721
83
103
388
356
551

tan/HCTZ 80/12.5 mg, 6 weeks with valsartan 320 mg, 3

weeks with the 160-mg combinations, and 2 weeks with
14.4

12.3

the 320-mg combination doses. In patients with stage 1

51.7 ⫾ 11.9
80/12.5 mg

4.9
9.5
1.4

4.9
Val/HCTZ

14 (14.6)

58 (60.4)
38 (39.6)

(71.9)
(12.5)
(15.6)
(51.0)
(41.7)
(58.3)
(n ⴝ 96)

hypertension, the median time-to-goal was approximately

⫾
⫾
⫾
⫾
⫾
⫾

6 weeks for valsartan 80 mg, 3 weeks for valsartan 160

153.0
101.0
142.3
97.4
160.7
103.5
69
12
15
49
40
56
Table 2. Patient baseline characteristics: ITT population

mg, and 2 weeks for the combinations doses. In patients

with stage 2 hypertension, the median time-to-goal was
⬎8 weeks with monotherapy; with combination therapy,
57.1 ⫾ 12.4

15.8

14.9
4.4
9.0
1.6

4.2
252 (32.2)

422 (54.0)
360 (46.0)

(88.1)

(39.5)
(31.5)
(68.5)
(n ⴝ 782)

(7.0)
(4.9)

the median time-to-goal was approximately 4 weeks with

80 mg
Val

⫾
⫾
⫾
⫾
⫾
⫾

valsartan 160 mg/HCTZ and 2 weeks with the 320-mg

102.4
158.3
100.7
145.9
96.9
164.0
689
55
38
309
246
536

combination doses.
56.3 ⫾ 12.6

15.5

14.2

Tolerability
(n ⴝ 1157)

4.3
9.7
1.4

4.3
343 (29.6)

607 (52.5)
550 (47.5)

(83.9)

(38.4)
(35.4)
(64.5)
Placebo

(7.5)
(8.6)

Adverse events occurring in ⱖ3% of any dose group are

⫾
⫾
⫾
⫾
⫾
⫾
156.3
100.2
144.8
96.9
162.7
102.1
971
87
99
444
409
746

shown in Table 4, presented in descending order of fre-

quency according to incidence in the highest combination
dose group. Overall, the most common adverse event was
Mean SBP/DBP (mm Hg) ⫾ SD

dizziness, which occurred in 2.4% to 5.2% of patients in

the valsartan monotherapy groups, 7.3% to 16.0% in the
valsartan/HCTZ groups, and 2.8% in the placebo group.
Parameter

Mean age (y) ⫾ SD

The incidence of headache was similar across all dose

Age ⱖ65 y, n (%)

BMI ⱖ30, n (%)

groups, including placebo. Fatigue occurred at similar

Stage 1, n (%)
Stage 2, n (%)

rates among patients receiving placebo or monotherapy

Race, n (%)
Sex, n (%)

Stage 1

Stage 2
Female

Overall

and was somewhat increased among patients receiving

White

Other
Black
Male

combination therapy. The incidence of peripheral edema

was low and similar across dose groups, ranging from
AJH–July 2007–VOL. 20, NO. 7 TIME TO BLOOD PRESSURE GOAL WITH VALSARTAN AND VALSARTAN/HCTZ 811

FIG. 1. Cumulative proportion of patients in the intent-to-treat population (N ⫽ 4278) achieving their JNC 7 goal of ⬍140/90 mm Hg by 2,
4, and 8 weeks (wk) of treatment using the Kaplan-Meier method. HCTZ ⫽ hydrochlorothiazide.

0.4% with valsartan/HCTZ 160/12.5 mg to 2.4% with
valsartan/HCTZ 320/12.5 mg and 320/25 mg, compared
with 2.0% with placebo. The rate of discontinuation be-
cause of adverse events was generally low at all doses
analyzed.
Discussion
The Kaplan-Meier approach applied to data pooled from
nine randomized, placebo-controlled trials and involving
⬎4000 patients improves our ability to describe the rela-
tionship between dose and time to achieving BP goal. The
results suggest that more prompt effects were attained with
increasing doses of valsartan monotherapy and combina-
tion valsartan/HCTZ. The 160-mg and 320-mg doses of
valsartan facilitated an earlier achievement of BP goal
compared with valsartan 80 mg, with and without the
addition of the diuretic, overall and in patients with stage
1 and stage 2 hypertension. Rates of achieving BP goal by
Week 4 with valsartan 160-mg monotherapy and valsartan
160-mg combination doses approximated those by Week 8
for the valsartan 80-mg monotherapy and valsartan/HCTZ
80/12.5-mg doses, respectively, for the ITT population
overall and for both subgroups. In this analysis, dizziness
was reported less frequently with valsartan 160 mg than
with valsartan/HCTZ 80/12.5 mg. The incremental anti-
hypertensive response observed with the addition of
HCTZ 12.5 mg to valsartan 80 mg may come at the cost
of more frequent adverse events (eg, dizziness), which are
common with thiazide diuretics. Thus, when patients who
are started on valsartan 80 mg do not have an adequate BP
response, clinical judgment should be used to determine

FIG. 2. Overall Kaplan-Meier estimates for time-to-goal using the JNC 7 threshold (⬍140/90 mm Hg) in the overall intent-to-treat
population. Number of patients in each dose group: placebo ⫽ 1156; valsartan 80 mg ⫽ 781; valsartan/HCTZ 80/12.5 mg ⫽ 96; valsartan
160 mg ⫽ 907; valsartan 160 mg/HCTZ ⫽ 355; valsartan 320 mg ⫽ 646; valsartan 320 mg/HCTZ ⫽ 335.
812 TIME TO BLOOD PRESSURE GOAL WITH VALSARTAN AND VALSARTAN/HCTZ AJH–July 2007–VOL. 20, NO. 7

FIG. 3. Kaplan-Meier estimates for time-to-goal using the JNC 7 threshold (⬍140/90 mm Hg) in the intent-to-treat population in patients
with stage 1 hypertension. Number of patients in each dose group: placebo ⫽ 409; valsartan 80 mg ⫽ 246; valsartan/HCTZ 80/12.5 mg ⫽
40; valsartan 160 mg ⫽ 356; valsartan 160 mg/HCTZ ⫽ 158; valsartan 320 mg ⫽ 271; valsartan 320 mg/HCTZ ⫽ 167.

whether to add HCTZ 12.5 mg to the regimen or to titrate
the valsartan dose up to 160 mg.
Consistently higher percentages of patients receiving
combination therapy achieved their BP goal at earlier time
points compared with valsartan monotherapy. However, at
all dose levels, the effect of therapy increased over time,
with the largest effect observed at the end of the study (8
weeks). By that time, 74.6% of patients overall had
reached their goal with valsartan 160 mg/HCTZ and
84.8% with 320 mg/HCTZ.
This analysis enables the estimation of the median
time-to-goal that can be expected across the range of
doses. In the overall population, the median time-to-
goal was approximately 8 weeks with valsartan 160 mg,
6 weeks with valsartan 320 mg, 3 weeks with valsartan
160 mg/HCTZ, and 2 weeks with 320 mg/HCTZ.
Among patients with stage 2 hypertension, who are
typically more difficult to treat and require greater BP
reductions to reach goal, the median time-to-goal was
approximately 4 weeks with valsartan 160 mg/HCTZ
and 2 weeks with 320 mg/HCTZ. Although the clinical
benefit derived from achieving BP goal in 2 weeks
versus 8 weeks is unknown, delays in the first months of
treatment were shown in clinical trials to increase car-
diovascular risk.4,5 Prompt treatment effect was also
shown to improve patient adherence to antihypertensive
therapy.8
Regardless of the patient population, BP control was
achieved more frequently and promptly when patients
received combination therapy. In stage 2 patients, only
those receiving higher doses of valsartan combination
therapy were able to achieve control in excess of 50%. In
stage 1, BP control rates ⬎50% were achieved with both
monotherapy and combination therapy, with the greatest
effect being observed with combination therapy and the
higher doses of valsartan monotherapy.
These results may have implications for both reaching
BP goals in the short term and potentially improving

FIG. 4. Kaplan-Meier estimates for time-to-goal using the JNC 7 threshold (⬍140/90 mm Hg) in the intent-to-treat population in patients
with stage 2 hypertension. Number of patients in each dose group: placebo ⫽ 745; valsartan 80 mg ⫽ 535; valsartan/HCTZ 80/12.5 mg ⫽
56; valsartan 160 mg ⫽ 551; valsartan 160 mg/HCTZ ⫽ 197; valsartan 320 mg ⫽ 375; valsartan 320 mg/HCTZ ⫽ 168.
 AJH–July 2007–VOL. 20, NO. 7
Table 3. Median time in weeks (⬍95% confidence interval) to achieve blood pressure goal (⬍140/90 mm Hg): ITT population
Placebo Val 80 mg Val/HCTZ 80/12.5 mg Val 160 mg Val 160 mg/HCTZ Val 320 mg Val 320 mg/HCTZ

Overall NE (n ⫽ 1156*) 9.7 (9.1–NE) (n ⫽ 781) 7.9 (4.1–NE) (n ⫽ 96) 8.1 (7.1–8.3) (n ⫽ 907) 2.6 (2.1–3.9) (n ⫽ 355) 6.1 (4.4–8.0) (n ⫽ 646) 2.1 (2.0–2.1) (n ⫽ 335)
Stage 1 8.3 (8.0–8.4) (n ⫽ 409) 6.0 (4.1–8.0) (n ⫽ 246) 2.4 (2.1–4.1) (n ⫽ 40) 3.1 (2.3–4.1) (n ⫽ 356) 2.14 (NE) (n ⫽ 158) 3.4 (2.1–4.1) (n ⫽ 271) 1.6 (1.3–1.9) (n ⫽ 167)
Stage 2 NE (n ⫽ 745) 9.7 (9.7–NE) (n ⫽ 535) NE (n ⫽ 56) 9.0 (8.6–10.1) (n ⫽ 551) 4.3 (4.1–6.1) (n ⫽ 197) 8.7 (8.1–NE) (n ⫽ 375) 2.4 (2.1–4.1) (n ⫽ 168)

HCTZ ⫽ hydrochlorothiazide; ITT ⫽ intent-to-treat; NE ⫽ not estimable; Val ⫽ valsartan.

* Two patients were not assigned to either the stage 1 or stage 2 subgroup.

TIME TO BLOOD PRESSURE GOAL WITH VALSARTAN AND VALSARTAN/HCTZ

Table 4. Occurrence of most common* adverse events, n (%)

Val Val/HCTZ Val Val/HCTZ Val/HCTZ Val Val/HCTZ Val/HCTZ

Placebo 80 mg 80/12.5 mg 160 mg 160/12.5 mg 160/25 mg 320 mg 320/12.5 mg 320/25 mg
Event (n ⴝ 1169) (n ⴝ 786) (n ⴝ 96) (n ⴝ 915) (n ⴝ 264) (n ⴝ 94) (n ⴝ 656) (n ⴝ 168) (n ⴝ 169)

Dizziness 33 (2.8) 19 (2.4) 7 (7.3) 23 (2.5) 21 (8.0) 15 (16.0) 34 (5.2) 12 (7.1) 16 (9.5)
URTI 25 (2.1) 14 (1.8) 4 (4.2) 21 (2.3) 10 (3.8) 1 (1.1) 22 (3.4) 9 (5.4) 9 (5.3)
Headache 112 (9.6) 48 (6.1) 11 (11.5) 47 (5.1) 22 (8.3) 9 (9.6) 37 (5.6) 10 (6.0) 7 (4.1)
Fatigue 16 (1.4) 11 (1.4) 6 (6.3) 10 (1.1) 8 (3.0) 9 (9.6) 13 (2.0) 4 (2.4) 7 (4.1)
Nasopharyngitis 17 (1.5) 19 (2.4) 1 (1.0) 37 (4.0) 11 (4.2) 1 (1.1) 17 (2.6) 15 (8.9) 7 (4.1)
Nausea 14 (1.2) 12 (1.5) 0 (0.0) 13 (1.4) 2 (0.8) 3 (3.2) 10 (1.5) 3 (1.8) 5 (3.0)
Diarrhea 12 (1.0) 12 (1.5) 2 (2.1) 14 (1.5) 9 (3.4) 2 (2.1) 12 (1.8) 5 (3.0) 4 (2.4)
Back pain 13 (1.1) 15 (1.9) 2 (2.1) 14 (1.5) 9 (3.4) 3 (3.2) 8 (1.2) 3 (1.8) 0 (0.0)
Discontinued because of adverse events 32 (2.7) 14 (1.8) 1 (1.0) 15 (1.6) 10 (3.8) 7 (7.4) 21 (3.2) 5 (3.0) 5 (3.0)

HCTZ ⫽ hydrochlorothiazide; URTI ⫽ upper respiratory tract infection; Val ⫽ valsartan.

* Incidence ⬎3% for any dose, listed in descending order of frequency for the highest combination dose.

813
814 TIME TO BLOOD PRESSURE GOAL WITH VALSARTAN AND VALSARTAN/HCTZ
clinical outcomes in the long term. According to recent
estimates from the National Health and Nutrition Exami-
nation Survey, approximately one-third of all hypertensive
adults in the US and two-thirds of those treated reach JNC
7 goals.29 Recent clinical trials suggest that it is important
to achieve prompt BP control, as this may translate into a
reduction of cardiovascular risk.4 – 6 The current analysis
demonstrates that prompt and substantial BP reductions
are possible in a high percentage of patients, even those
with stage 2 hypertension, and provides an estimate of the
time and magnitude of effect that may be expected with
valsartan monotherapy and combination therapy.
Higher doses of valsartan alone and in combination
with HCTZ were generally not associated with an increase
in adverse events over 8 weeks of treatment. The incidence
of adverse events remained low across doses, with the
possible exception of an increased rate of dizziness at
higher doses that appeared to be related to the diuretic
dose. Furthermore, adverse events commonly associated
with other classes of antihypertensive agents, such as
cough with angiotensin-converting enzyme inhibitors30 –32
and peripheral edema with calcium channel blockers,4,33
occurred infrequently in this patient population.
This analysis is subject to several limitations. This was
a secondary analysis of existing clinical-trial data that was
not designed to make definitive conclusions about differ-
ences in efficacy between doses. There was heterogeneity
among studies, and there may be unknown influences on
trial-specific effect rates. The valsartan/HCTZ 80/12.5-mg
and 160/25-mg dose groups were small and were evalu-
ated in single studies. Another inconsistency across trials
and treatment arms was the availability of Week 2 mea-
surements. However, the bias introduced by these missing
data would be expected to have a minimal impact on
results. The strengths of the dataset are its size, placebo-
controlled design, and lack of bias by not allowing any
dose titration.
Despite its limitations, this analysis contributes to our
understanding of the effect of dose on time to BP goal in
the absence of data from clinical trials designed to address
this question. Aggregating data from multiple studies may
provide better representation of the responses expected to
be observed in clinical practice. The large number of
observations at multiple time points also permits the anal-
ysis of time as a continuous variable, rather than catego-
rization in a limited set of time points with an attendant
loss of information. These results indicate a relationship
between increasing valsartan dose, with and without
HCTZ, and time to achievement of BP goal among hyper-
tensive populations and patient subgroups of interest.
Conclusions
In this pooled analysis of data from nine randomized,
double-blind, placebo-controlled trials of valsartan and
valsartan/HCTZ in uncomplicated hypertension, higher
doses of valsartan alone and combined with a thiazide
AJH–July 2007–VOL. 20, NO. 7
diuretic were more likely to allow patients to achieve their
BP goal and resulted in more rapid achievement of BP
goal than lower doses, with a favorable benefit-risk profile.
The greatest efficacy and the most rapid time-to-goal were
observed in patients receiving the two-drug combination
compared with monotherapy and placebo at all dose lev-
els. An adequate dosing of valsartan, alone and with
HCTZ, has the potential to help a substantial proportion of
patients achieve clinically meaningful BP reductions
within the first few weeks of initiating antihypertensive
therapy.
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