Hypertension Research (2013) 36, 627–633

& 2013 The Japanese Society of Hypertension All rights reserved 0916-9636/13
www.nature.com/hr

ORIGINAL ARTICLE

A meta-analysis of randomized trials of telmisartan vs.

valsartan therapy for blood pressure reduction
Hisato Takagi, Masao Niwa, Yusuke Mizuno, Shin-nosuke Goto and Takuya Umemoto for the ALICE
(All-Literature Investigation of Cardiovascular Evidence) Group

A previous meta-analysis of six randomized head-to-head trials suggests that the blood pressure (BP)-lowering capabilities
of telmisartan may be comparable to those of valsartan. We performed an updated meta-analysis of telmisartan vs. valsartan
therapy for the reduction of BP in hypertensive patients. MEDLINE, EMBASE and the Cochrane Central Register of Controlled
Trials were searched through August 2012 using web-based search engines (PubMed, OVID). Eligible studies were prospective
randomized controlled trials examining telmisartan vs. valsartan therapy and reporting clinic BP as an outcome. For each study,
the data regarding changes from baseline to final clinic systolic BP (SBP) and diastolic BP (DBP) in both the telmisartan and
valsartan groups were used to generate mean differences (MDs) and 95% confidence intervals (CIs). Of the 62 potentially
relevant articles initially screened, 17 reports about prospective randomized controlled clinical trials of telmisartan vs.
valsartan therapy, including a total of 5422 patients with hypertension, were identified and included. Pooled analysis
suggested significant differences in BP reductions among the patients randomized to telmisartan vs. valsartan therapy
(MD for SBP, –2.04 mm Hg; 95% CI, –2.80 to –1.28 mm Hg; Po0.00001; MD for DBP, –1.08 mm Hg; 95% CI, –1.55
to –0.62 mm Hg; Po0.00001). When data from the monotherapy and combination therapy (with hydrochlorothiazide) trials
were pooled separately, telmisartan therapy was associated with a statistically significant difference in BP reductions relative
to valsartan therapy in both the monotherapy and combination therapy groups. In conclusion, telmisartan therapy appears to
reduce BP more than valsartan therapy in patients with hypertension.
Hypertension Research (2013) 36, 627–633; doi:10.1038/hr.2012.233; published online 24 January 2013

Keywords: meta-analysis; randomized controlled trial; telmisartan; valsartan

INTRODUCTION METHODS
Angiotensin II type 1 receptor blockers (ARBs) have different Search strategy
molecular structures that lead to different pharmacological functions. All prospective randomized controlled trials of telmisartan vs. valsartan therapy
For example, telmisartan is the longest-acting ARB currently available, that enrolled patients with hypertension were identified using a two-level
and its mean elimination half-life is approximately 24 h in patients search strategy. First, public domain databases including MEDLINE, EMBASE
with mild-to-moderate hypertension who receive 20–160 mg day 1 and the Cochrane Central Register of Controlled Trials were searched using
web-based search engines (PubMed, OVID). Second, relevant studies were
telmisartan for 4 weeks.1 In addition, valsartan has the highest affinity
identified through a manual search of secondary sources, including references
ratio (30 000-fold) for the angiotensin II type 1 vs. type 2 receptors in of initially identified articles and a search of reviews and commentaries. The
the ARB family.2 On the basis of these findings, it is relevant databases were searched through August 2012. Keywords included telmisartan,
to compare the use of telmisartan with valsartan for blood pressure valsartan, randomized, randomly and randomization. All references were
(BP) reduction. A recent (published in 2010) meta-analysis by downloaded for consolidation, elimination of duplicates and further analysis.
Zeng et al.3 suggests that the BP-lowering capabilities of telmisartan
may be comparable to those of valsartan in monotherapy. When
combined with hydrochlorothiazide (HCTZ), telmisartan is likely Study selection and data abstraction
Studies considered for inclusion met the following criteria: the design was a
more effective than valsartan.3 However, that meta-analysis3 included
prospective randomized controlled clinical trial (including a quasi-randomized
only four randomized controlled trials of telmisartan vs. valsartan in crossover-design study), the study population was patients with hypertension,
monotherapy and two trials of the drugs in combination with HCTZ. patients were randomly assigned to telmisartan vs. valsartan therapy and the
Thus, we performed a more comprehensive literature search and an main outcomes included clinic BP. Data regarding detailed inclusion criteria,
updated meta-analysis of telmisartan vs. valsartan therapy for the duration of follow-up and clinic BP were abstracted (as available) from each
reduction of BP in hypertensive patients. individual study.

Department of Cardiovascular Surgery, Shizuoka Medical Center, Shizuoka, Japan

Correspondence: Dr H Takagi, Department of Cardiovascular Surgery, Shizuoka Medical Center, 762-1 Nagasawa, Shimizu-cho, Sunto-gun, Shizuoka 411-8611, Japan.
E-mail: [email protected]
Received 29 October 2012; revised 19 November 2012; accepted 26 November 2012; published online 24 January 2013
 Telmisartan vs. valsartan for BP reduction
H Takagi et al
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Statistical analysis To assess the impact of qualitative heterogeneity in trial design and
We conducted a meta-analysis of the summary statistics from the individual patient selection on the pooled effect estimate, we performed several
trials because detailed, patient-level data were not available for all trials. For sensitivity analyses. First, we excluded a trial by Georgescu et al.,17
each study, data regarding changes from baseline to final clinic systolic BP which enrolled a population with non-alcoholic steatohepatitis.
(SBP) and diastolic BP (DBP) in both the telmisartan and valsartan groups Second, we excluded a trial by Ichikawa et al.,20 which had a
were used to generate mean differences (MDs) and 95% confidence intervals
duration of only 4 weeks. In general, the exclusion of any single
(CIs). When an MD of BP changes in the two groups itself was reported, we
directly extracted it with its 95% CI. Missing s.d. were imputed according to
trial from the analysis did not substantively alter the overall results of
the Cochrane Handbook.4 Study-specific estimates were combined in both our analysis. In addition, when data from the monotherapy and
fixed- and random-effects models. Between-study heterogeneity was analyzed combination therapy (with HCTZ) trials were pooled separately,
by means of standard w2-tests. Where no significant statistical heterogeneity telmisartan therapy was associated with a statistically significant
was identified, the fixed-effects estimate was used preferentially as the reduction in BP compared with valsartan therapy in both
summary measure. Sensitivity analyses were performed to assess the monotherapy (fixed-effects MD for SBP/DBP, –1.38/–0.76 mm Hg;
contribution of each study to the pooled estimate by excluding individual 95% CI, –2.47 to –0.28/–1.42 to –0.09 mm Hg; P for effect ¼ 0.01/
trials one at a time and recalculating the pooled MD estimates for the 0.03; P for heterogeneity ¼ 0.31/0.57) and combination therapy
remaining studies. To assess the impact of combination therapy with HCTZ on (fixed-effects MD for SBP/DBP, –2.67/–1.40 mm Hg; 95% CI, –3.74
the pooled estimate, the effects of telmisartan therapy on BP changes were
to –1.61/–2.05 to –0.74 mm Hg; P for effect o0.00001/o0.00001;
explored separately in trials with monotherapy and combination therapy.
Publication bias was assessed graphically using a funnel plot and mathe-
P for heterogeneity ¼ 0.73/0.73; Figure 2).
matically using an adjusted rank-correlation test, according to the method of
Beg and Mazumdar.5 Furthermore, to assess the impact of age and sex among Publication bias
the studies on the study-specific estimate, we performed a mixed-effects To assess publication bias, we generated a funnel plot of the effect size
(unrestricted maximum likelihood) meta-regression analysis. The meta- vs. the precision (reciprocal of the standard error) for each trial. There
regression graphs depict the effect of telmisartan therapy on the outcome was no evidence of significant publication bias (P ¼ 0.20 for SBP;
(plotted as an MD of BP changes on the y axis) as a function of a given factor Figure 3a; P ¼ 0.34 for DBP; Figure 3b; by Begg’s adjusted rank-
(plotted as a mean age (year) or a percentage of men (%) on the x axis). Meta- correlation test).
regression coefficients (slopes of meta-regression lines) indicate the estimated
increase in MD per unit increase in the covariate. A positive coefficient would
Meta-regression analysis
indicate that as a given factor decreases, the MD decreases; that is, telmisartan
therapy is more beneficial in reducing the outcome of interest. All analyses
Meta-regression analysis was performed to determine whether the
were conducted using Review Manager version 5.1 (Nordic Cochrane Centre, effects of telmisartan therapy were modulated by the pre-specified
Copenhagen, Denmark) and Comprehensive Meta-Analysis version 2 software factors. All of the meta-regression coefficients (the slopes of the meta-
(Biostat, Englewood, NJ, USA). regression lines) for the age and sex were not statistically significant
(age (year) vs. MD of SBP/DBP changes, 0.17103/0.08217; 95%
CI, –0.00196/–0.03547 to 0.34401/0.19982, P ¼ 0.05265/0.17101; per-
RESULTS
centage of men (%) vs. MD of SBP/DBP changes, –0.00036/0.03801;
Search results
95% CI, –0.10733/–0.02805 to 0.10661/0.10407, P ¼ 0.99475/0.25945;
Of the 62 potentially relevant articles initially screened, 17 reports of
Table 2).
prospective randomized controlled clinical trials of telmisartan vs.
valsartan therapy, enrolling a total of 5422 patients with hypertension,
DISCUSSION
were identified and included (Table 1).6–22 These included three trials
The results of our analysis suggest that telmisartan therapy may
of 40-mg telmisartan vs. 80-mg valsartan,6–8 seven trials of 80-mg
reduce SBP/DBP, respectively, by 2.04/1.08 mm Hg over valsartan
telmisartan vs. 160-mg valsartan9–15 and seven trials of miscellaneous
therapy in hypertensive patients. The results from monotherapy are
comparisons.16–22 Of these studies, 14 studies provided data on the
the most compelling, with data from 14 different trials demonstrating
effectiveness for the comparison between telmisartan and valsartan in
a 1.38/0.76 mm Hg reduction in SBP/DBP with telmisartan therapy
monotherapy,6–11,13,16–22 and three studies compared these two agents
compared with valsartan therapy. Only a few trials10,21 demonstrated
in fixed-dose combination with 12.5 or 25-mg HCTZ.12,14,15 We did
a statistically significant benefit to telmisartan therapy, likely due to
not include a 2009 study by White et al.23 because of pooling results
the systematic underpowering of these trials in the design phase.
from a 2006 White et al. study14 and those from a 2008 White et al.
The meta-regression analysis in this study confirmed that differences
study.15 Furthermore, a 2004 study by White et al.24 was also excluded
in age or sex were not responsible for the treatment effects observed
because its results were included in a study by Lacourcière.10
across the trials.
A possible explanation for our findings may be linked to the
Qualitative findings inherent pharmacokinetic profile of telmisartan. Telmisartan achieves
Pooled analysis of all the 17 trials demonstrated a statistically peak plasma concentrations within 1 h after oral administration and
significant 2.04/1.08 mm Hg reduction in SBP/DBP (fixed-effects has an elimination half-life of approximately 24 h,25 which is a longer
MD for SBP, –2.04 mm Hg; 95% CI, –2.80 to –1.28 mm Hg; P for half-life than that of valsartan.1 In addition, the trough:peak ratio
effect o0.00001; P for heterogeneity ¼ 0.30; Figure 1a; fixed-effects (the average BP reduction during the last 2 h of the dosing interval
MD for DBP, –1.08 mm Hg; 95% CI, –1.55 to –0.62 mm Hg; P for compared with the average of the maximal reduction in BP over
effect o0.00001; P for heterogeneity ¼ 0.60; Figure 1b) for telmisar- 2 consecutive hours)26 for SBP is higher for telmisartan (85%) than
tan compared with valsartan therapy. There was minimal trial that for valsartan (73%).9 These pharmacokinetic advantages of
heterogeneity and, accordingly, little difference in the pooled results telmisartan may give hypertensive patients a better BP-lowering effect.
from random-effects modeling (MD for SBP, –1.91 mm Hg; 95% CI, The present meta-analysis further confirms the superiority of
–2.81 to –1.02 mm Hg; P for effect o0.0001; MD for DBP, telmisartan vs. valsartan when both are used in fixed-dose combina-
–1.08 mm Hg; 95% CI, –1.55 to –0.62 mm Hg; P for effect o0.00001). tion with HCTZ. However, the results are less robust despite the

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 Table 1 Trial characteristics

Inclusion criteria Randomization BP (mm Hg)

Patient Age Men

Trial Hypertension MS DM CAD Miscellaneous Telmisartan Valsartan Duration (n) (year) (%) SBP DBP

40-mg telmisartan vs. 80-mg valsartan

ADIPO6 SBP X140 mm Hg and/or DBP X90 mm Hg O 40 mg 80 mg 24 Weeks 19 55.6 47.4 145.6 87.4
Ozaki7 SBP 4130 mm Hg and/or DBP 480 mm Hg O 40 mg 80 mg 3 Months 148 64.5 50.7 153.7 81.8
Tomiyama8a SBP/DBP, o140/90 mm Hg by treatment with 8-mg can- 40 mg 80 mg 12 Weeks 40 61.0 70.0 135 79
desartan, 50-mg losartan or 20-mg olmesartan
Subtotal 207 63.0 54.1 149.3 81.8

80-mg telmisartan vs. 160-mg valsartan

Calvo9 SBP, 140–179 mm Hg or DBP, 90–109 mm Hg 80 mg 160 mg 3 Months 70 47.6 45.7 154.1 90.6
Lacourcière10 DBP X95–109 mm Hg 40 mg 80 mg 2 Weeks 910 53.9 69.0 156.7 100.1
- - -
80 mg 160 mg 4 Weeks
Lim11 SBP 4140 mm Hg or DBP 490 mm Hg 80 mg 160 mg 12 Weeks 60 48.5 63.3 152.5 100.2
SMOOTH12 SBP, 140–179 mm Hg and/or DBP, 95–109 mm Hg O Overweight 80 mg 160 mg 4 Weeks 743 58.8 55.8 156.9 91.9
- - -
80 þ 12.5-mg 160 þ 12.5-mg 6 Weeks
HCTZ HCTZ
VIVALDI13 SBP/DBP 4130/80 mm Hg O Proteinuria 40 mg 80 mg 2 Weeks 716 61.1 64.1 148.2 82.1
- - -
80 mg 160 mg 50 Weeks
White14 DBP X95 mm Hg 80 mg 160 mg 2 Weeks 946 53 58.5 154.4 101.9
H Takagi et al

- - -
80 þ 25-mg 160 þ 25-mg HCTZ 6 Weeks
HCTZ
White 200815 95p DBP o120 mm Hg 80 mg 160 mg 2 Weeks 946 53 54.5 154.5 101.7
- - -
80 þ 25-mg 160 þ 25-mg HCTZ 6 Weeks
HCTZ
Telmisartan vs. valsartan for BP reduction

Subtotal 4391 55.5 60.1 154.3 96.4

Miscellaneous comparison
Arai16 SBP/DBP X140/90 mm Hg O Albuminuria 48.0±16.4 mg 116.0±40.8 mg 12 Months 40 74.0 50.0 173.9 86.0
Georgescu17 SBP, 135–180 mm Hg and DBP, 85–120 mm Hg O Steatohepatitis 20 mg 80 mg 20 Months 54 48.89 51.9 156.53 101.65
Hong18 SBP X140 mm Hg or DBP X90 mm Hg O 40/80 mg 80/160 mg 8 Months 159 61 67.3 144 89
Hong19 SBP X130 mm Hg and/or DBP X80 mm Hg O O 40/80 mg 80/160 mg 8 Months 71 62.5 75.3 142.0 86.4
Ichikawa20 SBP/DBP X130/85 mm Hg O 20 mg 40 mg 4 Weeks 53 65.0 60.4 151.4 89.5
Littlejohn21 140p SBP p200 mm Hg and 95p DBP p114 mm Hg 80 mg 80 mg 8 Weeks 396 53.3 68.1 157.1 100.8
Yano22 Treated with valsartan O 20/40/80 mg 40/80/160 mg 12 Weeks 51 65 33.3 140.9 80.5
Subtotal 824 57.9 64.0 152.7 94.6

Total 5422 56.1 60.5 153.8 95.5

Abbreviations: BP, blood pressure; CAD, coronary artery disease; DBP, diastolic BP; DM, diabetes mellitus; HCTZ, hydrochlorothiazide; MS metabolic syndrome; SBP, systolic BP.
aQuasi-randomized crossover design.
629

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 Telmisartan vs. valsartan for BP reduction
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Figure 1 Forest plot of systolic (a) and diastolic blood pressure changes (b) among hypertensive patients randomized to telmisartan vs. valsartan therapy
according to treatment dosage. CI, confidence interval; IV, inverse variance. A full color version of this figure is available at the Hypertension Research
journal online.

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 Telmisartan vs. valsartan for BP reduction
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Figure 2 Forest plot of systolic (a) and diastolic blood pressure changes (b) among hypertensive patients randomized to telmisartan vs. valsartan therapy
according to treatment type (monotherapy or combination therapy). CI, confidence interval; IV, inverse variance. A full color version of this figure is available
at the Hypertension Research journal online.

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 Telmisartan vs. valsartan for BP reduction
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actions of the components. Fixed-dose combination therapy targets

different effector mechanisms, and each may counteract the counter
regulatory system activity triggered by the other.27
As the present meta-analysis did not evaluate the incidence of
cardiovascular or cerebrovascular events and the mortality incidence
from such events, some caution is needed in interpreting our results.
However, a meta-analysis of individual data for one million adults in
61 prospective studies indicates that even a 2 mm Hg lower SBP
would lead to an approximately 10% lower stroke mortality rate and
an approximately 7% lower mortality rate from ischemic heart disease
or other vascular causes in middle age.28 Furthermore, data from the
Framingham Heart Study (a longitudinal cohort study) and the
National Health and Nutrition Examination Survey II (a national
population survey) suggest that a 2 mm Hg reduction in DBP would
result in a 17% decrease in the prevalence of hypertension as well as a
6% reduction in the risk of coronary heart disease and a 15%
reduction in the risk of stroke and transient ischemic attacks.29
Thus, even the approximately 2/1 mm Hg reduction in SBP/DBP
with telmisartan relative to valsartan demonstrated in the present
meta-analysis would be expected to provide clinical benefits in
hypertensive patients.
Our analysis must be viewed in the context of its limitations. First,
we used the clinic, not ambulatory, BP. In the most recent (2011)
recommendations (updating the 2004 and 2006 clinical guidelines)
from the NICE (National Institute for Health and Clinical Excellence)
on the management of hypertension,30 it was suggested that
ambulatory BP monitoring should be used to confirm the diagnosis
of hypertension if the clinic BP is 140/90 mm Hg or higher.
Furthermore, for people identified as experiencing a ‘white coat
effect’ (that is, a discrepancy of 420/10 mm Hg between clinic and
average daytime ambulatory BP (or average home BP) measurements
at the time of diagnosis), ambulatory (or home) BP monitoring
Figure 3 Funnel plot of the effect size vs. the precision (reciprocal of the should be considered as an adjunct to clinic BP measurements
standard error) for systolic (a) and diastolic blood pressure (b).
for monitoring the response to antihypertensive treatment with
lifestyle modification or drugs.30 Among the 17 trials included in
Table 2 Meta-regression analysis the present meta-analysis, only 4 trials9,10,12,21 reported ambulatory
BP. Telmisartan is the longest-acting ARB currently available, and its
Coefficient Lower limit of Upper limit of mean elimination half-life is approximately 24 h in patients with
(slope) 95% CI 95% CI P-value mild-to-moderate hypertension who receive 20–160 mg day 1 telmi-
sartan for 4 weeks.1 Thus, telmisartan would be expected to reduce
Age (year) vs.
ambulatory BP more than the other ARBs, including valsartan.
Mean difference of 0.17103 0.00196 0.34401 0.05265
Second, our results may be influenced by a publication bias
SBP (mm Hg)
Mean difference of 0.08217 0.03547 0.19982 0.17101
favoring telmisartan, which was marketed 4 years later than valsartan.
DBP (mm Hg)
This risk was minimized through an exhaustive search of the available
literature. Although the statistical tests did not indicate publication
Percentage of men (%) vs. bias, there is clearly limited power to detect such bias, given the
Mean difference of 0.00036 0.10733 0.10661 0.99475 relatively small number of studies examined.
SBP (mm Hg) Third, we preferentially used the fixed-effects estimate as the
Mean difference of 0.03801 0.02805 0.10407 0.25945 summary measure. In order to calculate a CI for a fixed-effects
DBP (mm Hg) meta-analysis, the assumption is made that the true effect of
Abbreviations: CI, confidence interval; DBP, diastolic blood pressure; SBP; systolic blood
intervention (in both magnitude and direction) is the same value in
pressure. every study (that is, fixed across studies), which implies that the
observed differences among study results are due solely to chance,
that is, that there is no statistical heterogeneity.31 When there is
narrow CIs and statistical significance, primarily due to the small heterogeneity that cannot readily be explained, one analytical
number (n ¼ 3) of combined trials. Although single-drug therapy approach is to incorporate it into a random-effects model. For any
remains the preferred way to begin treatment of hypertension, particular set of studies in which heterogeneity is present, a CI around
it is ineffective in achieving target goals in 450% of patients.27 the random-effects pooled estimate is wider than a CI around a fixed-
On average, 2–4 antihypertensive medications are required to reach effects pooled estimate.31 In addition to the fixed-effects model, we
present BP targets. An attractive option, fixed-dose combination, has used the random-effects model to make a more conservative
improved antihypertensive efficacy because of the dual mechanistic evaluation despite minimal between-study heterogeneity of results

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as determined by means of standard w2-tests. The pooled results 14 White WB, Punzi HA, Murwin D, Koval SE, Davidai G, Neutel JM. Effects of the
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