Clinical Therapeutics/Volume 37, Number 6, 2015

Ambrisentan May Improve Exercise Tolerance and Cardiac

Function in Patients With Pulmonary Hypertension
Xue-Qin Li, PhD1; Yun-Jing Li, MM1; and Yong Wang, MM2
1

Department of Pharmacy, Zhongshan Hospital of Sun Yat-Sen University, Zhongshan 528400, Peoples
Republic of China; and 2Department of Pharmacy, China Medical University, Shenyang 110000, Peoples
Republic of China

ABSTRACT
Purpose: Pulmonary hypertension (PH) is characterized by a signicant increase in pulmonary vascular
resistance, which results in ventricular failure and
death. Ambrisentan appears to be an effective treatment in the pathogenesis and progression of ambrisentan, but some researchers disagree. Therefore, this
meta-analysis aims to examine the clinical efcacy of
ambrisentan in the treatment of PH.
Methods: A search of the scientic literature using
the Embase, Cochrane, and CHINAHL databases
retrieved published studies related to our topic of
interest. Eight cohort studies related to ambrisentan
and PH treatment were selected on the basis of our
strict inclusion and exclusion criteria for a systematic
meta-analysis. Statistical analyses were conducted
using STATA version 12.0 statistical software (StataCorp LP, College Station, Texas).
Findings: Our meta-analysis retrieved 124 studies
using our search criteria (90 studies in English and 34
studies in Chinese), and 8 studies (4 studies in English
and 4 studies in Chinese) were eventually selected for
this meta-analysis. The 8 studies contained data on a
total of 172 PH patients. Pooled data in our metaanalysis revealed that 6-minute walking distance in
PH patients signicantly improved after ambrisentan
treatment compared with before treatment. The mean
pulmonary arterial pressure, brain natriuretic peptide
level, and systolic pulmonary artery pressure in PH
patients decreased measurably after ambrisentan treatment compared with before treatment. Sensitivity
analysis results conrmed that the included studies
had no publication bias (all P 4 0.05).
Implications: Our meta-analysis results demonstrated that ambrisentan is highly effective in improving exercise tolerance and cardiac function in
PH patients, and the mean pulmonary arterial

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pressure, systolic pulmonary artery pressure, and

brain natriuretic peptide level levels in PH patients
signicantly decreased. However, with the limitations
of small sample size, insufcient data, and ethnic
difference in the study, further studies with larger
sample sizes and sufcient information are essential to
validate our ndings of the high safety prole and
efcacy of ambrisentan in treatment of PH. (Clin Ther.
2015;37:12701279) & 2015 Elsevier HS Journals,
Inc. All rights reserved.
Key words: 6-minute walking distance, ambrisentan, brain natriuretic peptide, mean pulmonary arterial
pressure, pulmonary hypertension, systolic pulmonary
artery pressure.

INTRODUCTION
Pulmonary hypertension (PH) is a rare but severe
condition characterized by vascular proliferation and
remodeling of small pulmonary arteries, leading to a
gradual increase in pulmonary vascular resistance and
eventually ventricular failure and death.1,2 Based on the
classication criteria of the World Health Organization,
PH is idiopathic or familial.3 PH can be associated with
a variety of conditions or diseases, including portal
hypertension, congenital heart disease, HIV infection,
connective tissue disease, as well as exposure to drugs
and toxins, such as appetite suppressants.4 It is estimated
that the incidence of PH is 2 to 3 cases per million per
year, and females are at 3 times increased risk for PH
compared with males.5 A number of factors lead to PH,
and among these, left heart disease, congenital heart
Accepted for publication March 9, 2015.
http://dx.doi.org/10.1016/j.clinthera.2015.03.011
0149-2918/$ - see front matter
& 2015 Elsevier HS Journals, Inc. All rights reserved.

Volume 37 Number 6

X.-Q. Li et al.
disease, hypoxic lesions, and pulmonary thromboembolism play leading roles.6,7 The common symptoms
of PH are fatigue, fainting or syncope, shortness of
breath, angina pectoris, nonproductive cough, peripheral
edema (swelling around the ankles and feet), and, rarely,
hemoptysis (coughing up blood).8,9 Current drugs for
treating PH are of 3 main types: prostacyclin drugs (such
as ventavis), endothelin (ET)-1 receptor antagonists (eg,
bosentan and ambrisentan), and phosphodiesterase-5
inhibitors (eg, sildenal and tadalal).10,11
Ambrisentan is a drug indicated for the treatment of
PH, requiring once-daily administration, with a low
potential for drug-drug interactions.12 It is a potent and
selective antagonist of the ETA receptor exhibiting
44000-fold higher selectivity toward ETA than the
ETB receptor.13 ETA receptors are predominantly
located on vascular smooth muscle cells and mediate
vasoconstriction and cell proliferation, whereas ETB
receptors are found on the endothelial and vascular
smooth muscle cells, and primarily mediate
vasodilation, antiproliferation, and ET-1 clearance.14,15
Ambrisentan is approved for PH treatment in several
countries, including the United States and the European
Union.16 Ambrisentan has a long half-life and high oral
bioavailability, is easy to take, and reduces endogenous
vasoconstriction, with antiproliferative, antibrosis,
and anti-inammation effects.17 However, it also has
some side effects such as angioedema, nasal congestion,
upper respiratory tract infection, headache, nausea,
blush, and liver damage.18,19 Multiple studies have
demonstrated that ambrisentan can signicantly reduce
clinical symptoms in patients, improve exercise tolerance and cardiac function, improve the survival rate
of PH patients, and decrease the incidence of
liver dysfunction.20,21 However, a few other studies
contradict these ndings.14,22 Therefore, the aim of this
meta-analysis was to evaluate the clinical efcacy of
ambrisentan in the treatment of PH.

MATERIALS AND METHODS

Data Sources and Key Words
We searched for studies published before September
1, 2014, that evaluated the efcacy and safety prole of
ambrisentan for the treatment of PH. The relevant
studies were retrieved from computerized databases of
PubMed, Embase, Ovid, Springerlink, Wiley, Cochrane
Library, China BioMedicine, Web of Science, and
China National Knowledge Infrastructure, using selected
common key words (ambrisentan or letairis or

June 2015

gilead brand of ambrisentan or LU208075 or

BSF208075) and (hypertension, pulmonary or
pulmonary hypertension). No restrictions were set
on language of publication or country of study. Manual
searches were used to identify other eligible studies from
cross-references.

Study Selection
After reading abstracts, full papers were retrieved
and assessed for their suitability in the present
meta-analysis using the following inclusion criteria:
(1) studies must be related to the efcacy and safety
prole of ambrisentan for the treatment of PH; (2) all
patients must be clinically diagnosed with PH; (3) all
PH patients must be treated with ambrisentan;
(4) studies must provide complete data on the number
of cases, age, sex, 6-minute walking distance
(6MWD), mean pulmonary arterial pressure (mPAP),
systolic pulmonary artery pressure (sPAP), and brain
natriuretic peptide (BNP). In addition, only the latest
study with the most complete data was extracted
when studies were published by same author. Furthermore, studies published only in English or Chinese were included in our meta-analysis. The
exclusion criteria were as follows: (1) publications
that did not satisfy the inclusion criteria designated in
this meta-analysis; (2) abstracts, reviews, letters, or
proceedings; (3) duplicated publications or studies
with incomplete data; and (4) studies unrelated to the
research subject.

Data Extraction and Quality Assessment

We used a standard data reporting form to extract
data from each study, and the following descriptive
information was collected: the rst author, date of
publication, country, ethnicity, language, disease, age,
sex, sample size, follow-up time, 6MWD, mPAP, sPAP,
and BNP. Discrepancies in the inclusion of a single study
were discussed with a third investigator. To select highquality studies, 2 authors independently used predened
NewcastleOttawa Scale (NOS) criteria for inclusion of
the studies.23 The NOS criteria were as follows:
(1) group selection: the exposure group has very good
or better representation (NOS01), the nonexposure
group and exposure group come from the same
populations (NOS02), the included studies have
reliable records or structured interviews (NOS03),
whether the beginning of study has no observational
outcomes (NOS04); (2) group comparability: the study

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Identification

Clinical Therapeutics

(n = 122)
Articles identified through
electronic database searching

(n = 2)
Additional articles identified
through a manual search

Eligibility

Screening

(n = 124)
Articles reviewed for duplicates

(n = 90)
Articles after duplicates
removed

Studies were excluded, due to:

(n = 1) Letters, reviews, meta-analysis
(n = 15) Not human studies
(n = 35) Not related to research topics

(n = 39)
Full-text articles assessed
for eligibility

Studies were excluded, due to:

(n = 4) Not case-control or cohort study
(n = 9) Not relevant to pulmonary
arterial hypertension
(n = 16) Not relevant to ambrisentan

Included

(n = 10)
Studies included in
qualitative synthesis

(n = 8)
Studies included in
quantitative synthesis
(meta-analysis)

Figure 1. Flow chart shows the study selection procedure. Eight studies were included in this meta-analysis.

is in accordance with the most important factors to select

and analyze the controls (NOS05), the study controls
other important confounding factors (NOS06); (3) group
results: the study is independent or belongs to a blind
method (NOS07), the follow-up time is sufcient
for the occurrence of results (NOS08), there is a small
number of subjects lost to follow-up in the follow-up of
all the subjects but does not introduce deviation (NOS09).

Statistical Analysis
Statistical analyses were performed using STATA
statistical software, version 12.0 (StataCorp, College
Station, Texas). The summary standard mean difference (SMD) and its corresponding 95% CI were
used for the evaluation of the efcacy and safety

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prole of ambrisentan for the treatment of PH, with

the use of the Z test. Cochrans Q statistic and I2 test
were also adopted to quantify heterogeneity among
studies.24,25 A random-effects model was applied in
case of signicant heterogeneity among the studies
(P o 0.05 or I2 4 50%); otherwise, a xed-effects
model was applied (P 4 0.05 or I2 o 50%).26 When
there was signicant heterogeneity, subgroup
analyses were performed to nd potential
explanatory variables. Furthermore, a sensitivity
analysis was performed to evaluate whether the
removal of 1 single study would inuence the
overall results. To identify the reliability of the
original analysis results, a funnel plot and Eggers
linear regression test were used to evaluate
publication bias.27

Volume 37 Number 6

X.-Q. Li et al.

F female; M male.

NOS8

NOS7

NOS6

NOS5

NOS4

NOS3

NOS2

NOS1

rti
nC
(2 eba
0
H 11 R
eJ
)
(2
0
13
Li
YP
)
(2
01
Li
4)
u
Y
Sa
(
2
gg
01
ar
4)
Ta
R
ka
(2
ts
01
uk
2)
iS
(2
W
01
en
3)
L
Yo
(2
sh
01
id
4)
a
S
(2
01
1)

18
42
35
15
13
11
25
13
hypertension
hypertension
hypertension
hypertension
hypertension
hypertension
hypertension
hypertension
arterial
arterial
arterial
arterial
arterial
arterial
arterial
arterial
Pulmonary
Pulmonary
Pulmonary
Pulmonary
Pulmonary
Pulmonary
Pulmonary
Pulmonary
Asian
Asian
Asian
Asian
Caucasian
Caucasian
Asian
Caucasian
China
China
China
China
United States
American
Japan
United States
2014
2014
2014
2013
2013
2012
2012
2011
Wen32
Liu31
Li30
He29
Takatsuki18
Saggar19
Yoshida33
Cartin-Ceba28

June 2015

NOS9

Ca

68
12
12
12
80
24
12
48
39 17
31.13 9.38
14 9
41 5

47.6 19.4
45.5 13.7
52 60

Figure 1 shows a ow chart of published studies

and the main exclusion criteria. Our present metaanalysis retrieved 124 studies through electronic database searches along with a manual search. From these
124 studies, 34 studies were removed due to duplication; 1 study for letters, reviews, or meta-analysis was
removed; 15 nonhuman studies were removed, and 35
studies unrelated to the research topic were removed.
After reviewing the remaining 39 studies, additional
29 studies were excluded for not being cohort study
(n 4), irrelevant to PH (n 9), or irrelevant to
ambrisentan (n 16). Finally, 8 studies were enrolled
in the meta-analysis,18,19,2833 after a nal exclusion
of studies containing insufcient information (n = 2).
The 8 cohort studies, published between 2011 and
2014, evaluated the efcacy and safety prole of
ambrisentan for the treatment of PH in Asian populations (5 studies) and Caucasian populations (4
studies) and contained a combined total of 172 PH
patients. The countries of the studies were the United

10/8
8/34
16/19
5/10

0/11
3/22
7/6

Follow-up, wk
Age, y
Sex, M/F
Sample Size
Disease
Ethnicity
Country
Year
First author

Table I. Main characteristics and methodological quality of all eligible studies.

RESULTS
Included Studies

Figure 2. Quality assessment of included studies

by the NewcastleOttawa Scale (NOS)
criteria. * yes; # no.

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Clinical Therapeutics

6MWD PAP value (Pre vs Post)

Included study

SMD (95% CI)

Weight%

Wen L (2014)

4.20 (5.39 to 3.01)

Liu Y (2014)

0.06 (0.49 0.36)

49.39

He J (2013)

0.82 (1.57 to 0.07)

16.19

Yoshida S (2011)

0.45 (1.02 0.12)

28.07

Heterogeneity test (I2 = 92.8%, P < 0.001)

Z test (Z = 3.64, P < 0.001)

0.56 (0.86 to 0.26) 100.00

5.39

6.35

5.39

mPAP value (Pre vs Post)

Included study

SMD (95% CI)

Weight%

Takatsuki S (2013)

0.39 (0.39 1.16)

38.80

Saggar R (2012)

0.28 (1.12 0.56)

33.14

Yoshida S (2011)

3.99 (2.98 5.01)

22.66

4.96 (2.88 7.04)

5.40

1.23 (0.75 1.71)

100.00

CartinCeba R (2011)
2

Heterogeneity test (I = 94.8%, P < 0.001)

Z test (Z = 4.98, P < 0.001)
0

7.04

7.04

sPAP value (Pre vs Post)

Included study

SMD (95% CI)

Weight%

Wen L (2014)

0.54 (0.12 1.21)

18.11

Liu Y (2014)

0.07 (0.36 0.50)

43.88

Li YP (2014)

2.17 (1.58 2.77)

22.76

He J (2013)

0.45 (0.27 1.18)

15.26

0.69 (0.41 0.98)

100.00

Heterogeneity test (I2 = 90.8%, P < 0.001)

Z test (Z = 4.79, P < 0.001)
2.77

2.77

BNP value (Pre vs Post)

Included study

SMD (95% CI)

Weight%

Wen L (2014)

10.14 (7.64 12.63)

1.51

Liu Y (2014)

0.07 (0.50 0.35)

51.52

He J (2013)

26.82 (19.76 33.88)

0.19

Takatsuki S (2013)

0.35 (0.35 1.05)

Yoshida S (2011)

0.40 (0.19 0.98)

27.45

0.34 (0.04 0.65)

100.00

Heterogeneity test (I2 = 96.6%, P < 0.001)

Z test (Z = 2.91, P = 0.028)
33.9

19.32

33.9

Figure 3. Forest plots for the differences of 6-minute walking distance (6MWD), mean pulmonary arterial
pressure (mPAP), systolic pulmonary artery pressure (sPAP), and brain natriuretic peptide (BNP)
level of pulmonary hypertension patients before and after ambrisentan treatment.

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X.-Q. Li et al.
States (n = 3), China (n = 4), and Japan (n = 1). The
baseline characteristics and NOS quality evaluation of
the enrolled studies are presented in Table I and
Figure 2, respectively.

Pooled Outcome of Meta-Analysis

As shown in Figure 3, 4 studies reported the
measurement results of 6MWD in PH patients before
and after ambrisentan treatment. A random-effects
model was applied to the pooled data of the 6MWD
due to evidence of heterogeneity (I2 = 92.8%, P o
0.001). The results of our meta-analysis revealed that
the 6MWD of PH patients increased signicantly after

receiving ambrisentan treatment, and this increase was

statistically signicant (SMD = 0.56, 95% CI, 0.26
0.86, P o 0.001). In addition, 4 studies reported the
differences in the mPAP, 4 studies discussed sPAP, and
5 studies investigated the BNP level in PH patients
before and after ambrisentan treatment. A randomeffects model was also applied to the pooled data of
these indexes due to the existence of heterogeneity
among the studies (I2 4 50%, P o 0.05). This metaanalysis suggested that the mPAP, sPAP, and BNP
levels of PH patients decreased signicantly after
receiving ambrisentan treatment compared with PH
patients before ambrisentan treatment (mPAP: SMD =

6MWD PAP value

mPAP value
(Pre vs. Post)

(Pre vs. Post)

Lower CI Limit

Estimate

Lower CI Limit

Upper CI Limit

Wen L (2014)

Takatsuki S (2013)

Liu Y (2014)

Saggar R (2012)

He J (2013)

Yoshida S (2011)

Estimate

Upper CI Limit

CartinCeba R (2011)

Yoshida S (2011)
3.56

2.48

1.26

0.04

1.03

0.32

0.11

sPAP value
Estimate

4.39

6.22

BNP value

(Pre vs. Post)

Lower CI Limit

2.14

(Pre vs. Post)

Lower CI Limit

Upper CI Limit

Estimate

Upper CI Limit

Wen L (2014)

Wen L (2014)

Liu Y (2014)
Liu Y (2014)

He J (2013)

Li YP (2014)
Takatsuki S (2013)

He J (2013)
0.44

Yoshida S (2011)
0.17

0.81

1.78

2.22

0.18

1.72

3.80

5.89

9.99

Figure 4. Sensitivity analysis for the differences of 6-minute walking distance (6MWD), mean pulmonary
arterial pressure (mPAP), systolic pulmonary artery pressure (sPAP), and brain natriuretic peptide
(BNP) level of pulmonary hypertension patients before and after ambrisentan treatment.

June 2015

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Clinical Therapeutics
1.23, 95% CI, 0.751.71, P o 0.001; sPAP:
SMD = 0.69, 95% CI, 0.410.98, P o 0.001; BNP:
SMD = 0.34, 95% CI, 0.040.65, P o 0.001).

DISCUSSION
To examine the clinical efcacy of ambrisentan for the
treatment of PH, a meta-analysis was conducted. This
meta-analysis demonstrated that ambrisentan improves exercise tolerance, with signicant reductions
in mPAP, sPAP, and BNP levels of PH patients,
implying that ambrisentan is a curative drug for PH
in light of the fact that the typical disease characteristics in PH patients include abnormal lung function
and decreased exercise tolerance, accompanied by
high levels of mPAP, sPAP, and BNP. PH is described
as a disease of the pulmonary vasculature, often
accompanied by serious functional impairment and a
poor prognosis.34 PH is reported to be the result
of an imbalance between pivotal mediators in
the pulmonary circulation, and this imbalance
results in vasoconstriction, increased thrombosis, and

Sensitivity Analysis and Publication Bias

A sensitivity analysis was performed, and the
removal of any single study had minimal impact
on the ndings of this meta-analysis, implying the
stability of our analysis. As shown in Figure 4, the
sensitivity analysis results suggested that all included
studies had no signicant effect on pooled SMD of
clinical efcacy of ambrisentan for the treatment of
PH. The graphical funnel plots of the 8 studies are
symmetrical, indicating no publication bias. The Egger
linear regression analysis further conrmed that the
included studies had no publication bias (all P values
4 0.05) (Figure 5).

6MWD PAP value (Pre vs Post)

Eggers test:
t = 3.09, P = 0.091

0.4

SE SMD

SE SMD

0.6

mPAP value (Pre vs Post)

1.0

Eggers test:
t = 0.92, P = 0.455

0.5

0.2

0
4

SMD

sPAP value (Pre vs Post)

0.4

Eggers test:
t = 0.33, P = 0.776

2
SMD

BNP value (Pre vs Post)

4

Eggers test:
t = 6.01, P = 0.009

SE SMD

SE SMD

3
0.2

2
1
0

0
0

1
SMD

10

10
SMD

20

30

Figure 5. Funnel plot of publication biases on the differences of 6-minute walking distance (6MWD), mean
pulmonary arterial pressure (mPAP), systolic pulmonary artery pressure (sPAP), and brain
natriuretic peptide (BNP) level of pulmonary hypertension patients before and after ambrisentan
treatment. SMD standard mean difference.

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X.-Q. Li et al.
proliferation of endothelial and smooth muscle cells
within the pulmonary vasculature.35,36 ET receptor
antagonists show signicant benets in the clinical
management of PH. Among the ET receptor antagonists, ambrisentan is a propanoic acid, nonsulfonamide, selective ETA receptor antagonist, approved for
human use by the US Food and Drug Administration in
2007 for the treatment of PH (especially in the World
Health Organization group 1).18 Sitaxentan, another
selective ET receptor antagonist, was also approved for
human use to treat PH and was marketed in Canada
and the European Union, but was later removed from
the market due to its idiosyncratic hepatotoxicity.37
Ambrisentan continues to be a leading drug in PH
treatment and exhibits signicant clinical benets in
patients, as seen improving exercise tolerance, reducing
the risk of functional class deterioration, and prolonging
the time to clinical decline. In addition, other favorable
qualities of ambrisentan include once-daily administration, a low risk of adverse drug reaction, a limited drug
drug interaction prole, and a low risk of liver enzyme
increase, which are acceptable to PH patients, in view of
the clinical benets.38 Ambrisentan signicantly
decreases mortality, and PH patients after ambrisentan
treatment had an 88% survival rate in 1 study, whereas
the survival rate estimated by the National Institute of
Health Registry was placed at 61%.39 Generally,
ambrisentan is well tolerated in all PH patients, but
sometimes causes side effects such as sinusitis, ushing,
peripheral edema, and nasal congestion, which are
considered as mild to moderate in nature.40 Consistent
with our meta-analysis results, a study concluded that
ambrisentan was capable of improving 6MWD, World
Health Organization functional class, and BNP level. In
PH patients who had completed a previous 24-week
study of the efcacy and safety prole of ambrisentan
and were followed by ambrisentan treatment for periods
ranging from 48 to 141 weeks, the long-term administration of ambrisentan was effective in controlling the
disease and the safety prole remained favorable.33
Although the clinical efcacy of ambrisentan remains
high, certain adverse side effects (eg, angioedema,
infection, sinusitis, ushing, and nasal congestion) in
severe PH patients still lead to poor patient tolerance of
the drug.20 Therefore, PH patients are strongly advised
to exercise caution when treated with ambrisentan.
This meta-analysis has limitations. First, the sample
sizes (only 172 patients from 8 studies) in the included
studies were relatively small, which might decrease the

June 2015

validity of our results. Second, insufcient data on age

and sex in some included studies may affect the overall
results. Third, previous studies have shown that there
might be ethnic difference in the clinical efcacy of
ambrisentan in PH treatment. Unfortunately, we were
unable to conduct a subgroup analysis of ethnicity in
our meta-analysis due to the lack of sufcient data. In
addition, ethnicity categories showed identical outcomes, which also contributed to the impossibility of
performing a subgroup analysis, which may have an
impact on the overall validity of our study outcome.
Last, the included studies were only published in
English and Chinese, whereas studies in other languages were not considered. Therefore, further studies
with larger sample sizes are essential to validate our
ndings of a high safety prole and efcacy of
ambrisentan in the treatment of PH.
In summary, our meta-analysis provided strong
evidence that ambrisentan improves exercise tolerance
and cardiac function in PH patients. The mPAP, sPAP,
and BNP levels in PH patients decreased signicantly.

ACKNOWLEDGMENTS
We express our gratitude to the support from Zhongshan
Hospital of Sun Yat-Sen University. Xue-Qin Li
contribute to literature search, study design; Yun-Jing Li
contribute to data collection and data interpretation;
YongWang contribute to writing, MM gure creation.

CONFLICTS OF INTEREST
The authors have indicated that they have no conicts
of interest regarding the content of this article.

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16.

17.

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Address correspondence to: Xue-Qin Li, PhD, Department of Pharmacy,

The First Afliated Hospital, Sun Yat-sen University, Zhongshan 2nd
Road No.58, Zhongshan 528400, Peoples Republic of China. E-mail:
lixueqin613@126.com

June 2015

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