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, People’s
Republic of China; and 2Department of Pharmacy, China Medical University, Shenyang 110000, People’s
Republic of China

ABSTRACT
Purpose: Pulmonary hypertension (PH) is characterized by a significant 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 efficacy of
ambrisentan in the treatment of PH.
Methods: A search of the scientific 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 significantly 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 confirmed 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

1270

pressure, systolic pulmonary artery pressure, and
brain natriuretic peptide level levels in PH patients
significantly decreased. However, with the limitations
of small sample size, insufficient data, and ethnic
difference in the study, further studies with larger
sample sizes and sufficient information are essential to
validate our findings of the high safety profile and
efficacy of ambrisentan in treatment of PH. (Clin Ther.
2015;37:1270–1279) & 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
classification 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

Wiley. whereas ETB receptors are found on the endothelial and vascular smooth muscle cells. sex. that evaluated the efficacy and safety profile of ambrisentan for the treatment of PH. and anti-inflammation effects. the nonexposure group and exposure group come from the same populations (NOS02). No restrictions were set on language of publication or country of study. (4) studies must provide complete data on the number of cases.14.19 Multiple studies have demonstrated that ambrisentan can significantly reduce clinical symptoms in patients. Ovid. (3) all PH patients must be treated with ambrisentan. mPAP. and. blush. it also has some side effects such as angioedema. nonproductive cough. pulmonary” or “pulmonary hypertension”). Li et al. antifibrosis. and (4) studies unrelated to the research subject. country.16 Ambrisentan has a long half-life and high oral bioavailability. the included studies have reliable records or structured interviews (NOS03). The exclusion criteria were as follows: (1) publications that did not satisfy the inclusion criteria designated in this meta-analysis. and BNP.-Q. Manual searches were used to identify other eligible studies from cross-references. reviews. 2 authors independently used predefined Newcastle–Ottawa Scale (NOS) criteria for inclusion of the studies.11 Ambrisentan is a drug indicated for the treatment of PH. endothelin (ET)-1 receptor antagonists (eg.21 However. and primarily mediate vasodilation. hypoxic lesions. rarely.12 It is a potent and selective antagonist of the ETA receptor exhibiting 44000-fold higher selectivity toward ETA than the ETB receptor. angina pectoris. and reduces endogenous vasoconstriction. a few other studies contradict these findings. 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 efficacy and safety profile of ambrisentan for the treatment of PH. with antiproliferative.X. peripheral edema (swelling around the ankles and feet). and the following descriptive information was collected: the first author. China BioMedicine.9 Current drugs for treating PH are of 3 main types: prostacyclin drugs (such as ventavis). whether the beginning of study has no observational outcomes (NOS04). Cochrane Library. age. age. fainting or syncope. with a low potential for drug-drug interactions. ethnicity. improve exercise tolerance and cardiac function. headache.10. and brain natriuretic peptide (BNP). shortness of breath. bosentan and ambrisentan).22 Therefore. and ET-1 clearance. improve the survival rate of PH patients.14. Data Extraction and Quality Assessment We used a standard data reporting form to extract data from each study. date of publication.17 However. is easy to take. sildenafil and tadalafil). To select highquality studies.23 The NOS criteria were as follows: (1) group selection: the exposure group has very good or better representation (NOS01). follow-up time. Study Selection After reading abstracts. sex. antiproliferation. and pulmonary thromboembolism play leading roles. 6-minute walking distance (6MWD).8.7 The common symptoms of PH are fatigue. (2) abstracts.6. 2014. disease. sPAP.13 ETA receptors are predominantly located on vascular smooth muscle cells and mediate vasoconstriction and cell proliferation. The relevant studies were retrieved from computerized databases of PubMed. and China National Knowledge Infrastructure. the aim of this meta-analysis was to evaluate the clinical efficacy of ambrisentan in the treatment of PH.20.18. In addition.15 Ambrisentan is approved for PH treatment in several countries. including the United States and the European Union. and decrease the incidence of liver dysfunction. and liver damage. systolic pulmonary artery pressure (sPAP). sample size. disease. letters. hemoptysis (coughing up blood). Embase. upper respiratory tract infection. language. (3) duplicated publications or studies with incomplete data. and phosphodiesterase-5 inhibitors (eg. nasal congestion. studies published only in English or Chinese were included in our meta-analysis. (2) group comparability: the study 1271 . 6MWD. using selected common key words (“ambrisentan” or “letairis” or June 2015 “gilead brand of ambrisentan” or “LU208075” or “BSF208075”) and (“hypertension. Web of Science. Discrepancies in the inclusion of a single study were discussed with a third investigator. Springerlink. or proceedings. only the latest study with the most complete data was extracted when studies were published by same author. MATERIALS AND METHODS Data Sources and Key Words We searched for studies published before September 1. nausea. (2) all patients must be clinically diagnosed with PH. mean pulmonary arterial pressure (mPAP). Furthermore. requiring once-daily administration.

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). The summary standard mean difference (SMD) and its corresponding 95% CI were used for the evaluation of the efficacy and safety 1272 profile of ambrisentan for the treatment of PH. subgroup analyses were performed to find potential explanatory variables. reviews. 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. due to: (n = 1) Letters. a sensitivity analysis was performed to evaluate whether the removal of 1 single study would influence the overall results. Statistical Analysis Statistical analyses were performed using STATA statistical software. version 12. a fixed-effects model was applied (P 4 0.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.27 Volume 37 Number 6 .05 or I2 4 50%). the follow-up time is sufficient for the occurrence of results (NOS08). To identify the reliability of the original analysis results. Eight studies were included in this meta-analysis.0 (StataCorp. is in accordance with the most important factors to select and analyze the controls (NOS05). Flow chart shows the study selection procedure. with the use of the Z test.05 or I2 o 50%).26 When there was significant heterogeneity. 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.25 A random-effects model was applied in case of significant heterogeneity among the studies (P o 0. Texas). (3) group results: the study is independent or belongs to a blind method (NOS07). Cochran’s Q statistic and I2 test were also adopted to quantify heterogeneity among studies. the study controls other important confounding factors (NOS06). Furthermore. College Station. a funnel plot and Egger’s linear regression test were used to evaluate publication bias.24. otherwise.

* * * # # * * * 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. * ¼ yes. additional 29 studies were excluded for not being cohort study (n ¼ 4). wk Age.X. M/F Sample Size Disease Ethnicity Country Year First author Table I.38 14 ⫾ 9 41 ⫾ 5 — 47. RESULTS Included Studies Figure 2. published between 2011 and 2014. Our present metaanalysis retrieved 124 studies through electronic database searches along with a manual search.13 ⫾ 9. reviews. evaluated the efficacy and safety profile 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. y Sex. 8 studies were enrolled in the meta-analysis.18. and 35 studies unrelated to the research topic were removed. # ¼ no. F ¼ female. Finally. M ¼ male. Li et al. Main characteristics and methodological quality of all eligible studies. 1 study for letters. After reviewing the remaining 39 studies. Quality assessment of included studies by the Newcastle–Ottawa Scale (NOS) criteria. The 8 cohort studies. 15 nonhuman studies were removed. or meta-analysis was removed.19. 34 studies were removed due to duplication.28–33 after a final exclusion of studies containing insufficient information (n = 2).6 ⫾ 19.5 ⫾ 13.-Q. From these 124 studies.4 45. irrelevant to PH (n ¼ 9). The countries of the studies were the United 10/8 8/34 16/19 5/10 — 0/11 3/22 7/6 Follow-up. 1273 . or irrelevant to ambrisentan (n ¼ 16).7 52 60 Figure 1 shows a flow chart of published studies and the main exclusion criteria.

and brain natriuretic peptide (BNP) level of pulmonary hypertension patients before and after ambrisentan treatment.001) Z test (Z = 4.98) 100.07) 16. P < 0.001) −2.49 – 0.63) 1.75 – 1.02 – 0.00 Cartin−Ceba R (2011) 2 Heterogeneity test (I = 94.26) 100.77) 22.39 He J (2013) −0.86 to −0.39 B 6. 1274 Volume 37 Number 6 .8%.11 Liu Y (2014) 0. systolic pulmonary artery pressure (sPAP).6%.20 (−5.14 (7.56) 33.04 C 7. P < 0. P < 0.80 Saggar R (2012) −0. P < 0.00 −5.98 – 5.12) 28.21) 18.8%.39 mPAP value (Pre vs Post) Included study SMD (95% CI) Weight% Takatsuki S (2013) 0.27 – 1.88 – 7.9 0 19.001) Z test (Z = 3.98) 27.98.88) 0.45 (−1.96 (2.9 Figure 3.35 (−0.50) 43.65) 100.8%.77 BNP value (Pre vs Post) Included study SMD (95% CI) Weight% Wen L (2014) 10. P < 0.36 – 0.Clinical Therapeutics A 6MWD PAP value (Pre vs Post) Included study SMD (95% CI) Weight% Wen L (2014) −4.56 (−0.06 (−0. mean pulmonary arterial pressure (mPAP).58 – 2.07 Heterogeneity test (I2 = 92.32 33.07 (−0.19 – 0.82 (19.35 – 1.17 (1.12 – 0.35) 51.91.001) −0.71) 100.39 to −3.41 – 0.35 0 5.001) Z test (Z = 2.04 sPAP value (Pre vs Post) Included study SMD (95% CI) Weight% Wen L (2014) 0.00 Heterogeneity test (I2 = 96.66 4.79.26 0. Forest plots for the differences of 6-minute walking distance (6MWD).50 – 0.19 Takatsuki S (2013) 0.82 (−1.001) Z test (Z = 4.07 (−0.04) 5.00 Heterogeneity test (I2 = 90.77 D 0 2.54 (−0.01) Liu Y (2014) −0.64.76 He J (2013) 0.57 to −0.18) 15.23 (0.40 1.04 – 0. P < 0.76 – 33.52 He J (2013) 26.19 Yoshida S (2011) −0.45 0.99 (2.40 (−0.36) 49.34 (0.05) Yoshida S (2011) 0.14 Yoshida S (2011) 3.12 – 1. P = 0.88 Li YP (2014) 2. P < 0.51 Liu Y (2014) −0.64 – 12.39 – 1.28 (−1.001) 0 −7.39 (−0.01) 22.028) −33.69 (0.45 (−0.16) 38.

72 3. Post) (Pre vs. 4 studies reported the measurement results of 6MWD in PH patients before and after ambrisentan treatment. Post) Lower CI Limit 2.22 −0. 4 studies reported the differences in the mPAP.05).26– 0.26 −0. P o 0. States (n = 3). June 2015 1275 .8%. The results of our meta-analysis revealed that the 6MWD of PH patients increased significantly after A receiving ambrisentan treatment.-Q. and brain natriuretic peptide (BNP) level of pulmonary hypertension patients before and after ambrisentan treatment.17 0. systolic pulmonary artery pressure (sPAP). respectively. A random-effects model was applied to the pooled data of the 6MWD due to evidence of heterogeneity (I2 = 92.001). and 5 studies investigated the BNP level in PH patients before and after ambrisentan treatment. 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 Cartin−Ceba R (2011) Yoshida S (2011) −3. and Japan (n = 1). Pooled Outcome of Meta-Analysis As shown in Figure 3.48 C −1. and this increase was statistically significant (SMD = 0.22 BNP value (Pre vs. 0. P o 0.X. sPAP. mean pulmonary arterial pressure (mPAP).04 −1. P o 0.44 Yoshida S (2011) −0. China (n = 4).81 1. 4 studies discussed sPAP. and BNP levels of PH patients decreased significantly after receiving ambrisentan treatment compared with PH patients before ambrisentan treatment (mPAP: SMD = B 6MWD PAP value mPAP value (Pre vs.80 5. 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. This metaanalysis suggested that the mPAP.11 D sPAP value Estimate 4.32 −0. 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%.03 0.14 (Pre vs. 95% CI.001). The baseline characteristics and NOS quality evaluation of the enrolled studies are presented in Table I and Figure 2. In addition. Sensitivity analysis for the differences of 6-minute walking distance (6MWD).56 −2.56.89 9.39 6. Li et al.99 Figure 4.78 2.18 1.86.

P = 0. The Egger linear regression analysis further confirmed that the included studies had no publication bias (all P values 4 0. The graphical funnel plots of the 8 studies are symmetrical.2 0 0 –4 –2 0 2 –2 0 SMD C sPAP value (Pre vs Post) 0.04–0.4 SE SMD SE SMD 0.41–0.69. systolic pulmonary artery pressure (sPAP).009 SE SMD SE SMD 3 0. P o 0. implying the stability of our analysis. 0. sPAP: SMD = 0. and BNP. 0. and BNP levels of PH patients. BNP: SMD = 0. 95% CI.5 0. sPAP. and this imbalance results in vasoconstriction.92. P = 0.Clinical Therapeutics 1.01. mean pulmonary arterial pressure (mPAP).98. As shown in Figure 4. P o 0.75–1. with significant reductions in mPAP. PH is described as a disease of the pulmonary vasculature. Funnel plot of publication biases on the differences of 6-minute walking distance (6MWD). indicating no publication bias.4 D Egger’s test: t = –0. 95% CI.001). SMD ¼ standard mean difference. This meta-analysis demonstrated that ambrisentan improves exercise tolerance.776 2 SMD 4 6 BNP value (Pre vs Post) 4 Egger’s test: t = –6.455 0.2 2 1 0 0 0 1 SMD 2 –10 0 10 SMD 20 30 Figure 5. sPAP. 1276 Volume 37 Number 6 .05) (Figure 5).65. and Sensitivity Analysis and Publication Bias A sensitivity analysis was performed. often accompanied by serious functional impairment and a poor prognosis. 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.001. P o 0. the sensitivity analysis results suggested that all included studies had no significant effect on pooled SMD of clinical efficacy of ambrisentan for the treatment of PH. P = 0.34 PH is reported to be the result of an imbalance between pivotal mediators in the pulmonary circulation. and brain natriuretic peptide (BNP) level of pulmonary hypertension patients before and after ambrisentan treatment. a meta-analysis was conducted. accompanied by high levels of mPAP.34.6 mPAP value (Pre vs Post) 1. 95% CI.33. 6MWD PAP value (Pre vs Post) A B Egger’s test: t = 3. and the removal of any single study had minimal impact on the findings of this meta-analysis. 0.09. DISCUSSION To examine the clinical efficacy of ambrisentan for the treatment of PH. P = 0.091 0. increased thrombosis.23.001.0 Egger’s test: t = –0.71.

Yaici A. selective ETA receptor antagonist.37 Ambrisentan continues to be a leading drug in PH treatment and exhibits significant clinical benefits in patients. the sample sizes (only 172 patients from 8 studies) in the included studies were relatively small.18 Sitaxentan.35. the long-term administration of ambrisentan was effective in controlling the disease and the safety profile remained favorable. flushing. Chaouat A. which also contributed to the impossibility of performing a subgroup analysis. et al. reducing the risk of functional class deterioration. Xue-Qin Li contribute to literature search. another selective ET receptor antagonist. insufficient data on age and sex in some included studies may affect the overall results. First.369:809–818. 2. and nasal congestion.39 Generally. peripheral edema.38 Ambrisentan significantly decreases mortality. Pulido T. et al. we were unable to conduct a subgroup analysis of ethnicity in our meta-analysis due to the lack of sufficient data. Sitbon O. In PH patients who had completed a previous 24-week study of the efficacy and safety profile of ambrisentan and were followed by ambrisentan treatment for periods ranging from 48 to 141 weeks. which may have an impact on the overall validity of our study outcome. Eur Respir J. McGoon MD. which are acceptable to PH patients. World Health Organization functional class. In addition. 2012. previous studies have shown that there might be ethnic difference in the clinical efficacy of ambrisentan in PH treatment. certain adverse side effects (eg.X. and a low risk of liver enzyme increase. the included studies were only published in English and Chinese.125:113–122. and PH patients after ambrisentan treatment had an 88% survival rate in 1 study. which are considered as mild to moderate in nature. which might decrease the June 2015 validity of our results. REFERENCES 1. Elliott CG. The mPAP. Second. Third. Adzerikho I. and BNP level. flushing. Circulation. ethnicity categories showed identical outcomes. Humbert M. N Engl J Med. 2010. and nasal congestion) in severe PH patients still lead to poor patient tolerance of the drug. PH patients are strongly advised to exercise caution when treated with ambrisentan. In summary. Li et al. et al. infection. and BNP levels in PH patients decreased significantly. Barst RJ. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. whereas studies in other languages were not considered. 2010. sPAP. Circulation. whereas the survival rate estimated by the National Institute of Health Registry was placed at 61%. ACKNOWLEDGMENTS We express our gratitude to the support from Zhongshan Hospital of Sun Yat-Sen University. but sometimes causes side effects such as sinusitis. 2013. sinusitis. Survival in patients with idiopathic. further studies with larger sample sizes are essential to validate our findings of a high safety profile and efficacy of ambrisentan in the treatment of PH. and anorexigenassociated pulmonary arterial hypertension in the modern management era. proliferation of endothelial and smooth muscle cells within the pulmonary vasculature.33 Although the clinical efficacy of ambrisentan remains high. study design. Therefore. familial. was also approved for human use to treat PH and was marketed in Canada and the European Union. as seen improving exercise tolerance. and prolonging the time to clinical decline. This meta-analysis has limitations. Last. Survival in childhood pulmonary arterial hypertension: Insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management.36 ET receptor antagonists show significant benefits in the clinical management of PH. our meta-analysis provided strong evidence that ambrisentan improves exercise tolerance and cardiac function in PH patients. CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article. 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). et al.122:156–163.40 Consistent with our meta-analysis results. Channick RN. a study concluded that ambrisentan was capable of improving 6MWD.-Q. MM figure creation. ambrisentan is a propanoic acid. 4. but was later removed from the market due to its idiosyncratic hepatotoxicity. nonsulfonamide. angioedema. other favorable qualities of ambrisentan include once-daily administration.20 Therefore. a limited drug– drug interaction profile. Sitbon O. Among the ET receptor antagonists. Yun-Jing Li contribute to data collection and data interpretation. 1277 . in view of the clinical benefits. a low risk of adverse drug reaction. ambrisentan is well tolerated in all PH patients. In addition. Unfortunately. Macitentan and morbidity and mortality in pulmonary arterial hypertension. Humbert M.36:549–555. YongWang contribute to writing. 3.

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