Effect of ambrisentan on echocardiographic and Doppler measures from patients in China with pulmonary arterial hypertension

ABSTRACT

Background

We retrospectively evaluated the echocardiographic data of ambrisentan-treated patients with pulmonary arterial hypertension (PAH) (NCT01808313).

Methods

Change from baseline in right ventricle (RV) systolic function, right heart structure, and pulmonary artery systolic pressure (PASP) prognosis to Weeks 12 and 24 was evaluated by echocardiography.

Results

In the overall population, the mean tissue Doppler-derived tricuspid lateral annular systolic velocity (S’) increased by 0.6 cm/s at both Weeks 12 (p < 0.001) and 24 (p = 0.004) and tricuspid annular plane systolic excursion increased by 0.13 cm at Week 12 and 0.15 cm at Week 24 (both p < 0.001). A marked decrease in transverse and longitudinal RV and RA diameter at Weeks 12 and 24 was observed. A significant decrease in diastolic eccentricity index at both Weeks 12 (−0.1; p = 0.02) and 24 (−0.1; p = 0.001). The decrease in PASP from baseline was significant at both Weeks 12 (−9.5 mmHg; p<0.001) and 24 (-7.6 mmHg; p<0.001), while a decrease in the estimated right atrium pressure was found to be significant at Week 24 (−0.8mmHg; p = 0.01).

Conclusion

Significant improvements in a number of RV echocardiographic parameters were observed at Weeks 12 and 24 after ambrisentan treatment in patients with PAH.

KEYWORDS:

• Ambrisentan
• echocardiography
• pulmonary artery systolic pressure
• right atrium diameter
• right ventricle diameter
• systolic and diastolic eccentricity index
• tricuspid annular plane systolic excursion

1. Introduction

Pulmonary arterial hypertension (PAH) is a condition defined by a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and a pulmonary vascular resistance of ≥3. Wood Units that leads to a restricted flow through the pulmonary arteries [1]. This complex, multifactorial disorder typically results in an overload of the right ventricle (RV), progressive right-sided heart failure, and premature death [2]. PAH can occur in multiple clinical conditions, including connective tissue disease (CTD)-PAH and idiopathic pulmonary arterial hypertension (IPAH) [3]. According to a retrospective cohort study conducted in China, 1- and 3-year survival estimates were 92.1% and 75.1%, respectively, in patients with IPAH, and 85.4% and 53.6%, respectively, in patients with CTD-PAH. The data points to the fact that PAH imposes a considerable disease burden in the Chinese population [4].

Ambrisentan has been demonstrated to be efficacious and safe in the treatment of PAH [5–7]. Pivotal trials focusing on ambrisentan either as a monotherapy or in combination with other molecules have been predominantly conducted on the Caucasian population [3,8]. Few studies have investigated PAH in the Chinese population [6,9,10]. However, majority of the studies have focused on the functional tests for PAH (6-minute walk distance, Borg Dyspnea Index, etc.). Studies on echocardiographic assessments in Chinese patients with PAH who are treated with ambrisentan are very sparse.

According to the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines, echocardiography should always be performed to screen PAH [11]; however, echocardiography alone is not sufficient to confirm a diagnosis of PAH [3,12]. Echocardiography is a noninvasive ultrasound technique that involves measurement of pulmonary artery systolic pressure (PASP) for assessment of disease severity. It also helps in predicting the prognosis of patients with PAH [13]. These measurements have been used to demonstrate the improvement in changes in the right heart structure and reflect the changes in heart function in patients with PAH [14,15]. The present study was carried out to retrospectively evaluate the echocardiography data of patients with PAH who were treated with ambrisentan in a previous study (NCT01808313).

2. Methods

2.1. Study design

An open-label, phase IIIb, single-arm, non-interventional study was carried out to determine the effect of ambrisentan on exercise capacity (6-minute walk test) in the Chinese patients with PAH (NCT01808313). The study consisted of a screening period of 4 weeks, a 12-week primary evaluation period and a 12-week dose-adjustment period. Ambrisentan (5 mg) once daily was administered to eligible patients (n = 134) for a 12-week dose adjustment period, during which dose titration to 10 mg was allowed. The total duration of the study was 28 weeks. Details about the average daily dose and exposure have been reported elsewhere [6]. The present study was conducted to retrospectively evaluate the echocardiography data from patients who participated in NCT01808313 conducted from December 2012 to August 2014.

2.2. Patients

The details of the patient population and the study design used in the NCT01808313 study have been reported elsewhere [6]. Briefly, patients aged 18–75 years who had a diagnosis of symptomatic or severe PAH (World Health Organization functional class II or III), as defined in Group 1 of the current treatment guidelines [11], were enrolled. The present study included the patients who had received more than one dose of ambrisentan 5 mg or 10 mg and had previously provided written informed consent for the collection of echocardiograms as part of the NCT01808313 study. In addition, reports from the right heart catheterization performed within 6 months of screening had to demonstrate mPAP ≥25 mmHg, pulmonary vascular resistance ≥240 dyn.s.cm⁻⁵, and pulmonary arterial wedge pressure or left ventricular end diastolic pressure ≤ 15 mmHg. Patients were excluded if they had severe hypotension (diastolic blood pressure <50 mmHg or systolic blood pressure <90 mmHg), clinically significant aortic or mitral valve disease, pericardial constriction, or restrictive or congestive cardiomyopathy. Patients with life-threatening cardiac arrhythmias, left ventricle (LV) ejection fraction <45%, LV outflow obstruction, symptomatic coronary artery disease, autonomic hypotension or fluid depletion, and severe hepatic and renal impairment were also excluded.

The echocardiographic assessment was performed both at baseline and after administration of the study medication in the patients with PAH.

The current study retrospectively evaluated echocardiography data from the previous study (NCT01808313) where patients provided written informed consent for participation; a separate consent was not obtained for this retrospective analysis. This study was conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice and the ethical principles laid down in the Declaration of Helsinki (2008) and the study protocol was approved by the independent ethics committee or institutional review board at each center.

2.3. Echocardiography

The primary efficacy endpoints were change from baseline to Week 12 and Week 24 in the right heart structure, RV systolic function, and PASP prognosis. The secondary endpoint included change from baseline to Weeks 12 and 24 in LV diastolic function/filling improvement.

For mitral valve E/A ≥ 0.8, mitral valve E peak/mitral valve Em (E/e’) < 10, patients were considered to be showing normal diastolic function [16].

The detailed protocol for the assessment of echocardiographic parameters has been described elsewhere [17].

2.4. Statistical analysis

The analysis in the present study was conducted using the intent-to-treat (ITT) population from the NCT01808313 study. The observed values at assessment visits and change from baseline were summarized for the echocardiography data. A paired t-test was performed for comparison between baseline and Weeks 12 and 24. For change from baseline, 95% confidence interval was presented. The normality was explored by histogram plots. In case of a substantial deviation from normal distribution, Wilcoxon signed-rank test was used. Statistical significance was defined as p value < 0.05. The analysis was performed using SAS Version 9.4.

3. Results

Out of the 134 patients treated in the NCT01808313 study, the baseline and post-baseline echocardiographic data were available for 95 patients, which included CTD-PAH (n = 41) and non CTD-PAH (n = 54) subgroups. For the missing data of 39 patients, 22 patients were not included because their sites (4 sites) did not allow them to participate in the post-hoc analysis and 17 patients did not meet the inclusion criteria due to the lack of data. In the overall population, the mean age of the patients was 35.7 years and most of the patients were women (81%). The mean age of patients in the CTD-PAH and non CTD-PAH subgroups was 38.6 years and 33.6 years, respectively. The demographics and baseline characteristics of the patients for overall population and for the CTD-PAH and non CTD-PAH subgroups are presented in Tables 1 and S1.

Table 1. Demographics and baseline characteristics of patients: ITT population.

Characteristics	Ambrisentan (n = 95)
Mean age, years (SD)	35.7 (9.88)
Women, n (%)	77 (81.05)
Not Hispanic or Latino	95 (100)
BMI (kg/m^2), Mean (SD)	21.53 (3.27)
PAH classification, n (%):
CTD-PAH	41 (43.16)
Non CTD-PAH population:	54 (56.8)
IPAH	41 (43.16)
HPAH	3 (3.16)
PAH-Congenital Heart disease	10 (10.53)

BMI, body mass index; CTD, connective tissue disease; HPAH, hereditable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; ITT, intention to treat; PAH, pulmonary arterial hypertension; SD, standard deviation.

3.1. RV systolic function improvement

In the overall population, the mean tissue Doppler-derived tricuspid lateral annular systolic velocity (S’) increased by 0.6 cm/s at both Weeks 12 (p < 0.001) and 24 (p = 0.004) and tricuspid annular plane systolic excursion (TAPSE) increased by 0.13 cm at Week 12 (p < 0.001) and 0.15 cm at Week 24 (p < 0.001). The mean tricuspid A peak values showed a significant increase (5 cm/s; p = 0.007) at Week 12; however, this increase was not sustained until Week 24 (p = 0.69) (Table 2).

Table 2. Change from baseline in echocardiographic measures of right ventricle systolic function after ambrisentan treatment: ITT population.

	Week 12				Week 24
		Change from baseline			Change from baseline
Efficacy measures	n	Mean (SD)	p-value	n	Mean (SD)	p-value
Tissue Doppler–derived tricuspid lateral annular systolic velocity (S’) (cm/s)
Overall	74	0.6 (1.55)	<0.001	77	0.6 (1.86)	0.004
CTD-PAH	27	0.7 (1.75)	0.04	31	0.9 (1.85)	0.01
Non CTD-PAH	47	0.6 (1.44)	0.012	46	0.4 (1.87)	0.12
TAPSE (cm)
Overall	77	0.13 (0.32)	<0.001	82	0.15 (0.34)	<0.001
CTD-PAH	28	0.15 (0.33)	0.02	34	0.22 (0.28)	<0.001
Non CTD-PAH	49	0.12 (0.32)	0.01	48	0.09 (0.37)	0.09
Tricuspid E peak (cm/s)
Overall	71	–0.8 (18.5)	0.72	75	–2.5 (16.56)	0.2
CTD-PAH	26	4.2 (18.42)	0.26	32	0.7 (13.18)	0.77
Non CTD-PAH	45	–3.7 (18.13)	0.18	43	–4.9 (18.48)	0.09
Tricuspid A peak (cm/s)
Overall	71	5 (15.23)	0.007	75	0.6 (13.93)	0.69
CTD-PAH	26	8.3 (16.03)	0.014	32	2.4 (12.40)	0.28
Non CTD-PAH	45	3.1 (14.58)	0.16	43	–0.7 (14.96)	0.76
RV-arterial coupling (TAPSE/PASP): (cm/mmHg)
Overall	72	0.005 (0.008)	<0.0001	77	0.006 (0.011)	<0.0001
CTD-PAH	26	0.006 (0.009)	0.0010	32	0.009 (0.014)	0.0013
Non CTD-PAH	46	0.005 (0.007)	<0.0001	45	0.004 (0.007)	0.0002

*p-value is from paired t-test between baseline and post-baseline values.

CTD, connective tissue disease; ITT, intention to treat; PAH, pulmonary arterial hypertension; PASP, pulmonary artery systolic pressure; RV, right ventricular; SD, standard deviation; TAPSE, Tricuspid annular plane systolic excursion.

In subgroups CTD-PAH and non CTD-PAH, tissue Doppler-derived tricuspid lateral annular systolic velocity (S’) and TAPSE showed an increase from baseline values at Weeks 12 and 24. This increase was significant in the CTD-PAH subgroup at Weeks 12 (0.7; p = 0.04) and 24 (0.9; p = 0.01) and only at Week 12 (0.12; p = 0.01) in the non CTD-PAH subgroup (Table 2). There was a minor but statistically significant change from baseline in RV-arterial coupling in the overall population and subgroups CTD-PAH and non CTD-PAH at Weeks 12 and 24 (Table 2).

3.2. Right heart structure change

Overall, the right atrium (RA) diameter (major/longitudinal and minor/transverse), RV diameter (longitudinal and transverse), systolic eccentricity index (sEI) and diastolic eccentricity index (dEI) were decreased after ambrisentan treatment, indicating an improvement in the right heart structure. This improvement (decrease) observed in RV diameter (minor/transverse) was significant at both Weeks 12 and 24 (Week 12: – 0.12; p = 0.04; Week 24: – 0.28; p < 0.001) while the decrease in RA diameter (minor/transverse) was significant only at Week 24: – 0.14; p = 0.004. The decrease in RA and RV (longitudinal) noted at Weeks 12 and 24 was not significant. Significant improvement (decrease) in sEI was observed at Week 24 (p = 0.01) and in dEI at both Weeks 12 (p = 0.02) and 24 (p = 0.001) (Table 3).

Table 3. Change from baseline in echocardiographic measures of right heart structure after ambrisentan treatment: ITT population.

	Week 12			Week 24
		Change from baseline			Change from baseline
Efficacy measures	n	Mean (SD)	p-value	N	Mean (SD)	p-value
Right atrium diameter (major/longitudinal, cm)
Overall	74	–0.04 (0.74)	0.67	77	–0.12 (0.64)	0.11
CTD-PAH	26	0.13 (0.72)	0.37	32	–0.05 (0.58)	0.63
Non CTD-PAH	48	–0.13 (0.74)	0.24	45	–0.17 (0.68)	0.11
Right atrium diameter (minor/transverse, cm)
Overall	74	–0.14 (0.76)	0.11	77	–0.23 (0.68)	0.004
CTD-PAH	26	–0.22 (0.71)	0.13	32	–0.26 (0.53)	0.01
Non CTD-PAH	48	–0.1 (0.80)	0.37	45	–0.21 (0.77)	0.08
Right ventricular diameter (transverse, cm)
Overall	74	–0.12 (0.51)	0.04	77	–0.28 (0.42)	<0.001
CTD-PAH	26	–0.21 (0.45)	0.03	32	–0.38 (0.41)	<0.001
Non CTD-PAH	48	–0.08 (0.54)	0.33	45	–0.22 (0.42)	0.001
Right ventricular diameter (longitudinal, cm)
Overall	74	–0.07 (0.81)	0.43	77	–0.04 (0.66)	0.58
CTD-PAH	26	0.13 (0.85)	0.43	32	0.06 (0.63)	0.60
Non CTD-PAH	48	–0.19 (0.78)	0.10	45	–0.11 (0.68)	0.27
Systolic eccentricity index
Overall	76	0 (0.42)	0.38	80	–0.1 (0.4)	0.01
CTD-PAH	29	–0.1 (0.36)	0.05	34	–0.2 (0.41)	0.01
Non CTD-PAH	47	0 (0.45)	0.80	46	–0.1 (0.39)	0.17
Diastolic eccentricity index
Overall	75	–0.1 (0.24)	0.02	80	–0.1 (0.21)	0.001
CTD-PAH	29	–0.1 (0.24)	0.17	34	–0.1 (0.20)	0.002
Non CTD-PAH	46	–0.1 (0.24)	0.06	46	–0.1 (0.22)	0.11

*p-value is from paired t-test between baseline and post-baseline values.

CTD, connective tissue disease; ITT, intention to treat; PAH, pulmonary arterial hypertension; SD, standard deviation.

As shown in Table 3, a significant decrease in RA (p = 0.01) and RV (p < 0.001) diameter (transverse), sEI (p = 0.01), and dEI (p = 0.002) indices was observed in the CTD-PAH subgroup at Week 24. In the non CTD-PAH subgroup, only the right ventricular diameter (transverse) decreased significantly (p = 0.001) at Week 24. None of the other changes in the non CTD-PAH subgroup were significant.

3.3. Pulmonary artery systolic pressure prognosis

In the overall population, the decrease in the PASP from the baseline (82.8 mmHg) was significant at both Weeks 12 (–9.5; p < 0.001) and 24 (–7.6; p < 0.001). The decrease in the estimated right atrium pressure (eRAP) was found to be significant only at Week 24 (–0.8; p = 0.01).

In the CTD-PAH subgroup, a significant decrease was observed in the PASP at Weeks 12 (p = 0.03) and 24 (p = 0.03) as well as eRAP at Weeks 12 (p = 0.02) and 24 (p = 0.003). In the non CTD-PAH subgroup, the decrease in PASP was significant at Weeks 12 (p < 0.001) and 24 (p = 0.001); however, the change in eRAP was not significant at either time points (Table 4).

Table 4. Change from baseline in echocardiographic measures of pulmonary artery systolic pressure prognosis after ambrisentan treatment: intention-to-treat population.

	Week 12			Week 24
		Change from baseline			Change from baseline
Efficacy measures	n	Mean (SD)	p-value	N	Mean (SD)	p-value
Pulmonary artery systolic pressure (mm Hg)
Overall	74	–9.5 (18.33)	<0.001	77	–7.6 (16.38)	<0.001
CTD-PAH	27	–8.0 (17.65)	0.03	32	–7.2 (17.73)	0.03
Non CTD-PAH	47	–10.3 (18.83)	<0.001	45	–7.9 (15.55)	0.001
Estimated right atrium pressure (mm Hg)
Overall	76	–0.4 (3.03)	0.31	79	–0.8 (2.89)	0.01
CTD-PAH	28	–0.6 (1.37)	0.02	33	–0.9 (1.58)	0.003
Non CTD-PAH	48	–0.2 (3.67)	0.73	46	–0.8 (3.57)	0.14

*p-value is from paired t-test between baseline and post-baseline values.

CTD-PAH, connective tissue disease-pulmonary arterial hypertension; ITT, intention to treat; PAH, pulmonary arterial hypertension; SD, standard deviation.

3.4. Pericardial effusion

Overall, pericardial effusion was observed in 24% (n = 22/91) of the patients at baseline. A decrease in pericardial effusion score was observed for 13 patients (59.1%) at Week 24.

In the CTD-PAH subgroup, 10 patients had pericardial effusion at baseline. An improvement (decrease) was observed in 20% patients (2/10) at Week 12 and 60% patients (6/10) at Week 24 while an increase was observed in 4 patients at Week 12 and 1 patient at Week 24.

In the non CTD-PAH subgroup, 12 patients were identified with pericardial effusion at baseline. A decrease in pericardial effusion volume from baseline was observed in 6 patients at Week 12 and 7 patients at Week 24. An increase was observed for 5 subjects at Week 12 and for 4 subjects at Week 24.

3.5. Left ventricle diastolic function/filling improvement

In the overall population, a significant increase in the LV end-diastolic diameter was observed at Weeks 12 (p < 0.001) and 24 (p = 0.01) and mitral valve E peak at Weeks 12 (p < 0.001) and 24 (p < 0.001). The mean tissue Doppler-derived early diastolic mitral annular velocity (Em) value at baseline was 9.0 cm/s, which increased significantly at Week 24 (p = 0.005) but not at Week 12. The mitral valve A peak, tissue Doppler-derived tricuspid lateral annular systolic velocity (S’), and tissue Doppler-derived late diastolic mitral annular velocity (Am) values at Week 12 and Week 24 were higher but not significantly different from their corresponding values at baseline (Table 5).

Table 5. Change from baseline in echocardiographic measures of left ventricle diastolic function after ambrisentan treatment: ITT population subgroups.

	Week 12			Week 24
		Change from baseline			Change from baseline
Efficacy measures	n	Mean (SD)	p-value	N	Mean (SD)	p-value
Left ventricular end-diastolic diameter (cm)
Overall	76	0.21 (0.51)	<0.001	79	0.16 (0.51)	0.01
CTD-PAH	28	0.23 (0.5)	0.03	33	0.27 (0.55)	0.01
Non CTD-PAH	48	0.20 (0.51)	0.01	46	0.07 (0.47)	0.3
Mitral valve E peak (cm/s)
Overall	73	8.6 (21.06)	<0.001	76	8.9 (17.28)	<0.001
CTD-PAH	26	6.1 (31.04)	0.33	30	14.3 (19.81)	<0.001
Non CTD-PAH	47	10 (12.85)	<0.001	46	5.5 (14.61)	0.01
Mitral valve A peak (cm/s)
Overall	73	1.4 (18.21)	0.51	76	3.1 (15.26)	0.08
CTD-PAH	26	–1.2 (21.11)	0.78	30	5 (16.13)	0.1
Non CTD-PAH	47	2.9 (16.45)	0.24	46	1.9 (14.72)	0.39
Tissue Doppler-derived tricuspid lateral annular systolic velocity (S’) (cm/s)
Overall	66	0 (1.75)	1	69	0.1 (2)	0.81
CTD-PAH	23	–0.5 (1.56)	0.16	31	–0.2 (1.75)	0.61
Non CTD-PAH	43	0.3 (1.8)	0.36	38	0.2 (2.19)	0.51
Tissue Doppler-derived early diastolic mitral annular velocity (Em) (cm/s)
Overall	66	0.8 (3.21)	0.06	69	1 (2.99)	0.005
CTD-PAH	23	0.2 (2.86)	0.72	31	1.2 (2.81)	0.02
Non CTD-PAH	43	1.1 (3.38)	0.04	38	0.9 (3.15)	0.09
Tissue Doppler-derived late diastolic mitral annular velocity (Am) (cm/s)
Overall	64	0.3 (2.71)	0.34	69	0.5 (2.96)	0.20
CTD-PAH	22	0 (2.67)	1	31	0.5 (1.98)	0.13
Non CTD-PAH	42	0.5 (2.75)	0.25	38	0.4 (3.6)	0.50

*p-value is from paired t-test between baseline and post-baseline values.

CTD, connective tissue disease; ITT, intention to treat; PAH, pulmonary arterial hypertension; SD, standard deviation.

There was an increase in the number of patients in the normal range in mitral valve E/A after ambrisentan treatment. The number of patients which lie in the normal range of combined E/A > 0.8 and E/e’ < 10 were 49, 51, 52 at baseline, Week 12, and Week 24, respectively.

A significant increase in the LV end-diastolic diameter was observed at Week 12 in both CTD-PAH (p = 0.03) and non CTD-PAH (p = 0.01) subgroups and at Week 24 only in CTD-PAH subgroup (p = 0.01) (Table 5). A significant increase in tissue Doppler-derived early diastolic mitral annular velocity (Em) was observed at Week 24 in the CTD-PAH subgroup (p = 0.02) and at Week 12 in the non CTD-PAH (p = 0.04) subgroup. A significant increase was also observed in mitral valve E peak (p < 0.001) at all the time points except in the CTD-PAH subgroup at Week 12. For other parameters, such as mitral valve A peak, tissue Doppler-derived tricuspid lateral annular systolic velocity (S’), and tissue Doppler-derived early diastolic mitral annular velocity (Em), the change was not significant.

4. Discussion

This retrospective study was planned to conduct additional analyzes from the completed NCT01808313 study, which evaluated the efficacy and safety of ambrisentan in Chinese patients with PAH by performing functional tests and biochemical assays [6]. In the present study, echocardiographic data of patients with PAH from the NCT01808313 study was analyzed to gain insights in the structural and functional changes of the heart by estimating the change from baseline in major prognostic factors. The echocardiographic data demonstrated that ambrisentan leads to an improvement in RV and LV structure and function and systolic and diastolic function in the overall population and in both the subgroups (CTD-PAH and non CTD-PAH). The patient population comprised women and men in the ratio of 4:1. Literature reports that women are more vulnerable to PAH than men [18]. Higher levels and altered metabolism of estrogen, lower levels of testosterone, and differential signaling have been identified to be the likely reasons responsible for this gender difference [19,20].

There was an improvement in RV structure remodeling and TAPSE with ambrisentan therapy at Weeks 12 and 24 in the overall population and the CTD-PAH subgroup. Previous studies have reported an increase in TAPSE values by around 0.5 cm with ambrisentan and tadalafil combination therapy in systemic sclerosis-PAH patients in 36 weeks [21] and a retrospective study with vasodilator combination therapy (ambrisentan was included as one of the components) [14]. This is in agreement with our results where a significant improvement of 0.15 cm and 0.22 cm was observed in TAPSE with ambrisentan treatment at Week 24 in the overall population and CTD-PAH subgroup, respectively. Contrastingly, a lower trend in TAPSE values was observed in a study where prostacyclin therapy was administered to patients with IPAH [15].

A meta-analysis, which captured the information from four Chinese studies, reported a significant decrease in PASP levels in patients with PAH who received ambrisentan Treatment [22]. According to the European Society of Cardiology/European Respiratory Society guidelines, an increase or decrease in PASP does not confirm an improvement or worsening of PAH. Changes in RV and RA, LV, EI, and TAPSE have been identified as important factors contributing to the improvement of PAH [3].

We were able to observe improvement at Week 24 in RA and RV diameter (transverse) and sEI and dEI in the overall population and the CTD-PAH subgroup. The decrease was, however, not significant at Week 12 in any of the populations. The major reason for this observation is that the investigative duration was not long enough for a significant change to occur. Previous reports have suggested a potent role of vasodilator therapies, including ambrisentan and prostacyclin, in improving the RV function. A comparable decrease of – 0.32 cm in RV diameter was reported with vasodilator therapies in IPAH subgroup in comparison to – 0.28 cm at Week 24 in the present study with ambrisentan treatment [14]. RV basal diameter was significantly larger (1 cm) in the patients after treatment with prostacyclin where majority of the patients fell in the IPAH subgroup [15]. EI measures the deformity in the LV but does not take into account the altered RV dimension, thus estimating the difference between volume and pressure overload of the right heart [23]. In the present study, a significant decrease was observed in RV diameter (transverse) and LV diameter at Weeks 12 and 24 in the overall population and the CTD-PAH subgroup. The improvement in LA size has been reported previously [14]. This could be due to the improvement in cardiac output and left-sided filling in response to ambrisentan treatment.

The present study reports the presence of 24% pericardial effusion with a mPAP of ≥25 mmHg, which is much lesser than that reported in literature, i.e. 47–48% pericardial effusion with a mPAP of >15 mmHg [13,24].

The study shows that the number of patients which lie in the normal range of combined E/A > 0.8 and E/e’ < 10 were 49, 51, 52 at baseline, Week 12, and Week 24, respectively. This implies that there was an improved trend in LV diastolic function after ambrisentan treatment from baseline to Weeks 12 and 24, which could be possibly due to an improvement in RV function. A review by Mitter et al [25] describes the role of E/A and E/e’ ratios in the advancement of echocardiographic diastolic function assessment. These ratios have been identified as effective tools in understanding the pathophysiology of heart failure and heart disease [25].

A major limitation in the study was the absence of a placebo or a comparator group. Moreover, out of 134 patients, echocardiographic data was missing for 39 patients. Despite these limitations, this remains a sizable echocardiographic study in Chinese patients with PAH. To the best of our knowledge, this is the first study evaluating the effect of ambrisentan on RV structure and function in Chinese patients with PAH. These findings also suggest that echocardiography can be effectively utilized to detect the treatment-associated improvement in RV structure and function in studies on patients with PAH. Moreover, according to the 2015 ESC/ERS guidelines for the diagnosis and the treatment of pulmonary hypertension, echocardiographic evaluation is necessary during follow-up in clinical practice [11].

5. Conclusions

Significant improvements in a number of echocardiographic parameters were observed at Week 12 and the effect was maintained up to 24 weeks after ambrisentan treatment in patients with PAH. A similar trend of improvement was observed in CTD and non CTD subgroups of ambrisentan-treated patients with PAH.

Article highlights

• Echocardiography of ambrisentan-treated pulmonary arterial hypertension (PAH) patients

• A number of echocardiographic parameters showed significant improvements at Week 12

• The effect was maintained up to 24 weeks with ambrisentan treatment

• Ambrisentan improved PAH in connective tissue disease (CTD) and non CTD subgroups

Declaration of interest

JH Li and L Zi were employed by GlaxoSmithKlein during the investigation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. 

Acknowledgments

The authors acknowledge the support of investigators, staff, and study volunteers for participation in the study. Medical writing assistance was provided by Ruchi Gupta (Tata Consultancy Services, India) and funded by GlaxoSmithKline.

Additional information

Funding

This paper was funded by GlaxoSmithKlein (China) R&D Company Limited.