Skip to main content
Download PDF

Efficacy and safety of ambrisentan in Chinese patients with connective tissue disease-pulmonary arterial hypertension: a post-hoc analysis

BMC Cardiovascular Disorders volume 20, Article number: 339 (2020) Cite this article

Abstract

Background

The efficacy and safety of ambrisentan has been previously evaluated in Chinese patients with pulmonary arterial hypertension (PAH). This post-hoc analysis assessed the efficacy and safety of ambrisentan in a subgroup of connective tissue disease (CTD) patients with PAH.

Methods

In this open-label, single-arm study, patients received ambrisentan 5 mg once daily for 12 weeks, followed by 12-week dose titration period (dose up to 10 mg). Efficacy endpoints included change from baseline in exercise capacity (measured by 6-min walk test [6MWT]), N-terminal pro B type natriuretic peptide (NT-proBNP) plasma levels, WHO Functional Class (FC) and Borg Dyspnoea Index (BDI) scores from baseline to weeks 12 and 24. Safety endpoints included time to clinical worsening and incidence of adverse events (AEs).

Results

In total, 71 Chinese patients with CTD-PAH were included in this analysis. Ambrisentan treatment significantly improved exercise capacity (6MWT) from baseline (mean: 366.4 m) to week 12 (63.8 m, p < 0.001) and week 24 (73.2 m, p < 0.001). A significant reduction in NT-proBNP levels was observed from baseline (mean: 1837.5 ng/L) to week 12 (− 1156.8 ng/L, p < 0.001) and week 24 (− 1095.5 ng/L, p < 0.001). BDI scores decreased significantly at week 12 (− 0.6, p < 0.001) and week 24 (− 0.4, p = 0.002) from baseline (mean: 2.7). The WHO FC improved in 29 (40.8%) and 34 (47.9%) patients at weeks 12 and 24, respectively. Adverse events were reported in 52 (73.2%) patients. One patient (1.4%) experienced clinical worsening at week 24.

Conclusion

Ambrisentan showed significant improvement in exercise capacity and no clinical worsening in the majority of Chinese patients with CTD-PAH in the 24-week treatment period. The AEs observed in the CTD-PAH subgroup were consistent with the known safety profile of ambrisentan in the overall Chinese PAH population.

Trial registration

ClinicalTrial.gov Identifier, https://clinicaltrials.gov/, NCT01808313 Registration date (first time): February 28, 2013.

Peer Review reports

Background

Pulmonary arterial hypertension (PAH) is a frequent and severe complication in patients with connective tissue diseases (CTD), a group of disorders which adversely affects the cardiac and the respiratory system. It is also known to have non-respiratory complications, such as renal disorders [1]. CTD is characterised by vascular injury, autoimmunity, tissue inflammation and organ dysfunction including systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and mixed CTD [2]. PAH affects approximately 3 to 13% of CTD patients (CTD-PAH), and it is one of the leading causes of death [3,4,5]. A recent registry in China has reported that out of all patients diagnosed with PAH, 43% had CTD-PAH [6]. High doses of steroids and immune suppressants have demonstrated beneficial effect in the treatment of CTD-PAH [7]. The use of vasodilators has been recommended in WHO functional class II to class IV patients [8]. Since immunosuppressive therapy does not provide long-term benefits, it is recommended to use vasodilators in combination with immunosuppressants for the treatment of CTD-PAH [1, 9, 10].

Ambrisentan, a vasodilator, which is an endothelin-A (ETA) receptor-selective antagonist. It is approved for the treatment of patients with PAH (World Health Organisation [WHO] functional class [FC] II or III symptoms) at oral doses of 5 and 10 mg once daily. The efficacy of ambrisentan, both alone and in combination, has been evaluated in previous studies in patients with CTD-PAH and the results have demonstrated an improvement in exercise capacity [11, 12] and freedom from clinical worsening in 80% of the patients at 1 year [11]. These studies included higher proportion of Caucasians and patients of Asian ethnicity were very limited.

The available data suggest that patients with CTD-PAH may have an attenuated response to short-term treatment than other forms of PAH [13], though they have a similar response to long-term treatment [14]. This could be explained by the heterogeneity in the treatment response in patients with PAH and wide variety of significant comorbidities such as rheumatoid arthritis, dermatomyositis, polymyositis, interstitial lung disease, limited mobility and deconditioning commonly seen in patients with CTD-PAH [15, 16]. In addition to the observed heterogeneity in treatment response, there is insufficient data in the existing literature for CTD-PAH subgroup that necessitate the understanding of specific therapeutic needs in managing individuals with different ethnicities. In the recent study conducted in Chinese patients with PAH, it was shown that ambrisentan improved exercise capacity, measured by 6-min walk test (6MWT) in the 24-week treatment period [17]. This study included about 53% patients with CTD at baseline, thus providing an opportunity to evaluate whether ambrisentan is efficacious in patients with CTD-PAH to the same extent as in the overall PAH population. The present post-hoc subgroup analysis was performed to evaluate the efficacy of ambrisentan in improving exercise capacity in Chinese patients with CTD-PAH. Additionally, we provided data on the patients with idiopathic PAH/heritable PAH (IPAH/HPAH) to explore the difference in response to treatment based on underlying disease.

Methods

Study design

An open-label, phase IIIb, single-arm study was conducted in China in patients with PAH between 21 December 2012 and 15 August 2014 (NCT01808313). The detailed study design and results of the study have been reported elsewhere [17]. This post-hoc analysis was conducted using a subgroup of patients with CTD-PAH and IPAH/HPAH. Briefly, eligible patients received oral 5 mg ambrisentan once daily for 12 weeks in the primary evaluation period, followed by a 12-week dose adjustment period, during which the dose of ambrisentan was titrated to 10 mg depending on patients’ dose tolerance [17].

All patients provided written informed consent before any study-specific procedure was performed. The study was conducted in accordance with International Conference on Harmonisation guidelines for Good Clinical Practice and the ethical principles laid down in the Declaration of Helsinki (2008). The study protocol was approved by independent ethics committee or institutional review board at each centre. The affiliations of all the ethics committees (IECs) that approved the study are available in the additional file. Anonymised individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

Patients

Patients aged 18–75 years who had a diagnosis of symptomatic or severe PAH (WHO FC II or III), as defined in Group 1 of the current treatment guidelines [18], were enrolled in the study. Patients were included if they performed the 6MWT with a minimum distance of 150 m and a maximum distance of 450 m, had a right heart catheterisation performed within 6 months of screening with mean pulmonary artery pressure ≥ 25 mmHg; pulmonary vascular resistance ≥240 dyne.sec.cm− 5; and pulmonary capillary wedge pressure or left ventricular end diastolic pressure ≤ 15 mmHg. Patients with serum transaminase values > 2 times upper limit of normal (ULN), serum bilirubin > 1.5 times ULN, or haemoglobin concentration < 10 g/dL at baseline were excluded from the study. CTD patients were in an inactive state after the treatment of steroid with or without immunosuppresants. The detailed inclusion and exclusion criteria of patients have been described previously [17].

Study assessments

This subgroup analysis assessed all primary and secondary endpoints from the primary study except for echocardiography assessments. The primary efficacy endpoint was change from baseline to week 12 in the exercise capacity, as measured by 6MWT. Other efficacy endpoints included change in 6MWT from baseline to week 24 and change in N-terminal pro B type natriuretic peptide (NT-proBNP) plasma levels, WHO FC and Borg Dyspnoea Index (BDI) scores from baseline to weeks 12 and 24. Changes in 6MWT, WHO FC and BDI scores were assessed at every visit, scheduled at 4-week intervals and changes in NT-pro BNP levels were assessed at weeks 12 and 24. Additionally, the effect of ambrisentan on heart rate recovery (defined as difference in heart rate at the end of 6MWT and at 1/2/3 min after completion of the 6MWT) at 1 min (HRR1min), 2 min (HRR2min) and 3 min (HRR3min) post-exercise was assessed.

Time to clinical worsening of PAH (defined as time from baseline to first occurrence of death, lung transplantation, hospitalisation for PAH treatment, atrial septostomy or discontinuation of ambrisentan due to change to other PAH treatment) was assessed.

Safety and tolerability assessments included monitoring and recording of adverse events (AEs) and serious AEs (SAEs), laboratory assessments, liver function tests, 12-lead electrocardiogram (ECG) and vital sign measurements.

Statistical analysis

Efficacy analyses were performed on the intent-to-treat (ITT) population, which consisted of all patients with CTD-PAH and IPAH/HPAH who received at least one dose of ambrisentan and had baseline and at least one post-baseline efficacy assessment.

The change from baseline in 6MWT was assessed using a paired t-test. Changes in plasma NT-proBNP levels and BDI were assessed using a Wilcoxon Signed-Rank test. WHO FC outcomes were summarised descriptively in both CTD-PAH and IPAH/HPAH subgroups and the comparison between the CTD-PAH and IPAH/HPAH subgroups was performed using Chi-square test. The change in 6MWT was compared between CTD-PAH and IPAH/HPAH subgroups using a 2-group t-test. The last observation carried forward (LOCF) method was used to impute missing data for 6MWT, WHO FC and BDI assessments.

Time to clinical worsening was reported using Kaplan-Meier estimates along with corresponding 95% confidence intervals. Overall safety data were summarised descriptively. The safety population included all patients with CTD-PAH and IPAH/HPAH who received at least one dose of ambrisentan. Statistical analyses were conducted using SAS® Version 9.4.

Results

Patient disposition and baseline characteristics

Of the 134 patients with PAH enrolled in the primary study [17], all received at least one dose of ambrisentan and were included in the safety analyses. One subject did not have post-baseline assessments, and thus 133 patients were included in the ITT population. A total of 71 patients (53.4% of the overall ITT population) had CTD-PAH at baseline, data from whom were used in the current subgroup analysis. Sixty-seven (94.4%) patients completed the study and four patients discontinued the study — two patients discontinued due to a protocol deviation, one discontinued due to protocol-defined stopping criteria and one discontinued due to an adverse event. The demographics and baseline characteristics of the CTD-PAH and IPAH/HPAH subgroups are summarised in Table 1. Among patients with CTD-PAH, the mean age of patients was 39.0 years; 97% of the patients were women. The WHO FC at baseline was predominantly class II or III. For the CTD-PAH subgroup, the mean duration of exposure of ambrisentan was 164.6 days. The CTD medications at baseline primarily included, hydroxychloroquine, glucocorticoids and immunosuppressants. All patients enrolled were inactive CTD with or without CTD medications. Of the 71 patients with CTD-PAH, data is available for 64 patients (SLE-CTD-PAH = 41 patients and Non SLE-CTD-PAH = 23 patients) in the supplementary Fig. 1, Table 1 and Table 2.

Table 1 Patient demographics and baseline characteristics (ITT population): post-hoc analysis
Full size table
Table 2 Mean change from baseline in 6MWT, BDI scores, and NT-proBNP levels after treatment with ambrisentan (ITT population): post-hoc analysis
Full size table

Efficacy

The time course of mean change from baseline in 6MWT in 24 weeks of treatment with ambrisentan is presented for patients with CTD-PAH in Fig. 1. In the CTD-PAH subgroup, a significant improvement of 63.8 m in 6MWT (baseline 366.4 m) was observed at 12 weeks and 73.2 m at 24 weeks of treatment with ambrisentan (p < 0.001 for both week 12 and week 24). The improvements in 6MWT were also significant for IPAH (p < 0.01). The improvement in 6MWT in the CTD-PAH subgroup was greater compared with the IPAH/HPAH subgroup resulting in a between-group difference of − 18.39 m at 12 weeks (p = 0.115) and − 10.97 m at 24 weeks (p = 0.478) (Table 2); however, the difference was not statistically significant.

Fig. 1
figure 1

Improvement in 6MWT over 24 weeks following ambrisentan treatment (patients with connective tissue disease) (ITT population-LOCF): post-hoc analysis. 6MWT, 6-min walk test; ITT, intent-to-treat; LOCF, last observation carried forward

Full size image

In the CTD-PAH subgroup, an improvement of 0.6 in BDI score (baseline 2.7) was observed at 12 weeks (p < 0.001) and 0.4 at 24 weeks (p = 0.002) of treatment with ambrisentan. The improvement in BDI scores was greater in the CTD-PAH subgroup compared with the IPAH/HPAH subgroup with a between-group difference of 0.35 and 0.19 at weeks 12 and 24, respectively; however, the difference was not statistically significant (Table 2).

In the CTD-PAH subgroup, NT-proBNP levels decreased significantly with ambrisentan treatment at week 12 (− 1156.8 ng/L, p < 0.001) and week 24 (− 1095.5 ng/L, p < 0.001) compared to baseline (mean 1837.5 ng/L). The reductions in NT-proBNP at weeks 12 and 24 were significant in both CTD-PAH (p < 0.001) and IPAH/HPAH (p < 0.001) subgroups, but the reduction in NT-proBNP at weeks 12 and 24 was greater in the CTD-PAH subgroup compared with the IPAH/HPAH subgroup (Table 2).

The WHO FC improved by one class in 29 (40.8%) patients at week 12 (improved from class III to II) and 34 (47.9%) patients at week 24 (class III to II, n = 31; class II to I, n = 3) in the CTD-PAH subgroup. Three patients at week 12 (worsened from class II to III) and two at week 24 (one patient worsened from class II to III and one patient worsened from class III to IV) showed deterioration in FC. A greater proportion of patients in CTD-PAH subgroup showed improvement in WHO FC at weeks 12 and 24 compared with IPAH/HPAH subgroup (Fig. 2).

Fig. 2
figure 2

Patients categorized under WHO functional classification after treatment with ambrisentan (ITT population-LOCF): post-hoc analysis of CTD-PAH and IPAH/HPAH sub-groups. CTD, connective tissue disease; HPAH, Heritable PAH; IPAH, Idiopathic PAH; ITT, intent-to-treat; LOCF, last observation carried forward; PAH, pulmonary arterial hypertension; WHO, World Health Organisation

Full size image

In the CTD-PAH subgroup, a significant decrease in heart rate recovery was observed at 1 and 2 min post-exercise at 24 weeks of treatment with ambrisentan (change in heart rate recovery from baseline: − 3.0 and − 3.5 beats/min from baseline at 1 and 2 min post-exercise, p < 0.05).

Safety

In the CTD-PAH subgroup, 52 (73.2%) patients experienced at least one AE (Table 3). One SAE (1.4%) was reported, which resulted in death. However, the death occurred due to cardiac failure and was not associated with ambrisentan treatment. The most common AE was flushing (n = 9 [12.7%]). Most of the AEs were mild (41%) or moderate (27%) in intensity. Six patients (8.5%) experienced SAEs that included bronchitis, lung infection, pneumonia, ascites, diarrhoea, cardiac failure and cystitis glandularis. None of these SAEs were considered to be related to ambrisentan treatment by the investigator. Elevation of AST and ALT was noted in 4.2 and 5.6% in the CTD-PAH and 11.8 and 9.8% in the IPAH/HPAH subgroups, respectively. Clinical worsening of PAH occurred in one (1.4%) patient, which resulted in death. Kaplan-Meier estimate of clinical worsening at week 24 was 98.5%. No significant changes were noted in the haematology parameters. No clinically relevant changes in vital signs, ECG and physical examination were observed.

Table 3 Summary of safety (safety population): post-hoc analysis
Full size table

Discussion

The results of this subgroup analysis showed that ambrisentan treatment significantly improved exercise capacity, as measured by the 6MWT, in Chinese patients with CTD-PAH as well as IPAH/HPAH. It was noteworthy that almost all the patients (97%) were women. Differential signalling, altered levels and altered metabolism of oestrogen have been reported to be the underlying factors responsible for the frequent occurrence of PAH in women than in men [19]. Almost all the patients in the CTD-PAH subgroup showed no clinical worsening up to 24 weeks of treatment with ambrisentan.

Following 12 weeks of treatment, the exercise capacity was significantly improved for patients in both CTD-PAH and IPAH/HPAH subgroups. The increase was noted further up to 24 weeks of treatment. The improvement seen in the CTD-PAH subgroup was more pronounced than that observed in the IPAH/HPAH subgroup; however, the between-group difference was not statistically significant. The improvement in exercise capacity in patients with CTD-PAH was also greater than that observed in the overall Chinese PAH population (53.6 m at week 12 and 64.4 m at week 24 from a baseline of 377.1 m) [17]. Additionally, the improvement in exercise capacity observed in this study in Chinese patients with CTD-PAH was substantially higher than that observed in a previous study in Caucasian patients with CTD-PAH [12, 20]. Although in this study, the magnitude of increase in 6MWT was greater in Chinese patients compared with Caucasians in other studies; this could be due to difference in disease characteristics of PAH associated with CTD between Chinese and Caucasian populations. The increased prevalence of SLE as underlying disease in Chinese patients compared with SSc in Caucasians may have resulted in better improvement in 6MWT in this subgroup analysis [12, 21].

The increased exercise capacity in 6MWT after treatment with ambrisentan was further supported by the significant improvement in BDI scores for patients with CTD-PAH but not for patients with IPAH/HPAH. In patients with CTD-PAH, the improvement seen in BDI scores was higher than the corresponding improvement seen in the overall population in the study (− 0.6 vs. -0.2 at week 12 and − 0.4 vs. -0.2 at week 24) indicating the pronounced effect of ambrisentan in CTD-PAH population [17]. These results are in agreement with previous studies, where improvement in BDI scores were observed at 12 and 24 weeks with both 5 mg and 10 mg doses [13, 22].

Clinical improvements were also observed in other efficacy parameters in this analysis. The NT-proBNP levels were significantly reduced in both CTD-PAH as well as IPAH/HPAH subgroups at 12 weeks of treatment, but the effect was more pronounced in the CTD-PAH subgroup. CTD-PAH and IPAH/HPAH subgroups did not show further improvements in plasma BNP levels, following 24 weeks of treatment. The decrease in NT-proBNP levels at 12 weeks of treatment with ambrisentan in patients with CTD-PAH was slightly higher to that observed in the overall PAH population in the study [17]. In contrast, there was 30 and 45% reduction in BNP levels at 5 mg and 10 mg doses of ambrisentan, respectively, in the ARIES-1 study [13].

Considering the progressive nature of disease, it is important to note the effect of ambrisentan on WHO FC. More than 40% of CTD-PAH patients and approximately 30% of IPAH/HPAH patients showed improvement in WHO FC in the present analysis. Among the overall PAH population in the study, 33.1 and 38.3% of the patients showed improvement in WHO FC at 12 and 24 weeks, respectively [17]. In the IPAH/HPAH subgroup, majority of the patients had not shown improvement in WHO FC, indicating less pronounced effect of ambrisentan in this subgroup. Previously, ambrisentan treatment has shown improvement in WHO FC in dose groups ranging from 2.5–10 mg in 12 weeks as well as 2 years [13, 22].

The heart rate recovery at 1 and 2 min post-exercise was faster following ambrisentan treatment at week 24. This finding was of significance as heart rate recovery post-exercise is known to be a strong predictor of clinical worsening and survival in patients with PAH [23, 24].

The majority of the AEs observed with ambrisentan were mild to moderate in intensity. The safety findings observed in the present analysis were similar to that in the earlier studies conducted in Western and overall Chinese PAH population [13, 17, 22, 24].

The results of the current subgroup analysis showed that the efficacy of ambrisentan is at least of a similar magnitude to, and possibly greater in, CTD/PAH than IPAH/HPAH. However, due to limited sample size of the subgroup and short-term treatment duration, definite conclusions cannot be derived. Nonetheless, results of the current analysis provide substantial evidence regarding the efficacy of ambrisentan in CTD-PAH population and warrant further research in this direction.

Conclusions

Ambrisentan showed significant improvement in exercise capacity in Chinese patients with CTD-PAH. Most of the patients in the CTD-PAH subgroup showed either improvement in the WHO FC or no change; almost all patients in the CTD-PAH subgroup did not show any clinical worsening. The AEs observed in the CTD-PAH subgroup were consistent with the known safety profile of ambrisentan in the overall Chinese PAH population.

Availability of data and materials

Anonymised individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

Abbreviations

ALT:

Alanine aminotransfera

AST:

Aspartate aminotransferase

AEs:

Adverse events

BDI:

Borg Dyspnoea index

CTD:

Connective tissue disease

ECG:

Electrocardiogram

ETA :

Endothelin-a

FC:

Functional class

HPAH:

Heritable PAH

HRR:

Heart rate recovery

IPAH:

Idiopathic PAH

ITT:

Intent-to-treat

LOCF:

Last observation carried forward

NT-proBNP:

N-terminal pro B type natriuretic peptide

PAH:

Pulmonary arterial hypertension

SAEs:

Serious AEs

SLE:

Systemic lupus erythematosus

SSc:

Systemic sclerosis

ULN:

Upper limit of normal

WHO:

World Health Organisation

6MWT:

6-min walk test

References

  1. Shirai Y, Yasuoka H, Okano Y, Takeuchi T, Satoh T, Kuwana M. Clinical characteristics and survival of Japanese patients with connective tissue disease and pulmonary arterial hypertension: a single-Centre cohort. Rheumatology. 2012;51:1846–54.

    Article  Google Scholar 

  2. Yang X, Mardekian J, Sanders KN, Mychaskiw MA, Thomas J 3rd. Prevalence of pulmonary arterial hypertension in patients with connective tissue diseases: a systematic review of the literature. Clin Rheumatol. 2013;32(10):1519–31.

    Article  Google Scholar 

  3. Galie N, Manes A, Farahani KV, Pelino F, Palazzini M, Negro L, et al. Pulmonary arterial hypertension associated to connective tissue diseases. Lupus. 2005;14:713–7.

    Article  CAS  Google Scholar 

  4. Hachulla E, De Groote P, Gressin V, Sibilia J, Diot E, Carpentier P, et al. The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France. Arthritis Rheum. 2009;60(6):1831–9.

    Article  Google Scholar 

  5. Mukerjee D, St George D, Coleiro B, Knight C, Denton CP, Davar J, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003;62(11):1088–93.

    Article  CAS  Google Scholar 

  6. Lau EM, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol. 2017;14(10):603–14.

    Article  CAS  Google Scholar 

  7. Jais X, Launay D, Yaici A, Le Pavec J, Tcherakian C, Sitbon O, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease–associated pulmonary arterial hypertension a retrospective analysis of twenty-three cases. Arthritis Rheum. 2008;58(2):521–31.

    Article  Google Scholar 

  8. Tang C-P, Lee K-L, Ying K-Y. Review of the diagnosis and pharmacological management of pulmonary arterial hypertension in connective tissue disease. Hong Kong Bull Rheum Dis. 2016;16(1):14–22.

    Article  Google Scholar 

  9. Yasuoka H, Shirai Y, Tamura Y, Takeuchi T, Kuwana M. Predictors of favorable responses to immunosuppressive treatment in pulmonary arterial hypertension associated with connective tissue disease. Pulmon Circ. 2018;82(2):546–54.

    CAS  Google Scholar 

  10. Fukuda K, Date H, Doi S, Fukumoto Y, Fukushima N, Hatano M. Guidelines for the treatment of pulmonary hypertension (JCS 2017/JPCPHS 2017). Circ J. https://doi.org/10.1253/circj CJ-66-0158.

  11. Fischer A, Denton CP, Matucci-Cerinic M, Gillies H, Blair C, Tislow J, et al. Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) - a subgroup analysis of the ARIES-E clinical trial. Respir Med. 2016;117:254–63.

    Article  Google Scholar 

  12. Coghlan JG, Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, et al. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial. Ann Rheum Dis. 2017;76(7):1219–27.

    Article  CAS  Google Scholar 

  13. Galiè N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117(23):3010–9.

    Article  Google Scholar 

  14. Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809–18.

    Article  CAS  Google Scholar 

  15. Rhee RL, Gabler NB, Sangani S, Praestgaard A, Merkel PA, Kawut SM. Comparison of treatment response in idiopathic and connective tissue disease-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;192(9):1111–7.

    Article  CAS  Google Scholar 

  16. Gutsche M, Rosen GD, Swigris JJ. Connective tissue disease-associated interstitial lung disease: a review. Curr Respir Care Rep. 2012;1:224–32.

    Article  CAS  Google Scholar 

  17. Huo Y, Jing ZC, Zeng XF, Liu JM, Yu ZX, Zhang GC, et al. Evaluation of efficacy, safety and tolerability of ambrisentan in Chinese adults with pulmonary arterial hypertension: a prospective open label cohort study. BMC Cardiovasc Disord. 2016;16(1):201.

    Article  CAS  Google Scholar 

  18. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Heart J. 2016;37(1):67–119.

    Article  Google Scholar 

  19. Pugh ME, Hemnes AR. Pulmonary hypertension in women. Expert Rev Cardiovasc Ther. 2010;8(11):1549–58.

    Article  Google Scholar 

  20. Galiè N, Richards D, Hutchinson T, Dufton C. on behalf of the ARIES Study Group. Ambrisentan therapy for patients with PAH associated with connective tissue disease (PAH-CTD): one year follow-up. In: European Respiratory Society Annual Congress Berlin; 2008. Abstract E1418.

    Google Scholar 

  21. Hao YJ, Jiang X, Zhou W, Wang Y, Gao L, Wang Y, et al. Connective tissue disease-associated pulmonary hypertension in Chinese patients. Eur Respir J. 2014;44(4):963–72.

    Article  CAS  Google Scholar 

  22. Oudiz RJ, Galiè N, Olschewski H, Torres F, Frost A, Ghofrani HA, et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(21):1971–81.

    Article  Google Scholar 

  23. Ramos RP, Arakaki JS, Barbosa P, Treptow E, Valois FM, Ferreira EV, et al. Heart rate recovery in pulmonary arterial hypertension: relationship with exercise capacity and prognosis. Am Heart J. 2012;163(4):580–8.

    Article  Google Scholar 

  24. Minai OA, Gudavalli R, Mummadi S, Liu X, McCarthy K, Dweik RA. Heart rate recovery predicts clinical worsening in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185(4):400–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Funding

This work was supported by GlaxoSmithKline (China) R&D Company Limited. The funding body played no role in the design of the study and collection, analysis, and interpretation of the data.

Author information

Author notes

  1. Mengtao Li and Zhicheng Jing contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, National Clinical Research Center for Immunologic Diseases, Ministry of Science & Technology, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China

    Mengtao Li & Xiaofeng Zeng

  2. Key Lab of Pulmonary Vascular Medicine & FuWai Hospital, State Key lab of Cardiovascular disease, National center for Cardiovascular disease, Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    Zhi-Cheng Jing

  3. 2nd Affiliated Hospital of Harbin Medical University, Harbin, China

    Yang Li & Bingxiang Wu

  4. 1st Affiliated Hospital of Peking University, Beijing, China

    Yong Huo

  5. Xiangya Hospital Central-South University, Changsha, Hunan, China

    Zaixin Yu

  6. Wuhan Asia Heart Hospital, Wuhan, Hubei, China

    Gangcheng Zhang

  7. 1st Affiliated Hospital of the Fourth Military Medical University, Xi’an, Shaanxi, China

    Ping Zhu

  8. Shanghai Pulmonary Hospital, Tongji University, Shanghai, China

    Jinming Liu

  9. Qilu Hospital, Shandong University, Jinan, Shandong, China

    Qiushang Ji

  10. GlaxoSmithKline (China) R&D Company Limited, Shanghai, China

    Jinhua Zhong, Pingping Wang & Wenjing Zhu

Authors
  1. Mengtao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi-Cheng Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zaixin Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gangcheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ping Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jinming Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qiushang Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bingxiang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jinhua Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Pingping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Wenjing Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xiaofeng Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZJ and PW were involved in the study conception and design, data acquisition and data analysis. XZ and ML contributed to data acquisition and data analysis. PZ, GZ, YL, ZY, YH, QJ, BW and JL contributed to acquisition of data. JZ contributed to data analysis. WZ was involved in the study data analysis and interpretation. All authors have reviewed the manuscript and made substantial revisions to improve the scientific credibility of the content. All authors approved the final version to be published.

Corresponding author

Correspondence to Xiaofeng Zeng.

Ethics declarations

Ethics approval and consent to participate

The study protocol was approved by independent ethics committee or institutional review board at each centre. All patients provided written informed consent before any study-specific procedure was performed.

Consent for publication

Not applicable.

Competing interests

Jinhua Zhong, Wenjing Zhu and Pingping Wang were employees of GSK during the conduct of this study and manuscript development. All other authors have nothing to disclose.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Additional file 1: Supplementary Figure 1.

Change from baseline in WHO functional classification after treatment with ambrisentan (ITT population-LOCF): post-hoc analysis of SLE-CTD-PAH and Non SLE-CTD-PAH sub-groups. CTD, connective tissue disease; PAH, pulmonary arterial hypertension; SLE, systemic lupus erythematosus; WHO, World Health Organisation.

Additional file 2: Supplementary Table 1.

Patient demographics and baseline characteristics (ITT population): post-hoc analysis.

Additional file 3: Supplementary Table 2.

Mean change from baseline in 6MWT, BDI scores, and NT-proBNP levels after treatment with ambrisentan (ITT population): post-hoc analysis.

Additional file 4.

Affiliations of all the ethics committees that approved the study.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, M., Jing, ZC., Li, Y. et al. Efficacy and safety of ambrisentan in Chinese patients with connective tissue disease-pulmonary arterial hypertension: a post-hoc analysis. BMC Cardiovasc Disord 20, 339 (2020). https://doi.org/10.1186/s12872-020-01591-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12872-020-01591-1

Keywords

BMC Cardiovascular Disorders

ISSN: 1471-2261

Contact us