Ambrisentan therapy in pulmonary hypertension: clinical use and tolerability in a referral centre

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1 532304TAR / Therapeutic Advances in Respiratory DiseaseR Condliffe, CA Elliot research-article2014 Therapeutic Advances in Respiratory Disease Original Research Ambrisentan therapy in pulmonary hypertension: clinical use and tolerability in a referral centre Robin Condliffe, Charlie A. Elliot, Judith Hurdman, Ian Sabroe, Catherine Billings, David G. Kiely and Neil Hamilton Ther Adv Respir Dis 2014, Vol. 8(3) DOI: / The Author(s), Reprints and permissions: journalspermissions.nav Abstract Introduction: Ambrisentan is an oral selective endothelin receptor antagonist licensed for use in pulmonary arterial hypertension (PAH). There are few data on clinical use and long-term tolerability in a wider range of patients with pulmonary hypertension (PH). Methods: All patients treated with ambrisentan over a 4-year period were identified. Baseline characteristics, liver function test (LFT) results and World Health Organization (WHO) functional class were retrieved from hospital databases. Results: 272 patients received ambrisentan between March 2009 and June 2013 (32% idiopathic PAH, 36% connective tissue disease PAH, 11% congenital heart disease PAH, 6% portopulmonary hypertension, 1% HIV PAH, 4% PH in association with lung disease, 8% chronic thromboembolic PH and 2% PH in association with sarcoidosis). 33.5% of patients received ambrisentan as monotherapy and 12% received ambrisentan as their initial PH therapy. 18% stopped treatment due to side effects and 12% stopped due to lack of efficacy. Oedema was the most common side effect leading to cessation of therapy, which occurred in 7% of patients. 57% of patients who discontinued ambrisentan due to side effects also discontinued other PAH therapies due to side effects previously or subsequently. Ambrisentan was discontinued in two (<1%) patients due to abnormal LFTs. The 3-year survival in congenital heart disease PAH, idiopathic PAH and systemic sclerosis-associated PAH was 80%, 62%, and 38%, respectively (p = 0.003). Survival was superior in patients in whom WHO functional class improved in response to therapy. Conclusion: Ambrisentan is used as an initial therapy and as monotherapy in a minority of patients in a large UK PH referral centre. Discontinuation due to side effects, and especially oedema, was higher than reported in previous studies while discontinuation due to abnormal LFTs was very uncommon. A majority of patients who discontinued therapy due to side effects also previously or subsequently discontinued other PAH therapies. Improvement in WHO functional class was associated with superior survival. Keywords: ambrisentan, pulmonary hypertension, side effects, liver function tests Introduction Pulmonary arterial hypertension (PAH) is a rare condition characterized by mean arterial pressure 25mmHg in the presence of normal left atrial pressure [Kiely et al. 2013]. It can be idiopathic or heritable in nature, or may be associated with other medical conditions such as connective tissue disease (CTD), congenital heart disease (CHD), liver disease and HIV. It may also occur as a result of exposure to various drugs, most notably anorexigens. Pulmonary hypertension (PH) may also be associated with left heart disease, respiratory disease (PH-Lung) or may occur due to chronic thromboembolic disease (CTEPH) and may also occur in association with other miscellaneous conditions including sarcoidosis [Simonneau et al. 2009]. Current available therapy for PAH includes phosphodiesterase-5 Correspondence to: Robin Condliffe, MD Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield S10 2JF, UK robin.condliffe@sth. nhs.uk Charlie A. Elliot, MBChB Judith Hurdman, MBChB Catherine Billings, PhD David G. Kiely, MD Neil Hamilton, DPhil Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK Ian Sabroe, PhD Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital and Department of Infection and Immunity, University of Sheffield, Sheffield, UK 71

2 Therapeutic Advances in Respiratory Disease 8(3) inhibitors (PDE5-I) sildenafil and tadalafil, endothelin receptor antagonists (ERAs) bosentan and ambrisentan and prostanoids (eposprostenol, iloprost and treprostinil) [Kiely et al. 2013]. Current guidelines do not recommend PAHspecific therapies for patients with PH associated with left heart or lung disease [Galiè et al. 2009]. Endothelin-1 is a potent vasoconstrictor and proproliferative peptide released predominantly in vascular endothelial cells. Endothelin-1 acts via two receptors, ETA and ETB. ETA mediates vasoconstriction and cellular proliferation while ETB promotes vasodilatation and has antiproliferative properties [D Alto, 2012]. Ambrisentan (Volibris, GSK, Brentford, UK; Letairis, Gilead, Foster City, California, USA) is a selective ETA receptor antagonist which was shown to significantly improve exercise capacity, quality of life and time to clinical worsening in two large concurrent randomized, controlled trials of monotherapy, ARIES-1 and ARIES-2 [Galiè et al. 2008]. These studies enrolled patients with idiopathic PAH or PAH associated with anorexigens, CTD and HIV. There are relatively few published data describing the use of ambrisentan in clinical practice and in other forms of PH [Badesch et al. 2012; Judson et al. 2011; Zuckerman et al. 2011]. In the present study we therefore describe tolerability and clinic utility of ambrisentan across the spectrum of PH patients treated in a large PH referral centre over a 4-year period. Methods A total of 272 patients who received ambrisentan between March 2009 and June 2013 were identified from our departmental pharmacy database. Our unit has a referral population of approximately 15 million and >900 patients on PAHspecific therapy. Hospital notes and records were then interrogated to capture demographics, baseline characteristics, concomitant therapies and treatment response. Monthly liver function test (LFT) results for each patient were reviewed. Survival to the census date of 1 July 2013 or date of death was determined via the National Health Service mortality database. Approval for the use of anonymized clinical data had previously been approved by our local research ethics committee. Statistical analysis Descriptive data was presented as mean ± standard deviation or median (interquartile range). Baseline data was compared where appropriate using one-way analysis of variance followed by post hoc Bonferroni corrections. Survival from date of commencement of ambrisentan was assessed using the Kaplan Meier method. Patients who stopped ambrisentan prior to date of death or 1 July 2013 were included in the survival analysis. Results Study population The aetiologies of PH in the 272 patients treated with ambrisentan during the study period were idiopathic/heritable (32%), CTD (36%, 82% of whom had systemic sclerosis), CHD (11%), portopulmonary (6%), HIV (1%), PH-Lung (4%), CTEPH (8%) and sarcoidosis (2%) (Figure 1). A total of 75% of patients were women and the mean age at commencement of therapy was 61.1 ± 16 years. Baseline characteristics of the main groups are described in Table 1. Patients with CHD were the youngest group while CTD patients had the least severely elevated pulmonary pressures and patients with portopulmonary hypertension had the highest cardiac outputs. Of the CHD patients, 16 (55%) had Eisenmenger s syndrome and had not undergone right heart catheterization at our unit, six (21%) had a large defect with significant left to right shunt, four (14%) had a small septal defect and three (10%) had a previously corrected defect. As only 45% of CHD patients underwent right heart catheterization, haemodynamic data is not presented in Table 1. Of the 21 CTEPH patients, 16 (76%) were deemed to have inoperable disease following assessment by the national pulmonary endarterectomy centre while three (14%) had persistent PH following pulmonary endarterectomy and two (10%) had refused surgery despite being operable candidates. Ambrisentan use and discontinuation Median duration of exposure to ambrisentan was 210 (range ) days. The cumulative number of patients prescribed ambrisentan increased exponentially throughout the study period (Figure 2). A total of 91 patients (33.5%) received ambrisentan as monotherapy, 174 patients (65.5%) in combination with a PDE5-I while one patient (0.5%) received combination therapy with intravenous prostanoid and a further single patient (0.5%) also received both a PDE5-I and 72

3 R Condliffe, CA Elliot et al. 272 PH patients treated with ambrisentan Group 1 89 (32%)IPAH 98 (36%) CTD 29 (11%) CHD 16 (6%) Portopulmonary 3 (1%) HIV Group 3 10 (4%) PH-Lung Group 4 21 (8%) CTEPH Group 5 6 (2%) Sarcoid 50 (18%) stopped due to side effects 33 (12%) stopped due to lack of perceived benefit 13 subsequently died 16 subsequently died 3 (1%) stopped due to poor compliance 41 (15%) died while on ambrisentan 145 (54%) receiving ambrisentan at census date 1 July 2013 Figure 1. Patient disposition. Groups 1 5 refer to pulmonary hypertension classification [Kiely et al. 2013]. Abbreviations: IPAH, idiopathic pulmonary arterial hypertension; CTD, connective tissue disease; CHD, congenital heart disease; PH-Lung, pulmonary hypertension in association with lung disease; CTEPH, chronic thromboembolic pulmonary hypertension. intravenous prostanoid. Only 32 patients (12%) commenced ambrisentan de novo. A total of 11 patients (4%) were switched from sitaxentan at its withdrawal from market. A total of 34 patients (13%) switched from bosentan due to abnormal LFTs on that medication while 15 (6%) switched from bosentan and 4 (2%) switched from PDE5-I due to symptomatic side effects. Maximum dosage of ambrisentan was 5 mg daily in 54% and 10 mg daily in 46%. A total of 145 patients (54%) were still receiving ambrisentan on 1 July Of those who were no longer receiving the medication on that date, 41 (15%) had died while still receiving ambrisentan while 50 patients (18%) had stopped treatment due to side effects and 33 (12%) had stopped due to lack of perceived benefit (Figure 1). Three patients (1%) had treatment discontinued due to lack of compliance with LFT monitoring. Oedema was the most common side effect, leading to cessation of therapy in 20 patients (7% of the total patients and 40% of patients stopping therapy due to side effects) (Table 2). Rates of cessation due to oedema were similar in the three main groups of IPAH, systemic sclerosis (SSc) and CHD (5 7%). A total of 29 (57%) of those patients who stopped ambrisentan due to side effects also stopped other PAH therapies previously or subsequently (19 bosentan, three sildenafil, six both bosentan and sildenafil and one prostanoid therapy). Median duration of therapy prior to stopping due to side effects was 43 (range ) days with 74% of those patients stopping within the first 100 days. The form of PH in the 50 patients who stopped therapy due to side effects was idiopathic PAH 73

4 Therapeutic Advances in Respiratory Disease 8(3) Table 1. Baseline characteristics at diagnosis of the whole cohort and main subgroups. PH IPAH SSc CHD Porto Lung CTEPH Sarcoid N Age, years 61 ± ± ± 12 #+ 48 ± 16 * 63 ± ± ± 14 #+ 60 ± 9 WHO II/III/IV, % 5/78/17 6/80/15 4/72/24 4/92/4 14/86/0 0/44/56 0/90/10 0/60/40 mrap, mmhg 11 ± 6 12 ± 6 9 ± 6 10 ± 6 13 ± 6 14 ± 6 14 ± 7 mpap, mmhg 51 ± ± ± 12 # 51 ± ± ± ± 5 PAWP, mmhg 12 ± 4 12 ± 3 10 ± 4 13 ± 5 12 ± 5 12 ± 5 11 ± 3 CI, L/min/m ± ± ± ± 0.4 # 2.7 ± ± ± 0.8 PVR, dyn/s/cm ± ± ± 354 # 432 ± 230 # 730 ± ± ± 262 No haemodynamics displayed for CHD as minority of group underwent right heart catheterization. Abbreviations: PH, pulmonary hypertension; IPAH, idiopathic pulmonary arterial hypertension; SSc, systemic sclerosis associated PAH; CHD, congenital heart disease associated PAH; Porto, portopulmonary hypertension; Lung, lung disease associated PH; CTEPH, chronic thromboembolic PH; Sarcoid, sarcoidosis associated PAH; WHO, World Health Organization; mrap, mean right atrial pressure; mpap, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; CI, cardiac index; PVR, pulmonary vascular resistance; # p < 0.05 compared with IPAH; p < 0.05 compared with SSc; + p < 0.05 compared with CHD; compared with portopulmonary; * p < 0.05 compared with PH-Resp; p < 0.05 compared with CTEPH; ± p < 0.05 compared with Sarcoid. Data is presented as mean ± standard deviation Patients initiated on ambrisentan Mar-09 Jun-09 Sep-09 Dec-09 Mar-10 Jun-10 Sep-10 Dec-10 (12; 24%), CTD (14; 28%), CHD (8; 16%), portopulmonary (1; 2%), PH-Lung (4; 8%), CTEPH (10; 20%) and sarcoidosis (1; 2%). There was no significant difference in gender or age between those patients who stopped therapy due to side effects or continued therapy. Patients who discontinued due to therapy did however have significantly higher mean right atrial pressure (13.7 ± 6 mmhg versus 10.9 ± 6 mmhg; p = 0.005) and pulmonary artery wedge pressure (13.1 ± 4 mmhg versus 11.1 ± 4 mmhg; p = 0.009) compared with patients who continued therapy. Out of the 10 patients with PH-Lung, four patients stopped therapy due to side effects and one due to lack of perceived benefit. Out of the 21 patients with CTEPH, 10 patients stopped due to side effects and two due to lack of perceived benefit. Only one out of six patients with sarcoidosis stopped therapy due to side effects. Mar-11 Jun-11 Date Figure 2. Cumulative number of patients initiated on ambrisentan during the study period. Sep-11 Dec-11 Mar-12 Jun-12 Sep-12 Dec-12 Mar-13 Jun-13 Two patients stopped due to abnormal LFTs. The first patient had previously stopped bosentan due to abnormal transaminases which had normalized on withdrawal of bosentan. This patient developed elevated transaminases >7 upper limit of normal (ULN) 16 months after commencing ambrisentan with no elevation in bilirubin. LFTs normalized on cessation of ambrisentan. The patient did have a history of severe eczema occasionally requiring flucloxacillin for superimposed infection but it was not clear whether flucloxacillin was being taken at the time of the transaminase abnormality. The patient has subsequently represented, despite not receiving an endothelin receptor antagonist, with elevated transaminases of unknown origin. A second patient developed transaminases >3 ULN, with normal bilirubin, following 9 months of ambrisentan. LFTs normalized on cessation and the abnormality recurred on rechallenging with ambrisentan with subsequent normalization on further cessation. No patients switching from sitaxentan developed abnormal LFTs. Survival and response to therapy Overall median survival from commencement of ambrisentan was 3.2 years. The 3-year survival in the three largest patient groups was CHD 80%, IPAH 62% and SSc-PAH 38% (p = 0.003, Figure 3). There was no significant difference in survival between those patients who continued ambrisentan or stopped due to lack of clinical benefit or side effects. Survival from commencement of ambrisentan was superior in those patients who improved 74

5 R Condliffe, CA Elliot et al. Table 2. Predominant side effect leading to cessation of ambrisentan therapy. Side effect Number (% of total patients exposed) Oedema 20 (7) Nausea 7 (3) Myalgia 3 (1) LFT abnormality 2 (1) Dyspnoea 4 (1.5) Headache 1 (0.5) Hair loss 1 (0.5) Dizziness 2 (1) Anaemia 1 (0.5) Rash 3 (1) Unclear 6 (2) LFT, liver function test. Improved Stable Worsened Figure 4. Survival by change in World Health Organization (WHO) functional class following commencement of ambrisentan treatment. Figure 3. Survival from commencing ambrisentan in the three main patient groups. their World Health Organization (WHO) functional class at 3 6 months following commencement of ambrisentan (p = 0.03, Figure 4). Follow-up exercise capacity at 3 6 months following commencement of ambrisentan was only located for 54% of patients making meaningful conclusions regarding effects on exercise capacity impossible. Discussion The current study reports clinical use and tolerability of ambrisentan in a general population of PH patients. The efficacy of ambrisentan as monotherapy in PAH (predominantly idiopathic PAH and CTD-PAH) over a 12-week period was demonstrated, in the ARIES-1 and ARIES-2 randomized, controlled studies [Galiè et al. 2008]. The ARIES-E extension study demonstrated persistent benefit in exercise capacity after up to 2 years of treatment with 82% of patients remaining on ambrisentan monotherapy [Oudiz et al. 2009]. Peripheral oedema was the most commonly reported side effect occurring in between 10 30% of patients and being reported as severe in only 1.3% of patients in the extension study. No LFT abnormalities in patients receiving ambrisentan in ARIES-1 and ARIES-2 were observed while the annual risk of transaminase levels > 3 ULN in ARIES-E was 2% with two out of 383 patients discontinuing ambrisentan as a result of LFT abnormalities. There are relatively few data describing the long-term use of ambrisentan in a less strictly defined population more reflective of the real world. The observational ARIES-3 study enrolled 224 patients across several PH classifications (69 idiopathic PAH, 40 CTD, 10 CHD, 13 drugs/toxins, 45 PH-Lung and 29 CTEPH) [Badesch et al. 2012]. Approximately 50% of patients were receiving concomitant PAH therapy at commencement of ambrisentan. Over a 24-week period significant improvements in 6 Minute Walk 75

6 Therapeutic Advances in Respiratory Disease 8(3) Distance (6MWD) and B-Type Natriuretic peptide (BNP) were observed in the majority of PH groups. Ambrisentan was generally well tolerated with discontinuation due to peripheral oedema occurring in 2.7% and only two episodes of abnormal LFTs. A small observational study followed 27 PAH patients over a longer period of time (52 weeks) and observed improvements in 6MWD, pro-nt BNP and pulmonary haemodynamics [D Alto et al. 2012] Further post hoc and subgroup analysis of patients enrolled in ARIES-1 has been published [Blalock et al. 2010; Klinger et al. 2011] while there are limited data suggesting benefits in patients with portopulmonary hypertension [Cartin-Ceba et al. 2011] and Eisenmenger s syndrome [Zuckerman et al. 2011]. The incidence of LFT abnormalities in a post-marketing surveillance study enrolling almost 11,000 patients in the USA (LEAP programme) reported possible hepatic events in 2.87% of patients with only 79 (0.72%) being deemed clinically significant events and only six cases having elevations in both transaminases and bilirubin [Ben-Yehuda et al. 2012]. In the current paper, only one-third of patients received ambrisentan as monotherapy and 88% of patients had previously been treated with other PAH therapies, most commonly PDE5-I. This reflects commissioning and prescribing practice in the UK whereby initial therapy for PAH is PDE5-I with subsequent addition or switch to other therapies if initial response is suboptimal. We observed a low rate of discontinuation due to abnormal LFTs despite regular monitoring but discontinuation due to peripheral oedema was 2 3 times greater than that seen in ARIES-E [Oudiz et al. 2009]. The proportion of patients stopping therapy due to any side effects was 18.5% which was approximately three times greater than that observed in ARIES-E. There are several possible reasons for the higher discontinuation rate we observed. As the majority of patients were not treatment-naïve, the greater incidence of peripheral oedema may reflect more advanced disease with worsened right ventricular function. A post hoc analysis of ARIES-1 and 2 data demonstrated, however, that oedema occurred even when BNP fell and 6MWD increased suggesting that, in patients enrolled in ARIES-1 and 2 at least, peripheral oedema did not reflect worsened right heart failure [Shapiro et al. 2012]. It was interesting to observe that 57% of patients stopping treatment in the current study also stopped other PAH therapies due to side effects. This may reflect a lower symptom threshold in clinical practice or an increased difficulty in withdrawing medication in patients enrolled in clinical trials. Survival from commencement of ambrisentan in the current study was inferior to that observed in ARIES-E where overall 2-year survival was 88% [Oudiz et al. 2009]. It is well recognized that survival in patients enrolled in randomized controlled trials is superior to that observed in registries due to the more stable disease state of study patients. Survival in patients with CHD was superior to that of patients with idiopathic PAH which in turn was superior to that seen in SSc-PAH. These differences in survival have previously been described elsewhere [Hurdman et al. 2012] and likely reflect differences in cardiac contractility and pulmonary vasculopathy between the groups [Dimopoulos et al. 2008; Overbeek et al. 2008, 2009]. Survival in patients continuing ambrisentan or stopping therapy due to side effects or lack of clinical benefit was not significantly different, however, due to the heterogeneous patient group and uncontrolled nature of this study it is not possible to infer a lack of efficacy based on these data. Although the data did not allow demonstration of response to therapies in terms of exercise capacity, patients with improvements in WHO functional class did have superior survival to patients who did not improve functional class. Limitations This data was derived in a single centre. Patients were managed and monitored as clinically required meaning a standardized therapeutic approach and follow-up data at set intervals was not present for all patients, limiting conclusions regarding possible efficacy. Conclusions Clinical use of ambrisentan differs from that seen in the original randomized controlled trials. The majority of patients treated with ambrisentan in a UK PH referral centre did not receive it as firstline therapy or as monotherapy and other forms of PH not studied in ARIES-1 and 2 were also treated with ambrisentan. LFT abnormalities were infrequent, although drug cessation due to side effects including peripheral oedema was more common than in the published literature to date. Patients who improved functional class in response to therapy had superior survival compared with those who did not improve FC. 76

7 R Condliffe, CA Elliot et al. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. Conflict of interest statement RC, CAE, DGK and NDH have received honoraria from GSK pharmaceuticals for lecturing, conference travel and advisory boards. References Badesch, D., Feldman, J., Keogh, A., Mathier, M., Oudiz, R., Shapiro, S. et al. (2012) Aries-3: ambrisentan therapy in a diverse population of patients with pulmonary hypertension. Cardiovasc Ther 30: Ben-Yehuda, O., Pizzuti, D., Brown, A., Littman, M., Gillies, H., Henig, N. et al. (2012) Long-term hepatic safety of Ambrisentan in patients with pulmonary arterial hypertension. J Am Coll Cardiol 60: Blalock, S., Matulevicius, S., Mitchell, L., Reimold, S., Warner, J., Peshock, R. et al. (2010) Longterm outcomes with ambrisentan monotherapy in pulmonary arterial hypertension. J Card Fail 16: Cartin-Ceba, R., Swanson, K., Wiesner, R. and Krowka, M. (2011) Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension. Chest 139: D Alto, M. (2012) An update on the use of ambrisentan in pulmonary arterial hypertension. Ther Adv Respir Dis 6: D alto, M., Romeo, E., Argiento, P., Correra, A., Sarubbi, B., Scognamiglio, G. et al. (2012) Ambrisentan for pulmonary arterial hypertension: long term effects on clinical status, exercise capacity and haemodynamics. Int J Cardiol 156: Dimopoulos, K., Giannakoulas, G., Wort, S. and Gatzoulis, M. (2008) Pulmonary arterial hypertension in adults with congenital heart disease: distinct differences from other causes of pulmonary arterial hypertension and management implications. Curr Opin Cardiol 23: Galiè, N., Hoeper, M., Humbert, M., Torbicki, A., Vachiery, J., Barbera, J. et al. (2009) Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 30: Galiè, N., Olschewski, H., Oudiz, R., Torres, F., Frost, A., Ghofrani, H. et al. (2008) Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebocontrolled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 117: Hurdman, J., Condliffe, R., Elliot, C., Davies, C., Hill, C., Wild, J. et al. (2012) ASPIRE registry: assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre. Eur Respir J 39: Judson, M., Highland, K., Kwon, S., Donohue, J., Aris, R., Craft, N. et al. (2011) Ambrisentan for sarcoidosis associated pulmonary hypertension. Sarcoidosis Vasc Diffuse Lung Dis 28: Kiely, D., Elliot, C., Sabroe, I. and Condliffe, R. (2013) Pulmonary hypertension: diagnosis and management. BMJ 346: f2028. Klinger, J., Oudiz, R., Spence, R., Despain, D. and Dufton, C. (2011) Long-term pulmonary hemodynamic effects of ambrisentan in pulmonary arterial hypertension. Am J Cardiol 108: Oudiz, R., Galiè, N., Olschewski, H., Torres, F., Frost, A., Ghofrani, H. et al. (2009) Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 54: Overbeek, M., Lankhaar, J., Westerhof, N., Voskuyl, A., Boonstra, A., Bronzwaer, J. et al. (2008) Right ventricular contractility in systemic sclerosisassociated and idiopathic pulmonary arterial hypertension. Eur Respir J 31: Overbeek, M., Vonk, M., Boonstra, A., Voskuyl, A., Vonk-Noordegraaf, A., Smit, E. et al. (2009) Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy. Eur Respir J 34: Shapiro, S., Pollock, D., Gillies, H., Henig, N., Allard, M., Blair, C. et al. (2012) Frequency of edema in patients with pulmonary arterial hypertension receiving ambrisentan. Am J Cardiol 110: Simonneau, G., Robbins, I., Beghetti, M., Channick, R., Delcroix, M., Denton, C. et al. (2009) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 54: S43 S54. Zuckerman, W., Leaderer, D., Rowan, C., Mituniewicz, J. and Rosenzweig, E. (2011) Ambrisentan for pulmonary arterial hypertension due to congenital heart disease. Am J Cardiol 107: Visit SAGE journals online SAGE journals 77