154. Pulmonary arterial hypertension and other ...

E-Communication Session

Room London 1 - 14:45-16:45

S UNDAY, O CTOBER 5 TH 2008

154. Pulmonary arterial hypertension and other pulmonary vascular diseases

E1413 Results of a 12-week outpatient cardiovascular rehabilitation in patients with idiopathic pulmonary arterial hypertension (iPAH) Kim Boutet 1 , Gilles Garcia 2 , Bruno Degano 1 , Michelle Gonzalves-Tavares 1 , Colas Tcherakian 1 , Xavier Jaïs 1 , Marc Humbert 1 , Pierre Escourrou 2 , Gérald Simonneau 1 , Olivier Sitbon 1 . 1 Service de Pneumologie, Hôpital Antoine Béclère, Clamart, France; 2 Service des Explorations Fonctionnelles, Hôpital Antoine Béclère, Clamart, France Background: Despite improvement in exercise capacity, quality of life and survival with medical therapy, patients with iPAH often have significant functional limitation. Moreover, avoidance of excessive physical exertion had been part of general recommendations. Nevertheless, one small study indicated a positive impact of an exercise training program in PAH. Objectives: To evaluate a 12-week cardiovascular rehabilitation outpatient program on functional class, endurance capacity, maximal exercise capacity and hemodynamics at rest and on exercise in iPAH patients. Methods: Prospective, monocentric study in 8 stable iPAH patients (44±13 y-o). Patients were evaluated on exercise parameters and hemodynamics at rest and on exercise, before and after rehabilitation. Results: Main results are as follows:

NYHA Class II:III, n 6-min walk distance, m Peak VO2 , ml/kg (% of predicted) Workload, Watts (% of predicted) VE/VCO2 Endurance time, s mPAP at rest, mmHg Cardiac index at rest, L/min/m2

Baseline

Post rehabilitation

P value

4:4 495±109 14.6±3.7 (48±12%) 83±30 (54±15%) 48±8 239±109 50±11 3.6±0.8

6:2 517±106 16.7±4.2 (51±11%) 98±30 (59±15%) 46±6 551±357 50±16 3.7±0.9

NS NS NS NS NS 0.01 NS NS

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S UNDAY, O CTOBER 5 TH 2008 There was no significant change in exercise hemodynamics between pre- and post-rehabilitation. There was no clinically relevant adverse event. Conclusion: These preliminary results indicate that a 12-week cardiovascular rehabilitation program in outpatients with iPAH improves endurance capacity without significant change in 6-min walk distance and hemodynamics. Further evaluation is needed to determine the place of rehabilitation program in PAH.

E1414 Non-invasive hemodynamic assessment in patients with pulmonary hypertension Susanna Desole 1 , Claudia Seemann 1 , Peter Heininger 1 , Renate Hiemetzberger 2 , Silvana Mueller 2 , Christian Matthias Kaehler 1 . 1 Pneumology Centre–Div. of General Internal Medicine, Dept. of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria; 2 Div. of Cardiology, Dept. of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria Aim of the study was to evaluate security, reproducibility and feasibility of a new non-invasive hemodynamic method in patients with pulmonary hypertension (PH). An inert gas rebreathing technique (Innocor® ) was investigated in 28 patients (mean-age 61±15, m:f 11:17) with suspected PH. Non-invasive assessment of hemodynamics was performed in front of invasive right heart catheterisation in each patient. Furthermore, NT-proBNP, transthoracic echo and the walking distance in the SMWT were determined. The investigated method was secure in all patients. The directly measured parameter by this system is pulmonary blood flow (PBF; 3.73±1.16 l/min). Reproducibility of measured PBF was high with a coefficient of variation of repeated PBF measurements being 0.18. PBF correlated significantly with invasively measured parameters: pulmonary vascular resistance (PVR; 646.41±447.07 dynes*s/cm5 ; r= -0,44*) and cardiac output (CO; Fick: 3.8±1.7 l/min, r= 0,62**; Thermo: 4.4±1.5, r= 0,84**). Interestingly, there was no correlation with mean PAP (45.3±15.6 mmHg). PBF did also not correlate with parameters of right heart function: right atrial pressure (15±6.1 mmHg) NT-pro BNP (1870,7±3179,5 ng/l) or the calculated pulmonary artery pressure (64.9±17.0 pg/ml), TEI (0.58±0.3) or TAPSE (1.76±0.4) assessed by echo. Furthermore, there was no correlation between PBF and SMWT (351.6±162.6 m). Non-invasive determination of PBF by a new rebreathing method correlates significantly with the hemodynamic parameters PVR and CO measured by right heart catheterisation. No correlation with right heart function was detectable. Further investigations might reveal its feasibility as a method for follow-up in PH patients.

E1415 The REVEAL registry: a tool for the evaluation of PAH disease management Robyn Barst 1 , Michael McGoon 2 , Raymond Benza 3 , David Badesch 4 , Scott Giles 5 , Kathy Feldkircher 5 , Dave Miller 6 . 1 Pulmonary Hypertension Center, Columbia University Medical Center, New York, NY, United States of America; 2 Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States of America; 3 Department of Medicine, Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, United States of America; 4 Pulmonary Sciences/Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, Denver, CO, United States of America; 5 Clinical Operations, Actelion Pharmaceuticals US, Inc., South San Francisco, CA, United States of America; 6 Statistical Analysis, ICON Clinical Research, San Francisco, CA, United States of America Purpose: The Registry to EValuate Early And Long-term PAH Disease Management (REVEAL) is a multicenter, observational, U.S.-based study designed to provide current, reliable information about pulmonary arterial hypertension (PAH) management. One objective is to characterize patient baseline characteristics. Methods: Consenting patients with PAH are being enrolled at 56 PH centers in the US. Enrollment data include clinical and treatment history, physical examination, and disease severity assessment. Results: In the initial 2980 patients (goal, 3500), diagnosis at enrollment was 47% idiopathic PAH, 50% PAH associated with other conditions, and 3% familial PAH. 86% were previously diagnosed and 14% were newly diagnosed with PAH. 8% were NYHA functional class (FC) I, 38% FC II, 49% FC III, and 5% FC IV. Median duration (25 percentile, 75 percentile) from onset of symptoms to diagnostic right heart catheterization (RHC) was 14 (5, 38) months. Excluding N=96 patients in blinded, randomized clinical trials (RCTs), at enrollment 8% of patients were not receiving any PAH-specific medication and 47% were receiving monotherapy (top 2 drugs: sildenafil, 15%; bosentan, 12%). 35% and 9% reported combination therapy with 2 or 3 agents, respectively. Top 2 combinations were sildenafil + bosentan (9%) and IV epoprostenol + sildenafil (6%). Conclusions: For the first patients enrolled in the REVEAL registry, >50% of patients were diagnosed with PAH (via confirmatory RHC) >1 year after symptom onset. Only 8% of patients were not on any PAH-specific medication and ∼45% were on ≥2 PAH medications at enrollment. Current practice includes combination therapy (although limited RCT data available) for patients with PAH.

E1416 Clinical characteristics of pulmonary arterial hypertension in Ireland: results of a national register Dermot O’Callaghan, Sinead Doherty, Sean Gaine. National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland Pulmonary arterial hypertension (PAH) is an incurable disease characterised by progressive right ventricular dysfunction and ultimately death. The purpose of this study was to determine the clinical characteristics of patients with PAH treated at the National Pulmonary Hypertension (PH) Unit. Data was gathered using the Irish National PH register. Of 241 patients referred to the PH Unit, we identified 84 patients with PAH (female:male ratio 2.2:1). Age at presentation was 48±14.7yr (mean±SD) with a range of 22-78yr. The commonest aetiologies were idiopathic (35.7%), connective tissue disease (32.1%) and congenital heart disease (22.6%) while familial (1.2%), portal hypertension (2.4%), HIV (3.6%), splenectomy (1.2%) and anorexigen exposure (1.2%) were uncommon causes. Most patients had functional class III symptoms (56%) at presentation and mean baseline 6-MWD was 332m. Mean pulmonary artery pressure was 50.4±13.9 mmHg. The endothelin antagonist bosentan was the most frequently prescribed therapy (85.5%). Atrial septostomy was performed in five patients and one patient underwent heart-lung transplantation. One-year survival was 87% in those with a minimum of 12 months follow-up. Most patients with PAH present with advanced disease and have severe functional limitation. However, our one-year survival rates are comparable to international figures.

E1417 Incidence of pulmonary arterial hypertension related to systemic sclerosis: a 3-year nationwide longitudinal study M. Humbert 1,2 , P. de Groote 2 , V. Gressin 2 , J. Sibilia 2 , E. Diot 2 , P. Carpentier 2 , L. Mouthon 2 , P.Y. Hatron 2 , P. Jego 2 , Y. Allanore 2 , K.P. Tiev 2 , C. Agard 2 , A. Cosnes 2 , D. Cirstea 2 , J. Constans 2 , D. Farge 2 , J.F. Viallard 2 , J.R. Harle 2 , P. Clerson 2 , E. Hachulla 2 . 1 Service de Pneumologie, Hopital A. Beclere, Université Paris-Sud 11, Clamart, France; 2 ItinerAIR Sclerodermie Investigators, ItinerAIR Sclerodermie, Paris, France Background: A screening algorithm for pulmonary arterial hypertension (PAH) based on dyspnea, Doppler echocardiographic evaluation of the peak velocity of tricuspid regurgitation (VTR), and right heart catheterisation (RHC) applied in a multicentre systemic sclerosis (SSc) population (ItinerAIR registry), indicated a prevalence of 7.85%. Objectives: To describe PAH incidence over 3 years of follow-up in the ItinerAIR SSc cohort. Methods: Patients had annual screening for PAH with Doppler echocardiography confirmed by RHC in patients with VTR of 2.8–3 m/s and unexplained dyspnea, or VTR >3 m/s. Results: Of 554 patients commencing follow-up, 170 were excluded: 29 with previously diagnosed PAH, 18 with PAH identified at baseline, 4 refused consent, 4 lost to follow-up, and 115 for lack of echocardiography screening or for protocol violations. The remaining 384 patients were followed for a mean of 41.0±5.6 months (median 41 months). The baseline characteristics of this population were: 87% female, 53±12 years, mean duration of SSc at study entry 8.7±7.6 years, and 24.0% with diffuse SSc. Elevated VTR was identified in 18 patients (incidence: 1.37 per 100 patient-years). Among these, RHC identified 8 patients with pre-capillary PAH (incidence: 0.61 per 100 patient-years), 8 with post-capillary pulmonary hypertension (PH) – despite the absence of left-heart dysfunction on echocardiography, and 2 with PH due to severe interstitial lung disease. Conclusion: The prospective follow-up of this multicentre SSc cohort indicates that the incidence of PAH in SSc is 0.61 per 100 patient-years. RHC is mandatory to confirm pre-capillary PAH, as post-capillary PH is frequent in SSc.

E1418 Ambrisentan therapy for patients with PAH associated with connective tissue disease (PAH-CTD): one year follow-up Nazzareno Galie 1 , Duncan Richards 2 , Tammy Hutchinson 2 , Chris Dufton 3 on behalf of the ARIES Study Group. 1 Institute of Cardiology, University of Bologna, Bologna, Italy; 2 CVM MDC, GSK, Harlow, Essex, United Kingdom; 3 Clinical Development, Gilead Sciences Inc, Westminster, CO, United States of America Introduction: Ambrisentan (AMB) is a high affinity, propanoic acid-based, ETA selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension (PAH). In two Phase 3, 12-week placebo-controlled studies (ARIES-1 and 2), AMB improved 6MWD in patients with PAH. ARIES-E is an on-going, long-term extension study of ARIES-1 and 2. These studies include patients with PAH-CTD. PAH-CTD has a poorer prognosis than IPAH and in general, a poorer response to PAH targeted therapies. Methods: Patients with PAH-CTD who were treated with ambrisentan in ARIES 1 or 2, received 2.5, 5, or 10 mg ambrisentan once-daily in ARIES E. Patients continuing treatment were allowed to increase or decrease dose after week 24 of ARIES-E. Results: A larger and more durable improvement from baseline 6MWD was

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Room London 1 - 14:45-16:45

S UNDAY, O CTOBER 5 TH 2008 observed with AMB 10 mg compared with AMB 5mg (LOCF; mean exposure 75.0 weeks). Week

12 24 48

Change from baseline 6MWD m (95% CI) 5mg AMB (n=38)

10mg AMB (n=22)

17.1 (-5.2, 39.3) 22.1 (6.1, 38.1) 15.8 (-4.6, 36.1)

22.1 (-9.2, 53.4) 38.8 (4.7, 72.9) 27.2 (-3.6, 57.9)

For the combined ambrisentan group (n=81), the rate of events of clinical worsening was (79.2% (95% CI: 71.7, 86.6), event-free at 1 year). A Kaplan Meier estimate of survival at one year was 90.3% (95% CI: 84.8, 95.8). This is substantially better than historical series. Conclusions: One year data indicate ambrisentan is a valuable treatment option for patients with PAH-CTD. The 10mg dose may provide greater long-term improvement in exercise capacity compared to the 5mg dose in patients with PAH-CTD.

E1419 Pulmonary pressure at rest and during slight exercise might have prognostic relevance in patients at risk for pulmonary arterial hypertension Gabor Kovacs 1 , Robert Maier 2 , Stefan Scheidl 1 , Christian Hesse 1 , Elisabeth Aberer 3 , Marianne Brodmann 4 , Wolfgang Salmhofer 3 , Winfried Graninger 5 , Ekkehard Gruenig 6 , Horst Olschewski 1 . 1 Pulmonology, Medical University Graz, Graz, Austria; 2 Cardiology, Medical University Graz, Graz, Austria; 3 Dermatology, Medical University Graz, Graz, Austria; 4 Angiology, Medical University Graz, Graz, Austria; 5 Rheumatology, Medical University Graz, Graz, Austria; 6 Cardiology, University of Heidelberg, Heidelberg, Germany The clinical relevance of resting and exercise pulmonary arterial pressure (PAP) in patients with systemic sclerosis, and its impact on prognostic parameters such as peak oxygen uptake (VO2peak) and six-minute-walk distance (6MWD) has not been studied. Following a screening by exercise tricuspid echo doppler and cardiopulmonary exercise test, 29 patients with connective tissue disease who presented with a systolic pulmonary arterial pressure (SPAP) >40mmHg during exercise or a VO2peak17mmHg was associated with decreased 6MWD (p26mmHg (median) was associated with decreased VO2peak and 6MWD (p23mmHg (median) were associated with decreased 6MWD (p