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Efficacy and safety of selexipag in pulmonary arterial hypertension (PAH) patients with and without significant cardiovascular (CV) comorbidities

Session New concepts in pulmonary hypertension

Speaker Stephan Rosenkranz

Event : ESC Congress 2019

  • Topic : valvular, myocardial, pericardial, pulmonary, congenital heart disease
  • Sub-topic : Pulmonary Hypertension
  • Session type : Abstract Sessions

Authors : S Rosenkranz (Cologne,DE), R Channick (Los Angeles,US), K Chin (Dallas,US), B Jenner (Allschwil,CH), S Gaine (Dublin,IE), N Galie (Bologna,IT), HA Ghofrani (London,GB), M M Hoeper (Hannover,DE), V V Mclaughlin (Ann Arbor,US), R Preiss (Allschwil,CH), L J Rubin (San Diego,US), G Simonneau (Le Kremlin Bicetre,FR), O Sitbon (Le Kremlin Bicetre,FR), V Tapson (Los Angeles,US), I M Lang (Vienna,AT)

Authors:
S. Rosenkranz1 , R. Channick2 , K. Chin3 , B. Jenner4 , S. Gaine5 , N. Galie6 , H.A. Ghofrani7 , M.M. Hoeper8 , V.V. McLaughlin9 , R. Preiss4 , L.J. Rubin10 , G. Simonneau11 , O. Sitbon11 , V. Tapson12 , I.M. Lang13 , 1University of Cologne - Cologne - Germany , 2University of California Los Angeles - Los Angeles - United States of America , 3UT Southwestern Medical Centre - Dallas - United States of America , 4Actelion Pharmaceuticals Ltd - Allschwil - Switzerland , 5Mater Misericordiae University Hospital - Dublin - Ireland , 6University of Bologna, Department of Experimental, Diagnostic and Specialty Medicine - DIMES - Bologna - Italy , 7University of Giessen and Marburg Lung Center, Giessen, Germany, member of the German Center for Lung Research, and Department of Medicine, Imperial College London - London - United Kingdom , 8Department of Respiratory Medicine, Hannover Medical School and German Center for Lung Research - Hannover - Germany , 9University of Michigan - Ann Arbor - United States of America , 10Division of Pulmonary and Critical Care Medicine, University of California - San Diego - United States of America , 11Hopital Universitaire de Bicetre, Universite Paris-Sud - Le Kremlin Bicetre - France , 12Cedars-Sinai Medical Center - Los Angeles - United States of America , 13Division of Cardiology, Medical University of Vienna - Vienna - Austria ,

Topic(s):
Pulmonary Hypertension

Citation:
European Heart Journal ( 2019 ) 40 ( Supplement ), 3038

Introduction: Many PAH patients today have a number of CV comorbidities, yet data on the efficacy and safety of therapies in such patients remain scarce. Most recent PAH clinical trials also include patients with comorbidities.

Purpose: To assess the long-term efficacy and safety of the oral, selective IP prostacyclin receptor agonist, selexipag, in PAH patients with and without significant CV comorbidities using post hoc analysis of GRIPHON data.

Methods: GRIPHON enrolled 1156 PAH patients randomised 1:1 to placebo:selexipag. The present analysis includes patients with right heart catheterisation within 1 year of randomisation who were categorised as with or without CV comorbidities. Patients with CV comorbidities were defined as having ≥3 of the following: body mass index (BMI) >30 kg/m2, history of essential hypertension, diabetes mellitus, or historical evidence of significant coronary artery disease; if PAWP/LVEDP was >12 but <15 mmHg, pulmonary vascular resistance (PVR) had to be >500 dyn.sec/cm5; if PAWP/LVEDP was <12, then PVR had to be >300 dyn.sec/cm5. Selexipag effect on time to first morbidity/mortality (M/M) event up to end of treatment was assessed for both subgroups. Baseline (BL) adjusted treatment hazard ratios with 95% CIs were calculated using Cox models. Model building involved stepwise backward elimination of BL covariates.

Results: 752 PAH patients could be categorised based on these criteria (99 with CV comorbidities, 653 without). At BL, patients with CV comorbidities were older (median [range] 60 [28–80] vs 46 [18–78] yrs), had higher BMI (mean [SD] 33.3 [7.23] vs 26.0 [5.64] kg/m2) and lower 6-minute walk distance (mean [SD] 319 [95.7] vs 354 [79.3] m) vs those without. A greater proportion were from Western Europe/Australia/North America (60.6% vs 38.9%) and in WHO functional class III (69.7% vs 49.9%). At BL, 82.8% of patients with CV comorbidities were receiving PAH therapies vs 75.7% of those without. As expected, at BL a higher proportion of patients with CV comorbidities (vs without) had previous/concomitant cardiac disease (62.6% vs 43.0%), metabolism/nutrition disorders (75.8% vs 31.2%), respiratory/thoracic/mediastinal disorders (59.6% vs 37.5%) and vascular disorders (76.8% vs 37.4%). Selexipag reduced the risk of M/M events vs placebo in both subgroups (Figure), with no evidence of an inconsistent treatment effect (interaction p-value=0.1544). Adverse events leading to treatment discontinuation were reported in 35.4% (25.9% selexipag, 46.7% placebo) of patients with CV comorbidities and 35.0% (32.0% selexipag, 38.0% placebo) of those without. Common prostacyclin associated side effects observed with selexipag (headache, diarrhoea, nausea) were reported at a similar incidence in both subgroups.

Conclusions: Selexipag had a beneficial effect on long-term outcome in PAH patients both with and without CV comorbidities. Safety in both groups was consistent with the known profile of selexipag.

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