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S109 Targeting the prostacyclin pathway in the treatment of connective tissue disease associated pulmonary arterial hypertension (pah): insights from the randomised controlled griphon trial with selexipag
  1. G Coghlan1,
  2. S Gaine2,
  3. R Channick3,
  4. L Di Scala4,
  5. N Galiè5,
  6. HA Ghofrani6,7,
  7. MM Hoeper8,
  8. I Lang9,
  9. V McLaughlin10,
  10. R Preiss4,
  11. LJ Rubin11,
  12. G Simonneau12,
  13. O Sitbon12,
  14. VF Tapson13,
  15. K Chin14
  1. 1National Pulmonary Hypertension Service, Royal Free Hospital, National Health Service Foundation Trust, London, UK
  2. 2National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland
  3. 3Massachusetts General Hospital, Boston, MA, USA
  4. 4Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
  5. 5Istituto di Malattie dell’Apparato Cardiovascolare, University of Bologna, Bologna, Italy
  6. 6University of Giessen and Marburg Lung Centre (UGMLC), member of the German Centre of Lung Research (DZL), Giessen, Germany
  7. 7Department of Medicine, Imperial College London, London, UK
  8. 8Department of Respiratory Medicine, Hannover Medical School and German Centre of Lung Research, Hannover, Germany
  9. 9Medical University of Vienna, Department of Internal Medicine II, Division of Cardiology, Allgemeines Krankenhaus, Vienna, Austria
  10. 10University of Michigan Health System Division of Cardiovascular Medicine, Ann Arbor, MI, USA
  11. 11Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA, USA
  12. 12Hôpital Universitaire de Bicêtre, Université Paris-Sud, Le Kremlin Bicêtre, France
  13. 13Cedars-Sinai Medical Centre, Los Angeles, CA, USA
  14. 14UT Southwestern Medical Centre, Dallas, TX, USA


Rationale Despite available therapies, patients with connective tissue disease-associated PAH (PAH-CTD) have a poor prognosis. The global phase III GRIPHON study (NCT01106014) enrolled 1,156 patients including 334 with PAH-CTD. Compared with placebo, selexipag reduced the risk of the primary composite outcome of morbidity/mortality up to end of treatment by 41% (hazard ratio [HR] 0.59; 99% CI: 0.37–0.96) among patients with PAH-CTD. We examined the effect of selexipag vs placebo in the PAH-CTD subgroups: PAH associated with systemic sclerosis (PAH-SSc), systemic lupus erythematous (PAH-SLE) and mixed CTD (PAH-MCTD).

Methods Patients (18–75 years) were randomised 1:1 to placebo or selexipag. HRs (95% CI) were calculated using Cox regression models to determine the effect of selexipag vs placebo on morbidity/mortality.

Results Of the 334 patients enrolled with PAH-CTD, 170 had PAH-SSc, 82 PAH-SLE, and 47 PAH-MCTD; CTD sub-classification was not reported in 35 patients. Across the subgroups, the majority of patients were female (84–99%) and were receiving an endothelin receptor antagonist, a phosphodiesterase type-5 inhibitor or both at baseline (73–83%). In the PAH-SSc, PAH-SLE and PAH-MCTD subgroups, the mean (SD) age was 60.0 (10.6), 39.0 (11.3) and 48.0 (14.7) years, respectively, and 65%, 33%, and 45% were in WHO functional class III, respectively. Selexipag reduced the risk of morbidity/mortality events by 44% (HR 0.56; 95% CI: 0.34–0.91) in PAH-SSc, 34% (HR 0.66; 95% CI: 0.30–1.48) in PAH-SLE, and 53% (HR 0.47; 95% CI: 0.15–1.48) in PAH-MCTD (Figure). The treatment effect was consistent across the subgroups (interaction test indicated no heterogeneity; p = 0.6737). By the end of study, 22 PAH-SSc, 7 PAH-SLE and 3 PAH-MCTD patients in the placebo, and 17 PAH-SSc, 4 PAH-SLE, 8 PAH-MCTD patients in the selexipag group had died. Common prostacyclin-associated side effects observed with selexipag in PAH-CTD patients generally occurred at a similar incidence to PAH-non-CTD patients and within the PAH-CTD subgroups.

Conclusion GRIPHON included the largest randomised cohort of patients with PAH-CTD to date. The treatment effect of selexipag on time to first morbidity/mortality event was consistent across the subgroups, suggesting that selexipag is an effective therapeutic option in these difficult-to-treat patients.

Please refer to page A270 for declarations of interest in relation to abstract S109.

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