Abstract 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. Acknowledgement/Funding Actelion Pharmaceuticals Ltd