Long-Term Survival, Safety and Tolerability with Selexipag in Patients with Pulmonary Arterial Hypertension: Results from GRIPHON and its Open-Label Extension

Adv Ther. 2022 Jan;39(1):796-810. doi: 10.1007/s12325-021-01898-1. Epub 2021 Oct 30.


Introduction: In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag.

Methods: Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019.

Results: Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan-Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively.

Conclusions: These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen.

Trial registration: ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306.

Keywords: Combination therapy; GRIPHON; Long-term outcomes; Open-label extension; PAH; Pulmonary arterial hypertension; Safety; Selexipag; Survival; Tolerability.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / adverse effects
  • Acetamides / therapeutic use*
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / therapeutic use*
  • Humans
  • Hypertension, Pulmonary* / drug therapy
  • Pulmonary Arterial Hypertension* / drug therapy
  • Pyrazines / adverse effects
  • Pyrazines / therapeutic use*


  • Acetamides
  • Antihypertensive Agents
  • Pyrazines
  • selexipag

Associated data

  • ClinicalTrials.gov/NCT01106014
  • ClinicalTrials.gov/NCT01112306