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

Nazzareno Galiè, Sean Gaine, Richard Channick, J Gerry Coghlan, Marius M Hoeper, Irene M Lang, Vallerie V McLaughlin, Cheryl Lassen, Lewis J Rubin, Shu-Fang Hsu Schmitz, Olivier Sitbon, Victor F Tapson, Kelly M Chin, Nazzareno Galiè, Sean Gaine, Richard Channick, J Gerry Coghlan, Marius M Hoeper, Irene M Lang, Vallerie V McLaughlin, Cheryl Lassen, Lewis J Rubin, Shu-Fang Hsu Schmitz, Olivier Sitbon, Victor F Tapson, Kelly M Chin

Abstract

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.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Patient disposition. Data cut-off 1 September 2019. PAH pulmonary arterial hypertension, OL open-label. aFour patients did not receive placebo as assigned. bCompleted study treatment in GRIPHON or GRIPHON OL: Patients who performed the end of study assessment. Green shading indicates patients who received selexipag
Fig. 2
Fig. 2
Survival in selexipag treated patients. Analyses performed in the survival analysis set. Kaplan–Meier curve for time from selexipag initiation to death up to data cut-off (1 September 2019). Kaplan–Meier estimates (95% CI) are shown at 1, 3, 5 and 7 years

References

    1. Farber HW, Miller DP, Poms AD, Badesch DB, Frost AE, Muros-Le Rouzic E, et al. Five-year outcomes of patients enrolled in the REVEAL Registry. Chest. 2015;148:1043–1054. doi: 10.1378/chest.15-0300.
    1. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest. 2012;142:448–456. doi: 10.1378/chest.11-1460.
    1. Uptravi USPI. Uptravi® (selexipag) prescribing information. 2021.
    1. Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galie N, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373:2522–2533. doi: 10.1056/NEJMoa1503184.
    1. Benza RL, Gomberg-Maitland M, Elliott CG, Farber HW, Foreman AJ, Frost AE, et al. Predicting survival in patients with pulmonary arterial hypertension: the REVEAL risk score calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies. Chest. 2019;156:323–337. doi: 10.1016/j.chest.2019.02.004.
    1. Benza RL, Seeger W, McLaughlin VV, Channick RN, Voswinckel R, Tapson VF, et al. Long-term effects of inhaled treprostinil in patients with pulmonary arterial hypertension: the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study open-label extension. J Heart Lung Transplant. 2011;30:1327–1333. doi: 10.1016/j.healun.2011.08.019.
    1. Ghofrani HA, Grimminger F, Grunig E, Huang Y, Jansa P, Jing ZC, et al. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016;4:361–371. doi: 10.1016/s2213-2600(16)30019-4.
    1. Simonneau G, Rubin LJ, Galiè N, Barst RJ, Fleming TR, Frost A, et al. Long-term sildenafil added to intravenous epoprostenol in patients with pulmonary arterial hypertension. J Heart Lung Transplant. 2014;33:689–697. doi: 10.1016/j.healun.2014.02.019.
    1. Rubin LJ, Badesch DB, Fleming TR, Galie N, Simonneau G, Ghofrani HA, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest. 2011;140:1274–1283. doi: 10.1378/chest.10-0969.
    1. Kim NH, Hemnes AR, Chakinala MM, Highland KB, Chin KM, McLaughlin V, et al. Patient and disease characteristics of the first 500 patients with pulmonary arterial hypertension treated with selexipag in real-world settings from SPHERE. J Heart Lung Transplant. 2021 doi: 10.1016/j.healun.2021.01.006.
    1. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) Eur Respir J. 2015;46:903–975. doi: 10.1183/13993003.01032-2015.
    1. Galiè N, Humbert M, Vachiéry JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) Eur Heart J. 2016;37:67–119. doi: 10.1093/eurheartj/ehv317.
    1. Galiè N, Channick RN, Frantz RP, Grünig E, Jing ZC, Moiseeva O, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J. 2019;53:1801889. doi: 10.1183/13993003.01889-2018.
    1. Heresi GA, Rao Y. Follow-up functional class and 6-minute walk distance identify long-term survival in pulmonary arterial hypertension. Lung. 2020;198:933–938. doi: 10.1007/s00408-020-00402-w.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren