15 February 2020 by Vallerie V. McLaughlin

The impact of time from diagnosis at baseline on long-term outcome in the GRIPHON Study: Selexipag in pulmonary arterial hypertension (PAH)

Purpose

Newly diagnosed PAH patients have a poor prognosis1,2.In the randomized, event-driven, long-term GRIPHON trial, the oral IP prostacyclin receptor agonist selexipag significantly reduced the risk of morbidity/mortality events compared with placebo in PAH patients. This post-hoc analysis explores whether early initiation of selexipag, with regards to time from diagnosis, improves outcomes for PAH patients. 

Methods

The treatment effect of selexipag versus placebo on the primary endpoint (composite morbidity / mortality) was evaluated for patients categorized based on their time from diagnosis at baseline using a 6-month threshold to define the newly diagnosed patients3:patients treated earlier (time from diagnosis ≤ 6 months) and later (time from diagnosis > 6 months). Kaplan-Meier estimates by treatment arm and subgroup were calculated. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional-hazard models and consistency of treatment effect across subgroups was assessed using an interaction test. 

Results

When patients were categorized by time from diagnosis, patients treated with selexipag earlier (time from diagnosis ≤ 6 months; N=404) were younger and more likely to be in WHO FC II, treatment-naïve and from Asia / Eastern Europe than those treated later (time from diagnosis > 6 months; N=752). Selexipag reduced the risk of morbidity / mortality in patients treated earlier (HR 0.45 [95% CI: 0.33-0.63]) and later (HR 0.70 [95% CI: 0.54-0.91]), with a more pronounced treatment effect in those treated earlier (interaction p-value 0.0391). Consistent results were observed in subgroup analyses by background PAH therapy. 

Conclusions

Consistent with other studies suggesting that earlier initiation of treatment for PAH results in a more pronounced treatment effect, this analysis shows that outcome was better in patients who were treated with selexipag closer to the time of diagnosis.This pattern was observed in all background PAH therapy subgroups.

 

1 - Humbert M, et al. Eur Respir J 2010; 36:549–555.
2 - D’Alonzo GE, et al. Ann Intern Med 1991; 115:343–349.
3 - Simonneau G, et al. Eur Respir J 2015; 46:1711–20.

Key Contributors

Sean Gaine1, Olivier Sitbon2, Richard N. Channick3, Kelly M. Chin4, Lilla Di Scala5, Nazzareno Galiè6, Marius M. Hoeper7, Vallerie V. McLaughlin8, Ralph Preiss5, Lewis J. Rubin9, Gérald Simonneau2, Victor Tapson10, Hossein-Ardeschir Ghofrani11, Irene Lang12 1National Pulmonary Hypertension Unit, Mater Misericordiae University Hospital, Dublin, Ireland; 2Hôpital Universitaire de Bicêtre, Université Paris-Sud, Le Kremlin Bicêtre, France; 3UCLA, Los Angeles, CA; 4UT Southwestern Medical Center, Dallas, TX; 5Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; 6Department of Experimental, Diagnostic and Specialty Medicine – DIMES, University of Bologna, Bologna, Italy; 7Department of Respiratory Medicine, Hannover Medical School and German Center of Lung Research, Hannover, Germany; 8Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI; 9Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA; 10Cedars-Sinai Medical Center, Los Angeles, CA; 11University of Giessen and Marburg Lung Center, Giessen, Germany, member of the German Center of Lung Research, and Department of Medicine, Imperial College London, London, UK; 12Medical University of Vienna, Department of Internal Medicine II, Division of Cardiology, Allgemeines Krankenhaus, Vienna, Austria


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