1. The composite of death from all causes or a complication related to pulmonary arterial hypertension (PAH) was significantly lower in the selexipag group than in the placebo group.
2. Death due to PAH or hospitalization for worsening of PAH was significantly lower in the selexipag group than in the placebo group.
Evidence Rating Level: 2 (Good)
Study Rundown: Current recommendations for the management of pulmonary arterial hypertension (PAH) support a combination of therapies that target the endothelin, nitric-oxide, and prostacyclin pathways. Selexipag is an oral, selective prostacyclin-receptor agonist that is structurally distinct from prostacyclin. The GRIPHON study was a multicenter, double-blinded, randomized, parallel-group, placebo-controlled, event-driven investigation of the use of selexipag for PAH.
In this study the placebo group had a significantly higher number of death or complication due to PAH compared to the selexipag group. Furthermore, a significantly greater number of participants in the placebo group experienced death due to PAH or hospitalization for worsening of PAH compared to the selexipag group.
This study draws strength through its large sample size, prespecified calculation of number of primary end-point events needed for the study to have 90% power to detect a prespecified hazard ratio, and its multicenter (181 centers in 39 countries), double-blinded, randomized, parallel-group, placebo-controlled design. However, it approximately 19% of the participants discontinued the study prematurely which is a limiting factor for this study.
In-Depth [randomized controlled trial]: The study population included patients aged 18 to 75 with acquired, heritable, or idiopathic PAH. Ineligible patients were those who were receiving prostacyclin analogues. Eligible patients were randomly assigned in a 1:1 ratio to receive placebo (n = 582) or selexipag (n = 574). In the initial 12-week dose adjustment phase, selexipag was initiated at a dose of 200 µg twice daily and was increased until unmanageable side effects developed or to a maximum dose of 1600 µg twice daily. The end of the treatment period for each patient, 7 days after the last intake of selexipag or placebo, was reached either due to an adverse event or the arrival at the end of the study. The end of the study was declared when the prespecified number of primary end-point events, 202, was reached.
The primary endpoint was a composite of death or a complication related to PAH, whichever occurred first, up to the end of the treatment period. Complications related to PAH were hospitalization for worsening PAH, disease progression, death from any cause, initiation of parenteral prostanoid therapy or long term O2, need for lung transplantation or balloon atrial septostomy. The hazard ratio for a primary endpoint event in the selexipag group was 0.60 (99% [CI], 0.46 to 0.78; P<0.001).
The secondary endpoints were death due to PAH or hospitalization for worsening of PAH up to the end of the treatment period and death up to the end of the study. At week 26, the 6-minute walk distance had decreased by a median of 9.0 m from baseline in the placebo group and had increased by 4.0 m from baseline in the selexipag group (99% [CI], 1 to 24; p = 0.003). By the end of the treatment period, death due to PAH or hospitalization for worsening of PAH had occurred in 23.5% placebo group patients (23.5%) vs 17.8% selexipag group patients (95% [CI], 0.74 to 1.28; P = 0.003); death from any cause had occurred in 18.0% placebo group patients vs 17.4% selexipag group patients (P = 0.42). No serious adverse events were reported more frequently (>1% higher) in the selexipag group than in the placebo group.
Image: CC/Yale Rosen
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