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Heart Failure Treatment and Management / Blood Pressure and Hypertension Studies / Pulmonary Hypertension Research and Treatments · Journal article
The Lancet · July 28, 2026
Strong and direct enough that it may change what you do.
ADVANCE OUTCOMES is a phase 3 RCT in 687 PAH patients demonstrating that ralinepag, an oral once-daily prostacyclin IP receptor agonist, significantly reduces the risk of first clinical worsening (composite of death, hospitalisation, prostacyclin-pathway therapy initiation, disease progression, or unsatisfactory response) compared with placebo. The benefit is offset by higher treatment discontinuation due to adverse events (19% vs 3%), but serious adverse event rates were similar between groups (28% vs 31%).
Multicentre, randomised, double-blind, placebo-controlled, event-driven phase 3 trial. Adults aged ≥18 years with PAH diagnosed per 2022 ESC/ERS guidelines; 687 analysed (350 ralinepag, 337 placebo) after exclusion of 41 patients from China.. Intervention: Ralinepag, oral, once-daily selective prostacyclin IP receptor agonist, initiated 50 μg daily, titrated weekly to highest tolerated dose. Compared with: Placebo. n = 687. Multicentre (specific number of sites and countries not stated in source); enrolled from January 24, 2019, to June 20, 2025..
64 (18%) of 350 ralinepag patients versus 121 (36%) of 337 placebo patients experienced first clinical worsening event (HR 0.45 [95% CI 0.33–0.62]; p<0.0001) Adverse event was primary reason for discontinuation in 65 (19%) ralinepag patients versus 10 (3%) placebo patients Serious adverse events occurred in 98 (28%) ralinepag patients and 104 (31%) placebo patients
Long-term safety and efficacy beyond median 85 weeks follow-up not characterised Adverse event was primary reason for discontinuation in 65 (19%) ralinepag patients versus 10 (3%) placebo patients
Ralinepag offers a new oral once-daily option for PAH that significantly delays or prevents clinical worsening in patients already receiving contemporary background therapy. Clinicians should weigh the demonstrated clinical benefit against the higher rate of adverse-event-related discontinuations (19% vs 3% with placebo) and carefully monitor tolerability during dose titration.
Phase 3 RCT demonstrates ralinepag significantly reduces clinical worsening in PAH (HR 0.45, p<0.0001) versus placebo in 687 patients with contemporary background therapy, with acceptable safety profile supporting clinical use.
As stated by the source record.
Quoted from the source exactly as published.
Ralinepag offers a new oral once-daily option for PAH that significantly delays or prevents clinical worsening in patients already receiving contemporary background therapy. Clinicians should weigh the demonstrated clinical benefit against the higher rate of adverse-event-related discontinuations (19% vs 3% with placebo) and carefully monitor tolerability during dose titration.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare, progressive disease characterised by elevated pulmonary vascular resistance that can lead to right ventricular failure and premature death. Ralinepag is an oral, once-daily, selective prostacyclin IP receptor agonist developed to treat PAH. We aimed to evaluate the efficacy and safety of ralinepag in patients with PAH. METHODS: ADVANCE OUTCOMES was a randomised, double-blind, placebo-controlled, event-driven, phase 3 trial of ralinepag in patients with PAH. Eligible patients were aged 18 years or older and PAH was diagnosed on the basis of the 2022 European Society of Cardiology and European Respiratory Society guidelines (mean pulmonary artery pressure >20 mm Hg, pulmonary artery wedge pressure ≤15 mm Hg, and pulmonary vascular resistance of >2 Wood units). Patients were randomly assigned (1:1) to ralinepag or placebo, initiated at a dose of 50 μg once daily and titrated weekly until the highest tolerated individualised dose was reached. Randomisation was stratified by baseline 6-minute walk distance (6MWD), PAH aetiology, and oral background therapy. A block size of four was used within each combination of stratification factors. The sponsor, patients, and all personnel directly involved with the conduct of the study were masked to study drug identity and randomisation assignments. The primary outcome was time to first clinical worsening event, a composite of death from any cause, admission to hospital due to worsening PAH or right heart failure, initiation of parenteral or inhaled prostacyclin-pathway therapy, disease progression, or unsatisfactory long-term clinical response. Efficacy analyses were done in the full analysis set and safety analyses in the safety set; both sets comprised 687 patients after exclusion of 41 randomly assigned and treated patients from sites in China (exclusions due to regulatory challenges and data integrity concerns). This study is registered with ClinicalTrials.gov (NCT03626688) and euclinicaltrials.eu (2023-509304-16-00) and is complete. FINDINGS: Patients were enrolled between Jan 24, 2019, and June 20, 2025. Of 1037 patients screened for eligibility, 728 were randomly assigned and received at least one dose of ralinepag or placebo; 687 were included in the full analysis and safety sets, of whom 350 received ralinepag and 337 received placebo. Median follow-up from randomisation to clinical worsening event, censoring, or study closure was 85·0 weeks (IQR 27·6-160·9) in the ralinepag group and 78·4 weeks (34·6-137) in the placebo group. At baseline, patients had a mean 6MWD of 438·9 m (SD 104·8) and 548 (80%) of 687 patients were receiving dual background PAH therapy. Overall, 64 (18%) of 350 patients in the ralinepag group and 121 (36%) of 337 patients in the placebo group had a first clinical worsening event (hazard ratio 0·45 [95% CI 0·33-0·62]; p<0·0001). The largest numerical between-group differences in components of the composite outcome were observed for disease progression, initiation of parenteral or inhaled prostacyclin-pathway therapy, and unsatisfactory long-term clinical response. Adverse event was the primary reason for treatment discontinuation in 65 (19%) of 350 patients in the ralinepag group and ten (3%) of 337 patients in the placebo group. Serious adverse events occurred in 98 (28%) patients in the ralinepag group and 104 (31%) patients in the placebo group. Adverse events leading to death occurred in 15 (4%) and 14 (4%) patients, respectively. INTERPRETATION: In patients with PAH receiving contemporary background therapy, ralinepag significantly reduced the risk of first clinical worsening compared with placebo, but was associated with more adverse-event-related treatment discontinuations. These results support the use of ralinepag as an oral, once-daily prostacyclin-pathway treatment option for PAH. FUNDING: United Therapeutics Corporation.
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