Efficacy and safety of macitentan in patients with portopulmonary hypertension: The randomized, placebo controlled portico trial

Background: There are few data on use of pulmonary arterial hypertension (PAH) therapies in patients with portopulmonary hypertension (PoPH). Dedicated randomized clinical trials in PoPH have not been conducted, due in part to the potential for safety and tolerability of investigational drugs to be affected by underlying advanced chronic liver disease. The endothelin receptor antagonist macitentan has demonstrated long‐term efficacy in PAH and displays a good hepatic safety profile. The 12‐week, randomized, double‐blind PORTICO trial (NCT02382016) evaluated efficacy and safety of macitentan in PoPH. Methods: Patients aged ≥18 years with a diagnosis of PoPH (pulmonary vascular resistance [PVR] >320 dynes/ sec/cm‐5; mean pulmonary arterial pressure [PAP] >25 mmHg) and without severe hepatic impairment, defined as Child‐Pugh class C or model for end‐stage liver disease score ≥19, were randomized 1:1 to macitentan 10 mg or placebo. Primary endpoint was change in PVR at Week 12, expressed as ratio of baseline. Safety and tolerability were assessed throughout. Results: 85 patients were randomized to macitentan (N=43) or placebo (N=42); 51.8% were male, 63.5% were receiving background PAH therapy, 58.8% were WHO functional class (FC) II and mean (±SD) 6‐minute walk distance (6MWD) was 385±104 m. Hepatic venous pressure gradient (HVPG, assessed and centrally reviewed in 26 patients) was 10.5 mmHg in both treatment arms. The most common causes of portal hypertension were alcoholic cirrhosis (62.4%) and hepatitis C (31.8%). Macitentan significantly improved PVR (35% reduction vs placebo), PAP and cardiac index vs placebo (Table). There was no significant difference between groups in change from baseline to Week 12 for FC or 6MWD. Macitentan did not affect mean HVPG (n=15) or mean systolic blood pressure (n=40). Most common adverse events (AEs; macitentan vs placebo) were peripheral edema (25.6 vs 11.9%) and headache (16.3 vs 16.7%). At Week 12, mean decrease in hemoglobin was 1.8g/dL with macitentan. Four patients (macitentan) discontinued due to AEs, all unrelated to the liver. No patients died. One macitentan patient experienced alanine aminotransferase and/or aspartate aminotransferase ≥3x upper limit of normal (ULN) with total bilirubin ≥2xULN. Conclusion: Macitentan led to significant improvement in PVR and other hemodynamic parameters in PoPH. Safety was consistent with previous clinical trials; there were no hepatic safety concerns in this population.