麻豆传媒

PARIS -- Treatment with the endothelin receptor antagonist macitentan (Opsumit) was safe and effective in adults with portopulmonary hypertension, the manufacturer-led PORTICO trial found.

At week 12, patients on macitentan had a 35% reduction in pulmonary vascular resistance (PVR) compared with those on placebo (model-adjusted ratio 0.65, 95% CI 0.59-0.72, P<0.0001), Olivier Sitbon, MD, PhD, of South Paris University in France, reported here at the European Respiratory Society congress.

"We observed a very nice reduction in PVR on macitentan," said Sitbon. "The effect was very consistent across the prespecified subgroups."

No change in PVR was seen among patients on placebo.

In the SERAPHIN study, macitentan demonstrated long-term efficacy in patients with pulmonary arterial hypertension, which led to FDA approval in 2013 in this setting, but this study -- like many other pulmonary arterial hypertension trials -- excluded patients with portopulmonary hypertension, and as such, PORTICO is the first randomized trial for this disease.

Macitentan treatment yielded a reduction of 99 mm Hg in mean pulmonary arterial pressure compared with placebo (P<0.0001) and increased cardiac index by 0.52 L/min/m² (P=0.0009). No effects on mean systolic blood pressure or hepatic venous pressure gradient were seen.

But these improvements failed to translate to two other secondary endpoints. The 6-minute walk distance (6MWD) showed a numerical advantage with the study drug of 9.73 m (95% CI -14.50 to 33.95, P=0.426). And for World Health Organization (WHO) functional class, six patients on the study drug had a worsening of disease compared with one placebo patient (OR 6.25, 95% CI 0.71-298.38, P=0.1278).

"So we have a nice improvement in hemodynamics, but no change in functional class and walk distance," said Sitbon.

At least one adverse event (AE) occurred in most patients (83.7% with macitentan versus 78.6% with placebo), and serious AEs were more common with the former (20.9% versus 14.3%). Four patients discontinued macitentan because of AEs compared with none in the placebo arm.

"The safety of macitentan in portopulmonary hypertension patients was consistent with previous clinical trial data, with no hepatic safety concerns, which is important," said Sitbon.

PORTICO was a double-blind multicenter trial that included 85 portopulmonary hypertension patients who were randomized to either 10-mg macitentan once daily (n=43) or placebo (n=42). Peripheral edema (25.6% with macitentan versus 11.9% with placebo) and headache (16.3% versus 16.7%, respectively) were the most common adverse events in the trial. No deaths occurred during this 12-week double-blind period of the trial. This portion of the trial will be followed by a 12-week open-label period.

Patients had to be 18 years or older to be included in the study and have a 6MWD ≥50 meters. Active pulmonary arterial hypertension therapy was allowed -- with soluble guanylate cyclase stimulators, PDE5 inhibitors, or inhaled prostanoids -- if patients were on a stable dose for 3 months or more prior to enrollment.

Those with severe liver impairment (Child-Pugh class C) or unstable liver disease were excluded. Alcohol-related liver cirrhosis was the cause of portal hypertension (55.8% in macitentan arm versus 42.9%), followed by hepatitis C (20.9% versus 19.0%, respectively).

Prespecified subgroups included used of pulmonary arterial hypertension therapy (with or without), patient region (North America, Latin America, or Europe), baseline WHO functional class, gender, esophageal varices (with or without), Child-Pugh classification at baseline, and age.

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