Portopulmonary Hypertension: Treatment

Ambrisentan

Ambrisentan is a highly selective ET-1A receptor antagonist with once daily dosing and a lower risk of hepatotoxicity compared to bosentan. Fourteen patients with moderate to severe POPH treated with ambrisentan in 4 German hospitals were retrospectively analyzed.²³ Median follow-up was 16 months, and the study demonstrated significant improvement in exercise capacity and clinical symptoms without significant change in liver function tests. Cartin-Ceba et al published their experience of 13 patients with moderate to severe POPH treated with ambrisentan monotherapy.²⁴ Patients were followed for a median of 613 days and on treatment for a median time of 390 days. Significant improvements were shown in pulmonary arterial pressure and PVR without adverse effect on hepatic function. Over 270 patients with PAH (6% with POPH) received ambrisentan from March 2009 through June 2013 at a large United Kingdom portal hypertension referral center.²⁵ Discontinuation due to side effects was higher than previously reported. Discontinuation due to abnormal transaminases was uncommon.

Macitentan

Macitentan is a dual endothelin-receptor antagonist developed by modifying the structure of bosentan to increase efficacy and safety. The SERAPHIN trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH, some of whom were also on a stable dose of oral or inhaled therapy for PAH.²⁶ Over a 2-year period, patients treated with macitentan were less likely to have progression of their disease or die on therapy (38% and 31% versus 46%), regardless of if they were receiving additional oral therapy and more likely to have improvement of their exercise capacity and WHO functional class. Nasopharyngitis and significant anemia were more common in the macitentan group, but there was no difference in the rate of liver function test abnormalities compared to placebo. Trials with macitentan are currently ongoing in patients with POPH.

Phosphodiesterase-5 Inhibitors

Cyclic guanosine monophosphate (cGMP) is the mediator of nitric oxide–induced vasodilation. Phosphodiesterase-5 (PDE-5) inhibitors prolong the vasodilatory effects of cyclic guanosine monophosphate by preventing its hydrolysis, thereby reducing the pulmonary arterial pressure.

Sildenafil

Sildenafil is the most widely accepted PDE-5 inhibitor for POPH. Fourteen patients with moderate to severe POPH were treated with sildenafil (50 mg 3 times per day) in an observational study published by Reichenberger et al in 2006.²⁷ Eight patients were newly started on sildenafil, whereas sildenafil was added to inhaled prostanoids in the remaining 6x patients. Sildenafil significantly decreased 66MWD, MPAP, PVR, and cardiac index alone or in combination with inhaled prostanoids.

Sildenafil has also been used as a bridge to transplant in liver transplant candidates with POPH. Ten patients with POPH treated with sildenafil monotherapy were followed for a 21±16 months.²⁸ Patients improved symptomatically and increased their 6MWD at 1 year by 30 meters or more. Three patients became transplant eligible and another 3 patients were stable, without progression of their liver disease or POPH. Four patients were not considered transplant candidates, 2 because of refractory POPH and 2 for other comorbidities. The authors concluded that sildenafil monotherapy could stabilize or improve pulmonary hemodynamics in patients with POPH and eventually lead to liver transplantation. Gough et al took a similar look at 9 patients with POPH treated with sildenafil.²⁹ All patients had initial and follow-up right heart catheterizations within a period of 3 years. Mean PVR improved in all patients, decreasing from 575 to 375 dynes/s/cm^–5. MPAP decreased to ≤ 35 mmHg in 4 patients, 1 of whom went on to receive a liver transplant. Overall sildenafil improved pulmonary hemodynamics in this small cohort of POPH patients.