Long-term safety and survival outcomes of patients with pulmonary arterial hypertension enrolled in an open label continuation study with tadalafil 40mg daily

Abstract

Purpose: Tadalafil 40mg was shown to be safe and efficacious in patients with pulmonary arterial hypertension (PAH) in the previous randomized, double-blind, placebo-controlled 16-week Pulmonary Arterial HypertensIon and ReSponse to Tadalafil (PHIRST†) study, with sustained improvements in 6MWD for up to 52 additional weeks under continuing blinded active treatment with tadalafil in PHIRST2-Part 1‡. Tadalafil 40mg was well-tolerated in both PHIRST and PHIRST2-Part 1. We now report long-term safety outcomes from the open-label extension (OLE) in PHIRST2-Part 2 for the patients who completed PHIRST2-Part 1. Methods: Patients who completed PHIRST2-Part 1 on 20mg (n=56) or 40mg (n=230) tadalafil were continued on once daily tadalafil 40mg in the PHIRST2-Part2 until tadalafil was commercially available for PAH treatment or the Sponsor concluded the study. All-cause mortality and PAH deterioration (using Kaplan-Meier analysis), and treatment-emergent adverse events (TEAEs) were evaluated. In PHIRST2-Part 2, PAH deterioration was defined as the 1st occurrence of either: death, lung transplantation, atrial septostomy, initiation of any new PAH therapy, or discontinuation due to worsening of WHO functional class or hospitalization for worsening PAH. Results: A total of 286 patients entered PHIRST2-Part 2 (176 [62%] reporting concomitant bosentan treatment). Mean (range) exposure is 818 days (29–1701 days) and 217 (76%) completed the study. The most common reason for discontinuation of tadalafil was death (n=40, 14%). Ninety-three patients (33%) experienced PAH deterioration [the most common reason: initiation of new PAH therapy (n=66, 23%) and death (n=40, 14%)]. After patients enrolled in PHIRST2-Part 2, the observed probability of having no PAH deterioration was 80% (95% CI=0.74, 0.84) at Year 1, 64% (95% CI=0.57, 0.70) at Year 3, and 56% (95% CI=0.42, 0.67) at Year 4. The observed survival probabilities were 96% (95% CI=0.93, 0.98), 82% (95% CI=0.75, 0.87), and 73% (95% CI=0.59, 0.83) at Years 1, 3 and 4, respectively, of PHIRST2-Part 2. Overall, the incidences of patients experiencing at least 1 TEAE during OLE were 92%, with headache most frequently reported. Conclusions: The TEAE profile from PHIRST2-Part 2 was similar to those reported from PHIRST and PHIRST2-Part 1; most events were considered disease related. The long-term survival in PHIRST2-Part 2 for those patients who completed PHIRST and PHIRST2-Part 1 appears similar to that observed other OLE studies in PAH patients.