Tadalafil for the Treatment of Pulmonary Arterial Hypertension: A Double-Blind 52-Week Uncontrolled Extension Study

Study Questions:

What is the long-term safety and durability of efficacy of tadalafil for patients with pulmonary arterial hypertension (PAH) enrolled in the extension of the PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study?


Eligible patients from PHIRST received once-daily tadalafil 20 mg (T20 mg) or 40 mg (T40 mg) (n = 357) in the double-blind, 52-week, uncontrolled extension study (PHIRST-2); 293 patients completed PHIRST-2. Durability of efficacy was explored using the 6-minute walk distance (6MWD) test. Clinical worsening and changes in World Health Organization functional class were evaluated.


Mean age was 53 years, and about 76% were female. About 60% were idiopathic/heritable, and 20% had connective tissue disease. The safety profile of tadalafil in PHIRST-2 was similar to that in PHIRST, with typical phosphodiesterase-5 inhibitor adverse events. The 6MWDs achieved in PHIRST for the subset of patients receiving T20 mg and T40 mg in both PHIRST and PHIRST-2 (406 ± 67 m [n = 52] and 413 ± 81 m [n = 59] at PHIRST-2 enrollment, respectively) were maintained at PHIRST-2 completion (415 ± 80 m [n = 51] and 410 ± 78 m [n = 59], respectively). Numerically fewer patients who were on T40 mg in PHIRST and PHIRST-2 experienced World Health Organization functional class deterioration (6% [n = 5]) compared with those randomized to T20 mg (9% [n = 7]) across both studies. Post hoc analyses showed that background bosentan use and higher 6MWD at PHIRST baseline were associated with fewer clinical worsening events.


Long-term treatment with tadalafil was well tolerated in patients with PAH. In patients receiving either T20 mg or T40 mg, the improvements in 6MWD demonstrated in the 16-week PHIRST study appeared sustained for up to 52 additional weeks of treatment in PHIRST-2.


This is among the few studies to prospectively evaluate the long-term safety and efficacy of drugs designed to treat PAH. The suggestion that tadalafil added to bosentan improves time to clinical worsening requires further study. Of note, with multivariate analysis, patients with connective tissue disease had a twofold greater likelihood of clinical worsening than those with idiopathic PAH.

Clinical Topics: Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Pulmonary Hypertension

Keywords: Phosphodiesterase 5 Inhibitors, Hypertension, Pulmonary

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