Tadalafil for the Treatment of Pulmonary Arterial Hypertension

• Published in: Journal of the American College of Cardiology Vol. 60; no. 8; pp. 768 - 774
• Main Authors: Oudiz, Ronald J., MD, Brundage, Bruce H., MD, Galiè, Nazzareno, MD, Ghofrani, Hossein Ardeschir, MD, Simonneau, Gerald, MD, Botros, Fady T., PhD, Chan, Melanie, MS, Beardsworth, Anthony, MBBS, Barst, Robyn J., MD
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 21.08.2012; Elsevier Limited
• Subjects: Cardiology; Cardiovascular; Confidence intervals; Demographics; Drug dosages; Drug therapy; Hypertension; Internal Medicine; Multivariate analysis; Patients; PDE-5; pulmonary arterial hypertension; Regulatory approval; Studies; tadalafil; Variables; T40 mg; World Health Organization functional class; tadalafil; AE; 6-min walk distance; T20 mg; adverse event(s); PDE; tadalafil 20 mg; PAH; tadalafil 40 mg; phosphodiesterase; WHO-FC; pulmonary arterial hypertension; 6MWD; PDE-5
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2012.05.004

Objectives The aim of this study was to evaluate the long-term safety and durability of efficacy of tadalafil for pulmonary arterial hypertension. Background Tadalafil is an oral phosphodiesterase-5 inhibitor approved for PAH treatment. In the multicenter, placebo-controlled, randomized, 16-week PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study, tadalafil 40 mg improved exercise capacity and delayed clinical worsening. Methods 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-min walk distance (6MWD) test. Clinical worsening and changes in World Health Organization functional class were evaluated. Results 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. Conclusions Long-term treatment with tadalafil was well tolerated in patients with pulmonary arterial hypertension. 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. (Pulmonary Arterial Hypertension and Response to Tadalafil Study; NCT00549302 )