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

https://doi.org/10.1016/j.jacc.2012.05.004Get rights and content
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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)

Key Words

PDE-5
pulmonary arterial hypertension
tadalafil

Abbreviations and Acronyms

AE
adverse event(s)
PAH
pulmonary arterial hypertension
PDE
phosphodiesterase
6MWD
6-min walk distance
T20 mg
tadalafil 20 mg
T40 mg
tadalafil 40 mg
WHO-FC
World Health Organization functional class

Cited by (0)

This study was supported by Eli Lilly & Company. A licensing agreement exists between Eli Lilly and United Therapeutics. Dr. Oudiz has received consulting and speaking fees, honoraria, and research support from Actelion, Bayer, Gilead, Eli Lilly & Company, Lung LLC, Medtronic, Novartis, Pfizer, and United Therapeutics. Dr. Brundage has chaired or been a member of data monitoring committees for clinical trials involving patients with pulmonary arterial hypertension for Actelion, Gilead, Novartis, Pfizer, Lung Rx, GlaxoSmithKline, and United Therapeutics; and is a member of the End-Point Adjudication Committee for Novartis and Medtronic and the Scientific Advisory Committee for Eli Lilly & Company regarding the PHIRST-1 clinical trial. Dr. Galiè has been involved with steering committee activities for Eli Lilly & Company, Actelion, Pfizer, United Therapeutics, Bayer-Schering, and GlaxoSmithKline; has been a paid lecturer for Actelion, Pfizer, Bayer-Schering, and GlaxoSmithKline; and has done contract research for Eli Lilly & Company, Actelion, Pfizer, United Therapeutics, Bayer-Schering, and GlaxoSmithKline. Dr. Ghofrani has received honoraria from, acted as a consultant for, and/or been a steering committee member for Actelion, Bayer-Schering, Eli Lilly & Company, Ergonex, GlaxoSmithKline, Novartis, Pfizer, and United Therapeutics. Dr. Simonneau has received research support and/or acted as a consultant for Actelion, Bayer-Schering, GlaxoSmithKline, Pfizer, and United Therapeutics. Dr. Botros is an employee of and stockholder in Eli Lilly & Company. Ms. Chan is an employee of and stockholder in Eli Lilly & Company. Mr. Beardsworth is an employee of and stockholder in Eli Lilly & Company. Dr. Barst has received support for serving as a consultant and scientific advisor to Actelion, Bayer, Eli Lilly & Company, Gilead, Ikaria, Merck, Novartis, and Pfizer.