Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study.

Abstract

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).

• Authors: Ronald J Oudiz, Bruce H Brundage, Nazzareno Galiè, Hossein Ardeschir Ghofrani, Gerald Simonneau, Fady T Botros, Melanie Chan, Anthony Beardsworth, Robyn J Barst, PHIRST Study Group
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 60 Issue 8 Pg. 768-74 (Aug 21 2012) ISSN: 1558-3597 [Electronic] United States
• PMID: 22818063 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antihypertensive Agents
• Carbolines
• Phosphodiesterase 5 Inhibitors
• Sulfonamides
• Vasodilator Agents
• Tadalafil
• Bosentan

Topics

• Adult
• Aged
• Analysis of Variance
• Antihypertensive Agents (administration & dosage, therapeutic use)
• Bosentan
• Carbolines (administration & dosage, therapeutic use)
• Double-Blind Method
• Drug Administration Schedule
• Familial Primary Pulmonary Hypertension
• Female
• Humans
• Hypertension, Pulmonary (drug therapy)
• Male
• Middle Aged
• Phosphodiesterase 5 Inhibitors (administration & dosage, therapeutic use)
• Prospective Studies
• Sulfonamides (therapeutic use)
• Tadalafil
• Treatment Outcome
• Vasodilator Agents (administration & dosage, therapeutic use)