Featured articleTadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension
Section snippets
Study design
PHIRST-1, a 16-week, randomized, double blind, PBO-controlled study, evaluated tadalafil in PAH. Patients were randomized 1:1:1:1:1 to 5 groups (2.5, 10, 20, 40 mg, or PBO orally once daily). Stratification included background bosentan (yes/no) at enrollment. The trial was conducted at 82 centers in Canada, the USA, Europe and Japan. Patients were enrolled starting on August 18, 2005 with last subject completing the study on August 16, 2007. The study was conducted in accordance with applicable
Results
The disposition of all patients enrolled in PHIRST-1 is presented in Figure 1. Of the 405 patients receiving study drug, 341 (84%) completed the 16-week study. For the data that follows, we have limited results to the patients who received PBO, 20 mg tadalafil or 40 mg tadalafil.
Discussion
Because there is no cure for PAH, treatment goals are to improve quality of life and survival.25 Because monotherapy can be sub-optimal,1, 25 combination therapies, with potentially additive or synergistic effects, are being explored.26, 27, 28, 29
PHIRST-1 was the first PBO-controlled study in which a targeted therapy was evaluated as both monotherapy and as add-on to a background treatment in the same trial.10 Although this study was not powered for safety and efficacy analysis of the
Disclosure statement
The authors thank the sub-investigators, site coordinators, study nurses and investigation-site personnel. Without the combined efforts of all these parties, this study would not have been possible. We thank Melanie Chan for her initial efforts with statistical analyses and providing suggestions and discussion early in the process, and Emel Guldogan, MA (i3 Statprobe, Cary, NC), for her statistical assistance and review.
This study was supported by Eli Lilly and Co. A license agreement exists
References (38)
- et al.
Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan
J Am Coll Cardiol
(2006) - et al.
Sitaxsentan treatment for patients with pulmonary arterial hypertension discontinuing bosentan
J Heart Lung Transplant
(2007) - et al.
Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival
Chest
(2008) - et al.
Metered dose inhaler delivery of treprostinil for the treatment of pulmonary hypertension
Pulmon Pharmacol Ther
(2009) - et al.
Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines
Chest
(2007) - et al.
Management of pulmonary arterial hypertension with a focus on combination therapies
J Heart Lung Transplant
(2007) Updated evidence-based treatment algorithm for pulmonary arterial hypertension
J Am Coll Cardiol
(2009)- et al.
Combination therapy and new types of agents for pulmonary arterial hypertension
Clin Chest Med
(2007) - et al.
Ambrisentan therapy for pulmonary arterial hypertension
J Am Coll Cardiol
(2005) - et al.
The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect
Vasc Pharmacol
(2005)
Survival in patients with cryptogenic fibrosing alveolitis: a population-based cohort study
Chest
New insights into a challenging disease—a review of the Third World Symposium on Pulmonary Arterial Hypertension
J Am Coll Cardiol
Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of diseaseA randomized, controlled trial
Ann Intern Med
A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension
N Engl J Med
Sitaxsentan therapy for pulmonary arterial hypertension
Am J Respir Crit Care Med
Sildenafil citrate therapy for pulmonary arterial hypertension
N Engl J Med
Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2
Circulation
Tadalafil therapy for pulmonary arterial hypertension
Circulation
Inhaled iloprost for severe pulmonary hypertension
N Engl J Med
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