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(Circulation. 2009;119:2894-2903.)
© 2009 American Heart Association, Inc.

Hypertension

Tadalafil Therapy for Pulmonary Arterial Hypertension

Nazzareno Galiè, MD; Bruce H. Brundage, MD; Hossein A. Ghofrani, MD; Ronald J. Oudiz, MD; Gerald Simonneau, MD; Zeenat Safdar, MD; Shelley Shapiro, MD; R. James White, MD; Melanie Chan, PhD; Anthony Beardsworth, MD; Lyn Frumkin, MD, PhD; Robyn J. Barst, MD, on behalf of the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group^*

From the Institute of Cardiology, Università di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor–University of California at Los Angeles, Torrance, Calif (R.J.O.); Antoine Béclère University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los Angeles Veterans Affairs Healthcare System, David Geffen University of California at Los Angeles School of Medicine (S.S.); Division of Pulmonary and Critical Care Medicine, University of Rochester, Rochester, NY (R.J.W.); Eli Lilly and Company, Erl Wood, United Kingdom (A.B.); Eli Lilly and Company, Toronto, Ontario, Canada (M.C.); ICOS Corporation, Bothell, Wash (L.F.); and Schneider Children’s Hospital North Shore–Long Island Jewish Health System, New Hyde Park, NY (R.J.B.).

Correspondence to Nazzareno Galiè, MD, Institute of Cardiology, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. E-mail nazzareno.galie{at}unibo.it

Received November 30, 2008; accepted April 10, 2009.

Background— Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway.

Methods and Results— In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance (P<0.01). Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95% confidence interval, –2 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to clinical worsening (P=0.041), incidence of clinical worsening (68% relative risk reduction; P=0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing.

Conclusions— In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.

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