J Heart Lung Transplant. 2011 Jun;30(6):632-43

J Heart Lung Transplant. 2011 Jun;30(6):632-43. Epub 2011 Jan 21.

Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension.

Barst RJ, Oudiz RJ, Beardsworth A, Brundage BH, Simonneau G, Ghofrani HA, Sundin DP, Galiè N; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group.

Collaborators (88) Galie N, Safdar Z, Shapiro S, White RJ, Barst RJ, Rosenzweig E, Girgis R, Grimminger F, Ghofrani A, Seeger W, Feldman J, Simonneau G, Klinger J, Cottin V, Granton J, Nakanishi N, Staehler G, Mehta S, Coghlan G, Ostrow D, Badesch D, Behr J, Bruch L, Farber H, Mubarak T, Lawrence C, Markin C, Minai O, Saydain G, Widmer M, Degano B, Fazio S, Gomberg-Maitland M, Langleben D, Meyer J, Michaelson J, Michelakis E, Naeije R, Peacock A, Rayburn B, Chakinala M, Louis S, DeMarco T, Fedele F, Frantz R, Gomez-Sanchez MA, Helmersen D, Hernandez P, Hurewitz A, Waxman A, Baratz D, Campana C, Hachulla E, Hill N, Knoper S, Kusano K, Mathier M, Murali S, Ogawa S, Pepke-Zaba J, Barbera J, Oudiz R, Beckman J, Camanga D, Bshouty Z, Delcroix M, Ewert R, Gossage J, Grimminger F, Matsubara H, Miera O, Mizoguchi M, Pfeifer M, Reynaud-Gaubert M, Watanabe H, Zwicke D, Corris P, Elliott G, Endo H, Fairman P, Gaine S, Kiely D, Kihara Y, Kuraishi H, Morales-Martin P, Suzuki J, Takeda Y, Ziedalski T.

Department of Pediatrics and Medicine, Columbia University, New York, New York, USA.

Abstract

BACKGROUND: Tadalafil 40 mg orally once daily, was shown to be well-tolerated and efficacious for pulmonary arterial hypertension in a 16-week, double-blind, placebo (PBO)-controlled trial. Inclusion criteria included the option for background bosentan. Analyses of tadalafil in treatment-naive patients and as add-on to bosentan were pre-specified. Objectives were to provide safety and efficacy data for both groups.

METHODS: Groups analyzed included: treatment-naive + PBO; treatment-naive + tadalafil; background bosentan + PBO; and background bosentan + tadalafil. Patients randomized to tadalafil or PBO (N = 405) were analyzed by bosentan use (yes = 216, no = 189). Treatment differences in 6-minute walk distance (6MWD, PBO-adjusted), functional class (FC), clinical worsening (CW) and adverse events were assessed. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented for FC and CW.

RESULTS: At Week 16, PBO-adjusted 6MWD increases were 44 m (CI: 20 to 69 m; n = 37) for tadalafil 40 mg in treatment-naive patients and 23 m (CI: -2 to 48 m; n = 42) for tadalafil 40 mg add-on to bosentan. The 6MWD for treatment-naive and background bosentan PBO patients decreased by 3 m and increased by 19 m, respectively, at Week 16 compared with baseline. Two (5%) treatment-naive patients had CW with tadalafil 40 mg vs 8 (22%) with PBO (HR = 3.3, CI: 1.1 to 10.0). Two (5%) background bosentan patients had CW with tadalafil 40 mg add-on vs 5 (11%) for PBO add-on (HR = 1.9, CI: 0.4 to 10.2). Adverse events for tadalafil monotherapy and as add-on were similar.

CONCLUSION: Tadalafil 40 mg was well-tolerated and provided clinical benefit in patients as monotherapy. It was also well-tolerated when added to background bosentan, but data are insufficient to conclude additional benefit.

PMID:21256048