BACKGROUND: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH. METHODS: In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints. RESULTS: At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05). CONCLUSIONS: Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).
BACKGROUND: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH. METHODS: In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints. RESULTS: At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05). CONCLUSIONS: Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).
Authors: Lorinda Chung; Juliana Liu; Lori Parsons; Paul M Hassoun; Michael McGoon; David B Badesch; Dave P Miller; Mark R Nicolls; Roham T Zamanian Journal: Chest Date: 2010-05-27 Impact factor: 9.410
Authors: Jens Vogel-Claussen; Monda L Shehata; Dirk Lossnitzer; Jan Skrok; Sukhminder Singh; Danielle Boyce; Noah Lechtzin; Reda E Girgis; Stephen C Mathai; Joao A Lima; David A Bluemke; Paul M Hassoun Journal: Invest Radiol Date: 2011-09 Impact factor: 6.016
Authors: D B Badesch; V F Tapson; M D McGoon; B H Brundage; L J Rubin; F M Wigley; S Rich; R J Barst; P S Barrett; K M Kral; M M Jöbsis; J E Loyd; S Murali; A Frost; R Girgis; R C Bourge; D D Ralph; C G Elliott; N S Hill; D Langleben; R J Schilz; V V McLaughlin; I M Robbins; B M Groves; S Shapiro; T A Medsger Journal: Ann Intern Med Date: 2000-03-21 Impact factor: 25.391
Authors: Mariëlle C van de Veerdonk; Taco Kind; J Tim Marcus; Gert-Jan Mauritz; Martijn W Heymans; Harm-Jan Bogaard; Anco Boonstra; Koen M J Marques; Nico Westerhof; Anton Vonk-Noordegraaf Journal: J Am Coll Cardiol Date: 2011-12-06 Impact factor: 24.094
Authors: Ryan J Tedford; Paul M Hassoun; Stephen C Mathai; Reda E Girgis; Stuart D Russell; David R Thiemann; Oscar H Cingolani; James O Mudd; Barry A Borlaug; Margaret M Redfield; David J Lederer; David A Kass Journal: Circulation Date: 2011-11-30 Impact factor: 29.690
Authors: Stephen C Mathai; Christopher T Sibley; Paul R Forfia; James O Mudd; Micah R Fisher; Ryan J Tedford; Noah Lechtzin; Danielle Boyce; Laura K Hummers; Traci Housten; Ari L Zaiman; Reda E Girgis; Paul M Hassoun Journal: J Rheumatol Date: 2011-10-01 Impact factor: 4.666
Authors: Valentina Mercurio; Monica Mukherjee; Ryan J Tedford; Roham T Zamanian; Rubina M Khair; Takahiro Sato; Omar A Minai; Fernando Torres; Reda E Girgis; Kelly Chin; Rachel Damico; Todd M Kolb; Stephen C Mathai; Paul M Hassoun Journal: Am J Respir Crit Care Med Date: 2018-02-01 Impact factor: 21.405
Authors: Elisabetta Zanatta; Pamela Polito; Giulia Famoso; Maddalena Larosa; Elena De Zorzi; Elena Scarpieri; Franco Cozzi; Andrea Doria Journal: Exp Biol Med (Maywood) Date: 2019-01-22
Authors: Zeling Cao; Stephen C Mathai; Laura K Hummers; Ami A Shah; Fredrick M Wigley; Noah Lechtzin; Paul M Hassoun; Reda E Girgis Journal: Pulm Circ Date: 2016-12 Impact factor: 3.017