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Ambrisentan and Tadalafil Upfront Combination Therapy in Scleroderma-Associated PAH

ARTICLE: Ambrisentan and Tadalafil Upfront Combination Therapy in Scleroderma-Associated PAH

AUTHORS: Paul M Hassoun, Roham T Zamanian, Rachel Damico, Noah Lechtzin, Rubina Khair, Todd M Kolb, Ryan J Tedford, Olivia L Hulme, Traci Housten, Chiara Pisanello, Takahiro Sato, Erica H Pullins, Celia P Corona-Villalobos, Stefan L Zimmerman, Mohamed A Gashouta, Omar A Minai, Fernando Torres, Reda E Girgis, Kelly Chin, and Stephen C Mathai

JOURNAL: Am J Respir Crit Care Med. 2015 Sep 11. [Epub ahead of print]


BACKGROUND: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by very dismal response to therapy and poor survival. We assessed the effects of upfront, combined PAH therapy in SSc-PAH.

METHODS: In this prospective multicenter open label trial, 24 treatment naïve SSc-PAH patients received ambrisentan (10 mg) and tadalafil (40 mg) daily for 36 weeks. Functional, hemodynamic and imaging (cardiac magnetic resonance and echocardiography) assessment at baseline and 36 weeks included changes in right ventricular mass and pulmonary vascular resistance (RV mass and PVR) as co-primary end-points, and stroke volume/pulmonary pulse pressure (SV/PP), tricuspid annular plane systolic excursion (TAPSE), six-minute walk distance (6MWD) and N-terminal pro-brain natriuretic peptide (NT-proBNP), all secondary end-points.

RESULTS: Treatment resulted in significant reductions in median RV mass (28.0 IQR 20.6-32.9 versus 32.5 IQR 23.2-41.4 gm; P<0.05) and PVR (3.1 IQR 2.0-5.7 versus 6.9 IQR 4.0-12.9 Wood Units; P<0.0001), and improvements in SV/PP (2.6 IQR 1.8-3.5 versus 1.4 IQR 8.9-2.4 ml/mmHg; P<0.0001), TAPSE (2.2 ± 0.12 versus 1.65 ± 0.11 cm; P< 0.0001), 6MWD (395 ± 99 vs 343 ± 131 m; P=0.001) and serum NT-proBNP (647 ± 1127 versus 1578 ± 2647 pgm/mL; P< 0.05).

CONCLUSIONS: Upfront ambrisentan and tadalafil therapy significantly improved hemodynamics, RV structure and function, and functional status in treatment naïve SSc-PAH patients and may represent a very effective therapy for this patient population. In addition, we have identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trial trials. Clinical trial registration available at, ID NCT01042158.

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Kelsey Bennett