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Published ahead of print on March 4, 2005, doi:10.1164/rccm.200410-1411OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 11, June 2005, 1292-1297

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Submitted on October 26, 2004
Accepted on February 24, 2005

Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) Study

Martin R Wilkins1*, Gideon A Paul1, Julian W Strange2, Nina Tunariu1, Wendy Gin-Sing3, Winston Banya4, Mark A Westwood5, Alexander Stefanidis3, Leong L Ng6, Dudley J Pennell5, Raad H Mohiaddin5, Petros Nihoyannopoulos4, and J Simon R Gibbs3

1 Experimental Medicine and Toxicology, Imperial College London, Hammersmith Hospital, London, United Kingdom, 2 Experimental Medicine and Toxicology, Imperial College London, Hammersmith Hospital, London, United Kingdom; CMR Unit, Imperial College London, National Heart and Lung Institute, London, United Kingdom, 3 Department of Cardiology, Imperial College London, Hammersmith Hospital, London, United Kingdom, 4 Care of the Elderly, Imperial College London, Hammersmith Hospital, London, United Kingdom, 5 CMR Unit, Imperial College London, National Heart and Lung Institute, London, United Kingdom, 6 Department of Cardiovascular Sciences, Leicester Royal Infirmary, Leicester, United Kingdom

* To whom correspondence should be addressed. E-mail: m.wilkins{at}imperial.ac.uk.

Rationale: Phosphodiesterase type 5 (PDE5) inhibition has been proposed for the treatment for pulmonary arterial hypertension (PAH). Objective: This study compared adding sildenafil, a PDE5 inhibitor, to conventional treatment with the current practice of adding bosentan, an endothelin receptor antagonist. Methods: Twenty-six patients with PAH, idiopathic or associated with connective tissue disease, WHO functional class III, were randomised, double-blind, to receive sildenafil (50mg twice daily for 4 weeks, then 50mg three times daily) or bosentan (62.5mg twice daily for 4 weeks, then 125mg twice daily) over 16 weeks. Measurements: Changes in right ventricle (RV) mass (using cardiovascular magnetic resonance), 6 minute walk distance, cardiac function, brain natriuretic peptide (BNP) and Borg dyspnoea index. Main results: When analysed by intention-to-treat, there were no significant differences between the two treatment groups. One patient on sildenafil died suddenly. Patients on sildenafil who completed the protocol showed significant changes from baseline - reductions in RV mass (-8.8g [95%CI -16, -2] n=13, p=0.015) and plasma BNP levels (-19.4fmol.ml-1 [95%CI -5, -33] p=0.014) and improvements in 6 minute walk distance (114m [95%CI 67, 160] p=0.0002), cardiac index (0.3 [95%CI 0.1, 0.4] p=0.008) and systolic left ventricular eccentricity index (-0.2 [95%CI -0.02, -0.37) p=0.031). Bosentan improved 6 minute walk distance (59m [95%CI 29, 89] n=12, p=0.001) and cardiac index (0.3 [95%CI 0.1, 0.4] p=0.008). Conclusions: Sildenafil added to conventional treatment reduces RV mass and improves cardiac function and exercise capacity in patients with PAH, WHO functional class III. Safety monitoring is important until more experience is obtained.
Key words: cardiovascular disease; pharmacology; magnetic resonance imaging




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