Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study.
BACKGROUND
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, World Health Organization (WHO) functional class III, were randomized in a double-blind fashion to receive sildenafil (50 mg twice daily for 4 weeks, then 50 mg three times daily) or bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily) over 16 weeks.


METHODS
Changes in right ventricular (RV) mass (using cardiovascular magnetic resonance), 6-minute walk distance, cardiac function, brain natriuretic peptide, and Borg dyspnea index.


RESULTS
When analyzed 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, namely, reductions in RV mass (-8.8 g; 95% confidence interval [CI], -2, -16; n = 13, p = 0.015) and plasma brain natriuretic peptide levels (-19.4 fmol x ml(-1); 95% CI, -5, -34; p = 0.014) and improvements in 6-minute walk distance (114 m; 95% CI, 67, 160; p = 0.0002), cardiac index (0.3 L x min(-1) x m(-2); 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 (59 m; 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.
Wilkins
Martin R
MR
Experimental Medicine and Toxicology, Imperial College London, W12 0NN, UK. m.wilkins@imperial.ac.uk
Paul
Gideon A
GA
Strange
Julian W
JW
Tunariu
Nina
N
Gin-Sing
Wendy
W
Banya
Winston A
WA
Westwood
Mark A
MA
Stefanidis
Alexander
A
Ng
Leong L
LL
Pennell
Dudley J
DJ
Mohiaddin
Raad H
RH
Nihoyannopoulos
Petros
P
Gibbs
J Simon R
JS
D000328:Adult; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines; D011788:Quality of Life; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000627:therapeutic use*; D013450:Sulfones; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D020097:Natriuretic Peptide, Brain; D000068677:Sildenafil Citrate; D000077300:Bosentan