Efficacy of 1, 5, and 20mg oral sildenafil in the treatment of adults with pulmonary arterial hypertension: A randomized, double-blind study with open-label extension

Background: In a previous study, 6-minute walk distance (6MWD) improvement with sildenafil was not dose dependent at the 3 doses tested (20, 40, and 80mg 3 times daily [TID]). This study assessed whether lower doses were less effective than the approved 20-mg TID dosage. Methods: Treatment-naive patients with pulmonary arterial hypertension were randomized to 12weeks of double-blind sildenafil 1, 5, or 20mg TID; 12weeks of open-label sildenafil 20mg TID followed. Changes from baseline in 6-minute walk distance (6MWD) for sildenafil 1 or 5mg versus 20mg TID were compared using a Williams test. Hemodynamics, functional class, and biomarkers were assessed. Results: The study was prematurely terminated for non-safety reasons, with 129 of 219 planned patients treated. At week 12, 6MWD change from baseline was significantly greater for sildenafil 20 versus 1mg (P=0.011) but not versus 5mg. At week 24, 6MWD increases from baseline were larger in those initially randomized to 20 versus 5 or 1mg (74 vs 50 and 47m, respectively). At week 12, changes in hemodynamic parameters were generally small and variable between treatment groups; odds ratios for improvement in functional class were not statistically significantly different. Improvements in B-type natriuretic peptide levels were significantly greater with sildenafil 20 versus 1 but not 5mg. Conclusions: Sildenafil 20mg TID appeared to be more effective than 1mg TID for improving 6MWD; sildenafil 5mg TID appeared to have similar clinical and hemodynamic effects as 20mg TID. Trial registration: ClinicalTrials.gov NCT00430716(Registration date: January 31, 2007).