Background: In a previous study, 6-minute walk distance (6MWD) improvement with sildenafil was not dose dependent\nat the 3 doses tested (20, 40, and 80 mg 3 times daily [TID]). This study assessed whether lower doses were less effective\nthan the approved 20-mg TID dosage.\nMethods: Treatment-naive patients with pulmonary arterial hypertension were randomized to 12 weeks of double-blind\nsildenafil 1, 5, or 20 mg TID; 12 weeks of open-label sildenafil 20 mg TID followed. Changes from baseline in 6-minute\nwalk distance (6MWD) for sildenafil 1 or 5 mg versus 20 mg TID were compared using a Williams test. Hemodynamics,\nfunctional class, and biomarkers were assessed.\nResults: The study was prematurely terminated for non-safety reasons, with 129 of 219 planned patients treated. At week\n12, 6MWD change from baseline was significantly greater for sildenafil 20 versus 1 mg (P = 0.011) but not versus 5 mg. At\nweek 24, 6MWD increases from baseline were larger in those initially randomized to 20 versus 5 or 1 mg (74 vs 50 and\n47 m, respectively). At week 12, changes in hemodynamic parameters were generally small and variable between\ntreatment groups; odds ratios for improvement in functional class were not statistically significantly different.\nImprovements in B-type natriuretic peptide levels were significantly greater with sildenafil 20 versus 1 but not 5 mg.\nConclusions: Sildenafil 20 mg TID appeared to be more effective than 1 mg TID for improving 6MWD; sildenafil 5 mg\nTID appeared to have similar clinical and hemodynamic effects as 20 mg TID.
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