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

Abstract

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 80 mg 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 12 weeks of double-blind sildenafil 1, 5, or 20 mg TID; 12 weeks of open-label sildenafil 20 mg TID followed. Changes from baseline in 6-minute walk distance (6MWD) for sildenafil 1 or 5 mg versus 20 mg 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 1 mg (P = 0.011) but not versus 5 mg. At week 24, 6MWD increases from baseline were larger in those initially randomized to 20 versus 5 or 1 mg (74 vs 50 and 47 m, 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 5 mg.

Conclusions: Sildenafil 20 mg TID appeared to be more effective than 1 mg TID for improving 6MWD; sildenafil 5 mg TID appeared to have similar clinical and hemodynamic effects as 20 mg TID.

Trial registration: ClinicalTrials.gov NCT00430716 (Registration date: January 31, 2007).

Keywords: Clinical trial; Dose; Echocardiography; Exercise test; Pulmonary hypertension; Sildenafil.

Figures

Fig. 1

Study design. Legend: TID = 3 times daily

Fig. 2

Patient disposition. Legend: TID = 3 times daily; SIL = sildenafil.*Right ventricular failure. †Drug hypersensitivity (n = 1) and rash (n = 1)

Fig. 3

Plot of observed plasma sildenafil concentrations vs time after sildenafil dosing. Legend: Plasma sildenafil concentrations (open circles), sildenafil doses of 1 mg (left), 5 mg (middle), and 20 mg (right). Median (solid line) and 90% prediction intervals (dashed lines) from simulations are overlaid. Tick marks on the horizontal time axis indicate concentration measures below the limit of quantification. The shaded area shows the concentration range between 3 ng/mL and 20 ng/mL, which are the average sildenafil plasma concentrations required to achieve 50% effect (EC50) and 90% effect (EC90) on PVRI, respectively. TID = 3 times daily

Fig. 4

Mean change from baseline in 6MWD. Legend: Mean (SE) overall change from double-blind baseline in 6MWD in double-blind (week 12) and open-label (week 24) phases of the study (a), and change from baseline to week 12 in 6MWD by baseline 6MWD (b). All patients received sildenafil 20 mg TID in the open-label phase of the study (weeks 13–24). 6MWD = 6-minute walk distance; TID = 3 times daily

Fig. 5

Mean change from baseline in 6MWD assessed by race. Legend: Mean (SE) overall change from double-blind baseline in 6MWD in the double-blind (week 12) phase of the study (a) and change from baseline to week 12 in 6MWD by baseline 6MWD (b) assessed by race (Asian vs non-Asian). 6MWD = 6-minute walk distance; TID = 3 times daily

Fig. 6

Changes from baseline in BNP (a) and pro-BNP (b) during double-blind (week 12) and open-label (week 24) phases of the study. All patients received sildenafil 20 mg TID in the open-label phase of the study (weeks 13–24). BNP = B-type natriuretic peptide; TID = 3 times daily