Sildenafil (Viagra) is a phosphodiesterase-5 inhibitor currently used for treating erectile dysfunction. Part of its mechanism is the inhibition of cyclic guanosine mono-phosphate (cGMP) metabolism. cGMP acts on vascular smooth muscle cells, generating relaxation and growth inhibition, and phosphodiesterase-5 is its primary metabolizer in the lung. Thus, sildenafil also may treat the vascular changes associated with pulmonary arterial hypertension. Galiè and associates conducted a 12-week, randomized, double-blind, placebo-controlled trial to assess the effect of sildenafil on walking distance (i.e., exercise capacity) in patients with pulmonary hypertension.

The study enrolled 278 patients with pulmonary arterial hypertension. The participants were randomized to placebo or 20-mg, 40-mg, or 80-mg doses of sildenafil three times daily. Participants could have pulmonary hypertension that was idiopathic or related to connective tissue disease, or have had repair of a congenital systemic-to-pulmonary shunt. Most patients were white women. Participants could not be taking other treatments for pulmonary hypertension, and those with walking distances of less than 100 meters or more than 450 meters were excluded.

Sildenafil treatment improved six-minute walking distance in all treatment groups compared with the placebo group. Functional status of the sildenafil group also improved. However, the difference in distances walked between the varying doses was nonsignificant. Adverse effects included diarrhea, flushing, and dyspepsia. Headache was common in all groups, including placebo. Two serious events were thought to be medication related: one case of left ventricular dysfunction and one case of postural hypotension. Four patients withdrew because of side effects.

The authors conclude that sildenafil treatment improves exercise capacity in patients with pulmonary arterial hypertension. No dose-response relationship was observed, and the question of a mortality benefit remains to be answered.