Sildenafil

Sildenafil citrate (Revatio®), an inhibitor of phosphodiesterase type 5 (PDE5), is approved for use in the US, Europe and other countries for the treatment of pulmonary arterial hypertension (PAH). Oral sildenafil 20 mg three times daily added to conventional background therapy was significantly more effective than placebo at increasing exercise capacity in patients with idiopathic PAH or PAH associated with connective tissue diseases or repaired congenital systemic-to-pulmonary shunts. Sildenafil was also associated with improvements in WHO functional class and haemodynamic parameters, and was generally well tolerated. Sildenafil provides benefits in terms of exercise capacity when added to epoprostenol; however, these findings come from a trial that did not use the approved dosage of sildenafil. In conclusion, sildenafil is an effective oral treatment option for patients with PAH.

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate-specific PDE5, and causes relaxation of smooth muscle, in particular, in the pulmonary vasculature and corpus cavernosum. It causes pulmonary vasodilation in patients with pulmonary hypertension and is associated with improvements in mean pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and, in some studies, cardiac index. At the approved dosage of 20 mg three times daily, sildenafil does not affect systemic blood pressure. Sildenafil potentiates the hypotensive effect of nitrates and these drugs should not be coadministered.

The Efficacy of sildenafil in adults with idiopathic PAH was demonstrated in a large, well designed, 12-week trial (SUPER-1). Dosages included 20 (the approved dosage), 40 and 80 mg three times daily. At baseline, most patients were in WHO functional class II or III and had a mean 6-minute walking distance of 344 m. All dosages of sildenafil significantly increased the placebo-corrected 6-minute walking distance (the primary endpoint) by 45—50 m after 12 weeks, but there was no significant difference in efficacy between the three dosages. At the approved dosage, sildenafil also led to significant increases in the proportion of patients improving by at least one functional class and exhibiting significant improvements in haemodynamic parameters, including mean PAP and PVR. Health-related quality of life (all dosages combined) significantly improved with sildenafil compared with placebo for domains addressing the physical impact of PAH and general health. In an open-label extension study of SUPER-1 (SUPER-2) in which all patients received sildenafil 80 mg three times daily (higher than the approved dosage), efficacy was maintained to 1 year and, among 141 patients with idiopathic PAH, 1-year survival was 96% compared with a predicted survival of 71%.

Studies comparing sildenafil with other specific PAH therapies, or evaluating combination therapy, all used dosages higher than the approved dosage. In a small, 16-week study in patients with PAH (functional class III), there was no significant difference between sildenafil and bosentan for change in right ventricular mass (primary endpoint) or 6-minute walking distance. The combination of sildenafil with intravenous epoprostenol was evaluated in a large, well designed, 16-week trial in patients with PAH. The addition of sildenafil to epoprostenol significantly increased 6-minute walking distance (placebo-corrected increase of 26 m; p = 0.0009) and improved most haemodynamic parameters compared with placebo.

Sildenafil was generally well tolerated by patients with PAH. Based on placebo-subtracted incidences, the most common adverse events with sildenafil 20 mg three times daily in SUPER-1 were epistaxis, headache, dyspepsia, flushing, insomnia and erythema. Retinal haemorrhage occurred in 1.4% of the sildenafil 20 mg three times daily group (vs 0% for placebo); most patients had risk factors for bleeding. Epistaxis was more common among patients with connective tissue disorders than in those with idiopathic PAH, and concomitant use of vitamin K antagonists also increased the risk of epistaxis.

Adverse events reported during combination therapy with sildenafil and epoprostenol were consistent with events reported during SUPER-1.