Selective phosphodiesterase type 5 inhibitors are capable of crossing the blood-retina barrier. Concerns have been raised about potential ocular side effects of sildenafil; the most common visual disturbance reported is a dose dependent reversible impairment of colour discrimination, principally in the blue-green to blue-purple range. Studies of the effects of sildenafil on ocular vasculature have not had consistent results. To evaluate potential effects on visual function and the ocular safety profile of sildenafil during chronic oral use, a placebo controlled trial in pulmonary arterial hypertension (PAH) and its open label extension included ophthalmic examinations and assessments of visual function. During the double blind period, sildenafil doses of 20, 40, or 80 mg or placebo were administered orally three times daily for 12 weeks. In the extension, doses were first up-titrated to a maximum of 80 mg three times daily at week 6 in a masked fashion while the 80 mg group had sham titration. After the last participant in the double masked study had completed 12 weeks of treatment, doses in the extension study were unmasked and then could be adjusted according to clinical need to a maximum of 80 mg three times daily or a minimum of 20 mg three times daily. The ocular findings have been reported in the BMJ.

The study was conducted in 53 institutions worldwide and involved 277 adults with PAH that was idiopathic or linked to connective tissue disease or after congenital heart disease repair. The main outcome measure was ocular safety (ocular examinations, visual function tests, participants’ reports of adverse events, and visual disturbance questionnaire completed by investigators) by treatment group at 12 weeks, 24 weeks, 18 months, and yearly. The following findings were reported:

• Intraocular pressure and visual function tests (visual acuity, colour vision, and visual field were similar across groups (20 mg, n=69; 40 mg, n=67; 80 mg, n=71; placebo, n=70). No clinically significant changes occurred between baseline and 12 weeks, except for an efficacy signal in contrast sensitivity for the sildenafil 40 mg tds group.

• In right eyes, changes in intraocular pressure from baseline to week 12 ranged from a mean of −0.5mm Hg with placebo, −0.2mm Hg with sildenafil 40 mg, and −0.1mm Hg with 80mg to 0.3mm Hg with sildenafil 20 mg (the approved dose for PAH).

• Mean changes from baseline to week 12 in contrast sensitivity in right eyes were −0.02 in the sildenafil 20 mg tds group vs. −0.05 in the placebo group (p=0.044).

• Percentages of participants with deterioration in visual acuity (Snellen) from baseline to week 12 ranged from 10% (n=7) in the placebo group to 3% (n=2) in the sildenafil 20 mg tds group; the same percentages had visual field changes from normal to abnormal during the period in these two groups.

• The investigators did not deem any findings on colour vision assessment to be clinically significant.

• Findings of the objective assessments in the 40 mg and 80mg tds sildenafil treatment groups and in left eyes were not substantially different, nor were any measures different throughout the open label extension compared with week 12. However, objective data were limited after month 18, as most participants had missing data or visual parameters were no longer collected by investigators.

• Incidence of ocular adverse events reported on the case report forms and assessed by the investigator was low with all doses, but a modest, dose related incidence of chromatopsia, cyanopsia, photophobia, and visual disturbance was reported with 80 mg TDS consistent with the indicated dosing for erectile dysfunction.

• Retinal haemorrhages, captured on funduscopy, occurred in 2% (4/207) of sildenafil treated participants and none in the placebo group during the double masked study and in 4% (10/259) during the open label extension.

The researchers conclude from these findings that “sildenafil dosing up to 80mg tds is safe and well tolerated from an ocular perspective in patients with PAH. Daily chronic dosing in this patient population was not associated with visual change and had no detrimental effect on best corrected visual acuity, contrast sensitivity, colour vision, or visual field, or on slit lamp examinations, funduscopy, or intraocular pressure during the duration of this study.”