Dallas, TX - Oral sildenafil (Viagra, Pfizer) appears to improve exercise tolerance and pulmonary hemodynamics in children and adolescents with primary and secondary pulmonary arterial hypertension (PAH), a new study shows. Results from six-minute-walk test in the 14 study participants increased significantly over a one-year period and appeared to be considerably greater than the improvements seen with other PAH drugs, including bosentan and prostacyclin, the authors note.

Dr Tilman Humpl (Hospital for Sick Children, Toronto, ON) and colleagues report the results of their study online June 13, 2005 in Circulation [1].

Inherited or secondary PAH is a progressive and fatal disease that develops when the arteries supplying the lung become constricted. It can be idiopathic in nature or secondary to other conditions, including connective-tissue disease, liver disease with portal hypertension, and HIV infection. Currently approved treatments include continuous intravenous prostacyclin infusion, oral calcium-channel blockers, bosentan, and anticoagulation.

To investigate the safety and efficacy of sildenafil—better known as the "little blue pill" used to treat erectile dysfunction—Humpl and colleagues tested oral sildenafil doses ranging from 0.25 to 1 mg per kilogram in 14 children and adolescents (mean age 10 years). Six-minute-walk test was performed at baseline, at six weeks, and again at three, six, and 12 months; cardiac catheterization to measure hemodynamic changes was performed at baseline and again a median of 10.8 months later.

As the authors report, significant improvement was seen in the distance walked between baseline and six months, with an apparent plateau between six and 12 months. Mean pulmonary artery pressure and median pulmonary resistance also decreased. The drug was well tolerated in all patients, and no changes were seen in tests of creatinine, urea, liver function, or platelet count.

Earlier studies suggested that improved six-minute-walk test is associated with better prognosis. Moreover, the improvement of 154 m over 12 months seen in the sildenafil-treated patients is superior to improvements seen in studies of bosentan and prostacyclin, in which six-minute-walk test improved by 44 and 70 m, respectively.

In an interview with heartwire, Humpl emphasized the unique aspects of the study. Previous studies of sildenafil in children have tended to be case reports, looking only at the effects of a single or short-term dose, he explained. "The important thing in this study is that we looked at hemodynamics and exercise tolerance in patients taking the drug over a 12-month period of time."

Side effects were minor, Humpl pointed out. Two patients had nosebleeds, and two female patients reported heavier menstrual periods. "Still," he said, "it is hard to know, with these numbers, whether this was related to sildenafil."

An unanswered question is whether the effects of sildenafil can be maintained beyond 12 months, particularly since the benefits appeared to reach a plateau after six months, Humpl said. "We don't know what happens with children if you use it for a longer time; that still needs to be determined."

The authors say their paper underscores the urgency of conducting a randomized trial of sildenafil for PAH in children. If the findings from this pilot study can be replicated, the drug would be a welcome alternative to prostacyclin, which Humpl says "works well" over a longer duration of time, but has the disadvantages of being an intravenous drug, requiring daily mixing of the drug and an infusion pump to administer, and of carrying a host of side effects. Further research must also determine whether the benefits of sildenafil are additive to bosentan, a dual endothelin-receptor antagonist, because the mechanisms of action are completely distinct from one another, Humpl added.