NEW YORK (Reuters Health) – Results of a dose-ranging study indicate that a medium dose of sildenafil given for 16 weeks improves peak oxygen consumption in children with pulmonary arterial hypertension (PAH), without undue risk of adverse effects.
“Further investigation is warranted to determine optimal dosing based on age and body weight,” conclude the authors of the report in Circulation issued online November 29.
Dr. Robyn J. Barst, at Columbia University in New York, New York, and colleagues note that eight drugs are approved for treating PAH in adults, but there are none for children.
The current randomized, double-blind trial, conducted in 16 countries, examined the safety and effectiveness of three different doses of sildenafil versus placebo in 235 children (ages 1-17 years) with PAH. The low, high, and medium doses, given TID, were adjusted based on body weight to achieve about 53%, 77% and 90% inhibition of PDE5, the investigators explain.
Cardiopulmonary exercise testing was performed in the 115 participants who were able to exercise. The results showed that for all sildenafil doses combined versus placebo, the mean change in peak oxygen consumption from baseline after 16 weeks was 7.7%. This was marginally significant (p=0.056).
However, the placebo-corrected change in pVO2 was significant with the medium and high doses of sildenafil, at 11.3% and 8.0%, respectively, the report indicates.
Similarly, hemodynamic assessments in all the children showed that mean pulmonary arterial pressure and pulmonary vascular resistance index improved from baseline in the medium-dose and high-dose groups, but not the low-dose groups.
Sildenafil appeared safe and well tolerated, with most adverse events being mild to moderate, the authors report. Serious adverse events occurred in 11 patients, but there were no more ocular adverse effects in the sildenafil groups than the placebo group.
Participants who completed the trial were enrolled in an ongoing extension study, with placebo patients randomized to one of the three sildenafil doses. Survival rates seen so far compare favorably with historical rates, the authors report, although increased mortality has been observed in the high-dose group compared with the lower-dose groups.
Summing up, Dr. Barst and colleagues conclude, “Although the primary comparison of percentage change in pVO2 for the three sildenafil groups combined was only marginally statistically significant, the improvements in exercise capacity, FC (functional class), and hemodynamics with medium- and high-dose sildenafil suggest efficacy with these doses. Combined with interim data from the ongoing extension study, the overall profile favors the medium dose.”