A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children with Pulmonary Arterial Hypertension.

Author(s): Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE, Sastry BK, Pulido T, Layton GR, Serdarevic-Pehar M, Wessel DL

Affiliation(s): 1 Columbia University, New York, NY;

Publication date & source: 2011-11-29, Circulation., [Epub ahead of print]

BACKGROUND: Safe, effective therapy is needed for pediatric pulmonary arterial hypertension (PAH). METHODS AND RESULTS: Treatment-naive children (n=235; 1-17 yrs; >/=8 kg) enrolled in STARTS-1 were randomized to low-, medium-, or high-dose sildenafil or placebo orally thrice daily for 16 weeks. The primary comparison was percentage change from baseline in peak oxygen consumption (pVO(2)) for the three sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary endpoints (assessed in all patients) included hemodynamics and functional class (FC). The estimated mean +/- SE percentage change in pVO(2) for the three doses combined versus placebo was 7.7% +/- 4.0% (95% CI, -0.2% to 15.6%; P=0.056). Peak VO(2), FC, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose while placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with high- versus lower-dose groups. CONCLUSIONS: Sixteen-week sildenafil monotherapy is well tolerated in pediatric PAH. Percentage change in pVO(2) for the three sildenafil doses combined was only marginally significant; however, pVO(2), FC, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov; NCT00159874.