A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension

Robyn J. Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Alberto E. Garcia, B. K.S. Sastry, Tomas Pulido, Gary R. Layton, Marjana Serdarevic-Pehar, David L. Wessel

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215 Citations (Scopus)

Abstract

Background - Safe, effective therapy is needed for pediatric pulmonary arterial hypertension. Methods and Results - Children (n=235; weight ≥8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PVO 2) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated mean±SE percent change in PVO 2 for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, -0.2% to 15.6%; P=0.056). PVO 2, functional class, 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, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses. Conclusions - Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PVO 2 for the 3 sildenafil doses combined was only marginally significant; however, PVO 2, functional class, 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.

Original languageEnglish
Pages (from-to)324-334
Number of pages11
JournalCirculation
Volume125
Issue number2
DOIs
Publication statusPublished - jan. 17 2012

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ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Barst, R. J., Ivy, D. D., Gaitan, G., Szatmari, A., Rudzinski, A., Garcia, A. E., Sastry, B. K. S., Pulido, T., Layton, G. R., Serdarevic-Pehar, M., & Wessel, D. L. (2012). A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation, 125(2), 324-334. https://doi.org/10.1161/CIRCULATIONAHA.110.016667