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

• Published in: Circulation (New York, N.Y.) Vol. 125; no. 2; pp. 324 - 334
• Main Authors: BARST, Robyn J, DUNBAR IVY, D, WESSEL, David L, GAITAN, Guillermo, SZATMARI, Andras, RUDZINSKI, Andrzej, GARCIA, Alberto E, SASTRY, B. K. S, PULIDO, Tomas, LAYTON, Gary R, SERDAREVIC-PEHAR, Marjana
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 17-01-2012
• Subjects: Administration, Oral; Adolescent; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Child; Child, Preschool; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Test - drug effects; Hemodynamics - drug effects; Humans; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - physiopathology; Infant; Medical sciences; Oxygen Consumption - drug effects; Pharmacology. Drug treatments; Piperazines - administration & dosage; Piperazines - adverse effects; Purines - administration & dosage; Purines - adverse effects; Sildenafil Citrate; Sulfones - administration & dosage; Sulfones - adverse effects; Vasodilator agents. Cerebral vasodilators; Human; Physical exercise; Vasodilator agent; 3',5'-Cyclic-GMP phosphodiesterase; Enzyme; Respiratory disease; Oral administration; Enzyme inhibitor; Citrate; Cardiovascular disease; Esterases; Phosphoric diester hydrolases; Pulmonary hypertension; Phosphodiesterase inhibitor; Phosphodiesterase 5 inhibitor; Treatment; pediatrics; Hydrolases; cardiopulmonary exercise; clinical trials; Sildenafil; Child; pulmonary arterial hypertension
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.110.016667

Safe, effective therapy is needed for pediatric pulmonary arterial hypertension.
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 (PV(O(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 PV(O(2)) for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, -0.2% to 15.6%; P=0.056). PV(O(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.
Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV(O(2)) for the 3 sildenafil doses combined was only marginally significant; however, PV(O(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.
http://www.clinicaltrials.gov. Unique identifier: NCT00159913.