title: STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension.
abstract: The double-blind, placebo-controlled Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study assessed sildenafil in pediatric patients with pulmonary arterial hypertension; improved hemodynamics and exercise capacity occurred in medium- and high-dose groups. STARTS-2 was the extension study.
  
  
  
  In STARTS-1, 234 children ≥8 kg were randomly assigned to low-, medium-, or high-dose sildenafil or placebo orally thrice daily; within-group dose depended on weight. In STARTS-2, sildenafil-treated patients continued STARTS-1 dosing; placebo-treated patients were randomized to 1 of the 3 sildenafil dose groups. Patients requiring additional pulmonary arterial hypertension-specific therapy discontinued study treatment; survival follow-up was attempted. As of August 2011, all children received ≥3 years of treatment (unless discontinued) from STARTS-1 baseline; 37 deaths were reported (26 on study treatment), 1 of which occurred within the first year of treatment. Most patients who died (28/37) had idiopathic/heritable pulmonary arterial hypertension (76% versus 33% overall) and baseline functional class III/IV disease (38% versus 15% overall); patients who died had worse baseline hemodynamics. Kaplan-Meier estimated 3-year survival rates from start of sildenafil were 94%, 93%, and 88% for patients randomized to low-, medium-, and high-dose sildenafil, respectively; 87%, 89%, and 80% were known to be alive at 3 years. Hazard ratios for mortality were 3.95 (95% confidence interval, 1.46-10.65) for high versus low and 1.92 (95% confidence interval, 0.65-5.65) for medium versus low dose; however, multiple analyses raised uncertainty about the survival/dose relationship.
  
  
  
  Although children randomized to higher compared with lower sildenafil doses had an unexplained increased mortality, all sildenafil dose groups displayed favorable survival for children with pulmonary arterial hypertension.
  
  
  
  http://clinicaltrials.gov/ct2/show/NCT00159874 (extension study of NCT00149913). Unique identifier: NCT00159874.
authors.affiliation: From Columbia University, New York, NY (R.J.B.); Department of the Child and Adolescent, University of Geneva, Geneva, Switzerland (M.B.); National Heart Institute, Mexico City, Mexico (T.P.); Pfizer Ltd, Sandwich, UK (during study conduct) (G.L., I.K.); Pfizer Inc, La Jolla, CA (M.Z.); and Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora (D.D.I.).
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Barst
authors.forename: Maurice
authors.initials: M
authors.lastname: Beghetti
authors.forename: Tomas
authors.initials: T
authors.lastname: Pulido
authors.forename: Gary
authors.initials: G
authors.lastname: Layton
authors.forename: Irina
authors.initials: I
authors.lastname: Konourina
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: D Dunbar
authors.initials: DD
authors.lastname: Ivy
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D017079:Exercise Tolerance / Q000187:drug effects / Q000502:physiology; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000401:mortality* / Q000503:physiopathology; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage; D012044:Regression Analysis; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage*; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000008:administration & dosage*
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate
keywords: clinical trial; pediatrics; pulmonary hypertension; sildenafil; survival