{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:22:20Z","timestamp":1790767340695,"version":"4.1.0"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"19","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2014,5,13]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>In STARTS-1, 234 children \u22658 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\u2013specific therapy discontinued study treatment; survival follow-up was attempted. As of August 2011, all children received \u22653 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\u201310.65) for high versus low and 1.92 (95% confidence interval, 0.65\u20135.65) for medium versus low dose; however, multiple analyses raised uncertainty about the survival\/dose relationship.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration\u2014<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\/ct2\/show\/NCT00159874\">http:\/\/clinicaltrials.gov\/ct2\/show\/NCT00159874<\/jats:ext-link>\n                      (extension study of NCT00149913). Unique identifier: NCT00159874.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.113.005698","type":"journal-article","created":{"date-parts":[[2014,3,18]],"date-time":"2014-03-18T02:17:49Z","timestamp":1395109069000},"page":"1914-1923","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":176,"title":["STARTS-2"],"prefix":"10.1161","volume":"129","author":[{"given":"Robyn J.","family":"Barst","sequence":"first","affiliation":[{"name":"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\u2019s Hospital Colorado, Aurora (D.D.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice","family":"Beghetti","sequence":"additional","affiliation":[{"name":"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\u2019s Hospital Colorado, Aurora (D.D.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Pulido","sequence":"additional","affiliation":[{"name":"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\u2019s Hospital Colorado, Aurora (D.D.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Layton","sequence":"additional","affiliation":[{"name":"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\u2019s Hospital Colorado, Aurora (D.D.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Konourina","sequence":"additional","affiliation":[{"name":"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\u2019s Hospital Colorado, Aurora (D.D.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"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\u2019s Hospital Colorado, Aurora (D.D.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Dunbar","family":"Ivy","sequence":"additional","affiliation":[{"name":"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\u2019s Hospital Colorado, Aurora (D.D.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.192230"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050010"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.016667"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000138104.83366.E9"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.2006.096412"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00053510"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2010.06.064"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.2008.150086"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.026591"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2010.02.023"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.2009.182378"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.9.1197"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.70.5.461"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2005.11.438"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.70.4.580"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-115-5-343"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.10-0969"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(94)00391-3"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(97)00155-1"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.969584"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1378\/chest.126.1_suppl.78S"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.898122"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00056110"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.mcp.0000370209.45756.a1"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2009.169904"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehp297"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.161.2.9906015"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000022687.18568.2A"},{"key":"e_1_3_4_30_2","unstructured":"Simonneau G Rubin L Galie N Fleming T Gillies H Barst R PACES Study Group. 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