Jean-Christophe Rozé1, Gilles Cambonie2, Aurelie Le Thuaut3, Thierry Debillon4, Isabelle Ligi5, Geraldine Gascoin6, Juliana Patkai7, Alain Beuchee8, Geraldine Favrais9, Cyril Flamant10, Xavier Durrmeyer11, Ronald Clyman12. 1. Department of Neonatalogy, Nantes University Hospital, Nantes, France; Centre d'Investigation Clinique CIC1413, INSERM-Nantes University Hospital, Nantes, France. Electronic address: jean-christophe.roze@inserm.fr. 2. Neonatal Medicine, Montpellier University Hospital, Montpellier, France. 3. Department of biostatistics, Nantes University Hospital, Nantes, France. 4. Department of Neonatalogy, University Hospital of Grenoble, Grenoble, France. 5. Department of Neonatalogy, Assistance Publique Hôpitaux de Marseille, Marseille, France. 6. Neonatal Medicine, Angers University Hospital, Angers, France. 7. Neonatal Intensive Care Unit, Cochin Hospital, Maternity of Port-Royal, Paris, France. 8. Department of Neonatalogy, Rennes University Hospital, Rennes, France. 9. Department of Neonatalogy, Tours University Hospital, Tours, France. 10. Department of Neonatalogy, Nantes University Hospital, Nantes, France; Centre d'Investigation Clinique CIC1413, INSERM-Nantes University Hospital, Nantes, France. 11. Department of Neonatalogy, Centre Hospitalier Intercommunal de Créteil, Créteil, France; Université Paris Est Créteil, Faculté de Médecine de Créteil, IMRB, GRC CARMAS, Créteil, France. 12. Departments of Pediatrics, and Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA.
Abstract
OBJECTIVE: To examine the effects of early echocardiography-targeted ibuprofen treatment of large patent ductus arteriosus (PDA) on survival without cerebral palsy at 24 months of corrected age. STUDY DESIGN: We enrolled infants born at <28 weeks of gestation with a large PDA on echocardiography at 6-12 hours after birth toibuprofen or placebo by 12 hours of age in a multicenter, double blind, randomized-controlled trial. Open-label ibuprofen was allowed for prespecified criteria of a hemodynamically significant PDA. The primary outcome was survival without cerebral palsy at 24 months of corrected age. RESULTS: Among 337 enrolled infants, 109 had a small or closed ductus and constituted a reference group; 228 had a large PDA and were randomized. The primary outcome was assessed at 2 years in 108 of 114 (94.7%) and 102 of 114 (89.5%) patients allocated to ibuprofen or placebo, respectively. Survival without cerebral palsy occurred in 77 of 108 (71.3%) after ibuprofen, 73 of 102 (71.6%) after placebo (adjusted relative risk 0.98, 95% CI 0.83-1.16, P = .83), and 77 of 101 (76.2%) in reference group. Infants treated with ibuprofen had a lower incidence of PDA at day 3. Severe pulmonary hemorrhage during the first 3 days occurred in 2 of 114 (1.8%) infants treated with ibuprofen and 9 of 114 (7.9%) infants treated with placebo (adjusted relative risk 0.22, 95% CI 0.05-1.00, P = .05). Open-label rescue treatment with ibuprofen occurred in 62.3% of infants treated with placebo and 17.5% of infants treated with ibuprofen (P < .001), at a median (IQR) age of 4 (3, 5) and 4 (4, 12) days, respectively. CONCLUSIONS:Early echocardiography-targeted ibuprofen treatment of a large PDA did not change the rate of survival without cerebral palsy. TRIAL REGISTRATION: Eudract 2011-003063-30 and ClinicalTrials.gov: NCT01630278.
RCT Entities:
OBJECTIVE: To examine the effects of early echocardiography-targeted ibuprofen treatment of large patent ductus arteriosus (PDA) on survival without cerebral palsy at 24 months of corrected age. STUDY DESIGN: We enrolled infants born at <28 weeks of gestation with a large PDA on echocardiography at 6-12 hours after birth to ibuprofen or placebo by 12 hours of age in a multicenter, double blind, randomized-controlled trial. Open-label ibuprofen was allowed for prespecified criteria of a hemodynamically significant PDA. The primary outcome was survival without cerebral palsy at 24 months of corrected age. RESULTS: Among 337 enrolled infants, 109 had a small or closed ductus and constituted a reference group; 228 had a large PDA and were randomized. The primary outcome was assessed at 2 years in 108 of 114 (94.7%) and 102 of 114 (89.5%) patients allocated to ibuprofen or placebo, respectively. Survival without cerebral palsy occurred in 77 of 108 (71.3%) after ibuprofen, 73 of 102 (71.6%) after placebo (adjusted relative risk 0.98, 95% CI 0.83-1.16, P = .83), and 77 of 101 (76.2%) in reference group. Infants treated with ibuprofen had a lower incidence of PDA at day 3. Severe pulmonary hemorrhage during the first 3 days occurred in 2 of 114 (1.8%) infants treated with ibuprofen and 9 of 114 (7.9%) infants treated with placebo (adjusted relative risk 0.22, 95% CI 0.05-1.00, P = .05). Open-label rescue treatment with ibuprofen occurred in 62.3% of infants treated with placebo and 17.5% of infants treated with ibuprofen (P < .001), at a median (IQR) age of 4 (3, 5) and 4 (4, 12) days, respectively. CONCLUSIONS: Early echocardiography-targeted ibuprofen treatment of a large PDA did not change the rate of survival without cerebral palsy. TRIAL REGISTRATION: Eudract 2011-003063-30 and ClinicalTrials.gov: NCT01630278.
Authors: Ömer Erdeve; Emel Okulu; Yogen Singh; Richard Sindelar; Mehmet Yekta Oncel; Gianluca Terrin; Giovanni Boscarino; Ali Bülbül; Hannes Sallmon; Begüm Atasay; Fahri Ovalı; Ronald I Clyman Journal: Turk Arch Pediatr Date: 2022-03