PMID- 31479749 OWN - NLM STAT- MEDLINE DCOM- 20200629 LR - 20200629 IS - 1096-1186 (Electronic) IS - 1043-6618 (Linking) VI - 148 DP - 2019 Oct TI - Efficacy and safety of pharmacological treatments for patent ductus arteriosus closure: A systematic review and network meta-analysis of clinical trials and observational studies. PG - 104418 LID - S1043-6618(19)31020-5 [pii] LID - 10.1016/j.phrs.2019.104418 [doi] AB - Efficacy and safety profiles of different pharmacological interventions used to treat patent ductus arteriosus (PDA) are relatively unexplored. Integrating the findings of randomized clinical trials (RCTs) with those from observational studies may provide key evidence on this important issue. We aimed at estimating the relative likelihood of failure to close the PDA, need for surgical closure, and occurrence of adverse events among preterm and full-term infants treated with indomethacin, ibuprofen, or acetaminophen, placebo, or no treatment including both RCTs and observational studies. We searched PubMed, Embase, and the Register of Controlled Trials from inception to October 30, 2018. We first estimated proportions of subjects with failure to close the PDA, subjects in whom surgical closure was performed after pharmacological treatment, death, and subjects with selected adverse events (AEs). These estimates were obtained using frequentist random-effect meta-analysis of arm-specific proportions. We then compared active drugs with each other and with control (either placebo or no treatment) by summarizing results at the end of treatment reported in the papers, regardless of number of administration(s), dose, route and type of administration, and study design and quality. We also summarized primary outcome results separately at first, second and third cycles of treatment. These estimates were obtained using Bayesian random-effects network meta-analysis for mixed comparisons, and frequentist random-effect pairwise meta-analysis for direct comparisons. We included 64 RCTs and 24 observational studies including 14,568 subjects (5339 in RCTs and 9229 in observational studies, 8292 subjects received indomethacin, 4761 ibuprofen, 574 acetaminophen, and 941 control (including placebo or no intervention).The proportion of subjects with failure to close the PDA was 0.24 (95% Confidence Interval, CI: 0.20, 0.29) for indomethacin, 0.18 (0.14, 0.22) for ibuprofen, 0.19 (0.09, 0.30) for acetaminophen, and 0.59 (0.48, 0.69) for control. At end of treatment, compared to control, we found inverse associations between all active drugs and failure to close PDA (for indomethacin Odds Ratio, OR, was 0.17 [95% Credible Interval, CrI: 0.11-0.24], ibuprofen 0.19 [0.12-0.28], and acetaminophen 0.15 [0.09-0.26]), without differences among active drugs. We showed inverse associations between effective drugs and need for surgical closure, as compared to control (for indomethacin OR was 0.28 [0.15-0.50], ibuprofen 0.30 [0.16-0.54], and acetaminophen 0.19 [0.07-0.46]), without differences among drugs. Indomethacin was directly associated with intraventricular hemorrhage (IVH) (1.27; 1.00, 1.62) compared to ibuprofen, and to oliguria as compared to ibuprofen (3.92; 1.69, 9.82) or acetaminophen (10.8; 1.86, 93.1). In conclusion, active pharmacological treatment, with indomethacin, ibuprofen, or acetaminophen, is inversely associated with failure to close the PDA compared to non-treatment. Ibuprofen should be preferred to indomethacin to avoid occurrence of IVH or oliguria, acetaminophen should be preferred to indomethacin to avoid oliguria. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Marconi, Ettore AU - Marconi E AD - Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139, Florence, Italy. FAU - Bettiol, Alessandra AU - Bettiol A AD - Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139, Florence, Italy. FAU - Ambrosio, Giuseppe AU - Ambrosio G AD - Division of Cardiology, University Hospital, Perugia, Italy. FAU - Perduca, Vittorio AU - Perduca V AD - Laboratoire de Mathematiques Appliquees - MAP5 (UMR CNRS 8145), Universite Paris Descartes, Paris, France. FAU - Vannacci, Alfredo AU - Vannacci A AD - Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139, Florence, Italy. FAU - Troiani, Stefania AU - Troiani S AD - Division Neonatology, University Hospital, Perugia, Italy. FAU - Dani, Carlo AU - Dani C AD - Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139, Florence, Italy; Division of Neonatology, Careggi University Hospital of Florence, Florence, Italy. FAU - Mugelli, Alessandro AU - Mugelli A AD - Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139, Florence, Italy. FAU - Lucenteforte, Ersilia AU - Lucenteforte E AD - Department of Clinical and Experimental Medicine University of Pisa, Pisa, Italy. Electronic address: ersilia.lucenteforte@unipi.it. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20190831 PL - Netherlands TA - Pharmacol Res JT - Pharmacological research JID - 8907422 RN - 0 (Pharmaceutical Preparations) SB - IM MH - Bayes Theorem MH - Clinical Trials as Topic MH - Ductus Arteriosus, Patent/*drug therapy MH - Humans MH - Network Meta-Analysis MH - Observational Studies as Topic MH - Pharmaceutical Preparations/*administration & dosage MH - Randomized Controlled Trials as Topic OTO - NOTNLM OT - Adverse events OT - Ibuprofen (PubChem CID: 1983) OT - Indomethacin (PubChem CID: 3715) OT - Intraventricular hemorrhage OT - Network meta-analysis OT - Observational studies OT - Oliguria OT - Paracetamol/acetaminophen (PubChem CID: 1983) OT - Patent ductus arteriosus EDAT- 2019/09/04 06:00 MHDA- 2020/07/01 06:00 CRDT- 2019/09/04 06:00 PHST- 2019/06/28 00:00 [received] PHST- 2019/08/27 00:00 [revised] PHST- 2019/08/27 00:00 [accepted] PHST- 2019/09/04 06:00 [pubmed] PHST- 2020/07/01 06:00 [medline] PHST- 2019/09/04 06:00 [entrez] AID - S1043-6618(19)31020-5 [pii] AID - 10.1016/j.phrs.2019.104418 [doi] PST - ppublish SO - Pharmacol Res. 2019 Oct;148:104418. doi: 10.1016/j.phrs.2019.104418. Epub 2019 Aug 31.