Efficacy and safety of pharmacological treatments for patent ductus arteriosus closure: A systematic review and network meta-analysis of clinical trials and observational studies

Abstract

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,

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“…Indomethacin is currently considered a first-line drug for inducing the closure of the ductus arteriosus in preterm infants, with an acceptable safety profile (Marconi et al, 2019). Also, indomethacin was markedly effective in other clinical settings, such as against renal pain (Pathan et al, 2018) and some types of headache (e.g., hemicrania continua) (Mehta et al, 2018).…”

Is high dose intravenous acetaminophen affect liver function in premature neonates with patent ductus arteriosus?

“…fluid restriction, diuretics, etc and waiting for spontaneous closure), pharmacological management and surgical ligation. (1,3,8,9) FDA approved intravenous (IV) indomethacin and ibuprofen (cyclooxygenase inhibitors) as first drug use for treatment of PDA. These drug reduce the levels of prostaglandin that promote ductus arteriosus muscular wall constriction lead to fibrosis as anatomical ductal closure.…”

“…(1,2) In neonates who have contraindication for treatment with indomethacin and ibuprofen or the NSAIDs have failed in closure of PDA administration of acetaminophen suggested as a choice before surgical ligation. (2) Evaluating of advantages and disadvantages of pharmacological treatment by assessment of following outcomes: PDA closure failure (according to clinical evaluation or echocardiography criteria) as primary outcome; require surgical ligation of PDA, death, and selected any untoward medical occurrence, as secondary outcomes., not certainly having a causal association with treatment (8) Prospective trials may support more perception of acetaminophen effectiveness and safety as a further or even as a first-line option for closure of PDA in neonates (12) Some hepatic side effects have been happened after usage of iv acetaminophen, which may determine a transient raise in liver enzymes or more serious acute liver toxicity. (13,14) acetaminophen itself not directly cause of hepatotoxicity in neonates but can be caused by N-acetylp-benzoquinoneimine (NAPQI) produced by hepatic cytochrome P450 (CYP) as metabolite productiondependent mixed function oxidase enzyme.…”

Does high dose intravenous acetaminophen affect liver function for PDA closure in premature neonate?

“…uid restriction, diuretics, etc and waiting for spontaneous closure), pharmacological management and surgical ligation. (1,3,8,9) FDA approved intravenous (IV) indomethacin and ibuprofen (cyclooxygenase inhibitors) as rst drug use for treatment of PDA. These drug reduce the levels of prostaglandin that promote ductus arteriosus muscular wall constriction lead to brosis as anatomical ductal closure.…”

“…(1,2) In neonates who have contraindication for treatment with indomethacin and ibuprofen or the NSAIDs have failed in closure of PDA administration of acetaminophen suggested as a choice before surgical ligation. 2Evaluating of advantages and disadvantages of pharmacological treatment by assessment of following outcomes: PDA closure failure (according to clinical evaluation or echocardiography criteria) as primary outcome; require surgical ligation of PDA, death, and selected any untoward medical occurrence, as secondary outcomes., not certainly having a causal association with treatment (8) Prospective trials may support more perception of acetaminophen effectiveness and safety as a further or even as a rst-line option for closure of PDA in neonates (12) Some hepatic side effects have been happened after usage of iv acetaminophen, which may determine a transient raise in liver enzymes or more serious acute liver toxicity. (13,14) acetaminophen itself not directly cause of hepatotoxicity in neonates but can be caused by N-acetyl-pbenzoquinoneimine (NAPQI) produced by hepatic cytochrome P450 (CYP) as metabolite productiondependent mixed function oxidase enzyme.…”