Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis

Abstract

Importance: Despite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to treat those developing a hemodynamically significant PDA.

Objectives: To estimate the relative likelihood of hemodynamically significant PDA closure with common pharmacotherapeutic interventions and to compare adverse event rates.

Data sources and study selection: The databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen vs each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA.

Data extraction and synthesis: Data were independently extracted in pairs by 6 reviewers and synthesized with Bayesian random-effects network meta-analyses.

Main outcomes and measures: Primary outcome: hemodynamically significant PDA closure; secondary: included surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage.

Results: In 68 randomized clinical trials of 4802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2867 of 4256 infants). A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199 [95% CrI, 95-258] more per 1000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08-5.31]; absolute risk difference, 124 [95% CrI, 14-188] more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities.

Conclusions and relevance: A high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure vs standard doses of intravenous ibuprofen or intravenous indomethacin; placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage.

Trial registration: PROSPERO Identifier: CRD42015015797.

Figure 1.. Literature Search and Study Selection Flow Diagram

PDA indicates patent ductus arteriosus.

Figure 2.. Network Plots for Patent Ductus Arteriosus Closure and Need for Repeat Pharmacotherapy

These 2 outcome measures for treatment of hemodynamically significant patent ductus arteriosus were evaluated in the Bayesian network meta-analysis. Each node indicates a treatment modality and is sized proportionally to the number of infants who received the treatment modality. Each line connecting 2 nodes indicates a direct comparison between 2 modalities, and the thickness of each is proportional to the number of trials directly comparing the 2 modalities. Seldom-used variations of indomethacin were condensed into a single node termed indomethacin, other types. A standard dose of ibuprofen is 10 mg/kg followed by 5 mg/kg every 12 to 24 hours for a total of 3 doses. A high dose of ibuprofen is 15 to 20 mg/kg followed by 7.5 to 10 mg/kg every 12 to 24 hours for a total of 3 doses. IV indicates intravenous.

Figure 3.. Network Plots for Surgical Patent Ductus Arteriosus Ligation and Neonatal Mortality

These 2 outcome measures for treatment of hemodynamically significant patent ductus arteriosus were evaluated in the Bayesian network meta-analysis. Each node indicates a treatment modality and is sized proportionally to the number of infants who received the treatment modality. Each line connecting 2 nodes indicates a direct comparison between 2 modalities, and the thickness of each is proportional to the number of trials directly comparing the 2 modalities. Seldom-used variations of indomethacin were condensed into a single node termed indomethacin, other types. A standard dose of ibuprofen is 10 mg/kg followed by 5 mg/kg every 12 to 24 hours for a total of 3 doses. A high dose of ibuprofen is 15 to 20 mg/kg followed by 7.5 to 10 mg/kg every 12 to 24 hours for a total of 3 doses. IV indicates intravenous.

Figure 4.. Network Plots for Necrotizing Enterocolitis and Bronchopulmonary Dysplasia

These 2 outcome measures for treatment of hemodynamically significant patent ductus arteriosus were evaluated in the Bayesian network meta-analysis. Each node indicates a treatment modality and is sized proportionally to the number of infants who received the treatment modality. Each line connecting 2 nodes indicates a direct comparison between 2 modalities, and the thickness of each is proportional to the number of trials directly comparing the 2 modalities. Seldom-used variations of indomethacin were condensed into a single node termed indomethacin, other types. A standard dose of ibuprofen is 10 mg/kg followed by 5 mg/kg every 12 to 24 hours for a total of 3 doses. A high dose of ibuprofen is 15 to 20 mg/kg followed by 7.5 to 10 mg/kg every 12 to 24 hours for a total of 3 doses. IV indicates intravenous.

Figure 5.. Network Plots for Intraventricular Hemorrhage and Oliguria

These 2 outcome measures for treatment of hemodynamically significant patent ductus arteriosus were evaluated in the Bayesian network meta-analysis. Each node indicates a treatment modality and is sized proportionally to the number of infants who received the treatment modality. Each line connecting 2 nodes indicates a direct comparison between 2 modalities, and the thickness of each is proportional to the number of trials directly comparing the 2 modalities. Seldom-used variations of indomethacin were condensed into a single node termed indomethacin, other types. A standard dose of ibuprofen is 10 mg/kg followed by 5 mg/kg every 12 to 24 hours for a total of 3 doses. A high dose of ibuprofen is 15 to 20 mg/kg followed by 7.5 to 10 mg/kg every 12 to 24 hours for a total of 3 doses. IV indicates intravenous.

Figure 6.. Network Effect Estimates and Ranking Statistics for Patent Ductus Arteriosus Closure and the Need for Repeat Pharmacotherapy

Figure 7.. Network Effect Estimates and Ranking Statistics for Need for Surgical Patent Ductus Arteriosus Ligation and Neonatal Mortality

Figure 8.. Network Effect Estimates and Ranking Statistics for Necrotizing Enterocolitis and Bronchopulmonary Dysplasia

Figure 9.. Network Effect Estimates and Ranking Statistics for Intraventricular Hemorrhage and Oliguria

Figure 10.. Heat Maps of 10 Treatment Modalities Studied in Preterm Infants With Hemodynamically Significant PDA for 8 Outcomes

Each column represents a treatment modality and each row represents an outcome. For each outcome (column 1), the No. of studies included in the analysis is presented in parentheses. IV indicates intravenous; PDA, patent ductus arteriosus; SUCRA, surface under the cumulative ranking curve. Each box is colored according to the mean SUCRA value of the corresponding treatment and outcome. The color scale consists of values that represent mean SUCRA which range from 0 (red, indicating a treatment is always last) to 1 (green, indicating a treatment is always first). Uncolored boxes labeled NA (data not available) show that the underlying treatment was not included for that particular outcome. The values in each box represent the mean (SD) SUCRA value of the corresponding treatment and outcome. A standard dose of ibuprofen is 10 mg/kg followed by 5 mg/kg every 12 to 24 hours for a total of 3 doses. A high dose of ibuprofen is 15 to 20 mg/kg followed by 7.5 to 10 mg/kg every 12 to 24 hours for a total of 3 doses. ^aHigh-quality studies indicates there is a low or probably low risk of bias.