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Efficacy and safety of intravenous paracetamol in comparison to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: study protocol for a randomized control trial.

ABSTRACT: Patent ductus arteriosus (PDA) is one of most common complications in preterm infants. Although ibuprofen represents the first choice for the closure of PDA, this treatment can cause severe gastrointestinal and adverse renal effects and worsen platelet function. The successful closure of the PDA with paracetamol has been recently reported in several preterm infants, and the safety of paracetamol for this use has been suggested by the available data.We present the design of a randomized, multicenter, controlled study, whose aim is to assess the effectiveness and safety of intravenous paracetamol in comparison to intravenous ibuprofen for the treatment of PDA in preterm infants. A total of 110 infants born at 25(+0) to 31(+6) weeks of gestational age will be enrolled and randomized to receive paracetamol or ibuprofen (55 patients per group) starting at 24-72 h of life. The primary endpoint of the study is the comparison of the PDA closing rate observed after a 3-day course with paracetamol or ibuprofen. The secondary endpoints include the closure rate of PDA after the second course of treatment with ibuprofen, the re-opening rate of the PDA, the incidence of surgical ligation, and the occurrence of adverse effects.The results of this study will provide new information about the possible use of paracetamol in the treatment of PDA. Paracetamol could offer several important therapeutic advantages over current treatment options, and it could become the treatment of choice for the management of PDA, mainly due to its more favorable side effect profile.Clinicaltrials.gov NCT02422966 . Eudract no. 2013-003883-30.

SUBMITTER: Dani C

PROVIDER: S-EPMC4818852 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Efficacy and safety of intravenous paracetamol in comparison to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: study protocol for a randomized control trial.

Dani Carlo C Poggi Chiara C Mosca Fabio F Schena Federico F Lista Gianluca G Ramenghi Luca L Romagnoli Costantino C Salvatori Enrica E Rosignoli Maria Teresa MT Lipone Paola P Comandini Alessandro A

Trials 20160402

<h4>Background</h4>Patent ductus arteriosus (PDA) is one of most common complications in preterm infants. Although ibuprofen represents the first choice for the closure of PDA, this treatment can cause severe gastrointestinal and adverse renal effects and worsen platelet function. The successful closure of the PDA with paracetamol has been recently reported in several preterm infants, and the safety of paracetamol for this use has been suggested by the available data.<h4>Methods/design</h4>We pr ...[more]

PMID: 27038924

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Project description:BackgroundSymptomatic patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. In these infants, prophylactic use of indomethacin, a non-selective cyclooxygenase inhibitor, has demonstrated short-term clinical benefits. The effect of indomethacin in preterm infants with a symptomatic PDA remains unexplored.ObjectivesTo determine the effectiveness and safety of indomethacin (given by any route) compared to placebo or no treatment in reducing mortality and morbidity in preterm infants with a symptomatic PDA.Search methodsWe used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 31 July 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs.Selection criteriaWe included RCTs and quasi-RCTs that compared indomethacin (any dose, any route) versus placebo or no treatment in preterm infants.Data collection and analysisWe used the standard methods of Cochrane Neonatal, with separate evaluation of trial quality and data extraction by at least two review authors. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of PDA closure within one week of administration of the first dose of indomethacin; bronchopulmonary dysplasia (BPD) at 28 days' postnatal age and at 36 weeks' postmenstrual age; proportion of infants requiring surgical ligation or transcatheter occlusion; all-cause neonatal mortality; necrotizing enterocolitis (NEC) (≥ Bell stage 2); and mucocutaneous or gastrointestinal bleeding.Main resultsWe included 14 RCTs (880 preterm infants). Four out of the 14 included studies were judged to have high risk of bias in one or more domains. Indomethacin administration was associated with a large reduction in failure of PDA closure within one week of administration of the first dose (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.23 to 0.38; risk difference (RD) -0.52, 95% CI -0.58 to -0.45; 10 studies, 654 infants; high-certainty evidence). There may be little to no difference in the incidence of BPD (BPD defined as supplemental oxygen need at 28 days' postnatal age: RR 1.45, 95% CI 0.60 to 3.51; 1 study, 55 infants; low-certainty evidence; BPD defined as supplemental oxygen need at 36 weeks' postmenstrual age: RR 0.80, 95% CI 0.41 to 1.55; 1 study, 92 infants; low-certainty evidence) and probably little to no difference in mortality (RR 0.78, 95% CI 0.46 to 1.33; 8 studies, 314 infants; moderate-certainty evidence) with use of indomethacin for symptomatic PDA. No differences were demonstrated in the need for surgical PDA ligation (RR 0.66, 95% CI 0.33 to 1.29; 7 studies, 275 infants; moderate-certainty evidence), in NEC (RR 1.27, 95% CI 0.36 to 4.55; 2 studies, 147 infants; low-certainty evidence), or in mucocutaneous or gastrointestinal bleeding (RR 0.33, 95% CI 0.01 to 7.58; 2 studies, 119 infants; low-certainty evidence) with use of indomethacin compared to placebo or no treatment. Certainty of evidence for BPD, surgical PDA ligation, NEC, and mucocutaneous or gastrointestinal bleeding was downgraded for very serious or serious imprecision.Authors' conclusionsHigh-certainty evidence shows that indomethacin is effective in closing a symptomatic PDA compared to placebo or no treatment in preterm infants. Evidence is insufficient regarding effects of indomethacin on other clinically relevant outcomes and medication-related adverse effects.

Project description:ImportancePersistent patent ductus arteriosus (PDA) in preterm infants is associated with increased mortality and respiratory morbidities, including bronchopulmonary dysplasia (BPD). Despite recent increasing use of noninterventional approaches, no study to our knowledge has yet directly compared the nonintervention vs pharmacologic treatment for mediating PDA closure for decreasing mortality and preventing BPD.ObjectiveTo determine the noninferiority of nonintervention vs oral ibuprofen treatment for PDA in decreasing BPD incidence or death in very preterm infants.Design, setting, and participantsA randomized, double-blind, placebo-controlled, noninferiority clinical trial was conducted on preterm infants (gestational age [GA] 23-30 weeks) with hemodynamically significant PDA (ductal size >1.5 mm plus respiratory support) diagnosed between postnatal days 6 and 14. Participants included 383 infants screened between July 24, 2014, and March 15, 2019.InterventionsInfants were stratified by GA and randomly assigned (1:1) to receive either oral ibuprofen (initial dose of 10 mg/kg followed by a 5-mg/kg dose after 24 hours and a second 5-mg/kg dose after 48 hours) or placebo.Main outcomes and measuresThe primary outcome was BPD or death; the secondary outcomes included major morbidities and ductal closure rates. Per-protocol analysis was used.ResultsAmong 383 infants screened for participation, 146 infants were randomly assigned, with 72 in the nonintervention and 70 in the ibuprofen treatment group in the final analyses. The PDA closure rate at 1 week after randomization was significantly higher with ibuprofen (11 [34%]) than nonintervention (2 [7%]) in infants at GA 27 to 30 weeks (P = .007); however, the findings were not significant at GA 23 to 26 weeks (ibuprofen, 3 [8%] vs nonintervention, 1 [2%], P = .34). In addition, the ductal closure rates before hospital discharge (ibuprofen, 62 [89%] vs nonintervention, 59 [82%], P = .27) and device closure (ibuprofen, 2 [3%] vs nonintervention, 4 [6%], P = .40) were not significantly different between the 2 groups. The nonintervention approach was noninferior to ibuprofen treatment in terms of BPD incidence or death (nonintervention, 44%; ibuprofen, 50%; 95% CI, -0.11 to 0.22; noninferiority margin -0.2; P = .51). One infant in the ibuprofen arm received oral ibuprofen backup rescue treatment owing to cardiopulmonary compromise refractory to conservative management, and another infant in the ibuprofen group received surgical ligation; none of the infants in the placebo group received backup treatment.Conclusions and relevanceNonintervention showed noninferiority compared with ibuprofen treatment in closing of hemodynamically significant PDA and reduction of BPD or death. The noninferiority of nonintervention over ibuprofen might be attributable to the low efficacy of oral ibuprofen for closing PDA, especially in infants born at 23 to 26 weeks' gestation.Trial registrationClinicalTrials.gov Identifier: NCT02128191.

Dataset Information

Efficacy and safety of intravenous paracetamol in comparison to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: study protocol for a randomized control trial.

Publications

Efficacy and safety of intravenous paracetamol in comparison to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: study protocol for a randomized control trial.

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