Oral Paracetamol vs Oral Ibuprofen in Patent Ductus Arteriosus: A Randomized, Controlled, Noninferiority Trial

Abstract

Objective To test the hypothesis that oral paracetamol is non-inferior to oral ibuprofen in closing hemodynamically significant patent ductus arteriosus (hsPDA) with an a priori noninferiority (NI) margin of 15%. Study design Multicenter, randomized, controlled, NI trial conducted in level III neonatal intensive care units. Consecutively inborn preterm neonates of <32 weeks of gestation with hsPDA were included. Those with structural heart disease, major malformations, and contraindications for enteral feeding or for administration of study drugs were excluded. Interventions included oral paracetamol in the experimental arm and oral ibuprofen in the active control arm. The primary outcome was closure of hsPDA by 24 hours from the last dose of the study drug. Secondary outcome measures included closure of hsPDA by 24 hours after the first course of the study drug, rate of reopening after the first course, and adverse events associated with the study drug. Results Out of 1250 neonates screened, 161 were randomized. Oral paracetamol was noninferior to oral ibuprofen in closure of hsPDA by both per protocol analysis (62 [95.4%] vs 63 [94%]; relative risk [RR], 1.01 [95% CI, 0.94-1.1]; risk difference [RD], 1.4 [95% CI, À6 to 9]; P = .37) and intention-to-treat analysis (63 [89%] vs 65 [89%]; RR, 0.99 [95% CI, 0.89-1.12]; RD, À0.3 [95% CI, À11 to 10]; P = .47). All adverse events were comparable in the 2 study arms. Conclusions Oral paracetamol is noninferior to oral ibuprofen for the closure of hsPDA in preterm neonates of <32 weeks of gestation. No difference was observed in the adverse events studied.

Predictors of successful patent ductus arteriosus closure with acetaminophen in preterm infants

“…We report a lower probability of successful PDA closure (42.4%) following acetaminophen compared to the previous published RCTs, which range from 70 to 100% successful PDA closure [ 4 , 6 – 12 , 14 ]. This is likely related to differences in the patient population of the enrolled subject as well as our unit’s clinical practice of symptomatic PDA treatment strategy used to treat hs-PDA, which were potentially causing pulmonary comorbidity of continued need for mechanical ventilation and inability to wean.…”

“…Acetaminophen is increasingly being used for initial medical management of PDA as demonstrated by multiple case series [ 23 , 27 , 28 ] and recent randomized controlled trials [ 4 , 6 – 10 , 12 , 14 ]. In our study, with symptomatic PDA treatment strategy, we found that infants >26 weeks GA or with PDA size ≤0.2 cm were nearly twice as likely to have successful PDA closure after acetaminophen compared to infants ≤26 weeks or with PDA size >0.2 cm.…”

“…This is likely related to differences in the patient population of the enrolled subject as well as our unit’s clinical practice of symptomatic PDA treatment strategy used to treat hs-PDA, which were potentially causing pulmonary comorbidity of continued need for mechanical ventilation and inability to wean. Most published RCTs to date are from the eastern hemisphere, enrolling larger GA infants with mean GA > 30 weeks [ 6 , 9 , 10 , 12 , 13 ], larger BW infants with BW 1000–1500 g [ 7 , 11 ] and >1500 g [ 6 , 9 , 10 ] infant with only one study enrolling infants <28 weeks GA [ 11 ]. Most preterm infant ≥28 weeks of gestation spontaneously close the PDA by the end of the first postnatal week [ 16 , 17 , 32 , 33 ], while 50–70% of infants <28 weeks of gestation may have a moderate-to-large PDA shunt persisting for weeks after birth [ 34 , 35 ].…”

Early closure mechanisms of the ductus arteriosus in immature infants

“…Paired comparisons between AA, indomethacin and ibuprofen revealed no difference in PDA closure rates (Table 1A; many oral drug trials not shown). A recent non‐inferiority trial in which oral AA and ibuprofen were compared confirmed the result 18 . In placebo‐controlled trials, NSAIDs increased the PDA closure and AA showed a similar trend (Table 1B).…”

Paracetamol vs. Ibuprofen in Preterm Infants With Hemodynamically Significant Patent Ductus Arteriosus: A Non-inferiority Randomized Clinical Trial Protocol

“…Of published clinical trials, only study of Kumar et al ( 31 , 42 ) has a non-inferiority design but administration of treatment was oral and patients included were <32 weeks of gestation. One of the main inconveniences of this design is the large population size needed to demonstrate non-inferiority.…”