Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: a secondary analysis of the PDA-TOLERATE trial (NCT01958320)

Abstract

Objective: To evaluate the effectiveness of drugs used to constrict patent ductus arteriosus (PDA) in newborns <28 weeks. Methods: We performed a secondary analysis of the multi-center PDA-TOLERATE trial ( ). Infants with moderate-to-large PDAs were randomized 1:1 at 8.1±2.1 days to either Drug treatment (n=104) or Conservative management (n=98). Drug treatments were assigned by center rather than within center (acetaminophen: 5 centers, 27 infants; ibuprofen: 7 centers, 38 infants; indomethacin: 7 centers, 39 infants). Results: Indomethacin produced the greatest constriction (compared with spontaneous constriction during Conservative management): RR (95% CI) = 3.21 (2.05-5.01)), followed by ibuprofen=2.03 (1.05-3.91), and acetaminophen=1.33 (0.55-3.24). The initial rate of acetaminophen-induced constriction was 27%. Infants with persistent moderate-to-large PDA after acetaminophen were treated with indomethacin. The final rate of constriction after acetaminophen±indomethacin was 60% (similar to the rate in infants receiving indomethacin-alone (62%)). Conclusion: Indomethacin was more effective than acetaminophen in producing ductus constriction.

Management of Patent Ductus Arteriosus in Preterm Patients Who Were Given Surfactant

“…The authors found that early routine treatment of medium and large PDAs at the end of the first week in infants born during the 28th gestational week does not reduce the presence of PDA ligations or PDAs during discharge, does not improve any of the predetermined secondary results and delays full enteral nutrition. Furthermore, they found that it increases the risk of late-onset sepsis and death in infants ≥ 26 week gestation [30].…”

Paracetamol (Acetaminophen) for Patent Ductus Arteriosus: Where Do We Stand?

“…2,[4][5][6][7][8][9][10][11][21][22][23][24][25] To address this concern, a recent multicenter RCT compared the efficacy of the 3 drugs in infants delivered exclusively before 28 weeks of gestation who still had a moderate-tolarge PDA at the end of the first week. 26 The trial found that infants treated with indomethacin had the greatest rate of constriction among the 3 drugs tested: when compared with the rate of spontaneous PDA constriction (which was 20%) during the 7-10 days after enrollment, the relative risk of indomethacin-induced closure was 3.21 (95% CI, 2.05-5.01), followed by ibuprofen at 2.03 (95% CI, 1.05-3.91), and acetaminophen at 1.33 (95% CI, 0.55-3.24). 26 It should be noted that, even in the infants studied by Kumar et al, the rate of ductus closure after paracetamol appeared to be less robust than after ibuprofen.…”

“…26 The trial found that infants treated with indomethacin had the greatest rate of constriction among the 3 drugs tested: when compared with the rate of spontaneous PDA constriction (which was 20%) during the 7-10 days after enrollment, the relative risk of indomethacin-induced closure was 3.21 (95% CI, 2.05-5.01), followed by ibuprofen at 2.03 (95% CI, 1.05-3.91), and acetaminophen at 1.33 (95% CI, 0.55-3.24). 26 It should be noted that, even in the infants studied by Kumar et al, the rate of ductus closure after paracetamol appeared to be less robust than after ibuprofen. 4 Although the ultimate rate of PDA closure after 1 or 2 courses of paracetamol was similar to the rate of closure after ibuprofen, the rate of PDA reopening was higher after paracetamol and more neonates who were treated initially with paracetamol required a second course of the drug.…”

“…However, few pharmacokinetic or pharmacodynamic studies have been undertaken to determine the best dose, frequency, duration and route of administration of paracetamol for effective PDA closure. 3,26,31,32 Only 2 small trials have compared the effects of intravenous with enteral paracetamol administration; unfortunately, each had opposing results. 3,31 Similarly, the range of effective July 2020 EDITORIALS paracetamol serum concentrations is still in doubt.…”

“…Bin-Nun et al found that serum concentrations of 20 mg/L or greater predicted ductus constriction; in contrast, Liebowitz et al found no difference in paracetamol concentrations between infants who constricted their ductus and those who did not. 26,32 Future pharmacodynamics trials will be needed to determine if serum paracetamol concentrations can predict ductus constriction and whether these concentrations can be achieved safely by increasing enteral or intravenous dosing.…”