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

Melissa Liebowitz, Joseph Kaempf, Omer Erdeve, Ali Bulbul, Stellan Håkansson, Johanna Lindqvist, Aijaz Farooqi, Anup Katheria, Jason Sauberan, Jaideep Singh, Kelly Nelson, Andrea Wickremasinghe, Lawrence Dong, Denise C Hassinger, Susan W Aucott, Madoka Hayashi, Anne Marie Heuchan, William A Carey, Matthew Derrick, Ilene Sue Wolf, Amy Kimball, Meera Sankar, Tina Leone, Jorge Perez, Arturo Serize, Ronald I Clyman, Melissa Liebowitz, Joseph Kaempf, Omer Erdeve, Ali Bulbul, Stellan Håkansson, Johanna Lindqvist, Aijaz Farooqi, Anup Katheria, Jason Sauberan, Jaideep Singh, Kelly Nelson, Andrea Wickremasinghe, Lawrence Dong, Denise C Hassinger, Susan W Aucott, Madoka Hayashi, Anne Marie Heuchan, William A Carey, Matthew Derrick, Ilene Sue Wolf, Amy Kimball, Meera Sankar, Tina Leone, Jorge Perez, Arturo Serize, Ronald I Clyman

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 (NCT01958320). 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.

Conflict of interest statement

Conflict of Interest: Neither the authors nor any of the individuals listed in the Acknowledgement section have any conflicts of interest.

Figures

Figure 1
Figure 1
Flow diagram of patient distribution and ductus outcomes among Conservative management and Drug treatment groups. No RX*: Thirty infants with a moderate-to-large PDA did not receive rescue treatment because they either did not meet the Rescue clinical criteria (n=17) or the clinical team chose not to treat them despite having met Rescue criteria (n=13) (see Methods). 26/30 (87%) constricted their ductus spontaneously by the time of discharge from the hospital. Note: among the 38 infants treated with Early Rx Ibuprofen 34 received a loading dose of 10 mg/kg followed by maintenance doses of 5 mg/kg. Four infants received 20 mg/kg loading and 10 mg/kg maintenance doses. Only one of the four (25%) infants in the high dose group had successful ductus constriction.

References

    1. Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR. Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics 2006;117:1113–1121.
    1. Nemerofsky SL, Parravicini E, Bateman D, Kleinman C, Polin RA, Lorenz JM. The ductus arteriosus rarely requires treatment in infants > 1000 grams. Am J Perinatol 2008;25:661–666.
    1. Sung SI, Chang YS, Chun JY, Yoon SA, Yoo HS, Ahn SY, et al. Mandatory Closure Versus Nonintervention for Patent Ductus Arteriosus in Very Preterm Infants. J Pediatr 2016;177:66–71
    1. Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics 2011;128:e1618–1621.
    1. Allegaert KS, Anderson B, Simons S, Van Overmeire B. Paracetamol to induce ductus arteriosus closure: is it valid? Arch Dis Child 2013;98:462–466.
    1. El-Khuffash A, Jain A, Corcoran D, Shah PS, Hooper CW, Brown N, et al. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatric Research 2014;76:238–244.
    1. Al-Lawama M, Alammori I, Abdelghani T, Badran E. Oral paracetamol versus oral ibuprofen for treatment of patent ductus arteriosus. J Int Med Res 2018;46:811–818.
    1. Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PLoS One 2013;8:e77888.
    1. Dash SK, Kabra NS, Avasthi BS, Sharma SR, Padhi P, Ahmed J. Enteral paracetamol or Intravenous Indomethacin for Closure of Patent Ductus Arteriosus in Preterm Neonates: A Randomized Controlled Trial. Indian Pediatr 2015;52:573–578.
    1. El-Mashad AE, El-Mahdy H, El Amrousy D, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr 2017;176:233–240.
    1. Harkin P, Harma A, Aikio O, Valkama M, Leskinen M, Saarela T, et al. Paracetamol Accelerates Closure of the Ductus Arteriosus after Premature Birth: A Randomized Trial. J Pediatr 2016;177:72–77
    1. Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, et al. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 2014;164:510–514
    1. Yang B, Gao X, Ren Y, Wang Y, Zhang Q. Oral paracetamol vs. oral ibuprofen in the treatment of symptomatic patent ductus arteriosus in premature infants: A randomized controlled trial. Exp Ther Med 2016;12:2531–2536.
    1. Bagheri MM, Niknafs P, Sabsevari F, Torabi MH, Bahman Bijari B, Noroozi E, et al. Comparison of Oral Acetaminophen Versus Ibuprofen in Premature Infants With Patent Ductus Arteriosus. Iran J Pediatr 2016;26:e3975.
    1. El-Farrash RA, El Shimy MS, El-Sakka AS, Ahmed MG, Abdel-Moez DG. Efficacy and safety of oral paracetamol versus oral ibuprofen for closure of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Matern Fetal Neonatal Med 2018:1–8.
    1. Asbagh PA, Zarkesh MR, Nili F, Sadat Nayeri FS, Naeem AT. Prophylactic treatment with oral paracetamol for patent ductus arteriosus in preterm infants: a randomized clinical trial. Tehran University Medical Journal 2015;73:86–92.
    1. Terrin G, Conte F, Oncel MY, Scipione A, McNamara PJ, Simons S, et al. Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2016;101:F127–136.
    1. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev 2018;4:CD010061.
    1. Mitra S, Florez ID, Tamayo ME, Mbuagbaw L, Vanniyasingam T, Veroniki AA, et al. Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis. JAMA 2018;319:1221–1238.
    1. Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Hakansson S, et al. PDA-TOLERATE trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at one week of age. J Pediatr. 2018. [Epub ahead of print].
    1. Schena F, Francescato G, Cappelleri A, Picciolli I, Mayer A, Mosca F, et al. Association between Hemodynamically Significant Patent Ductus Arteriosus and Bronchopulmonary Dysplasia. J Pediatr 2015;166:1488–1492.
    1. Sellmer A, Bjerre JV, Schmidt MR, McNamara PJ, Hjortdal VE, Host B, et al. Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed 2013;98:F505–510.
    1. Jhaveri N, Moon-Grady A, Clyman RI. Early surgical ligation versus a conservative approach for management of patent ductus arteriosus that fails to close after indomethacin treatment. J Pediatr 2010;157:381–387.
    1. El Hajjar M, Vaksmann G, Rakza T, Kongolo G, Storme L. Severity of the ductal shunt: a comparison of different markers. Arch Dis Child Fetal Neonatal Ed 2005;90:F419–422.
    1. Hochwald O, Mainzer G, Borenstein-Levin L, Jubran H, Dinur G, Zucker M, et al. Adding Paracetamol to Ibuprofen for the Treatment of Patent Ductus Arteriosus in Preterm Infants: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. Am J Perinatol 2018;epub ahead of print May 21 2018. doi: 10.1055/s-0038-1653946.
    1. Furzan JA, Reisch J, Tyson JE, Laird P, Rosenfeld CR. Incidence and risk factors for symptomatic patent ductus arteriosus among inborn very-low-birth-weight infants. Early Hum Dev 1985;12:39–48.
    1. Clyman RI, Ballard PL, Sniderman S, Ballard RA, Roth R, Heymann MA, et al. Prenatal administration of betamethasone for prevention of patient ductus arteriosus. J Pediatr 1981;98:123–126.
    1. Chorne N, Jegatheesan P, Lin E, Shi R, Clyman RI. Risk factors for persistent ductus arteriosus patency during indomethacin treatment. J Pediatr 2007. 151:629–634.
    1. Durrmeyer X, Hovhannisyan S, Medard Y, Jacqz-Aigrain E, Decobert F, Barre J, et al. Are cytochrome P450 CYP2C8 and CYP2C9 polymorphisms associated with ibuprofen response in very preterm infants? PLoS One 2010;5:e12329.
    1. Cotton RB, Haywood JL, FitzGerald GA. Symptomatic patent ductus arteriosus following prophylactic indomethacin. A clinical and biochemical appraisal. Biol Neonate 1991;60:273–282.
    1. Waleh N, Barrette AM, Dagle JM, Momany A, Jin C, Hills NK, et al. Effects of Advancing Gestation and Non-Caucasian Race on Ductus Arteriosus Gene Expression. J Pediatr 2015;167:1033–1041
    1. Shelton EL, Waleh N, Plosa EJ, Benjamin JT, Milne GL, Hooper CW, et al. Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data. Pediatric Research 2018; e-pub ahead of print 6 July 2018 doi: 10.1038/s41390-018-0006-z.
    1. Momma K, Takao A. Transplacental cardiovascular effects of four popular analgesics in rats. Am J Obstet Gynecol 1990;162:1304–1310.
    1. Momma K, Hagiwara H, Konishi T. Constriction of fetal ductus arteriosus by non-steroidal anti-inflammatory drugs: study of additional 34 drugs. Prostaglandins 1984;28:527–536.
    1. Sancak S, Gokmen Yildirim T, Topcuoglu S, Yavuz T, Karatekin G, Ovali F. Oral versus intravenous paracetamol: which is better in closure of patent ductus arteriosus in very low birth weight infants? J Matern Fetal Neonatal Med 2016;29:135–139.
    1. Bin-Nun A, Fink D, Mimouni FB, Algur N, Hammerman C. Paracetamol Serum Concentrations in Neonates Treated Enterally for Ductal Closure: A Pilot Study. J Pediatr 2018;198:304–307.
    1. Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 2010:CD000174.
    1. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2011:CD004213.
    1. van den Anker JN, Allegaert K. Acetaminophen in the Neonatal Intensive Care Unit: Shotgun Approach or Silver Bullet. J Pediatr 2018;198:10–11.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi