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

Journal of Perinatology volume 39, pages 599–607 (2019)Cite this article

Subjects

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.

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Data availability

After de-identification individual participant data that underlie the results reported in this article will be available to researchers who provide a methodologically sound proposal. Proposals should be directed to clymanr@ucsf.edu. To gain access, data requestors will need to sign a data access agreement.

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Acknowledgements

We would like to thank the following PDA-TOLERATE investigators without whom this study would not have been possible: University of California San Francisco, San Francisco, CA: Scott Fields, PharmD; Providence St. Vincent Medical Center, Portland, OR: Lora Whitten, RN, Stefanie Rogers, MD; Ankara University School of Medicine Children’s Hospital, Ankara, Turkey: Emel Okulu, MD, Begum Atasay, MD, Saadet Arsan, MD; Sisli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey: Ebru Türkoglu Ünal, MD; Sharp Mary Birch Hospital, San Diego, CA: Jane Steen, RN, Kathy Arnell, RN; University of Chicago, Chicago, IL: Sarah Holtschlag, RN, Michael Schreiber, MD; Morristown Medical Center, Morristown, NJ: Caryn Peters, RN; Johns Hopkins Hospital, Baltimore, MD: Maureen Gilmore, MD; University of Glasgow, Royal Hospital for Sick Children, Glasgow, Scotland, UK: Lorna McKay, RN, Dianne Carole, RN, Annette Shaw, RN; Mayo Clinic, Rochester, MN: Malinda Harris, MD, Amy Amsbaugh, RRT, Lavonne M. Liedl, RRT; Northshore University Health System, Evanston, IL: Avi Groner, MD; University of California San Diego and Rady Children’s Hospital, San Diego, CA: Erika Fernandez, MD, Jae Kim, MD, Renee Bridge, RN, Ellen Knodel, RN; Good Samaritan Hospital, San Jose, CA: Chrissy Weng, RN; South Miami Hospital/Baptist Health South Florida, Miami, FL: Magaly Diaz Barbosa, MD; Columbia University Medical Center, New York, NY: Richard Polin, MD, Marilyn Weindler, RN; Data Safety Monitoring Committee: Shahab Noori, MD, University of Southern California, Los Angeles, CA, Jeffrey Reese, MD, Vanderbilt University, Nashville, TN, Yao Sun, MD, University of California San Francisco, San Francisco, CA. We also would like to thank Dr. Mark Cocalis and the cardiologists at all of the participating institutions for their expert help in reading the echocardiograms. This work was supported by grants from the Gerber Foundation, U.S. Public Health Service National Heart, Lung and Blood Institute (HL109199), National Center for Advancing Translational Sciences, National Institutes of Health, through (UL1 TR001872, UL1 TR000004 and UL1TR001873), and a gift from the Jamie and Bobby Gates Foundation.

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of California, San Francisco, CA, USA

    Melissa Liebowitz & Ronald I. Clyman

  2. Providence St. Vincent Medical Center, Portland, OR, USA

    Joseph Kaempf

  3. Ankara University School of Medicine Children’s Hospital, Ankara, Turkey

    Omer Erdeve

  4. Sisli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey

    Ali Bulbul

  5. Umea University Hospital, Umea, Sweden

    Stellan Håkansson, Johanna Lindqvist & Aijaz Farooqi

  6. Sharp Mary Birch Hospital, San Diego, CA, USA

    Anup Katheria & Jason Sauberan

  7. University of Chicago, Chicago, IL, USA

    Jaideep Singh & Kelly Nelson

  8. Kaiser Permanente Santa Clara Medical Center, Santa Clara, CA, USA

    Andrea Wickremasinghe & Lawrence Dong

  9. Morristown Medical Center, Morristown, NJ, USA

    Denise C. Hassinger

  10. Johns Hopkins University, Baltimore, MD, USA

    Susan W. Aucott & Madoka Hayashi

  11. University of Glasgow, Royal Hospital for Sick Children, Glasgow, Scotland, UK

    Anne Marie Heuchan

  12. Mayo Clinic, Rochester, MN, USA

    William A. Carey

  13. Northshore University Health System, Evanston, IL, USA

    Matthew Derrick & Ilene Sue Wolf

  14. University of California San Diego and Rady Children’s Hospital, San Diego, CA, USA

    Amy Kimball

  15. Good Samaritan Hospital, San Jose, CA, USA

    Meera Sankar

  16. Columbia University Medical Center, New York, NY, USA

    Tina Leone

  17. South Miami Hospital/Baptist Health South Florida, Miami, FL, USA

    Jorge Perez & Arturo Serize

  18. Cardiovascular Research Institute, University of California, San Francisco, CA, USA

    Ronald I. Clyman

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  1. Melissa Liebowitz
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Correspondence to Ronald I. Clyman.

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Liebowitz, M., Kaempf, J., Erdeve, O. et al. Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: a secondary analysis of the PDA-TOLERATE trial (NCT01958320). J Perinatol 39, 599–607 (2019). https://doi.org/10.1038/s41372-019-0347-4

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