Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia the start randomized clinical trial

Jorge A. Bezerra, Cathie Spino, John C. Magee, Benjamin L. Shneider, Philip Rosenthal, Kasper S. Wang, Jessi Erlichman, Barbara Haber, Paula M. Hertel, Saul J. Karpen, Nanda Kerkar, Kathleen M. Loomes, Jean P. Molleston, Karen F. Murray, Rene Romero, Kathleen Schwarz, Ross Shepherd, Frederick J. Suchy, Yumirle P. Turmelle, Peter F. WhitingtonJeffrey Moore, Averell H. Sherker, Patricia R. Robuck, Ronald J. Sokol

Research output: Contribution to journalArticle

Abstract

IMPORTANCE: Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome. OBJECTIVE: To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver. DESIGN, SETTING, AND PATIENTS: The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013. INTERVENTIONS: Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy. MAIN OUTCOMES AND MEASURES: The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events. RESULTS: The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70] of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, -10.4% to 27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% [57/70] of the steroids group and 80.0% [56/70] of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0% [95% CI, 11.5% to 30.4%] of placebo group; P = .008). CONCLUSIONS AND RELEVANCE: Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00294684.

Original languageEnglish (US)
Pages (from-to)1750-1759
Number of pages10
JournalJournal of the American Medical Association
Volume311
Issue number17
DOIs
StatePublished - 2014

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Biliary Atresia
Bile
Drainage
Adrenal Cortex Hormones
Randomized Controlled Trials
Steroids
Placebos
Survival
Liver
End Stage Liver Disease
Methylprednisolone
Therapeutics
Prednisolone
Bilirubin
Transplants

ASJC Scopus subject areas

  • Medicine(all)

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Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia the start randomized clinical trial. / Bezerra, Jorge A.; Spino, Cathie; Magee, John C.; Shneider, Benjamin L.; Rosenthal, Philip; Wang, Kasper S.; Erlichman, Jessi; Haber, Barbara; Hertel, Paula M.; Karpen, Saul J.; Kerkar, Nanda; Loomes, Kathleen M.; Molleston, Jean P.; Murray, Karen F.; Romero, Rene; Schwarz, Kathleen; Shepherd, Ross; Suchy, Frederick J.; Turmelle, Yumirle P.; Whitington, Peter F.; Moore, Jeffrey; Sherker, Averell H.; Robuck, Patricia R.; Sokol, Ronald J.

In: Journal of the American Medical Association, Vol. 311, No. 17, 2014, p. 1750-1759.

Research output: Contribution to journalArticle

Bezerra, JA, Spino, C, Magee, JC, Shneider, BL, Rosenthal, P, Wang, KS, Erlichman, J, Haber, B, Hertel, PM, Karpen, SJ, Kerkar, N, Loomes, KM, Molleston, JP, Murray, KF, Romero, R, Schwarz, K, Shepherd, R, Suchy, FJ, Turmelle, YP, Whitington, PF, Moore, J, Sherker, AH, Robuck, PR & Sokol, RJ 2014, 'Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia the start randomized clinical trial', Journal of the American Medical Association, vol. 311, no. 17, pp. 1750-1759. https://doi.org/10.1001/jama.2014.2623
Bezerra, Jorge A. ; Spino, Cathie ; Magee, John C. ; Shneider, Benjamin L. ; Rosenthal, Philip ; Wang, Kasper S. ; Erlichman, Jessi ; Haber, Barbara ; Hertel, Paula M. ; Karpen, Saul J. ; Kerkar, Nanda ; Loomes, Kathleen M. ; Molleston, Jean P. ; Murray, Karen F. ; Romero, Rene ; Schwarz, Kathleen ; Shepherd, Ross ; Suchy, Frederick J. ; Turmelle, Yumirle P. ; Whitington, Peter F. ; Moore, Jeffrey ; Sherker, Averell H. ; Robuck, Patricia R. ; Sokol, Ronald J. / Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia the start randomized clinical trial. In: Journal of the American Medical Association. 2014 ; Vol. 311, No. 17. pp. 1750-1759.
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abstract = "IMPORTANCE: Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome. OBJECTIVE: To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver. DESIGN, SETTING, AND PATIENTS: The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013. INTERVENTIONS: Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy. MAIN OUTCOMES AND MEASURES: The primary end point (powered to detect a 25{\%} absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events. RESULTS: The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6{\%} [41/70] of steroids group vs 48.6{\%} [34/70] of placebo group; adjusted relative risk, 1.14 [95{\%} CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7{\%} (95{\%} CI, -10.4{\%} to 27.7{\%}). Transplant-free survival was 58.7{\%} in the steroids group vs 59.4{\%} in the placebo group (adjusted hazard ratio, 1.0 [95{\%} CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4{\%} [57/70] of the steroids group and 80.0{\%} [56/70] of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2{\%} [95{\%} CI, 26.9{\%} to 50.0{\%}] of steroids group vs 19.0{\%} [95{\%} CI, 11.5{\%} to 30.4{\%}] of placebo group; P = .008). CONCLUSIONS AND RELEVANCE: Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00294684.",
author = "Bezerra, {Jorge A.} and Cathie Spino and Magee, {John C.} and Shneider, {Benjamin L.} and Philip Rosenthal and Wang, {Kasper S.} and Jessi Erlichman and Barbara Haber and Hertel, {Paula M.} and Karpen, {Saul J.} and Nanda Kerkar and Loomes, {Kathleen M.} and Molleston, {Jean P.} and Murray, {Karen F.} and Rene Romero and Kathleen Schwarz and Ross Shepherd and Suchy, {Frederick J.} and Turmelle, {Yumirle P.} and Whitington, {Peter F.} and Jeffrey Moore and Sherker, {Averell H.} and Robuck, {Patricia R.} and Sokol, {Ronald J.}",
year = "2014",
doi = "10.1001/jama.2014.2623",
language = "English (US)",
volume = "311",
pages = "1750--1759",
journal = "JAMA - Journal of the American Medical Association",
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TY - JOUR

T1 - Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia the start randomized clinical trial

AU - Bezerra, Jorge A.

AU - Spino, Cathie

AU - Magee, John C.

AU - Shneider, Benjamin L.

AU - Rosenthal, Philip

AU - Wang, Kasper S.

AU - Erlichman, Jessi

AU - Haber, Barbara

AU - Hertel, Paula M.

AU - Karpen, Saul J.

AU - Kerkar, Nanda

AU - Loomes, Kathleen M.

AU - Molleston, Jean P.

AU - Murray, Karen F.

AU - Romero, Rene

AU - Schwarz, Kathleen

AU - Shepherd, Ross

AU - Suchy, Frederick J.

AU - Turmelle, Yumirle P.

AU - Whitington, Peter F.

AU - Moore, Jeffrey

AU - Sherker, Averell H.

AU - Robuck, Patricia R.

AU - Sokol, Ronald J.

PY - 2014

Y1 - 2014

N2 - IMPORTANCE: Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome. OBJECTIVE: To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver. DESIGN, SETTING, AND PATIENTS: The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013. INTERVENTIONS: Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy. MAIN OUTCOMES AND MEASURES: The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events. RESULTS: The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70] of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, -10.4% to 27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% [57/70] of the steroids group and 80.0% [56/70] of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0% [95% CI, 11.5% to 30.4%] of placebo group; P = .008). CONCLUSIONS AND RELEVANCE: Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00294684.

AB - IMPORTANCE: Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome. OBJECTIVE: To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver. DESIGN, SETTING, AND PATIENTS: The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013. INTERVENTIONS: Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy. MAIN OUTCOMES AND MEASURES: The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events. RESULTS: The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70] of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, -10.4% to 27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% [57/70] of the steroids group and 80.0% [56/70] of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0% [95% CI, 11.5% to 30.4%] of placebo group; P = .008). CONCLUSIONS AND RELEVANCE: Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00294684.

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