Jorge A Bezerra1, Cathie Spino2, John C Magee2, Benjamin L Shneider3, Philip Rosenthal4, Kasper S Wang5, Jessi Erlichman6, Barbara Haber7, Paula M Hertel8, Saul J Karpen9, Nanda Kerkar10, Kathleen M Loomes6, Jean P Molleston11, Karen F Murray12, Rene Romero9, Kathleen B Schwarz13, Ross Shepherd8, Frederick J Suchy14, Yumirle P Turmelle15, Peter F Whitington16, Jeffrey Moore2, Averell H Sherker17, Patricia R Robuck17, Ronald J Sokol14. 1. Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 2. University of Michigan, Ann Arbor. 3. Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania. 4. UCSF Benioff Children's Hospital, San Francisco, California. 5. Children's Hospital Los Angeles and University of Southern California, Los Angeles. 6. Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 7. Children's Hospital of Philadelphia, Philadelphia, Pennsylvania17Dr Haber is now with Merck Research Laboratories, Upper Gwynedd, Pennsylvania. 8. Baylor College of Medicine and Texas Children's Hospital, Houston. 9. Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia. 10. Mount Sinai School of Medicine, New York, New York18Dr Kerkar is now with Children's Hospital Los Angeles and University of Southern California, Los Angeles. 11. Indiana University School of Medicine and Riley Hospital for Children, Indianapolis. 12. Seattle Children's Hospital, Seattle, Washington. 13. Johns Hopkins University School of Medicine, Baltimore, Maryland. 14. University of Colorado School of Medicine and Children's Hospital Colorado, Aurora. 15. Washington University School of Medicine, St Louis, Missouri. 16. Lurie Children's Hospital of Chicago, Chicago, Illinois. 17. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.
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.
RCT Entities:
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.
Authors: Mark Davenport; J De Ville de Goyet; M D Stringer; G Mieli-Vergani; D A Kelly; P McClean; L Spitz Journal: Lancet Date: 2004-04-24 Impact factor: 79.321
Authors: Rebecka L Meyers; Linda S Book; Molly A O'Gorman; W Daniel Jackson; Richard E Black; Dale G Johnson; Michael E Matlak Journal: J Pediatr Surg Date: 2003-03 Impact factor: 2.545
Authors: Vicky L Ng; Lisa G Sorensen; Estella M Alonso; Emily M Fredericks; Wen Ye; Jeff Moore; Saul J Karpen; Benjamin L Shneider; Jean P Molleston; Jorge A Bezerra; Karen F Murray; Kathleen M Loomes; Philip Rosenthal; Robert H Squires; Kasper Wang; Ronen Arnon; Kathleen B Schwarz; Yumirle P Turmelle; Barbara H Haber; Averell H Sherker; John C Magee; Ronald J Sokol Journal: J Pediatr Date: 2018-03-05 Impact factor: 4.406