Глюкокортикостероиды в лечении алкогольного гепатита (Кокрейновский метаанализ)
Глюкокортикостероиды в лечении алкогольного гепатита (Кокрейновский метаанализ)
Павлов Ч.С., Варганова Д.Л., Касаца Д. и др. Глюкокортикостероиды в лечении алкогольного гепатита (Кокрейновский метаанализ). Терапевтический архив. 2019; 91 (8): 52–66. DOI: 10.26442/00403660.2019.08.000354
For citation: Pavlov C.S., Varganova D.L., Casazza G., et al. Glucocorticosteroids for people with alcoholic hepatitis (Cochrane review). Therapeutic Archive. 2019; 91 (8): 52–66. DOI: 10.26442/00403660.2019.08.000354
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For citation: Pavlov C.S., Varganova D.L., Casazza G., et al. Glucocorticosteroids for people with alcoholic hepatitis (Cochrane review). Therapeutic Archive. 2019; 91 (8): 52–66. DOI: 10.26442/00403660.2019.08.000354
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Аннотация
Рост заболеваемости алкогольной болезнью печени и смертности от нее остается актуальной международной проблемой. В настоящее время среди многообразия лекарственных препаратов, применяющихся для терапии алкогольного гепатита, препаратами первой линии являются глюкокортикостероиды (ГКС).
Цель исследования. Оценить эффективность и безопасность ГКС в терапии алкогольного гепатита.
Материалы и методы. Поиск рандомизированных клинических исследований (РКИ) проводился в международных электронных базах данных. Отбирались РКИ со взрослыми участниками, сравнивающие терапию ГКС и плацебо (контрольную группу), допускалась идентичная сопутствующая терапия в обеих группах. Мы использовали методологию Кокрейна, Кокрейновской гепатобилиарной группы. Mетаанализы выполнены с использованием программного обеспечения Review Manager 5 и последовательного экспертного анализа.
Результаты и обсуждение. Критериям включения соответствовали 16 РКИ, в метаанализ включены результаты 15 РКИ (927 участников получали ГКС, 934 – плацебо). ГКС назначались внутрь или парентерально в среднем на 28 дней. Мы не получили убедительных данных о влиянии ГКС на показатели смертности в течение 3 мес после рандомизации (ОР 0,90; 95% ДИ 0,70–1,15; n=1861), на качество жизни (MD – 0,04 балла; 95% ДИ от –0,11 до 0,03; n=377; РКИ = 1) (шкала EQ-5D-3L), частоту возникновения серьезных нежелательных явлений во время лечения (ОР 1,05; 95% ДИ 0,85–1,29; n=1861) по результатам метаанализа. Качество доказательств оказалось очень низким или низким при оценке по шкале GRADE, а уровень ошибки – высоким во всех РКИ, кроме одного. Одно РКИ не спонсировалось фармацевтическими фирмами.
Заключение. Мы не нашли убедительной разницы между группами терапии ГКС и плацебо в отношении показателей смертности, качества жизни и серьезных нежелательных явлений во время лечения. Мы не можем достоверно исключить увеличение числа нежелательных явлений, преимуществ и вреда терапии ГКС. Необходимы клинические исследования с предоставлением индивидуальных обезличенных данных участников.
Ключевые слова: глюкокортикостероиды, алкогольный гепатит, рандомизированные клинические исследования, метаанализ.
Aim. To assess the benefits and harms of GCS in people with AH.
Material and methods. We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, and Science Citation Index Expanded. We considered for inclusion randomised clinical trials (RCTs) assessing GCS versus placebo/no intervention in adult participants with AH. We allowed co-interventions in the trial groups if they were similar. We followed Cochrane methodology, CHB Group methodology using Review Manager 5 and Trial Sequential Analysis(TSA) to perform meta-analysis (M-A), assessed bias risk of the trials, сertainty of evidence using GRADE.
Results and discussion. Sixteen trials fulfilled the inclusion criteria. Fifteen trials provided data for analysis (927 participants received GCS, 934 – placebo/no intervention). The GCS were administered to adult participants at different stages of AH orally or parenterally for a median of 28 days. There was no evidence of effect of GCCs on our primary outcomes all-cause mortality up to 3 months following randomisation (RR 0.90, 95% CI 0.70–1.15; n=1861), on health-related quality of life (MD – 0.04 points; 95% CI –0.11–0.03; n=377; trial = 1) (EQ-5D-3L scale), on the occurrence of serious adverse events during treatment (RR 1.05, 95% CI 0.85–1.29; n=1861). We found no evidence of a difference between the intervention groups. The risk of bias was high in all the trials except one. The certainty of evidence was very low or low. One of the trials seems to be not industry-funded.
Conclusion. We found no evidence of a difference between GCS and placebo or no intervention on all-cause mortality, health-related quality of life, and serious adverse events during treatment. We cannot exclude increases in adverse events and cannot rule out significant benefits and harms of GCSs. Future trials ought to report depersonalised individual participant data.
Keywords: glucocorticosteroids, alcoholic hepatitis, randomized clinical trial, meta-analysis.
Цель исследования. Оценить эффективность и безопасность ГКС в терапии алкогольного гепатита.
Материалы и методы. Поиск рандомизированных клинических исследований (РКИ) проводился в международных электронных базах данных. Отбирались РКИ со взрослыми участниками, сравнивающие терапию ГКС и плацебо (контрольную группу), допускалась идентичная сопутствующая терапия в обеих группах. Мы использовали методологию Кокрейна, Кокрейновской гепатобилиарной группы. Mетаанализы выполнены с использованием программного обеспечения Review Manager 5 и последовательного экспертного анализа.
Результаты и обсуждение. Критериям включения соответствовали 16 РКИ, в метаанализ включены результаты 15 РКИ (927 участников получали ГКС, 934 – плацебо). ГКС назначались внутрь или парентерально в среднем на 28 дней. Мы не получили убедительных данных о влиянии ГКС на показатели смертности в течение 3 мес после рандомизации (ОР 0,90; 95% ДИ 0,70–1,15; n=1861), на качество жизни (MD – 0,04 балла; 95% ДИ от –0,11 до 0,03; n=377; РКИ = 1) (шкала EQ-5D-3L), частоту возникновения серьезных нежелательных явлений во время лечения (ОР 1,05; 95% ДИ 0,85–1,29; n=1861) по результатам метаанализа. Качество доказательств оказалось очень низким или низким при оценке по шкале GRADE, а уровень ошибки – высоким во всех РКИ, кроме одного. Одно РКИ не спонсировалось фармацевтическими фирмами.
Заключение. Мы не нашли убедительной разницы между группами терапии ГКС и плацебо в отношении показателей смертности, качества жизни и серьезных нежелательных явлений во время лечения. Мы не можем достоверно исключить увеличение числа нежелательных явлений, преимуществ и вреда терапии ГКС. Необходимы клинические исследования с предоставлением индивидуальных обезличенных данных участников.
Ключевые слова: глюкокортикостероиды, алкогольный гепатит, рандомизированные клинические исследования, метаанализ.
________________________________________________
Aim. To assess the benefits and harms of GCS in people with AH.
Material and methods. We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, and Science Citation Index Expanded. We considered for inclusion randomised clinical trials (RCTs) assessing GCS versus placebo/no intervention in adult participants with AH. We allowed co-interventions in the trial groups if they were similar. We followed Cochrane methodology, CHB Group methodology using Review Manager 5 and Trial Sequential Analysis(TSA) to perform meta-analysis (M-A), assessed bias risk of the trials, сertainty of evidence using GRADE.
Results and discussion. Sixteen trials fulfilled the inclusion criteria. Fifteen trials provided data for analysis (927 participants received GCS, 934 – placebo/no intervention). The GCS were administered to adult participants at different stages of AH orally or parenterally for a median of 28 days. There was no evidence of effect of GCCs on our primary outcomes all-cause mortality up to 3 months following randomisation (RR 0.90, 95% CI 0.70–1.15; n=1861), on health-related quality of life (MD – 0.04 points; 95% CI –0.11–0.03; n=377; trial = 1) (EQ-5D-3L scale), on the occurrence of serious adverse events during treatment (RR 1.05, 95% CI 0.85–1.29; n=1861). We found no evidence of a difference between the intervention groups. The risk of bias was high in all the trials except one. The certainty of evidence was very low or low. One of the trials seems to be not industry-funded.
Conclusion. We found no evidence of a difference between GCS and placebo or no intervention on all-cause mortality, health-related quality of life, and serious adverse events during treatment. We cannot exclude increases in adverse events and cannot rule out significant benefits and harms of GCSs. Future trials ought to report depersonalised individual participant data.
Keywords: glucocorticosteroids, alcoholic hepatitis, randomized clinical trial, meta-analysis.
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13. www.lillemodel.com
14. Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology (Baltimore, Md.). 2007;45(6):1348-54. doi: 10.1002/hep.21607
15. Lefkowitch JH. Morphology of alcoholic liver disease. Clin Liv Dis. 2005;9(1):37-53. doi: 10.1016/j.cld.2004.11.001
16. Christensen E, Gluud C. Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables [see comments]. Gut. 1995;37(1):113-8. doi: 10.1136/gut.37.1.113
17. Rambaldi A, Saconato HH, Christensen E, Thorlund K, Wetterslev J, Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis – a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Aliment Pharmacol Ther. 2008;27(12):1167-78. doi: 10.1111/j.1365-2036.2008.03685.x
18. Reynolds TB, Benhamou JP, Blake J, Naccarato R, Orrego H. Treatment of acute alcoholic hepatitis. Gastroenterol Int. 1989;2(4):208-16.
19. Imperiale TF, McCullough AJ. Do corticosteroids reduce mortality from alcoholic hepatitis? A meta-analysis of the randomized trials. Ann Intern Med. 1990;113(4):299-307. doi: 10.7326/0003-4819-113-4-299
20. Daures J-P, Peray P, Bories P, Blanc P, Yousfi A, Michel H, et al. Steroid therapy in acute alcoholic hepatitis: a pooled estimate based on published randomized controlled trials [Place de la corticotherapie dans le traitement des hépatites alcooliques aiguës. Résultants d'une méta-analyse]. Gastroenterologie Clinique et Biologique. 1991;51:223-8.
21. Christensen E, Gluud C. Glucocorticosteroids are not effective in alcoholic hepatitis. Am J Gastroenterol. 1999;94(10)(3065):66.
22. Mathurin P, O'Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-60. doi: 10.1136/gut.2010.224097
23. Louvet A, Thursz M, Kim DJ, Labreuche J, Atkinson SR, Sidhu SS, et al. Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo-a meta-analysis of individual data from controlled trials. Gastroenterology. 2018;155:458-68. doi: 10.1053/j.gastro.2018.05.011
24. Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C. Glucocorticosteroids for people with alcoholic hepatitis. Cochrane Database Syst Rev. 2017;(11):Art. No.: CD001511. doi: 10.1002/14651858.CD001511.pub3
25. Pavlov CS, Tsochatzis E, Casazza G, Nikolova D, Volcek E, Gluud C. Glucocorticosteroids for people with alcoholic hepatitis [Protocol]. Cochrane Database Syst Rev. 2016;(6). doi: 10.1002/14651858
26. International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice CFR & ICH Guidelines. Vol. 1. Philadelphia (PA): Barnett International/PAREXEL, 1997.
27. Higgins JPT, Altman DG, Sterne JAC (eds). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from: handbook.cochrane.org
28. Gluud C, Nikolova D, Klingenberg SL. Cochrane Hepato-Biliary Group. About Cochrane (Cochrane Review Groups (CRGs)) 2017, Issue 2. Art. No.: LIVER 2017.
29. Jakobsen J, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol. 2014;14:120. doi: 10.1186/1471-2288-14-120
30. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-58. doi: 10.1002/sim.1186
31. GRADE [Computer program]. Available from: http://www.gradeworkinggroup.org/
32. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration; 2014. Available from: https://community.cochrane.org/help/tools-and-software/revman-5. Accessed Sep 9, 2018.
33. TSA – Trial Sequential Analysis [Computer program]. Version 0.9 Beta. Copenhagen: Copenhagen Trial Unit, 2011. Available from: www.ctu.dk/tsa/downloads.aspx
34. Wetterslev J, Jakobsen JC, Gluud C. Trial Sequential Analysis in systematic reviews with meta-analysis. BMC Med Res Methodol. 2017;17(1):39. doi: 10.1186/s12874-017-0315-7
35. Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). Available from: ctu.dk/tsa/files/tsa_manual.pdf
36. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial Sequential Analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol. 2008;61:763-9. doi: 10.1016/j.jclinepi.2007.10.007
37. Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive – Trial Sequential Analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. Int J Epidemiol. 2009;38(1):287-98. doi: 10.1093/ije/dyn188
38. Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses. Int J Epidemiol. 2009;38(1):276-86. doi: 10.1093/ije/dyn179
39. Thorlund K, Anema A, Mills E. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clin Epidemiol. 2010;2:57-66. doi: 10.2147/СLEP.S9242
40. Helman RA, Temko MH, Nye SW, Fallon HJ. Alcoholic hepatitis. Natural history and evaluation of prednisolone therapy. Ann Intern Med. 1971;74(3):311-21. doi:10.7326/0003-4819-74-3-311
41. Porter HP, Simon FR, Pope CE II, Volwiler W, Fenster LF. Corticosteroid therapy in severe alcoholic hepatitis. A double-blind drug trial. N Engl J Med. 1971;284(24):1350-5. doi: 10.1056/NEJM197106172842404
42. Blitzer BL, Mutchnick MG, Joshi PH, Phillips MM, Fessel JM, Conn HO. Adrenocorticosteroid therapy in alcoholic hepatitis. A prospective, double-blind randomized study. Dig Dis. 1977;22(6):477-84.
43. Mendenhall CL, Goldberg S. Risk factors and therapy in alcoholic hepatitis (AH). Gastroenterology. 1977;72(5):1100.
44. Mendenhall CL, Anderson S, Garcia-Pont P, Goldberg S, Kiernan T, Seeff LB, et al. Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med. 1984;311(23):1464-70. doi: 10.1053/jhep.2000.8627
45. Shumaker JB, Resnick RH, Galambos JT, Makopour H, Iber FL. A controlled trial of 6-methylprednisolone in acute alcoholic hepatitis. With a note on published results in encephalopathic patients. Am J Gastroenterol. 1978;69(4):443-9.
46. Depew W, Boyer T, Omata M, Redeker A, Reynolds T. Double-blind controlled trial of prednisolone therapy in patients with severe acute alcoholic hepatitis and spontaneous encephalopathy. Gastroenterology. 1980;78(3):524-9.
47. Ramond MJ, Poynard T, Rueff B, Mathurin P, Theodore C, Chaput JC, et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. New Engl J Med. 1992;326:507-12. doi: 10.1056/NEJM199202203260802
48. De BK, Mandal SK, Sau D, Mani S, Chatterjee S, Mondal SS, et al. Pentoxifylline plus prednisolone versus pentoxifylline only for severe alcoholic hepatitis: a randomized controlled clinical trial. Ann Med Health Sci Res. 2014; 4(5):810-16. doi: 10.4103/2141-9248.141562
49. Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, et al. Prednisolone or pentoxifylline for alcoholic hepatitis. New Engl J Med. 2015;372(17):1619-28. doi: 10.1056/NEJMoa1412278
50. Campra JL, Hamlin EM Jr, Kirshbaum RJ, Olivier M, Redeker AG, Reynolds TB. Prednisone therapy of acute alcoholic hepatitis. Report of a controlled trial. Ann Intern Med. 1973;79(5):625-31. doi: 10.7326/0003-4819-79-5-625
51. Theodossi A, Eddleston AL, Williams R. Controlled trial of methylprednisolone therapy in severe acute alcoholic hepatitis. Gut. 1982;23(1):75-9. doi: 10.1136/gut.23.1.75
52. Bories P, Guedj JY, Mirouze D, Yousfi A, Michel H. Prednisolone treatment of alcoholic hepatitis: forty-five patients [Traitement de l'hepatite alcoolique aigue par la prednisolone. Quarante-cinq malades]. La Presse Medicale. 1987;16:769-72.
53. Richardet JP, Dehoux M, Mal F, Roulot D, Labadie H, Pol S, et al. Influence of corticosteroids (CS) on plasma cytokines concentrations in patients with severe alcoholic hepatitis (HA): results of a randomized study. J Hepatol. 1993;18:S75.
54. Lesesne HR, Bozymski EM, Fallon HJ. Treatment of alcoholic hepatitis with encephalopathy. Comparison of prednisolone with caloric supplements. Gastroenterology. 1978;74(2 Pt 1):169-73.
55. Cabré E, Rodríguez-Iglesias P, Caballería J, Quer JC, Sánchez-Lombraña JL, Parés A, et al. Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial. Hepatology (Baltimore, Md.). 2000;32:36-42. doi: 10.1053/jhep.2000.8627
56. Harbord RM, Egger M, Sterne JAC. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Statist Med. 2006;25(20):3443-57. doi:10.1002/sim.2380
57. Student. The probable error of a mean. Biometrika. 1908;6(1):1-25.
58. Buzzetti E, Kalafateli M, Thorburn D, Davidson BR, Thiele M, Gluud LL, et al. Pharmacological interventions for alcoholic liver disease (alcohol-related liver disease). Cochrane Database System Rev. 2017;(3):Art. No.: CD011646. doi: 10.1002/14651858
59. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200-7. doi: 10.7326/0003-4819-158-3-201302050-00583
11. O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Hepatology (Baltimore, Md.). 2010;51:307-28. doi: 10.1002/hep.23258
12. Ивашкин В.Т., Маевская М.В., Павлов Ч.С., Сиволап Ю.П., Луньков В.Д., Жаркова М.С., Масленников Р.В. Клинические рекомендации Российского общества по изучению печени по ведению взрослых пациентов с алкогольной болезнью печени. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2017;27(6):20-40 [Ivashkin VT, Mayevskaya MV, Pavlov ChS, Sivolap YuP, Lunkov VD, Zharkova MS, Maslennikov RV. Management of adult patients with alcoholic liver disease: clinical guidelines of the Russian Scientific Liver Society. Rossiiskii Zhurnal Gastroenterologii, Gepatologii, Koloproktologii. 2017;27(6):20-40 (In Russ.)]. doi: 10.22416/1382-4376-2017-27-6-20-40
13. www.lillemodel.com
14. Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology (Baltimore, Md.). 2007;45(6):1348-54. doi: 10.1002/hep.21607
15. Lefkowitch JH. Morphology of alcoholic liver disease. Clin Liv Dis. 2005;9(1):37-53. doi: 10.1016/j.cld.2004.11.001
16. Christensen E, Gluud C. Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables [see comments]. Gut. 1995;37(1):113-8. doi: 10.1136/gut.37.1.113
17. Rambaldi A, Saconato HH, Christensen E, Thorlund K, Wetterslev J, Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis – a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Aliment Pharmacol Ther. 2008;27(12):1167-78. doi: 10.1111/j.1365-2036.2008.03685.x
18. Reynolds TB, Benhamou JP, Blake J, Naccarato R, Orrego H. Treatment of acute alcoholic hepatitis. Gastroenterol Int. 1989;2(4):208-16.
19. Imperiale TF, McCullough AJ. Do corticosteroids reduce mortality from alcoholic hepatitis? A meta-analysis of the randomized trials. Ann Intern Med. 1990;113(4):299-307. doi: 10.7326/0003-4819-113-4-299
20. Daures J-P, Peray P, Bories P, Blanc P, Yousfi A, Michel H, et al. Steroid therapy in acute alcoholic hepatitis: a pooled estimate based on published randomized controlled trials [Place de la corticotherapie dans le traitement des hépatites alcooliques aiguës. Résultants d'une méta-analyse]. Gastroenterologie Clinique et Biologique. 1991;51:223-8.
21. Christensen E, Gluud C. Glucocorticosteroids are not effective in alcoholic hepatitis. Am J Gastroenterol. 1999;94(10)(3065):66.
22. Mathurin P, O'Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-60. doi: 10.1136/gut.2010.224097
23. Louvet A, Thursz M, Kim DJ, Labreuche J, Atkinson SR, Sidhu SS, et al. Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo-a meta-analysis of individual data from controlled trials. Gastroenterology. 2018;155:458-68. doi: 10.1053/j.gastro.2018.05.011
24. Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C. Glucocorticosteroids for people with alcoholic hepatitis. Cochrane Database Syst Rev. 2017;(11):Art. No.: CD001511. doi: 10.1002/14651858.CD001511.pub3
25. Pavlov CS, Tsochatzis E, Casazza G, Nikolova D, Volcek E, Gluud C. Glucocorticosteroids for people with alcoholic hepatitis [Protocol]. Cochrane Database Syst Rev. 2016;(6). doi: 10.1002/14651858
26. International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice CFR & ICH Guidelines. Vol. 1. Philadelphia (PA): Barnett International/PAREXEL, 1997.
27. Higgins JPT, Altman DG, Sterne JAC (eds). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from: handbook.cochrane.org
28. Gluud C, Nikolova D, Klingenberg SL. Cochrane Hepato-Biliary Group. About Cochrane (Cochrane Review Groups (CRGs)) 2017, Issue 2. Art. No.: LIVER 2017.
29. Jakobsen J, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol. 2014;14:120. doi: 10.1186/1471-2288-14-120
30. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-58. doi: 10.1002/sim.1186
31. GRADE [Computer program]. Available from: http://www.gradeworkinggroup.org/
32. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration; 2014. Available from: https://community.cochrane.org/help/tools-and-software/revman-5. Accessed Sep 9, 2018.
33. TSA – Trial Sequential Analysis [Computer program]. Version 0.9 Beta. Copenhagen: Copenhagen Trial Unit, 2011. Available from: www.ctu.dk/tsa/downloads.aspx
34. Wetterslev J, Jakobsen JC, Gluud C. Trial Sequential Analysis in systematic reviews with meta-analysis. BMC Med Res Methodol. 2017;17(1):39. doi: 10.1186/s12874-017-0315-7
35. Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). Available from: ctu.dk/tsa/files/tsa_manual.pdf
36. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial Sequential Analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol. 2008;61:763-9. doi: 10.1016/j.jclinepi.2007.10.007
37. Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive – Trial Sequential Analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. Int J Epidemiol. 2009;38(1):287-98. doi: 10.1093/ije/dyn188
38. Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses. Int J Epidemiol. 2009;38(1):276-86. doi: 10.1093/ije/dyn179
39. Thorlund K, Anema A, Mills E. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clin Epidemiol. 2010;2:57-66. doi: 10.2147/СLEP.S9242
40. Helman RA, Temko MH, Nye SW, Fallon HJ. Alcoholic hepatitis. Natural history and evaluation of prednisolone therapy. Ann Intern Med. 1971;74(3):311-21. doi:10.7326/0003-4819-74-3-311
41. Porter HP, Simon FR, Pope CE II, Volwiler W, Fenster LF. Corticosteroid therapy in severe alcoholic hepatitis. A double-blind drug trial. N Engl J Med. 1971;284(24):1350-5. doi: 10.1056/NEJM197106172842404
42. Blitzer BL, Mutchnick MG, Joshi PH, Phillips MM, Fessel JM, Conn HO. Adrenocorticosteroid therapy in alcoholic hepatitis. A prospective, double-blind randomized study. Dig Dis. 1977;22(6):477-84.
43. Mendenhall CL, Goldberg S. Risk factors and therapy in alcoholic hepatitis (AH). Gastroenterology. 1977;72(5):1100.
44. Mendenhall CL, Anderson S, Garcia-Pont P, Goldberg S, Kiernan T, Seeff LB, et al. Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med. 1984;311(23):1464-70. doi: 10.1053/jhep.2000.8627
45. Shumaker JB, Resnick RH, Galambos JT, Makopour H, Iber FL. A controlled trial of 6-methylprednisolone in acute alcoholic hepatitis. With a note on published results in encephalopathic patients. Am J Gastroenterol. 1978;69(4):443-9.
46. Depew W, Boyer T, Omata M, Redeker A, Reynolds T. Double-blind controlled trial of prednisolone therapy in patients with severe acute alcoholic hepatitis and spontaneous encephalopathy. Gastroenterology. 1980;78(3):524-9.
47. Ramond MJ, Poynard T, Rueff B, Mathurin P, Theodore C, Chaput JC, et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. New Engl J Med. 1992;326:507-12. doi: 10.1056/NEJM199202203260802
48. De BK, Mandal SK, Sau D, Mani S, Chatterjee S, Mondal SS, et al. Pentoxifylline plus prednisolone versus pentoxifylline only for severe alcoholic hepatitis: a randomized controlled clinical trial. Ann Med Health Sci Res. 2014; 4(5):810-16. doi: 10.4103/2141-9248.141562
49. Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, et al. Prednisolone or pentoxifylline for alcoholic hepatitis. New Engl J Med. 2015;372(17):1619-28. doi: 10.1056/NEJMoa1412278
50. Campra JL, Hamlin EM Jr, Kirshbaum RJ, Olivier M, Redeker AG, Reynolds TB. Prednisone therapy of acute alcoholic hepatitis. Report of a controlled trial. Ann Intern Med. 1973;79(5):625-31. doi: 10.7326/0003-4819-79-5-625
51. Theodossi A, Eddleston AL, Williams R. Controlled trial of methylprednisolone therapy in severe acute alcoholic hepatitis. Gut. 1982;23(1):75-9. doi: 10.1136/gut.23.1.75
52. Bories P, Guedj JY, Mirouze D, Yousfi A, Michel H. Prednisolone treatment of alcoholic hepatitis: forty-five patients [Traitement de l'hepatite alcoolique aigue par la prednisolone. Quarante-cinq malades]. La Presse Medicale. 1987;16:769-72.
53. Richardet JP, Dehoux M, Mal F, Roulot D, Labadie H, Pol S, et al. Influence of corticosteroids (CS) on plasma cytokines concentrations in patients with severe alcoholic hepatitis (HA): results of a randomized study. J Hepatol. 1993;18:S75.
54. Lesesne HR, Bozymski EM, Fallon HJ. Treatment of alcoholic hepatitis with encephalopathy. Comparison of prednisolone with caloric supplements. Gastroenterology. 1978;74(2 Pt 1):169-73.
55. Cabré E, Rodríguez-Iglesias P, Caballería J, Quer JC, Sánchez-Lombraña JL, Parés A, et al. Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial. Hepatology (Baltimore, Md.). 2000;32:36-42. doi: 10.1053/jhep.2000.8627
56. Harbord RM, Egger M, Sterne JAC. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Statist Med. 2006;25(20):3443-57. doi:10.1002/sim.2380
57. Student. The probable error of a mean. Biometrika. 1908;6(1):1-25.
58. Buzzetti E, Kalafateli M, Thorburn D, Davidson BR, Thiele M, Gluud LL, et al. Pharmacological interventions for alcoholic liver disease (alcohol-related liver disease). Cochrane Database System Rev. 2017;(3):Art. No.: CD011646. doi: 10.1002/14651858
59. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200-7. doi: 10.7326/0003-4819-158-3-201302050-00583
________________________________________________
11. O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Hepatology (Baltimore, Md.). 2010;51:307-28. doi: 10.1002/hep.23258
12. [Ivashkin VT, Mayevskaya MV, Pavlov ChS, Sivolap YuP, Lunkov VD, Zharkova MS, Maslennikov RV. Management of adult patients with alcoholic liver disease: clinical guidelines of the Russian Scientific Liver Society. Rossiiskii Zhurnal Gastroenterologii, Gepatologii, Koloproktologii. 2017;27(6):20-40 (In Russ.)]. doi: 10.22416/1382-4376-2017-27-6-20-40
13. www.lillemodel.com
14. Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology (Baltimore, Md.). 2007;45(6):1348-54. doi: 10.1002/hep.21607
15. Lefkowitch JH. Morphology of alcoholic liver disease. Clin Liv Dis. 2005;9(1):37-53. doi: 10.1016/j.cld.2004.11.001
16. Christensen E, Gluud C. Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables [see comments]. Gut. 1995;37(1):113-8. doi: 10.1136/gut.37.1.113
17. Rambaldi A, Saconato HH, Christensen E, Thorlund K, Wetterslev J, Gluud C. Systematic review: glucocorticosteroids for alcoholic hepatitis – a Cochrane Hepato-Biliary Group systematic review with meta-analyses and trial sequential analyses of randomized clinical trials. Aliment Pharmacol Ther. 2008;27(12):1167-78. doi: 10.1111/j.1365-2036.2008.03685.x
18. Reynolds TB, Benhamou JP, Blake J, Naccarato R, Orrego H. Treatment of acute alcoholic hepatitis. Gastroenterol Int. 1989;2(4):208-16.
19. Imperiale TF, McCullough AJ. Do corticosteroids reduce mortality from alcoholic hepatitis? A meta-analysis of the randomized trials. Ann Intern Med. 1990;113(4):299-307. doi: 10.7326/0003-4819-113-4-299
20. Daures J-P, Peray P, Bories P, Blanc P, Yousfi A, Michel H, et al. Steroid therapy in acute alcoholic hepatitis: a pooled estimate based on published randomized controlled trials [Place de la corticotherapie dans le traitement des hépatites alcooliques aiguës. Résultants d'une méta-analyse]. Gastroenterologie Clinique et Biologique. 1991;51:223-8.
21. Christensen E, Gluud C. Glucocorticosteroids are not effective in alcoholic hepatitis. Am J Gastroenterol. 1999;94(10)(3065):66.
22. Mathurin P, O'Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-60. doi: 10.1136/gut.2010.224097
23. Louvet A, Thursz M, Kim DJ, Labreuche J, Atkinson SR, Sidhu SS, et al. Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo-a meta-analysis of individual data from controlled trials. Gastroenterology. 2018;155:458-68. doi: 10.1053/j.gastro.2018.05.011
24. Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C. Glucocorticosteroids for people with alcoholic hepatitis. Cochrane Database Syst Rev. 2017;(11):Art. No.: CD001511. doi: 10.1002/14651858.CD001511.pub3
25. Pavlov CS, Tsochatzis E, Casazza G, Nikolova D, Volcek E, Gluud C. Glucocorticosteroids for people with alcoholic hepatitis [Protocol]. Cochrane Database Syst Rev. 2016;(6). doi: 10.1002/14651858
26. International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice CFR & ICH Guidelines. Vol. 1. Philadelphia (PA): Barnett International/PAREXEL, 1997.
27. Higgins JPT, Altman DG, Sterne JAC (eds). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from: handbook.cochrane.org
28. Gluud C, Nikolova D, Klingenberg SL. Cochrane Hepato-Biliary Group. About Cochrane (Cochrane Review Groups (CRGs)) 2017, Issue 2. Art. No.: LIVER 2017.
29. Jakobsen J, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol. 2014;14:120. doi: 10.1186/1471-2288-14-120
30. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-58. doi: 10.1002/sim.1186
31. GRADE [Computer program]. Available from: http://www.gradeworkinggroup.org/
32. Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration; 2014. Available from: https://community.cochrane.org/help/tools-and-software/revman-5. Accessed Sep 9, 2018.
33. TSA – Trial Sequential Analysis [Computer program]. Version 0.9 Beta. Copenhagen: Copenhagen Trial Unit, 2011. Available from: www.ctu.dk/tsa/downloads.aspx
34. Wetterslev J, Jakobsen JC, Gluud C. Trial Sequential Analysis in systematic reviews with meta-analysis. BMC Med Res Methodol. 2017;17(1):39. doi: 10.1186/s12874-017-0315-7
35. Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). Available from: ctu.dk/tsa/files/tsa_manual.pdf
36. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial Sequential Analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol. 2008;61:763-9. doi: 10.1016/j.jclinepi.2007.10.007
37. Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive – Trial Sequential Analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. Int J Epidemiol. 2009;38(1):287-98. doi: 10.1093/ije/dyn188
38. Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses. Int J Epidemiol. 2009;38(1):276-86. doi: 10.1093/ije/dyn179
39. Thorlund K, Anema A, Mills E. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clin Epidemiol. 2010;2:57-66. doi: 10.2147/СLEP.S9242
40. Helman RA, Temko MH, Nye SW, Fallon HJ. Alcoholic hepatitis. Natural history and evaluation of prednisolone therapy. Ann Intern Med. 1971;74(3):311-21. doi:10.7326/0003-4819-74-3-311
41. Porter HP, Simon FR, Pope CE II, Volwiler W, Fenster LF. Corticosteroid therapy in severe alcoholic hepatitis. A double-blind drug trial. N Engl J Med. 1971;284(24):1350-5. doi: 10.1056/NEJM197106172842404
42. Blitzer BL, Mutchnick MG, Joshi PH, Phillips MM, Fessel JM, Conn HO. Adrenocorticosteroid therapy in alcoholic hepatitis. A prospective, double-blind randomized study. Dig Dis. 1977;22(6):477-84.
43. Mendenhall CL, Goldberg S. Risk factors and therapy in alcoholic hepatitis (AH). Gastroenterology. 1977;72(5):1100.
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Авторы
Ч.С. Павлов 1,2, Д.Л. Варганова 2,3, Д. Касаца 1,4, И. Тсочатис 5, Д. Николова 1, К. Глуд 1
1 Гепатобилиарная группа Кокрейна, Отдел клинических исследований Копенгагена, Университетский госпиталь Копенгагена, Дания;
2 Центр доказательной медицины ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия;
3 ГУЗ «Ульяновская областная клиническая больница», Ульяновск, Россия;
4 Клиника «Л. Сакко», Миланский университет, Милан, Италия;
5 Гепатологический центр Шейлы Шерлок, Королевский госпиталь, Институт изучения печени и пищеварительного тракта, Лондон, Великобритания
1 The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;
2 Center for Evidence Based Medicine, Sechenov First Moscow State Medical University, Moscow, Russia;
3 Department of Gastroenterology, Ulyanovsk Regional Clinical Hospital, Ulyanovsk, Russia;
4 Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano, Milan, Italy;
5 Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
1 Гепатобилиарная группа Кокрейна, Отдел клинических исследований Копенгагена, Университетский госпиталь Копенгагена, Дания;
2 Центр доказательной медицины ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия;
3 ГУЗ «Ульяновская областная клиническая больница», Ульяновск, Россия;
4 Клиника «Л. Сакко», Миланский университет, Милан, Италия;
5 Гепатологический центр Шейлы Шерлок, Королевский госпиталь, Институт изучения печени и пищеварительного тракта, Лондон, Великобритания
________________________________________________
1 The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;
2 Center for Evidence Based Medicine, Sechenov First Moscow State Medical University, Moscow, Russia;
3 Department of Gastroenterology, Ulyanovsk Regional Clinical Hospital, Ulyanovsk, Russia;
4 Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano, Milan, Italy;
5 Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
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