ESPEN Congress Cannes Education and Clinical Practice Programme

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1 ESPEN Congress Cannes 2003 Organised by the Israel Society for Clinical Nutrition Education and Clinical Practice Programme Session: Pharmacist Session: Amino Acids Branched Chain Amino Acids for Hepatic Encephalopathy: a Cochrane Systematic Review Doctor Bodil Als-Nielsen and R. Koretz, L.L. Kjaergard, C. Gluud Copenhagen, Denmark bodil.a@ctu.rh.dk Background Hepatic encephalopathy an otherwise unexplained altered mental status in patients with acute or chronic hepatic failure associated with a decreased plasma ratio of branched-chain amino acids (BCAA) to aromatic amino acids BCAA may have a beneficial effect ESPEN For personal use only. 1

2 Objectives To evaluate the beneficial and harmful effects of BCAA for patients with hepatic encephalopathy Methods Cochrane Systematic Review analogous to other research projects systematic collection, appraisal and summary of the best available evidence to answer a focused clinical question based on a prespecified, peer-reviewed protocol ESPEN For personal use only. 2

3 Methods Selection Criteria We included randomised trials comparing BCAA with any kind of control therapy for hepatic encephalopathy, regardless of blinding, language, or publication status Methods Outcome Measures Primary Secondary Improvement Time to improvement Survival Adverse events ESPEN For personal use only. 3

4 Methods Search Strategy Electronic databases the Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register, MEDLINE and EMBASE. Last search performed September 2002 Manual searches of bibliographies, journals, and reference lists, authors of trials, and pharmaceutical companies Methods Statistical methods Intention-to-treat (using carry forward ) Binary outcomes, as relative risks (RR) based on a random effects model Statistical heterogeneity, by the Chi-square test with significance set at P < 0.1 Sensitivity analyses methodological quality form of hepatic encephalopathy ESPEN For personal use only. 4

5 Methods Selection bias systematic differences in comparisons groups Performance bias systematic differences in the provided care Detection bias systematic differences in outcome assessment Attrition bias systematic differences in withdrawals Description of trials 11 trials 556 patients randomised All included patients had cirrhosis and Acute hepatic encephalopathy (7 trials) Chronic hepatic encephalopathy (2 trials) Minimal hepatic encephalopathy (2 trials) ESPEN For personal use only. 5

6 Description of trials Intervention parenteral administration of BCAA (7 trials, AHE) enteral administration (4 trials, CHE + MHE) median amount BCAA: 28 gram/day (range 11 to 57 gram) Control therapies glucose (1 trial) isonitrogenous (4 trials) neomycin or lactulose (5 trials) placebo (1 trials) Methodological quality - adequate Generation of the allocation sequence: 27% Allocation concealment: 45% Double-blind: 45% Descriptions of dropouts/withdrawals: 55% Intention-to-treat: 27% ESPEN For personal use only. 6

7 Results - improvement of HE Test for heterogeneity: _ 2 =16.35, df=8; P= [1.04 to 1.66] Results - time to improvement Test for heterogeneity: _ 2 =8.95, df=2; P= hours [-38 to 10] ESPEN For personal use only. 7

8 Results - survival Test for heterogeneity: _ 2 =6.37, df=7; P= [0.98 to 1.12] Results - adverse events Test for heterogeneity: _ 2 =0.14, df=1; P= [0.41 to 2.31] ESPEN For personal use only. 8

9 Sensitivity analyses improvement of HE 1.01 [0.84 to 1.23] 1.60 [1.24 to 2.06] Sensitivity analyses improvement of HE 1.09 [0.89 to 1.33] 1.63 [1.16 to 2.38] ESPEN For personal use only. 9

10 Sensitivity analyses improvement of HE [0.83 to 1.73] 1.42 [1.00 to 2.02] Sensitivity analyses improvement of HE 3.08 [0.97 to 9.76] 1.17 [1.00 to 1.66] ESPEN For personal use only. 10

11 Conclusion No convincing evidence that BCAA has a significant beneficial effect on patients with hepatic encephalopathy Most trials had low quality Absence of evidence is not evidence of absence of effect Further randomised trials are justified References to trials included in review Cerra FB et al. Disease-specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized double-blind, controlled trial. Journal of Parenteral and Enteral Nutrition 1985;9(3): Egberts EH et al. Branched chain amino acids in the treatment of latent portosystemic encephalopathy. A double-blind placebo-controlled crossover study. Gastroenterology 1985;88(4): Fiaccadori F et al. Branched chain amino acid enriched solutions in the treatment of hepatic encephalopathy: a controlled trial. Italian Journal of Gastroenterology 1985;17:5-10. Hayashi S et al. A randomized controlled study of an elementary diet (ED-H) in cirrhotica with hepatic encephalopathy [unpublished data]. Hwang SJ et al. A randomized controlled trial for the evaluation of the efficacy of branched chain amino acid enriched amino acid solution in the treatment of patients with hepatic encephalopathy. Chinese Journal of Gastroenterology 1988;5: Marchesini G et al. Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein-controlled trial. The Italian Multicenter Study Group. Journal of Hepatology 1990;11(1): Michel H et al. Treatment of acute hepatic encephalopathy in cirrhotics with a branched-chain amino acids enriched versus a conventional amino acids mixture. A controlled study of 70 patients. Liver 1985;5(5): Plauth M et al. Long-term treatment of latent portosystemic encephalopathy with branched-chain amino acids. A double-blind placebo-controlled crossover study. Journal of Hepatology 1993;17(3): Rossi Fanelli F et al. Use of branched chain amino acids for treating hepatic encephalopathy: clinical experiences. Gut 1986;27(Suppl 1): Strauss E et al. Treatment of hepatic encephalopathy: a randomized clinical trial comparing a branched chain enriched amino acid solution to oral neomycin. Nutritional Support Services 1986;6: Vilstrup H et al. Branched chain enriched amino acid versus glucose treatment of hepatic encephalopathy. A double-blind study of 65 patients with cirrhosis. Journal of Hepatology 1990;10(3): ESPEN For personal use only. 11

12 Additional references Als-Nielsen B et al. Branched-chain amino acids for hepatic encephalopathy (Cochrane Review). In: The Cochrane Library, Issue 3, Oxford: Update Software. CD Ferenci P et al. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, Hepatology 2002;35(3): Groeneweg M et al. Screening of subclinical hepatic encephalopathy. Journal of Hepatology 2000;32: Marchesini G et al. Nutritional treatment with branched-chain amino acids in advanced liver cirrhosis. Journal of Gastroenterology 2000;35(12):7-12. Naylor CD et al. Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy. A meta-analysis. Gastroenterology 1989;97: Gøtzsche PC. Why we need a broad perspective on meta-analysis [editorial]. BMJ 2000;321: Jüni P et al. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001;323(7303): Kjaergard LL et al. Reported methodological quality and discrepancies between small and large randomized trials in meta-analyses. Annals of Internal Medicine 2001;135: Schulz KF. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Journal of the American Medical Association 1995;273: Egger M, Smith SG, Altman DG, editor(s). Systematic reviews in health care. Meta-analysis in the context. London: BMJ Books, ESPEN For personal use only. 12