Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials
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《英国医生杂志》
1 Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Department 7102, H:S Rigshospitalet, DK-2100 Copenhagen, Denmark
Correspondence to: B Als-Nielsen bodil.a@ctu.rh.dk
Abstract
Figure 1 summarises the literature search. We included 22 trials that assessed lactulose or lactitol versus placebo, no treatment, or antibiotics.5 6 20-39 Two trials were published as abstracts.32 37 The remaining were published as full articles. Eighteen trials used a parallel group design and four a crossover design. All trials were described as randomised, but adequate generation of the allocation sequence was described in only four.22 30 31 39 Treatment allocation was adequately concealed in 10 trials,5 6 20-23 26 30 36 39 double blinding was reported in 15 trials,5 6 20-25 27 32-34 36 38 39 and one trial had blinded outcome assessment.30 We classified nine trials as high quality.5 6 20-23 30 36 39
Fig 1 Selection process of eligible randomised trials from all identified references
Lactulose or lactitol v placebo or no intervention
Ten trials with 280 patients (75% men) assessed lactulose or lactitol versus placebo or no intervention (table 1).20-29 All patients had cirrhosis and acute,25 chronic,20 22-24 acute or chronic,21 or minimal hepatic encephalopathy.26-29 Eight trials assessed oral lactulose,20-24 26 28 29 one assessed oral lactitol,27 and one assessed lactitol enemas.25 The daily mean doses of lactulose ranged from 30 g to 84 g (median 50 g). In six trials the dose was adjusted to obtain two to three semisoft stools per day. The median duration of treatment was 15 days (range 5 to 360 days). None of the trials followed up patients after the end of treatment.
Table 1 Randomised trials of non-absorbable disaccharides versus placebo or no intervention in treatment of patients with hepatic encephalopathy
Trial results were homogeneous. Compared with placebo or no intervention, lactulose and lactitol seemed to reduce the risk of no improvement of hepatic encephalopathy (relative risk 0.62, 95% confidence interval 0.46 to 0.84, six trials; fig 2). This result was not robust when trials were stratified by quality. High quality trials found no significant effect of lactulose or lactitol on the risk of no improvement (0.92, 0.42 to 2.04, two trials; fig 2), whereas low quality trials found a significant beneficial effect of lactulose or lactitol (0.57, 0.40 to 0.83, four trials; fig 2). Although this difference in treatment response was not significant (P = 0.3 by test of interaction), it is noteworthy that the event rate in the control groups was significantly associated with quality of methods (high quality trials 38%, low quality trials 78%; P = 0.0005 with 2 test). The event rate in the experimental group was not significantly different in trials with high (35%) and low (43%) quality (P = 0.5 with 2 test). The treatment responses in acute, chronic, and minimal hepatic encephalopathy did not differ significantly. However, there was no significant effect of lactulose or lactitol on acute (0.27, 0.02 to 3.28, two trials) or chronic hepatic encephalopathy (1.33, 0.41 to 4.33, one trial). Trials in patients with minimal hepatic encephalopathy found that lactulose or lactitol significantly reduced the risk of no improvement assessed by various psychometric tests (0.61, 0.47 to 0.79, three trials). These trials were all of low methodological quality.
Fig 2 Number of patients without improvement of hepatic encephalopathy in trials on non-absorbable disaccharides versus placebo or no intervention, stratified according to quality of methods
Compared with placebo or no intervention, lactulose and lactitol had no significant effect on mortality (0.41, 0.02 to 8.68, four trials) or the number connection test result (weighted mean difference -9.0 seconds, -20.1 to 2.1, one trial) but tended to lower blood ammonia (-8.16 μmol/l, -16.44 μmol/l to 0.18 μmol/l, four trials). Data on adverse events were incompletely reported. Most trials mentioned adverse events associated only with non-absorbable disaccharides. We were therefore unable to perform a reliable meta-analysis of this outcome. None of the reported adverse events were serious, and all originated from the gastrointestinal tract (diarrhoea, flatulence, abdominal pain, or nausea).
Lactulose or lactitol versus antibiotics
Twelve trials with 698 patients (72% men) assessed lactulose or lactitol versus antibiotics (table 2).5 6 30-39 All patients had cirrhosis and acute,6 32 39 chronic,5 31 35 36 38 acute or chronic,30 or presumed chronic hepatic encephalopathy.33 34 37 Nine trials assessed oral lactulose,5 6 30 31 33-37 and three trials assessed oral lactitol.32 38 39 The daily mean dose of lactulose ranged from 30 g to 120 g (median 59 g) and of lactitol from 30 g to 60 g (median 60 g). The antibiotics were neomycin,5 6 30 ribostamycin,31 vancomycin,32 or rifaximin.33-39 The median duration of treatment was 15 days (range 5-90 days). One trial assessed all outcomes 15 days after the end of treatment,38 and one reported mortality 28 days after the end of treatment.39 All other trials followed the patients only to the end of treatment.
Table 2 Randomised trials on non-absorbable disaccharides versus antibiotics in treatment of patients with hepatic encephalopathy
Trial results were homogeneous. Compared with antibiotics, patients taking lactulose or lactitol had a significantly higher risk of no improvement of hepatic encephalopathy (1.24, 1.02 to 1.50, 10 trials; fig 3). We found no significant difference in response to treatment between aminoglycosides and rifaximin (P = 0.2 by test of interaction) or when trials were stratified by quality or type of hepatic encephalopathy. We found no significantly different effect on mortality between nonabsorbable disaccharides and antibiotics (0.90, 0.48 to 1.67, five trials) or on adverse events (1.62, 0.57 to 4.58, eight trials). None of the reported adverse events were serious, and all originated from the gastrointestinal tract (diarrhoea, flatulence, abdominal pain, or nausea). Compared with antibiotics, patients on lactulose or lactitol took on average six more seconds to complete the number connection test (weighted mean difference 6.4 seconds, 1.4 seconds to 11.3 seconds, six trials) and had higher blood ammonia concentrations (2.35 μmol/l, 0.06 μmol/l to 4.64 μmol/l, 10 trials).
Fig 3 Number of patients without improvement of hepatic encephalopathy in trials on non-absorbable disaccharides versus antibiotics, stratified according to type of antibiotic
Discussion
We did not find sufficient evidence to determine whether lactulose or lactitol have a significant beneficial effect on patients with hepatic encephalopathy. In our overall analysis non-absorbable disaccharides seemed to improve encephalopathy, but this effect was seen in only low quality trials.
The beneficial effect in low quality trials was related to significantly worse rates of improvement in the control group. This finding concurs with empirical evidence showing that low quality trials exaggerate the beneficial effects of treatment.15 16 40 Accordingly, the overall result may reflect bias because of the low methodological quality of most of the included trials. Our results may also be inflated by publication bias.
We found no significant effect of non-absorbable disaccharides on acute or chronic hepatic encephalopathy. Only low quality trials in patients with minimal hepatic encephalopathy found that lactulose had a beneficial effect, as assessed by various non-validated psychometric tests. The clinical relevance of these tests is uncertain.41
Lactulose has been used as the standard treatment for hepatic encephalopathy, and its efficacy has been considered to be beyond doubt.2 7 24 25 42 However, when it was introduced, the few trials that compared lactulose against placebo found no beneficial effect of lactulose.21 23 It was implemented in clinical practice because two trials found it "equally effective" to neomycin,5 6 which had been the standard treatment for hepatic encephalopathy since 1957.43 There are two major pitfalls in this reasoning. Firstly, the efficacy of neomycin in hepatic encephalopathy has never been shown. We identified only one randomised trial that compared neomycin with placebo44 and one that compared neomycin plus lactulose with placebo,45 both for acute hepatic encephalopathy. Both trials found no significant beneficial effects of neomycin. Secondly, lactulose was considered as equally effective to neomycin because event rates in intervention groups were not significantly different.5 6 However, lack of statistical significance does not imply that treatments have equal effects.46 Both trials were small,5 6 and neither reported sample size calculations based on an equivalence hypothesis or stated a margin of equivalence.46 47 It would require a far larger sample size than these two trials (a total of 78 patients) to establish with confidence that lactulose and neomycin have comparable effects.
Later on, new trials compared other antibiotics to non-absorbable disaccharides for hepatic encephalopathy. None was set up as an equivalence trial. Sample size calculations with statements implying an equivalence hypothesis or a margin of equivalence were not reported in any of the trials. All were underpowered to show equivalence. Nevertheless, all trials concluded equivalence from the lack of statistical significance.30-39 It seems that the research was continuously building up on both insufficient evidence and inadequate methods. Our analyses indicate that antibiotics are statistically superior to non-absorbable disaccharides in improving hepatic encephalopathy and lowering blood ammonia concentrations. However, it is unclear whether the effects are clinically important. Considering this, the lack of effect of antibiotics in placebo controlled trials,44 45 the risk of multiresistance,48 and the potential risk of severe adverse events5 lead us to conclude that there is insufficient evidence to recommend the use of antibiotics for hepatic encephalopathy.
Mechanisms
When assessing intervention effects for hepatic encephalopathy, it is important to consider the fluctuating course as well as the impact of treating precipitating factors in acute hepatic encephalopathy. Well conducted placebo controlled trials on the use of ornithine aspartate in patients with minimal or chronic hepatic encephalopathy49 50 and lactulose plus neomycin45 in those with acute hepatic encephalopathy found improvement rates in the placebo group ranging from 40% to 70%. Many clinicians claim to have witnessed beneficial effects of nonabsorbable disaccharides on patients with hepatic encephalopathy. This effect may represent a high rate of spontaneous improvement and successful treatment of precipitating factors.
Implications
Non-absorbable disaccharides seem to have been introduced into clinical practice without appropriate documentation. This leads to at least three major problems. Firstly, patients are given a treatment of uncertain efficacy. It might be beneficial; it might be unfavourable. Secondly, there is reluctance towards performing randomised trials to assess lactulose or lactitol versus placebo because it is considered unethical. Thirdly, most randomised trials on new treatments for hepatic encephalopathy use lactulose as comparator. New treatments are considered effective if improvement rates do not differ significantly from the group treated with lactulose, although trials are vastly underpowered to show equivalence. This approach is most problematic. Nonabsorbable disaccharides should not serve as comparator in randomised trials on hepatic encephalopathy until other trials have shown that lactulose or lactitol has any beneficial effect on hepatic encephalopathy.
What is already known on this topic
Non-absorbable disaccharides are considered standard treatment for hepatic encephalopathy
Non-absorbable disaccharides serve as control treatment in most trials of new drugs for hepatic encephalopathy
What this study adds
There is insufficient evidence to determine whether non-absorbable disaccharides are of benefit to patients with hepatic encephalopathy
Antibiotics seem superior to non-absorbable disaccharides in improving hepatic encephalopathy, but it is unclear whether this difference is clinically important
Non-absorbable disaccharides should not be used as the comparator in randomised trials on hepatic encephalopathy
We thank the patients who took part in the reviewed trials; the researchers who provided us with additional information; J?rgen Hilden, department of biostatistics, University of Copenhagen, for statistical support; and Peter G?tzsche, Nordic Cochrane Centre, for valuable comments on an earlier draft of this review. This review is an abbreviated version of a Cochrane systematic review. The full version will be published in the Cochrane Library 2004, Issue 2. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Library should be consulted for the most recent version of the review.
Contributors: BA-N drafted the protocol and paper, performed the literature searches, identified trials, extracted data, and performed the statistical analyses. LLG identified trials and extracted data. All reviewers contributed to the writing of the protocol and review and all have approved of the final version. BA-N is guarantor.
Funding: Danish Centre for Evaluation and Health Technology Assessment (DACEHTA), Danish Medical Research Council, and Copenhagen Hospital Corporation's Medical Research Council.
Competing interests: None declared.
Ethical approval: Not required.
References
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Elkington SG, Floch MH, Conn HO. Lactulose in the treatment of chronic portal-systemic encephalopathy. A double-blind clinical trial. N Engl J Med 1969;281: 408-12.
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Rodgers JB Jr, Kiley JE, Balint JA. Comparison of results of long-term treatment of chronic hepatic encephalopathy with lactulose and sorbitol. Am J Gastroenterol 1973;60: 459-65.
Germain L, Frexinos J, Louis A, Ribet A. Double blind study of lactulose in 18 patients with chronic hepatic encephalopathy after portocaval shunt. Arch Fr Mal App Dig 1973;62: 293-302.
Corazza GR, Tacconi C, Zoli G, Somarolli M, D'Ambro A, Bernardi M. Use of pyridoxine-alpha-ketoglutarate (PAK) in hepatic encephalopathy. Int J Clin Pharmacol Res 1982;2: 7-13.
Uribe M, Campollo O, Vargas F, Ravelli GP, Mundo F, Zapata L. Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind, randomized clinical trial. Hepatology 1987;7: 639-43.
Watanabe A, Sakai T, Sato S, Imai F, Ohto M, Arakawa Y. Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 1997;26: 1410-4.
Shi H, Liu HY, Fu Z, Zhu L, Chen WZ. Lactitol in treatment of subclinical hepatic encephalopathy: a double blind placebo-controlled randomised trial . Chinese J Digestion 1997;17: 221-3.
Li Z, Zhang H, Hong Y. Clinical effect of lactulose in the treatment of subclinical hepatic encephalopathy. Zhongguo Zhong Xi Yi Jie He Za Zhi 1999;9: 13-5.
Dhiman RK, Sawhney MS, Chawla YK, Das G, Ram S, Dilawari JB. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Dig Dis Sci 2000;45: 1549-52.
Orlandi F, Freddara U, Candelaresi MT, Morettini A, Corazza GR, Di Simone A. Comparison between neomycin and lactulose in 173 patients with hepatic encephalopathy: a randomized clinical study. Dig Dis Sci 1981;26: 498-506.
Russo M, Galanti B, Nardiello S, Pizzella T, Ronga C, Giusti G. Ribostamycin for the treatment of hepatic encephalopathy: a crossover study with lactulose. Curr Ther Res Clin Exp 1989;45: 133-41.
Blanc P, Couderc M, Peray P, Liautard J, Larrey D, Michel H, et al. Lactitol versus vancomycin in the treatment of acute hepatic encephalopathy: a double blind, randomized trial . Gut 1993;34: 46.
Bucci L, Palmieri GC. Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy. Curr Med Res Opin 1993;13: 109-18.
Fera G, Agostinacchio F, Nigro M, Schiraldi O, Ferrieri A. Rifaximin in the treatment of hepatic encephalopathy. Rev Eur Etud Clin Biol 1993;4: 57-66.
Festi D, Mazzella G, Orsini M, Sottili S, Sangermano A, Li B. Rifaximin in the treatment of chronic hepatic encephalopathy; results of a multicenter study of efficacy and safety. Curr Ther Res Clin Exp 1993;54: 598-609.
Massa P, Vallerino E, Dodero M. Treatment of hepatic encephalopathy with rifaximin: double-blind, double dummy study versus lactulose. Eur J Clin Res 1993;4: 7-18.
Song H, Lee KS, Kim MH, Paik YH, Moon BS, Yoon SH. The clinical efficacy of rifaximin in the treatment of hepatic encephalopathy (comparison with lactulose) . Hepatology 2000;32: 407.
Loguercio C, Federico A, De Girolamo V, Ferrieri A, Del Vicchio BD. Cyclic treatment of chronic hepatic encephalopathy with rifaximin. Results of a double-blind clinical study. Minerva Gastroenterol Dietol 2003;49: 53-62.
Mas A, Rodes J, Sunyer L, Rodrigo L, Planas R, Vargas V. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol 2003;38: 51-8.
Jüni P, Altman D, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001;323: 42-6.
Weissenborn K. Minimal hepatic encephalopathy: a permanent source of discussion. Hepatology 2002;35: 494-6.
Conn HO. A clinical hepatologist's predictions about non-absorbed carbohydrates for the early twenty-first century. Scand J Gastroenterol Suppl 1997;222: 88-92.
Dawson AM, McLaren J, Sherlock S. Neomycin in the treatment of hepatic coma? Lancet 1957;273: 1263-8.
Strauss E, Tramote R, Silva EP, Caly WR, Honain NZ, Maffei RA. Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology 1992;39: 542-5.
Blanc P, Daures JP, Liautard J, Buttigieg R, Desprez D, Pageaux G. Lactulose-neomycin combination versus placebo in the treatment of acute hepatic encephalopathy. Results of a randomized controlled trial. Gastroenterol Clin Biol 1994;18: 1063-8.
Pocock SJ. The size of a clinical trial. In: Clinical trials: a practical approach. Chichester: John Wiley, 1983: 123-42.
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Kircheis G, Nilius R, Held C, Berndt H, Buchner M, Gortelmeyer R. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology 1997;25: 1351-60.
Stauch S, Kircheis G, Adler G, Beckh K, Ditschuneit H, Gortelmeyer R. Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study. J Hepatol 1998;28: 856-64.(Bodil Als-Nielsen, resear)
Correspondence to: B Als-Nielsen bodil.a@ctu.rh.dk
Abstract
Figure 1 summarises the literature search. We included 22 trials that assessed lactulose or lactitol versus placebo, no treatment, or antibiotics.5 6 20-39 Two trials were published as abstracts.32 37 The remaining were published as full articles. Eighteen trials used a parallel group design and four a crossover design. All trials were described as randomised, but adequate generation of the allocation sequence was described in only four.22 30 31 39 Treatment allocation was adequately concealed in 10 trials,5 6 20-23 26 30 36 39 double blinding was reported in 15 trials,5 6 20-25 27 32-34 36 38 39 and one trial had blinded outcome assessment.30 We classified nine trials as high quality.5 6 20-23 30 36 39
Fig 1 Selection process of eligible randomised trials from all identified references
Lactulose or lactitol v placebo or no intervention
Ten trials with 280 patients (75% men) assessed lactulose or lactitol versus placebo or no intervention (table 1).20-29 All patients had cirrhosis and acute,25 chronic,20 22-24 acute or chronic,21 or minimal hepatic encephalopathy.26-29 Eight trials assessed oral lactulose,20-24 26 28 29 one assessed oral lactitol,27 and one assessed lactitol enemas.25 The daily mean doses of lactulose ranged from 30 g to 84 g (median 50 g). In six trials the dose was adjusted to obtain two to three semisoft stools per day. The median duration of treatment was 15 days (range 5 to 360 days). None of the trials followed up patients after the end of treatment.
Table 1 Randomised trials of non-absorbable disaccharides versus placebo or no intervention in treatment of patients with hepatic encephalopathy
Trial results were homogeneous. Compared with placebo or no intervention, lactulose and lactitol seemed to reduce the risk of no improvement of hepatic encephalopathy (relative risk 0.62, 95% confidence interval 0.46 to 0.84, six trials; fig 2). This result was not robust when trials were stratified by quality. High quality trials found no significant effect of lactulose or lactitol on the risk of no improvement (0.92, 0.42 to 2.04, two trials; fig 2), whereas low quality trials found a significant beneficial effect of lactulose or lactitol (0.57, 0.40 to 0.83, four trials; fig 2). Although this difference in treatment response was not significant (P = 0.3 by test of interaction), it is noteworthy that the event rate in the control groups was significantly associated with quality of methods (high quality trials 38%, low quality trials 78%; P = 0.0005 with 2 test). The event rate in the experimental group was not significantly different in trials with high (35%) and low (43%) quality (P = 0.5 with 2 test). The treatment responses in acute, chronic, and minimal hepatic encephalopathy did not differ significantly. However, there was no significant effect of lactulose or lactitol on acute (0.27, 0.02 to 3.28, two trials) or chronic hepatic encephalopathy (1.33, 0.41 to 4.33, one trial). Trials in patients with minimal hepatic encephalopathy found that lactulose or lactitol significantly reduced the risk of no improvement assessed by various psychometric tests (0.61, 0.47 to 0.79, three trials). These trials were all of low methodological quality.
Fig 2 Number of patients without improvement of hepatic encephalopathy in trials on non-absorbable disaccharides versus placebo or no intervention, stratified according to quality of methods
Compared with placebo or no intervention, lactulose and lactitol had no significant effect on mortality (0.41, 0.02 to 8.68, four trials) or the number connection test result (weighted mean difference -9.0 seconds, -20.1 to 2.1, one trial) but tended to lower blood ammonia (-8.16 μmol/l, -16.44 μmol/l to 0.18 μmol/l, four trials). Data on adverse events were incompletely reported. Most trials mentioned adverse events associated only with non-absorbable disaccharides. We were therefore unable to perform a reliable meta-analysis of this outcome. None of the reported adverse events were serious, and all originated from the gastrointestinal tract (diarrhoea, flatulence, abdominal pain, or nausea).
Lactulose or lactitol versus antibiotics
Twelve trials with 698 patients (72% men) assessed lactulose or lactitol versus antibiotics (table 2).5 6 30-39 All patients had cirrhosis and acute,6 32 39 chronic,5 31 35 36 38 acute or chronic,30 or presumed chronic hepatic encephalopathy.33 34 37 Nine trials assessed oral lactulose,5 6 30 31 33-37 and three trials assessed oral lactitol.32 38 39 The daily mean dose of lactulose ranged from 30 g to 120 g (median 59 g) and of lactitol from 30 g to 60 g (median 60 g). The antibiotics were neomycin,5 6 30 ribostamycin,31 vancomycin,32 or rifaximin.33-39 The median duration of treatment was 15 days (range 5-90 days). One trial assessed all outcomes 15 days after the end of treatment,38 and one reported mortality 28 days after the end of treatment.39 All other trials followed the patients only to the end of treatment.
Table 2 Randomised trials on non-absorbable disaccharides versus antibiotics in treatment of patients with hepatic encephalopathy
Trial results were homogeneous. Compared with antibiotics, patients taking lactulose or lactitol had a significantly higher risk of no improvement of hepatic encephalopathy (1.24, 1.02 to 1.50, 10 trials; fig 3). We found no significant difference in response to treatment between aminoglycosides and rifaximin (P = 0.2 by test of interaction) or when trials were stratified by quality or type of hepatic encephalopathy. We found no significantly different effect on mortality between nonabsorbable disaccharides and antibiotics (0.90, 0.48 to 1.67, five trials) or on adverse events (1.62, 0.57 to 4.58, eight trials). None of the reported adverse events were serious, and all originated from the gastrointestinal tract (diarrhoea, flatulence, abdominal pain, or nausea). Compared with antibiotics, patients on lactulose or lactitol took on average six more seconds to complete the number connection test (weighted mean difference 6.4 seconds, 1.4 seconds to 11.3 seconds, six trials) and had higher blood ammonia concentrations (2.35 μmol/l, 0.06 μmol/l to 4.64 μmol/l, 10 trials).
Fig 3 Number of patients without improvement of hepatic encephalopathy in trials on non-absorbable disaccharides versus antibiotics, stratified according to type of antibiotic
Discussion
We did not find sufficient evidence to determine whether lactulose or lactitol have a significant beneficial effect on patients with hepatic encephalopathy. In our overall analysis non-absorbable disaccharides seemed to improve encephalopathy, but this effect was seen in only low quality trials.
The beneficial effect in low quality trials was related to significantly worse rates of improvement in the control group. This finding concurs with empirical evidence showing that low quality trials exaggerate the beneficial effects of treatment.15 16 40 Accordingly, the overall result may reflect bias because of the low methodological quality of most of the included trials. Our results may also be inflated by publication bias.
We found no significant effect of non-absorbable disaccharides on acute or chronic hepatic encephalopathy. Only low quality trials in patients with minimal hepatic encephalopathy found that lactulose had a beneficial effect, as assessed by various non-validated psychometric tests. The clinical relevance of these tests is uncertain.41
Lactulose has been used as the standard treatment for hepatic encephalopathy, and its efficacy has been considered to be beyond doubt.2 7 24 25 42 However, when it was introduced, the few trials that compared lactulose against placebo found no beneficial effect of lactulose.21 23 It was implemented in clinical practice because two trials found it "equally effective" to neomycin,5 6 which had been the standard treatment for hepatic encephalopathy since 1957.43 There are two major pitfalls in this reasoning. Firstly, the efficacy of neomycin in hepatic encephalopathy has never been shown. We identified only one randomised trial that compared neomycin with placebo44 and one that compared neomycin plus lactulose with placebo,45 both for acute hepatic encephalopathy. Both trials found no significant beneficial effects of neomycin. Secondly, lactulose was considered as equally effective to neomycin because event rates in intervention groups were not significantly different.5 6 However, lack of statistical significance does not imply that treatments have equal effects.46 Both trials were small,5 6 and neither reported sample size calculations based on an equivalence hypothesis or stated a margin of equivalence.46 47 It would require a far larger sample size than these two trials (a total of 78 patients) to establish with confidence that lactulose and neomycin have comparable effects.
Later on, new trials compared other antibiotics to non-absorbable disaccharides for hepatic encephalopathy. None was set up as an equivalence trial. Sample size calculations with statements implying an equivalence hypothesis or a margin of equivalence were not reported in any of the trials. All were underpowered to show equivalence. Nevertheless, all trials concluded equivalence from the lack of statistical significance.30-39 It seems that the research was continuously building up on both insufficient evidence and inadequate methods. Our analyses indicate that antibiotics are statistically superior to non-absorbable disaccharides in improving hepatic encephalopathy and lowering blood ammonia concentrations. However, it is unclear whether the effects are clinically important. Considering this, the lack of effect of antibiotics in placebo controlled trials,44 45 the risk of multiresistance,48 and the potential risk of severe adverse events5 lead us to conclude that there is insufficient evidence to recommend the use of antibiotics for hepatic encephalopathy.
Mechanisms
When assessing intervention effects for hepatic encephalopathy, it is important to consider the fluctuating course as well as the impact of treating precipitating factors in acute hepatic encephalopathy. Well conducted placebo controlled trials on the use of ornithine aspartate in patients with minimal or chronic hepatic encephalopathy49 50 and lactulose plus neomycin45 in those with acute hepatic encephalopathy found improvement rates in the placebo group ranging from 40% to 70%. Many clinicians claim to have witnessed beneficial effects of nonabsorbable disaccharides on patients with hepatic encephalopathy. This effect may represent a high rate of spontaneous improvement and successful treatment of precipitating factors.
Implications
Non-absorbable disaccharides seem to have been introduced into clinical practice without appropriate documentation. This leads to at least three major problems. Firstly, patients are given a treatment of uncertain efficacy. It might be beneficial; it might be unfavourable. Secondly, there is reluctance towards performing randomised trials to assess lactulose or lactitol versus placebo because it is considered unethical. Thirdly, most randomised trials on new treatments for hepatic encephalopathy use lactulose as comparator. New treatments are considered effective if improvement rates do not differ significantly from the group treated with lactulose, although trials are vastly underpowered to show equivalence. This approach is most problematic. Nonabsorbable disaccharides should not serve as comparator in randomised trials on hepatic encephalopathy until other trials have shown that lactulose or lactitol has any beneficial effect on hepatic encephalopathy.
What is already known on this topic
Non-absorbable disaccharides are considered standard treatment for hepatic encephalopathy
Non-absorbable disaccharides serve as control treatment in most trials of new drugs for hepatic encephalopathy
What this study adds
There is insufficient evidence to determine whether non-absorbable disaccharides are of benefit to patients with hepatic encephalopathy
Antibiotics seem superior to non-absorbable disaccharides in improving hepatic encephalopathy, but it is unclear whether this difference is clinically important
Non-absorbable disaccharides should not be used as the comparator in randomised trials on hepatic encephalopathy
We thank the patients who took part in the reviewed trials; the researchers who provided us with additional information; J?rgen Hilden, department of biostatistics, University of Copenhagen, for statistical support; and Peter G?tzsche, Nordic Cochrane Centre, for valuable comments on an earlier draft of this review. This review is an abbreviated version of a Cochrane systematic review. The full version will be published in the Cochrane Library 2004, Issue 2. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Library should be consulted for the most recent version of the review.
Contributors: BA-N drafted the protocol and paper, performed the literature searches, identified trials, extracted data, and performed the statistical analyses. LLG identified trials and extracted data. All reviewers contributed to the writing of the protocol and review and all have approved of the final version. BA-N is guarantor.
Funding: Danish Centre for Evaluation and Health Technology Assessment (DACEHTA), Danish Medical Research Council, and Copenhagen Hospital Corporation's Medical Research Council.
Competing interests: None declared.
Ethical approval: Not required.
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