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Meta-Analysis
. 2012 Jan 18;1(1):CD009145.
doi: 10.1002/14651858.CD009145.pub2.

Bezafibrate for primary biliary cirrhosis

Jelena S Rudic  1 , Goran Poropat, Miodrag N Krstic, Goran Bjelakovic, Christian Gluud
Affiliations
Meta-Analysis

Bezafibrate for primary biliary cirrhosis

Jelena S Rudic et al. Cochrane Database Syst Rev. .

Abstract

Background: Treatment of primary biliary cirrhosis is complicated. There are studies suggesting that bezafibrate, alone or in combination with ursodeoxycholic acid (UDCA), is effective in the treatment of primary biliary cirrhosis, but no systematic review has summarised the evidence yet.

Objectives: To assess the beneficial and harmful effects of bezafibrate in patients with primary biliary cirrhosis.

Search methods: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, Clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011. The searches in Chinese Bio-medical Literature Database, China Network Knowledge Information, Chinese Science Journal Database, Chinese Medical Citation Index, Wanfang Database, and full text searches were conducted until January 2011. Manufacturers and authors were contacted.

Selection criteria: All randomised clinical trials comparing bezafibrate at any dose or regimen in patients with primary biliary cirrhosis with placebo or no intervention, or with another drug. Any concomitant interventions were allowed if received equally by all treatment groups in a trial.

Data collection and analysis: Two authors extracted data. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD), and of continuous data with mean difference (MD), both with 95% confidence intervals (CI). Methodological domains were used to assess risk of systematic errors (bias). Trial sequential analysis was used to control for random errors (play of chance).

Main results: Six trials with 151 Japanese patients were included. All trials had high risk of bias. Four trials compared bezafibrate plus UDCA with no intervention plus UDCA (referenced as bezafibrate versus no intervention in the remaining text), and two trials compared bezafibrate with UDCA. No patient died and no patient developed liver-related complications in any of the included trials. Bezafibrate was without significant effects on the occurrence of adverse events compared with no intervention (5/32 (16%) versus 0/28 (0%)) (RR 5.40, 95% CI 0.69 to 42.32; 3 trials with 60 patients; I² = 0%) or with UDCA (2/32 (6%) versus 0/37 (0%)) (RR 6.19, 95% CI 0.31 to 122.05; 2 trials with 69 patients; I² = 0%). Bezafibrate significantly decreased the activity of serum alkaline phosphatases compared with no intervention (MD -186.04 U/L, 95% CI -249.03 to -123.04; 4 trials with 79 patients; I² = 34%) and when compared with UDCA (MD -162.90 U/L, 95% CI -199.68 to -126.12; 2 trials with 48 patients; I² = 0%). These results were supported by trial sequential analyses. Bezafibrate compared with no intervention significantly decreased plasma immunoglobulin M (MD -164.00 mg/dl, 95% CI -259.47 to -68.53; 3 trials with 50 patients; I² = 46%) and serum bilirubin concentration (MD -0.19 mg/dl, 95% CI -0.38 to -0.00; 2 trials with 34 patients; I² = 0%). However, the latter two results were not supported by trial sequential analyses. Bezafibrate compared with no intervention had no significant effect on the activity of serum gamma-glutamyltransferase (MD -1.22 U/L, 95% CI -11.97 to 9.52; 4 trials with 79 patients; I² = 42%) and serum alanine aminotransferase (MD -5.61 U/L, 95% CI -24.50 to 13.27; 2 trials with 35 patients; I² = 34%). Bezafibrate compared with UDCA had no significant effect on the activity of serum gamma-glutamyltransferase (MD 38.44 U/L, 95% CI -180.67 to 257.55; 2 trials with 49 patients; I² = 89%), serum alanine aminotransferase (MD -2.34 U/L, 95% CI -34.73 to 30.06; 2 trials with 49 patients; I² = 95%), and plasma immunoglobulin M concentration (MD -20.23 mg/dl, 95% CI -218.71 to 178.25; 2 trials with 41 patients; I² = 90%) in random-effects model meta-analyses, but bezafibrate significantly decreased the activity of serum gamma-glutamyltransferase (MD -58.18, 95% CI -76.49 to -39.88; 2 trials with 49 patients; I² = 89%), serum alanine aminotransferase (MD -13.94, 95% CI -18.78 to -9.09; 2 trials with 49 patients; I² = 95%), and plasma immunoglobulin M concentration (MD -99.90, 95% CI -130.72 to -69.07; 2 trials with 41 patients; I² = 90%) in fixed-effect model meta-analyses. One patient had bezafibrate withdrawn due to an adverse event compared to no intervention (RD 0.03, 95% CI -0.09 to 0.16; 2 trials with 60 patients; I² = 0%).

Authors' conclusions: This systematic review did not demonstrate any effect of bezafibrate versus no intervention on mortality, liver-related morbidity, adverse events, and pruritus in patients with primary biliary cirrhosis. Furthermore, we found no significant effects of bezafibrate on mortality, liver-related morbidity, or adverse events when compared with ursodeoxycholic acid, None of the trials assessed quality of life or fatigue. The data seem to indicate a possible positive intervention effect of bezafibrate on some liver biochemistry measures compared with the control group, but the observed effects could be due to systematic errors or random errors. We need more randomised clinical trials on the effects of bezafibrate on primary biliary cirrhosis with low risks of systematic errors and random errors.

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Conflict of interest statement

None known.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Figure 4. Trial sequential analysis of the cumulative meta‐analysis of the effect of bezafibrate versus no intervention on the activity of serum alkaline phosphatases in patients with primary biliary cirrhosis. The diversity‐adjusted required information size (DARIS) of 216 patients is calculated based on a minimal relevant intervention effect (MIREDIF) of 100 U/L, a standard deviation of 200 U/L, a risk of type I error of 5%, a power of 80%, and a diversity of 41%. The cumulated Z‐curve (blue curve) crosses the trial sequential monitoring boundary (red curve) implying that there is firm evidence for a beneficial effect of 100 U/L decrease in the activity of serum alkaline phosphatases when the cumulative meta‐analysis is adjusted for sparse data and multiple testing on accumulating data.
5
5
Figure 5. Trial sequential analysis of the cumulative meta‐analysis of the effect of bezafibrate versus no intervention on concentration of plasma immunoglobulin M in patients with primary biliary cirrhosis. The diversity‐adjusted required information size (DARIS) of 239 patients is calculated based on a minimal relevant intervention effect (MIREDIF) of 121.5 mg/dl, a standard deviation of 243 mg/dl, a risk of type I error of 5%, a power of 80%, and a diversity of 47%. The cumulated Z‐curve (blue curve) does not cross the trial sequential monitoring boundary implying that there is no firm evidence for a beneficial effect of 121.5 mg/dl decrease in plasma immunoglobulin M concentration when the cumulative meta‐analysis is adjusted for sparse data and multiple testing on accumulating data.
6
6
Figure 6. Trial sequential analysis of the cumulative meta‐analysis of the effect of bezafibrate versus no intervention on concentration of serum bilirubin concentration in patients with primary biliary cirrhosis. The diversity‐adjusted required information size (DARIS) of 126 patients is calculated based on a minimal relevant intervention effect (MIREDIF) of 0.20 mg/dl, a standard deviation of 0.40 mg/dl, a risk of type I error of 5%, a power of 80%, and a diversity of 0%. The cumulated Z‐curve (blue curve) does not cross the trial sequential monitoring boundary implying that there is no firm evidence for a potentially beneficial effect of 0.20 mg/dl decrease in serum bilirubin concentration when the cumulative meta‐analysis is adjusted for sparse data and multiple testing on accumulating data.
7
7
Figure 7. Trial sequential analysis of the cumulative meta‐analysis of the effect of bezafibrate versus ursodeoxycholic acid on the activity of serum alkaline phosphatases in patients with primary biliary cirrhosis. The diversity‐adjusted required information size (DARIS) of 127 patients is calculated based on a minimal relevant intervention effect (MIREDIF) of 45.5 U/L, a standard deviation of 91 U/L, a risk of type I error of 5%, a power of 80%, and a diversity of 0%. The cumulated Z‐curve (blue curve) crosses the trial sequential monitoring boundary (red curve) implying that there is firm evidence for a beneficial effect of 45.5 U/L decrease in the activity of serum alkaline phosphatases when the cumulative meta‐analysis is adjusted for sparse data and multiple testing on accumulating data.
1.1
1.1. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 1 All‐cause mortality.
1.2
1.2. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 2 Liver morbidity.
1.3
1.3. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 3 Adverse events.
1.4
1.4. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 4 Pruritus.
1.5
1.5. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 5 Serum alkaline phosphatases (U/L).
1.6
1.6. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 6 Serum gamma‐glutamyltransferase (U/L).
1.7
1.7. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 7 Serum alanine aminotransferase (U/L).
1.8
1.8. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 8 Plasma immunoglobulin M (mg/dl).
1.9
1.9. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 9 Total cholesterol (mg/dl).
1.10
1.10. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 10 Triglycerides (mg/dl).
1.11
1.11. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 11 Serum bilirubin (mg/dl).
1.12
1.12. Analysis
Comparison 1 Bezafibrate vs no intervention, Outcome 12 Number of patients having bezafibrate withdrawn due to adverse events.
2.1
2.1. Analysis
Comparison 2 Bezafibrate vs ursodeoxycholic acid, Outcome 1 All‐cause mortality.
2.2
2.2. Analysis
Comparison 2 Bezafibrate vs ursodeoxycholic acid, Outcome 2 Liver morbidity.
2.3
2.3. Analysis
Comparison 2 Bezafibrate vs ursodeoxycholic acid, Outcome 3 Adverse events.
2.4
2.4. Analysis
Comparison 2 Bezafibrate vs ursodeoxycholic acid, Outcome 4 Serum alkaline phosphatases (U/L).
2.5
2.5. Analysis
Comparison 2 Bezafibrate vs ursodeoxycholic acid, Outcome 5 Serum gamma‐glutamyltransferase (U/L).
2.6
2.6. Analysis
Comparison 2 Bezafibrate vs ursodeoxycholic acid, Outcome 6 Serum alanine aminotransferase (U/L).
2.7
2.7. Analysis
Comparison 2 Bezafibrate vs ursodeoxycholic acid, Outcome 7 Plasma immunoglobulin M (mg/dl).
2.8
2.8. Analysis
Comparison 2 Bezafibrate vs ursodeoxycholic acid, Outcome 8 Number of patients having bezafibrate withdrawn due to adverse effects.
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Update of

  • doi: 10.1002/14651858.CD009145

References

References to studies included in this review

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