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Hepatology Research 2014
doi: 10.1111/hepr.12373
Review Article
Combination therapy of bezafibrate and ursodeoxycholic acid for primary biliary cirrhosis: A meta-analysis Yan Zhang,1* Kan Chen,1* Weiqi Dai,1 Yujing Xia,1 Fan Wang,1 Miao Shen,1 Ping Cheng,1 Chengfen Wang,1 Jing Yang,1 Rong Zhu,2 Huawei Zhang,3 Jingjing Li,1 Yuanyuan Zheng,1 Junshan Wang,1 Jie Lu,1 Yingqun Zhou1 and Chuanyong Guo1 1
Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Department of Gastroenterology, Clinical Medical College of Shanghai Tenth People’s Hospital of Nanjing Medical University, Shanghai, and 3Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China 2
The aim of this study was to assess the efficiency and safety of combination therapy of ursodeoxycholic acid (UDCA) and bezafibrate for primary biliary cirrhosis. A meta-analysis of all long-term randomized controlled trials comparing the combination of UDCA and bezafibrate with UDCA monotherapy was performed via electronic searches. Seven trials, which included 177 patients, were assessed. Combination therapy with UDCA and bezafibrate was more effective than UDCA monotherapy in improving liver biochemistry, alkaline phosphatase (mean difference [MD], −146.15 IU/L; 95% confidence interval [CI], −193.58 to −98.72; P < 0.00001), γ-glutamyltransferase (MD, −20.64 IU/L; 95% CI, −30.86 to −10.43; P < 0.0001), immunoglobulin M (MD, −90.96 mg/dL; 95% CI, −137.36 to −44.56; P = 0.0001) and triglycerides (MD, −15.49 mg/dL; 95% CI, −30.25 to −0.74; P = 0.04). However, their effects on pruritus (odds ratio [OR], 0.82; 95% CI, 0.30–
2.24; P = 0.70) and alanine aminotransferase (MD, −8.41 IU/L; 95% CI, −22.57 to 5.75; P = 0.24) did not differ significantly. This meta-analysis revealed no significant differences in the incidence of all-cause mortality (OR, 0.72; 95% CI, 0.10–5.49; P = 0.75) and adverse events (OR, 0.35; 95% CI, 0.07–1.84; P = 0.22) between patients treated with combination therapy and those treated with monotherapy. In this meta-analysis, combination therapy with UDCA and bezafibrate was more effective than UDCA monotherapy. Combination therapy improved liver biochemistry, but did not improve clinical symptoms, incidence of death or adverse events more effectively than monotherapy.
INTRODUCTION
leading to liver failure.1,2 Ursodeoxycholic acid (UDCA) is currently the only US Food and Drug Administration approved drug and the 2000 American Association for the Study of Liver Diseases Practice Guidelines recommend UDCA for the treatment of PBC.3 UDCA therapy for PBC is very effective, and can improve clinical symptoms and liver function abnormality indicators, delay histological progression, improve quality of life, prolong survival and has a good safety record. However, many patients with PBC are resistant to UDCA and do not show a significant improvement in liver function.4,5 Therefore, alternative effective treatments are required for these patients. Bezafibrate is a peroxisome proliferator-activated receptor-α (PPAR-α) agonist and is involved in immune function and inflammation control.6,7 Studies have found that in UDCA-resistant patients with PBC treated
P
RIMARY BILIARY CIRRHOSIS (PBC) is a chronic progressive inflammatory autoimmune-mediated cholestatic disease which primarily occurs in elderly women. It is characterized by intrahepatic bile ducts and non-suppurative inflammation, and the subsequent development of liver fibrosis and cirrhosis, eventually
Correspondence: Professor Chuanyong Guo, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China. Email: [email protected] *These authors contributed equally to this paper. Conflict of interest: The authors declare that they have no competing interests. Received 11 April 2014; revision 25 May 2014; accepted 11 June 2014.
© 2014 The Japan Society of Hepatology
Key words: bezafibrate, meta-analysis, primary biliary cirrhosis, ursodeoxycholic acid
1
2
Y. Zhang et al.
with bezafibrate monotherapy, a good effect can be achieved in 50% of these patients. Other researchers reported that combination therapy with UDCA and bezafibrate can improve biochemical and immunological indicators to normal levels, and significantly improve clinical symptoms without side-effects.8–10 The proposal that PBC can only be effectively treated with UDCA combined with bezafibrate therapy is still controversial. Therefore, we conducted a meta-analysis, with suitable inclusion and exclusion criteria, to evaluate the efficacy and safety of combination therapy with UDCA and bezafibrate compared to UDCA monotherapy in patients with PBC.
METHODS Study identification
R
ELEVANT STUDIES WERE identified and selected by searching PubMed, Cochrane Library, EMBASE and CINAHL databases, and the Science Citation Index (updated to September 2013) using the search terms “ursodeoxycholic acid”, “bezafibrate”, “PBC” and “randomized controlled trial”.11 We also carried out a full manual search of all review articles, retrieved original studies and abstracts.
Inclusion criteria The following selection criteria were applied: 1 Study design: randomized controlled trials (RCT) comparing combination therapy with UDCA/ bezafibrate and monotherapy with UDCA 2 Study population: the diagnosis of PBC was made on the basis of any two of the following criteria: (i) positive test for antimitochondrial antibody (AMA); (ii) biochemical evidence of cholestasis; and/or (iii) liver biopsy compatible with the diagnosis.12 3 Duplicated publications were excluded and no language or date limitations were imposed. There was also no limitation on the form of publication.
Data extraction Data were independently abstracted from each study by two researchers (Yan Zhang and Kan Chen) and any disagreement was resolved by consensus. The following data were extracted from each included article: name of the first author, year of publication, number of patients, daily dose of oral therapy, duration of treatment, method used to deal with missing data, liver biochemistry, symptoms, death and adverse events.
© 2014 The Japan Society of Hepatology
Hepatology Research 2014
Assessment of risk of bias in included studies Numerous tools are available for assessing the methodological quality of clinical trials. According to the Cochrane Handbook 5.0.2, The Cochrane Collaboration recommends a specific tool for assessing risk of bias in each included study.13,14 This comprises a description and a judgment for each entry in a “risk of bias” table, where each entry addresses a specific feature of the study. For parallel group trials, the features of interest in a standard “risk of bias” table of a Cochrane review are allocation sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other potential sources of bias (Table 1). The judgment for each entry involves answering a question, with answers “low risk of bias”, “high risk of bias” and “unclear risk of bias”. Any disagreement was resolved by consensus.
Statistical analyses All analyses were performed with RevMan 5.2 (The Nordic Cochrane Center, The Cochrane Collaboration, 2012). For dichotomous outcomes, we calculated the odds ratio (OR) and/or risk difference (RD), and for continuous outcomes the mean difference (MD), all with 95% confidence intervals (CI). We tested heterogeneity using the χ2-test and the I2-test, and a P-value of less than 0.10 or an I2-value of more than 50% was considered to indicate substantial heterogeneity. A fixed-effects model was used when the heterogeneity test showed a P-value of more than 0.10 and an I2-value of less than 50%; otherwise, a random-effects model was used. We also constructed funnel plots to evaluate the presence of publication bias.
RESULTS Descriptive and qualitative assessments
F
ROM 147 STUDIES, we finally selected seven RCT (Fig. 1).15–21 These studies involved 177 patients: 93 were randomized to the UDCA monotherapy groups and 84 to the combination therapy (UDCA and bezafibrate) groups. The baseline characteristics of the seven trials are listed in Table 2. The mean age ranged 54–64 years and the mean follow-up interval ranged 6–24 months. The daily dose of UDCA ranged 600– 900 mg/day, and the daily dose of bezafibrate was 400 mg/day. Six trials were published as full text articles.16–21 One trial was published as an abstract and
Hepatology Research 2014
Meta-analysis of bezafibrate and UDCA for PBC 3
Table 1 Criteria used to assess risk of bias in included studies Trials assessed as having “low risk of bias” in all the specified individual domains were considered “trials with low risk of bias”. Trials assessed as having “uncertain risk of bias” or “high risk of bias” in one or more of the specified individual domains were considered “trials with high risk of bias”. Allocation sequence generation Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards and throwing dice are adequate if performed by an independent adjudicator. Unclear risk of bias: the trial is described as randomized, but the method of sequence generation was not specified. High risk of bias: the sequence generation method is not, or may not be, random. Quasi-randomized studies, those using dates, names or admittance numbers in order to allocate patients are inadequate and will be excluded for the assessment of benefits, but not for harms. Allocation concealment Low risk of bias: allocation was controlled by a central and independent randomization unit, sequentially numbered, opaque and sealed envelopes or similar, so that intervention allocations could not have been foreseen in advance of, or during, enrolment. Unclear risk of bias: the trial was described as randomized, but the method used to conceal the allocation was not described, so that intervention allocations might have been foreseen in advance of, or during, enrolment. High risk of bias: if the allocation sequence was known to the investigators who assigned patients or if the study was quasi-randomized. Quasi-randomized studies will be excluded for the assessment of benefits, but not for harms. Blinding Low risk of bias: the trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial. Unclear risk of bias: the trial was described as blind, but the method of blinding was not described, so that knowledge of allocation was possible during the trial. High risk of bias, the trial was not blinded, so that the allocation was known during the trial. Incomplete outcome data Low risk of bias: the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals. Unclear risk of bias: the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated. High risk of bias: the number or reasons for dropouts and withdrawals were not described. Selective outcome reporting Low risk of bias: pre-defined, or clinically relevant and reasonably expected outcomes are reported on. Unclear risk of bias: not all pre-defined, or clinically relevant and reasonably expected outcomes are reported on or are not reported fully, or it is unclear whether data on these outcomes were recorded or not. High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported on; data on these outcomes were likely to have been recorded. Other bias Low risk of bias: the trial appears to be free of other components that could increase risk of bias. Unclear risk of bias: the trial may or may not be free of other components that could increase risk of bias. High risk of bias: there are other factors in the trial that could increase risk of bias (e.g. for-profit involvement, authors have conducted trials on the same topic).
as a letter to the editor.15 The results of the meta-analysis are shown in Table 3.
Evaluation of the effects of therapy Three RCT reported the impact of treatment on the patients’ symptoms, and demonstrated an improvement in pruritus.16,17,20 All the included studies concluded that
the combination therapy significantly improved liver function and reduced the serum levels of alkaline phosphatase (ALP), γ-glutamyltransferase (γ-GT) and immunoglobulin (Ig)M. Six studies also reported adverse effects (myalgia, polydipsia, aggravated pruritus and arthritis), however, no serious adverse events were reported.15–20
© 2014 The Japan Society of Hepatology
4
Y. Zhang et al.
Hepatology Research 2014
147 identified studies from the databases 58 excluded for duplication 89 potentially relevant studies
66 excluded titles and abstract were not relevant for the end point of the study 23 full-text articles reviewed
16 studies excluded: 5 case report 6 combined with other therapies 5 no controls
7 articles included in the meta-analysis
Figure 1 Flow diagram of the studies included in the meta-analysis.
Meta-analysis 1 Pruritus: three trials, which included 75 patients, reported data regarding this end-point. Symptomsimproved in 13 of 42 patients in the monotherapy groups and in 12 of 33 patients in the combination therapy groups.16,17,20 There was no significant heterogeneity (P = 0.96, I2 = 0%) and no significant differences between the groups (OR, 0.82; 95% CI, 0.30–2.24; P = 0.70; Fig. 2). 2 ALP levels: seven trials, which included 177 patients, reported data regarding this end-point.15–21 Combi-
nation therapy with UDCA and bezafibrate was more effective than UDCA monotherapy in decreasing serum ALP (MD, −146.15 IU/L; 95% CI, −193.58 to −98.72; P < 0.00001; Fig. 3). There was no significant heterogeneity (P = 0.20, I2 = 30%). 3 γ-GT levels: six trials, which included 140 patients, reported data regarding this end-point.15–19,21 Combination therapy significantly decreased serum γ-GT compared with UDCA monotherapy (MD, −20.64 IU/L; 95% CI, −30.86 to −10.43; P < 0.0001;
Table 2 Baseline characteristics of the trials included in the meta-analysis First author, year
Mean age (years)
Monotherapy (n)
Combination therapy (n)
UDCA dose (mg/day)
Bezafibrate dose (mg/day)
Duration of treatment, months
Publication type
Nakai, 2000 Kanda, 2003 Itakura, 2004 Iwasaki, 2008 Hazzan, 2010 Takeuchi, 2011 Honda, 2013
58 56 57 54 64 57 58
13 11 7 10 8 22 22
10 11 9 12 8 15 19
600 600 600 600 900–1500 600 600
400 400 400 400 400 400 400
12 6 6 12 24 24 6
Letter Full text Full text Full text Full text Full text Full text
UDCA, ursodeoxycholic acid.
© 2014 The Japan Society of Hepatology
Hepatology Research 2014
Meta-analysis of bezafibrate and UDCA for PBC 5
Table 3 Meta-analysis of clinical events and biochemical parameter changes in the included studies Outcome title
No. of studies
No. of participants
Pruritus
3
75
Mortality
5
120
Adverse events
7
177
Alkaline phosphatase
7
177
γ-Glutamyltransferase
6
140
Immunoglobulin M
6
161
Alanine aminotransferase
3
75
Triglycerides
5
132
Statistical method Odds ratio (M-H, fixed, 95% CI) Odds ratio (M-H, fixed, 95% CI) Odds ratio (M-H, fixed, 95% CI) Mean difference (IV, fixed, 95% CI) Mean difference (IV, fixed, 95% CI) Mean difference (IV, fixed, 95% CI) Mean difference (IV, fixed, 95% CI) Mean difference (IV, fixed, 95% CI)
Effect size
P-value
0.82 (0.30–2.24)
0.70
0.72 (0.10–5.49)
0.75
0.35 (0.07–1.84)
0.22
−146.15 (−193.58 to −98.72)
Hepatology Research 2014
doi: 10.1111/hepr.12373
Review Article
Combination therapy of bezafibrate and ursodeoxycholic acid for primary biliary cirrhosis: A meta-analysis Yan Zhang,1* Kan Chen,1* Weiqi Dai,1 Yujing Xia,1 Fan Wang,1 Miao Shen,1 Ping Cheng,1 Chengfen Wang,1 Jing Yang,1 Rong Zhu,2 Huawei Zhang,3 Jingjing Li,1 Yuanyuan Zheng,1 Junshan Wang,1 Jie Lu,1 Yingqun Zhou1 and Chuanyong Guo1 1
Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Department of Gastroenterology, Clinical Medical College of Shanghai Tenth People’s Hospital of Nanjing Medical University, Shanghai, and 3Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China 2
The aim of this study was to assess the efficiency and safety of combination therapy of ursodeoxycholic acid (UDCA) and bezafibrate for primary biliary cirrhosis. A meta-analysis of all long-term randomized controlled trials comparing the combination of UDCA and bezafibrate with UDCA monotherapy was performed via electronic searches. Seven trials, which included 177 patients, were assessed. Combination therapy with UDCA and bezafibrate was more effective than UDCA monotherapy in improving liver biochemistry, alkaline phosphatase (mean difference [MD], −146.15 IU/L; 95% confidence interval [CI], −193.58 to −98.72; P < 0.00001), γ-glutamyltransferase (MD, −20.64 IU/L; 95% CI, −30.86 to −10.43; P < 0.0001), immunoglobulin M (MD, −90.96 mg/dL; 95% CI, −137.36 to −44.56; P = 0.0001) and triglycerides (MD, −15.49 mg/dL; 95% CI, −30.25 to −0.74; P = 0.04). However, their effects on pruritus (odds ratio [OR], 0.82; 95% CI, 0.30–
2.24; P = 0.70) and alanine aminotransferase (MD, −8.41 IU/L; 95% CI, −22.57 to 5.75; P = 0.24) did not differ significantly. This meta-analysis revealed no significant differences in the incidence of all-cause mortality (OR, 0.72; 95% CI, 0.10–5.49; P = 0.75) and adverse events (OR, 0.35; 95% CI, 0.07–1.84; P = 0.22) between patients treated with combination therapy and those treated with monotherapy. In this meta-analysis, combination therapy with UDCA and bezafibrate was more effective than UDCA monotherapy. Combination therapy improved liver biochemistry, but did not improve clinical symptoms, incidence of death or adverse events more effectively than monotherapy.
INTRODUCTION
leading to liver failure.1,2 Ursodeoxycholic acid (UDCA) is currently the only US Food and Drug Administration approved drug and the 2000 American Association for the Study of Liver Diseases Practice Guidelines recommend UDCA for the treatment of PBC.3 UDCA therapy for PBC is very effective, and can improve clinical symptoms and liver function abnormality indicators, delay histological progression, improve quality of life, prolong survival and has a good safety record. However, many patients with PBC are resistant to UDCA and do not show a significant improvement in liver function.4,5 Therefore, alternative effective treatments are required for these patients. Bezafibrate is a peroxisome proliferator-activated receptor-α (PPAR-α) agonist and is involved in immune function and inflammation control.6,7 Studies have found that in UDCA-resistant patients with PBC treated
P
RIMARY BILIARY CIRRHOSIS (PBC) is a chronic progressive inflammatory autoimmune-mediated cholestatic disease which primarily occurs in elderly women. It is characterized by intrahepatic bile ducts and non-suppurative inflammation, and the subsequent development of liver fibrosis and cirrhosis, eventually
Correspondence: Professor Chuanyong Guo, Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China. Email: [email protected] *These authors contributed equally to this paper. Conflict of interest: The authors declare that they have no competing interests. Received 11 April 2014; revision 25 May 2014; accepted 11 June 2014.
© 2014 The Japan Society of Hepatology
Key words: bezafibrate, meta-analysis, primary biliary cirrhosis, ursodeoxycholic acid
1
2
Y. Zhang et al.
with bezafibrate monotherapy, a good effect can be achieved in 50% of these patients. Other researchers reported that combination therapy with UDCA and bezafibrate can improve biochemical and immunological indicators to normal levels, and significantly improve clinical symptoms without side-effects.8–10 The proposal that PBC can only be effectively treated with UDCA combined with bezafibrate therapy is still controversial. Therefore, we conducted a meta-analysis, with suitable inclusion and exclusion criteria, to evaluate the efficacy and safety of combination therapy with UDCA and bezafibrate compared to UDCA monotherapy in patients with PBC.
METHODS Study identification
R
ELEVANT STUDIES WERE identified and selected by searching PubMed, Cochrane Library, EMBASE and CINAHL databases, and the Science Citation Index (updated to September 2013) using the search terms “ursodeoxycholic acid”, “bezafibrate”, “PBC” and “randomized controlled trial”.11 We also carried out a full manual search of all review articles, retrieved original studies and abstracts.
Inclusion criteria The following selection criteria were applied: 1 Study design: randomized controlled trials (RCT) comparing combination therapy with UDCA/ bezafibrate and monotherapy with UDCA 2 Study population: the diagnosis of PBC was made on the basis of any two of the following criteria: (i) positive test for antimitochondrial antibody (AMA); (ii) biochemical evidence of cholestasis; and/or (iii) liver biopsy compatible with the diagnosis.12 3 Duplicated publications were excluded and no language or date limitations were imposed. There was also no limitation on the form of publication.
Data extraction Data were independently abstracted from each study by two researchers (Yan Zhang and Kan Chen) and any disagreement was resolved by consensus. The following data were extracted from each included article: name of the first author, year of publication, number of patients, daily dose of oral therapy, duration of treatment, method used to deal with missing data, liver biochemistry, symptoms, death and adverse events.
© 2014 The Japan Society of Hepatology
Hepatology Research 2014
Assessment of risk of bias in included studies Numerous tools are available for assessing the methodological quality of clinical trials. According to the Cochrane Handbook 5.0.2, The Cochrane Collaboration recommends a specific tool for assessing risk of bias in each included study.13,14 This comprises a description and a judgment for each entry in a “risk of bias” table, where each entry addresses a specific feature of the study. For parallel group trials, the features of interest in a standard “risk of bias” table of a Cochrane review are allocation sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other potential sources of bias (Table 1). The judgment for each entry involves answering a question, with answers “low risk of bias”, “high risk of bias” and “unclear risk of bias”. Any disagreement was resolved by consensus.
Statistical analyses All analyses were performed with RevMan 5.2 (The Nordic Cochrane Center, The Cochrane Collaboration, 2012). For dichotomous outcomes, we calculated the odds ratio (OR) and/or risk difference (RD), and for continuous outcomes the mean difference (MD), all with 95% confidence intervals (CI). We tested heterogeneity using the χ2-test and the I2-test, and a P-value of less than 0.10 or an I2-value of more than 50% was considered to indicate substantial heterogeneity. A fixed-effects model was used when the heterogeneity test showed a P-value of more than 0.10 and an I2-value of less than 50%; otherwise, a random-effects model was used. We also constructed funnel plots to evaluate the presence of publication bias.
RESULTS Descriptive and qualitative assessments
F
ROM 147 STUDIES, we finally selected seven RCT (Fig. 1).15–21 These studies involved 177 patients: 93 were randomized to the UDCA monotherapy groups and 84 to the combination therapy (UDCA and bezafibrate) groups. The baseline characteristics of the seven trials are listed in Table 2. The mean age ranged 54–64 years and the mean follow-up interval ranged 6–24 months. The daily dose of UDCA ranged 600– 900 mg/day, and the daily dose of bezafibrate was 400 mg/day. Six trials were published as full text articles.16–21 One trial was published as an abstract and
Hepatology Research 2014
Meta-analysis of bezafibrate and UDCA for PBC 3
Table 1 Criteria used to assess risk of bias in included studies Trials assessed as having “low risk of bias” in all the specified individual domains were considered “trials with low risk of bias”. Trials assessed as having “uncertain risk of bias” or “high risk of bias” in one or more of the specified individual domains were considered “trials with high risk of bias”. Allocation sequence generation Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards and throwing dice are adequate if performed by an independent adjudicator. Unclear risk of bias: the trial is described as randomized, but the method of sequence generation was not specified. High risk of bias: the sequence generation method is not, or may not be, random. Quasi-randomized studies, those using dates, names or admittance numbers in order to allocate patients are inadequate and will be excluded for the assessment of benefits, but not for harms. Allocation concealment Low risk of bias: allocation was controlled by a central and independent randomization unit, sequentially numbered, opaque and sealed envelopes or similar, so that intervention allocations could not have been foreseen in advance of, or during, enrolment. Unclear risk of bias: the trial was described as randomized, but the method used to conceal the allocation was not described, so that intervention allocations might have been foreseen in advance of, or during, enrolment. High risk of bias: if the allocation sequence was known to the investigators who assigned patients or if the study was quasi-randomized. Quasi-randomized studies will be excluded for the assessment of benefits, but not for harms. Blinding Low risk of bias: the trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial. Unclear risk of bias: the trial was described as blind, but the method of blinding was not described, so that knowledge of allocation was possible during the trial. High risk of bias, the trial was not blinded, so that the allocation was known during the trial. Incomplete outcome data Low risk of bias: the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals. Unclear risk of bias: the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated. High risk of bias: the number or reasons for dropouts and withdrawals were not described. Selective outcome reporting Low risk of bias: pre-defined, or clinically relevant and reasonably expected outcomes are reported on. Unclear risk of bias: not all pre-defined, or clinically relevant and reasonably expected outcomes are reported on or are not reported fully, or it is unclear whether data on these outcomes were recorded or not. High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported on; data on these outcomes were likely to have been recorded. Other bias Low risk of bias: the trial appears to be free of other components that could increase risk of bias. Unclear risk of bias: the trial may or may not be free of other components that could increase risk of bias. High risk of bias: there are other factors in the trial that could increase risk of bias (e.g. for-profit involvement, authors have conducted trials on the same topic).
as a letter to the editor.15 The results of the meta-analysis are shown in Table 3.
Evaluation of the effects of therapy Three RCT reported the impact of treatment on the patients’ symptoms, and demonstrated an improvement in pruritus.16,17,20 All the included studies concluded that
the combination therapy significantly improved liver function and reduced the serum levels of alkaline phosphatase (ALP), γ-glutamyltransferase (γ-GT) and immunoglobulin (Ig)M. Six studies also reported adverse effects (myalgia, polydipsia, aggravated pruritus and arthritis), however, no serious adverse events were reported.15–20
© 2014 The Japan Society of Hepatology
4
Y. Zhang et al.
Hepatology Research 2014
147 identified studies from the databases 58 excluded for duplication 89 potentially relevant studies
66 excluded titles and abstract were not relevant for the end point of the study 23 full-text articles reviewed
16 studies excluded: 5 case report 6 combined with other therapies 5 no controls
7 articles included in the meta-analysis
Figure 1 Flow diagram of the studies included in the meta-analysis.
Meta-analysis 1 Pruritus: three trials, which included 75 patients, reported data regarding this end-point. Symptomsimproved in 13 of 42 patients in the monotherapy groups and in 12 of 33 patients in the combination therapy groups.16,17,20 There was no significant heterogeneity (P = 0.96, I2 = 0%) and no significant differences between the groups (OR, 0.82; 95% CI, 0.30–2.24; P = 0.70; Fig. 2). 2 ALP levels: seven trials, which included 177 patients, reported data regarding this end-point.15–21 Combi-
nation therapy with UDCA and bezafibrate was more effective than UDCA monotherapy in decreasing serum ALP (MD, −146.15 IU/L; 95% CI, −193.58 to −98.72; P < 0.00001; Fig. 3). There was no significant heterogeneity (P = 0.20, I2 = 30%). 3 γ-GT levels: six trials, which included 140 patients, reported data regarding this end-point.15–19,21 Combination therapy significantly decreased serum γ-GT compared with UDCA monotherapy (MD, −20.64 IU/L; 95% CI, −30.86 to −10.43; P < 0.0001;
Table 2 Baseline characteristics of the trials included in the meta-analysis First author, year
Mean age (years)
Monotherapy (n)
Combination therapy (n)
UDCA dose (mg/day)
Bezafibrate dose (mg/day)
Duration of treatment, months
Publication type
Nakai, 2000 Kanda, 2003 Itakura, 2004 Iwasaki, 2008 Hazzan, 2010 Takeuchi, 2011 Honda, 2013
58 56 57 54 64 57 58
13 11 7 10 8 22 22
10 11 9 12 8 15 19
600 600 600 600 900–1500 600 600
400 400 400 400 400 400 400
12 6 6 12 24 24 6
Letter Full text Full text Full text Full text Full text Full text
UDCA, ursodeoxycholic acid.
© 2014 The Japan Society of Hepatology
Hepatology Research 2014
Meta-analysis of bezafibrate and UDCA for PBC 5
Table 3 Meta-analysis of clinical events and biochemical parameter changes in the included studies Outcome title
No. of studies
No. of participants
Pruritus
3
75
Mortality
5
120
Adverse events
7
177
Alkaline phosphatase
7
177
γ-Glutamyltransferase
6
140
Immunoglobulin M
6
161
Alanine aminotransferase
3
75
Triglycerides
5
132
Statistical method Odds ratio (M-H, fixed, 95% CI) Odds ratio (M-H, fixed, 95% CI) Odds ratio (M-H, fixed, 95% CI) Mean difference (IV, fixed, 95% CI) Mean difference (IV, fixed, 95% CI) Mean difference (IV, fixed, 95% CI) Mean difference (IV, fixed, 95% CI) Mean difference (IV, fixed, 95% CI)
Effect size
P-value
0.82 (0.30–2.24)
0.70
0.72 (0.10–5.49)
0.75
0.35 (0.07–1.84)
0.22
−146.15 (−193.58 to −98.72)
