Elsevier

The Lancet

Volume 354, Issue 9184, 25 September 1999, Pages 1053-1060
The Lancet

Articles
Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis

https://doi.org/10.1016/S0140-6736(98)11293-XGet rights and content

Summary

Background

Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis, but its effect on disease progression and survival is uncertain. The aim of this study was to clarify the efficacy of UDCA in primary biliary cirrhosis.

Methods

A systematic review, including the use of meta-analysis, was done for the randomised and switch-over phases of trials comparing UDCA with placebo, obtained from Medline and Embase databases, and from manual searches derived from review articles and abstracts of major international meetings. All trials had more than a mean of 6 months' follow-up and only included patients with primary biliary cirrhosis (PBC) according to established diagnostic criteria.

Findings

17 relevant articles were identified: 11 randomised controlled trials, including 1272 patients, and six reports of the switch-over phases. UCDA had a favourable effect on liver biochemistry in most of the studies but not on symptoms or the progression of histological stage; two studies did not assess survival, liver transplantation, or complications of liver disease. Meta-analysis showed no difference between UDCA and placebo in the incidence of death (odds ratio 1·21, 95% Cl 0·71–2·04), liver related death (0·72, 0·22–2·32), liver transplantation (1·27, 0·78–2·07), death or liver transplantation (1·26, 0·87–1·82), and in the development of complications of liver disease (1·11, 0·64–1·92). With the primary end point defined by the authors (a combined end point in three studies, and death or liver transplantation in the others) an odds ratio of 1·53 (0·97–2·42) was obtained. Assessment of the switch-over phases, during which there was a longer follow-up, did not change the results of the meta-analysis.

Interpretation

Published randomised controlled trials of UDCA do not show evidence of therapeutic benefit in PBC and its use as standard therapy needs to be re-examined.

Introduction

Primary biliary cirrhosis (PBC) is a slowly progressive cholestatic liver disease that occurs with a male/female ratio of 1/9. The chronic cholestasis, due to immune-mediated destruction of small septal and interlobular bile ducts, can result in hepatic fibrosis, biliary cirrhosis, and eventually liver failure in many cases.1 Although liver transplantation offers very good results in patients with end-stage PBC, effective pharmacological treatment for patients with earlier stages of the disease is needed.

Currently, ursodeoxycholic acid (UDCA) is the only drug approved for the treatment of PBC and is widely prescribed by gastroenterologists and hepatologists.2 UDCA is believed to protect bile ducts against injury by hydrophobic bile acids and stimulate the hepatocellular elimination in bile of hydrophobic bile acids and other potential hepatotoxins.3 In 1987 Poupon and colleagues first reported benefit from UDCA;4 several randomised clinical trials have been reported since. Most showed a sustained improvement in biochemical factors, in particular serum bilirubin, which has been used as a good prognostic marker in PBC.5 Improved biochemical factors, however, have not been validated as surrogate markers of efficacy. Moreover, the effect of UDCA on survival and the clinical and histological progression of the disease is uncertain.

A combined analysis of three randomised trials,6 suggested that survival, free of transplantation, was significantly better in patients with PBC who received UDCA treatment for 4 years, than those who initially received placebo for 2 years followed by UDCA for the next 2 years. However, the extended follow-up of two other clinical trials7·8 with the same treatment design, as well as a randomised controlled trial with the longest follow-up,9 did not show a favourable effect of UDCA on the incidence of death or liver transplantation.

To clarify the real effect of UDCA on the progression of PBC, applying the methodology of evidence based medicine, we did a systematic review of the randomised clinical trials comparing UDCA with placebo, including the use of meta-analysis when this was applicable. We also did a critical assessment of the studies reporting the extended follow-up of the randomised trials, focusing on the switch-over phase from placebo to UDCA.

Section snippets

Study identification

We searched the Medline database and the Embase database from January, 1987, to July, 1998, to identify all English-language research included under the search textwords “primary biliary cirrhosis”, “ursodeoxycholic acid”, and “treatment”. We also did a full manual search of all review articles, of the retrieved original studies, and of all abstracts from the following major international meetings held between January, 1995, and October, 1998: American Digestive Disease Week; American

Descriptive and qualitative assessment

Searches of the Medline and Embase databases yielded 164 articles. Overall 11 randomised, placebo-controlled trials met the inclusion criteria.9, 14, 23 In one study22 three treatment groups were used on UDCA, colchicine, or placebo—only the data on UDCA and placebo were used for our analysis. We excluded only one study24 because it did not fulfil the inclusion criteria due to a follow-up interval of only 3 months.

The extended follow-up, reported for five trials, was evaluated separately,

Discussion

Although a meta-analysis does not replace the value of a large-scale, well-designed, randomised controlled trial to establish evidence for therapeutic efficacy, it is nonetheless useful when individual studies may be limited by small sample sizes and the paucity of endpoints. This is particularly the case in PBC, a disease with a very long natural history, which extends over decades.

Survival analysis is the “gold standard” for assessment of therapeutic efficacy in clinical trials of PBC.

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