Does ursodeoxycholic acid prolong survival in patients with primary sclerosing cholngitis : a meta-analysis

Gruchy, Steven (2010) Does ursodeoxycholic acid prolong survival in patients with primary sclerosing cholngitis : a meta-analysis. Masters thesis, Memorial University of Newfoundland.

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Abstract

Primary Sclerosing Cholangitis (PSC) is a progressive liver disease of unknown etiology. This disease can lead to many potential lethal clinical situations including liver cirrhosis. Ursodeoxycholic acid (UDCA) has been shown to be effective in other cholestatic liver diseases, most notably primary biliary cirrhosis. A number of randomized controlled trials (RCTs) using UDCA for the treatment of PSC have been carried out with varying results. The main objective of this study was to determine if the literature provides evidence that UDCA is effective at prolonging survival in patients with PSC. -- Meta-analysis was used to evaluate the effect of UDCA on disease progression in patients with PSC. Only RCTs that compared UDCA to placebo in patients with PSC were included. Six fully published RCTs that met the inclusion criteria for this metaanalysis were identified in the literature. The outcome measurements used for this study included overall mortality and the requirement for liver transplant. Surrogate markers for the primary outcome of overall mortality were also analyzed and included worsening of liver histology, AST (U/L), ALP (U/L), albumin (g/L) and bilirubin (umol/L) levels. Subgroup analysis was also performed comparing high dose (>15mg/kg/day) to low/standard dosing (10-15mg/kg/day) of UDCA in patients with PSC for the primary outcome of overall mortality. -- Pooling of the six fully published RCTs, identified a non-significant difference between treatment groups for the outcome of all cause mortality with an odds ratio of 0.859 and (95% confidence interval (CI), 0.365-2.022, p=0.728). A subgroup analysis of overall mortality stratified according to UDCA dosing did not identify any statistically significant difference in survival regardless of the dose of UDCA administered. A non-significant difference between treatment groups for the pooled results of the outcome liver transplant required yielded an odds ratio 1.243 with (95%CI, 0.667-2.317, p=0.494). A non-significant difference between treatment groups was observed for the surrogate outcome worsening of liver histology with an odds ratio of 0.903 and (95%CI, 0.316-2.582, p=0.849). The pooled standardized mean difference (SMD) was calculated for the surrogate outcomes of liver biochemistry (AST (U/L), ALP (U/L)) and liver function (bilirubin (umol/L), albumin (g/L)). All surrogate outcomes suggested a benefit favoring UDCA, however, only AST (U/L), ALP (U/L) and bilirubin (umol/L) were statistically significant with a p-value <0.05. -- These results indicate that although UDCA improved surrogate outcomes such as liver biochemistry and liver function, the results did not translate into a reduction in endpoints such as mortality or a need for liver transplant. This meta-analysis suggests that high dose UDCA (>15mg/kg/day) does not offer any treatment benefit over low/standard dosing (10-15mg/kg/day) for the outcome overall mortality in patients with PSC. Further research is needed to identify an effective medication to halt the progression of this disease. Future research may determine if starting therapy with UDCA at an earlier stage of disease translates into a survival advantage for patients with PSC.

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