Elsevier

Journal of Hepatology

Volume 71, Issue 2, August 2019, Pages 357-365
Journal of Hepatology

Research Article
Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis

https://doi.org/10.1016/j.jhep.2019.04.001Get rights and content

Highlights

  • Ursodeoxycholic acid is associated with prolonged survival in primary biliary cholangitis.

  • This positive association is significant irrespective of age, sex, or disease stage.

  • The association remains significant in cases where the established criteria for therapeutic response are not met.

Background & Aims

The clinical efficacy of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) remains subject to debate as definitive randomized controlled trials are lacking. We aimed to determine whether UDCA prolongs liver transplant (LT)-free survival in patients with PBC.

Methods

This international cohort study included patients from the Global PBC Study Group database, originating from 8 countries in Europe and North America. Both UDCA-treated and untreated patients were included. LT and death were assessed as a combined endpoint through Cox regression analyses, with inverse probability treatment weighting (IPTW).

Results

In the 3,902 patients included, the mean (SD) age was 54.3 (11.9) years, 3,552 patients (94.0%) were female, 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated. The median (interquartile range) follow-up was 7.8 (4.1–12.1) years. In total, 721 UDCA-treated patients and 145 untreated patients died or underwent LT. After IPTW, the 10-year cumulative LT-free survival was 79.7% (95% CI 78.1–81.2) among UDCA-treated patients and 60.7% (95% CI 58.2–63.4) among untreated patients (p <0.001). UDCA was associated with a statistically significant reduced risk of LT or death (hazard ratio 0.46, 95% CI 0.40–0.52; p <0.001). The hazard ratio remained statistically significant in all stages of disease. Patients classified as inadequate biochemical responders after 1 year of UDCA had a lower risk of LT or death than patients who were not treated (adjusted hazard ratio 0.56; 95% CI 0.45–0.69; p <0.001).

Conclusion

The use of UDCA improves LT-free survival among patients with PBC, regardless of the disease stage and the observed biochemical response. These findings support UDCA as the current universal standard of care in PBC.

Lay summary

In this international multicenter study of 3,902 patients with primary biliary cholangitis, we found that treatment with ursodeoxycholic acid is associated with prolonged liver transplant-free survival. This association was significant, irrespective of sex, age, or disease stage. The survival benefit remained statistically significant in patients with an incomplete biochemical response to ursodeoxycholic acid therapy.

Introduction

Primary biliary cholangitis (PBC) is a chronic and usually slowly progressive liver disease with autoimmune features, histologically characterized by destruction of the small intrahepatic bile ducts.[1], [2] The disease is primarily diagnosed based on an otherwise unexplained chronic elevation of serum alkaline phosphatase levels and the presence of anti-mitochondrial antibodies. Early identification of individuals with PBC is clinically challenging as symptoms are frequently absent. Identifying and managing patients with PBC is important, however, as the disease may silently progress towards cirrhosis and the survival of affected patients is substantially impaired.3

Ursodeoxycholic acid (UDCA) is a choleretic and hydrophilic endogenous bile acid that is considered a safe and well-tolerated drug.[4], [5], [6] Based on the cumulative experience obtained with this drug over the past decades, UDCA is recommended as the standard treatment for PBC.[4], [6] Long-term cohort studies have suggested an association between UDCA and improved liver transplant (LT)-free survival, but this was only based on the comparison of observed versus predicted LT-free survival according to the Mayo Risk Score, which estimates the prognosis when patients are left untreated.[7], [8], [9] Numerous randomized controlled trials (RCTs) have been performed as well, but all failed to show a difference in LT-free survival between placebo and UDCA-treated groups.[10], [11], [12], [13], [14], [15], [16], [17], [18], [19] As did other more extensive meta-analyses, the Cochrane hepatobiliary group recently concluded once again that there is no demonstrated benefit of UDCA on LT and/or mortality.[17], [18], [19], [20] Such positioning statements, in absence of definitive trials, have fueled the ongoing discussion about the therapeutic potential of UDCA.[21], [22], [23], [24] This might explain the observation in a well-executed national PBC registry that, until recently, as many as 20% of patients remained untreated.25 In another recent US-based cohort study the percentage of UDCA untreated patients was even as high as 30%.26 However, the meta-analyses are based on inadequate RCTs that were limited by a small number of patients, insufficient dosages of UDCA, and short follow-up. Therefore, the evaluation of the clinical efficacy of UDCA in PBC should not be based on these RCTs alone. Nonetheless, there is an understandable reluctance to initiate new long-term, placebo-controlled RCTs in which many patients would be denied UDCA therapy, because of minimal safety concerns of UDCA and practical implications.

To support current practice, alternative study designs are thus needed to assess the potential benefit of treatment with UDCA in PBC. This would be relevant both to increase awareness for timely diagnosis and referral by physicians working in other fields, and to optimize future patient management by PBC-treating physicians. A contemporary causal inference method – used to emulate a randomized controlled trial in observational data – is inverse probability of treatment weighting (IPTW). The Global PBC Study Group cohort, which includes long-term follow-up data of both UDCA-treated and untreated patients, provides the opportunity to apply this method. In our first publication, we substantiated alkaline phosphatase (ALP) and bilirubin as surrogate markers for clinical outcome in our cohort of 4,845 patients with PBC.27 In the second publication, in which only the 4,119 UDCA-treated patients were included, we developed the GLOBE score, a model that accurately predicts long-term outcome.28 In the current study performed in this cohort, we aimed to assess the effect of UDCA therapy on LT-free survival. The second objective was to evaluate the difference in LT-free survival between patients who do not meet biochemical criteria for response after 1 year of UDCA therapy and patients who remained untreated.

Section snippets

Study population and design

Patients were derived from the Global PBC Study Group database. This study group is an international collaboration between 15 liver units across 8 countries in Europe and Northern America. The database contains individual patient data from long-term follow-up cohorts. Both UDCA-treated and untreated patients with an established diagnosis of PBC in accordance with internationally accepted guidelines[4], [5], [6] were eligible for inclusion in this study. In order to be eligible, we required the

Study population

In total, 3,902 patients with PBC were included. At baseline, the mean (SD) age was 54.3 (11.9) and the vast majority of patients were female (n = 3,552, 91.0%). A total of 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated with UDCA. Table 1 shows the baseline characteristics according to treatment with UDCA. Patients treated with UDCA were younger and had higher circulating serum liver tests, while in the subgroup of patients with available baseline

Discussion

In this large, international follow-up study including both UDCA-treated and untreated patients, we report that UDCA therapy improves LT-free survival in PBC, with a dose-response relationship. Importantly, a statistically significant association between UDCA therapy and reduced all-cause mortality or LT was found in all stages of disease. These findings imply a strong recommendation for all patients with PBC to use UDCA. Even in UDCA-treated patients classified as inadequately responding to

Financial support

This investigator-initiated study was supported by an unrestricted grant from Intercept Pharmaceuticals, and was funded by the Foundation for Liver and Gastrointestinal Research (a not-for-profit foundation) in Rotterdam, the Netherlands. The supporting parties had no influence on the study design, data collection and analyses, writing of the manuscript, or on the decision to submit the manuscript for publication.

Conflict of interest

The following authors declared that they have no conflicts of interest: P.M. Battezzati, F. Nevens, M.J. Mayo. M.H. Harms reports a speaker fee from Zambon Nederland B.V. H.R. van Buuren is a consultant for Intercept Pharma Benelux and received unrestricted research grants from Intercept Pharmaceuticals and from Zambon Nederland B.V. C. Corpechot is consultant for Intercept Pharmaceuticals France. D. Thorburn reports consulting activities for Intercept Pharmaceuticals. K.D. Lindor reports that

Authors’ contributions

Maren H. Harms, Bettina E. Hansen and Adriaan J. van der Meer had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of data analyses. Study concept and design: Maren H. Harms; Henk R. van Buuren; Christophe Corpechot; Douglas Thorburn; Harry L.A. Janssen; Keith D. Lindor; Gideon M. Hirschfield; Albert Parés; Annarosa Floreani; Marlyn J. Mayo; Pietro Invernizzi; Pier M. Battezzati; Frederik Nevens; Cyriel Y. Ponsioen; Andrew L. Mason;

Acknowledgements

This study was performed on behalf of the Global PBC Study Group.

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