Su1651 IMPACT OF COMBINATION THERAPY WITH URSODEOXYCHOLIC ACID AND BEZAFIBRATE ON PATIENT OUTCOMES IN PRIMARY BILIARY CHOLANGITIS: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Abstract

Introduction: Ursodeoxycholic acid (UDCA) is the first-line treatment for primary biliary cholangitis (PBC), but up to 40% of patients demonstrate an incomplete response. Obeticholic acid became available as second-line therapy in 2016 and only half of patients respond. These incomplete responders are at high risk for disease progression and represent an unmet need. Bezafibrate has been proposed as an alternative to benefit UDCA-refractory patients. Thus, our aim was to evaluate the impact of combination therapy with UDCA and bezafibrate on liver chemistries and pruritus by conducting a meta-analysis of randomized controlled trials (RCT). Methods: PubMed, EMBASE, Scopus and the Cochrane Library were searched from inception to October 2019 to identify articles analyzing the use of UDCA and bezafibrate in PBC. Only RCTs that compared combination therapy with UDCA and bezafibrate to UDCA monotherapy were included. 56 potentially relevant articles were identified. Two authors selected papers meeting inclusion criteria and abstracted the data. Principal authors were contacted to obtain missing data. Statistical analysis was performed using RevMan Analysis. For dichotomous data and continuous data, risk ratio (RR) or risk difference (RD) and 95% confidence intervals (CI), or mean difference (MD) and standard deviation (SD) were calculated, respectively. Risk of bias was assessed using the Cochrane Risk of Bias tool and overall certainty of evidence was assessed using the GRADE framework. Results: Seven trials with 234 patients were included. All trials had high risk of bias and the overall certainty of evidence was very low. Three studies including 138 patients were used to assess the effect of treatment on liver chemistries. The standardized mean difference (SMD) for serum alkaline phosphatase (ALP) was -2.19 (95% CI -2.62, -1.76), favoring combination therapy, and the SMD for total bilirubin (TB) was -0.09 (95% CI -0.2, 0.02). With respect to all-cause mortality evaluated by 5 trials, there were very few deaths. 3 deaths were observed in the combination therapy arm as compared to 0 deaths in the UDCA only arm (RD 0.02; 95% CI -0.06 to 0.09). Adverse events leading to drug discontinuation occurred in 5 vs. 7 patients treated with combination vs. UDCA only (RD -0.02; 95% CI -0.02, 0.04). In 3 studies that evaluated pruritis, only one used visual analogue scale (VAS) and the reduction in itch score was 1.0 in the combination arm vs. 0.22 in the UDCA arm. Conclusions: Combination therapy with bezafibrate and UDCA demonstrated a significant reduction in serum ALP in PBC patients with an inadequate response to UDCA and possible effect in reducing TB. However, we were unable to demonstrate any effect of combination therapy on all-cause mortality or itching. Further RCTs are necessary to elucidate the long-term benefits of this combination therapy in PBC.