Network meta-analysis of randomized controlled trials: efficacy and safety of UDCA-based therapies in primary biliary cirrhosis

Abstract

Major ursodeoxycholic acid (UDCA)-based therapies for primary biliary cirrhosis (PBC) include UDCA only, or combined with either methotrexate (MTX), corticosteroids (COT), colchicine (COC), or bezafibrate (BEF). As the optimum treatment regimen is unclear and warrants exploration, we aimed to compare these therapies in terms of patient mortality or liver transplantation (MOLT) and adverse events (AE).PubMed, the Cochrane Library, and Scopus were searched for randomized controlled trials up to August 31, 2014. We estimated the hazard ratios (HRs) for MOLT and odds ratios (ORs) for AE. A sensitivity analysis based on the dose of UDCA was also executed.Thirty-one eligible articles were included. Compared with COT plus UDCA, UDCA (HR 0.38, 95% confidence interval [CI] 0.09-1.39), BEF plus UDCA (HR 0.29, 95% CI 0.02-4.83), COC plus UDCA (HR 0.39, 95% CI 0.07-2.25), MTX plus UDCA (HR 0.28, 95% CI 0.05-1.63), or OBS (HR 0.49, 95% CI 0.11-2.01) all provided an increased risk of MOLT. With respect to drug AE profile, although not differing appreciably, BEF plus UDCA was associated with more AEs compared with UDCA (OR 3.16, 95% CI 0.59-20.67), COT plus UDCA (OR 2.27, 95% CI 0.15-33.36), COC plus UDCA (OR 1.00, 95% CI 0.09-12.16), MTX plus UDCA (OR 2.03, 95% CI 0.23-17.82), or OBS (OR 3.00, 95% CI 0.53-20.75). The results of sensitivity analyses were highly consistent with previous analyses.COT plus UDCA was the optimal UDCA-based regimen for both MOLT and AEs. BEF plus UDCA was most likely to cause AEs, whereas monotherapy with UDCA and coadministriation of COT plus UDCA appeared to be associated with the fewest AEs for PBC treatment.

FIGURE 1

Study selection.

FIGURE 2

Network of the comparisons for the Bayesian network meta-analysis. (A) Mortality or liver transplantation. (B) Adverse events. The numbers along the link lines indicate the number of trials or pairs of trial arms. Lines connect the interventions that have been studied in head-to-head (direct) comparisons in the eligible controlled trials. The width of the lines represents the cumulative number of trials for each comparison and the size of every node is proportional to the number of enrolled participants (sample size). BEF = bezafibrate, COC = colchicine, COT = corticosteroids, MTX = methotrexate, OBS = observation, UDCA = ursodeoxycholic acid.

FIGURE 3

Clinical efficacy and safety of all treatments according to network meta-analysis. (A) Mortality or liver transplantation. (B) Adverse events. Treatments are reported in alphabetical order. The ORs were estimated in upper and lower triangle comparing column-defining with row-defining treatment. For mortality or liver transplantation, HRs >1 favor the column-defining treatment, whereas for adverse effects, ORs <1 favor the row-defining treatment. BEF = bezafibrate, COC = colchicine, COT = corticosteroids, HR = hazard ratio, MTX = methotrexate, OBS = observation, OR = odds ratio, UDCA = ursodeoxycholic acid.

FIGURE 4

Rankograms showing probability of each strategy having each specific rank (1–6) for mortality or liver transplantation and adverse events. Ranking indicates the probability to be the best treatment, the second best, the third best, and so on. Rank 1 is the worst and rank N is the best. BEF = bezafibrate, COC = colchicines, COT = corticosteroids, MTX = methotrexate, OBS = observation, UDCA = ursodeoxycholic acid.

FIGURE 5

Comparison-adjusted funnel plot for the treatment network in terms of (A) mortality or liver transplantation and (B) adverse events. The red line represents the null hypothesis that the study-specific effect sizes do not differ from the respective comparison-specific pooled effect estimates. Different colors correspond to different comparisons. Estimates <1 indicate that the benefit of the experimental intervention is more pronounced in the trial than the pooled estimate. Observations from small studies missing on the right side of the line of null effect (ratio of rate ratios > 1) indicate that small studies tend to exaggerate the effectiveness of experimental treatments. BEF = bezafibrate, COC = colchicines, COT = corticosteroids, MTX = methotrexate, OBS = observation, UDCA = ursodeoxycholic acid.