Optimal drug regimens for primary biliary cirrhosis: a systematic review and network meta-analysis

Abstract

Objective: Most comprehensive treatments for PBC include UDCA, combination of methotrexate (MTX), corticosteroids (COT), colchicine (COC) or bezafibrate (BEF), cyclosporin A (CYP), D-penicillamine (DPM), methotrexate (MTX), or azathioprine (AZP). Since the optimum treatment regimen remains inconclusive, we aimed to compare these therapies in terms of patient mortality or liver transplantation (MOLT) and adverse event (AE).

Methods: We searched PubMed, Embase, Scopus and the Cochrane Library for randomized controlled trials until August 2014. We estimated HRs for MOLT and ORs for AE. The sensitivity analysis based on dose of UDCA was also performed.

Results: The search identified 49 studies involving 12 different treatment regimens and 4182 patients. Although no statistical significance can be found in MOLT, COT plus UDCA was ranked highest for efficacy outcome amongst all the treatment regimes. While for AEs, compared with OBS or UDCA, monotherapy with COC (OR 5.6, P < 0.001; OR 5.89, P < 0.001), CYP (OR 3.24, P < 0.001; OR 3.42, P < 0.001), DPM (OR 8.00, P < 0.001; OR 8.45, P < 0.001) and MTX (OR 5.31, P < 0.001; OR 5.61, P < 0.001) were associated with statistically significant increased risk of AEs. No significant differences were found for other combination regimes. Effect estimates from indirect comparisons matched closely to estimates derived from pairwise comparisons. Consistently, in the sensitivity analysis, results closely resembled our primary analysis.

Conclusions: COT plus UDCA was the most efficacious among treatment regimens both for MOLT and AEs.

Keywords: UDCA-based therapy; adverse events; indirect comparison; network meta-analysis; primary biliary cirrhosis.

Figure 1. Network of the comparisons for the Bayesian network meta-analysis

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). COC: colchicine; BEF: bezafibrate; COT: corticosteroids; MTX: methotrexate; UDCA: ursodeoxycholic acid; CYP: cyclosporin A; DPM: D-penicillamine; AZP: azathioprine; OBS: observation. A. Mortality or liver transplantation; B. Adverse events.

Figure 2. Clinical efficacy and safety of all treatments according to network meta-analysis

Treatments are reported in alphabetical order. The ORs were estimated in upper and lower triangle comparing column-defining with row-defining treatment. A. Mortality or liver transplantation; B. Adverse events. For mortality or liver transplantation, HRs higher than 1 favor the column-defining treatment, while for adverse effects, ORs lower than 1 favor the row-defining treatment. COC: colchicine; BEF: bezafibrate; COT: corticosteroids; MTX: methotrexate; UDCA: ursodeoxycholic acid; CYP: cyclosporin A; DPM: D-penicillamine; AZP: azathioprine; OBS: observation. A. Mortality or liver transplantation; B. Adverse events.

Figure 3. 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 worst and rank N is best. COC: colchicine; BEF: bezafibrate; COT: corticosteroids; MTX: methotrexate; UDCA: ursodeoxycholic acid; CYP: cyclosporin A; DPM: D-penicillamine; AZP: azathioprine; OBS: observation.

Figure 4. Comparison-adjusted funnel plot for the treatment network in terms of mortality or liver transplantation and 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 below one 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. COC: colchicine; BEF: bezafibrate; COT: corticosteroids; MTX: methotrexate; UDCA: ursodeoxycholic acid; CYP: cyclosporin A; DPM: D-penicillamine; AZP: azathioprine; OBS: observation. A. Mortality or liver transplantation; B. Adverse events.