Safety and tolerability of combination treatment with pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis: a systemic review and meta-analysis

Abstract

Background: The role of combination treatments with two antifibrotic agents, pirfenidone and nintedanib, has been not established in idiopathic pulmonary fibrosis (IPF). This study was performed to investigate the safety and tolerability of combination antifibrotic treatment in patients with IPF.Methods: We conducted a proportional meta-analysis and searched PubMed, EMBASE, and the Cochrane Central Register for relevant clinical trials. The primary outcome was the proportion of discontinuation of combination treatment over the treatment period. We also examined the pooled proportions of serious and any adverse drug reactions (ADRs).Results: Four clinical trials involving 191 patients were analyzed. In pooled estimates, 29% of patients discontinued treatment during the study period [95% confidence interval (CI): 17-41%, I2=65.42%]. The pooled proportions of serious and any ADRs were 10% (95% CI: 1-19%; I2=79.13%) and 82% (95% CI: 75-90%; I2=39.20%), respectively. During the follow-up period, gastrointestinal symptoms were the most frequent ADR. Acute exacerbation (AE) of IPF was reported in 7.0% of patients.Conclusions: Our findings showed relatively frequent incidence of discontinuation and ADRs for combination therapy in IPF. Further large-scale, randomized, controlled trials are needed to support our results because of the methodological limitations of the included trials and a scarcity of trials for analysis.