Background: Pirfenidone and nintedanib are generally safe and well tolerated in patients with idiopathic pulmonary fibrosis, with a quite similar spectrum of adverse events (AEs). When discontinuation of one drug for intolerance becomes necessary, it is usually followed by initiation of the second one.

Aim of the study: The aim of this cross-sectional retrospective study was to analyze tolerability and efficacy of the subsequent administration of the two antifibrotics in those patients who did not tolerate the first-line therapy.

Methods: We analyzed data of 27 patients who have assumed both drugs due to intolerance to the first. A group of 233 patients starting an antifibrotic for the first time was used as a control to compare the outcomes of second-line therapy (SLT).

Results: Patients assuming SLT were more prone to develop AEs (92.6% vs 65.2%, p<0.01) than the control group, and seemed to manifest more AEs each (2.4 vs 1.9, p=0.06). This led to a higher discontinuation rate (48.1% vs. 5.2%, p<0.0001) and also to a more frequent need of dose reduction and temporary interruption (64.3% vs. 33%, p=0.02). No patients manifested severe AEs with both drugs and recurrence was observed only for anorexia, weight loss and nausea. Patients taking SLT showed a decrease in DLCO comparable to that of the control group, but a trend toward FVC preservation over the long term (+70 mL vs -269 mL after 3 years of therapy, p<0.05).

Conclusions: Patients who discontinue antifibrotic treatment for intolerance represent a particularly high-risk population, more prone to develop AEs and therefore more at risk of discontinuing also SLT. Reduced tolerance does not seem to affect the efficacy of antifibrotics.