The safety of nintedanib for the treatment of interstitial lung disease: A systematic review and meta-analysis of randomized controlled trials

INTRODUCTION: Nintedanib can inhibit processes involved in the progression of fibrosis and can reduce the decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF) and fibrotic-interstitial lung disease (fibrotic-ILDs). Although the adverse events associated with nintedanib in IPF patients are well known, its safety in other fibrotic-ILD patients remained unclear. METHODS: We searched PubMed, EMBASE, Cochrane CENTRAL and Cochrane CDSR for randomized controlled studies which compared nintedanib with a placebo in ILD patients. We estimated pooled odds ratios (ORs) and 95% confidence intervals (CIs) for adverse events using the DerSimonian–Laird random-effects model. RESULTS: Six studies with a total of 2,583 patients were included in the meta-analysis. The pooled estimates showed that patients treated with nintedanib had a significantly higher likelihood of having any adverse events (OR = 2.39; 95% CI = 1.71–3.36) or adverse events leading to treatment discontinuation (OR = 1.73; 95% CI = 1.34–2.25). However, they had trend to lower likelihood of having fatal adverse events (OR = 0.69; 95% CI = 0.41–1.14) compared with the placebo group. Use of nintedanib was positively associated with diarrhea (OR = 5.96; 95% CI = 4.35–8.16), nausea (OR = 3.00; 95% CI = 1.93–4.66), vomiting (OR = 3.22; 95% CI = 2.17–4.76) and weight loss (OR = 3.38; 95% CI = 1.1.76–6.47). Whereas, patients treated with nintedanib were less likely to have a cough (OR = 0.73; 95% CI = 0.56–0.96) and dyspnea (OR = 0.70; 95% CI = 0.53–0.94). CONCLUSIONS: Compared to a placebo, nintedanib was associated with a higher risk of adverse events, especially for diarrhea, nausea, vomiting and weight loss, but it was also associated with a lower risk of cough and dyspnea in IPF and fibrotic-ILD patients.