Amiodarone and the risk for pulmonary fibrosis. A Danish nationwide study

Abstract

Abstract Background Amiodarone may cause pulmonary fibrosis. However, very few studies have investigated this possible association. This study will evaluate whether amiodarone is associated with pulmonary fibrosis, and furthermore, if there is an exposure-response relationship. Method and results Using Danish national patient registries, we conducted an observational population-based study. Individuals diagnosed with pulmonary fibrosis were identified between 1996 and 2020 using ICD codes and then included in a nested case-control study, where cases were matched with 5 controls. The exposure to amiodarone was defined by dispensed amiodarone recipes from the national prescription registry. Cox regression analysis was used to derive the crude hazard ratio (HR) and the confidence interval (CI). The analyses were also adjusted and stratified for pre-specified comorbidities to derive multivariate Hazard ratio. Furthermore, we analysed the outcome in respect to amiodarone exposure time (<3 months, 3-6 months, 6-12 months, 1-3 years, 3-5 years, over 5 years) and also in respect to the cumulative dosage. A total of 27 948 cases diagnosed with pulmonary fibrosis over the 24 years period of study in Danish population were matched with 139 740 controls. The average age was 69 years and 45% was females. We found that amiodarone treatment was associated with significant risk of pulmonary fibrosis (HR: 4.20, 95%CI: [3.83-4.60], p<0.001). After adjusting for comorbidities including hypertension, diabetes mellitus, asthma, chronic obstructive pulmonary disease, ischemic heart disease, heart failure, stroke, any cancer, liver failure, chronic kidney disease, and alcohol, the association remained significant (HR:2.55, 95%CI: [2.30-2.82], p<0.001) (Figure 1), and its remained also significant after excluding COPD patients from the population (HR: 3.93, 95%CI: [3.50-4.40], p<0.001). Finally, the treatment exposure relationship, 0-3 months (HR:2.34, 95%CI [1.82-3.02], p<0.001), and over 5 years (HR: 5.90, 95%CI [4.56-7.65], p<0.001) (figure 2), and dose response relationship, 0-18gm (HR: 2.48, 95%CI: [1.93-3.18], p<0.001), 120-240gm (HR: 4.34, 95%CI: [3.46-5.45], p<0.001), and over 840gm (HR: 7.06, 95%CI: [3.08-16.15], p<0.001) (figure 3). Conclusion Amiodarone use was found associated with an independent incident pulmonary fibrosis, 4-fold crude risk and with a more than 2-fold hazard already within the first 3 months of treatment. The association showed also a dose- and duration relationship, where larger doses and longer treatment were associated with higher hazard of pulmonary fibrosis.