Risk of aortic aneurysm or dissection following use of fluoroquinolones: a retrospective multinational network cohort study

Abstract

Background: Fluoroquinolones (FQs) are commonly used to treat urinary tract infections (UTIs), but some studies have suggested they may increase the risk of aortic aneurysm or dissection (AA/AD). However, no large-scale international study has thoroughly assessed this risk.

Methods: A retrospective cohort study was conducted using a large, distributed network analysis across 14 databases from 5 countries (United States, South Korea, Japan, Taiwan, and Australia). The study included 13,588,837 patients aged 35 or older who initiated systemic fluoroquinolones (FQs) or comparable antibiotics (trimethoprim with or without sulfamethoxazole [TMP] or cephalosporins [CPHs]) for UTI treatment in the outpatient setting between JAN 01, 2010 and DEC 31, 2019. Patients were included if at the index date they had at least 365 days of prior observation and were not hospitalised for any reason on or within 7 days prior to the index date. The primary outcome was AA/AD occurrence within 60 days of exposure, with secondary outcomes examining AA and AD separately. Cox proportional hazards models with 1:1 propensity score (PS) matching were used to estimate the risk, with results calibrated using negative control outcomes. Analyses were subjected to pre-defined study diagnostics, and only those passing all diagnostics were reported. Hazard ratios (HRs) were pooled using Bayesian random-effects meta-analysis.

Findings: Among analyses that passed diagnostics there were 1,954,798 and 1,195,962 propensity-matched pairs for the FQ versus TMP and FQ versus CPH comparisons respectively. For the 60-day follow-up there was no difference in risk of AA/AD between FQ and TMP (absolute rate difference [ARD], 0.21 per 1000 person-year; calibrated HR, 0.91 [95% CI 0.73-1.10]). There was no significant difference in risk for FQ versus CPH (ARD, 0.11 per 1000 person-year; calibrated HR, 1.01 [95% CI 0.82-1.25]).

Interpretation: This large-scale study used a rigorous design with objective diagnostics to address bias and confounding. There was no increased risk of AA/AD associated with FQ compared to TMP or CPH in patients treated for UTI in the outpatient setting. As we only examined FQ used to treat UTIs in the outpatient setting, the results may not be generalisable to other indications with different severity.

Funding: Yonsei University College of Medicine, Government-wide R&D Fund project for infectious disease research (GFID), Republic of Korea, National Health and Medical Research Council (NHMRC) Australian Government. Department of Veterans Affairs (VA) Informatics and Computing Infrastructure (VINCI), Department of Veterans Affairs, the United States Government.