What Fluoroquinolones Have the Highest Risk of Aortic Aneurysm? A Case/Non-case Study in VigiBase®

Abstract

INTRODUCTIONFluoroquinolones have a broad antimicrobial activity and are one of the most commonly prescribed groups of antibiotics. They are widely used for the treatment of many infections affecting among others the urinary, gastro-intestinal, abdominal, or respiratory tract. Recently, fluoroquinolones were associated with an increased risk of aortic aneurysms and dissections, 1-3 with an excess risk of 0.5 cases per 1000 personyears for fluoroquinolone users versus amoxicillin users. 3 However, these studies were underpowered to distinguish between different fluoroquinolones. Therefore, we assessed the specific risk of individual fluoroquinolones for aortic aneurysms and dissections, using the case/non-case design, a method validated to detect very rare events. 4 METHODSThe study was conducted using Vigibase®, the World Health Organization Global Individual Case Safety Reports (ICSRs) database which includes more than 16 million reports forwarded to the WHO Uppsala Monitoring Center by national pharmacovigilance systems from over 130 countries around the world since 1967. Only ICSRs registered between 1972 and 2017, with known age and sex and concerning patients ≥ 50 years, were included. Cases were ICSRs containing the term Baortic aneurysms and dissections^according to the MedDRA dictionary. Reports registered under the term Baortic aneurysm syphilitic^were excluded. Non-cases were all other reports during the same period. Exposure to fluoroquinolones was compared to amoxicillin exposure. We also assessed the risk of individual fluoroquinolones, thereby excluding ICSRs with more than one fluoroquinolone. The case/non-case method allows the calculation of reporting odds ratios (ROR) with their 95% confidence intervals (CI) of the exposure odds among reported cases of aortic aneurysms and dissections to the exposure odds among reported non-cases. 4 ROR adjusted for age, sex, year of report, continent of report, notifier type, and number of drugs prescribed were analyzed by multivariable logistic regression. Similar investigations were made with the ICSRs of Btendon injury, pain, rupture, and tendinitis,^, a known adverse drug reaction of fluoroquinolones. Institutional review board approval was not required because VigiBase® is an unlikable anonymized database open to pharmacovigilance centers. RESULTSAmong the 6,383,318 ICSRs registered in Vigibase® between 1972 and 2017, 172,588 were reported with fluoroquinolones and 40,658 with amoxicillin. We found 113 aortic aneurysms or dissections with fluoroquinolones (including 12 with more than 1 fluoroquinolone) and 8 with amoxicillin. Fluoroquinolone exposure was associated with a higher risk of reporting aneurysms/dissections compared to amoxicillin exposure (ROR 2.13, 95% CI 1. 03-4.37). Compared with use of other fluoroquinolones, an elevated ROR was observed only with levofloxacin (ROR 2.78, 95% CI 1.83-4.23) ( Table 1). For tendon disorders, an increase in the ROR was found for fluoroquinolones versus amoxicillin (ROR 122.48,. When each fluoroquinolone was com...

Relationship between fluoroquinolones and the risk of aortic diseases: a meta-analysis of observational studies

“…After reviewing the full-text articles, our meta-analysis finally included 5 observational studies. [3,4,[18][19][20] No randomized controlled trials were included because the 6 incidence of aortic diseases is low and cannot be captured in randomized controlled trials with adequate power. [21,22]…”

“…The group sizes ranged from 2,426 to 1,744,360, with 2,829,385 patients in total. All included studies were observational in nature, including two cohort studies, [19,20] one nested casecontrol study, [18] one case-crossover design study [4] and one case/no case study [3]. The follow-up ranged from 60 days to 17 years; one article [3] did not report the follow-up duration.…”

“…All included studies were observational in nature, including two cohort studies, [19,20] one nested casecontrol study, [18] one case-crossover design study [4] and one case/no case study [3]. The follow-up ranged from 60 days to 17 years; one article [3] did not report the follow-up duration. All studies adjusted the RRs, HRs or ORs, including 3 trials that used propensity score matching, [18][19][20] 1 trial that used a conditional logistic regression model [4] and 1 trial that used multivariable logistic regression [3].…”

“…The follow-up ranged from 60 days to 17 years; one article [3] did not report the follow-up duration. All studies adjusted the RRs, HRs or ORs, including 3 trials that used propensity score matching, [18][19][20] 1 trial that used a conditional logistic regression model [4] and 1 trial that used multivariable logistic regression [3]. All studies evaluated different fluoroquinolones, and the trials used a combination of administrative diagnostic codes to identify new-onset aortic diseases.…”

“…[1] For this reason, they are routinely prescribed by internists, family practitioners, specialists, subspecialists and surgeons. [2] However, several studies have reported serious adverse events, such as aortic aneurysm and aortic dissection, [3,4] in patients using fluoroquinolones. Aortic aneurysm and aortic dissection have high complication rates and carry a high risk of mortality, [5,6] so the FDA announced the addition of these severe side effects to the warning about fluoroquinolones on December 20, 2018.…”