Association of Fluoroquinolone Use With Short-term Risk of Development of Aortic Aneurysm

Abstract

Importance: Although fluoroquinolones are commonly prescribed antibiotics in the US, recent international studies have shown an increased risk of aortic aneurysm and dissection after fluoroquinolone use, leading to US Food and Drug Administration warnings limiting use for high-risk patients. It is unclear whether these data are true for the US population and who is truly high risk.

Objective: To assess aortic aneurysm and dissection risks in a heterogeneous US population after fluoroquinolone use.

Design, setting, and participants: Prescription fills for fluoroquinolones or a comparator antibiotic from 2005 to 2017 among commercially insured individuals aged 18 to 64 years were identified in this retrospective analysis of MarketScan health insurance claims. This cohort study included 27 827 254 US adults (47 596 545 antibiotic episodes), aged 18 to 64 years, with no known previous aortic aneurysm or dissection, no recent antibiotic exposure, and no recent hospitalization.

Exposures: Outpatient fill of an oral fluoroquinolone or comparator antibiotic (amoxicillin-clavulanate, azithromycin, cephalexin, clindamycin, and sulfamethoxazole-trimethoprim).

Main outcomes and measures: The 90-day incidence of aortic aneurysm and dissection. Inverse probability of treatment weighting in Cox regression was used to estimate the association between fluoroquinolone fill and 90-day aneurysm incidence. Interaction terms were used to assess the association of known risk factors (ie, sex, age, and comorbidities) with aneurysm after fluoroquinolone use. Data analysis was performed March 2019 to May 2020.

Results: Of 47 596 545 prescription fills, 9 053 961 (19%) were fluoroquinolones and 38 542 584 (81%) were comparator antibiotics. The median (interquartile range) age of adults with fluoroquinolone fills was 47 (36-57) years vs 43 (31-54) years with comparator antibiotic fills. Women comprised 61.3% of fluoroquinolone fills and 59.5% of comparator antibiotic fills. Before weighting, the 90-day incidence of newly diagnosed aneurysm was 7.5 cases per 10 000 fills (6752 of 9 053 961) after fluoroquinolones compared with 4.6 cases per 10 000 fills (17 627 of 38 542 584) after comparator antibiotics. After weighting for demographic characteristics and comorbidities, fluoroquinolone fills were associated with increased incidence of aneurysm formation (hazard ratio [HR], 1.20; 95% CI, 1.17-1.24). More specifically, compared with comparator antibiotics, fluoroquinolone fills were associated with increased 90-day incidence of abdominal aortic aneurysm (HR, 1.31; 95% CI, 1.25-1.37), iliac artery aneurysm (HR, 1.60; 95% CI, 1.33-1.91), and other abdominal aneurysm (HR, 1.58; 95% CI, 1.39-1.79), and adults were more likely to undergo aneurysm repair (HR, 1.88; 95% CI, 1.44-2.46). When stratified by age, all adults 35 years or older appeared at increased risk (18-34 years: HR, 0.99 [95% CI, 0.83-1.18]; 35-49 years: HR, 1.18 [95% CI, 1.09-1.28]; 50-64 years: HR, 1.24 [95% CI, 1.19-1.28]; P = .04).

Conclusions and relevance: This study found that fluoroquinolones were associated with increased incidence of aortic aneurysm formation in US adults. This association was consistent across adults aged 35 years or older, sex, and comorbidities, suggesting fluoroquinolone use should be pursued with caution in all adults, not just in high-risk individuals.

Figure 1.. Flow Diagram and Study Design to Evaluate Episodes of Fluoroquinolone (FQ) or Comparator Antibiotic Fills in US Adults (Aged 18-64 Years) From 2005 to 2017

A, Flow diagram. B, Study design; the color coding of the boxes is as follows: exclusion criteria (light blue), washout (light gray), covariates (dark gray), and follow-up (tan). The varying sizes of the boxes are due to the fact that they are to scale for the duration of the period (180-day exclusion period longer than 30-day washout period). ^aIndividuals could contribute episodes to both FQ and the comparator group. ^bUp to 8-day gaps in insurance enrollment allowed. ^cAdults were excluded if they were admitted or discharged from a hospital within 30 days of their index fill date. ^dFollowed up until insurance disenrollment, second antibiotic prescription fill, or end of follow-up 90 days after initial fill date.

Figure 2.. Associations Between 90-Day Incidence of Aneurysm Diagnosis After Fluoroquinolone (FQ) vs Antibiotic Comparator Prescription Fills

Inverse probability of treatment weighting was used to account for potential confounding; weights and repeated observations in individuals were accounted for using robust sandwich estimators. C indicates comparator; HR, hazard ratio.

Figure 3.. Disaggregation of Cohort Showing Breakdown of the Fluoroquinolone (FQ) Group Into the Specific FQ Prescribed

Ciprofloxacin and levofloxacin account for the majority of prescriptions.

Figure 4.. Association of Fluoroquinolones vs Antibiotic Comparator With Aneurysm Risk Overall and Stratified by Sex, Age, and Comorbidity Status

The only significant difference is the stratification by age (eFigure 3 in the Supplement). P values represent comparison of tiers within each stratified group. C indicates comparator; FQ, fluoroquinolone; and HR, hazard ratio.