Risk of aortic aneurysm and dissection following exposure to fluoroquinolones, common antibiotics, and febrile illness using a self-controlled case series study design: Retrospective analyses of three large healthcare databases in the US

PLoS One. 2021 Aug 16;16(8):e0255887. doi: 10.1371/journal.pone.0255887. eCollection 2021.

Abstract

Objective: Recent observational studies suggest increased aortic aneurysm or dissection (AAD) risk following fluoroquinolone (FQ) exposure but acknowledge potential for residual bias from unreported patient characteristics. The objective of our study is to evaluate the potential association between FQ, other common antibiotics and febrile illness with risk of AAD using a self-controlled case series (SCCS) study design.

Design: Retrospective database analysis-SCCS.

Setting: Primary and Secondary Care.

Study population: 51,898 patients across 3 US claims databases (IBM® MarketScan® commercial and Medicare databases, Optum Clinformatics).

Exposure: FQ or other common antibiotics or febrile illness.

Outcome: AAD.

Methods: We studied patients with exposures and AAD between 2012 and 2017 in 3 databases. Risk windows were defined as exposure period plus 30 days. Diagnostic analyses included p-value calibration to account for residual error using negative control exposures (NCE), and pre-exposure outcome analyses to evaluate exposure-outcome timing. The measure of association was the incidence rate ratio (IRR) comparing exposed and unexposed time.

Results: Most NCEs produced effect estimates greater than the hypothetical null, indicating positive residual error; calibrated p (Cp) values were therefore used. The IRR following FQ exposure ranged from 1.13 (95% CI: 1.04-1.22 -Cp: 0.503) to 1.63 (95% CI: 1.45-1.84 -Cp: 0.329). An AAD event peak was identified 60 days before first FQ exposure, with IRR increasing between the 60- to 30- and 29- to 1-day pre-exposure periods. It is uncertain how much this pre-exposure AAD event peak reflects confounding versus increased antibiotic use after a surgical correction of AADs.

Conclusion: This study does not confirm prior studies. Using Cp values to account for residual error, the observed FQ-AAD association cannot be interpreted as significant. Additionally, an AAD event surge in the 60 days before FQ exposure is consistent with confounding by indication, or increased use of antibiotics post-surgery.

Registration: NCT03479736.

MeSH terms

  • Adult
  • Aged
  • Anti-Bacterial Agents* / adverse effects
  • Anti-Bacterial Agents* / therapeutic use
  • Aortic Aneurysm* / chemically induced
  • Aortic Aneurysm* / epidemiology
  • Aortic Aneurysm* / etiology
  • Aortic Dissection* / chemically induced
  • Aortic Dissection* / epidemiology
  • Aortic Dissection* / etiology
  • Databases, Factual*
  • Female
  • Fever / epidemiology
  • Fluoroquinolones* / adverse effects
  • Humans
  • Male
  • Middle Aged
  • Retrospective Studies
  • Risk Factors
  • United States / epidemiology

Substances

  • Fluoroquinolones
  • Anti-Bacterial Agents

Associated data

  • ClinicalTrials.gov/NCT03479736

Grants and funding

This study was supported by Janssen Research & Development, LLC, who provided financial support for the work in the form of salaries for all the authors, and its commitment to pay the associated publishing fees. Janssen Research & Development, LLC’s Standard Operating Procedures require publication of studies that, like this one, concern its products and were intended for publication when they were begun. For the present study, that intention is documented by its registration with ClinicalTrails.gov. The funding organization’s Standard Operating Procedures also require that the study undergo a standard internal company review before it is submitted for publication. Internal company review is limited to roles not responsible for sales or marketing functions. Janssen Research & Development, LLC. did not have any additional role in the study design, data collection, analysis, or preparation of the manuscript. The specific roles of the authors are articulated in the ’author contributions’ section.