By Michael H. Crawford, MD

Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco

SYNOPSIS: An analysis revealed fluoroquinolone antibiotic use was associated with later aortic diseases and mortality in patients without known aortic disease.

SOURCE: Chen SW, Chan YH, Chien-Chia Wu V, et al. Effects of fluoroquinolones on outcomes of patients with aortic dissection or aneurysm. J Am Coll Cardiol 2021;77:1875-1887.

Fluoroquinolone antibiotics (FA) have been associated with diseases of the aorta in some general population studies, but little data exist on their effect on patients with known aortic disease or a genetic predisposition to aortic disease (e.g., Marfan syndrome).

Investigators interrogated the Taiwan National Health Insurance Research Database to identify patients admitted to hospitals for aortic diseases from 2001 through 2013 using ICD-9 codes. Chen et al excluded patients younger than age 20 years, those with previously diagnosed aortic disease, and those who died during index admission. Among these patients on at least three days of FA or amoxicillin (AM) as a control, use was assessed every two months. Three study designs were used: self-control, comparing outcomes on FA vs. not on FA; active control, comparing outcomes on FA vs. those on AM; and confounding by indication, where only periods where an infection was diagnosed are used to compare outcomes on FA and AM. The primary outcomes were all-cause mortality, aortic disease mortality, aortic surgery, or aortic stent placement.

The study population consisted of 31,570 patients (mean age, 70 years; 73% men) with 697,171 episodes of aorta disease: aortic dissection (AD) in 43% and aortic aneurysm (AA) in 57%. During the study period, the incidence of AD and AA increased from 4.4% and 6.5%, respectively, to 6.9% and 9.9% (P < 0.001). Also, the use of FA and AM in the two months before index hospital admission increased from 3.6% and 7.1% to 11.5% and 8.8%, respectively (P < 0.001).

Over the entire study period, FA and AM were prescribed to 24% and 36%, respectively of the study population. On FA, after a mean follow-up of 3.5 years, the adjusted hazard ratio of all-cause mortality on FA was 1.61 (95% CI, 1.50-1.73), 1.80 for aortic death (95% CI, 1.50-2.15), 1.49 for aortic surgery (95% CI, 1.24-1.79), and 1.64 for aortic stenting (95% CI, 1.30-2.06). AM use was not associated with any of these outcomes. When only active infection periods were considered, the results were similar. Sensitivity analyses did not show FA associations with traumatic fractures or strokes. Also, these results were not different for patients with AD or AA. The authors concluded the use of FA, but not AM, increased the risk of all-cause mortality and adverse aortic outcomes. Further, they suggested FA should not be used in patients with known AD unless there are no other suitable treatment options available.

COMMENTARY

FAs, such as levofloxacin and ciprofloxacin, are some of the most frequently prescribed antibiotics in the world. They are used for a long list of infectious diseases, from anthrax to urinary tract infections. It is estimated FAs represent about 25% of all antibiotics prescribed, and that 10% of adults will receive one in their lifetime. Considering this ubiquity, rare complications are more likely to be seen. Thus, it is important physicians know their potential serious adverse effects, such as torsade de pointes, hepatic toxicity, and connective tissue disorders. The latter include atraumatic Achilles tendon rupture, retinal detachment, and aortic and mitral valve regurgitation. Experience with general population surveys have suggested an increase in aortic diseases, but some are concerned that the increase in imaging performed when an infection is suspected may have produced confounding by indication. Also, such studies lack a control group. The study by Chen et al addresses these concerns and others. Among the three analyses of the data was the active comparator design, in which AM was used as a control group and no association with aortic disease was found. Also, the authors reduced confounding by indication by only including periods when an infection was present when comparing FA to AM. Therefore, for a retrospective, observational study, it was robust.

However, there were limitations beyond study design. The authors used ICD-9 codes to establish diagnoses, which are subject to human error. There were no data on adherence to therapy. This was an East Asian study population; the results here may not be applicable to other populations. Finally, Chen et al did not provide any data on patients with known connective tissue disorders, such as Marfan syndrome.

The FDA and the European Medicine Agency have suggested avoiding FAs for patients with genetic diseases that affect the aorta and known aortic disease, but these warnings are based on the general population experience rather than data from high-risk groups.1 The Chen et al study addressed this deficiency in the data and provided strong support for this warning.

REFERENCE

  1. Bennett AC, Bennett CL, Witherspoon BJ, Knopf KB. An evaluation of reports of ciprofloxacin, levofloxacin, and moxifloxacin-association neuropsychiatric toxicities, long-term disability, and aortic aneurysms/dissections disseminated by the Food and Drug Administration and the European Medicines Agency. Expert Opin Drug Saf 2019;18:1055-1063.