Fluoroquinolones: The New Heartbreaker?

Fluoroquinolones: The New Heartbreaker?
Mo Abotteen, PharmD Intern and Jennifer Seltzer, PharmD
March 15, 2018

Fluoroquinolones (FQ) are a class of antibiotics riddled with severe toxicities. In 1999, grepafloxacin was pulled from the market for adverse cardiac events, and trovafloxacin was removed just a year later for hepatic toxicity.1 In addition to this, the FQ class carries a black box warning for tendonitis and tendon rupture. The latest class toxicity to be identified is FQ-induced aortic dissection and aneurysm.2 The mechanism behind these FQ toxicities comes from upregulation of matrix metalloproteinases that reduce collagen production and quality. FQs are also known to impose oxidative stress on tendon cells, causing loss of structural integrity. 2
Lee et al.,2 in a nested case-control study, evaluated the relationship between FQ use and development of an aortic aneurysm or dissection in a cohort of nearly one million Taiwanese individuals monitored from January 2000 to December 2011. In this study, 1477 cases of an aortic aneurysm or dissection were found and matched to 147,700 control cases that were not prescribed FQs. Investigators found that patients with current FQ use, defined as having a prescription for a FQ within 60 days of an aortic aneurysm or dissection diagnosis, had an increased risk of an aortic aneurysm (odds ratio, 2.43; 95% confidence interval (95% CI), 1.83-3.22) when compared to a controlled cohort. Limitations of this study included not knowing whether patients in this cohort may have had existing cardiac issues that would have predisposed them to aortic dissection regardless of FQ use.
A population-based longitudinal cohort study from Canada by Daneman et al.3 assessed FQ-associated toxicities in a cohort of 1.7 million aged 65 years or older, with 657,950 receiving FQs. Results showed that FQ use was associated with an increased risk of aortic aneurysm compared to those patients who had never received a FQ (1.7% vs 0.7%, p < 0.001). Investigators used amoxicillin as a comparator of FQ use and found that FQs still had an increased risk of aortic complications [adjusted hazard ratio (HR) FQ vs amoxicillin, 2.24 (95% CI, 2.02 to 2.49) vs 1.50 (95% CI, 1.32 to 1.70)].
The latest study in the FQ aortic complication debate was conducted by Pasternak et al.4 and published in early March 2018. This nationwide historical cohort in Sweden found consistent results with the studies above. FQ use was associated with an increased risk of an aortic aneurysm or dissection compared to patients prescribed amoxicillin within 60 days of starting treatment (1.2 cases/1000 patient years vs 0.7 cases/1000 patient years; HR 1.66; 95% CI, 1.12 to 2.46).
Currently, the FDA does not support the position that FQs cause aortic aneurysms or dissections.5 This is due to the retrospective nature of the studies discussed above and their inability to establish causality between FQs and aortic dissections and aneurysms.
The incidence of aortic aneurysm and dissection is low with FQ use. Aortic aneurysm data from available observational studies may be considered when contemplating FQ therapy in patients with a history of cardiac complications, but should not be the only evidence to guide clinical decisions. Further investigation is warranted to establish the cause and effect relationship between FQ-induced aortic aneurysms and dissections.
1. Hooper DC. Fluoroquinolones. In: Post T, eds. UpToDate. (Internet). Waltham, MA. UpToDate; 2018. Available from: www.uptodate.com. Accessed March 9, 2018.
2. Lee C, Lee MG, Chen Y, et al. Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone. JAMA Intern Med. 2015;175(11):1839-47.
3. Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open. 2015;5:e010077.
4. Pasternak B, Inghammar M, Svanström H. Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. BMJ. 2018;360:k678.
5. FDA drug safety communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects. (May 10, 2017) https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm (Accessed on March 09, 2018).