Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort studyBMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k678 (Published 08 March 2018) Cite this as: BMJ 2018;360:k678
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We read with interest the recent study by Pasternak and colleagues on vascular complications from fluoroquinolone use (1). Despite the huge number of patients included, we have serious doubts about the validity of the study results and its implicit causation.
The difference in event rates is so small (0.05%) that even the slightest imbalances in the populations studied could bear major confounding effects. Although the authors meticulously included 47 covariates as predictors in their propensity score matching covering demographic information, medical history, prescription drugs, and healthcare use, they omitted major factors such as indication for the antibiotic prescription and more importantly the site of infection. Having a few percentage points higher abdominal infections (e.g. gastrointestinal or pyelonephritis) in one group could alter (a) the detection rate of abdominal aneurysms by a more careful clinically focused examination, (b) the vulnerability by adjacent inflammatory processes and (c) the chance of a slightly higher misdiagnosis of abdominal symptoms as infectious than an aortic process. As the primary differences were found primarily in the abdominal aorta, the above effects should be considered carefully
Even though the information on side effects of different antibiotics is of utmost interest, we have serious concerns that the results of the study, which could well influence future recommendations by the National Institute of Health on prescription procedures, are heavily affected by the above-mentioned biases, and that the implicit causation is not as strong (if existing at all) as suggested.
(1) BMJ 2018;360:k678
Competing interests: No competing interests
In an article in a recent issue of BMJ on the association between fluoroquinolone (FQ) use and the risk of aortic aneurysm and dissection, Pastermaket al1 reported that FQ use was associated with an increased risk of aortic aneurysm and dissection using amoxicillin as a comparator. However, we have several serious concerns.
When antibiotics are prescribed, there will be increased chances of a physician to prescribe an image study to survey for the infection source. Therefore there will probably be more aortic aneurysms that were incidentally discovered, and even more after usage of 2nd/3rd line antibiotics. Hence the authors need to clarify that the increased aortic aneurysms associated with the usage of FQ is not related to more utilization of image studying. Both this study1 and Daneman et al‘s study2 failed to demonstrate that amoxicillin is a negative tracer, ie. the usage of amoxicillin was associated with increase of aortic aneurysms too, though to a lesser extent than FQ.
In addition, the indication and the use of FQ should be largely different from amoxicillin. In contrast to amoxicillin, FQ is a broad-spectrum antibiotic, and ciprofloxacin – the most common FQ in this study can be indicated in complicated intra-abdominal infection, infectious diarrhea and complicated urinary tract infection. Therefore, it should be expected that FQ users are more ill than amoxicillin users, and FQ users may have more image studying, especially abdominal examinations than amoxicillin users. Moreover, the risk being highest during the first 10 days from the start of FQ use may be due to more examinations having been performed during the initial treatment period. All of these things suggest that more incidental aortic aneurysms can be found in FQ users than amoxicillin users, and help to explain why the most common type of aortic aneurysm is abdominal aneurysm among FQ users in this study.
Furthermore, it is supposed that after excluding the cases whose aortic aneurysm is incidentally diagnosed, the difference between FQ and amoxicillin users may disappear. It may help explain why the significant association is largely drive by aortic aneurysm in this study. This hypothesis can be demonstrated in the sensitivity analysis in this study. Regarding cases with dissection or rupture alone, which should cause severe discomfort, the difference did not reach statistical significance.
1. Pasternak B, Inghammar M, Svanström H. Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. BMJ 2018;360:k678. doi: 10.1136/bmj.k678.
2. Daneman N, Lu H2, Redelmeier DA. Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open. 2015;5(11):e010077. doi: 10.1136/bmjopen-2015-010077.
Competing interests: No competing interests