Fluoroquinolones and the aortaBMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k988 (Published 08 March 2018) Cite this as: BMJ 2018;360:k988
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In his editorial piece on Pasternak's article, which highlights an association between the prescription of fluoroquinolone and the occurrence of an aneurysm (AA) or dissection (AD) within 60 days, Juurlink questions the two curves of patients in the fluoroquinolones (FQ) group and the amoxicillin group. Some issues are raised in this editorial but we would like to point out a misconception.
1/ The curves in the paper are not survival curves but incidence curves of AA or AD within 60 days: “Cumulative incidence of aortic aneurysm or dissection within 60 day risk period from start of study treatment”.
As a matter of fact, the Y-axis is the cumulative number of patients who are diagnosed with an AA or an AD and the X-axis is the time in days. The number of patients who died of AA or AD was not an endpoint and is not mentioned to my knowledge.
2/ Keeping in mind this difference, the question asked at the end of the editorial is: "Does it seem plausible that the anatomy of the aorta could be seriously compromised by fluoroquinolones in a matter of days, as the authors postulate, or is another explanation at play?"
3/ Indeed it is the question asked by the authors which is less appropriate: “Does it seem plausible that the anatomy of the aorta could be seriously compromised by fluoroquinolones in a matter of days“. Obviously, FQ are not bacterial or mycotic micro-organisms which destroy the bacterial wall in a matter of days. FQ are chemical molecules which destroy slowly the collagen matrix of the aortic wall. So it is more probable that all the patients displayed in the figure are patients with previous aneurysms or degenerating aorta which presented some evolution through the infectious episode. Inflammation is a known factor of aortic aneurysm expansion (https://www.ncbi.nlm.nih.gov/pubmed/28720724). In the study, FQ are associated with a greater aggravation of this evolution compared to amoxicillin. In front of this evidence, the temporality criterion is fulfilled and the mention, that the difference between the two curves disappears after 60 days, reinforces this interpretation.
4/ the question of a bias through more frequent imaging is weakened by the criteria of selection of events related to AA and AD (cf Methods).
Competing interests: No competing interests
Jeffrey Aronson draws a distinction between guidelines and criteria. I purposefully employed the latter because, as he has observed (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677430/), the phrase "Bradford Hill criteria" is in common usage. This is especially true among clinicians. Because my commentary was written primarily for a clinical audience with the goal of helping readers feel more comfortable when evaluating an association generated by an observational study, reference to the "Bradford Hill criteria" is justifiable on the grounds of familiarity. In my view, the concepts and their application matter more than what we call them.
Competing interests: No competing interests
In his commentary on the research report by Pasternak et al. on a proposed association of fluoroquinolone antibiotics with aortic damage, David Juurlink refers to the "Bradford Hill criteria". But the items in Bradford Hill's 1965 list (which he called "aspects of an association" and "nine different viewpoints") are, all but one, guidelines, not criteria. Juurlink also writes that "temporality is Bradford Hill's only essential criterion"; this is a pleonasm--a criterion is essential by definition ("A test, principle, rule, canon, or standard, by which anything is judged or estimated", OED)--it requires to be met for the test to be passed. Temporality is the only item in Bradford Hill's list that is a criterion; the rest are guidelines.
This is not a mere verbal quibble. It emphasizes, as Bradford Hill did, that the items in his list do not definitively point to a cause and effect association.
It is also important to note that Bradford's Hill's items are asymmetrical, and that not only their presence but also their absence should be taken into account. For example, the absence of temporality is strong evidence against an association; its presence is of little confirmatory value. Conversely, the presence of similar effects produced by analogous interventions provides strong evidence in favour of an association; its absence is unhelpful. The presence of gradient (i.e. dose responsiveness) supports an association, but its absence is strong evidence against (https://www.ncbi.nlm.nih.gov/pubmed/26119837). Unfortunately, dose relations in pharmacological studies are, as here, rarely investigated.
Competing interests: JKA has written elsewhere about the Bradford Hill guidlines (e.g. https://www.ncbi.nlm.nih.gov/pubmed/19417051) and has published widely on adverse drug reactions.