Fluoroquinolones and risk of aortic aneurysm and dissection

HSA would like to bring to the attention of healthcare professionals the potential risk of aortic aneurysm and dissection associated with fluoroquinolones for systemic use. This rare risk was highlighted by the European Medicines Agency (EMA) and the US Food and Drug Administration (US FDA) following their review of overseas cases of aortic aneurysm and dissection in patients who received fluoroquinolones, and data from epidemiological and non-clinical studies which suggest an increased risk of aortic aneurysm and dissection after treatment with systemic fluoroquinolones. Patients at increased risk included those with a history of pre-existing aneurysm, atherosclerosis, hypertension and the elderly.

Fluoroquinolones are a class of broad spectrum antibiotics that interfere with bacterial DNA replication and exert bactericidal activity by inhibiting the activity of DNA gyrase and topoisomerase. There are seven systemic fluoroquinolones registered locally, namely ciprofloxacin, ofloxacin, norfloxacin, lomefloxacin, levofloxacin, moxifloxacin and pefloxacin.

About aortic aneurysm and dissection

Aortic aneurysm is defined as a localised or diffuse dilation of the aorta, while aortic dissection occurs when there is separation of the layers within the aortic wall. These conditions are associated with alterations in collagen content, concentrations and structure.  Since the majority of collagen in the Achilles tendon and aorta comprises the same types, it has been postulated that drugs which contribute to tendon ruptures could also cause or aggravate aortic aneurysm and dissection via a similar mechanism.¹ Fluoroquinolones can destroy the collagen and connective tissue along the aortic wall by upregulating multiple matrix metalloproteinases and causing degenerative changes in tenocyte cells, resulting in reduction in the diameter and amount of certain type of collagen fibrils. As such, they may contribute acutely to aneurysm progression and rupture although the exact mechanism remains to be confirmed.

The background risk of aortic aneurysm or dissection can vary depending on the population, ranging from nine aortic aneurysm events per 100,000 people per year in the general population to 300 aortic aneurysm events per 100,000 people per year in individuals at highest risk (e.g. those over the age of 85 years).² Conditions predisposing to this risk include a family history of aneurysm disease, pre-existing aortic aneurysm or dissection, genetic predisposition (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome), atherosclerosis, hypertension and the elderly.

Findings from epidemiological studies

Across multiple epidemiological studies published between 2015 to 2018,^1,3-5 there appears to be consistent evidence pointing to an approximately two-fold increased risk over the baseline risk of aortic aneurysm or dissection observed with fluoroquinolone use. However, study limitations such as confounding by indication and small sample sizes precluded determination of a definite causal association for this risk.

In a retrospective cohort study by Pasternak et al⁴ to evaluate the risk of aortic aneurysm or dissection with oral fluoroquinolone use compared to amoxicillin use in patients aged 50 years or older, the fluoroquinolone group had a 1.66-fold increased risk (95% CI=1.12-2.46) within a 60-day risk period, with the increased risk occurring mainly in the first 10 days after the start of treatment. Another self-controlled study by Lee et al⁵ in elderly patients with a mean age of 71 years old showed an increased risk of aortic aneurysm or dissection associated with exposure to fluoroquinolones (odds ratio [OR]=2.71; 95% CI=1.14-6.46).

International regulatory actions

(a)   EMA

In September 2018, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) concluded that there was a risk of aortic aneurysm and dissection associated with the use of systemic and inhaled fluoroquinolones. Their safety review took into consideration evidence from epidemiological^1,3,4 and non-clinical studies,⁶ spontaneous reports and responses from marketing authorisation holders (i.e. pharmaceutical companies). The PRAC subsequently recommended that the package inserts (PIs) of systemic and inhaled fluoroquinolones be updated to include the risk of aortic aneurysm and dissection, and a Dear Healthcare Professional Letter be distributed to communicate on this safety concern.

(b)   US FDA

In December 2018, the US FDA issued a drug safety communication to warn about the risk of aortic aneurysm and dissection associated with fluoroquinolones. In addition to the published observational studies,^1,3-5 their review also included 56 cases of aortic aneurysm or dissection reported to US FDA during or after treatment with fluoroquinolones from 2015 to 2018. However, the agency noted that all patients from these cases had at least one risk factor for aortic aneurysm and dissection and the cause of these specific events could not be determined. Based on their review, the US FDA recommended a class-wide labelling update to the PIs of systemic fluoroquinolones to include warnings on the risk of aortic aneurysm and dissection.

Local situation and HSA’s advisory

To date, HSA has not received any local reports of aortic aneurysm or dissection associated with fluoroquinolones. The Singapore PIs for systemic fluoroquinolones are being updated to include the risk of aortic aneurysm and dissection.

Healthcare professionals are advised to take into consideration the above safety information when prescribing fluoroquinolones, especially in patients who are at risk of aortic aneurysm and dissection. This includes patients with a history of peripheral atherosclerotic vascular disease, hypertension, certain genetic disorders that involve blood vessel changes (such as Marfan syndrome and Ehlers-Danlos syndrome), and the elderly.

Healthcare professionals are also encouraged to counsel their patients on other adverse effects associated with fluoroquinolones as appropriate, such as those involving the tendons, muscles and joints, and the nervous system.     

References

1. BMJ Open 2015; 5:e010077

2. BJS 2015; 102: 907-15

3. JAMA Intern Med 2015;175:1839-47

4. BMJ 2018; 360: k678

5. J Am Coll Cardiol 2018; 72:1369-78

6. JAMA Surg 2018; 153:e181804