Azithromycin Use and The Risk of Cardiovascular and Non-Cardiovascular Death

A recent study, published online in JAMA Network Open on June 17, 2020, found a statistically significantly increased relative risk and absolute risk of cardiovascular death and noncardiovascular death with the outpatient use of azithromycin when compared with the use of amoxicillin (an antibiotic not known to increase cardiovascular events) within a five-day window after exposure.

Interestingly, the study found an increased risk of cardiovascular death within 5 days of exposure but not within 6 to 10 days. Also, the study found an increased risk of noncardiovascular and all-cause death within 5 days of exposure to azithromycin.

The results of this study are of particular concern in dentistry. The use of local anesthetics, both with and without epinephrine, may increase the risk of cardiovascular events in predisposed patients. In addition, the use of amoxicillin as a “first-line” agent and azithromycin as a “second-line” agent in dentistry for the treatment of infection and prophylaxis of infective endocarditis is well established.

Azithromycin, a macrolide (along with erythromycin and clarithromycin), is one of the most commonly prescribed antibiotics in the US, with an estimated 44.9 million prescriptions dispensed to outpatients in 2016.

Reports of an association of macrolides with QT interval prolongation and cardiac arrhythmias first appeared more than 20 years ago. Most of the case reports involved patients who were at increased risk for cardiac arrhythmias, including underlying cardiac disease, metabolic anomalies that increase the risk of arrhythmia, or concomitant use of other medications known to prolong the QT interval.

The relative safety of azithromycin was first questioned following a study published in 2012, which reported an association between azithromycin use and sudden cardiac death. At that time, the FDA made changes to product information advising against the use of azithromycin in patients with known risk factors for ventricular arrhythmia, due to concern over QT prolongation and reports of cardiac deaths.

This recent retrospective cohort study included two community-based integrated care delivery systems that captured encounters and prescriptions from January 1, 1998, to December 31, 2014. Data were included for 7.8 million antibiotic exposures (22.2 and 77.8% azithromycin and amoxicillin, respectively) among 2.9 million unique individuals. The study included patients aged 30 to 74 years who had at least 12 months of health-plan enrollment prior to antibiotic exposure. The risk of cardiovascular death associated with azithromycin vs amoxicillin exposure was calculated after controlling for confounding factors using a propensity score.

The authors indicated that while the risk of cardiovascular death is consistent with proposed mechanisms, the increased risk of noncardiovascular mortality is not. The authors stated that “causality could not be established, particularly for noncardiovascular death, owing to the likelihood of residual confounding” but, they added, “prescribers should be aware of this potential association”.

Zaroff JG, Cheetham TC, Palmetto N, et al. Association of Azithromycin Use With Cardiovascular Mortality. JAMA Network Open.2020;3(6):e208199. doi:10.1001/jamanetworkopen.2020.8199

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