In this recently published cohort study, Zaroff et al attempted to estimate the relative and absolute risks of cardiovascular (CV) and sudden cardiac death after outpatient use of azithromycin compared with amoxicillin, an antibiotic not known to increase CV events. This retrospective cohort study included two large, diverse, community-based integrated care delivery systems with comprehensive capture of encounters and prescriptions from January 1, 1998, to December 31, 2014. The cohort included patients aged 30 to 74 years who had at least 12 months of health-plan enrollment prior to antibiotic exposure. The exclusion criteria were absence of prescription benefits, prescription for more than one study antibiotic within 10 days, hospitalization or nursing home residence, and serious medical conditions. 

Risk of CV death associated with azithromycin versus amoxicillin exposure was calculated after controlling for confounding factors using a propensity score. Data from December 1, 2016, to March 30, 2020 were analyzed. The primary outcomes were CV death and sudden cardiac death. A subgroup analysis quantified the effects of azithromycin exposure among patients with increased baseline CV risk. The secondary outcomes were non-CV death and all-cause mortality. The study included 7,824,681 antibiotic exposures, including 1,736,976 azithromycin exposures (22.2%) and 6,087,705 amoxicillin exposures (77.8%), among 2,929,008 unique individuals (mean standard deviation [SD] age, 50.7 [12.3] years; 1,810,127 [61.8%] women). Azithromycin was linked to a substantially heightened risk of CV death (hazard ratio [HR], 1.82; 95% CI, 1.23-2.67) but not sudden cardiac death (HR, 1.59; 95% CI, 0.90-2.81) within 5 days of exposure. No escalations in risk were found 6 to 10 days after exposure. 

Comparable results were observed in patients within the top decile of CV risk (HR, 1.71; 95% CI, 1.06-2.76). Azithromycin was also linked to an enhanced risk of non-CV death (HR, 2.17; 95% CI, 1.44-3.26) and all-cause mortality (HR, 2.00; 95% CI, 1.51-2.63) within 5 days of exposure. The authors noted that patients prescribed azithromycin also had a greater risk of non-CV death within 5 days. The most common non–CV deaths observed among the study participants were lung disease, infection, cancer, and diabetes. 

Dr. Zaroff and colleagues concluded that this cohort study found an estimated twofold increased risk of CV death and non-CV death after outpatient azithromycin use compared with use of amoxicillin within a 5-day window after dispensing. Although these analyses cannot establish causality, prescribers should be aware of this potential association.
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