Azithromycin is a broad-spectrum macrolide antibiotic that has been reported to be relatively free of cardiotoxicity. Recent accumulating evidence suggests that azithromycin may have proarrhythmic effects similar to erythromycin and clarithromycin.1 This accumulating evidence prompted Ray W and colleagues to conduct this retrospective cohort study to investigate the risk of cardiovasulcar death amongst patients who received azithromycin.2
Ray W and colleagues evaluated the Tennessee Medicaid cohort to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious non-cardiovascular illness and person-time during and shortly after hospitalization. The cohort included patients who took azithromycin (347,795 prescriptions), propensity-score–matched persons who took no antibiotics (1,391,180 control periods), and patients who took amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), or levofloxacin (193,906 prescriptions).2
The primary study end points were cardiovascular death and death from any cause. The authors hypothesized that the incidence of cardiovascular death should be increased if azithromycin is pro-arrhythmic. The authors also included an analysis of death from any cause to ensure against differential misclassification of deaths related to use of a study antibiotic. The analysis conducted estimated the cumulative incidence, or risk, of death during a course of antibiotic therapy. Each study comparison was adjusted for a set of covariates that were possibly associated with both the use of the study antibiotic and the risk of death, using the propensity score.2
The mean summary cardiovascular risk scores for patients taking amoxicillin (9.5), ciprofloxacin (10.3), and levofloxacin (10.6) were higher than the scores for those taking azithromycin (9.3). Among patients who took azithromycin, there were 29 cardiovascular deaths during the 5-day course of treatment (85.2 per 1 million courses). Of these, 22 (64.6 per 1 million courses) were sudden cardiac deaths. When a 5-day course of azithromycin therapy was compared with a matched period of no antibiotic treatment, azithromycin was associated with an increased risk of both cardiovascular death and death from any cause during that 5-day interval. For cardiovascular death, the hazard ratio was 2.88 (95% confidence interval [CI], 1.79 to 4.63; P<0.001). The authors estimate this would result in an additional 47 cardiovascular-related deaths per 1 million courses of azithromycin. They also observed that the potential harm is even greater among patients who were already at elevated risk of cardiovascular adverse events, with azithromycin use associated with an estimated 245 cardiovascular deaths among such at-risk individuals.2
A concern of this observational study, are confounding variables which may have impacted the results. The authors have tried to minimize the impact of confounding variables by including two distinct control groups. The study findings, nevertheless, carry important clinical implications for this frequently prescribed antimicrobial especially for patients with pre-existing cardiovascular risk factors who may benefit from alternative antimicrobial therapy. The Food and Drug Administration (FDA) as a result issued a MedWatch alert in mid May as a result of those study findings and will now update the azithromycin label to reflect the increased risk of cardiovascular death.3
1. Del Rosario ME, Weachter R, Flaker GC. Drug-induced QT prolongation and sudden death. Mo Med 2010;107:53-8.
2. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012;366:1881-90. ...