Dr Wayne A. Ray from the Department of Preventative Medicine, Vanderbilt University School of Medicine, Nashville, US, examined data from patients enrolled in the Tennessee Medicaid program between 1992 and 2006. The study cohort included patients who were adminstered azithromycin (347,795 prescriptions), amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), levofloxacin (193,906 prescriptions) or no antibiotics, in four control periods (1 391 180 control periods). The control patients were matched with patients taking azithromycin using a propensity score for 153 covariates. The primary endpoints were cardiovascular death and death from any cause.

Patients receiving azithromycin during a five-day course exhibited an increased risk of cardiovascular death (HR, 2.88; 95% CI, 1.79 – 4.63; P < .001) and death from any cause (HR, 1.85; 95% CI, 1.25 – 2.75; P = .002). Interestingly, the increased risk of cardiovascular death did not persist after the course of therapy ended. Furthermore, patients treated with amoxicillin had no increase in the risk of death during this period.

Relative to amoxicillin, a five-day course of azithromycin was associated with an increased risk for cardiovascular death (HR, 2.49; 95% CI, 1.38 – 4.50; P = .002) and death from any cause (HR, 2.02; 95% CI, 1.24 – 3.30; P = .005), with an estimated 47 additional cardiovascular deaths per 1 million 5-day courses of treatment.

An estimated 245 additional cardiovascular deaths per 1 million five-day courses were calculated among patients with a high baseline risk. The risk for cardiovascular death was significantly greater than with azithromycin than with either amoxicillin or ciprofloxacin, but did not differ significantly from the risk with levofloxacin.


Ray WAMurray KTHall KArbogast PGStein CM. Azithromycin and the risk of cardiovascular death. New Engl J Med 2012;366:1881-1890.

Cardio Debate Expert Comments

Macrolide antibiotics, used to treat gram-positive bacterial infections, have been known to produce proarrhythmic effects and are associated with an increased risk of sudden cardiac death. Recent studies have shown that one such macrolide antibiotic, azithromycin, has minimal cardiotoxicity but may be associated with a risk of cardiovascular death, albeit small. Studies were carried out to assess the cardiovascular risk associated with the use of macrolide antibiotics, particularly the incidence of ventricular arrhythmias associated with azithromycin use, which are often life-threatening.  Other macrolide antibiotics (e.g erythromycin and clarithromycin) can also increase the risk of life-threatening ventricular arrhythmias and have been also shown to be associated with an increase in sudden cardiac death. The study by Ray et al. demonstrates that a five-day course treatment with azithromycin is associated with a small but significant absolute increase in cardiovascular mortality compared to amoxicillin and ciprofloxacin.  This information needs to be taken into account by the treating pohysician, particularly when prescribing this agent to patients with high cardiovascular risk.  The study also shows that azithromycin is not devoid of cardiotoxic effects.  Further prospective studies in real-life patients are needed to confirm or refute the findings by Ray et al.