Azithromycin and the Risk of Cardiovascular Death

Study Questions:

Macrolide antibiotics are considered proarrhythmic, but azithromycin is thought to have minimal cardiotoxicity. Does azithromycin increase the risk of cardiovascular death?

Methods:

A Tennessee Medicaid cohort designed to detect an increased risk of death related to short-term cardiac effects of medication was assessed from 1992 (introduction of azithromycin) through 2006. The study design excluded patients with serious noncardiovascular illness and time shortly after hospitalization. The cohort included patients who took azithromycin (347,795 prescriptions), propensity-scoreā€“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).

Results:

Mean age was 48.6 years, and 77.5% were female. During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio [HR], 2.88; 95% confidence interval [CI], 1.79-4.63; p < 0.001) and death from any cause (HR, 1.85; 95% CI, 1.25-2.75; p = 0.002). Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (HR, 2.49; 95% CI, 1.38-4.50; p = 0.002) and death from any cause (HR, 2.02; 95% CI, 1.24-3.30; p = 0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin, but did not differ significantly from that with levofloxacin.

Conclusions:

During 5 days of azithromycin therapy, there was a small absolute increase in cardiovascular deaths, which was most pronounced among patients with a high baseline risk of cardiovascular disease.

Perspective:

Azithromycin is very often the antibiotic of choice for respiratory infections because of simplicity and prolonged tissue concentration. The increased risk of cardiovascular death was found during the 5 days of use, but not in the subsequent 5 days. Physicians need to consider the proarrhythmic effect when prescribed alone or with antiarrhythmic drugs and drug interactions with some statins (28% in this study were on statins). Ciprofloxacin did not cause an increase in cardiovascular events compared to amoxicillin or the control group.

Keywords: Drug Interactions, Incidence, Respiratory Tract Infections, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiovascular Diseases, Macrolides, Risk Factors, Tennessee, United States


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