Best Evidence Analyses and Commentary

FDA Reviews Risk of Cardiotoxicity with Azithromycin
June 2012

 The U.S. Food and Drug Administration (FDA) issued a statement regarding a study recently published in the New England Journal of Medicine (NEJM) that indicates a risk of mortality in patients taking azithromycin. Azithromycin is a macrolide antibiotic, related to clarithromycin and erythromycin which have known associations with cardiotoxicity. All macrolides currently carry a warning for the possibility of prolonged Qt intervals during a course of treatment.

This new study published in the May 17, 2012 issue looked at Tennessee Medicaid records for patients prescribed azithromycin from 1992 to 2006. Patients were age 30 – 74 and generally healthy with no history of life-threatening disease or recent hospitalization.

The primary outcomes measure were cardiovascular and all-cause mortality. Patients receiving azithromycin prescriptions were compared with patients who received prescriptions of amoxicillin/amoxicillin with clavulanate, ciprofloxacin and levofloxacin. More than 3.5 million prescriptions were reviewed. Five days of treatment with azithromycin was compared to a ten-day course with other antibiotics and a control group of patients not taking an antibiotic.

Deaths due to cardiovascular reasons occurred in nearly three times the number of patients taking amoxicillin or no antibiotic. Deaths were similar in patients taking amoxicillin or no antibiotic. Total numbers included approximately 30 deaths per 1 million treatment courses in the control group and amoxicillin group with 85.2 deaths per 1 million treatment courses in the azithromycin group. Deaths in patients on azithromycin were determined to be statistically significant with a p value of < 0.001. Sudden cardiac death and mortality due to other cardiac reasons in patients taking azithromycin were similar.

Total deaths were nearly twice as high in the azithromycin group with an odds ratio of 1.85 (95% CI 1.25-2.75).

Patients taking ciprofloxacin did not show any difference in mortality as compared to patients taking amoxicillin whereas azithromycin was associated with 3.5 times more deaths than ciprofloxacin. When compared with levofloxacin, there was no significant difference in mortality for azithromycin.

The FDA is reviewing information and has not issued any new warnings for cardiovascular risk during azithromycin use. The benefits of this medication may still outweigh the risks for most patients. This new study indicates only a small absolute risk of mortality of 0.01% with the use of azithromycin when compared with a risk of 0.006% in patients not using antibiotics. This translates into a number needed to harm (NNH) of 1 in 21400 where one death would be expected for approximately every 21400 courses of treatment. Until more information is available, consider caution when prescribing azithromycin to patients with known cardiac problems. 


FDA Statement regarding azithromycin (Zithromax) and the risk of cardiovascular death. Accessed May 31, 2012.

Ray, W.A. et al. Azithromycin and the Risk of Cardiovascular Death. N Engl J Med 2012;366:1881-90.

Schwartz, Alan. Risk Reduction Calculator. University of Illinois at Chicago. Accessed May 31, 2012.


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