Risk of Cardiovascular Death and Azrithomycin

Erythromycin and clarithromycin, broad-spectrum macrolide antibiotics, have been shown to increase the risk of serious ventricular arrhythmias and are associated with an increased risk of sudden cardiac death. Azithromycin is closely related to those drugs and has been considered relatively free of cardiotoxic effects. Recent evidence has begun to suggest that azithromycin may also have proarrhythmic effects. The FDA’s Adverse Event Reporting System includes >20 reports of torsades de pointes associated with azithromycin.

Researchers recently conducted a retrospective cohort study of mortality in patients who were treated with azithromycin. They based their study on the hypothesis that patients who took the antibiotic, compared with individuals who did not take any antibiotics as well as with patients who took other antibiotics, would be at an increased risk of cardiovascular death, particularly sudden cardiac death. Results were reported in the New England Journal of Medicine [2012;366(20):1881-1890].

Data from the Tennessee Medicaid program were utilized to identify the 3 study cohorts: (1) patients who took azithromycin (347,795 prescriptions); (2) a propensity-score-matched group who did not take any antibiotics (1,391,180 control periods); and (3) patients who took amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), or levofloxacin (193,906 prescriptions).

In the azithromycin cohort, 77.5% were female, mean age was 49 years, 24% were current or past users of an angiotensin-converting-enzyme inhibitor, 11.3% had visited the emergency department within the past 30 days, and 28.4% had used an antibiotic in the past 30 days. Characteristics of the azithromycin group and the controls were similar. Patients who were taking ciprofloxacin or levofloxacin were more likely to have complications of diabetes, incontinence, and use a wheelchair or walker. The mean summary cardiovascular risk scores were higher for patients taking any of the other antibiotics compared with those for patients taking azithromycin.

Compared with individuals not taking an antibiotic, during 5 days of therapy, patients taking azithromycin had an increased risk of cardiovascular death (hazard ratio [HR], 2.88; 95% confidence interval [CI], 1.79-4.63; P <.001). The risk was increased for both sudden cardiac death as well as other cardiovascular deaths. There was no increased risk of death from noncardiovascular causes; however, the risk of death from any cause was increased (HR, 1.85; 95% CI, 1.25-1.75; P=.002) for those taking azithromycin.

For patients taking amoxicillin, there was no increase in the risk of death during the 5-day treatment period. Compared with patients taking amoxicillin, those taking azithromycin had an increased risk of 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). The increased risk of death with azithromycin compared with ciprofloxacin was significant during the first 5-days of treatment (HR, 3.49; 95% CI, 1.32-9.26; P =.01); there was also a nonsignificant trend toward an increase in death from any cause. There was no significant difference in mortality with azithromycin compared with levofloxacin during the 5-day treatment period.

For the 10-day period following the prescription fill date, use of azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 1.86; 95% CI, 1.27-2.73; P =.002). There was no significant increase in the risk of death from any cause.

“During 5 days of azithromycin therapy, there was a small absolute increase in cardiovascular death, which was most pronounced among patients with a high baseline risk of cardiovascular disease," the researchers said.