Azithromycin and the risk of cardiovascular death

Abstract

Background: Although several macrolide antibiotics are proarrhythmic and associated with an increased risk of sudden cardiac death, azithromycin is thought to have minimal cardiotoxicity. However, published reports of arrhythmias suggest that azithromycin may increase the risk of cardiovascular death.

Methods: We studied a Tennessee Medicaid cohort designed to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious noncardiovascular 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).

Results: 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, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 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 (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P=0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 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. (Funded by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics.).

Figure 1. Cumulative Incidence of Cardiovascular Death and Death from Any Cause among Patients Who Took Azithromycin and Persons Who Did Not Take Study Antibiotics during a 10-Day Period

The 10-day period began with the date on which the prescription was filled for patients who took azithromycin, with a matched period for persons who did not take study antibiotics (the reference group). The cumulative incidence in the reference group was not adjusted; the cumulative incidence in the group of patients who took azithromycin was adjusted for demographic factors and propensity score by multiplying the unadjusted incidence by the ratio of the adjusted to the unadjusted hazard ratio for the 10-day period.

Figure 2. Cumulative Incidence of Cardiovascular Death and Death from Any Cause for Patients Who Took Azithromycin or Amoxicillin during a 10-Day Period

The 10-day period began with the date on which the prescription was filled. The cumulative incidence for patients who took amoxicillin (the reference group) was not adjusted; the cumulative incidence for patients who took azithromycin was adjusted for demographic factors and propensity score by multiplying the unadjusted incidence by the ratio of adjusted to unadjusted hazard ratios for the 10-day period.

Figure 3. Excess Risk of Cardiovascular Death with Azithromycin as Compared with Amoxicillin, According to Decile of Cardiovascular Risk Score

The analysis of excess risk was adjusted for demographic factors and propensity score, which included the recorded antibiotic indication. The excess risk of cardiovascular death with azithromycin (i.e., the difference in the cumulative incidence of cardiovascular death with azithromycin and with amoxicillin) is shown, with the 95% confidence interval (CI), according to the risk-score decile. The characteristics of the patients who took azithromycin, according to decile of risk score for cardiovascular disease, are shown in Table 12 in the Supplementary Appendix.