We found that a 5-day course of azithromycin was associated with a small absolute increase in the risk of cardiovascular death, which was most pronounced for patients in the highest decile of the baseline risk of cardiovascular disease. There was no increased risk of death from noncardiovascular causes among patients who took azithromycin, but there was an increase in the risk of death from any cause. The risk of cardiovascular death was significantly greater with azithromycin than with either amoxicillin or ciprofloxacin but did not differ significantly from the risk with levofloxacin.
An important concern in this observational study was confounding by factors associated with both azithromycin use and an increased risk of cardiovascular death. These factors include cardiovascular disease and other coexisting conditions, behavioral risk factors associated with cardiovascular disease (e.g., smoking, high bodymass index, poor diet, and low physical activity), and indication for antibiotic therapy.
We included two distinct control groups in an effort to minimize confounding. One group comprised control periods that were propensity-score– matched with courses of azithromycin therapy. This balanced the prevalence of recorded cardiovascular disease and other coexisting conditions and probably provided some control for behavioral risk factors, given that their effects may be partially mediated through variables more readily identified in the database, such as diagnosed hyperlipidemia, hypertension, diabetes, heart failure, angina, or myocardial infarction. To minimize confounding by the short-term effects of infections, we included a second control group that comprised courses of amoxicillin therapy, which has indications similar to those for azithromycin. Patients who took amoxicillin had no increase in the risk of either cardiovascular death or death from any cause during the study period, which is consistent with our previous findings.8
When azithromycin was directly compared with amoxicillin, in an analysis that also controlled for recorded antibiotic indication, the increased risk persisted for azithromycin.
Our study was prompted by evidence that azithromycin is proarrhythmic,11–17
which led us to hypothesize that it would increase the risk of sudden cardiac death. Patients who took azithromycin did have an increased risk of sudden cardiac death, as identified from a previously developed computer definition.26
However, they also had a similarly increased risk of other, out-of-hospital cardiovascular deaths, although the numbers of these deaths were small. This finding could be due to misclassification, given that our definition of sudden cardiac death was designed to be specific; our prior study suggested that as many as 25% of patients would be misclassified as having died from other cardiovascular causes.26
Alternatively, a proarrhythmic effect of azithromycin might increase the risk of other types of cardiovascular death. Thus, although our data are consistent with an adverse cardiac effect of azithromycin, they cannot establish a specific causal mechanism.
The increased risk of cardiovascular death during the usual 5-day course of azithromycin therapy did not persist after the course of therapy ended. Although concentrations of azithromycin remain elevated in tissue for several days after cessation of oral therapy, serum concentrations decline more rapidly, falling to trough levels within 24 hours.31
For many other drugs with proarrhythmic effects, an elevated serum concentration is a key determinant of increased risk,32
which is an important reason why rapid infusion of erythromycin is not recommended.25
The cohort also included patients who had taken ciprofloxacin and levofloxacin, which provided information on the relative safety of these broad-spectrum fluoroquinolones. For ciprofloxacin, the risks of both cardiovascular death and death from any cause during the study period were similar to those for amoxicillin, a finding that is consistent with the current opinion that ciprofloxacin has limited proarrhythmic liability.1,25
In contrast, levofloxacin, which has recognized proarrhythmic potential,1,25
was associated with a trend toward an increased risk of cardiovascular death, although the point estimates were not significant. When azithromycin was compared directly with levofloxacin, there was no significant difference in the risk of either cardiovascular death or death from any cause.
In conclusion, during 5 days of azithromycin therapy, there was a small absolute increase in cardiovascular deaths. As compared with amoxicillin, there were 47 additional cardiovascular deaths per 1 million courses of azithromycin therapy; for patients in the highest decile of baseline risk of cardiovascular disease, there were 245 additional cardiovascular deaths per 1 million courses.