The acute effects of azithromycin use on cardiovascular mortality as compared with amoxicillin–clavulanate in US Veterans

Purpose Azithromycin is a common first‐line antibiotic for respiratory infection; however, there is conflicting evidence regarding risk of cardiovascular death. We assessed cardiovascular and noncardiovascular mortality associated with azithromycin versus amoxicillin–clavulanate among US Veterans treated for nonear–nose–throat respiratory infection (“respiratory”) or ear–nose–throat infection indication. Methods Electronic health record data from the US Veterans Health Administration database were used to identify Veterans (30–74 years) with outpatient dispensings of oral azithromycin versus amoxicillin–clavulanate for respiratory or ear–nose–throat infection (January 01, 2000–December 31, 2014). Outcomes assessed were risk of cardiovascular death and noncardiovascular death within 1–5 and 6–10 days postdispensing. Inverse probability of treatment‐weighted proportional hazards models and binomial regression models were used to estimate hazard ratios (HRs) and compute risk differences (RD) per million courses of therapy. Cardiac death (subset of cardiovascular death) was assessed in sensitivity analyses. Results There were 629 345 azithromycin and 168 429 amoxicillin–clavulanate dispensings for respiratory indications, 143 783 azithromycin, and 203 142 amoxicillin–clavulanate dispensings for ear–nose–throat indications. For respiratory indications, azithromycin was not associated with a significantly different risk of cardiovascular death versus amoxicillin–clavulanate within 1–5 days postdispensing (HR [95% confidence interval (CI)]: 1.12 [0.63, 2.00]; RD [95% CI]: 11 [−43, 64] deaths/million courses of therapy). No elevated risk for azithromycin was found for ear–nose–throat indications. Pooled results for both indications via meta‐analysis showed no association between antibiotics and cardiovascular mortality. There was no significant difference in risk of noncardiovascular or cardiac death between antibiotics postdispensing. Conclusion Azithromycin was not associated with elevated risk of cardiovascular or noncardiovascular death versus amoxicillin–clavulanate among US Veterans.