Risk of Cardiovascular Death May Increase With Use of Azithromycin


Compared with amoxicillin, azithromycin was shown in a recent study to increase both the relative and absolute risks of cardiovascular death among patients being treated on an outpatient basis.

Compared with amoxicillin, azithromycin increased both the relative and absolute risks of cardiovascular death (CVD) among patients being treated on an outpatient basis in 2 community-based integrated care delivery systems in California, report study results in JAMA Network Open.

“Azithromycin is one of the most commonly prescribed antibiotics in the United States,” the study authors noted. “It has been associated with an increased risk of cardiovascular death in some observational studies.”

Because of these safety concerns, by 2013, the FDA had changed azithromycin’s label to include a caution against using the macrolide in patients at high risk for ventricular arrhythmia. Nevertheless, study results on the drug’s safety and effectiveness continue to be mixed.

The present retrospective cohort study enrolled 2.9 million-plus individuals, all members of Kaiser Permanente Northern California (KPNC) or Southern California (KPSC), who ranged in age from 30 to 74 years (mean [SD], 50.7 [12.3]). Overlapping study periods covered January 1, 1998, through December 31, 2013, for KPSC and January 1, 1998, through December 31, 2014 for KPNC.

The prescription dispense date for azithromycin or amoxicillin, including amoxicillin-clavulanate, was considered the index date for this study, and everyone had to be in their health plan for at least 1 year before the index date. Data were analyzed between December 1, 2016, and March 30, 2020.

The results showed that of the 7.8 million antibiotic exposures, 1.7 (22.2%) million were for azithromycin versus 6.1 (77.8%) million for amoxicillin. Despite the 2.4-fold greater prescription rate for amoxicillin, the mortality risk for CVD from azithromycin was still significantly increased (HR, 1.82; 95% CI, 1.23-2.67). However, this risk did not carry over for sudden cardiac death (HR, 1.59; 95% CI, 1.23-2.67).

Study results also show that there were more prescriptions for azithromycin in the back half of the study period, for a mean (SD) of 2008.3 (4.4) calendar years compared with 2005.5 (4.8) for amoxicillin.

“A hypothesized mechanism of harm is potential increased risk of cardiac arrhythmia during therapy, and the typical duration of use for azithromycin and amoxicillin is between 7 to 10 days,” the authors noted. Therefore, their analysis was divided into 2 periods: 0 to 5 days and 6 to 10 days.

The greater risk of CVD death from azithromycin use was only shown to exist in the 0-to-5-day period, as was an increased risk of death from noncardiovascular causes (HR, 2.17; 95% CI, 1.44-3.26) and all-cause mortality (HR, 2.00; 95% CI, 1.51-2.63). This risk was also elevated for study participants in the top decile of the cardiovascular risk score (HR, 1.71; 95% CI, 1.06-2.76).

Additional results detail that patients prescribed or exposed to azithromycin had greater rates of respiratory-related diseases or more often received cardioprotective medications, respectively, compared with amoxicillin.

Patients had higher rate of the following respiratory conditions for the year leading up to the azithromycin prescription:

  • Pneumonia: 14.0% vs 3.5% (P <.001)
  • Chronic obstructive pulmonary disease: 20.6% vs (P < .001)
  • Asthma: 22.6% vs 10.4% (P < .001)

They also received these cardioprotective medications more often after having taken azithromycin:

  • Angiotensin-converting enzyme inhibitors: 17.5% vs 14.7% (P < .001)
  • Angiotensin receptor blockers: 5.8% 3.4% (P < .001)
  • Statins: 24.9% vs 19.6% (P < .001)
  • β-blockers: 15.3% vs 13.8% (P < .001)

When interpreting their results, the authors mention to do so with caution, owing to the following confounders:

  • Missing data on medication indication of use
  • Varying disease severity
  • Comorbid conditions that increase the likelihood of needing azithromycin
  • Changes in disease risk and prescribing patterns
  • Misclassification of study outcome

“These findings suggest that outpatient azithromycin use was associated with an increased risk of cardiovascular death and noncardiovascular death,” the authors concluded. “Causality cannot be established, particularly for noncardiovascular death, owing to the likelihood of residual confounding.”


Zaroff JG, Cheetham TC, Palmetto N, et al. Association of azithromycin use with cardiovascular mortality. JAMA Netw Open. Published online June 17, 2020. doi:10.1001/jamanetworkopen.2020.8199

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