The Association of Azithromycin Use with Cardiovascular Mortality

The Association of Azithromycin Use with Cardiovascular Mortality
Timothy Isdahl, Pharm.D., Minnesota Community Care

Background: Azithromycin is one of the most commonly prescribed antibiotics in the United States, with over 44 million prescriptions dispensed in 2016, and has been associated with increased risk of cardiac death in some studies. It is commonly prescribed for community-acquired pneumonia, uncomplicated skin infections, strep throat, and other infections.  Azithromycin was also investigated in combination with hydroxychloroquine as a potential treatment for COVID-19, introducing the general public to the risks of additive QT-prolongation and discussion about possible negative cardiac outcomes.  A more full understanding of possible cardiac risks with use of this medication will allow physicians and pharmacists to better evaluate its safety compared to other antibiotics used to treat the same indications.

Objective: To estimate relative and absolute risk of cardiovascular and sudden cardiac death after outpatient azithromycin use compared to amoxicillin.

Study Design: The study by Zaroff et al. was designed as a retrospective cohort based on two large, diverse, community-based care delivery systems over a 16 year time period from 1998 through 2014. A total of 7,824,681 exposures to either azithromycin or amoxicillin among 2,929,009 patients were analyzed. Inclusion criteria included patients between 30 and 74 years old who had 12 months of health-plan enrollment prior to exposure. Exclusion criteria included receiving both studied antibiotics within a ten day period, hospitalization or nursing home residence, and serious medical conditions. Endpoints were measured in exposure windows of 0-5 and 6-10 days after initial exposure to either antibiotic, with the primary outcomes of cardiovascular death and sudden cardiac death and secondary outcomes of noncardiovascular death and all-cause mortality.

Results: Azithromycin was associated with a significantly increased risk of cardiovascular death (RR 1.82 [95% CI 1.23-2.67]), noncardiovascular death (RR 2.17 [95% CI 1.44-3.26]), and all-cause mortality (RR 2.00 [95% CI 1.51-2.63]) compared to amoxicillin within five days of initiation. It was not found to have a statistically significant difference in rate of sudden cardiac death (RR 1.59 [95% CI, 0.90-2.81]) within five days of initiation, and no significant differences were found in the 6-10 day exposure window. 

Conclusions: Use of azithromycin was associated with an increased risk of cardiovascular death, noncardiovascular death, and all-cause mortality compared to amoxicillin within five days of initiation. Multiple confounding variables were found – patients exposed to azithromycin were more likely to receive cardioprotective medications such as ACEs and ARBs, statins, and beta-blockers. Azithromycin was used more often for pulmonary infections, while amoxicillin was used more often for ear, nose, and throat infections. Due to these differences in use by indication and other confounders, no direct causality can be drawn between azithromycin use and the associated risks.

Key Point: Outpatient azithromycin use was found to be associated with an increased risk of cardiovascular death and noncardiovascular death compared to amoxicillin.  This retrospective study is insufficient to establish causality, particularly for noncardiovascular death, due to likely confounding factors.  Pharmacists should continue to assess cardiovascular risk factors for patients receiving azithromycin.


  1. Zaroff JG, Cheetham TC, Palmetto N, et al. Association of Azithromycin Use With Cardiovascular Mortality. JAMA Netw Open. 2020;3(6). doi:10.1001/jamanetworkopen.2020.8199