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    1 Comment for this article
    Non-Comparability of the groups invalidates the conclusions
    George Anstadt, MD | University of Rochester
    Patients were not randomly allocated to the azithromycin group and the amoxicillin groups; if I had to hazard a guess, I would expect that sicker patients were given azithromycin vs amoxicillin. This guess is corroborated by the greater use by the azithromycin group of many medications used to treat chronic diseases by the authors, who report pharma COI. Is so, the better, and hence safer drug, azithromycin would appear worse. In actual numbers, both of these familiar drug cause few problems even in people with infections e.g. 15 death per million in one series cited.
    Views 30,557
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    Original Investigation
    June 17, 2020

    Association of Azithromycin Use With Cardiovascular Mortality

    Author Affiliations
    • 1Division of Research, Kaiser Permanente Northern California, Oakland
    • 2School of Pharmacy, Chapman University, Irvine, California
    • 3Department of Epidemiology, Pfizer, New York, New York
    JAMA Netw Open. 2020;3(6):e208199. doi:10.1001/jamanetworkopen.2020.8199
    Key Points español 中文 (chinese)

    Question  Is use of azithromycin in an outpaitent setting associated with an increased short-term risk of cardiovascular death and sudden cardiac death in a diverse, community-based population?

    Findings  In this cohort study including 7 824 681 antibiotic exposures, after propensity score adjustment, an outpatient prescription for azithromycin was associated with a significantly increased risk of cardiovascular death within 5 days of exposure compared with amoxicillin, an antibiotic not associated with adverse cardiovascular events.

    Meaning  These findings suggest that prescribers should be aware of the potential association between azithromycin and cardiovascular death.


    Importance  Azithromycin is one of the most commonly prescribed antibiotics in the US. It has been associated with an increased risk of cardiovascular death in some observational studies.

    Objective  To estimate the relative and absolute risks of cardiovascular and sudden cardiac death after an outpatient azithromycin prescription compared with amoxicillin, an antibiotic not known to increase cardiovascular events.

    Design, Setting, and Participants  This retrospective cohort study included 2 large, diverse, community-based integrated care delivery systems with comprehensive capture of encounters and prescriptions from January 1, 1998, to December 31, 2014. The cohort included patients aged 30 to 74 years who had at least 12 months of health-plan enrollment prior to antibiotic exposure. The exclusion criteria were absence of prescription benefits, prescription for more than 1 type of study antibiotic within 10 days, hospitalization or nursing home residence, and serious medical conditions. Risk of cardiovascular death associated with azithromycin vs amoxicillin exposure was calculated after controlling for confounding factors using a propensity score. Data were analyzed from December 1, 2016, to March 30, 2020.

    Exposures  Outpatient prescription of azithromycin or amoxicillin.

    Main Outcomes and Measures  The primary outcomes were cardiovascular death and sudden cardiac death. An a priori subgroup analysis quantified the effects of azithromycin exposure among patients with increased baseline cardiovascular risk. The secondary outcomes were noncardiovascular death and all-cause mortality.

    Results  The study included 7 824 681 antibiotic exposures, including 1 736 976 azithromycin exposures (22.2%) and 6 087 705 amoxicillin exposures (77.8%), among 2 929 008 unique individuals (mean [SD] age, 50.7 [12.3] years; 1 810 127 [61.8%] women). Azithromycin was associated with a significantly increased hazard of cardiovascular death (hazard ratio [HR], 1.82; 95% CI, 1.23-2.67) but not sudden cardiac death (HR, 1.59; 95% CI, 0.90-2.81) within 5 days of exposure. No increases in risk were found 6 to 10 days after exposure. Similar results were observed in patients within the top decile of cardiovascular risk (HR, 1.71; 95% CI, 1.06-2.76). Azithromycin was also associated with an increased risk of noncardiovascular death (HR, 2.17; 95% CI, 1.44-3.26) and all-cause mortality (HR, 2.00; 95% CI, 1.51-2.63) within 5 days of exposure.

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