Reference: JAMA Netw Open. 2020 Jun 1;3(6)
Recent concern regarding the potential QTc-prolonging effects of azithromycin, alone or in combination with other factors, has dampened enthusiasm for prescribing this convenient, relatively inexpensive drug. Zaroff and colleagues from the Kaiser Permanente group in California conducted a retrospective cohort study with about 3 million individuals receiving about 8 million prescriptions for either amoxicillin/amoxicillin-clavulanic acid (78%) or azithromycin alone (22%) and looked at ICD codes to try to discern whether azithromycin was associated with cardiac death.
First, the authors excluded patients who were hospitalized or had significant pre-existing conditions such as cancer. However, compared to patients who received amoxicillin, those who received azithromycin were different at baseline. Very different. There were significant differences between the groups in age, sex, and 43 clinical characteristics ranging from cardiovascular medication use and pre-morbid conditions to recent utilization of health care. Obviously, these potential confounding factors could result in important differences in outcomes even before accounting for drug indication. About 21% of the indications for azithromycin prescriptions were classified as highly severe (such as pneumonia) versus only 4% of indications for amoxicillin prescriptions.
A total of 256 deaths, 112 of which were initially classified as sudden cardiac in etiology, occurred within 10 days among patients who had received one of these two antibiotics. At least 82 of these sudden deaths could not be attributed to an alternative cause after chart review. The adjusted hazard ratio (HR) was significant for all-cause cardiac death within five days of azithromycin prescription (HR 1.8, 95% CI 1.2-2.7), but was not significant for all-cause cardiac death at 6-10 days or sudden cardiac death at any time within 10 days of azithromycin prescription. The most striking results from this study are increased noncardiovascular death (HR 2.2, 95% CI 1.4-3.3) and all-cause death (HR 2, 95% CI 1.5-2.6).
The authors used propensity analysis to try to correct for baseline group differences as well as the severity of the indication for the antibiotic. They report that analyzing the data using this tool for each individual characteristic and groups of variables (such as pulmonary diagnoses combined with steroid or inhaler use) did not change the results. Propensity scoring is a powerful tool to account for differences between two groups at baseline, but it is not possible to predict all the differences that might be important. The authors did not provide much detail, even in the supplement, about how they adjusted for antibiotic indication. Compared with patients who have strep throat, it is not surprising that those with pneumonia have a propensity for receiving azithromycin and a propensity for death.
For more information, see the topic Antibiotics for Adult Outpatients With Community-acquired Pneumonia in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Dan Randall, MD, Deputy Editor for Internal Medicine at DynaMed. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School, and Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia and Clinical Editor at DynaMed.