The Weight of Evidence From Electrophysiology, Observational, and Cardiovascular End Point Studies Demonstrates the Safety of Azithromycin

Abstract

Increased use of azithromycin (AZ) in treating infections associated with coronavirus disease 2019 (COVID-19) and reports of increased incidence of prolonged corrected QT (QTc) interval associated with AZ used with hydroxychloroquine prompted us to review the latest evidence in the literature, present additional analyses of human cardiovascular (CV) electrophysiology studies, and to describe sequential steps in research and development that were undertaken to characterize the benefit-risk profile of AZ. Combined QTc findings from electrocardiograms taken during oral and i.v. pharmacokinetic-pharmacodynamic studies of AZ suggest that clinically meaningful QTc prolongation is unlikely. Findings from several observational studies were heterogeneous and not as consistent as results from at least two large randomized controlled trials (RCTs). The QTc findings presented and observational data from studies with large numbers of events are not consistent with either a proarrhythmic action of AZ or an increase in frequency of CV deaths. Well-powered RCTs do not suggest a presence of increased risk of CV or sudden cardiac death after short-term or protracted periods of AZ usage, even in patients at higher risk from pre-existing coronary disease.

Figure 1

Relationship between azithromycin (AZ) concentration and Fridericia’s rate‐corrected QT interval (∆QTcF) on day 3 following oral administration of AZ and chloroquine (CQ) for 3 days (left panel) or following a single i.v. infusion of AZ (right panel). In the left panel, the mean differences in time matched changes from baseline in ∆QTcF between CQ plus AZ groups and CQ were regressed against corresponding mean AZ concentrations. In the regression model, treatment group was included as a random effect, AZ was included as a fixed effect, and there was no intercept term. (Legend: triangles: CQ + 500 mg AZ; diamonds: CQ + 1,000 mg AZ; squares: CQ + 1,500 mg AZ; solid line: regression model predictions). Right panel legend: circles represent individual subject data; solid line: regression model prediction; arrows represent corresponding mean peak plasma concentration (C_max) values from the oral study after 500 mg and 1,500 mg dose of AZ as noted in Table 1 .

Figure 2

Comparison of hazard ratios at various censoring times in the Weekly Intervention with Azithromycin for Atherosclerosis and its Related Disorders (WIZARD) trial. ¹⁶ Hazard ratio (± 95% confidence interval (CI)) for treatment effect with azithromycin at various times after randomization. Reproduced with permission from JAMA 2003; 290(11):1459‐1466. ©2003 American Medical Association. All rights reserved.