Estimated Cardiac Risk Associated With Macrolides and Fluoroquinolones Decreases Substantially When Adjusting for Patient Characteristics and Comorbidities

Abstract

BackgroundSome studies have found that antimicrobials, especially macrolides, increase the risk of cardiovascular death. We investigated potential cardiac‐related events associated with antimicrobial use in a population of patients with acute myocardial infarction.Methods and ResultsFor 185 010 Medicare beneficiaries, we recorded prescriptions for azithromycin, clarithromycin, levofloxacin, moxifloxacin, doxycycline, and amoxicillin‐clavulanate. In the following week, we recorded death, acute myocardial infarction, atrial fibrillation or atrial flutter, a non–atrial fibrillation/atrial flutter arrhythmia, or ventricular arrhythmia. We fit unadjusted and adjusted logistic regression models using generalized estimating equations. Adjusted models included patients’ comorbidities, medications, procedures, demographics, insurance status, time since index acute myocardial infarction, number of visits, and the influenza rate. In unadjusted analyses, macrolides and fluoroquinolones were associated with a risk of cardiac events. However, the risk associated with macrolide use was substantially attenuated after adjustment for a wide range of variables, and the risk associated with fluoroquinolones was no longer statistically significant. For example, for azithromycin, the odds ratio for any cardiac event or death was 1.35 (95% confidence interval, 1.27–1.44; P<0.0001), but after controlling for a wide range of covariates, the odds ratio decreased to 1.01 (95% confidence interval, 0.95–1.08; P<0.6688).ConclusionsControlling for covariates explains much of the adverse cardiac risk associated with antimicrobial use found in other studies. Most antimicrobials are not associated with risk of cardiac events, and others, specifically azithromycin and clarithromycin, may pose a small risk of certain cardiac events. However, the modest potential risks attributable to these antimicrobials must be weighed against the drugs’ considerable and immediate benefits.

The Cardiovascular Effects of Treatment with Hydroxychloroquine and Azithromycin

“…We calculated the incidence of CV adverse event codes for acute myocardial infarction ( 19 These codes were converted to ICD-10 using the Centers for Medicare and Medicaid Services (CMS) General Equivalence Mapping Crosswalk. 21 We identified all events where the enrollee had one of these diagnostic codes in either an inpatient or an outpatient claim.…”

“…Given the public health significance of coronavirus disease 2019 (COVID- 19) and the lack of suitable antiviral agents, hydroxychloroquine alone or in combination with azithromycin has been suggested as a possible therapy. 1 However, there is no evidence from randomized controlled trials that this therapeutic regimen is effective for COVID-19.…”

“…18 Cardiovascular risks with azithromycin are associated with underlying patient comorbidities. 19 The risk of serious CV events with hydroxychloroquine have generally occurred in patients with underlying CV, renal, or hepatic disorders. 13,14 The risk of serious CV events associated with the combination of hydroxychloroquine and azithromycin is currently unknown.…”

Azithromycin in COVID-19 Patients: Pharmacological Mechanism, Clinical Evidence and Prescribing Guidelines

“…These studies report conflicting evidence [49][50][51][52][53][54][55][56]. There is very limited and contrasting real-world evidence concerning the risk of azithromycin use and ventricular arrhythmia [57][58][59].…”

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

“…Evidence for Azithromycin Cardiovascular Safety Cook et al were proportionately greater than after a 5-day course of amoxicillin, wherein 42 CV deaths and 29 'sudden cardiac deaths' occurred. By comparison, two observational studies 20,21 highlighted in rows 4 and 7 of Table 2, which involved thousands of CV deaths in each treatment group and populations with intrinsically greater CV risk, demonstrated an odds ratio for death of 0.77 and 0.74, respectively, favoring AZ, and did not suggest excess CV risk when AZ was compared with short-term use of other antibiotics. The disparate findings might be explained by several factors, including the number and magnitude of increase in CV end points, the ability to discern different CV causes of death, and the measures taken to mitigate the impacts of confounders.…”