Use of azithromycin and risk of ventricular arrhythmia

Abstract

Background: There are conflicting findings from observational studies of the arrhythrogenic potential of azithromycin. Our aim was to quantify the association between azithromycin use and the risk of ventricular arrhythmia.

Methods: We conducted a nested case-control study within a cohort of new antibiotic users identified from a network of 7 population-based health care databases in Denmark, Germany, Italy, the Netherlands and the United Kingdom for the period 1997-2010. Up to 100 controls per case were selected and matched by age, sex and database. Recency of antibiotic use and type of drug (azithromycin was the exposure of interest) at the index date (occurrence of ventricular arrhythmia) were identified. We estimated the odds of ventricular arrhythmia associated with current azithromycin use relative to current amoxicillin use or nonuse of antibiotics (≥ 365 d without antibiotic exposure) using conditional logistic regression, adjusting for confounders.

Results: We identified 14 040 688 new antibiotic users who met the inclusion criteria. Ventricular arrhythmia developed in 12 874, of whom 30 were current azithromycin users. The mean age of the cases and controls was 63 years, and two-thirds were male. In the pooled data analyses across databases, azithromycin use was associated with an increased risk of ventricular arrhythmia relative to nonuse of antibiotics (adjusted odds ratio [OR] 1.97, 95% confidence interval [CI] 1.35-2.86). This increased risk disappeared when current amoxicillin use was the comparator (adjusted OR 0.90, 95% CI 0.48-1.71). Database-specific estimates and meta-analysis confirmed results from the pooled data analysis.

Interpretation: Current azithromycin use was associated with an increased risk of ventricular arrhythmia when compared with nonuse of antibiotics, but not when compared with current amoxicillin use. The decreased risk with an active comparator suggests significant confounding by indication.

Figure 1:

Selection of study cohort from 7 databases. AARHUS = Aarhus University Hospital Database, ERD = Emilia-Romagna Database, GePaRD = German Pharmacoepidemiological Research Database, HSD-CSD-LPD = Health Search Database Cegedim Strategic Data Longitudinal Patient Database, IPCI = Integrated Primary Care Information, PHARMO = PHARMO Database Network, THIN = The Health Improvement Network.

Figure 2:

Database-specific risk of ventricular arrhythmia associated with current use of azithromycin compared with current use of amoxicillin (2-stage random-effects model). Values greater than 1.0 indicate an increased risk of ventricular arrhythmia with use of azithromycin (values plotted on logarithmic scale). Cochran Q = 0.08; p = 0.1; I² = 51%. CI = confidence interval, OR = odds ratio. *Databases with fewer than 3 exposed cases were not included in the model.

Figure 3:

Database-specific risk of ventricular arrhythmia associated with current use of azithromycin versus nonuse of antibiotics (2-stage random-effects model). Values greater than 1.0 indicate an increased risk of ventricular arrhythmia with use of azithromycin (values plotted on logarithmic scale). Cochran Q = 3.4; p = 0.3; I² = 11.4%. CI = confidence interval, OR = odds ratio. *Databases with fewer than 3 exposed cases were not included in the model.