Azithromycin is a macrolide antibiotic commonly used to treat infections of the respiratory tract. Cases of cardiac toxicity following administration of oral azithromycin have been reported. This study was a statewide, retrospective multigroup cohort performed on Tennessee residents enrolled in Medicaid who had been prescribed azithromycin. Its objective was to determine if azithromycin ingestion increased risk of cardiovascular disease compared to using amoxicillin, ciprofloxacin, levofloxacin, or no antibiotic at all. Funding was from a grant by the National Heart, Lung, and Blood Institute, and a cooperative agreement from the Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics.

Patient data (death certificates, statewide hospital-discharge database, Medicaid enrollment medical car receivers, dates, antibiotics, and other medications, and causes of death) were obtained from the Tennessee Medicaid program, and then de-identified. Prescriptions for azithromycin created between 1992 and 2006 were obtained for patients who had: no life-threatening non-cardiovascular disease, diagnosis of drug abuse, residence in a nursing home in the previous year, hospitalization or antibiotic use in the previous 30 days. Patients also had to have at least 365 days of enrollment in Medicaid, and were excluded if they had a high risk of death from causes unrelated to short-term effects of proarrhythmic medications (full exclusion criteria are available in the Supplement Appendix, which was not accessible).

Since the study was not controlled, 153 covariates were used to create propensity scores to increase the likelihood that similar patients were compared. Patients who had been prescribed a 5-day regimen of azithromycin were compared to those had also received a 10-day regimen of amoxicillin, ciprofloxacin, and levofloxacin, or a control period with no antibiotic use. The same patient could have been received more than one intervention; patients assigned to a control group could not have used antibiotics in the last 30 days. Repeated-measures analysis and stratification of propensity-score deciles were done to test the validity of the assumptions.

The outcomes studied were cardiovascular disease (defined in the Supplement Appendix) and death from any cause. Among the cardiovascular diseases, sudden cardiac death was measured, which was defined as a sudden pulseless condition (arrest) that was immediately fatal and consistent with a ventricular tachyarrhythmia that occurred in the absence of a known non-cardiac condition as the proximate cause of death. The endpoints were measured over 10 days for all interventions, with day 1 being the date the prescription was prescribed.

In total, there were 1,391,180 control periods, 347,795 prescriptions for azithromycin, 1,348,672 for amoxicillin, 264,626 for ciprofloxacin, and 193,906 for levofloxacin. After matching patients by propensity scores, their baseline characteristics were similar, except those prescribed ciprofloxacin or levofloxacin were more likely to have diabetes complications (specified in article), incontinence, and wheelchair or walker use. Azithromycin users were mostly women (77.5%) and on average, 48.6 years old. Unfortunately, I can only include text here on EzineArticles so please refer to the original article to view tables.

Results for cumulative incidences of cardiovascular disease and sudden cardiac death, and cardiovascular death and death from any cause during days 1-10 are given (two-sided p-value, 95% confidence interval). During days 1-5, there was no significant difference in cardiovascular death or death from any cause between azithromycin and levofloxacin, and in death from any cause between azithromycin and ciprofloxacin. For all days 1-10, there was no significant difference in death from any cause between any comparisons. In regards to cardiovascular death, there was no significant difference between azithromycin and levofloxacin. The repeated-measures analysis and stratification of propensity scores by deciles yielded similar results (in Table 11 of Supplement Appendix).

The authors believe there is a small absolute increase in risk of cardiovascular death with 5-day course of azithromycin, but no increase in risk of non-cardiovascular death. The risk of cardiovascular disease was significantly higher with azithromycin than with any intervention, except levofloxacin. The increased risk of cardiovascular death did not persist beyond the 5-day regimen of azithromycin therapy. The authors attribute this finding to the decline in serum concentration within 24 hours. There was also an increased risk in other, out-of-hospital cardiovascular deaths. Based on their prior study, they claim up to 25% of deaths could have misclassified as having other cardiovascular causes, or that azithromycin could have potentiated these cases.

1. Poluzzi E, Raschi E, Moretti U, et al. Drug-induced torsades de pointses: data mining of the public version of the FDA Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf. 2009; 18: 512-8.
2. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular disease. N Engl J Med. 2012; 366: 1881-90.