Increased Risk of Cardiac Arrhythmia and Death with Azithromycin and Levofloxacin

Since the 2012 FDA warning of QT prolongation risks with azithromycin, the drug has been associated with increased risk of death among patients at high baseline risk, but not for younger and middle-aged adults. A recent study examined the risks for cardiac arrhythmia and mortality for older, mostly male individuals receiving azithromycin, amoxicillin, or levofloxacin [Ann Fam Med. 2014;12(2):121-127].

This retrospective, cohort study among US veterans took place between September 1, 1999, and April 30, 2012. Information was collected from 14 million individuals who received care at 140 Veterans Affairs (VA) medical centers and 600 community-based clinics using national VA electronic health record data.

The primary and secondary outcomes were all-cause mortality and serious cardiac arrhythmia, defined as any inpatient or emergency department encounter/utilization for cardiac arrhythmia according to the International Classification of Disease, Ninth Revision, Clinical Modification coding for:

• Long QT syndrome

• Ventricular tachycardia

• Ventricular fibrillation

• Ventricular flutter

• Cardiac arrest

Patients were included in the study if they were aged 33 to 74 years; had no life-threatening noncardiovascular illness; had no diagnosis of drug abuse; were not residing in a nursing home during the previous year; had no hospitalization in the preceding 30 days; had not received another antibiotic in the previous 29 days; and were enrolled in VA care, already experiencing at least 1 VA clinical, laboratory, or pharmacy encounter for 1 year preceding the study index date.

During the study, >1.6 million antibiotics were dispensed for amoxicillin (n=979,380), azithromycin (n=594,792), and levofloxacin (n=201,798). Two treatment follow-up periods were examined: (1) the first 5 days following dispensing; and (2) days 6 through 10 after antibiotics were dispensed.

The mean age of study participants was 56.5 years, 71% were white, 88% were male, and 68% had a history or current or prior tobacco use.

Amoxicillin was given most frequently for 10 days (57.9% of patients), while azithromycin was more likely taken for 5 days (81% of patients).

During the first 5 days of treatment, patients receiving azithromycin had significantly increased risk of death (hazard ratio [HR], 1.48; 95% confidence interval (CI), 1.05-2.09) and serious arrhythmia (HR, 1.77; 95% CI, 1.2-2.62) compared with patients receiving amoxicillin. From days 6 through 10 following treatment dispensing, the risks were not statistically significant between the groups.

Patients receiving levofloxacin in the first 5 days had a greater risk of death (HR, 2.49; 95% CI, 1.7-3.64) and serious cardiac arrhythmia (HR, 2.43; 95% CI, 1.56-3.79) compared to patients receiving amoxicillin. This risk remained significantly different for days 6 to 10 for death (HR, 1.95; 95% CI, 1.32-2.88) and arrhythmia (HR, 1.75; 95% CI, 1.09-2.82). See Table 1 and Table 2 (Below) for more specific between-group information. These study findings support the safety announcements from the FDA.

The study’s authors indicated some limitations. For example, patients given azithromycin or levofloxacin may be different from patients who were not for reasons such as the antibiotics used, severity of the disease, and comorbidities. Also, patients with comorbidities and/or higher disease severity may be more likely prescribed azithromycin and levofloxacin, which could have biased the results. Lastly, the study’s exclusion criteria did not allow for patients at high risk for death from causes unrelated to a short-term effect of arrhythmia-inducing medication, which could minimize the effect of the disease severity.

Because there are a number of antibiotics available for use in older patients, especially patients with cardiac comorbidities, the researchers suggested that physicians consider prescribing medications other than azithromycin and levofloxacin in this situation.