A Recent Meta-analysis on Azithromycin and the Risk of Cardiotoxicity


By R.L. Wynn

In a review of 12 randomized, placebo-controlled trials, no significant association was found between azithromycin therapy and the risk for death or hospitalization from cardiovascular causes. This report, by authors from the University of Cincinnati Academic Health Center, is the first meta-analysis of the cardiac safety of azithromycin in randomized clinical trials.

Azithromycin has been associated in the past with a risk of cardiotoxicity. An alert was issued by the FDA in 2013 that its use was associated with an increased risk of cardiovascular death compared with placebo or amoxicillin. That alert was in response to the results of an observational study out of Tennessee by Ray and colleagues involving patients with Medicaid coverage who had a high risk of cardiovascular events and showed an increased risk for such events among those receiving a 5-day course of azithromycin. Since observational studies can be misleading, it was of interest to conduct a search for double-blind, placebo-controlled trials involving high-risk patients to further investigate whether azithromycin is associated with increased cardiovascular death among these types of patients.  The authors of this new meta-analysis report concluded that there is no such risk of cardiotoxicity with azithromycin.

A look at the recent meta-analysis

This trial can be accessed at:

Almalki, Z.S.; Guo, J.J. “Cardiovascular events and safety outcomes associated with azithromycin therapy: a meta-analysis of randomized controlled trials.” Am Health Drug Benefits 2014; 7(6):318-328.

The authors selected clinical trials comparing azithromycin therapy with placebo or with standard of care. The specific populations of interest were patients identified in the studies as high risk for cardiovascular complications, such as those with a history of heart problems, coronary disease, myocardial infarction, unstable angina, or peripheral artery disease. The trials described the use of azithromycin for the treatment of infection or for secondary prevention of coronary events. 

All studies reporting cardiovascular outcomes were collected and were stratified into 3 subgroups: mortality, hospitalization and coronary intervention:

  • Mortality subgroup included studies that reported patients who had died from cardiovascular causes, such as death resulting from arrhythmias or myocardial infarction
  • Hospitalization subgroup included studies that reported the number of hospitalized patients as a result of cardiovascular problems
  • Coronary intervention subgroup included all studies that reported patients who had coronary artery bypass grafting surgery or percutaneous coronary intervention

A total of 12 randomized controlled trials, published between 1997 and 2013, met the inclusion criteria for this analysis. Combined, the trials involved 15,588 patients who received active treatment or placebo.

Of the 12 studies, nine were double-blind trials, and three were open-label trials. A total of five studies randomized patients with stable coronary artery disease, three trials randomized patients presenting with chronic obstructive pulmonary disease, and two trials randomized patients with acute coronary syndrome. Patients with peripheral artery disease or with severe sepsis were involved in two of the studies.

All 12 studies included patients aged 65 years or greater. The mean duration of follow-up ranged from 18 weeks to 6 years. The trials were rated as being of good methodologic quality: randomized, double-blind, and placebo-controlled.

The majority of the trials included two study groups, a treatment group and a placebo group.  Azithromycin was the only drug included in the treatment group in most studies, except for one which included azithromycin combined with metronidazole and a proton pump inhibitor, and a few others which included azithromycin combined with standard care.


  • Mortality subgroup – the combined mortality rate was 3.7% among 7,769 azithromycin patients versus 4.2 % among 7,723 placebo patients
  • Hospitalization subgroup – the overall hospitalization rate was 7.6% among the 7,498 patients receiving active treatment compared with a 10.1% rate among the 7,478 patients receiving placebo
  • Coronary intervention subgroup – five of the trials reported outcomes of coronary intervention, and there was no relationship between azithromycin use and coronary intervention rate

The findings from the meta-analysis trial are opposite from those of the earlier Tennessee study:

Ray, W.A.; Murray, K.T.; Hall, K.; et al. “Azithromycin and the risk of cardiovascular death.” N Engl J Med 2012; 366: 1881-1890.

The Tennessee study analyzed data on millions of prescriptions for several antibiotics given to Tennessee Medicaid patients over a 14-year period. The study was designed to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious non-cardiovascular illness, during and shortly after hospitalization. The cohort included patients who were prescribed azithromycin between 1992 and 2006, persons in a matched control period who took no antibiotics, and patients who took amoxicillin, ciprofloxacin, or levofloxacin.

The primary endpoints were cardiovascular death and death from any cause. There were 29 heart-related deaths among those who took azithromycin during five days of treatment. Their risk of death while taking the drug was almost triple that of those patients taking no antibiotic. Their risk of death while taking azithromycin was more than double that of those patients taking amoxicillin. Patients who took amoxicillin had no increase in the risk of death. Within the azithromycin group, the highest risks of cardiovascular deaths were in those patients taking azithromycin and who had existing heart problems. 

Calculated in another way: If a course of treatment for azithromycin was defined as one five-day period of therapy, then there were 85 cardiovascular deaths per one million courses of treatment among azithromycin users. During the first five days of a course of amoxicillin therapy, there were 32 cardiovascular deaths per one million five-day courses. During matched five-day intervals among persons who did not take antibiotics, there were 30 cardiovascular deaths per one million periods.

The current meta-analysis report reviewed studies that were randomized, placebo-controlled trials, whereas the Tennessee study was an observational study. Also with that study, it was unclear for which disease state patients were receiving azithromycin. The meta-analysis report selected all randomized clinical trial data with azithromycin used for the treatment of infection or for the secondary prevention of coronary disease. In the Tennessee study, the population of the Tennessee Medicaid beneficiaries may have had a higher prevalence of coexisting conditions and higher mortality rates compared with patients in the randomized clinical trials included in the meta-analysis study. 

In conclusion, for the meta-analysis trial, in a review of 12 randomized, placebo-controlled trials, no significant association was found between azithromycin therapy and the risk for death or hospitalization from cardiovascular causes. The authors did comment that additional trials and follow-up are needed to study patients with preexisting bacterial infection and cardiovascular risk factors in relation to the effects of azithromycin therapy.

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