HealthDay News — There was no greater risk for cardiovascular death among Danish patients taking azithromycin compared with penicillin after adjusting for pretreatment mortality, study results indicate.

Using data from a National Health Registry in Denmark from 1997 to 2010, Henrik Svanström, MSc, from the Statens Serum Institut in Copenhagen and colleagues determined the propensity score-adjusted rate of cardiovascular death was 1.1 per 1,000 patient-years among those prescribed azithromycin vs. 1.5 per 1,000 patient-years among those prescribed penicillin (ratio 0.93; 95% CI: 0.56-1.55).

This translates to about one fewer patient dying of cardiovascular disease per million treatment episodes after taking azithromycin compared with penicillin, they reported in New England Journal of Medicine.

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Last year, the FDA initiated a safety review for azithromycin after reports that the antibiotic nearly tripled the risk for heart-related deaths in Tennessee Medicaid patients. This past March, the agency issued a formal warning about the potential risk for life-threatening arrhythmia in patients taking the medication.

So Svanström and colleagues analyzed data from nearly 5 million Danish adults to determine the incidence of death from cardiovascular and noncardiovascular causes within 35 days after treatment with azithromycin versus penicillin V.

Overall, they identified 1.1 million episodes of azithromycin use and 7.4 million episodes of penicillin V among patients without complicating factors such as recent hospitalizations and other antibiotic use. The researchers also included 11 million control episodes, tracking outcomes among individuals with the same sex and birth date as azithromycin users, but who were not taking the medication.

Each azithromycin user was matched to a control who had similar baseline cardiovascular propensity scores based on medical history and demographic information contained in the registry data.

The researchers found that CV mortality was significantly increased with current use of azithromycin (defined as a five-day treatment episode), compared with no use of antibiotics (rate ratio=2.85; 95% CI 1.13- 7.24). Azithromycin use was also associated with increased risk of non-CV death (RR=1.60; 95% CI; 1.00-2.54) relative to controls. 

However, fatal cardiac events were rare in both groups — with 17 CV-related deaths occurring among the 1.1 million azithromycin episodes compared with just six among matched controls. 

The researchers then used a statistical model to adjust for CV risk propensity as a covariate to compare outcomes in azithromycin and penicillin V users. They found here was no increased risk for CV death among current episodes of azithromycin use vs. penicillin V episodes (RR=0.93; P=0.79), nor for recent or past azithromycin use. Subgroups stratified by age, sex and history of CVD also did not show increased CV mortality risk from either drug.

Svanström and colleagues concluded that azithromycin may pose extra risk for patients with preexisting CVD, but that the results were “reassuring” for most patients seen in general practice. For these patients, “azithromycin can be prescribed without concern about an increased risk of death from cardiovascular causes.”

In an accompanying editorial, Andrew D. Mosholder, MD, MPH, and colleagues at the FDA cautioned that results from the Danish study did not conclusively prove azithromycin does not increase risk for CV mortality. 

“The upper bound of the 95% confidence interval [for the adjusted rate ratio versus penicillin] does not exclude an increased risk of as much as 55%,” they wrote.

They also pointed out that the Danish participants included in the current study were generally in better CV health than the Tennessee Medicaid patients, and cited data from clinical studies linking azithromycin to prolonged QT intervals.

“Pharmacologic and epidemiologic data point to lethal arrhythmias as a potential consequence of QT-interval prolongation with use of azithromycin, other macrolides and fluoroquinolones,” Mosholder and colleagues wrote. “This possibility should give clinicians pause when they’re considering prescribing antibacterial drugs, especially for patients with preexisting [CV] risk factors or clinical conditions in which antibacterial drug therapy has limited benefits.”


  1. Svanström H et al. New Engl J Med. 2013; 368: 1704-1712.
  2. Mosholder A et al. New Engl J Med. 2013; 368: 1665-1668.