May 8, 2013
Does Azithromycin Raise Cardiac Risks in the
General Population?

Copenhagen, Denmark A new Danish study involving young and middle-aged adults suggests that use of the antibiotic azithromycin does not raise the risk of cardiovascular death.

The authors of the study, which was published in the New England Journal of Medicine, were quick to point out, however, that their findings should not be assumed to contradict an earlier Vanderbilt University study that found cardiovascular risk was two to three times as high with azithromycin as the risk associated with no antibiotic use and with amoxicillin treatment.

“Given the profound differences in the characteristics of the study participants and the baseline risk of death between the two studies, our results provide a clinically relevant complement to, rather than a contrast with, the findings,” the Danish authors write. “Whereas their study, which examined the risk of death from cardiovascular causes associated with azithromycin in a population of U.S. Medicaid beneficiaries, provides evidence to support the hypothesis that azithromycin has an effect on cardiovascular mortality in a selected population, our study shows that this effect is not present in the general population.”

Cardiovascular mortality rates in the earlier study, published last year in the New England Journal of Medicine, were 85.2 deaths per 1 million courses of azithromycin, compared with 15.4 deaths per 1 million courses in the recently published Danish research.

“The difference in the results of the two studies could thus probably be attributed to treatment-effect heterogeneity—that is, an increased risk that was largely restricted to high-risk patients,” the authors note. “Our results also point toward an increased risk among patients with a history of cardiovascular disease, although no significant difference was observed in a comparison with patients who did not have such a history.”

The nationwide cohort study, including more than a million episodes of azithromycin use documented in Danish national health care records, suggests that “the risk of cardiac toxic effects associated with azithromycin may not be generalizable but may rather be limited to high-risk populations,” according to the researchers.

“The implications of these findings for clinical decision making are reassuring; they indicate that for the general population of patients seen in office practice, azithromycin can be prescribed without concern about an increased risk of death from cardiovascular causes, whereas the benefits of therapy need to be weighed against the risk of death from cardiovascular causes among patients with a high baseline risk of cardiovascular disease,” the Danish authors write.

An accompanying perspective article from the Center for Drug Evaluation and Research at the FDA suggests the issue might not be that clear-cut.

Those authors point out that, while the Danish study found no difference between azithromycin and penicillin in the 5-day risk of cardiovascular death, the “upper bound of the 95% confidence interval does not exclude an increased risk of as much as 55%,” adding that, “Overall, the Danish patients had better cardiovascular health than the Tennessee Medicaid patients.”

The FDA authors also note the widespread use of azithromycin in the U.S. In 2011, approximately 40.3 million patients, about one-eighth of the population, received an outpatient prescription for the macrolide antibiotic. The authors also acknowledge growing concerns about the drug’s effect on cardiovascular health.

Over the last several years, the FDA has revised azithromycin labels regarding risks of QT-interval prolongation and the associated ventricular arrhythmia torsades de pointes, advising against using azithromycin in patients with known risk factors such as QT-interval prolongation, hypokalemia, hypomagnesemia, bradycardia, or use of certain antiarrhythmic agents, including class IA (e.g., quinidine and procainamide) and class III (e.g., dofetilide, amiodarone, and sotalol).

In March, azithromycin labels were further revised to reflect the results of a clinical study showing that azithromycin can prolong the corrected QT interval.

Although the new study using Danish health care data found no difference between azithromycin and penicillin in the 5-day risk of cardiovascular death, the earlier study found a significant different in the “rates of death from any cause and from cardiovascular causes spanned Days 1 through 5, reflecting the typical 5-day duration of azithromycin administration (e.g., Zithromax Z-Pak),” according to the perspective article.

As a result, according to the commentators, “The risks and benefits of antibacterial therapy should be considered in prescribing decisions. Pharmacologic and epidemiologic data point to lethal arrhythmias as a potential consequence of QT-interval prolongation with use of azithromycin, other macrolides, and fluoroquinolones. This possibility should give clinicians pause when they're considering prescribing antibacterial drugs, especially for patients with preexisting cardiovascular risk factors or clinical conditions in which antibacterial drug therapy has limited benefits.”

They further caution that alternative antibacterial drugs also can have arrhythmogenic potential. Labels for erythromycin and clarithromycin include warnings regarding QT-interval prolongation and arrhythmias, and fluoroquinolone products have similar warnings regarding QT-interval prolongation, according to the report.

U.S. Pharmacist Social Connect