Azithromycin May up Chance of Sudden Cardiac Death

Marlene Busko

May 17, 2012

Read the Medscape Alert on the FDA’s follow-up on this study.

May 16, 2012 (Nashville, Tennessee)— During a five-day course of azithromycin, patients had a small, increased risk of sudden cardiac death compared with those receiving amoxicillin or no antibiotics, in an observational study [1]. The small, heightened risk was greater among patients with the most baseline cardiovascular risk factors. Although the study tried to account for differences in patients receiving amoxicillin vs azithromycin, some deaths may be explained by differences in illness severity, an outside expert suggests.

The study is published in the May 17, 2012 issue of the New England Journal of Medicine.

"All antibiotics have risks and benefits, and our study will add important information concerning the risks of azithromycin," lead author Dr Wayne Ray (Vanderbilt University School of Medicine, Los Angeles) told heartwire . "For patients with high baseline cardiovascular risk, the cardiovascular effects of azithromycin are likely to be an important factor in the prescribing decision." Levofloxacin can in rare cases cause serious arrhythmias and sudden death, and this study suggests that azithromycin has a similar level of adverse cardiac effects, he added.

However, the findings should be interpreted with caution, Dr David Juurlink (University of Toronto, ON) told heartwire , since azithromycin may have been prescribed for sicker patients. "I think it is possible that some patients who died on azithromycin may have died as a result of a proarrhythmic effect of the drug," he said. "But it's simply not possible to know how many of the deaths in the sample were drug-related and how many were related to illness."

The macrolide antibiotics erythromycin and clarithromycin can increase the risks of serious ventricular arrhythmias and sudden cardiac death, but only recently have reports suggested that this is also true for azithromycin, the authors write.

They examined data from patients enrolled in the Tennessee Medicaid program between 1992 and 2006.

The cohort included patients taking:

  • Azithromycin (347 795 prescriptions).

  • No antibiotics, in four control periods (1 391 180 control periods).

  • Amoxicillin (1 348 672 prescriptions).

  • Ciprofloxacin (264 626 prescriptions).

  • Levofloxacin (193 906 prescriptions).

The patients were aged 30 to 74 with a mean age 49, and 77% were women. Their cardiovascular risk score was based on factors including prior MI, heart failure, diabetes, age, and sex.

The control patients were matched with patients taking azithromycin using a propensity score for 153 covariates.

Amoxicillin has similar indications to azithromycin, the authors write, and is without adverse cardiac effects. "The indications [for these two drugs] overlap and . . . may depend on organism susceptibility," Ray said. "Common indications . . . were minor infections such as chronic sinusitis or acute bronchitis."

Compared with patients receiving amoxicillin therapy, during five days of azithromycin therapy, there were an estimated 47 additional cardiovascular deaths per one million courses of therapy. Among patients in the highest decile of cardiovascular risk score, there were an estimated 245 additional cardiovascular deaths per one million courses of azithromycin therapy.

The risks of cardiovascular death were similar for ciprofloxacin and amoxicillin and for levofloxacin and azithromycin.

Azithromycin Proarrhythmic, Degree of Risk Debatable

"The study raises awareness of a potential rare side effect of azithromycin and other drugs of that class, which is useful especially when the outcome is serious, [and it] should serve to remind clinicians that perhaps they need to be more judicious when they are prescribing," Juurlink agreed.

However, in practice, azithromycin is often used for patients with respiratory infections such as pneumonia or chronic obstructive pulmonary disease (COPD) exacerbations, whereas amoxicillin is often used as a treatment for urinary tract infection (UTI), so patients prescribed azithromycin will be sicker, he noted. "Patients prescribed azithromycin were more likely to have a respiratory process, be on a beta blocker, a statin, and an ACE inhibitor [and, of special note, were] more likely to have received a beta agonist [suggesting respiratory infection]. . . . Although the design and analysis of this study are really quite sophisticated, these sorts of imbalances are very hard to overcome."

In reply, Ray noted that "the azithromycin risk returns to baseline on days 6 to10, suggesting strongly that we are not measuring the effect of underlying comorbidity, [and] all of the factors mentioned . . . were controlled for in the statistical analysis."

The study was supported by a grant from the National Heart, Lung, and Blood Institute and a cooperative agreement from the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics. Ray had no disclosures. Disclosures for the coauthors are available at www.nejm.org .

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