The Hospice Clinician Blog

A study was recently published in the New England Journal of Medicine that found that a 5-day course of azithromycin was associated with a small increased risk of cardiovascular death or death from any cause when compared with amoxicillin, ciprofloxacin, or no antibiotic. After the publishing of this study, the FDA issued a statement to healthcare provides indicating that it is aware of the study and will be conducting a review of this study and of the risk of QT prolongation associated with azithromycin.

Azithromycin is a macrolide antibiotic. Other macrolides, such as erythromycin and clarithromycin, are known to cause QT prolongation and can increase the risk of arrhythmias and sudden cardiac death. Prior to this study in the NEJM, there were many published reports of patients with normal baseline QT intervals who had adverse cardiac events while taking azithromycin. These adverse cardiac events included torsades de pointes and polymorphic ventricular tachycardia—ventricular arrhythmias which are often fatal. The FDA had also received a number of reports of this type of adverse outcome associated with azithromycin via their Adverse Event Reporting System.

Armed with this background information, the authors of the NEJM study conducted a retrospective cohort study of mortality among patients who took azithromycin. They found that a 5-day course of azithromycin, when compared to no antibiotic, was associated with both an increased risk of cardiovascular death during the 5-day course of therapy (hazard ratio 2.88) and for the 10-day period after the prescription was filled (hazard ratio 1.86). Azithromycin was also associated with an increased risk of death from any cause (hazard ratio 1.85).

When compared with amoxicillin, azithromycin had a higher risk of cardiovascular death (hazard ratio 2.49) and death from any cause (hazard ratio 2.02). This works out to an estimated 47 additional cardiovascular deaths per 1 million courses of azithromycin. The risk of cardiovascular death was also significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin.

The risk of cardiovascular death was most pronounced in patients with a high baseline risk of cardiovascular disease.

In hospice, azithromycin is often used to treat respiratory infection, including community-acquired pneumonia, particularly in patients with COPD. Some patients with COPD have started to take azithromycin every day as a preventative measure, after the results of a large clinical trial, published last year, showed that routine daily prophylactic antibiotic therapy with azithromycin can reduce the occurrence of acute exacerbations of COPD (See our article "Post Prophylactic Antibiotic Therapy: Implications for Hospice Patients with Severe COPD"). The results of this NEJM study, and the FDA’s subsequent warning statement, should serve as a reminder to hospice professionals to be aware of the potential for QT interval prolongation and arrhythmias when prescribing or administering azithromycin or other macrolides. Patient selection is important as the risk of adverse outcome is most pronounced in patients at high cardiovascular risk:

• History of heart disease including heart failure, previous MI, or arrhythmia
• Older age
• Concurrently using known QT-prolonging meds such as amiodarone, methadone, ziprasidone (Geodon), citalopram, haloperidol
• Patients at risk of electrolyte abnormalities, such as patients with renal failure

Reference:
Ray WA, Murray KT, Hall K, Arbogast PG, Stein M. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012;366:1881-1890.
 

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