Azithromycin and cardiovascular risk

Since 2012, the FDA has made two statements regarding the safety of azithromycin related to cardiovascular risk.  These warnings were largely in response to an observational cohort study that found a small absolute increase in cardiovascular deaths in patients receiving azithromycin versus those receiving amoxicillin or no antibiotic in a Tennessee Medicaid population¹.  This excess risk varied based on patients’ baseline cardiovascular risk and was found to be highest in the highest decile of cardiovascular risk.  While a warning from the FDA does seem concerning, it is important to examine some of the details of the data.

• Of the 347,795 azithromycin prescriptions in the study cohort, there were 29 cardiovascular deaths (absolute risk = 0.008%)
• Of the 1,391,180 matched controls, there were 41 cardiovascular deaths (absolute risk = 0.003%)
• These above cardiovascular deaths occurred during the five day treatment course, whereas the analysis that also included the following five days had no difference in death from any cause
• 4,082 prescriptions would have to be used in patients at the highest cardiovascular risk decile to cause one additional cardiovascular death

A recent historical Danish cohort study using multiple strategies to control for confounding also attempted to resolve this issue².  They determined that azithromycin was not associated with an increased risk of death from cardiovascular causes.

An additional study in 2014 is discussed in a later post here.

So while it is yet to be determined how, if at all, these FDA warnings should affect practice, it is prudent to look at the proposed mechanism for these adverse events to identify patients who may be at the highest risk.

Azithromycin, a macrolide antibiotic, belongs to a class of drugs that has been known for many years to carry an arrhythmia risk by prolonging the QT interval.  Risks for macrolide-induced torsades de pointes include increasing age, female sex, and concomitant drug use³.  Other drugs that prolong the QT interval include class IA, IC, and III antiarrhythmics, “azole” antifungals, atypical antipsychotics, tricyclic antidepressants, haloperidol, citalopram, and methadone (list not all-inclusive).  Notably other antimicrobials, particularly fluoroquinolones also prolong the QT interval.  Several electrolyte disturbances (or the drugs that induce them) also prolong the QT interval including hypocalcemia, hypokalemia, and hypomagnesemia.  It has been demonstrated that macrolides cause QT prolongation through blockade of the delayed rectifier potassium currents and patients with congenital long QT syndrome are particularly at risk for these and other triggers⁴.

References:

1. Ray WA, Murray KT, Hall K, et al.  Azithromycin and the Risk of Cardiovascular Death. N Engl J Med 2012;366:1881-90.

2. Svanstrom H, Pasternak B, Hviid A.  Use of Azithromycin and Death from Cardiovascular Causes. N Engl J Med 2013;368:1704-12.

3. Sivapalasingam S, Steigbigel NH. Macrolides, Clindamycin, and Ketolides. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases Vol 1. 7^th ed. Philadelphia, PA: Elsevier; 2010:436.

4. Stork CM. Antibacterials, Antifungals, and Antivirals. In: Nelson LS, Lewin NA, Howland MA, et al. eds. Goldfrank’s Toxicologic Emergencies 9^th ed. McGraw-Hill, 2011:823-4.