Macrolides and the Risk of Ventricular Dysrhythmias

Background

When it comes to treating community acquired respiratory tract infections, macrolide antibiotics (azithromycin, clarithromycin and erythromycin) are a common choice of agent. In 2010, 57.4 million macrolide prescriptions were written in the U.S. with azithromycin being the most commonly prescribed individual antibiotic agent overall with ~51.5 million prescriptions (Hicks 2013)

With more and more patients being prescribed macrolide antibiotics, an increasing amount of research has been put forth dealing with the safety concerns regarding these medications; specifically the thought that azithromycin use can lead to fatal ventricular arrhythmias. In addition to case reports a 2012 observational study published in the New England Journal of Medicine highlighted an association between  azithromycin use and higher rate of both cardiovascular death and all-cause mortality (Ray 2012). This prompted the US Food and Drug Administration to issue warnings about the use of azithromycin and potential QT-interval prolongation and fatal ventricular dysrhythmias.

However, recent studies suggest that these concerns and warnings may not be accurate. A retrospective cohort study comparing older patients hospitalized with pneumonia that were treated with azithromycin to those who received other guideline appropriate antibiotics actually showed a lower risk of 90-day mortality in the azithromycin group. Further, there was no significant difference between the 2 groups in regards to risk of arrhythmia, heart failure or any cardiac event. (Mortensen 2014).

Primary Results

Critical Results

• 503,612 patients taking macrolide antibiotics were successfully matched with an equal number of patients taking non-macrolide antibiotics.
• Primary Outcome (30-day risk of ventricular dysrhythmia)
  • No significant difference between groups
  • Macrolide antibiotic 0.03% vs. Non-macrolide antibiotic 0.03% (RR 1.06 95% CI: 0.83-1.36)
• Secondary Outcome (all-cause mortality)
  • Lower risk in macrolide antibiotic group
  • Macrolide antibiotic 0.62% vs. Non-macrolide antibiotic 0.76% (RR 0.82 95% CI: 0.78-.086)
• Subgroup analysis showed that presence or absence of CKD, CHF, CAD or use of other QT-prolonging drugs did not significantly modify the primary/secondary outcomes.
• Similar results found when looking at a 14-day endpoint as well.

Strengths

• Large database allowing for representative sample of patients
• Assessed clinically important, patient centered adverse events (hospital encounter with ventricular arrhythmia and death)
• Compared patients with similar indications for treatment to reduce bias (chose antibiotics that would be used commonly for URIs)

Limitations

• Retrospective data collection using diagnosis codes from prior records as opposed to prospective data collection
• No guarantee that patients actually took the medications they were prescribed
• Presentations for dysrhythmia or even death may not have been captured
• No cardiac rhythm tracings available
• Unable to determine exact indication for antibiotics
• Results may have been confounded if prescribers were deliberately avoiding prescribing macrolide antibiotics to those at high risk for ventricular arrhythmia

Author's Conclusions

“Among older adults prescribed macrolide antibiotics compared with nonmacrolide antibiotics, we found no difference in risk of a hospital encounter with ventricular arrhythmia within 30 days of a new prescription and a lower risk of 30-day all- cause mortality. These findings are reassuring for health care providers who prescribe macrolide antibiotics to a wide range of patients in routine care”

Our Conclusions

This study, while not without its limitations, is another piece of evidence that suggests that the risk of ventricular dysrhythmias and death secondary to macrolide antibiotic use may not be as high as once thought. The authors of this study provided a very large sample size, with clinically important outcomes.

Potential Impact To Current Practice

This study may make ED physicians more comfortable in prescribing macrolide antibiotics, although it appears that this is already the case.

Bottom Line

While this study is another step towards determining the risks of macrolide antibiotics and clinically relevant outcomes, caution should still be exercised when prescribing them to high-risk patients with poor drug clearance or with already impaired electrical activity of the heart.

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References

Hicks LA et al. US outpatient antibiotic prescribing, 2010. NEJM 2013;368:1461-2. PMID: 23574140

Mortensen EM et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA 2014; 311:2199-208. PMID: 24893087

Ray WA  et al. Azithromycin and the risk of cardiovascular death. NEJM 2012; 366:1881-90. PMID: 22591294