Introduction
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It has long been known that some macrolides (e.g. erythromycin) cause torsade de pointes. However, azithromycin has a much lower affinity for cardiac potassium channels than erythromycin, so it has less effect on the heart. For many years it was believed that azithromycin lacked cardiac toxicity.
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Controversy was sparked in 2012 when a retrospective study by Ray et al found that azithromycin use correlated with an increased risk of cardiovascular death. However, this correlational study may have been confounded because patients treated with azithromycin were more likely to have COPD or pneumonia.
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Subsequent correlational studies revealed conflicting findings, with one large study failing to replicate Ray's findings (Svanstrom 2013). More importantly, meta-analyses of prospective RCTs of azithromycin have found it to be safe. This topic was previously explored in detail here.
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New meta-analysis by Cheng 2015, J Am Coll Cardiol
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This article is a meta-analysis of all studies relating macrolide use to cardiac events, with an impressive total sample size of over twenty million patients. Unfortunately, this includes several large retrospective studies (including conflicting studies by Ray 2012 and Svanstrom 2013). These large retrospective studies will over-power and drown out any signal from smaller, higher quality RCTs included in the meta-analysis.
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The study found that azithromycin was associated with greater rates both of cardiovascular death and of the composite of sudden cardiac death or ventricular tachyarrhythmia:
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It is accepted that erythromycin is considerably more arrhythmogenic than azithromycin. However, this study found these two drugs to have nearly identical effects on the risk of arrhythmia (green boxes above). This should cast doubt on the external validity of these results.
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Heterogeneity was found between different types of studies and between different macrolides (blue boxes above; note that these p-values test homogeneity between strata). Such heterogeneity challenges the validity combining these studies together into a single meta-analysis.
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For a moment, let's suspend skepticism and suppose that this data is entirely accurate. In that case, the most important finding might be that azithromycin is associated with a trend toward reduced all-cause mortality (red box above). The only way to explain this would be that azithromycin exerts some life-saving effect (e.g. anti-inflammatory or anti-infective) which offsets the increase in cardiac death that it causes. Thus, even if we were to accept the validity of this study, it may still support the use of azithromycin.
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Ultimately, this meta-analysis is driven largely by retrospective, correlational studies. Thus, it constitutes a lower level of evidence than meta-analyses of RCTs, which have found azithromycin to be safe (e.g. Baker 2007, Almalki 2014). Ironically, this paper concludes with the statement that “large RCTs are warranted to confirm these findings” — which unfortunately neglects the fact that numerous RCTs and meta-analyses of these RCTs have already been done.
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Accompanying editorial by Viskin et al. , J Am Coll Cardiol
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This is a disquieting editorial, which raises the possibility that litigation of the pharmaceutical industry could lead to the discontinuation of the entire class of macrolide antibiotics. Really? Azithromycin is notable for its excellent safety profile. Eliminating azithromycin would increase the use of fluoroquinolones, which probably have more side effects (e.g. delirium and the selection of MRSA and clostridium difficile).
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The editorial suggests that correlative data can be used to establish causation for two reasons (see highlighted text below). These arguments are based on data from erythromycin, but do no apply to azithromycin. As previously discussed, neither electrophysiologic data nor RCTs suggest that azithromycin causes arrhythmia.
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- It is accepted that azithromycin is significantly safer than erythromycin. Thus, it is not valid to combine different types of macrolides within the same study.
- This meta-analysis is primarily driven by retrospective observational studies. As such it constitutes a lower level of evidence than pre-existing meta-analyses of RCTs (which have found azithromycin to be safe).
- If we are worried that azithromycin is killing patients, the most robust and patient-centered outcome to evaluate is all-cause mortality. This study and meta-analyses of RCTs have all found a trend toward reduced all-cause mortality with azithromycin.
- Available evidence suggests that azithromycin does not cause torsade de pointes or increased mortality.
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Related posts
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Conflicts of Interest: Never.
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Josh is the creator of PulmCrit.org. He is an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.
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Great rant Josh! I think azithromycin can be used in most patients without thinking twice about cardiac risks. I have encountered two patients who had a self-limited run of torsades after receiving azithromycin, but they also had other medications, baseline prolonged QTc, and co-morbidities that put them at risk. I’ll use doxycycline if I feel the need to be risk-averse such as in a little old lady with a baseline QTc of 500 msec.
Hi Joe, thanks for weighing in. Yes, doxycycline is a good alternative to azithromycin and probably one that is under-utilized in general. For sicker patients I still like the potential anti-inflammatory effect of azithromycin however.