CardioExchange Archive

We asked three experts to comment on a recent study in the New England Journal of Medicine showing that the antibiotic azithromycin is associated with increased risk for cardiovascular death.

Study Results

Data from a large retrospective cohort study, in a Medicaid population, showed that azithromycin conferred a nearly threefold increase in risk for CV death and a nearly twofold increase in all-cause mortality during the 5 days of therapy, relative to no treatment.

When azithromycin and amoxicillin were compared, there were 47 excess CV deaths per 1 million courses of azithromycin. For patients with the highest CV risk at baseline, there were 245 excess deaths per 1 million azithromycin treatments, compared with amoxicillin. Azithromycin also posed greater risk for CV mortality compared with ciprofloxacin, but not compared with levofloxacin.

Expert Comments

Paul Sax, Brigham and Women’s Hospital

As an ID specialist, I have come to use azithromycin only in limited contexts: as a single-dose therapy for chlamydia or as the key drug in treating atypical mycobacterial infections. Azithromycin also retains its role, in combination with ceftriaxone, as a treatment for community-acquired pneumonia in the hospital. But the bottom line is that azithromycin is no longer that good for common respiratory infections in the clinic, given the high rate of resistance among common pathogens. These data suggesting possible cardiovascular risk from the drug make me even more likely to choose alternatives (such as amoxicillin-clavulanate or doxycyline) in patients at high cardiac risk.

Joseph Ross, Yale University School of Medicine

We have all been in a situation where a patient with symptoms suggestive of viral illness asks for antibiotics. We justify a decision to prescribe them by telling ourselves, “The patient will just go to the ED or another doctor for them anyway. Besides, the medication is safe.” This has led to many unnecessary prescriptions for azithromycin over the years because, we think, 5 days of an inappropriate antibiotic is somehow better than 10. Now we know, from studies like the one just published in the NEJM, that some of these medications are not safe. It often takes a large prospective study of this sort to illuminate small – but real – risks. Avoidable deaths should indeed be avoided. To do that, patients and physicians need to start having tough conversations about the risks from using antibiotics when they are not indicated.

Jeffrey L. Anderson, Intermountain Heart Institute

Azithromycin is frequently prescribed for patients who have extensive comorbidities, as it is well tolerated, easy to use (a 5-day course), and seemingly safe. However, large database studies, like the present one, can document rare but serious adverse reactions (witness the 47 excess CV deaths per 1 million courses of azithromycin, compared with amoxicillin, and the 245 excess deaths per 1 million courses among patients with the highest CV risk at baseline).

The efforts to control for selection bias in this study were commendable, but observational studies can never completely eliminate residual (unaccounted) bias. Also, it is not clear that azithromycin was prespecified as the primary focus of the investigation, as no confirmatory registry number (i.e., at clinicaltrials.gov) is given. In addition, at least 2 other suspect drugs (ciprofloxacin, levofloxacin) were studied, with levofloxacin also showing risk potential. Hence, was a correction in P values for multiple comparisons needed? The sudden disappearance of CV risk at days 6 to 10 is also curious, given the expected persistence of azithromycin drug levels during that time frame. Moreover, the equal increase in nonsudden and sudden CV death does not fully support the proposed mechanism of arrhythmic risk, raising the aforementioned question of unaccounted-for CV selection bias.

This high-quality report should nevertheless be taken seriously. However, it needs prospective replication in other large database studies with a broader representation of patients (e.g., the present report has an unusually high proportion of younger women) and with a clear prespecified hypothesis. Meanwhile, alternative, safer antibiotics (e.g., amoxicillin, ciprofloxacin) should be considered in clinical practice, especially in patients at increased CV risk. Finally, the prior negative results of CV prevention trials of azithromycin (as well as clarithromycin and gatifloxacin) may need to be reconsidered in light of our growing knowledge that the potentially beneficial effects of an antibiotic may be offset by drug-related adverse CV risk.

What’s your response to the new data on azithromycin and to our experts’ views?