Azithromycin — The Heart of the Matter Redux: Pre-existing Risks Tell the Tale

Abstract & Commentary

By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University, Hospital Epidemiologist, Sequoia Hospital, Redwood City, CA

Dr. Deresinski does research for the National Institutes of Health and is an advisory board member and consultant for Merck. This article originally appeared in the July 2013 issue of Infectious Disease Alert.

Source: Svanström H, et al. Use of azithromycin and death from cardiovascular causes. N Engl J Med 2013;368:1704-1712.

Svanström and colleagues in copenhagen examined the risk of cardiovascular deaths in association with azithromycin use in a nationwide historical cohort study of Danish adults aged 18-64 years. They compared 1,102,050 episodes of azithromycin use with the same number of episodes of no use of antibiotic agents with 1:1 matching using propensity scoring. The risk of cardiovascular mortality with current use of the azalide (but not with past or future use) was increased (rate ratio, 2.85; 95% CI, 1.13-7.24). There was, however, no excess cardiovascular mortality with current azithromycin use when compared to current use of penicillin V with crude rates of 1.1 and 1.5 per 1000 person years, respectively, and when adjusted, a rate ratio of 0.93 (95% CI, 0.56-1.55). Thus, the investigators concluded that "Azithromycin use was not associated with an increased risk of death from cardiovascular causes in a general population of young and middle-aged adults."

COMMENTARY

The FDA recently updated the azithromycin prescribing information to state: "Health care professionals should consider the risk of fatal heart rhythms with azithromycin when considering treatment options for patients who are already at risk for cardiovascular events. FDA notes that the potential risk of QT prolongation with azithromycin should be placed in appropriate context when choosing an antibacterial drug: Alternative drugs in the macrolide class, or non-macrolides such as the fluoroquinolones, also have the potential for QT prolongation or other significant side effects that should be considered when choosing an antibacterial drug."¹

This statement was based, in part, on extensive analysis of data by Ray and colleagues,² which has been previously discussed in Infectious Disease Alert.³ Those investigators retrospectively examined the risk of cardiovascular death among patients 30-74 years of age enrolled in the Tennessee Medicaid program and who had been prescribed azithromycin between 1992 and 2006. Compared to "no antibiotic" controls, the hazard ratio for cardiovascular death during 5 days of prescribed azithromycin therapy was 2.88 (95% confidence interval [CI], 1.79-4.63; P < 0.001) and that of death from any cause was 1.85 (95% CI, 1.25-2.75; P = 0.002). In contrast to the findings of the Danish investigators in a comparison with penicillin V use, Ray et al found that azithromycin therapy was also associated with an increased hazard ratio for both cardiovascular and total deaths when compared to amoxicillin therapy, which itself had no increased hazard relative to "no antibiotic" controls. Relative to amoxicillin, azithromycin was associated with an estimated 47 added cardiovascular deaths per 1 million prescriptions. The degree of hazard was, however, strongly associated with the presence of pre-existing cardiac risk factors.

It is likely to be the prevalence of such pre-existing conditions that distinguishes the patient populations in the two studies, with the Danes apparently being the healthier group. This is consistent with the observation that the cardiovascular mortality in azithromycin recipients was 85.2 deaths per million courses in Tennessee and only 15.4 per million courses in Denmark, suggesting significant differences in baseline risk.

Another potential confounding factor could be differences in the genetic makeup of the populations studied. Analysis of DNA from 44 victims of sudden cardiac death in Denmark from 2000-2006 who were < 35 years of age found that only 11% had one of the three major long-QT syndrome mutations associated with increased risk of sudden cardiac death.⁴ This contrasts with reports of rates of approximately 20% found in New Zealand and at the Mayo Clinic in Minnesota. The population of Denmark is much more homogenous than that of the United States and the prevalence of genetic polymorphisms that put individuals at risk of death due to cardiac arrhythmias may differ.

There may, however, be additional poorly understood factors that could confound our understanding of this problem. As pointed out by Molsholder and colleagues in a commentary accompanying the article by Svanström et al, a recent Canadian study found lower 30-day mortality in outpatients with community-acquired pneumonia (CAP) who were treated with azithromycin than in those treated with a fluoroquinolone.⁵ Also pointed out is a recent meta-analysis of inpatients with CAP in which those receiving a macrolide had significantly lower mortality than in those receiving non-macrolides. Azithromycin is now widely used in trachoma control and eradication programs, which could be disrupted by unequivocal evidence of associated increased risk of cardiovascular deaths. A recent report, however, found no difference in mortality between individuals aged at least 30 years or those 10-29 years of age who received azithromycin and those who did not in an eradication program in Ethiopia.⁶ In fact, those who received azithromycin had a lower risk of mortality than did members of the same household who never received the drug.

Approximately one-eighth of the U.S. population — 40.3 million people — received an outpatient prescription for azithromycin in 2011. Thus, resolving the issue of the potential increase in cardiovascular deaths with azithromycin use is no trivial matter. The most reasonable analysis of the data available to date is that azithromycin may be associated with increased risk of cardiovascular death in individuals with pre-existing risk factors, such as cardiac disease or coadministration of drugs that prolong cardiac repolarization.

References

1. FDA Drug Safety Communication. http://www.fda.gov/Drugs/DrugSafety/ucm341822.htm. Accessed September 5, 2013.
2. Ray WA, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012;366:1881-1890.
3. Deresinski S. The Heart of the matter. Infect Dis Alert 2012;31:97-99.
4. Winkel BG, et al. The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases.
   J Cardiovasc Electrophysiol 2012;23:1092-1098.
5. Mosholder AD, et al. Cardiovascular risks with azithromycin and other antibacterial drugs. N Engl J Med 2013;368:1665-1668.
6. Keenan JD, et al. Adult mortality in a randomized trial of mass azithromycin for trachoma. JAMA Intern Med 2013;173:821-823.