Dr. Richard L. Wynn is Professor of Pharmacology at the University of Maryland Dental School. He holds a BS degree in pharmacy and a PhD degree in pharmacology. More »He chaired the Department of Pharmacology at the University of Maryland Dental School from 1980 to 1995. He is the lead author of the Drug Information Handbook for Dentistry, co-author of many other dental drug publications, author of over 300 refereed scientific journal articles, consultant to the Academy of General Dentistry, featured columnist, and a featured speaker presenting more than 500 courses in continuing dental education. One of his primary interests continues to be keeping dental professionals informed of all aspects of drug use in dental practice.
By R.L. Wynn
The medical community and the Food and Drug Administration (FDA) have expressed concern for some time about the association between azithromycin (Z-Pak) and cardiovascular events, including death. A Tennessee Medicaid study first reported an increased risk of death from cardiovascular causes associated with a 5-day course of azithromycin (“Azithromycin associated with increased risk of cardiovascular death,” July 2012). A later study reported that U.S. veterans receiving azithromycin or levofloxacin while under the care of the Department of Veterans Affairs had significantly increased risk of serious cardiac arrhythmias and cardiovascular death (“New studies examine links between antibiotics dental professionals use and cardiac issues,” April 2014).
The finding that azithromycin increased the risk of cardiovascular death was not confirmed, however, in a third study in young healthy Danish adults. Two new reports on azithromycin suggest that the drug is devoid of cardiovascular risk when used in populations being treated for sexually transmitted diseases and pneumonia (both diseases are commonly treated by azithromycin). Data have been lacking on the use of azithromycin and the risk of death from cardiovascular causes in these two patient populations. These new reports show a lack of association between azithromycin and death from cardiovascular causes.
First study: Azithromycin use in STD population
Khosropour, C.M., et al. “Lack of association between azithromycin and death from cardiovascular causes.” N Eng J Med, 370; 20: 1961-1962.
Azithromycin is an antibiotic recommended by the Centers for Disease Control (CDC) for the treatment of chlamydia and part of a regimen recommended by the CDC for the treatment of gonorrhea. The authors wanted to determine the risk of death from cardiovascular causes in patients taking azithromycin for the treatment of sexually transmitted diseases. They studied data from Public Health Divisions in Oregon and Washington state on cases of chlamydia and gonorrhea who received treatment between 1996 and 2012 (Oregon) and between 1993 and 2010 (Washington). They then matched case reports to death-record data to determine how many patients died within 10 days after treatment.
The results were the following:
The STD study showed data consistent with those of the Danish study by Svanström, et al, that examined the association between azithromycin and the risk of death from cardiovascular causes among healthy Danish adults. That study did not find any increased risk of cardiovascular death associated with azithromycin.
The findings in the STD study, however, differed from the findings in the Tennessee Medicaid study, which included an older patient population. However, the authors of the STD study suggested that their findings should be reassuring to healthcare providers who prescribe azithromycin to treat gonorrhea and chlamydia.
Second study: Azithromycin use in pneumonia population
Mortensen, E.M., et al. “Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia.” JAMA 2014; 311(21): 2199-208.
This retrospective cohort study compared older patients hospitalized with pneumonia between 2002 to 2012 who received azithromycin therapy with patients receiving other antibiotic therapy. The study used national Department of Veterans Affairs data of patients hospitalized at any Veterans Administration care hospital. The patients were all 65 years or older, had been hospitalized for pneumonia, and received antibiotic therapy. Outcomes included cardiovascular events and death within 90 days of hospital admission.
The final analysis included 31,863 patients who received azithromycin and 31,863 who did not. The results showed that 90-day mortality was significantly lower in those who received azithromycin - 17.4% vs. 22.3%. There was an increased odds of heart attack (5.1% vs. 4.4%), but not of any other cardiac event (43.0% vs. 42.7%), cardiac arrhythmias (25.8% vs. 26.0%), or heart failure (26.3% vs. 26.2%).
The study authors concluded that, among older patients hospitalized with pneumonia, treatment with azithromycin compared with other antibiotics was associated with a lower risk of 90-day mortality and a smaller increased risk of heart attack. The findings indicated a net benefit associated with azithromycin use in this patient population.
Summary: Azithromycin studies reported to date
The report by Ray, et al, (N Eng J Med 2012; 366) involving Tennessee Medicaid patients quantified the risk of death from cardiovascular causes associated with azithromycin as compared with other antimicrobial agents. Both the risk of death from any cause and from cardiovascular causes were greater with azithromycin use compared with amoxicillin use. Calculated in another way: If a course of treatment for azithromycin was defined as one 5-day period of therapy, then there were 85 cardiovascular deaths per one million courses of treatment among azithromycin users. During the first 5 days of a course of amoxicillin therapy, there were 32 cardiovascular deaths per one million 5-day courses. During matched 5-day intervals among persons who did not take antibiotics, there were 30 cardiovascular deaths per one million courses.
The report by Svanström, et al, in 2013 (N Eng J Med 2013; 368) involving young healthy Danish adults did not find an increased risk of cardiovascular death associated with azithromycin. The study results pointed to an increased risk among patients with a history of cardiovascular disease, and no significant differences were observed in comparison with patients who did not have that history.
The 2014 report by Rao, et al, (Annals Family Medicine 2014; 12) involving U.S. veterans receiving care in VA hospitals showed that those patients receiving azithromycin or levofloxacin had significantly increased risk of serious cardiac arrhythmias and cardiovascular death.
The two most recent reports are described in this newsletter. The STD study by Khosropour, C.M., et al, reported no deaths from cardiovascular causes among patients treated with azithromycin or another drug, also expressed as 0 deaths from cardiovascular causes per 1 million doses of azithromycin for the treatment of sexually transmitted diseases.
The Mortensen, et al, study concluded that, among older patients hospitalized with pneumonia, treatment with azithromycin compared with other antibiotics was associated with a lower risk of 90-day mortality along with a smaller increased risk of heart attack. The findings indicated a net benefit associated with azithromycin use in this patient population.
Even though the latest two studies show no association between azithromycin and cardiovascular risk, the FDA safety announcement released in March 2013 remains.
FDA azithromycin safety announcement
“The azithromycin drug labels have been updated to strengthen the Warnings and Precautions section with information related to the risk of QT interval prolongation and torsades de pointes, a specific, rare heart rhythm abnormality. Information has also been added regarding the results of a clinical QT study which showed that azithromycin can prolong the QTc interval.
“Healthcare 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.”