Azithromycin cardiovascular risk perhaps in subgroup only

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Think twice in high-risk patients

Pharmacologic and epidemiologic evidence that macrolide antibiotics, including azithromycin, and fluoroquinolones can prolong the QT interval and cause lethal arrhythmias should give clinicians pause before prescribing these drugs, especially if the treatment is expected to be of limited benefit or the patient has cardiovascular risk factors, FDA officials said in an editorial.

In the Danish study, the upper bound of the 95% confidence interval did not exclude an increased risk of cardiovascular death of as much as 55% from using azithromycin, compared with penicillin V, they noted. The Danish patients, in general, had better cardiovascular health than did the Tennessee Medicaid patients.

Any potential cardiovascular risk from azithromycin was associated with current use of the drug and did not affect cardiovascular risk afterward. Separate studies suggest that macrolides may improve survival from community-acquired pneumonia, compared with treatment using other antibacterial agents, an attribute that may not have been incorporated in the Tennessee study’s analysis. It’s possible that the drug may reduce longer-term death rates from pneumonia that outweigh any potential cardiovascular risk during its 5-day course, Dr. Andrew D. Mosholder and his FDA associates suggested (N. Engl. J. Med. 2013;368:1704-12).

Pneumonia was seldom the reason azithromycin was used in the Tennessee study, however. Physicians discuss azithromycin with patients most commonly for chronic sinusitis or bronchitis, according to a separate FDA analysis of data from a survey of about 3,200 office-based physicians conducted by Encuity Research in 2002 through 2011.

When considering prescribing an antibiotic, weigh the potential cardiovascular risks not only of azithromycin but of its alternatives, Dr. Mosholder and his associates advised. The FDA has warned that erythromycin, clarithromycin, and fluoroquinolones can prolong QT intervals, and the Tennessee study found a cardiac death risk from levofloxacin that was similar to that of azithromycin.

More than 40 million U.S. residents received prescriptions for azithromycin in 2011. The Tennessee study found an extra cardiovascular death for every 21,000 outpatient prescriptions of azithromycin, compared with amoxicillin prescriptions. Consider the potential benefits and risks of antibiotic options when prescribing, Dr. Mosholder said.

Dr. Mosholder is with the FDA’s Office of Surveillance and Epidemiology at the Center for Drug Evaluation and Research. He and his associates reported having no financial disclosures.



A large study of Danish national data found no significantly increased cardiovascular risk from taking azithromycin, results that are different from, but perhaps not contradictory to, a recent report that prompted the Food and Drug Administration to beef up warnings about the antibiotic.

The discordance may be attributable to the different populations in the two studies. The earlier study found a doubled or tripled risk of cardiovascular-related death in a higher-risk U.S. cohort of Medicaid recipients while taking azithromycin, compared with no antibiotic or amoxicillin. The current study found a tripled risk of cardiovascular-related deaths in a lower-risk, young- to middle-age Danish cohort while on azithromycin, compared with no antibiotic use, but there was no increased risk from azithromycin use, compared with taking penicillin V, an antibiotic with similar indications.

Clinicians should find the Danish study "reassuring" because it appears that any cardiovascular risk from azithromycin is not generalizable to all patients seen in office practices, Henrik Svanström and his associates concluded.

They analyzed data from multiple Danish national databases from 1997 through 2010 to conduct two comparisons: one of 1,102,050 episodes of azithromycin use, compared with the same number of matched patients on no antibiotics; and a comparison of 1,102,419 episodes of azithromycin use and 7,364,292 episodes of penicillin V use.

There were 6 deaths from cardiovascular causes while on no antibiotics, 17 while on a 5-day course of azithromycin, and 146 while on penicillin V, which translated into cardiovascular death rates of 0.4/1,000 patient-years on no antibiotics, 1.1/1,000 patient-years on azithromycin, and 1.5/1,000 patient-years on penicillin V, reported Mr. Svanström, a statistician at the Statens Serum Institut, Copenhagen, Denmark.

The adjusted difference in absolute risk was one less cardiovascular death per 1 million treatment episodes of azithromycin, compared with penicillin V, the investigators calculated (N. Engl. J. Med. 2013;368:1704-12).

The lack of any significantly increased risk on azithromycin compared with penicillin V suggests that the increase in cardiovascular deaths on azithromycin, compared with no antibiotics, was not attributable to the drug but was entirely brought about by mortality risks from the acute infections or other health problems being treated, Mr. Svanström suggested.

A post hoc analysis also compared episodes of azithromycin use with matched patients given amoxicillin and found no significantly increased risk of cardiovascular death from azithromycin, he reported.

In subgroup analyses, the risk of cardiovascular death appeared to be increased in patients on azithromycin who’d had cardiovascular disease, compared with patients on the drug with no history of cardiovascular disease (rates of 10 and 1 cardiovascular death per 1,000 patient-years, respectively), but the difference did not reach statistical significance.

The FDA recently issued a warning of increased risk for fatal arrhythmia associated with azithromycin use and strengthened the existing warning on the drug’s label about the risk of QT interval prolongation and torsades de pointes. The people at greatest risk are those with known risk factors such as existing QT interval prolongation, low blood levels of potassium or magnesium, a slower-than-normal heart rate, or use of certain drugs to treat abnormal heart rhythms or arrhythmias, the FDA said.

The FDA action followed a retrospective cohort study of Tennessee Medicaid patients from 1992 through 2006, including 347,795 episodes of azithromycin use, 1.4 million matched episodes with no antibiotics, and 1.3 million prescriptions for amoxicillin. That study found a small absolute increase in the risk of cardiovascular death while on azithromycin: 85.2 deaths per million courses of azithromycin, compared with 29.8 per million periods with no antibiotics and 31.5 per million with amoxicillin. The risk was most pronounced among the 10% of patients who already were at highest risk for cardiovascular disease (N. Engl. J. Med. 2012;366:1881-90).

Considering the "profound differences" between the two studies’ patient cohorts and their baseline risks of death, the Danish study should be considered "a clinically relevant complement to, rather than a contrast with," the U.S. study, Mr. Svanström suggested.

The Danish Medical Research Council funded the study.

Mr. Svanström and his associates reported having no financial disclosures.

On Twitter @sherryboschert

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