Azithromycin Slightly Raises Risk of Cardiovascular Death

A small absolute increase in the risk of cardiovascular death occurs during a 5-day course of azithromycin therapy, according to a report in the May 17 issue of the New England Journal of Medicine.

This rise is most pronounced among the 10% of patients who are already at highest risk for cardiovascular disease, said Wayne A. Ray, Ph.D., of the division of pharmacoepidemiology at Vanderbilt University in Nashville, Tenn., and his associates.

Azithromycin "has been reported to be relatively free of cardiotoxic effects," but it is closely related to erythromycin and clarithromycin, which are known to raise the risk of serious ventricular arrhythmias and sudden cardiac death. In addition, there have been isolated reports of patients with normal heart rhythms developing arrhythmia-related adverse events while taking azithromycin, including 20 cases of torsades de pointes reported to the Food and Drug Administration.

Dr. Ray and his colleagues performed a retrospective cohort study testing their hypothesis that patients taking azithromycin would show a higher rate of cardiovascular death – particularly sudden cardiac death – than would people who were not taking antibiotics and people who were taking different antibiotics.

The researchers analyzed data from the Tennessee Medicaid program on patients aged 30-74 years in 1992 (when azithromycin was first introduced in the United States) through 2006. They compared cardiovascular mortality and all-cause mortality during 347,795 5-day courses of azithromycin vs. 1,391,180 matched-control periods with no antibiotic treatment.

To control for possible confounding by treatment indication, the investigators included a second control group of 1,348,672 prescriptions for amoxicillin; 264,626 for ciprofloxacin; and 193,906 for levofloxacin. The most common indications for both azithromycin and amoxicillin were ear, nose, or throat infections and bronchitis.

Compared with no antibiotic treatment, the use of azithromycin was associated with an increased rate of cardiovascular death (85.2 CV deaths per million courses with azithromycin vs. 29.8 per million courses with no treatment). The hazard ratio for cardiovascular death was 2.88 during a course of azithromycin, compared with no antibiotic therapy.

Similarly, the use of azithromycin was associated with an increased risk of cardiovascular death, compared with amoxicillin treatment, for which the rate was 31.5 CV deaths per million courses.

"As compared with amoxicillin, there were 47 additional cardiovascular deaths per 1 million courses of azithromycin therapy; for patients in the highest decile of baseline risk of CV disease, there were 245 additional cardiac deaths per 1 million courses," Dr. Ray and his associates said (N. Engl. J. Med. 2012;366:1881-90).

Azithromycin raised the risk of sudden cardiac death as well as that of other cardiovascular deaths.

The findings were similar when azithromycin was compared with ciprofloxacin, but mortality risks did not differ significantly between azithromycin and levofloxacin. Levofloxacin "has [a] recognized proarrhythmic potential" and has been linked to increased risk of cardiovascular death in previous studies, Dr. Ray and his associates said.

These increased mortality risks did not persist beyond the 5-day course of treatment, even though concentrations of azithromycin remain elevated in tissue for several more days. This may be because serum concentrations of the drug decline more rapidly, "falling to trough levels within 24 hours" of completing the course of therapy.

"Although our data are consistent with an adverse cardiac effect of azithromycin, they cannot establish a specific causal mechanism," they added.

In a statement May 17, Food and Drug Administration officials noted that the agency is aware of the study and its findings and is reviewing the results; they noted that any new information that results from the FDA review would be shared.*

This study was supported by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics. Dr. Ray reported ties to XL Insurance regarding conjugated estrogens, and providing expert testimony in litigation involving zoledronic acid.

*This story was updated May 17, 2012.

A small absolute increase in the risk of cardiovascular death occurs during a 5-day course of azithromycin therapy, according to a report in the May 17 issue of the New England Journal of Medicine.

This rise is most pronounced among the 10% of patients who are already at highest risk for cardiovascular disease, said Wayne A. Ray, Ph.D., of the division of pharmacoepidemiology at Vanderbilt University in Nashville, Tenn., and his associates.

Azithromycin "has been reported to be relatively free of cardiotoxic effects," but it is closely related to erythromycin and clarithromycin, which are known to raise the risk of serious ventricular arrhythmias and sudden cardiac death. In addition, there have been isolated reports of patients with normal heart rhythms developing arrhythmia-related adverse events while taking azithromycin, including 20 cases of torsades de pointes reported to the Food and Drug Administration.

Dr. Ray and his colleagues performed a retrospective cohort study testing their hypothesis that patients taking azithromycin would show a higher rate of cardiovascular death – particularly sudden cardiac death – than would people who were not taking antibiotics and people who were taking different antibiotics.

The researchers analyzed data from the Tennessee Medicaid program on patients aged 30-74 years in 1992 (when azithromycin was first introduced in the United States) through 2006. They compared cardiovascular mortality and all-cause mortality during 347,795 5-day courses of azithromycin vs. 1,391,180 matched-control periods with no antibiotic treatment.

To control for possible confounding by treatment indication, the investigators included a second control group of 1,348,672 prescriptions for amoxicillin; 264,626 for ciprofloxacin; and 193,906 for levofloxacin. The most common indications for both azithromycin and amoxicillin were ear, nose, or throat infections and bronchitis.

Compared with no antibiotic treatment, the use of azithromycin was associated with an increased rate of cardiovascular death (85.2 CV deaths per million courses with azithromycin vs. 29.8 per million courses with no treatment). The hazard ratio for cardiovascular death was 2.88 during a course of azithromycin, compared with no antibiotic therapy.

Similarly, the use of azithromycin was associated with an increased risk of cardiovascular death, compared with amoxicillin treatment, for which the rate was 31.5 CV deaths per million courses.

"As compared with amoxicillin, there were 47 additional cardiovascular deaths per 1 million courses of azithromycin therapy; for patients in the highest decile of baseline risk of CV disease, there were 245 additional cardiac deaths per 1 million courses," Dr. Ray and his associates said (N. Engl. J. Med. 2012;366:1881-90).

Azithromycin raised the risk of sudden cardiac death as well as that of other cardiovascular deaths.

The findings were similar when azithromycin was compared with ciprofloxacin, but mortality risks did not differ significantly between azithromycin and levofloxacin. Levofloxacin "has [a] recognized proarrhythmic potential" and has been linked to increased risk of cardiovascular death in previous studies, Dr. Ray and his associates said.

These increased mortality risks did not persist beyond the 5-day course of treatment, even though concentrations of azithromycin remain elevated in tissue for several more days. This may be because serum concentrations of the drug decline more rapidly, "falling to trough levels within 24 hours" of completing the course of therapy.

"Although our data are consistent with an adverse cardiac effect of azithromycin, they cannot establish a specific causal mechanism," they added.

In a statement May 17, Food and Drug Administration officials noted that the agency is aware of the study and its findings and is reviewing the results; they noted that any new information that results from the FDA review would be shared.*

This study was supported by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics. Dr. Ray reported ties to XL Insurance regarding conjugated estrogens, and providing expert testimony in litigation involving zoledronic acid.

*This story was updated May 17, 2012.

A small absolute increase in the risk of cardiovascular death occurs during a 5-day course of azithromycin therapy, according to a report in the May 17 issue of the New England Journal of Medicine.

This rise is most pronounced among the 10% of patients who are already at highest risk for cardiovascular disease, said Wayne A. Ray, Ph.D., of the division of pharmacoepidemiology at Vanderbilt University in Nashville, Tenn., and his associates.

Azithromycin "has been reported to be relatively free of cardiotoxic effects," but it is closely related to erythromycin and clarithromycin, which are known to raise the risk of serious ventricular arrhythmias and sudden cardiac death. In addition, there have been isolated reports of patients with normal heart rhythms developing arrhythmia-related adverse events while taking azithromycin, including 20 cases of torsades de pointes reported to the Food and Drug Administration.

Dr. Ray and his colleagues performed a retrospective cohort study testing their hypothesis that patients taking azithromycin would show a higher rate of cardiovascular death – particularly sudden cardiac death – than would people who were not taking antibiotics and people who were taking different antibiotics.

The researchers analyzed data from the Tennessee Medicaid program on patients aged 30-74 years in 1992 (when azithromycin was first introduced in the United States) through 2006. They compared cardiovascular mortality and all-cause mortality during 347,795 5-day courses of azithromycin vs. 1,391,180 matched-control periods with no antibiotic treatment.

To control for possible confounding by treatment indication, the investigators included a second control group of 1,348,672 prescriptions for amoxicillin; 264,626 for ciprofloxacin; and 193,906 for levofloxacin. The most common indications for both azithromycin and amoxicillin were ear, nose, or throat infections and bronchitis.

Compared with no antibiotic treatment, the use of azithromycin was associated with an increased rate of cardiovascular death (85.2 CV deaths per million courses with azithromycin vs. 29.8 per million courses with no treatment). The hazard ratio for cardiovascular death was 2.88 during a course of azithromycin, compared with no antibiotic therapy.

Similarly, the use of azithromycin was associated with an increased risk of cardiovascular death, compared with amoxicillin treatment, for which the rate was 31.5 CV deaths per million courses.

"As compared with amoxicillin, there were 47 additional cardiovascular deaths per 1 million courses of azithromycin therapy; for patients in the highest decile of baseline risk of CV disease, there were 245 additional cardiac deaths per 1 million courses," Dr. Ray and his associates said (N. Engl. J. Med. 2012;366:1881-90).

Azithromycin raised the risk of sudden cardiac death as well as that of other cardiovascular deaths.

The findings were similar when azithromycin was compared with ciprofloxacin, but mortality risks did not differ significantly between azithromycin and levofloxacin. Levofloxacin "has [a] recognized proarrhythmic potential" and has been linked to increased risk of cardiovascular death in previous studies, Dr. Ray and his associates said.

These increased mortality risks did not persist beyond the 5-day course of treatment, even though concentrations of azithromycin remain elevated in tissue for several more days. This may be because serum concentrations of the drug decline more rapidly, "falling to trough levels within 24 hours" of completing the course of therapy.

"Although our data are consistent with an adverse cardiac effect of azithromycin, they cannot establish a specific causal mechanism," they added.

In a statement May 17, Food and Drug Administration officials noted that the agency is aware of the study and its findings and is reviewing the results; they noted that any new information that results from the FDA review would be shared.*

This study was supported by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Research and Quality Centers for Education and Research on Therapeutics. Dr. Ray reported ties to XL Insurance regarding conjugated estrogens, and providing expert testimony in litigation involving zoledronic acid.

*This story was updated May 17, 2012.