FDA alert on clarithromycin

December 12, 2005

Rockville, MD - The FDA has issued an alert on the antibiotic clarithromycin (Biaxin, Abbott Laboratories) after it was associated with an increased mortality in patients with heart disease taking part in a clinical trial. Despite the warning, however, the agency does not recommend any specific changes to the use of clarithromycin at this time.

The study, CLARICOR, involved patients with stable coronary heart disease given clarithromycin or placebo for two weeks to examine whether antibiotics would be of benefit (there is some evidence of an association between Chlamydia pneumoniae and heart disease). However, those given clarithromycin had a higher mortality that became apparent after one year, as reported in the paper by Dr Christian P Jespersen (Bispebjerg Hospital, Copenhagen, Denmark) and colleagues, published online in BMJ December 8, 2005[1].

The FDA says its advice is in line with that of the Danish Medicines Agency and it is carrying out additional investigations to see whether any changes to the use of clarithromycin in those with heart disease are needed.

First study to show significant effect on mortality with clarithromycin

In the study, all-cause mortality at one year was significantly higher in the clarithromycin arm, primarily driven by cardiovascular mortality.

CLARICOR: Mortality at one year

Mortality Clarithromycin (n=2172), n (%) Placebo (n=2200), n (%) Hazard ratio (95% CI) p
Cardiovascular 111 (5.1) 78 (3.5) 1.45 (1.09-1.92) 0.01
Noncardiovascular 85 (3.9) 84 (3.8) 1.03 (0.76-1.41) 0.82
Nonclassified 16 (0.7) 10 (0.5) 1.64 (0.75-2.11) 0.22
All cause 212 (9.8) 172 (7.8) 1.27 (1.03-1.54) 0.03

No benefit of clarithromycin was seen. There was no difference between the clarithromycin and placebo arms in either the composite primary end point (all-cause mortality, MI, or unstable angina [UA] during three years of follow-up) or the secondary outcome (cardiovascular mortality or nonfatal cardiac outcomes). The tertiary outcome (cardiovascular mortality, MI, UA, cerebrovascular attack, or peripheral vascular disease) was significantly more frequent in the antibiotic arm (hazard ratio 1.20; p=0.03).

Previous studies of antibacterial drugs to prevent heart disease and other trials of clarithromycin have not shown a statistically significant effect on mortality, the agency notes.

No clear explanation for the finding

In its alert to healthcare professionals, the FDA says: "There is no clear explanation for how clarithromycin would lead to more deaths than placebo and no biological mechanism to account for deaths occurring one year or longer after a single two-week treatment course of clarithromycin in the CLARICOR study."

It adds that it has reviewed Abbott Laboratories' clinical-trials database. "These analyses do not show significant differences in the adverse events or death rates, but most of these studies ended after a few weeks or months. They do not continue for long enough to be able to see whether the difference in deaths reported in the CLARICOR trial would occur." 

The FDA says it has not yet had access to the primary data for the CLARICOR study to perform an independent review. 

"It is possible that further evaluation of the study will help in understanding the observed results. We also cannot exclude the possibility that other factors or chance could have contributed to the observed mortality difference." For example, the agency notes, the authors say they would like to know about New York Heart Association class, ejection fraction at baseline, and medical treatment and lifestyle during the study period.

In conclusion, healthcare professionals and patients should be aware of these findings and should weigh the benefits and risks of using clarithromycin pending further investigation and advice, the agency says.


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