FDA seeks more information about potential CV mortality risk related to short-term clarithrycin use

"We found no beneficial effect of short-term clarithromycin for patients with stable coronary heart disease," the authors stated. "On the contrary, the significantly increased cardiovascular mortality in the clarithromycin-treated patients surprised us."

Patients enrolled in the CLARICOR trial were treated with clarithromycin 500 mg/d or placebo for 14 days. Increased mortality was evident at 1 year or longer. Beyond that time frame, the authors recommended further examination of the drug and its effect on mortality.

FDA, after discussing the findings with the Danish Medicines Agency (DMA), issued an advisory but did not recommend any specific changes to the use of clarithromycin. Previous trials of the drug and other antibacterial drugs to prevent heart disease had not shown a statistically significant effect on mortality. FDA is seeking to gather more information regarding the CLARICOR study and its findings before issuing any recommendations.

Of the 13,702 patients (aged 18 to 85 y) enrolled in the blinded study, 4,373 (32%) were randomized to either clarithromycin (n=2,172) or placebo (n=2,201).

The primary outcome-all-cause mortality or non-fatal cardiac outcomes-did not differ significantly between the clarithromycin and placebo arms (15.8% vs 13.8%; HR 1.15; 95% CI, 0.99–1.34; P=.08).

Likewise, the secondary outcome-cardiovascular mortality or non-fatal cardiac outcomes-did not differ significantly between the 2 arms (11.5% vs 9.9%; HR 1.17; 95% CI, 0.98–1.40; P=.09).

However, the tertiary outcome-cardiovascular mortality, myocardial infarction, unstable angina, cerebrovascular attack or peripheral vascular disease-was significantly more frequent in the clarithromycin arm than in the placebo arm (16.2% vs 13.7%; HR 1.20; 95% CI, 1.02–1.39; P=.03). The number of non-fatal tertiary outcomes was insignificantly increased by 16% in the clarithromycin arm (HR 1.16; 95% CI, 0.97–1.39; P=.09).

All-cause mortality was significantly higher in the clarithromycin group (HR 1.27; 95% CI, 1.03–1.54; P=.03) as a result of significantly higher cardiovascular mortality (HR 1.45; 95% CI, 1.09–1.92; P=.01). Non-cardiovascular mortality and non-classified mortality did not differ significantly.

The strengths of the study included its size, central randomization, stratification at randomization, and the placebo-controlled intervention with blinded outcome assessment and intention-to-treat (ITT) analyses, according to the authors.

"Compliance was excellent," the authors stated. "We obtained all outcomes from public registers, securing follow-up of more than 99% of patients."

Study limitations included the fact that only 32% of the potentially eligible patients were randomized, which may affect the external validity. Also, the study could not exclude chance imbalance at randomization or after randomization as a cause of the increased mortality.

As part of their discussion, the authors noted that it "remains unclear" as to why clarithromycin might have an unfavorable effect in patients with coronary heart disease. Regarding the risk of coadministration of macrolides and drugs metabolized by cytochrome P450 3A isoenzymes, the authors stated that they "did not observe differences in cardiovascular mortality during the first month, and drug interactions cannot readily explain the observed difference in cardiovascular mortality."

SOURCES Jespersen CM, Als-Nielsen B, Damgaard M, et al; for the CLARICOR Trial Group. Randomized placebo-controlled multicenter trial to assess short-term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ. 2006; 332:22–27.

FDA Alert: Clarithromycin (marketed as Biaxin) information. Available at: http:// http://www.fda.gov/cder/drug/infopage/clarithromycin/default.htm. Accessed December 29, 2005.