Clarithromycin Tied to Risk of Cardiac Death in Cohort Study

Marlene Busko

August 19, 2014

COPENHAGEN, DENMARK — During treatment with clarithromycin, but not roxithromycin, patients, especially women, had an increased risk of cardiac death compared with those who were receiving penicillin V for similar infections, in a population-based Danish study[1]. There were 37 excess cardiac deaths (95% CI 4–90) per one million treatment courses of clarithromycin.

However, "given that this was an observational study, it cannot be ruled out that there were differences in the underlying risk of cardiac death between users of clarithromycin and users of other types of antibiotics that we weren't able to take into account," Dr Henrik Svanström (Statens Serum Institut, Copenhagen, Denmark) stressed to heartwire in an email. "Therefore, the results must be confirmed in independent studies and preferably other populations before they are used to guide clinical recommendations.

"For individual clinicians and patients it is important to emphasize that we are talking about very small [absolute] risks for cardiac death . . . when using clarithromycin," he added. "So this finding should probably have limited, if any, effect on prescribing practice in individual patients (with the possible exception of patients who have strong risk factors for drug-induced arrhythmia [such as female sex, old age, and organic heart disease])," the researchers write.

"On the other hand, clarithromycin is one of the more commonly used antibiotics in many countries, and many millions of people are prescribed this drug each year," they add. "Thus, the total number of excess (potentially avoidable) cardiac deaths may not be negligible . . . [so] confirmation [of these findings] in independent populations is an urgent priority."

The study was published online August 19, 2014, in the BMJ.

Macrolides Prolong the QT Interval

Since macrolide antibiotics prolong the QT interval, they may increase the risk of potentially fatal arrhythmia, the researchers write, but evidence to confirm this is limited. In March 2013, the US Food and Drug Administration warned that azithromycin could cause sudden death in people vulnerable to ventricular arrhythmia.

In Denmark, roxithromycin is the most commonly prescribed macrolide, followed by azithromycin and clarithromycin; erythromycin use has dropped considerably, Svanström said. This drug is not available in the US but has been used since the mid-1990s in Denmark, he continued. Clarithromycin is commonly used worldwide for a wide range of bacterial infections, especially respiratory-tract infections. Both drugs are used for the same indications, except clarithromycin is also indicated for treatment of peptic ulcer. "Otherwise, Danish guidelines do not state any specific advantages or disadvantages with one or the other; they are used interchangeably," he explained. Both drugs are metabolized by the cytochrome P450 3A, but only clarithromycin is classed as a strong inhibitor of this enzyme.

The researchers performed a nationwide registry-based cohort study to investigate sudden cardiac death or death from arrhythmia or other cardiac causes associated with clarithromycin and roxithromycin vs penicillin V (which has similar indications but no known cardiac risk).

They found that from 1997 to 2011, adults aged 40 to 74 years with a low baseline risk of cardiac death who were living in Denmark received over five million seven-day treatment courses of the studied antibiotics: 4 355 309 with penicillin V, 588 988 with roxithromycin, and 160 297 with clarithromycin.

There were 285 cardiac deaths: 5.3 per 1000 person-years during the use of clarithromycin, but only 2.5 per 1000 person years during use of roxithromycin or penicillin V.

Compared with a regimen of penicillin V, in propensity-score–adjusted analysis, use of clarithromycin was associated with a 1.76-fold higher risk of cardiac death during treatment. The risk was 2.83-fold higher with women and only 1.09-fold higher with men.

"Again, it should be emphasized that the absolute risk of cardiac death is small on the level of the individual patient and is still small in women using clarithromycin," Svanström said. "Decisions on the choice of treatment in individual patients should always include considerations such as the type of infection and characteristics of the patient."

The researchers did not detect any increase in risk of cardiac death with concomitant use of cytochrome-P450-3A–inhibiting drugs, possibly because of the small number of cases of this concomitant use, which is contraindicated in treatment guidelines.

"Our study expands on the available knowledge of the cardiac safety of macrolides, being the first large-scale population-based observational study to show significantly increased cardiac risk with clarithromycin and the relative cardiac safety of roxithromycin," the authors summarize.

"Earlier studies have suggested that individual macrolides have different potential for QT prolongation; for instance, clarithromycin seems to have higher potency for QT prolongation than roxithromycin," Svanström said. "Therefore, if the association we observe is true, this could be an explanation for the increased risk with clarithromycin but not roxithromycin."

The authors have no disclosures.

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