Clarithromycin linked with increased risk of cardiac death

1. Patients taking clarithromycin had a significantly increased risk of cardiac death. This risk was more pronounced in women. 

2. Roxithromycin use was not associated with any such increased risk of cardiac death. 

Evidence Rating Level: 2 (Good)       

Study Rundown: The macrolide class of antibiotics is prescribed to millions of people per year for respiratory tract infections and skin and soft tissue infections. Several drugs in this class are known to prolong the QT interval on an electrocardiogram, and thus thought to increase the risk of fatal arrhythmias. Studies have demonstrated the increased cardiovascular risks associated with erythromycin and azithromycin, but evidence regarding the other macrolides is lacking. The purpose of this study was to determine the risk of cardiac death associated with use of clarithromycin and roxithromycin.

This study looked at all Danish adults between the ages of 40 and 74 who received a 7 day treatment course with clarithromycin, roxithromycin, and penicillin V between 1997 and 2011. Compared to patients taking penicillin V, the most commonly used antibiotic in Denmark with similar indications as the macrolides, clarithromycin use was associated with a 76% higher risk of cardiac death. This risk was higher in women than in men. Roxithromycin use was not associated with an increased risk of cardiac death. Finally, concomitant use of medications that inhibit the cytochrome P450 3A enzyme, which metabolizes the macrolides, did not increase the risk of cardiac death.

The study’s strengths lie in its generalizability as it studied an entire country’s population and its lack of confounding given the comparative design of the macrolides to penicillin V. Additionally, the study only included relatively healthy people with no recent antibiotic use or hospital admissions in order to attribute any effect to the drug itself. However, important information such as smoking history and body mass index were lacking even with propensity score adjustment.

Click to read the study, published today in the BMJ

Relevant Reading: Azithromycin and the risk of cardiovascular death

In-Depth [retrospective cohort]: This study was a cohort analysis of Danish adults 40-74 years old who received over 5,000,000 courses of either clarithromycin, roxithromycin, or penicillin V based on the Danish National Prescription Registry from 1997-2011. The authors determined cardiac deaths from the Danish Register of Causes of Death. Clarithromycin use was associated with significantly increased risk of cardiac death (RR 2.07, CI_95% 1.28-3.35) which persisted after propensity score adjustment (RR1.76, CI_95% 1.08-2.85). Roxithromycin, however, was not associated with an increased risk of cardiac death (RR 1.04, CI_95% 0.72-1.51). The absolute risk difference for clarithromycin use was 37 cardiac deaths per 1 million treatment courses (CI_95% 4-90) but only 2 cardiac deaths per 1 million treatment courses (95% CI -14-25) for roxithromycin. Interestingly, the risk of cardiac death was higher in women than in men for clarithromycin use [adjusted rate 2.83, (CI_95% 1.50-5.36) in women, 1.09 (CI_95% 0.51-2.35) in men; p=0.07)] but not for roxithromycin use [adjusted rate 1.13 (CI_95% 0.63-2.00) in women, 0.97 (CI_95% 0.59-1.59) in men; p=0.71].

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