A nationwide based study in Denmark assessed the risk of cardiac death associated with the use of clarithromycin and roxithromycin. Participants included Danish adults, 40-74 years of age, who received seven day treatment courses with clarithromycin (n=160 297), roxithromycin (n=588 988), or penicillin V (n=4 355 309). The main study endpoint was risk of cardiac death associated with the use of clarithromycin and roxithromycin, compared with penicillin V. The authors carried out subgroup analyses to explore =the contribution of gender, age, cardiovascular risk score, and concomitant use of drugs that inhibit the cytochrome P450 3A enzyme, which metabolises macrolides.

A total of 285 cardiac deaths were observed. Compared with the use of penicillin V, the administration of clarithromycin was associated with a significantly increased risk of cardiac death (5.3 per 1000 person years; adjusted rate ratio 1.76, 95% confidence interval 1.08 to 2.85) compared with roxithromycin (2.5 per 1000 person years; adjusted rate ratio 1.04, 0.72 to 1.51). interestingly, the association with clarithromycin was most pronounced among women (adjusted rate ratios 2.83 (1.50 to 5.36) in women and 1.09 (0.51 to 2.35) in men). Compared with penicillin V, the adjusted absolute risk difference was 37 (95% confidence interval 4 to 90) cardiac deaths per 1 million courses with clarithromycin and 2 (–14 to 25) cardiac deaths per 1 million courses with roxithromycin.

Thus this large cohort study reported a significantly increased risk of cardiac death associated with the use of clarithromycin but not with roxithromycin. Several major issues emerge from this study:

  1. Given the widespread use of clarithromycin worldwide, these findings raise concerns as to a potentially large excess death linked to cardiotoxicity with the use of clarithromycin
  2. Patient selection may be critical to avoid undesirable side effects and serious cardiovascular complications in real life clinical practice
  3. Will findings in the Danish study have an impact on macrolide prescription in Europe?
Cardio Debate Expert Comments

Macrolide antibiotics are widely used for the treatment of infections caused by gram-positive organisms. Cardiotoxicity related to macrolides has been related to the blockade of HERG channels leading to QT interval prolongation and serious arrhythmias, including torsade de pointes (1-6). There are important differences, however, regarding the potency of individual macrolides to inhibit HERG channels, which may translate in differences in their potential for producing serious cardiovascular events such as sudden cardiac death (7,8). A small case-control study suggested an association between sudden cardiac death and the use of the macrolide clarithromycin (9). Importantly, the risk of cardiac death was recently assessed in a large Danish nationwide cohort study enrolling patients (40-74 years of age) free from serious cardiac disease, who received seven day treatment courses with clarithromycin (n=160,297), roxithromycin (n=588,988), and penicillin V (n=4,355,309), the latter having no known association with cardiac risk (10). A total of 285 cardiac deaths were observed with the use of the study drugs. Compared with the use of penicillin V (incidence rate 2.5 per 1000 person years), the use of clarithromycin was associated with a significantly increased risk of cardiac death (5.3 per 1000 person years; adjusted RR 1.76, 95% CI 1.08-2.85) while the use of roxithromycin was not significantly different to penicillin V regarding cardiac death incidence (2.5 per 1000 person years, RR 1.04, 95% CI 0.72-1.51). Thus, clarithromycin would account for an estimated 37 cardiac death excess per 1 million treatment courses. The risk was found to be higher in women, but there were no differences according to age, cardiac risk score or concomitant use of cytochrome P450 3A inhibiting drugs.

Despite several study limitations (i.e. there were more patients with respiratory diseases in the clarithromycin group), the Danish study showed a significantly increased cardiac risk with the use of clarithromycin compared with roxithromycin. It can be argued however that as the absolute cardiovascular risk associated with the use of clarithromycin is small, the results of the Danish study are likely to have limited effect on prescribing practice, albeit it would be desirable that particular attention is paid to use of this agent in patients with an increased risk of drug-induced arrhythmia. Given the widespread use of clarithromycin, however, the total number of potentially avoidable cardiac deaths is not negligible. Therefore, the present results and those previously reported with the administration of other macrolides, indicate that it is an urgent need to define the cardiac safety profiles of individual drugs in clinical practice. Well designed prospective randomized clinical trials are needed to guide drug choice in the individual patient, ensuring an effective and safer use of macrolide antibiotics.

References

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  2. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 2004;351:1089-96.
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  8. Volberg WA, Koci BJ, Su W,et al. Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics. J Pharmacol Exp Ther 2002;302:320-7.
  9. Straus SM, Sturkenboom MC, Bleumink GS et al. Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. Eur Heart J 2005;26:2007-12.
  10. Svanström H, Pasternak B, Hviid A. Use of clarithromycin and roxithromycin and risk of cardiac death: cohort study. BMJ. 2014;349:g4930.