Use of clarithromycin and roxithromycin and risk of cardiac death: cohort study

Abstract

Objective: To assess the risk of cardiac death associated with the use of clarithromycin and roxithromycin.

Design: Cohort study.

Setting: Denmark, 1997-2011.

Participants: Danish adults, 40-74 years of age, who received seven day treatment courses with clarithromycin (n = 160,297), roxithromycin (n = 588,988), and penicillin V (n = 4,355,309).

Main outcome measures: The main outcome was risk of cardiac death associated with clarithromycin and roxithromycin, compared with penicillin V. Subgroup analyses were conducted according to sex, age, risk score, and concomitant use of drugs that inhibit the cytochrome P450 3A enzyme, which metabolises macrolides.

Results: A total of 285 cardiac deaths were observed. Compared with use of penicillin V (incidence rate 2.5 per 1000 person years), use 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) but use of roxithromycin was not (2.5 per 1000 person years; adjusted rate ratio 1.04, 0.72 to 1.51). 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.

Conclusions: This large cohort study found a significantly increased risk of cardiac death associated with clarithromycin. No increased risk was seen with roxithromycin. Given the widespread use of clarithromycin, these findings call for confirmation in independent populations.

Fig 1 Enrolment of participants in cohort of users of clarithromycin, roxithromycin, and penicillin V. *People living in Denmark, aged 40-74 years, 1997-2011. †Numbers do not sum because some participants were excluded for more than one reason. ‡Including cancer, serious neurological disease, congenital anomalies/childhood conditions, liver disease,

Fig 2 Rate of cardiac death and number of excess cardiac deaths with clarithromycin and roxithromycin, compared with penicillin V. *As calculated from unadjusted rate of cardiac death. †Adjusted for propensity scores

Fig 3 Subgroup analyses of risk of cardiac death associated with clarithromycin and roxithromycin, compared with penicillin V. *Cardiac risk score was covariate summary score aiming to capture baseline risk of cardiac death and derived from all variables shown in table 1; score was categorised according to tenths of score’s distribution and strata defined as low (tenths 1-6), medium (6-8), and high (9-10). †Adjusted for propensity score, categorised according to tenths of score’s distribution; analyses stratified according to cardiac risk score were not adjusted for propensity scores