Abstract
There are conflicting reports regarding the association of the macrolide antibiotic clarithromycin with cardiovascular (CV) events. A possible explanation may be that this risk is partly mediated through drug-drug interactions and only evident in at-risk populations. To the best of our knowledge, no studies have examined whether this association might be mediated via P-glycoprotein (P-gp), a major pathway for clarithromycin metabolism. The aim of this study was to examine CV risk following prescription of clarithromycin versus amoxicillin and in particular, the association with P-gp, a major pathway for clarithromycin metabolism. We conducted an observational cohort study of patients prescribed clarithromycin or amoxicillin in the community in Tayside, Scotland (population approximately 400,000) between 1 January 2004 and 31 December 2014 and a genomic observational cohort study evaluating genotyped patients from the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) study, a longitudinal cohort study of 18,306 individuals with and without type 2 diabetes recruited between 1 December 1988 and 31 December 2015. Two single-nucleotide polymorphisms associated with P-gp activity were evaluated (rs1045642 and rs1128503 -AA genotype associated with lowest P-gp activity). The primary outcome for both analyses was CV hospitalization following prescription of clarithromycin versus amoxicillin at 0-14 days, 15-30 days, and 30 days to 1 year. In the observational cohort study, we calculated hazard ratios (HRs) adjusted for likelihood of receiving clarithromycin using inverse proportion of treatment weighting as a covariate, whereas in the pharmacogenomic study, HRs were adjusted for age, sex, history of myocardial infarction, and history of chronic obstructive pulmonary disease. The observational cohort study included 48,026 individuals with 205,227 discrete antibiotic prescribing episodes (34,074 clarithromycin, mean age 73 years, 42% male; 171,153 amoxicillin, mean age 74 years, 45% male). Clarithromycin use was significantly associated with increased risk of CV hospitalization compared with amoxicillin at both 0-14 days (HR 1.31; 95% CI 1.17-1.46, p < 0.001) and 30 days to 1 year (HR 1.13; 95% CI 1.06-1.19, p < 0.001), with the association at 0-14 days modified by use of P-gp inhibitors or substrates (interaction p-value: 0.029). In the pharmacogenomic study (13,544 individuals with 44,618 discrete prescribing episodes [37,497 amoxicillin, mean age 63 years, 56% male; 7,121 clarithromycin, mean age 66 years, 47% male]), when prescribed clarithromycin, individuals with genetically determined lower P-gp activity had a significantly increased risk of CV hospitalization at 30 days to 1 year compared with heterozygotes or those homozygous for the non-P-gp-lowering allele (rs1045642 AA: HR 1.39, 95% CI 1.20-1.60, p < 0.001, GG/GA: HR 0.99, 95% CI 0.89-1.10, p = 0.85, interaction p-value < 0.001 and rs1128503 AA 1.41, 95% CI 1.18-1.70, p < 0.001, GG/GA: HR 1.04, 95% CI 0.95-1.14, p = 0.43, interaction p-value < 0.001). The main limitation of our study is its observational nature, meaning that we are unable to definitively determine causality. In this study, we observed that the increased risk of CV events with clarithromycin compared with amoxicillin was associated with an interaction with P-glycoprotein.
Highlights
Clarithromycin is a widely prescribed macrolide antibiotic, comprising around 15% of all primary care antibiotic prescriptions in the United Kingdom, recommended for treatment of patients with lower respiratory tract infections either as monotherapy or in combination [1,2,3]
We observed that the increased risk of CV events with clarithromycin compared with amoxicillin was associated with an interaction with P-glycoprotein
We performed a propensity-weighted observational population cohort analysis comparing clarithromycin versus amoxicillin prescription and cardiovascular outcome in patients in Tayside, Scotland. In this analysis, we found that that patients prescribed clarithromycin were significantly more likely to have a cardiovascular hospitalization at 0–14 days and 30 days to 1 year after prescription than those prescribed amoxicillin and that individuals who were coprescribed P-glycoprotein substrates or inhibitors and clarithromycin had a significantly higher risk of cardiovascular hospitalization
Summary
Clarithromycin is a widely prescribed macrolide antibiotic, comprising around 15% of all primary care antibiotic prescriptions in the United Kingdom, recommended for treatment of patients with lower respiratory tract infections either as monotherapy or in combination [1,2,3]. The Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease (CLARICOR) trial in patients with high CV risk [4], designed to test the hypothesis that clarithromycin would reduce CV risk, found that 2 weeks of clarithromycin caused a 45% relative risk increase in CV mortality compared with placebo These results were supported by a number of observational studies [5,6,7,8] and meta-analyses [9, 10] suggesting that clarithromycin and other macrolide antibiotics were associated with adverse outcome, in the short term during and after exposure, and in the longer term after drug discontinuation, leading to a recent United States Food and Drug Administration (FDA) safety alert on the use of clarithromycin in patients with heart disease [11, 12]. The aim of this study was to examine CV risk following prescription of clarithromycin versus amoxicillin and in particular, the association with P-gp, a major pathway for clarithromycin metabolism
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