Risk of cardiovascular events, arrhythmia and all-cause mortality associated with clarithromycin versus alternative antibiotics prescribed for respiratory tract infections: a retrospective cohort study

Abstract

ObjectiveTo determine whether treatment with clarithromycin for respiratory tract infections was associated with an increased risk of cardiovascular (CV) events, arrhythmias or all-cause mortality compared with other antibiotics.DesignRetrospective cohort design comparing clarithromycin monotherapy for lower (LRTI) or upper respiratory tract infection (URTI) with other antibiotic monotherapies for the same indication.SettingRoutine primary care data from the UK Clinical Practice Research Datalink and inpatient data from the Hospital Episode Statistics (HES).ParticipantsPatients aged ≥35 years prescribed antibiotic monotherapy for LRTI or URTI 1998–2012 and eligible for data linkage to HES.Main outcome measuresThe main outcome measures were: adjusted risk of first-ever CV event, within 37 days of initiation, in commonly prescribed antibiotics compared with clarithromycin. Secondarily, adjusted 37-day risks of first-ever arrhythmia and all-cause mortality.ResultsOf 700 689 treatments for LRTI and eligible for the CV analysis, there were 2071 CV events (unadjusted event rate: 29.6 per 10 000 treatments). Of 691 998 eligible treatments for URTI, there were 688 CV events (9.9 per 10 000 treatments). In LRTI and URTI, there were no significant differences in CV risk between clarithromycin and all other antibiotics combined: OR=1.00 (95% CI 0.82 to 1.22) and 0.82 (0.54 to 1.25), respectively. Adjusted CV risk in LRTI versus clarithromycin ranged from OR=1.42 (cefalexin; 95% CI 1.08 to 1.86) to 0.92 (doxycycline; 0.64 to 1.32); in URTI, from 1.17 (co-amoxiclav; 0.68 to 2.01) to 0.67 (erythromycin; 0.40 to 1.11). Adjusted mortality risk versus clarithromycin in LRTI ranged from 0.42 to 1.32; in URTI, from 0.75 to 1.43. For arrhythmia, adjusted risks in LRTI ranged from 0.68 to 1.05; in URTI, from 0.70 to 1.22.ConclusionsCV events were more likely after LRTI than after URTI. When analysed by specific indication, CV risk associated with clarithromycin was no different to other antibiotics.

Managing Cardiovascular Risk of Macrolides: Systematic Review and Meta-Analysis

“…No increased long-term risk of myocardial infarction associated with clarithromycin was shown across study designs. We could observe a short-term increased risk of arrhythmia in a case-crossover study (RR 2.49; 95% CI 1.09-5.69) [37] and no increased risk in four cohort studies [22,32,37,44]. For long-term arrhythmia, we observed a marginal increased risk in two case- With roxithromycin, the number of observational studies was inadequate to obtain an overall effect summary for all outcomes.…”

“…The pooled estimate did not give an increased risk (OR 1.18; 95% CI 0.96-1.44). Six cohort studies or self-controlled case series analysis [15,22,33,37,44,56] reported that the pooled estimate for long-term arrhythmia was 1.10 (95% CI 0.99-1.21) with heterogeneity of 69%. However, when results from at least two studies with the same follow-up periods were combined, no increased risk could be found (data not shown).…”

“…There were six cohort studies reporting a short-term risk of arrhythmia associated with macrolides [22,32,34,36,37,44] and no increased risk was observed (RR 1.36, 95% CI 0.97-1.92) (Fig.6). No RCT was identified in reporting the short-term risk of arrhythmia associated with macrolides.…”

“…As they reported results in different follow-up periods in different reports [11,20,21], the reported measures of effect were extracted and pooled according to different follow-up periods. For one report of multiple studies which reported estimates from different cohorts of patients, we extracted the data from different cohorts [12,15,22,23]. Each cohort could contribute a proportion of weights in the meta-analysis.…”

Management of arrhythmia in sepsis and septic shock

“…QTc altered after trimethroprim-sulfamethoxazole may be rare [53]. Two studies on non-septic patients [54,55] showed no difference in the incidence of arrhythmia between different groups of macrolides, indicating that illness severity is probably the most important factor. A recent meta-analysis found no significant potential for provoking arrhythmias in macrolides [56].…”