Abstract

Objective To study the association of clarithromycin with cardiovascular events in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia.

Design Analysis of two prospectively collected datasets.

Setting Chronic obstructive pulmonary disease dataset including patients admitted to one of 12 hospitals around the United Kingdom between 2009 and 2011; Edinburgh pneumonia study cohort including patients admitted to NHS Lothian Hospitals between 2005 and 2009.

Population 1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease and 1631 patients admitted with community acquired pneumonia.

Main outcome measures Hazard ratios for cardiovascular events at one year (defined as hospital admissions with acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina). Secondary outcomes were all cause and cardiovascular mortality at one year.

Results 268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and 171 in the community acquired pneumonia cohort over one year. After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease was associated with an increased risk of cardiovascular events and acute coronary syndrome—hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68). After multivariable adjustment, clarithromycin use in community acquired pneumonia was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38) but not acute coronary syndrome (1.65, 0.97 to 2.80). The association between clarithromycin use and cardiovascular events persisted after matching for the propensity to receive clarithromycin. A significant association was found between clarithromycin use and cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26) but not all cause mortality (1.16, 0.90 to 1.51) in acute exacerbations of chronic obstructive pulmonary disease. No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality. Longer durations of clarithromycin use were associated with more cardiovascular events. Use of β lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin.

Conclusions The use of clarithromycin in the setting of acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia may be associated with increased cardiovascular events. These findings require confirmation in other datasets.

Discussion

This is the first study showing that use of clarithromycin in the context of exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia may be associated with excess cardiovascular events that last beyond the period of prescription. Clarithromycin is the most widely used macrolide in the UK and is strongly recommended for use in patients with severe community acquired pneumonia. Previous studies have suggested an excess cardiovascular morbidity after clarithromycin use,¹⁴ but these patients were selected on the basis of pre-existing cardiovascular risk rather than having a defined infective episode requiring treatment with this drug. Other studies have shown a short term association seen only during the time of administration.^12 13 The observed association with cardiovascular events is of a similar magnitude to that seen in stable non-infected patients with established coronary artery disease.¹⁴ Our data suggest that the increased risk may persist beyond the time when clarithromycin is stopped.

Possible explanations for findings

Although short term events may be associated with clarithromycin’s pro-arrhythmic effects mediated through prolongation of the QT interval,²⁷ this would not affect outcome after cessation of the drug and would support an ischaemic mechanism. Clarithromycin may activate macrophages, leading to an inflammatory cascade resulting in more vulnerable plaques that over time may lead to acute coronary syndromes or sudden cardiac death by plaque rupture.²⁵ This may explain why clarithromycin seems to increase cardiovascular events and mortality beyond the time of prescription.

We did several hypothesis generating analyses to explore the relation between clarithromycin use and cardiovascular events in these cohorts. We found a strong association between prolonged (more than seven days) courses of clarithromycin and cardiovascular events, which strengthens the case for a true biological cause. The association between duration of antibiotic treatment and cardiovascular events could also represent residual confounding by severity of illness. Although prolonged courses of antibiotics are common for respiratory tract infections in clinical practice, a considerable body of evidence suggests that short courses of antibiotics are equivalent to prolonged courses in community acquired pneumonia and other respiratory tract infections.

Source:BMJ