To elucidate the role of macrolides in cardiovascular events : the use of different observational study designs and methodologies

Abstract

Macrolides are one of the most commonly prescribed class of antibiotics including azithromycin, clarithromycin, erythromycin and roxithromycin. Despite their favourable safety profiles, a randomised controlled trial demonstrated a long-term risk of cardiovascular mortality associated with clarithromycin. Some observational studies reported a short-term risk of cardiovascular events with other macrolide use versus non-use in the general population but no long-term cardiovascular risk was observed. Notably, such an association and the respective temporal relationship with clarithromycin lacked observational evidence from population-based studies. Therefore, this thesis mainly investigated the cardiovascular risk associated with clarithromycin using population-based observational study designs. Notably, clarithromycin is frequently prescribed with proton pump inhibitors to treat Helicobacter pylori infection. As proton pump inhibitors have been suggested to increase the risk of myocardial infarction, such an association was also examined. To assess and reduce the bias due to baseline health differences between individuals, a range of study designs including cohort study with a propensity score method, self-controlled case series study, case-crossover study, case-time-control study and negative control tracer analyses were adopted in this thesis. A systematic review with meta-analysis was also conducted to evaluate the overall cardiovascular risk associated with macrolides. The findings of this thesis confirm no long-term risk of cardiovascular events associated with clarithromycin. Similarly, no increased long-term cardiovascular risk was observed for macrolides in the systematic review. However, an approximately three-fold increase in short-term risk of myocardial infarction for clarithromycin was consistently identified in the cohort, self-controlled case series and case-crossover studies. A short-term risk of arrhythmia and cardiac death associated with clarithromycin was also found. For proton pump inhibitors, there was an increased risk of myocardial infarction during the first 60 days since treatment started. An increased risk with a similar temporal pattern was also found among patients receiving H2 receptor antagonists which have similar indications to proton pump inhibitors but no reported association with myocardial infarction. Therefore, the observed risk is not specific to proton pump inhibitors and is likely due to the symptoms that prompted the use of drug rather than the drug itself. Due to the limited evidence to support the causal association between proton pump inhibitors and myocardial infarction, the effect of myocardial infarction was very likely attributed to clarithromycin rather than proton pump inhibitors as a component of H. pylori therapy. The acute cardiovascular risk of macrolides could also be found after pooling the results from this thesis with the current literature in the systematic review. Given that the absolute risk of the cardiovascular adverse events was not considerably high, prescribers should identify and assess cardiovascular profiles of high risk patients including patients aged 75 years or above, with hypertension or diabetes mellitus before prescribing macrolides. As limited studies investigated the cardiovascular effects of macrolides other than clarithromycin, future studies are warranted to examine the association between myocardial infarction and other macrolides to understand the class effect of macrolides. Future pharmacoepidemiological studies should also be conducted to compare the magnitude of cardiovascular toxicity among different antibiotics to better inform prescribing decisions.