Clopidogrel and Proton Pump Inhibitors: A Propensity Score Adjusted Cohort Study to Examine a Possible Interaction: A CALIBER Study

Background

Patients who have experienced and survived non-ST segment elevation acute coronary syndromes are often prescribed a combination of aspirin and clopidogrel to thin the blood and prevent further acute coronary episodes. Both clopidogrel and aspirin may cause stomach bleeds and so a prophylactic proton pump inhibitor is frequently co-prescribed in order to prevent such bleeds. Recent mechanistic and observational studies suggest proton pump inhibitors may reduce the effectiveness of clopidogrel and so patients may not benefit as much as expected from combined aspirin and clopidogrel. The investigators propose a cohort study of patients prescribed clopidogrel + aspirin. Amongst these patients the investigators will measure the relative rate of acute coronary syndrome and death comparing patients with and without proton pump inhibitor treatment. To provide a more complete picture of the risks and benefits of treatment the investigators will also measure the relative rate of stomach bleeds in the same groups of patients. In addition, whether the inhibitory effect of proton pump inhibitors on the protective effect of clopidogrel is due to their inhibition of drug metabolising enzymes will be explored by assessing the effects of other drugs that inhibit the same enzymes.

Background Clopidogrel is an antiplatelet drug used to prevent coronary events, particularly in patients who have already experienced acute coronary syndrome (ACS). It is often used in combination with aspirin, and due to the propensity of both drugs to cause gastrointestinal (GI) bleeds, prophylactic therapy with proton pump inhibitor (PPI) is frequently prescribed. Some proton pump inhibitors and clopidogrel share a common metabolic pathway involving the cytochrome P450 2C19 isoenzyme. Clopidogrel relies on P450 2C19 for conversion to its active metabolite whilst some PPIs inhibit this enzyme; recent mechanistic studies suggest that PPIs may reduce the platelet inhibitory effect of clopidogrel (Gilard et al 2006, Gilard et al 2008). Subsequent observational studies appear to show this effect may translate directly to a reduction in clopidogrel efficacy with patients more likely to experience secondary coronary events or death. Odds ratios of 1.25 (95% confidence interval (CI) 1.11-1.41; Ho et al 2009) and 1.27 (1.03-1.57; Juurlink et al 2009) have been reported, comparing clopidogrel and PPI users with patients using clopidogrel without PPI. A further study suggests the effect may be limited to clopidogrel in combination with omeprazole only (Sibbing et al 2009).

Scientific hypothesis

Main Research Questions: To investigate a possible drug interaction between clopidogrel and proton pump inhibitors (PPI). Specific questions to be answered are: