Risk of combining clopidogrel with proton pump inhibitors - significance and possible solutions
Jan Bultas1
+ Affiliation
Summary
Proton pump inhibitors (PPIs) and clopidogrel are very frequently used drugs; unfortunately, their concurrent administration may result in failure of the antiplatelet effect and in an acute atherothrombotic event. The basis of this drug interaction is an insufficient bioactivation of the prodrug-clopidogrel-by inhibition of the key isoenzyme CYP2C19 induced by certain PPIs.
Studies monitoring platelet functions, in particular aggregability, demonstrate distinctive long-term reduction of the clopidogrel effect on the inhibition of both activation and aggregation of thrombocytes in co-medication with omeprazole and lanzoprazole; less if pantoprazole or esomeprazole are administered. Within the laboratory testing of primary haemostasis and the effect of inhibition of bioactivation of clopidogrel by PPIs, results are consistent. However, the situation is different in studies monitoring prognostic indicators. Here, the results of observation studies, often analyzing a high risk population, demonstrate a distinctive increase in coronary events; meta-analysisof almost 60 thousand patients demonstrates an increase of more than 50 %. Analyses of randomized studies, unfortunately of the post hoc type, identify a significantly lower risk, the occurrence of acute coronary events increased with co-medication insignificantly, by just 15 %. Nevertheless, comprehensive analyses of all studies, featuring more than 90 thousand patients, identify an increased risk of coronary events of 43 % and of all serious cardiovascular events of 25 %. When analysing this schism, it is shown that randomised studies were performed on a significantly lower risk population (with an annual event risk below 10 %). When monitoring the effect of co-medication of clopidogrel with PPIs on low- and high-risk populations of cardiac patients, it is shown that the increased risk of occurrence of a serious cardiovascular event (death, myocardial infarction or ictus) occurs only in patients with an annual event risk over 10 %.
In practice, such drug interaction can be avoided by selecting a therapy other than PPI administration, or perhaps by administering pantoprazole, esomeprazole or optimally rabeprazole, by selecting another platelet ADP receptor inhibitor, in particular prasugrel, or by increasing the dose of clopidogrel.
Keywords
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