Prescrire International - Free Special Edition - 2022

ADVERSE EFFECTS

Clopidogrel + a proton pump inhibitor: increased mortality

● Since 2009, several meta-analyses of epidemio logical studies and post-hoc analyses of clinical trials have studied the interaction between clopi dogrel and proton pump inhibitors (PPIs) such as omeprazole . They show a higher risk of cardio vascular events with all PPIs and, overall, increased mortality. ● Apharmacokinetic interactionwith clopidogrel has been documented for omeprazole , esome prazole and pantoprazole . PPIs inhibit formation of the activemetabolite of clopidogrel , thus redu cing its antiplatelet effect. ● It seems prudent to avoid combining PPIs with clopidogrel whenever possible. There is no justi fication for the routine use of a PPI during clopi dogrel treatment. C lopidogrel is an antiplatelet drug used after angioplasty with stent placement, for example, in combination with aspirin (1,2). Proton pump inhibitors (PPIs) such as omeprazole are sometimes given to patients who are on anti platelet medication, mainly to prevent upper gastrointestinal bleeding (3,4). A pharmacokinetic interaction that may reduce clopidogrel ’s antithrombotic effect has been described between clopidogrel and omeprazole . On the basis of the data available in 2009, it was not possible to establish whether an interaction between clopidogrel and omeprazole increases the incidence of cardio vascular events. However, a prudent approach to the arguments in favour of this risk was to avoid this combination (5). Other epidemiological studies have since shown higher all cause and cardiovascular mortality in patients using PPIs for any reason, than in non-users (6). What more is known as of mid-2021? Do the data available from clinical trials and epidemiological studies indicate that clopidogrel is less effective when combined with a PPI? Do all PPIs have this effect?

Higher mortality A systematic review and meta-analysis identified 47 epidemio logical studies and 3 randomised trials that compared patients taking clopidogrel and a PPI versus patients taking clopidogrel alone, published between 2009 and 2018 (7). Differences of about 15% to 30% in general. According to this systematic review, 19 case-control and cohort studies have evaluated all-cause mortality. Ameta-analysis of these studies found that all-causemortality was about 1.26 times higher in patients taking clopidogrel + PPI than in patients taking clopidogrel (95% confidence interval (95CI) 1.11-1.42). However, when themeta-analysis only took into account the 7most robust studies, i.e. the results of randomised trials and the results of epidemiological studies adjusted for factors that influence the choice between these treatments (propensity score), the difference appeared slightly smaller (risk ratio (RR) 1.17) and did not reach statistical significance. There was considerable heterogeneity in both cases (7). Similarly, cardiovascular mortality appeared higher with clopidogrel + PPI than with clopidogrel (RR 1.21; 95CI 1.09-1.34). When the analysis only took into account the 5 most robust studies, the difference appeared slightly smaller (RR 1.16) and did not reach statistical significance (7). Meta-analysis of 15 case-control and cohort studies that evalu ated the risk of myocardial infarction found a higher risk with clopidogrel + PPI than with clopidogrel (RR 1.23; 95CI 1.04-1.47). A similar difference was found when the analysis only took into account the 7most robust studies (RR 1.15; 95CI 1.00-1.32) (7). Meta-analysis of 5 epidemiological studies that evaluated the risk of stroke did not show a higher risk with clopidogrel + PPI (RR 1.05; 95CI 0.85-1.29). However, when the analysis was restricted to the two most robust studies (epidemiological studies with propensity score adjustment), the risk was higher in patients receiving clopidogrel + PPI than in patients receiving clopidogrel (RR 1.75; 95CI 1.45-2.11) (7). Other meta-analyses with similar results. Several other meta-analyses have produced similar results, showing either a slightly higher risk of cardiovascular events with clopi dogrel in various settings, or no difference (8-10).

Full review(3 pages) available to subscribers at english.prescrire.org ▶ Translated from Rev Prescrire October 2021 Volume 41 N° 456 • Pages 751-753

intervention showed a higher risk of major adverse cardio vascular events (odds ratio (OR) 1.37; 95CI 1.23-1.53) with clopidogrel + PPI than with clopidogrel . Analysis of short-term Prescrire Int • January 2022

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