[Proton pump inhibitors and clopidogrel: a hazardous association?]

Proton pump inhibitors (PPI) and antiplatelet agents, especially aspirin and clopidogrel, are among the most prescribed medications worldwide. Their co-administration is justified by the increased risk of gastrointestinal bleeding related to the antiplatelet therapy. The issue of the interaction between PPI and clopidogrel has been raised with the emergence of the concept of "high on-clopidogrel platelet reactivity" (or "clopidogrel resistance") together with the discovery of the role of CYP2C19 isoform in the pharmacokinetics of those two medications. Indeed, CYP2C19 is involved in the conversion of the clopidogrel pro-drug into its active metabolite and is involved in the metabolisation of PPI into inactive metabolites, acting as substrates/inhibitors of CYP2C19. Despite their heterogeneity, most pharmacodynamic studies have shown a decreased clopidogrel antiplatelet effect when associated to PPI, especially those with the highest CYP2C19 inhibiting activity (omeprazole, lansoprazole, rabeprazole). On the other hand, clinical studies are inconclusive. Retrospective studies have shown an increased risk of major cardiovascular events or mortality when clopidogrel and PPI are associated in comparison with clopidogrel alone, particularly in the patients with the higher cardiovascular risk. However, the two prospective randomized studies published so far did not find any interaction and confirmed the benefit of PPI on the gastrointestinal bleeding. As a conclusion, as the clinical studies are not conclusive, the French health authorities have recently removed the alert about this interaction. PPI and clopidogrel can thus be co-prescribed.