36 Michael A. Gaglia, Jr University of Southern California Keck School of Medicine, Los Angeles, CA, USA Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor, often clopidogrel, is indicated for patients with an acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention [1, 2]. This places such patients, however, at considerably higher risk of gastrointestinal (GI) bleeding [3, 4]. Concurrent proton pump inhibitor (PPI) therapy is thus recommended for most patients on DAPT [5], as this strategy has been shown to reduce the incidence of GI bleeding and ulcers [6, 7]. The US Food and Drug Administration (FDA), however, issued a statement in November 2009, recommending against the administration of clopidogrel with the PPIs omeprazole and esomeprazole [8]. This was largely based upon pharmacokinetic studies of clopidogrel and omeprazole, which showed that concurrent administration increased the levels of platelet reactivity when compared to clopidogrel alone [9]. This spawned considerable controversy; retrospective studies were inconclusive in regard to an increased risk of adverse cardiac events, and the randomized Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) showed no clinically apparent interaction [7]. This chapter reviews the pharmacokinetic, pharmacodynamic, and clinical evidence for, and against, this interaction between clopidogrel and PPIs. Clopidogrel, a thienopyridine, acts by irreversibly binding the P2Y12 adenosine diphosphate receptor on the surface of platelets, ultimately attenuating platelet activation. The majority of clopidogrel is hydrolyzed by esterases to an inactive compound, whereas the remainder requires activation by the cytochrome P450 (CYP) system in the liver. Importantly, this generation of the active metabolite involves a two-step pathway that consists of the CYP isoenzymes 3A4 and 2C19 [10, 11, 12, 13]. The latter pathway appears to be the most important, as carriers of the reduced function allele of 2C19 (the so-called poor metabolizers) generate less active metabolite and have reduced levels of platelet inhibition [14]. PPIs inhibit the H+/K+ ATPase of gastric parietal cells, which results in decreased production of gastric acid. PPIs are also prodrugs, but they are converted to an active sulfenamide derivative in nonenzymatic fashion [15]. The CYP system converts PPIs via 3A4 and 2C19 to inactive metabolites, with 2C19 again playing a key role. The affinity of different PPIs for CYP2C19, however, appears to vary, with omeprazole having the highest affinity [16]. The metabolism of PPIs is relevant because they are in essence competitive inhibitors of CYP2C19. Given that clopidogrel has less affinity than PPIs for CYP2C19, it is at least plausible that an interaction may occur [17]. Therefore, in the presence of a PPI that is a strong inhibitor of CYP2C19 (e.g., omeprazole), the metabolism of clopidogrel might be reduced. Evidence from pharmacodynamic studies generally supports the conclusion that certain PPIs reduce ex vivo platelet inhibition in subjects taking clopidogrel, although the studies are quite heterogeneous. A recent systematic review by Focks et al. counted 28 pharmacokinetic studies examining the interaction, with 18 studies demonstrating reduced platelet inhibition in at least one platelet function test in those on clopidogrel and a PPI [18]. Two recent randomized, crossover design studies, albeit in healthy volunteers, examined the effects of different PPIs upon the pharmacokinetics and pharmacodynamics of clopidogrel. Angiolillo et al. found that omeprazole decreased the levels of the active metabolite of clopidogrel and increased the levels of platelet aggregation, as measured by both light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. Furthermore, these effects did not vary significantly when clopidogrel and omeprazole doses were separated by 12 h. Pantoprazole resulted in a less dramatic, but still significant, reduction in the active metabolite; it had inconclusive effects upon platelet aggregation [9]. Similarly, Frelinger et al. showed that among CYP2C19 “extensive metabolizers,” omeprazole and esomeprazole increased the levels of platelet aggregation; lansoprazole and dexlansoprazole did not. All PPIs reduced the peak levels of the active metabolite of clopidogrel, but omeprazole had the most pronounced effect [19]. It thus appears that all PPIs likely have some degree of interaction with clopidogrel as measured by ex vivo assays, but the effect is most pronounced with omeprazole and esomeprazole. The pharmacokinetic and pharmacodynamic data summarized earlier prompted numerous retrospective data analyses examining the interaction between PPIs and clopidogrel. One of the first, by Pezalla et al., showed an increase of more than 300% in the relative risk of acute myocardial infarction (MI) among patients taking clopidogrel and highly adherent to PPI therapy [20]. This was a relatively small study, however, based upon claims data and with limited adjustment for comorbidities. Larger retrospective studies with multivariable adjustment therefore followed, including one by Ho et al. showing an increased risk of death or rehospitalization with concurrent PPI therapy [21] and another by Juurlink et al. showing an increased risk of recurrent MI [22]. A large number of retrospective studies were ultimately reported, with widely varying populations, follow-up, methods of multivariable adjustment, and end points. Siller-Matula et al
Proton Pump Inhibitors and Clopidogrel
Introduction
Metabolism of clopidogrel and proton pump inhibitors
Pharmacodynamic studies of clopidogrel and proton pump inhibitors
Retrospective clinical studies and meta-analyses
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