Is there a clinically significant interaction between clopidogrel and omeprazole?

Fråga: Is there a clinically significant interaction between clopidogrel and omeprazole?

Sammanfattning: Bioactivation of clopidogrel by CYP2C19 is a major pathway in vivo. Clinical outcome of clopidogrel therapy is influenced by CYP2C19 genotype and by concomitant omeprazole use (at least in extensive metabolisers). The combination should probably be avoided, at least long-term.

The picture is not as clear regarding other proton pump inhibitors, but pantoprazole seems not to influence platelet inhibition by clopidogrel in ex vivo studies. However, clinical outcome data are not in agreement with a lesser risk for pantoprazole.

Switching to either prasugrel (a novel P2Y12 antagonist not yet marketed in Sweden) or to another acid reducing therapy (H2-blocker) could be an alternative. In CYP2C19*2 carriers, however, clopidogrel bioactivation is already impaired and omeprazole will probably not further influence the lack of response to clopidogrel.

Svar: Clopidogrel is a thienopyridine prodrug that needs to be converted to an active metabolite (a thiol acid) that irreversibly binds to and inactivates the platelet ADP-receptor P2Y12. Thus platelet aggregation is inhibited (1). Clopidogrel is mainly metabolised by esterases to inactive metabolites and partly by cytochrome P450s (CYPs) to 2-oxo-clopidogrel (a thiolactone), that is further hydrolysed (enzymatically or non-enzymatically) to the active thiol acid (2). There has been some controversy regarding which CYPs are important for the bioactivation of clopidogrel; in vitro studies have shown that many enzymes (CYP1A2, 2B6, 2C19, 3A4 and 3A5), can bioactivate clopidogrel, but CYP3A4 has been judged to be most important in vivo (1).

However, poor response (3, 4, 5) to and worse clinical outcome (5, 6) on clopidogrel therapy has been shown in carriers of the loss of function allele CYP2C19*2. This need not necessarily mean that CYP2C19 is important for the bioactivation of clopidogrel; this correlation might be due to a genetic linkage between CYP2C19*2 and a functional polymorphism in another gene influencing platelet aggregation (1).

Omeprazole is a proton pump inhibitor (PPI) used for treatment and prevention of gastric acid related disease. It is metabolised by CYP2C19 to yield 5-hydroxyomepraxole and by CYP3A4 to omeprazole sulphone. CYP2C19 further catalyses the formation of hydroxyomeprazole sulphone (7). Furthermore omeprazole inhibits its own metabolism (8). This effect is at least as pronounced for the pure S-enantiomer of omeprazole (8) esomeprazole although esomeprazole is metabolised to a lesser extent by CYP2C19 (70% compared to 90% of racemic omeprazole (7)). This can be explained by the fact that omeprazole sulphone also inhibits CYP2C19 and that esomeprazole yields higher levels of this metabolite. Interestingly, R-omeprazole does not inhibit its own metabolism (8).

Omeprazole has been shown to influence clopidogrel platelet aggregation inhibition, resulting in a poorer response (9, 10). Sibbing et al were able to show that concomitant omeprazole, but not pantoprazole, diminished platelet inhibition by clopidogrel in a cohort of 1000 patients (732 not on PPIs, 162 on pantoprazole, 64 on omeprazole and 42 on esomeprazole) (10). Pantoprazole is also a CYP3A4 and CYP2C19 substrate, but has lower affinity to these enzymes than other PPIs. It is also further metabolised by sulphate conjugation and this might be an explanation for its lower potential for drug interactions (7). Esomeprazole could not be shown to influence the response to clopidogrel in neither the former study or in another study, where pantoprazole (n=152) and esomeprazole (n=74) was compared to placebo (n=74) (11). These results may be due to lack of power.

Concomitant use of clopidogrel and PPIs in acute coronary syndrome (ACS) patients was associated to increased risk of death or recurrent ACS in a retrospective cohort of 8205 patients in the Veterans Health Administration system (12). There is no description of what PPIs were prescribed to the 5244 PPI users. Another very recent epidemiological study (9862 non-users, 6828 PPI-users) has shown that concomitant use of PPIs is associated with an increased risk of major acute cardiovascular events during a 12 month period post-PCI (percutaneous coronary intervention). The results were significant for esomeprazole, omeprazole, pantoprazole, and lansoprazole (hazard ratios 1.39-1.61, p < 0.001). Rabeprazole data could not be evaluated due to low numbers (13).

To further complicate the matter, clopidogrel has been shown to significantly inhibit CYP2C19 mediated omeprazole hydroxylation in CYP2C19 wildtype carriers but not in *2 carriers (14).

The elegant work by Jessica Mega and co-workers defeats the scepticism by Neville Ford as they shows that, indeed, the exposure to the active metabolite of clopidogrel as well as the platelet inhibition by clopidogrel are both related to CYP2C19 genotype in healthy volunteers and to clinical outcome in patients (both to a composite endpoint of cardiovascular death, myocardial infarction or stroke in 1459 subjects and stent thrombosis in 1389 subjects) (5). The same authors have shown that the clinical outcome of prasugrel treatment is not related to CYP polymorphisms (2). Ford NF. Clopidogrel resistance: pharmacokinetic or pharmacogenetic? J Clin Pharmacol 2009;49(5):506-512 Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT et al. Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel. Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes. Circulation 2009 Frere C, Cuisset T, Morange PE, Quilici J, Camoin-Jau L, Saut N et al. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008;101(8):1088-1093 Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006;108(7):2244-2247 Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360(4):354-362 Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009;373(9660):309-317 Blume H, Donath F, Warnke A, Schug BS. Pharmacokinetic drug interaction profiles of proton pump inhibitors. Drug Saf 2006;29(9):769-784 Hassan-Alin M, Andersson T, Niazi M, Rohss K. A pharmacokinetic study comparing single and repeated oral doses of 20 mg and 40 mg omeprazole and its two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, in healthy subjects. Eur J Clin Pharmacol 2005;60(11):779-784 Gilard M, Arnaud B, Cornily JC, Le GG, Lacut K, Le CG et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008;51(3):256-260 Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009;101(4):714-719 Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009;157(1):148-5 Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301(9):937-944 Stanek EJ. Society for Cardiovascular Angiography and Interventions 2009 Scientific Sessions; May 6, 2009; Las Vegas, NV (Congress report available at www.theheart.org). Chen BL, Chen Y, Tu JH, Li YL, Zhang W, Li Q et al. Clopidogrel Inhibits CYP2C19-Dependent Hydroxylation of Omeprazole Related to CYP2C19 Genetic Polymorphisms. J Clin Pharmacol 2009;49(5):574-581