Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy

Abstract

Clopidogrel has become part of the mainstay of therapy for acute coronary syndromes and in patients post stenting. Clopidogrel is a pro drug and is metabolised by liver enzymes, particularly CYP2C19, into its active form. A considerable proportion of patients have a poor response to clopidogrel and this may be due to several factors. Genetic polymorphisms involved in clopidogrel's absorption, metabolism and activity at the platelet may interfere with its antiplatelet actions. Further, proton pump inhibitors (PPI) may interfere with clopidogrel's actions by functionally reducing the ability of CYP2C19 to convert clopidogrel to its active metabolite. By attenuating clopidogrel's actions, both polymorphisms and drug interactions may increase the risk of thrombotic events during clopidogrel therapy. This review will explore the current evidence relating to the association between PPIs, genetic polymorphisms and poor response to clopidogrel. Routine genetic testing cannot be recommended for patients receiving dual antiplatelet therapy (DAPT). However, it may have a role for patients with an episode of stent thrombosis, prior to planned high-risk stenting or major bleeding. Regarding concomitant clopidogrel and PPI therapy, it is recommended that only patients with previous gastrointestinal (GI) bleeding or multiple risk factors for GI bleeding should be prescribed gastroprotection. This is due to the uncertainty surrounding the clinical significance of this interaction given the discordant biochemical and clinical data, conflicting results from observational studies and the limitations of the COGENT study. Pantoprazole seems least likely to interact with clopidogrel and most suitable for use in patients receiving DAPT.

Meta-Analysis of Randomized Controlled Trials Comparing Risk of Major Adverse Cardiac Events and Bleeding in Patients With Prasugrel Versus Clopidogrel

“…However, there remains about 10% risk of recurrent thrombotic events within one year after PCI, even after the use of traditional DAT 4 . Furthermore, over the past years, several drawbacks of clopidogrel therapy have been identified [5][6][7] . The search for the ideal antiplatelet agents is still on.…”

Variant recurrent risk among stroke patients with differentCYP2C19phenotypes and treated with clopidogrel

“…Only clinical events occurring under clopidogrel exposure were retained for data analysis. As suggested by previous research [14][15][16], simultaneous use of proton-pump inhibitors (PPIs) and clopidogrel were avoided as possible. If a PPI was warranted, pantoprazole were usually prescribed.…”

Cytochrome P450 2C19*2 polymorphism in patients with stable coronary heart disease and risk for secondary cardiovascular disease events: results of a long-term follow-up study in routine clinical care

“…Current evidence suggests that the CYP2C19 polymorphisms may be clinically relevant mainly through the effects on metabolism of clopidogrel prodrug, but further data are needed to determine if other mechanisms are possible too and whether routine testing at the point of care may be beneficial for the patients [7]. The Food and Drug Administration (FDA) released a Boxed Warning in the year 2010 that patients with a poor metabolizer phenotype may not effectively metabolize clopidogrel prodrug and therefore may not experience its full benefits [8].…”