Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence.

Clopidogrel is a prodrug which requires cytochrome P450 2C19 (CYP 2C19) enzyme for its conversion to an active thiol metabolite. Proton pump inhibitors (PPIs) inhibits enzyme CYP 2C19 interfering with the conversion of clopidogrel into its active metabolite. Studies document the possible interaction of clopidogrel and PPIs leading to a decrease in the antiplatelet efficacy of clopidogrel. A PubMed/MEDLINE database literature search was carried out and the bibliographies of found articles were checked for other relevant literature. Most retrospective cohort studies and studies using platelet markers found a significant association between PPI use especially omeprazole and decreased efficacy of clopidogrel while few comparative trials using clinical outcomes found no association between the same. Pantoprazole was not associated with the decrease in the antiplatelet efficacy of clopidogrel. Patients on dual antiplatelet therapy and/or with a history of gastrointestinal bleed will require gastroprotection in the form of PPIs. In such cases, pantoprazole should be the preferred PPI. Rabeprazole can be used as an alternative.

Introduction

The thienopyridine derivative clopidogrel is an antiplatelet drug approved in patients with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), stroke, and established peripheral artery disease.[1] In the long-term management of ACS and/or PCI, the combination of clopidogrel and aspirin is superior to monotherapy with aspirin.[2] The most serious adverse outcome of the dual antiplatelet therapy is gastrointestinal hemorrhage. The current consensus recommends gastroprotection in the form of proton pump inhibitors (PPIs) in patients on clopidogrel who are receiving aspirin and/or are with multiple risk factors like history of gastrointestinal bleeding, concomitant anticoagulant, age more than 60 years, on corticosteroids, and dyspepsia/gastroesophageal reflux disorder (GERD).[3] Recent evidences suggest a possible interaction between PPIs and clopidogrel, leading to a decreased efficacy of clopidogrel and thus increase in cardiovascular morbidity.[4]

Clopidogrel is a prodrug which requires the CYP 2C19 enzyme for its conversion to an active thiol metabolite which finally inhibits P2Y12 ADP receptors present on platelets.[56] The enzyme cytochrome P450 3A4 may also be involved in the conversion.[7] Most of the PPIs inhibit enzyme CYP 2C19, which is required for their major metabolic pathway. The concomitant administration of PPIs reduces the conversion of clopidogrel into its active metabolite and reduces its antiplatelet action. Additional hypothesis suggested is that the absorption of clopidogrel is decreased in the presence of PPIs which reduces the gastric acidic environment.[8] Enzyme CYP 2C19 exhibits genetic polymorphism with 3-5% Caucasians and 12–25% Asians being poor metabolizers for the substrates.[910] There were diminished levels of the active metabolite of clopidogrel in patients carrying CYP 2C19 loss-of-function alleles, exposing them to three times higher risk of cardiovascular events.[11]

Methods of Review

A systematic literature search was conducted which consisted of a Pubmed/MEDLINE database search and a world wide web search using the keywords “Clopidogrel, Omeprazole, Proton pump inhibitors, Drug interactions and Platelet aggregation.” Relevant original articles for clinical studies published in the English language were selected. The bibliographies of these articles were then reviewed for other literature and articles addressing the clopidogrel and PPI interaction. Studies selected for review included retrospective cohort studies, cross-sectional and randomized controlled trials using platelet markers, and comparative studies using clinical outcomes [Table 1].

Table 1

Summary of studies conducted on the interaction between clopidogrel and PPIs

Results

Observational Studies

A nested population-based case control study in Canada included patients aged 66 years or older who received clopidogrel within 3 days following hospital discharge after acute myocardial infarction (MI).[4] Cases were defined as patients who died or were readmitted for MI within 90 days. Controls were matched and were defined as those who were not readmitted with MI. PPI use was categorized as either current within 30 days or previous within 31–90 days, or remote within 91–180 days with respect to readmission. After extensive multivariate adjustment, the current use of PPIs was associated with increased risk of recurrent MI. The study also showed no significant association of pantoprazole with recurrent MI. This study met with various drawbacks and imitations. There were major differences between control and case groups in terms of comorbidities like diabetes, renal failure, and heart failure.[12] Others included lack of data on cardiac risk factors, type of MI, use of over-the-counter aspirin, and no account of genetic polymorphism. Despite these limitations, this observational study was a landmark in proving the association between clopidogrel and PPIs and cardiovascular event. The Clopidogrel Medco Outcome Study was a retrospective cohort study which included patients with coronary stent on clopidogrel therapy.[13] There was an increased incidence of major cardiovascular events within 1 year in patients taking clopidogrel and PPIs.

In contrast to the above-mentioned studies, another observational study by Rassen et al. done in three large cohorts including 18,565 patients on clopidogrel found that the risk of subsequent MI associated with the PPI use was unlikely to exceed 20%.[14] In a recently published retrospective study, the primary composite endpoint was death due to cardiac cause and hospitalization due to myocardial infarction within 1 year in patients on clopidogrel after undergoing successful coronary stenting. This underpowered study found no association between the use of omeprazole and effectiveness of clopidogrel.[15]

Ex vivo platelet assays as surrogate markers

Most of the evidence of the interaction comes from studies using ex vivo platelet assays. These assays used vasodilator-stimulated phosphoprotein phosphorylation (VASP) expressed as a platelet reactivity index (PRI) and measurement of platelet aggregation induced by adenosine diphosphate (ADP) by light transmission aggregometry. In the double-blind placebo-controlled Omeprazole Clopidogrel Aspirin (OCLA) study, patients undergoing coronary stent implantation received aspirin and clopidogrel and were randomized to receive either omeprazole or placebo.[16] The mean PRI was significantly lower in omeprazole group compared to placebo. A cross-sectional study studied platelet aggregation with multiple electrode aggregometry (MEA) in patients under clopidogrel maintenance treatment.[17] Platelet aggregation was significantly higher in patients who were under omeprazole treatment at the time of the platelet function test. In another study, such attenuating effect on the platelet response to clopidogrel was not seen in patients on pantoprazole or esomeprazole.[18] In the double-blind PRINCIPLE-TIMI trial, the primary endpoint of the inhibition of platelet aggregation at 6 h was significantly lower for patients on clopidogrel and PPI.[8] Though this difference was modest on day 15, the proportion of patients with clopidogrel hyporesponsiveness (defined as the inhibition of ADP-induced platelet aggregation <20%) was more than sixfold higher in the PPI group than the non-PPI group.

TRITON -TIMI 38 trial

A comprehensive post hoc analysis of the TRITON -TIMI 38 trial was done by O’Donoghue et al.[8] In this study, patients with acute coronary syndrome (ACS) were randomly assigned to prasugrel or clopidogrel and were followed up for the composite of cardiovascular death, nonfatal MI, or nonfatal stroke. About 33% of patients were on PPIs at the time of randomization. The multivariable Cox proportional hazard model found no significant association between the use of PPIs and risk of primary endpoint for patients treated with clopidogrel or prasugrel. Notably, though this was a post hoc analysis and lacked randomization and blinding for the PPI use, it was adjusted for about 13 potential covariates and the propensity to treat with PPIs.

COGENT trial

The randomized double-blind, double dummy, placebo-controlled COGENT trial included 3761 patients for studying the safety and efficacy of the fixed dose combination (FDC) of clopidogrel and omeprazole compared with clopidogrel alone.[19] This study was a prematurely terminated study due to sponsor bankruptcy and had both cardiovascular and gastrointestinal endpoints. The authors found no clinically relevant adverse cardiovascular interaction between clopidogrel and omeprazole (HR 0.99, 95% CI 0.68–1.44).

Discussion

In vitro studies using human liver microsomal preparations and recombinant CYP 2C19 found the inhibition of CYP 2C19 by PPIs in the following descending order: lansoprazole, omeprazole, esomeprazole, rabeprazole, and pantoprazole.[20] Omeprazole was found to be the most important PPI having an interaction with clopidogrel and is obvious from the fact that omeprazole is mostly metabolized by CYP 2C19.[416172122] Lansoprazole is the most potent inhibitor of CYP 2C19 but clear evidence from studies are lacking.[20] The case control study by Juurlink et al.[4] concluded that “other PPIs” (omeprazole, lansoprazole, rabeprazole) were associated with 40% increase in the risk of recurrent MI but the data regarding the contributions of individual PPIs to the odds ratio was lacking. This was important because rabeprazole is less likely to inhibit CYP 2C19 but its active thioether metabolite does inhibit CYP 2C19.[20] Siller-Matula et al. using their ex vivo study compared effects of pantoprazole and esomeprazole on the clopidogrel activity and found neither of them influencing the antiplatelet effect of clopidogrel.[18] Pantoprazole can be considered as a safe PPI as demonstrated in observational studies and ex vivo platelet studies.[41823] The difference in the metabolism of individual PPIs may contribute to the lack of class effect of PPIs in interacting with clopidogrel.

An association could possibly exist between the use of PPIs especially omeprazole and the decrease in the antiplatelet efficacy of clopidogrel as evident by most of observational studies.[4] But the causal relationship and its clinical significance could not be ascertained due to conflicting results shown by prospective studies using clinical outcomes.[819] In addition to limitations of observational studies, certain questions can be raised regarding ex vivo platelet assay studies. Atorvastatin was found to decrease the antiplatelet efficacy of clopidogrel in an ex vivo study which was proven clinically insignificant.[2425] In the PRINCIPLE-TIMI trial, the mean inhibition of platelet aggregation on day 15 was significantly lower in the prasugrel group using PPIs, though the antiplatelet effect of prasugrel is not dependent on CYP 2C19.[26]

The United States Food and Drug Administration (FDA) has issued information for healthcare professionals regarding the update on the labeling of clopidogrel about the drug interaction with omeprazole.[27] Following considerations are issued by FDA for healthcare professionals:

The concomitant use of omeprazole and clopidogrel should be avoided because of the effect on clopidogrel's active metabolite levels and anticlotting activity.

Other drugs that should be avoided in combination with clopidogrel because they may have a similar interaction include esomeprazole and cimetidine.

At this time, FDA does not have sufficient information about drug interactions between clopidogrel and PPIs other than omeprazole and esomeprazole to make specific recommendations.

Considering the extensive use of PPIs and clopidogrel, the interaction between them assumes immense importance. The beneficial effect of PPIs in preventing upper gastrointestinal bleeding in patients of antiplatelet therapy cannot be totally overweighed by observational studies and studies using platelet markers. Till further evidence becomes available, patients on clopidogrel maintenance therapy should be reevaluated for PPI use. Those having well-controlled symptoms may be candidates for H2 blockers, except cimetidine. Patients on dual antiplatelet therapy and/or with history of gastrointestinal bleed will require gastroprotection in the form of PPIs. In such cases, pantoprazole should be the preferred PPI.[28] Rabeprazole is less likely to inhibit CYP 2C19 and there is no direct evidence of the association of rabeprazole with the decreased efficacy of clopidogrel. Thus, rabeprazole can be considered for gastroprotection. Consequently, prospective, randomized clinical studies on patients on clopidogrel treatment taking PPIs for gastroprotection are highly warranted.