Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy

doi:10.1016/j.thromres.2009.08.016

Thrombosis Research

Volume 125, Issue 2, February 2010, Pages e51-e54

https://doi.org/10.1016/j.thromres.2009.08.016 Get rights and content

Abstract

Introduction

Currently, there is an intense debate about whether comedication with proton pump inhibitors (PPIs) weakens the antiplatelet effect of clopidogrel in patients undergoing coronary stent implantation. Competing mechanisms on the hepatic cytochrome 2C19 level are proposed. The aim of this study was to assess the impact of PPI treatment on clopidogrel response by measuring the ex vivo platelet aggregation in patients with coronary intervention.

Methods

1425 consecutive patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention were enrolled in this single centre study. PPI comedication was defined as PPI intake ≥ 1 week prior to a 600 mg clopidogrel loading dose. PPI treatment was based on physician preference. Residual platelet aggregation (RPA) was measured by optical aggregometry. To correct for potential selection bias, propensity score matching was applied.

Results

RPA was significantly higher in PPI-treated patients compared with non-PPI-users (final aggregation 34.0% vs. 29.8%, p < 0.001). Low responder defined as RPA in the upper tertile were more often found in PPI-users. After adjustment for relevant confounders, PPI treatment was independently associated with higher RPA-levels.

Discussion

We demonstrated that peri-procedural co-administration of PPIs significantly decreases the effect of clopidogrel on RPA. To assess if clopidogrel-PPI interaction results in a higher susceptibility for cardiovascular events remains subject to further investigations.

Introduction

Drug–drug interactions have been considered to adversely influence the variability of clopidogrel response. Recently, the negative impact of proton pump inhibitors (PPIs) on clopidogrel response was suggested in the Omeprazole CLopidogrel Aspirin trial [1]. Here, 124 patients with elective coronary stenting and dual antiplatelet therapy received either omeprazole or placebo. The platelet reactivity index was significantly higher in patients with omeprazole co-medication compared to non-users (51.4% vs 39.8%; p < 0.0001). Initially, an observational study of 105 patients with coronary artery disease (CAD) indicated for the first time an association between PPI use and clopidogrel poor response [2]. Since the hepatic isozyme CYP2C19 is involved in both clopidogrel bioactivation and PPI metabolism [3], [4], [5], a competitive effect at CYP2C19 level is proposed as underlying mechanism. Moreover, a retrospective analysis of acute myocardial infarction (MI) rates in a one year follow up of 5512 patients receiving clopidogrel with and without PPIs showed a significant increased rate for MI in the PPI high exposure group (5.03%) compared to non-users (1.38%) [6]. Most recently, a case control study demonstrated that in patients receiving clopidogrel after MI, concomitant therapy with PPIs other than pantoprazole was associated with an increased risk of reinfarction [7]. However, conflicting data were presented at the AHA meeting November 2008, where a retrospective analysis of the CREDO trial demonstrated no difference in event rates between PPI users in the placebo and the clopidogrel group [8]. Based on these controversial results and since both drugs are routinely clinically applied, we aimed to assess the impact of PPI interaction on clopidogrel response by measurement of the ex vivo platelet aggregation in patients undergoing coronary stenting.

Section snippets

Methods

1425 consecutive unselected patients with symptomatic CAD admitted to our clinic for elective or urgent coronary intervention were included in our monocenter study from May 2005 until May 2008. After a 600-mg clopidogrel loading dose patients were treated with a maintenance dose of 75 mg/day. Concomitant drug use, assumed by patients`or physicians`report, and clinical characteristics were registered. All patients received aspirin before intervention, 500 mg intravenously in acute coronary

Results

A total of 424 patients (29.8%) received peri-procedural PPI-treatment. Omeprazole (mean dose 24.9 ± 11.2 mg), esomeprazole (mean dose 24.3 ± 9.2 mg) and pantoprazole (mean dose 35.7 ± 16.6 mg) were used in 36, 108 and 280 patients, respectively. Mean platelet count in the study collective was 288,000/µl (standard deviation (SD) ± 106.1). Age, gender, rate of ACS and the co-medication with statins were significantly different between PPI users and non-users (Table 1, Table 2). RPA was significantly

Discussion

We demonstrated in a large and unselected cohort of patients with symptomatic CAD undergoing coronary stenting treated with dual antiplatelet therapy that peri-procedural co-administration of PPIs diminishes the effect of clopidogrel on platelet function as assessed by RPA. To our knowledge, this is the largest study investigating the influence of PPIs on ex vivo platelet aggregation.

Currently available data on clopidogrel-PPI interaction are inconsistent. Most [1], [2], [6], [7], [16], [17],

Acknowledgment

Meinrad Gawaz had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of data analysis.

There was no industrial financial or material support for the research and work.

No conflict of interest exist for any author of this manuscript.

Everyone who contributed significantly to the manuscript was listed.

The study was supported in part by the ”Deutsche Forschungsgemeinschaft“, the ”Sonderforschungsbereich Transregio TR-19“, and the Robert

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Proton pump inhibitors (PPIs) are conventionally used in combination with antithrombotic therapy to prevent gastrointestinal bleeding. However, there are a few studies showed that PPIs not only impaired the antiplatelet effects of clopidogrel but also increased the incidence of cardiovascular events [4–7]. In different with that, some other studies suggested that PPIs did not increase the risk of cardiovascular events [8,9].
Proton pump inhibitors (PPIs) are often prescribed in association with clopidogrel and aspirin to patients with myocardial infraction (MI), but their effects on heart is controversial. The purpose of this study was to investigate the effects and potential mechanism of omeprazole (OME) and esomeprazole (ESO) in myocardial ischemia reperfusion (I/R) injury. In the present study, mice were treated with OME, ESO or vehicle for 3 weeks and then subjected to myocardial I/R or sham surgery. At 1 day after surgery, echocardiography was performed to access cardiac injury. Hematoxylin and eosin (H&E) staining was performed to evaluate cardiomyocyte morphology. The IL1β was evaluated by Immunohistochemistry (IHC). Elisa was used to detect cTnt content in serum. The expression of CD86, CD206, CHOP, ATF6, eIF2α and p eIF2α were determined by Western blot (WB). The result showed that ESO markedly improved the left ventricular ejection fraction (LVEF), shortening fraction (FS), suppressed inflammatory infiltration, endoplasmic reticulum stress (ERS) and decreased proinflammatory macrophages in I/R hearts, while OME had no significant effects on cardiac function, inflammation and ERS in the I/R heart. In conclusion, ESO but not OME pretreatment reduces the proportion of proinflammatory macrophages, inhibits endoplasmic reticulum stress, and alleviates I/R injury in mice, indicating that ESO maybe a more proper PPI than OME for application in I/R injury.
The opioid-P2Y<inf>12</inf> inhibitor interaction: Potential strategies to mitigate the interaction and consideration of alternative analgesic agents in myocardial infarction
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Citation Excerpt :
The platelet function tests utilized to define HPR in this state-of-the-art paper comprised of platelet aggregometry based assays such as the VerifyNow (whole blood light transmittance aggregometry) and Multiplate analyzer (impedance aggregometry), thromboelastography and measurement of intracellular VASP phosphorylation by flow cytometry which is downstream from the platelet P2Y12 receptor and therefore very specific to its inhibition (Tantry et al., 2013). Most notably, the proton pump inhibitor (PPI) omeprazole and to a lesser extent esomeprazole were the focus of concerns regarding drug interactions with clopidogrel with studies suggesting a significant pharmacokinetic and pharmacodynamic interaction with observational clinical data suggesting worse outcomes with this combination (Fernando, Bassler, et al., 2011; Ho, Maddox, & Wang, 2009; Juurlink et al., 2009; Kwok & Loke, 2010; Zuern et al., 2010). The mechanism of this interaction appeared to involve utilization of common hepatic cytochrome pathways, particularly CYP2C19, leading to impaired conversion of clopidogrel to its active form (Wedemeyer & Blume, 2014).
Despite advances in medical and interventional management of acute myocardial infarction, treatment of the associated chest pain has remained relatively unchanged since opioids were first utilized in the 1930’s. This dominance can be partially attributed to initial studies suggesting hemodynamic benefits with opioid treatment. However, delayed gastrointestinal absorption of P2Y₁₂ inhibitors due to opioids and the consequent impairment in antiplatelet activity of this established therapy is cause for concern. Coupled with the lack of randomized clinical trial evidence to support widespread opioid use, there is now an opportunity to re-evaluate our approach to analgesia in myocardial infarction. This review characterizes the mechanism of the opioid-P2Y₁₂ inhibitor interaction, strategies aimed at mitigating the interaction and appraises promising alternative agents to opioid therapy in patients with myocardial infarction.
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Reduction of the anti-platelet effect of clopidogrel by omeprazole, measured by VASP phosphorylation analysis, has been described [12]. Co-administration of PPIs in patients undergoing PCI significantly decreases the effect of clopidogrel on platelets [13]. In clinical pharmacokinetic studies, omeprazole has been shown to reduce the formation of the active metabolite of clopidogrel [14].
Concerns have been raised about the potential adverse interaction between clopidogrel and PPIs. We studied the impact of esomeprazole and ranitidine on the antiplatelet action of clopidogrel and aspirin and sought to determine whether doubling the dose of clopidogrel could restore its efficacy.
In a randomized prospective crossover study, we tested platelet reactivity to aspirin and clopidogrel (75 and 150 mg) with and without esomeprazole or ranitidine using the VerifyNow system (Accumetrics Inc, San Diego, CA, USA) in 4 stages, each lasting 7 days: T1, 160 mg aspirin and 75 mg clopidogrel; T2 : 160 mg aspirin + 75 mg clopidogrel + 20 mg esomeprazole, T3 : 160 mg aspirin + 150 mg clopidogrel + 20 mg esomeprazole and T4 : 160 mg aspirin + 75 mg clopidogrel + 150 mg ranitidine. Results are expressed in P2Y12 Reaction Units (PRU%) and Aspirin Reaction Units (ARU).
In 21 patients with stable coronary artery disease, esomeprazole reduced the effect of clopidogrel with a 38.6% ± 24 loss in PRU% (p < 0.001) (absolute mean difference − 16.7 PRU% [− 21;− 12.5]), increasing 8-fold the prevalence of low responders to clopidogrel (defined as patients with PRU% below 20%). Doubling clopidogrel dosage to 150 mg restored the basal response. Ranitidine did not modify the antiplatelet effect of clopidogrel.
Our study demonstrates a strong negative clopidogrel/esomeprazole interaction, compensated by increasing the dose of clopidogrel to 150 mg or replacing esomeprazole with ranitidine. That could offer a simple solution to the PPI-induced clopidogrel resistance.
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¹: Contributed equally to this report.

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Regular ArticleEffect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy

Abstract

Introduction

Methods

Results

Discussion

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgment

J Am Coll Cardiol

J Thromb Haemost

J Am Coll Cardiol

J Am Coll Cardiol

J Thromb Haemostasis

J Thromb Haemost

J Am Coll Cardiol

Thromb Res

Am J Cardiol

CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation

Pharmacogenomics

Review article: cytochrome P450 and the metabolism of proton pump inhibitors–emphasis on rabeprazole

Aliment Pharmacol Ther

Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently

Clin Pharmacol Ther

A population-based study of the drug interaction between proton pump inhibitors and clopidogrel

CMAJ

Regular Article
Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy