Elsevier

Thrombosis Research

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

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

https://doi.org/10.1016/j.thromres.2009.08.016Get 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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