Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy. Thromb Res 125(2):e51-e54

Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, University of Tuebingen, Otfried-Mueller-Strasse 10, 72076 Tuebingen, Germany.
Thrombosis Research (Impact Factor: 2.43). 09/2009; 125(2):e51-4. DOI: 10.1016/j.thromres.2009.08.016
Source: PubMed

ABSTRACT 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.
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 > or =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.
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.
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.

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    • "Both concomitant treatment with strong CYP3A4 inhibitors (Suh et al., 2006; Farid et al., 2007; Siller-Matula et al., 2008) as well as a reduced activity of CYP2C19 in patients with CYP2C19 single nucleotide polymorphisms were associated with an impaired pharmacological activity of clopidogrel (Kim et al., 2008; Mega et al., 2009; Simon et al., 2009). Several clinical studies with ex vivo determination of residual platelet aggregation demonstrated that CYP2C19 inhibitors such as proton pump inhibitors (PPIs) decrease the pharmacological effect of clopidogrel (Gilard et al., 2008; O&apos;Donoghue et al., 2009; Price et al., 2009; Zuern et al., 2010). These findings are supported by two retrospective studies with clinical endpoints (death, re-hospitalization and/or re-infarction) (Ho et al., 2009; Juurlink et al., 2009), whereas a third clinical study failed to show an increased cardiovascular risk for patients with concomitant ingestion of clopidogrel and a PPI (O'Donoghue et al., 2009). "
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    ABSTRACT: The conversion of clopidogrel to its active metabolite, R-130964, is a two-step cytochrome P450 (CYP)-dependent process. The current investigations were performed to characterize in vitro the effects of different CYP inhibitors on the biotransformation and on the antiplatelet effect of clopidogrel. Clopidogrel biotransformation was studied using human liver microsomes (HLM) or specific CYPs and platelet aggregation using human platelets activated with ADP. Experiments using HLM or specific CYPs (3A4, 2C19) revealed that at clopidogrel concentrations >10 microM, CYP3A4 was primarily responsible for clopidogrel biotransformation. At a clopidogrel concentration of 40 microM, ketoconazole showed the strongest inhibitory effect on clopidogrel biotransformation and clopidogrel-associated inhibition of platelet aggregation with IC(50) values of 0.03 +/- 0.07 microM and 0.55 +/- 0.06 microM respectively. Clarithromycin, another CYP3A4 inhibitor, impaired clopidogrel biotransformation and antiplatelet activity almost as effectively as ketoconazole. The CYP3A4 substrates atorvastatin and simvastatin both inhibited clopidogrel biotransformation and antiplatelet activity, less potently than ketoconazole. In contrast, pravastatin showed no inhibitory effect. As clopidogrel itself inhibited CYP2C19 at concentrations >10 microM, the CYP2C19 inhibitor lansozprazole affected clopidogrel biotransformation only at clopidogrel concentrations < or =10 microM. The carboxylate metabolite of clopidogrel was not a CYP substrate and did not affect platelet aggregation. At clopidogrel concentrations >10 microM, CYP3A4 is mainly responsible for clopidogrel biotransformation, whereas CYP2C19 contributes only at clopidogrel concentrations < or =10 microM. CYP2C19 inhibition by clopidogrel at concentrations >10 microM may explain the conflicting results between in vitro and in vivo investigations regarding drug interactions with clopidogrel.
    British Journal of Pharmacology 09/2010; 161(2):393-404. DOI:10.1111/j.1476-5381.2010.00881.x · 4.99 Impact Factor
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    • "Fig. 3. Outcome prediction by CYP2C19*2 genotype in different settings of cardiovascular patients in recent literature [5] [58] [61] [62] [103]. 1152 C. S. Zuern et al Ó 2010 International Society on Thrombosis and Haemostasis "
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    ABSTRACT: Platelet responsiveness to conventional antiplatelet therapy underlies a high interindividual variability influenced by various factors. For instance, antiplatelet therapy does not curtail the expected effects in a relevant number of patients as demonstrated by the occurrence of repeated cardiovascular events including stent thrombosis and/or by inadequate platelet inhibition measured by in vitro platelet function assays. Besides non-genetic factors such as age, gender, liver and renal function and co-medication, considerable variation of antiplatelet drug responsiveness can be attributed to genetic factors including polymorphisms and genetic variants of platelet surface proteins and drug metabolizing enzymes. Nowadays, platelet pharmacogenomics has started a new field with the goal to link genetic information of various drug targets to interindividual variability of drug response. Evolving data from large cohort studies suggest a promising role for pharmacogenomics in the context of antiplatelet therapy. Additionally, with the revolution of low cost and high-throughput genotyping techniques, genetic testing has become affordable for clinical application and individualization of therapy. However, a key issue to define the future role of pharmacogenomics will rely on the benefit and the timeliness of implementing the genetic information into therapeutic decision. Hence, it warrants further investigations to document the prognostic effects of therapeutic alterations in distinct genotypes. Concerning the safety profile of emerging antiplatelet and antithrombotic drugs in certain risk groups it would be fatal to individualize treatment barely on behalf of an atherothrombotic genotype. In contrast, individual risk assessment combining non-genetic information and pharmacogenetic analysis represents a reasonable concept. Here, we provide a review on current data describing the role of pharmacogenomics in the field of antiplatelet drug treatment in cardiovascular patients with future directions.
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