Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation

Schmidt, Morten; Johansen, Martin Berg; Robertson, Douglas J.; Mæng, Michael; Kaltoft, Anne; Jensen, Lisette Okkels; Tilsted, Hans Henrik; Bøtker, Hans Erik; Sørensen, Henrik Toft; Baron, John A.

doi:10.1111/j.1365-2036.2011.04890.x

Cited by 49 publications

(64 citation statements)

References 39 publications

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“…In two early retrospective studies, patients treated with clopidogrel and either omeprazole or pantoprazole had higher risk of recurrent cardiovascular events than those who were given clopidogrel alone [11,26] (Table 1). In contrast, several other retrospective studies reported that neither omeprazole nor pantoprazole increase cardiovascular morbidity when combined with clopidogrel [10,12,[27][28][29][30] (Table 1). A post-hoc analysis of the randomized controlled Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 also reported similar findings [31] (Table 1).…”

Section: Introductionmentioning

confidence: 92%

Clinical relevance of clopidogrel-proton pump inhibitors interaction

Bouziana

Τζιόμαλος

2015

WJGPT

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Clopidogrel is a widely used antiplatelet agent for the secondary prevention of cardiovascular events in patients with stable coronary heart disease, acute coronary syndromes and ischemic stroke. Even though clopidogrel is safer than aspirin in terms of risk for gastrointestinal (GI) bleeding, the elderly, and patients with a history of prior GI bleeding, with Helicobacter pylori infection or those who are also treated with aspirin, anticoagulants, corticosteroids or nonsteroidal antiinflammatory drugs are at high risk for GI complications when treated with clopidogrel. Accordingly, proton pump inhibitors are frequently administered in combination with clopidogrel to reduce the risk for GI bleeding. Nevertheless, pharmacodynamic studies suggest that omeprazole might attenuate the antiplatelet effect of clopidogrel. However, in observational studies, this interaction does not appear to translate into increased cardiovascular risk in patients treated with this combination. Moreover, in the only randomized, double-blind study that assessed the cardiovascular implications of combining clopidogrel and omeprazole, patients treated with clopidogrel/ omeprazole combination had reduced risk for GI events and similar risk for cardiovascular events than patients treated with clopidogrel and placebo. However, the premature interruption of the study and the lack of power analysis in terms of the cardiovascular endpoint do not allow definite conclusions regarding the cardiovascular safety of clopidogrel/omeprazole combination. Other proton pump inhibitors do not appear to interact with clopidogrel. Nevertheless, given the limitations of existing observational and interventional studies, the decision to administer proton pump inhibitors to patients treated with clopidogrel should be individualized based on the patient's bleeding and cardiovascular risk. Core tip: Even though pharmacodynamic studies suggest that omeprazole can attenuate the antiplatelet effect of clopidogrel, this interaction does not appear to translate into increased cardiovascular risk in patients treated with this combination in observational studies. In the only randomized, double-blind, placebo-controlled study that assessed the cardiovascular implications of combining clopidogrel and omeprazole, patients treated with clopidogrel/omeprazole combination had reduced risk for MINIREVIEWS

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Section: Introductionmentioning

confidence: 92%

Clinical relevance of clopidogrel-proton pump inhibitors interaction

Bouziana

Τζιόμαλος

2015

WJGPT

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“…Some studies have reported adverse clinical outcomes following concurrent use of a PPI and clopidogrel compared with clopidogrel alone [83][84][85]. Other studies have failed to confirm this observation [86][87][88][89]. Whether or not concurrent use of clopidogrel with a PPI adversely affects the clinical outcome remains unresolved at present, but the precautionary principle requires that until the issue is resolved, association studies should adjust for the use of CYP2C19 inhibitors that may induce phenoconversion.…”

Section: Genotype-dependent Susceptibility To Phenoconversionmentioning

confidence: 99%

Addressing phenoconversion: the Achilles' heel of personalized medicine

Shah

Smith

2015

Brit J Clinical Pharma

221

217

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Phenoconversion is a phenomenon that converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, thereby modifying their clinical response to that of genotypic PMs. Phenoconversion, usually resulting from nongenetic extrinsic factors, has a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies and personalizing therapy in routine clinical practice. The high phenotypic variability or genotype-phenotype mismatch, frequently observed due to phenoconversion within the genotypic EM population, means that the real number of phenotypic PM subjects may be greater than predicted from their genotype alone, because many genotypic EMs would be phenotypically PMs. If the phenoconverted population with genotype-phenotype mismatch, most extensively studied for CYP2D6, is as large as the evidence suggests, there is a real risk that genotype-focused association studies, typically correlating only the genotype with clinical outcomes, may miss clinically strong pharmacogenetic associations, thus compromising any potential for advancing the prospects of personalized medicine. This review focuses primarily on co-medication-induced phenoconversion and discusses potential approaches to rectify some of the current shortcomings. It advocates routine phenotyping of subjects in genotype-focused association studies and proposes a new nomenclature to categorize study populations. Even with strong and reliable data associating patients' genotypes with clinical outcome(s), there are problems clinically in applying this knowledge into routine pharmacotherapy because of potential genotype-phenotype mismatch. Drug-induced phenoconversion during routine clinical practice remains a major public health issue. Therefore, the principal challenges facing personalized medicine, which need to be addressed, include identification of the following factors: (i) drugs that are susceptible to phenoconversion; (ii) co-medications that can cause phenoconversion; and (iii) dosage amendments that need to be applied during and following phenoconversion. Pharmacogenetics and personalized medicineThe majority of drug-metabolizing enzymes (DMEs) are subject to genetic polymorphism and show some degree of functionally significant polymorphism in the population. The clearest data in this regard relate to cytochromes P450 CYP2D6 and CYP2C19 and thiopurine methyltransferase (TPMT). These genetically determined polymorphisms give rise to three distinct genotype-based subpopulations with respect to each DME, namely extensive metabolizers (EMs), poor metabolizers (PMs) and a subgroup in between, the intermediate metabolizers (IMs). In addition, for CYP2D6 and CYP2C19, there is a fourth genotype, the ultrarapid metabolizer (UM) genotype, resulting from inheritance of either multiple copies of the functional wild-type allele, such as CYP2D6*1, or a higher metabolic capacity resulting from increased transcription of DME due to the presence of a genetic variant found in the promoter ...

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“…The use of PPIs itself has been reported to increase the risk for major adverse cardiovascular events and a biological mechanism linking PPIs and those events in the general population has been proposed [6,7]. In observational studies drug use in general has been reported to increase in the period before acute hospitalization due to a cardiac event suggesting no causal relationship between drug use and the adverse event but rather an effect of unmeasured confounding [8,9].…”

Section: Introductionmentioning

confidence: 99%