Cardiovascular Risk in Clopidogrel-Treated Patients According to Cytochrome P450 2C19*2 Loss-of-Function Allele or Proton Pump Inhibitor Coadministration

Hulot, Jean‐Sébastien; Collet, Jean Philippe; Silvain, Jean‐François; Peña, Ana; Bellemain-Appaix, Anne; Barthélémy, Olivier; Cayla, Guillaume; Beygui, Farzin; Montalescot, Gilles

doi:10.1016/j.jacc.2009.12.071

Cited by 351 publications

(286 citation statements)

References 38 publications

Supporting

Mentioning

265

Contrasting

Unclassified

Order By: Relevance

“…[30][31][32][33] Our study supported this observation, since 80% of our patients were carriers of the CYP2C19 reduced-function allele. All platelet function tests, expressed by LTA, VASP index, and VerifyNow-P2Y12 showed a tendency to increase according to the degree of CYP2C19 loss-of-function genotype (PM > IM > EM) indicating a gene-dose effect.…”

Section: Discussionsupporting

confidence: 87%

Hyper-Response to Clopidogrel in Japanese Patients Undergoing Transcatheter Aortic Valve Implantation

et al. 2016

View full text Add to dashboard Cite

SummaryDual antiplatelet therapy is empirically recommended following transcatheter aortic valve implantation (TAVI). The aims of the present study were to analyze the effect of clopidogrel on platelet function and to determine the relative contribution of each CYP2C19 loss-of-function genotype undergoing TAVI.Thirty-two patients undergoing TAVI and with clopidogrel treatment were studied. All patients were treated with an Edwards SapienXT valve. Platelet reactivity was measured by the VerifyNow P2Y12 point-of-care assay at 7 days and 30 days after the procedure and a cutoff value of 95 PRU was used to identify a hyper-response of platelet reactivity. The Spartan RX TM sample-to-result point-of-care DNA testing system was used to identify CYP2C19 loss-of-function genotypes. Hyper-response of platelet reactivity was identified in 11 (34.3%) patients, although 24 (80%) were carriers of at least one CYP2C19 reduced-function allele. The PRU values did not change significantly from 7 days to 30 days after TAVI (136.7 ± 73.4 versus 150.4 ± 83.2, P = 0.13). The incidences of life-threatening bleeding, minor bleeding, and transfusion were significantly higher among the hyper-response of platelet reactivity group (27.3% versus 0%, P = 0.03, 36.4% versus 4.8%, P = 0.04, 81.8% versus 42.9%, P = 0.04, respectively).A hyper-response to clopidogrel was observed in one-third of patients undergoing TAVI and was related to bleeding events, even though 80% of the patients were carriers of the CYP2C19 reduced-function allele. (Int Heart J 2016; 57: 190-197) Key words: Platelet function tests, Antiplatelet therapy T ranscatheter aortic valve implantation (TAVI) has emerged as a viable therapeutic option for patients with severe symptomatic aortic stenosis (AS). 1,2)However, special attention should be paid to potential periprocedural and early complications, including ischemic (stroke, myocardial infarction) or bleeding (access site complication) events. 3,4) After TAVI, guidelines recommend the use of clopidogrel in addition to aspirin for a 3-to 6-month period. 5-7)While this strategy has been accepted as the usual practice following TAVI, the recommendation remains empirical and prospective controlled trials are lacking. Few data have been reported regarding the effectiveness of clopidogrel in the TAVI setting or its possible impact on adverse events.Results from previous studies in patients treated with clopidogrel have shown wide variability in platelet responsiveness, and high platelet reactivity under clopidogrel treatment has been linked to stent thrombosis and adverse cardiovascular events after coronary stenting. [8][9][10][11][12][13][14] Notably, there exists a subset of patients with a hyper-response to clopidogrel who may be at increased risk of bleeding complications. 15,16) Genetic polymorphism of the CYP2C19 allele, crucial to the metabolism of clopidogrel into its active metabolite, has been implicated as a mechanism of both hyper-and hypo-response. A loss-of-function polymorphism in CYP2C19, known as the CYP2...

show abstract

Section: Discussionsupporting

confidence: 87%

Hyper-Response to Clopidogrel in Japanese Patients Undergoing Transcatheter Aortic Valve Implantation

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The results revealed that the carriers of the CYP2C19*2 allele had about a 35% higher risk for major adverse cardiovascular events (MACE) compared to non-carriers [18]. This gene variant also correlated with increased mortality rates.…”

Section: Genotyping -The Influence Of Gene Profile On Platelet Reactimentioning

confidence: 98%

“…The CYP2C19*2 allele carriers have higher a PR, as PR inhibition by the drug is insufficient. It can result in a substantial number of thrombotic events [18]. Another mechanism which influences the effectiveness of clopidogrel is a drug-efflux intestinal transporter P-glycoprotein, which acts against several other drugs as well.…”

Section: Genotyping -The Influence Of Gene Profile On Platelet Reactimentioning

confidence: 99%

Most Recent Evidence Behind Aggregometry and Genotyping Methods as Platelet Function Testing for Tailored Anti-Platelet Treatment Among PCI Patients

Gajda¹,

Kołtowski²,

Tomaniak³

2015

Adv Clin Exp Med

View full text Add to dashboard Cite

Aggregometry and genotyping are methods of platelet function testing, which can be beneficial for high-risk patients undergoing invasive cardiac procedures. An optimal level of platelet reactivity (PR) should be maintained. There are discrepancies between individuals and their response to clopidogrel, accounting for the incidence of poor responders from 5% to 44%. This phenomenon predisposes the patients to increased risk of ischaemic events and thereby overall poorer clinical outcome. Prasugrel and tricagrelor are newer without genetic correlation to their action, however associated with increased bleeding risk. Aggregometry methods assess platelet reactivity at the exact moment of blood sampling. They reflect "phenotype" of the patient and vary after drug administration or dose change. The most popular tests are Light Transmission Aggregometry, Vasodilator-Stimulated Protein, VerifyNow, Multiple Electrode Aggregometry and Thrombelastography. There is proven genetic correlation between some cytochrome enzymes on clopidogrel response. The most widely tested is gene CYP2C19, which produces the enzyme transforming clopidogrel into an active metabolite. The CYP2C19*2 allele carriers have higher PR which can result in more thrombotic events. The manuscript shows the most recent evidence behind platelet function testing. Aggregometry is shown to be beneficial in 5 trials and 1 meta-analysis, while one paper was of different opinion. Ten studies show a positive clinical effect of genotyping on patients' outcome, while one does not support it. The best method of identifying high-risk individuals could be both methods and personalisation of antiplatelet therapy may decrease adverse ischaemic outcomes (Adv Clin Exp Med 2015, 24, 4, 687-693).

show abstract

“…ST was typically defined according to the Academic Research Consortium definitions. 23 Five meta-analyses used a checklist to assess the quality of the primary studies, 5,7,8,24,25 and three meta-analyses used their own approach 6,26,27 or did not check the quality.…”

Section: Meta-analyses Characteristicsmentioning

confidence: 99%

“…Some meta-analyses on CYP2C19 loss-of-function and clinical efficacy of clopidogrel conclude that the association is proven, 7,8 whereas others conclude the opposite. 5,6 Our objective was to systematically evaluate the discordant evidence for the association between CYP2C19 loss-offunction alleles and clinical efficacy of clopidogrel through a critical methodological appraisal of published meta-analyses.…”

mentioning

confidence: 99%

A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users

Osnabrugge

Head

Zijlstra

et al. 2015

Genetics in Medicine

View full text Add to dashboard Cite

Clopidogrel, in combination with aspirin, is a standard treatment for patients with acute coronary syndrome and is one of the top-selling drugs in the world.1,2 However, there is substantial interindividual variability in response. Polymorphisms of the cytochrome P450 (CYP) gene have been identified as a potential risk factor for nonresponse.3 This gene plays a central role in drug-metabolizing processes in the liver, and clopidogrel makes use of these processes to transform into an active metabolite capable of inhibiting platelet aggregation. Identification of CYP2C19 polymorphisms could lead to personalized treatment based on genotype in patients with acute coronary syndrome, and therefore, the US Food and Drug Administration recommends CYP2C19 genotyping for individualized antiplatelet management. 4 The association between CYP2C19 loss-of-function alleles and clinical efficacy of clopidogrel has been studied extensively, and several meta-analyses have summarized the results of those studies.5-8 Systematic reviews and meta-analyses are often considered the highest level of evidence, 9-11 and their popularity in the cardiovascular field increased almost 13 times as fast as the increase in number of published randomized clinical trials. 12However, the interpretation of meta-analyses is confusing when the conclusions of overlapping meta-analyses are discordant. Some meta-analyses on CYP2C19 loss-of-function and clinical efficacy of clopidogrel conclude that the association is proven, 7,8 whereas others conclude the opposite. 5,6 Our objective was to systematically evaluate the discordant evidence for the association between CYP2C19 loss-offunction alleles and clinical efficacy of clopidogrel through a critical methodological appraisal of published meta-analyses. MATERIALS AND METHODSOur review adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement, 13 and we consulted the Cochrane Handbook for Systematic Reviews of Interventions for methodological aspects of meta-analyses. We systematically investigated how 11 overlapping meta-analyses on the association between CYP2C19 loss-of-function alleles and clinical efficacy of clopidogrel could yield contradictory outcomes. The results of the meta-analyses differed because more recent metaanalyses included more primary studies and some had not included conference abstracts. Conclusions differed because between-study heterogeneity and publication bias were handled differently across meta-analyses. All meta-analyses on the clinical end point observed significant heterogeneity and several reported evidence for publication bias, but only one out of eight statistically significant meta-analyses concluded that therefore the association was unproven and one other refrained from quantifying a pooled estimate because of heterogeneity. For the end point stent thrombosis, all meta-analyses reported statistically significant associations with CYP2C19 loss-of-function alleles with no statistically significant evidence for heterogeneity, b...

show abstract

Cardiovascular Risk in Clopidogrel-Treated Patients According to Cytochrome P450 2C19*2 Loss-of-Function Allele or Proton Pump Inhibitor Coadministration

Abstract: In this global meta-analysis, reduced CYP2C19 function appears to expose clopidogrel-treated patients to excess cardiovascular risk and mortality. Conflicting results among studies may be explained by differences in types and/or levels of risk of patients.

Cited by 351 publications

References 38 publications

Hyper-Response to Clopidogrel in Japanese Patients Undergoing Transcatheter Aortic Valve Implantation

Hyper-Response to Clopidogrel in Japanese Patients Undergoing Transcatheter Aortic Valve Implantation

Most Recent Evidence Behind Aggregometry and Genotyping Methods as Platelet Function Testing for Tailored Anti-Platelet Treatment Among PCI Patients

A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users

Contact Info

Product

Resources

About