Cytochrome P450 2C19 681G&gt;A Polymorphism and High On-Clopidogrel Platelet Reactivity Associated With Adverse 1-Year Clinical Outcome of Elective Percutaneous Coronary Intervention With Drug-Eluting or Bare-Metal Stents

Trenk, Dietmar; Hochholzer, Willibald; Fromm, Martin F.; Chialda, Ligia-Emilia; Pahl, Andreas; Valina, Christian; Stratz, Christian; Schmiebusch, Peter; Bestehorn, Hans-Peter; Büttner, Heinz Joachim; Neumann, Franz‐Josef

doi:10.1016/j.jacc.2007.12.056

Cited by 514 publications

(404 citation statements)

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“…Concerning the latter, work by Hulot et al [10] has demonstrated the influence of CYP2C19 loss-of-function (LoF) polymorphisms on the biological responsiveness in healthy volunteers. More recently, a paper by Trenk et al, [11] in the Journal of American College of Cardiology, two papers by Simon et al and Mega et al published in the New England Journal of Medicine and one paper in The Lancet by Collet et al confirmed and extended previous reports that the polymorphism of CYP450 2C19 subtypes is an important determinant of responsiveness to clopidogrel and subsequent cardiovascular events [12][13][14]. These observations point to the interest of genotyping patients for whom clopidogrel therapy is indicated.…”

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confidence: 98%

CYP2C19*2 polymorphism is not the sole determinant of the response to clopidogrel: implications for its monitoring

Aleil

Léon

Cazenave

et al. 2009

Journal of Thrombosis and Haemostasis

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The biological response to clopidogrel displays wide interindividual variability [1] and hyporesponsiveness is associated with a poorer clinical outcome after an acute coronary syndrome or percutaneous coronary intervention [2]. [12][13][14]. These observations point to the interest of genotyping patients for whom clopidogrel therapy is indicated.We would like to contribute our own data to the debate on the appropriateness of determining the patientÕs genomic profile. Our vasodilator-stimulated phosphoprotein (VASP)-02 study comparing the responses of 153 patients to 75 and 150 mg day )1 maintenance doses of clopidogrel [15] was reanalyzed after determining the 2C19*2 polymorphisms in these patients. The 2C19*2 profiles were matched to the response to clopidogrel as measured using the VASP assay. Patients with a platelet reactivity index (PRI) of > 69% were classed as poor responders. Among 37 poor responders (32/95 receiving 75 and 5/58 receiving 150 mg day )1 clopidogrel), 42% were CY-P2C19*2LoF carriers (60% of poor responders to 150 mg day )1) vs. 22% among responder patients (P = 0.022), confirming a significant determination of the response to clopidogrel. Interestingly, CYP2C19*2LoF carriers displayed the same PRI (62.1 ± 19.1%) as G/G genotypes receiving a proton pump inhibitor (63.9 ± 17.1%, P = 0.94). As such inhibitors are known to be 2C19 substrates, this confirms the presence of a drug-drug interaction effect.However, the existence of poor responders not carrying the LoF mutation and responders carrying the mutation indicates that other factors also influence the responsiveness. Thus, in poor responders with the 2C19*2 wild type (G/G), the body weight was significantly higher than in responders carrying the 2C19*2LoF variant (90.2 ± 13.0 vs. 79.9 ± 13.6 kg respectively, P = 0.021). A multivariate analysis showed 2C19*2LoF and high body weight to be two independent predictors of a high PRI [odds ratio (95% confidence interval

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confidence: 98%

CYP2C19*2 polymorphism is not the sole determinant of the response to clopidogrel: implications for its monitoring

Aleil

Léon

Cazenave

et al. 2009

Journal of Thrombosis and Haemostasis

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“…5 One of the common causes of individual variations in drug response is genetic polymorphism associated with drug absorption and metabolism. [6][7][8] Clopidogrel is a prodrug that requires active enteric absorption and conversion into an active metabolite in the liver. 9 A key protein involved in clopidogrel absorption is the intestinal efflux transporter P-glycoprotein which is encoded by the ABCB1 gene.…”

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confidence: 99%

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Park

Her

Kim

et al. 2016

Genetics in Medicine

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Original research article INTRODUCTIONThe identification of individuals at risk of future adverse cardiovascular outcomes is important after percutaneous coronary intervention (PCI). Thus, the use of novel risk markers such as genetic polymorphisms to augment standard risk algorithms, including conventional clinical risk factors, has attracted increasing attention in recent years.Dual antiplatelet therapy with aspirin and clopidogrel is the current standard of treatment after PCI with drug-eluting stent to reduce the rate of recurrent ischemic events. 1,2 However, considerable interindividual variability exists in response to clopidogrel, and those with high on-clopidogrel platelet reactivity are at increased risk of cardiovascular events. 3,4 Several clinical, genetic, and cellular factors have been suggested as mechanisms for clopidogrel response variability. 5 One of the common causes of individual variations in drug response is genetic polymorphism associated with drug absorption and metabolism. [6][7][8] Clopidogrel is a prodrug that requires active enteric absorption and conversion into an active metabolite in the liver. 9 A key protein involved in clopidogrel absorption is the intestinal efflux transporter P-glycoprotein which is encoded by the ABCB1 gene. Purpose: We evaluated the incremental prognostic value of combining the CYP2C19 poor metabolizer (PM) and ABCB1 3435 TT for adverse clinical outcomes over conventional risk factors in a percutaneous coronary intervention (PCI) cohort. Methods:We enrolled 2,188 patients. The primary end point was a composite of death from any cause, nonfatal myocardial infarction (MI), and stroke during 1-year follow-up. The population was stratified into the following four groups: CYP2C19 EM/IM+ABCB1 3435 CC/CT, CYP2C19 EM/IM+ABCB1 3435 TT, CYP2C19 PM+ABCB1 3435 CC/CT, and CYP2C19 PM+ABCB1 3435 TT. Results:A total of 87 (3.97%) primary end-point events occurred (64 deaths, 8 non-fatal MIs and 15 strokes). Multivariate Cox analysis indicated that CYP2C19 PM+ABCB1 3435 TT status was a significant predictor of the primary end point (hazard ratio = 4.51, 95% confidence interval (CI) = 1.92-10.58). However, addition of combined genetic status to the clinical risk model did not improve the model discrimination (C-statistic = 0.786 (95% CI = 0.734-0.837) to 0.785 (95% CI = 0.733-0.838)) or risk reclassification (categorical net reclassification improvement (0.040, P = 0.32), integrated discrimination improvement (0.021, P = 0.026)). Conclusions:In a real-world East Asian PCI population taking clopidogrel, although the concurrent presence of CYP2C19 PM and ABCB1 TT is a strong independent predictor of adverse outcomes, the combined status of two at-risk variants does not have an incremental prognostic value beyond that of the conventional clinical risk factors. Genet Med

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“…Observational studies have demonstrated that a high level of on-clopidogrel platelet aggregation (PA) can result in adverse cardiovascular events after PCI, including stent thrombosis [10][11][12][13] . In this regard, carriers of at least one reduced-function cytochrome P450 2C19 (CYP2C19) allele treated with DAPT have been reported to have low levels of the active metabolites of clopidogrel, diminished platelet inhibition and a high rate of major adverse cardiovascular events among ACS patients undergoing PCI 14) .…”

Section: Platelet Function Testsmentioning

confidence: 99%

Impact of CYP2C19 Polymorphism on Platelet Function Tests and Coagulation and Inflammatory Biomarkers in Patients Undergoing Percutaneous Coronary Intervention

Kaikita

Ono

Iwashita

et al. 2014

JAT

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Aim:Carriers of the reduced-function CYP2C19 allele receiving dual antiplatelet therapy (DAPT) with aspirin and clopidogrel exhibit diminished platelet inhibition and an increased risk of events. The purpose of this study was to investigate the effects of CYP2C19 gene variants on platelet function tests and coagulation and inflammatory biomarkers in patients undergoing elective percutaneous coronary intervention (PCI). Methods: This prospective, observational, multicenter study enrolled 104 consecutive Japanese patients undergoing elective PCI. We examined the CYP2C19 genotype, platelet function tests, the levels of coagulation and inflammatory biomarkers and the serum levels of high-sensitivity troponin T (hsTnT) before, immediately after and one, two and 28 days after PCI. Results: A total of 68 (65%) of the 104 enrolled patients were carriers of the CYP2C19 reducedfunction allele. On-clopidogrel platelet aggregation (PA), measured using light transmittance aggregometry and the VerifyNow ® P2Y12 system, and the platelet reactivity index (PRI) were significantly higher at all time points in the carriers than in the noncarriers (p＜0.05), whereas there were no differences in the levels of the coagulation and inflammatory biomarkers or serum hs-TnT. Simple and multiple logistic regression analyses identified on-clopidogrel PA and PRI as being significant predictors of carriers of the CYP2C19 reduced-function allele. Conclusions: The present study suggests that platelet function tests, but not coagulation, inflammatory or cardiac biomarkers, are useful for identifying carriers of CYP2C19 reduced-function gene variants and monitoring the efficacy of DAPT in patients undergoing elective PCI. J Atheroscler Thromb, 2014; 21:64-76.

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Cytochrome P450 2C19 681G>A Polymorphism and High On-Clopidogrel Platelet Reactivity Associated With Adverse 1-Year Clinical Outcome of Elective Percutaneous Coronary Intervention With Drug-Eluting or Bare-Metal Stents

Abstract: Patients carrying at least one CYP2C19*2 allele are more prone to high-on clopidogrel platelet reactivity, which is associated with poor clinical outcome after coronary stent placement (Effect of Clopidogrel Loading and Risk of PCI [EXCELSIOR]; NCT00457236).

Cited by 514 publications

References 34 publications

CYP2C19*2 polymorphism is not the sole determinant of the response to clopidogrel: implications for its monitoring

CYP2C19*2 polymorphism is not the sole determinant of the response to clopidogrel: implications for its monitoring

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Impact of CYP2C19 Polymorphism on Platelet Function Tests and Coagulation and Inflammatory Biomarkers in Patients Undergoing Percutaneous Coronary Intervention

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