Reduced-Function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes Among Patients Treated With Clopidogrel Predominantly for PCI

TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 10/2010; 304(16):1821-30. DOI: 10.1001/jama.2010.1543
Source: PubMed


Clopidogrel, one of the most commonly prescribed medications, is a prodrug requiring CYP450 biotransformation. Data suggest its pharmacologic effect varies based on CYP2C19 genotype, but there is uncertainty regarding the clinical risk imparted by specific genotypes.
To define the risk of major adverse cardiovascular outcomes among carriers of 1 (≈ 26% prevalence in whites) and carriers of 2 (≈ 2% prevalence in whites) reduced-function CYP2C19 genetic variants in patients treated with clopidogrel. Data Sources and
A literature search was conducted (January 2000-August 2010) in MEDLINE, Cochrane Database of Systematic Reviews, and EMBASE. Genetic studies were included in which clopidogrel was initiated in predominantly invasively managed patients in a manner consistent with the current guideline recommendations and in which clinical outcomes were ascertained.
Investigators from 9 studies evaluating CYP2C19 genotype and clinical outcomes in patients treated with clopidogrel contributed the relevant hazard ratios (HRs) and 95% confidence intervals (CIs) for specific cardiovascular outcomes by genotype.
Among 9685 patients (91.3% who underwent percutaneous coronary intervention and 54.5% who had an acute coronary syndrome), 863 experienced the composite end point of cardiovascular death, myocardial infarction, or stroke; and 84 patients had stent thrombosis among the 5894 evaluated for such. Overall, 71.5% were noncarriers, 26.3% had 1 reduced-function CYP2C19 allele, and 2.2% had 2 reduced-function CYP2C19 alleles. A significantly increased risk of the composite end point was evident in both carriers of 1 (HR, 1.55; 95% CI, 1.11-2.17; P = .01) and 2 (HR, 1.76; 95% CI, 1.24-2.50; P = .002) reduced-function CYP2C19 alleles, as compared with noncarriers. Similarly, there was a significantly increased risk of stent thrombosis in both carriers of 1 (HR, 2.67; 95% CI, 1.69-4.22; P < .0001) and 2 (HR, 3.97; 95% CI, 1.75-9.02; P = .001) CYP2C19 reduced-function alleles, as compared with noncarriers.
Among patients treated with clopidogrel for percutaneous coronary intervention, carriage of even 1 reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.

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    • "The study identified carriers with at least one of the CYP2C19 loss-of-function alleles who showed higher residual platelet reactivity compared to noncarriers with stable angina (SA) status. High residual platelet reactivity status is known as a risk factor for ischemic events after percutaneous coronary intervention (PCI) [12], and some studies reported a close relation between presence of CYP2C19 reduced-function allele and adverse cardiovascular events [13] [14]. However, the clinical outcome of carriers of CYP2C19 loss-of-function alleles has not been fully elucidated [15] [16]. "
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    ABSTRACT: Aim CYP2C19 polymorphism modulates platelet reactivity in coronary artery disease patients with stent implants. However, the impact of the CYP2C19 genotype on clopidogrel response and clinical outcome has not been fully understood to date. Methods We enrolled 518 consecutive patients with acute coronary syndrome (ACS) (n = 214) and stable angina (SA) (n = 304). All patients received stent implants followed by dual antiplatelet therapy of aspirin and clopidogrel. We determined CYP2C19 phenotype, measured platelet reactivity, and assessed the risk of cardiovascular events. Results During a median follow-up of 894 days, the rate of cardiovascular events was higher in patients of the ACS group than the SA group (ACS: 20.1%, SA: 12.5%, p = 0.015). The mean platelet reactivity was significantly higher in the CYP2C19 loss-of-function allele carriers of the two groups (ACS, non-carriers: 3909 ± 1836 AU min, carriers: 4854 ± 1594 AU min, respectively, p < 0.01; SA, 3606 ± 1579 AU min, 4381 ± 1373 AU min, ±SD, p < 0.01). In the ACS group, cardiovascular events were higher in the loss-of-function allele carriers (24.6%) versus non-carriers (11.1%, p < 0.05), but no such difference was noted in the SA group (carriers: 14.8%; non-carriers: 7.9%, p = 0.078). Furthermore, landmark analysis from 30 days did not show differences in ACS group (carriers: 14.8%, non-carriers: 11.1%, p = 0.315). Multivariate Cox proportional hazards analysis identified the presence of loss-of-function allele as an independent predictor of cardiovascular events (hazard ratio, 2.1, 95% CI, 1.194–3.587, p = 0.010). Conclusions The impact of CYP2C19 loss-of-function gene on clinical outcome is more powerful in early phase of ACS compared with SA.
    Journal of Cardiology 08/2014; 65(6). DOI:10.1016/j.jjcc.2014.07.016 · 2.78 Impact Factor
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    • "Carriage of a loss-of-function (LoF) allele for the CYP2C19 enzyme (primarily the CYP2C19*2 or CYP2C19*3 alleles) has most commonly been assessed as a potential predictive marker of therapeutic response to clopidogrel therapy [Holmes et al. 2011; Mega et al. 2010; Sorich et al. 2013b]. CYP2C19 is thought to be important in the activation of clopidogrel, which is a prodrug. "
    Therapeutic Advances in Drug Safety 03/2014; 5(2):62-66. DOI:10.1177/2042098613520030
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    • "Early studies published in 2006 – 2007 indicated that clopidogrel is a pro-drug requiring activation by cytochrome P450 2C19 (CYP2C19) and that healthy subjects and coronary artery disease patients with common loss-of-function mutations in the CYP2C19 gene had decreased blood levels of active metabolite and increased residual on-treatment platelet reactivity [Brandt et al., 2007; Hulot et al., 2006]. Subsequent larger studies [Mega et al., 2010a; "
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    ABSTRACT: Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 03/2014; 166(1). DOI:10.1002/ajmg.c.31396 · 3.91 Impact Factor
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