CYP2C19 Reduced-function Allele Research Articles

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

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. 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.

Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON–TIMI 38 trial: a pharmacogenetic analysis

Clopidogrel and prasugrel are subject to efflux via P-glycoprotein (encoded by ABCB1, also known as MDR1). ABCB1 polymorphisms, particularly 3435C→T, may affect drug transport and efficacy. We aimed to assess the effect of this polymorphism by itself and alongside variants in CYP2C19 on cardiovascular outcomes in patients treated with clopidogrel or prasugrel in TRITON-TIMI 38. We also assessed the effect of genotype on the pharmacodynamic and pharmacokinetic properties of these drugs in healthy individuals. We genotyped ABCB1 in 2932 patients with acute coronary syndromes undergoing percutaneous intervention who were treated with clopidogrel (n=1471) or prasugrel (n=1461) in the TRITON-TIMI 38 trial. We evaluated the association between ABCB1 3435C→T and rates of the primary efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) until 15 months. We then assessed the combined effect of ABCB1 3435C→T genotype and reduced-function alleles of CYP2C19. 321 healthy individuals were also genotyped, and we tested the association of genetic variants with reduction in maximum platelet aggregation and plasma concentrations of active drug metabolites. In patients treated with clopidogrel, ABCB1 3435C→T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0·0064). TT homozygotes had a 72% increased risk of the primary endpoint compared with CT/CC individuals (Kaplan-Meier event rates 12·9% [52 of 414] vs 7·8% [80 of 1057 participants]; HR 1·72, 95% CI 1·22-2·44, p=0·002). ABCB1 3435C→T and CYP2C19 genotypes were significant, independent predictors of the primary endpoint, and 681 (47%) of the 1454 genotyped patients taking clopidogrel who were either CYP2C19 reduced-function allele carriers, ABCB1 3435 TT homozygotes, or both were at increased risk of the primary endpoint (HR 1·97, 95% CI 1·38-2·82, p=0·0002). In healthy participants, 3435 TT homozygotes had an absolute reduction in maximum platelet aggregation with clopidogrel that was 7·3 percentage points less than for CT/CC individuals (p=0·0127). ABCB1 genotypes were not significantly associated with clinical or pharmacological outcomes in patients with an acute coronary syndrome or healthy individuals treated with prasugrel, respectively. Individuals with the ABCB1 3435 TT genotype have reduced platelet inhibition and are at increased risk of recurrent ischaemic events during clopidogrel treatment. In patients with acute coronary syndromes who have undergone percutaneous intervention, when both ABCB1 and CYP2C19 are taken into account, nearly half of the population carries a genotype associated with increased risk of major adverse cardiovascular events while on standard doses of clopidogrel. Daiichi Sankyo Company Ltd and Eli Lilly and Company.

ACCF/AHA Clopidogrel Clinical Alert: Approaches to the FDA “Boxed Warning”

The recent US Food and Drug Administration (FDA) “boxed warning” on clopidogrel raises important questions for practitioners and patients. The warning addresses the need for pharmacogenomic testing to identify patients’ altered clopidogrel metabolism and thus their risk for a suboptimal clinical response to clopidogrel. Although there is an expanding database on genetic polymorphisms that may affect clopidogrel metabolism and thus clinical outcomes, there are no evidence-based data upon which todevelop specific recommendations on the role of genetic testing in routine care nor strategies proven to improve the safety/efficacy of specific pharmacologic approaches. To provide guidance on this issue, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) convened a writing committee. The ACCF and AHA adhere to a rigorous policy regarding relationships with industry and other entities (RWI) of authors and peer reviewers for clinical document development (see http://www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/Relationships-With-Industry-Policy.aspx). This policy requires that a majority of writing committee members have no relevant relationships with industry to this topic, a standard that has been achieved for this document as indicated in Appendix 1. In the spirit of full disclosure, comprehensive RWI (RWI not relevant to this document) for all authors is available online for public view. RWI …

New P2Y12 antagonists

The P2Y12 antagonist clopidogrel has a well established role as an antithrombotic agent in the settings of percutaneous coronary intervention and acute coronary syndromes. However, clopidogrel has a number of disadvantages that have led to the development of new P2Y12 antagonists. This article reviews the current status of clopidogrel and these new P2Y12 antagonists. A poor response to clopidogrel as measured by in-vitro platelet function assays is associated with a poor clinical response to clopidogrel. A patient's response to clopidogrel is partly dependent on factors that decrease (reduced-function CYP2C19 allele; omeprazole) or increase (cigarette smoking) the metabolism of clopidogrel through cytochrome P450 in the liver. Novel P2Y12 antagonists (prasugrel, ticagrelor, cangrelor, and elinogrel) that have advantages over clopidogrel - including more rapid, less variable, and more complete inhibition of platelet function - are in various phases of development. The clinical benefit of changing clopidogrel treatment based on platelet function tests, single-nucleotide polymorphisms, or both is as yet unproven. Novel P2Y12 antagonists are under investigation to determine whether they can result in better, more rapid, or both, antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic or other side effects.

Cytochrome P-450 Polymorphisms and Response to Clopidogrel

Conclusion: Persons with a reduced function of the CYP2C19 allele have significantly lower levels of active metabolite of clopidogrel, with diminished platelet inhibition and higher rates of major cardiovascular events than noncarriers of the CYP2C19 allele. Summary: Clopidogrel is a thienopyridine inhibitor of the platelet P2Y12 adenosine diphosphate (ADP) receptor. It is a “prodrug” that requires biotransformation to an active metabolite by a cytochrome P-450 enzyme. Esterases shunt most of clopidogrel to an inactive pathway, with the remaining prodrug requiring two separate CYP-dependent oxidative steps. Genes encoding CYP enzymes are polymorphic, with some alleles conferring reduced enzymatic function. Therefore, it is possible CYP polymorphisms can effect conversion of clopidogrel to active metabolite and hence affect the degree of clopidogrel induced platelet inhibition. In this study the authors tested the association between functional variance in CYP genes, plasma concentration of active clopidogrel drug metabolite, and platelet inhibition in response to clopidogrel. There were 162 healthy subjects analyzed as well as 1477 individuals with acute coronary syndromes treated with clopidogrel in a trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition in patients with myocardial infarction (TRITON-TIMI 38). Approximately 30% of the healthy participants were carriers of at least one CYP2C19 reduced-function allele. These individuals had a reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel compared with noncarriers (P < .001). Carriers also had reduced reduction in maximal platelet aggregation compared with noncarriers (P < .001). Among clopidogrel-treated patients in TRITON-TIMI 38, carriers of reduced-function alleles had a relative increase of 53% in the composite primary end point of death due to cardiovascular causes, myocardial infarction, or stroke compared with noncarriers (12.1% vs 8%; hazard ratio [HR] for carriers, 1.53; 95% confidence interval [CI] 1.07-2.19; P = .01). Carriers had an increase by a factor of three in the risk of stent thrombosis (2.6% vs 0.8%; HR, 3.09; 95% CI, 1.19-8.00; P = .02). Comment: This study, along with the similar study also appearing in the same issue of the New England Journal of Medicine (2009;360:363-75), provides strong evidence linking genetic variations in CYP genes to reduced exposure to active drug metabolite in patients treated with clopidogrel. These polymorphisms are seen in approximately 30% of white patients, 40% of African Americans, and >55% of people of East Asian origin. Of course multiple other genetic and environmental factors can also contribute to platelet aggregation. Nevertheless, the data are quite convincing that genetic variation in the genes encoding CYP enzymes can result in meaningful and profound clinical effects.

Cytochrome P-450 Polymorphisms and Response to Clopidogrel

Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function.We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38.In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P<0.001). Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9 percentage points less than that seen in noncarriers (P<0.001). Among clopidogrel-treated subjects in TRITON-TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval [CI], 1.07 to 2.19; P=0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P=0.02).Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.

Abstract 1439: Cytochrome P450 Genetic Variants Predict Cardiovascular Outcomes following Treatment with Clopidogrel but not with Prasugrel

Background : Prasugrel and clopidogrel require transformation into active metabolites by cytochrome P450 (CYP) enzymes. Variants in CYP genes, particularly CYP2C19 , are associated w/ reduced levels of metabolite and platelet inhibition w/ clopidogrel but not prasugrel. We investigated the impact of variants in CYP genes on clinical outcomes. Methods : TRITON-TIMI 38 randomized ACS patients w/ planned PCI to prasugrel (60 mg load, 10 mg qd) or clopidogrel (300 mg, 75 mg qd) for 6–15 mos. DNA was available in 2943 subjects who were genotyped for functional polymorphisms in CYP2C19 , 2C9 , 3A4/5 , 2B6 , and 1A2 and classified for each gene as carriers or non-carriers of ≥1 reduced function allele. Results : Among subjects treated with clopidogrel, CYP2C19 reduced function allele carriers (27% of population) had a 53% increased risk of the primary efficacy endpoint of CV death, MI, or stroke (HR 1.53, P=0.007, Fig ) and a 3-fold increased risk of ARC-defined definite or probable stent thrombosis (HR 3.09, P=0.038) compared w/ non-carriers. In contrast, with prasugrel CYP2C19 reduced function allele carriers were not at increased risk of CV death, MI, or stroke (HR 0.89, P=0.86) or stent thrombosis (HR 0.60, P=0.57). No association between genotype and bleeding was observed w/ either treatment. There were no statistically significant associations between any other tested CYP genotypes and outcomes. Conclusions : CYP2C19 genetic variants identify patients at significantly higher risk for CV death, MI, or stroke and for stent thrombosis among those treated with clopidogrel but not among those treated with prasugrel. CYP2C19 genotyping offers the potential to help tailor antiplatelet therapy.