Reduced-function CYP2C19 Research Articles

Effect of CYP2D6 and CYP2C19 genotypes on atomoxetine serum levels: A study based on therapeutic drug monitoring data.

Atomoxetine is mainly metabolized by CYP2D6 while CYP2C19 plays a secondary role. It is known that patients carrying genotypes encoding decreased/absent CYP2D6 metabolism obtain higher atomoxetine concentrations and are at increased risk of adverse effects. Here, we aimed to investigate the added effects of reduced-function CYP2C19 genotype on atomoxetine concentrations in real-world settings. Serum atomoxetine concentrations and CYP2D6/2C19 genotypes were included from a therapeutic drug monitoring service. Patients were first subgrouped according to CYP2D6 encoding normal, reduced or absent CYP2D6 metabolism, referred to as normal (NM), intermediate (IM) or poor metabolizers (PM). Then, the effect of reduced-function CYP2C19 genotypes was investigated. Genotyping of the CYP2D6 nonfunctional or reduced variant alleles comprised CYP2D6*3-*6, *9-*10 and *41. For CYP2C19, the CYP2C19*2 was analysed to define metabolizer phenotype. Dose-adjusted serum atomoxetine concentration was the exposure measure. Using a patient cohort (n= 315), it was found that CYP2D6 IM and PM patients had 1.9-fold (95% confidence interval: 1.4-2.7) and 9.6-fold (5.9-16) higher exposure of atomoxetine compared with CYP2D6 NMs. CYP2C19*2 carriers had 1.5-fold (1.1-2.2) higher atomoxetine exposure than noncarriers regardless of CYP2D6 genotype. CYP2D6 genotype has a great impact on atomoxetine exposure, where our real-world data suggest atomoxetine dose requirements to be around half and 1/10 in CYP2D6 IM and PM vs. NM patients, respectively. When adding CYP2C19 genotype as a factor of relevance for personalized atomoxetine dosing, CYP2C19*2 carriers should further reduce the dose by a third. These findings suggest that pre-emptive CYP2D6/CYP2C19 genotyping should be performed to individualize atomoxetine dosing and prevent adverse effects.

Tailored Adjunctive Cilostazol Therapy Based on CYP2C19 Genotyping in Patients With Acute Myocardial Infarction - The CALDERA-GENE Study.

Patients with reduced-function CYP2C19 genotypes on dual antiplatelet therapy (DAPT) with aspirin and clopidogrel show higher clinical risk for acute myocardial infarction (AMI). We investigated the effect of CYP2C19 genotype-tailored adjunctive cilostazol therapy on treatment of AMI.Methods and Results:The study group of 138 patients with suspected AMI were screened for CYP2C19 genotype immediately after percutaneous coronary intervention (PCI) using a SPARTAN RX point-of-care device. Carriers of the CYP2C19 reduced-function allele were randomized into DAPT (Carrier/DAPT) and DAPT plus 14-day cilostazol (Carrier/DAPT+Cilostazol) groups, while noncarriers were treated with DAPT (Noncarrier/DAPT). After exclusion of 10 patients, the remaining 128 patients were analyzed for P2Y12 reaction unit (PRU) using VerifyNow®P2Y12 system, and levels of biomarkers immediately after, and 1, 14, and 28 days after PCI. DAPT+Cilostazol reduced PRU levels in carriers (n=46) to those found in the Noncarrier/DAPT group (n=40), and significantly lower than those of the Carrier/DAPT group (n=42) at 14 days post-PCI. Discontinuation of cilostazol for 14 days was associated with a significant rise in PRU levels to those of the Carrier/DAPT group at 28 days post-PCI. Plasma B-type natriuretic peptide levels at 14 days post-PCI were lower in Carrier/DAPT+Cilostazol than in the other 2 groups, and the levels increased to those of the other groups at 28 days post-PCI after withdrawal of cilostazol. Adjunctive cilostazol therapy tailored to CYP2C19 genotype seemed useful in AMI patients with the CYP2C19 reduced-function allele.

The secondary prevention of stroke according to cytochrome P450 2C19 genotype in patients with acute large-artery atherosclerosis stroke.

PurposeTo investigated the effectiveness of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype in patients with ischemic stroke (IS).MethodsBetween August 2009 and December 2011, 570 acute IS patients with acute large-artery atherosclerosis were randomly assigned to receive either combined clopidogrel and aspirin for the first 30 day, and clopidogrel thereafter (clopidogrel group, n=284) or aspirin monotherapy (aspirin group, n=286). CYP2C19 genotypes were measured and masked until the end-of-study. The primary outcome was a composite of IS, transient ischemic attack (TIA), myocardial infarction (MI), and death.ResultsDuring the 5 years follow-up, the primary outcome occurred in 105 patients (18.4%) (71 had IS, 10 had TIA, 12 had MI, and 12 died). There were no significant differences in the primary outcome between clopidogrel group and aspirin group (16.5% vs. 20.3%) or between carriers of the CYP2C19 reduced-function alleles and noncarriers (21.8% vs.15.7%). In patients with aspirin therapy, CYP2C19 polymorphism was not associated with the primary outcome. However, in patients treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele had a 3-fold higher adjusted risk for primary outcome compared with noncarriers (95% confidence interval, 1.23 to 8.74).ConclusionsAmong IS patients treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had a significantly higher rate of adverse vascular events than did noncarriers. It should avoid prescribing clopidogrel to these patients with known CYP2C19 polymorphisms.

Concomitant Use of Proton Pump Inhibitors and Clopidogrel Is Not Associated with Adverse Outcomes after Ischemic Stroke in Chinese Population

Conflicting data exist as to whether proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel. We, therefore, assessed the effect of concomitant PPI use in ischemic stroke (IS) patients receiving clopidogrel. We consecutively enrolled 535 IS patients receiving clopidogrel, 166 of whom were concomitantly taking PPIs. Platelet aggregation was measured before and after 7-10 days of treatment with clopidogrel. Single nucleotide polymorphisms of CYP3A4, CYP3A5, CYP2C19*2, and CYP2C19*3 were examined. The primary outcome was a composite of recurrent ischemic stroke (RIS), myocardial infarction (MI), and vascular death occurring during the 6-month follow-up. The secondary outcome was the modified Rankin Scale score at the end of follow-up. The primary outcome occurred in 45 patients and the frequency did not differ in patients with or without PPI treatment. The percentage inhibition of platelet aggregation and the frequency of clopidogrel resistance were similar between patients treated with or without PPIs after clopidogrel treatment. However, for patients carrying a reduced-function CYP2C19*2 (AG/AA genotype) or CYP3A5 (GG/AG genotype), the inhibition of platelet aggregation was significantly lower in patients treated with PPIs. Cox regression analysis showed that diabetes mellitus, clopidogrel resistance, CYP2C19*2 AG/AA genotype, and patients carrying two loss-of-function variant alleles were independent risk factors for the primary outcome, but not the use of PPIs. The concomitant use of PPIs and clopidogrel in patients with IS may not be associated with an increased risk of RIS, MI, or vascular death. Further well-designed randomized controlled studies are necessary to confirm our current results.

Non-Carriers of Reduced-Function CYP2C19 Alleles are Most Susceptible to Impairment of the Anti-Platelet Effect of Clopidogrel by Proton-Pump Inhibitors: A Pilot Study.

The phenomenon of CYP2C19 polymorphism affects the metabolism of both clopidogrel and proton-pump inhibitors (PPI). However, concomitant use of both drugs may reduce the desired therapeutic effects. In this study, we evaluated whether individuals with different numbers of reduced-function CYP2C19 alleles were equally affected and whether PPIs with different dependencies on CYP2C19 metabolism were equally involved. Thirty healthy volunteers were recruited to a six-week regimen of clopidogrel. Three PPIs with different metabolic dependencies on CYP2C19 were included and separately administered in this order. Each PPI was given for a week, followed by a one-week washout period before the intervention of the next PPI. The anti-platelet effect was examined by Thromboelastography Platelet Mapping(TM) (TEG®) and vasodilator-stimulated phosphoprotein (VASP) assays. Both TEG® and VASP tests showed the same general qualitative trend, but TEG® detected a statistically significant fluctuation of platelet aggregation in response to different drug interventions. The TEG® results also demonstrated that non-carriers experienced the most significant impairment of anti-platelet effect of clopidogrel after concomitant use of PPIs. This impairment was closely related to the metabolic dependence on CYP2C19 of PPI. Our study indicated that non-carriers of reduced-function CYP2C19 alleles are most susceptible to impairment of the anti-platelet effect of clopidogrel after concomitant PPI use. Individual subjects are not equally affected, and PPIs are not equally involved. However, large-scale randomized clinical trials are needed to evaluate the clinical outcome. Clopidogrel • CYP2C19 polymorphism • Platelet aggregation • Proton pump inhibitors • TEG • VASP.

HM4 - How Much Evidence Do We Need Before Implementing Pharmacogenomic Testing In The Clinic?

Consensus on the evidence required to recommend clinical pharmacogenomic testing is unclear. A formal assessment of pharmacogenomic evidence levels in relation to other clinical interventions, such as avoiding drug-drug interactions (DDI), may be helpful for policymakers. The objective of this study was to quantitatively compare the evidence levels of two contested drug-attenuating interactions with clopidogrel antiplatelet therapy, and assess the value of obtaining additional evidence to inform clinical practice guidelines. We developed analogous value of information (VOI) decision models for: (1) avoidance of proton pump inhibitors (PPIs) in clopidogrel patients, and (2) pharmacogenomic-guided antiplatelet selection, both versus no intervention. Interaction-specific parameters and model structures were the only dissimilarities. We calculated the expected value of obtaining perfect information (EVPI) per patient, and the expected population value of obtaining additional information through future studies (EVSI). Current evidence for interaction-1 was slightly less uncertain (a 20% probability of making a non-optimal recommendation) than for interaction-2 (23%). The relative risk for cardiovascular death (conferred by concomitant PPI use in interaction-1, and reduced-function CYP2C19 alleles in interaction-2) was the greatest source of uncertainty in both models. The expected value of perfect information for interaction-1 was $139 per patient, compared to $242 per patient for interaction-2. In simulated 10,000-patient clinical trials, the expected population value of future research for interaction-1 was $2 million, versus $110 million for interaction-2. The evidence levels for clopidogrel DDI and pharmacogenomic effects appear to be fairly similar. However, the value of conducting future research on clopidogrel pharmacogenomics is higher because of greater uncertainty about the impact of pharmacogenomic testing on cardiovascular mortality. Our findings imply that evidence-based clinical guidelines for DDI and pharmacogenomic effects should be generally similar with regard to direction and strength of recommendation. This contrasts to some degree with current guidelines and drug labeling.

CYP2C19 polymorphism and clinical outcomes among patients of different races treated with clopidogrel: A systematic review and meta-analysis

Several studies have investigated the association between CYP2C19 polymorphism and clinical outcomes of patients treated with clopidogrel, but few have noticed the difference in association between Westerners and Asians. We searched MEDLINE, EMBASE and Cochrane Library database and conducted a systematic review and meta-analysis. Thirty-six studies involving 44 655 patients with coronary artery disease (CAD) treated with clopidogrel were included, of which more than 68% had undergone percutaneous coronary intervention (PCI). The primary outcome of our interest was the recurrence of major adverse cardiovascular events (MACE) in those CAD patients. Firstly, we found that the distribution of reduced-function CYP2C19 allele varied between Westerners and Asians. Among Asians, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 42.5% and 10%, respectively. While among Westerners, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 25.5% and 2.4%, respectively. Secondly, the impact of CYP2C19 polymorphism on clinical outcomes of patients treated with clopidogrel varied with races. Among Asians, only 2 reduced-function CYP2C19 mutant allele carriers had the reduced effect of clopidogrel. And the reduced effect was significant only after the 30th day of treatment. While among Westerners, both 1 and 2 reduced-function CYP2C19 allele carriers had the reduced effect, and it mainly occurred within the first 30 days. Thirdly, the safety of clopidogrel was almost the same among races. Reduced-function allele non-carriers had higher risk for total bleeding but did not have higher risk for major bleeding. It is suggested that CYP2C19 polymorphism affects the efficacy of clopidogrel differently among Westerners and Asians.

Optimal cutoff value of P2Y12 reaction units to prevent major adverse cardiovascular events in the acute periprocedural period: Post-hoc analysis of the randomized PRASFIT-ACS study

BackgroundFew studies have examined the effects of on-treatment platelet reactivity on the risk of major adverse cardiovascular events (MACE). We aimed to determine the optimal cutoff value of P2Y12 reaction units (PRUs) to prevent MACE occurring within 3days after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). MethodsWe performed post-hoc analyses of 1363 patients enrolled in PRASFIT-ACS, which compared the effects of a prasugrel regimen adjusted for Japanese patients (loading dose/maintenance dose: 20mg/3.75mg) with those of clopidogrel (300mg/75mg) on MACE and bleeding events for 24–48weeks after PCI in ACS patients. PRU was serially measured using the VerifyNow® P2Y12 assay and we assessed the relationship between PRU and MACE. ResultsReceiver operating characteristic curve analysis showed that PRU ≤262 at 5–12h after ADP receptor antagonist loading was the optimal cutoff value for preventing MACE at up to 3days after PCI. The incidences of MACE were 5.2% and 10.8% in patients with PRU ≤262 or >262, respectively (odds ratio 0.50, 95% confidence interval 0.25–0.99, p<0.01). Significantly more prasugrel-treated patients had lower on-treatment platelet reactivity (defined as PRU ≤262) compared with clopidogrel-treated patients (79.9% vs. 30.4%, p<0.0001). Similar differences were observed between the prasugrel and clopidogrel groups for patients with normal or reduced-function CYP2C19 alleles. ConclusionsThe optimal PRU cutoff value for preventing MACE was 262 in Japanese ACS patients. Prasugrel rapidly reduced PRU with a large proportion of patients having low on-treatment platelet reactivity.

The Prospect of Genotyping Assay-Point of Care (Individualized Medicine): The Fast Track

Background: The basis of the genotyping assay is derived from the worldwide data which suggested that the pharmacologic effects of Clopidogrel vary based on CYP2C19 genotype. However; it is not apparent if this interprets into adverse clinical outcomes. It is imperative to examine the risk of adverse cardiovascular outcomes in patients treated with Clopidogrel who carry 1 or 2 reduced-function CYP2C19 genetic variants in other population that preliminary data from the western countries suggests is more frequent. Aim: The aim of this short communication is to raise the awareness of the presence of alleles CYP4502C19*2 in some populations receiving Clopidogrel. We need to investigate the existence of CYP2C19 genetic variants in some populations such as African, Asians (Chinese) and Middle East (Arabs). The risk of major adverse cardiovascular outcomes in patients treated with Clopidogrel who carries any form of CYP2C19 genetic variants needs further attention. We need to explore the use of genotyping assay as an evolving approach to individualized medicine. The Proposed Research: Patients are in great need for this sophisticated technology coupled with experience derived by researches that delineate the Clopidogrel-genetic variability of certain populations. It has been well demonstrated that detecting a patient's polymorphism is essential to understanding his or her clinical response. Genetic testing can in assisting with allele determination, and pairing this result to a specification of a patient's level of drug metabolism response (extensive, intermediate, and poor). Testing, independent of prior or concurrent usage of Clopidogrel, reveals whether a patient should be considered for Clopidogrel or alternative (Prasugrel or Ticagrelor).

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.

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 meta-analyses 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, but only three had investigated publication bias and also found evidence for it. One study therefore concluded that there was no evidence for an association, and one other doubted the association because of a high level of heterogeneity. In summary, meta-analyses on the association between CYP2C19 loss-of-function alleles and clinical efficacy of clopidogrel differed widely with regard to assessment and interpretation of heterogeneity and publication bias. The substantial heterogeneity and publication bias implies that personalized antiplatelet management based on genotyping is not supported by the currently available evidence.Genet Med advance online publication 19 June 2014.

Evaluation of the INNOVANCE PFA P2Y assay and its association with CYP2C19 genotypes

The purpose of this study was to evaluate associations between INNOVANCE PFA P2Y (PFA P2Y) test results and CYP2C19 genotypes and provide baseline data for PFA P2Y testing to establish a therapeutic monitoring strategy for clopidogrel. A total of 75 new patients with acute coronary syndrome with planned percutaneous coronary intervention were enrolled between June 2012 and September 2012. All patients received clopidogrel at an initial loading dose of 600 mg followed by a 75-mg daily maintenance dose. Blood samples were obtained on the third morning after clopidogrel loading. PFA P2Y, VerifyNow P2Y12 and VASP assays were used to determine platelet inhibition due to clopidogrel, and the Verigene CYP2C19 test was used for CYP2C19 genotyping. The genotype frequency of 75 patients was as follows: CYP2C19 *1/*1 (wild type), 28 (37.3%); *1/*2, 31 (41.3%); *1/*3, 4 (5.3%); *2/*2, 5 (6.7%); *2/*3, 5 (6.7%); *1/*17, 1 (1.3%); and *2/*17, 1 (1.3%). Classified according to CYP2C19 genotypes, there were 29 (38.7%) extensive metabolizers (EM) or ultra rapid metabolizers (UM), 35 (46.7%) intermediate metabolizers (IM), and 10 (13.3%) poor metabolizers (PM). Median (interquartile range) PFA P2Y closure times (seconds) were 119 (101–260), 300 (130–300) and 300 (300–300) in the PM, IM and EM or UM groups, respectively (p < 0.05). Median (interquartile range) VerifyNow PRUs were 294 (213–297), 215 (165–320) and 189 (118–279); and the VASP platelet reactivity index (%) was 52.7 (33.3–91.9), 59.9 (41.4–72.8) and 38.9 (26.8–62.2) in the PM, IM and EM or UM groups, respectively (p > 0.05). Compared with non-carriers, carriers of reduced function CYP2C19 alleles tended to have higher platelet reactivity after clopidogrel treatment. The cut-off for PM versus other groups (IM and EM or UM) was ≤141 seconds (AUC 0.704, sensitivity 70%, specificity 76.6%) on the ROC curve. A statistically significant correlation between PFA P2Y (seconds) and VerifyNow (PRU) was found (ρ = −0.47, p < 0.0001). In conclusion, the PFA P2Y test showed a statistically significant association with CYP2C19 metabolizer phenotypes based on CYP2C19 genotyping and effectively determined the risk groups resistant to clopidogrel therapy, including PM.

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

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). 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 (hs-TnT) before, immediately after and one, two and 28 days after PCI. 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. 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.

Influence of Genetic Polymorphisms on the Effect of High- and Standard-Dose Clopidogrel After Percutaneous Coronary Intervention: The GIFT (Genotype Information and Functional Testing) Study

This study sought to evaluate the influence of single nucleotide polymorphisms (SNPs) on the pharmacodynamic effect of high- or standard-dose clopidogrel after percutaneous coronary intervention (PCI). There is a lack of prospective, multicenter data regarding the effect of different genetic variants on clopidogrel pharmacodynamics over time in patients undergoing PCI. The GRAVITAS (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety) trial screened patients with platelet function testing after PCI and randomly assigned those with high on-treatment reactivity (OTR) to either high- or standard-dose clopidogrel; a cohort of patients without high OTR were also followed. DNA samples obtained from 1,028 patients were genotyped for 41 SNPs in 17 genes related to platelet reactivity. After adjusting for clinical characteristics, the associations between the SNPs and OTR using linear regression were evaluated. CYP2C19*2 was significantly associated with OTR at 12 to 24 h (R(2) = 0.07, p = 2.2 × 10(-15)), 30 days (R(2) = 0.10, p = 1.3 × 10(-7)), and 6 months after PCI (R(2) = 0.07, p = 1.9 × 10(-11)), whereas PON1, ABCB1 3435 C→T, and other candidate SNPs were not. Carriers of 1 and 2 reduced-function CYP2C19 alleles were significantly more likely to display persistently high OTR at 30 days and 6 months, irrespective of treatment assignment. The portion of the risk of persistently high OTR at 30 days attributable to reduced-function CYP2C19 allele carriage was 5.2% in the patients randomly assigned to high-dose clopidogrel. CYP2C19, but not PON1 or ABCB1, is a significant determinant of the pharmacodynamic effects of clopidogrel, both early and late after PCI. In patients with high OTR identified by platelet function testing, the CYP2C19 genotype provides limited incremental information regarding the risk of persistently high reactivity with clopidogrel 150-mg maintenance dosing. (Genotype Information and Functional Testing Study [GIFT]; NCT00992420).

Antiplatelet Therapy and Proton Pump Inhibition

A 77-year-old man with history of diabetes mellitus and coronary artery disease presented with angina and evidence of ischemia despite maximal medical therapy. He underwent a percutaneous coronary intervention with a drug-eluting stent and was started on long-term dual antiplatelet therapy with aspirin and clopidogrel. His medical history was significant for an episode of gastrointestinal (GI) bleeding in the setting of using nonsteroidal antiinflammatory drugs. Dual antiplatelet therapy, typically the addition of an ADP receptor antagonist to aspirin, has become the cornerstone of management of patients with acute coronary syndromes and after percutaneous coronary intervention. However, along with the reduction of thrombotic outcomes, this therapeutic strategy has the untoward effect of increasing the risk of bleeding events, including GI bleeding.1 The use of gastroprotective strategies, most notably proton pump inhibitors (PPIs), has become a widely adopted and recommended practice in this patient population.2 Currently, the most commonly prescribed ADP receptor antagonist is clopidogrel, a prodrug that undergoes activation by the cytochrome P450 system, in particular CYP2C19. The importance of this reaction on the overall platelet inhibitory effects of clopidogrel is highlighted by the fact that patients with reduced-function CYP2C19 alleles exhibit a reduced response to clopidogrel compared with those with the wild-type alleles. This finding might translate into increased risk of adverse events after acute coronary syndromes and percutaneous coronary intervention. Given that PPIs are inhibitors of CYP2C19, coupled with reports suggesting a clinically significant interaction,3 regulatory agencies issued a cautionary statement advising against the combined use of PPIs (specifically omeprazole and esomeprazole) and clopidogrel.4 Aspirin causes direct damage to the gastric epithelium and inhibits prostaglandin production by the gastric mucosa, leading to ulcerations and an estimated 2-fold increased risk of GI bleeding with low-dose aspirin alone.1 The risk increases with the additional use of …

Review: Reduced function CYP2C19 genotypes may increase risk for stent clots in patients receiving clopidogrel

Source Citation Bauer T, Bouman HJ, van Werkum JW, et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. B...

Determination of cut-off levels for on-clopidogrel platelet aggregation based on functional CYP2C19 gene variants in patients undergoing elective percutaneous coronary intervention

Introduction Carriers of reduced-function CYP2C19 allele on antiplatelet therapy show diminished platelet inhibition and higher rate of clinical risk. The purpose of this study was to determine cut-off levels of VerifyNow P2Y12 system associated with effective inhibition of on-clopidogrel platelet aggregation to predict carriers of CYP2C19 reduced-function allele among patients undergoing percutaneous coronary intervention (PCI). Materials and Methods We enrolled 202 consecutive patients with stable coronary artery disease (CAD) undergoing PCI and treated with clopidogrel. All patients underwent CYP2C19 genotyping and measurement of residual platelet aggregation by VerifyNow system. Results Carriers of CYP2C19 reduced-function allele constituted 131 (65%) of 202 CAD patients. Platelet inhibition measured by P2Y12 reaction units (PRU) and %inhibition was diminished in carriers compared with noncarriers (PRU: 290.0 ± 81.2 vs 217.6 ± 82.4, p < 0.001, %inhibition: 17.9 ± 17.8 vs 35.5 ± 22.8, p < 0.001, respectively). Multiple logistic regression analysis identified PRU and %inhibition as significant predictors of carrier state [odds ratio (OR) 4.95; 95% confidence interval (95%CI): 2.49 to 9.85; p < 0.001, OR 5.55; 95%CI: 2.80 to 10.99; p < 0.001, respectively]. Receiver-operating characteristic analysis showed that PRU and %inhibition were significant predictors of carrier state [area under the curve (AUC) 0.736 (95%CI: 0.664 to 0.808; p < 0.001), AUC 0.727 (95%CI: 0.651 to 0.803; p < 0.001), respectively]. The cut-off levels of PRU and %inhibition were 256 and 26.5% for the identification of carriers. Conclusions Our results suggested that the cut-off levels of PRU and %inhibition to discriminate carriers of CYP2C19 reduced-function allele from noncarriers are potentially useful clinically to provide optimal clopidogrel therapy in patients with stable CAD undergoing PCI.

Beyond CYP2C19 – A New Chapter in Clopidogrel Pharmacogenomics

Journal of Pharmacy Practice and ResearchVolume 41, Issue 1 p. 14-16 EditorialFree Access Beyond CYP2C19 – A New Chapter in Clopidogrel Pharmacogenomics Dr Thomas M Polasek BSc, BPharm (Hons), PhD, MSHP, Dr Thomas M Polasek BSc, BPharm (Hons), PhD, MSHP Lecturer in Clinical Pharmacology [email protected] Department of Clinical Pharmacology, Flinders University and Flinders Medical Centre, Adelaide, SA, 5042Search for more papers by this author Dr Thomas M Polasek BSc, BPharm (Hons), PhD, MSHP, Dr Thomas M Polasek BSc, BPharm (Hons), PhD, MSHP Lecturer in Clinical Pharmacology [email protected] Department of Clinical Pharmacology, Flinders University and Flinders Medical Centre, Adelaide, SA, 5042Search for more papers by this author First published: 13 April 2015 https://doi.org/10.1002/j.2055-2335.2011.tb00054.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Winslow R. Plavix rival gains from studies. Wall St 30 August 2010. 2Sofi F, Marcucci R, Gori AM, Giusti B, Abbate R, Gensini GF. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost 2010; 103: 841– 8. 3Hagihara K, Kazui M, Kurihara A, Yoshiike M, Honda K, Okazaki O, et al. A possible mechanism for the differences in efficiency and variability of active metabolite formation from thienopyridine antiplatelet agents, prasugrel and clopidogrel. Drug Metab Dispos 2009; 37: 2145– 52. 4Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 2010; 38: 92– 9. 5Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI. JAMA 2010; 304: 1821– 30. 6Bouman HJ, Schömig E, van Werkum JW, Velder J, Hackeng CM, Hirschhäuser C, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med 2011; 17: 110– 16. Citing Literature Volume41, Issue1March 2011Pages 14-16 ReferencesRelatedInformation

Carriage of Reduced-Function CYP2C19 Allele Among Patients Treated With Clopidogrel

Carriage of Reduced-Function <i>CYP2C19</i> Allele Among Patients Treated With Clopidogrel

Top Advances in Functional Genomics and Translational Biology for 2010

In recent years, major advances have been made in transcriptomics, metabolomics, proteomics, and particularly population genetics. More than 850 genome-wide association studies (GWAS) were published by the end of 2010, now covering a vast number of diseases and phenotypes and often incorporating tens of thousands of subjects or, in some cases, more than 100 000 subjects, increasing statistical power to identify and replicate contributing loci. Sequencing throughput advances and decreasing costs per sample have allowed the application of genome-wide genotyping and sequencing technology to larger DNA samples as well as transcriptome and epigenome features. This year was marked not only by continuing progress with GWAS, sequencing, and copy number variation studies but also by follow-up of GWAS and other findings with functional studies that uncover new molecular pathways contributing to disease and pave the way for future clinical applications. The American Heart Association Functional Genomics and Translational Biology Interdisciplinary Council (http://www.americanheart.org/presenter.jhtml?identifier=3016539) provides a forum for a multidisciplinary group of volunteers committed to making a substantial contribution to reduce the burden of heart disease and stroke through genetics, genomics, proteomics, and metabolomics research and translational science. With input from the Early Career Committee of the Council on Functional Genomics and Translational Biology, we considered many papers and selected 10 outstanding manuscript groups (15 articles) published in 2010 that reflect these advances, and we briefly summarize each below in chronological order.

Association between CYP2C19*2 variant and clinical outcome in Clopidogrel treated patients from Republic of Macedonia

Clopidogrel is the thienopyridine of choice for prevention of ischemic events and stent thrombosis in patients with atherotrombotic disease. Recent studies suggest that certain genetic variants involving CYP450 system are responsible for wide interindividual variability in treatment response profiles among clopidogrel treated individuals. The aim of this study was to define the prevalence of most common CYP2C19*2: 681G&gt;A (rs4244285) allelic variant in Macedonian population and determine the risk association with major cardiovascular adverse events in clopidogrel treated patients with atherotrombotic cardiovascular disease. CYP2C19 *2 genotype was assessed in 198 subjects from R.Macedonia. The association between the reduced function CYP2C19 *2 A allele and clinical outcome was evaluated in 67 clopidogrel treated patients within a follow up period of at least 6 months (from 6 to 60 months) after initializing clopidogrel therapy. The population frequency of polymorphic A allele responsible for impaired clopidogrel metabolism in Macedonian population was 0.18. CYP2C19*2 variant was significantly associated with increased rate of adverse cardiovascular events in the allelic (OR= 3.188; 95% CI= 1.437-7.058), dominant (OR=3.477; 95% CI= 1.256-9.630) and co-dominant model ( OR=6.750, 95% CI: 1.186-38.410) of statistical analysis (adjusted OR= 2.619; Ptrend=0.0088). The influence of CYP2C19*2 was most strongly correlated with worse event free survival in patients carrying AA genotype (log rank P = 0.0024) and patients carrying at least one CYP2C19*2 reduced function allele (log rank P=0.0058). CYP2C19*2 genetic variant in the population from Republic of Macedonia has similar distribution as determined in other European populations. Carriage of reduced function CYP2C19 *2 allele is associated with worse event free survival in clopidogrel treated patients with atherotrombotic disorders.