Clopidogrel Bioactivation Research Articles

Abstract WP150: Correlation Between CYP2C19 Genotype and Platelet Reactivity Units in Patients Receiving Clopidogrel After Acute Ischemic Stroke

Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard of care for secondary prevention in non-cardioembolic minor acute ischemic stroke (AIS) and high-risk transient ischemic attack (TIA). However, clopidogrel is a prodrug metabolized to its active form by the CYP2C19 enzyme and therefore has decreased efficacy in patients with at least one loss-of-function (LOF) allele in the CYP2C19 gene that encodes the enzyme. The use of ticagrelor over clopidogrel for DAPT improves outcomes in CYP2C19 LOF carriers; however, CYP2C19 genotyping is not currently standard practice in the cerebrovascular population. P2Y12 assays that measure P2Y12 receptor-mediated platelet aggregation in platelet reactivity units (PRUs) are more widely accessible, but it is unclear if this assay correlates with CYP2C19 genotype in this population. Therefore, we aimed to investigate the correlation between CYP2C19 genotype and PRUs to evaluate PRUs as a potential surrogate biomarker for identifying suboptimal clopidogrel response. We hypothesized that PRUs would be increased in CYP2C19 LOF carriers compared to non-carriers due to the reduced bioactivation of clopidogrel in patients with decreased CYP2C19 enzymatic function. This prospective, observational study enrolled patients > 18 years of age presenting with minor AIS or high-risk TIA and discharged from University of Virginia Health on DAPT for secondary stroke prevention. A whole blood sample for P2Y12 assay and CYP2C19 genotyping was obtained at least 12 hours after a 300 milligram clopidogrel loading dose. The primary outcome was the correlation between PRUs and CYP2C19 LOF allele carrier status. Of 35 patients genotyped, 27 (77%) subjects self-reported European ancestry, 7 (20%) African ancestry, and 1 (3%) Asian ancestry. Six participants (17%) were found to be LOF carriers. LOF carriers had significantly increased PRUs compared to non-carriers (mean difference +103.7; 95% CI +30.71 to +176.1; p<0.01), indicating diminished pharmacodynamic response to clopidogrel. This suggests that measurement of PRUs via an accessible and established P2Y12 assay may be a viable surrogate biomarker for identifying suboptimal clopidogrel response in the cerebrovascular population.

Effects of treatment with clopidogrel with or without proton pump inhibitor omeprazole on the risk of ischemic stroke: a nationwide cohort study

Most proton pump inhibitors (PPIs) inhibit the bioactivation of clopidogrel to its active metabolite. There is controversy concerning whether PPIs alter the effectiveness of clopidogrel in reducing the risk of ischemic stroke (IS). We therefore aimed to examine the risk of IS associated with concomitant use of clopidogrel and omeprazole, a PPI commonly used in clinical settings. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohorts comprised 407 patients diagnosed with acute coronary syndrome (ACS) and with concomitant use of clopidogrel and omeprazole (the exposed cohort), 814 ACS patients with single use of clopidogrel (the comparison cohort), and 230 ACS patients with concurrent use of clopidogrel and pantoprazole (the reference cohort). The primary outcome was incident IS. The hazard ratios (HRs) and 95% confidence intervals (CIs) derived from the time-dependent Cox regression model were used to assess the association between concomitant use of clopidogrel and omeprazole and the risk of IS. The incidence rate of IS was significantly higher in the exposed cohort (81.67 per 1000 person-years) than in the comparison cohort (57.45 per 1000 person-years), resulting in an adjusted HR of 1.39 (95% CI 1.03–1.74). By contrast, there was no significant difference in the risk of IS between the exposed and reference cohorts (adjusted HR 1.11; 95% CI 0.81–1.52). The present study revealed that patients taking both clopidogrel and omeprazole was associated with an increased risk of IS.

The diversity and clinical implications of genetic variants influencing clopidogrel bioactivation and response in the Emirati population

BackgroundClopidogrel is a widely prescribed prodrug that requires activation via specific pharmacogenes to exert its anti-platelet function. Genetic variations in the genes encoding its transporter, metabolizing enzymes, and target receptor lead to variability in its activation and platelet inhibition and, consequently, its efficacy. This variability increases the risk of secondary cardiovascular events, and therefore, some variations have been utilized as genetic biomarkers when prescribing clopidogrel.MethodsOur study examined clopidogrel-related genes (CYP2C19, ABCB1, PON1, and P2Y12R) in a cohort of 298 healthy Emiratis individuals. The study used whole exome sequencing (WES) data to comprehensively analyze pertinent variations of these genes, including their minor allele frequencies, haplotype distribution, and their resulting phenotypes.ResultsOur data shows that approximately 37% (n = 119) of the cohort are likely to benefit from the use of alternative anti-platelet drugs due to their classification as intermediate or poor CYP2C19 metabolizers. Additionally, more than 50% of the studied cohort exhibited variants in ABCB1, PON1, and P2YR12 genes, potentially influencing clopidogrel’s transport, enzymatic clearance, and receptor performance.ConclusionsRecognizing these alleles and genotype frequencies may explain the clinical differences in medication response across different ethnicities and predict adverse events. Our findings underscore the need to consider genetic variations in prescribing clopidogrel, with potential implications for implementing personalized anti-platelet therapy among Emiratis based on their genetic profiles.

Post-percutaneous coronary intervention CYP2C19 genotyping in an Irish population: The potential role in identifying clopidogrel therapy-related bleeding risks.

Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) remains the standard of care. CYP2C19 genetic polymorphisms cause variable clopidogrel bioactivation. Increased function (CYP2C19*17) allele carriers (rapid metabolizers [RM] or ultrarapid metabolizers [UM]) are clopidogrel hyper-responders, hence are more susceptible to clopidogrel-related bleeding. Since current guidelines recommend against routine genotyping following PCI, data on the clinical utility of CYP2C19*17 genotype guided strategy are sparce. Our study provides real-world data on the 12-month follow-up of CYP2C19 genotyping in patients post-PCI. This is a cohort study within an Irish population receiving 12-month DAPT following PCI. It identifies the prevalence of CYP2C19 polymorphisms within an Irish population and describes the ischaemic and bleeding outcomes after 12 months of DAPT. A total of 129 patients were included with the following CYP2C19 polymorphism prevalence: 30.2% hyper-responders (26.4% RM [1*/17*], 3.9% UM [17*/17*]) and 28.7% poor-responders (22.5% IM [1*/2*], 3.9% IM [2*/17*], 2.3% PM [2*/2*]). A total of 53 and 76 patients received clopidogrel and ticagrelor, respectively. At 12 months, total bleeding incidence within the clopidogrel group was positively correlated with CYP2C19 activity: IM/PM (0.0%), NM (15.0%) and RM/UM (25.0%). The positive relationship showed a moderate association that was statistically significant: rτ = 0.28, P = 0.035. The prevalence of CYP2C19 polymorphisms in Ireland is 58.9% (30.2% CYP2C19*17, 28.7% CYP2C19*2) with an approximately one in three chance of being a clopidogrel hyper-responder. Positive correlation between bleeding and increasing CYP2C19 activity within the clopidogrel group (n = 53) suggests possible clinical utility of a genotype-guided strategy identifying high bleeding risk with clopidogrel in CYP2C19*17 carriers, but further studies are required.

Navigating Antiplatelet Treatment Options for Stroke: Evidence-Based and Pragmatic Strategies.

The benefit of using antiplatelet monotherapy in acute ischemic stroke and secondary stroke prevention is well established. In the last few years, several large randomized trials showed that the use of short-term dual antiplatelet therapy in particular stroke subtypes may reduce the risk of recurrent ischemic events. The aim of this article is to provide a critical analysis of the current evidence and recommendations for the use of antiplatelet agents for stroke prevention. Long-term therapy with aspirin, clopidogrel, or aspirin plus extended-release dipyridamole is recommended for secondary stroke prevention in patients with noncardioembolic ischemic stroke. Short-term dual antiplatelet therapy with aspirin and clopidogrel is superior to antiplatelet monotherapy in secondary stroke prevention when used in patients with mild noncardioembolic stroke or high-risk transient ischemic attack. Dual therapy, however, is associated with an increased risk of major bleeding, particularly when the treatment is extended for greater than 30days. Similarly, aspirin plus ticagrelor is superior to aspirin monotherapy for the prevention of recurrent ischemic stroke, although this combination is associated with a higher risk of hemorrhagic complications when compared to other dual antiplatelet regimens. Among patients who carry CYP2C19 genetic polymorphisms associated with a slow bioactivation of clopidogrel, short-term treatment with aspirin plus ticagrelor is superior to aspirin plus clopidogrel for the reduction of recurrent stroke; however, the use of ticagrelor is associated with a higher risk of any bleeding. In patients with symptomatic intracranial stenosis, aggressive medical management in addition to dual antiplatelet therapy up to 90days is recommended. Antiplatelet therapy has an essential role in the management of ischemic stroke. The specific antiplatelet regimen should be individualized based on the stroke characteristics, time from symptom onset, and patient-specific predisposition to develop hemorrhagic complications.

CYP2C19 loss-of-function alleles and the use of omeprazole or esomeprazole increase the risk of cardiovascular outcomes in patients using clopidogrel – a real-world study

Abstract Background Patients carrying loss-of-function (LOF) variants of CYP2C19 or using the CYP2C19-inhibitors omeprazole or esomeprazole cannot fully bioactivate clopidogrel, and thus are lacking optimal thrombosis prevention. However, clopidogrel is a relevant alternative to ticagrelor due to its lower incidence of hemorrhagic events and lower cost. Purpose The purpose of this study was to investigate in a real-life prospective patient cohort how loss-of-function (LOF) CYP2C19 variants and omeprazole or esomeprazole influence the incidence of cardiovascular events (cardiovascular deaths, reinfarction and strokes) in patients using clopidogrel. Methods A cohort of prospective patients (N=1972) with acute coronary syndrome (ACS) (N=1302) or symptomatic chronic coronary disease (N=670) were followed for 365 days. Information of purchased prescription drugs, hospital discharge, and death registry was available for all patients. The patients were retrospectively genotyped for the CYP2C19*2, CYP2C19*3, and CYP2C19*8 LOF variants. Results A total of 608 (30.8%) patients carried CYP2C19 LOF alleles. During the 365 days follow-up, 252 patients had a recurring ischemic vascular event, either myocardial infarction (N=189), stroke (N=24) or cardiovascular death (N=39). Vascular events were significantly more frequent among carriers of CYP2C19 LOF alleles [14.8% (95% CI 11.7–17.8] than in non-carriers [10.8% (95% CI 9.0–12.6)], p=0.016. Omeprazole or esomeprazole use was similar among the LOF allele carriers and non-carriers, but inclusion of their use in the analysis strengthened the association. Vascular events were significantly more common in a composite group of carriers of CYP2C19 LOF alleles and non-carriers who were using omeprazole or esomeprazole than in non-carriers who were not using omeprazole or esomeprazole 14.8% (95% CI 12.2–17.3) vs 9.9% (95% CI 8.0–11.9) p=0.002. There was a tendency towards lower risk of hemorrhagic complications in carriers of LOF alleles than in non-carriers (p=0.07). Conclusions Patients with impaired clopidogrel bioactivation due to loss-of-function CYP2C19 variants or concomitant omeprazole or esomeprazole use are at increased risk of cardiovascular events. For relevant patient care both genetics and concomitant medication should be considered both in everyday patient care and further randomised studies. Funding Acknowledgement Type of funding sources: None.

Semi-mechanistic population pharmacokinetics analysis reveals distinct CYP2C19 dependency in the bioactivation of vicagrel and clopidogrel to active metabolite M15–2

AimsVicagrel is a novel antiplatelet drug used to mitigate clopidogrel resistance due to CYP2C19 polymorphism. This study aimed to develop a semi-mechanistic population pharmacokinetic (PopPK) model to characterize the pharmacokinetic (PK) profile of M15-2, the active metabolite of vicagrel and clopidogrel, and to evaluate the influence of CYP2C19 polymorphisms and other covariates in healthy subjects and patients with acute coronary syndrome (ACS) after oral administration. MethodsThe analysis utilized data from 213 subjects, including 178 healthy subjects and 35 patients, from five clinical trials. PopPK modeling and simulation were used to estimate PopPK parameters and evaluate the impact of covariates. ResultsThe M15-2 PK profiles were well characterized by a model incorporating transit compartments, two-compartment parent models and two-compartment M15-2 models for both vicagrel and clopidogrel. The parameter estimates indicated the dose fraction of vicagrel that formed M15-2 was approximately 20-fold that of clopidogrel. Covariate analysis identified a significant effect of CYP2C19 on M15-2 apparent clearance (CL/F) and apparent volume of distribution (V3/F) for clopidogrel but only CL/F for vicagrel. The analysis suggested that the nonlinear PK of M15-2 for clopidogrel was due the first-step bioactivation of clopidogrel to 2-oxoclopidogrel. ConclusionThe model illustrated the bioactivation of vicagrel is more efficient and less dependent on CYP2C19 than that of clopidogrel. M15-2 is formed in a linear process from vicagrel, versus a nonlinear and less predictable process from clopidogrel. Advantages in both PK and pharmacogenetics suggest that vicagrel may reduce the complexity of currently recommended CYP2C19-based dosage adjustment for clopidogrel.

Reinvestigation of clopidogrel bioactivation unveils new cytochrome P450-catalyzed thioester cleavage mechanism

The serendipitous prodrug clopidogrel (CPG, M0) is the mainstay antiplatelet drug in clinical use. The thiophene moiety of CPG undergoes ring opening to form the active metabolite (M13) through two steps of cytochrome P450 (CYP)-catalyzed oxidation. The stable intermediate resulting from the first oxidation, 2-oxo-CPG (M2), is proposed to be oxidized to form an S-oxide intermediate (M11), which proceeds with a hydrolytic pathway to yield a sulfenic acid (M12) and subsequently the bioreduced active metabolite (M13). To test the long-standing pathway of M2 to M13 via M11, we have chemically synthesized M11 but found it does not undergo the proposed hydrolytic activation in various conditions including in liver microsomal incubations. To seek an alternative mechanism, 18O tracing studies were performed with both H218O and 18O2, and LC-MS studies show that the carboxylate product moiety acquires its O-atom from oxygen instead of water, which rules out M11 as the bioactivation intermediate. To explain the 18O tracing results, a one-step Baeyer-Villiger-like mechanism is proposed for the CYP-dependent thioester cleavage, which features the incorporation of the two O-atoms of O2 into the two product moieties of carboxylate and sulfenic acid. The research presented herein provides a biochemical basis for delineating the clinical pharmacology of a mainstay treatment and expands our understanding of CYP catalysis.

Incidence of Device-Related Thrombosisin WatchmanPatients Undergoing a Genotype-Guided Antithrombotic Strategy.

This study sought to report the incidence of device-related thrombosis (DRT) and thromboembolic (TE) events when an alternative to clopidogrel is prescribed in loss-of-function (LOF) allele carriers of the cytochrome P450 2C19 (CYP2C19) gene. LOF polymorphisms of the CYP2C19 gene are associated with reduced hepatic bioactivation of clopidogrel. A total of 1,002 Watchman patients were included. Six hundred forty-five patients underwent CYP2C19 genetic testing; among patients with clopidogrel resistance, clopidogrel was replaced by either prasugrel (pilot cohort) or half dose direct oral anticoagulant ([DOAC]/Group 1), both in combination with aspirin. We compared the incidence of DRT/TE events among genotyped patients and a control group which received standard dual antiplatelet therapy (DAPT) (Group 2; n=357). All reported events occurred during a timeframe between 45- and 180-day follow-up transesophageal echocardiograms, when the 2 different antithrombotic strategies (genotype-guided vs standard DAPT) were adopted. In the pilot cohort (n=244), bleeding events occurred in 10.2% of patients who received aspirin plus prasugrel, leading to early discontinuation of the prasugrel-based protocol. DOAC Group 1 patients (n=401), 25.7% were reduced metabolizers, and clopidogrel was replaced by half dose direct oral anticoagulant. DRT was documented in 1 (0.2%) patient of Group 1 and 7 (1.96%) patients of Group 2 (log-rank P =0.021). The composite endpoint of DRT/TE events was significantly loweramong patients receiving a genotype-guided antithrombotic strategy (0.75% vs 3.10%; log-rank P =0.017). In Watchman patients, a genotype-based antithrombotic strategy with aspirin plus half dose DOAC in reduced clopidogrel metabolizers was superior to standard DAPT with respect to DRT/TE events.

B-PO02-157 INCIDENCE OF DEVICE-RELATED THROMBOSIS IN WATCHMAN PATIENTS UNDERGOING A GENOTYPE-GUIDED ANTITHROMBOTIC STRATEGY

Loss of Function (LOF) polymorphisms of cytochrome P450 2C19 (CYP2C19) are associated with reduced hepatic bioactivation of clopidogrel. To report the incidence of device-related thrombosis (DRT) and thromboembolic (TE) events when an alternative to clopidogrel is prescribed in patients with a LOF allele of CYP2C19 gene. Among 1002 Watchman patients, 645 underwent CYP2C19 genetic testing; among patients with clopidogrel resistance, clopidogrel was replaced by either prasugrel (pilot cohort) or half dose novel oral anticoagulant (NOAC; Group 1) both in combination with aspirin. We compared the incidence of DRT/TE events among genotyped patients and a control group which received standard dual antiplatelet therapy (DAPT; Group 2; n=357). All reported events occurred during a timeframe between 45- and 180-day follow-up TEEs, when the genotype-guided or standard DAPT strategies were adopted. In the pilot cohort (n=244), bleeding events occurred in 10.2% of patients receiving prasugrel, leading to discontinuation of the prasugrel-based protocol. Among Group 1 patients (n=401), 25.7% were reduced metabolizers and clopidogrel was replaced with half dose NOAC. DRT was documented in 1 (0.2%) patient of Group 1 and 7 (1.96%) of Group 2 (log-rank p-value=0.021). The composite endpoint of DRT/TE events was significantly lower among patients receiving a genotype-guided strategy (0.75% vs. 3.1%; log-rank p-value=0.017). In Watchman patients, a genotype-based antithrombotic strategy with aspirin plus half dose NOAC in reduced clopidogrel metabolizers was superior to standard DAPT with respect to DRT/TE events.

CYP2C19*2 genetic polymorphism and incidence of in-stent restenosis in patients on clopidogrel: a matched case-control study.

The cytochrome P450 2C19*2 (CYP2C19*2) genetic polymorphism is associated with reduced clopidogrel bioactivation, increasing the risk of atherothrombotic complications after percutaneous coronary intervention (PCI). In-stent restenosis (ISR) is a complication that limits the long-term prognosis of PCI. The aim was to investigate the association between presence of the CYP2C19*2 allele and ISR within one-year after PCI in patients prescribed dual antiplatelet therapy with aspirin and clopidogrel. Sixty patients with angiographically-confirmed drug eluting stent (DES)-ISR within 12months post-PCI when on DAPT with aspirin and clopidogrel were retrospectively identified (Cases). Another 60 patients with no documented ISR post-PCI in the study period (Controls) were case-matched for age, gender, ethnicity, diabetes mellitus and estimated glomerular filtration rate value, and were invited for CYP2C19*2 genotyping. The association between presence of the CYP2C19*2 allele and ISR was analysed using the Fisher's exact test and binary logistic regression. Twenty-six (43.3%) cases and 5 (8.3%) controls were carriers of one or two CYP2C19*2 alleles. As to non-carrier status of the CYP2C19*2 allele, 34 (56.7%) cases and 55 (91.7%) controls were identified. The association between CYP2C19*2 carrier status and DES-ISR within one-year post-PCI was statistically significant (p<0.001) in both the univariate and multivariate analysis. The proportion of patients who were carriers of one or two CYP2C19*2 alleles who presented with DES-ISR within one-year post-PCI while on clopidogrel was significantly higher compared to patients with no documented ISR.

Abstract 17102: Lower Rate of Device-Related Thrombosis in Watchman Patients Undergoing a Genotype-Tailored Antithrombotic Strategy

Introduction: Loss-of-function (LOF) polymorphisms of the cytochrome P450 2C19 (CYP2C19) gene are associated with reduced hepatic bioactivation of clopidogrel. Hypothesis: To evaluate the prevalence of LOF polymorphisms of CYP2C19 and the incidence of device-related thrombosis (DRT) when clopidogrel is replaced with half dose novel oral anticoagulant (NOAC) in patients with reduced clopidogrel metabolism. Methods: Consecutive Watchman patients were genotyped for CYP2C19 polymorphisms. Patients with reduced clopidogrel metabolism received half dose NOAC plus aspirin during the “dual antiplatelet therapy (DAPT) phase” post-Watchman implantation (between 45 days and 6 months). The incidence of DRT among genotyped patients (Group I, n=401) and a control group without genotypization (Group II, n=357) which received standard DAPT is reported. Results: Overall, 758 Watchman patients were included (mean age: 75±8 yrs, 63% males, CHA 2 DS 2 -VASc: 4.6±1.5; HAS-BLED: 3.2±1.1). Of the 401 Group 1 patients, 25.69% (n=103) were reduced clopidogrel metabolizers. In 87.4% of them, clopidogrel was replaced with half-dose NOAC during the “DAPT phase” post-Watchman implantation whereas 12.6% received ASA plus full-dose NOAC due to the presence of a significant peri-device leak. During the “DAPT phase”, DRT was documented in 1 (0.2%) patient of Group I and 7 (1.96%) patients of Group II (p=0.029). On multivariate analysis, a genotype-tailored antithrombotic strategy was associated with a significant reduction in DRT (odds ratio: 0.11; 95% confidence interval: 0.01 - 0.98; p-value: 0.048). Conclusions: Approximately 25% of our Watchman patients had clopidogrel resistance. Substitution of clopidogrel with half dose NOAC in reduced clopidogrel metabolizers significantly reduced the incidence of DRT.

Jsou inhibitory protonové pumpy účinným a bezpečným lékem nejen v profylaxi gastrointestinálního krvácení při antitrombotické léčbě?

Proton pump inhibitors (PPIs) are popular and widely used &#8220;gastroprotectives&#8221;. More than 10% of our population is treated. In addition to classical indications such as gastroduodenal peptic disease or gastroesophageal reflux disease, they are indicated for the reduction of hemorrhagic complications in the digestive tract during antithrombotic treatment. The effect of PPIs on reducing upper gastrointestinal bleeding in antithrombotic treatment (rivaroxaban, acetylsalicylic acid or a combination) was called into question by a recently published randomised mega-study - COMPASS pantoprazole. Treatment of PPIs is accompanied by a number of significant drug interactions, in particular a severe reduction in the bioactivation of clopidogrel and a reduction in the absorption of acetylsalicylic acid or dabigatran. As a result, the effect of these antithrombotics is reduced. A number of observational studies - in the indication of PPIs in the treatment of gastroduodenal or gastrooesophageal disease or when used in the treatment of PPIs in antithrombotic treatment - found a greater incidence of major vascular events and an increase in mortality. So are PPIs effective in protecting gastrointestinal bleeding and are they safe?

Enhanced responsiveness of platelets to vicagrel in IL‐10‐deficient mice through STAT3‐dependent up‐regulation of the hydrolase arylacetamide deacetylase in the intestine

Vicagrel is a novel promising antiplatelet drug designed for overcoming clopidogrel resistance. There is limited evidence indicating that exogenous IL-10 suppresses CYP3A4 activity in healthy subjects and that IL-10 knockout (KO) mice exhibit increased clopidogrel bioactivation compared with wild-type (WT) mice. In this study, we sought to determine whether IL-10 could play an important role in the metabolism of and platelet response to vicagrel in mice. IL-10 KO and WT mice were administered vicagrel, then their plasma H4 (active metabolite of vicagrel) concentrations were determined by LC-MS/MS, and inhibition of ADP-induced whole-blood platelet aggregation by vicagrel was assessed with an aggregometer. The mRNA and protein levels of several relevant genes between IL-10 KO and WT mice were measured by qRT-PCR and Western blots, respectively. Intestinal Aadac protein levels were measured in IL-10 WT mice injected i.p. with vehicle control, Stattic, or BAY 11-7082. Compared with WT mice, IL-10 KO mice exhibited significantly increased plasma levels of H4 and enhanced platelet responses to vicagrel, as well as significantly higher mRNA and protein levels of arylacetamide deacetylase (Aadac) in the intestine. In WT mice, STAT3, not NF-κB, mediated Aadac expression in the intestine. IL-10 suppresses metabolic activation of vicagrel through down-regulation of Aadac in mouse intestine in a STAT3-dependent manner and, consequently, attenuates platelet responses to vicagrel, suggesting that the antiplatelet effect of vicagrel may be modulated by changes in plasma IL-10 levels in relevant clinical settings.

Influence of Amlodipine on Haemostatic Measurements during Clopidogrel Treatment in Patients with Coronary Artery Disease.

Amlodipine has a potential to reduce clopidogrel bioactivation through the cytochrome P450 3A4 enzyme in vivo, but the clinical impact of this interaction remains controversial. This randomized, open-label, two-period, crossover study was performed to evaluate the influence of amlodipine on the haemostatic profiles of high-risk patients during clopidogrel treatment. We recruited 40 Asian patients (Male/Female: n = 36/4) receiving clopidogrel (75 mg/day), aspirin (100 mg/day) and rosuvastatin for at least 6 months following percutaneous coronary intervention. Patients were randomly assigned to receive either 5 mg daily amlodipine or not for 2 weeks, and then were crossed over to the other treatment for 2 weeks. Haemostatic measurements were conducted with the VerifyNow assay and thromboelastography (TEG). Primary endpoint was P2Y12 Reaction Units (PRU) during on- versus off-amlodipine treatment. The on-amlodipine strategy showed higher level of PRU compared with the off-amlodipine strategy (176.8 ± 75.4 vs. 150.7 ± 65.5 PRU; ∆mean: 26.1 PRU; ∆95% confidence interval [CI]: 4.5-47.7 PRU; p = 0.019). Platelet-fibrin clot strength measured by TEG was lower during on- versus off-amlodipine treatment (7,712 ± 1,889 vs. 8,559 ± 2,174 dyne/cm2; ∆mean: -847 dyne/cm2; ∆95% CI: -1,632 to -62 dyne/cm2; p = 0.035). After amlodipine discontinuation, 27 patients (67.5%) showed a decrease in PRU, which was associated with 'PRU ≥ 160 on-amlodipine' in multivariate analysis (odds ratio: 62.014; 95% CI: 2.302-1670.328; p = 0.014). In conclusion, amlodipine increases platelet reactivity and decreases platelet-fibrin clot strength during clopidogrel treatment. In addition, the effect of amlodipine discontinuation on clopidogrel responsiveness is associated with on-amlodipine platelet reactivity.

CYP3A4*22 Impairs the Elimination of Ticagrelor, But Has No Significant Effect on the Bioactivation of Clopidogrel or Prasugrel.

CYP3A enzymes participate in the elimination of ticagrelor and the bioactivation of clopidogrel and prasugrel. We studied the effects of functional CYP3A genetic variants (CYP3A4*22; rs35599367 and CYP3A5*3; rs776746) on the pharmacokinetics and pharmacodynamics of ticagrelor, clopidogrel, and prasugrel. Six healthy volunteers with the CYP3A4*1/*22 and CYP3A5*3/*3 genotype (CYP3A4*22 carriers), eight with the CYP3A4*1/*1 and CYP3A5*1/*3 genotype (CYP3A5 expressors), and 11-13 with the CYP3A4*1/*1 and CYP3A5*3/*3 genotypes (controls) ingested single doses of ticagrelor, clopidogrel, and prasugrel on separate occasions. Ticagrelor area under the plasma concentration-time curve (AUC) was 89% (P=0.004) higher in CYP3A4*22 carriers than in controls. CYP3A4*22 carriers also showed more pronounced platelet inhibition at 24hours after ticagrelor ingestion than the controls (43% vs. 21%; P=0.029). The CYP3A5 genotype did not affect ticagrelor pharmacokinetics. Neither CYP3A5 nor CYP3A4 genotypes significantly affected prasugrel or clopidogrel. In conclusion, the CYP3A4*22 allele markedly impairs ticagrelor elimination enhancing its antiplatelet effect.

Clinical outcomes of CYP2C19 genotype-guided antiplatelet therapy: existing evidence and future directions.

It is well established that theCYP2C19nonfunctional *2 and *3 polymorphisms impair the bioactivation and antiplatelet effects of clopidogrel, and increase the risk of adverse cardiovascular events following percutaneous coronary intervention. In contrast,CYP2C19genotype does not impact clinical response to prasugrel or ticagrelor. Recent studies have evaluated the impact ofCYP2C19genotype-guided selection of antiplatelet therapy on clinical outcomes and begun to close some of the gaps in knowledge and uncertainty that have impeded widespread clinical implementation of this precision medicine approach. This review will critically evaluate recent data and offer new insight into the potential clinical utility of genotype-guided antiplatelet therapy in the context of current clinical practice guidelines.

Impact of hepatitis B virus (HBV) infection on platelet response to clopidogrel in patients undergoing coronary stent implantation

BackgroundHepatitis B virus (HBV) infection has been reported to down-regulate the expression of CYP2C19 gene, which may decrease the bioactivation of clopidogrel into active metabolites. We aimed to evaluate the impact of HBV infection on platelet response to clopidogrel in patients undergoing coronary stent implantation. MethodsA total of 1805 patients who had received coronary stent implantation and taken aspirin 100 mg in combination with clopidogrel 75 mg daily ≥5 days were consecutively recruited. The serologic identifications for HBV, platelet aggregations in response to arachidonic acid (PLAA) and adenosine diphosphate (PLADP), as well as ABCB1, CYP2C19, CYP3A5, PON1 and P2RY12 genotypes were determined. Clopidogrel low response (CLR) was defined as PLADP > 40%. ResultsAmong the recruited subjects, 102 patients showed hepatitis B surface antigen (HBsAg) positive and 1703 patients negative. PLADP was significantly higher in HBsAg positive group than that in HBsAg negative group [38 (24–48) % vs. 29 (20–39) %, p < 0.001] while the difference of PLAA was not statistically significant (p = 0.329). The incidence of CLR was significantly higher in HBsAg positive group compared with that in HBsAg negative group (43.1% vs. 23.4%, p < 0.001). After adjusted for CYP2C19 genotype and known risk factors, HBsAg positive patients exhibited a significantly higher risk of CLR (adjusted odds ratio: 2.81, 95% confidence interval: 1.73 to 4.58, p < 0.001). ConclusionsHBV infection is an independent risk factor of CLR, in addition to CYP2C19 gene mutations. (Pharmacogenetic and Pharmacokinetic Study of Clopidogrel; NCT01968499).

CYP2C19*2 Allele Carrier Status and Coronary In-stent Restenosis: Is There an Association?

The CYP2C19*2 allele is associated with reduced clopidogrel bioactivation, increasing the risk of complications after percutaneous coronary intervention (PCI), particularly stent thrombosis. Recently published data suggests that CYP2C19*2 allele carriers have a higher risk for in-stent restenosis (ISR) after endovascular treatment. Very few studies have investigated the relationship between CYP2C19*2 and coronary ISR, with no significant association reported. The objective of this study was to assess the relationship between CYP2C19*2 allele carrier status and coronary ISR.

CLOPIDOGREL RESISTANCE IN PATIENTS UNDERGOING LEFT ATRIAL APPENDAGE CLOSURE WITH THE WATCHMAN DEVICE

Loss-of-function (LOF) polymorphisms of the cytochrome P450 2C19 (CYP2C19) gene lead to reduced hepatic bioactivation of clopidogrel with potential clinical consequences. Clopigodrel is used after Watchman implant to prevent device-related thrombosis that might occur before endothelialization is