CYP2C19 Polymorphisms and Clinical Outcomes Following Percutaneous Coronary Intervention (PCI) in the Million Veterans Program.

Background: CYP2C19 loss-of-function (LOF) alleles decrease the antiplatelet effect of clopidogrel following percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS). The impact of genotype in stable ischemic heart disease (SIHD) is unclear. Objectives: Determine the association of CYP2C19 genotype with major adverse cardiac events (MACE) after PCI for ACS or SIHD. Methods: Million Veterans Program (MVP) participants age <65 years with a PCI documented in the VA Clinical Assessment, Reporting and Tracking (CART) Program between 1/1/2009 to 9/30/2017, treated with clopidogrel were included. Time to MACE defined as the composite of all-cause death, stroke or myocardial infarction within 12 months following PCI. Results: Among 4,461 Veterans (mean age 59.1 ± 5.1 years, 18% Black); 44% had ACS, 56% had SIHD and 29% carried a CYP2C19 LOF allele. 301 patients (6.7%) experienced MACE while being treated with clopidogrel, 155 (7.9%) in the ACS group and 146 (5.9%) in the SIHD group. Overall, MACE was not significantly different between LOF carriers vs. noncarriers (adjusted hazard ratio [HR] 1.18, confidence interval [95%CI] 0.97-1.45, p=0.096). Among patients presenting with ACS, MACE risk in LOF carriers versus non-carriers was numerically higher (HR 1.30, 95%CI 0.98-1.73, p=0.067). There was no difference in MACE risk in patients with SIHD (HR 1.09, 95%CI 0.82-1.44; p=0.565). Conclusions: CYP2C19 LOF carriers presenting with ACS treated with clopidogrel following PCI experienced a numerically greater elevated risk of MACE events. CYP2C19 LOF genotype is not associated with MACE among patients presenting with SIHD.

Does the clopidogrel CYP2C19 genotype assay predict postprocedure stenosis in cerebral aneurysms treated with a flow diverter?

OBJECTIVE: Flow diverters have emerged as a popular modality for treating cerebral aneurysms but require dual antiplatelet therapy (DAPT) after placement. Clopidogrel is a common choice but is a prodrug that some patients may not convert into an active metabolite. The CYP2C19 genotype assay is used to predict activation speed; however, limited data exist showcasing whether this genotype accurately predicts postprocedure complications after flow diversion treatment of cerebral aneurysms. Therefore, the authors sought to characterize whether CYP2C19 genotype correlated with the development of postprocedure intimal hyperplasia (stenosis) after flow diverter placement. METHODS: Medical records were reviewed for patients who underwent flow diverter treatment of cerebral aneurysm at a single academic institution between January 1, 2012, and May 31, 2020. Patient demographics and comorbidities were reviewed alongside CYP2C19 genotype assay, DAPT regimen, and postprocedure angiogram data. Stenosis was defined based on review of angiogram data by two independent physicians. RESULTS: In this review of 120 unique cerebral aneurysms, 102 received DAPT with clopidogrel and 18 received DAPT with an alternative agent. Stenosis was present on 3-month follow-up angiogram for 35/102 (34.3%) aneurysms receiving DAPT with clopidogrel and in 11/18 (61.1%) aneurysms receiving an alternative DAPT regimen (p = 0.031). The CYP2C19 genotype did not correlate with postprocedure stenosis (p = 0.35). CONCLUSIONS: Clopidogrel was a significantly more effective DAPT agent for preventing stenosis when compared to nonclopidogrel DAPT regimens. The clopidogrel CYP2C19 genotype did not predict postprocedure stenosis in this cohort of 120 cerebral aneurysms treated with a flow diverter.

Use of Tirofiban to Prevent Ischemic Events in Patients with CYP2C19 Loss-of-Function Alleles during Flow Diversion of Intracranial Aneurysm: A Multicenter Cohort Study.

To analyze the effect of tirofiban on ischemic events in CYP2C19 loss-of-function (LOF) allele carriers during pipeline embolization device (PED) implantation. Demographic information, imaging data, ischemic complications, CYP2C19 genotyping, and platelet function test results were collected from patients with PED-treated intracranial aneurysms at three centers. Multivariate logistic regression was used to analyze risk factors for ischemic events. Patients were grouped according to LOF alleles and antiplatelet drugs, the baseline information of LOF allele carriers and non-carriers were compared, and the efficacy of tirofiban was analyzed by comparing the incidence of ischemic events in each group. In total, 278 patients were included in the study, 24 of whom had an ischemic event. 157 (56.5%) patients carried the LOF allele and were more likely to develop resistance to clopidogrel (P < 0.001) and hypertension (P = 0.010). Multivariate logistic regression analysis revealed that the independent risk factors for ischemic events were age of > 55 years (OR = 3.308, P = 0.028), LOF alleles (OR = 3.960, P = 0.036), and clopidogrel nonresponsiveness (OR = 3.301, P = 0.014). For LOF allele carriers, prophylactic use of tirofiban after PED implantation helped to reduce ischemic events (4.3% vs. 16.4%, P = 0.039). This study supports CYP2C19 genotyping before flow diversion because LOF alleles increase the risk of ischemic events. Prophylactic use of tirofiban may help reduce ischemic events in LOF allele carriers.

The contribution of genotype-guided selection of P2Y12 inhibitor on prognosis in ACS /CCS patients undergoing percutaneous coronary intervention: a retrospective cohort study.

PURPOSE: We aimed to explore the contribution of genotype-guided selection of P2Y12 inhibitors on prognosis in Chinese patients with acute coronary syndromes (ACS) or chronic coronary syndromes (CCS) undergoing percutaneous coronary intervention (PCI). METHODS: Totally, 2063 patients were included. They were divided into empiric treatment group (n = 1025) and individualized treatment group (n = 1038) depending on whether taken CYP2C19 genetic testing. The incidences of clinical endpoint events were compared in two groups at 1-year follow-up. The effective endpoint events were major adverse cardiovascular events (MACEs), including all-cause mortality, in-stent restenosis, nonfatal myocardial infarction, nonfatal stroke and severe recurrent ischemia. Meanwhile, the safe endpoint was bleeding events defined by the Bleeding Academic Research Consortium (BARC) criteria. RESULTS: Finally, 66.83% patients were diagnosed with ACS and 33.17% patients were diagnosed with CCS in empiric group. 68.11% patients were diagnosed with ACS and 31.89% patients were diagnosed with CCS in individualized group. At 1-year follow-up, individualized group showed lower MACEs rate than empiric group (19.61% vs. 10.69%, HR: 1.915; 95% CI: 1.534 to 2.392; P < 0.0001, log-rank test; adjusted HR: 1.983; 95% CI: 1.573 to 2.501; P = 0.000, cox proportional hazards regression models), while bleeding events were significantly less common in empiric group than in individualized group (7.32% vs. 10.40%, HR: 0.693; 95% CI: 0.519 to 0.926; P = 0.0132, log-rank test; adjusted HR: 0.695; 95% CI: 0.518 to 0.933; P = 0.016, cox proportional hazards regression models). It was mainly manifested in BARC class 1 bleeding, which did not warrant the interruption of antiplatelet therapy (ITA). Further, subgroup analyses illustrated that no significant difference existed in cumulative MACEs-free survival rate between all treatment arms of individualized group (P = 0.6579 by log-rank test), and CYP2C19 intermediate metabolizer (IM) genetype appeared to be significantly associated with bleeding events for patients treated with ticagrelor (clopidogrel vs. ticagrelor: 6.80% vs. 14.88%; adjusted HR:0.440; 95% CI: 0.246 to 0.787; adjusted P = 0.006). CONCLUSIONS: Genotype-guided selection of P2Y12 inhibitor made a very positive contribution on the prognosis in Chinese ACS/CCS patients undergoing PCI. Instead of intensifying antiplatelet strategies, conventional-dose clopidogrel could be recommended as P2Y12 inhibitor after weighing MACEs and bleeding events in CYP2C19 IM patients.

Clinical Impact of CYP2C19 Genotype on Clopidogrel-Based Antiplatelet Therapy After Percutaneous Coronary Intervention.

BACKGROUND: Although there is a growing body of evidence that CYP2C19 genotyping can be beneficial when considering treatment with clopidogrel after percutaneous coronary intervention (PCI), whether a genotype-guided strategy can be generally adopted in routine practice remains unclear among East Asians. OBJECTIVES: This study sought to investigate long-term outcomes of patients undergoing clopidogrel-based antiplatelet therapy after drug-eluting stent (DES) implantation according to CYP2C19 genotypes. METHODS: From the nationwide multicenter PTRG-DES (Platelet function and genoType-Related long-term proGnosis in DES-treated patients) consortium, patients who underwent CYP2C19 genotyping were selected and classified according to CYP2C19 loss-of-function allele: rapid metabolizers (RMs) or normal metabolizers (NMs) vs intermediate metabolizers (IMs) or poor metabolizers (PMs). The primary outcome was a composite of cardiac death, myocardial infarction, and stent thrombosis at 5 years after the index procedure. RESULTS: Of 8,163 patients with CYP2C19 genotyping, 56.7% presented with acute coronary syndrome. There were 3,098 (37.9%) in the RM or NM group, 3,906 (47.9%) in the IM group, and 1,159 (14.2%) in the PM group. IMs or PMs were associated with an increased risk of 5-year primary outcome compared with RMs or NMs (HRadj: 1.42; 95% CI: 1.01-1.98; P = 0.041), and the effect was more pronounced in the first year (HRadj: 1.67; 95% CI: 1.10-2.55; P = 0.016). The prognostic implication of being an IM and PM was significant in acute coronary syndrome patients (HRadj: 1.88; 95% CI: 1.20-2.93; P = 0.005) but not in those with stable angina (HRadj: 0.92; 95% CI: 0.54-1.55; P = 0.751) (interaction P = 0.028). CONCLUSIONS: Among East Asians with clopidogrel-based antiplatelet therapy after DES implantation, CYP2C19 genotyping could stratify patients who were likely to have an increased risk of atherothrombotic events. (Platelet Function and genoType-Related Long-term progGosis in DES-treated Patients: A Consortium From Multi-centered Registries [PTRG-DES]; NCT04734028).

CYP2C19 genotype and platelet aggregation test-guided dual antiplatelet therapy after off-pump coronary artery bypass grafting: A retrospective cohort study.

Background: Dual antiplatelet therapy (DAPT) is recommended in patients undergoing off-pump coronary artery bypass graft surgery (OPCAB). Clopidogrel is less effective among patients with loss-of-function (LoF) of CYP2C19 alleles, while ticagrelor has direct effects on P2Y12 receptor. Whether a CYP2C19 genotype plus platelet aggregation test (PAgT)-guided DAPT after CABG could improve clinical outcomes remain uncertain. Materials and methods: From August 2019 to December 2020, 1,134 consecutive patients who underwent OPCAB received DAPT for 1 year after surgery in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. According to the actual treatment they received in real-world, 382 (33.7%) of them received a traditional DAPT: aspirin 100 mg qd + clopidogrel 75 mg qd, no matter the CYP2C19 genotype and response in platelet aggregation test (PAgT). The other 752 (66.3%) patients received an individual DAPT based on CYP2C19 genotype and PAgT: aspirin 100 mg qd + clopidogrel 75 mg qd if CYP2C19 was extensive metabolizer, or moderate metabolizer but normal response in PAgT; aspirin 100 mg qd + ticagrelor 90 mg bid if CYP2C19 was poor metabolizer, or moderate metabolizer but no or low response in PAgT. One-year follow-up was achieved for all patients. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. The safety outcome was thrombolysis in myocardial infarction (TIMI) criteria major bleeding. Results: Compared with the traditional DAPT group, the risk of MACE in the individual DAPT group was significantly lower (5.5 vs. 9.2%, HR 0.583; 95% CI, 0.371-0.915; P = 0.019), mainly due to the decreased risk of MI (1.7 vs. 4.2%, HR 0.407; 95% CI, 0.196-0.846; P = 0.016). The risk of TIMI major bleeding events was similar between the two groups (5.3 vs. 6.0%, RR 0.883; 95% CI, 0.537-1.453; P = 0.626). Conclusion: For patients who underwent OPCAB, individual DAPT (CYP2C19 genotype plus PAgT-guided strategy) was associated with a lower risk of MACE and a similar risk of major bleeding.

Population pharmacokinetics model for escitalopram in Chinese psychiatric patients: effect of CYP2C19 and age.

Objective: To establish a population pharmacokinetic model in Chinese psychiatric patients to characterize escitalopram pharmacokinetic profile to identify factors influencing drug exposure, and through simulation to compare the results with the established therapeutic reference range. Methods: Demographic information, dosing regimen, CYP2C19 genotype, concomitant medications, and liver and kidney function indicators were retrospectively collected for inpatients taking escitalopram with therapeutic drug monitoring from 2018 to 2021. Nonlinear mixed-effects modeling was used to model the pharmacokinetic characteristics of escitalopram. Goodness-of-fit plots, bootstrapping, and normalized prediction distribution errors were used to evaluate the model. Simulation for different dosing regimens was based on the final estimations. Results: The study comprised 106 patients and 337 measurements of serum sample. A structural model with one compartment with first-order absorption and elimination described the data adequately. The population-estimated apparent volume of distribution and apparent clearance were 815 and 16.3 L/h, respectively. Age and CYP2C19 phenotype had a significant effect on the apparent clearance (CL/F). CL/F of escitalopram decreased with increased age, and CL/F of poor metabolizer patients was significantly lower than in extensive and immediate metabolizer patients. The final model-based simulation showed that the daily dose of adolescents with poor metabolizer might be as high as 15 mg or 20 mg and referring to the therapeutic range for adults may result in overdose and a high risk of adverse effects in older patients. Conclusion: A population pharmacokinetics model of escitalopram was successfully created for the Chinese population. Depending on the age of the patients, CYP2C19 genotype and serum drug concentrations throughout treatment are required for adequate individualization of dosing regimens. When developing a regimen for older patients, especially those who are poor metabolizers, vigilance is required.

Population pharmacokinetics of omeprazole in obese and normal-weight adults.

BACKGROUND: Obesity is related to many pathophysiological changes that may result in altered drug disposition. Omeprazole is the most common option utilized for acid-related disorders ; however, the pharmacokinetic (PK) and dosing recommendations for the obese patient population are lacking. METHODS: Data from 40 healthy subjects with normal weights and data from 61 obese subjects were included. The subjects all received a single dose of 20 mg of omeprazole. Nonlinear mixed effects modeling were performed to characterize the effect of obesity on omeprazole PK. RESULTS: A one-compartment model with twelve transit absorption compartments and linear elimination described the data best. A lower clearance was observed in the obese patient population than in the normal-weight subjects. Moreover, the CYP2C19 genotype was identified as a significant covariate for clearance. CONCLUSION: Given the potential adverse events related to high exposure to proton pump inhibitors over time, obese patients may require a lower dose of omeprazole for long-term treatment. Further studies in obese individuals into other drugs metabolized by CYP2C19 are warranted, especially those with a narrow therapeutic window. CLINICAL TRIAL REGISTRATION: www.chictr.org.cn identifier is ChiCTR2100046578; www.chinadrugtrials.org.cn identifier is CTR20190175.

Effect of major CYP2C19 genetic polymorphisms on Helicobacter pylori eradication based on different treatment regimens.

Helicobacter pylori (H. pylori) infection is a global issue. Its eradication in affected individuals is important to prevent several further complications that may occur if left untreated. Proton pump inhibitors (PPIs) serve an important role in the eradication regimens of H. pylori. PPIs are metabolized primarily through the CYP2C19 enzyme in the liver. Inter-individual variation in the response to eradication treatment may partly be due to variations in the metabolism of PPIs. The aim of this study was to determine whether there was any association between CYP2C19 genetic polymorphisms and the response to eradication therapy amongst Jordanians infected with H. pylori receiving lansoprazole-based regimens. The present study was approved by the Institutional Review Board of The University of Jordan Hospital. A total of 141 patients infected with H. pylori were genotyped for the polymorphisms CYP2C19*2 and CYP2C19*17 using the PCR-restriction fragment length polymorphism assay method. Patients received lansoprazole-based triple or sequential therapy. The assessment of eradication was performed using either a H. pylori stool antigen test or from feedback from patients regarding their improvement. Eradication rates were 84.6% and 64.5% in the intermediate-metabolizer and extensive-metabolizer group, respectively. This difference was not statistically significant. Moreover, no significant association was found between the carriers of the CYP2C19*17 polymorphism and the response to eradication therapy. These findings suggest that there was no significant association between the CYP2C19 genotype and the response to eradication therapy amongst Jordanians infected with H. pylori.

Utility of a pharmacogenetic-driven algorithm in guiding dual antiplatelet therapy for patients undergoing coronary drug-eluting stent implantation in China.

PURPOSES: The POPular Risk Score (PRiS), a pharmacogenetic-driven algorithm consisting of CYP2C19 genotype, platelet reactivity, and clinical risk factors, is developed to evaluate ischemic risk and guide dual antiplatelet therapy (DAPT). This study aimed to evaluate the efficacy and safety of DAPT in accordance with the PRiS in patients undergoing drug-eluting stent (DES) implantation. METHODS: A total of 1757 patients recruited in this cohort study were divided into four groups according to the PRiS and type of P2Y12 receptor inhibitor treatment at discharge. The primary endpoint was major adverse cardiovascular events (MACE, a composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis, and target vessel revascularization) during 1-year follow-up. The safety endpoints were defined by Bleeding Academic Research Consortium (BARC) criteria as major bleeding (BARC 3a, 3b, 3c, and 5) and clinically relevant bleeding (BARC 2, 3a, 3b, 3c, and 5). RESULTS: Among 1046 patients with PRiS < 2 and 711 patients with PRiS ≥ 2, 34.2% and 38.3% of them were treated with ticagrelor, respectively. The PRiS ≥ 2 was an independent predictor for the 1-year incidence of MACE (HR(95%CI): 2.09 (1.37-3.20), p = 0.001). Multivariable Cox regression indicated that in the PRiS ≥ 2 group, ticagrelor was superior to clopidogrel in reducing the risk of MACE (HR(95%CI): 0.53 (0.29-0.98), p = 0.042), without increasing the bleeding risk. On the other hand, in the PRiS < 2 group, clopidogrel treatment was related to a remarkably lower rate of BARC class ≥ 2 bleeding (HR(95%CI): 0.39 (0.20-0.72), p = 0.003), but comparable incidences of MACE and BARC class ≥ 3 bleeding during 1-year follow-up. Similar associations between P2Y12 receptor inhibitors and 1-year endpoints in the PRiS < 2 and PRiS ≥ 2 group could also be identified in propensity score-weighted analysis and propensity score-matched analysis. CONCLUSION: Tailored DAPT based on the PRiS could assist in improving the prognosis of patients undergoing DES implantation. Further randomized controlled trials are required to provide more evidence for PRiS-guided DAPT.

Relationship between clopidogrel responsiveness and CYP2C19 genotype by thromboelastography in patients with coronary heart disease after PCI / 中国输血杂志

【Objective】 To explore the relationship between clopidogrel responsiveness and CYP2C19 gene polymorphism by thromboelastography(TEG) after PCI in patients with coronary heart disease, and its guiding significance for the use of clopidogrel after PCI. 【Methods】 A total of 246 patients who underwent PCI surgery in our hospital from June 2018 to May 2021 and routinely took clopidogrel maintenance treatment after the operation were selected.The platelet inhibition rate of the patients was detected by TEG to obtain their response to clopidogrel.The CYP2C19 genotype was detected, and the relationship between the patient′s responsiveness to clopidogrel and the CYP2C19 genotype was analyzed. 【Results】 The CYP2C19 genotypes in 246 patients were fast metabolizer (n=95), intermediate metabolizer (n=104) and slow metabolizer (n=47), with the mean ADP inhibition rate(%) at 46.27±21.41, 40.99±25.53 and 24.77±21.68, respectively.They were divided into clopidogrel resistant group (n=98) and clopidogrel normal response group (n=148). The three groups of patients with different CYP2C19 genotypes had no statistically significant differences in gender composition, age and platelet count (P>0.05), while significant differences in hypertension, diabetes and hyperlipidemia(P0.05), but they were all lower than those with slow metabolism patients (both P0.5). Statistically significant difference was noticed in the low responsiveness to clopidogrel by different CYP2C19 genotypes (P<0.05). The drug responsiveness of clopidogrel measured by TEG had strong correlation with the patient′s CYP2C19 genotype.When the ADP inhibition rate was the best cut-off value (27.10%), the sensitivity and specificity of CYP2C19 genotype being diagnosed as the slow metabolite type, was 73.37% and 70.21%, respectively. 【Conclusion】 The response of clopidogrel after PCI in patients with coronary heart disease is associated with CYP2C19 genotype polymorphism.The use of TEG to detect the ADP inhibition rate of patients has strong predictive effect on CYP2C19 genotype and has guiding significance on antiplatelet therapy in patients with coronary heart disease after PCI.

Two-dimension Tailor-made Therapy: A New Salvage Therapy After Multiple Eradication Failures for Helicobacter pylori Infection.

Background and Aims: Vonoprazan-based eradication therapies have a higher eradication rate than usual proton pump inhibitor (PPI)-based therapies in treating Helicobacter pylori infection. Should we use vonoprazan to treat patients who failed multiple eradication therapies? Because the drug is not available in most countries, we propose 2-dimension tailor-made therapy (2dTMT) without using vonoprazan. Methods: Patients who failed twice or more PPI-based triple therapies were recruited. Patients underwent CYP2C19 genotype and antibiotic susceptibility tests (ASTs). PPI doses per day were decided as per the CYP2C19 genotype: twice for poor and 4 times for extensive metabolizers (dimension 1). Two antibiotics were selected as per the results of the AST in each patient (dimension 2). Regimens of 2dTMT included 2 susceptible antibiotics and a PPI. For those who could not have enough information with the AST, tailor-made PPI dosing was indicated with empirically selected 2 antibiotics (one-dimension tailor-made therapy [1dTMT]). Results: Of 51 candidates with multiple eradication failures, 37 patients underwent the genotype test and AST, and 24 succeeded to obtain sufficient information to select 2 susceptible antibiotics. Of them, 22 patients accepted to receive 14-day 2dTMT. Of the residual patients, 12 accepted to receive 14-day 1dTMT. The mean eradication rate of 2dTMT was 86.4% (95% confidence interval [CI]: 65.1%-98.8%) in intention-to-treat and 90.5% (95% CI: 69.6%-98.8%) in per-protocol analyses, whereas that of 1dTMT was 75.0% (95% CI: 42.8%-94.5%) in intention-to-treat and 90.0% (95% CI: 55.5%-99.7%) in per-protocol analyses. Conclusion: Without vonoprazan, 14-day 2dTMT could be one of the salvage therapies for patients with multiple eradication failures. In cases of insufficient information with the AST, 14-day 1dTMT could be an alternative therapy. Clinical Trials Registry number, UMIN000022154 (https://www.umin.ac.jp/icdr/index.html).

CYP2C19 genotype-directed P2Y12 inhibitor antiplatelet therapy normalizes risk for major adverse cardiovascular events after percutaneous coronary intervention.

OBJECTIVE: To study the use of CYP2C19 genotyping to guide P2Y12 inhibitor selection to maximize efficacy, and attenuate risk in appropriate patients who underwent PCI for CAD. METHODS: We performed a retrospective analysis of 868 patients with CAD who received CYP2C19 genotyping after PCI and changed P2Y12 inhibitor based on the results. Patients were divided into two groups based on clopidogrel metabolizer status. Group I: Intermediate (IM) and poor metabolizers (PM). Group II: Ultra-rapid (UM), rapid (RM) and normal metabolizers (NM). Each group was then categorized to one of two treatment arms guided by CYP2C19 genotype. Category 1: IM/PM started on clopidogrel, switched to ticagrelor or prasugrel; 2:IM/PM started on ticagrelor/prasugrel, continued these medications; 3: UM/RM/NM started on ticagrelor/prasugrel, switched to clopidogrel; 4: UM/RM/NM started on clopidogrel, continued clopidogrel. Death due to cardiac causes, bleeding events, non-fatal MI, target vessel revascularization (TVR), and MACE in all four categories were considered at 1, 6 and 12 months. RESULTS: We did not observe significant difference between phenotypes for MACE at 1 (p = 0.274), 6 (p = 0.387), and 12 months (p = 0.083). Death due to cardiac causes, MI, and bleeding events were not significant at 1, 6, and 12 months. There was no significant difference in TVR at 6 (p = 0.491), and 12 months (p = 0.423) except at 1 month (p = 0.012). CONCLUSION: CYP2C19 genotype-based intervention can be implemented effectively and reliably to guide selection of P2Y12 inhibitor to optimize patient quality and safety when appropriate in post PCI patients.

Is monitoring of antiplatelet therapy by light transmission aggregometry dependent on instrument and reagent used?

INTRODUCTION: Light transmission aggregometry (LTA), used to detect clopidogrel resistance in patients under antiplatelet therapy, is prone to multiple variables potentially influencing results and interpretation. Currently, no attention is given to type of aggregometer or reagent used. The aim of this study was to evaluate the interassay variability between two aggregometers (Chronolog700 and TA-8V), using two different ADP reagents (Chrono-Par® and Agro-Bio ADP) in patients under clopidogrel therapy. Additionally, LTA results were correlated to CYP2C19-polymorphism. METHODS: Light transmission aggregometry was performed in 20 healthy individuals and 30 patients using both aggregometers, and applying two different reagents (2.5 and 5 µmol/L). The maximum platelet aggregation (ADPmax ), the platelet aggregation at 6 minutes (ADP6min ), and the percentage of disaggregation at 6 min (ADP%disaggr ) were compared between four applied combinations. Additionally, 23 clopidogrel-resistant patients according to Chronolog700-Chrono-par® ADP reagent analysis were tested for CYP2C19*2 polymorphism. RESULTS: Comparison of the LTA of healthy individuals revealed a significant lower ADPmax , lower ADP6min , and higher ADP%disaggr with the TA-8V aggregometer compared to Chronolog700, regardless of the reagent. In contrast, LTA results in patients are depending on the reagent, with significant higher ADPmax and ADP6min and lower ADP%disaggr using Chrono-Par® compared to Agro-Bio ADP reagent. All intermediate clopidogrel metabolizers (CYP2C19*2 carriers) were correctly classified as clopidogrel resistant using Chrono-Par® , in contrast to the Agro-Bio ADP reagent. CONCLUSION: Light transmission aggregometry in clopidogrel-treated patients is mainly depending on the type of ADP reagent. Comparison of LTA with genotype reveals that the choice of instrument seems less influencing. In contrast, in the healthy individuals, differences could be attributed to the instrument.

Effect of CYP2C19 Genotype on Ischemic Outcomes During Oral P2Y12 Inhibitor Therapy: A Meta-Analysis.

OBJECTIVES: The aim of this study was to examine the effect of CYP2C19 genotype on clinical outcomes in patients with coronary artery disease (CAD) who predominantly underwent percutaneous coronary intervention (PCI), comparing those treated with ticagrelor or prasugrel versus clopidogrel. BACKGROUND: The effect of CYP2C19 genotype on treatment outcomes with ticagrelor or prasugrel compared with clopidogrel is unclear. METHODS: Databases through February 19, 2020, were searched for studies reporting the effect of CYP2C19 genotype on ischemic outcomes during ticagrelor or prasugrel versus clopidogrel treatment. Study eligibility required outcomes reported for CYP2C19 genotype status and clopidogrel and alternative P2Y12 inhibitors in patients with CAD with at least 50% undergoing PCI. The primary analysis consisted of randomized controlled trials (RCTs). A secondary analysis was conducted by adding non-RCTs to the primary analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia. Meta-analysis was conducted to compare the 2 drug regimens and test interaction with CYP2C19 genotype. RESULTS: Of 1,335 studies identified, 7 RCTs were included (15,949 patients, mean age 62 years; 77% had PCI, 98% had acute coronary syndromes). Statistical heterogeneity was minimal, and risk for bias was low. Ticagrelor and prasugrel compared with clopidogrel resulted in a significant reduction in ischemic events (relative risk: 0.70; 95% confidence interval: 0.59 to 0.83) in CYP2C19 loss-of-function carriers but not in noncarriers (relative risk: 1.0; 95% confidence interval: 0.80 to 1.25). The test of interaction on the basis of CYP2C19 genotype status was statistically significant (p = 0.013), suggesting that CYP2C19 genotype modified the effect. An additional 4 observational studies were found, and adding them to the analysis provided the same conclusions (p value of the test of interaction <0.001). CONCLUSIONS: The effect of ticagrelor or prasugrel compared with clopidogrel in reducing ischemic events in patients with CAD who predominantly undergo PCI is based primarily on the presence of CYP2C19 loss-of-function carrier status. These results support genetic testing prior to prescribing P2Y12 inhibitor therapy.

A comparison of three platelet function tests in ischemic stroke patients with antiplatelet therapy.

Predicting the effectiveness of antiplatelet drugs is critical to precision antiplatelet therapy. However, there is a lack of an acceptable method, although there are a variety of methods for detecting platelet function. In this study, we compared three major platelet function tests to assess their performance and found better methods for platelet function evaluation after aspirin or clopidogrel treatment in ischemic stroke patients by comparative study. A total of 249 ischemic stroke patients were enrolled who were treated with aspirin or clopidogrel or both. Three platelet function tests including light transmittance aggregometry (LTA), thromboelastography (TEG), platelet function analyzer (PFA) were performed as well as CYP2C19 genotype determination. Correlation analyses and kappa statistics were used. All three methods were effective in evaluating aspirin function. However, only LTA and TEG had good correlation and consistency (r = -0.37, kappa = 0.634). TEG-ADP was the least sensitive for clopidogrel, as the platelet inhibition ratio did not differ between the clopidogrel-user group and the control (P = 0.074), while LTA and PFA were sensitive (P ＜ 0.001). Correlations between platelet assays were poor for clopidogrel (the absolute value of r range from 0.13 to 0.35) and so was the agreement (Kappa from 0.232 to 0.314). LTA and PFA have a good correlation with CYP2C19 genotyping (P = 0.034 and 0.014). In conclusion, all three tests were able to evaluate aspirin effect, LTA-AA and TEG-AA had a good correlation. TEG perform badly for clopidogrel effect detection. The fair-to-modest agreement among assays indicated further study was indispensable.

Economic Evaluations of CYP2C19 Genotype-Guided Antiplatelet Therapy Compared to the Universal Use of Antiplatelets in Patients With Acute Coronary Syndrome: A Systematic Review.

BACKGROUND AND OBJECTIVES: Clopidogrel is widely used after the percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and requires activation by cytochrome P450 (CYP), primarily CYP2C19. Patients with CYP2C19 loss-of-function alleles are at increased risk of major adverse cardiovascular events, while more expensive novel antiplatelet agents (ticagrelor and prasugrel) are unaffected by the CYP2C19 mutations. This systematic review aims to answer the question about whether overall evidence supports the genotype-guided selection of antiplatelet therapy as a cost-effective strategy in post-PCI ACS. METHODS: A systematic literature search of PubMed, EMBASE, EconLit, and PharmGKB was done to identify all the economic evaluations related to genotype-guided therapy compared to the universal use of antiplatelets in ACS patients. Quality of Health Economic Studies tool was used for quality assessment. RESULTS: The search identified 13 articles, where genotype-guided treatment was compared to universal clopidogrel, ticagrelor, and/or prasugrel. Six studies showed that genotype-guided therapy was cost-effective compared to universal clopidogrel, while 5 studies showed that it was dominant. One study specified that genotype-guided with ticagrelor is cost-effective only in both CYP2C19 intermediate and poor metabolizers. Genotype-guided therapy was dominant when compared to universal prasugrel, ticagrelor, or both in 5, 1, and 3 studies, respectively. Only 2 studies reported that universal ticagrelor was cost-effective compared to genotype-guided treatment. All the included articles had good quality. CONCLUSION: Based on current economic evaluations in the literature, implementing CYP2C19 genotype-guided therapy is a cost-effective approach in guiding the selection of medication in patients with ACS undergoing PCI.

Cost-effectiveness of CYP2C19 LOF-guided antiplatelet therapy in Chinese patients with acute coronary syndrome.

Aim: This study aimed to evaluate the cost-effectiveness of CYP2C19 loss-of-function(LOF) allele-guided antiplatelet therapy compared with the universal use of clopidogrel or ticagrelor among Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention. Methods: A two-part cost-effectiveness model comprising of a 1-year decision tree and a long-term Markov model was utilized to simulate outcomes of three treatment strategies: universal use of clopidogrel (75 mg daily) or universal use of ticagrelor 90 mg twice daily for all patients and CYP2C19 LOF-guided therapy (LOF allele carriers receiving ticagrelor, LOF allele noncarriers receiving clopidogrel). Model outcomes included quality-adjusted life years (QALYs) gained, direct medical costs and incremental cost-effectiveness ratios (ICERs). ICERs less than one-time gross domestic product per capita in China 59,660 yuan/QALY were considered cost-effective. Results: Base-case analysis showed 'universal ticagrelor use' was cost-effective for an ICER of 33,875 yuan per QALY gained compared with 'universal clopidogrel use' of which gained a 1.6932 QALYs at lowest life-long cost of 2450 yuan. CYP2C19 LOF-guided therapy had an effectiveness of 1.6975 QALYs at a cost of 2812 yuan, for an ICER of 84,118 yuan per QALY gained relative to 'universal clopidogrel use'. Sensitivity analysis demonstrated that base-case results were significantly affected by five factors: the risk ratio of 'non-fatal myocardial infarction', 'non-fatal stroke' and 'cardiovascular death' in ticagrelor versus clopidogrel and the annual costs of clopidogrel and ticagrelor. According to the results of Monte Carlo simulation, when willing to pay is about 32,000 yuan, patients willing to receive clopidogrel or ticagrelor are approximately equal. Conclusion: Optimal antiplatelet treatment is affected by lots of factors. The results of our study demonstrated that 'universal ticagrelor use' was cost-effective compared with 'universal clopidogrel use' for Chinese acute coronary syndrome patients with percutaneous coronary intervention.

CYP2C19 Genotype, CagA Genotype and Antibiotic Resistant Strain of Helicobacter pylori Infection

Background: H. pylori is a class I carcinogen and major cause of gastric cancer. Few previous studies reported relationship between H. pylori infection, CYP2C19 genotype and functional dyspepsia (FD) subtype. The aim of this study was to determine relationship between CYP2C19 genotype and FD subtype patients(host factor) with antibiotic resistant strains of H. pylori infection and CagA genotype(bacterial factor). Methods: FD patients who were investigated with gastroscopy at Thammasat University Hospital, Thailand during March 2017-November 2017 were enrolled. Two antral gastric biopsies were obtained for rapid urease test, E-test and cultures. CagA genotypes (CagA1a and CagA2a) were determined by PCR and CYP2C19 genotype was determined by PCR-RFLP. FD patients were categorized as epigastric pain syndrome(EPS) and postprandial distress syndrome (PDS). Results: 93 FD patients with H. pylori infection were enrolled (37 male, 56 female, mean age 54.5 years). There were 33 patients with EPS and 60 patients with PDS. CYP2C19 genotype revealed 55.9% rapid metabolizer (RM), 40.9% intermediate metabolizer (IM) and 3.2% poor metabolizer (PM) genotypes. Antibiotics susceptibility tests demonstrated 62.8% resistant to metronidazole, 12.9% resistant to clarithromycin and 27.1% resistant to fluoroquinolone. CagA 1a and CagA 2a were demonstrated in 6 patients(11.5%) and 46 patients(88.5%). CagA2a genotype was more prevalent in PDS than EPS patients (94.3%vs.76.5%; P =0.08) without significance. In intermediate metabolizer (IM), CagA2a genotype was significant higher in PDS than EPS(100% vs.25%; P=0.004). Conclusions: PDS, CYP2C19 RM genotype and CagA 2a gene of H. pylori infection were the predominant type of FD in Thailand. Metronidazole remain the most common antibiotic resistant strain of H. pylori infection in FD patients. PDS (host factor) was significantly related to CagA2a genotype (bacterial factors) only in patients with intermediate metabolizer. Appropriate dose of proton pump inhibitor (PPI) and correct regimens for H. pylori eradication in FD patients should be consider to improve clinical outcomes.