Antiplatelet and myocardial protective effect of Shexiang Tongxin Dropping Pill in patients undergoing percutaneous coronary intervention: A randomized controlled trial / 中西医结合学报

BACKGROUND@#High on-clopidogrel platelet reactivity could be partially explained by loss-of-function alleles of CYP2C19, the enzyme that converts clopidogrel into its active form. Shexiang Tongxin Dropping Pill (STDP) is a traditional Chinese medicine to treat angina pectoris. STDP has been shown to improve blood flow in patients with slow coronary flow and attenuate atherosclerosis in apolipoprotein E-deficient mice. However, whether STDP can affect platelet function remains unknown.@*OBJECTIVE@#The purpose of this study is to examine the potential effects of STDP on platelet function in patients undergoing percutaneous coronary intervention (PCI) for unstable angina. The interaction between the effects of STDP with polymorphisms of CYP2C19 was also investigated.@*DESIGN, PARTICIPANTS AND INTERVENTION@#This was a single-center, randomized controlled trial in patients undergoing elective PCI for unstable angina. Eligible subjects were randomized to receive STDP (210 mg per day) plus dual antiplatelet therapy (DAPT) with clopidogrel and aspirin or DAPT alone.@*MAIN OUTCOME MEASURES@#The primary outcome was platelet function, reflected by adenosine diphosphate (ADP)-induced platelet aggregation and platelet microparticles (PMPs). The secondary outcomes were major adverse cardiovascular events (MACEs) including recurrent ischemia or myocardial infarction, repeat PCI and cardiac death; blood biomarkers for myocardial injury including creatine kinase-MB isoenzyme (CK-MB) and high-sensitive troponin I (hsTnI); and biomarkers for inflammation including intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and galectin-3.@*RESULTS@#A total of 118 subjects (mean age: [66.8 ± 8.9] years; male: 59.8%) were included into analysis: 58 in the control group and 60 in the STDP group. CYP2C19 genotype distribution was comparable between the 2 groups. In comparison to the control group, the STDP group had significantly lower CK-MB (P < 0.05) but similar hsTnI (P > 0.05) at 24 h after PCI, lower ICAM-1, VCAM-1, MCP-1 and galectin-3 at 3 months (all P < 0.05) but not at 7 days after PCI (P > 0.05). At 3 months, the STDP group had lower PMP number ([42.9 ± 37.3] vs. [67.8 ± 53.1] counts/μL in the control group, P = 0.05). Subgroup analysis showed that STDP increased percentage inhibition of ADP-induced platelet aggregation only in slow metabolizers (66.0% ± 20.8% in STDP group vs. 36.0% ± 28.1% in the control group, P < 0.05), but not in intermediate or fast metabolizers. The rate of MACEs during the 3-month follow-up did not differ between the two groups.@*CONCLUSION@#STDP produced antiplatelet, anti-inflammatory and cardioprotective effects. Subgroup analysis indicated that STDP inhibited residual platelet reactivity in slow metabolizers only.@*TRIAL REGISTRATION@#This study was registered on www.chictr.org.cn: ChiCTR-IPR-16009785.

Evaluation of the relationship between the platelet reactivity detected by two methods and CYP2C19 gene polymorphism in patients with ACS after receiving clopidogrel / 解放军医学杂志

Objective To evaluate the relationship between the platelet reactivity detected by two methods and CYP2C19 gene polymorphism in patients with ACS after taking clopidogrel, and analyze the correlation between different platelet detection methods. Methods Forty-three patients with ACS, admitted in the General Hospital of Northern Theater Command from July to October 2019, met the diagnostic criteria and received dual antiplatelet therapy, were enrolled in present study. The gene chip was used for CYP2C19 genotype detection, vasodilatory stimulated phosphorylated protein (VASP) method and two revulsiveinduced phototurbidimetric methods [arachidonic acid-induced phototurbidimetry (AA-LTA), diphosphate adenosine-induced phototurbidimetry (ADP-LTA)] were used to evaluate the antiplatelet reactivity, and the correlation between different evaluation methods was compared. Results Of the 43 patients, 17(39.5%) were EMs, 19(44.2%) were IMs, and 7(16.3%) were PMs. The results of VASP were higher in PMs and IMs patients than those in EMs, and the results of AA-LTA were higher in PMs than those in IMs and EMs. The differences were significant (P<0.01). The platelet reactivity of VASP was positively correlated with AA-LTA and ADP-LTA (r=0.383, 0.369, P<0.05); and AA-LTA was positively correlated with ADP-LTA (r=0.496, P=0.011). Conclusions There is a difference between CYP2C19 gene polymorphism and platelet reactivity, and the correlation between VASP method and LTA method is low. CYP2C19 genotype can be used as a reference for the platelet reactivity of patients after clopidogrel therapy.

Study on high on-aspirin platelet reactivity in diabetic mice based on metabonomics / 中国临床药理学与治疗学

AIM: To explore the underlying mechanism of aspirin-related high on-aspirin platelet reactivity (HAPR) in diabetic state from the perspective of endogenous metabolic changes in metabolomics. METHODS:Type 2 diabetes mellitus (T2DM) mice model was established by the combination treatment of high-fat diet and streptozotocin injections. Mice were randomly divided into Normal group, T2DM group, Normal+aspirin group and T2DM+aspirin group. GC/TOF-MS was used to determine the plasmatic endogenous metabolites of mice. The data were analyzed applying multivariate statistical method. RESULTS:The expression of platelet CD62P and ratio of TXB2/6-keto-PGF1α in the plasma of female T2DM mice showed no significant difference compared with that of the model group. The degree of divergence between normal and normal+aspirin groups was significantly greater than that between T2DM and T2DM+aspirin groups. Biochemical metabolic pathway analysis revealed that HAPR in diabetic mice was linked to glycolysis, gluconeogenesis, pyruvate metabolism, citric acid cycle, ascorbic acid metabolism, and arachidonic acid metabolic pathways. CONCLUSION:The different metabolites obtained in metabolome assay suggests that the HAPR in diabetic state involved several different metabolic pathways, which can better elucidate the biological mechanism of diabetes-associated HAPR.

Association of CMTM5 gene expression with the risk of in-stent restenosis in patients with coronary artery disease after drug-eluting stent implantation and the effects and mechanisms of CMTM5 on human vascular endothelial cells / 北京大学学报(医学版)

OBJECTIVE@#To elucidate the correlation between CKLF-like marvel transmembrane domain containing member (CMTM5) gene and the risk of in-stent restenosis (ISR) with coronary artery disease (CAD) patients and to detect the effects and mechanisms of CMTM5-stimulated genes on human vascular endothelial cells (ECs) proliferation and migration.@*METHODS@#A total of 124 hospitalized patients in Shijitan Hospital were enrolled in this study. All the CAD patients were detected with platelet reactivity and grouped into two groups according to platelet reactivity; ISR was conformed by coronary angiography; RT-PCR method was used to detect CMTM5 gene expression; The CMTM5 over expression, reduction and control EC lines were established; Cell count, MTT, Brdu and flow cytometry methods were used to detect the proliferation of ECs, scratch and transwell experiments to test the migration of ECs, Western blot was used to detect signal path expressions.@*RESULTS@#CMTM5 gene expression in HAPR (High on aspirin platelet reactivity) group was 1.72 times compared with No-HAPR group, which was significantly higher than No-HAPR group. HAPR group ISR rate was 25.8% (8 cases), the incidence of No-HAPR ISR group was 9.7% (9 cases), and the results showed that in HAPR group, the incidence of ISR was significantly higher than that in No-HAPR group (P=0.04, OR=0.04, 95%CI=1.16－7.52), which showed that CMTM5 gene was significantly correlated with the risk of ISR. In HAPR group ISR rate was 25.8% (8 cases), the incidence of ISR in No-HAPR group was 9.7% (9 cases), and the results showed that the risk of ISR in HAPR group was significantly higher than that in No-HAPR group. All the results showed that CMTM5 was significantly correlated with the risk of ISR in CAD patients (P < 0.05). CMTM5 overexpression inhibited the proliferation and migration ability of ECs (P < 0.05), PI3K/Akt signaling pathways were involved in the role of regulation on ECs.@*CONCLUSION@#Our results revealed that CMTM5 gene was closely related with ISR, CMTM5 overexpression may repress ECs proliferation and migration through regulating PI3K-Akt signaling.

Clinical outcomes and predictive model of platelet reactivity to clopidogrel after acute ischemic vascular events / 中华医学杂志(英文版)

Background:@#High on-treatment platelet reactivity (HTPR) has been suggested as a risk factor for patients with ischemic vascular disease. We explored a predictive model of platelet reactivity to clopidogrel and the relationship with clinical outcomes.@*Methods:@#A total of 441 patients were included. Platelet reactivity was measured by light transmittance aggregometry after receiving dual antiplatelet therapy. HTPR was defined by the consensus cutoff of maximal platelet aggregation >46% by light transmittance aggregometry. CYP2C19 loss-of-function polymorphisms were identified by DNA microarray analysis. The data were compared by binary logistic regression to find the risk factors. The primary endpoint was major adverse clinical events (MACEs), and patients were followed for a median time of 29 months. Survival curves were constructed with Kaplan-Meier estimates and compared by logrank tests between the patients with HTPR and non-HTPR.@*Results:@#The rate of HTPR was 17.2%. Logistic regression identified the following predictors of HTPR: age, therapy regimen, body mass index, diabetes history, CYP2C19*2, or CYP2C19*3 variant. The area under the curve of receiver operating characteristic for the HTPR predictive model was 0.793 (95% confidence interval: 0.738–0.848). Kaplan-Meier analysis showed that patients with HTPR had a higher incidence of MACE than those with non-HTPR (21.1% vs. 9.9%; χ2 = 7.572, P = 0.010).@*Conclusions:@#Our results suggest that advanced age, higher body mass index, treatment with regular dual antiplatelet therapy, diabetes, and CYP2C19*2 or CYP2C19*3 carriers are significantly associated with HTPR to clopidogrel. The predictive model of HTPR has useful discrimination and good calibration and may predict long-term MACE.

A study on platelet reactivity and associated clinical characteristics in acute coronary syndrome patients treated with Ticagrelor and Clopidogrel

Background: The pathophysiology of the acute coronary syndrome (ACS) is characterized by the rupture of an atherosclerotic plaque within the coronary artery, with subsequent platelet aggregation, thrombus formation, and ischemia. Before platelets aggregate, they must first be activated to express activated glycoprotein IIb/IIIa receptors on the cell surface. This activation is the result of stimulation from endogenous platelet agonists, such as thromboxane A2 and adenosine diphosphate (ADP). ADP activates platelets by binding to P2Y12 receptors on the cell surface. Despite clinical efficacy in a broad range of coronary artery disease patients, pharmacodynamic studies conducted in patients undergoing stenting showed that clopidogrel therapy was associated with variable and moderate platelet inhibition (50% inhibition at steady state as demonstrated by ex-vivo ADP-induced platelet aggregation) as well. Ticagrelor, a cyclopentyl-triazolo-pyrimidine acting as an analog of adenosine triphosphate (ATP), constitutes a first non-thienopyridine direct platelet P2Y12 receptor blocker. Aim of the study: To investigate factors linked to HOTPR on ticagrelor and whether they differ from factors linked to HOTPR on clopidogrel. Materials and methods: Totally 300 patients were included in the study Patients presenting to the Department of Cardiology, SRM Medical College Hospital and Research Institute, Kattangulathur, Veeraraghavan Sriram, Venkatesh Munusamy, Dhandapani Vellala Elumalai. A study on platelet reactivity and associated clinical characteristics in acute coronary syndrome patients treated with Ticagrelor and Clopidogrel. IAIM, 2019; 6(8): 26- 34. Page 27 Kanchipuram District, Chennai with an ACS between January 2018 to May 2019 were eligible for inclusion in the study if coronary angiography (±PCI) was planned and they were adequately pretreated with Ticagrelor or clopidogrel and aspirin. An ACS was defined as symptoms suggestive of myocardial ischemia lasting > 15 min with either troponin elevation or new electrocardiogram (ECG) changes consistent with myocardial ischemia. ECG changes consistent with myocardial ischemia included ≥ 1 mm of ST-segment deviation or T wave inversion ≥ 1 mm in at least 2 contiguous leads. Troponin was considered elevated if greater than 14 ng/L, with a rise and/or fall of 50% if 14-50 ng/L or 20% if >50 ng/L in a subsequent measure. Results: The mean age was 63 ± 12 years with 71.9% being male and 18% having diabetes. Patients predominantly presented with NSTEMI 76% and 24% as STEMI. Patients treated with Ticagrelor were younger, more likely to be male, less likely to present with STEMI, have suffered a previous MI, experience atrial fibrillation and be taking proton pump inhibitors or calcium channel blockers. Patients who were administered Ticagrelor demonstrated significantly lower platelet reactivity when stimulated with ADP compared to patients administered clopidogrel (30.3 AU vs 43.7 AU respectively, p<0.0001). Conclusion: This study demonstrates that Ticagrelor provides more potent platelet inhibition than clopidogrel measured by MEA. This is reflected in ticagrelor’s ability to reduce the proportion of ACS patients experiencing HOTPR. Different clinical factors contribute to HOTPR in ACS patients treated with Ticagrelor or clopidogrel. Clopidogrel dose, renal insufficiency, clinical presentation, and platelet count are linked to clopidogrel HOTPR. In contrast, only a history of myocardial infarction is associated with Ticagrelor HOTPR.

Effectiveness of Platelet Function Analyzer-100 for Laboratory Detection of Anti-Platelet Drug-Induced Platelet Dysfunction

BACKGROUND: High on-treatment platelet reactivity (HTPR) is the phenomenon wherein patients exhibit normal platelet activity in laboratory testing despite adequate adherence to anti-platelet treatment. We investigated the detection rates of Platelet Function Analyzer (PFA)-100 (Dade Behring AG, Düdingen, Switzerland) for drug-induced platelet dysfunction and analyzed potential contributors to HTPR with practical PFA-100 data over six years. METHODS: We used data from 6,957 patients who underwent PFA-100 testing after receiving aspirin, clopidogrel, or non-steroidal anti-inflammatory drugs (NSAIDs). Of these, 6,163 patients were tested with only the collagen/epinephrine cartridge (Col/EPI) of PFA-100; 794 were tested with both Col/EPI and the collagen/ADP cartridge (Col/ADP). We calculated PFA-100 closure time (CT) for each drug and compared the clinical and laboratory characteristics of the patients with prolonged CTs and normal CTs (i.e., HTPR). RESULTS: In Col/EPI, 73.2% (365/499), 72.6% (390/537), and 55.3% (3,442/6,228) patients showed prolonged CTs for aspirin, clopidogrel, and NSAIDs, respectively. In Col/ADP, prolonged CTs were observed in 37.4% (34/91), 43.2% (35/81), and 29.6% (200/676) of patients receiving aspirin, clopidogrel, and NSAIDs, respectively. Of the patients tested with both cartridges, 88.9% (48/54), 95.3% (41/43), and 89.0% (577/648) of the patients receiving aspirin, clopidogrel, and NSAIDs had prolonged CTs, and 10.0% (79/794) showed normal CTs regardless of drugs. For clopidogrel users (both cartridges), there were more patients with malignancies in the normal CT than prolonged CT group. CONCLUSIONS: PFA-100 is not sufficiently effective for laboratory screening of drug-induced platelet dysfunction. Malignancy may contribute to clopidogrel-related HTPR in PFA-100.

Current status of secondary prevention medication usage and their relation with on-treatment platelet reactivity / 中国介入心脏病学杂志

Objective To observe the current status of secondary prevention medication usage and their relation with on-treatment platelet reactivity in patients with Acute Coronary Syndrome(ACS) treated with aspirin and clopidogrel. Methods A total of 176 patients hospitalized from 2014 to 2015 due to ACS in the Department of Cardiology, Peking University People's Hospital were enrolled and on-treatment platelet reactivity was tested by thromboelastography(TEG)and CYP2C19*2,*3 and*17 alleles were analysed. Details of secondary prevention medication and patients' clinical characteristics were recorded. The relation of secondary prevention medication and on-treatment platelet reactivity was analyzed by multi-logistic regression after adjusting for CYP2C19 alleles and clinical characteristics covariates.Results A 94.89% of patients was treated with statins while 80.68% with beta blocker. The platelet inhibition rate were (45.33±28.78)% and the high on-treatment platelet reactivity (HTPR) rate tested by TEG was 37.50%. In the multivariate logistic regression analysis, usage of β-blockers during hospitalization as well as phenotypes of CYP2C19*2,*3 and *17,clinical presentation with ST-segment elevation myocardial infarction and the length of stents were associated with HTPR defi ned by TEG. The percentage of HTPR rate was signifi cantly lower in patients treated with than those without β-blockers (72.73% vs. 85.45%,OR 0.18,95%CI 0.06-0.53,P=0.002)after adjusting genetic factors and other covariates.Conclusions There was a signifi cant correlation between beta blockers usage and high clopidogrel on-treatment platelet reactivity.

Obstructive Sleep Apnea Affecting Platelet Reactivity in Patients Undergoing Percutaneous Coronary Intervention / 中华医学杂志(英文版)

<p><b>Background</b>The relationship between obstructive sleep apnea (OSA) and platelet reactivity in patients undergoing percutaneous coronary intervention (PCI) has not been defined. The present prospective, single-center study explored the relationship between platelet reactivity and OSA in patients with PCI.</p><p><b>Methods</b>A total of 242 patients were finally included in the study. OSA was screened overnight by polysomnography. Platelet reactivity was assessed with a sequential platelet counting method, and the platelet maximum aggregation ratio (MAR) and average aggregation ratio were calculated. All patients were assigned per apnea-hypopnea index (AHI) to non-OSA (n = 128) and OSA (n = 114) groups. The receiver operating characteristic curve analysis was used to evaluate the accuracy of AHI for high platelet reactivity (HPR) on aspirin and clopidogrel, and multivariable logistic regression was used to determine the independent predictors of HPR on aspirin and clopidogrel.</p><p><b>Results</b>Median AHI was significantly higher in the OSA group than in the non-OSA group (34.5 events/h vs. 8.1 events/h, Z = -13.422, P < 0.001). Likewise, median arachidonic acid- and adenosine diphosphate-induced maximum aggregation rate (MAR) in the OSA group was significantly higher than those in the non-OSA group (21.1% vs. 17.7%, Z = -3.525, P < 0.001 and 45.8% vs. 32.2%, Z = -5.708, P < 0.001, respectively). Multivariable logistic regression showed that OSA was the only independent predictor for HPR on aspirin (odds ratio [OR]: 1.055, 95% confidence interval [CI]: 1.033-1.077, P < 0.001) and clopidogrel (OR: 1.036, 95% CI: 1.017-1.056, P < 0.001). The cutoff value of AHI for HPR on aspirin was 45.2 events/h (sensitivity 47.1% and specificity 91.3%), whereas cutoff value of AHI for HPR on clopidogrel was 21.3 events/h (sensitivity 68.3% and specificity 67.7%).</p><p><b>Conclusion</b>Platelet reactivity appeared to be higher in OSA patients with PCI despite having received a loading dose of aspirin and clopidogrel, and OSA might be an independent predictor of HPR on aspirin and clopidogrel.</p>

Establishment of a clinical risk score for predicting high on-treatment platelet reactivity in patients with acute myocardial infarction after percutaneous coronary intervention / 第二军医大学学报

Objective To construct a risk score for predicting high on-treatment platelet reactivity (HTPR) in patients with acute myocardial infarction after percutaneous coronary intervention ? so as to guide individualized antiplatelet therapy. Methods A total of 547 patients with acute myocardial infarction undergoing percutaneous coronary intervention in Fuwti Hospital from Jan. 2013 to Dec. 2013 were enrolled in this study ? and their general clinical data and post-operative thrombelastograms (TEG) were collected. The HTPR was defined as ADP-induced platelet-fibrin clot strength (MAADP) by TEG (TEG-MAADP)>47 mm. Clinical factors available in daily routine were analyzed to screen the related risk factors of HTPR. Clinical factors with a significance level of P75 years) was weighted by score 3, female and diabetes mellitus both by score 2 according to OR values, thus a score ranging from 0 to 7 was developed to predict HTPR. The platelet reactivity (TEG-MAADP) was (37. 79 ± 18. 45) mm, (50.04±15.91) mm and (56.50 ± 15.78) mm for score 0-2, 3-5 and 6-7 patients, respectively, and it showed a significant difference among three score ranges (P2 was the best cut-off value to predict HTPR (area under the curve was 0.627,95% CI 0.579-0. 675, P<0. 001). Conclusion Clinical risk score can help to identify patient with high risk of HTPR, so as to guide intensified antiplatelet therapy.

Using IPA rate to assess the high platelet reactivity of patient with coronary heart disease / 实用医学杂志

Objective Using IPA rate to assess platelet reactivity of coronary heart disease patients re-ceived the dual antiplatelet therapy after PCI. Methods CHD patients received the loading dose of clopidogrel (300 mg)on the first day of hospitalization or before PCI,then received clopidogrel(75 mg/d)and aspirin(100 mg/d) for one year. IPA was measured after administration of the loading dose of clopidogrel. The patients were divided into the HPR and LPR group according to the rate of IPA. Observe patients incidences of cardiovascular events were followed up for one year. Results A total of 102 patients were enrolled into this study ,including 77 males and 25 females with average age of 65.7 ± 10.9. Patients were divided into the HPR and LPR group with 69 and 33 patients,respectively. The average IPA value of HPR group was obvious lower than that of LPR group(P<0.01). The accumulative 12-month cardiovascular events incidence in the HPR and LPR group were 15.9% and 3.0% respectively ,with significant difference (P < 0.05). Conclusion IPA could be used to evaluate platelet reactivity,which suggests that clinicians can detect IPA to reduce or avoid the recurrence of cardiovascular events.

Using IPA rate to assess the high platelet reactivity of patient with coronary heart disease / 实用医学杂志

Objective Using IPA rate to assess platelet reactivity of coronary heart disease patients re-ceived the dual antiplatelet therapy after PCI. Methods CHD patients received the loading dose of clopidogrel (300 mg)on the first day of hospitalization or before PCI,then received clopidogrel(75 mg/d)and aspirin(100 mg/d) for one year. IPA was measured after administration of the loading dose of clopidogrel. The patients were divided into the HPR and LPR group according to the rate of IPA. Observe patients incidences of cardiovascular events were followed up for one year. Results A total of 102 patients were enrolled into this study ,including 77 males and 25 females with average age of 65.7 ± 10.9. Patients were divided into the HPR and LPR group with 69 and 33 patients,respectively. The average IPA value of HPR group was obvious lower than that of LPR group(P<0.01). The accumulative 12-month cardiovascular events incidence in the HPR and LPR group were 15.9% and 3.0% respectively ,with significant difference (P < 0.05). Conclusion IPA could be used to evaluate platelet reactivity,which suggests that clinicians can detect IPA to reduce or avoid the recurrence of cardiovascular events.

Effect of CYP2C19 polymorphism on platelet P2Y12 receptor signaling pathway in Chinese patients with stable coronary artery disease after the treatment of clopidogrel / 复旦学报（医学版）

Objective To investigate the molecular mechanism of the effect of CYP2C19 polymorphism on the efficacy of clopidogrel in patients with stable coronary artery disease (SCAD).Methods A total of 208 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) were included.The CYP2C19 variant alleles were detected by gene sequencing.Platelet reactivity was assessed by thrombelastograph at 24 h after 300 mg clopidogrel loading.P2Y12-Gi signaling was measured by flow cytometric analysis of vasodilator-stimulated phosphorylation-platelet reactivity index (VASP-PRI) and Akt phosphorylation (P-Akt) index.Results Among 208 patients,40.9％ were classified as CYP2C19 * 1/* 1 (non-carriers) with no loss-of-function (LOF),44.7％ as CYP2C19 * 1/* 2 or CYP2C19 * 1/* 3 (one LOF carriers) and 14.4％ as CYP2C19 * 2/*2 or CYP2C19 * 2/* 3 (two LOF carriers).Both postclopidogrel platelet aggregation and VASP-PRI increased by the presence of one LOF allele,and were even more pronounced with the presence of two LOF alleles.In contrast,P-Akt index only increased in two LOF carriers.VASP-PRI was positively associated with postclopidogrel platelet aggregation (r =0.661,P＜0.001),but not with P-Akt index.Conclusions The two CYP2C19 LOF carriage was associated with more active state of P2Y12-Gi signaling in postclopidogrel platelet in Chinese patients with SCAD.

Evaluation of clopidogrel response variability and identification of the CYP2C19 polymorphism in Mexican patients / Evaluación de la variabilidad en la respuesta a clopidogrel e identificación del polimorfismo CYP2C19 en pacientes mexicanos

Abstract Objective Drug inhibition of platelet P2Y12 adenosine diphosphate receptor has reduced the incidence of adverse cardiovascular events after percutaneous coronary interventions. The analysis of the phosphorylation status of vasodilator-stimulated phosphoprotein by flow cytometry has shown a predictive value for adverse events and stent thrombosis. Polymorphisms of CYP2C19 in high risk patients may also relate to adverse cardiovascular events. Methods Ninety patients were enrolled. Patients received a 600 mg clopidogrel loading dose. Blood samples were obtained at the time of the procedure and 24 h later, platelet reactivity was assessed by vasodilator-stimulated phosphoprotein phosphorylation measurement using flow cytometry. Low response to clopidogrel was defined as a platelet reactivity index ≥ 50%. The presence of CYP2C19*2 was identified with the restriction enzyme Smal. Results Mean platelet reactivity index: 53.45 ± 22.48% in the baseline sample and 57.14 ± 23.08% at 24 h (p = 0.183); 40% of patients behaved as good responders, the rest behaved as non-responders with 38% of patients showing platelet reactivity indexes between 50-70% and 22% showing indexes above 70%. The CYP2C19*2 polymorphism was found in 17% of patients, with a 3.9% AA homozygous genotype carriers. Conclusion Response to the clopidogrel loading dose showed a wide variability among patients with 40% responding to the drug according to previously established cut-off values. Our results showed that 3.9% of patients show the AA genotype. To our knowledge, this is the first study involving clopidogrel response by flow citometry and genotype typification in Mexican Mestizo population.

Resumen Objetivo La inhibición del receptor plaquetario P2Y12 se ha asociado con reducción en incidencia de eventos cardiovasculares mayores en pacientes sometidos a intervenciones coronarias percutáneas. El estudio de la fosfoproteína estimulada por vasodilatadores mediante citometría de flujo tiene valor predictivo para desarrollo de eventos adversos y trombosis del stent. Los polimorfismos del CYP2C19 en pacientes de alto riesgo pueden también asociarse con eventos adversos. Método 90 pacientes, dosis de carga de clopidogrel: 600 mg. Se obtuvieron muestras de sangre basales y post-24 horas. La reactividad plaquetaria se estudió mediante medición de fosfoproteína estimulada por vasodiatadores por citometría de flujo. Se consideró baja respuesta al clopidogrel un índice de reactividad plaquetaria ≥50%. La presencia del CYP2C19*2 se identificó con enzima de restricción Smal. Resultados La media del índice de reactividad plaquetaria fue: 53.45 ± 22.48% en muestras basales y 57.14 ± 23.08% a 24 h (p = 0.183); 40% de los pacientes repondieron a clopidogrel, el resto de comportó como no-respondedores, un 38%, mostró índices de reactividad plaquetaria entre 50 -70% y 22%, índices > 70%. El polimorfismo CYP2C19*2 se encontró en 17% pacientes, con un 3.9% portadores de genotipo homozigótico AA. Conclusiones La respuesta a clopidogrel mostró amplia variabilidad entre pacientes, el 40% presentó respuesta de acuerdo con puntos de corte pre establecidos. Un 3.9% de los pacientes presentó genotipo AA. Consideramos que este es el primer estudio realizado en población mestizo-mexicana utilizado citometría de flujo para evaluar la respuesta a clopidogrel así como la tipificación genética de los pacientes.

Effect of Ticagrelor versus Prasugrel on Platelet Reactivity:A Meta-analysis / 中国药房

OBJECTIVE:To systematically review the effect of ticagrelor versus prasugrel on platelet reactivity,and provide evi-dence-based reference for clinical treatment. METHODS:Retrieved from PubMed,CJFD and Wanfang Database,randomized con-trolled trials(RCT)about the effect of ticagrelor versus prasugrel on platelet reactivity were collected. Meta-analysis was performed by using Rev Man software after data extract and quality evaluation by Cochrane 5.1.0. RESULTS:Totally 17 RCTs were enrolled,involv-ing 2 757 patients. Results of Meta-analysis showed,regardless of Verity Now(VN)detection method [MD=15.43,95%CI(-0.39, 31.25),P=0.06] or vasodilator stimulus phosphoprotein(VASP)detection method [MD=-3.04,95%CI(-8.98,2.90),P=0.32], ticagrelor and prasugrel had the same effects on platelet reactivity under loading dose,the differences were not statistically significant;regardless of VN detection method [MD=-48.94,95%CI(-58.04,-39.84),P<0.001] or VASP detection method [MD=-14.32, 95%CI(-20.45,-8.20),P<0.001],the effects of ticagrelor were better than prasugrel on platelet reactivity under maintenance dose,the differences were statistically significant. CONCLUSIONS:At the loading dose,there was no difference between ticagrelor and prasugrel,but ticagrelor has more benefits than prasugrel under maintenance dose.

Safety and efficacy of policosanol in elder patients with high on-treatment platelet reactivity after ;drug-eluting stent implantation:a subgroup analysis of the SPIRIT study / 中国介入心脏病学杂志

Objective To explore the safety and efficacy of policosanol in elder patients with high on-treatment platelet reactivity ( HPR) after drug-eluting stent ( DES) implantation. Methods This study was a prespecified subgroup analysis of the multicenter, randomized SPIRIT trial,in which there were a total of 169 elder patients (≥60 years old) with HPR. Among these patients, 30 patients were in group A ( given clopidogrel 75 mg/d for one year) , 75 patients in group B ( given clopidogrel 150 mg/d for 30 days followed by 75 mg/d until one year ) and 64 patients in group C ( given policosanol 40 mg/d for 6 month and clopidgrel 75 mg/d for one year ) . All patients were treated with aspirin at the same time. The primary endpoint was the reversion rate of HPR at 30 days (reversion was defined as platelet aggregation ﹤65%). The secondary endpoint was 2-year major adverse cardiac events ( MACE ) rate, which included cardiac death, non-fatal myocardial infarction and ischemic symptoms driven target vessel revascularization. The safety endpoint was any bleeding as defined by the Bleeding Academic Research Consortium ( BARC ) definition. Results At 30 days, the reversion rate of HPR in group C was numerically higher as compared with group A ( 42. 9% vs. 23. 3. 0%, P=0. 068 ) , and similar with group B ( 42. 9% vs. 49. 3%, P=0.447). MACE occurred in 4 (13.3%), 5(6.7%) and 3(4.7%) patients in group A, B and C respictively ( P=0. 352). Bleeding events in group A and group C were both markedly lower in comparison to group B (3. 3% vs. 17. 3% vs. 1. 6%, P=0. 001). At the 24-month follow-up, the MACE-free survival rates were not significantly different (95. 3% vs. 93. 3% vs. 86. 7%, P=0. 146). Conclusions For elder patients with HPR, policosanol reduced platelet reactivity to a similar extent in comparison of high maintenance dose of clopidogrel without increasing bleeding risk.

High residual platelet reactivity in patients with acute coronary syndrome and diabetes mellitus receiving dual antiplatelet therapy with clopidogrel or ticagrelor and its influence on prognosis / 中国介入心脏病学杂志

Objective To observe high residual platelet reactivity in patients with acute coronary syndrome and diabetes mellitus receiving dual antiplatelet therapy with clopidogrel or ticagrelor and its influence on prognosis. Methods A total of 175 patients with acute coronary syndrome and diabetes mellitus in Wuhan Asia Heart Hospital were included in this retrospective study, and all patients were divided into two groups : ticagrelor group ( n = 22 ) and clopidogrel group ( n = 153 ) . The platelet aggregation function was tested by light transmission platelet aggregation (LTA). The high residual platelet reactivity was defined as maximum platelet aggregation rate ﹥46. 0%. The differences of high residual platelet reactivity and the effect of high residual platelet reactivity on cardiovascular events were compared between the two groups. Results The number of patients with high residual platelet reactivity in the clopidogrel group were 99 patients (64. 7%), and 8 patients(36. 4%) in the ticagrelor group (P=0. 011) . For stent thrombosis developed in three months, 3 patients were from the high residual platelet reaction group ( n=107 ) , none from the normal residual platelet reaction group ( n =68 ) ( P =0. 016 ) . For bleeding events at 3 months, there were 2 patients (1. 9%, 2/107) from the high residual platelet reaction group and 2 patients (2. 9%, 2/68) were from the normal residual platelet reaction group (P=0. 631). Conclusions Ticagrelor significantly decreases high residual platelet reactivity than clopidogrel. High residual platelet reactivity increases stent thrombosis risk for ACS and type 2 diabetes mellitus.

Correlation study of gene polymorphism of CYP2 C19 and clopidogrel response after percutaneous translu-minal angioplasty and stenting in patients with ischemic cerebrovascular disease / 医学研究生学报

Objective There is little research on the relationship of gene polymorphism of CYP2C19 and clopidogrel response after percutaneous transluminal angioplasty and stenting ( PTAS) in patients with ischemic cerebrovascular disease.The study aimed to investigate the relationship between gene polymorphism and high on-treatment platelet reactivity ( HTPR ) after PTAS and 6 months of regular dual antiplatelet administration in patients. Methods A total of 145 Chinese patients treated with PTAS in our de-partment from January 2011 to March 2014 were enrolled in this study.According to the gene sequencing, patients were divided into wild-type group(CYP2C19*1/*1,69 cases) and mutation group(heterozygous mutation CYP2C19*1/*2 and homozygous mutation CYP2C19*2/*2, 76 cases).Patients received a 100mg/d aspirin and 75mg/d clopidogrel maintenance dose (MD) as dual anti-platelet therapy after PTAS.The clopidogrel inhibition effect was measured by thrombelastography ( TEG) system 6 months after PTAS. Routine cerebral artery digital subtraction angiography was applied to evaluate whether there was restenosis in stent and logistic regres-sion analysis was used to analyze the influential factors of HTPR after PTAS and clopidogrel adminstration. Results After 6 months'regular administration of clopidogrel after PTAS, the platelet adenosine diphosphate ( ADP ) receptor inhibition rates in wild-type group, heterozygous mutation and homozygous mutation group were respectively (58.43 ±21.98)%, (47.80 ±22.93)%, (37.53 ± 21.84)%.The platelet ADP receptor inhibition rate was significantly decreased compared with wild-type group(P=0.001).Carriers of at least one CYP2C19 loss-of-function ( LOF) allele had a higher frequency of clopidogrel HTPR (35.5% vs17.4 % for patients with and without LOF alleles, respectively;P=0.014) .Using multivariate logistic regression analysis, the carriage of CYP2C19 LOF alleles was an independent predictor of the post-procedure HTPR (OR=2.356, 95% CI:1.053-5.272, P=0.037).The rate of ISR was remarkably higher in patients with at least one CYP2C19*2 alleles compared with wild-type patients(11.8%vs 1.4%, P=0.019) . Conclusion In patients with ischemic cerebrovascular disease, the CYP2C19 LOF allele had significant impact on post-procedure clopidogrel HTPR and the prognosis of ISR after PTAS.

Antiplatelet Effect of Clopidogrel Can Be Reduced by Calcium-Channel Blockers

PURPOSE: Clopidogrel is metabolized by the hepatic cytochrome P450 (CYP) system into its active thiol metabolite. CYP3A4 is involved in the metabolism of both clopidogrel and dihydropyridine calcium channel blockers (CCBs). A few reports have suggested an inhibitory interaction between CCBs and clopidogrel. Accordingly, the aim of this study was to determine the effect of CCBs on the antiplatelet activity of clopidogrel by serial P2Y12 reaction unit (PRU) measurements. MATERIALS AND METHODS: We assessed changes in antiplatelet activity in patients receiving both clopidogrel and CCBs for at least 2 months prior to enrollment in the study. The antiplatelet activity of clopidogrel was measured by VerifyNow P2Y12 assay in the same patient while medicated with CCBs and at 8 weeks after discontinuation of CCBs. After discontinuation of the CCBs, angiotensin receptor blockers were newly administered to the patients or dosed up for control of blood pressure. RESULTS: Thirty patients finished this study. PRU significantly decreased after discontinuation of CCBs (238.1+/-74.1 vs. 215.0+/-69.3; p=0.001). Of the 11 patients with high post-treatment platelet reactivity to clopidogrel (PRU> or =275), PRU decreased in nine patients, decreasing below the cut-off value in seven of these nine patients after 8 weeks. Decrease in PRU was not related to CYP2C19 genotype. CONCLUSION: CCBs inhibit the antiplatelet activity of clopidogrel.

The Impact of Smoking on Post-Clopidogrel Platelet Reactivity in Patients With Acute Myocardial Infarction

BACKGROUND AND OBJECTIVES: Smoking increases inhibition of clopidogrel-induced platelet reactivity in patients undergoing elective coronary stenting. However, an association between pre-admission smoking (PS) and post-clopidogrel platelet reactivity in patients with acute myocardial infarction (AMI) has not been determined. SUBJECTS AND METHODS: Study cohorts were recruited from a pool of patients at our hospital who were undergoing coronary stenting for AMI (n=134). Immediately after arrival at the emergency room (ER), all patients received a 600 mg loading dose of clopidogrel followed by a maintenance dose of 75 mg/day. Platelet aggregation was measured with light transmittance aggregometry (LTA) after addition of 5 or 20 micromol/L adenosine diphosphate (ADP). RESULTS: Maximal platelet aggregation (Agg(max)) was lower in PS patients after 5 micromol/L ADP (43.6+/-15.7% vs. 48.4+/-12.5%, p=0.096) and 20 micromol/L ADP stimuli (56.2+/-15.6% vs. 61.3+/-11.6%, p=0.073) compared with non-smoking (NS) patients. However, there were no differences in 5 micromol/L (42.6+/-16.3% vs. 43.8+/-15.6%, p=0.776) and 20 micromol/L ADP-induced Agg(max) (54.8+/-14.3% vs. 56.5+/-15.9%, p=0.692) between PS patients or =0.5 pack/day. Although more PS patients met the criteria for low post-clopidogrel platelet reactivity (LPPR) (< or =37%; the lowest quartile of 5 micromol/L ADP-induced Agg(max)) than NS patients (30.9% vs. 13.5%, p=0.048), advancing age was the only independent predictor of LPPR {odds ratio (OR) 0.960, 95% confidence interval (CI) 0.929 to 0.993, p=0.019}. CONCLUSION: PS is significantly not associated with decreased residual platelet reactivity in AMI patients.