Safety of early surgery for geriatric hip fracture patients taking clopidogrel: a retrospective case-control study of 120 patients in China / 中华医学杂志(英文版)

BACKGROUND@#Geriatric hip fracture patients receiving clopidogrel are a surgical challenge. In China, most of these patients undergo delayed surgical treatment after clopidogrel withdrawal for at least 5 to 7 days. However, delayed surgery is associated with increased complications and mortality in the older adults. This retrospective paralleled comparison study investigated the safety of early surgery for geriatric hip fracture patients within 5 days of clopidogrel withdrawal.@*METHODS@#Acute hip fracture patients (≥65 years) who were hospitalized in the orthogeriatric co-management ward of Beijing Jishuitan Hospital between November 2016 and April 2018 were retrospectively reviewed. Sixty patients taking clopidogrel before injury and discontinued  0.050). The percentages of patients with coronary heart disease (61.7% vs. 18.3%; P  0.050). There was no significant difference in perioperative complications, and 30-day and 1-year mortality rates between the groups.@*CONCLUSIONS@#Early hip fracture surgery is safe for elderly patients within 5 days of clopidogrel withdrawal, without increased perioperative blood loss, transfusion requirement, complications, and mortality compared with patients not taking antiplatelet drugs.

The variation of serum uric acid levels among patients with myocardial infarction treated with ticagrelor and the association between serum uric acid and platelet reactivity / 中华心血管病杂志

Objectives: To compare the impact of ticagrelor or clopidogrel on serum uric acid levels among patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) and further evaluate the effects of variation of serum uric acid levels on platelet reactivity. Methods: STEMI patients who admitted to Fuwai Hospital from April 2017 to January 2020, and underwent primary PCI and discharged alive with aspirin and ticagrelor or clopidogrel were included in this study. Patients were divided into ticagrelor group and clopidogrel group. The baseline clinical data were collected. Serum uric acid and creatinine levels at baseline and 30 days post-PCI were measured. Light transmittance aggregometry was used to assess maximum aggregation rate induced by adenosine diphosphate and arachidonic acid. The changes of serum uric acid and creatinine were compared between the two groups. Multivariate logistic regression was performed to evaluate independent related factors for rise in the uric acid levels, and the effect of variation of serum uric acid level on platelet reactivity was analyzed. Results: A total of 967 patients were included, the age was (59.4±12.1) years, and 163 case were female. There were 550 cases in ticagrelor group (56.9%) and 417 cases in clopidogrel group (43.1%). Baseline serum uric acid and creatinine levels were similar between the 2 groups. At 30 days, the serum uric acid level [(347.2±96.5) mmol/L vs. (341.2±105.3) mmol/L, P=0.009] and absolute [46.4 (-2.4, 88.1) mmol/L vs. 25.0 (-21.9, 73.0) mmol/L, P=0.001] and percentage [13.2 (-0.01, 29.0) % vs. 7.9 (-5.7, 25.0) %, P=0.007] increase in the serum uric acid levels were significantly higher in ticagrelor group than in clopidogrel group. The level of serum creatinine at 30 days was significantly lower in ticagrelor group than in clopidogrel group [(89.7±21.3) μmol/L vs. (94.4±43.9) μmol/L, P<0.05], whereas there were no differences in absolute [8.0 (-1.4, 16.6) μmol/L vs. 7.8 (-2.0, 16.6) μmol/L] and percentage [10.5 (-1.7%, 22.6%) vs. 9.8 (-2.4%, 22.1%)] change in the serum creatinine between the 2 groups (all P>0.05). Logistic regression analysis showed that, after adjusting for confounding factors, ticagrelor therapy was an independent related factor of serum uric acid elevation (OR=1.582, 95% CI:1.023-2.447, P=0.039). The variation of the serum uric acid levels did not affect platelet aggregation and the percentage of high platelet reactivity in both groups. Conclusions: Ticagrelor use is related to a significant increase in the serum uric acid levels at 30 days post-PCI in this patient cohort. The variations in the uric acid levels do not increase the percentage of high platelet reactivity in STEMI patients treated with ticagrelor or clopidogrel.

Diferencias en el tratamiento antitrombótico y pronóstico en función del sexo en pacientes con síndrome coronario agudo tratados con stent / Sex-specific differences in antithrombotic therapy and prognosis in patients with acute coronary syndrome treated with stent

Resumen Antecedentes y objetivo: El interés sobre la influencia del sexo en pacientes con síndrome coronario agudo (SCA) tratados con stent y nuevos antiagregantes inhibidores de P2Y12 en la práctica clínica es creciente. Se analizan las diferencias en función del sexo en el tratamiento con doble antiagregación plaquetaria (DAPT) y los eventos adversos isquémicos y hemorrágicos Materiales y métodos: Estudio prospectivo de pacientes consecutivos con diagnóstico de SCA tratados con stent coronario desde julio de 2015 hasta enero de 2016. Resultados: De un total de 283 pacientes incluidos, 75 (26.5%) correspondió a mujeres y 208 (73.5%) a hombres. La edad media fue de 71 ± 13 y 66.5 ± 13 años, respectivamente. Un 44% de mujeres se presentó como SCA con elevación del segmento ST contra un 52.4 de los hombres, p = 0.21. Las mujeres mostraron un mayor riesgo de sangrado (CRUSADE), sin diferencias en el riesgo isquémico (GRACE y TIMI). Se usaron stents farmacoactivos con más frecuencia en mujeres (88.9 vs. 75.5%, p = 0.04). Se observó una tendencia de menor prescripción del ticagrelor en mujeres (42.6 vs. 50.9%, p = 0.29) en favor de un mayor uso del clopidogrel. No se identificaron diferencias en cuanto a la prescripción del prasugrel. Las mujeres presentaron al año una menor mortalidad (1.4 vs. 6.7%, p = 0.19), aunque mayor sangrado (23.3 vs. 17.4%, p = 0.27). Conclusiones: En este estudio de pacientes consecutivos con SCA tratados con stent se registró una mayor prescripción de clopidogrel en las mujeres que en los hombres. Las mujeres presentaron una menor incidencia anual de mortalidad, pero mayor sangrado en comparación con los hombres, no significativo.

Abstract Aims and objective: Impact of sex-related differences in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention and treated with new P2Y12 inhibitors is not adequately characterised. We aimed to analyse gender-based differences in dual antiplatelet therapy, and adverse cardiovascular events and bleeding. Materials and methods: Prospective-observational study of the consecutive ACS patients treated with stent from July 2016 to January 2016, with a follow-up of 1 year. Results: We examined 283 patients, 75 (26.5%) women and 208 (73.5%) men. Women were older than men (71 ± 13 vs. 66,5 ± 13 years). There were 44% of women and 52% of men presenting with ST-elevation ACS (p = 0.21). Women had a higher bleeding risk (CRUSADE), without differences in the ischaemic risk (GRACE and TIMI). More women were treated with drug-eluting stent (88.9 vs. 75.5%, p = 0.04). There was a lower rate of ticagrelor prescription in women (42.6 vs. 50.9%, p = 0.29), in favour of clopidogrel. No differences were observed in prasugrel prescription. No significant differences were observed after a year of follow up, but women had a tendency towards lower mortality (1.4 vs. 6.7%, p = 0.19) and higher bleeding rates (23.3 vs. 17.4%, p = 0.27). Conclusions: In our study of patients presenting with ACS treated with stent, clopidogrel was preferred in women, whereas ticagrelor was the most frequent prescription in men. No significant differences were noted in clinical outcomes, but women experienced a tendency towards less mortality and more bleeding events.

Status quo and countermeasure of clopidogrel resistance predicted by gene testing / 中华医学遗传学杂志

Clopidogrel is the cornerstone of antiplatelet therapy, but there are ethnic and individual differences in the suppression of platelets. Some patients regularly taking drugs still cannot prevent the recurrence of cardio- and cerebrovascular thrombosis, thereby manifest low drug reactivity, i.e., clopidogrel resistance. Genetic polymorphism is the main reason for individual difference. Genetic testing has been used for evaluating the efficacy of antiplatelet therapy, adjusting therapeutic plan, and predicting the risk of cardio- and cerebrovascular thromboembolic events by determining the genetic polymorphisms related with antiplatelet drugs. This article provides a review for the status quo and countermeasure of clopidogrel resistance predicted by gene testing.

Impact of Baseline Bleeding Risk on Efficacy and Safety of Ticagrelor versus Clopidogrel in Chinese Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention / 中华医学杂志(英文版)

Background@#There was still conflict on the antithrombotic advantage of ticagrelor versus clopidogrel among East Asian population with acute coronary syndrome (ACS). We considered that the baseline bleeding risk might be an undetected key factor that significantly affected the efficacy of ticagrelor.@*Methods@#A total of 20,816 serial patients who underwent percutaneous coronary intervention (PCI) from October 2011 to August 2014 in the General Hospital of Shenyang Military Region were enrolled in the present study. Patients receiving ticagrelor or clopidogrel were further subdivided according to basic bleeding risk. The primary outcome was net adverse clinical events (NACEs) defined as major adverse cardiac or cerebral events (MACCE, including all-cause death, myocardial infarction, ischemia-driven target vessel revascularization, or stroke) and any bleeding during 1-year follow-up. Comparison between ticagrelor and clopidogrel was adjusted by propensity score matching (PSM).@*Results@#Among the 20,816 eligible PCI patients who were included in this study, there were 1578 and 779 patients in the clopidogrel and ticagrelor groups, respectively, after PSM, their clinical parameters were well matched. Patients receiving ticagrelor showed comparable NACE risk compared with those treated by clopidogrel (5.3% vs. 5.1%, P = 0.842). Furthermore, ticagrelor might reduce the MACCE risk in patients with low bleeding risk but increase MACCE in patients with moderate-to-high bleeding potential (ticagrelor vs. clopidogrel, low bleeding risk: 2.5% vs. 4.9%, P = 0.022; moderate-to-high bleeding risk: 4.8% vs. 3.0%, P = 0.225; interaction P = 0.021), with vast differences in all bleeding (low bleeding risk: 1.5% vs. 0.8%, P = 0.210; moderate-to-high bleeding risk: 4.8% vs. 3.0%, P = 0.002; interaction P = 0.296).@*Conclusion@#Among real-world Chinese patients with ACS treated by PCI, ticagrelor only showed superior efficacy in patients with low bleeding risk but lost its advantage in patients with moderate-to-high bleeding potential.

Evidencias para el uso combinado de ácido acetilsalicílico (aspirina) y clopidogrel en síndromes coronarios agudos / Evidences about combination use of acetylsalicylic acid (aspirin) and clopidogrel in acute coronary syndrome

Las enfermedades tromboembólicas siguen siendo una de las causas más importantes de morbilidad y mortalidad en todo el mundo. El mecanismo fisiopatológico subyacente en los síndromes coronarios agudos es la trombosis coronaria. Por eso, la base de su tratamiento se ha centrado en los fármacos antiplaquetarios, fibrinolíticos y anticoagulantes. En un número importante de individuos deben emplearse medidas adicionales como, por ejemplo, el intervencionismo percutáneo coronario (angioplastia y la colocación de los llamados stentsintracoronarios). La aspirina se ha considerado como el fármaco de primera elección en la prevención de las afecciones tromboembólicas. La combinación aspirina-clopidogrel ha representado una terapéutica sumamente eficiente en el tratamiento de los eventos tromboembólicos. La introducción de tabletas de combinación fija representa un avance para facilitar el cumplimiento de la terapia.

Thromboembolic diseases remain one of the most important causes of morbidity and mortality worldwide. The pathophysiologic mechanism underlying the acute coronary syndromes is coronary thrombosis. That is why the basis of its treatment has focused on antiplatelet, fibrinolytic and anticoagulant drugs. In a significant number of individuals, additional measures must be used, such as, for example, the coronary percutaneous intervention (angioplasty and placement of the so-called intracoronary stents). Aspirin has been regarded as the drug of first choice in the prevention of thromboembolic diseases. The combination aspirin-clopidogrel has represented a highly efficient therapeutic measure for thromboembolic events. The introduction of fixed combination tablets represents a step forward in order to facilitate therapeutic compliance.

Impact of drug combination of clopidogrel and pantoprazole In the prognosis of patients with transient ischemic attack

The study aimed to investigate the impact of clopidogrel combined with proton pump inhibitors [PPI] pantoprazole treatment on the prognosis of patients with transient ischemic attack [TIA]. A total of 478 cases of TIA patients treated with clopidogrel were randomly assigned half to clopidogrel combined with pantoprazole treatment and the control groups [clopidogrel treatment alone] from January 2012 to January 2014. The platelet aggregation before and after treatment and cerebrovascular events incidence within 90 days were compared and analyzed. Multivariate analysis was used to estimate the incidence of cerebrovascular events within 90 days. The platelet aggregation rate before treatment was 73.2 +/- 6.1% in the treatment group, 74.1 +/- 8.8% in the control group. The platelet aggregation rate after treatment was 38.1 +/- 10.7% in the treatment group, 36.8 +/- 9.7% in the control group. The platelet aggregation before and after treatments between the two groups had not significant difference [P>0.05]. The incidence of cerebrovascular events within 90 days [11.7% in the treatment group, 9.6% in the control group] between the two groups had not significant difference [P>0.05]. Multivariate analysis showed that the incidence of cerebrovascular events within 90 day was associated with hypertension [P=0.008], diabetes [P=0.000], hyperlipidemia [P=0.002] and ABCD2 score >3 points [P=0.000]. Clopidogrel combined with pantoprazole treatment had no significant effect on the prognosis of TIA patients

Decreased platelet responsiveness to clopidogrel correlates with CYP2C19 and PON1 polymorphisms in atherosclerotic patients

Clopidogrel and aspirin are the most commonly used medications worldwide for dual antiplatelet therapy after percutaneous coronary intervention. However, clopidogrel hyporesponsiveness related to gene polymorphisms is a concern. Populations with higher degrees of genetic admixture may have increased prevalence of clopidogrel hyporesponsiveness. To assess this, we genotyped CYP2C19, ABCB1, and PON1 in 187 patients who underwent percutaneous coronary intervention. Race was self-defined by patients. We also performed light transmission aggregometry with adenosine diphosphate (ADP) and arachidonic acid during dual antiplatelet therapy. We found a significant difference for presence of the CYP2C19*2 polymorphism between white and non-white patients. Although 7% of patients had platelet resistance to clopidogrel, this did not correlate with any of the tested genetic polymorphisms. We did not find platelet resistance to aspirin in this cohort. Multivariate analysis showed that patients with PON1 and CYP2C19 polymorphisms had higher light transmission after ADP aggregometry than patients with native alleles. There was no preponderance of any race in patients with higher light transmission aggregometry. In brief, PON1 and CYP2C19 polymorphisms were associated with lower clopidogrel responsiveness in this sample. Despite differences in CYP2C19 polymorphisms across white and non-white patients, genetic admixture by itself was not able to identify clopidogrel hyporesponsiveness.

Influence of CYP2C19 gene polymorphisms on the efficacy of clopidogrel treatment for the prevention of ischemic stroke following coronary stent implantation / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To assess the association of CYP2C19 gene polymorphisms with the incidence of ischemic stroke among patients receiving clopidogrel therapy following coronary stenting for coronary artery disease.</p><p><b>METHODS</b>Clinical data of patients receiving clopidogrel therapy after coronary stenting were retrospectively studied. For a case-control study, 137 patients with acute cerebral infarction and 122 non-stroke patients were selected. Based on the variants of the CYP2C19 gene detected by a DNA microarray assay, the patients were further divided into the wild-type group(CYP2C19*1/*1) and mutant group(defined by the presence of at least one loss-of-function allele, including CYP2C19*1/*2, CYP2C19*1/*3, CYP2C19*2/*2, CYP2C19*2/*3 and CYP2C19*3/*3). The incidences of ischemic stroke in the two groups were compared through a chi-square analysis. The influence of CYP2C19 gene polymorphisms and clopidogrel therapy on the incidence of ischemic stroke was analyzed through multivariable logistic regression.</p><p><b>RESULTS</b>A total of 259 patients were enrolled. The case and control groups showed no difference in terms of gender and age. There were 123 cases (47.5%) in the CYP2C19 wild-type group and 136 cases (52.5%) in the mutant group. The incidence of ischemic stroke of mutant group was significantly higher than that of wild-type group (59.9% vs. 44.3%, X2=6.398, P=0.042). Multivariate analysis revealed that loss-of-function polymorphisms of the CYP2C19 gene carried a 1.13 times greater risk for ischemic stroke compared to wild-type genotype (OR=2.13, 95%CI: 1.23-3.71).</p><p><b>CONCLUSION</b>The efficacy of clopidogrel for the prevention of ischemic stroke in post-coronary stent patients may be reduced by the insufficiency of the CYP2C19 gene. The dosage of clopidogrel therapy should be adjusted based on its polymorphisms.</p>

Clinical Pharmacogenetic Testing and Application: Laboratory Medicine Clinical Practice Guidelines

Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings.

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.

Time-To-Treatment of Acute Coronary Syndrome and Unit of First Contact in the ERICO Study / Tempo para Tratamento durante Síndrome Coronariana Aguda e Unidade de Primeiro Contato no Estudo ERICO

Abstract Background: To the best of our knowledge, there are no studies evaluating the influence of the unit of the first contact on the frequency and time of pharmacological treatment during an acute coronary syndrome (ACS) event. Objectives: The main objective was to investigate if the unit of first contact influenced the frequency and time of aspirin treatment in the Strategy of Registry of Acute Coronary Syndrome (ERICO) study. Methods: We analyzed the pharmacological treatment time in 830 ERICO participants - 700 individuals for whom the hospital was the unit of first contact and 130 who initially sought primary care units. We built logistic regression models to study whether the unit of first contact was associated with a treatment time of less than three hours. Results: Individuals who went to primary care units received the first aspirin dose in those units in 75.6% of the cases. The remaining 24.4% received aspirin at the hospital. Despite this finding, individuals from primary care still had aspirin administered within three hours more frequently than those who went to the hospital (76.8% vs 52.6%; p<0.001 and 100% vs. 70.7%; p=0.001 for non ST-elevation ACS and ST-elevation myocardial infarction, respectively). In adjusted models, individuals coming from primary care were more likely to receive aspirin more quickly (odds ratio: 3.66; 95% confidence interval: 2.06-6.51). Conclusions: In our setting, individuals from primary care were more likely to receive aspirin earlier. Enhancing the ability of primary care units to provide early treatment and safe transportation may be beneficial in similar settings.

Resumo Fundamento: Em nosso conhecimento, não há estudos que avaliam a influência da unidade de primeiro contato na frequência e tempo para o tratamento farmacológico durante um evento de síndrome coronariana aguda (SCA). Objetivos: O principal objetivo foi investigar se a unidade de primeiro contato influencia a frequência e o tempo para tratamento com aspirina no estudo "Estratégia de Registro de Insuficiência Coronariana" (ERICO). Métodos: Analisamos o tempo para o tratamento farmacológico em 830 participantes do estudo ERICO - 700 indivíduos cuja primeira unidade de contato foi o hospital, e 130 que procuraram, num primeiro momento, unidades de atenção primária. Construímos modelos de regressão logística para estudar se a unidade de primeiro contato estava associada a um tempo de tratamento de menos de três horas. Resultados: Indivíduos que buscaram unidades de atenção primária receberam a primeira dose de aspirina nestas unidades em 75,6% dos casos. Os outros 24,4% receberam a aspirina no hospital. Apesar deste achado, indivíduos de unidades de atenção primária receberam aspirina em três horas mais frequentemente do que aqueles que foram ao hospital (76,8% vs 52,6%; p<0,001 e 100% vs, 70,7%; p=0,001 para SCA sem elevação do segmento ST e infarto agudo do miocárdio com elevação do ST, respectivamente). Em modelos ajustados, indivíduos vindos de unidades de atenção primária tinham mais probabilidade de receber aspirina mais rapidamente (razão de chances: 3,66; 95% intervalo de confiança: 2,06-6,51). Conclusões: Neste contexto, indivíduos provenientes de unidades de atenção primária tinham maior chance de receber aspirina mais rapidamente. O aprimoramento da capacidade das unidades de atenção primária para proporcionar tratamento precoce e transporte seguro pode ser benéfico em contextos similares.

Clopidogrel use after myocardial revascularization: prevalence, predictors, and one-year survival rate

Abstract Introduction: Antiplatelet therapy after coronary artery bypass graft (CABG) has been used. Little is known about the predictors and efficacy of clopidogrel in this scenario. Objective: Identify predictors of clopidogrel following CABG. Methods: We evaluated 5404 patients who underwent CABG between 2000 and 2009 at Duke University Medical Center. We excluded patients undergoing concomitant valve surgery, those who had postoperative bleeding or death before discharge. Postoperative clopidogrel was left to the discretion of the attending physician. Adjusted risk for 1-year mortality was compared between patients receiving and not receiving clopidogrel during hospitalization after undergoing CABG. Results: At hospital discharge, 931 (17.2%) patients were receiving clopidogrel. Comparing patients not receiving clopidogrel at discharge, users had more comorbidities, including hyperlipidemia, hypertension, heart failure, peripheral arterial disease and cerebrovascular disease. Patients who received aspirin during hospitalization were less likely to receive clopidogrel at discharge (P≤0.0001). Clopidogrel was associated with similar 1-year mortality compared with those who did not use clopidogrel (4.4% vs. 4.5%, P=0.72). There was, however, an interaction between the use of cardiopulmonary bypass and clopidogrel, with lower 1-year mortality in patients undergoing off-pump CABG who received clopidogrel, but not those undergoing conventional CABG (2.6% vs 5.6%, P Interaction = 0.032). Conclusion: Clopidogrel was used in nearly one-fifth of patients after CABG. Its use was not associated with lower mortality after 1 year in general, but lower mortality rate in those undergoing off-pump CABG. Randomized clinical trials are needed to determine the benefit of routine use of clopidogrel in CABG.

When is the Best Time for the Second Antiplatelet Agent in Non-St Elevation Acute Coronary Syndrome? / Qual o Melhor Momento para o Segundo Antiplaquetário na Síndrome Coronariana Aguda sem Elevação do ST?

Abstract Dual antiplatelet therapy is a well-established treatment in patients with non-ST elevation acute coronary syndrome (NSTE-ACS), with class I of recommendation (level of evidence A) in current national and international guidelines. Nonetheless, these guidelines are not precise or consensual regarding the best time to start the second antiplatelet agent. The evidences are conflicting, and after more than a decade using clopidogrel in this scenario, benefits from the routine pretreatment, i.e. without knowing the coronary anatomy, with dual antiplatelet therapy remain uncertain. The recommendation for the upfront treatment with clopidogrel in NSTE-ACS is based on the reduction of non-fatal events in studies that used the conservative strategy with eventual invasive stratification, after many days of the acute event. This approach is different from the current management of these patients, considering the established benefits from the early invasive strategy, especially in moderate to high-risk patients. The only randomized study to date that specifically tested the pretreatment in NSTE-ACS in the context of early invasive strategy, used prasugrel, and it did not show any benefit in reducing ischemic events with pretreatment. On the contrary, its administration increased the risk of bleeding events. This study has brought the pretreatment again into discussion, and led to changes in recent guidelines of the American and European cardiology societies. In this paper, the authors review the main evidence of the pretreatment with dual antiplatelet therapy in NSTE-ACS.

Resumo A indicação de dupla terapia antiplaquetária para o tratamento da síndrome coronariana aguda sem elevação do ST está bem estabelecida e é recomendação classe I (Nível de Evidência A) nas atuais diretrizes nacionais e internacionais. No entanto, essas mesmas diretrizes não são muito claras e consensuais quanto ao melhor momento para utilização do segundo antiplaquetário. As evidências sobre este tema são conflitantes e, após mais de uma década do uso do clopidogrel neste cenário, ainda há discussão se o pré-tratamento com dupla terapia antiplaquetária teria benefício de maneira rotineira, ou seja, quando aplicada sem conhecer a anatomia coronária. A recomendação de tratamentoupfront com clopidogrel na síndrome coronariana aguda sem elevação do ST se baseia em redução de eventos não fatais identificados em estudos que utilizavam estratégia conservadora, com eventual estratificação invasiva tardia, vários dias após o evento agudo. Essa abordagem é bastante diferente da que é feita atualmente, tendo em vista os benefícios já demonstrados da estratégia invasiva precoce nos pacientes de risco intermediário/alto. O único ensaio clínico randomizado que testou a hipótese do pré-tratamento na síndrome coronariana aguda sem elevação do ST sob a atual estratégia invasiva precoce utilizou o antiplaquetário prasugrel e mostrou que não houve benefício em redução de eventos isquêmicos, tendo, por outro lado, aumentado o risco de eventos hemorrágicos. Este estudo trouxe novamente o pré-tratamento à discussão e modificou recomendações nas atuais diretrizes das sociedades americana e europeia de cardiologia. Neste artigo, os autores apresentam uma revisão sobre as principais evidências do pré-tratamento com dupla terapia antiplaquetária na síndrome coronariana aguda sem elevação do ST.

Correlation between cytochrome 3A4+894C>T P450 gene polymorphism and outcomes of coronary intervention in patients with acute coronary syndrome / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the relationship between plasma cytochrome P450 3A4 (CYP3A4) 894C>T gene polymorphism and the risk of recurrence of adverse cardiac events after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS).</p><p><b>METHODS</b>A total of 275 patients with ACS received standard dual antiplatelet therapy and PCI. Platelet aggregation rate (PAR) was detected in each patient before and 7 days after administration of the anti-platelet drugs. Single nucleotide polymorphism of CYP3A4 gene 894C>T was detected with PCR and microarray technique. The number of coronary artery lesions was determined by PCI and the Gensini score was calculated. The patients were followed up for 3-12 months after discharge.</p><p><b>RESULTS</b>No significant difference was found in CYP3A4 gene polymorphism between patients with clopidogrel resistance (CR group) and those without CR (NCR group) (P>0.05). Multivariate logistic regression analysis showed that CYP3A4 gene 894C>T polymorphism was not correlated with CR in patients with ACS (OR 1.359, P>0.05). During the follow-up, the incidence of cardiovascular events was significantly higher in CR group than in NCR group (P<0.05), but this difference was not related to the mutation type of 894C>T locus of CYP3A4 gene.</p><p><b>CONCLUSION</b>The CYP3A4 gene 894C>T polymorphism is not associated with the effect of anti-platelet therapy and the risk of cardiovascular event in patients with ACS following PCI.</p>

Evaluation of PFA P2Y assay in monitoring platelet function in elderly patients with cardiovascular disease receiving clopidogrel treatment / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate the value of a new platelet function test PFA P2Y (PFA-200) in monitoring clopidogrel treatment for cardiovascular disease in elderly patients.</p><p><b>METHODS</b>Fifty-six elderly patients receiving clopidogrel therapy in the Department of Cardiology of General Hospital of PLA from March to August in 2016 and 85 healthy volunteers were recruited for analysis. All the subjects underwent PFA P2Y, LTA (light transmittance aggregometry) and TEG (Thromboelastograph) tests, and Spearman correlation coefficients were used to test the associations between test results. The agreement among the 3 platelet function test methods was assessed using Cohen's kappa coefficient.</p><p><b>RESULTS</b>Correlation coefficient (r) was -0.701 (P<0.001) between PFA P2Y and LTA, and 0.475 (P<0.001) between PFA P2Y and TEG. The agreement was 75% between PFA P2Y and LTA and 67.9% between PFA P2Y and TEG. The κ value was 0.434 (P=0.001) between PFA P2Y and LTA and 0.242 (P=0.046) between PFA P2Y and TEG. With ADP-induced maximum platelet aggregation rate of LTA >50% as the laboratory clopidogrel resistance, the cut-off value of PFA P2Y was 119 s (AUC=0.733) with a sensitivity of 75.6% and a specificity of 73.3%.</p><p><b>CONCLUSION</b>PFA P2Y has a moderate correlation and agreement with LTA, but has a poor correlation and agreement with TEG. PFA P2Y can be useful for assessing the effects of clopidogrel therapy and the association of the cut-off value (119 s) with the long-term clinical ischemic events needs be confirmed in further study.</p>

Efficacy of Leflunomide, Telmisartan, and Clopidogrel for Immunoglobulin A Nephropathy: A Randomized Controlled Trial / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for immunoglobulin A nephropathy (IgAN) are unclear. This study was designed to evaluate the efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for IgAN.</p><p><b>METHODS</b>It is a multicenter, prospective, double-dummy randomized controlled trial. Primary IgAN patients were recruited in 13 renal units across Beijing, China, from July 2010 to June 2012. After a 4-week telmisartan (80 mg/d) wash-in, 400 patients continuing on 80 mg/d telmisartan were randomly assigned to additionally receive placebo (Group A), 50 mg/d clopidogrel (Group B), 20 mg/d leflunomide (Group C), or 50 mg/d clopidogrel and 20 mg/d leflunomide (Group D). The 24-week intervention was completed by 360 patients. The primary endpoint was change in 24-h proteinuria at 24 weeks. A linear mixed-effect model was used to analyze the changes at 4, 12, and 24 weeks. Generalized estimating equations were used to evaluate changes in hematuria grade. This trial was registered at the Chinese Clinical Trial Registry.</p><p><b>RESULTS</b>The effects of telmisartan combined with leflunomide on changes in proteinuria (0.36 [95% confidence interval (CI) 0.18-0.55] g/d, P < 0.001), in serum uric acid (76.96 [95% CI 57.44-96.49] μmol/L, P < 0.001), in serum creatinine (9.49 [95% CI 6.54-12.44] μmol/L, P < 0.001), and in estimated glomerular filtration rate (-6.72 [95% CI-9.46 to -3.98] ml·min-1·1.73 m-2, P < 0.001) were statistically significant, whereas they were not statistically significant on changes in systolic and diastolic blood pressure and weight (P > 0.05). Telmisartan combined with clopidogrel had no statistical effect on any outcome, and there was no interaction between the interventions. No obvious adverse reactions were observed.</p><p><b>CONCLUSIONS</b>Telmisartan combined with leflunomide, not clopidogrel, is safe and effective for decreasing proteinuria in certain IgAN patients.</p><p><b>TRIAL REGISTRATION</b>chictr.org.cn, ChiCTR-TRC-10000776; http://www.chictr.org.cn/showproj.aspx?proj=8760.</p>

Intensified Antiplatelet Treatment Reduces Major Cardiac Events in Patients with Clopidogrel Low Response: A Meta-analysis of Randomized Controlled Trials / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Clopidogrel low response (CLR) is an independent risk factor of adverse outcomes in patients undergoing percutaneous coronary intervention (PCI), and intensified antiplatelet treatments (IAT) guided by platelet function assays might overcome laboratory CLR. However, whether IAT improves clinical outcomes is controversial.</p><p><b>METHODS</b>Relevant trials were identified in PubMed, the Cochrane Library, and the Chinese Medical Journal Network databases from their establishment to September 9, 2014. Trials were screened using predefined inclusion criteria. Conventional meta-analysis and cumulative meta-analysis were performed using the Review Manager 5.0 and STATA 12.0 software programs.</p><p><b>RESULTS</b>Thirteen randomized controlled trials involving 5111 patients with CLR were recruited. During a follow-up period of 1-12 months, the incidences of cardiovascular (CV) death, nonfatal myocardial infarction (MI), and stent thrombosis were significantly lower in the IAT arm than in the conventional antiplatelet treatment arm (relative risk [RR] = 0.45, 95% confidence interval [CI]: 0.36-0.57, P < 0.000,01), whereas bleeding was similar between the two arms (RR = 1.05, 95% CI: 0.86-1.27, P = 0.65).</p><p><b>CONCLUSIONS</b>IAT guided by platelet function assays reduces the risk of CV death, nonfatal MI, and stent thrombosis (ST) without an increased risk of bleeding in patients undergoing PCI and with CLR.</p>

Head to Head Comparison of Two Point-of-care Platelet Function Tests Used for Assessment of On-clopidogrel Platelet Reactivity in Chinese Acute Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Platelet function tests are widely used in clinical practice to guide personalized antiplatelet therapy. In China, the thromboelastography (TEG) test has been well accepted in clinics, whereas VerifyNow, mainly used for scientific research, has not been used in routine clinical practice. The aim of the current study was to compare these two point-of-care platelet function tests and to analyze the consistency between the two tests for evaluating on-clopidogrel platelet reactivity in Chinese acute myocardial infarction patients undergoing percutaneous coronary intervention (PCI).</p><p><b>METHODS</b>A total of 184 patients admitted to Fuwai Hospital between August 2014 and May 2015 were enrolled in the study. On-clopidogrel platelet reactivity was assessed 3 days after PCI by TEG and VerifyNow using adenosine diphosphate as an agonist. Based on the previous reports, an inhibition of platelet aggregation (IPA) <30% for TEG or a P2Y12 reaction unit (PRU) >230 for VerifyNow was defined as high on-clopidogrel platelet reactivity (HPR). An IPA >70% or a PRU <178 was defined as low on-clopidogrel platelet reactivity (LPR). Correlation and agreement between the two methods were analyzed using the Spearman correlation coefficient (r) and kappa value (κ), respectively.</p><p><b>RESULTS</b>Our results showed that VerifyNow and TEG had a moderate but significant correlation in evaluating platelet reactivity (r = -0.511). A significant although poor agreement (κ = 0.225) in identifying HPR and a significantly moderate agreement in identifying LPR (κ = 0.412) were observed between TEG and VerifyNow. By using TEG as the reference for comparison, the cutoff values of VerifyNow for the Chinese patients in this study were identified as PRU >205 for HPR and PRU <169 for LPR.</p><p><b>CONCLUSIONS</b>By comparing VerifyNow to TEG which has been widely used in clinics, VerifyNow could be an attractive alternative to TEG for monitoring on-clopidogrel platelet reactivity in Chinese patients.</p>

Impact of novel P2Y12 receptor inhibitors on platelet reactivity in acute coronary syndrome patients undergoing percutaneous coronary intervention / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the impact of novel P2Y(12) receptor inhibitors including prasugrel or ticagrelor on platelet reactivity in patients with acute coronary syndrome (ACS) receiving percutaneous coronary intervention (PCI), and provide clinical data for novel oral P2Y(12) receptor inhibitors use among Chinese patients.</p><p><b>METHODS</b>Between October 2011 to February 2014, 174 consecutive patients (135 males; (67.8±11.8) years old) with ACS undergoing PCI in Kiang Wu Hospital, Macau were prospectively enrolled in this study. Oral aspirin and one P2Y(12) receptor inhibitor were administered for 5 days or above after PCI, patients were divided into clopidogrel, prasugrel and ticagrelor groups in accordance with the agent administered. Platelet reactivity of the patients was detected by VerifyNow P2Y(12) reaction unit (PRU); and the high on-treatment platelet reactivity (HPR) and non-HPR were defined as PRU≥208 and PRU<208 respectively. Patients with HPR during clopidogrel therapy were switched either to prasugrel or ticagrelor, or continued the same treatment; and then the platelet reactivity was monitored again.</p><p><b>RESULTS</b>There were 113 clopidogrel cases (64.9%), 20 prasugrel cases (11.5%) and 41 ticagrelor cases (23.6%). Fifty-seven cases (32.8%) were defined as HPR post P2Y(12) receptor inhibitor use, in which 55 cases (55/113, 48.7%) were treated with clopidogrel. The degree of inhibition of platelet reactivity was significantly different in patients on clopidogrel, prasugrel and ticagrelor therapy, percent inhibition assayed by the VerifyNow P2Y(12) system was 28.2%±23.5%, 61.4%±26.7% and 81.3%±19.8% respectively (P<0.05). Different degree of platelet reactivity was achieved by the 3 P2Y(12) receptor inhibitors at multiple time points. The among-group differences in platelet reactivity became apparent at the early treatment stage (P<0.05). Platelet aggregation decreased significantly in patients switched from clopidogrel to prasugrel or ticagrelor (P<0.05).</p><p><b>CONCLUSION</b>Novel oral P2Y(12) receptor inhibitors are more effective in inhibiting platelet reactivity in ACS patients, and our results show that novel oral P2Y(12) receptor inhibitors provide a new option for ACS patients with HPR post clopidogrel or high-risk features of ischemic complications, including stent thrombosis and post-PCI ischemic events.</p>