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.

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 the CYP2C19 Phenotype Status and the Results of Three Different Platelet Function Tests in Cardiovascular Disease Patients Receiving Antiplatelet Therapy: An Emphasis on Newly Introduced Platelet Function Analyzer-200 P2Y Test

BACKGROUND: An association has been reported between CYP2C19 polymorphism and the altered antiplatelet activity of clopidogrel. We investigated this association using the newly introduced platelet function analyzer (PFA)-200 (INNOVANCE PFA-200 System; Siemens Healthcare, Germany) P2Y test. METHODS: Polymorphisms of CYP2C19*2, *3, *17 and the degree of inhibition of platelet function were determined in 83 patients. Three different platelet function tests were used to evaluate the degree of platelet inhibition and to check the association with genotype. RESULTS: The post-procedure PFA-200 values of extensive metabolizers (EM) patients (285.3+/-38.8) were higher than those of intermediate metabolizers (IM) and poor metabolizers (PM) patients (227.7+/-98.3 and 133.7+/-99.2, respectively; P=0.024). Light transmittance aggregometry (LTA) and the VerifyNow system showed that the post-procedure values for EM patients were lower than those of IM and PM patients (LTA: 24.4+/-15.7, 34.1+/-17.6, and 42.2+/-16.9, respectively, P<0.001; VerifyNow: 133.2+/-60.5, 171.5+/-42.6, and 218.7+/-59.3, respectively, P<0.001). The high residual platelet reactivity (HPR) rates were significantly different among the EM, IM, and PM groups using PFA-200 (PM:IM:EM=82.4:40.6:11.8, P<0.001). CONCLUSIONS: Approximately, 59.0% of Korean patients with cardiovascular disease receiving clopidogrel had CYP2C19 loss-of-function genotypes classified as IM or PM, and the frequency was similar to the data from Asian people. The PFA-200, LTA, and VerifyNow platelet function tests revealed evidence of a significant association between the efficacy of clopidogrel and CYP2C19 genotypes.

Cost-effectiveness analysis of ticagrelor compared to clopidogrel for the treatment of patients with acute coronary syndrome in Colombia / Análisis de costo-efectividad del ticagrelor en comparación con el clopidogrel para el tratamiento de pacientes con síndrome coronario agudo en Colombia

Introduction: Acute coronary syndrome is one of the most frequent medical emergencies in developing countries. Objective: To determine, from the perspective of the Colombian health system, the cost-effectiveness of ticagrelor compared to clopidogrel for the treatment of patients with acute coronary syndrome. Materials and methods: We conducted a cost-effectiveness analysis from the perspective of the Colombian health system comparing ticagrelor and clopidogrel for the treatment of patients with acute coronary syndrome. To estimate the expected costs and outcomes, a Markov model was constructed in which patients could remain stable without experiencing new cardiovascular events, suffer from a new event, or die. For the baseline case, a 10-year time horizon and a discount ratio of 3% for costs and benefits were adopted. The transition probabilities were extracted from the PLATO (Platelet Inhibition and Patient Outcomes) clinical trial. Vital statistics were drawn from the Departmento Administrativo Nacional de Estadística (DANE) and additional information from Colombian patients included in the Access registry. To identify and measure resource use, a standard case was built by consulting guidelines and protocols. Unit costs were obtained from Colombian rate lists. A probabilistic sensitivity analysis was conducted in which costs were represented by a triangular distribution, and the effectiveness through a beta distribution. Results: In the base case, the additional cost per quality-adjusted life-year gained with ticagrelor was COP$ 28,411,503. The results were sensitive to changes in the time horizon and the unit cost of clopidogrel. For a willingness-to-pay equivalent to three times the Colombian per capita gross domestic product, the probability of ticagrelor being cost-effective was 75%. Conclusions: Ticagrelor is a cost-effective strategy for the treatment of patients with acute coronary syndrome in Colombia.

Introducción. El síndrome coronario agudo es una de las emergencias médicas más frecuentes en los países en desarrollo. Objetivo. Determinar, desde la perspectiva del sistema de salud colombiano, la relación de costo-efectividad del ticagrelor comparado con el clopidogrel para el tratamiento de pacientes con síndrome coronario agudo. Materiales y métodos. Se hizo un análisis de costo-efectividad desde la perspectiva del sistema de salud colombiano, comparando el ticagrelor y el clopidogrel para el tratamiento de pacientes con síndrome coronario agudo. Para estimar los costos y resultados esperados de las dos alternativas, se construyó un modelo de Markov en el cual los pacientes podían permanecer estables sin experimentar nuevos eventos cardiovasculares, sufrir de un nuevo evento coronario o morir. Para el caso de base, se adoptó un horizonte temporal de 10 años y una tasa de descuento de 3 % para los costos y beneficios. Las probabilidades de transición se extrajeron del estudio Platelet Inhibition and Patient Outcomes , PLATO. Las estadísticas vitales se consultaron en informes del Departamento Administrativo Nacional de Estadística (DANE) y los parámetros adicionales del modelo se basaron en la información de los pacientes colombianos incluidos en el registro en Access. Para identificar y medir el uso de recursos, se construyó un caso estándar a partir de guías y protocolos. Los costos unitarios se obtuvieron de manuales tarifarios colombianos. Se hizo un análisis de sensibilidad probabilístico en el que los costos se representaron por una distribución triangular y, las probabilidades de transición, mediante una distribución beta. Resultados. En el caso de base, el costo adicional por años de vida ajustados por calidad ganados con el ticagrelor fue de COP$ 28´411.503. Los resultados fueron sensibles a los cambios en el horizonte temporal y al costo unitario del clopidogrel. Para un umbral de costo-efectividad equivalente a tres veces el producto interno bruto per cápita de Colombia, la probabilidad de que el ticagrelor fuera costo-efectivo fue de 75 %. Conclusiones. El ticagrelor es una estrategia costo-efectiva para el tratamiento de los pacientes con síndrome coronario agudo en Colombia.

Clopidogrel versus prasugrel en síndrome coronario agudo tratado con angioplastia / Clopidogrel versus prasugrel in acute coronary syndrome treated with coronary angioplasty

Al uso del clopidogrel se han agregado nuevos antiagregantes como prasugrel y ticagrelor. El objetivo de este estudio fue comparar la incidencia de eventos isquémicos y hemorrágicos en pacientes que han recibido clopidogrel o prasugrel.Se incluyeron de manera consecutiva todos los pacientes con angioplastia durante la internación por síndrome coronario agudo entre diciembre 2011 y diciembre 2012.Fueron incluidos 398 pacientes. No se observaron diferencias en la mortalidad de causa cardiovascular (clopidogrel 2.5% vs. prasugrel 2.9%, p = 0.48). El grupo prasugrel presentó una reducción en la tasa de infarto (1.9% vs. 6.8%, p = 0.01) con sangrado totales (18.5% vs. 8.5%, p = 0.001) a expensas de sangrados menores (12.4% vs. 3.4%, p < 0.001), sin diferencia en sangrados mayores (p = 0.27) y sangrados con peligro de vida (p =.0.20). Por análisis multivariado los predictores independientes de mortalidad cardiovascular fueron edad (odds ratio 1.08, intervalo de confianza, IC, 95% 1.02-1.16, p = 0.02) insuficiencia renal (odds ratio 6.98, IC 95% 1.23-39.71, p < 0.0001). En cuanto al sangrado total se identificaron la edad (odds ratio 1.06, IC 95% 1.02-1.09, p = 0.002), elevación del segmento ST (odds ratio 1.99, IC 95% 1.05-3.79, p = 0.02), insuficiencia renal (odds ratio 3.32, IC 95% 1.62-6.78, p = 0.002) y utilización de prasugrel (odds ratio 3.97, IC 95% 1.87-8.41, p < 0.0001). La utilización de prasugrel se asocia a una menor tasa de infarto agudo de miocardio al año de seguimiento, con incremento de hemorragias menores. No se observaron diferencias significativas en la mortalidad cardiovascular entre ambos grupos.

Greater antithrombotic potency new antiplatelet agents have been added such as prasugrel (PR) and ticagrelor to the traditional use of clopidogrel (CL) in the treatment of acute coronary syndrome (ACS). This study was aimed at comparing the incidence of long term ischemic and hemorrhagic events in patients treated with CL or PR during hospitalization. Retrospective ACS data base analysis performed by our cardiology service was completed prospectively. There were consecutively included all patients with percutaneous coronary intervention (PCI) during hospitalization due to ACS from December 2011 thru December 2012. A total of 398 ACS patients who underwent PCI with stent implantation were recruited. No differences in cardiovascular related deaths were observed in both groups (PR 2.9% vs. CL 2.5%, p = 0.48). PR group showed less re-infraction (1.9% vs. 6.8%, p = 0.01) with more total bleedings (18.5% vs. 8.5%, p = 0.001) and minor bleedings (12.4% vs. 3.4%, p < 0.001) with no differences in major and life threatening bleedings (p = ns). Multivariate analysis showed that independent predictors of cardiovascular mortality were age (OR 1.08, CI 95% 1.02-1.16) and renal failure (OR 6.98, CI 95% 1.23-39.71). Independent predictors for total bleeding were age (OR 1.06, CI 95% 1.02-1.09),ST segment elevation myocardial infarction (OR 1.99, CI 95% 1.05-3.79), renal failure (OR 3.32, CI 95% 1.62-6.78) and prasugrel use (OR 3.97, CI 95% 1.87-8.41). Use of prasugrel, in the ACS that requires PCI with stent, is associated with a lower myocardial infarction a year after follow-up, and it also leads to an increase of milder hemorrhage. No significant differences were observed in the cardiovascular mortality of both groups.

Comparison of Angiographic Outcomes of Side Branch Ostium at Bifurcation Coronary Lesion between Two-stent and One-stent Techniques

Although the favored strategy for coronary bifurcation intervention is stenting main vessel with provisional side branch (SB) stenting, we occasionally use two-stent strategy. The objective of this study was to investigate the angiographic outcome of SB ostium in two-stent group, compared with one-stent group. We analyzed 199 patients with bifurcation lesion who underwent percutaneous coronary intervention (PCI) with drug-eluting stent and follow up angiography. The patients were divided into one-stent group (167 lesions, 158 patients) and two-stent group (41 lesions, 41 patients). Prior to intervention, SB ostium minimal luminal diameter (MLD) was smaller in two-stent group than in one-stent group (1.08+/-0.55 mm vs. 1.39+/-0.60 mm; P=0.01). But, immediately after PCI, SB MLD of two-stent group became greater than that of one-stent group (2.41+/-0.40 mm vs. 1.18+/-0.68 mm; P<0.01). Six to nine months after PCI, this angiographic superiority in SB MLD of two-stent group persisted (1.56+/-0.71 mm vs. 1.13+/-0.53 mm; P<0.01), although there was larger late loss in two-stent group (0.85+/-0.74 mm vs. 0.05+/-0.57 mm; P<0.01). In terms of target lesion revascularization and target vessel revascularization rates, one-stent group showed better results than two-stent group. We could attain wider long term SB ostium after two-stent strategy than after one-stent strategy.

Effects of simvastatin/ezetimibe on microparticles, endothelial progenitor cells and platelet aggregation in subjects with coronary heart disease under antiplatelet therapy

It is not known whether the addition of ezetimibe to statins adds cardiovascular protection beyond the expected changes in lipid levels. Subjects with coronary heart disease were treated with four consecutive 1-week courses of therapy (T) and evaluations. The courses were: T1, 100 mg aspirin alone; T2, 100 mg aspirin and 40 mg simvastatin/10 mg ezetimibe; T3, 40 mg simvastatin/10 mg ezetimibe, and 75 mg clopidogrel (300 mg initial loading dose); T4, 75 mg clopidogrel alone. Platelet aggregation was examined in whole blood. Endothelial microparticles (CD51), platelet microparticles (CD42/CD31), and endothelial progenitor cells (CD34/CD133; CDKDR/CD133, or CD34/KDR) were quantified by flow cytometry. Endothelial function was examined by flow-mediated dilation. Comparisons between therapies revealed differences in lipids (T2 and T3<T1 and T4 for total cholesterol, LDL-C, and triglycerides; P<0.002 for all), as well as for endothelial function (T2>T1 and T4, P=0.001). Decreased platelet aggregation was observed after aspirin (arachidonic acid, T1<T3 and T4, P=0.034) and clopidogrel (adenosine, T3 and T4<T1 and T2, P<0.0001) therapy. Simvastatin/ezetimibe diphosphate did not change platelet aggregation, the amount of circulating endothelial and platelet microparticles, or endothelial progenitor cells. Cardiovascular protection following therapy with simvastatin/ezetimibe seems restricted to lipid changes and improvement of endothelial function not affecting the release of microparticles, mobilization of endothelial progenitor cells or decreased platelet aggregation.

Farmacogenómica cardiovascular / Cardiovascular pharmacogenomics

La enfermedad cardiovascular representa la primera causa de morbimortalidad a nivel mundial. Actualmente, la evidencia que sustenta la implementación de determinadas intervenciones terapéuticas se origina a partir de datos provenientes de grupos poblacionales. Sin embargo, los pacientes presentan variaciones interindividuales relacionadas tanto con la eficacia como con la toxicidad ante un mismo tratamiento farmacológico. Estas variaciones pueden ser explicadas principalmente por diferencias en la adherencia, interacciones no reconocidas y diferencias genéticas. Las alteraciones en el genoma explican entre un 20 y un 95% de la variabilidad interindividual tanto en la disponibilidad como en la respuesta a fármacos. En el tratamiento de las enfermedades cardiovasculares existen diversos ejemplos de dicha variabilidad genética interindividual y su impacto en la eficacia o toxicidad de diferentes fármacos. La variabilidad genética que determina la respuesta al clopidogrel radica fundamentalmente en el polimorfismo del citocromo (CYP) 2C19. Los polimorfismos en los genes CYP 2C9 y VKORC1 explican gran parte de la variabilidad en la respuesta a los anticoagulantes dicumarínicos. Con respecto al tratamiento hipolipidemiante, el polimorfismo del gen SLCO1B1 se ha asociado a la aparición de miopatía en pacientes tratados con simvastatina. Muchos otros polimorfismos han sido postulados pero sin un impacto clínico definido hasta la fecha. La utilización de la farmacogenómica en la práctica cotidiana ofrece la oportunidad de poder predecir toxicidad o eficacia terapéutica.

Cardiovascular disease remains a major cause of morbidity and mortality worldwide. Current medical practice takes into account information based on population studies and benefits observed in large populations or cohorts. However, individual patients present great differences in both toxicity and clinical efficacy that can be explained by variations in adherence, unknown drug to drug interactions and genetic variability. The latter seems to explain from 20% up to 95% of patient to patient variability. Treating patients with cardiovascular disorders faces the clinician with the challenge to include genomic analysis into daily practice. There are several examples within cardiovascular disease of treatments that can vary in toxicity or clinical usefulness based on genetic changes. One of the main factors affecting the efficacy of Clopidogrel is the phenotype associated with polymorphisms in the gene CYP 2C9. Furthermore, regarding oral anticoagulants, changes in CYP2C9 and VKORC1 play an important role in changing the clinical response to anticoagulation. When analyzing statin treatment, one of their main toxicities (myopathy) can be predicted by the SLCO1B1 polymorphism. The potential for prediction of toxicity and clinical efficacy from the use of genetic analysis warrants further studies aiming towards its inclusion in daily clinical practice.

Delayed Cerebral Infarction due to Stent Folding Deformation Following Carotid Artery Stenting

We report a case of delayed cerebral infarction due to stent longitudinal folding deformation following carotid artery stenting using a self-expandable stent with an open-cell design. The stented segment of the left common carotid artery was divided into two different lumens by this folding deformation, and the separated lumens became restricted with in-stent thrombosis. Although no established method of managing this rare complication exists, a conservative approach was taken with administration of anticoagulant and dual antiplatelet therapy. No neurological symptoms were observed during several months of clinical follow-up after discharge.

Does Dual Antiplatelet Therapy Increase the Risk of Peptic Ulcer Disease? / 대한소화기학회지

No abstract available.

Clinical Impact of Dual Antiplatelet Therapy on Peptic Ulcer Disease / 대한소화기학회지

BACKGROUND/AIMS: Increased incidence of coronary artery disease has led to the increased use of dual antiplatelet therapy composed of aspirin and clopidogrel. We investigated the incidence of gastrointestinal complications in patients who received single or dual antiplatelet therapy and analyzed their clinical characteristics in order to predict the prognostic factors. METHODS: Between January 2009 and December 2011, we retrospectively reviewed the medical records of patients who underwent coronary angiography at Chung-Ang University Hospital (Seoul, Korea). One hundred and ninety-four patients were classified into two groups: aspirin alone group and dual antiplatelet group. Clinical characteristics, past medical history, and presence of peptic ulcer were analyzed. RESULTS: During the follow-up period, 11 patients had duodenal ulcer; the event rate was 2.02% in the aspirin alone group and 9.47% in the dual antiplatelet group (hazard ratio [HR] 5.24, 95% CI 1.03-26.55, p<0.05). There was no significant difference in the rate of significant upper gastrointestinal bleeding: 0% vs. 4.2% (p=0.78). In patients who received proton pump inhibitor (PPI), 24 patients had gastric ulcer; the event rate was significantly different between the two groups: 4.87% vs. 22.98% (HR 3.40, 95% CI 1.02-11.27, p<0.05). CONCLUSIONS: Dual antiplatelet groups had a higher incidence of duodenal ulcers without significant bleeding compared with the aspirin alone group. In patients who received PPI, the dual antiplatelet therapy group had a higher incidence of gastric ulcers without significant bleeding compared with the aspirin alone group. Therefore, physicians must pay attention to high risk groups who receive dual antiplatelet therapy and aggressive diagnostic endoscopy should also be considered.

The Influence of Hypothermia on Transfusion Requirement in Patients Who Received Clopidogrel in Proximity to Off-Pump Coronary Bypass Surgery

PURPOSE: Hypothermia adversely affects the coagulation that could be of clinical significance in patients receiving clopidogrel. We evaluated the influence of hypothermia on transfusion requirements in patients undergoing isolated off-pump coronary artery bypass surgery (OPCAB) who continued clopidogrel use within 5 days of surgery. MATERIALS AND METHODS: Protocol-based, prospectively entered data of 369 patients were retrospectively reviewed. The time-weighted average of intraoperative temperatures and the temperature upon ICU admission (TWA-temp) was assessed. Patients were divided into normothermia (> or =36degrees C, n=224) and hypothermia (<36degrees C, n=145) group. The transfusion requirement for perioperative blood loss was assessed and compared. RESULTS: Patients with hypothermia were older and had lower body surface area (BSA) than patients with normothermia. Age and BSA adjusted transfusion requirement was significantly larger in the hypothermia group [patients requiring transfusion: 64% versus 48%, p=0.003; number of units: 0 (0-2) units versus 2 (0-3) units, p=0.002]. In multivariate analysis of predictors of perioperative multiple transfusion requirements, hypothermia was identified as an independent risk factor along with age, female gender, BSA, chronic kidney disease, and congestive heart failure. CONCLUSION: Hypothermia was associated with increased transfusion requirement in patients undergoing OPCAB who received clopidogrel in proximity to surgery. Considering the high prevalence and the possibility of hypothermia being a modifiable risk factor, aggressive measures should be undertaken to maintain normothermia in those patients.

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.

P2Y12 inhibitors in acute coronary syndromes: Which and when.

Acute coronary syndromes (ACS) are the commonest acute manifestation of coronary artery disease and a major cause of hospitalization and death. Plaque rupture and subsequent platelet activation are the key factors in its pathogenesis. Platelet inhibitors are crucial in the management of ACS. Aspirin remains the standard antiplatelet but use of dual antiplatelet drugs is beneficial in ACS. Platelet P2Y12 receptor inhibitors are an important group of antiplatelet compounds that can be combined with aspirin in the management of ACS. P2Y12 inhibitors may belong to the thienopyridine or nonthienopyridine group of compounds. The former (clopidogrel, prasugrel) combine irreversibly with the receptor and therefore have a prolonged duration of action. On the other hand, the non-thienopyridine compounds (ticagrelor, elinogrel) have a reversible action and hence a shorter duration of action. Several new compounds in this group have become or are likely to become available. The newer agents have a more uniform and complete antiplatelet effect and are much less likely to be affected by genetic variability of CYP2C19 enzyme activity compared with that of clopidogrel. Large phase 3 trials have shown that ticagrelor and prasugrel reduce major cardiovascular events in ACS compared to clopidogrel when given in addition to aspirin. This is accompanied by some increase in bleeding. This review discusses the properties, clinical profile and possible place of P2Y12 receptor inhibitors in clinical practice.