RESUMEN
Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Importantly, these factors are less explored in underrepresented populations, such as Latin-American countries. Identifying patients at risk of high-on-treatment platelet reactivity (HTPR) is highly valuable in translational medicine. In this study we used a custom next-generation sequencing (NGS) panel composed of 91 single nucleotide polymorphisms (SNPs) and 28 genes related to clopidogrel metabolism, to analyze 70 patients with platelet reactivity values, assessed through closure time (CT). Our results demonstrated the association of SNPs with HTPR and non-HTPR, revealing the strongest associations with rs2286823 (OR: 5,0; 95% CI: 1,02-24,48; p: 0,03), rs2032582 (OR: 4,41; 95% CI: 1,20-16,12; p: 0,019), and rs1045642 (OR: 3,38; 95% CI: 0,96-11,9; p: 0,05). Bivariate regression analysis demonstrated the significant association of several SNPs with the CT value, a "surrogate" biomarker of clopidogrel response. Exploratory results from the LASSO regression model showed a high discriminatory capacity between HTPR and non-HTPR patients (AUC: 0,955), and the generated PgxPRS demonstrated a significant negative association between the risk score, CT value, and the condition of HTPR and non-HTPR. To our knowledge, our study addresses for the first time the analysis of the polygenic contribution in platelet reactivity using NGS and establishes PgxPRS derived from the LASSO model. Our results demonstrate the polygenic implication of clopidogrel response and offer insights applicable to the translational medicine of antiplatelet therapy in an understudied population.
Asunto(s)
Plaquetas , Clopidogrel , Secuenciación de Nucleótidos de Alto Rendimiento , Inhibidores de Agregación Plaquetaria , Polimorfismo de Nucleótido Simple , Humanos , Clopidogrel/uso terapéutico , Clopidogrel/farmacología , Masculino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Femenino , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/farmacología , Persona de Mediana Edad , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Anciano , Herencia Multifactorial/genética , Ticlopidina/análogos & derivados , Ticlopidina/uso terapéutico , Ticlopidina/farmacologíaRESUMEN
INTRODUCTION: This prospective pharmacodynamic nutraceutical study assessed the effect of a 1-week trial of 30 g/day of 65% cocoa (dark chocolate) (Theobroma cacao L.) consumption intervention on platelet reactivity. METHODS: Patients with stable coronary artery disease (CAD) (n=20) who were on maintenance dual antiplatelet therapy of aspirin (ASA) 81 mg/day and clopidogrel 75 mg/day were recruited. Platelet function was evaluated with the VerifyNow P2Y12 reaction unit (PRU) and aspirin reaction unit (ARU) assays (Werfen, Bedford, Massachusetts, USA) and assessed prior to initiation of and after a 1-week trial of 30 g/day of 65% cocoa consumption intervention. Results were compared with a paired t-test. RESULTS: Cocoa augmented the inhibitory effect of clopidogrel, demonstrated by a reduction of 11.9% (95% CI 5.7% to 18.0%, p value 0.001), significantly decreasing the PRU by 26.85 (95% CI 12.22 to 41.48, p value 0.001). The inhibitory effect of ASA was not impacted by cocoa, reflected by a non-significant reduction in ARU of 17.65 (95% CI 21.00 to 56.3, p value 0.351). No patients experienced any serious adverse events. CONCLUSIONS: Cocoa augmented the inhibitory effect of clopidogrel but not ASA. This nutraceutical study could be potentially informative and applicable for patients with stable CAD. Further long-term studies are required to confirm these exploratory findings. TRIAL REGISTRATION NUMBER: NCT04554901.
Asunto(s)
Cacao , Chocolate , Enfermedad de la Arteria Coronaria , Aspirina/uso terapéutico , Clopidogrel , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Humanos , Proyectos Piloto , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Estudios Prospectivos , Ticlopidina/farmacologíaRESUMEN
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.
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.
Asunto(s)
Síndrome Coronario Agudo/terapia , Intervención Coronaria Percutánea/métodos , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Stents , Síndrome Coronario Agudo/mortalidad , Anciano , Anciano de 80 o más Años , Clopidogrel/administración & dosificación , Stents Liberadores de Fármacos , Femenino , Hemorragia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Pautas de la Práctica en Medicina/estadística & datos numéricos , Pronóstico , Estudios Prospectivos , Factores Sexuales , Ticagrelor/administración & dosificación , Ticlopidina/administración & dosificaciónRESUMEN
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.
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Stents , Síndrome Coronario Agudo/terapia , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Intervención Coronaria Percutánea/métodos , Pronóstico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Ticlopidina/administración & dosificación , Factores Sexuales , Estudios Prospectivos , Síndrome Coronario Agudo/mortalidad , Stents Liberadores de Fármacos , Clopidogrel/administración & dosificación , Ticagrelor/administración & dosificación , Hemorragia/epidemiologíaRESUMEN
BACKGROUND: Antiplatelet therapy with clopidogrel is recommended to reduce cardiovascular events in patients with peripheral artery disease (PAD); however, clopidogrel efficacy has not been adequately studied in this patient population. Therefore, we aimed to determine the effects of cilostazol therapy on platelet reactivity among PAD patients on clopidogrel. METHODS: We performed a cross-sectional pilot study of 46 Puerto Rican patients diagnosed with PAD. The cohort was divided based on use of clopidogrel and cilostazol (n=24) or clopidogrel alone (n=22). Platelet function was measured ex vivo using the VerifyNow P2Y12 assay. Genomic DNA was extracted from peripheral blood samples using the QIAamp DNA Blood Midi Kit, which was subjected to candidate variant genotyping (CYP2C19, ABCB1, PON1 and P2RY12) using TaqMan quantitative polymerase chain reaction assays. All analyses were performed using SAS version 9.4 (SAS Institute). RESULTS: Among all enrolled patients, 18 (39%) had high on-treatment platelet reactivity (HTPR). The mean platelet reactivity was 207±53 (range, 78-325) with higher P2Y12 reaction units in the non-cilostazol group, 224±45 vs. 191±55 on the cilostazol group (p=0.03). No significant differences were observed in the clinical or genetic variables between the two groups. A multiple regression analysis determined that history of diabetes mellitus (p=0.03), use of cilostazol (p=0.03) and hematocrit (p=0.02) were independent predictors of platelet reactivity. CONCLUSIONS: In Puerto Rican PAD patients on clopidogrel therapy, history of diabetes mellitus, use of cilostazol and hematocrit are independent predictors of platelet reactivity. Adjunctive cilostazol therapy may enhance clopidogrel efficacy among PAD patients with HTPR.
Asunto(s)
Plaquetas/efectos de los fármacos , Enfermedad Arterial Periférica/complicaciones , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Tetrazoles/farmacología , Ticlopidina/análogos & derivados , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Anciano , Arildialquilfosfatasa/genética , Cilostazol , Clopidogrel , Estudios Transversales , Citocromo P-450 CYP2C19 , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Humanos , Masculino , Proyectos Piloto , Pruebas de Función Plaquetaria , Receptores Purinérgicos P2Y12/genética , Tetrazoles/uso terapéutico , Ticlopidina/farmacología , Ticlopidina/uso terapéuticoRESUMEN
BACKGROUND: Early reperfusion of the occluded coronary artery during acute myocardial infarction is considered crucial for reduction of infarcted mass and recovery of ventricular function. Effective microcirculation and the balance between protective and harmful lymphocytes may have roles in reperfusion injury and may affect final ventricular remodeling. METHODS/DESIGN: BATTLE-AMI is an open-label, randomized trial comparing the effects of four therapeutic strategies (rosuvastatin/ticagrelor, rosuvastatin/clopidogrel, simvastatin plus ezetimibe/ticagrelor, or simvastatin plus ezetimibe/clopidogrel) on infarcted mass and left ventricular ejection fraction (LVEF) (blinded endpoints) in patients with ST-segment elevation myocardial infarction submitted to fibrinolytic therapy before coronary angiogram (pharmacoinvasive strategy). All patients (n = 300, 75 per arm) will be followed up for six months. The effects of treatment on subsets of B and T lymphocytes will be determined by flow-cytometry/ELISPOT and will be correlated with the infarcted mass, LVEF, and microcirculation perfusion obtained by cardiac magnetic resonance imaging. The primary hypothesis is that the combined rosuvastatin/ticagrelor therapy will be superior to other therapies (particularly for the comparison with simvastatin plus ezetimibe/clopidogrel) for the achievement of better LVEF at 30 days (primary endpoint) and smaller infarcted mass (secondary endpoint) at 30 days and six months. The trial will also evaluate the improvement in the immune/inflammatory responses mediated by B and T lymphocytes. Omics field (metabolomics and proteomics) will help to understand these responses by molecular events. DISCUSSION: BATTLE-AMI is aimed to (1) evaluate the role of subsets of lymphocytes on microcirculation improvement and (2) show how the choice of statin/antiplatelet therapy may affect cardiac remodeling after acute myocardial infarction with ST elevation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02428374 . Registered on 28 September 2014.
Asunto(s)
Antiinflamatorios/administración & dosificación , Linfocitos B/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Mediadores de Inflamación/sangre , Inhibidores de Agregación Plaquetaria/administración & dosificación , Infarto del Miocardio con Elevación del ST/tratamiento farmacológico , Linfocitos T/efectos de los fármacos , Terapia Trombolítica , Adenosina/administración & dosificación , Adenosina/análogos & derivados , Antiinflamatorios/efectos adversos , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biomarcadores/sangre , Brasil , Protocolos Clínicos , Clopidogrel , Angiografía Coronaria , Quimioterapia Combinada , Ensayo de Immunospot Ligado a Enzimas , Ezetimiba/administración & dosificación , Femenino , Citometría de Flujo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Imagen por Resonancia Magnética , Masculino , Metabolómica , Inhibidores de Agregación Plaquetaria/efectos adversos , Proteómica , Proyectos de Investigación , Rosuvastatina Cálcica/administración & dosificación , Infarto del Miocardio con Elevación del ST/sangre , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/inmunología , Simvastatina/administración & dosificación , Volumen Sistólico/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Terapia Trombolítica/efectos adversos , Ticagrelor , Ticlopidina/administración & dosificación , Ticlopidina/análogos & derivados , Factores de Tiempo , Resultado del Tratamiento , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Clopidogrel is by far the most prescribed platelet adenosine diphosphate (ADP) antagonist in Puerto Rico despite the advent of newer agents (prasugrel and ticagrelor). Given the paucity of data on clopidogrel responsiveness in Hispanics, we sought to determine the association between clinical characteristics and platelet reactivity in Puerto Rican patients on clopidogrel therapy. STUDY POPULATION: A total of 100 Puerto Rican patients on clopidogrel therapy were enrolled and allocated into two groups: Group I, without high on-treatment platelet reactivity (HTPR); and Group II, with HTPR. Platelet function was measured ex vivo using the VerifyNow® P2Y12 assay. RESULTS: The cohort was comprised of Hispanic patients with coronary artery disease (57%), peripheral artery disease (32%), carotid artery stenosis (7%), cerebral artery aneurysm (2%), and stroke (2%). Mean platelet reactivity was 200 ± 61 P2Y12 reaction units (PRUs) (range: 8-324), and 35% of patients had HTPR (PRUs ⩾ 230). Multivariable logistic regression analysis determined that diabetes mellitus (DM) [odds ratio (OR) = 3.27; 95% confidence interval (CI): 1.20-8.96], use of proton-pump inhibitors (PPIs) (OR = 3.60; 95% CI: 1.09-11.82), and calcium channel blockers (CCBs) (OR = 3.10; 95% CI: 1.09-8.83) were independent predictors of HTPR ( p < 0.05) after adjusting for other clinical variables. CONCLUSIONS: In a sample of 100 Puerto Rican Hispanic patients on clopidogrel, 35% had HTPR. Furthermore, DM, PPIs and CCBs predicted HTPR. Clinical outcome data are needed to identify appropriate PRU thresholds for risk prediction in the Puerto Rican population.
Asunto(s)
Plaquetas/efectos de los fármacos , Enfermedades Cardiovasculares/tratamiento farmacológico , Resistencia a Medicamentos , Hispánicos o Latinos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Ticlopidina/análogos & derivados , Anciano , Anciano de 80 o más Años , Plaquetas/metabolismo , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/etnología , Distribución de Chi-Cuadrado , Clopidogrel , Estudios Transversales , Femenino , Humanos , Modelos Lineales , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Inhibidores de Agregación Plaquetaria/efectos adversos , Pruebas de Función Plaquetaria , Valor Predictivo de las Pruebas , Puerto Rico/epidemiología , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Receptores Purinérgicos P2Y12/sangre , Receptores Purinérgicos P2Y12/efectos de los fármacos , Medición de Riesgo , Factores de Riesgo , Ticlopidina/efectos adversos , Ticlopidina/uso terapéutico , Resultado del TratamientoRESUMEN
In spite of the possibility of triggering thromboembolic events, many professionals indicate the suspension of antiplatelet agents before dental surgical procedures. The aim of this study was to perform a quantitative assessment of intraoperative bleeding in patients on dual antiplatelet therapy. A case-control study was conducted in patients on dual antiplatelet therapy (APT group) and in patients who did not use these medications (control group). The following examinations were requested: complete blood cell count, blood coagulation tests, and platelet aggregation. The quantity of bleeding was measured intraoperatively by collection of aspirated blood. The mean volume of blood lost during the surgical procedure was 6.10ml in the control group and 16.07ml in the APT group (P=0.002). The mean volume of blood lost per minute was 0.60ml/min in the control group and 1ml/min in the APT group (P=0.001), with local haemostatic methods being sufficient to control the bleeding. There was no postoperative bleeding complication in any case. Patients on dual antiplatelet therapy presented a larger volume of bleeding, but this could be controlled by means of local haemostatic measures. Therefore, there is no need to stop either of the two dual antiplatelet therapy medications before dental extractions.
Asunto(s)
Aspirina/administración & dosificación , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Hemorragia/epidemiología , Inhibidores de Agregación Plaquetaria/administración & dosificación , Ticlopidina/análogos & derivados , Extracción Dental , Enfermedades Cardiovasculares/tratamiento farmacológico , Estudios de Casos y Controles , Clopidogrel , Atención Dental para Enfermos Crónicos , Femenino , Hemostasis Quirúrgica/métodos , Humanos , Masculino , Persona de Mediana Edad , Ticlopidina/administración & dosificaciónRESUMEN
OBJECTIVES: The aim of this study was to compare aspirin plus clopidogrel with aspirin alone as antithrombotic treatment following transcatheter aortic valve replacement (TAVR) for the prevention of ischemic events, bleeding events, and death. BACKGROUND: Few data exist on the optimal antithrombotic therapy following TAVR. METHODS: This was a randomized controlled trial comparing aspirin (80 to 100 mg/day) plus clopidogrel (75 mg/day) (dual antiplatelet therapy [DAPT]) versus aspirin alone (single-antiplatelet therapy [SAPT]) in patients undergoing TAVR with a balloon-expandable valve. The primary endpoint was the occurrence of death, myocardial infarction (MI), stroke or transient ischemic attack, or major or life-threatening bleeding (according to Valve Academic Research Consortium 2 definitions) within the 3 months following the procedure. The trial was prematurely stopped after the inclusion of 74% of the planned study population. RESULTS: A total of 222 patients were included, 111 allocated to DAPT and 111 to SAPT. The composite of death, MI, stroke or transient ischemic attack, or major or life-threatening bleeding tended to occur more frequently in the DAPT group (15.3% vs. 7.2%, p = 0.065). There were no differences between groups in the occurrence of death (DAPT, 6.3%; SAPT, 3.6%; p = 0.37), MI (DAPT, 3.6%; SAT, 0.9%; p = 0.18), or stroke or transient ischemic attack (DAPT, 2.7%; SAPT, 0.9%; p = 0.31) at 3 months. DAPT was associated with a higher rate of major or life-threatening bleeding events (10.8% vs. 3.6% in the SAPT group, p = 0.038). There were no differences between groups in valve hemodynamic status post-TAVR. CONCLUSIONS: This small trial showed that SAPT (vs. DAPT) tended to reduce the occurrence of major adverse events following TAVR. SAPT reduced the risk for major or life-threatening events while not increasing the risk for MI or stroke. Larger studies are needed to confirm these results. (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation: The ARTE Trial [ARTE], NCT01559298; Aspirin Versus Aspirin+Clopidogrel as Antithrombotic Treatment Following TAVI [ARTE], NCT02640794).
Asunto(s)
Válvula Aórtica/cirugía , Aspirina/administración & dosificación , Valvuloplastia con Balón , Fibrinolíticos/administración & dosificación , Prótesis Valvulares Cardíacas , Inhibidores de Agregación Plaquetaria/administración & dosificación , Trombosis/prevención & control , Ticlopidina/análogos & derivados , Reemplazo de la Válvula Aórtica Transcatéter/instrumentación , Anciano , Anciano de 80 o más Años , Aspirina/efectos adversos , Valvuloplastia con Balón/efectos adversos , Canadá , Clopidogrel , Quimioterapia Combinada , Terminación Anticipada de los Ensayos Clínicos , Europa (Continente) , Femenino , Fibrinolíticos/efectos adversos , Hemorragia/inducido químicamente , Humanos , Ataque Isquémico Transitorio/etiología , Ataque Isquémico Transitorio/prevención & control , Estimación de Kaplan-Meier , Masculino , Infarto del Miocardio/etiología , Infarto del Miocardio/prevención & control , Inhibidores de Agregación Plaquetaria/efectos adversos , Diseño de Prótesis , Factores de Riesgo , América del Sur , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Trombosis/diagnóstico , Trombosis/etiología , Trombosis/mortalidad , Ticlopidina/administración & dosificación , Ticlopidina/efectos adversos , Factores de Tiempo , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Reemplazo de la Válvula Aórtica Transcatéter/mortalidad , Resultado del TratamientoRESUMEN
INTRODUCTION: Clopidogrel is commonly used in prevention and treatment of atherothrombosis. Some previous studies have suggested a pleiotropic effect of clopidogrel; however, when this drug causes platelet-independent effects on endothelial function remains unclear. AIMS: To evaluate the influence of clopidogrel on inflammatory biomarkers and adhesion molecules in human endothelial cells and the role of nitric oxide (NO) in this process. METHODS: TNF-α-induced human umbilical vein endothelial cells (HUVEC) were exposed to clopidogrel. Gene expression and protein expression of ICAM-1, P-selectin, IL-8, IL-6, and MCP-1 were evaluated by qPCR, flux cytometry, or milliplex technology. Expression of endothelial nitric oxide synthase (NOS3) and NO release were also evaluated. Influence of clopidogrel was further evaluated in NOS3 downregulated HUVEC by RNAi. RESULTS: Clopidogrel at 20 µmol/L induced NO release in HUVEC after 24-hours treatment. Gene expressions of inflammatory markers IL-8 and MCP1 were reduced after clopidogrel treatment (P<.05); however, only MCP-1 remained reduced at protein level. IL-6 was not modified by clopidogrel treatment. Gene expression and protein expression of ICAM-1 were diminished by 24-hours clopidogrel exposure, whereas P-selectin was not modified. NOS3 downregulated HUVEC model revealed that ICAM-1 modification by clopidogrel is dependent of this via, whereas MCP-1 is modulated in an NO-independent form. CONCLUSIONS: Our results support new evidence for pleiotropic effects of clopidogrel on inflammation and endothelial function. Reduction in ICAM-1 and MCP-1 in human endothelium is an important extent of the use of this drug for treatment of cardiovascular diseases, and NO has an important role in this process.
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Moléculas de Adhesión Celular/biosíntesis , Citocinas/biosíntesis , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Óxido Nítrico/fisiología , Inhibidores de Agregación Plaquetaria/farmacología , Ticlopidina/análogos & derivados , Quimiocina CCL2/biosíntesis , Quimiocina CCL2/genética , Clopidogrel , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adhesión Intercelular/biosíntesis , Molécula 1 de Adhesión Intercelular/genética , Óxido Nítrico Sintasa de Tipo III/biosíntesis , Óxido Nítrico Sintasa de Tipo III/genética , Ticlopidina/farmacologíaRESUMEN
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.
Asunto(s)
Humanos , Ticlopidina/análogos & derivados , Inhibidores de Agregación Plaquetaria/administración & dosificación , Aspirina/administración & dosificación , Síndrome Coronario Agudo/tratamiento farmacológico , Fibrinolíticos/administración & dosificación , Ticlopidina/administración & dosificación , Interacciones Farmacológicas , Quimioterapia Combinada , ClopidogrelRESUMEN
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.
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Aspirina/farmacología , Plaquetas/efectos de los fármacos , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/farmacología , Ticlopidina/análogos & derivados , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Alelos , Arildialquilfosfatasa/genética , Clopidogrel , Enfermedad de la Arteria Coronaria/genética , Citocromo P-450 CYP2C19/genética , Quimioterapia Combinada , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea , Polimorfismo Genético , Estudios Prospectivos , Ticlopidina/farmacologíaRESUMEN
OBJECTIVE: To evaluate the incremental cost-effectiveness ratio (ICER) of the use of ticagrelor as a substitute for clopidogrel for secondary prevention of acute coronary syndrome in Chile. STUDY DESIGN AND SETTING: Cost-effectiveness analysis based on a Markov model: Safety and effectiveness data of ticagrelor were obtained from a systematic review of the literature. Costs are expressed in Chilean pesos (CLP) as of 2013. The evaluation was conducted from the payer standpoint. A probabilistic sensitivity analysis comprising discount rates and national cost variability was done. A budget impact analysis estimated for 2015 was conducted to calculate the total cost for both treatments. RESULTS: The ICER with a discount rate of 6% for ticagrelor vs. clopidogrel was CLP 4,893,126 per quality-adjusted life-year (QALY) gained (=9,689 US$). In the budget impact analysis for the baseline scenario, considering 100% of treatment, coverage, and adherence, ticagrelor represented an additional cost of CLP 5,233,854,272, for 979 QALYs gained compared with clopidogrel. CONCLUSIONS: Ticagrelor is cost-effective in comparison with clopidogrel for the secondary prevention of acute coronary syndrome. These findings are similar to those reported in other international cost-effectiveness studies.
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Síndrome Coronario Agudo/prevención & control , Adenosina/análogos & derivados , Análisis Costo-Beneficio/economía , Ticlopidina/análogos & derivados , Adenosina/economía , Adenosina/uso terapéutico , Anciano , Clopidogrel , Estudios Epidemiológicos , Femenino , Humanos , América Latina , Masculino , Persona de Mediana Edad , Antagonistas del Receptor Purinérgico P2Y/economía , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Ticagrelor , Ticlopidina/economía , Ticlopidina/uso terapéuticoRESUMEN
Acetylsalicylic acid (ASA) and clopidogrel combined therapy has been reported to be beneficial in patients with acute coronary syndrome (ACS). Antiplatelet drug resistance, especially to clopidogrel, is a multifactorial phenomenon that affects a large number of ACS patients. The genetic contribution to this drug response is not fully elucidated. We investigated the relationship of ABC-type efflux subfamily C member 3 (ABCC3) polymorphisms and mRNA expression with plasma concentrations of clopidogrel, salicylic acid (SA) and a carboxylic acid metabolite (CAM). Clopidogrel, CAM and SA plasma concentrations were measured simultaneously by liquid chromatography-tandem mass spectrometry (LCMS/MS) from 83 ACS patients undergoing percutaneous coronary intervention. ABCC3 (rs757421, rs733392 and rs739923) and CYP2C19*2 (rs4244285) polymorphisms as well as mRNA expression were evaluated. A positive correlation was found between CAM concentrations and ABCC3 mRNA expression (r = 0.494, p < 0.0001). Patients carrying genotype AA (rs757421 variant) had higher CAM concentrations and ABCC3 mRNA expression as compared to those of GG + GA carriers (p = 0.017). A multiple linear regression analysis revealed that ABCC3 mRNA expression (p = 0.017), rs757421 AA genotype (p = 0.001), blood collection time (p = 0.018) and clopidogrel dose (p = 0.001) contributed to the concentration of CAM. No associations were observed for the CYP2C19*2 polymorphism. These results suggest that up-regulation of ABCC3 mRNA expression leads to increased plasma CAM levels through MRP3-mediated cell efflux. The ABCC3 rs757421 polymorphism may contribute to gene expression. Therefore, ABCC3 may be a potential biomarker for the response to clopidogrel.
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Aspirina/administración & dosificación , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Inhibidores de Agregación Plaquetaria/administración & dosificación , Ticlopidina/análogos & derivados , Síndrome Coronario Agudo/terapia , Anciano , Aspirina/farmacocinética , Aspirina/farmacología , Ácidos Carboxílicos/metabolismo , Cromatografía Liquida/métodos , Clopidogrel , Citocromo P-450 CYP2C19/genética , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/métodos , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Polimorfismo Genético , ARN Mensajero/metabolismo , Ácido Salicílico/metabolismo , Espectrometría de Masas en Tándem/métodos , Ticlopidina/administración & dosificación , Ticlopidina/farmacocinética , Ticlopidina/farmacología , Regulación hacia ArribaRESUMEN
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.
Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Aspirina/administración & dosificación , Fibrinolíticos/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Ticlopidina/análogos & derivados , Clopidogrel , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Ticlopidina/administración & dosificaciónRESUMEN
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.
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Aspirina/farmacología , Plaquetas/efectos de los fármacos , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/farmacología , Ticlopidina/análogos & derivados , Alelos , Arildialquilfosfatasa/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Enfermedad de la Arteria Coronaria/genética , Citocromo P-450 CYP2C19/genética , Quimioterapia Combinada , Genotipo , Intervención Coronaria Percutánea , Polimorfismo Genético , Estudios Prospectivos , Ticlopidina/farmacologíaRESUMEN
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.
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Humanos , Masculino , Femenino , Persona de Mediana Edad , Polimorfismo Genético , Ticlopidina/análogos & derivados , Inhibidores de Agregación Plaquetaria/uso terapéutico , Citocromo P-450 CYP2C19/genética , Ticlopidina/uso terapéutico , Estudios Transversales , Clopidogrel , MéxicoRESUMEN
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.