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Variabilidad Farmacodinámica En La Respuesta a Clopidogrel: Mecanismos Implicados Y Uso De Inhibidores Más Potentes Del Recept

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Variabilidad Farmacodinámica En La Respuesta a Clopidogrel: Mecanismos Implicados Y Uso De Inhibidores Más Potentes Del Recept Variabilidad Farm acodinámica en la Respuesta a Clopidogrel: Mecanismos Implicados y Uso de Inhibidores Más Potentes del Receptor Plaquetario P2Y 12 en Pacientes con Enfermedad Coronaria Jorge Carlos Espinós Pérez ADVERTIMENT . La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX ( www.tdx.cat ) i a través del Dipòsit Digital de la UB ( diposit.ub.edu ) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB . No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de prese ntació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA . La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La dif usión de esta tesis por medio del servicio TDR ( www.tdx.cat ) y a través del Repositorio Digital de la UB ( diposit.ub.edu ) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB . No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR o al Repositorio Digital de la UB (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING . On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX ( www.tdx.cat ) service and by the UB Digital Repository ( diposit.ub.edu ) has been authorized by the titular of the intellect ual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized n or its spreading and availability from a site foreign to the TDX service or to the UB Digital Repository . Introdu cing its content in a window or frame foreign to the TDX service or to the UB Digital Repository is not authorized (framing). Tho s e rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author. Universidad de Barcelona Facultad de Medicina – Campus de Ciencias de la Salud de Bellvitge Departamento de Ciencias Clínicas Variabilidad Farmacodinámica en la Respuesta a Clopidogrel: Mecanismos Implicados y Uso de Inhibidores Más Potentes del Receptor Plaquetario P2Y12 en Pacientes con Enfermedad Coronaria Tesis doctoral presentada por JOSÉ LUIS FERREIRO GUTIÉRREZ para optar al grado de Doctor en Medicina Directores: Dr. DOMINICK J. ANGIOLILLO y Dr. ÁNGEL CEQUIER FILLAT Barcelona, 1 de diciembre de 2015 A Mariana, mi esposa, y a José Luis, mi hijo, las personas más importantes de mi vida... mi inspiración y motivación A mis padres y mi hermano, por su amor y apoyo incondicional... por estar siempre ahí AGRADECIMIENTOS ¿Qué es la vida? Una ilusión, una sombra, una ficción, y el mayor bien es pequeño: que toda la vida es sueño, y los sueños, sueños son. (SEGISMUNDO EN “LA VIDA ES SUEÑO”) PEDRO CALDERÓN DE LA BARCA Es difícil no cometer un descuido al intentar recordar a todas las personas que han contribuido a mi desarrollo personal o profesional y que han podido aportar de algún modo a la realización de esta tesis, pero voy a intentarlo con la mejor intención. Por todo ello: “Si no están todos los que son, mis disculpas; pero sin duda todos los que están, son.” Quiero expresar mi agradecimiento sincero: A mis directores de tesis, quienes además de dirigirla con dedicación han contribuido de manera capital a mi formación clínica, en investigación y en otros muchos aspectos importantes para mi carrera profesional; he aprendido, y sigo aprendiendo, mucho de vosotros. Al Dr. Angiolillo por ser mi mentor en el “mundo de las plaquetas”, por todo el tiempo y esfuerzo que me ha dedicado con extrema generosidad, por el impulso que le ha dado a mi carrera y, lo más importante, por ser un tipo excepcional y convertirse en mi amigo; Dominick, siempre podrás contar conmigo. Al Dr. Cequier por animarme a emprender un camino distinto, por haber creído en mí y por apoyarme de manera personal e institucional para crear el Laboratorio de Investigación Cardiovascular y confiarme su dirección. A todo el personal del Cardiovascular Research Center y de la Division of Cardiology de la University of Florida College of Medicine – Jacksonville por su profesionalidad, por el magnífico trato personal y por su colaboración en todos los proyectos en los que participé. Un agradecimiento especial a Bhaloo Desai y Jennifer Zhai, por portarse maravillosamente bien conmigo, y a los otros fellows de investigación con los que compartí penas y alegrías. A mi gran amigo el Dr. Masafumi Ueno, por ser mi inseparable compañero de fatigas durante mi estancia en Jacksonville y “my Japanese brother” para siempre; Masa, siempre podrás contar conmigo. A todo el personal (médicos, enfermeras, auxiliares…) del Área de Enfermedades del Corazón del Hospital Universitario de Bellvitge por la formación, el trato humano y la ayuda recibida todos estos años. A todo el personal de la Unidad de Hemodinámica del Hospital Universitari de Bellvitge, por convertir el trabajo diario en un auténtico placer. Al Dr. Gómez-Hospital, por sus enseñanzas y su confianza, y a todos mis compañeros sin excepción (los actuales y los pasados, como el Dr. Jara), por sus enseñanzas y su compañerismo, con un recuerdo particular al Dr. Gómez-Lara y al Dr. Roura, ya son muchos años juntos. A la enfermería y auxiliares de la unidad por ser como sois y por colaborar en mis proyectos de investigación de manera desinteresada. A todos ellos, por aguantar mis “escasos” momentos de “ligero” mal humor. A todos los que hacen posible el funcionamiento del Laboratorio de Investigación Cardiovascular; a Gaby, por su dedicación, a la Dra. Marcano, la primera fellow en esta aventura, y a todos los residentes que colaboran. A mis compañeros de residencia, principalmente a “Los Animales de Bellota”, a mis compañeros de pool y a mis compañeros (R grandes y pequeños) en Cardiología, por vuestra ayuda, enseñanzas y cariño. A mis compañeros de facultad, destacando a mis amigos de “Las 5 Jotas”, el Dr. Sánchez, el Dr. Sabadell, el Dr. Cortés y el Dr. Vilaseca; siempre podréis contar conmigo. A mis compañeros en los equipos de balonmano, por aportarme valores que sólo el deporte puede ofrecer. A mis amigos de siempre, al “BEJA” (Paco, Rober, Diego), y a otros como Josep, por los momentos vividos y los que vendrán, además de por haberse adaptado a mi perenne falta de disponibilidad. Un agradecimiento especial a Paco y Mari Carmen, por estar siempre ahí.; siempre podréis contar conmigo. A mi familia, gallega y castellana, porque nunca hay que olvidar los orígenes. A mi familia política peruana, por su magnífica acogida y hacerme sentir parte de sus vidas. A mis padres, por todo el cariño que me han dado, por los valores que me han transmitido y por el esfuerzo y los sacrificios que han realizado para que yo tuviera siempre lo que necesitaba. A mi hermano, por su apoyo y por estar siempre ahí cuando era necesario. A ellos, por ser capaces de aguantar mi temperamento y porque soy absolutamente consciente de lo afortunado que soy por tenerlos. A mi mujer, Mariana, y a mi hijo, José Luis, porque vosotros le dais sentido a todo. ÍNDICE 1. Introducción 1 1.1. Receptor purinérgico plaquetario P2Y12: Generalidades 5 1.2. Clopidogrel: Variabilidad de respuesta 7 1.2.1. Mecanismos de variabilidad de respuesta 9 1.3. Antagonistas potentes del receptor P2Y12 18 1.4. Justificación 23 1.5. Escenario del proyecto 25 2. Hipótesis 27 3. Objetivos 31 4. Publicaciones 35 4.1. Mecanismos implicados en la variabilidad de respuesta a clopidogrel 37 I. Pharmacodynamic effects of concomitant versus staggered clopidogrel and omeprazole intake: results of a prospective randomized crossover study. 37 II. Pharmacodynamic evaluation of pantoprazole therapy on clopidogrel- effects: results of a prospective randomized crossover study. 45 III. Cigarette smoking is associated with a dose-response effect in clopidogrel-treated patients with diabetes mellitus and coronary artery disease: results of a pharmacodynamic study. 55 IV. Clopidogrel pretreatment in primary percutaneous coronary intervention: Prevalence of high on-treatment platelet reactivity and impact on preprocedural patency of the infarct-related artery. 65 V. Impact of mild hypothermia on platelet responsiveness to aspirin and clopidogrel: an in vitro pharmacodynamic investigation. 75 4.2. Bloqueo potente del receptor P2Y12 en pacientes con enfermedad coronaria 85 VI. Effects of cangrelor in coronary artery disease patients with and without diabetes mellitus: an in vitro pharmacodynamic investigation. 85 4.3. Artículos de revisión 97 VII. Platelet adenosine diphosphate P2Y12 receptor antagonism: Benefits and limitations of current treatment strategies and future directions. 97 VIII. Diabetes and anti-platelet therapy in acute coronary syndrome. 117 IX.
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