RESUMEN
Antithrombotic therapy is a critical component of the management of ST-elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI). Rapid and profound inhibition of platelet reactivity has been shown to mitigate the ischemic risks and improve myocardial salvage. High residual platelet reactivity (HRPR) has been reported up to 4 or 6 h after loading dose of prasugrel or ticagrelor; therefore, multiple alternative strategies, including crushed or chewed oral tables or intravenous agents, have been investigated to provide a more rapid and sustained inhibition of platelet function and bridge the initial treatment gap. The FABOLUS FASTER is the first investigator-initiated, multicentre, open-label, prospective, randomized study to directly compare the pharmacodynamics effects of cangrelor, tirofiban, chewed or integer prasugrel. This study will add new insights in the management of antiplatelet therapy in patients with STEMI undergoing primary PCI and might be hypothesis-generating for future clinical trials in this field. The trial is registered on clinicaltrials.gov NCT02978040, and EudraCT 2017-001065-24.
Asunto(s)
Adenosina Monofosfato/análogos & derivados , Intervención Coronaria Percutánea , Clorhidrato de Prasugrel/administración & dosificación , Infarto del Miocardio con Elevación del ST/terapia , Tirofibán/administración & dosificación , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/farmacocinética , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacocinética , Clorhidrato de Prasugrel/farmacocinética , Estudios Prospectivos , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Antagonistas del Receptor Purinérgico P2Y/farmacología , Infarto del Miocardio con Elevación del ST/metabolismo , Tirofibán/farmacocinéticaRESUMEN
Platelets play an important role in the early stage of arterial remodeling after injury. Integrin GPIIb/IIIα (αIIbß3) regulates platelet activation in the inside-out and outside-in signaling pathways. The use of tirofiban, an integrin αIIbß3 inhibitor, in clinical therapy is limited by its short in vivo circulation time. Herein, a controlled drug-release system was formulated using CuS@mSiO2-PEG core-shell nanoparticles as near-infrared-triggered nanocarriers to release tirofiban on demand. The nanocarriers possessed good colloidal stability and very high loading efficiency for the integrin αIIbß3 inhibitor (14.5 wt% for tirofiban). Local application of αIIbß3 antagonist-tirofiban on an injured arterial wall inhibited platelet activation, which was accelerated by laser irradiation. Ex vivo platelet-promoted monocyte transmigration trans-well assays revealed decreased monocyte transmigration after platelet activation was inhibited by tirofiban. Two weeks after the wire-induced injury, the intimal area and cellular content were analyzed. The neointimal area was decreased in ApoE-/- mice with CuS@mSiO2-PEG/tirofiban and laser irradiation-promoted tirofiban release, which had limited the neointima formation. The lesions showed a decreased content of macrophages and smooth muscle cells compared with ApoE-/- mice without tirofiban inhibition. Therefore, the action of platelet-integrin αIIbß3 in neointima formation after vascular injury was successfully inhibited in vivo through the controlled release of tirofiban using a near-infrared-triggered nanocarrier, leading to the decrease of early-stage neointima formation. This study also emphasizes the role of platelets in vascular remodeling and provides a new target, namely integrin αIIbß3, for the inhibition of neointimal hyperplasia during vascular inflammation.