RESUMEN

OBJECTIVES: To assess whether genotype-guided selection of oral antiplatelet drugs using a clinical decision support (CDS) algorithm reduces the rate of major adverse cardiovascular and cerebrovascular events (MACCEs) among Caribbean Hispanic patients, after 6 months. DESIGN: An open-label, multicentre, non-randomised clinical trial. SETTING: Eight secondary and tertiary care hospitals (public and private) in Puerto Rico. PARTICIPANTS: 300 Caribbean Hispanic patients on clopidogrel, both genders, underwent percutaneous coronary intervention (PCI) for acute coronary syndromes, stable ischaemic heart disease and documented extracardiac vascular diseases. INTERVENTIONS: Patients were separated into standard-of-care (SoC) and genotype-guided (pharmacogenetic (PGx)-CDS) groups (150 each) and stratified by risk scores. Risk scores were calculated based on a previously developed CDS risk prediction algorithm designed to make actionable treatment recommendations for each patient. Individual platelet function, genotypes, clinical and demographic data were included. Ticagrelor was recommended for patients with a high-risk score ≥2 in the PGx-CDS group only, the rest were kept or de-escalated to clopidogrel. The intervention took place within 3-5 days after PCI. Adherence medication score was also measured. PRIMARY AND SECONDARY OUTCOMES: The occurrence rate of MACCEs (primary) and bleeding episodes (secondary). Statistical associations between patient time free of events and predictor variables (ie, treatment groups, risk scores) were tested using Kaplan-Meier survival analyses and Cox proportional-hazards regression models. RESULTS: The genotype-guided group had a clinically lower but not significantly different risk of MACCEs compared with the SoC group (8.7% vs 10.7%, p=0.56; HR=0.56). Among high-risk score patients, genotype-driven guidance of antiplatelet therapy showed superiority over SoC in reducing MACCE incidence 6 months postcoronary stenting (adjusted HR=0.104; p< 0.0001). CONCLUSIONS: The potential benefit of implementing our PGx-CDS algorithm to significantly reduce the incidence rate of MACCEs in post-PCI Caribbean Hispanic patients on clopidogrel was observed exclusively among high-risk patients, with apparently no evident effect in other patient groups. TRIAL REGISTRATION NUMBER: NCT03419325.

Asunto(s)

Algoritmos , Clopidogrel , Hispánicos o Latinos , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Ticagrelor , Humanos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Clopidogrel/uso terapéutico , Puerto Rico , Anciano , Ticagrelor/uso terapéutico , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/genética , Síndrome Coronario Agudo/terapia , Sistemas de Apoyo a Decisiones Clínicas , Genotipo , Farmacogenética , Citocromo P-450 CYP2C19/genética , Medición de Riesgo , Región del Caribe/etnología , Hemorragia/inducido químicamente

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/farmacología

Asunto(s)

Inhibidores de Agregación Plaquetaria , Síndrome de Sneddon , Humanos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Síndrome de Sneddon/tratamiento farmacológico , Femenino , Clopidogrel/uso terapéutico , Adulto

RESUMEN

BACKGROUND: Dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin is a well-established practice after a minor stroke or transient ischemic attack (TIA). However, ticagrelor plus aspirin may be an alternative. AIMS: We systematically searched PubMed, Embase, and Cochrane Central from inception to January 2024. We included randomized controlled trials (RCTs) enrolling adults with acute minor stroke or TIA within 72 hours of the onset of the symptoms. RESULTS: A total of 8 RCTs were included in our meta-analysis. Ticagrelor plus aspirin (RR, 0.70; 95% CrI 0.52, 0.91) and clopidogrel plus aspirin (RR, 0.79; 95% CrI 0.64, 0.98) were superior to aspirin in preventing stroke recurrence in overall analysis. Excluding studies with dual antiplatelet up to 90 days, ticagrelor plus aspirin was the only strategy that maintained superiority compared with aspirin regarding stroke recurrence (RR, 0.70; 95% CrI 0.51, 0.95) and ischemic stroke (RR, 0.68; 95% CrI 0.47, 0.94). There was no significant difference between treatment groups regarding hemorrhagic stroke, functional disability, and mortality. CONCLUSIONS: DAPTs were superior to aspirin in preventing recurrence or ischemic stroke. Although no significant difference was observed between DAPTs, ticagrelor plus aspirin may be related to worse major bleeding results, including intracranial bleeding. Ticagrelor plus aspirin is a considerable option for patients after a minor stroke or TIA.

Asunto(s)

Clopidogrel , Terapia Antiplaquetaria Doble , Ataque Isquémico Transitorio , Metaanálisis en Red , Inhibidores de Agregación Plaquetaria , Accidente Cerebrovascular , Ticagrelor , Humanos , Ticagrelor/administración & dosificación , Clopidogrel/administración & dosificación , Ataque Isquémico Transitorio/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Aspirina/administración & dosificación , Aspirina/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Quimioterapia Combinada , Accidente Cerebrovascular Isquémico/tratamiento farmacológico

RESUMEN

Cardiovascular disease (CVD) is one of the leading causes of death in Puerto Rico, where clopidogrel is commonly prescribed to prevent ischemic events. Genetic contributors to both a poor clopidogrel response and the severity of CVD have been identified mainly in Europeans. However, the non-random enrichment of single-nucleotide polymorphisms (SNPs) associated with clopidogrel resistance within risk loci linked to underlying CVDs, and the role of admixture, have yet to be tested. This study aimed to assess the possible interaction between genetic biomarkers linked to CVDs and those associated with clopidogrel resistance among admixed Caribbean Hispanics. We identified 50 SNPs significantly associated with CVDs in previous genome-wide association studies (GWASs). These SNPs were combined with another ten SNPs related to clopidogrel resistance in Caribbean Hispanics. We developed Python scripts to determine whether SNPs related to CVDs are in close proximity to those associated with the clopidogrel response. The average and individual local ancestry (LAI) within each locus were inferred, and 60 random SNPs with their corresponding LAIs were generated for enrichment estimation purposes. Our results showed no CVD-linked SNPs in close proximity to those associated with the clopidogrel response among Caribbean Hispanics. Consequently, no genetic loci with a dual predictive role for the risk of CVD severity and clopidogrel resistance were found in this population. Native American ancestry was the most enriched within the risk loci linked to CVDs in this population. The non-random enrichment of disease susceptibility loci with drug-response SNPs is a new frontier in Precision Medicine that needs further attention.

Asunto(s)

Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , Clopidogrel/farmacología , Etnicidad/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética

RESUMEN

Metastatic melanoma is a very aggressive skin cancer. Platelets are constituents of the tumor microenvironment and, when activated, contribute to cancer progression, especially metastasis and inflammation. P2Y12 is an adenosine diphosphate receptor that triggers platelet activation. Inhibition of P2Y12 by clopidogrel bisulfate (CB) decreases platelet activation, which is also controlled by the extracellular concentration and the metabolism of purines by purinergic enzymes. We evaluated the effects of CB on the viability and proliferation of cultured B16-F10 cells. We also used a metastatic melanoma model with C57BL-6 mice to evaluate cancer development and purine metabolism modulation in platelets. B16-F10 cells were administered intraperitoneally to the mice. Two days later, the animals underwent a 12-day treatment with CB (30 mg/kg by gavage). We have found that CB reduced cell viability and proliferation in B16-F10 culture in 72 h at concentrations above 30 µm. In vivo, CB decreased tumor nodule counts and lactate dehydrogenase levels and increased platelet purine metabolism. Our results showed that CB has significant effects on melanoma progression.

Asunto(s)

Melanoma Experimental , Melanoma , Neoplasias Cutáneas , Animales , Ratones , Clopidogrel/farmacología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Melanoma Experimental/tratamiento farmacológico , Microambiente Tumoral

RESUMEN

Introducción: El desarrollo de las ciencias médicas trae consigo un incremento en la expectativa de vida, junto a la detección temprana de un gran número de enfermedades crónicas como las cerebrovasculares y cardiovasculares, que son tratadas rutinariamente con medicamentos antiagregantes plaquetarios. El conocimiento del manejo de estos pacientes ante los procedimientos quirúrgicos estomatológicos constituye un reto en la práctica diaria profesional. Objetivo: Determinar el nivel de sangramiento posextracción dentaria en pacientes con enfermedad cardiovascular y cerebrovascular, según el tipo de antiagregantes plaquetarios y grupo dentario, así como la frecuencia de utilización de las medidas para su control. Métodos: Se efectuó un estudio observacional, descriptivo, longitudinal y prospectivo con un universo de 136 pacientes de más de 20 años, remitidos por su cardiólogo y que necesitaban realizarse extracciones dentarias sin modificar su tratamiento con antiagregantes plaquetarios. Las variables estudiadas fueron la enfermedad sistémica, el tipo de antiagregante plaquetario, el nivel de sangramiento, grupo dentario intervenido y método hemostático utilizado. Resultados: La mitad de los pacientes estudiados no presentó sangramiento posextracción dentaria. En los pacientes tratados con aspirina o clopidogrel predominaron los sujetos sin sangramiento para un 84,3 por ciento y 62,5 por ciento, respectivamente. En los de doble antiagregación prevaleció el sangramiento moderado con un 46,3 por ciento. Los grupos dentarios incisivo, canino y premolar no presentaron episodios de sangramiento para un 64,1 por ciento, 51,6 por ciento y 53,3por ciento, respectivamente. El método hemostático más utilizado fue la compresión de las corticales y termoterapia fría (47,8 por ciento). Conclusiones: La mitad de los pacientes con enfermedades cardiovasculares y cerebrovasculares no presentaron sangramiento posextracción dentaria(AU)

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Introduction: The development of medical sciences brings with it an increase in life expectancy, together with the early detection of a large number of chronic diseases such as cerebrovascular and cardiovascular diseases, which are routinely treated with antiplatelet aggregation drugs. Knowledge on the treatment of these patients before stomatological surgical procedures constitutes a challenge in daily professional practice. Objective: To determine the level of bleeding after tooth extraction in patients with cardiovascular and cerebrovascular disease, according to the type of antiplatelet agents and dental group, as well as the frequency of use of measures for their control. Methods: An observational, descriptive, longitudinal and prospective study was carried out with a universe of 136 patients over 20 years of age, referred by their cardiologist, who needed dental extractions without modifying their treatment with antiplatelet agents. The variables studied were systemic disease, type of antiplatelet agent, level of bleeding, dental group treated and hemostatic method used. Results: Half of the patients studied did not present bleeding after tooth extraction. In patients treated with aspirin or clopidogrel, 84.3 percent and 62.5por ciento, respectively, had no bleeding. In those with double antiplatelet therapy, modera te bleeding prevailed with 46.3 The incisor, canine and premolar tooth groups did not present bleeding episodes (64.1 percent, 51.6and 53.3 percent respectively). The most commonly used hemostatic method was cortical compression and cold thermotherapy (47.8%). Conclusions: Half of the patients with cardiovascular and cerebrovascular diseases did not present bleeding after tooth extraction(AU)

Asunto(s)

Humanos , Extracción Dental/métodos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Hemorragia/terapia , Aspirina/uso terapéutico , Epidemiología Descriptiva , Estudios Longitudinales , Estudio Observacional , Clopidogrel/uso terapéutico

RESUMEN

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/farmacología

RESUMEN

BACKGROUND: Despite lipid-lowering and antiplatelet therapy, the pattern of residual lipoproteins seems relevant to long-term cardiovascular outcomes. This study aims to evaluate the effects of combined therapies, commonly used in subjects with acute myocardial infarction, in the quality of low-density lipoprotein (LDL) particles. METHODS: Prospective, open-label trial, included patients with acute myocardial infarction. Patients were randomized to antiplatelet treatment (ticagrelor or clopidogrel) and subsequently to lipid-lowering therapy (rosuvastatin or simvastatin/ezetimibe) and were followed up for six months. Nonlinear optical properties of LDL samples were examined by Gaussian laser beam (Z-scan) to verify the oxidative state of these lipoproteins, small angle X-ray scattering (SAXS) to analyze structural changes on these particles, dynamic light scattering (DLS) to estimate the particle size distribution, ultra violet (UV)-visible spectroscopy to evaluate the absorbance at wavelength 484 nm (typical from carotenoids), and polyacrylamide gel electrophoresis (Lipoprint) to analyze the LDL subfractions. RESULTS: Simvastatin/ezetimibe with either clopidogrel or ticagrelor was associated with less oxidized LDL, and simvastatin/ezetimibe with ticagrelor to lower cholesterol content in the atherogenic subfractions of LDL, while rosuvastatin with ticagrelor was the only combination associated with increase in LDL size. CONCLUSIONS: The quality of LDL particles was influenced by the antiplatelet/lipid-lowering strategy, with ticagrelor being associated with the best performance with both lipid-lowering therapies. Trial registration: NCT02428374.

Asunto(s)

Anticolesterolemiantes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Infarto del Miocardio , Anticolesterolemiantes/efectos adversos , Clopidogrel , Ezetimiba/uso terapéutico , Humanos , Lipoproteínas , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/tratamiento farmacológico , Estudios Prospectivos , Rosuvastatina Cálcica/uso terapéutico , Dispersión del Ángulo Pequeño , Simvastatina/uso terapéutico , Ticagrelor , Difracción de Rayos X

RESUMEN

Pharmacogenetics (PGx) is the relationship between an individual's genetic variations and the response to pharmacological treatment. We chose to perform an overview of reviews on PGx testing-guided treatment for cardiovascular diseases, based on clinically relevant gene-drug pairs. We conducted a search on Medline, Embase and Cochrane Library, from their inception to 18 June 2020. The most studied gene-drug pairs were clopidogrel and warfarin associated with cytochrome p450 and vitamin K epoxide reductase complex subunit 1 genes (CYP2C19, CYP2C9 and VKORC1), classified as critically low quality. There is a need for more quality primary studies and systematic reviews that assess the risk of bias, with consistent definitions of clinical outcomes to consider the benefits of PGx testing for cardiovascular diseases.

Asunto(s)

Enfermedades Cardiovasculares , Warfarina , Anticoagulantes/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , Clopidogrel/uso terapéutico , Citocromo P-450 CYP2C9/genética , Genotipo , Humanos , Farmacogenética , Literatura de Revisión como Asunto , Vitamina K Epóxido Reductasas/genética , Warfarina/uso terapéutico

Asunto(s)

Femenino , Anciano de 80 o más Años , Clopidogrel , Infarto del Miocardio , Neutropenia , Tienopiridinas , Ticagrelor , Factores de Riesgo de Enfermedad Cardiaca

RESUMEN

INTRODUCTION: Clopidogrel has been demonstrated to be effective in improving coronary microcirculation (CM) among patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolytics. Ticagrelor is a more potent adenosine diphosphate (ADP) receptor blocker proven to be superior to clopidogrel among patients with acute coronary syndromes. The present study aimed to compare the effects of ticagrelor and clopidogrel on CM in patients with STEMI treated with fibrinolytics. METHODS: The present study prospectively included 48 patients participating in the TREAT trial, which randomly assigned patients with STEMI undergoing fibrinolysis to ticagrelor versus clopidogrel. The primary endpoint of this study was the evaluation of the CM using the global myocardial perfusion score index (global MPSI) obtained by myocardial contrast echocardiography (MCE). Platelet aggregation to ADP was evaluated by Multiplate® and expressed as area under the curve (AUC). RESULTS: The global MPSI demonstrated no differences between the groups [mean 1.4 (1.2-1.5) in the ticagrelor group and 1.2 (1.2-1.5) in the clopidogrel group (p = 0.41)]. Platelet aggregability was lower in the ticagrelor group (18.1 ± 9.7 AUC), compared to the clopidogrel group (26.1 ± 12.5 AUC, p = 0.01). CONCLUSION: We found no improvement in coronary microcirculation with ticagrelor compared to clopidogrel among patients with STEMI treated with fibrinolytics, despite the fact that platelet aggregation to ADP was lower with ticagrelor. CLINICAL TRIALS REGISTRATION: NCT03104062.

Asunto(s)

Infarto del Miocardio , Infarto del Miocardio con Elevación del ST , Adenosina Difosfato/farmacología , Adenosina Difosfato/uso terapéutico , Clopidogrel/uso terapéutico , Humanos , Microcirculación , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/tratamiento farmacológico , Infarto del Miocardio con Elevación del ST/etiología , Ticagrelor/uso terapéutico

RESUMEN

Abstract The aim of our study was to assess risk factors for potential drug-drug interactions (pDDIs) of statins across different phases of treatment of acute coronary syndrome (ACS) patients: from the point of first medical contact to the coronary angiography (first phase), after coronary angiography to the last day of hospitalization (second phase) and at discharge from hospital (third phase). This was a post hoc analysis of the data collected during the retrospective observational cohort study conducted at the Clinic for Cardiology of the Clinical Centre Kragujevac, Serbia. Patients prescribed statins were identified from the original study population: 156, 240 and 236 patients for the first, second and third phases, respectively. At least one statin pDDI was present in 113 (72.4%), 161 (67.1%) and 139 (58.9%) patients in the first, second and third phases, respectively. Heart failure, arrhythmias after ACS, CRP, triglycerides, length of hospitalization, number of prescribed drugs, antiarrhythmic drugs, and clopidogrel seem to increase the risk of statin pDDIs in at least one treatment phase. Physicians should be vigilant to the possibility of statin pDDIs in ACS patients who have factors that may increase their rate.

Asunto(s)

Humanos , Masculino , Femenino , Adulto , Pacientes/clasificación , Factores de Riesgo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Interacciones Farmacológicas , Síndrome Coronario Agudo/patología , Preparaciones Farmacéuticas/administración & dosificación , Cardiología/clasificación , Angiografía Coronaria/instrumentación , Serbia , Clopidogrel

RESUMEN

Introducción: el ticagrelor es un medicamento antiagregante plaquetario utilizado como prevención secundaria en pacientes con síndrome coronario agudo. Dentro de las reacciones adversas reportadas secundarias a su administración se encuentran hemorragias, cefalea, disnea, epistaxis, pausas ventriculares o bradicardia, hiperuricemia y elevación de la creatinina. No obstante, las reacciones de hipersensibilidad han sido raras. Presentación del caso: paciente masculino de 63 años con infarto agudo del miocardio, elevación de ST y documentándose en cateterismo cardíaco ectasia y enfermedad de flujos lentos. Requirió terapia de antiagregación dual con ácido acetilsalicílico (ASA) y ticagrelor, con posterior urticaria de origen medicamentoso según concepto de dermatología. Se manejó con esteroide tópico, antihistamínico oral y retiro de ticagrelor. Se considera un caso raro de reacción al antiagregante plaquetario descrito.

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Introduction: ticagrelor is an antiplatelet therapy used for secondary prevention in patients with acute coronary syndrome. Adverse effects of ticagrelor are hemorrhage, headache, dyspnea, epistaxis, ventricular pauses or bradycardia, hyperuricemia and elevation of creatinine level. However, hypersensitivity reaction of ticagrelor is rarely recognized. Case report: we present a 63-year-old male patient diagnosed with acute myocardial infarction, ST-segment elevation and ectasia and low blood flow disease documented by coronary angiogram. He required dual antiplatelet therapy with acetylsalicylic acid (ASA) and ticagrelor, developing drug-induced urticaria according to dermatology consultation. He was treated with topical steroids, oral antihistamines and ticagrelor discontinuation. This case is considered a rare case of reaction to the antiplatelet agent described herein.

Asunto(s)

Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria , Clopidogrel , Ticagrelor , Hipersensibilidad

RESUMEN

BACKGROUND: Paraoxonase-1 (PON1), a glycoprotein associated with serum high-density lipoprotein (HDL), has a central role in metabolizing lipid peroxides, exhibiting antiatherogenic properties. The polymorphism p.Q192R has been previously associated with coronary artery disease (CAD) susceptibility and clopidogrel response. PURPOSE: We aimed at investigating the association of PON1 p.Q192R with CAD and clopidogrel response in Colombian population. PATIENTS AND METHODS: The study was conducted among 163 patients diagnosed with CAD and treated with clopidogrel. The allele frequencies for the PON1 192Q and 192R alleles were determined in cases and Latin-American controls obtained from the public database gnomAD (n = 17,711). Response to clopidogrel was determined by assessing the platelet function using the INNOVANCE PFA-200 System. We determined the association between PON1 p.Q192R polymorphism, increased susceptibility to CAD and high on-treatment platelet reactivity (HPR) by using odds ratio (OR) and 95% confidence interval (CI) on four genetic models. RESULTS: The allele frequencies for the PON1 192Q and 192R alleles were 0.60 and 0.40, respectively. The allele distribution was found to be statistically different from the control group and other ethnic groups. The allele 192R was positively associated with decreased susceptibility to CAD under a dominant model (OR, 0.58; 95% CI, 0.42-0.8; P < 0.01). We found no association between the polymorphism and HPR. CONCLUSION: We propose that PON1 p.Q192R is a potentially useful marker for CAD susceptibility in the Colombian population and lacks association with HPR under clopidogrel treatment.

Asunto(s)

Arildialquilfosfatasa , Enfermedad de la Arteria Coronaria , Arildialquilfosfatasa/genética , Clopidogrel/uso terapéutico , Colombia/epidemiología , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Genotipo , Humanos , Inhibidores de Agregación Plaquetaria/uso terapéutico

RESUMEN

In the field of interventional neuroradiology, antiplatelet agents are commonly used to prepare patients before the implantation of permanent endovascular materials. Among the available drugs, clopidogrel is the most frequently used one, but resistance phenomena are considered to be relatively common. Prasugrel and ticagrelor were recently added to the pharmacologic arsenal, but the safety of these agents in patients undergoing neurointerventional procedures is still a subject of discussion. The cumulative experience with both drugs is less extensive than that with clopidogrel, and the experience with patients in the neurology field is less extensive than in the cardiology domain. In the present article, we provide a narrative review of studies that investigated safety issues of oral P2Y12 inhibitors in interventional neuroradiology and discuss potential routes for future research.

Asunto(s)

Inhibidores de Agregación Plaquetaria , Antagonistas del Receptor Purinérgico P2Y , Clopidogrel , Humanos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Clorhidrato de Prasugrel , Antagonistas del Receptor Purinérgico P2Y/efectos adversos , Ticagrelor , Resultado del Tratamiento

RESUMEN

Anticoagulant and antiplatelet drugs effectively prevent thrombotic events in patients with cardiovascular diseases, ischemic stroke, peripheral vascular diseases, and other thromboembolic diseases. However, genetic and non-genetic factors affect the response to antithrombotic therapy and can increase the risk of adverse events. This narrative review discusses pharmacogenomic studies on antithrombotic drugs commonly prescribed in Brazil. Multiple Brazilian studies assessed the impact of pharmacokinetic (PK) and pharmacodynamic (PD) gene variants on warfarin response. The reduced function alleles CYP2C9*2 and CYP2C9*3, and VKORC1 rs9923231 (c.-1639G>A) are associated with increased sensitivity to warfarin and a low dose requirement to prevent bleeding episodes, whereas CYP4F2 rs2108622 (p.Val433Met) carriers have higher dose requirements (warfarin resistance). These deleterious variants and non-genetic factors (age, gender, body weight, co-administered drugs, food interactions, and others) account for up to 63% of the warfarin dose variability. Few pharmacogenomics studies have explored antiplatelet drugs in Brazilian cohorts, finding associations between CYP2C19*2, PON1 rs662 and ABCC3 rs757421 genotypes and platelet responsiveness or clopidogrel PK in subjects with coronary artery disease (CAD) or acute coronary syndrome (ACS), whereas ITGB3 contributes to aspirin PK but not platelet responsiveness in diabetic patients. Brazilian guidelines on anticoagulants and antiplatelets recommend the use of a platelet aggregation test or genotyping only in selected cases of ACS subjects without ST-segment elevation taking clopidogrel, and also suggest CYP2C9 and VKORC1 genotyping before starting warfarin therapy to assess the risk of bleeding episodes or warfarin resistance.

Asunto(s)

Fibrinolíticos , Warfarina , Anticoagulantes/efectos adversos , Arildialquilfosfatasa/genética , Brasil , Clopidogrel , Citocromo P-450 CYP2C9/genética , Genotipo , Humanos , Errores Innatos del Metabolismo , Farmacogenética , Inhibidores de Agregación Plaquetaria/efectos adversos , Vitamina K Epóxido Reductasas/genética , Warfarina/efectos adversos

RESUMEN

This multicenter clinical study was aimed at conducting a targeted pharmacogenomic association analysis of residual on-clopidogrel platelet reactivity in 474 Caribbean Hispanic patients. Platelet reactivity was measured using the VerifyNow P2Y12 assay and clopidogrel resistance was defined as P2Y12 reaction units (PRUs) greater than or equal to 208. Genotyping was performed using the whole-genome Infinium MEGA BeadChip array. An ancestry-adjusted, weighted polygenic risk score (wPGxRS) was developed to account for the effect of multiple variants on PRU and compared between clopidogrel responders and nonresponders. The mean PRU across the study cohort was 173.8 ± 68.5 and 33.5% of patients were defined as clopidogrel resistant. Multivariate linear regression showed that 19% of PRU variability was attributed to nine independent predictors, with CYP2C19*2 (rs4244285) accounting for ~ 7% of observed PRU variation (p < 0.001). PON1 rs662, ABCB1/MDR1 rs2032582, PEAR1 rs12041331 carrier status, and the interaction between African ancestry and rs12041331 carriers also predicted PRU among the participants (p ≤ 0.05). A clear gene-dose effect was detected between PRU and CYP2C19*2 genotype, consistent with previous studies in European patient populations, as well as rs12777823. Importantly, a significant positive correlation was detected between our novel wPGxRS (4 variants) and PRU among the Hispanic patient population (rp  = 0.35, p < 0.001). Moreover, the wPGxRS discriminated between nonresponders and responders (p = 0.003), indicating that this multigene-based score is a useful predictor of clopidogrel resistance among Caribbean Hispanics. Taken together, these results help close the gap of knowledge on clopidogrel pharmacogenomics and its potential clinical implementation in this under-represented population.

Asunto(s)

Clopidogrel/farmacología , Hispánicos o Latinos/genética , Herencia Multifactorial , Farmacogenética , Inhibidores de Agregación Plaquetaria/farmacología , Anciano , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Indias Occidentales/etnología

RESUMEN

BACKGROUND: Dual antiplatelet therapy (DAT) is a therapeutic option for patients with minor ischemic stroke (IS) or transient ischemic attack (TIA). No study has evaluated the incidence of early bleeding in patients with moderate to major ischemic stroke. The current study aimed to analyze both the frequency of early bleeding and hospital morbidity related to DAT for either acute IS or TIA regardless of admission National Institute of Health Stroke Scale (NIHSS) score. METHODS: This was a retrospective analysis based on data collected from a prospective data bank of a single center. We included patients who underwent DAT in the first 24 hours of symptom onset with a loading dose (aspirin 300 mg + clopidogrel 300 mg) on the first day, followed by a maintenance dose (aspirin 100 mg + clopidogrel 75 mg). We analyzed intracranial and/or extracranial hemorrhage that had occurred during the hospital admission, symptomatic bleeding, modified Rankin Scale (mRS) score at discharge, and death rates as outcomes. RESULTS: Of the 119 patients analyzed, 94 (79 %) had IS and 25 (21 %) had TIA. Hemorrhage occurred in 11 (9.2 %) and four (3.4 %) patients with TIA or NIHSS ≤ 3, respectively, although none were symptomatic. Patients with bleeding as a complication had higher admission NIHSS [4 (3-7) vs. 2 (1-4), p = 0.044] and had higher mRS at discharge (mRS 2 [1-5] vs. mRS 1 [0-2], p = 0.008). These findings did not indicate increased mortality, as one (9 %) patient died from bleeding and two (1.8 %) patients died without bleeding (p = 0.254). CONCLUSION: DAT seems to be a safe therapy in patients regardless of admission NIHSS if started within the first 24 h after symptom onset because only 1.6 % of patients had symptomatic bleeding.

Asunto(s)

Aspirina/efectos adversos , Clopidogrel/efectos adversos , Evaluación de la Discapacidad , Terapia Antiplaquetaria Doble/efectos adversos , Hemorragias Intracraneales/inducido químicamente , Ataque Isquémico Transitorio/tratamiento farmacológico , Admisión del Paciente , Inhibidores de Agregación Plaquetaria/efectos adversos , Accidente Cerebrovascular/tratamiento farmacológico , Tiempo de Tratamiento , Anciano , Aspirina/administración & dosificación , Brasil/epidemiología , Clopidogrel/administración & dosificación , Bases de Datos Factuales , Esquema de Medicación , Terapia Antiplaquetaria Doble/mortalidad , Femenino , Estado Funcional , Humanos , Incidencia , Hemorragias Intracraneales/diagnóstico , Hemorragias Intracraneales/mortalidad , Ataque Isquémico Transitorio/diagnóstico , Ataque Isquémico Transitorio/mortalidad , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/mortalidad , Factores de Tiempo , Resultado del Tratamiento

Asunto(s)

Cardiólogos , Enfermedades Cardiovasculares , Humanos , Clopidogrel/farmacología , Citocromo P-450 CYP2C19/genética , Genotipo , Factores de Riesgo de Enfermedad Cardiaca , México , Inhibidores de Agregación Plaquetaria/farmacología , Polimorfismo de Nucleótido Simple , Factores de Riesgo