RESUMEN
BACKGROUND: Dabigatran directly inhibits thrombin and is used in primary and secondary stroke prevention in individuals with nonvalvular atrial fibrillation. The prodrug dabigatran etexilate is absorbed by enteral P-glycoprotein (ABCB1) and then activated by hepatic and intestinal carboxylesterases (CES1) to produce active metabolites. Variations in dabigatran metabolism because of genetics may affect concentration levels and clinical outcomes. STUDY QUESTION: We conducted a study to assess how polymorphisms in the CES1 (rs2244613) and ABCB1 (rs4148738) genes affect the through plasma level (c min ) of dabigatran and its correlation to clinical outcomes. STUDY DESIGN: Retrospective multicentric study of consecutive patients on dabigatran therapy. Examination of CES1 rs2244613 and ABCB1 rs4148738 polymorphisms, c min 12 hours after administration, clinical follow-up (ischemic stroke, major or clinically relevant hemorrhage, myocardial infarction, other thromboembolism, and death). MEASURES AND OUTCOMES: A total of 432 patients received treatment for an average of 19.78 months (SD of 20.165). The sex distribution of the patients was 56.5% male, and the average age was 67.56 years (SD of 14.7). The ABCB1 variant genotype was present in 67.8% of patients, whereas 37.5% carried the CES1 polymorphism. RESULTS: Compared with wild-type patients, patients with the CES1 variant had significantly lower dabigatran plasma levels (with a mean difference of 16.986; 95% confidence interval, 5.794-28.178 ng/mL, P = 0.003). We also found a significant risk of major bleeding in patients carrying the ABCB1 rs4148738 allele (hazard ratio = 1.99, confidence interval 95% 1.10 to 3.59, P = 0.024). CONCLUSIONS: The CES1 variant genotype rs2244613 is closely linked with reduced c min of dabigatran. Carriers of the ABCB1 rs4148738 polymorphism exhibit a tendency toward higher plasma levels of dabigatran, which leads to a significantly increased risk of bleeding.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP , Antitrombinas , Hidrolasas de Éster Carboxílico , Dabigatrán , Hemorragia , Accidente Cerebrovascular Isquémico , Humanos , Dabigatrán/efectos adversos , Dabigatrán/farmacocinética , Dabigatrán/sangre , Dabigatrán/administración & dosificación , Masculino , Femenino , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Anciano , Estudios Retrospectivos , Accidente Cerebrovascular Isquémico/prevención & control , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/sangre , Hidrolasas de Éster Carboxílico/genética , Hidrolasas de Éster Carboxílico/sangre , Persona de Mediana Edad , Antitrombinas/efectos adversos , Antitrombinas/sangre , Antitrombinas/farmacocinética , Antitrombinas/administración & dosificación , Hemorragia/inducido químicamente , Hemorragia/sangre , Polimorfismo de Nucleótido Simple , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/genética , Fibrilación Atrial/complicaciones , Fibrilación Atrial/sangre , Anciano de 80 o más AñosRESUMEN
Anticoagulant therapy is essential for the prevention of risks associated with the formation of thrombus in patients after surgery, especially in orthopedics. Recently, new oral anticoagulants were introduced in the therapeutic arsenal. This fact is important, because the current drug of choice in clinical practice is enoxaparin, a low molecular weight heparin. As all injecting drugs, enoxaparin may reduce patients' adherence to treatment by dissatisfaction with and resistance to the administration. This article reviews the available literature on the overall utility of these innovative medicines, approaching the pharmacology, the compared efficacy in relation to current agents, and the potential targets for new agents, as well as points to new trends in research and development. The article also contributes with a practical guide for use and recommendations to health professionals, especially focusing on the reversibility of hemorrhagic events, and discusses the importance of convenience/satisfaction of use, the cost of treatment, and the risk-benefit profile for patients.
A terapia anticoagulante é fundamental para a prevenção de riscos associados à formação de trombos em pacientes pós-cirúrgicos, principalmente em ortopedia. Recentemente, novos anticoagulantes orais foram introduzidos no arsenal terapêutico. Tal fato é importantíssimo, visto que o atual medicamento de primeira escolha na prática clínica é a enoxaparina, uma heparina de baixo peso molecular. Por ser de uso injetável, a enoxaparina pode diminuir a adesão do paciente ao tratamento, devido à insatisfação e à resistência quanto à via de administração. Este artigo revisa a literatura disponível sobre a utilidade total desses medicamentos inovadores ao abordar a farmacologia, a eficácia em comparação com os agentes atuais e os alvos potenciais para novos agentes, bem como aponta as novas tendências em pesquisa e desenvolvimento. O artigo também contribui com um guia prático de uso e recomendações aos profissionais de saúde, com um enfoque especial sobre a reversibilidade de eventos hemorrágicos e, finalmente, discute a importância da conveniência/satisfação de uso, o custo de tratamento e o perfil risco-benefício para o paciente.