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Biomarcadores farmacogenómicos como fonte de evidência para a efetividade e segurança dos anticoagulantes orais diretos
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Abstract(s)
A trombose é uma condição frequentemente evitável, subjacente a várias doenças cardiovasculares graves, como o enfarte agudo do miocárdio, o acidente vascular cerebral tromboembólico e o tromboembolismo venoso (TEV). Assim, a prevenção efetiva e o tratamento adequado da trombose são essenciais para reduzir a mortalidade e a morbilidade cardiovascular. Nos últimos anos, os anticoagulantes orais diretos (DOAC) surgiram como uma alternativa promissora aos anticoagulantes convencionais, como os antagonistas da vitamina K e as heparinas, apresentando uma eficácia comparável e um perfil de segurança mais favorável. No entanto, o uso desses medicamentos não está isento de riscos. De facto, estudos recentes têm documentado uma variabilidade interindividual significativa nos níveis plasmáticos dos DOAC, o que pode levar a efeitos adversos graves, como hemorragias, ou à redução da efetividade terapêutica. A farmacogenómica desempenha um papel crucial na compreensão dessa variabilidade, constituindo uma ferramenta essencial na personalização da terapêutica com DOAC. Método: O estudo desenvolveu-se em duas fases: i) pesquisa dos biomarcadores farmacogenómicos presentes nos resumos das características dos medicamentos (RCM) dos DOAC com autorização de introdução no mercado (AIM) em Portugal; e ii) revisão sistemática da literatura (RSL), com o objetivo de descrever e caracterizar os biomarcadores farmacogenómicos encontrados tanto nos RCM, como na literatura internacional. No final, os estudos incluídos na RSL foram classificados de acordo com o seu nível de evidência e grau de recomendação. Resultados: Dos 5 DOAC com RCM em Portugal, 4 continham informação farmacogenómica. O biomarcador farmacogenómico mais frequentemente identificado foi o ABCB1/P-gp (glicoproteína-P), seguido do CYP3A4. A RSL confirmou parcialmente esses resultados, destacando também o ABCB1/P-gp como o biomarcador mais comum, seguido do CYP3A5. Além disso, a RSL identificou outros biomarcadores relevantes, especialmente para o dabigatrano e o apixabano. Relativamente, à base de dados criada com a informação farmacogenómica extraída dos RCM, os resultados foram meramente informativos e não geraram recomendações específicas. A maioria dos estudos incluídos foi classificada com um elevado nível de evidência, assegurando a confiabilidade dos resultados e um bom grau de recomendação. Conclusão: As variantes farmacogenómicas estudadas ainda não foram validadas nem incorporadas nos testes genéticos de rotina. Assim, são necessários estudos adicionais, incluindo estudos de coortes independentes, para confirmar a validade e a utilidade clínica dessas variantes. Além disso, é fundamental considerar as diferenças interpopulacionais na distribuição das variantes genéticas de modo a garantir a aplicabilidade e a efetividade dos testes genéticos e das recomendações farmacogenómicas em diferentes populações. A integração da farmacogenómica na prática clínica é essencial para otimizar a terapêutica com DOAC e reduzir os riscos de hemorragia e de eventos tromboembólicos.
Thrombosis is an often preventable condition that underlies several major cardiovascular diseases, including acute myocardial infarction (AMI), thromboembolic stroke and venous thromboembolism (VTE). Effective prevention and appropriate treatment of thrombosis are therefore essential to reduce cardiovascular mortality and morbidity. In recent years, direct oral anticoagulants (DOAC) have emerged as a promising alternative to conventional anticoagulants, such as vitamin K antagonists and heparins, with comparable efficacy and a more favorable safety profile. However, the use of these drugs is not without risk. In fact, recent studies have documented significant inter-individual variability in plasma levels of these drugs, which can lead to serious adverse effects such as bleeding or reduced therapeutic efficacy. Pharmacogenomics plays a crucial role in understanding this variability and is an essential tool for personalizing DOAC therapy. Methods: The study was performed in two phases: i) a search for pharmacogenomic biomarkers in the summary of product characteristics (SmPC) of direct oral anticoagulants with marketing authorization in Portugal; and ii) a systematic literature review (SLR), with the aim of describing and characterizing the pharmacogenomic biomarkers found both in the SmPC and in the international literature. Finally, the studies included in the SLR were classified according to their level of evidence and level of recommendation. Results: Of the 5 direct oral anticoagulants with RCMs in Portugal, 4 contained pharmacogenomic information. The most frequently identified pharmacogenomic biomarker was ABCB1/P-gp, followed by CYP3A4. RSL partially confirmed these results, also highlighting ABCB1/P-gp as the most common biomarker, followed by CYP3A5. In addition, the RSL identified other relevant biomarkers, especially for dabigatran and apixaban. Regarding the database created with the pharmacogenomic information extracted from the RCMs, the results were only informative and did not generate specific recommendations. Most of the included studies were classified as having a high level of evidence, which ensures the reliability of the results and a good level of recommendation. Conclusions: The pharmacogenomic variants studied have not yet been validated or incorporated into routine genetic testing. Therefore, additional studies, including independent cohort studies, are needed to confirm the validity and clinical utility of these variants. In addition, interpopulation differences in the distribution of genetic variants must be considered to ensure the applicability and effectiveness of genetic testing and pharmacogenomic recommendations in different populations. The integration of pharmacogenomics into clinical practice is essential to optimize DOAC therapy and reduce the risk of bleeding and thromboembolic events.
Thrombosis is an often preventable condition that underlies several major cardiovascular diseases, including acute myocardial infarction (AMI), thromboembolic stroke and venous thromboembolism (VTE). Effective prevention and appropriate treatment of thrombosis are therefore essential to reduce cardiovascular mortality and morbidity. In recent years, direct oral anticoagulants (DOAC) have emerged as a promising alternative to conventional anticoagulants, such as vitamin K antagonists and heparins, with comparable efficacy and a more favorable safety profile. However, the use of these drugs is not without risk. In fact, recent studies have documented significant inter-individual variability in plasma levels of these drugs, which can lead to serious adverse effects such as bleeding or reduced therapeutic efficacy. Pharmacogenomics plays a crucial role in understanding this variability and is an essential tool for personalizing DOAC therapy. Methods: The study was performed in two phases: i) a search for pharmacogenomic biomarkers in the summary of product characteristics (SmPC) of direct oral anticoagulants with marketing authorization in Portugal; and ii) a systematic literature review (SLR), with the aim of describing and characterizing the pharmacogenomic biomarkers found both in the SmPC and in the international literature. Finally, the studies included in the SLR were classified according to their level of evidence and level of recommendation. Results: Of the 5 direct oral anticoagulants with RCMs in Portugal, 4 contained pharmacogenomic information. The most frequently identified pharmacogenomic biomarker was ABCB1/P-gp, followed by CYP3A4. RSL partially confirmed these results, also highlighting ABCB1/P-gp as the most common biomarker, followed by CYP3A5. In addition, the RSL identified other relevant biomarkers, especially for dabigatran and apixaban. Regarding the database created with the pharmacogenomic information extracted from the RCMs, the results were only informative and did not generate specific recommendations. Most of the included studies were classified as having a high level of evidence, which ensures the reliability of the results and a good level of recommendation. Conclusions: The pharmacogenomic variants studied have not yet been validated or incorporated into routine genetic testing. Therefore, additional studies, including independent cohort studies, are needed to confirm the validity and clinical utility of these variants. In addition, interpopulation differences in the distribution of genetic variants must be considered to ensure the applicability and effectiveness of genetic testing and pharmacogenomic recommendations in different populations. The integration of pharmacogenomics into clinical practice is essential to optimize DOAC therapy and reduce the risk of bleeding and thromboembolic events.
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Keywords
Biomarcadores Farmacogenómica Anticoagulantes orais diretos Efetividade Segurança