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Thrombotic events with specific NOAC antidotes : systematic review and meta-analysis
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Autores
Orientador(es)
Resumo(s)
Introdução
Os NOACs são alternativas adequadas aos antagonistas da Vitamina K e parecem apresentar melhor perfil de segurança. No entanto, mesmo os doentes medicados com NOACs sofrem de eventos hemorrágicos. Doentes com hemorragia ativa podem beneficiar da reversão do efeito farmacológico dos NOACs apesar dos possíveis efeitos adversos, como, eventos trombóticos. Por isso mesmo, sumarizámos a evidência disponível sobre os antídotos específicos para os NOACs, nomeadamente, o Idarucizumab, o Andexanet alfa e o PER977. Após esta recolha, avaliámos a incidência de eventos trombóticos e mortalidade, aquando da utilização destes antídotos em doentes, com hemorragia ativa ou submetidos a cirurgia/procedimento invasivo.
Métodos
Esta revisão incluiu todos os estudos intervencionais publicados até Outubro de 2019 nas seguintes bases de dados: Cochrane Central Register of Controlled Trials, MEDLINE(R) e PsycINFO. Os estudos incluídos foram aqueles que descreveram doentes elegíveis para a administração do antídoto específico e que reportaram pelo menos um evento trombótico ou uma morte.
O risco de viés foi avaliado através de uma adaptação da Critical Appraisal Skills Programme (CASP) Checklist. Utilizou-se o software Openmeta-analyst, e os resultados encontram-se expressos em percentagens e com intervalos de confiança de 95% (CI). Foi usada a Freeman-Turkey transformation (double arcsine transformation), de forma a estimar a frequência dos eventos, limitando o IC entre 0-100%. A heterogeneidade foi avaliada recorrendo ao I2 statistics.
Resultados
Nove estudos, maioria estudos coorte, que reuniram um total de 1292 doentes, foram incluídos na revisão sistemática e meta-análise. Estudos sobre o PER977 não foram encontrados. A análise combinada de eventos trombóticos incluiu cinco estudos e resultou numa incidência de 6,1% (95%CI 1.8–12.3%). Em relação à mortalidade, a análise combinada incluiu nove estudos e resultou numa incidência de 15% (95%CI 10.6–19.8%). Heterogeneidade moderada a alta foi observada em ambos os resultados.
Conclusão
O tratamento com Idarucizumab e Andexanet alpha reduz de forma marcada a atividade anti-trombina e anti-fator Xa, respectivamente, o que conduz a uma hemostasia eficaz nos doentes hemorrágicos. Apesar da eficácia destes fármacos, os doentes poderão sofrer de eventos trombóticos com uma incidência de 6.1%. Sendo que esta incidência é superior nos doentes que foram tratados com o Andexanet alpha.
Introduction NOACs are suitable alternatives to VKAs and seem to be safer. However, even patients under NOACs can have hemorrhagic events. Patients with acute bleeding may benefit from reversing the pharmacological effect of NOACs in addition to the standard measures, although the possible side effects, such as thrombotic events. Therefore, we reviewed the current evidence about specific NOAC antidotes, namely Idarucizumab, Andexanet alpha and PER977, evaluating the incidence of thrombotic events and mortality, when used in patients with active bleeding or undergoing urgent surgery or invasive procedure. Methods The review included all published interventional studies until October 2019 from Cochrane Central Register of Controlled Trials, MEDLINE(R) and PsycINFO. Studies, describing eligible patients for reversal with specific antidotes and that reported at least one thrombotic event or death, were included. The risk of bias was assessed using an adapted Critical Appraisal Skills Programme (CASP) Checklist. Openmeta-analyst software was used, and the results were expressed in percentages (frequency) and 95%-confidence intervals (CI). Freeman-Turkey transformation (double arcsine transformation) was used to adjust the dataset to estimate the frequency of the events, limiting the CI among 0-100%. Heterogeneity was evaluated using the I2 statistics. Results Nine studies with a total of 1292 patients were included in the review and meta-analysis, eight of them were cohort studies and one was case series. Studies about PER977 were not found. Five studies were included in the thrombotic events pooled analysis with an incidence of 6.1% (95%CI 1.8–12.3%). Regarding all-cause mortality pooled analysis included nine studies with an incidence of 15% (95%CI 10.6–19.8%). A moderate to high heterogeneity was observed in both outcomes. Conclusions The best available evidence indicates that even with the demonstrated effectiveness of the treatment with Idarucizumab and Andexanet alpha reducing anti-thrombin and anti–factor Xa activity, respectively, to achieve haemostasis, patients can suffer from thrombotic events with an incidence of 6.1%. This incidence was higher in patients who needed Andexanet alpha.
Introduction NOACs are suitable alternatives to VKAs and seem to be safer. However, even patients under NOACs can have hemorrhagic events. Patients with acute bleeding may benefit from reversing the pharmacological effect of NOACs in addition to the standard measures, although the possible side effects, such as thrombotic events. Therefore, we reviewed the current evidence about specific NOAC antidotes, namely Idarucizumab, Andexanet alpha and PER977, evaluating the incidence of thrombotic events and mortality, when used in patients with active bleeding or undergoing urgent surgery or invasive procedure. Methods The review included all published interventional studies until October 2019 from Cochrane Central Register of Controlled Trials, MEDLINE(R) and PsycINFO. Studies, describing eligible patients for reversal with specific antidotes and that reported at least one thrombotic event or death, were included. The risk of bias was assessed using an adapted Critical Appraisal Skills Programme (CASP) Checklist. Openmeta-analyst software was used, and the results were expressed in percentages (frequency) and 95%-confidence intervals (CI). Freeman-Turkey transformation (double arcsine transformation) was used to adjust the dataset to estimate the frequency of the events, limiting the CI among 0-100%. Heterogeneity was evaluated using the I2 statistics. Results Nine studies with a total of 1292 patients were included in the review and meta-analysis, eight of them were cohort studies and one was case series. Studies about PER977 were not found. Five studies were included in the thrombotic events pooled analysis with an incidence of 6.1% (95%CI 1.8–12.3%). Regarding all-cause mortality pooled analysis included nine studies with an incidence of 15% (95%CI 10.6–19.8%). A moderate to high heterogeneity was observed in both outcomes. Conclusions The best available evidence indicates that even with the demonstrated effectiveness of the treatment with Idarucizumab and Andexanet alpha reducing anti-thrombin and anti–factor Xa activity, respectively, to achieve haemostasis, patients can suffer from thrombotic events with an incidence of 6.1%. This incidence was higher in patients who needed Andexanet alpha.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2020
Palavras-chave
NOAC antidotes Idarucizumab Andexanet alpha Thrombotic events