Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC Dk8nFXw4xXWDN9VLyjncGLB S0066-782X2024000700305 00305 10.36660/abc.20230738 Artigo Original Anticoagulantes Orais Diretos versus Antagonistas da Vitamina K para Trombo Ventricular Esquerdo: Uma Metanálise com Análise Sequencial de Ensaios 0000-0002-6484-1162 Pasqualotto Eric Concepção e desenho da pesquisa Obtenção de dados Análise e interpretação dos dados Análise estatística Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo 1 0000-0001-9393-2445 Gewehr Douglas Mesadri Concepção e desenho da pesquisa Obtenção de dados Análise e interpretação dos dados Análise estatística Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo 2 0000-0002-3203-0509 Ferreira Rafael Oliva Morgado Análise e interpretação dos dados Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo 1 Chavez Matheus Pedrotti Análise e interpretação dos dados Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo 1 0000-0001-8009-004X Silva Caroliny Hellen Obtenção de dados Análise e interpretação dos dados Redação do manuscrito; Revisão crítica do manuscrito quanto ao conteúdo 3 0000-0003-2814-9627 Cruz Sara Almeida Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo 4 0000-0002-1869-2362 Limachi-Choque Jhonny Obtenção de dados Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo 5 0000-0001-5142-7723 Park Amanda Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo 6 0000-0002-8025-9084 Coutinho Mário Sérgio Soares de Azeredo Concepção e desenho da pesquisa Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo 1 Kubrusly Luiz Fernando Concepção e desenho da pesquisa Redação do manuscrito Revisão crítica do manuscrito quanto ao conteúdo 2 Universidade Federal de Santa Catarina Florianópolis SC Brasil Universidade Federal de Santa Catarina, Florianópolis, SC – Brasil Faculdade Evangélica Mackenzie do Paraná Curitiba PR Brasil Faculdade Evangélica Mackenzie do Paraná, Curitiba, PR – Brasil Universidade Federal do Rio Grande do Norte Natal RN Brasil Universidade Federal do Rio Grande do Norte, Natal, RN – Brasil Immanuel Kant Baltic Federal University Institute of Medicine Kaliningrad Rússia Immanuel Kant Baltic Federal University Institute of Medicine, Kaliningrad – Rússia Universidad Mayor de San Simón Centro Universitario de Medicina Tropical Cochabamba Bolívia Universidad Mayor de San Simón - Centro Universitario de Medicina Tropical (CUMETROP), Cochabamba – Bolívia Centro Universitário Lusíada Faculdade de Ciências Médicas de Santos Santos SP Brasil Centro Universitário Lusíada - Faculdade de Ciências Médicas de Santos, Santos, SP – Brasil Correspondência: Eric Pasqualotto • Universidade Federal de Santa Catarina – Rua Profa. Maria Flora, s/n. CEP 88036-800, Pausewang, Florianópolis, SC – Brasil. E-mail: ericpasqualotto02@gmail.com

Editor responsável pela revisão: Marcio Bittencourt

Potencial conflito de interesse

Não há conflito com o presente artigo

 26 07 2024 06 2024 121 7 e20230738 23 10 2023 28 02 2024 13 03 2024 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

: Anticoagulantes Orais Diretos versus Antagonistas da Vitamina K para Trombo Ventricular Esquerdo: Uma Metanálise com Análise Sequencial de Ensaios

Resumo Fundamento

Os antagonistas da vitamina K (AVKs) são o tratamento de primeira linha recomendado para trombo ventricular esquerdo (TVE); entretanto, os anticoagulantes orais diretos (AODs) têm sido considerados uma terapia alternativa.

 Objetivos

Avaliar a eficácia e a segurança dos AODs em comparação com a terapia com AVKs em pacientes com TVE.

 Métodos

PubMed, Embase e Cochrane foram sistematicamente pesquisados em busca de ensaios clínicos randomizados ou estudos de coorte que comparassem AODs versus AVKs para TVE. As razões de risco (RR) foram calculadas para desfechos binários, com intervalos de confiança (IC) de 95%. A significância estatística foi definida como valor de p < 0,05.

 Resultados

Foram incluídos um total de 4 ensaios clínicos randomizados e 29 estudos de coorte, com 4.450 pacientes designados para AODs ou AVKs. Não houve diferença significativa entre os grupos para acidente vascular cerebral ou eventos embólicos sistêmicos (AVC/EES) (RR 0,84; IC 95% 0,65 a 1,07; p = 0,157), acidente vascular cerebral (RR 0,73; IC 95% 0,48 a 1,11; p = 0,140), eventos embólicos sistêmicos (EES) (RR 0,69; IC 95% 0,40 a 1,17; p = 0,166), resolução do trombo (RR 1,05; IC 95% 0,99 a 1,11; p = 0,077), qualquer sangramento (RR 0,78; IC 95% 0,60 a 1,00; p = 0,054), sangramento clinicamente relevante (RR 0,69; IC 95% 0,46 a 1,03; p = 0,066), sangramento menor (RR 0,73; IC 95% 0,43 a 1,23; p = 0,234), sangramento maior (RR 0,87; IC 95% 0,42 a 1,80; p = 0,705) e mortalidade por todas as causas (RR 1,05; IC 95% 0,79 a 1,39; p = 0,752). Em comparação com AVKs, a rivaroxabana reduziu significativamente AVC/EES (RR 0,35; IC 95% 0,16 a 0,91; p = 0,029) e EES (RR 0,39; IC 95% 0,16 a 0,95; p = 0,037).

 Conclusões

Os AODs tiveram uma taxa semelhante de eventos tromboembólicos e hemorrágicos, bem como de resolução do trombo, em comparação com os AVKs no tratamento de TVE. A terapia com rivaroxabana teve uma redução significativa nos eventos tromboembólicos, em comparação com os AVKs.

 Varfarina Inibidores do Fator Xa Trombose Introdução

O trombo ventricular esquerdo (TVE) frequentemente ocorre como uma complicação de infarto agudo do miocárdio (IAM), cardiomiopatia não isquêmica ou disfunção cardíaca grave.1 Nos Estados Unidos, infartos do miocárdio ocorrem a uma taxa de 1 milhão por ano, e entre 4% e 39% desses pacientes podem desenvolver TVE, apresentando alta demanda por cuidados médicos.2-4 Apesar dos avanços na medicina cardiovascular, o tratamento de TVE, muitas vezes, permanece desafiador, devido a recomendações limitadas das diretrizes.5

Os antagonistas da vitamina K (AVKs) foram estabelecidos como prevenção e tratamento de TVE.6 O uso de AVKs está associado à necessidade de monitoramento frequente da razão normalizada internacional (RNI) e de vigilância para interações medicamentosas ou alimentares.7 A falha em manter a RNI na zona terapêutica está associada ao aumento da incidência de trombos.7 Nesse sentido, os anticoagulantes orais diretos (AODs) têm demonstrado eficácia semelhante aos AVKs, ao mesmo tempo em que apresentam menos complexidades de tratamento, levando ao aumento da sua utilização, apesar da ausência de orientação definitiva quanto à sua segurança como opção para pacientes com TVE.8

Metanálises anteriores, ensaios controlados randomizados (ECRs) e estudos retrospectivos comparando AODs com AVKs para o tratamento de TVE apresentam dados que apoiam o uso de AODs; no entanto, nem todos são consistentes, uma vez que foram observados resultados diferentes em relação aos eventos tromboembólicos e hemorrágicos.9-11 Assim, o regime de anticoagulação ideal para pacientes com TVE permanece desconhecido. Portanto, nosso objetivo foi realizar uma revisão sistemática e metanálise de ECRs e estudos observacionais, juntamente com uma análise sequencial de ensaios (TSA, do inglês trial sequential analysis) para comparar a eficácia e segurança de AODs versus AVKs em pacientes com TVE.

 Métodos

A presente revisão sistemática e metanálise seguiram as recomendações das diretrizes Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).12 O protocolo do estudo foi registrado no International Prospective Register of Systematic Reviews (PROSPERO) sob número de registro CRD42023409287.

Estratégia de pesquisa e extração de dados

Os bancos de dados PubMed, Embase e Cochrane Library foram pesquisados sistematicamente desde o início até março de 2023, com a seguinte estratégia de pesquisa em inglês: (“left ventricular thrombus” OU “left ventricular thrombi” OU LVT OU LVTs) E (DOAC OU NOAC OU “direct anticoagulant” OU “direct oral anticoagulants” OU “direct oral anticoagulant” OU “oral anticoagulation” OU “new oral anticoagulant” OU rivaroxaban OU apixaban OU edoxaban OU dabigatran) E (“vitamin K antagonist” OU “vitamin K antagonists” OU VKA OU VKAs OU warfarin OU varfarin). Visando incluir estudos adicionais, foram analisadas referências de revisões sistemáticas e estudos incluídos para verificar a possibilidade de quaisquer outros estudos elegíveis. As características basais e os dados dos desfechos foram extraídos independentemente por dois autores (E.P. e R.O.M.F.). As divergências foram resolvidas por consenso com o autor sênior (E.P., R.O.M.F. e L.F.K.).

 Critérios de eligibilidade

Foram incluídos estudos que atenderam aos seguintes critérios: (1) ECRs ou estudos de coorte; (2) comparação de AODs com AVKs; (3) inscrição de pacientes com TVE; e (4) relato de pelo menos um parâmetro de interesse. Excluímos (1) populações sobrepostas; e (2) estudos que não eram ECRs ou estudos de coorte.

 Desfechos e análise de subgrupos

Os desfechos de interesse foram: (1) acidente vascular cerebral ou eventos embólicos sistêmicos (AVC/EES), (2) acidente vascular cerebral (AVC), (3) eventos embólicos sistêmicos (EES); (4) resolução do trombo; (5) qualquer sangramento; (6) sangramento clinicamente relevante; (7) sangramento menor; (8) sangramento maior; e (9) mortalidade por todas as causas.

A definição dos desfechos foi de acordo com os critérios estabelecidos nos estudos incluídos na presente revisão sistemática e metanálise. Qualquer sangramento incluiu todo sangramento. O sangramento clinicamente relevante incluiu sangramento não maior clinicamente relevante, sangramento menor e sangramento maior. Os ataques isquêmicos transitórios não foram considerados para análise do desfecho de AVC ou do desfecho composto de AVC ou EES.

As análises de subgrupos foram realizadas de acordo com: (1) tratamento com apixabana versus AVKs, (2) tratamento com rivaroxabana versus AVKs, (3) apenas ECRs, (4) pacientes com TVE pós-IAM e (5) exclusão de resumos de conferências.

 Avaliação de risco de viés

Os ECRs foram avaliados com a ferramenta da Cochrane Collaboration para avaliação de risco de viés em ensaios randomizados (RoB-2), com 5 domínios: seleção, desempenho, detecção, atrito e relato.13 O risco de viés de estudos de intervenção não randomizados (ROBINS-I, do inglês Risk of Bias Summary for Non-randomized Studies) foi utilizado para avaliar os estudos de coorte, com 7 domínios: confusão, seleção de participantes, classificação de intervenções, desvios das intervenções pretendidas, falta de dados, mensuração dos desfechos e resultado relatado.14 Dois autores independentes (E.P. e R.O.M.F.) realizaram a avaliação da qualidade. As divergências foram resolvidas por consenso com o autor sênior (E.P., R.O.M.F. e L.F.K.).

 Avaliação de qualidade

A qualidade geral da evidência foi analisada de acordo com as diretrizes de Classificação de Recomendações, Avaliação, Desenvolvimento e Análises (GRADE, do inglês Grading of Recommendation, Assessment, Development and Evaluations).15 Os desfechos foram classificados como evidência de qualidade muito baixa, baixa, moderada ou alta com base na presença de risco de viés, inconsistência de resultados, imprecisão, viés de publicação e magnitude dos efeitos do tratamento.

 Avaliação do risco de viés entre estudos

O potencial viés de publicação foi julgado para o desfecho de AVC/EES por inspeção visual de gráficos de funil com contorno aprimorado e avaliado pela assimetria de regressão de Egger e pelo teste de correlação de postos de Begg.16,17

 Análise estatística

Os efeitos do tratamento para desfechos binários foram comparados usando razões de risco (RR), com intervalos de confiança (IC) de 95%. A significância estatística foi definida como valor de p < 0,05. A heterogeneidade foi avaliada com o teste Q de Cochran e estatística I2; p < 0,10 e I2 > 25% foram considerados significativos para a heterogeneidade.18 O modelo de efeitos aleatórios do estimador de máxima verossimilhança restrita (REML, do inglês restricted maximum-likelihood estimator) foi usado para todos os desfechos.19 O software estatístico R, versão 4.2.1 (R Foundation for Statistical Computing) foi utilizado para a análise estatística.

 Análise de sensibilidade

A análise leave-one-out (exclusão de um estudo por vez) foi utilizada para identificar estudos influentes e seus efeitos nas estimativas agrupadas. Este procedimento foi realizado removendo dados de um estudo e reanalisando os dados restantes. Quando os valores de p do tamanho do efeito agrupado mudaram de significativo para não significativo ou vice-versa, a dominância do estudo foi atribuída.

 Análise sequencial de ensaios

Foi realizada TSA nos ECRs incluídos para avaliar se a evidência cumulativa tinha poder estatístico suficiente nos desfechos de resolução de trombos, AVC e sangramento clinicamente relevante. Nosso plano estatístico envolveu testes bilaterais com um erro tipo I de 5% e um erro tipo II de 20%. Os limites de monitoramento sequencial de teste (TSMBs, do inglês trial sequential monitoring boundaries) e convencionais foram gerados para os grupos AODs e VKAs. Uma correção de heterogeneidade foi aplicada na TSA utilizando o modelo de efeitos aleatórios com IC de 95%. Foi gerada uma curva de escore z para avaliar a confiança e adequação das evidências. O ajuste dos limiares para o escore z foi baseado na função de consumo alfa de O’Brien–Fleming. Além disso, foi realizada uma análise para determinar o número necessário de pacientes para aceitar ou rejeitar a intervenção. Utilizamos o programa TSA versão 0.9.5.10 beta (Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Dinamarca).20

 Resultados Seleção e características dos estudos

Conforme ilustrado na Figura 1, a busca inicial rendeu 366 resultados. Após a remoção dos registros duplicados e dos estudos inelegíveis por título e resumo, restaram 40 estudos para revisão completa conforme critérios de inclusão. Além disso, foram identificados 5 estudos através do método de revisão de referências (backward snowballing). Destes, 4 ECRs e 29 estudos de coorte foram incluídos nesta revisão sistemática e metanálise, compreendendo 4.450 pacientes.8,11,21-51 Um total de 1.332 (29,9%) pacientes receberam AODs, enquanto 3.118 (70,3%) receberam AVKs. O período de acompanhamento variou de 3 meses a 3 anos. A média de idade variou de 49,6 a 69 anos. As características dos estudos e dos pacientes estão resumidas na Tabela 1 e no Material Suplementar 1, Tabelas S1 e S2.

– Fluxograma PRISMA de triagem e seleção dos estudos.

– Características de linha de base dos estudos incluídos
Estudo Desenho do estudo Número de pacientes, n Acompanhamento, mediana ou média Idade, anos, média (DP) ou mediana (IIQ) Sexo, n AODs
AODs AVKs Total AODs AVKs Total Feminino Masculino
Al-abcha 2021* Coorte retrospectivo 48 146 194 ND ND ND 61,6 (13,3) 46 148 ND
Albabtain 2021† Coorte retrospectivo 28 35 63 ND 58,25 (17,73) 59 (15,62) ND 5 58 Rivaroxabana
Alcalai 2021† ECR 17 15 32 3 meses 55,5 (12,9) 58,8 (10,2) 57,1 (11,7) 4 28 Apixabana
Aldaas 2022† Coorte retrospectivo 76 146 222 ND ND ND ND ND ND ND
Ali 2020* Coorte retrospectivo 32 60 92 12 meses 59,2 (11,9) 58,0 (16,3) 59 (14) 17 75 Rivaroxabana, apixabana, dabigatrana
Alizadeh 2019† Coorte prospectivo 38 60 98 1,8 anos ND ND ND ND ND Rivaroxabana, apixabana, edoxabana
Bass 2019† Coorte retrospectivo 180 769 949 3 meses 63,4 (16,7) 61,6 (15,3) ND 279 670 Rivaroxabana, apixabana, dabigatrana
Byrne 2022* Coorte retrospectivo 16 41 57 12 meses 63 (58-67) 60 (50-70) 60 (53-69) 13 44 ND
Cochran 2021† Coorte retrospectivo 14 59 73 13 meses 51,5 (39-73) 62 (34-84) ND 17 56 Rivaroxabana, apixabana, dabigatrana, edoxabana
Conant 2022† Coorte retrospectivo 29 135 164 ND ND ND ND ND ND ND
Daher 2020† Coorte retrospectivo 17 42 59 ND ND ND 62 (14) 10 49 Rivaroxabana, apixabana, dabigatrana
Durrer-Ariyakuddy 2019* Coorte 20 33 53 20 meses ND ND 63 14 39 ND
Gama 2019† Coorte retrospectivo 12 52 64 ND ND ND 69 (12) 13 51 ND
Guddeti 2020† Coorte retrospectivo 19 80 99 10,4 meses 60,7 (13,1) 61,3 (12,2) 61 (12,3) 29 70 Rivaroxabana, apixabana, dabigatrana
Haniff 2021* ECR 14 13 27 3 meses 55,36 (11,04) 55,00 (11,42) 55,19 (11,01) 2 25 Apixabana
Harb 2022* Coorte retrospectivo 22 59 81 6 meses ND ND ND ND ND ND
Iqbal 2020† Coorte retrospectivo 22 62 84 3,0 anos 62 (13) 62 (14) 62 (14) 9 75 Rivaroxabana, apixabana, dabigatrana
Iskaros 2021† Coorte retrospectivo 32 45 77 3 meses 62 (55–74) 63 (55–73) ND 8 69 Rivaroxabana, apixabana, dabigatrana
Isom 2020* Coorte retrospectivo 32 60 92 12 meses ND ND 59 (14) ND ND ND
Jaidka 2018* Coorte retrospectivo 12 37 49 6 meses 57,2 (9,3) 61,3 (12,1) ND 12 37 ND
Jones 2020† Coorte prospectivo 41 60 101 2,2 anos 58,73 (14,2) 60,81 (14,3) ND 17 84 Rivaroxabana, apixabana, edoxabana
Mihm 2021* Coorte retrospectivo 33 75 108 6 meses 63,3 (14,4) 60,3 (13,9) ND 31 77 Rivaroxabana, apixabana
Minciunescu 2020* Coorte retrospectivo 57 140 197 ND 60,4 (15,9) 59,5 (13,9) ND 45 152 ND
No-LVT Trial 2021* ECR 39 40 79 6 meses ND ND 49,6 (12,5) 34 45 Rivaroxabana
Robinson 2018* Coorte retrospectivo 35 40 75 12 meses ND ND ND ND ND Rivaroxabana, apixabana, dabigatrana
Robinson 2020† Coorte retrospectivo 121 236 357 351 dias 58,1 (14,9) 58,2 (15,1) ND 93 264 Rivaroxabana, apixabana, dabigatrana
Seiler 2022* Coorte retrospectivo 48 53 101 12 meses ND ND 63,3 (13,2) 18 83 ND
Willeford 2021† Coorte retrospectivo 22 129 151 12 meses 54 (48-64) 56 (49-65,5) 56 (49-65) 30 121 Rivaroxabana, apixabana
Xu 2021† Coorte retrospectivo 25 62 87 2,37 anos 59,4 (11,5) 61,9 (12,2) 61,5 (12,7) 21 66 Rivaroxabana, dabigatrana
Youssef 2023† ECR 25 25 50 6 meses 52 (8,2) 53 (7,9) ND ND ND Apixabana
Yunis 2020† Coorte retrospectivo 64 200 264 24 meses ND ND ND ND ND ND
Zhang 2021† Coorte retrospectivo 33 31 64 25,0 meses 60,3 (14,7) 61,3 (9,0) ND 17 47 Rivaroxabana
Zhang 2022† Coorte retrospectivo 109 78 187 17,0 meses 64,5 (54,2–70,8) 63,0 (54,5–71,0) ND 36 151 Rivaroxabana

*O nível de significância dos resultados não foi apresentado. †A significância estatística foi definida como valor de p < 0,05. AODs: anticoagulantes orais diretos; AVKs: antagonistas da vitamina K; DP: desvio padrão; ECR: ensaio controlado randomizado; IIQ: intervalo interquartil; ND: não disponível.

Análise agrupada de todos os estudos

Não houve diferença significativa entre a terapia com AODs e AVKs em relação a AVC/EES, AVC, EES e resolução de trombos (Figuras 2 e 3). Não houve diferença significativa entre os grupos em relação a qualquer sangramento, sangramento clinicamente relevante, sangramento menor, sangramento maior e mortalidade por todas as causas (Figuras 4 e 5).

– Anticoagulantes orais diretos versus antagonistas da vitamina K. A) AVC ou eventos embólicos sistêmicos. B) AVC. AODs: anticoagulantes orais diretos; AVC: acidente vascular cerebral; AVKs: antagonistas da vitamina K; df: graus de liberdade; IC: intervalo de confiança; MH: Mantel-Haenszel.

– Anticoagulantes orais diretos versus antagonistas da vitamina K. A) Eventos embólicos sistêmicos. B) Resolução de trombos. AODs: anticoagulantes orais diretos; AVKs: antagonistas da vitamina K; df: graus de liberdade; IC: intervalo de confiança; MH: Mantel-Haenszel.

– Anticoagulantes orais diretos versus antagonistas da vitamina K. A) Qualquer sangramento. B) Sangramento clinicamente relevante. AODs: anticoagulantes orais diretos; AVKs: antagonistas da vitamina K; df: graus de liberdade; IC: intervalo de confiança; MH: Mantel-Haenszel.

– Anticoagulantes orais diretos versus antagonistas da vitamina K. A) Sangramento menor. B) Sangramento maior. C) Mortalidade por todas as causas. AODs: anticoagulantes orais diretos; AVKs: antagonistas da vitamina K; df: graus de liberdade; IC: intervalo de confiança; MH: Mantel-Haenszel.

Análise de subgrupos

Na análise de subgrupo de pacientes tratados com rivaroxabana,21,22,47,48 os AVC/EES e os EES foram significativamente reduzidos no grupo tratado com rivaroxabana. Não houve diferença significativa entre os grupos em relação a AVC, resolução de trombos, qualquer sangramento, sangramento clinicamente relevante, sangramento menor, sangramento maior e mortalidade por todas as causas. As análises agrupadas estão detalhadas no Material Suplementar 1, Figuras S1 e S2.

Na análise de subgrupo de pacientes tratados com apixabana,8,49,51 não houve diferença significativa entre os grupos em relação a AVC, resolução de trombos, sangramento clinicamente relevante e mortalidade por todas as causas. As análises agrupadas estão detalhadas no Material Suplementar 1, Figura S3.

Somente na análise de subgrupo dos ECRs,8,22,49,51 não houve diferença significativa entre os grupos em relação a AVC/EES, AVC, resolução de trombos, sangramento clinicamente relevante, sangramento maior e mortalidade por todas as causas. As análises agrupadas estão detalhadas no Material Suplementar 1, Figura S4.

Na análise de subgrupo incluindo pacientes com TVE após IAM,8,26,28,39,40,47,51 não houve diferença significativa entre os grupos em relação a AVC/EES, AVC, EES, resolução de trombos, qualquer sangramento, sangramento clinicamente relevante, sangramento leve, sangramento grave ou mortalidade por todas as causas. As análises agrupadas estão detalhadas no Material Suplementar 1, Figuras S5 e S6.

Na análise de subgrupo, excluindo resumos de conferências,8,11,21,27,29,31,34,36,37,40,44,45,47,48,50,51 qualquer sangramento foi significativamente reduzido no grupo tratado com AODs. No entanto, não houve diferença significativa entre os grupos em relação a AVC/EES, AVC, EES, resolução de trombos, sangramento clinicamente relevante, sangramento menor, sangramento maior ou mortalidade por todas as causas. As análises agrupadas estão detalhadas no Material Suplementar 1, Figuras S7, S8 e S9.

 Análise de sensibilidade

Realizamos uma análise de sensibilidade de exclusão para todos os desfechos. Houve uma diminuição significativa nos EES a favor da terapia com AODs, excluindo Robinson et al.11 Houve uma diferença significativa a favor da terapia com AODs em relação a qualquer sangramento, excluindo Al-abcha et al., Albabtain et al., Jaidka et al., Yunis et al., ou Zhang et al.21,23,39,46,48 Houve uma diferença significativa no sangramento clinicamente relevante em favor da terapia com AODs, excluindo Jaidka et al., Seiler et al. ou Mihm et al.39,43,50 Houve uma diferença significativa na resolução de trombos em favor da terapia com AODs, excluindo Robinson et al.11 Os gráficos de análise de sensibilidade de exclusão estão detalhados no Material Suplementar 1, Figuras S10 a S18.

 Avaliação de qualidade e evidências

Avaliações individuais dos ECR, de acordo com a ferramenta RoB-2, são ilustradas no Material Suplementar 1, Figura S19. No geral, todos os ECRs levantaram algumas preocupações devido a desvios das intervenções pretendidas,8,49,51 e um ECR levantou algumas preocupações devido à seleção dos resultados relatados.49

Não foi detectado viés de publicação significativo para o desfecho de AVC/EES pelo teste de Egger (p = 0,702) ou teste de Begg (p = 0,327). O gráfico de funil do desfecho de AVC/EES está disponível no Material Suplementar 1, Figura S21.

A avaliação crítica dos estudos de coorte está detalhada no Material Suplementar 1, Figura S20. Quatro estudos de coorte apresentaram baixo risco de viés,29,40,47,48 enquanto 10 estudos de coorte apresentaram risco moderado de viés, devido a vieses na seleção dos participantes.11,21,27,31,34,36,37,44,45,50 Um ECR e 15 estudos de coorte não forneceram informações suficientes para avaliar o risco de viés.22-26,28,30,32,33,35,38,39,41-43,46

De acordo com a avaliação GRADE, foi atribuída qualidade muito baixa a todos os desfechos, principalmente devido à inclusão de resumos e múltiplos estudos sem informações sobre risco de viés. O Material Suplementar 2 relata a avaliação GRADE completa e o resumo dos achados.

 Análise sequencial de ensaios

A curva z cumulativa para AVC e sangramento clinicamente relevante não ultrapassou os limites convencionais e de monitoramento e não atingiu o tamanho de informações necessárias (RIS, do inglês required information size). Neste caso, não podemos concluir se os resultados neutros resultam de falta de poder ou se é pouco provável que a intervenção tenha um impacto significativo. Para resolução de trombos, o último ponto da curva z encontra-se dentro dos limites de futilidade, indicando que dificilmente alcançará significância estatística, mesmo se procedermos com inclusão de ensaios randomizados de pacientes até o RIS de 367. Os gráficos sequenciais dos ensaios estão detalhados nas Figura 6 e 7.

– Análise sequencial de ensaios para (A) acidente vascular cerebral e (B) sangramento clinicamente relevante. AODs: anticoagulantes orais diretos; AVC: acidente vascular cerebral; AVKs: antagonistas da vitamina K.

– Análise sequencial de ensaios para resolução de trombos. AODs: anticoagulantes orais diretos; AVKs: antagonistas da vitamina K.

Discussão

Na presente revisão sistemática e metanálise composta por 33 estudos e 4.450 pacientes, comparamos a eficácia de 2 tipos de anticoagulantes, AODs e AVKs, para o tratamento de TVE. Nossos achados foram: (I) a terapia com AODs foi equivalente aos AVKs para TVE na ocorrência de eventos tromboembólicos e resolução de trombos; (II) a rivaroxabana reduziu significativamente os eventos tromboembólicos; e (III) a ocorrência de complicações hemorrágicas foi semelhante entre os grupos.

TVE constitui um fator etiológico proeminente para AVC embólico subsequente a IAM e insuficiência cardíaca congestiva.52,53 Maniwa et al. revelaram que indivíduos com TVE podem apresentar EES com uma taxa de incidência de até 16,3%, que é 5 vezes maior do que aqueles sem TVE,54 e mais de 10% morrem dentro de 1 ano.55 As diretrizes europeias e estadunidenses recomendam terapia anticoagulante por 3 a 6 meses em pacientes com TVE.6,56 Os AVKs, principalmente a varfarina, são indicados como anticoagulantes orais de primeira linha para o tratamento de TVE.9 No entanto, o uso da varfarina apresenta desvantagens, incluindo interações com medicamentos e alimentos, variabilidade nas respostas individuais, exigência de monitoramento frequente e necessidade de usar heparina não fracionada ou heparina de baixo peso molecular durante, pelo menos, os 3 dias iniciais devido a um atraso na inibição do fator II.57

Na última década, novos AODs foram aprovados para tratamento anticoagulante da fibrilação atrial (FA) não valvar e doenças tromboembólicas venosas.58,59 A ação anticoagulante dos AODs é baseada na inibição da trombina, com dabigatrana, ou fator Xa, com rivaroxabana, edoxabana e apixabana.57,59 Atualmente, está comprovado que os AODs são superiores à varfarina no tratamento e prevenção de eventos tromboembólicos em pacientes com FA não valvular.60 Para TVE, os AODs podem ser aplicáveis, pois o mecanismo fisiopatológico é semelhante ao da trombose relacionada à FA.57 No entanto, nenhuma diretriz formal atualizada recomendou o uso de AODs em pacientes com TVE. As diretrizes sobre IAMCSST da American College of Cardiology/American Heart Association de 2013 e as diretrizes sobre IAMCSST da Sociedade Europeia de Cardiologia de 2017 não fazem referência ao uso de AODs na anticoagulação para TVE.6,56 No entanto, a diretriz sobre AVC de 2021 da American Heart Association/American Stroke Association apresentou uma recomendação de classe IIb apoiando o uso de AODs para reduzir o risco de trombose recorrente em pacientes com AVC ou ataque isquêmico transitório e novos TVEs.5,9 Assim, os AODs têm sido usados como tratamento off-label para TVE, com orientações muito limitadas sobre seu uso.57,61

Em uma metanálise publicada como declaração científica pela American Heart Association, os AODs foram considerados uma alternativa razoável aos AVKs em pacientes com TVE.9 Essa abordagem de tratamento foi particularmente interessante para pacientes para os quais a manutenção de uma faixa terapêutica consistente da RNI se mostra um desafio ou para aqueles que não podem realizar monitoramento frequente da RNI.9 Em metanálises anteriores, Michael et al. mostraram taxas reduzidas de AVC em pacientes tratados com AODs em comparação com AVKs, com resolução de trombos e eventos hemorrágicos semelhantes.62 Da mesma maneira, Trongtorsak et al. demonstraram taxas semelhantes de eventos tromboembólicos sistêmicos, resolução de trombos e sangramento.63 Chen et al. e Kido et al. mostraram uma redução significativa no sangramento em pacientes tratados com AODs em comparação com AVKs, com taxas semelhantes de eventos tromboembólicos.57,64 Na presente metanálise, verificamos uma redução significativa em qualquer sangramento em favor dos AODs apenas na análise de subgrupo, excluindo resumos de conferências. Considerando que a exclusão de resumos de conferências reduz a possibilidade de viés na análise estatística, esse resultado favorece a interpretação da existência de benefício dos AODs para o tratamento de TVE em comparação aos AVKs.

Li et al. e Ferreira et al. não encontraram diferenças entre AODs e AVKs para eventos tromboembólicos ou sangramento.61,65 Assim, a nossa metanálise também não indicou diferenças estatísticas para os resultados de AVC, EES ou o resultado composto de AVC/EES. No entanto, até onde sabemos, esta é a primeira metanálise que realizou análises de subgrupos para apixabana e rivaroxabana, encontrando um benefício da rivaroxabana na redução de eventos tromboembólicos, avaliado pela redução significativa de AVC/EES e EES quando comparado com AVKs.

Na TSA, a evidência sólida é alcançada quando o tamanho amostral de pacientes excede o necessário para se chegar a uma conclusão definitiva ou quando as curvas z cruzam os TSMBs antes de atingir a contagem essencial de pacientes para obter evidências conclusivas. Pelo contrário, nos casos em que a curva z cruza os limiares estatísticos convencionais, mas não os TSMBs e a amostra de pacientes necessária para aceitar ou rejeitar a hipótese, o efeito significativo da metanálise pode resultar de testes repetitivos, em vez de efeitos subjacentes genuínos. Nos casos em que o número de participantes na metanálise excede a linha RIS, isso sugere que existem evidências suficientes para tirar conclusões confiáveis sobre o efeito da intervenção. Em nossa metanálise, a TSA não mostrou evidências suficientes do benefício dos AODs em relação aos AVKs no tratamento de TVE em relação à resolução de trombos, AVC e sangramento clinicamente relevante.

O presente estudo deve ser interpretado considerando suas limitações. Primeiro, a maioria dos estudos incluídos nesta metanálise eram estudos de coorte, e os tamanhos das amostras, especialmente nos ECR incluídos, eram pequenos. Segundo, as características dos pacientes, o tipo dos AODs, a definição de eventos clínicos e o acompanhamento mostraram variações entre os estudos incluídos, contribuindo para a heterogeneidade entre estudos. Terceiro, a inclusão de resumos de conferências representa uma fonte potencial de viés na análise, uma vez que os resumos muitas vezes não incluem informações sobre a população de pacientes e não é possível avaliar os riscos de viés devido à falta inerente de informações detalhadas sobre o desenho do estudo. Além disso, devido à informação limitada fornecida nos resumos da conferência, a sobreposição de populações é uma preocupação, embora nenhum resumo incluído na nossa metanálise tenha tido o mesmo número de pacientes que os estudos publicados na íntegra. Quarto, a avaliação GRADE exibiu uma qualidade de evidência muito baixa devido à heterogeneidade significativa entre estudos e um grave risco de viés. Quinto, as análises de subgrupos foram realizadas com um tamanho amostral pequeno. Sexto, as análises de subgrupos para diferentes AODs, exceto rivaroxabana e apixabana, não foram viáveis devido à falta de dados adequados. Portanto, a generalização dos resultados é limitada. São necessários ECRs maiores para confirmar a eficácia e segurança dos AODs em comparação aos AVKs para o tratamento de TVE.

 Conclusão

Os AODs tiveram uma taxa semelhante de eventos tromboembólicos e hemorrágicos, bem como de resolução de trombos, em comparação com os AVKs no tratamento de TVE. A terapia com rivaroxabana teve uma redução significativa nos eventos tromboembólicos, em comparação com os AVKs.

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Iqbal H Straw S Craven TP Stirling K Wheatcroft SB Witte KK Direct Oral Anticoagulants Compared to Vitamin K Antagonist for the Management of Left Ventricular Thrombus ESC Heart Fail 2020 7 5 2032 2041 10.1002/ehf2.12718 37. Iskaros O, Marsh K, Papadopoulos J, Manmadhan A, Ahuja T. Evaluation of Direct Oral Anticoagulants Versus Warfarin for Intracardiac Thromboses. J Cardiovasc Pharmacol. 2021;77(5):621-31. doi: 10.1097/FJC.0000000000000987. Iskaros O Marsh K Papadopoulos J Manmadhan A Ahuja T Evaluation of Direct Oral Anticoagulants Versus Warfarin for Intracardiac Thromboses J Cardiovasc Pharmacol 2021 77 5 621 631 10.1097/FJC.0000000000000987 38. Isom N, Ali Z, Dalia T, Sami F, Mahmood U, Buechler T, et al. Effectiveness of Direct Oral Anticoagulant versus Warfarin in the Treatment of Left Ventricular Thrombus. Circulation. 2020;142(Suppl 3). doi: 10.1161/circ.142.suppl_3.15803. Isom N Ali Z Dalia T Sami F Mahmood U Buechler T et al Effectiveness of Direct Oral Anticoagulant versus Warfarin in the Treatment of Left Ventricular Thrombus Circulation 2020 142 Suppl 3 10.1161/circ.142.suppl_3.15803 39. Jaidka A, Zhu T, Lavi S, Johri A. Treatment of Left Ventricular Thrombus Using Warfarin Versus Direct Oral Anticoagulants Following Anterior Myocardial Infarction. Can J Cardiol. 2018;34(10):143. doi: https://doi.org/10.1016/j.cjca.2018.07.194. Jaidka A Zhu T Lavi S Johri A Treatment of Left Ventricular Thrombus Using Warfarin Versus Direct Oral Anticoagulants Following Anterior Myocardial Infarction Can J Cardiol 2018 34 10 143 https://doi.org/10.1016/j.cjca.2018.07.194 40. Jones DA, Wright P, Alizadeh MA, Fhadil S, Rathod KS, Guttmann O, et al. The Use of Novel Oral Anticoagulants Compared to Vitamin K Antagonists (Warfarin) in Patients with Left Ventricular Thrombus After Acute Myocardial Infarction. Eur Heart J Cardiovasc Pharmacother. 2021;7(5):398-404. doi: 10.1093/ehjcvp/pvaa096. Jones DA Wright P Alizadeh MA Fhadil S Rathod KS Guttmann O et al The Use of Novel Oral Anticoagulants Compared to Vitamin K Antagonists (Warfarin) in Patients with Left Ventricular Thrombus After Acute Myocardial Infarction Eur Heart J Cardiovasc Pharmacother 2021 7 5 398 404 10.1093/ehjcvp/pvaa096 41. Minciunescu A, Ijaz N, Donthi N, Genovese LD, Tehrani BN, Tran HA. Direct Oral Anticoagulants Compared to Warfarin for the Treatment of Left Ventricular Thrombus: A Multi-Center Experience. Circulation. 2020;142(Suppl 3). doi: 10.1161/circ.142.suppl_3.16816. Minciunescu A Ijaz N Donthi N Genovese LD Tehrani BN Tran HA Direct Oral Anticoagulants Compared to Warfarin for the Treatment of Left Ventricular Thrombus: A Multi-Center Experience Circulation 2020 142 Suppl 3 10.1161/circ.142.suppl_3.16816 42. Robinson A, Ruth B, Dent J. Direct Oral Anticoagulants Compared to Warfarin for Left Ventricular Thrombi: A Single Center Experience. J Am Coll Cardiol. 2018;71(Suppl 11):981. Robinson A Ruth B Dent J Direct Oral Anticoagulants Compared to Warfarin for Left Ventricular Thrombi: A Single Center Experience J Am Coll Cardiol 2018 71 Suppl 11 981 43. Seiler T, Madanchi M, Cioffi G, Tersalvi G, Fankhauser P, Attinger A, et al. Direct Oral Anticoagulants Compared to Vitamin K-antagonists in Patients with Left Ventricular Thrombus. Swiss Med Wkly. 2022;152(Suppl 260):3-4. doi: 10.1093/eurheartj/ehac544.1282 Seiler T Madanchi M Cioffi G Tersalvi G Fankhauser P Attinger A et al Direct Oral Anticoagulants Compared to Vitamin K-antagonists in Patients with Left Ventricular Thrombus Swiss Med Wkly 2022 152 Suppl 260 3 4 10.1093/eurheartj/ehac544.1282 44. Willeford A, Zhu W, Stevens C, Thomas IC. Direct Oral Anticoagulants Versus Warfarin in the Treatment of Left Ventricular Thrombus. Ann Pharmacother. 2021;55(7):839-45. doi: 10.1177/1060028020975111. Willeford A Zhu W Stevens C Thomas IC Direct Oral Anticoagulants Versus Warfarin in the Treatment of Left Ventricular Thrombus Ann Pharmacother 2021 55 7 839 845 10.1177/1060028020975111 45. Xu Z, Li X, Li X, Gao Y, Mi X. Direct Oral Anticoagulants Versus Vitamin K Antagonists for Patients with Left Ventricular Thrombus. Ann Palliat Med. 2021;10(9):9427-34. doi: 10.21037/apm-21-1683. Xu Z Li X Li X Gao Y Mi X Direct Oral Anticoagulants Versus Vitamin K Antagonists for Patients with Left Ventricular Thrombus Ann Palliat Med 2021 10 9 9427 9434 10.21037/apm-21-1683 46. Yunis A, Seese L, Stearns B, Genuardi M, Thoma F, Kilic A. Direct Oral Anticoagulants are Effective Therapy in Treating Left Ventricular Thrombi. J Am Coll Cardiol. 2020;75(11):948. Yunis A Seese L Stearns B Genuardi M Thoma F Kilic A Direct Oral Anticoagulants are Effective Therapy in Treating Left Ventricular Thrombi J Am Coll Cardiol 2020 75 11 948 47. Zhang Z, Si D, Zhang Q, Qu M, Yu M, Jiang Z, et al. Rivaroxaban Versus Vitamin K Antagonists (Warfarin) Based on the Triple Therapy for Left Ventricular Thrombus After ST-Elevation Myocardial Infarction. Heart Vessels. 2022;37(3):374-84. doi: 10.1007/s00380-021-01921-z. Zhang Z Si D Zhang Q Qu M Yu M Jiang Z et al Rivaroxaban Versus Vitamin K Antagonists (Warfarin) Based on the Triple Therapy for Left Ventricular Thrombus After ST-Elevation Myocardial Infarction Heart Vessels 2022 37 3 374 384 10.1007/s00380-021-01921-z 48. Zhang Q, Zhang Z, Zheng H, Qu M, Li S, Yang P, et al. Rivaroxaban in Heart Failure Patients with Left Ventricular Thrombus: A Retrospective Study. Front Pharmacol. 2022;13:1008031. doi: 10.3389/fphar.2022.1008031. Zhang Q Zhang Z Zheng H Qu M Li S Yang P et al Rivaroxaban in Heart Failure Patients with Left Ventricular Thrombus: A Retrospective Study Front Pharmacol 2022 13 1008031 10.3389/fphar.2022.1008031 49. Haniff WY. NCT02982590: Apixaban Versus Warfarin in Patients with Left Ventricular Thrombus. Washington D.C: ClinicalTrials; 2021. Haniff WY NCT02982590: Apixaban Versus Warfarin in Patients with Left Ventricular Thrombus Washington D.C ClinicalTrials 2021 50. Mihm AE, Hicklin HE, Cunha AL, Nisly SA, Davis KA. Direct Oral Anticoagulants Versus Warfarin for the Treatment of Left Ventricular Thrombosis. Intern Emerg Med. 2021;16(8):2313-17. doi: 10.1007/s11739-021-02788-8. Mihm AE Hicklin HE Cunha AL Nisly SA Davis KA Direct Oral Anticoagulants Versus Warfarin for the Treatment of Left Ventricular Thrombosis Intern Emerg Med 2021 16 8 2313 2317 10.1007/s11739-021-02788-8 51. Youssef AA, Alrefae MA, Khalil HH, Abdullah HI, Khalifa ZS, Al Shaban AA, et al. Apixaban in Patients with Post-Myocardial Infarction Left Ventricular Thrombus: A Randomized Clinical Trial. CJC Open. 2022;5(3):191-9. doi: 10.1016/j.cjco.2022.12.003. Youssef AA Alrefae MA Khalil HH Abdullah HI Khalifa ZS Al Shaban AA et al Apixaban in Patients with Post-Myocardial Infarction Left Ventricular Thrombus: A Randomized Clinical Trial CJC Open 2022 5 3 191 199 10.1016/j.cjco.2022.12.003 52. Vandvik PO, Lincoff AM, Gore JM, Gutterman DD, Sonnenberg FA, Alonso-Coello P, et al. Primary and Secondary Prevention of Cardiovascular Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):637-68. doi: 10.1378/chest.11-2306. Vandvik PO Lincoff AM Gore JM Gutterman DD Sonnenberg FA Alonso-Coello P et al Primary and Secondary Prevention of Cardiovascular Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest 2012 141 2 Suppl 637 668 10.1378/chest.11-2306 53. Massussi M, Scotti A, Lip GYH, Proietti R. Left Ventricular Thrombosis: New Perspectives on an Old Problem. Eur Heart J Cardiovasc Pharmacother. 2021;7(2):158-67. doi: 10.1093/ehjcvp/pvaa066. Massussi M Scotti A Lip GYH Proietti R Left Ventricular Thrombosis: New Perspectives on an Old Problem Eur Heart J Cardiovasc Pharmacother 2021 7 2 158 167 10.1093/ehjcvp/pvaa066 54. Maniwa N, Fujino M, Nakai M, Nishimura K, Miyamoto Y, Kataoka Y, et al. Anticoagulation Combined with Antiplatelet Therapy in Patients with Left Ventricular Thrombus After First Acute Myocardial Infarction. Eur Heart J. 2018;39(3):201-8. doi: 10.1093/eurheartj/ehx551. Maniwa N Fujino M Nakai M Nishimura K Miyamoto Y Kataoka Y et al Anticoagulation Combined with Antiplatelet Therapy in Patients with Left Ventricular Thrombus After First Acute Myocardial Infarction Eur Heart J 2018 39 3 201 208 10.1093/eurheartj/ehx551 55. McCarthy CP, Murphy S, Venkateswaran RV, Singh A, Chang LL, Joice MG, et al. Left Ventricular Thrombus: Contemporary Etiologies, Treatment Strategies, and Outcomes. J Am Coll Cardiol. 2019;73(15):2007-9. doi: 10.1016/j.jacc.2019.01.031. McCarthy CP Murphy S Venkateswaran RV Singh A Chang LL Joice MG et al Left Ventricular Thrombus: Contemporary Etiologies, Treatment Strategies, and Outcomes J Am Coll Cardiol 2019 73 15 2007 2009 10.1016/j.jacc.2019.01.031 56. O'Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, Lemos JA, et al. 2013 ACCF/AHA Guideline for the Management of ST-elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):362-425. doi: 10.1161/CIR.0b013e3182742cf6. O'Gara PT Kushner FG Ascheim DD Casey DE Jr Chung MK Lemos JA et al 2013 ACCF/AHA Guideline for the Management of ST-elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Circulation 2013 127 4 362 425 10.1161/CIR.0b013e3182742cf6 57. Chen Y, Zhu M, Wang K, Xu Q, Ma J. Direct Oral Anticoagulants Versus Vitamin K Antagonists for the Treatment of Left Ventricular Thrombus: An Updated Meta-Analysis of Cohort Studies and Randomized Controlled Trials. J Cardiovasc Pharmacol. 2022;79(6):935-40. doi: 10.1097/FJC.0000000000001270. Chen Y Zhu M Wang K Xu Q Ma J Direct Oral Anticoagulants Versus Vitamin K Antagonists for the Treatment of Left Ventricular Thrombus: An Updated Meta-Analysis of Cohort Studies and Randomized Controlled Trials J Cardiovasc Pharmacol 2022 79 6 935 940 10.1097/FJC.0000000000001270 58. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, et al. The 2018 European Heart Rhythm Association Practical Guide on the Use of non-vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Eur Heart J. 2018;39(16):1330-93. doi: 10.1093/eurheartj/ehy136. Steffel J Verhamme P Potpara TS Albaladejo P Antz M Desteghe L et al The 2018 European Heart Rhythm Association Practical Guide on the Use of non-vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation Eur Heart J 2018 39 16 1330 1393 10.1093/eurheartj/ehy136 59. Makam RCP, Hoaglin DC, McManus DD, Wang V, Gore JM, Spencer FA, et al. Efficacy and Safety of Direct Oral Anticoagulants Approved for Cardiovascular Indications: Systematic Review and Meta-analysis. PLoS One. 2018;13(5):e0197583. doi: 10.1371/journal.pone.0197583. Makam RCP Hoaglin DC McManus DD Wang V Gore JM Spencer FA et al Efficacy and Safety of Direct Oral Anticoagulants Approved for Cardiovascular Indications: Systematic Review and Meta-analysis PLoS One 2018 13 5 e0197583 10.1371/journal.pone.0197583 60. Fanaroff AC, Ohman EM. Non-Vitamin K Antagonist Oral Anticoagulants in the Treatment of Atrial Fibrillation. Annu Rev Med. 2019;70:61-75. doi: 10.1146/annurev-med-042617-092334. Fanaroff AC Ohman EM Non-Vitamin K Antagonist Oral Anticoagulants in the Treatment of Atrial Fibrillation Annu Rev Med 2019 70 61 75 10.1146/annurev-med-042617-092334 61. Ferreira HS, Lopes JL, Augusto J, Simões J, Roque D, Faria D, et al. Effect of Direct Oral Anticoagulants Versus Vitamin K Antagonists or Warfarin in Patients with Left Ventricular Thrombus Outcomes: A Systematic Review and Meta-analysis. Rev Port Cardiol. 2023;42(1):63-70. doi: 10.1016/j.repc.2021.11.013. Ferreira HS Lopes JL Augusto J Simões J Roque D Faria D et al Effect of Direct Oral Anticoagulants Versus Vitamin K Antagonists or Warfarin in Patients with Left Ventricular Thrombus Outcomes: A Systematic Review and Meta-analysis Rev Port Cardiol 2023 42 1 63 70 10.1016/j.repc.2021.11.013 62. Michael F, Natt N, Shurrab M. Direct Oral Anticoagulants vs Vitamin K Antagonists in Left Ventricular Thrombi: A Systematic Review and Meta-analysis. CJC Open. 2021;3(9):1169-81. doi: 10.1016/j.cjco.2021.04.007. Michael F Natt N Shurrab M Direct Oral Anticoagulants vs Vitamin K Antagonists in Left Ventricular Thrombi: A Systematic Review and Meta-analysis CJC Open 2021 3 9 1169 1181 10.1016/j.cjco.2021.04.007 63. Trongtorsak A, Thangjui S, Kewcharoen J, Polpichai N, Yodsuwan R, Kittipibul V, et al. Direct Oral Anticoagulants vs. Vitamin K Antagonists for Left Ventricular Thrombus: A Systematic Review and Meta-analysis. Acta Cardiol. 2021;76(9):933-42. doi: 10.1080/00015385.2020.1858538. Trongtorsak A Thangjui S Kewcharoen J Polpichai N Yodsuwan R Kittipibul V et al Direct Oral Anticoagulants vs. Vitamin K Antagonists for Left Ventricular Thrombus: A Systematic Review and Meta-analysis Acta Cardiol 2021 76 9 933 942 10.1080/00015385.2020.1858538 64. Kido K, Ghaffar YA, Lee JC, Bianco C, Shimizu M, Shiga T, et al. Meta-analysis Comparing Direct Oral Anticoagulants Versus Vitamin K Antagonists in Patients with Left Ventricular Thrombus. PLoS One. 2021;16(6):e0252549. doi: 10.1371/journal.pone.0252549. Kido K Ghaffar YA Lee JC Bianco C Shimizu M Shiga T et al Meta-analysis Comparing Direct Oral Anticoagulants Versus Vitamin K Antagonists in Patients with Left Ventricular Thrombus PLoS One 2021 16 6 e0252549 10.1371/journal.pone.0252549 65. Li J, Hu Y, Wu Z. Direct Oral Anticoagulants versus Vitamin K Antagonists for the Treatment of Left Ventricular Thrombosis: A Meta-Analysis. Rev Cardiovasc Med. 2022;23(9):312. Li J Hu Y Wu Z Direct Oral Anticoagulants versus Vitamin K Antagonists for the Treatment of Left Ventricular Thrombosis: A Meta-Analysis Rev Cardiovasc Med 2022 23 9 312

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 10.36660/abc.20230738i Original Article Direct Oral Anticoagulants versus Vitamin K Antagonists for Left Ventricular Thrombus: A Meta-Analysis with Trial Sequential Analysis 0000-0002-6484-1162 Pasqualotto Eric Conception and design of the research Acquisition of data Analysis and interpretation of the data Statistical analysis Writing of the manuscript Critical revision of the manuscript for content 1 0000-0001-9393-2445 Gewehr Douglas Mesadri Conception and design of the research Acquisition of data Analysis and interpretation of the data Statistical analysis Writing of the manuscript Critical revision of the manuscript for content 2 0000-0002-3203-0509 Ferreira Rafael Oliva Morgado Analysis and interpretation of the data Writing of the manuscript Critical revision of the manuscript for content 1 Chavez Matheus Pedrotti Analysis and interpretation of the data Writing of the manuscript Critical revision of the manuscript for content 1 0000-0001-8009-004X Silva Caroliny Hellen Acquisition of data Analysis and interpretation of the data Writing of the manuscript Critical revision of the manuscript for content 3 0000-0003-2814-9627 Cruz Sara Almeida Writing of the manuscript Critical revision of the manuscript for content 4 0000-0002-1869-2362 Limachi-Choque Jhonny Acquisition of data Writing of the manuscript Critical revision of the manuscript for content 5 0000-0001-5142-7723 Park Amanda Writing of the manuscript Critical revision of the manuscript for content 6 0000-0002-8025-9084 Coutinho Mário Sérgio Soares de Azeredo Conception and design of the research Writing of the manuscript Critical revision of the manuscript for content 1 Kubrusly Luiz Fernando Conception and design of the research Writing of the manuscript Critical revision of the manuscript for content 2 Brazil Universidade Federal de Santa Catarina, Florianópolis, SC – Brazil Brazil Faculdade Evangélica Mackenzie do Paraná, Curitiba, PR – Brazil Brazil Universidade Federal do Rio Grande do Norte, Natal, RN – Brazil Russia Immanuel Kant Baltic Federal University Institute of Medicine, Kaliningrad – Russia Bolivia Universidad Mayor de San Simón - Centro Universitario de Medicina Tropical (CUMETROP), Cochabamba – Bolivia Brazil Centro Universitário Lusíada - Faculdade de Ciências Médicas de Santos, Santos, SP – Brazil Mailing Address: Eric Pasqualotto • Universidade Federal de Santa Catarina – Rua Profa. Maria Flora, s/n. Postal Code 88036-800, Pausewang, Florianópolis, SC – Brazil. E-mail: ericpasqualotto02@gmail.com

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No potential conflict of interest relevant to this article was reported.

Editor responsible for the review: Marcio Bittencourt

: Direct Oral Anticoagulants versus Vitamin K Antagonists for Left Ventricular Thrombus: A Meta-Analysis with Trial Sequential Analysis

Abstract Background

Vitamin K antagonists (VKAs) are the recommended first-line treatment for left ventricular thrombus (LVT); however, direct oral anticoagulants (DOACs) have been considered an alternative therapy.

 Objectives

To evaluate the efficacy and safety of DOACs compared with VKAs therapy in patients with LVT.

 Methods

PubMed, Embase, and Cochrane were systematically searched for randomized clinical trials or cohort studies that compared DOACs versus VKAs for LVT. Risk ratios (RRs) were computed for binary endpoints, with 95% confidence intervals (95% CIs). Statistical significance was defined as p value < 0.05.

 Results

A total of 4 randomized clinical trials and 29 cohort studies were included, with 4,450 patients assigned to either DOACs or VKAs. There was no significant difference between groups for stroke or systemic embolic (SSE) events (RR 0.84; 95% CI 0.65 to 1.07; p = 0.157), stroke (RR 0.73; 95% CI 0.48 to 1.11; p = 0.140), systemic embolic (SE) events (RR 0.69; 95% CI 0.40 to 1.17; p = 0.166), thrombus resolution (RR 1.05; 95% CI 0.99 to 1.11; p = 0.077), any bleeding (RR 0.78; 95% CI 0.60 to 1.00; p = 0.054), clinically relevant bleeding (RR 0.69; 95% CI 0.46 to 1.03; p = 0.066), minor bleeding (RR 0.73; 95% CI 0.43 to 1.23; p = 0.234), major bleeding (RR 0.87; 95% CI 0.42 to 1.80; p = 0.705), and all-cause mortality (RR 1.05; 95% CI 0.79 to 1.39; p = 0.752). Compared with VKAs, rivaroxaban significantly reduced SSE events (RR 0.35; 95% CI 0.16 to 0.91; p = 0.029) and SE events (RR 0.39; 95% CI 0.16 to 0.95; p = 0.037).

 Conclusions

DOACs had a similar rate of thromboembolic and hemorrhagic events, as well as thrombus resolution, compared to VKAs in the treatment of LVTs. Rivaroxaban therapy had a significant reduction in thromboembolic events, compared to VKAs.

 Warfarin Factor Xa Inhibitors Thrombosis Introduction

Left ventricular thrombus (LVT) commonly occurs as a complication of acute myocardial infarction (AMI), nonischemic cardiomyopathy, or severe cardiac dysfunction.1 In the United States, myocardial infarctions occur at a rate of 1 million per year, and 4% to 39% of these patients can develop LVT, presenting a high demand for medical care.2-4 Despite the advances in cardiovascular medicine, the treatment of LVT often remains challenging, due to limited guideline recommendations.5

Vitamin K antagonists (VKAs) have been established as the prevention and treatment of LVT.6 The use of VKAs is associated with the need for frequent international normalized ratio (INR) monitoring and vigilance for drug or food interactions.7 The failure to maintain the INR in the therapeutic zone is associated with an increase in the incidence of thrombus.7 In this sense, direct oral anticoagulants (DOACs) have demonstrated similar effectiveness to VKAs while presenting fewer treatment complexities, leading to their increased utilization, despite the absence of definitive guidance regarding their safety as an option for patients with LVT.8

Previous meta-analyses, randomized controlled trials (RCTs), and retrospective studies comparing DOACs with VKAs for the treatment of LVT present data that support the use of DOACs; however, not all are consistent since different results were observed regarding thromboembolic and hemorrhagic events.9-11 Thus, the optimal anticoagulation regimen for patients with LVT remains unknown. Therefore, we aimed to perform a systematic review and meta-analysis of RCTs and observational studies along with a trial sequential analysis (TSA) to compare the efficacy and safety of DOACs versus VKAs in patients with LVT.

 Methods

This systematic review and meta-analysis followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.12 The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with registration number CRD42023409287.

Search strategy and data extraction

PubMed, Embase, and Cochrane Library databases were systematically searched from inception to March 2023, with the following search strategy: (“left ventricular thrombus” OR “left ventricular thrombi” OR LVT OR LVTs) AND (DOAC OR NOAC OR “direct anticoagulant” OR “direct oral anticoagulants” OR “direct oral anticoagulant” OR “oral anticoagulation” OR “new oral anticoagulant” OR rivaroxaban OR apixaban OR edoxaban OR dabigatran) AND (“vitamin K antagonist” OR “vitamin K antagonists” OR VKA OR VKAs OR warfarin OR varfarin). Aiming to include additional studies, references of systematic reviews and included studies were analyzed to verify the possibility of any other eligible studies. Baseline characteristics and outcome data were extracted independently by two authors (E.P. and R.O.M.F.). Disagreements were resolved by consensus with the senior author (E.P., R.O.M.F., and L.F.K.).

 Eligibility criteria

Studies that met the following criteria were included: (1) RCTs or cohort studies; (2) comparing DOACs with VKAs; (3) enrolling patients with LVT; and (4) reporting at least one endpoint of interest. We excluded (1) overlapping populations; and (2) non-RCTs or non-cohort studies.

 Endpoints and subgroup analysis

Outcomes of interest were: (1) stroke or systemic embolic (SSE) events, (2) stroke, (3) systemic embolic (SE) events; (4) thrombus resolution; (5) any bleeding; (6) clinically relevant bleeding; (7) minor bleeding; (8) major bleeding; and (9) all-cause mortality.

The definition of outcomes was in accordance with the criteria established in the studies included in this systematic review and meta-analysis. Any bleeding included all bleeding. Clinically relevant bleeding included clinically relevant non-major bleeding, minor bleeding, and major bleeding. Transient ischemic attacks were not considered for analysis of the stroke outcome or the composite outcome of stroke or systemic embolic events.

Subgroup analyses were performed according to: (1) treatment with apixaban versus VKAs, (2) treatment with rivaroxaban versus VKAs, (3) RCTs only, (4) patients with LVT post-AMI, and (5) excluding conference abstracts.

 Risk of bias assessment

RCTs were appraised with the Cochrane Collaboration’s tool for assessing risk of bias in randomized trials (RoB-2), with 5 domains: selection, performance, detection, attrition, and reporting.13 Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) was used to evaluate the cohort studies, with 7 domains: confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and reported result.14 Two independent authors (E.P. and R.O.M.F.) conducted the quality assessment. Disagreements were resolved by consensus with the senior author (E.P., R.O.M.F, and L.F.K.).

 Quality assessment

The overall quality of evidence was analyzed according to the Grading of Recommendation, Assessment, Development and Evaluations (GRADE) guidelines.15 The outcomes were labeled as very low, low, moderate, or high-quality evidence based on the presence of risk of bias, inconsistency of results, imprecision, publication bias, and magnitude of treatment effects.

 Assessment of risk of bias across studies

Potential publication bias was judged for the SSE events outcome by visual inspection of contour-enhanced funnel plots and assessed by Egger’s regression asymmetry and Begg’s rank correlation test.16,17

 Statistical analysis

The treatment effects for binary endpoints were compared using risk ratios (RRs), with 95% confidence intervals (CIs). Statistical significance was defined as p value < 0.05. The heterogeneity was assessed with Cochran Q test and I2 statistics; p < 0.10 and I2 > 25% were considered significant for heterogeneity.18 Restricted maximum-likelihood estimator (REML) random-effects model was used for all endpoints.19 R statistical software, version 4.2.1 (R Foundation for Statistical Computing) was used for statistical analysis.

 Sensitivity analyses

Leave-one-out procedures were used to identify influential studies and their effect on the pooled estimates. This procedure was carried out by removing data from one study and reanalyzing the remaining data. When pooled effect size p values changed from significant to non-significant or vice-versa, study dominance was assigned.

 Trial sequential analysis

A TSA was conducted on the included RCTs to assess whether the cumulative evidence had sufficient statistical power in thrombus resolution, stroke, and clinically relevant bleeding outcomes. Our statistical plan involved two-sided testing with a type I error of 5% and a type II error of 20%. Both conventional and trial sequential monitoring boundaries (TSMBs) were generated for the DOACs and VKAs groups. A heterogeneity correction was applied in the TSA using the random effects model with 95% CIs. A z score curve was generated to assess the confidence and adequacy of evidence. The adjustment of the thresholds for the z score was based on the O’Brien–Fleming alpha spending function. Additionally, an analysis to determine the required number of patients to either accept or reject the intervention was performed. We used the TSA program version 0.9.5.10 beta (Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark).20

 Results Study selection and characteristics

As illustrated in Figure 1, the initial search yielded 366 results. After the removal of duplicate records and ineligible studies by title and abstract, 40 studies remained for full review according to inclusion criteria. In addition, 5 studies were identified through backward snowballing. Of these, 4 RCTs and 29 cohort studies were included in this systematic review and meta-analysis, comprising 4,450 patients.8,11,21-51 A total of 1,332 (29.9%) patients received DOACs, while 3,118 (70.3%) received VKAs. The follow-up period ranged from 3 months to 3 years. The mean age ranged from 49.6 to 69 years. Study and patient characteristics are summarized in Table 1 and Supplementary Material 1, Tables S1 and S2.

– PRISMA flow diagram of study screening and selection.

– Baseline characteristics of included studies
Study Study design Number of patients, n Follow-up, median or mean Age, years, mean (SD) or median (QR) Sex, n DOACs
DOACs VKAs Total DOACs VKAs Total Female Male
Al-abcha 2021* Retrospective cohort 48 146 194 NA NA NA 61.6 (13.3) 46 148 NA
Albabtain 2021† Retrospective cohort 28 35 63 NA 58.25 (17.73) 59 (15.62) NA 5 58 Rivaroxaban
Alcalai 2021† RCT 17 15 32 3 months 55.5 (12.9) 58.8 (10.2) 57.1 (11.7) 4 28 Apixaban
Aldaas 2022† Retrospective cohort 76 146 222 NA NA NA NA NA NA NA
Ali 2020* Retrospective cohort 32 60 92 12 months 59.2 (11.9) 58.0 (16.3) 59 (14) 17 75 Rivaroxaban, apixaban, dabigatran
Alizadeh 2019† Prospective cohort 38 60 98 1.8 years NA NA NA NA NA Rivaroxaban, apixaban, edoxaban
Bass 2019† Retrospective cohort 180 769 949 3 months 63.4 (16.7) 61.6 (15.3) NA 279 670 Rivaroxaban, apixaban, dabigatran
Byrne 2022* Retrospective cohort 16 41 57 12 months 63 (58-67) 60 (50-70) 60 (53-69) 13 44 NA
Cochran 2021† Retrospective cohort 14 59 73 13 months 51.5 (39-73) 62 (34-84) NA 17 56 Rivaroxaban, apixaban, dabigatran, edoxaban
Conant 2022† Retrospective cohort 29 135 164 NA NA NA NA NA NA NA
Daher 2020† Retrospective cohort 17 42 59 NA NA NA 62 (14) 10 49 Rivaroxaban, apixaban, dabigatran
Durrer-Ariyakuddy 2019* Cohort 20 33 53 20 months NA NA 63 14 39 NA
Gama 2019† Retrospective cohort 12 52 64 NA NA NA 69 (12) 13 51 NA
Guddeti 2020† Retrospective cohort 19 80 99 10.4 months 60.7 (13.1) 61.3 (12.2) 61 (12.3) 29 70 Rivaroxaban, apixaban, dabigatran
Haniff 2021* RCT 14 13 27 3 months 55.36 (11.04) 55.00 (11.42) 55.19 (11.01) 2 25 Apixaban
Harb 2022* Retrospective cohort 22 59 81 6 months NA NA NA NA NA NA
Iqbal 2020† Retrospective cohort 22 62 84 3.0 years 62 (13) 62 (14) 62 (14) 9 75 Rivaroxaban, apixaban, dabigatran
Iskaros 2021† Retrospective cohort 32 45 77 3 months 62 (55–74) 63 (55–73) NA 8 69 Rivaroxaban, apixaban, dabigatran
Isom 2020* Retrospective cohort 32 60 92 12 months NA NA 59 (14) NA NA NA
Jaidka 2018* Retrospective cohort 12 37 49 6 months 57.2 (9.3) 61.3 (12.1) NA 12 37 NA
Jones 2020† Prospective cohort 41 60 101 2.2 years 58.73 (14.2) 60.81 (14.3) NA 17 84 Rivaroxaban, apixaban, edoxaban
Mihm 2021* Retrospective cohort 33 75 108 6 months 63.3 (14.4) 60.3 (13.9) NA 31 77 Rivaroxaban, apixaban
Minciunescu 2020* Retrospective cohort 57 140 197 NA 60.4 (15.9) 59.5 (13.9) NA 45 152 NA
No-LVT Trial 2021* RCT 39 40 79 6 months NA NA 49.6 (12.5) 34 45 Rivaroxaban
Robinson 2018* Retrospective cohort 35 40 75 12 months NA NA NA NA NA Rivaroxaban, apixaban, dabigatran
Robinson 2020† Retrospective cohort 121 236 357 351 days 58.1 (14.9) 58.2 (15.1) NA 93 264 Rivaroxaban, apixaban, dabigatran
Seiler 2022* Retrospective cohort 48 53 101 12 months NA NA 63.3 (13.2) 18 83 NA
Willeford 2021† Retrospective cohort 22 129 151 12 months 54 (48-64) 56 (49-65.5) 56 (49-65) 30 121 Rivaroxaban, apixaban
Xu 2021† Retrospective cohort 25 62 87 2.37 years 59.4 (11.5) 61.9 (12.2) 61.5 (12.7) 21 66 Rivaroxaban, dabigatran
Youssef 2023† RCT 25 25 50 6 months 52 (8.2) 53 (7.9) NA NA NA Apixaban
Yunis 2020† Retrospective cohort 64 200 264 24 months NA NA NA NA NA NA
Zhang 2021† Retrospective cohort 33 31 64 25.0 months 60.3 (14.7) 61.3 (9.0) NA 17 47 Rivaroxaban
Zhang 2022† Retrospective cohort 109 78 187 17.0 months 64.5 (54.2–70.8) 63.0 (54.5–71.0) NA 36 151 Rivaroxaban

*The significance level of the results was not presented. †Statistical significance was defined as p value < 0.05. DOACs: direct oral anticoagulants; IQR: interquartile range; NA: not available; RCT: randomized controlled trial; SD: standard deviations; VKAs: vitamin K antagonists.

Pooled analysis of all studies

There was no significant difference between DOAC and VKA therapy regarding SSE events, stroke, SE events, and thrombus resolution (Figures 2 and 3). There was no significant difference between groups regarding any bleeding, clinically relevant bleeding, minor bleeding, major bleeding, and all-cause mortality (Figures 4 and 5).

– Direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs). A) Stroke or systemic embolic events. B) Stroke. CI: confidence interval; MH: Mantel-Haenszel.

– Direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs). A) Systemic embolic events. B) Thrombus resolution. CI: confidence interval; MH: Mantel-Haenszel.

– Direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs). A) Any bleeding. B) Clinically relevant bleeding. CI: confidence interval; MH: Mantel-Haenszel.

– Direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs). A) Minor bleeding. B) Major bleeding. C) All-cause mortality. CI: confidence interval; MH: Mantel-Haenszel.

Subgroup analysis

In the subgroup analysis of patients treated with rivaroxaban,21,22,47,48 SSE events and SE events were significantly reduced in the group treated with rivaroxaban. There was no significant difference between groups regarding stroke, thrombus resolution, any bleeding, clinically relevant bleeding, minor bleeding, major bleeding, and all-cause mortality. The pooled analyses are detailed in Supplementary Material 1, Figures S1 and S2.

In the subgroup analysis of patients treated with apixaban,8,49,51 there was no significant difference between groups regarding stroke, thrombus resolution, clinically relevant bleeding, and all-cause mortality. The pooled analyses are detailed in Supplementary Material 1, Figure S3.

In the subgroup analysis of RCTs only,8,22,49,51 there was no significant difference between groups regarding SSE events, stroke, thrombus resolution, clinically relevant bleeding, major bleeding, and all-cause mortality. The pooled analyses are detailed in Supplementary Material 1, Figure S4.

In the subgroup analysis including patients with LVT post-AMI,8,26,28,39,40,47,51 there was no significant difference between groups regarding SEE events, stroke, SE events, thrombus resolution, any bleeding, clinically relevant bleeding, minor bleeding, major bleeding, or all-cause mortality. The pooled analyses are detailed in Supplementary Material 1, Figures S5 and S6.

In the subgroup analysis excluding conference abstracts,8,11,21,27,29,31,34,36,37,40,44,45,47,48,50,51any bleeding was significantly reduced in the group treated with DOACs. However, there was no significant difference between groups regarding SEE events, stroke, SE events, thrombus resolution, clinically relevant bleeding, minor bleeding, major bleeding, or all-cause mortality. The pooled analyses are detailed in Supplementary Material 1, Figures S7, S8, and S9.

 Sensitivity analysis

We performed a leave-one-out sensitivity analysis for all outcomes. There was a significant decrease in SSE events in favor of DOAC therapy omitting Robinson et al.11 There was a significant difference in favor of DOAC therapy in any bleeding omitting Al-abcha et al., Albabtain et al., Jaidka et al., Yunis et al., or Zhang et al. (2022).21,23,39,46,48 There was a significant difference in clinically relevant bleeding in favor of DOAC therapy omitting Jaidka et al., Mihm et al., or Seiler et al.39,43,50 There was a significant difference in thrombus resolution in favor of DOAC therapy omitting Robinson et al.11 The leave-one-out sensitivity analysis plots are detailed in Supplementary Material 1, Figures S10 to S18.

 Quality and evidence assessment

Individual RCT appraisals according to the RoB-2 tool are illustrated in Supplementary Material 1, Figure S19. Overall, all RCTs raised some concerns due to deviations from intended interventions,8,49,51 and one RCT raised some concerns due to selection of reported results.49

No significant publication bias was detected for the SSE outcome by Egger’s test (p = 0.702) or Begg’s test (p = 0.327). The funnel plot of the SSE outcome is available in Supplementary Material 1, Figure S21.

Critical appraisal of the cohort studies is detailed in Supplementary Material 1, Figure S20. Four cohort studies showed a low risk of bias,29,40,47,48 while 10 cohort studies had a moderate risk of bias, due to biases in participant selection.11,21,27,31,34,36,37,44,45,50 One RCT and 15 cohort studies did not provide enough information to assess the risk of bias.22-26,28,30,32,33,35,38,39,41-43,46

According to the GRADE assessment, very low quality was assigned to all outcomes, mostly due to the inclusion of abstracts and multiple studies with no information regarding risk of bias. Supplementary Material 2 reports the full GRADE assessment and summary of findings.

 Trial sequential analysis

The cumulative z curve for stroke and clinically relevant bleeding did not surpass the conventional and monitoring boundaries and did not reach the required information size (RIS). In this case, we cannot conclude whether the neutral results arise from a lack of power or the intervention is unlikely to provide a significant impact. For thrombus resolution, the last point in the z curve lies within the futility boundaries, indicating that it will unlikely reach statistical significance, even if we proceeded to include trials randomizing patients until the RIS of 367. The trial sequential graphs are detailed in Figure 6 and Figure 7.

– Trial sequential analysis for (A) stroke and (B) clinically relevant bleeding. DOACs: direct oral anticoagulants; VKAs: vitamin K antagonists

– Trial sequential analysis for thrombus resolution. DOACs: direct oral anticoagulants; VKAs: vitamin K antagonists.

Discussion

In this systematic review and meta-analysis comprising 33 studies and 4,450 patients, we compared the efficacy of two types of anticoagulants, DOACs and VKAs, for the treatment of LVT. Our findings were: (I) DOAC therapy was equivalent to VKAs for LVT in the occurrence of thromboembolic events and thrombus resolution; (II) rivaroxaban significantly reduced thromboembolic events; and (III) the occurrence of bleeding complications was similar between groups.

LVT constitutes a prominent etiological factor for embolic stroke subsequent to AMI and congestive heart failure.52,53 Maniwa et al. revealed that individuals with LVT can experience SE events with an incidence rate as high as 16.3%, which is 5 times greater than those without LVT,54 and more than 10% die within 1 year.55 European and American guidelines recommend anticoagulant therapy for 3 to 6 months in patients with LVT.6,56 VKAs, mainly warfarin, are indicated as first-line oral anticoagulants for the treatment of LVT.9 Nevertheless, the use of warfarin comes with drawbacks, including interactions with drugs and food, variability in individual responses, the requirement for frequent monitoring, and the necessity of using unfractionated heparin or low molecular weight heparin for at least the 3 initial days due to a delay in factor II inhibition.57

In the last decade, new DOACs have been approved for anticoagulant treatment of nonvalvular atrial fibrillation (AF) and venous thromboembolic diseases.58,59 The anticoagulant action of DOACs is based on thrombin inhibition, with dabigatran, or factor Xa, with rivaroxaban, edoxaban, and apixaban.57,59 DOACS are now proven to be superior to warfarin in the treatment and prevention of thromboembolic events in patients with non-valvular AF.60 For LVTs, DOACs may be applicable, as the pathophysiological mechanism is similar to AF-related thrombus.57 However, no formal updated guideline has recommended the use of DOACs in patients with LVTs. The 2013 American College of Cardiology/American Heart Association STEMI and the 2017 European Society of Cardiology STEMI guidelines do not make reference to the use of DOACs in anticoagulation for LVT.6,56 Nonetheless, the 2021 American Heart Association/American Stroke Association stroke guideline featured a class IIb recommendation supporting the use of DOACs to reduce the risk of recurrent thrombosis in patients with stroke or transient ischemic attack and new LVTs.5,9 Thus, DOACs have been used as an off-label treatment for LVTs, with very limited guidance on their use.57,61

In a meta-analysis published as a scientific statement by the American Heart Association, DOACs were considered to be a reasonable alternative to VKAs in patients with LVT.9 This treatment approach was particularly attractive for patients for whom maintaining a consistent therapeutic INR range proves challenging or for those who cannot undergo frequent INR monitoring.9 In previous meta-analyses, Michael et al. showed reduced stroke rates in patients treated with DOACs compared to VKAs, with similar thrombus resolution and bleeding events.62 Accordingly, Trongtorsak et al. demonstrated similar rates of systemic thromboembolic events, thrombus resolution, and bleeding.63 Chen et al. and Kido et al. showed a significant reduction in bleeding in patients treated with DOACs compared with VKAs, with similar rates of thromboembolic events.57,64 In our meta-analysis, we found a significant reduction in any bleeding in favor of DOACs only in the subgroup analysis excluding conference abstracts. Considering that the exclusion of conference abstracts reduces the possibility of bias in the statistical analysis, this result favors the interpretation of the existence of a benefit of DOACs for the treatment of LVT in comparison to VKAs.

Li et al. and Ferreira et al. found no differences between DOACs and VKAs for thromboembolic events or bleeding.61,65 Accordingly, our meta-analysis has also indicated no statistical differences for the outcomes of stroke, SE events, or the composite outcome of SSE events. However, to the best of our knowledge, this is the first meta-analysis that performed subgroup analyses for apixaban and rivaroxaban, finding a benefit of rivaroxaban in reducing thromboembolic events, assessed by the significant reduction of SSE and SE events when compared with VKAs.

In TSA, firm evidence is reached when the patient sample size exceeds that required for achieving a definitive conclusion, or when z curves cross the TSMBs before reaching the essential patient count for conclusive evidence. Conversely, in instances in which the z curve crosses the conventional statistical thresholds but not the TSMBs and the necessary patient sample to accept or reject the hypothesis, the significant effect from the meta-analysis may stem from repetitive testing, rather than genuine underlying effects. In cases where the number of participants in the meta-analysis exceeds the RIS line, this suggests that there is sufficient evidence to draw reliable conclusions about the effect of the intervention. In our meta-analysis, TSA did not show sufficient evidence of the benefit of DOACs over VKAs for the treatment of LVT regarding thrombus resolution, stroke, and clinically relevant bleeding.

This study must be interpreted considering its limitations. First, most of the studies included in this meta-analysis were cohort studies, and the sample sizes, especially in the RCTs included, were small. Second, patient characteristics, type of DOACs, definition of clinical events, and follow-up showed variations among the included studies, contributing to inter-study heterogeneity. Third, the inclusion of conference abstracts represents a potential source of bias in the analysis, as abstracts often lack information about the patient population, and it is not possible to assess the risks of bias due to the inherent lack of detailed information about the study design. Furthermore, due to the limited information provided in the conference abstracts, population overlap is a concern, although no abstract included in our meta-analysis had the same number of patients as fully published studies. Fourth, GRADE assessment exhibited a very low quality of evidence due to significant inter-study heterogeneity and a severe risk of bias. Fifth, subgroup analyses were performed with a small sample size. Sixth, subgroup analyses for different DOACs, except rivaroxaban and apixaban, were not feasible due to a lack of adequate data. Therefore, the generalizability of the findings is limited. Larger RCTs are needed to confirm the efficacy and safety of DOACs compared to VKAs for the treatment of LVTs.

 Conclusion

DOACs had a similar rate of thromboembolic and hemorrhagic events, as well as thrombus resolution, compared to VKAs in the treatment of LVTs. Rivaroxaban therapy had a significant reduction in thromboembolic events, compared to VKAs.

Supplemental Materials

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For additional information Supplemental Material 2, please click here.

Study association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Sources of funding

There were no external funding sources for this study.