Anticoagulantes profiláticos para pacientes não-hospitalizados com COVID-19: revisão sistemática Cochrane
Data
2023-11-30
Autores
Santos, Brena Costa dos 
Orientadores
Flumignan, Ronald Luiz Gomes
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A pandemia causada pela doença por coronavírus (COVID-19) impactou os sistemas de saúde em todo o mundo. Vários relatos de complicações tromboembólicas relacionadas à COVID-19 foram publicados e diversos autores descrevem que pacientes com COVID-19 possuem alto risco de desenvolver tromboembolismo venoso (TEV). Os anticoagulantes têm sido utilizados como intervenção farmacológica para prevenir trombose arterial e venosa e o seu uso extra-hospitalar pode potencialmente reduzir a prevalência de trombose vascular e a mortalidade associada a este evento nos pacientes com COVID-19. Entretanto, mesmo as baixas doses utilizadas como profilaxia podem resultar em eventos adversos como sangramento. É importante considerar as evidências disponíveis para o uso de anticoagulantes em pacientes não hospitalizados com COVID-19. Objetivos: Avaliar os benefícios e riscos do uso de anticoagulantes profiláticos versus um comparador ativo, placebo ou nenhuma intervenção em pacientes não hospitalizados com COVID-19. Métodos de pesquisa: Pesquisamos no Registro Especializado através do CRS-Web, CENTRAL, MEDLINE, Embase, CINAHL, plataforma internacional de registro de ensaios clínicos da Organização Mundial de Saúde (OMS) e ClinicalTrials.gov em 18 de abril de 2022. Buscamos todos os ensaios clínicos randomizados (ECR), quase-ECR, cluster-ECR e estudos de coorte que compararam anticoagulantes profiláticos com placebo ou nenhum tratamento, outro comparador ativo ou intervenções não farmacológicas em pessoas não hospitalizadas com COVID-19. Foram incluídos estudos que compararam anticoagulantes com diferentes doses do mesmo anticoagulante. Foram excluídos estudos com duração inferior a duas semanas. Os desfechos primários foram 1. mortalidade por todas as causas, 2. tromboembolismo venoso ((TEV) trombose venosa profunda (TVP) ou embolia pulmonar (EP)) e 3. sangramento importante. Os desfechos secundários foram 4. TVP, 5. EP, 6. necessidade de hospitalização, 7. sangramento menor, 8. eventos adversos (EAs) e 9. qualidade de vida (QoL). Usamos procedimentos metodológicos padrão da Cochrane. Usamos a ferramenta Cochrane para avaliar o risco de viés para ECR e GRADE para analisar a certeza das evidências. Nós meta-analisamos os dados quando apropriado. Resultados: Foram incluídos cinco ECRs com até 90 dias de acompanhamento (curto prazo). Os dados para meta-análise utilizados foram fornecidos por 1.777 participantes. Cinco estudos compararam anticoagulantes com placebo ou nenhum tratamento e forneceram dados para três de nossos desfechos de interesse (mortalidade por todas as causas, sangramento maior e eventos adversos). As evidências sugerem que, em comparação com placebo ou nenhum tratamento, os anticoagulantes profiláticos podem levar a pouca ou nenhuma diferença na mortalidade por todas as causas (risco relativo (RR) 0,36, intervalo de confiança (IC) de 95% 0,04 a 3,61; 5 estudos, 1777 participantes; evidência de baixa certeza); e provavelmente reduz TEV de 3% no grupo placebo para 1% no grupo dos anticoagulantes (RR 0,36, IC 95% 0,16 a 0,85; 4 estudos; 1259 participantes; número necessário para tratar para um desfecho benéfico adicional (NNTB) = 50; evidência de certeza moderada). Pode haver pouca ou nenhuma diferença em sangramento maior (RR 0,36, IC 95% 0,01 a 8,78; 5 estudos; 1.777 participantes; evidência de baixa certeza). Os anticoagulantes provavelmente resultam em pouca ou nenhuma diferença na ocorrência de TVP quando comparados com placebo ou nenhum tratamento (RR 1,02, IC 95% 0,30 a 3,46; 3 estudos; 1.009 participantes; evidência de certeza moderada), mas provavelmente reduzem o risco de EP de 2,7% no grupo placebo para 0,7% no grupo anticoagulante (RR 0,25, IC 95% 0,08 a 0,79; 3 estudos; 1.009 participantes; NNTB 50; evidência de certeza moderada). Os anticoagulantes provavelmente levam a pouca ou nenhuma diferença na redução da hospitalização (RR 1,01, IC 95% 0,59 a 1,75; 4 estudos; 1.459 participantes; evidência de certeza moderada) e podem levar a pouca ou nenhuma diferença nos eventos adversos (pequeno sangramento) (RR 2,46, IC 95% 0,90 a 6,72; 5 estudos, 1777 participantes; evidência de baixa certeza). Um estudo comparou anticoagulantes com uma dose diferente do mesmo anticoagulante e relatou cinco resultados relevantes. Nenhum caso de mortalidade por todas as causas, TEV ou sangramento importante ocorreu em nenhum dos grupos durante os 45 dias de acompanhamento (evidência de certeza moderada). Dose mais alta de anticoagulante em comparação com anticoagulantes de dose padrão pode levar a pouca ou nenhuma diferença na redução da necessidade de hospitalização (RR 1,89, IC 95% 0,17 a 20,58; 1 estudo; 278 participantes; evidência de baixa certeza) ou no número de eventos adversos (sangramento menor, RR 0,47, IC 95% 0,09 a 2,54; 1 estudo; 278 participantes; evidência de baixa certeza). Um estudo comparou anticoagulantes com agentes antiplaquetários e relatou cinco resultados relevantes. Nenhum caso de mortalidade por todas as causas ou sangramento maior ocorreu durante o acompanhamento de 45 dias (evidência de certeza moderada). Os anticoagulantes podem levar a pouca ou nenhuma diferença no TEV (RR 0,36, IC 95% 0,01 a 8,65; 1 estudo; 279 participantes; evidência de baixa certeza), na necessidade de hospitalização (RR 3,20, IC 95% 0,13 a 77,85; 1 estudo; 279 participantes; evidência de baixa certeza) ou em eventos adversos (sangramento leve) (RR 2,13, IC 95% 0,40 a 11,46; 1 estudo; 279 participantes; evidência de baixa certeza). Nenhum estudo incluído relatou sobre QoL ou investigou anticoagulantes em comparação com um anticoagulante diferente, ou anticoagulantes em comparação com intervenções não farmacológicas. Conclusões: Observamos evidências de baixa a moderada certeza de cinco ECRs de que anticoagulantes profiláticos provavelmente resultam em pouca ou nenhuma diferença em sangramento maior, TVP, necessidade de hospitalização ou EAs quando comparados com placebo ou nenhum tratamento em pessoas não hospitalizadas com COVID-19. Observamos moderada certeza de evidência de que anticoagulantes profiláticos podem reduzir a incidência de TEV e EP e podem resultar em pouca ou nenhuma diferença na mortalidade por todas as causas, em comparação com placebo ou nenhum tratamento. Além disso, evidências de baixa certeza sugerem que diferentes doses do mesmo anticoagulante profilático podem resultar em pouca ou nenhuma diferença no risco de necessidade de hospitalização ou EAs. Os anticoagulantes profiláticos podem resultar em pouca ou nenhuma diferença no risco de TEV, hospitalização ou EAs quando comparados com agentes antiplaquetários (evidência de baixa certeza). Estudos adicionais de duração suficiente são necessários para determinar claramente qualquer efeito nos resultados clínicos.
Background: The coronavirus disease 2019 (COVID-19) pandemic has impacted healthcare systems worldwide. Multiple reports on thromboembolic complications related to COVID-19 have been published and researchers have described that people with COVID-19 are at high risk for developing venous thromboembolism (VTE). Anticoagulants have been used as pharmacological interventions to prevent arterial and venous thrombosis and their use in the outpatient setting could potentially reduce the prevalence of vascular thrombosis and associated mortality in people with COVID-19. However, even lower doses used for a prophylactic purpose may result in adverse events such as bleeding. It is important to consider the evidence for anticoagulant use in non-hospitalised people with COVID-19. Objectives: To evaluate the benefits and harms of prophylactic anticoagulants versus an active comparator, placebo or no intervention in non-hospitalised people with COVID‐19. Methods: We conducted systematic searches of the following the Cochrane Vascular Specialised Register via the Cochrane Register of Studies, the Cochrane COVID Register via the Cochrane Register of Studies Online, CENTRAL, MEDLINE, Embase, CINAHL and the Latin American and Caribbean Health Science Information databases and the World Health Organization (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov up to 18 April 2022. We searched randomised controlled trials (RCTs), quase-RCT, cluster RCT and cohort studies that compared prophylactic anticoagulants with either placebo or no treatment, another active comparator, or non-pharmacological interventions in non-hospitalised people with COVID-19. We included studies which compared anticoagulants with a different dose of the same anticoagulant. We excluded studies with a duration of under two weeks. Our primary outcomes were 1. all-cause mortality, 2. Venous thromboembolism ((VTE) deep vein thrombosis (DVT) or pulmonary embolism (PE)) and 3. major bleeding. Our secondary outcomes were 4. DVT, 5. PE, 6. necessity for hospitalisation, 7. minor bleeding, 8. adverse events (AEs) and 9. quality of life (QoL). We used GRADE to assess certainty of evidence for the outcomes. Results: We included five RCTs with up to 90 days of follow‐up (short-term). Data for meta-analysis were available from 1777 participants. Anticoagulants compared to placebo or no treatment: five studies compared anticoagulants with placebo or no treatment and provided data for three of our outcomes of interest (all-cause mortality, major bleeding and adverse events). The evidence suggests that compared to placebo or no treatment, prophylactic anticoagulants may lead to little or no difference in all-cause mortality (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.04 to 3.61; 5 studies, 1777 participants; moderate-certainty evidence); and may reduce VTE (RR 0.36, 95% CI 0.16 to 0.85; 4 studies; 1259 participants; number needed to treat for an additional beneficial outcome (NNTB) = 50; moderate-certainty evidence). There was little to no difference in major bleeding (RR 0.36, 95% CI 0.01 to 8.78; 5 studies; 1777 participants; low-certainty evidence). Anticoagulants may result in little or no difference in DVT when compared with placebo or no treatment (RR 1.02, 95% CI 0.30 to 3.46; 3 studies; 1009 participants; moderate-certainty evidence), but may reduce the risk of PE (RR 0.25, 95% CI 0.08 to 0.79; 3 studies; 1009 participants; NNTB 50; moderate-certainty evidence). Anticoagulants may lead to little or no difference in reducing hospitalisation (RR 1.01, 95% CI 0.59 to 1.75; 4 studies; 1459 participants; moderate-certainty evidence) or adverse events (minor bleeding, RR 2.46, 95% CI 0.90 to 6.72; 5 studies, 1777 participants; low-certainty evidence). Anticoagulants compared to a different dose of the same anticoagulant: one study compared anticoagulants with a different dose of the same anticoagulant and reported five relevant outcomes. No cases of all-cause mortality, VTE or major bleeding occurred in either group during the 45-day follow‐up. Higher dose anticoagulant compared to standard dose anticoagulants may lead to little or no difference in reducing the necessity for hospitalisation (RR 1.89, 95% CI 0.17 to 20.58; 1 study; 278 participants; low-certainty evidence); or in the number of adverse events (minor bleeding, RR 0.47, 95% CI 0.09 to 2.54; 1 study; 278 participants; low-certainty evidence). Anticoagulants compared to antiplatelet agents: one study compared anticoagulants with antiplatelet agents and reported five relevant outcomes. No cases of all-cause mortality or major bleeding occurred during the 45-day follow‐up. Anticoagulants probably lead to little or no difference in VTE (RR 0.36, 95% CI 0.01 to 8.65; 1 study; 279 participants; low-certainty evidence), in the necessity for hospitalization (RR 3.20, 95% CI 0.13 to 77.85; 1 study; 279 participants; low-certainty evidence) or to adverse events (minor bleeding, RR 2.13, 95% CI 0.40 to 11.46; 1 study; 279 participants; low-certainty evidence). No included studies reported on QoL or investigated anticoagulants compared to a different anticoagulant, or anticoagulants compared to non‐pharmacological interventions. Conclusions: We found low to moderate‐certainty evidence from five RCTs that prophylactic anticoagulants may result in little or no difference in all-cause mortality, major bleeding, DVT, the necessity for hospitalization or AEs when compared with placebo or no treatment in non-hospitalised people with COVID-19. There was moderate-certainty evidence that prophylactic anticoagulants may reduce the incidence of VTE and PE compared with placebo or no treatment. Moderate to low certainty evidence suggests that prophylactic anticoagulants compared with a different dose of the same anticoagulant probably result in little or no difference in the risk of the necessity for hospitalisation or AEs. Prophylactic anticoagulants probably result in little or no difference in risk of VTE, hospitalisation or AEs when compared with antiplatelet agents (moderate-certainty evidence). These results should be interpreted with caution because we only had short-term data from one study. Additional trials of sufficient duration are necessary to clearly determine any effect on clinical outcomes.
Background: The coronavirus disease 2019 (COVID-19) pandemic has impacted healthcare systems worldwide. Multiple reports on thromboembolic complications related to COVID-19 have been published and researchers have described that people with COVID-19 are at high risk for developing venous thromboembolism (VTE). Anticoagulants have been used as pharmacological interventions to prevent arterial and venous thrombosis and their use in the outpatient setting could potentially reduce the prevalence of vascular thrombosis and associated mortality in people with COVID-19. However, even lower doses used for a prophylactic purpose may result in adverse events such as bleeding. It is important to consider the evidence for anticoagulant use in non-hospitalised people with COVID-19. Objectives: To evaluate the benefits and harms of prophylactic anticoagulants versus an active comparator, placebo or no intervention in non-hospitalised people with COVID‐19. Methods: We conducted systematic searches of the following the Cochrane Vascular Specialised Register via the Cochrane Register of Studies, the Cochrane COVID Register via the Cochrane Register of Studies Online, CENTRAL, MEDLINE, Embase, CINAHL and the Latin American and Caribbean Health Science Information databases and the World Health Organization (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov up to 18 April 2022. We searched randomised controlled trials (RCTs), quase-RCT, cluster RCT and cohort studies that compared prophylactic anticoagulants with either placebo or no treatment, another active comparator, or non-pharmacological interventions in non-hospitalised people with COVID-19. We included studies which compared anticoagulants with a different dose of the same anticoagulant. We excluded studies with a duration of under two weeks. Our primary outcomes were 1. all-cause mortality, 2. Venous thromboembolism ((VTE) deep vein thrombosis (DVT) or pulmonary embolism (PE)) and 3. major bleeding. Our secondary outcomes were 4. DVT, 5. PE, 6. necessity for hospitalisation, 7. minor bleeding, 8. adverse events (AEs) and 9. quality of life (QoL). We used GRADE to assess certainty of evidence for the outcomes. Results: We included five RCTs with up to 90 days of follow‐up (short-term). Data for meta-analysis were available from 1777 participants. Anticoagulants compared to placebo or no treatment: five studies compared anticoagulants with placebo or no treatment and provided data for three of our outcomes of interest (all-cause mortality, major bleeding and adverse events). The evidence suggests that compared to placebo or no treatment, prophylactic anticoagulants may lead to little or no difference in all-cause mortality (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.04 to 3.61; 5 studies, 1777 participants; moderate-certainty evidence); and may reduce VTE (RR 0.36, 95% CI 0.16 to 0.85; 4 studies; 1259 participants; number needed to treat for an additional beneficial outcome (NNTB) = 50; moderate-certainty evidence). There was little to no difference in major bleeding (RR 0.36, 95% CI 0.01 to 8.78; 5 studies; 1777 participants; low-certainty evidence). Anticoagulants may result in little or no difference in DVT when compared with placebo or no treatment (RR 1.02, 95% CI 0.30 to 3.46; 3 studies; 1009 participants; moderate-certainty evidence), but may reduce the risk of PE (RR 0.25, 95% CI 0.08 to 0.79; 3 studies; 1009 participants; NNTB 50; moderate-certainty evidence). Anticoagulants may lead to little or no difference in reducing hospitalisation (RR 1.01, 95% CI 0.59 to 1.75; 4 studies; 1459 participants; moderate-certainty evidence) or adverse events (minor bleeding, RR 2.46, 95% CI 0.90 to 6.72; 5 studies, 1777 participants; low-certainty evidence). Anticoagulants compared to a different dose of the same anticoagulant: one study compared anticoagulants with a different dose of the same anticoagulant and reported five relevant outcomes. No cases of all-cause mortality, VTE or major bleeding occurred in either group during the 45-day follow‐up. Higher dose anticoagulant compared to standard dose anticoagulants may lead to little or no difference in reducing the necessity for hospitalisation (RR 1.89, 95% CI 0.17 to 20.58; 1 study; 278 participants; low-certainty evidence); or in the number of adverse events (minor bleeding, RR 0.47, 95% CI 0.09 to 2.54; 1 study; 278 participants; low-certainty evidence). Anticoagulants compared to antiplatelet agents: one study compared anticoagulants with antiplatelet agents and reported five relevant outcomes. No cases of all-cause mortality or major bleeding occurred during the 45-day follow‐up. Anticoagulants probably lead to little or no difference in VTE (RR 0.36, 95% CI 0.01 to 8.65; 1 study; 279 participants; low-certainty evidence), in the necessity for hospitalization (RR 3.20, 95% CI 0.13 to 77.85; 1 study; 279 participants; low-certainty evidence) or to adverse events (minor bleeding, RR 2.13, 95% CI 0.40 to 11.46; 1 study; 279 participants; low-certainty evidence). No included studies reported on QoL or investigated anticoagulants compared to a different anticoagulant, or anticoagulants compared to non‐pharmacological interventions. Conclusions: We found low to moderate‐certainty evidence from five RCTs that prophylactic anticoagulants may result in little or no difference in all-cause mortality, major bleeding, DVT, the necessity for hospitalization or AEs when compared with placebo or no treatment in non-hospitalised people with COVID-19. There was moderate-certainty evidence that prophylactic anticoagulants may reduce the incidence of VTE and PE compared with placebo or no treatment. Moderate to low certainty evidence suggests that prophylactic anticoagulants compared with a different dose of the same anticoagulant probably result in little or no difference in the risk of the necessity for hospitalisation or AEs. Prophylactic anticoagulants probably result in little or no difference in risk of VTE, hospitalisation or AEs when compared with antiplatelet agents (moderate-certainty evidence). These results should be interpreted with caution because we only had short-term data from one study. Additional trials of sufficient duration are necessary to clearly determine any effect on clinical outcomes.