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Clinical effects of off-label reduced doses of direct oral anticoagulants : a systematic review and meta-analysis
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Introdução: A Fibrilhação Auricular (FA) é a arritmia mais prevalente entre os doentes mais idosos, associada a eventos tromboembólicos. Os Novos Anticoagulantes Orais Diretos (DOACs) são o tratamento de eleição para a maioria destes doentes, mas o seu uso pode ter riscos numa dose standard. No entanto, os efeitos relacionados com o seu uso numa dose off label reduzida são ainda pouco conhecidos Objetivos: Foi realizada uma revisão sistemática com meta-análise para avaliar os efeitos de DOACs numa dose off label reduzida, em doentes com FA. Métodos: Foram incluídos estudos observacionais das bases de dados MEDLINE, Cochrane Central Register of Controlled Trials, PsycIN FO databases and EMBASE (Abril 2021) que avaliaram os efeitos da toma de DOACs em doentes com FA, com dose off label reduzida, em comparação com dose standard. O risco de viés foi avaliado através da ferramenta Risk of Bias in Non Randomized Studies of Interventions (ROBINS-I). Realizou-se uma meta-análise de efeitos aleatórios para estimar o Hazard Ratio (HR) com intervalos de confiança de 95%, e a heterogeneidade foi avaliada através das estatísticas I2. Resultados: Dezoito estudos coorte com a análise de 237 533 doentes com FA foram incluídos na meta-análise. O uso de DOAC off label dose reduzida está associado a maior risco de mortalidade por todas as causas [HR = 1.27 (95% CI 1.09 to 1.48), com I2=71%] e a eventos cardiovasculares [HR = 1.51 (95% CI 1.32 to 1.71), com I2=0%], quando comparado a dose standard. O seu efeito em eventos tromboembólicos (acidente vascular cerebral/embolismo sistémico), hemorragia major, e eventos isquémico e hemorrágicos não foi estatisticamente significativo [HR=1.14 (95% CI 1.00 to 1.31), com I2=62%; HR=1.02 (95% CI 0.91 to 1.15), com I2=44%; e HR=1.22 (95% CI 0.79 to 1.88), com I2=49%, respetivamente]. A maioria dos eventos dos estudos incluídos teve um risco de viés grave e quase todos os estudos incluídos revelaram uma avaliação da confiança no efeito estimado muito baixa a baixa, segundo Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). Conclusões: DOACs em dose off label reduzida estão associados a um maior risco de mortalidade por todas as causas e a maior eventos cardiovasculares, em comparação com DOACs em dose standard.
Backgound: Atrial Fibrillation (AF) is the most prevalent cardiac arrhythmia among older patients, associated with thromboembolic events. Direct Oral Anticoagulants (DOACs) are the treatment of choice for most patients, but its use may have risks on standard dose. However, it is still unclear the effects related with the use of a lower dose off labelled (DOAC). Objectives: We conducted a systematic review and meta-analysis to assess the effects of off label underdose use of DOAC in patients with AF. Methods: MEDLINE, Cochrane Central Register of Controlled Trials, PsycIN FO databases and EMBASE (April 2021) were searched for observational longitudinal studies evaluating the outcomes on off label underdosed patients compared with standard dosed patients with AF. The risk of bias was assessed according to the ROBINS-I tool. We performed a random-effects meta-analysis to estimate the pooled Hazard Ratios (HR) with 95% CIs, and heterogeneity was evaluated using the I2 statistics. Results: Eighteen cohort studies evaluating 237 533 patients with AF were included in the meta-analysis. Off label underdose DOAC use is associated with higher risk of allcause mortality [HR = 1.27 (95% CI 1.09 to 1.48), with I2=71%] and composite cardiovascular outcomes [HR = 1.51 (95% CI 1.32 to 1.71), with I2=0%], when compared with standard dose DOAC use. The effect in thromboembolic events (stroke/systemic embolism), major bleeding, and composite of ischemic and bleeding events was not statistically significant [HR=1.14 (95% CI 1.00 to 1.31), with I2=62%; HR=1.02 (95% CI 0.91 to 1.15), with I2=44%; and HR=1.22 (95% CI 0.79 to 1.88), with I2=49%, respectively]. The majority of outcomes in the included studies had a serious risk of bias and almost all evaluated outcomes had very low to low Grading of Recommendation, Assessment, Development and Evaluation (GRADE) evidence. Conclusions: Off label underdose DOAC use is associated with higher risk of all-cause mortality and composite cardiovascular outcomes, when compared with standard dose DOAC use.
Backgound: Atrial Fibrillation (AF) is the most prevalent cardiac arrhythmia among older patients, associated with thromboembolic events. Direct Oral Anticoagulants (DOACs) are the treatment of choice for most patients, but its use may have risks on standard dose. However, it is still unclear the effects related with the use of a lower dose off labelled (DOAC). Objectives: We conducted a systematic review and meta-analysis to assess the effects of off label underdose use of DOAC in patients with AF. Methods: MEDLINE, Cochrane Central Register of Controlled Trials, PsycIN FO databases and EMBASE (April 2021) were searched for observational longitudinal studies evaluating the outcomes on off label underdosed patients compared with standard dosed patients with AF. The risk of bias was assessed according to the ROBINS-I tool. We performed a random-effects meta-analysis to estimate the pooled Hazard Ratios (HR) with 95% CIs, and heterogeneity was evaluated using the I2 statistics. Results: Eighteen cohort studies evaluating 237 533 patients with AF were included in the meta-analysis. Off label underdose DOAC use is associated with higher risk of allcause mortality [HR = 1.27 (95% CI 1.09 to 1.48), with I2=71%] and composite cardiovascular outcomes [HR = 1.51 (95% CI 1.32 to 1.71), with I2=0%], when compared with standard dose DOAC use. The effect in thromboembolic events (stroke/systemic embolism), major bleeding, and composite of ischemic and bleeding events was not statistically significant [HR=1.14 (95% CI 1.00 to 1.31), with I2=62%; HR=1.02 (95% CI 0.91 to 1.15), with I2=44%; and HR=1.22 (95% CI 0.79 to 1.88), with I2=49%, respectively]. The majority of outcomes in the included studies had a serious risk of bias and almost all evaluated outcomes had very low to low Grading of Recommendation, Assessment, Development and Evaluation (GRADE) evidence. Conclusions: Off label underdose DOAC use is associated with higher risk of all-cause mortality and composite cardiovascular outcomes, when compared with standard dose DOAC use.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2022
Palavras-chave
Fibrilhação auricular Dose off label reduzida Anticoagulantes orais diretos (DOAC) Revisão sistemática Cardiologia