Systematic Review and Meta-Analysis of Direct Oral Anticoagulants Versus Warfarin in Atrial Fibrillation With Low Stroke Risk

•This study aimed to compare direct oral anticoagulants (DOACs) versus warfarin in patients with atrial fibrillation and low stroke risk. •This was a systematic review and meta-analysis of 11 studies and 132,980 patients. •DOACs had significantly lower risks of stroke/systemic embolism, mortality, major bleeding, and intracranial hemorrhage. •In network meta-analysis, dabigatran had the best balance of stroke prevention and reduction in major bleeding. •DOACs should be the standard of care in low-risk patients with atrial fibrillation who require anticoagulation. Pivotal trials comparing direct oral anticoagulants (DOACs) against warfarin in patients with atrial fibrillation (AF) predominantly involved patients with high stroke risk. This study aimed to evaluate the efficacy and safety of DOAC versus warfarin in patients with low stroke risk. An online literature search was conducted to retrieve studies comparing clinical outcomes between patients treated with DOAC versus warfarin for AF, reporting outcomes for patients at low or minimal risk of stroke (CHA2DS2-VASc scores ranging from 0 to 2 or CHADS2 scores ranging from 0 to 1). The primary outcome was the occurrence of stroke or systemic embolism. Secondary outcomes included major bleeding, intracranial hemorrhage, and all-cause mortality. Hazard ratios for all outcomes were pooled in random-effects meta-analyses. A network meta-analysis of individual DOACs versus warfarin was also conducted. In total, 11 studies (132,980 patients) were included. DOAC was associated with a significantly lower risk of stroke or systemic embolism (hazard ratio 0.85, 95% confidence interval 0.75 to 0.96, p = 0.008, I2 = 0%), major bleeding, intracranial hemorrhage, and mortality compared with warfarin. This benefit persisted even when study arms which had CHA2DS2-VASc scores of 2 were excluded. When restricted to 3 studies investigating only patients with a single nongender-related stroke risk factor, significant benefit was seen only for the outcome of major bleeding. In the network meta-analysis, only dabigatran was superior to warfarin for all 4 outcomes. In conclusion, DOACs should be the standard of care in low-risk patients with AF who require anticoagulation. In particular, dabigatran appears to have the best balance of stroke prevention and reduction in major bleeding. Pivotal trials comparing direct oral anticoagulants (DOACs) against warfarin in patients with atrial fibrillation (AF) predominantly involved patients with high stroke risk. This study aimed to evaluate the efficacy and safety of DOAC versus warfarin in patients with low stroke risk. An online literature search was conducted to retrieve studies comparing clinical outcomes between patients treated with DOAC versus warfarin for AF, reporting outcomes for patients at low or minimal risk of stroke (CHA2DS2-VASc scores ranging from 0 to 2 or CHADS2 scores ranging from 0 to 1). The primary outcome was the occurrence of stroke or systemic embolism. Secondary outcomes included major bleeding, intracranial hemorrhage, and all-cause mortality. Hazard ratios for all outcomes were pooled in random-effects meta-analyses. A network meta-analysis of individual DOACs versus warfarin was also conducted. In total, 11 studies (132,980 patients) were included. DOAC was associated with a significantly lower risk of stroke or systemic embolism (hazard ratio 0.85, 95% confidence interval 0.75 to 0.96, p = 0.008, I2 = 0%), major bleeding, intracranial hemorrhage, and mortality compared with warfarin. This benefit persisted even when study arms which had CHA2DS2-VASc scores of 2 were excluded. When restricted to 3 studies investigating only patients with a single nongender-related stroke risk factor, significant benefit was seen only for the outcome of major bleeding. In the network meta-analysis, only dabigatran was superior to warfarin for all 4 outcomes. In conclusion, DOACs should be the standard of care in low-risk patients with AF who require anticoagulation. In particular, dabigatran appears to have the best balance of stroke prevention and reduction in major bleeding.