Effects of Direct Oral Anticoagulants’ Nonrecommended Dose in Atrial Fibrillation: A Meta-Analysis

Background: The efficacy and safety profiles of nonrecommended direct oral anticoagulant (DOAC) doses in patients with nonvalvular atrial fibrillation (NVAF) are still undefined. Summary: We searched for randomized controlled trials and observational studies that compared nonrecommended versus recommended doses of DOACs, published up to December 2021. Primary study outcomes were ischemic stroke/transient ischemic attack/systemic embolism (IS/TIA/SE) and major bleeding (MB). All-cause mortality was a secondary outcome. We determined pooled odds ratios (ORs) between groups of patients with a random-effect model. Twenty-three studies with 175,801 patients were included. Nonrecommended doses were associated with a higher risk of IS/TIA/SE and all-cause mortality, but not of MB as compared to recommended doses of DOACs (OR 1.25 [95% CI: 1.14–1.38], OR 1.69 [95% CI: 1.31–2.18] and OR 1.10 [95% CI: 0.93–1.31], respectively). The nonrecommended low dose was associated with an increased risk of IS/TIA/SE and all-cause death (OR 1.21 [95% CI: 1.05–1.39] and OR 1.66 [95% CI: 1.18–2.35], respectively) but not of MB (OR 1.01 [95% CI: 0.83–1.22] as compared to recommended doses. Subgroup analysis of nonrecommended low doses of DOACs showed a nonsignificant increase in IS/TIA/SE in Asians (OR 1.17 [95% CI: 0.89–1.54] vs. non-Asian (OR 1.21 [95% CI: 1.07–1.36]). Key Messages: Compared with recommended doses, nonrecommended low doses of DOACs increase the risk of ischemic events without decreasing the risk of bleeding. For Asians, the efficacy of DOACs seemed preserved despite the nonrecommended low-dose prescription. Clinicians should carefully adhere to recommended DOAC prescription advice in managing NVAF patients.