Effectiveness and Safety of Under or Over-dosing of Direct Oral Anticoagulants in Atrial Fibrillation: A Systematic Review and Meta-analysis of 148909 Patients From 10 Real-World Studies.

Background: In routine clinical practice, non-standard doses of direct oral anticoagulants (DOACs) are commonly used in patients with atrial fibrillation (AF). However, data on the clinical outcomes of non-standard doses of DOACs are limited. Methods: The MEDLINE, Embase, and Cochrane Library databases were systematically searched from their inception until 30 June 2020 for studies that reported the effectiveness or safety outcomes of non-standard doses of DOACs compared with on-label doses of DOACs in patients with atrial fibrillation. Non-standard doses of DOACs were defined as under or over-dose of DOACs based on the recommended standard doses in drug labels. A random-effects meta-analysis was performed to calculate the pooled hazard ratio and associated 95% confidence interval (95% confidence interval). Subgroup analyses were conducted according to individual DOACs and different geographic regions. Results: Ten articles involving 148,909 patients with AF were included. There were no significant differences between under-dosing and on-label dosing with respect to stroke/systematic embolism (HR: 1.01, 95% CI: 0.93-1.09), major bleeding (HR: 0.98, 95% CI: 0.77-1.19), intracranial haemorrhage (HR: 1.07, 95% CI: 0.74-1.40), gastrointestinal bleeding (HR: 1.10, 95% CI: 0.82-1.39), and myocardial infarction (HR: 1.07, 95% CI: 0.89-1.25), except for an increased risk of death (HR: 1.37, 95% CI: 1.01-1.73). We observed a significant association between over-dosing of DOACs and increased risk of stroke/systematic embolism (HR: 1.18, 95% CI: 1.04-1.32), major bleeding (HR: 1.16, 95% CI: 1.03-1.29), and death (HR: 1.21, 95% CI: 1.03-1.38) compared with on-label dosing. Furthermore, over-dosing of DOACs increased the risk of stroke/systematic embolism (HR: 1.16; 95% CI: 1.00-1.33) and major bleeding events (HR: 1.18; 95% CI: 1.00-1.37) in Asian patients. Conclusion: A reduced dose of DOACs might be safely and effectively used in clinical practice, especially in Asian patients, whereas high-dose DOACs might not be well tolerated by Asian patients.