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

• Published in: Frontiers in pharmacology 2021-03, Vol.12, p.645479-645479
• Main Authors: Shen, Nan-Nan, Zhang, Chi, Wang, Na, Wang, Jia-Liang, Gu, Zhi-Chun, Han, Hua
• Format: Article
• Language: English
• Subjects: atrial fibrillation; bleeding; direct oral anticoagulants; Pharmacology; real-world; stroke; under-dose
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2021.645479

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. 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. 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. 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.