Abstract
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.
Highlights
Treatments to prevent stroke, especially oral anticoagulant use, are crucial for the management of patients with atrial fibrillation (AF)
direct oral anticoagulants (DOACs) were assessed as a camp in 5 studies, dabigatran in 2 studies, rivaroxaban in 3 studies, and apixaban in 2 studies (Figure 1)
The definition of non-standard dosing of DOACs and clinical outcomes in each included study are presented in (Supplementary Tables S4–S5)
Summary
Treatments to prevent stroke, especially oral anticoagulant use, are crucial for the management of patients with atrial fibrillation (AF). Studies have focused on the clinical outcomes of non-standard dosing of DOACs. A previous United States national registry study including 5738 AF patients treated with DOACs reported that over-dosing of DOACs was closely related to increased all-cause mortality, whereas under-dosing was associated with increased cardiovascular disease-related hospitalisation (Steinberg et al, 2016). A previous United States national registry study including 5738 AF patients treated with DOACs reported that over-dosing of DOACs was closely related to increased all-cause mortality, whereas under-dosing was associated with increased cardiovascular disease-related hospitalisation (Steinberg et al, 2016) Another registry study conducted in Japan reported similar stroke/systemic embolism (SE) and death events in patients with AF administered standard doses and under-doses of DOACs, and higher composite events (stroke/ SE, major bleeding, or death) in patients administered overdoses than in those administered standard doses of DOACs (Murata et al, 2019). Data on the clinical outcomes of non-standard doses of DOACs are limited
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