Comparison on effectiveness and safety of dose-specific DOACs versus warfarin in AF

In a systematic review and network meta-analysis in >2 million AF patients, edoxaban and standard-dose apixaban showed a favorable balance between preventing stroke/systemic embolism and reducing major bleeding risk.

This summary is based on the publication of Oh SH, Cheon S, Choi SY, et al. - Effectiveness and Safety of Dose-Specific DOACs in Patients With Atrial Fibrillation: A Systematic Review and Network Meta-Analysis. Cardiovasc Ther. 2025 Jan 6;2025:9923772. doi: 10.1155/cdr/9923772

Introduction and methods

Background

In AF, personalized dose adjustments of DOACs may be necessary because of specific patient factors, such as reduced kidney function, lower body weight, advanced age, or concomitant medication [1-5]. However, physicians sometimes prescribe lower-than-recommended DOAC doses regardless of individual patient characteristics, particularly in East Asia [6]. Concerns regarding the risk of bleeding may play a role, but undertreatment can compromise the effectiveness of DOACs in preventing stroke/systemic embolism [7,8].

Aim of the study

The study aim was to compare the effectiveness and safety of dose-specific DOACs (versus warfarin) in AF patients.

Methods

In a systematic review and network meta-analysis, the authors performed a systematic literature search in the MEDLINE, Embase, and CENTRAL databases up to March 5, 2024, to identify studies comparing the effectiveness and safety of DOAC dosing regimens and warfarin for AF. Using a naïve pooling method—thereby not assigning additional weight to studies with higher quality methodology or adjusting for potential biases—they included 32 multinational and single-nation studies (6 RCTs and 26 cohort studies), with a total of 2,332,770 patients. Follow-up duration ranged from 122 days to 50 months; 22 studies had a follow-up time ≥6 months.

To identify the most effective treatments in the network meta-analysis, treatment ranking was expressed as a rank probability value (range: 0–1, with a higher value indicating a better performance relative to the endpoint).

Outcomes

Primary endpoints were the incidences of stroke/systemic embolism and major bleeding events. The secondary endpoint was all-cause mortality.

Main results

Effectiveness and safety

• In direct pairwise meta-analyses comparing each dose-specific DOAC with warfarin, the incidence of stroke/systemic embolism was lower in patients treated with standard-dose apixaban (HR: 0.76; 95%CI: 0.67–0.86; I²=73%), standard-dose dabigatran (HR: 0.81; 95%CI: 0.73–0.89; I²=46%), standard-dose edoxaban (HR: 0.65; 95%CI: 0.45–0.93; I²=62%), standard-dose rivaroxaban (HR: 0.83; 95%CI: 0.75–0.91; I²=62%), low-dose dabigatran (HR: 0.80; 95%CI: 0.68–0.94; I²=71%), or low-dose rivaroxaban (HR: 0.82; 95%CI: 0.69–0.97; I²=60%), compared with patients receiving warfarin.
• There was no significant difference in the frequency of stroke/systemic embolism between patients taking low-dose apixaban (HR: 0.84; 95%CI: 0.70–1.02; I²=85%) or low-dose edoxaban (HR: 0.80; 95%CI: 0.61–1.06; I²=64%) and those on warfarin.
• Compared with warfarin-treated patients, the incidence of major bleeding events was reduced in patients taking standard-dose apixaban (HR: 0.63; 95%CI: 0.58–0.69; I²=74%), standard-dose dabigatran (HR: 0.73; 95%CI: 0.67–0.80; I²=43%), standard-dose edoxaban (HR: 0.60; 95%CI: 0.37–0.97; I²=82%), low-dose apixaban (HR: 0.64; 95%CI: 0.57–0.72; I²=68%), low-dose dabigatran (HR: 0.73; 95%CI: 0.61–0.86; I²=76%), or low-dose edoxaban (HR: 0.58; 95%CI: 0.51–0.65; I²=0%).
• Rivaroxaban treatment did not lead to a significant difference in the frequency of major bleeding events compared with warfarin (standard-dose: HR: 1.00; 95%CI: 0.93–1.07; I²=52%; low-dose: HR: 0.91; 95%CI: 0.72–1.15; I²=83%).
• With regard to the secondary endpoint of all-cause mortality, comparisons between DOAC dosing regimens and warfarin supported the preference for standard doses of apixaban, dabigatran, and edoxaban.

East Asian patients

• In a sensitivity analysis among East Asian patients (n=12 studies), all doses of DOACs (except for edoxaban, for which there were insufficient relevant studies) showed lower HRs for both stroke/systemic embolism and major bleeding events than those observed in the primary analysis.
• Of note, low-dose rivaroxaban versus warfarin significantly reduced the number of major bleeding events (HR: 0.66; 95%CI: 0.53–0.82; I²=53%), in contrast to in the primary analysis.

Rank probability

• Rank probability analysis demonstrated standard-dose edoxaban was associated with the lowest risk of stroke/systemic embolism (value: 0.77 at rank 1), whereas low-dose edoxaban was related to the lowest incidence of major bleeding events (value: 0.45 at rank 1). Regarding all-cause mortality, standard-dose edoxaban was the most preferred DOAC (value: 0.67 at rank 1).
• When assessing both primary endpoints together, standard-dose apixaban (stroke/systemic embolism: rank 2; major bleeding events: rank 2), standard-dose edoxaban (stroke/systemic embolism: rank 1; major bleeding events: rank 4), and low-dose edoxaban (stroke/systemic embolism: rank 4; major bleeding events: rank 1) all had high ranks.
• Low-dose apixaban showed the most significant difference in ranking for stroke/systemic embolism from standard-dose apixaban (rank 8 vs. rank 2).

Conclusion

In this systematic review and network meta-analysis including RCTs and real-world data from cohort studies and comprising over 2.3 million AF patients, all DOACs, regardless of dose, demonstrated effectiveness and safety in AF patients that were either superior to or not significantly different from warfarin. Standard-dose apixaban and standard-dose and low-dose edoxaban achieved a favorable balance between preventing stroke/systemic embolism and reducing the risk of major bleeding events. According to the authors, the “dose-dependent effectiveness of apixaban highlights the need for further research to optimize dosing.”

Find this article online at Cardiovasc Ther.

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