Effectiveness and Safety of Off-label Dosing of Non\u2013vitamin K Antagonist Anticoagulant for Atrial Fibrillation in Asian Patients

Kwang-No Lee,Jaemin Shim,Jin Seok Kim,Young-Hoon Kim,Do Young Kim,Seung-Young Roh,Dae In Lee,Jong-Il Choi,Yong-Soo Baek,Yun Gi Kim,Suk-Kyu Oh,Ki Yung Boo

doi:10.1038/s41598-020-58665-5

Abstract

Non–vitamin K antagonist anticoagulants (NOACs) have been used to prevent thromboembolism in patients with atrial fibrillation (AF) and shown favorable clinical outcomes compared with warfarin. However, off-label use of NOACs is frequent in practice, and its clinical results are inconsistent. Furthermore, the quality of anticoagulation available with warfarin is often suboptimal and even inaccurate in real-world data. We have therefore compared the effectiveness and safety of off-label use of NOACs with those of warfarin whose anticoagulant intensity was accurately estimated. We retrospectively analyzed data from 2,659 and 3,733 AF patients at a tertiary referral center who were prescribed warfarin and NOACs, respectively, between 2013 and 2018. NOACs were used at off-label doses in 27% of the NOAC patients. After adjusting for significant covariates, underdosed NOAC (off-label use of the reduced dose) was associated with a 2.5-times increased risk of thromboembolism compared with warfarin, and overdosed NOAC (off-label use of the standard dose) showed no significant difference in either thromboembolism or major bleeding compared with warfarin. Well-controlled warfarin (TTR ≥ 60%) reduced both thromboembolism and bleeding events. In conclusion, the effectiveness of NOACs was decreased by off-label use of the reduced dose.

Highlights

Phase III randomized controlled trials for non–vitamin K antagonist anticoagulants (NOACs) in patients with non-valvular atrial fibrillation (NVAF) have demonstrated, at a minimum, their noninferiority to warfarin in preventing thromboembolism and bleeding events[1,2,3,4]
Suboptimal anticoagulation is frequently reported with warfarin in Asian patients, which could affect the comparison between Non–vitamin K antagonist anticoagulants (NOACs) and warfarin[13,14,15]
The all NOAC group was older with a higher rate of prior ischemic events and higher proportion of women, which coincided with a higher CHA2DS2-VASc score, than the all warfarin group

Summary

Introduction

Phase III randomized controlled trials for non–vitamin K antagonist anticoagulants (NOACs) in patients with non-valvular atrial fibrillation (NVAF) have demonstrated, at a minimum, their noninferiority to warfarin in preventing thromboembolism and bleeding events[1,2,3,4]. Recent real-world studies have shown that both the standard and reduced doses of NOACs are effective and safe compared with warfarin[5,6,7]. Those real-world data showed a high prescription rate for the reduced dose, 50–90% of all NOAC prescriptions, which might be underdosing a considerable number of patients[5,6,7]. The off-label use of a reduced dose in Asian patients was found to be safe and effective compared with warfarin[11,12]. Our objective in this study was to compare the effectiveness and safety of NOACs (by dose and adherence with the drug label) with that of warfarin after adjusting for heterogeneous covariates

Methods

Results

Conclusion