Effectiveness and Safety of Reduced and Standard Daily Doses of Direct Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation: A Cohort Study Using National Database Representing the Japanese Population

Abstract

Purpose: To compare the effectiveness and safety of reduced or standard daily doses of direct oral anticoagulants (DOACs) with warfarin in Japanese patients with nonvalvular atrial fibrillation (NVAF). We used post-hoc analyses to identify patient groups that could benefit from reduced-dose DOACs.

Patients and methods: Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, we identified 944,776 patients with NVAF who had started an oral anticoagulant after at least one year of non-use between April 2011 and March 2016. We matched patients taking any, reduced, or standard doses of DOACs 1:1 with those taking warfarin. We measured treatment effectiveness based on admission due to stroke or systemic embolism (S/SE) and safety based on admission due to any bleeding (defined as major bleeding, MB). We compared both outcomes between DOACs and warfarin using the Cox proportional hazards model. We used post-hoc analysis to match patients receiving reduced-dose DOACs to those receiving standard-dose DOACs and compared treatment effectiveness and safety.

Results: More than half of patients receiving DOACs used a reduced dose. The occurrences of S/SE and MB in patients receiving any, reduced, or standard doses of DOACs were equal to or lower than those receiving warfarin. In the post-hoc analysis, the risk of S/SE and MB was similar between reduced and standard doses of DOACs except for those with a history of cerebral infarction and CHA₂DS₂-VASc score ≥3, where the risk of S/SE was lower for reduced doses of any and individual DOACs.

Conclusion: Findings from the current study are consistent with recent Asian and global studies but different from most studies conducted in North America and Europe, where patients receiving a reduced dose of DOACs had an increased risk of S/SE. Future studies should test the reproducibility of results from the current study.

Keywords: CHA2DS2-VASc score; atrial fibrillation; database; oral anticoagulant; pharmacoepidemiology; propensity score.

Figure 1

Flow chart for selection of new users of DOAC and warfarin with NVAF. ^aFigure S1 diagrammatically shows the exclusion process.

Figure 2

Number of new users of an oral anticoagulant between FY 2011 and FY 2015.

Figure 3

Hazard ratios and their 95% confidence intervals for main and individual outcomes in patients with any, reduced, and standard doses of any DOAC, compared with the same number of patients with warfarin selected by 1:1 matching by propensity score.