Pattern and Impact of Off-label Underdosing of Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation Who are Indicated for Standard Dosing

Abstract

With safety concerns about increasing bleeding, off-label underdosing of non-vitamin K antagonist anticoagulants (NOACs) is common in East Asian patients with atrial fibrillation (AF). We tried to investigate the pattern of NOAC underdosing and associated clinical outcomes in patients with AF who are indicated for standard dosing. Using the Korean National Health Insurance Service database, we evaluated 16,568 patients with a new prescription of NOAC who are indicated for standard NOAC dosing and compared 4,536 patients with warfarin with respect to thromboembolic events (ischemic stroke or systemic embolization), all-cause mortality and major bleeding. Of the 16,568 patients indicated for standard NOAC dosing, 8,549 (51.9%) received off-label underdosing (50.6% rivaroxaban, 53.0% apixaban). During a median follow up of 15.0 months, as compared with warfarin, underdosing of rivaroxaban was associated with lower risks of major thromboembolic events (hazard ratio [HR]: 0.53; 95% confidence interval [CI]: 0.41 to 0.69) and all-cause mortality (HR 0.57, 95% CI: 0.41 to 0.82), and a similar risk of major bleeding (HR 1.10, 95% CI: 0.82 to 1.46). However, underdosing of apixaban was associated with similar risks of major thromboembolic events (HR: 0.90; 95% CI: 0.70 to 1.16), all-cause mortality (HR 0.94, 95 CI: 0.71 to 1.24) and major bleeding (HR 0.84, 95% CI: 0.61 to 1.17). In conclusion, in this Korean population with AF who are indicated for standard NOAC dosing, off-label underdosing is common and its clinical benefit over warfarin was inconsistent according to types of NOAC. Notably, apixaban underdosing provides no benefit in effectiveness compared with warfarin.