Dose of Direct Oral Anticoagulants and Adverse Outcomes in Asia

Abstract

The present study aimed to assess the associations between dosing of DOACs and outcomes in patients with non-valvular atrial fibrillation (NVAF). Direct oral anticoagulants (DOACs) require dose adjustment according to patient or clinical factors for patients with NVAF. We conducted a single-center prospective registry of NVAF patients with DOACs: DIRECT registry (UMIN000033283). In the present analysis, we categorized the patients (n = 2,216) into 5 groups: appropriate standard-dose (n = 907, 40.9%), appropriate low-dose (n = 833, 37.6%), overdose (n = 117, 5.3%), underdose (n = 338, 15.3%), and contraindication (n = 21, 0.9%). The efficacy endpoints were major adverse cardiovascular event (MACE: a composite of all-cause death, myocardial infarction, and stroke/systemic embolism) and its individual components. The safety end points were adverse bleeding events including clinically significant bleeding, major bleeding, and gastro-intestinal bleeding. All NVAF patients treated with DOACs in our institution from 2011 to 2017 were enrolled (71.6 ± 10.8 years, 36.4% female, follow-up duration: 407.2 ± 388.3 days). Appropriate low-dose group were older, more likely female, had a higher CHADS2 and ORBIT scores than the other groups. MACE (7.4%) and clinically significant bleeding (26.2%) occurred most frequently in the appropriate low-dose group. However, after adjustment for various confounders, appropriate dose reduction of DOAC showed 35.4% risk reduction of clinically significant bleeding (adjusted hazard ratio 0.646, 95% CI [0.469 to 0.890], p = 0.007) with no impairment of efficacy end points. In the real-world Asian clinical practice, four fifths of the NVAF patients received appropriate dose of DOACs. Appropriate dose reduction was associated with decrease in clinically significant bleeding and no significant impairment in efficacy end points.