Clinical Outcomes of Off-Label Dosing of Direct Oral Anticoagulant Therapy Among Japanese Patients With Atrial Fibrillation Identified From the SAKURA AF Registry

• Published in: Circulation Journal Vol. 83; no. 4; pp. 727 - 735
• Main Authors: Murata, Nobuhiro, Okumura, Yasuo, Yokoyama, Katsuaki, Matsumoto, Naoya, Tachibana, Eizo, Kuronuma, Keiichiro, Oiwa, Koji, Matsumoto, Michiaki, Kojima, Toshiaki, Hanada, Shoji, Nomoto, Kazumiki, Arima, Ken, Takahashi, Fumiyuki, Kotani, Tomobumi, Ikeya, Yukitoshi, Fukushima, Seiji, Itoh, Satoru, Kondo, Kunio, Chiku, Masaaki, Ohno, Yasumi, Onikura, Motoyuki, Hirayama, Atsushi, for the SAKURA AF Registry Investigators
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Circulation Society 25.03.2019
• Subjects: Aged; Atrial fibrillation; Atrial Fibrillation - complications; Atrial Fibrillation - drug therapy; Atrial Fibrillation - epidemiology; Atrial Fibrillation - mortality; Direct oral anticoagulants; Dose-Response Relationship, Drug; Factor Xa Inhibitors - administration & dosage; Factor Xa Inhibitors - adverse effects; Factor Xa Inhibitors - therapeutic use; Female; Hemorrhage - chemically induced; Humans; Japan; Male; Middle Aged; Off-label dose therapy; Off-Label Use; Registries; Stroke - chemically induced; Stroke - etiology; Survival Analysis; Treatment Outcome; Japan; Atrial fibrillation; Direct oral anticoagulants; Off-label dose therapy
• ISSN: 1346-9843; 1347-4820
• DOI: 10.1253/circj.CJ-18-0991

Background: Off-label dosing of direct oral anticoagulants (DOACs) is encountered clinically among patients with atrial fibrillation (AF), although data on the clinical outcomes of over- and under-dosing are lacking in Japan. Methods and Results: We examined the clinical outcomes of off-label DOAC dosing using the SAKURA AF Registry, a prospective multicenter registry in Japan. Among 3,237 enrollees, 1,676 under any of the 4 DOAC regimens were followed up for a median of 39.3 months: 746 (45.0%), appropriate standard-dose; 477 (28.7%), appropriate low-dose; 66 (4.0%), over-dose; and 369 (22.2%) under-dose. Compared with the standard-dose group, patients in the under- and over-dose groups were significantly older and had a higher stroke risk. After multivariate adjustment, stroke/systemic embolism (SE) and death events were equivalent between the standard- and under-dose groups, but major bleeding events tended to be lower in the under-dose group (hazard ratio [HR] 0.474, P=0.0739). Composite events (stroke/SE, major bleeding, or death) were higher in the over-dose than in the standard-dose group (HR 2.714, P=0.0081). Conclusions: Clinical outcomes were not worse for under-dose than for standard-dose users among patients with different backgrounds. Over-dose users, however, were at higher risk for all clinical events and required careful follow-up. Further studies are needed to clarify the safety and effectiveness of off-label DOAC dosing in Japan.