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

Murata, Nobuhiro; Okumura, Yasuo; Yokoyama, Kenichi; 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

doi:10.1253/circj.cj-18-0991

Cited by 66 publications

(82 citation statements)

References 31 publications

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“…ETNA‐AF‐Japan included patients with CHADS 2 score ≤1, severe renal dysfunction (CLcr <30 mL/min) and DAPT use, which were excluded from ENGAGE AF‐TIMI 48 1 . Patient backgrounds such as age, body weight, and risk scores in terms of ETNA‐AF‐Japan were similar to those in the real‐world SAKURA AF Registry, 20,21 Fushimi AF Registry, 22 and other DOAC observational studies, 23‐27 suggesting that ETNA‐AF‐Japan reflected a real‐world population of Japanese patients with NVAF.…”

Section: Discussionmentioning

confidence: 94%

Postmarketing surveillance on the clinical use of edoxaban in patients with nonvalvular atrial fibrillation (ETNA‐AF‐Japan): One‐year safety and effectiveness analyses

Yamashita

Koretsune

Nagao

et al. 2020

Journal of Arrhythmia

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Background:The safety and effectiveness of edoxaban in real-world clinical settingshave not yet been elucidated thoroughly among Japanese patients with nonvalvular atrial fibrillation (NVAF). We report the one-year interim results of ETNA-AF-Japan (Edoxaban Treatment in routiNe clinical prActice in patients with nonvalvular Atrial Fibrillation: UMIN000017011), an ongoing two-year study.Methods: ETNA-AF-Japan is a prospective, real-world multicenter observational study that analyzes the long-term safety and effectiveness of edoxaban. Physicians recorded clinical characteristics, bleeding events, and clinical events of ischemic stroke and systemic embolism, among others. Results:In total, 11 569 patients with NVAF were enrolled. The demographic and clinical characteristics of the patients in the safety analysis set (n = 11 107) were a mean age of 74.2 ± 10.0 years; female sex, 40.6%; age ≥75 years, 52.4%; body weight ≤60 kg, 54.3%; creatinine clearance ≤50 mL/min, 31.2%; mean CHADS 2 score of 2.2 ± 1.3. The mean treatment period was 311.2 days (median; 366.0 days), and ~80% of patients continued edoxaban treatment. In the safety analysis, the incidence of all bleeding events was 6.32% [95% CI: 5.87, 6.79] (n = 702), and for major bleeding, it was 1.08% [0.90, 1.29] (n = 120). In the effectiveness analysis set (n = 11 059), the incidence of ischemic stroke (excluding TIA) or systemic embolism was 1.10% [0.92, 1.32] (n = 122). Conclusions:At one-year follow-up, the results showed no major concerns about the safety and effectiveness of edoxaban in Japanese patients with NVAF in a real-world clinical setting. K E Y W O R D S anticoagulants, atrial fibrillation, DOAC, edoxaban, postmarketing surveillance S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Yamashita T, Koretsune Y, Nagao T, Shiosakai K. Postmarketing surveillance on the clinical use of edoxaban in patients with nonvalvular atrial fibrillation (ETNA-AF-Japan): One-year safety and effectiveness analyses.

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Section: Discussionmentioning

confidence: 94%

Postmarketing surveillance on the clinical use of edoxaban in patients with nonvalvular atrial fibrillation (ETNA‐AF‐Japan): One‐year safety and effectiveness analyses

Yamashita

Koretsune

Nagao

et al. 2020

Journal of Arrhythmia

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“…There are two large registries that show the prevalence of the inappropriate dosing of DOACs in Japan, namely, the Fushimi AF Registry [5] and the SAKURA AF Registry [6,15]. In the Fushimi AF Registry, 32.2% (37/115) of dabigatran, 21.2% (47/222) of rivaroxaban, and 25.7% (52/202) of apixaban users were prescribed an off-label under-dose (i.e., underdosing) [5].…”

Section: Discussionmentioning

confidence: 99%

“…In the Fushimi AF Registry, 32.2% (37/115) of dabigatran, 21.2% (47/222) of rivaroxaban, and 25.7% (52/202) of apixaban users were prescribed an off-label under-dose (i.e., underdosing) [5]. The SAKURA AF Registry revealed that inappropriate doses of DOACs were prescribed in 26.2% patients (underdosing in 22.2% and overdosing in 4.0% of patients, respectively) [6,15]. Furthermore, a retrospective cohort study conducted at a single Japanese center showed that 22.6% of patients receiving DOACs were inappropriately prescribed, with 21.3% underdosed and 1.3% overdosed [7].…”

Section: Discussionmentioning

confidence: 99%

“…However, the dosing of these drugs should be appropriately adjusted based on one or more clinical features such as renal function, age, body weight, and concomitant drug use. In Japan, the prescription dose for each DOAC is determined by the manufacturer's recommendations in the drug package insert, and the physician's prescription is usually audited by pharmacists; however, physicians occasionally prescribe inappropriate doses of DOACs in real-world clinical settings [5][6][7]. Because few hospitals in Japan describe clinical laboratory data for out-of-hospital prescriptions, proper dosing adjustments may not be performed with prescriptions for outpatients compared with those for inpatients [8].…”

Section: Introductionmentioning

confidence: 99%

“…However, to date, little is known in Japan about clinical factors associated with an inappropriate DOAC dosing, including whether it is prescribed for inpatients or outpatients. The inappropriate dosing of DOACs has been associated with clinical safety and efficacy [6,9]. Therefore, it is essential to clarify the factors associated with the inappropriate dosing of DOACs to better educate physicians and improve their correct use.…”

Section: Introductionmentioning

confidence: 99%

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Inappropriate direct oral anticoagulant dosing in atrial fibrillation patients is associated with prescriptions for outpatients rather than inpatients: a single-center retrospective cohort study

Miyazaki

Matsuo

Uchiyama

et al. 2020

J Pharm Health Care Sci

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Background: Inappropriate dosing of direct oral anticoagulants (DOACs) has been associated with clinical safety and efficacy; however, little is known about clinical data associated with an inappropriate DOAC dosing in Japan. In addition, there is no report in which the appropriateness of DOAC dosing between prescription for inpatients and for outpatients was examined. In this study, we aimed to investigate the prevalence and factors associated in the inappropriate dosing of DOACs in patients with atrial fibrillation (AF).Methods: The retrospective cohort study was conducted at a single Japanese university hospital. Both inpatients and outpatients, who were diagnosed with AF and for whom treatment with either dabigatran, rivaroxaban, apixaban, or edoxaban was initiated between April 1, 2014 and March 31, 2018, were enrolled in the study. Appropriateness of DOAC dosing was assessed according to the manufacturer's labeling recommendations (dose reduction criteria) of each DOAC. Inappropriate reduced dose, namely, underdosing, was defined as prescription of a reduced dose of DOAC despite the patient not meeting the dose reduction criteria. Inappropriate standard dose, namely, overdosing, was defined as prescription of a standard dose of DOAC despite the patient meeting the dose reduction criteria. Inappropriate DOAC dosing was defined as a deviation of the recommended dose (both underdosing and overdosing). Results: A total of 316 patients (dabigatran, 28; rivaroxaban, 107; apixaban, 116; and edoxaban, 65) were included, with a median (interquartile range) age of 75 (66-81) years and 62.3% male. DOACs were prescribed at an appropriate standard dose in 39.2% of patients, an appropriate reduced dose in 36.7%, an inappropriate standard dose in 2.5%, and an inappropriate reduced dose in 19.3%. Multivariate analysis revealed that the inappropriate dosing of DOACs was significantly associated with prescriptions for outpatients (vs. inpatients; odds ratio [OR] 2.87, 95% confidence interval [CI] 1.53-5.62, p < 0.001) and those with higher HAS-BLED scores (OR 1.87, 95% CI 1.42-2.51, p < 0.001).

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Effect of non‐recommended doses versus recommended doses of direct oral anticoagulants in atrial fibrillation patients: A meta‐analysis

Liu

Huang

et al. 2021

Clinical Cardiology

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Background Several observational studies have shown that the inappropriate dosing use of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) that does not conform to recommendations is becoming a widespread phenomenon. Therefore, we performed a meta‐analysis and systematic review to assess the effect of non‐recommended doses versus recommended doses of DOACs on the effectiveness and safety outcomes among AF patients. Methods The PubMed and Ovid databases were systematically searched to identify the relevant studies until December 2020. The effect estimates were hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled using a fixed‐effects model (I2 ≤ 50%) or a random‐effects model (I2 > 50%). Results A total of 11 studies were included in this meta‐analysis. Compared with recommended dosing of DOACs, non‐recommended low dosing of DOACs was associated with increased risks of stroke or systemic embolism (SSE, HR = 1.29, 95% CI 1.12–1.49) and all‐cause death (HR = 1.37, 95% CI 1.15–1.62), but not the ischemic stroke, myocardial infarction, gastrointestinal bleeding, intracranial bleeding, and major bleeding. Compared with recommended dosing of DOACs, non‐recommended high dosing of DOACs was associated with increased risks of SSE (HR = 1.44, 95% CI 1.01–2.04), major bleeding (HR = 1.99, 95% CI 1.48–2.68), and all‐cause death(HR = 1.38, 95% CI 1.02–1.87). Conclusion Compared with recommended dosing of DOACs, non‐recommended low dosing of DOACs was associated with increased risks of SSE and all‐cause death. Further study should confirm the findings of non‐recommended high dosing versus recommended dosing of DOACs.

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

Cited by 66 publications

References 31 publications

Postmarketing surveillance on the clinical use of edoxaban in patients with nonvalvular atrial fibrillation (ETNA‐AF‐Japan): One‐year safety and effectiveness analyses

Postmarketing surveillance on the clinical use of edoxaban in patients with nonvalvular atrial fibrillation (ETNA‐AF‐Japan): One‐year safety and effectiveness analyses

Inappropriate direct oral anticoagulant dosing in atrial fibrillation patients is associated with prescriptions for outpatients rather than inpatients: a single-center retrospective cohort study

Effect of non‐recommended doses versus recommended doses of direct oral anticoagulants in atrial fibrillation patients: A meta‐analysis

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