Prescription of oral anticoagulation (OAC) is a crucial measure for preventing stroke in patients with atrial fibrillation (AF) (1–3). Direct oral anticoagulant (DOAC) is prioritized except for low stroke risk or contraindications (1–3). In South Korea, similar to global trends, DOAC prescriptions for patients with AF have increased rapidly over the past decade (4).

Guidelines emphasize DOAC dose reduction based on approved criteria for optimal patient benefit (1, 3, 5). However, off-label DOAC dosing, especially underdosing in Asian patients, is common (6–11). DOAC off-label underdosing is linked to a higher risk of ischemic stroke according to several (largely retrospective) observational studies (8, 11, 12).

Based on the pivotal randomised clinical trial (RCT) and practical guideline (5, 13), apixaban dose should be reduced from 5 mg twice daily to 2.5 mg twice daily in patients who met two or more criteria (age ≥80 years, body weight ≤60 kg, and serum creatinine ≥1.5 mg/dL). Given the stringent requirements for apixaban dose reduction, only 4.7% (n = 428) of the apixaban group was prescribed a reduced dose in the ARISTOTLE trial (13). In South Korea, apixaban 2.5 mg is widely prescribed in real-world settings and is mostly used for off-label underdosing (9, 14). The factors associated with off-label underdosing often align with traits of frail patients and dose reduction criteria (e.g., old age, underweight, and renal impairment) (9). Among anticoagulated patients with AF, older adults, those who are underweight or have renal impairment are at high risk of bleeding and stroke (15–17). Although off-label reduced dose apixaban is generally associated with a higher risk of stroke, based on previous observational studies (8, 11, 18), the risk of off-label reduced dose apixaban in patients with AF who meet a single criterion for dose reduction has not been demonstrated. E

In this study, we aimed to describe real-world apixaban dosing patterns in patients meeting a single criterion for dose reduction and assess factors related to off-label reduced dose prescriptions.

The efficacy and Safety of aPixaban In REal-world practice in Korean frail patients with atrial fibrillation (ASPIRE) study was a prospective, multicentre, non-interventional observational study covering all geographical regions of the Republic of Korea. The study enrolled participants aged >19 years with non-valvular AF receiving apixaban in the outpatient clinics of 32 centres.

The ASPIRE study aimed to delineate the effectiveness and safety results among the participating patients. The data were recorded in a common electronic database at each centre with regular audits. The data gathered was recorded in the iCReaT (Internet-based Clinical Research and Trial Management System), a web-based system for managing clinical research, which is a service provided by the Korean government. The participants were followed up on regularly at 3-month intervals via personal interviews.

Each centre's ethics committee gave their approval for the protocols, which were carried out in compliance with the principles set forth in the Declaration of Helsinki (H-2108-110-1245). This study was registered at ClinicalTrials.gov (NCT05773222). All the patients provided informed consent for inclusion in the study.

From 12 March 2020 to 15 September 2022 2,000 patients were included in this analysis. The mean age of the total population was 74.3 ± 7.9 years (55.8% women; n = 1,115) and the mean body weight was 60.1 ± 10.0 kg. Overall, 593 (29.7%) patients were aged ≥80 years, 1,251 (62.6%) had body weight ≤60 kg, and 156 (7.8%) had serum creatinine ≥1.5 mg/dL. Baseline characteristics of the study population according to apixaban dosage are shown in Table 1. Patients taking off-label reduced dose apixaban were more likely to have hypertension, heart failure, prior history of bleeding, CKD, and anaemia than those taking on-label standard-dose apixaban. The on-label standard-dose group was more likely to have a history of stroke or TIA. The prevalence of diabetes mellitus, liver disease, and malignancy were similar between the two groups. Concomitant APT use was more common in the off-label reduced dose group. Among the total population, 26.4% were newly prescribed OAC upon enrolment in this study, and 73.6% of participants were prescribed OAC before enrolment. Both groups had similar AF types, mostly paroxysmal (52.2%, n = 1,044), then persistent (35.3%, n = 705). The most common EHRA symptom category was IIa (39.5%, n = 790), followed by category I (23.9%, n = 478).

In this prospective, multicentre, non-interventional observational study of 2,000 Asian patients with a single criterion for dose reduction for apixaban, we found that (Figure 4) (1) low body weight was the most common cause of off-label dose reduction, followed by old age and renal dysfunction; (2) almost half of the patients received the off-label reduced dose apixaban; (3) the off-label reduced dose group had more hypertension, heart failure, bleeding history, CKD, anaemia, and concomitant APT; and (4) marginal values of other criteria also influenced the off-label prescription.

Currently, DOACs are considered the primary treatment option among participants with AF for stroke prevention (1–3). The optimal dose for each patient is an area of interest. Previous observational studies have shown that off-label reduced dose of DOACs is associated with an increased stroke risk (8, 11, 12). Although previous studies used different types of DOACs and study populations, dose reduction of apixaban was associated with increased stroke in both Western and Asian countries (8, 11). Thus, prescribing an on-label dose of apixaban is strongly recommended unless patients fulfil more than two dose reduction criteria (5, 13).

Despite the current dosing guidelines, low-dose apixaban is more likely to be prescribed to Asian populations (9, 14, 23). Among Korean patients with AF prescribed DOAC, apixaban 2.5 mg twice daily was prescribed to more patients than those prescribed 5 mg apixaban twice daily (54.1 vs. 45.9%) (14). In the COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation (CODE-AF) registry, a prospective multicentre registry of Korean patients with AF, the proportion of off-label reduced dose was higher in patients taking apixaban than in those taking other DOACs (9). A nationwide retrospective cohort study in Taiwan also showed a high prevalence of low-dose DOAC use (24). However, few studies have reported clinical outcomes according to the number of dose reduction criteria for apixaban. We previously reported the clinical outcomes of off-label reduced dose apixaban using the Korean nationwide claims database (12). In a previous study, participants taking off-label reduced dose apixaban, despite not fulfilling the dose reduction criteria, exhibited a twice as high risk of ischaemic stroke compared to those receiving the on-label standard dose of apixaban.” (12). However, among patients who met the single criterion for dose reduction, there was no significant difference in the risk of ischaemic stroke between off-label reduced dose and on-label standard-dose apixaban (12).

Although a previous retrospective cohort study based on the Korean nationwide claims database suggested that the clinical impact of off-label reduced dose apixaban on the risk of ischaemic stroke could be negligible in patients with a single criterion for dose reduction, we aimed to evaluate the difference between the on-label standard-dose and off-label reduced dose apixaban among participants who met single dose reduction criteria in a prospectively collected cohort, the ASPIRE study. In the current study, even though the patients only met a single criterion for dose reduction, over 50% of the study population received off-label reduced dose apixaban. One concern regarding off-label reduced dose of apixaban is whether it increases the risk of stroke.

Prior landmark clinical trials have mostly included Caucasian participants with different anthropometric measurements from the Asian population (e.g., heavier mean body weight) (13, 25–28). Thus, concerns remain regarding whether off-label reduced dose in participants who fulfil only a single criterion for dose reduction would result in benefits or harm. A post hoc study using the ENGAGE AF-TIMI 48 trial data showed that a lower-dose edoxaban regimen (LDER) was associated with significantly better net clinical outcomes than the higher-dose edoxaban regimen (HDER) due to less frequent major bleeding events in the Western population (29). Although the previously published ENGAGE AF-TIMI 48 trial showed a 41% increased risk of ischaemic stroke in patients with LDER (25), a recent analysis supports that reduced dose may be a feasible alternative option for patients at high bleeding risk. Similarly, the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial showed that low-dose edoxaban 15 mg in older adults with bleeding risk factors was beneficial for stroke prevention compared to placebo, with no significant increase in major bleeding in the Japanese population (30).

Pharmacokinetic and pharmacodynamic studies of rivaroxaban in Asian populations indicate higher apparent clearance in Caucasians than in Asians, suggesting that a lower dose might offer comparable thromboembolic event protection in Asians as the standard dose does in Caucasians (31). In a small study that monitored the plasma concentrations of rivaroxaban and apixaban in Asian participants, off-label reduced dose showed an appropriate plasma concentration with no bleeding or thromboembolic events (32). These studies underscore the potential need for dose adjustments based on ethnicity and patient-specific factors.

In previous studies, factors such as age, renal dysfunction, past medical history (prior bleeding, hypertension, and congestive heart failure), anaemia, and concomitant APT were found to affect the physicians' prescription of a reduced dose of DOACs (33–35). In our study, the off-label reduced dose group had more comorbidities, such as hypertension, heart failure, and a history of bleeding, suggesting that physicians might be prescribing reduced doses to mitigate bleeding risks. This practice reflects the delicate balance clinicians must maintain between preventing thromboembolic events and minimizing bleeding risks in frail populations. The three dose reduction criteria for apixaban were not completely exclusive in this study. Although the participants only fully satisfied the single criterion for dose reduction and no other criteria, they were likely to have marginal zone values for the other two dose reduction criteria. Again, such accompanying “marginal zone” factors would have influenced clinicians in prescribing off-label reduced dose apixaban rather than using the on-label standard-dose apixaban. We also assessed additional factors other than the dose reduction criteria that affected the physician in prescribing off-label reduced dose apixaban. In participants aged ≥80 years, female sex significantly affected the physician in choosing a lower dose. In those with a body weight of ≤60 kg, concomitant APT was significantly associated with reduced dose. These factors overlapped with previously reported factors associated with off-label reduced dose (33–35). Therefore, physicians are likely to adopt a lower dose of apixaban for patients with a marginal value of additional dose reduction criteria or other factors that represent frailty.

The apixaban prescription data shown in this study depict the biggest concern that Korean clinicians face in real-life clinical settings, that is, low body weight. This concern arises from the finding that underweight Korean patients with AF receiving OAC have a higher risk of experiencing various clinical events, such as stroke, intracranial haemorrhage, gastrointestinal bleeding, major bleeding, and all-cause death than those with normal body weight (36). Owing to concerns about low body weight, the safety and effectiveness of DOACs have been addressed in low (body weight of ≤60 kg) and very low (body weight <50 kg) body weight patients, resulting in DOACs being a safer and more effective option than warfarin (28). Furthermore, the ENGAGE AF-TIMI 48 trial showed that patients with body weight ≤60 kg may benefit from a lower dose of edoxaban in relation to bleeding events (37). However, the outcome of apixaban off-label reduced dose in patients with only one dose-reduction criterion has not been addressed. Further analysis of the clinical outcomes of these apixaban off-label reduced dose groups will provide an overall insight into the feasibility of an off-label reduced dose of apixaban in the Korean population.

Although this study was not an RCT, it included data from 2,000 Asians with a single frail component and an off-label reduced prescription. As a previous pivotal RCT showed prescription data of reduced dose apixaban among less than 500 participants, our study has strength in a larger real-world study population (13).

In practical clinical settings within the Korean population, nearly 50% of patients who met a single criterion for dose reduction of apixaban received an off-label reduced dose of the drug. Korean physicians tended to prescribe this off-label reduced dose to patients exhibiting more signs of frailty, while those with a history of stroke were more likely to receive the on-label standard dose. Further analysis of the clinical outcomes in these apixaban off-label reduced dose groups will provide deeper insights into the feasibility and safety of such practices, especially in the Korean population.