A multicenter prospective cohort study to investigate the effectiveness and safety of apixaban in Japanese elderly atrial fibrillation patients (J‐ELD AF Registry)

Abstract Background A global, randomized clinical trial indicated the efficacy and safety of apixaban in stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). However, data in the elderly NVAF patients ≥75 years, especially those on reduced dose, are limited. Hypothesis To confirm the current dose reduction criteria of apixaban in elderly NVAF patients. Method With a large‐scale, multicenter prospective observational study, one‐year outcomes after administration of on‐label doses of apixaban were analyzed in Japanese NVAF patients aged ≥75 years. Endpoints were stroke or systemic embolism, bleeding requiring hospitalization, total death, and cardiovascular death. Results A total of 3031 patients (average age, 81.7 years; female, 48.2%) taking standard (5 mg bid) or reduced dose (2.5 mg bid) of apixaban were enrolled from 110 facilities. Standard and reduced apixaban doses were administered in 1284 (42.4%) and 1747 (57.6%) patients, respectively. Event rates (/100 person‐years) in standard and reduced dose groups were 1.67 and 1.56, respectively, for stroke or systemic embolism, 1.42 and 2.25 for bleeding requiring hospitalization, 1.41 and 4.46 for total death, and 0.41 and 1.36 for cardiovascular death. Reduced apixaban dose was not significantly associated with stroke or systemic embolism and bleeding requiring hospitalization, but was independently associated with total and cardiovascular death. Conclusions Incidences of stroke or systemic embolism and bleeding requiring hospitalization were similar between standard and reduced apixaban doses in the elderly NVAF patients. The incidences of total and cardiovascular death were significantly higher in the reduced dose group due to the coexisting higher risks in this group.


| INTRODUCTION
Atrial fibrillation (AF) is one of the major causes of stroke, 1 and older age is associated with both higher prevalence of AF 2 and increased incidence of stroke. 3 Many of the Japanese AF patients are of advanced age (≥75 years) 2,4,5 and thus at high risk of stroke and systemic embolism. 3 The same situation is predicted in the world wide in the near future. 6,7 While warfarin, a vitamin K antagonist, has mainly been used as an oral therapeutic agent in AF for stroke prevention for more than 50 years, its application in elderly patients is not common because of its instability of effect and high incidence rate of serious bleeding. 8,9 Several direct oral anticoagulants (DOACs) have been developed as alternatives to warfarin 10 and are currently available worldwide.
Apixaban, a direct factor Xa inhibitor, was shown by a worldwide large-scale randomized clinical trial (ARISTOTLE study) to be effective and safe in stroke prevention for nonvalvular AF patients in comparison with warfarin. 11 In Asian countries including Japan, AF patients with advanced age often have low body weight and renal dysfunction, being associated with a high risk of bleeding. Thus, many of the elderly AF patients meet the dose reduction criteria configured in each DOAC, although Beers criteria issue a warning on the use of DOACs in these patients. 12 A recent meta-analysis of the Asian patients with DOACs in the RE-LY and ENGAGE AF-TIMI 48 trials revealed that a risk of stroke or systemic embolism was significantly reduced with standard dose compared with low dose while the rates of major bleeding were similar between the two dosing regimens. 13 It should be pointed out that in the global ARISTOTLE study, although the benefits of apixaban were consistently observed in patients aged ≥75 years, 14 a reduced dose (2.5 mg bid) or placebo (ie, warfarin) was administered only to 790 patients (13.9%) among them. Further, in the subanalysis of patients from East Asia (n = 1993), 15 only 255 patients aged ≥75 years were assigned to apixaban. Thus, evidence of apixaban in the elderly AF patients, especially those on reduced dose, is quite limited. On the other hand, DOAC doses prescribed are often inconsistent with each labeling in real-world clinical practice, and the off-label reduced dose of apixaban was shown to be associated with a higher risk of stroke than and no significant difference in major bleeding from the on-label standard dose. 16 To elucidate the unmet clinical issue on on-label doses of apixaban especially on-label reduced dose in the elderly AF patients, we conducted J-ELD AF Registry, a large-scale multicenter prospective observational study on the effectiveness and safety of on-label doses of apixaban in the Japanese nonvalvular AF patients aged ≥75 years.

| Study population
The research physician registered patients who satisfied the selection criteria and did not meet any of the exclusion criteria. The selection criteria were AF patients aged ≥75 years without mitral valve stenosis or prosthetic valve who visited the participating facilities after the start of this study and were taking or started taking apixaban. Exclusion criteria were AF patients with (a) a history of hypersensitivity to apixaban, (b) active bleeding symptoms, (c) liver disease with coagulopathy, (d) creatinine clearance <15 mL/min, and (e) a reduced dose administered although two or more of the dose reduction criteria were not present, which were diagnosed or judged by each investigator. Apixaban was administered according to the package inserts with the reduced dose (2.5 mg bid) when they fulfilled two or more of the following three criteria: ≥80 years of age, body weight <60 kg, and serum creatinine ≥1.5 mg/dL. Otherwise, the patients received the standard dose (5 mg bid). The registration period was from September 2015 to August 2016, and the observation period of each patient was 1 year.
The paucity of previous data on Japanese elderly AF patients taking apixaban made it difficult to set a rational sample size. As this was not a comparative study with warfarin but an exploratory study, to clarify the effectiveness and safety of apixaban in elderly AF patients, the sample size was set to 3000 patients considering the feasibility of the analysis.

| Ethics and informed consent
The study design of J-ELD AF Registry 17 was published previously (UMIN Clinical Trials Registry: UMIN000017895). The study protocol was approved by the ethics committee of each research facility where the study was conducted. Prior to the registration of patients, the research physician explained the study to the patient using explanatory and agreement documents, and obtained written consent. If the patient withdrew consent during the participation period (observation period) of this study, the study for the patient was discontinued and all existing data collected from the patient were discarded.

| Data acquisition
In this study, observation and examination items prescribed in the clinical study implementation plan were collected using an Electronic  18 Creatinine clearance was estimated using the Cockcroft-Gault formulae. 19 The events were (a) diagnosed stroke with head computed tomography or magnetic resonance imaging with clinical symptoms,

| DISCUSSION
In this study, on-label doses of apixaban were administered to the Japanese elderly AF patients aged ≥75 years, and one-year outcomes were prospectively analyzed for standard and reduced dose groups.
We found that the incidences of stroke or systemic embolism and bleeding requiring hospitalization after apixaban were both low and similar between the two dose groups. The predictors for stroke or systemic embolism were histories of cerebral infarction/TIAs and bleeding requiring hospitalization, while those for major bleeding were history of bleeding requiring hospitalization, reduced renal dysfunction (eGFR <45 mL/min/m 2 ) and coadministration of antiplatelet drug. Importantly, a reduced dose (2.5 mg bid) was not associated with increased risk of either stroke or major bleeding, but was with increased mortality due to higher age and more comorbidities in this group.

| Incidences of outcomes in elderly patients under on-label doses of apixaban
In this J-ELD AF Registry, we prospectively enrolled and analyzed 3031 patients with an average age of 81.7 years, and included more elderly AF patients than in previous studies. 8

| Comparison of outcomes in on-label standard and reduced doses of apixaban
The patients in the reduced dose group in this study were older, included more females, and had lower body weight and lower estimated creatinine clearance in comparison to the standard dose group.
Further, significantly higher rates of previous histories of heart failure and cerebral infarction or TIAs were noted in the reduced dose group.
Thus, the reduced dose group in the present study was considered to consist of patients with higher risks of stroke compared with previous studies. 8,11,[20][21][22][23] Meanwhile, the HAS-BLED score was slightly but significantly lower in the reduced dose group than in the standard dose group.
Despite their estimated higher risk in the reduced dose group, no significant differences in the primary event rates were observed between standard and reduced dose groups.

| CLINICAL IMPLICATIONS
The Asian elderly AF patients often have low body weight and low renal function compared with the Western patients, 15 and therefore, many of them receive a reduced-dose apixaban. This study revealed the effectiveness and safety of the on-label reduced dose apixaban in >1700 elderly AF patients, supporting the conclusions shown in the ARISTOTLE subanalysis for the elderly patients. 14 Since underdosing of apixaban is associated with a higher stroke risk but a similar major bleeding risk, 16 it would be important to follow the labeling in the elderly AF patients.

| LIMITATIONS
There were several limitations in the present study. First, this J-ELD AF Registry was a prospective, single-arm, observational study, and therefore, there was no control arm with which the effect of apixaban was compared. Second, there may have been selection bias for patients. Research physicians might not have enrolled patients at a very high risk who were not suitable for longterm on-label doses of apixaban. Third, this study consisted of patients with relatively well-managed AF since they could be fully followed up by medical institution with cardiovascular specialists on staff. Thus, the patients' health conditions and medical environments may have affected the event incidence rates. Fourth, the observation period was limited to 1 year, and therefore, the results could not be extrapolated to a long-term clinical course of more than 1 year. Fifth, the outcome events were reported by each participating center, and central adjudication was not performed.
However, by simplifying the definition of the stroke and bleeding events, we believe the variation in the local diagnosis between participating centers was modest. Sixth, the status of adherence, discontinuation, or change to other anticoagulants, which would affect the patient outcomes, was not recorded in the present study.
Lastly, this study does not include patients taking off-label underdose, which is common in real-world clinical practice. The benefit of underdose DOAC is an important matter of debate, but this was not the scope of the present study.

| CONCLUSIONS
We examined the clinical course of the Japanese nonvalvular AF patients with advanced age in whom on-label doses of apixaban were administered. The incidences of stroke or systemic embolism and bleeding requiring hospitalization were relatively low and were similar between the standard and reduced dose groups. The incidences of total death and cardiovascular death were both significantly higher in the reduced dose group due to the coexisting higher risks in this group.