Comparative Safety and Effectiveness of Apixaban vs. Warfarin in Oral Anticoagulant-Naïve Japanese Patients With Non-Valvular Atrial Fibrillation　― A Retrospective Chart Review Study ―

Abstract

Background: The risk of bleeding and stroke/systemic embolism (SE) events associated with apixaban vs. warfarin among oral anticoagulant-naïve Japanese patients with non-valvular atrial fibrillation (NVAF) has not been well studied in daily clinical practice.

Methods and Results: Clinical data for 12,090 patients were retrospectively extracted from the medical records of patients with NVAF (aged ≥20 years, creatinine clearance [CrCl] ≥15 mL/min) newly initiated to apixaban or warfarin treatment between January 1, 2010, and December 31, 2017, at 315 general practitioner clinics and 87 hospitals across Japan. After applying propensity score matching, patient characteristics were well-balanced between the apixaban and warfarin groups (4,523 patients each). The incidence rate (per 100 person-years) of major bleeding was lower in the apixaban vs. warfarin group (1.17 vs. 1.64; hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.54–0.93; P=0.01), as was that of stroke/SE (1.14 vs. 1.73; HR, 0.65; 95% CI, 0.50–0.85; P<0.01). When patients were stratified by CrCl (≥50 mL/min and <50 mL/min), the P value for interaction was not statistically significant between subgroups (P=0.31 for major bleeding and P=0.32 for stroke/SE).

Conclusions: The benefit of apixaban over warfarin for the reduction in risk of major bleeding and stroke/SE could be generalizable to daily clinical practice and to patients with reduced renal function.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with a 5-fold increased risk of stroke.¹ AF affects 0.5% of the population worldwide and has shown an increasing incidence and prevalence over the last 20 years.² In East-Asian countries such as Japan, China, and South Korea, the community-based AF prevalence is reported to be 0.6–2.2%, 0.37–3.75%, and 1.3%, respectively.³

Direct oral anticoagulants (DOACs), such as apixaban,⁴ dabigatran,⁵ rivaroxaban,⁶ and edoxaban,⁷ have demonstrated comparable or superior efficacy and safety vs. warfarin in large-scale randomized clinical trials (RCTs) involving patients with non-valvular AF (NVAF). However, RCT findings may not accurately represent daily clinical practice because of potential limitations resulting from strict patient eligibility criteria,^8,9 thereby warranting real-world studies to extend the information obtained from RCTs to daily clinical settings.⁹ To establish real-world evidence regarding the safety and effectiveness of DOACs in oral anticoagulant (OAC)-naïve patients with NVAF, several retrospective cohort studies were conducted using nationwide administrative claims databases and have shown results to be consistent with those obtained from RCTs.^10–16

Apixaban is one of the most commonly prescribed DOACs in Japan for the treatment of patients with NVAF,^14,16,17 particularly in elderly patients with NVAF and moderate renal impairment.¹⁸ A statistically significant risk reduction in both major bleeding and stroke/systemic embolism (SE) associated with apixaban vs. warfarin was demonstrated in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial,⁴ and in analyses of the Diagnosis Procedure Combination (DPC) claims database that included nationwide administrative claims data from acute care hospitals in Japan.^14–16 Although decreased renal function is one of the causes of increased bleeding risk in patients with NVAF,¹⁹ there is insufficient large-scale evidence regarding the safety and effectiveness of DOACs compared with warfarin in patients with reduced renal function in Japan. Apixaban, whose renal excretion rate is the lowest among the DOACs currently available in Japan,²⁰ is considered to have a lesser effect on blood concentrations in patients with decreased renal function than other DOACs, and is expected to be beneficial in this patient population. From the viewpoint of a more realistic drug comparison; however, previously published claim database studies have a limitation in that the data on body weight and renal function of patients are not sufficiently captured.^14–16 Therefore, real-world evidence on the safety and effectiveness of apixaban in Japanese patients with NVAF that takes into consideration the factors associated with increased bleeding risks, including decreased renal function, is warranted.

Thus, we conducted this retrospective cohort study to compare the risk of incidence of bleeding and stroke/SE events in patients with NVAF newly prescribed apixaban vs. those newly prescribed warfarin (ClinicalTrials.gov identifier: NCT03765242).

Methods

Study Design

We conducted a retrospective cohort study using medical records extracted from 402 Japanese institutions, comprising 315 general practitioner clinics and 87 hospitals (Supplementary Appendix). The medical records of patients with NVAF newly initiated on apixaban or warfarin treatment were extracted using electronic case report forms of consecutive patients meeting the eligibility criteria. The index date was defined as the date of the first prescription for apixaban or warfarin between January 1, 2010, and December 31, 2017. Patients were followed up from the day after the index date until any of the following events, whichever occurred first, with a maximum follow-up period of 3 years: (1) discontinuation of the index OAC (the index OAC was not prescribed within 45 days after its prescription refill date, although the patient had medical encounter records); (2) switch to another OAC (a non-index OAC was prescribed within 45 days after the prescription refill date of the index OAC); (3) withdrawal from the study (the index OAC was not prescribed within 45 days after its prescription refill date and there were no data on the patient in the medical record after the prescription refill date); (4) death; or (5) end of the study period (September 30, 2019).

This study was conducted in accordance with the International Society for Pharmacoepidemiology Guidelines for Good Pharmacoepidemiology Practices, the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects, and the principles of the Declaration of Helsinki. The study was reviewed and approved by the ethics committee or the independent review committee of each participating site. Informed consent from patients was not applicable to this study, and an opt-out approach was adopted where public disclosure of the study content to the patients gave them an opportunity to request exclusion from the study.²¹

Patient Selection

Patients were included based on the following inclusion criteria: (1) age ≥20 years as of the index date; (2) diagnosis of NVAF prior to or on the index date; and (3) apixaban or warfarin newly prescribed between January 1, 2010, and December 31, 2017. Patients were excluded if they were pregnant; were taking warfarin, apixaban, dabigatran, rivaroxaban, or edoxaban during the 6 months prior to the index date; had ≥2 OAC prescriptions on the index date; had major bleeding, stroke/SE, or transient ischemic attack events 7 days prior to the index date; or had missing serum creatinine, creatinine clearance (CrCl), estimated glomerular filtration rate, and body weight data. Patients undergoing dialysis or with a CrCl <15 mL/min during the 6 months prior to the index date were also excluded.

Outcomes and Definitions

The primary outcome was major bleeding events defined based on the criteria established by the International Society on Thrombosis and Haemostasis²² (fatal hemorrhage, symptomatic intracranial hemorrhage, reduction of ≥2 g/dL in hemoglobin level from the previous level, transfusion of ≥2 units of whole blood or red blood cells, or other significant hemorrhages [intraspinal, retroperitoneal, intra-articular, pericardial, or intraocular hemorrhage or intramuscular hemorrhage accompanied by compartment syndrome]). The key secondary outcome was stroke/SE events (a composite endpoint, where stroke was defined as ischemic, hemorrhagic, or unknown). In addition, any bleeding events, which were identified as bleeding observed during the follow-up period, were assessed as a secondary outcome.

Statistical Analyses

The framework of this study was a comparison between the apixaban and warfarin groups, which were matched using propensity scores. Based on the incidence rate of major bleeding reported in a Japanese postmarketing surveillance of apixaban use in patients with NVAF (2.36% per year)²³ and the risk reduction in major bleeding reported in the ARISTOTLE trial (apixaban vs. warfarin, hazard ratio [HR], 0.69),⁴ 4,287 patients were required per group after propensity score matching (PSM) to detect the difference in major bleeding events between the groups using a Cox proportional hazards analysis with an α value of 0.05, power of 80%, and mean observational period of 52 weeks. In view of the matching rate observed in a previous claims database study (apixaban group, 74%; warfarin group, 80%),¹⁵ the number of patients required before PSM was set at 5,716 per group. The final sample size of 12,000 patients was determined considering the reduction in patient numbers because of operational reasons.

PSM was applied to the total cohort, and patients in each group were matched 1:1 based on propensity scores calculated using a logistic regression model. The covariates are listed in Supplementary Table 1. Covariate balance between the matched apixaban and warfarin groups was assessed using a standardized mean difference (SMD) with a threshold of 0.1.

Continuous variables are expressed as mean±standard deviation (SD) or median (interquartile range) and were compared using a t-test or Wilcoxon rank-sum test. Categorical variables are expressed as the number and percentage of patients and were compared using a Chi-squared test.

The incidence rate of major bleeding and stroke/SE in each group was estimated using the person-years method and compared between groups using the Cox proportional hazards model by calculating the HR and 95% confidence interval (CI). The cumulative incidence of major bleeding and stroke/SE was estimated by using Kaplan-Meier curves and compared between groups using the log-rank test. We also estimated the incidence rate per 100 person-years. Patients were stratified into subgroups by baseline CrCl (<50 mL/min and ≥50 mL/min) to further assess the risk of major bleeding and stroke/SE in the apixaban vs. warfarin groups using the same Cox proportional hazards model. The P value for interaction between groups and by baseline CrCl (<50 mL/min and ≥50 mL/min) was calculated using the Cox proportional hazards model in the total PSM cohort. All statistical tests were performed at a significance level of 5% (2 sided) and no imputation was performed for missing data. All analyses were performed using Statistical Analysis System (SAS) software version 9.2 (SAS Institute, Cary, NC, USA).

Post Hoc Analyses

In this study, type of AF was not included in the factors prespecified for propensity score calculation. As an association between paroxysmal AF and a lower risk of stroke/SE vs. sustained AF has been suggested in Japanese patients,²⁴ type of AF was added as an additional variable in the Cox proportional hazards model to confirm whether it affected the effectiveness and safety of apixaban vs. warfarin.

In view of the possibility of intersite bias in the results of the primary and secondary outcomes, a Cox proportional hazards regression model was constructed, with cohort as the fixed-effect factor and site as the random-effect factor, to assess the effect of variability among centers in assessing the incidence of bleeding and stroke.

Results

Patient Characteristics

A total of 12,354 patients were screened, of whom 264 were excluded (260 for not meeting the eligibility criteria and 4 for other reasons). Among the 12,090 patients enrolled, 5,853 (48.4%) were treated at general practitioner clinics. After excluding 18 patients whose index date and study completion date were unknown, 12,072 patients (7,074 for apixaban and 4,998 for warfarin) were eligible for inclusion in the analysis (Figure 1).

Figure 1.

Patient disposition. ^aPatients whose index date and study completion date were unknown. EDC, electronic data capture; GP, general practitioner; HP, hospital; PSM, propensity score matching.

Patient age was significantly higher in the apixaban vs. warfarin group (mean±SD, 73.5±10.9 years vs. 72.4±11.2 years, P<0.01; age ≥75 years, 50.9% vs. 47.0%), as was the proportion of female patients (41.9% vs. 38.7%, P<0.01). There was no significant difference in body weight (60.7±13.4 kg vs. 60.9±13.4 kg, P=0.41) or CrCl (65.7±28.1 mL/min vs. 65.8±29.5 mL/min, P=0.84) between the apixaban and warfarin groups, respectively. The risk of stroke or bleeding was similar between the apixaban and warfarin groups, as illustrated by the CHADS₂ (median [interquartile range], 2.0 [1.0–3.0] vs. 2.0 [1.0–3.0]; P=0.54), CHA₂DS₂-VASc (3.0 [2.0–4.0] vs. 3.0 [2.0–4.0]; P=0.14), and HAS-BLED (2.0 [1.0–3.0] vs. 2.0 [1.0–3.0]; P=0.72) scores (Table 1). The index apixaban dose was 5 mg twice daily (b.i.d.) and 2.5 mg b.i.d. in 53.0% and 45.4% of overall patients, respectively (Table 1). Non-recommended 5 mg b.i.d. and 2.5 mg b.i.d. doses were prescribed to 2.0% and 22.3% of patients, respectively. The mean±SD prothrombin time–international normalized ratio (PT-INR) that could be collected at week 4 and week 24 was 1.76±0.78 (n=3,190) and 1.82±0.52 (n=2,782), respectively.

Table 1. Patient Characteristics

Variable	Before matching			After matching
	Apixaban (n=7,074)	Warfarin (n=4,998)	P value*	Apixaban (n=4,523)	Warfarin (n=4,523)	SMD
Female sex	2,961 (41.9)	1,936 (38.7)	<0.01	1,813 (40.1)	1,766 (39.0)	0.021
Age (years)	73.5±10.9	72.4±11.2	<0.01	73.0±11.2	72.5±11.2	0.042
75 to <85	2,544 (36.0)	1,678 (33.6)		1,558 (34.4)	1,511 (33.4)
≥85	1,053 (14.9)	669 (13.4)		662 (14.6)	625 (13.8)
Body weight (kg)	60.7±13.4	60.9±13.4	0.41	60.7±13.3	60.8±13.4	0.008
≤40.0	308 (4.4)	221 (4.4)		195 (4.3)	201 (4.4)
>40.0–50.0	1,283 (18.1)	898 (18.0)		819 (18.1)	819 (18.1)
>50.0–60.0	2,017 (28.5)	1,382 (27.7)		1,271 (28.1)	1,259 (27.8)
Body mass index (kg/m2)	23.9±4.1a	23.9±4.1b	0.62	23.8±4.0c	23.9±4.1d	0.031
Systolic blood pressure (mmHg)	130.2±20.4e	129.1±19.8f	<0.01	130.3±20.7g	129.2±20.0h	0.056
Diastolic blood pressure (mmHg)	76.7±15.0i	76.2±14.3j	0.09	76.8±15.4k	76.4±14.5l	0.029
CrCl (mL/min)	65.7±28.1	65.8±29.5	0.84	65.5±27.9	65.7±29.6	0.006
15 to <30	415 (5.9)	411 (8.2)		280 (6.2)	371 (8.2)
30 to <50	1,757 (24.8)	1,177 (23.5)		1,121 (24.8)	1,064 (23.5)
Paroxysmal AF	3,049 (43.1)	1,847 (37.0)	<0.01	1,944 (43.0)	1,679 (37.1)	0.120
CHADS2 score	2.0 [1.0–3.0]	2.0 [1.0–3.0]	0.54	2.0 [1.0–3.0]	2.0 [1.0–3.0]	0.003
CHA2DS2-VASc score	3.0 [2.0–4.0]	3.0 [2.0–4.0]	0.14	3.0 [2.0–4.0]	3.0 [2.0–4.0]	0.012
HAS-BLED score	2.0 [1.0–3.0]	2.0 [1.0–3.0]	0.72	2.0 [1.0–3.0]	2.0 [1.0–3.0]	0.004
Comorbidities
Congestive heart failure	1,822 (25.8)	1,453 (29.1)	<0.01	1,253 (27.7)	1,312 (29.0)	0.029
Hypertension	5,412 (76.5)	3,838 (76.8)	0.65	3,482 (77.0)	3,482 (77.0)	0.000
Diabetes	1,508 (21.3)	1,099 (22.0)	0.36	951 (21.0)	983 (21.7)	0.017
Dyslipidemia	2,260 (31.9)	1,471 (29.4)	<0.01	1,382 (30.6)	1,317 (29.1)	0.031
Coronary artery disease	1,037 (14.7)	846 (16.9)	<0.01	748 (16.5)	756 (16.7)	0.005
Peripheral vascular disease†	273 (3.9)	246 (4.9)	<0.01	177 (3.9)	224 (5.0)	0.051
Medical history
Stroke/TIA	831 (11.7)	572 (11.4)	0.68	526 (11.6)	512 (11.3)	0.010
Bleeding‡	97 (1.4)	76 (1.5)	0.48	64 (1.4)	70 (1.5)	0.011
Concomitant medication
Antiplatelet drugs	1,699 (24.0)	1,353 (27.1)	<0.01	1,163 (25.7)	1,225 (27.1)	0.031
ACE inhibitor and ARB	2,973 (42.0)	2,229 (44.6)	<0.01	2,012 (44.5)	2,024 (44.7)	0.005
β-blocker	1,323 (18.7)	885 (17.7)	0.16	859 (19.0)	810 (17.9)	0.028
Amiodarone	105 (1.5)	81 (1.6)	0.55	68 (1.5)	71 (1.6)	0.005
PPI and H2 receptor antagonist	2,140 (30.3)	1,249 (25.0)	<0.01	1,282 (28.3)	1,158 (25.6)	0.062
NSAIDs	338 (4.8)	208 (4.2)	0.11	213 (4.7)	196 (4.3)	0.018
Index dose of apixaban
5 mg b.i.d.	3,751 (53.0)	NA		2,408 (53.2)	NA
2.5 mg b.i.d.	3,214 (45.4)	NA		2,040 (45.1)	NA
Other	109 (1.5)	NA		75 (1.7)	NA

Data are presented as mean±SD, n (%), or median [IQR]. *Student’s t-test for continuous variables, Chi-squared test for categorical variables, and Wilcoxon rank-sum test for CHADS₂, CHA₂DS₂-VASc, and HAS-BLED scores. ^†Includes peripheral artery disease and other peripheral vascular disease. ^‡Intracranial hemorrhage, gastrointestinal bleeding, and other types of bleeding. ^an=5,771. ^bn=4,122. ^cn=3,748. ^dn=3,813. ^en=6,832. ^fn=4,869. ^gn=4,455. ^hn=4,480. ⁱn=6,831. ^jn=4,866. ^kn=4,454. ^ln=4,477. ACE, angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; b.i.d., twice daily; CrCl, creatinine clearance; IQR, interquartile range; NA, not applicable; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor; SD, standard deviation; SMD, standardized mean difference; TIA, transient ischemic attack.

After PSM, the apixaban and warfarin groups included 4,523 patients each (Figure 1). The median (95% CI) follow-up period for the apixaban and warfarin groups after matching was 717 (699–737) and 735 (701–782) days, respectively. SMDs in patient characteristics between the matched groups were within a threshold of 0.1 in the baseline variables used for the calculation of propensity scores (Supplementary Table 1). However, after PSM, the SMD was >0.1 for paroxysmal AF, and the proportion of patients with paroxysmal AF was higher in the apixaban (43.0%) vs. warfarin (37.1%) group (Table 1), which prompted a post hoc analysis that included the type of AF in the Cox proportional hazards model.

Clinical Outcomes of Apixaban vs. Warfarin in PSM

The incidence rate (per 100 person-years) of major bleeding was lower in the apixaban vs. warfarin group (1.17 vs. 1.64; HR [95% CI], 0.71 [0.54–0.93]; P=0.01), as was that of stroke/SE (1.14 vs. 1.73; HR [95% CI], 0.65 [0.50–0.85]; P<0.01; Table 2). The incidence rate (per 100 person-years) of any bleeding was higher in the apixaban vs. warfarin group (11.73 vs. 9.51; HR [95% CI], 1.21 [1.10–1.34]; P<0.01). The cumulative incidence of major bleeding (3.05% vs. 4.42%, P=0.01) and stroke/SE (3.05% vs. 4.52%, P<0.01) was lower in the apixaban vs. warfarin group (Figure 2A,B).

Table 2. Incidence Rates of Major Bleeding and Stroke/SE (After Matching)

Event	Apixaban (n=4,523)			Warfarin (n=4,523)			Cox proportional hazards regression
	Number of events	Person- years	Incidence rate* (95% CI)	Number of events	Person- years	Incidence rate* (95% CI)	HR (95% CI)	P value
Major bleeding	91	7,755	1.17 (0.95–1.44)	132	8,037	1.64 (1.37–1.95)	0.71 (0.54–0.93)	0.01
Stroke/SE	88	7,745	1.14 (0.91–1.40)	138	8,002	1.73 (1.45–2.04)	0.65 (0.50–0.85)	<0.01

*Per 100 person-years. CI, confidence interval; HR, hazard ratio; SE, systemic embolism.

Figure 2.

Cumulative incidence of (A) major bleeding and (B) stroke/SE (after matching). The incidence rates are the data derived at month 36. SE, systemic embolism.

Clinical Outcomes of Apixaban vs. Warfarin Stratified by CrCl

When patients were stratified by baseline CrCl, 1,394 and 3,074 patients were categorized into the CrCl <50 mL/min and ≥50 mL/min subgroups, respectively (Table 3). In patients with a baseline CrCl of <50 mL/min, the incidence rate (per 100 person-years) of major bleeding was lower in the apixaban vs. warfarin group (1.84 vs. 3.10; HR [95% CI], 0.59 [0.41–0.87]; P<0.01), as was that of stroke/SE (1.62 vs. 2.71; HR [95% CI], 0.60 [0.40–0.90]; P=0.01; Table 4). Although the incidence rate of major bleeding or stroke/SE was not different between the apixaban and warfarin groups in patients with CrCl ≥50 mL/min (Table 4), the P value for interaction was not statistically significant between the CrCl subgroups (P=0.31 for major bleeding and P=0.32 for stroke/SE), indicating that the effects of apixaban on major bleeding and stroke/SE were consistent between patients with CrCl <50 mL/min and ≥50 mL/min (Figure 3).

Table 3. Patient Characteristics Stratified by CrCl (After Matching)

Variable	CrCl <50 mL/min			CrCl ≥50 mL/min
	Apixaban (n=1,394)	Warfarin (n=1,394)	SMD	Apixaban (n=3,074)	Warfarin (n=3,074)	SMD
Female sex	772 (55.4)	744 (53.4)	0.040	1,040 (33.8)	1,008 (32.8)	0.022
Age (years)	81.8±7.0	81.5±7.1	0.046	69.1±10.6	68.4±10.3	0.065
75 to <85	666 (47.8)	688 (49.4)		869 (28.3)	807 (26.3)
≥85	525 (37.7)	494 (35.4)		150 (4.9)	115 (3.7)
Body weight (kg)	51.7±10.3	52.2±10.6	0.043	64.7±12.6	64.8±12.7	0.007
≤40.0	179 (12.8)	161 (11.5)		26 (0.8)	37 (1.2)
>40.0–50.0	476 (34.1)	491 (35.2)		327 (10.6)	316 (10.3)
>50.0–60.0	455 (32.6)	460 (33.0)		821 (26.7)	783 (25.5)
Body mass index (kg/m2)	21.9±3.6a	22.1±3.6b	0.063	24.5±3.9c	24.7±4.1d	0.037
Systolic blood pressure (mmHg)	127.7±22.3e	126.6±20.2f	0.051	131.0±19.7g	130.4±19.7h	0.032
Diastolic blood pressure (mmHg)	72.9±15.3i	72.4±14.4j	0.030	78.4±14.6k	78.2±14.1l	0.015
CrCl (mL/min)	36.9±8.8	36.2±9.0	0.081	78.8±25.3	79.6±25.3	0.029
15 to <30	298 (21.4)	345 (24.7)		0 (0.0)	0 (0.0)
30 to <50	1,096 (78.6)	1,049 (75.3)		0 (0.0)	0 (0.0)
Paroxysmal AF	614 (44.0)	507 (36.4)	0.157	1,364 (44.4)	1,159 (37.7)	0.136
CHADS2 score	2.0 [2.0–3.0]	2.0 [2.0–3.0]	0.019	2.0 [1.0–2.0]	2.0 [1.0–2.0]	0.006
CHA2DS2-VASc score	4.0 [3.0–5.0]	4.0 [3.0–5.0]	0.040	3.0 [2.0–4.0]	3.0 [2.0–4.0]	0.020
HAS-BLED score	3.0 [2.0–3.0]	3.0 [2.0–3.0]	0.016	2.0 [1.0–2.0]	2.0 [1.0–3.0]	0.019
Comorbidities
Congestive heart failure	537 (38.5)	540 (38.7)	0.004	711 (23.1)	740 (24.1)	0.022
Hypertension	1,161 (83.3)	1,153 (82.7)	0.015	2,268 (73.8)	2,282 (74.2)	0.010
Diabetes	300 (21.5)	303 (21.7)	0.005	642 (20.9)	666 (21.7)	0.019
Dyslipidemia	425 (30.5)	400 (28.7)	0.039	961 (31.3)	909 (29.6)	0.037
Coronary artery disease	266 (19.1)	263 (18.9)	0.005	440 (14.3)	485 (15.8)	0.041
Peripheral vascular disease*	74 (5.3)	63 (4.5)	0.037	96 (3.1)	159 (5.2)	0.103
Medical history
Stroke/TIA	254 (18.2)	240 (17.2)	0.026	281 (9.1)	261 (8.5)	0.023
Bleeding†	21 (1.5)	23 (1.6)	0.012	38 (1.2)	37 (1.2)	0.003
Concomitant medication
Antiplatelet drugs	477 (34.2)	488 (35.0)	0.017	637 (20.7)	712 (23.2)	0.059
ACE inhibitor and ARB	677 (48.6)	703 (50.4)	0.037	1,250 (40.7)	1,293 (42.1)	0.028
β-blocker	295 (21.2)	286 (20.5)	0.016	536 (17.4)	518 (16.9)	0.016
Amiodarone	38 (2.7)	30 (2.2)	0.037	38 (1.2)	38 (1.2)	0.000
PPI and H2 receptor antagonist	524 (37.6)	487 (34.9)	0.055	698 (22.7)	654 (21.3)	0.035
NSAIDs	93 (6.7)	86 (6.2)	0.020	116 (3.8)	108 (3.5)	0.014
Index dose of apixaban
5 mg b.i.d.	250 (17.9)	NA		2,126 (69.2)	NA
2.5 mg b.i.d.	1,121 (80.4)	NA		894 (29.1)	NA
Other	23 (1.6)	NA		54 (1.8)	NA

Data are presented as mean±SD, n (%), or median [IQR]. *Includes peripheral artery disease and other peripheral vascular disease. ^†Intracranial hemorrhage, gastrointestinal bleeding, and other types of bleeding. ^an=1,126. ^bn=1,131. ^cn=2,587. ^dn=2,634. ^en=1,378. ^fn=1,379. ^gn=3,022. ^hn=3,047. ⁱn=1,377. ^jn=1,379. ^kn=3,022. ^ln=3,044. Abbreviations as in Table 1.

Table 4. Incidence Rates of Major Bleeding and Stroke/SE Stratified by CrCl (After Matching)

Event / CrCl (mL/min)	Apixaban*			Warfarin*			Cox proportional hazards regression
	Number of events	Person- years	Incidence rate† (95% CI)	Number of events	Person- years	Incidence rate† (95% CI)	HR (95% CI)	P value
Major bleeding
<50	42	2,283	1.84 (1.33–2.49)	71	2,291	3.10 (2.42–3.91)	0.59 (0.41–0.87)	<0.01
≥50	43	5,354	0.80 (0.58–1.08)	57	5,683	1.00 (0.76–1.30)	0.80 (0.54–1.18)	0.26
Stroke/SE
<50	37	2,283	1.62 (1.14–2.23)	62	2,286	2.71 (2.08–3.48)	0.60 (0.40–0.90)	0.01
≥50	55	5,337	1.03 (0.78–1.34)	73	5,656	1.29 (1.01–1.62)	0.78 (0.55–1.11)	0.17

*CrCl <50 mL/min, n=1,394; CrCl ≥50 mL/min, n=3,074. ^†Per 100 person-years. Abbreviations as in Tables 1,2.

Figure 3.

Subgroup analysis for the risk of major bleeding and stroke/SE stratified by CrCl (after matching). CI, confidence interval; CrCl, creatinine clearance; HR, hazard ratio; SE, systemic embolism.

Post Hoc Analyses

Results of the post hoc analysis that included type of AF in the Cox proportional hazards model showed a reduction in the risk of major bleeding (HR [95% CI], 0.69 [0.53–0.90]; P<0.01) and stroke/SE (HR [95% CI], 0.64 [0.49–0.84]; P<0.01), favoring apixaban. In patients with a baseline CrCl of <50 mL/min, the risk of major bleeding was lower in the apixaban vs. warfarin group (HR [95% CI], 0.57 [0.39–0.84]; P<0.01), as was that of stroke/SE (HR [95% CI], 0.57 [0.38–0.86]; P<0.01). In patients with a CrCl of ≥50 mL/min, the risk of major bleeding (HR [95% CI], 0.79 [0.53–1.18]; P=0.25) and stroke/SE (HR [95% CI], 0.78 [0.55–1.12]; P=0.18) was not different between groups. All these data were consistent with the analysis results that did not include AF type in the model.

The inclusion of site as a random-effect factor, given the variability among centers, showed a reduction in the risk of major bleeding (HR [95% CI], 0.72 [0.54–0.96]; P=0.02) and stroke/SE (HR [95% CI], 0.63 [0.47–0.83]; P<0.01), favoring apixaban. When the same model was tested for the risk of any bleeding, no difference was observed between the apixaban and warfarin groups (HR [95% CI], 1.06 [0.94–1.19]; P=0.35; Supplementary Table 2).

Discussion

Evidence has not been fully established on the real-world safety and effectiveness of apixaban for the prevention of stroke/SE in Japanese OAC-naïve patients with NVAF treated in daily clinical practice. In addition, there is insufficient large-scale evidence regarding the safety and effectiveness of DOACs compared with warfarin in patients with decreased renal function in Japan. This is the first large, retrospective cohort study that assessed the safety and effectiveness of apixaban vs. warfarin in OAC-naïve patients with NVAF in Japan using medical chart review. This study aimed to clarify the safety and effectiveness of apixaban compared with warfarin in patients with impaired renal function vs. those with normal renal function in a large-scale nationwide setting.

In the current study, the mean PT-INR at weeks 4 and 24 was 1.76 and 1.82, respectively, and maintained a stable level (<2.0) until the end of the study (week 156). Non-recommended 2.5 mg b.i.d. apixaban was prescribed to 22.3% of patients in this study. As non-recommended 2.5 mg b.i.d. apixaban was prescribed to 14.9% of patients in the postmarketing STANDARD study²⁵ and 25.1% of patients in the All Nippon Atrial Fibrillation In the Elderly (ANAFIE) registry,¹⁷ it was inferred that apixaban is used in non-recommended doses in 15% to 25% of patients with NVAF in daily clinical practice. Notably, the current study included approximately 30% of patients with decreased renal function (CrCl <50 mL/min). Approximately half of the patients included in the current study were treated by general practitioners. In general, it is not feasible to fully capture clinical data essential to OAC therapy, such as body weight and serum creatinine levels, using claims databases. In contrast, in this study, we collected these data from patients’ medical records, which enabled a realistic evaluation of the safety and effectiveness of newly prescribed apixaban and newly prescribed warfarin in daily clinical practice. Consequently, this study verified the safety and effectiveness of apixaban in patients with decreased renal function in a real-world setting, and the results support the previous findings demonstrated in the ARISTOTLE trial.^4,26,27

In this study, apixaban was associated with a lower incidence of major bleeding and stroke/SE vs. warfarin in patients with NVAF, which is consistent with the findings for patients with or without decreased renal function in the ARISTOTLE trial⁴ and previous analyses of the DPC claims database in Japan.^14–16 The incidence rate of any bleeding (per 100 person-years) observed in the apixaban group (11.73) was higher vs. that in the warfarin group (9.51) in the current study, but lower than that reported in previous DPC claims database studies in Japan that applied PSM (apixaban, 18.6; warfarin, 23.1)¹⁵ or inverse probability of treatment weighting (apixaban, 15.5; warfarin, 19.8).¹⁶ The higher risk of any bleeding observed in the apixaban vs. warfarin group may be partly attributed to site bias. However, when site was included as a random-effect factor to adjust bias in post hoc analyses, the results were consistent with those from the overall Cox proportional hazards model. A reporting bias may be another factor that can explain the increased risk of any bleeding associated with apixaban. In England, where healthcare professionals were mandated to report any adverse drug reactions associated with apixaban after its approval, the total number of adverse drug reactions (normalized to the number of anticoagulant items prescribed) for apixaban decreased from 2013 to 2019 in a primary care setting, but was consistently higher vs. warfarin during this period.²⁸ Although studies on adverse events reporting the association with apixaban or DOACs have not been published in Japan, the situation reported in England is presumably similar to that in this country.

An increase in the risk of bleeding events in patients with reduced renal function is one of the major safety concerns perceived by physicians for patients with NVAF treated with DOACs. For example, findings from the ANAFIE Registry show that chronic kidney disease (CKD) is one of the factors associated with favoring warfarin over DOACs in the treatment of elderly (aged ≥75 years) Japanese patients with NVAF in daily clinical practice.¹⁷ In the current study, treatment with apixaban showed a reduction in the risk of major bleeding and stroke/SE events vs. warfarin in patients with decreased renal function (CrCl <50 mL/min). Moreover, reduction in the risk of major bleeding and stroke/SE events was not different from the overall trend, regardless of patients’ renal function (CrCl ≥50 mL/min or <50 mL/min). As these results are consistent with the findings reported in a subgroup analysis of patients with advanced CKD (CrCl 25–30 mL/min) enrolled in the ARISTOTLE trial,²⁷ the reduction in the risk of stroke/SE and bleeding events associated with apixaban may be extrapolated to Japanese patients with reduced renal function. Of note, in an analysis of the J-ELD AF Registry that included more than 3,000 patients with NVAF (aged ≥75 years, receiving on-label doses of apixaban), no significant difference was observed in the incidence rate (per 100 person-years) of bleeding requiring hospitalization (CrCl ≥50 mL/min, 1.39; 30–49 mL/min, 1.93; 15–29 mL/min, 3.13; P=0.16) or stroke/SE (CrCl ≥50 mL/min, 1.76; 30–49 mL/min, 1.39; 15–29 mL/min, 1.67; P=0.76) across CrCl subgroups.²⁹

This study has some limitations. First, some variables, such as left atrial dimension, blood pressure, and alcohol abuse, were not considered for PSM, and there is no guarantee that such characteristics were fully balanced between groups, owing to which the influence of unexamined confounding factors could not be fully excluded. Second, the incidence of bleeding or stroke/SE events could be underestimated if patients decided to visit a different hospital or general practitioner. Nevertheless, the results of the current study are highly generalizable to daily clinical practice in Japan, as this study included patients with decreased renal function or those treated by general practitioners, and there was successful collection of clinical data essential to OAC therapy, including body weight and renal function, by implementing a retrospective chart review.

Conclusions

This retrospective cohort study with medical chart review showed that treatment with apixaban was associated with a reduced risk of major bleeding and stroke/SE events vs. warfarin in OAC-naïve patients with NVAF, including those with renal dysfunction or those treated by general practitioners. The results from the present study are consistent with those obtained from the ARISTOTLE trial and DPC claims database studies involving apixaban, indicating that previous findings of these studies are generalizable to daily clinical practice. The benefit of apixaban over warfarin for reduction in the risk of stroke/SE and bleeding extended to patients treated at general practitioner clinics as well as to those with reduced renal function.

Acknowledgments

The authors thank all medical institutions and physicians who participated in this retrospective cohort study for their cooperation.

Sources of Funding

This study was funded and conducted by Bristol Myers Squibb K.K. and Pfizer Japan Inc. Medical writing and editorial assistance was provided by Mami Hirano, MS, of Cactus Life Sciences (part of Cactus Communications) and funded by Bristol Myers Squibb K.K. and Pfizer Japan Inc.

Disclosures

Y.K. reports remuneration (lecture fees) from Daiichi Sankyo, Bristol Myers Squibb, and Boehringer Ingelheim, outside the submitted work. H.H. reports remuneration (lecture fees) from Bristol Myers Squibb, Daiichi Sankyo, Pfizer, and Bayer, outside the submitted work. Y.M. is an employee of Bristol Myers Squibb K.K. T.I. is a current employee of Pfizer Japan, Inc. for this study and a former employee of Otsuka Pharmaceutical. T.M. reports remuneration (lecture fees) from Bristol Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Kyocera, Novartis, and Toray; manuscript fees from Bristol Myers Squibb and Kowa; and consultancy fees from Sanofi.

IRB Information

The study was reviewed and approved by the ethics committee or the independent review committee of each participating site (Representative facility: Saga Memorial Hospital Ethics Committee, reference number: 16000061).

Data Availability

Deidentified participant data will not be shared.

Supplementary File

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0682

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