Age-Related Differences in the Clinical Characteristics and Treatment of Elderly Patients With Atrial Fibrillation in Japan　― Insight From the ANAFIE (All Nippon AF In Elderly) Registry ―

Abstract

Background: Atrial fibrillation (AF) is increasing as the global population ages. Elderly AF patients (≥75 years) have a worse prognosis than younger patients, and effective management is often difficult due to multiple comorbidities. This analysis examined the age-related differences in clinical characteristics and treatment in real-world elderly Japanese AF patients.

Methods and Results: The ANAFIE Registry is a multicenter, prospective, observational registry of 32,726 non-valvular AF patients aged ≥75 years. The present study assessed the age-related differences in baseline clinical status and anticoagulant therapy between age groups 75–<80, 80–<85, 85–<90, and ≥90 years. The prevalence of persistent or permanent AF increased, and that of paroxysmal AF decreased, with increasing age (trend P<0.0001). The risk of stroke, based on CHADS₂ and CHA₂DS₂-VASc scores, and bleeding, based on HAS-BLED score, increased with age. Both warfarin and apixaban were used more often as age increased (trend P<0.0001, for each), while other anticoagulants were used less. Anticoagulant doses were significantly lower in older patients.

Conclusions: Permanent/persistent AF, comorbidities, and cardiovascular and bleeding risk all increased significantly with age. Furthermore, use of warfarin and apixaban increased with age, accompanied by a decrease in other oral anticoagulant usage.

Atrial fibrillation (AF) is the most common arrhythmia and an important risk factor for thromboembolic events, including ischemic stroke, acute mesenteric ischemia, and acute limb ischemia.¹ The prevalence is 1–2% in the general adult population and as high as 2–3% according to age.^2,3 The proportion of individuals with AF is 0.1–0.9% in those aged <60 years, 1.0–4.5% in 60–69-year-olds, 3.4–7.3% in 70–79-year-olds, and 7.2–17% in ≥80-year-olds.^2,4,5 In Japan, the prevalence of AF also increases with age and is 4.4% for men and 2.2% for women aged ≥80 years.⁶

In Europe, it is estimated that 14–17 million individuals will have AF in 2030,^2,7 and in the USA, the number of adults with AF is predicted to at least double by 2050.^5,8 In 2050, it is projected that 1.034 million people in Japan will have AF.⁶ The increasing prevalence of AF is most likely due to global aging⁹ and improved survival from other forms of cardiovascular disease.⁴ In addition, age-related thyroid dysfunction (hyperthyroidism or hypothyroidism) is associated with an increased risk of AF in elderly patients.¹⁰ Along with heart failure, AF makes a significant contribution to the marked increase in the prevalence of cardiovascular disease with advancing age,¹¹ and cardiovascular disease is the leading cause of death in individuals aged ≥75 years.^12,13

Patients with AF aged ≥75 years have a worse prognosis than those aged 64–74 years, with higher rates of major adverse cardiac events (MACE) and mortality.¹⁴ Although increasing age is an independent predictor of stroke in patients with AF, it is also a risk factor for adverse events (e.g., bleeding) associated with anti-thrombotic therapy to prevent stroke.¹⁵ It is therefore not surprising that adverse events, multiple comorbidities, and polypharmacy are important issues in AF patients aged ≥75 years.¹⁶

Japan has the most rapidly aging population worldwide,¹⁷ highlighting a need for management data specifically relevant to older Japanese patients. Despite, however, the high prevalence of cardiovascular disease in elderly non-valvular AF (NVAF) patients, randomized controlled trials evaluating warfarin and direct oral anticoagulants (DOAC) in Japanese patients with AF have involved populations with a mean age well below 75 years.¹⁸ This lack of clinical trial data in older patients^19,20 makes it difficult to generalize these results to patients aged ≥75 years who may present with multiple comorbidities.^19,21 Furthermore, available AF treatment guidelines do not provide specific information regarding the management of older patients.^22,23 Anticoagulants have been reported to be underused in the elderly,^24–29 and the presence of comorbidities further limited the use of anticoagulants in elderly patients.^29–31

The ANAFIE registry was designed to obtain real-world information on patients with NVAF aged ≥75 years, including current status, current anticoagulant therapy, and prognosis.^32,33 The aim of this analysis of ANAFIE registry data was to compare age-related differences in clinical characteristics and treatment between age groups in a large cohort of elderly Japanese patients with AF.

Methods

Study Design

In brief, the ANAFIE Registry (UMIN Clinical Trials Registry UMIN000024006) is a multicenter, prospective, observational (non-interventional) registry of elderly NVAF patients (aged ≥75 years) from across Japan; full details of the registry have been reported previously.^32,33 Patient enrollment in the registry started in October 2016 (target, 30,000 patients), and follow-up data were collected at month 12 and month 24.³² Ethics approval was obtained from all relevant institutional review boards, and all patients provided written informed consent and were free to withdraw from the registry at any time. In the present analysis, all enrolled patients were divided into 4 age categories (75–<80, 80–<85, 85–<90, ≥90 years), and characteristics and treatment were compared between groups.

Patients

Eligible patients had electrocardiogram (ECG)-confirmed NVAF, were aged ≥75 years, and were able to visit the hospital for specified visits. Those participating in an interventional study, and those with mitral stenosis, artificial heart valves or life expectancy <1 year, and patients with a recent (<1-month) history of cardiovascular events were excluded. Full details of inclusion/exclusion criteria were published previously.³²

Data Collection

Data on the following parameters were collected at baseline, and at the month 12 and month 24 follow-up visits: demographic and clinical data, type of anticoagulant, other medication, and blood coagulation test results in warfarin recipients. Invasive procedures (except those related to AF) and other clinical events were also recorded.³²

Statistical Analysis

The target sample size of 30,000 patients was based on incidence data for stroke/systemic embolism (the primary registry study outcome). Full details of the sample size calculation have been reported previously; based on this, the significance level was set at 5% (2-sided).³²

All patients meeting the study eligibility criteria who were enrolled in the registry were included in this analysis. Prevalence was assessed as a categorical variable, and summary statistics were calculated for continuous variables.

P-values for trends were estimated using a general linear model, and categorical P-values were calculated using the Cochran-Mantel-Haenszel correlation statistic. Patients classified as unknown for a particular variable were excluded from the analysis. All calculations were performed using SAS version 9.4 or higher (SAS Institute, Tokyo, Japan).

Results

Patient Characteristics

A total of 33,278 patients were registered,³³ 32,726 of whom were included in this analysis. Prior to enrollment, 163 patients were excluded, primarily due to duplicate registrations (n=85) or withdrawal of consent (n=76; Figure 1). A further 389 patients were excluded from the analysis; the most frequent reasons were contract breach (n=232), lack of informed consent (n=71), no definitive diagnosis of NVAF (n=27), and retrospective identification of previous valve replacement (n=17). The analysis population was divided into 4 age groups: 75–<80 years (13,059 patients), 80–<85 years (11,103 patients), 85–<90 years (6,401 patients), and ≥90 years (2,163 patients; Figure 1).

Figure 1.

Flow chart of patient selection. NVAF, non-valvular atrial fibrillation.

Patient demographic data and clinical characteristics are listed according to age group in Table 1. A number of variables showed a significant decreasing trend as age increased: the proportion of male patients, current or ex-smokers, alcohol intake, creatinine clearance, systolic and diastolic blood pressure, and patients who had had surgery during the previous 3 months (Table 1). Fewer older patients had received previous non-drug therapy for AF (P-value for trend <0.0001). The prevalence of paroxysmal AF decreased and that of persistent or permanent AF increased as age increased (P-value for trend <0.0001; Table 1).

Table 1. Patient Demographics and Characteristics at Baseline by Age Category

	75–<80 years (n=13,059)	80–<85 years (n=11,103)	85–<90 years (n=6,401)	≥90 years (n=2,163)	P-value for trend†
Age (years)
Mean±SD	76.9±1.4	81.8±1.4	86.7±1.4	92.0±2.1	–
Median (IQR)	77.0 (76.0–78.0)	82.0 (81.0–83.0)	86.0 (85.0–88.0)	91.0 (90.0–93.0)
Sex
Male	8,278 (63.4)	6,447 (58.1)	3,146 (49.1)	862 (39.9)	<0.0001
Creatinine clearance (mL/min‡)
Mean±SD	56.7±17.1	47.7±18.8	39.1±28.8	31.0±11.6	<0.0001
Median (IQR)	56.1 (45.7–67.1)	47.1 (36.9–56.9)	38.0 (29.3–46.8)	29.9 (22.8–37.9)
<15 mL/min or with dialysis	96 (0.7)	109 (1.0)	115 (1.8)	108 (5.0)
15–<30 mL/min	461 (3.5)	991 (8.9)	1,273 (19.9)	791 (36.6)
30–<50 mL/min	3,111 (23.8)	4,145 (37.3)	2,849 (44.5)	781 (36.1)
50–<80 ml/min	5,958 (45.6)	3,543 (31.9)	967 (15.1)	109 (5.0)
≥80 mL/min	871 (6.7)	224 (2.0)	26 (0.4)	1 (0.0)
Unknown	2,562 (19.6)	2,091 (18.8)	1,171 (18.3)	373 (17.2)
Smoking habit					<0.0001
Non-smoker	5,899 (45.2)	5,609 (50.5)	3,570 (55.8)	1,274 (58.9)
Ex-smoker	4,508 (34.5)	3,350 (30.2)	1,661 (25.9)	501 (23.2)
Current smoker	736 (5.6)	358 (3.2)	133 (2.1)	23 (1.1)
Unknown	1,916 (14.7)	1,786 (16.1)	1,037 (16.2)	365 (16.9)
Alcohol consumption					<0.0001
Habitual	3,014 (23.1)	1,894 (17.1)	772 (12.1)	167 (7.7)
Occasional	2,658 (20.4)	2,039 (18.4)	944 (14.7)	284 (13.1)
None	5,280 (40.4)	5,264 (47.4)	3,574 (55.8)	1,336 (61.8)
Unknown	2,107 (16.1)	1,906 (17.2)	1,111 (17.4)	376 (17.4)
SBP (mmHg)§
Mean±SD	127.5±16.5	127.3±17.1	127.5±17.7	126.5±18.1	0.0340
Median (IQR)	128.0 (117.0–138.0)	128.0 (116.0–138.0)	127.0 (116.0–138.0)	126.0 (114.0–138.0)
DBP (mmHg)§
Mean±SD	71.9±11.4	70.3±11.4	69.5±12.0	68.2±12.0	<0.0001
Median	71.0 (64.0–80.0)	70.0 (62.0–78.0)	70.0 (61.0–77.0)	68.0 (60.0–76.0)
Type of AF					<0.0001
Paroxysmal	5,851 (44.8)	4,608 (41.5)	2,534 (39.6)	758 (35.0)
Persistent	2,133 (16.3)	1,811 (16.3)	1,078 (16.8)	401 (18.5)
Long-standing persistent	1,682 (12.9)	1,529 (13.8)	898 (14.0)	318 (14.7)
Permanent	3,393 (26.0)	3,155 (28.4)	1,891 (29.5)	686 (31.7)
Prior non-pharmacological treatment
Catheter ablation	1,908 (14.6)	847 (7.6)	218 (3.4)	29 (1.3)	<0.0001
Electrical cardioversion	354 (2.7)	246 (2.2)	99 (1.5)	18 (0.8)	<0.0001
ICD	86 (0.7)	50 (0.5)	14 (0.2)	3 (0.1)	<0.0001
Pacemaker	761 (5.8)	799 (7.2)	591 (9.2)	225 (10.4)	<0.0001
Other non-drug therapy	55 (0.4)	45 (0.4)	11 (0.2)	3 (0.1)	0.0024
Comorbidities
Any comorbidity	12,595 (96.4)	10,826 (97.5)	6,277 (98.1)	2,128 (98.4)	<0.0001
Hypertension	9,581 (73.4)	8,458 (76.2)	4,921 (76.9)	1,655 (76.5)	<0.0001
Diabetes mellitus	3,728 (28.5)	3,111 (28.0)	1,580 (24.7)	414 (19.1)	<0.0001
Dyslipidemia	5,583 (44.8)	4,696 (42.3)	2,615 (40.9)	723 (33.4)	<0.0001
Hyperuricemia	2,860 (21.9)	2,534 (22.8)	1,491 (23.3)	517 (23.9)	0.0059
CKD	2,174 (16.6)	2,266 (20.4)	1,684 (26.3)	663 (30.7)	<0.0001
Severe hepatic impairment	132 (1.0)	107 (1.0)	47 (0.7)	13 (0.6)	0.0178
Respiratory disease	1,649 (12.6)	1,421 (12.8)	839 (13.1)	285 (13.2)	0.2922
Heart disease¶	6,946 (53.2)	6,556 (59.0)	4,183 (65.3)	1,568 (72.5)	<0.0001
Cerebrovascular disease††	2,756 (21.1)	2,535 (22.8)	1,535 (24.0)	584 (27.0)	<0.0001
Other vascular disease‡‡	650 (5.0)	638 (5.7)	326 (5.1)	126 (5.8)	0.1657
Thromboembolic disease§§	1,060 (8.1)	1,026 (9.2)	529 (8.3)	194 (9.0)	0.2222
Hyperthyroidism	231 (1.8)	148 (1.3)	85 (1.3)	18 (0.8)	0.0002
Gastrointestinal disease	3,654 (28.0)	3,288 (29.6)	1,947 (30.4)	695 (32.1)	<0.0001
Malignancy	1,409 (10.8)	1,300 (11.7)	701 (11.0)	179 (8.3)	0.0712
Dementia	453 (3.5)	827 (7.4)	829 (13.0)	451 (20.9)	<0.0001
Other comorbidity	4,055 (31.1)	3,657 (32.9)	2,168 (33.9)	749 (34.6)	<0.0001
Abnormal brain imaging¶¶	561 (48.7)	492 (51.1)	261 (46.4)	112 (57.1)	0.4004
Falls in the previous year†††	681 (5.2)	781 (7.0)	630 (9.8)	287 (13.3)	<0.0001
Other history
Major surgery in ≤3 months‡‡‡	168 (1.3)	94 (0.8)	59 (0.9)	17 (0.8)	0.0028
History of major bleeding§§§	471 (3.6)	452 (4.1)	262 (4.1)	80 (3.7)	0.2017

Data given as n (%) unless otherwise indicated. ^†The continuous variable was the P-value for trend estimated using a general linear model, and the categorical variable was the P-value associated with the Cochran-Mantel-Haenszel correlation statistic. Patients classified as “unknown”, however, were excluded from the analysis. ^‡Creatinine clearance data were available for 10,481, 9,001, 5,227, and 1,789 patients aged 75–<80, 80–<85, 85–<90, and ≥90 years, respectively. ^§Office blood pressure readings were available for 11,872, 10,252, 5,927, and 2,025 patients aged 75–<80, 80–<85, 85–<90, and ≥90 years, respectively. ^¶Including myocardial infarction, angina pectoris, left ventricular systolic dysfunction, heart failure, valvular disease, cardiomyopathy, hypertensive heart disease, congenital heart disease, and others. ^††Including atherosclerotic stroke, cardiogenic cerebral infarction, lacunar stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, and others. ^‡‡Includes peripheral angiography, aortic plaque, and others. ^§§Includes pulmonary embolism, deep vein thrombosis, internal carotid artery stenosis, arteriosclerosis obliterans, and others. ^¶¶Brain imaging data were available for 1,151, 963, 563, and 196 patients aged 75–<80, 80–<85, 85–<90, and ≥90 years, respectively. ^†††Falls data were available for 11,608, 9,837, 5,685, and 1,924 patients aged 75–<80, 80–<85, 85–<90, and ≥90 years, respectively. ^‡‡‡Surgical history for indications other than AF was available for 12,886, 10,937, 6,295, and 2,127 patients aged 75–<80, 80–<85, 85–<90, and ≥90 years, respectively. ^§§§Includes intracranial, upper gastrointestinal, lower gastrointestinal, and other bleeding. AF, atrial fibrillation; CKD, chronic kidney disease; DBP, diastolic blood pressure; ICD, implantable cardioverter defibrillator; SBP, systolic blood pressure.

Comorbidities and Risk

The prevalence of hypertension, kidney diseases, heart disease, cerebrovascular disease, and dementia significantly increased as age increased. Conversely, dyslipidemia, diabetes mellitus, severe hepatic impairment, and hyperthyroidism were significantly less common with advancing age (Table 1).

CHADS₂, CHA₂DS₂-VASc, and HAS-BLED scores increased as age increased, but numerical increases in scores and the proportion of patients in each risk category were relatively small (Figure 2).

Figure 2.

Risk scores: (A) CHADS₂; (B) CHA₂DS₂-VASc; and (C) HAS-BLED in elderly patients with atrial fibrillation in Japan. *Positive trend of score against age, P<0.0001 (general linear model). ^aNo patient with score ≥7 was observed. y, years.

Anti-Thrombotic Agents

Both warfarin and apixaban were used more often and other anticoagulants less often as age increased (P-value for trend <0.0001, each; Table 2). There was a significant trend for the use of lower anticoagulant doses in older patients (Table 2). For all anticoagulants, treatment had been initiated at least 1 month previously in the majority of patients (≥84%), without any significant differences across the different age groups. In the vast majority of patients (≥98%), dabigatran and apixaban were given twice daily, and rivaroxaban and edoxaban were given once daily.

Table 2. Anticoagulant Use and Dose at Baseline by Age Category

	75–<80 years (n=13,059)	80–<85 years (n=11,103)	85–<90 years (n=6,401)	≥90 years (n=2,163)	P-value for trend*
Use of anticoagulants
None	978 (7.5)	783 (7.1)	591 (9.2)	293 (13.5)	<0.0001
Any	12,081 (92.5)	10,320 (92.9)	5,810 (90.8)	1,870 (86.5)	<0.0001
Warfarin†	3,030 (25.1)	2,887 (28.0)	1,781 (30.7)	656 (35.1)	<0.0001
Dabigatran†	1,250 (10.3)	776 (7.5)	272 (4.7)	55 (2.9)	<0.0001
Rivaroxaban†	2,852 (23.6)	2,146 (20.8)	1,154 (19.9)	311 (16.6)	<0.0001
Apixaban†	2,930 (24.3)	2,890 (28.0)	1,714 (29.5)	551 (29.5)	<0.0001
Edoxaban†	2,013 (16.7)	1,618 (15.7)	885 (15.2)	297 (15.9)	0.0265
Non-oral anticoagulant†	6 (0.0)	3 (0.0)	4 (0.1)	0 (0.0)	0.7834
Daily anticoagulant dose (mg)
Dabigatran
No. patients	1,250	776	272	55
Mean±SD	214.2±43.6	208.7±40.6	203.6±39.0	196.6±45.0	0.0011
Median (IQR)	220.0 (220.0–220.0)	220.0 (220.0–220.0)	220.0 (220.0–220.0)	220.0 (150.0–220.0)
75 mg	3 (0.2)	3 (0.4)	4 (1.5)	1 (1.8)
110 mg	111 (8.9)	68 (8.8)	21 (7.7)	6 (10.9)
150 mg	48 (3.8)	42 (5.4)	26 (9.6)	8 (14.5)
220 mg	973 (77.8)	627 (80.8)	218 (80.1)	39 (70.9)
300 mg	113 (9.0)	32 (4.1)	3 (1.1)	1 (1.8)
Others	2 (0.2)	4 (0.5)	0 (0.0)	0 (0.0)
Rivaroxaban
No. patients	2,852	2,146	1,154	311
Mean±SD	12.4±2.7	11.4±2.3	10.6±1.8	10.4±1.9	<0.0001
Median (IQR)	10.0 (10.0–15.0)	10.0 (10.0–15.0)	10.0 (10.0–10.0)	10.0 (10.0–10.0)
10 mg	1,468 (51.5)	1,556 (72.5)	1,009 (87.4)	280 (90.0)
15 mg	1,370 (48.0)	584 (27.2)	138 (12.0)	26 (8.4)
Others	14 (0.5)	6 (0.3)	7 (0.6)	5 (1.6)
Apixaban
No. patients	2,930	2,890	1,714	551
Mean±SD	7.6±2.7	5.9±2.2	5.2±1.6	4.8±1.2	<0.0001
Median	10.0 (5.0–10.0)	5.0 (5.0–5.0)	5.0 (5.0–5.0)	5.0 (5.0–5.0)
2.5 mg	107 (3.7)	184 (6.4)	163 (9.5)	68 (12.3)
5 mg	1,224 (41.8)	2,078 (71.9)	1,412 (82.4)	469 (85.1)
10 mg	1,593 (54.4)	624 (21.6)	139 (8.1)	14 (2.5)
Others	6 (0.2)	4 (0.1)	0 (0.0)	0 (0.0)
Edoxaban
No. patients	2,013	1,618	885	297
Mean±SD	35.7±12.3	32.4±9.9	29.7±7.7	28.4±7.6	<0.0001
Median (IQR)	30.0 (30.0–30.0)	30.0 (30.0–30.0)	30.0 (30.0–30.0)	30.0 (30.0–30.0)
15 mg	34 (1.7)	74 (4.6)	87 (9.8)	48 (16.2)
30 mg	1,578 (78.4)	1,376 (85.0)	761 (86.0)	241 (81.1)
60 mg	399 (19.8)	167 (10.3)	36 (4.1)	8 (2.7)
Others	2 (0.1)	1 (0.1)	1 (0.1)	0 (0.0)

Data given as n (%) unless otherwise indicated. ^†Percentage calculated using the no. patients in the ‘Any’ group as the denominator. IQR, interquartile range (quartile 1 to quartile 3); SD, standard deviation.

For patients receiving warfarin, mean±SD prothrombin time-international normalized ratio (PT-INR) decreased with age (2.0±0.4, 2.0±0.4, 1.9±0.4, and 1.9±0.4 in patients aged 75–<80, 80–<85, 85–<90, and ≥90 years, respectively; P-value for trend <0.0001). Corresponding values for the proportion of time in the therapeutic range (TTR) also decreased with age (77.7%, 75.7%. 73.3%, and 68.7%, respectively; P-value for trend<0.0001).

There was no significant difference in antiplatelet use between the different age groups. Antiplatelet agents were used in 18.3%, 18.9%, 18.9%, and 18.7% of patients aged 75–<80, 80–<85, 85–<90, and ≥90 years, respectively (P-value for trend=0.4043).

Discussion

The ANAFIE registry is the first prospective observational registry to include specifically elderly patients with NVAF. In the present study, the prevalence of permanent/persistent forms of AF, comorbidities, and the cardiovascular and bleeding risks all increased significantly with age. In contrast, use of warfarin and apixaban increased with age, accompanied by a corresponding decrease in the use of DOAC.

The present findings of increased comorbidities and cardiovascular risk in elderly patients with AF are consistent with previous reports. In the Akershus Cardiac Examination (ACE) 1950 study, 87.6% of men with AF and 86.4% of women with AF had comorbidities, compared with 74.4% and 66.3%, respectively, without AF.⁴ Data from a Chinese AF registry indicated that older patients (≥75 years) with AF were more likely to have higher mean CHADS₂ score, as well as higher risk of death and higher risk of MACE, compared with younger patients (≥65–<75 years).¹⁴ Similarly, in a US National Health and Wellness Survey, almost all patients with AF (98%) had at least 1 additional comorbidity, and 81% were at high or moderate risk for stroke according to CHADS₂ score.³⁴

A population study showed that although elderly AF patients (age ≥75 years) were at higher risk of stroke and of bleeding, the benefits of anticoagulant therapy for stroke prevention persist despite increasing age.³⁵ Nevertheless, given the greater risks associated with anticoagulation therapy in elderly patients, appropriate treatment is underprescribed and underused in this patient group.³⁶ Such decisions are not evidence based, given that a recent systematic review, meta-analysis, and cost-effectiveness analysis confirmed that oral anticoagulation is an important therapeutic strategy for stroke prevention in AF.³⁷

It is important to note that the ANAFIE registry included a patient population with different patient baseline characteristics³³ compared with previous large-scale analyses of patients with AF, such as the ENGAGE AF-TIMI 48 clinical trial,^38,39 and other Japanese registries including the J-RHYTHM Registry,^40–42 the Fushimi AF Registry,²⁸ and the SAKURA AF Registry.⁴³ In general, patients in ANAFIE were older, included a higher proportion of women, and had impaired kidney function. Despite this, the anticoagulant treatment rate was extremely high (92%), with 66% using DOAC. This is in contrast to a European registry study in elderly AF patients, in which similar CHADS₂, CHA₂DS₂-VASc, and HAS-BLED scores were observed, but anticoagulation treatment rates were much lower compared with the ANAFIE population.⁴⁴ Use of warfarin therapy was also relatively high in this analysis, particularly for the oldest patients, and PT-INR and TTR data indicated good anticoagulation control. Warfarin has been shown to be of clinical benefit in elderly (age ≥80 years) Chinese patients with AF.⁴⁵ Increased warfarin use might be due to prior renal function in older patients. As a result, warfarin might be used in place of DOAC in elderly patients with renal dysfunction. Interestingly, the use of apixaban increased in a similar way and was used more often as age increased compared with other anticoagulants. This is consistent with the ARISTOTLE trial, in which apixaban was effective for stroke prevention, bleeding complications, and mortality consistently across all age groups, including patients aged ≥80 years.⁴⁶

The overall uptake of anticoagulation in patients with AF has been much lower in Asia (57.4%) than in Europe (90.2%).⁴⁷ In addition, approximately one-third of patients are not treated in accordance with guideline recommendations.⁴⁷ In contrast, anticoagulants were used in a much higher proportion of patients in this analysis (86.5–92.5%). The large proportion of patients using anticoagulants in the ANAFIE registry may be partially attributable to the recommendation for anticoagulant therapy in elderly patients in the 2013 Japanese AF guidelines;²³ since their publication, physicians likely prescribed the treatment to older patients more frequently and gained experience and confidence in doing so. In addition, it is possible that selection bias in the present analysis, based on the inclusion of patients able to complete the 24-month observation period, may have contributed to the high rates of anticoagulation therapy observed. Thus, the present study shows the current status of treatment in elderly patients who were considered by the treating physician to be relatively healthy as to be able to obtain long-term benefit from an anticoagulant treatment regimen. It should be noted that the physicians who participated in the ANAFIE study consisted of many general practitioners who were eager to treat AF, rather than of specialists. Those practitioners might have considered anticoagulant therapy to provide clinical benefit for patients; this, in turn, may explain the increased rate of anticoagulant therapy observed in this study. Data from another registry in Japan, J-RHYTHM, also showed relatively high rates of anticoagulant use: J-RHYTHM enrolled 7,937 patients across a wider age range, of whom 34% were ≥75 years old.⁴² The overall rate of oral anticoagulant use in that population was relatively high (87.3%), and 53% achieved target INR.^40,42,48,49 In contrast, in the present study, patients had an INR within the therapeutic range 68.7–77.7% of the time.

Of note, some elderly patients in this study received lower daily doses of DOAC than those recommended in the package inserts for these agents (e.g., dabigatran 75 mg and 110 mg; apixaban 2.5 mg; and edoxaban 15 mg). Furthermore, the dose reductions increased with age. We speculate that physicians decided to reduce the dosage for their older patients in an attempt to mitigate these bleeding risks. Further studies are needed to ascertain whether this strategy is widespread, both in Japan and in other countries, and how it may affect patient outcomes.

The present study had several potential limitations, including the observational registry-based design. Despite this, however, the patients included are representative of routine clinical settings and therefore the findings are likely to have good external validity, at least in Japan. The study is based on 1 ethnicity (Japanese) and extrapolation of these findings to different populations should be done with caution. Finally, this study reports only baseline data from the ANAFIE registry, and the identification of prognostic information (for stroke/systemic embolism and bleeding) must await future data collection and evaluation.

Conclusions

The prevalence of persistent or permanent AF, comorbidities, and the stroke and bleeding risk increased in parallel with increasing age in elderly patients with AF. Despite a higher bleeding risk, the use of oral anticoagulants in this elderly population was relatively high, with high levels of warfarin use. This might be due to poor renal function, commonly observed in older patients, and which can lead to limited use of DOAC.

Acknowledgments

We thank the physicians, nurses, institutional staff, and patients involved in the ANAFIE Registry. We also thank IQVIA Services Japan and EP-CRSU for their partial support in the conduct and the data analysis of this registry, and Sally-Anne Mitchell, PhD, and Nicola Ryan, BSc, of Edanz Medical Writing for providing medical writing support, which was funded by Daiichi Sankyo.

Funding

This research was sponsored by Daiichi Sankyo.

Author Contributions

H.I., T. Yamashita, M.A., H.A., Y.K., K.O., W.S., T.I., K.T., A.H., M.Y., T. Yamaguchi, and H.T. designed and conducted the study; K.H. and H.T. interpreted the data; S.T. and A.T. carried out statistical analysis; K.H., H.K., T.K., J.K., and H.T. wrote and reviewed the manuscript; all authors revised and commented on the manuscript, and approved the final version.

Disclosures

K.H. received remuneration from Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Bayer, and Otsuka Pharmaceutical. H.I. received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. T. Yamashita received research funding from Bristol-Myers Squibb, Bayer, and Daiichi Sankyo; manuscript fees from Daiichi Sankyo, and Bristol-Myers Squibb; donations from Daiichi Sankyo; and remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Toa Eiyo, and Ono Pharmaceutical. M.A. received research funding from Bayer; donations from Bayer and Daiichi Sankyo; and remuneration from Pfizer, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Bayer, and Daiichi Sankyo. H.A. received remuneration from Daiichi Sankyo. Y.K. received remuneration from Daiichi Sankyo. K.O. received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. W.S. received research funding from Daiichi Sankyo and Nippon Boehringer Ingelheim; donations from Daiichi Sankyo, Nippon Boehringer Ingelheim, Bristol-Myers Squibb, Bayer, Mitsubishi-Tanabe Pharma, Otsuka Pharmaceutical, and Ono Pharmaceutical; and remuneration from Daiichi Sankyo, Pfizer, Bristol-Myers Squibb, Bayer, Ono Pharmaceutical, and Nippon Boehringer Ingelheim. T.I. received research funding from Daiichi Sankyo, Medtronic, and Japan Lifeline, and remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, Ono Pharmaceutical, and Bristol-Myers Squibb. K.T. received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. A.H. participated in a course endowed by Boston Scientific Japan, Otsuka Pharmaceutical, Fukuda Denshi, St. Jude Medical, Medtronic, and Japan Lifeline; and has received remuneration from Bayer, Daiichi Sankyo, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Sanofi, Astellas Pharma, Sumitomo Dainippon Pharma, Amgen Astellas BioPharma, Toa Eiyo, and AstraZeneca. M.Y. received research funding from Nippon Boehringer Ingelheim, and remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Bayer, Bristol-Myers Squibb, and CSL Behring. T. Yamaguchi received remuneration from Daiichi Sankyo, and manuscript fees from Bristol-Myers Squibb, and others from Otsuka Pharmaceutical. S.T. received research funding from Nippon Boehringer Ingelheim and remuneration from Daiichi Sankyo and Solasia Pharma. T.K., J.K., and A.T. are employees of Daiichi Sankyo. H.T. received remuneration from Otsuka Pharmaceutical, Takeda Pharmaceutical, Mitsubishi-Tanabe Pharma, Daiichi Sankyo, Nippon Boehringer Ingelheim, Bayer, Pfizer, Novartis Pharma, MSD, Teijin Pharma, Bristol-Myers Squibb, Kowa Pharmaceutical, and Astellas Pharma; research funding from Nippon Boehringer Ingelheim, Mitsubishi-Tanabe Pharma, Japan Tobacco, Daiichi Sankyo, IQVIA Services Japan, Acterion Pharmaceuticals Japan, and Omron Healthcare; donations from Astellas Pharma, Novartis Pharma, Daiichi Sankyo, Takeda Pharmaceutical, Mitsubishi-Tanabe Pharma, Teijin Pharma, and MSD; and consultancy from Nippon Boehringer Ingelheim, Bayer, Novartis Pharma, and Ono Pharmaceutical. H.K. declares no conflict of interest.

References

• 1.   Wasilewska M, Gosk-Bierska I. Thromboembolism associated with atrial fibrillation as a cause of limb and organ ischemia. Adv Clin Exp Med 2013; 22: 865–873.
• 2.   Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014; 6: 213–220.
• 3.   Friberg L, Bergfeldt L. Atrial fibrillation prevalence revisited. J Intern Med 2013; 274: 461–468.
• 4.   Berge T, Lyngbakken MN, Ihle-Hansen H, Brynildsen J, Pervez MO, Aagaard EN, et al. Prevalence of atrial fibrillation and cardiovascular risk factors in a 63–65 years old general population cohort: The Akershus Cardiac Examination (ACE) 1950 Study. BMJ Open 2018; 8: e021704.
• 5.   Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285: 2370–2375.
• 6.   Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, Kubota I, et al. Prevalence of atrial fibrillation in the general population of Japan: An analysis based on periodic health examination. Int J Cardiol 2009; 137: 102–107.
• 7.   Krijthe BP, Kunst A, Benjamin EJ, Lip GY, Franco OH, Hofman A, et al. Projections of the number of individuals with atrial fibrillation in the European Union from 2000 to 2060. Eur Heart J 2013; 34: 2746–2751.
• 8.   Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006; 114: 119–125.
• 9.   World Health Organization. World population ageing 2015. http://www.un.org/en/development/desa/population/publications/pdf/ageing/WPA2015_Report.pdf (accessed June 11, 2019).
• 10.   Manolis AA, Manolis TA, Melita H, Manolis AS. Subclinical thyroid dysfunction and cardiovascular consequences: An alarming wake-up call? Trends Cardiovasc Med 2019; pii: S1050-1738(19)30029-5. doi:10.1016/j.tcm.2019.02.011.
• 11.   Braunwald E. Shattuck lecture – Cardiovascular medicine at the turn of the millennium: Triumphs, concerns, and opportunities. N Engl J Med 1997; 337: 1360–1369.
• 12.   Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics – 2016 update: A report from the American Heart Association. Circulation 2016; 133: e38–e60.
• 13.   Heron M. Deaths: Leading causes for 2010. Natl Vital Stat Rep 2013; 62: 1–96.
• 14.   Shao XH, Yang YM, Zhu J, Zhang H, Liu Y, Gao X, et al. Comparison of the clinical features and outcomes in two age-groups of elderly patients with atrial fibrillation. Clin Interv Aging 2014; 9: 1335–1342.
• 15.   Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: An update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33: 2719–2747.
• 16.   Suárez Fernández C, Camafort M, Cepeda Rodrigo JM, Díez-Manglano J, Formiga F, Pose Reino A, et al. Antithrombotic treatment in elderly patients with atrial fibrillation. Rev Clin Esp 2015; 215: 171–181.
• 17.   Japan Ministry of Health, Labour and Welfare. [Statistics 2015.] http://www.mhlw.go.jp/toukei_hakusho/index.html (accessed June 11, 2019) (in Japanese).
• 18.   Senoo K, Lau YC, Dzeshka M, Lane D, Okumura K, Lip GY. Efficacy and safety of non-vitamin K antagonist oral anticoagulants vs. warfarin in Japanese patients with atrial fibrillation: Meta-analysis. Circ J 2015; 79: 339–345.
• 19.   Herrera AP, Snipes SA, King DW, Torres-Vigil I, Goldberg DS, Weinberg AD. Disparate inclusion of older adults in clinical trials: Priorities and opportunities for policy and practice change. Am J Public Health 2010; 100(Suppl 1): S105–S112.
• 20.   Heiat A, Gross CP, Krumholz HM. Representation of the elderly, women, and minorities in heart failure clinical trials. Arch Intern Med 2002; 162: 1682–1688.
• 21.   Kitzman DW, Rich MW. Age disparities in heart failure research. JAMA 2010; 304: 1950–1951.
• 22.   Rich MW, Chyun DA, Skolnick AH, Alexander KP, Forman DE, Kitzman DW, et al. Knowledge gaps in cardiovascular care of the older adult population: A scientific statement from the American Heart Association, American College of Cardiology, and American Geriatrics Society. Circulation 2016; 133: 2103–2122.
• 23.   JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013): Digest version. Circ J 2014; 78: 1997–2021.
• 24.   Denoël P, Vanderstraeten J, Mols P, Pepersack T. Could some geriatric characteristics hinder the prescription of anticoagulants in atrial fibrillation in the elderly? J Aging Res 2014; 2014: 693740.
• 25.   Granziera S, Cohen AT, Nante G, Manzato E, Sergi G. Thromboembolic prevention in frail elderly patients with atrial fibrillation: A practical algorithm. J Am Med Dir Assoc 2015; 16: 358–364.
• 26.   Hanon O, Vidal JS, Pisica-Donose G, Benattar-Zibi L, Bertin P, Berrut G, et al. Therapeutic management in ambulatory elderly patients with atrial fibrillation: The S.AGES cohort. J Nutr Health Aging 2015; 19: 219–227.
• 27.   Bahrmann P, Wehling M, Ropers D, Flohr J, Leischker A, Röther J. [Optimal stroke prevention in the geriatric patient with atrial fibrillation: Position paper of an interdisciplinary expert panel.] MMW Fortschr Med 2014; 156(Suppl 3): 84–88 (in German).
• 28.   Akao M, Chun YH, Wada H, Esato M, Hashimoto T, Abe M, et al. Current status of clinical background of patients with atrial fibrillation in a community-based survey: The Fushimi AF Registry. J Cardiol 2013; 61: 260–266.
• 29.   Yamashita Y, Hamatani Y, Esato M, Chun YH, Tsuji H, Wada H, et al. Clinical characteristics and outcomes in extreme elderly (age ≥85 years) Japanese patients with atrial fibrillation: The Fushimi AF Registry. Chest 2016; 149: 401–412.
• 30.   Gheorghe GS, Hodorogea AS, Nanea LT, Gheorghe ACD. Comorbidities in the elderly with atrial fibrillation and the decision of oral anticoagulation in the real world. Eur J Int Med 2013; 24(Suppl 1): e9.
• 31.   Kodani E, Atarashi H, Inoue H, Okumura K, Yamashita T, Origasa H. Use of warfarin in elderly patients with non-valvular atrial fibrillation: Subanalysis of the J-RHYTHM Registry. Circ J 2015; 79: 2345–2352.
• 32.   Inoue H, Yamashita T, Akao M, Atarashi H, Ikeda T, Okumura K, et al. Prospective observational study in elderly patients with non-valvular atrial fibrillation: Rationale and design of the All Nippon AF In the Elderly (ANAFIE) Registry. J Cardiol 2018; 72: 300–306.
• 33.   Koretsune Y, Yamashita T, Akao M, Atarashi H, Ikeda T, Okamura K, et al. Baseline demographics and clinical characteristics in the All Nippon AF in the Elderly (ANAFIE) registry. Circ J 2019; 83: 1538–1545.
• 34.   LaMori JC, Mody SH, Gross HJ, daCosta DiBonaventura M, Patel AA, Schein JR, et al. Burden of comorbidities in patients with atrial fibrillation. Ther Adv Cardiovasc Dis 2013; 7: 53–62.
• 35.   Lip GY, Clementy N, Pericart L, Banerjee A, Fauchier L. Stroke and major bleeding risk in elderly patients aged ≥75 years with atrial fibrillation: The Loire Valley atrial fibrillation project. Stroke 2015; 46: 143–150.
• 36.   Pugh D, Pugh J, Mead GE. Attitudes of physicians regarding anticoagulation for atrial fibrillation: A systematic review. Age Ageing 2011; 40: 675–683.
• 37.   Lopez-Lopez JA, Sterne JAC, Thom HHZ, Higgins JPT, Hingorani AD, Okoli GN, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: Systematic review, network meta-analysis, and cost effectiveness analysis. BMJ 2017; 359: j5058.
• 38.   Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093–2104.
• 39.   Yamashita T, Koretsune Y, Yang Y, Chen SA, Chung N, Shimada YJ, et al. Edoxaban vs. warfarin in East Asian patients with atrial fibrillation: An ENGAGE AF-TIMI 48 subanalysis. Circ J 2016; 80: 860–869.
• 40.   Atarashi H, Inoue H, Okumura K, Yamashita T, Kumagai N, Origasa H, et al. Present status of anticoagulation treatment in Japanese patients with atrial fibrillation: A report from the J-RHYTHM Registry. Circ J 2011; 75: 1328–1333.
• 41.   Ogawa S, Yamashita T, Yamazaki T, Aizawa Y, Atarashi H, Inoue H, et al. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circ J 2009; 73: 242–248.
• 42.   Atarashi H, Inoue H, Okumura K, Yamashita T, Origasa H; J-RHYTHM Registry Investigators. Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation: The J-RHYTHM Registry study design. J Cardiol 2011; 57: 95–99.
• 43.   Okumura Y, Yokoyama K, Matsumoto N, Tachibana E, Kuronuma K, Oiwa K, et al. Current use of direct oral anticoagulants for atrial fibrillation in Japan: Findings from the SAKURA AF Registry. J Arrhythm 2017; 33: 289–296.
• 44.   Fumagalli S, Said SA, Laroche C, Gabbai D, Marchionni N, Boriani G, et al. Age-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: The EORP-AF general pilot registry (EURObservational Research Programme-Atrial Fibrillation). JACC Clin Electrophysiol 2015; 1: 326–334.
• 45.   Siu CW, Tse HF. Net clinical benefit of warfarin therapy in elderly Chinese patients with atrial fibrillation. Circ Arrhythm Electrophysiol 2014; 7: 300–306.
• 46.   Halvorsen S, Atar D, Yang H, De Caterina R, Erol C, Garcia D, et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: Observations from the ARISTOTLE trial. Eur Heart J 2014; 35: 1864–1872.
• 47.   Mazurek M, Huisman MV, Lip GYH. Registries in atrial fibrillation: From trials to real-life clinical practice. Am J Med 2017; 130: 135–145.
• 48.   J-RHYTHM Registry Investigators. Determinants of warfarin use and international normalized ratio levels in atrial fibrillation patients in Japan: Subanalysis of the J-RHYTHM Registry. Circ J 2011; 75: 2357–2362.
• 49.   Inoue H, Okumura K, Atarashi H, Yamashita T, Origasa H, Kumagai N, et al. Target international normalized ratio values for preventing thromboembolic and hemorrhagic events in Japanese patients with non-valvular atrial fibrillation: Results of the J-RHYTHM Registry. Circ J 2013; 77: 2264–2270.