10-Year Trends of Antithrombotic Therapy Status and Outcomes in Japanese Atrial Fibrillation Patients　― The Fushimi AF Registry ―

Masaharu Akao; Hisashi Ogawa; Nobutoyo Masunaga; Kimihito Minami; Kenjiro Ishigami; Syuhei Ikeda; Kosuke Doi; Yasuhiro Hamatani; Takashi Yoshizawa; Yuya Ide; Akiko Fujino; Mitsuru Ishii; Moritake Iguchi; Hiromichi Wada; Koji Hasegawa; Hikari Tsuji; Masahiro Esato; Mitsuru Abe; for the Fushimi AF Registry Investigators

doi:10.1253/circj.CJ-22-0023

Abstract

Background: Atrial fibrillation (AF) increases the risk of stroke and death. Oral anticoagulants (OAC) are highly effective in reducing the risk of stroke, and direct oral anticoagulants (DOAC) became available worldwide in 2011.

Methods and Results: The Fushimi AF Registry is an on-going prospective survey of AF patients in Fushimi-ku, Kyoto, Japan. The study cohort consisted of 4,489 patients (mean age 73.6 years, 59.6% male, mean CHADS₂ score 2.03), enrolled in 2011–2017. From 2011 to 2021, antithrombotic therapy has undergone a major transition; the proportion of patients receiving OAC has increased from 53% to 70%, with a steady uptake of DOAC (from 2% to 52%), whereas the proportion of patients receiving antiplatelet agents has decreased from 32% to 14%. Over a median follow-up of 5.1 years, the incidence of stroke/systemic embolism (SE), major bleeding, and all-cause death was 2.2%, 1.9%, and 4.9% per patient-year, respectively. The incidence of stroke/SE (1.6% vs. 2.3%; P<0.01), major bleeding (1.6% vs. 2.0%; P=0.07), and death (4.2% vs. 5.0%; P<0.01) was lower among patients enrolled in 2014–2017 than in 2011–2013, despite comparable baseline characteristics (age 73.2 vs. 73.7 years, CHADS₂ score 2.03 vs. 2.04, and HAS-BLED score 1.67 vs. 1.77, respectively).

Conclusions: Over the past 10 years, there has been a major transition in antithrombotic therapy and a decline in the incidence of adverse events in AF patients.

Atrial fibrillation (AF) is a common arrhythmia in the elderly and increases the risk of stroke and death.¹ Oral anticoagulants (OAC) are highly effective in reducing the risk of stroke, although they are associated with bleeding complications.² Until a decade ago, warfarin, a vitamin K antagonist (VKA), was the only OAC available; in 2011, direct OAC (DOAC; i.e., dabigatran, rivaroxaban, apixaban, and edoxaban) that selectively inhibit coagulation factors were launched worldwide for stroke prevention in patients with AF. Large-scale randomized clinical trials have demonstrated similar efficacy and safety for DOAC as warfarin.³ Furthermore, DOAC have predictable pharmacokinetics without the need for routine monitoring, like warfarin, and a low likelihood of food and drug interactions. Due to the preferable results of clinical trials and the ease of use in daily clinical practice, DOAC have become the predominant OAC therapy worldwide over the past 10 years. After the release of DOAC, several national guidelines for the management of AF were updated and now recommend DOAC as broadly preferable to VKA in patients with non-valvular AF.⁴^,⁵ Also in Japan, updated guidelines released in 2014 recommended DOAC as the first-line OAC therapy.⁶

The Fushimi AF Registry is a community-based observational prospective all-comer cohort study of AF patients in Fushimi-ku, Kyoto, Japan, with the aim of demonstrating the clinical characteristics and prognoses of Japanese AF patients in real-world clinical practice.⁷^,⁸ This study was started in 2011, which preceded the release of DOAC, and is currently collecting 10-year follow-up data. The objective of the present analysis was to describe the 10-year trends of antithrombotic therapy status and outcomes in Japanese AF patients enrolled in the Fushimi AF Registry.

Methods

Study Population

The detailed study design of the Fushimi AF Registry (University Hospital Medical Information Network [UMIN] Clinical Trials Registry ID: UMIN5834, June 22, 2011) has been described elsewhere.⁷^,⁸ The inclusion criterion for the Registry is documentation of AF on a 12-lead electrocardiogram or Holter monitor at any time. There were no exclusion criteria. In all, 81 institutions have participated in the Registry, consisting of 2 cardiovascular centers, 10 small- and medium-sized hospitals (<400 beds), and 69 primary-care clinics (full list in the Supplementary Appendix). Patient enrollment started in March 2011 and ended in May 2017. Clinical background data, including underlying diseases, medications, laboratory data, and follow-up data, were collected using an electronic case report form of a web-based database system. Collection of follow-up data, including the incidence of events and prescription data, was conducted once a year through a review of inpatient and outpatient medical records, and additional follow-up information was collected through contact with patients, relatives, and/or referring physicians by mail or telephone. Patient follow-up is planned to finish in February 2022, and the longest follow-up period is 10 years. The study protocol was approved by the ethics committees of National Hospital Organization Kyoto Medical Center and Ijinkai Takeda General Hospital.

The study cohort for the present analysis consisted of 4,489 patients with AF enrolled in the Fushimi AF Registry whose follow-up data were available as of August 2021. The median follow-up period was 1,844 days (interquartile range [IQR] 823–2,926 days).

Definitions

CHADS₂ and CHA₂DS₂-VASc scores were calculated to stratify the risk of stroke and the HAS-BLED score was used to stratify the risk of bleeding. The CHADS₂ score adds together points corresponding to the following conditions: congestive heart failure (HF), hypertension, age ≥75 years, diabetes, prior stroke, or transient ischemic attack (two points).⁹ The CHA₂DS₂-VASc score is a refinement of the CHADS₂ score and extends it by including additional common stroke risk factors, namely age (patient age ≥75 years=2 points; age 65–74 years=1 point), vascular disease and female sex.¹⁰ The HAS-BLED score adds together points corresponding to the following conditions: hypertension (systolic blood pressure >160 mmHg), abnormal renal function (presence of chronic dialysis or serum creatinine ≥200 mmol/L), abnormal liver function (aspartate aminotransferase or alanine aminotransferase 3-fold the upper limit of normal), stroke history, bleeding history, labile international normalized ratio (INR; INR >2.6 in patients aged ≥70 years or INR >3.0 in patients <70 years), elderly (age >65 years), antiplatelet drugs (APD), and excess alcohol (consumption of ≥8 units alcohol/week).¹¹ Bilirubin values and details regarding non-steroidal anti-inflammatory drugs were unavailable in the Registry.

Antithrombotic therapies were categorized as either APD (aspirin, clopidogrel, ticlopidine, cilostazol, and prasugrel) or OAC (warfarin and 4 DOAC [dabigatran, rivaroxaban, apixaban, and edoxaban]). INR values were collected at the time of enrollment for patients taking warfarin. Japanese guidelines set different target INR ranges for patients taking warfarin: 1.6–2.6 for elderly (≥70 years) patients and 2.0–3.0 for younger (<70 years) patients.⁶

Endpoints

The primary endpoints in the present analysis were the composite of stroke or systemic embolism (SE) and major bleeding. Stroke was defined as the sudden onset of a focal neurologic deficit in a location consistent with the territory of a major cerebral artery, and was confirmed by computed tomography (CT) or magnetic resonance imaging. SE was defined as acute vascular occlusion of an extremity or organ and was confirmed by CT or angiography. Major bleeding was defined as a reduction in the hemoglobin level by at least 2 g/dL, the transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ, following the definition of the International Society on Thrombosis and Hemostasis.¹² Secondary endpoints in the present analysis were the individual components of the primary endpoint, namely stroke (all, ischemic, hemorrhagic), SE, intracranial hemorrhage, death (all-cause, cardiovascular, non-cardiovascular), hospitalization for HF, and myocardial infarction.

Statistical Analysis

Continuous variables are expressed as the mean±SD. Categorical variables are presented as absolute numbers and percentages. Annualized event rates of endpoints are expressed as the percentage per patient-year. The Kaplan-Meier method was used to estimate the cumulative incidence of clinical events. A Cox proportional hazards model was used to compare outcomes between groups, with the results expressed as hazard ratios (HRs) with a 95% confidence intervals (CIs).

The entire cohort (n=4,464, after excluding 25 patients whose data for prescription were unavailable) was divided into 3 groups according to OAC therapy status at baseline: No-OAC (n=1,976; 44.2%), warfarin (n=1,842; 41.3%), and DOAC (n=646; 14.5%). The entire cohort (n=4,489) was also divided into 2 groups according to year enrolled (2011–2013 [n=3,490; 77.7%] and 2014–2017 [n=999; 22.3%]) to compare patient backgrounds and outcomes before and after the release of updated Japanese guidelines for AF issued in 2014.⁶ The log-rank test was used to compare event incidences among groups.

Multivariate analysis was used to determine risk factors of the primary endpoints using a Cox proportional hazards model. Results were summarized using HRs and 95% CIs with adjustment for baseline variables (adjusted by including all the components of the CHA₂DS₂-VASc score for stroke/SE, and all the components of the HAS-BLED score for major bleeding, as well as other clinically relevant factors).

Two-sided P<0.05 was considered significant. All statistical analyses were performed using JMP version 16.1 (SAS Institute, Cary, NC, USA).

Results

Baseline Characteristics

Baseline characteristics are presented in Table 1. The study population reflected contemporary real-world clinical practice in Japan, including a large proportion of patients with advanced age. The mean age was 73.6±10.9 years, with patients >80 years accounting for 30.2% of the cohort. Almost half the patients had paroxysmal-type AF (49.5%). The mean body weight was 59.4 kg. Patients were likely to have various major comorbidities, including previous stroke (18.0%), HF (27.3%), hypertension (63.1%), diabetes (23.7%), coronary artery disease (14.5%), chronic kidney disease (35.9%), and a history of major bleeding (4.6%). At the time of enrollment, 6.5% of patients had undergone catheter ablation.

Table 1. Baseline Characteristics (n=4,489)

Male sex (%)	2,674 (59.6)
Age (years)	73.6±10.9
20–29	11 (0.2)
30–39	31 (0.7)
40–49	90 (2.0)
50–59	259 (5.8)
60–69	1,031 (23.0)
70–79	1,712 (38.1)
80–89	1,143 (25.5)
>90	212 (4.7)
≥70	3,067 (68.3)
≥75	2,279 (50.8)
≥80	1,355 (30.2)
Range	20–106
Type of AF
Paroxysmal	2,223 (49.5)
Persistent	464 (10.3)
Permanent	1,801 (40.1)
Height (cm)	160.0±10.1
Weight (kg)	59.4±13.5
<50	952 (23.8)
<60	2,070 (51.8)
Body mass index (kg/m²)	23.1±4.0
<18.5	425 (11.0)
18.5–25	2,313 (60.0)
≥25	1,117 (29.0)
Systolic BP (mmHg)	125.2±19.0
Diastolic BP (mmHg)	71.2±13.1
Heart rate (beats/min)	78.3±16.5
Asymptomatic	2,426 (54.1)
Symptomatic	2,062 (45.9)
Palpitation	1,440 (32.1)
Shortness of breath	583 (13.0)
Easy fatigue	339 (7.6)
Chest pain	123 (2.7)
Faintness	197 (4.4)
Enrollment year
2011	2,626 (58.5)
2012	399 (8.9)
2013	465 (10.4)
2014	389 (8.7)
2015	287 (6.4)
2016	221 (4.9)
2017	102 (2.3)
Type of institution
CV center	3,520 (78.4)
Small- and medium-sized hospitals	319 (7.1)
Primary care clinic	650 (14.5)
CHADS₂ score	2.03±1.33
CHA₂DS₂-VASc score	3.37±1.69
HAS-BLED score	1.75±1.04
Stroke/TIA/SE	902 (20.1)
Stroke	808 (18.0)
Ischemic	726 (16.2)
Hemorrhagic	84 (1.9)
Unknown	14 (0.3)
TIA	81 (1.8)
SE	54 (1.2)
HF	1,227 (27.3)
Hospitalization	732 (16.3)
NYHA class ≥II	729 (16.2)
EF <40%	205 (4.6)
Valvular heart disease	772 (17.2)
Mitral stenosis or prosthetic valve	131 (2.9)
Valve surgery	194 (4.3)
Cardiomyopathy	125 (2.8)
Hypertrophic	49 (1.1)
Dilated	60 (1.3)
Others	16 (0.4)
Hypertension	2,833 (63.1)
Diabetes	1,062 (23.7)
Dyslipidemia	1,983 (44.2)
Coronary artery disease	651 (14.5)
Previous MI	267 (5.9)
Previous PCI	366 (8.2)
Previous CABG	100 (2.2)
Peripheral artery disease	184 (4.1)
Previous PTA	70 (1.6)
Previous bypass surgery	25 (0.6)
Chronic kidney disease	1,611 (35.9)
Hemodialysis	108 (2.4)
COPD	238 (5.3)
Major bleeding	205 (4.6)
Device implantation	338 (7.5)
Pacemaker	293 (6.5)
ICD	23 (0.5)
CRT	9 (0.2)
CRT-D	13 (0.3)
Catheter ablation	294 (6.5)
Anticoagulation drugs	2,488 (55.7)
Warfarin	1,842 (41.3)
Dabigatran	164 (3.7)
Rivaroxaban	181 (4.1)
Apixaban	246 (5.5)
Edoxaban	55 (1.2)
Antiplatelet drugs	1,199 (26.9)
Aspirin	1,002 (22.4)
Clopidogrel	209 (4.7)
Cilostazol	105 (2.4)
Rhythm control drugs	880 (19.7)
Class Ia	188 (4.2)
Class Ic	580 (13.0)
Amiodarone	32 (0.7)
Rate control drugs	2,026 (45.4)
Digitalis	493 (11.0)
Verapamil	431 (9.7)
β-blockers	1,370 (30.7)
Antihypertensive drugs	2,511 (56.3)
ARB	1,613 (36.1)
ACEI	416 (9.3)
CCB	1,419 (31.8)
Diuretics	1,275 (28.6)
Loop	1,009 (22.6)
Spironolactone	436 (9.8)
Thiazides	192 (4.3)
Statins	1,095 (24.5)
Insulin	145 (3.2)
Oral hypoglycemic drugs	461 (10.3)

Data are given as n (%) or the mean±SD. ACEI, angiotensin-converting enzyme inhibitors; AF, atrial fibrillation; ARB, angiotensin receptor blockers; BP, blood pressure; CABG, coronary artery bypass grafting; CCB, calcium channel blockers; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronization therapy; CRT-D, cardiac resynchronization therapy with defibrillator; CV, cardiovascular; EF, ejection fraction; HF, heart failure; ICD, implantable cardioverter defibrillator; MI, myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; PTA, percutaneous transluminal angioplasty; SE, systemic embolism; TIA, transient ischemic attack.

Because of the large number of pre-existing AF patients enrolled during the first year of enrollment, the number of patients enrolled in 2011 was the highest (n=2,626; 58.5%), with approximately 400 patients per year enrolled in subsequent years.

The distribution of risk scores (CHADS₂, CHA₂DS₂-VASc, and HAS-BLED scores) is shown in Figure 1. The mean CHADS₂, CHA₂DS₂-VASc, and HAS-BLED scores were 2.03, 3.37, and 1.75, respectively. The proportion of patients determined to be at high risk of stroke was 61.4% according to a CHADS₂ of ≥2 and 85.9% according to a CHA₂DS₂-VASc of ≥2; the proportion of patients at high risk of bleeding was 21.7% (HAS-BLED score ≥3).

Figure 1.

Distribution of the risk scores (CHADS₂, CHA₂DS₂-VASc and HAS-BLED scores). Mean (±SD) scores are shown, as are the number of patients in each score category.

The distribution of antithrombotic therapy status according to CHADS₂ score is shown in Figure 2. At the time of enrollment, 55% of patients were receiving OAC (warfarin, 41%; DOAC, 14%) and 27% were receiving APD; 12% of patients were receiving a combination of OAC and APD. The use of OAC increased as the CHADS₂ score increased (37% for a score of 0, 48% for a score of 1 and 63% for a score of ≥2). Compared with patients enrolled in 2011–2013, those enrolled in 2014–2017 more often received OAC (53% vs. 65%, respectively) and less often received APD (30% vs. 17%, respectively). Warfarin was the predominant OAC therapy in patients enrolled in 2011–2013 (warfarin, 48%; DOAC, 5%), but DOAC surpassed warfarin among those enrolled in 2014–2017 (warfarin, 18%; DOAC, 47%).

Figure 2.

Distribution of antithrombotic therapy status (oral anticoagulants [OAC], OAC+antiplatelet drugs [APD], APD alone, or none) and OAC status (warfarin, direct oral anticoagulants [DOACs], or no OACs) according to CHADS₂ score among all patients (n=4,489), patients enrolled in 2011–2013 (n=3,490), and those enrolled in 2014–2017 (n=999).

Transition in Antithrombotic Therapy Status Over Time

Follow-up data, including prescription status, were collected every year and the year-by-year transition in antithrombotic therapy status was calculated from 2011 to 2021 (Figure 3). OAC prescriptions gradually increased with a growing proportion of DOAC, whereas APD prescriptions decreased, along with a decrease of in combination therapy. In 2011, 53% of patients were prescribed an OAC and warfarin was the predominant OAC therapy (warfarin, 51%; DOAC, 2%). Also in 2011, 32% of patients were receiving APD, with 14% receiving combination therapy. With a steadily increasing trend in the use of DOAC, DOAC overtook warfarin in 2016. As of 2021, 70% of patients were receiving OAC (warfarin, 18%; DOAC, 52%), and 14% were receiving APD (combination therapy, 7%).

Figure 3.

Year-by-year transition in antithrombotic therapy status (oral anticoagulants [OAC], OAC+antiplatelet drugs [APD], APD alone, or none) and OAC status (warfarin, direct oral anticoagulants [DOACs], or no OACs) from 2011 to 2021, calculated from annual follow-up data of prescription status.

Clinical Outcomes

The incidence of major clinical events is shown in Figure 4 and Table 2. Over a median follow-up period of 1,844 days (5.1 years; maximum 10 years), the annual incidence (% per patient-year) of stroke/SE, major bleeding, all-cause death, and hospitalization for HF was 2.2%, 1.9%, 4.9%, and 3.2%, respectively. Despite comparable baseline characteristics (age 73.7 vs. 73.2 years, CHADS₂ score 2.04 vs. 2.03, and HAS-BLED score 1.77 vs. 1.67 for the 2011–2013 vs. 2014–2017 cohort, respectively; Supplementary Table), event rates were generally lower for patients enrolled in 2014–2017 than 2011–2013 (stroke/SE, 2.3% vs. 1.6% [P<0.01]; major bleeding, 2.0% vs. 1.6% [P=0.07]; all-cause death, 5.0% vs. 4.2% [P<0.01]), except for hospitalization for HF (3.1% vs. 3.6%; P=0.27).

Figure 4.

Kaplan-Meier curves for the incidences of stroke/systemic embolism (SE), major bleeding, hospitalization for heart failure (HHF), and all-cause death for all patients (n=4,489), patients enrolled in 2011–2013 (n=3,490), and those enrolled in 2014–2017 (n=999).

Table 2. Incidence of Major Clinical Events

	All patients		No-OAC		Warfarin		DOAC		Enrolled in 2011–2013		Enrolled in 2014–2017		P value
	n	% per patient-year	n	% per patient-year	n	% per patient-year	n	% per patient-year	n	% per patient-year	n	% per patient-year	P value
Stroke/SE	497	2.2	205	2.1	247	2.5	43	1.5	433	2.3	64	1.6	<0.01
Stroke	479	2.1	195	2.0	241	2.4	41	1.4	418	2.2	61	1.5
Ischemic	353	1.5	145	1.5	176	1.7	31	1.0	307	1.6	46	1.1
Hemorrhagic	153	0.6	60	0.6	75	0.7	13	0.4	130	0.7	20	0.5
SE	22	0.1	11	0.1	9	0.1	2	0.1	19	0.1	3	0.1
Major bleeding	440	1.9	165	1.7	221	2.2	50	1.7	374	2.0	66	1.6	0.07
Intracranial	157	0.7	62	0.6	80	0.8	13	0.4	137	0.7	20	0.5
All-cause death	1,166	4.9	558	5.5	512	4.8	88	2.8	987	5.0	179	4.2	<0.01
CV death	195	0.8	74	0.7	108	1.0	13	0.4	161	0.8	34	0.8
Non-CV death	971	4.1	484	4.8	404	3.8	75	2.4	826	4.2	145	3.4
Hospitalization for HF	702	3.2	240	2.5	374	3.9	86	3.0	562	3.1	140	3.6	0.27
MI	47	0.2	21	0.2	24	0.2	2	0.1	41	0.2	6	0.1	0.26

DOAC, direct oral anticoagulants; OAC, oral anticoagulants. Other abbreviations as in Table 1. P value for comparison between patients enrolled in 2011–2013 and those enrolled in 2014–2017.

The incidence of major clinical events according to OAC status is shown in the Supplementary Figure and Table 2. In the presence of substantial differences in clinical background among the 3 groups (Supplementary Table), compared with the No-OAC groups as a reference, warfarin use was associated with a non-significantly higher incidence of stroke/SE (HR 1.17; 95% CI 0.97–1.41; P=0.09), whereas DOAC use was associated with significantly lower incidence of stroke/SE (HR 0.69; 95% CI 0.49–0.96; P=0.03). Warfarin use was associated with a significantly higher incidence of major bleeding (HR 1.32; 95% CI 1.08–1.61; P<0.01), whereas DOAC use was not (HR 0.99; 95% CI 0.73–1.37; P=0.99). Patients enrolled in 2011–2013 showed a similar trend, but, in patients enrolled in 2014–2017, the incidence of stroke/SE was numerically lower in both the warfarin (HR 0.67; 95% CI 0.32–1.39; P=0.28) and DOAC (HR 0.68; 95% CI 0.40–1.17; P=0.16) groups, whereas the incidence of major bleeding was higher (HR 1.85 [95% CI 0.91–3.74; P=0.09] and HR 1.49 [95% CI 0.81–2.74; P=0.20], respectively), although the differences did not reach statistical significance.

Risk Factors of Events

The risk factors for the primary endpoints (stroke/SE and major bleeding) are presented in Table 3. Multivariate analysis using a Cox proportional hazard model revealed that the independent risk factors for stroke/SE were age 75–84 years (HR 1.70; 95% CI 1.38–2.10; P<0.01), age ≥85 years (HR 2.27; 95% CI 1.68–3.07; P<0.01), a history of stroke/SE (HR 1.72; 95% CI 1.39–2.12; P<0.01), chronic kidney disease (HR 1.31; 95% CI 1.07–1.60; P<0.01), and low (≤50 kg) body weight (HR 1.59; 95% CI 1.24–2.05; P<0.01). The independent risk factors for major bleeding were abnormal renal function (HR 1.92; 95% CI 1.26–2.93; P<0.01), bleeding history (HR 1.77; 95% CI 1.39–2.26; P<0.01), labile INR (HR 2.17; 95% CI 1.27–3.73; P<0.01), age >65 years (HR 2.17; 95% CI 1.58–2.97; P<0.01), and APD use (HR 1.25; 95% CI 1.02–1.53; P=0.03).

Table 3. Risk Factors for Events

Variable	Univariate		Multivariate
Variable	HR (95% CI)	P value	HR (95% CI)	P value
Stroke/SE
Heart failure	1.24 (1.12–1.51)	0.03	1.00 (0.80–1.25)	0.98
Hypertension	1.11 (0.93–1.34)	0.25	1.02 (0.84–1.26)	0.78
Age (years)
<75	1 [Ref.]		1 [Ref.]
75–84	1.96 (1.62–2.39)	<0.01	1.70 (1.38–2.10)	<0.01
≥85	3.09 (2.38–4.01)	<0.01	2.27 (1.68–3.07)	<0.01
Diabetes	1.25 (1.03–1.52)	0.02	1.22 (0.99–1.50)	0.06
History of stroke/SE	1.95 (1.60–2.37)	<0.01	1.72 (1.39–2.12)	<0.01
Vascular disease	1.31 (0.98–1.74)	0.07	1.02 (0.75–1.39)	0.88
Female sex	1.10 (0.92–1.32)	0.27	0.78 (0.63–0.98)	0.03
Non-paroxysmal AF	1.24 (1.03–1.47)	0.02	1.15 (0.94–1.40)	0.16
Chronic kidney disease	1.58 (1.32–1.89)	<0.01	1.31 (1.07–1.60)	<0.01
Low body weight (≤50 kg)	1.66 (1.35–2.05)	<0.01	1.59 (1.24–2.05)	<0.01
No OAC	1.06 (0.89–1.27)	0.51	1.12 (0.73–1.09)	0.27
Major bleeding
Hypertension (SBP ≥160 mmHg)	1.48 (0.98–2.25)	0.07	1.47 (0.97–2.24)	0.07
Abnormal renal function	2.41 (1.61–3.62)	<0.01	1.92 (1.26–2.93)	<0.01
Abnormal liver function	0.56 (0.18–1.75)	0.32	0.59 (0.19–1.85)	0.37
Stroke history	1.32 (1.04–1.68)	0.02	1.06 (0.83–1.35)	0.66
Bleeding history	2.07 (1.65–2.60)	<0.01	1.77 (1.39–2.26)	<0.01
Labile INR	2.66 (1.56–4.53)	<0.01	2.17 (1.27–3.73)	<0.01
Elderly (age >65 years)	2.40 (1.77–3.27)	<0.01	2.17 (1.58–2.97)	<0.01
Antiplatelet drugs	1.30 (1.06–1.59)	0.01	1.25 (1.02–1.53)	0.03
Excess alcohol	1.03 (0.82–1.30)	0.78	1.12 (0.88–1.41)	0.36
OAC	1.24 (1.02–1.51)	0.03	1.19 (0.97–1.45)	0.09

Variables were the components of CHA₂DS₂-VASc score for stroke/systemic embolism (SE) and HAS-BLED score for major bleeding, and other clinically relevant factors. AF, atrial fibrillation; CI, confidence interval; HR, hazard ratio; INR, international normalized ratio of prothrombin time; OAC, oral anticoagulants; SBP, systolic blood pressure.

Discussion

The main findings of the present study are as follows. First, over the past 10 years, after the release of DOAC, antithrombotic therapy has undergone a major transition, with a steady increase in the use of OAC (from almost 50% to 70%) and a decrease in the use of APD (from 30% to 15%). Second, the approximate annual incidence rates of major clinical events were stroke/SE 2%, major bleeding 2%, death 5%, and hospitalization for heart failure 3%. Except for hospitalization for HF, the rates of these major clinical events were generally lower among patients enrolled after the Japanese guidelines issued in 2014,⁶ suggesting that growing use of DOAC may have, at least in part, contributed to the lower incidence of events. Third, the independent risk factors for stroke/SE were advanced age, previous stroke/SE, low body weight, and chronic kidney disease, whereas those for major bleeding were abnormal renal function, bleeding history, labile INR for warfarin users, being elderly, and the use of APD.

Major Change in OAC Therapy

Since the sequential launch of DOAC (dabigatran in 2011, rivaroxaban in 2012, apixaban in 2013, and edoxaban in 2014), and the release of new Japanese AF guidelines in 2014 recommending DOAC as the first-line OAC therapy,⁶ the market share of DOACs has steadily increased. In the early years, DOACs were used in relatively younger patients and in those with preserved renal function, but recently they have been more frequently used in elderly patients and those with renal dysfunction.¹³ This indicates that the effectiveness and safety of DOACs have been accepted in real-world clinical practice.

Position of APD and Combination Therapy in AF

In the warfarin era, APDs (mostly aspirin) were frequently prescribed as a substitute for warfarin, and more than 30% of patients were receiving an APD when the Registry was started in 2011. Many studies have demonstrated that the use of APD alone is not effective in stroke prevention in AF patients.¹⁴^,¹⁵ Randomized clinical trials, such as AFIRE¹⁶ and OAC-ALONE,¹⁷ and observational studies¹⁸^,¹⁹ have not shown benefits of combination OAC and APD therapy in patients with AF and coronary artery disease. Subanalysis of the AFIRE trial recently demonstrated that major bleeding, which prevailed in the combination group, was associated with subsequent major adverse cardiac and cerebrovascular events.²⁰ We also reported higher mortality after major bleeding in AF patients enrolled in the Registry.²¹ We have observed a steady decrease in APD therapy over the past 10 years, but 8% of patients still received APD monotherapy and 7% received combination therapy as of 2021. Further optimization of antithrombotic therapy is needed.

Outcomes of Patients With AF

The incidence of major adverse events appeared to decrease over the past 10 years. The reason for this could be multifactorial; there have been major advances in medical therapeutics and management, as well as changes in patient awareness and self-care. Catheter ablation had been performed in 294 patients (6.5% of the entire cohort) at the time of enrollment, but it has been performed in 532 patients (11.9%), including during the follow-up period, and this may have contributed to the decrease in the incidence of events among AF patients.²² As shown in the present study, there was a major transition in antithrombotic therapy with the more widespread use of DOAC, and this may also have contributed to the decreased incidence of events. Doctors have been relieved of the cumbersome management of warfarin, and patients have been more likely to receive the benefit of OAC therapy. Based on 1-year outcome data of the Registry, we previously reported that the use of OAC, mainly warfarin, was not associated with better outcomes,⁸ but the situation may have been improved by the efforts of many people involved in this field. Suzuki et al reported 9-year trends (from 2004 to 2013) of anticoagulation therapy and outcomes of Japanese AF patients in the Shinken database.²³ Despite the different study periods and different clinical backgrounds of patients between Shinken and Fushimi, Suzuki et al also reported an increased use of DOAC and a decreased incidence of thromboembolism and bleeding.²³

Risk Factors of Events

To stratify the risk of stroke, Japanese guidelines⁶ recommend using the CHADS₂ score and Western guidelines⁴^,⁵ recommend using the CHA₂DS₂-VASc score, but the predictive performance of these scores is not high and, in the present analysis, only age and previous stroke remained significant factors predictive of clinical events. We have reported other risk factors from the Registry, including low body weight,²⁴ creatinine clearance,²⁵ type of AF,²⁶ progression of AF type,²⁷ left atrial enlargement,²⁸ and left ventricular hypertrophy.²⁹ Recently, risk factors of Japanese AF patients have been identified from a combined cohort of 5 major AF registries, including ours,³⁰ and a novel risk score, HELT-E₂S₂, has been developed.³¹ We hope this score will be implemented in practice and contribute to better management of AF patients. There have been no well-established bleeding risk scores, and it is expected that a novel score will be developed with international consensus, such as the Academic Research Consortium for High Bleeding Risk in the field of coronary intervention.³²

Study Limitations

This study has several limitations. First, this is an observational study and it provides only associative, not causative, evidence. We cannot rule out the possibility of unmeasured confounders. Second, prescription status was measured annually, and many patients have gone through several transitions of OAC status during follow-up. However, all patients were categorized by OAC status at enrollment, and these transitions were not considered in the present analysis. Third, we investigated neither the time in therapeutic range for patients taking warfarin during follow-up nor the drug adherence of OAC therapy, and therefore it is difficult to know how the quality of warfarin control and drug adherence of OAC therapy influenced outcomes. Fourth, although the frequent use of ‘under-dosing’ of DOAC may have some effect on clinical outcomes, we were unable to incorporate this important issue in the present analysis. Fifth, DOAC appeared to perform better than warfarin in terms of effectiveness and safety, as shown in the Supplementary Figure. However, this unadjusted comparison should be interpreted with caution because the indication or selection of OAC was according to the discretion of the attending physicians, and each the DOACs were launched in different years. Statistical comparisons among different DOACs can be misleading, and therefore we decided not to conduct such comparisons in the present analysis. Finally, this study involved AF patients recruited from a small region of Japan, and so the study results may not be applicable to other populations.

Conclusions

Over the past 10 years, there has been a major transition in antithrombotic therapy and a decline in the incidence of adverse events in patients with AF.

Acknowledgments

The authors sincerely appreciate the help of all the institutions participating in the Registry and the clinical research coordinators (T. Shinagawa, M. Mitamura, M. Fukahori, M. Kimura, M. Fukuyama, C. Kamata, N. Nishiyama).

Sources of Funding

This study was supported, in part, by the Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus from Japan Agency for Medical Research and Development (AMED; 19ek210082 h3 and 18ek210056 h3).

The Fushimi AF Registry is supported by research funding from Boehringer Ingelheim, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Astellas Pharma, AstraZeneca, Daiichi Sankyo, Novartis Pharma, MSD, Sanofi-Aventis, and Takeda Pharmaceutical. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Disclosures

M. Akao has received research funding from Bayer Yakuhin, scholarship funds from Bayer Yakuhin and Daiichi-Sankyo, and lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Yakuhin, and Daiichi-Sankyo. The remaining authors have no relationships relevant to the content of this paper to disclose.

IRB Information

The study protocol was approved by the institutional review boards of the National Hospital Organization Kyoto Medical Center and Ijinkai Takeda General Hospital (Reference no. 10-058 and 14-033).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-22-0023

References

Corresponding author

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