Sex-Related Differences in the Clinical Events of Patients With Atrial Fibrillation　― The Fushimi AF Registry ―

Hisashi Ogawa; Yasuhiro Hamatani; Kosuke Doi; Yuji Tezuka; Yoshimori An; Mitsuru Ishii; Moritake Iguchi; Nobutoyo Masunaga; Masahiro Esato; Yeong-Hwa Chun; Hikari Tsuji; Hiromichi Wada; Koji Hasegawa; Mitsuru Abe; Gregory YH Lip; Masaharu Akao; on behalf of the Fushimi AF Registry Investigators

doi:10.1253/circj.CJ-17-0071

Abstract

Background: Female sex is considered a risk factor for thromboembolism in patients with atrial fibrillation (AF), and is included in the risk stratification scheme, CHA₂DS₂-VASc score. The purpose of the present study was to investigate the clinical outcomes of female Japanese AF patients.

Methods and Results: The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto. Follow-up data were available for 3,878 patients. Female AF patients (n=1,551, 40.0%) were older (77.0 vs. 71.4 years; P<0.001) than male patients (n=2,327, 60.0%). Female patients were more likely to have heart failure (31.1% vs. 23.7%; P<0.001). Previous stroke incidence (19.2% vs. 21.4%; P=0.083) was comparable between male and female patients. During the median follow-up period of 1,102 days, Cox regression analysis demonstrated that female sex was not independently associated with a risk of stroke or systemic embolism (adjusted hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.54–1.00, P=0.051). However, female sex showed an association with a lower risk of intracranial hemorrhage (adjusted HR 0.54; 95% CI: 0.30–0.95, P=0.032) and all-cause death (adjusted HR 0.56; 95% CI: 0.46–0.68, P<0.001).

Conclusions: We demonstrated that female sex is not independently associated with an increased risk of thromboembolism, but is associated with a decreased risk of intracranial hemorrhage and all-cause death in Japanese AF patients enrolled in the Fushimi AF Registry.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and increases the risk of ischemic stroke and death.¹^,² Previous studies have indicated sex-related differences in the clinical characteristics and outcomes of AF patients.³^–⁶ Female sex is considered an increased risk for thromboembolism in patients with AF, albeit with an age-dependency (being relevant at age ≥65 or with other risk factors) and is included in the CHA₂DS₂-VASc score for stroke risk stratification.⁷^–¹⁰ A recent Swedish study also demonstrated that female AF patients aged ≥75 years are at higher risk of ischemic stroke,¹¹ but other studies have reported conflicting results.¹²^,¹³

In Japanese patients with AF, the J-RHYTHM registry concluded that female sex was not an independent risk factor for thromboembolic events and that male sex was a risk factor for major bleeding and all-cause death.¹⁴ In addition, they validated that the ‘CHA₂DS₂-VA score’, excluding female sex, was performed similarly for risk stratification for thromboembolic events.¹⁵ However, a Taiwanese study indicated that females had a higher rate of ischemic stroke than males among patients with AF who were not taking anticoagulants and aged <65 years.¹⁶ In a Chinese AF registry, it was shown that female sex was also a risk factor for stroke in Chinese AF patients.¹⁷ Quinn et al recently reported that the global incidence rates of stroke were highly heterogeneous in different cohorts of patients with AF.¹⁸ These observations suggest that the sex-related differences in the event risk of AF patients might differ among races or countries.

The aim of this present study was to assess the characteristics of female AF patients and the effect of female sex on thromboembolism and various clinical events in a cohort of AF patients enrolled in a specific region of Japan.

Methods

Study Patients

The detailed study design, patient enrollment, the definition of the measurements, and subjects’ baseline clinical characteristics of the Fushimi AF Registry have been previously described (UMIN Clinical Trials Registry: UMIN000005834).¹⁹ The inclusion criterion for the registry was the documentation of AF on 12-lead ECG or Holter monitoring at any time. There were no exclusion criteria. A total of 80 institutions, all of which are members of Fushimi-Ishikai (Fushimi Medical Association), participated in the registry. The participating institutions comprised 2 cardiovascular centers (National Hospital Organization Kyoto Medical Center and Ijinkai Takeda Hospital), 9 small- and medium-sized hospitals, and 69 primary care clinics. The enrollment of patients started in March 2011 and all participating institutions attempted to enroll consecutive patients with AF under regular outpatient care or under admission. Clinical data of the patients were registered in the Internet Database System (https://edmsweb16.eps.co.jp/edmsweb/002001/FAF/top.html) by the doctors in charge at each institution. Data were automatically checked for missing or contradictory entries and values out of the normal range. Additional editing checks were performed by clinical research coordinators in the General Office of the registry. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, and was approved by the ethics committees of the National Hospital Organization Kyoto Medical Center and Ijinkai Takeda General Hospital.

Valvular AF was defined as AF with a rheumatic mitral stenosis or a prosthetic heart valve. The primary endpoint in the analysis was the incidence of stroke or systemic embolism (SE) during the follow-up period. Other clinical endpoints included the incidence of major bleeding, all-cause death, cardiovascular death, hospitalization for heart failure (HF) and myocardial infarction (MI) during the follow-up period. 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 the diagnosis of ischemic or hemorrhagic stroke was confirmed by computed tomography or magnetic resonance imaging. SE was defined as an acute vascular occlusion of an extremity or organ. Major bleeding was defined as a reduction in the hemoglobin level of at least 2 g/dL, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. Intracranial hemorrhage (ICH) was defined as the bleeding within the intracranial vault, including intracerebral hemorrhage, subarachnoid hemorrhage, epidural hemorrhage, and subdural hemorrhage. Oral anticoagulants (OAC) included warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban. Antiplatelet drugs (APD) included aspirin, clopidogrel, prasugrel, ticlopidine and cilostazol. The prothrombin time-international normalized ratio (PT-INR) values were collected at the time of enrollment.

Statistical Analysis

Continuous variables are expressed as mean and standard deviation (SD). Categorical variables are presented as numbers and percentages. We compared categorical variables using the chi-square test and continuous variables using independent samples t-test for normally distributed data or the Mann-Whitney U-test for non-normal distribution. The Kaplan-Meier method was used to estimate the cumulative incidences of clinical events. We carried out multivariate analysis using the Cox proportional hazards model. The covariates chosen to be included were age, body weight, paroxysmal AF, previous stroke or transient ischemic attack (TIA) or SE, HF, hypertension, diabetes mellitus (DM), coronary artery disease (CAD), peripheral artery disease (PAD), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), previous major bleeding, β-blocker prescription, prescription of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB), APD prescription and OAC prescription at baseline.

The analyses were performed using JMP version 12.2.0 (SAS Institute, Cary, NC, USA). Statistical significance was set at a two-sided P-value <0.05.

Results

Of 4,392 patients who were enrolled 1 year before (by the end of July 2015), follow-up data (collected annually) 3,979 patients (90.6%) were available as of July 2016. Of these 3,979 patients, we excluded patients whose prescription data were unavailable and those with valvular AF. Analyses were performed on 3,878 non-valvular AF patients. Characteristics of the patients at baseline, stratiﬁed by sex, are shown in Table 1. Female AF patients (n=1,551, 40.0%) were significantly older (77.0 vs. 71.4 years, P<0.001) and had lower mean body weight and body mass index (BMI) (51.2 vs. 64.9 kg, P<0.001; 22.5 vs. 23.5 kg/m², P<0.001). Female patients were more likely to have HF (31.1% vs. 23.7%, P<0.001), dyslipidemia (46.2% vs. 41.4%, P=0.004) and CKD (39.1% vs. 33.7%, P<0.001). Female patients were less likely to have DM (19.5% vs. 25.5%, P<0.001), CAD (12.9% vs. 16.1%, P=0.006) or COPD (2.9% vs. 6.8%, P<0.001). Previous stroke, TIA or SE (19.2% vs. 21.4%; P=0.083) and hypertension (64.4% vs. 61.5%; P=0.072) were comparable between male and female patients. Female patients had higher CHADS₂ score, and higher CHA₂DS₂-VASc score without the ‘Sc’ factor. They had lower HAS-BLED scores despite older age, because they were less likely to have the ‘D’ factor (antiplatelet drugs and alcohol excess) of HAS-BLED.

Table 1. AF Patients’ Characteristics and Medications at Baseline

	Overall 3,878 (100.0)	Female 1,551 (40.0)	Male 2,327 (60.0)	P value
Mean age (SD), years	73.7 (11.0)	77.0 (10.5)	71.4 (10.7)	<0.001
Age <65 years, number (%)	689 (17.8)	179 (11.5)	510 (21.9)	<0.001
Age 65–74 years, number (%)	1,205 (31.1)	385 (24.8)	820 (35.2)
Age ≥75 years, number (%)	1,984 (51.2)	987 (63.6)	997 (42.8)
Mean body weight (SD), kg	59.4 (13.3)	51.2 (11.0)	64.9 (11.8)	<0.001
Mean body mass index (SD), kg/m²	23.1 (4.0)	22.5 (4.3)	23.5 (3.7)	<0.001
Mean systolic blood pressure (SD), mmHg	124.9 (19.0)	125.3 (19.8)	124.7 (18.3)	0.473
Mean diastolic blood pressure (SD), mmHg	70.9 (12.8)	70.3 (13.0)	71.3 (12.7)	0.002
Mean heart rate (SD), beats/min	78.3 (16.4)	79.5 (17.7)	77.4 (15.5)	0.005
Type of AF
Paroxysmal, n (%)	1,906 (49.1)	793 (51.1)	1,113 (47.8)	0.118
Persistent, n (%)	367 (9.5)	145 (9.4)	222 (9.5)
Permanent, n (%)	1,605 (41.4)	613 (39.5)	992 (42.6)
Asymptomatic, n (%)	2,059 (53.1)	743 (47.9)	1,316 (56.6)	<0.001
Mean CHADS₂ score (SD)	2.03 (1.34)	2.15 (1.31)	1.95 (1.34)	<0.001
Mean CHA₂DS₂-VASc score (SD)	3.37 (1.70)	4.13 (1.52)	2.86 (1.62)	<0.001
Mean CHA₂DS₂-VASc score excluding “Sc” (SD)	2.97 (1.59)	3.13 (1.52)	2.86 (1.62)	<0.001
Mean HAS-BLED score (SD)	1.75 (1.04)	1.70 (0.99)	1.79 (1.08)	0.007
Previous stroke/TIA/SE, n (%)	796 (20.5)	297 (19.2)	499 (21.4)	0.083
Heart failure, n (%)	1,034 (26.7)	482 (31.1)	552 (23.7)	<0.001
Hypertension, n (%)	2,429 (62.6)	998 (64.4)	1,431 (61.5)	0.072
Diabetes mellitus, n (%)	896 (23.1)	302 (19.5)	594 (25.5)	<0.001
Dyslipidemia, n (%)	1,680 (43.3)	716 (46.2)	964 (41.4)	0.004
Coronary artery disease, n (%)	575 (14.8)	200 (12.9)	375 (16.1)	0.006
Peripheral artery disease, n (%)	160 (4.1)	56 (3.6)	104 (4.5)	0.188
Chronic kidney disease, n (%)	1,391 (35.9)	606 (39.1)	785 (33.7)	<0.001
Chronic obstructive pulmonary disease, n (%)	202 (5.2)	45 (2.9)	157 (6.8)	<0.001
History of major bleeding, n (%)	161 (4.2)	70 (4.5)	91 (3.9)	0.357
OAC, n (%)	2,086 (53.8)	774 (49.9)	1,312 (56.4)	<0.001
Warfarin, n (%)	1,703 (43.9)	634 (40.9)	1,069 (45.9)	0.002
DOAC, n (%)	383 (9.9)	140 (9.0)	243 (10.4)	0.148
Dabigatran, n (%)	147 (3.8)	45 (2.9)	102 (4.4)	0.018
Rivaroxaban, n (%)	121 (3.1)	49 (3.2)	72 (3.1)	0.909
Apixaban, n (%)	113 (2.9)	46 (3.0)	67 (2.9)	0.875
Edoxaban, n (%)	2 (0.1)	0 (0.0)	2 (0.1)	0.248
APD, n (%)	1,096 (28.3)	392 (25.3)	704 (30.3)	0.001
Aspirin, n (%)	922 (23.8)	333 (21.5)	589 (25.3)	0.006
Clopidogrel, n (%)	183 (4.7)	51 (3.3)	132 (5.7)	0.001
Digitalis, n (%)	446 (11.5)	195 (12.6)	251 (10.8)	0.088
Verapamil, n (%)	391 (10.1)	189 (12.2)	202 (8.7)	<0.001
β-blockers, n (%)	1,152 (29.7)	474 (30.6)	678 (29.1)	0.342
Antiarrhythmic drugs, n (%)	771 (19.9)	297 (19.2)	474 (20.4)	0.351
Amiodarone, n (%)	23 (0.6)	7 (0.5)	16 (0.7)	0.348
ACE-I/ARB, n (%)	1,721 (44.4)	681 (43.9)	1,040 (44.7)	0.630
CCB, n (%)	1,218 (31.4)	480 (31.0)	738 (31.7)	0.614
Loop diuretics, n (%)	864 (22.3)	419 (27.0)	445 (19.1)	<0.001
Spironolactone, n (%)	366 (9.4)	177 (11.4)	189 (8.1)	0.001
Statins, n (%)	924 (23.8)	433 (27.9)	491 (21.1)	<0.001
Insulin, n (%)	128 (3.3)	49 (3.2)	79 (3.4)	0.687

ACE-I, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; APD, antiplatelet drugs; ARB, angiotensin II receptor blocker; CCB, calcium-channel blocker; DOAC, direct oral anticoagulants; OAC, oral anticoagulants; SD, standard deviation; SE, systemic embolism; TIA, transient ischemic attack.

The age distribution of the female and male patients is shown in Figure 1A. The histogram of female patients shifted rightward, and patients aged ≥85 years were more prevalent among females. Figure 1B shows the distribution of the CHADS₂ score. The distribution histogram of the female patients shifted rightward, with a CHADS₂ score of 2 being the most common category. A CHADS₂ score of 1 was the most prevalent among the male patients.

Figure 1.

Distribution of age (A) and CHADS₂ score (B) in female and male patients. The proportions of patients prescribed OAC by sex according to age (C) and according to CHADS₂ score (D). OAC, oral anticoagulant.

OAC Prescription and PT-INR Control of Patients Taking Warfarin

Female patients had less baseline prescriptions of OAC and APD than male patients (OAC: 49.9% vs. 56.4%, P<0.001; APD: 25.3% vs. 30.3%, P=0.001). OAC prescription according to age is shown in Figure 1C and according to CHADS₂ score in Figure 1D. Female patients were prescribed less OAC for each stratum of age (Figure 1C) and CHADS₂ score (Figure 1D) than males. OAC prescription for both male and female patients increased according to CHADS₂ score, but the prescription of OAC was generally less for female patients than for males, in all age and CHADS₂ strata.

Table 2 shows the PT-INR values of patients taking warfarin. The mean PT-INR value was significantly lower in female patients than in males (1.78 vs. 1.84, P=0.040). The PT-INR values were comparable between male and female patients across all age subgroups subdivided by the different PT-INR targets, given that Japanese treatment guidelines²⁰ recommend different target PT-INR for patients taking warfarin: 1.6–2.6 for elderly patients (≥70 years old) and 2.0–3.0 for younger patients (<70 years old).

Table 2. Proportions of AF Patients in PT-INR Range While Taking Warfarin

n (%)	Overall			Age <70 years			Age ≥70 years
n (%)	Female	Male	P value	Female	Male	P value	Female	Male	P value
PT-INR range
<1.60	144 (33.3)	230 (29.8)	0.372	32 (40.0)	89 (33.0)	0.505	112 (31.7)	141 (28.1)	0.392
1.60–1.99	169 (39.0)	287 (37.2)		30 (37.5)	103 (38.2)		139 (39.4)	184 (36.7)
2.00–2.59	101 (23.3)	209 (27.1)		16 (20.0)	58 (21.5)		85 (24.1)	151 (30.1)
2.60–2.99	13 (3.0)	29 (3.8)		1 (1.3)	11 (4.1)		12 (3.4)	18 (3.6)
≥3.00	6 (1.4)	17 (2.2)		1 (1.3)	9 (3.3)		5 (1.4)	8 (1.6)
Mean, (SD)	1.78 (0.46)	1.84 (0.47)	0.040	1.72 (0.47)	1.82 (0.51)	0.105	1.80 (0.45)	1.85 (0.45)	0.063

PT-INR, prothrombin time-international normalized ratio. Other abbreviations as in Table 1.

Incidence of Clinical Events by Sex

Outcomes by sex and unadjusted hazard ratios (HR) for female patients are shown in Table 3. During the median follow-up of 1,102 days, stroke/SE occurred in 109 female patients (2.46 per 100 person-years) and 167 male patients (2.39 per 100 person-years), with an unadjusted HR for female of 1.03 (95% confidence interval [CI]: 0.81–1.31, P=0.800). Major bleeding occurred in 73 female patients (1.64 per 100 person-years) and 146 male patients (2.08 per 100 person-years) (unadjusted HR 0.79 (95% CI: 0.60–1.05, P=0.104). Of note, ICH occurred in 24 females (0.53 per 100 person-years) and 61 males (0.85 per 100 person-years), with an unadjusted HR for females of 0.63 (95% CI: 0.38–0.99, P=0.045). A total of 291 female patients (6.42 per 100 person-years) and 373 male patients (5.16 per 100 person-years) died from any cause during the follow-up period; unadjusted HR 1.23 (95% CI: 1.05–1.43, P=0.009). Subgroup analysis of the effect of DM for all-cause death demonstrated that unadjusted HRs for all-cause death were 1.31 (95% CI: 0.97–1.77, P=0.079) in patients with DM and 1.22 (95% CI: 1.02–1.45, P=0.033) in patients without DM. There was no significant interaction for sex-related difference and DM (P=0.665). Cardiovascular death occurred in 55 female patients (1.21 per 100 person-years) and 52 male patients (0.72 per 100 person-years), with an unadjusted HR for female of 1.68 (95% CI: 1.15–2.46, P=0.008). The majority of patients died of non-cardiovascular causes: 173 patients among females (3.82 per 100 person-years) and 250 patients among males (3.46 per 100 person-years). In particular, 47 females (16.2% of all deceased patients) and 110 males (29.5%) died from any malignancy, and 49 females (16.8%) and 61 males (16.4%) died from infection or sepsis. Undetermined deaths occurred in 63 females and 71 males. Causes of death were significantly different between females and males (P<0.001). A total of 182 female patients (4.25 per 100 person-years) and 207 male patients (3.01 per 100 person-years) were hospitalized for HF (unadjusted HR 1.41; 95% CI 1.16–1.72, P=0.001).

Table 3. Incidence of Clinical Events During Follow-up (per 100 Person-Years)

	Female		Male		Unadjusted hazard ratio (95% CI)	P value
	No. of events	Event rate (per 100 person-years)	No. of events	Event rate (per 100 person-years)	Unadjusted hazard ratio (95% CI)	P value
Stroke/systemic embolism	109	2.46	167	2.39	1.03 (0.81–1.31)	0.800
Any-cause stroke	103	2.32	165	2.36	0.99 (0.77–1.26)	0.910
Hemorrhagic stroke	22	0.49	57	0.80	0.62 (0.37–0.99)	0.046
Ischemic stroke	82	1.84	111	1.57	1.17 (0.88–1.55)	0.282
Ischemic stroke/systemic embolism	88	1.98	114	1.61	1.22 (0.92–1.61)	0.156
Systemic embolism	6	0.13	3	0.04	3.15 (0.83–14.92)	0.092
Major bleeding	73	1.64	146	2.08	0.79 (0.60–1.05)	0.104
Intracranial	24	0.53	61	0.85	0.63 (0.38–0.99)	0.045
Extracranial	50	1.12	91	1.28	0.88 (0.62–1.24)	0.466
All-cause death	291	6.42	373	5.16	1.23 (1.05–1.43)	0.009
Cardiovascular death	55	1.21	52	0.72	1.68 (1.15–2.46)	0.008
Non-cardiovascular death	173	3.82	250	3.46	1.09 (0.89–1.32)	0.396
Hospitalization for heart failure	182	4.25	207	3.01	1.41 (1.16–1.72)	0.001
Myocardial infarction	15	0.33	13	0.18	1.84 (0.87–3.93)	0.108

CI, confidence interval; NA, not applicable. Other abbreviations as in Table 1.

Kaplan-Meier curves for stroke/SE (Figure 2A) and ischemic stroke/SE (Figure 2B) demonstrated that the crude incidences of stroke/SE and ischemic stroke/SE were comparable between females and males. Furthermore, Kaplan-Meier analysis for the incidence of major bleeding (Figure 2C) and ICH (Figure 2D) demonstrated that the crude incidence of ICH was significantly higher in male patients (log-rank test: P=0.0498).

Figure 2.

Kaplan-Meier curves for the incidences of stroke/SE (A), ischemic stroke/SE (B), major bleeding (C) and intracranial hemorrhage (D) in female and male patients. SE, systemic embolism.

Unadjusted HR of ischemic stroke/SE for female patients, according to important subgroups, is shown in Figure 3A. The risk of ischemic stroke/SE was comparable in the subgroups of OAC, APD and CHADS₂ score; however, female sex was associated with a lower incidence of ischemic stroke/SE in patients aged <75 years (HR 0.54, 95% CI: 0.27–0.98, P=0.043). There was significant interaction for sex-related difference and age for ischemic stroke/SE (P=0.014 for interaction). The number of events and unadjusted HR of ICH with and without major cofactors are shown in Figure 3B. Generally, female patients had a lower risk of ICH in almost all of the subgroups. Notably, the risk of ICH was significantly lower in female patients aged ≥75 years (HR 0.37, 95% CI: 0.19–0.66; P<0.001). Significant interaction for a sex-related difference and age was shown for the incidence of ICH (P=0.017 for interaction).

Figure 3.

Unadjusted hazard ratios for ischemic stroke/SE (A) and intracranial hemorrhage (B) in female patients, according to major subgroups. Forest plots show hazard ratios with error bars indicating 95% CI. APD, antiplatelet drug; CI, confidence interval; OAC, oral anticoagulant; SE, systemic embolism.

On multivariate Cox regression analysis, female sex (HR 0.74; 95% CI: 0.54–1.00; P=0.051) was not significantly associated with an increased risk of stroke/SE in the overall study cohort (Table 4). Using multivariate analysis on patients without OAC, female sex did not show an independent association with the risk of stroke/SE (HR 0.92, 95% CI: 0.58–1.45, P=0.716) or ischemic stroke/SE (HR 1.19, 95% CI: 0.70–2.02, P=0.523). Multivariate Cox regression analysis indicated that female sex was associated with a decreased risk of ischemic stroke (HR 0.57, 95% CI: 0.35–0.94, P=0.026) in patients with OAC and of hemorrhagic stroke (HR 0.38, 95% CI: 0.14–0.94, P=0.035) in patients without OAC. Hence, female sex was not independently associated with an increased risk of major bleeding (HR 0.79; 95% CI: 0.56–1.12; P=0.187), but was associated with a decreased risk of ICH (HR 0.54; 95% CI: 0.30–0.95, P=0.032). Female sex was associated with a reduced risk of all-cause death (HR 0.56; 95% CI: 0.46–0.68; P<0.001), but not cardiovascular death, hospitalization for HF and MI.

Table 4. Multivariate Adjusted Hazard Ratios for Clinical Events in Female AF Patients

	Overall		OAC (+)		OAC (−)
	Hazard ratio (95% CI)	P value	Hazard ratio (95% CI)	P value	Hazard ratio (95% CI)	P value
Stroke/systemic embolism	0.74 (0.54–1.00)	0.051	0.64 (0.42–0.96)	0.031	0.92 (0.58–1.45)	0.716
Any-cause stroke	0.71 (0.52–0.96)	0.027	0.62 (0.41–0.93)	0.022	0.87 (0.54–1.38)	0.559
Hemorrhagic stroke	0.53 (0.29–0.95)	0.032	0.66 (0.30–1.37)	0.272	0.38 (0.14–0.94)	0.035
Ischemic stroke	0.77 (0.53–1.11)	0.162	0.57 (0.35–0.94)	0.026	1.14 (0.66–1.97)	0.639
Ischemic stroke/systemic embolism	0.81 (0.56–1.16)	0.248	0.60 (0.36–0.97)	0.039	1.19 (0.70–2.02)	0.523
Systemic embolism	3.21 (0.41–31.76)	0.271	NA	NA	1.67 (0.15–21.21)	0.669
Major bleeding	0.79 (0.56–1.12)	0.187	0.80 (0.50–1.25)	0.324	0.85 (0.50–1.44)	0.540
Intracranial	0.54 (0.30–0.95)	0.032	0.69 (0.33–1.36)	0.290	0.39 (0.14–0.96)	0.041
Extracranial	0.96 (0.63–1.47)	0.866	0.88 (0.49–1.54)	0.657	1.23 (0.64–2.35)	0.534
All-cause death	0.56 (0.46–0.68)	<0.001	0.64 (0.48–0.86)	0.003	0.51 (0.39–0.67)	<0.001
Cardiovascular death	0.90 (0.55–1.46)	0.662	0.73 (0.40–1.35)	0.322	1.58 (0.70–3.65)	0.269
Non-cardiovascular death	0.51 (0.40–0.65)	<0.001	0.57 (0.39–0.84)	0.005	0.48 (0.35–0.66)	<0.001
Hospitalization for heart failure	0.97 (0.75–1.25)	0.807	0.92 (0.67–1.25)	0.589	1.08 (0.69–1.68)	0.740
Myocardial infarction	1.47 (0.57–3.73)	0.420	1.24 (0.30–4.75)	0.757	1.67 (0.44–6.39)	0.447

Hazard ratio was adjusted by age, body weight, paroxysmal AF, previous stroke/TIA/SE, heart failure, hypertension, DM, CAD, PAD, CKD, COPD, major bleeding, prescription of β-blockers, ACE-I/ARB, antiplatelet drugs and OAC. CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; PAD, peripheral artery disease. Other abbreviations as in Tables 1,3.

Discussion

In this study, our principal findings were as follows: (1) female AF patients were older and had more comorbidities than male patients, particularly HF; and (2) female sex was not independently associated with a risk of stroke or SE, but with a lower risk of ICH and all-cause death.

Previous studies have shown that females, especially elderly female patients, are less likely to receive warfarin for AF.¹²^,²¹^,²² In the present study, female patients were significantly less likely to be prescribed OAC than males, regardless of age and CHADS₂ score. In addition to the under-use of OAC in female patients, they were more likely to be given OAC in sub-therapeutic doses. In a recently published study, females taking warfarin spent more time outside the therapeutic range than males, and more time below the therapeutic range, putting them at higher risk for ischemic stroke compared with males.²³ Unfortunately, we do not have data about time in the therapeutic range (TTR) with PT-INR in the patients taking warfarin. However, in this study, control of PT-INR was likely to be marginally lower in female than male patients, especially in those aged ≥70 years. Indeed, previous studies suggest that physicians avoid prescribing warfarin because of concerns about hemorrhage,²^,²¹²² but the precise reason(s) why use and control of OAC are generally lower in females remains unknown.

Sex Differences in Stroke/SE

The present study indicated that female sex was not associated with an increased risk of stroke/SE, even in those not prescribed OAC at baseline. Recent studies considered female sex as a risk factor for stroke in AF patients with and without OAC.³^,⁸^–¹¹^,²⁴^,²⁵ However, there are other studies concluding that female sex is not a significant independent predictor of stroke.¹²^,¹³ A recent meta-analysis concluded that female patients are at increased risk of stroke, particularly if aged ≥75 years.²⁶^,²⁷ In Japanese AF patients, Inoue and Atarashi reported that male sex is an independent risk factor for thromboembolic events among paroxysmal AF patients.²⁸ Recently, the J-RHYTHM registry reported that female sex was not associated with an increased risk of thromboembolic events.¹⁴ Our present study was consistent with the result from the J-RHYTHM registry.¹⁵

Sex Differences in Major Bleeding

OAC therapy may cause severe bleeding events. The ISCOAT study indicated that sex was not associated with major bleeding, but female sex was an independent risk factor for minor bleeding in patients on OAC therapy.²⁹ In the ATRIA cohort, females had similar rates of major hemorrhage, compared with males, on warfarin therapy.³ The SPORTIF trials and CARAF registry also demonstrated that warfarin was associated with more major bleeding in females than in males.⁴^,¹² However, conflicting results were shown in the ROCKET-AF trial substudy in which female patients were at significantly lower risk for major bleeding.³⁰ In the J-RHYTHM registry study, male sex was an independent risk factor for major bleeds.¹⁴ In the present study, however, we found that female sex was not associated with a significant risk of major bleeding. Suzuki et al reported that the incidence of major bleeding tended to be greater in males than in females, although there was no significant statistical difference in Japanese non-valvular AF patients.³¹ Hence, our results are generally in agreement with prior findings for Japanese AF patients.

In the present study, female sex was associated with a decreased risk of ICH in AF patients without OAC, but was not associated with a risk of ICH in those with OAC. In the population-based Hisayama study from Japan, ICH incidence was higher in males as compared with females.³² Sex differences in the incidence of ICH appear to exist in Japanese populations, where males have a higher incidence. Our data showed that the mean PT-INR value at baseline was marginally lower in female than in male patients, and thus sex differences in warfarin control may affect the incidence of ICH in patients taking OAC.

Sex Differences in Mortality

Male AF patients may be at greater risk of all-cause death than female patients.⁴^,⁸ In the Euro Heart Survey and Minnesota cohort, no significant differences between sexes were observed regarding death.⁵^,⁶ Also, females were not associated with a higher risk of all-cause death in the GARFIELD-AF cohort.³³ We showed that female sex was associated with a decreased risk for all-cause death, even after adjustment by age, comorbidities and medications, consistent with prior results from the J-RHYTHM registry.¹⁴

Study Limitations

There were several limitations to this study. We analyzed data from an observational cohort of Japanese AF patients, and although one of the largest community-based cohorts from Japan, it has relatively smaller numbers compared with some prior nationwide cohorts reporting a relationship of female sex to thromboembolism. Antithrombotic drugs and doses were selected at the discretion of the attending physician and were not randomized. We also had no data on TTR for individual patients taking warfarin. We had PT-INR data at baseline only where PT-INR values were not different between females and males.

Nonetheless, the strengths of the present study are the large sample size and detailed clinical evaluation. To our knowledge, this is the first report on sex-related differences of various clinical events, including hospitalization for HF in AF patients.

Conclusions

We found that female sex was not independently associated with an increased risk of thromboembolism, but was associated with a decreased risk of intracranial hemorrhage and all-cause death in Japanese AF patients.

Acknowledgments

We sincerely appreciate the help of all the institutions participating in the registry and the clinical research coordinators (Shinagawa T, Mitamura M, Fukahori M, Kimura M, Fukuyama M, Kamata C).

Appendices

The participating physicians are listed in reference 19.

Disclosures

H.O. has no disclosures to make.

M. Akao received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare and Daiichi-Sankyo.

G.Y.H.L.: Consultant for Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Microlife and Daiichi-Sankyo. Speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Microlife, Roche and Daiichi-Sankyo.

All other authors report that they have no relationships relevant to the content of this paper to disclose.

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. This research was partially supported 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 (15656344, 16768811).

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