Methods

The details of the study design, the subjects’ characteristics, and the main analyses have been reported elsewhere. Briefly, the study protocol conformed to the Declaration of Helsinki and was approved by each of the participating institutions. Consecutive patients with AF were recruited at the outpatient clinic of each participating institution from January 2009 to July 2009. All the patients gave their written informed consent. Patients who had maintained sinus rhythm for >1 year with antiarrhythmic treatment were not included in the study. As shown in the design paper, a sample size of at least 4,000 patients would be needed to obtain 200 thromboembolic events, because the event rate was expected as 5% for a 2-year follow-up period among Japanese patients with AF. Allowing for dropouts, deaths, and so on, a total of 6,000 patients would be needed to obtain sufficient data for analysis of thromboembolic events. A total of 7,937 patients with AF (mean age 70 years) were enroled. Of these, 421 patients had mitral stenosis or had undergone valve replacement, and therefore, the remaining 7,516 patients with NVAF were examined in the present subanalysis. The antithrombotic drugs used and their doses were selected by the participating physicians.

The patients were followed-up for 2 years or until an end point occurred, whichever occurred first. The end points consisted of thromboembolic events including symptomatic cerebral infarction (CI), transient ischemic attack (TIA), and systemic embolism; major hemorrhaging requiring hospital admission; and all-cause or cardiovascular mortality. CI and TIA were diagnosed according to the standard criteria.

Data are presented as percentage or mean ± SD values. Frequency values were compared using Pearson’s chi-square test, and mean values were compared using the Student t test. Odds ratios were calculated with multivariate logistic regression analysis. Gender and variables that exhibited p values of <0.25 in the univariate analysis were included as explanatory variables in the multivariate analysis. p Values of <0.05 were regarded as statistically significant. All statistical analyses were performed using the SAS statistical software, version 9.1 (SAS Institute Inc., Cary, North Carolina).

Results

Of the 7,516 patients with NVAF enrolled in the J-RHYTHM registry, 110 (2%) were lost to follow-up. Therefore, the remaining 7,406 patients constituted the study group for this subanalysis ( Table 1 ). There were 5,241 men and 2,165 women in the study population. Compared with male patients with AF, female patients were older and displayed greater prevalences of paroxysmal AF, heart failure and hypertension but less prevalences of diabetes, previous CI or TIA, cardiomyopathy, and coronary artery disease. Congestive heart failure, Hypertension, Age of 75 years or more, Diabetes mellitus and prior Stroke or transient ischemic attack (CHADS ₂ ) score distribution differed significantly between male and female patients, and female patients had a slightly but significantly higher mean CHADS ₂ score than male patients.

More than 85% of male and female patients with NVAF were taking warfarin at baseline ( Table 2 ). The present study started before novel anticoagulants were approved for use in Japan; therefore, only warfarin was used as an anticoagulant. Antiplatelet drugs (aspirin in 86% of the cases in which antiplatelet drugs were administered) were administered to male patients more frequently than female patients. Male patients received a slightly but significantly higher mean dosage of warfarin than female patients; however, the 2 groups displayed similar mean baseline international normalized ratios of prothrombin time. During the follow-up period, warfarin was discontinued in 194 (3%) of 6,404 patients who had received warfarin at baseline. The discontinuation rate of warfarin was only slightly but significantly higher in male patients than female patients ( Table 2 ). In contrast, treatment with warfarin was initiated in 234 (23%) of 1,002 patients who had not received warfarin at baseline. There was no gender-specific difference in the proportion of patients who initiated treatment with warfarin during the follow-up period ( Table 2 ).

Rates of thromboembolic events, hemorrhagic events, all-cause deaths, and cardiovascular deaths are listed in Table 3 . Univariate analysis found that major hemorrhaging and all-cause mortality exhibited male predominance. However, thromboembolic events and cardiovascular mortality did not show any gender bias. When male and female patients were subdivided into elderly groups in which the subjects were aged ≥75 years and younger groups in which they were aged <75 years, it was found that the frequency of thromboembolic events did not differ between the male and female patients in either age group (elderly group: men vs women 2.8% vs 2.4%, respectively, p = 0.528; younger group: men vs women 1.3% vs 0.9%, respectively, p = 0.257).

Results of the multivariate analysis are listed in Tables 4 and 5 . Male gender emerged as an independent risk factor for major hemorrhaging and all-cause mortality but was not a risk factor for thromboembolic events or cardiovascular mortality. Warfarin use at baseline was found to be a risk factor for major hemorrhaging but was also associated with a decreased risk of thromboembolic events and all-cause mortality. Being aged ≥75 years emerged as a risk factor for all 4 of the end points studied in this subanalysis. Previous CI or TIA emerged as a risk factor for thromboembolic events, and coronary artery disease and heart failure emerged as risk factors for all-cause and cardiovascular mortalities. Unexpectedly, permanent AF was found to be a risk factor for thromboembolic events, and hypertension was found to be a predictor of improved prognosis in terms of all-cause mortality.

Table 5

Risks ll-cause mortality and cardiovascular mortality (multivariate logistic regression analysis)

Variable	All-Cause Mortality			Cardiovascular Mortality
	Odds Ratio	95% Confidence Interval	p Value	Odds Ratio	95% Confidence Interval	p Value
CHADS = 2 ∗	1.54	0.92–2.76	0.097	0.93	0.40–2.18	0.866
CHADS ≥ 3 ∗	2.04	0.87–4.76	0.099	1.25	0.42–3.71	0.692
Male sex	1.78	1.25–2.55	<0.002	0.96	0.56–1.66	0.893
Permanent AF †	1.23	0.87–1.75	0.246	1.32	0.73–2.40	0.359
Coronary artery disease	2.31	1.58–3.36	<0.001	2.16	1.17–4.00	0.014
Cardiomyopathy	0.97	0.60–1.58	0.904	1.89	0.98–3.65	0.059
Heart failure	2.61	1.73–3.94	<0.001	4.39	2.24–8.63	<0.001
Diabetes mellitus	1.02	0.67–1.56	0.923	1.33	0.71–2.49	0.381
Hypertension	0.59	0.40–0.88	0.010	0.58	0.32–1.08	0.085
CI or TIA	1.09	0.64–1.85	0.747	—	—	—
Age ≥ 75 yrs	3.04	2.01–4.59	<0.001	2.89	1.50–5.57	<0.002
Warfarin	0.50	0.33–0.75	<0.001	—	—	—
Antiplatelet drugs	0.94	0.66–1.34	0.739	1.44	0.82–2.51	0.203

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