Greater Severity of Neurological Defects in Women Admitted With Atrial Fibrillation-Related Stroke

Abstract

Background: The magnitude of the CHA₂DS₂-VASc score is associated with not only stroke incidence but also long-term outcomes. The association between sex and initial stroke severity in AF-related cardioembolic stroke patients has not been clarified. The present study aimed to elucidate the risk factors for initial stroke severity among patients with cardioembolic stroke enrolled in a multicenter registry.

Methods and Results: We selected 12,701 patients (age, 77±10 years; 5,653 women) with AF-related cardioembolic stroke from the Japan Standard Stroke Registry Study between January 2000 and July 2013. Indicators of National Institutes of Health Stroke Scale (NIHSS) scores at admission were identified using a multiple linear regression. Increased NIHSS scores positively correlated with CHA₂DS₂-VASc score (ρ=0.197; P<0.001). The initial neurological deficits were more severe in women than in men (NIHSS scores, median [interquartile range] 14 [5–22] vs. 8 [3–18]; P<0.001). Multiple regression analysis revealed that higher age (standardized partial regression coefficient [β] 0.162; P<0.001), female sex (β 0.120; P<0.001), diabetes mellitus (β 0.020; P=0.019), dyslipidemia (β −0.076; P<0.001), congestive heart failure (β 0.039; P<0.001), vascular disease (β 0.030; P=0.001), prior stroke/TIA (β 0.085; P<0.001) and prior anticoagulant use (β −0.020; P=0.028) were associated with the NIHSS score at admission.

Conclusions: Female sex was independently associated with the initial neurological severity among AF-related cardioembolic stroke patients. (Circ J 2016; 80: 250–255)

Female sex is associated with poor long-term outcomes after stroke.^1,2 Although various indicators, such as acute and chronic medical management after stroke onset and rehabilitation, are thought to contribute to the relationship between sex differences and stroke outcomes, initial stroke severity is also strongly associated with stroke outcomes. However, it remains controversial whether sex difference is related to the initial stroke severity.^3,4 In general, patients with cardioembolic stroke exhibit more severe neurological defects on admission than those with non-cardioembolic stroke.⁵ Therefore, the stroke subtype should be considered when evaluating the association between stroke severity and sex.

Editorial p 74

Atrial fibrillation (AF), the most common arrhythmia, is associated with cardioembolic stroke. The overall number of men and women with AF is similar, but more than 60% patients with AF aged >75 years are women.⁶ In addition, multivariate analyses in several large studies of AF patients have independently associated female sex with an increased risk of stroke.^7–9 Therefore, female sex is identified in the CHA₂DS₂-VASc score as a risk factor for stroke. The CHA₂DS₂-VASc score, as well as the CHADS₂ scoring system, has been widely applied to select patients with AF who should be treated with an anticoagulant.^10,11 The magnitude of the CHADS₂ and the CHA₂DS₂-VASc scores is also associated with initial stroke severity and the likelihood of poor stroke outcomes.^12–14 An association between sex and initial stroke severity in AF-related cardioembolic patients has not been clarified. The present study aimed to elucidate the association between initial stroke severity, sex difference and clinical risk factors in patients with cardioembolic stroke, based on a computerized database derived from the 94 hospitals that treated stroke patients included in the multicenter Japan Standard Stroke Registry Study (JSSRS).^15,16

Methods

Subjects

The central ethical institutional review board of the Japan Stroke Association approved the present registration study,^15,16 which was a prospective, multicenter and observational study. All data forms were completed at discharge. Between January 2000 and July 2013, 101,165 patients were hospitalized in 94 hospitals within 7 days of the onset of acute stroke. Among these patients, we excluded intracranial hemorrhage-related stroke (17,723 patients), subarachnoid hemorrhage-related stroke (5,344 patients) or transient ischemic attack (TIA; 5,321 patients). Of the remaining 72,777 ischemic stroke patients, we diagnosed 20,134 cardioembolic, 19,485 atherothrombotic, 22,675 lacunar and 5,833 other or unknown stroke type according to the National Institute of Neurological Disorders and Stroke (NINDS) criteria.¹⁷ Among the cardioembolic stroke patients, we identified 13,791 patients suffering from AF-related cardioembolism for analysis. Computed tomography or magnetic resonance imaging was performed in all patients for diagnosis of ischemic stroke. The basis for a clinical diagnosis of cardioembolic stroke is the demonstration of a cardiac-transcardiac source of embolus and no evidence of other causes of stroke. The attending physicians evaluated the baseline data of all of the patients in the registry. The data included information regarding age, sex, oral anticoagulant use prior to stroke, comorbidities (ie, hypertension, diabetes mellitus, dyslipidemia, AF, congestive heart failure and vascular disease), and prior stroke. Ischemic stroke severity upon admission was evaluated using the National Institutes of Health Stroke Scale (NIHSS). The criteria for hypertension, diabetes mellitus and dyslipidemia were as previously defined.¹⁶ AF was defined as follows: (1) a history of sustained or paroxysmal AF or (2) AF detection upon arrival or during admission. An ECG, Holter ECG and/or continuous heart rate monitoring were primarily used in each hospital to detect AF. The patients with AF who were diagnosed with cardioembolic stroke according to the NINDS criteria were described as “AF-related cardioembolic stroke patients” in the present study. We evaluated the history of congestive heart failure and vascular disease (ie, coronary artery disease, peripheral artery disease, or aortic atherosclerosis) from the database. The detailed criteria for congestive heart failure and vascular disease were based on the decisions of attending physicians.

Of the 13,791 patients suffering from AF-related cardioembolic stroke, 713 were excluded because of insufficient information regarding their baseline characteristics (ie, hypertension, diabetes mellitus, congestive heart disease, vascular disease, and prior stroke) as this information is required to calculate the CHA₂DS₂-VASc score. Of the remaining 13,078 patients, 89, 49 and 239 patients were excluded from the analysis because of insufficient data regarding dyslipidemia, insufficient data regarding anticoagulant use prior to stroke, and a lack of recorded NIHSS scores at admission, respectively. We noted that older patients, female patients and patients with higher initial stroke severity were more frequently excluded because of a lack of sufficient clinical data on comorbidities (Table S1). Ultimately, 12,701 patients (12.6% of all patients in JSSRS cohorts) were analyzed in the present study.

Statistical Analysis

The data were analyzed using JMP 10.0 software (SAS Institute Inc, Cary, NC, USA). The values are expressed as the mean±standard deviation, median (interquartile range [IQR]) for continuous variables, and frequencies and percentages for discrete variables. The significance of intergroup differences was assessed using the χ² test, the unpaired t-test, or the Mann-Whitney U test where appropriate. The relationship among the CHADS₂ score,¹⁰ CHA₂DS₂-VASc score,¹¹ age, and the NIHSS scores at admission was assessed using Spearman’s rank test. Indicators of NIHSS score at admission were identified using a multiple linear regression that included age, sex, hypertension, diabetes mellitus, dyslipidemia, congestive heart failure, vascular disease, prior stroke/TIA, and prior anticoagulant use for all patients. In particular, a backward selection procedure was used, with P>0.10 in the likelihood ratio test as the exclusion criterion. These analyses were later repeated for patients with premorbid modified Rankin scale scores 0–1. Significance was set at P<0.05.

Results

Table 1 summarizes the characteristics of the patients. Increased CHADS₂ score positively correlated with the NIHSS score at admission (ρ=0.137; P<0.001). Increased CHA₂DS₂-VASc score also positively correlated with the NIHSS score at admission (ρ=0.197; P<0.001, Figure). The initial neurological deficits were more severe in women than in men (NIHSS scores, median [IQR] 14 [5–22] vs. 8 [3–18]; P<0.001). Among all the patients, 3,336 (26.3%) received anticoagulant treatment prior to stroke onset. The rates of prior anticoagulant therapy were 16.8%, 16.6%, 23.1%, 35.1%, and 41.9% in patients with CHADS₂ scores of 0, 1, 2, 3, and ≥4, respectively (P<0.001). The NIHSS scores at admission were somewhat, although not significantly, lower in patients treated with an anticoagulant compared with those who were not (10 [3–20] vs. 11 [4–20]; P=0.077). Multiple regression analysis revealed that higher age (standardized partial regression coefficient [β] 0.162; P<0.001), female sex (β 0.120; P<0.001), diabetes mellitus (β 0.020; P=0.019), dyslipidemia (β −0.076; P<0.001), congestive heart failure (β 0.039; P<0.001), vascular disease (β 0.030; P=0.001), prior stroke/TIA (β 0.085; P<0.001) and prior anticoagulant use (β −0.020; P=0.028) were associated with the NIHSS score at admission (Table 2).

Table 1. Baseline Characteristics of the Study Patients With AF-Related Stroke

	Total (n=12,701)	Men (n=7,048)	Women (n=5,653)	P value
Age, years	76.6±10.2	73.7±9.9	80.3±9.4	<0.001
Hypertension	8,331 (65.6)	4,528 (64.3)	3,803 (67.3)	<0.001
Diabetes mellitus	2,548 (20.1)	1,559 (22.1)	989 (17.5)	<0.001
Dyslipidemia	2,472 (19.5)	1,289 (18.3)	1,183 (20.9)	<0.001
Congestive heart failure	701 (5.5)	326 (4.6)	375 (6.6)	<0.001
Vascular disease	1,335 (10.5)	818 (11.6)	517 (9.2)	<0.001
Prior stroke or TIA	3,920 (30.8)	2,237 (31.7)	1,683 (29.8)	0.017
CHADS2 score	2 (1–3)	2 (1–3)	2 (1–3)	<0.001
CHA2DS2-VASc score	4 (2–5)	3 (2–4)	4 (3–5)	<0.001
Prior anticoagulant use	3,336 (26.3)	1,980 (28.1)	1,356 (24.0)	<0.001
NIHSS score at admission	11 (3–20)	8 (3–18)	14 (5–22)	<0.001

The data are presented as the mean±SD for age; as the median (interquartile range) for the CHADS₂ score, the CHA₂DS₂-VASc score and the NIHSS score at admission; and as the number (%) of patients for the remaining characteristics. AF, atrial fibrillation; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack.

Figure.

Association between the National Institutes of Health Stroke Scale (NIHSS) score at admission and the CHA₂DS₂-VASc score. The band near the middle of each box represents the median. The bottom and top of each box represent the 25^th and 75^th percentiles, respectively; the upper and lower lines represent the 10^th and 90^th percentiles, respectively.

Table 2. Indicators for Predicting the NIHSS Score at Admission Among Cardioembolic Patients

Indicator	All patients (n=12,701)		Patients with premorbid mRS score 0–1 (n=10,005)
	β coefficient	P value	β coefficient	P value
Age (/1 year)	0.162	<0.001	0.153	<0.001
Female	0.120	<0.001	0.112	<0.001
Diabetes mellitus	0.020	0.019	–	–
Dyslipidemia	−0.076	<0.001	−0.064	<0.001
Congestive heart failure	0.039	<0.001	0.029	0.003
Vascular disease	0.030	0.001	0.020	0.041
Prior stroke or TIA	0.085	<0.001	–	–
Prior anticoagulant use	−0.020	0.028	−0.033	0.001

Multiple linear regression analysis using a backward selection procedure for predictors that included age, sex, hypertension, diabetes mellitus, dyslipidemia, congestive heart failure, vascular disease, prior stroke/TIA, and prior anticoagulant use. “β coefficient”, standardized partial regression coefficient. mRS, modified Rankin scale. Other abbreviations as in Table 1.

Analysis of Patients With Premorbid Modified Rankin Scale Score 0–1

Of the 12,701 patients, 2,696 (21.2%) had a premorbid modified Rankin scale (mRS) score ≥2. The patients with premorbid mRS scores ≥2 were older (P<0.001) and more often female (P<0.001) and exhibited higher rates of congestive heart failure (P<0.001), vascular disease (P=0.006), prior stroke/TIA (P<0.001) and prior anticoagulant use (P<0.001) compared with those without (Table S2). After excluding 2,696 patients with a premorbid mRS score ≥2, 10,005 patients with a premorbid mRS score 0–1 were analyzed. Increased CHADS₂ and CHA₂DS₂-VASc scores positively correlated with the NIHSS score at admission (ρ=0.079; P<0.001 and ρ=0.145; P<0.001, respectively). The initial neurological deficits were more severe in women than in men (NIHSS score, median [IQR] 12 [4–21] vs. 7 [2–17]; P<0.001). Multiple regression analysis revealed that higher age (β 0.153; P<0.001), female sex (β 0.112; P<0.001), dyslipidemia (β −0.064; P<0.001), congestive heart failure (β 0.029; P=0.003), vascular disease (β 0.020; P=0.041) and prior anticoagulant use (β −0.033; P=0.001) were associated with the NIHSS score at admission (Table 2).

Discussion

Certain CHA₂DS₂-VASc score risk factors, and especially female sex, were independently associated with initial neurological severity among patients with AF-related cardioembolic stroke. In addition, the presence of dyslipidemia and prior anticoagulant use were inversely associated with the neurological severity.

An increased CHADS₂ score is associated with initial neurological severity.^12,13 The reason for this might be that blood coagulability is associated with increased amounts of thrombi, because aging, hypertension, and diabetes are associated with hypercoagulable conditions.^18,19 In addition, a decreased ejection fraction in congestive heart failure is also associated with large thrombi.²⁰ Large thrombi cause severe initial neurological symptoms with a larger infarct size.²¹ Increased CHA₂DS₂-VASc scores are also associated with initial stroke severity and stroke outcomes.¹⁴ In this study, increased CHA₂DS₂-VASc scores, as well as CHADS₂ scores, positively correlated with the NIHSS scores at admission. Naturally, the presence of prior stroke was associated with the neurological severity. Therefore, we analyzed the patients without neurological deficits according to premorbid mRS scores 0–1. After excluding patients with premorbid mRS scores ≥2, increased CHA₂DS₂-VASc scores were also positively correlated with the NIHSS scores at admission. The strengths of the present investigation compared with previous studies include the large sample size from a multicenter registry.

A unique finding of our study was the effect of female sex. Maeda et al found that female sex was associated with higher NIHSS scores at admission after adjusting for age, stroke subtype, risk factors, and onset-to-arrival time among 33,953 patients in the JSSRS suffering from acute ischemic stroke between January 2000 and November 2007, which included some of our patients with cardioembolic stroke.¹⁵ Based on Scandinavian stroke scale scores, an examination of another large registry in Denmark revealed that women exhibited more severe neurological symptoms at admission than men among 39,484 patients.²² However, whether sex is associated with stroke severity after considering age and stroke subtype remains controversial.^3,4 In the present study, female sex was independently associated with initial neurological severity among patients with AF-related cardioembolic stroke.

The reasons for the association between initial neurological severity and sex difference remain to be fully elucidated. One possible factor is that the severity of neurological symptoms can influence the choice of anticoagulant therapy. In the present study, a significant association between prior anticoagulant use and the NIHSS scores at admission was noted, especially for patients with premorbid mRS scores 0–1. However, we were unable to collect data on the management of anticoagulation. The present study was primarily performed before the approval of novel oral anticoagulants (NOACs) in Japan. Therefore, in the present database, “anticoagulation” essentially refers to warfarin therapy. Some studies have associated the admission prothrombin time international normalized ratio (PT-INR) with initial neurological severity and infarct volumes in cardioembolic stroke patients.^23,24 Female sex is associated with a poor time in the therapeutic range (TTR) of PT-INR among Japanese patients suffering from AF,²⁵ which may contribute to the neurological severity and infarct volumes at admission among female patients suffering from cardioembolic stroke. Second, increasing blood coagulability might be more prevalent in older females than older males. Although female AF patients are at higher risk of thromboembolism compared with males, especially if aged ≥75 years,^26,27 the J-RHYTHM registry for Japanese AF patients recently showed that female sex is not a risk factor for thromboembolic events.^28,29 Therefore, the factors related to stroke severity may be different from those related to stroke incidence. Certain biological factors, such as sex hormones, genes and vascular anatomy, might be considered.³⁰ In addition, sex differences in lifestyle factors such as physical activity levels, diet and social support levels might contribute to the initial stroke severity.

It was unclear why the presence of dyslipidemia was inversely associated with initial neurological severity in our study. Olsen et al reported that higher total serum cholesterol levels were inversely related to stroke severity.³¹ In addition, some studies demonstrated that prior statin use was associated with lower initial stroke severity.^32,33 Dyslipidemia is also closely associated with obesity, nutrition, lifestyle and physical inactivity.³⁴ Some reports have shown that premorbid undernutrition was associated with initial stroke severity and poor stroke outcomes.^35,36 Kim et al reported that ischemic stroke patients with higher body mass index (BMI) were likely to have mild stroke (NIHSS 0–7) at admission.³⁷ However, data on those factors (ie, lipid profile levels, prior statin use, BMI and the status of nutrition) were not collected in the present study. Considering the effect of dyslipidemia on stroke severity, additional data regarding lipid profiles, prior statin use, BMI and the status of nutrition are necessary.

Study Limitations

First, we excluded some patients suffering from cardioembolic stroke, because of a lack of information required to calculate preadmission CHA₂DS₂-VASc scores, which may have caused a selection bias. Second, we were unable to collect PT-INR and TTR data from the JSSRS database. The management of warfarin therapy and the type of anticoagulation therapy (ie, warfarin or NOAC) should be considered in the future. Third, the detailed methods of AF detection and the detailed criteria for congestive heart failure and vascular disease were not standardized for all of the hospitals. Widely accepted and shared definitions of those diseases are necessary to improve clinical research. Finally, we were unable to analyze the clinical factors related to neurological severity at admission in non-cardioembolic patients in the JSSRS. It remains unclear whether the association between components of the CHA₂DS₂-VASc score and initial neurological severity is specific to AF-related cardioembolic stroke patients. Hoshino et al showed that the CHADS₂ and CHA₂DS₂-VASc scores were associated with functional outcomes in stroke patients with coronary artery disease, irrespective of the presence of AF.³⁸

In conclusion, women with AF-related cardioembolic stroke had more severe initial stroke deficits than men. Regarding the initial stroke severity, physicians may need to consider the sex difference when managing AF patients. In the future, we should investigate the sex-related biological and lifestyle factors associated with the neurological severity of AF-related cardioembolic stroke.

Acknowledgments

The Japan Standard Stroke Registry Study Group was supported by the Japanese Ministry of Health, Labor and Welfare (developed with support from 1999 to 2001) and the Japan Stroke Association (2002–present). This study was also supported in part by research grant from Japan Heart Foundation to T.N., and research grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant no. 23590598 and 15K08615), the Smoking Research Foundation, and the Tsuchiya Foundation to M.M. and N.H.

Conflicts of Interest/Disclosures

M.M. reports grants from Mochida Pharmaceutical Co, Ltd, Otsuka Pharmaceutical, and Daiichi Sankyo Co, Ltd and honoraria from Sanofi K.K., Bayer Health Care, Otsuka Pharmaceutical, Daiichi Sankyo Co, Ltd, Boehringer Ingelheim, and Sumitomo Dainippon Pharma Co, Ltd, which are outside the submitted work.

N.H. reports an honorarium from Mochida Pharmaceutical Co, Ltd, which is outside the submitted work.

The other authors report no conflicts of interest.

Supplementary Files

Supplementary File 1

Table S1. Comparison of the clinical characteristics of cardioembolic patients included in this study and those excluded because of a lack of sufficient data

Table S2. Comparison of clinical characteristics according to premorbid mRS score of cardioembolic patients

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-15-0873

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