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Abstract

Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia. The most serious complication of AF is thromboembolic stroke. The individual risk of stroke in the setting of AF varies. Several clinical factors have been identified as independent predictors of stroke in AF, including prior stroke, age, hypertension and diabetes. The bulk of available data identifies female gender as another independent predictor of stroke risk in AF. In this article, we review the link between AF and an elevated stroke risk in women, explore the potential pathophysiologic basis for this association and examine the data regarding the effectiveness of anticoagulation in reducing this risk.

Keywords

anticoagulation atrial fibrillation stroke thromboembolism women

Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia [1]. It is well established that AF increases the risk of thromboembolism and stroke. However, individual risk of stroke in the setting of AF varies and may be influenced by the presence or absence of several clinical risk factors [2,3]. Prior thromboembolic events (stroke or transient ischemic attack [TIA]), advanced age, hypertension, heart failure and diabetes have been most consistently identified as predictors of stroke associated with nonvalvular AF [3 –5]. Dissenting opinions exist as to whether female gender represents another risk factor. In this article, we explore the evidence for an association between AF and an increased risk of stroke in women. If female gender truly represents an independent predictor for stroke in AF, enhanced clinician awareness and understanding of gender-specific differences is essential to mitigate this risk.

Evidence for female gender as a clinical risk factor for stroke in AF

Several early observational studies pointed to a significant association between AF, female gender and increased risk of thromboembolism [6 –8]. Other studies argued against such a relationship [9,10]. A recent systematic review of clinical predictors of stroke in paroxysmal and chronic AF identified 11 studies that assessed female gender as a risk [11]. Five of these 11 studies identified female gender as an independent predictor of stroke [6,12 –15], five studies showed no significant interaction between female sex and stroke risk [9,10,16 –18], and one identified males as being at a higher risk of stroke in the setting of paroxysmal AF [19]. Notably, several of the studies identified in this analysis were relatively small observational cohorts [11].

Women are under-represented in randomized trials of stroke prevention in AF, and data regarding female gender as a risk is somewhat contradictory. In a collaborative effort led by the Atrial Fibrillation Investigators (AFI), data from five early randomized trials evaluating the efficacy of warfarin therapy for the prevention of stroke in AF patients were pooled and risk factors for stroke were evaluated [20]. In multivariate analysis of patients assigned to the control group, previous stroke or TIA, old age, hypertension and diabetes proved to be independent predictors of stroke. Women assigned to the control groups in these studies had a slightly elevated, but nonsignificant, stroke risk compared with male controls (relative risk [RR]: 1.2; 95% CI: 0.8–1.8; p = 0.18) [20].

In the Stroke Prevention in Atrial Fibrillation (SPAF) I–III trials, female gender proved to be one of the five independent predictors for stroke (along with age, hypertension, systolic blood pressure >160 mmHg and prior stroke or TIA) in patients with sustained or recurrent AF receiving aspirin therapy (RR: 1.6; p = 0.01) [14]. In addition, a strong interaction between gender and age was noted in this analysis. Although there was little influence on stroke rate in younger women, the stroke rate in elderly women (aged >75 years) was substantially higher than in elderly men (9.7 vs 3.2%/year, respectively; p < 0.001). For participants aged >75 years without other identifiable thromboembolic risk factors, the stroke rate for women was 7.8 versus 1.2%/year for men (p = 0.002) [14].

Female gender was also found to be a significant risk factor for stroke in the analysis of large prospective observational cohort studies. In the Framingham Heart Study, in multivariate analysis among warfarin-censored patients with AF, female gender was identified as an independent predictor of stroke (hazard ratio [HR]: 1.92; 95% CI: 1.20–3.07) [12]. Other independent predictors of stroke risk were hypertension, age, diabetes, and prior stroke or TIA [12]. In the Copenhagen City Heart Study, AF increased the risk of first stroke significantly in both genders; however, the effect of AF on the risk of stroke was over four-times greater in women than in men (HR: 4.5; 95% CI: 2.2–9.2) [21]. In analysis of only the participants with AF, women showed a higher age-adjusted risk of stroke than men (HR: 2.6; 95% CI: 1.3–5.4). In addition, AF was a significant risk factor for overall mortality in both genders; however, the effect of AF continued to be almost twice as large in women as in men (HR: 1.9; 95% CI: 1.2–2.9) [21].

The large Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study cohort included 5795 women and 7764 men [22]. Rates of thromboembolism between male and female patients not taking anticoagulants were assessed, while controlling for other known risk factors of stroke. Women had a higher annual incidence of ischemic stroke (RR: 1.5; 95% CI: 1.2–1.8). Notably, the interaction between older age and female gender seen in the SPAF studies was not observed in the ATRIA cohort. Higher rates of thromboembolism in women were observed at both younger and older ages and across all stroke risk factor categories. The RR for stroke was 1.6 (95% CI: 1.032.3) for those aged ≤75 years and 1.8 (95% CI: 1.4–2.3) for those aged >75 years [22].

In summary, early observational data revealed conflicting evidence for a higher risk of stroke in women. However, the bulk of data from larger, contemporary cohorts and randomized trials identifies female gender as an independent predictor of stroke in the setting of AF. Female gender appears to confer a relative stroke risk of 1.5–1.9 (Table 1).

Table 1.

Gender differences of thromboembolic risk in atrial fibrillation.

Study	Event rate (%/year)	Thromboembolic risk	Ref.
Analysis of nonanticoagulated patients
Randomized trials
AFI	F: 5.8M: NR	1.2 (0.8–1.8)†p = 0.18	[20]
SPAF	F: 4.4M: 2.1	1.6 (NR)†p = 0.01	[14]
Observational studies
ATRIA	F: 3.5M: 1.8	1.6 (1.3–1.9)†	[22]
Framingham		1.9 (1.2–3.1)‡	[12]
Copenhagen City Heart	F: 5.17M: 1.98	2.6 (1.3–5.4)‡	[21]
Euro Heart Survey	F: 2.2M: 1.2	1.83 (1.10–3.03)§p = 0.019	[32]
Analysis of anticoagulated patients
Randomized trials
SPORTIF	WarfarinF: 1.98M: 1.51	NR	[28]
	XimelagatranF: 2.17M: 1.38p = 0.03	NR
Observational studies
Poli et al.	F: 2.4M: 1.2	2.0 (1.3–3.1)†p = 0.004	[45]

†

Reported as relative risk.

‡

Reported as hazard ratio.

Reported as odds ratio.

AFI: Atrial Fibrillation Investigators; ATRIA: Anticoagulation and Risk Factors in Atrial Fibrillation

F: Female; M: Male; NR: Not reported; SPAF: Stroke Prevention in Atrial Fibrillation; SPORTIF: Stroke

Prevention Using an Oral Thrombin Inhibitor in Patients with Atrial Fibrillation.

Female gender & thromboembolism in AF: biology, bias or both?

Prothrombotic biomarkers

Mechanisms for sex-related differences in stroke risk remain uncertain. It is possible that women exhibit increased thrombogenicity in the setting of AF owing to hormonal differences or other procoagulant traits [23]. Elevated markers of endothelial dysfunction and prothrombotic factors have been demonstrated in women with AF [24,25]. Plasma von Willebrand factor level is a marker of endothelial dysfunction, and elevated levels have been linked to atherosclerosis and thrombosis. Recently, elevated von Willebrand factor levels were shown to increase the risk of stroke in the Rotterdam Study, a prospective, elderly population-based cohort [26]. Furthermore, in the Rotterdam Study, the presence of AF was significantly associated with increased levels of von Willebrand factor in women but not in men [24]. The relationship between female gender and elevated von Willebrand factor suggests a greater prothrombotic state and might contribute to the higher stroke risk that is apparent in women with AF.

Hormone replacement therapy

The issue of procoagulant effects of hormone replacement therapy has also been assessed. Among healthy postmenopausal women evaluated in the Women's Health Initiative, estrogen replacement therapy was shown to increase the risk of stroke [27]. In the SPAF trials, hormone replacement therapy was associated with higher rates of ischemic stroke in women with AF (RR: 3.2; p = 0.007) [14]; however, in the ATRIA study, oral estrogen replacement therapy did not result in increased thromboembolic risk [22]. Owing to small numbers, the effect of estrogen replacement in the Stroke Prevention Using an Oral Thrombin Inhibitor in Patients with Atrial Fibrillation (SPORTIF) trials was inconclusive [28].

Thyrotoxicosis

The link between thyrotoxicosis, AF and heightened thromboembolic risk remains controversial [2]. Reports suggest that the risk for thromboembolic stroke is elevated in hyperthyroidism, but a causal relationship is not proven [2,29]. A higher risk of thromboembolic stroke has recently been described in young adults with hyperthyroidism [30]. Hyperthyroidism is known to be associated with an increased risk of AF and is more common in women with AF than in men [31,32]; however, the overall contribution of hyperthyroidism to the increased risk of stroke in women with AF is largely uncertain.

Sex differences in medical management

Risk factor profiles appear to differ significantly between men and women with AF (Table 2). Men develop coronary disease more frequently. Women with AF tend to be older and have more comorbidities than men, including a history of valvular heart disease and hypertension [22,28,32,33]. Furthermore, it has been noted that compared with men, an elevated risk of stroke is apparent at midlife and beyond in women [34]. This elevated risk corresponds with poorer control of traditional risk factors for stroke in women as compared with men – including higher blood pressure and cholesterol levels [34]. The potential role of gender bias needs be considered. Gender disparities in management of disease have been seen in a number of areas, including cardiovascular disease [35,101]. These studies indicate that societal attitudes towards gender might inappropriately affect clinical decision-making and result in differences in management and outcomes of disease states [101]. Data indicate that clinicians continue to underestimate cardiovascular risk in women and that modifiable cardiovascular risk factors continue to be managed less aggressively [36,37]. Hypertension is an independent risk factor for stroke and further raises the stroke risk in patients with AF [38]. In the SPORTIF trials, more women were hypertensive and had higher overall systolic blood pressure values than men [28]. In the setting of AF, improved blood pressure control has been shown to reduce the risk of cardiovascular events beyond appropriate anticoagulation therapy alone [38,39]. Thus, disparities in clinical risk profiles and inappropriate management of modifiable cardiovascular risk factors might in part account for the higher thromboembolic risk apparent in women. In addition, it appears that certain thromboembolic risk factors might have different effects on men and women. For example, data suggest that diabetes and metabolic syndrome increase the risk of stroke in women to a greater degree than they do in men [23,40,41]. How these types of interactions are affected by the presence of AF is unclear.

Table 2.

Gender differences in stroke risk factors in selected atrial fibrillation trials.

Study	n (% female)	Mean age (years)	Hypertension (%)	Prior stroke (%)	Diabetes (%)	Heart failure (%)	Coronary disease (%)	Peripheral vascular disease (%)	Ref.
Randomized trials
AFI†	1238 (27)	69	46	6	15	20	14	10	[20]
SPAF†	2012 (28)	69	52	8	15	19	NR	7	[14]
SPORTIF	7329 (31)	M: 69.8F: 73.4p < 0.0001	M: 75F: 81p < 0.0001	M: 21F: 22	M: 24F: 22p = 0.03	M: 38F: 33p < 0.0001	M: 48F: 38p < 0.0001	NR	[28]
Observational studies
ATRIA	13,559 (43)	NR	M: 47.9F: 57.7p < 0.0001	M: 6.0F: 7.1p = 0.02	M: 16.0F: 14.2p = 0.01	M: 26.6F: 26.7	M: 31.0F: 23.9p < 0.0001	NR	[22]
Framingham†	705 (48)	75	50	14	15	34‡	NR	NR	[12]
Euro Heart Survey	5333 (42)	M: 64F: 70p < 0.001	M: 60F: 69p < 0.001	M: 5F: 7p < 0.05	M: 16F: 21p < 0.001	M: 33F: 35	M: 36F: 30p < 0.001	NR	[32]
Copenhagen City Heart	276 (40)	M: 67F: 69	M: 30.7F: 25.5	NR	M: 12.0F: 10.9	NR	M: 7.8F: 6.4	NR	[21]
Poli et al.	780 (35)	M: 74F: 76p < 0.001	M: 62.1F: 66.2	M: 27.5F: 32.6	M: 19.7F: 21.3	M: 32.0F: 19.6p = 0.02	M: 26.1F: 12.1p < 0.001	M: 16.6F: 9.8p = 0.01	[45]

†

Data not reported separately for males and females.

‡

Congestive heart failure or myocardial infarction.

AFI: Atrial Fibrillation Investigators; ATRIA: Anticoagulation and Risk Factors in Atrial Fibrillation; F: Female; M: Male; NR: Not reported; SPAF: Stroke Prevention in Atrial Fibrillation; SPORTIF: Stroke Prevention Using an Oral Thrombin Inhibitor in Patients with Atrial Fibrillation.

Finally, there exists the possibility that other risk factors that have not been systematically evaluated in the setting of AF could account for gender differences. For example, in one study, obesity as measured by increasing waist circumference has been shown to be an independent predictor of stroke in women [34]. Most studies that have identified female gender as an independent risk for stroke in AF do not correct for weight or BMI.

Anticoagulant therapy for stroke prevention in women with AF

The benefit of anticoagulation for the prevention of thromboembolism in AF is clear [42,43]. Current guidelines recommend oral anticoagulation for patients with either paroxysmal or chronic AF who have stroke risk factors [2,102]. This is supported by data from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, in which a comparison was performed of rhythm control versus rate control strategies for AF [44]. In both groups, the majority of strokes occurred after cessation of warfarin or during times of subtherapeutic international normalized ratio (INR) [44]. Thus, maintenance of sinus rhythm has no bearing on stroke prevention. However, women with AF are often more symptomatic than men [32]. Because of women's proclivity for QT prolongation and torsades de pointes, restoration and maintenance of sinus rhythm with specific antiarrhythmic agents is reserved for symptomatic relief [1]. Regardless of whether a rate or rhythm control strategy is used, anticoagulation remains pivotal in patients with risk factors for stroke.

Few studies have examined gender differences in response to anticoagulation therapy. In pooled data from five randomized trials evaluating the efficacy of warfarin for stroke prevention in AF, anticoagulation decreased the risk of stroke by 84% in women (95% CI: 55–95%; p < 0.001) compared with a 60% reduction in men (95% CI: 35–76%; p < 0.001) [20]. In the ATRIA study, despite similar distribution of INR intensities, the reduction in rates of thromboembolism on warfarin was again larger in women than in men [22]. Anticoagulation with warfarin reduced annual rates of thromboembolism from 3.5 to 1.5% in women versus reduction from 1.8 to 1.2% in men (p = 0.001 for the interaction of sex and warfarin use) [22].

Interestingly, despite the previously mentioned data suggesting that anticoagulation is at least as effective – if not more so – at reducing thromboembolic event rates in women, a recent study suggests that anticoagulated women might still remain at a higher overall risk than men. In a recent analysis of AF patients followed prospectively in an outpatient anticoagulation clinic, women remained at higher risk for stroke than men with no difference in the intensity of anticoagulation [45]. Thromboembolic event rates were 1.2 × 100 patient/years in men versus 2.43 × 100 patient/years in women (RR: 2.0; 95% CI: 1.3–3.1; p = 0.004). A report from the Euro Heart Survey also showed that women were at higher risk for stroke than men, despite no difference in oral anticoagulation prescription rates [32]. However, this difference appeared to be largely driven by women who did not receive oral anticoagulation and were managed with a rhythm control strategy.

Bleeding risks of anticoagulant therapy in women with AF

Despite the apparent efficacy of anticoagulation in women, data suggest that anticoagulant therapy might be underused in women, particularly in the elderly [43,46]. It is believed that this disparity is due to a presumed higher bleeding risk in elderly women. In the ATRIA study, women had similar rates of major hemorrhage compared with men (1.0 vs 1.1%; adjusted RR: 0.8; 95% CI: 0.6–1.1) and were less likely to develop intracranial hemorrhage on warfarin therapy [22]. In the SPORTIF trial, there was again no difference in major bleeding between men and women (2.25 vs 2.15%/year; p = 0.765), although women had higher rates of combined major and minor bleeding (41.3 vs 33.9%/year; p < 0.001) [28]. These findings were in contrast to those of the Euro Heart Survey, which reported a higher major bleeding risk in women (2.2 vs 1.3%; p = 0.028). The Canadian Registry of Atrial Fibrillation (CARAF), also reported that women on warfarin were 3.35-times more likely to experience a major bleed than were men [33]. Of note, the mean INR of the women who experienced major bleeds in this trial was 4.02 ± 2.96. More recently, Poli et al. prospectively analyzed AF patients followed in an outpatient anticoagulation clinic with careful INR management. There was no difference in major bleeding between women and men (1.3 vs 1.4%; p = 1.0) [45]. The use of INR self-management might further improve the quality of oral anticoagulation with vitamin K antagonists and maintain patients more frequently in the therapeutic range. A 2006 meta-analysis of 14 randomized trials of INR self-monitoring revealed significant reductions in thromboembolic events, all-cause mortality and major hemorrhage. A total of 11 of these trials reported improvements in the mean proportion of INRs in the therapeutic range [47].

In summary, anticoagulation clearly reduces stroke risk in women. The available evidence does not justify withholding this therapy based on an unproven bleeding risk.

Incorporation of gender in risk stratification schemes

Several risk stratification schemes have been developed to help clinicians gauge individual patient thromboembolic risk in AF and to guide the use of anticoagulant therapy. Predictors of thromboembolic risk derived from both randomized trials and large community cohorts have been used to construct these risk schemes. Prior stroke, old age, hypertension and diabetes have most consistently been identified as predictors of stroke associated with nonvalvular AF and have been incorporated into all major risk schemes [2,12,20,48,49]. In addition, history of heart failure or low ejection fraction is also commonly included. Based on risk scheme scores, the individual thromboembolic risk is often categorized as low, intermediate or high risk.

Pooled data from control patients in five stroke prevention trials were analyzed by the AFI [20]. Female gender was associated with a slightly elevated risk of stroke, but was not a significant predictor and thus, was not incorporated into this risk scheme. Analysis of patients on aspirin therapy in the SPAF trials revealed women over 75 years of age to be at increased risk of thromboembolism [14]. AFI and SPAF were used to develop the congestive heart failure, hypertension, age, diabetes, previous stroke (double point; CHADS₂) risk score, which owing to its ease of use has become the most widely utilized risk scheme [48]. Female gender is not included among the clinical risk predictors in CHADS₂. The 2006 American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines include female gender among a list of ‘less validated or weaker risk factors' [2]. However, use of anticoagulation is given a class I recommendation for women aged >75 years with AF.

The UK NICE national guidelines for AF management evolved from that of the AFIs [37]. The NICE guidelines were further refined into the Birmingham 2009 risk scheme that includes female gender as a risk factor [49]. This point-based scheme, cardiac failure or dysfunction, hypertension, age ≥75 (double point), diabetes, previous stroke (double point), vascular disease, age 65–74 and female sex (CHA₂DS₂-VASc), was recently validated in the Euro Heart Survey on Atrial Fibrillation cohort [49]. In comparison with other contemporary risk stratification schemes, the CHA₂DS₂-VASc score improves identification of patients at high risk for stroke and minimizes classification of patients in the intermediate risk category [50 –52]. It has been suggested that the CHA₂DS₂-VASc score be applied as a complement to the more straightforward CHADS₂ scheme, affording a more comprehensive assessment of thromboembolic risk to patients with a CHADS₂ score of 0–1 [51]. In doing so, CHA₂DS₂-VASc might more clearly guide physicians in the use of oral anticoagulant therapy in those patients who might otherwise have been labeled at intermediate risk by CHADS₂.

Conclusion

Women with AF appear to have a higher thromboembolic stroke risk than men. The mechanism of an elevated stroke risk in women with AF remains unclear and could be multifactorial. Women with AF tend to be older and to have more comorbidities than men with AF. Whether the elevated stroke risk in women with AF is due to a higher clinical risk profile and undertreatment of known cardiovascular risk factors, or rather that female gender itself is associated with an inherent thromboembolic risk, requires further elucidation. Anticoagulation therapy clearly reduces stroke risk in women with AF, with bleeding risks that appear to be similar to those seen in men. Clinicians should be aware of the elevated stroke risk associated with female gender, and manage women aggressively as per guidelines, targeting effective anticoagulation as well as the management of all modifiable cardiovascular risk factors. Gender differences in response to newer oral anticoagulants will need to be monitored closely in the coming years (see following section).

Future perspective

Although vitamin K antagonists have proven to be the agents of choice for reducing stroke risk in AF, the recent introduction of newer anticoagulants makes it likely that the field of stroke prevention will change substantially during this decade. In the Randomized Evaluation of Long-term anticoagulation therapy (RE-LY) trial, the direct thrombin inhibitor, dabigatran, at a dose of 150 mg twice daily was associated with lower rates of stroke and systemic thromboembolism and similar rates of major hemorrhage as compared to adjusted-dose warfarin [53]. Of the 18,113 participants in this trial, 36% were women. Subgroup analysis revealed no significant interaction between sex and treatment effect of dabigatran (p = 0.24) [53]. Interestingly, gender analysis of the SPORTIF trial revealed that treatment with another direct thrombin inhibitor, ximelagatran, was associated with higher rates of stroke or systemic embolism in women as compared to men (2.17%/year; 95% CI: 1.48–2.87%/year vs 1.38%/year; 95% CI: 1.0–1.75%/year; p = 0.03) [28]. Ximelagatran has been removed from the market owing to high incidence of hepatotoxicity; however, the use of other new anticoagulants is on the horizon. As compared to aspirin, the novel factor Xa inhibitor, apixaban, reduced the risk of stroke and systemic embolism without significantly increasing the bleeding risk in patients with AF who were deemed unsuitable for management with vitamin K antagonists [54]. Subgroup analysis revealed no significant gender difference in rates of stroke or systemic embolism (1.9%/year female vs 1.4%/year male; p = 0.42) or in rates of major bleeding (1.5%/year female vs 1.4%/year male; p = 0.97) [54]. In addition, in a Phase III trial, rivaroxaban, an oral direct factor Xa inhibitor, was recently proven noninferior to warfarin in management of AF [55].

Introduction of these newer agents is likely to challenge the role of warfarin as the primary agent for stroke prevention in AF [56]. Although these new anticoagulants appear at least as effective, safer and more convenient than warfarin, the choice to use such agents must take into account potential disadvantages. These include the need for twice-daily dosing with certain agents, the lack of a laboratory test to assess patient compliance, higher cost and the lack of a specific antidote in the case of severe hemorrhage [57,58]. In the coming years, any gender differences in response to these agents will have to be monitored closely.

Executive summary

Women with atrial fibrillation (AF) have a higher thromboembolic stroke risk than men.

The mechanism of an elevated stroke risk in women with AF is likely to be multifactorial; however, women with AF tend to be older and to have more comorbidities than men with AF.

Anticoagulation therapy clearly reduces stroke risk in women with AF, with bleeding risks that appear to be similar to those seen in men.

Clinicians should be aware of the elevated stroke risk associated with female gender, and manage women aggressively as per the guidelines, targeting effective anticoagulation as well as the management of all modifiable cardiovascular risk factors.

Gender differences in response to newer oral anticoagulants will need to be monitored closely in the coming years.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:

of interest

of considerable interest

Volgman

Manankil

Mookherjee

Trohman

: Women with atrial fibrillation: greater risk, less attention. Gend. Med. 6, 419–432 (2009).

Fuster

Ryden

Cannom

: ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation – executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation). J. Am. Coll. Cardiol. 48, 854–906 (2006).

Singer

Albers

Dalen

: Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133, 546S–592S (2008).

Stroke Risk in Atrial Fibrillation Working Group: Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology 69, 546–554 (2007).

Stroke Risk in Atrial Fibrillation Working Group: Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation. Stroke 39, 1901–1910 (2008).

Cabin

Clubb

Hall

Perlmutter

Feinstein

: Risk for systemic embolization of atrial fibrillation without mitral stenosis. Am. J. Cardiol. 65, 1112–1116 (1990).

10.

Boysen

Nyboe

Appleyard

: Stroke incidence and risk factors for stroke in Copenhagen, Denmark. Stroke 19, 1345–1353 (1988).

11.

Novello

Ajmar

Bianchini

: Ischemic stroke and atrial fibrillation. A clinical study. Ital. J. Neurol. Sci. 14, 571–576 (1993).

12.

Aronow

Gutstein

Hsieh

: Risk factors for thromboembolic stroke in elderly patients with chronic atrial fibrillation. Am. J. Cardiol. 63, 366–367 (1989).

13.

Petersen

Kastrup

Helweg-Larsen

Boysen

Godtfredsen

: Risk factors for thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Arch. Intern. Med. 150, 819–821 (1990).

14.

Hughes

Lip

: Stroke and thromboembolism in atrial fibrillation: a systematic review of stroke risk factors, risk stratification schema and cost effectiveness data. Thromb. Haemost. 99, 295–304 (2008).

15.

Systematic review of stroke risk factors in atrial fibrillation, including gender.

16.

Wang

Massaro

Levy

: A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study. JAMA 290, 1049–1056 (2003).

17.

Derivation of the Framingham risk score for stroke in atrial fibrillation. Female gender was identified as an independent predictor of stroke.

18.

Hart

Pearce

Rothbart

McAnulty

Asinger

Halperin

: Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators. J. Am. Coll. Cardiol. 35, 183–187 (2000).

19.

Hart

Pearce

McBride

Rothbart

Asinger

: Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. Stroke 30, 1223–1229 (1999).

20.

Analysis of participants given aspirin alone or in combination with low, inefficacious doses of warfarin in the Stroke Prevention in Atrial Fibrillation I–III trials. Female gender proved to be one of five independent predictors of stroke.

21.

van Latum

Koudstaal

Venables

van Gijn

Kappelle

Algra

: Predictors of major vascular events in patients with a transient ischemic attack or minor ischemic stroke and with nonrheumatic atrial fibrillation. European Atrial Fibrillation Trial (EAFT) Study Group. Stroke 26, 801–806 (1995).

22.

Aronow

Ahn

Kronzon

Gutstein

: Risk factors for new thromboembolic stroke in patients > or = 62 years of age with chronic atrial fibrillation. Am. J. Cardiol. 82, 119–121 (1998).

23.

Nakagami

Yamamoto

Ikeda

Mitsuhashi

Goto

Shimada

: Mitral regurgitation reduces the risk of stroke in patients with nonrheumatic atrial fibrillation. Am. Heart J. 136, 528–532 (1998).

24.

The SPAF III Writing Committee for the Stroke Prevention in Atrial Fibrillation Investigators: Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin: Stroke Prevention in Atrial Fibrillation III Study. The SPAF III Writing Committee for the Stroke Prevention in Atrial Fibrillation Investigators. J. Am. Geriat. Soc. 279, 1273–1277 (1998).

25.

Inoue

Atarashi

: Risk factors for thromboembolism in patients with paroxysmal atrial fibrillation. Am. J. Cardiol. 86, 852–855 (2000).

26.

Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch. Intern. Med. 154, 1449–1457 (1994).

27.

Data were pooled from five randomized trials assessing the effectiveness of warfarin or aspirin versus control in patients with atrial fibrillation. Stroke risk was not significantly elevated in women.

28.

Friberg

Scharling

Gadsboll

Truelsen

Jensen

: Comparison of the impact of atrial fibrillation on the risk of stroke and cardiovascular death in women versus men (the Copenhagen City Heart Study). Am. J. Cardiol. 94, 889–894 (2004).

29.

Fang

Singer

Chang

: Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. Circulation 112, 1687–1691 (2005).

30.

Gender analysis of the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) cohort reveals female sex as an independent risk factor for thromboembolism in atrial fibrillation.

31.

Reeves

Bushnell

Howard

: Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 7, 915–926 (2008).

32.

Conway

Heeringa

Van Der Kuip

: Atrial fibrillation and the prothrombotic state in the elderly: the Rotterdam Study. Stroke 34, 413–417 (2003).

33.

Wang

Chen

: Increased levels of tissue plasminogen activator antigen and factor VIII activity in nonvalvular atrial fibrillation: relation to predictors of thromboembolism. J. Cardiovasc. Electrophysiol. 12, 877–884 (2001).

34.

Wieberdink

van Schie

Koudstaal

: High von Willebrand factor levels increase the risk of stroke: the Rotterdam study. Stroke 41, 2151–2156 (2010).

35.

Wassertheil-Smoller

Hendrix

Limacher

: Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA 289, 2673–2684 (2003).

36.

Gomberg-Maitland

Wenger

Feyzi

: Anticoagulation in women with non-valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials. Eur. Heart J. 27, 1947–1953 (2006).

37.

Squizzato

Gerdes

Brandjes

Buller

Stam

: Thyroid diseases and cerebrovascular disease. Stroke 36, 2302–2310 (2005).

38.

Sheu

Kang

Lin

: Hyperthyroidism and risk of ischemic stroke in young adults: a 5-year follow-up study. Stroke 41, 961–966 (2010).

39.

Frost

Vestergaard

Mosekilde

: Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. Arch. Intern. Med. 164, 1675–1678 (2004).

40.

Dagres

Nieuwlaat

Vardas

: Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Heart Survey on Atrial Fibrillation. J. Am. Coll. Cardiol. 49, 572–577 (2007).

41.

Gender analysis of the Euro Heart Survey revealed women with atrial fibrillation have more comorbidities and a higher chance of stroke.

42.

Humphries

Kerr

Connolly

: New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome. Circulation 103, 2365–2370 (2001).

43.

Towfighi

Saver

Engelhardt

Ovbiagele

: A midlife stroke surge among women in the United States. Neurology 69, 1898–1904 (2007).

44.

Daly

Clemens

Lopez Sendon

: Gender differences in the management and clinical outcome of stable angina. Circulation 113, 490–498 (2006).

45.

Mosca

Merz

Blumenthal

: Opportunity for intervention to achieve American Heart Association guidelines for optimal lipid levels in high-risk women in a managed care setting. Circulation 111, 488–493 (2005).

46.

Mosca

Linfante

Benjamin

: National study of physician awareness and adherence to cardiovascular disease prevention guidelines. Circulation 111, 499–510 (2005).

47.

Lip

Frison

Grind

: Effect of hypertension on anticoagulated patients with atrial fibrillation. Eur. Heart J. 28, 752–759 (2007).

48.

Arima

Hart

Colman

: Perindopril-based blood pressure-lowering reduces major vascular events in patients with atrial fibrillation and prior stroke or transient ischemic attack. Stroke 36, 2164–2169 (2005).

49.

Almdal

Scharling

Jensen

Vestergaard

: The independent effect of Type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch. Intern. Med. 164, 1422–1426 (2004).

50.

Ford

Giles

Dietz

: Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287, 356–359 (2002).

51.

Hart

Pearce

Aguilar

: Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann. Intern. Med. 146, 857–867 (2007).

52.

Hylek

Chang

: Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 290, 2685–2692 (2003).

53.

Wyse

Waldo

DiMarco

: A comparison of rate control and rhythm control in patients with atrial fibrillation. N. Engl. J. Med. 347, 1825–1833 (2002).

54.

Poli

Antonucci

Grifoni

Abbate

Gensini

Prisco

: Gender differences in stroke risk of atrial fibrillation patients on oral anticoagulant treatment. Thromb. Haemost. 101, 938–942 (2009).

55.

Kapral

Fang

Hill

: Sex differences in stroke care and outcomes: results from the Registry of the Canadian Stroke Network. Stroke 36, 809–814 (2005).

56.

Heneghan

Alonso-Coello

Garcia-Alamino

Perera

Meats

Glasziou

: Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet 367, 404–411 (2006).

57.

Gage

Waterman

Shannon

Boechler

Rich

Radford

: Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 285, 2864–2870 (2001).

58.

Lip

Nieuwlaat

Pisters

Lane

Crijns

: Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest 137, 263–272 (2010).

59.

Development of the Birmingham 2009 risk schema, cardiac failure or dysfunction, hypertension, age ≥75 (double point), diabetes, previous stroke (double point), vascular disease, age 65–74 and female sex.

60.

Lip

Frison

Halperin

Lane

: Identifying patients at high risk for stroke despite anticoagulation: a comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort. Stroke 41, 2731–2738 (2010).

61.

Van Staa

Setakis

Di Tanna

Lane

Lip

: A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice. J. Thromb. Haemost. 9, 39–48 (2011).

62.

Olesen

Lip

Hansen

: Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 342, D124 (2011).

63.

Stroke risk associated with a specific risk stratification score depends on the risk factors composing the score. Cardiac failure or dysfunction, hypertension, age ≥75 (double point), diabetes, previous stroke (double point), vascular disease, age 65–74 and female sex, performed better than congestive heart failure, hypertension, age, diabetes, previous stroke (double point) in predicting patients at a high risk of stroke.

64.

Connolly

Ezekowitz

Yusuf

: Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, 1139–1151 (2009).

65.

In patients with atrial fibrillation, dabigatran compared with warfarin was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage.

66.

Connolly

Eikelboom

Joyner

: Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 364, 806–817 (2011).

67.

Gensch

Hoppe

Bohm

Laufs

: Late-breaking clinical trials presented at the American Heart Association Congress in Chicago 2010. Clin. Res. Cardiol. 100(1), 1–9 (2010).

68.

Ezekowitz

Aikens

Brown

Ellis

: The evolving field of stroke prevention in patients with atrial fibrillation. Stroke 41, S17–S20 (2010).

69.

Giorgi

Cohen Arazi

Gonzalez

Di Girolamo

: Changing anticoagulant paradigms for atrial fibrillation: dabigatran, apixaban and rivaroxaban. Expert Opin. Pharmacother. 12, 567–577 (2011).

70.

Wann

Curtis

January

: 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 123, 104–123 (2011).

71.

CEJA Report B – I-90: Gender disparities in clinical decision-making www.ama-assn.org/ama1/pub/upload/mm/code-medical-ethics/9122a.pdf (Accessed 12 January 2011)

72.

National Collaborating Centre for Chronic Conditions: Atrial fibrillation. National clinical guideline for management in primary and secondary care. Royal College of Physicians, UK (2006) http://guidance.nice.org.uk/CG36/Guidance/pdf/English (Accessed 12 January 2011)

The Link between Atrial Fibrillation and Stroke in Women

Abstract

Keywords

Evidence for female gender as a clinical risk factor for stroke in AF

Female gender & thromboembolism in AF: biology, bias or both?

Prothrombotic biomarkers

Hormone replacement therapy

Thyrotoxicosis

Sex differences in medical management

Anticoagulant therapy for stroke prevention in women with AF

Bleeding risks of anticoagulant therapy in women with AF

Incorporation of gender in risk stratification schemes

Conclusion

Future perspective

Footnotes

References