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Gender Differences of Thromboembolic Events in Atrial Fibrillation

Open AccessPublished:December 31, 2015DOI:https://doi.org/10.1016/j.amjcard.2015.12.040
      Atrial fibrillation (AF) is the most common clinically relevant arrhythmia and increases the risk of thromboembolism and stroke; however, these risks are not the same for women and men. This review examines the evidence and clinical significance of increased thromboembolic risk in women with AF. The balance of results from over 30 recent studies suggests that female gender is an independent stroke risk factor in AF, and the inclusion of female gender in stroke risk stratification models, such as CHA2DS2-VASc, has improved risk assessment. Reasons for the increased thrombogenicity in women remain incompletely elucidated, but biological factors including increased hypertension, renal dysfunction, and hyperthyroidism in female patients with AF; cardiovascular remodeling; increased hypercoagulability, and estrogen hormone replacement therapy in women have been proposed. More importantly, gender differences exist in medical management of patients with AF, and compared with men, women have been found to have greater thromboembolic risk when not on anticoagulants, but may benefit from greater risk reduction when systemically anticoagulated. In conclusion, increased clinician awareness of these gender differences may help to improve the management of patients with AF.
      Atrial fibrillation (AF), the most common clinically relevant arrhythmia, affects 2.7 to 6.1 million Americans, with prevalence projected to double by the year 2050.
      American Heart Association Statistics Committee and Stroke Statistics Subcommittee
      Heart disease and stroke statistics—2014 update: a report from the American Heart Association.
      The prevalence of AF is 3.2% of the population aged ≥20 years and reaches 20% at age 80.
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      Men have a greater risk of developing AF than women by a factor of 1.5 after adjusting for other risk factors.
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      Women make up about 60% of the population with AF aged >75, the median age of AF onset.
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      AF is associated with a fivefold increased risk of stroke
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      Many risk stratification models have been proposed to quantify the risk of stroke in AF. The inclusion of female gender as an independent risk factor has been the subject of recent examination. AF is more frequently noted in women presenting with stroke than in men.
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      Thus, these gender differences are clinically relevant to make accurate estimations of inherent stroke risk in patients with AF. This is important because patients with AF with the highest stroke risk derive the greatest absolute benefit from systemic anticoagulation.
      Stroke Prevention in Atrial Fibrillation Investigators
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      As such, clinician awareness of such gender differences becomes useful when a decision regarding anticoagulation is needed and few or no other risk factors exist. Current European Society of Cardiology (ESC) guidelines recommend that no systemic anticoagulation is required for female patients aged <65 years with lone AF (CHA2DS2-VASc = 1) because these patients are considered low risk for stroke, which stands in contrast to other subgroups with CHA2DS2-VASc = 1. The primary objective of this review is to provide an updated overview of the existing evidence for gender differences in thromboembolic risk and to discuss the clinical importance of such differences.

      Methods

      The PubMed database was used to review the English language reports addressing gender differences and thromboembolic risk in AF from 1994 to the present. The search used combinations of terms including “atrial fibrillation,” “gender OR sex OR female OR women,” and “thromboembolism OR stroke.” References of retrieved studies were further reviewed in detail for additional relevant studies and reviews.
      Studies were selected for inclusion if they published stroke incidence data in men and in women. The number of women, number of total study participants, mean age of men and women, percent incidence of stroke in men and women, and relative risk (RR) for stroke for women were collected from each study when available. Difference in stroke risk was evaluated by examining the reported RR values, and if these were unavailable, by examining the p-value for statistically significant differences in stroke rates between men and women.
      No extramural funding was used to support this work. The investigators are solely responsible for the design and conduct of this study, all study analyses, the drafting, and editing of the study and its final contents.

       Evidence for Gender Differences in Thromboembolic Risk

      We compiled over 30 studies published since 1999 that examine gender and thromboembolic risk, including 5 randomized controlled trials (RCTs) and 24 observational studies (Tables 1 and 2). Of these 30 studies, 17 studies reported that female gender is a significant risk factor,
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      • Larson M.G.
      • Kannel W.B.
      • Benjamin E.J.
      A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study.
      • Friberg J.
      • Scharling H.
      • Gadsbøll N.
      • Truelsen T.
      • Jensen G.B.
      Comparison of the impact of atrial fibrillation on the risk of stroke and cardiovascular death in women versus men (the Copenhagen City Heart Study).
      • Dagres N.
      • Nieuwlaat R.
      • Vardas P.E.
      • Andresen D.
      • Lévy S.
      • Cobbe S.
      • Kremastinos D.T.
      • Breithardt G.
      • Cokkinos D.V.
      • Crijns H.J.
      Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe.
      • Poli D.
      • Antonucci E.
      • Grifoni E.
      • Abbate R.
      • Gensini G.F.
      • Prisco D.
      Gender differences in stroke risk of atrial fibrillation patients on oral anticoagulant treatment.
      • Oleson J.B.
      • Lip G.Y.H.
      • Hansen M.L.
      • Hansen P.R.
      • Tolstrup J.S.
      • Lindhardsen J.
      • Selmer C.
      • Ahlehoff O.
      • Olsen A.M.
      • Gislason G.H.
      • Torp-Pedersen C.
      Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.
      • Chao T.F.
      • Liu C.J.
      • Chen S.J.
      Atrial fibrillation and the risk of ischemic stroke: does it still matter in patients with a CHA2DS2-VASc score of 0 or 1?.
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      • Lip G.Y.H.
      Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study.
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      • Behlouli H.
      • Pilote L.
      Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation.
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      Comparison of clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation.
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      Atrial fibrillation, stroke, and anticoagulation in Medicare beneficiaries: trends by age, sex, and race, 1992-2010.
      • Siu C.W.
      • Lip G.Y.H.
      • Lam K.F.
      • Tse H.F.
      Risk of stroke and intracranial hemorrhage in 9727 Chinese with atrial fibrillation in Hong Kong.
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      • Zhao L.
      • Yu P.H.
      • Zhang H.
      • He Q.
      • Gu X.D.
      Risk factors and incidence of stroke and MACE in Chinese atrial fibrillation patients presenting to emergency departments: a national wide database analysis.
      • Fang M.C.
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      • Jensvold N.G.
      • Go A.S.
      Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors in Atrial fibrillation (ATRIA) study.
      • Gomberg-Maitland M.
      • Wenger N.K.
      • Feyzi J.
      • Lengyel M.
      • Volgman A.S.
      • Petersen P.
      • Frison L.
      • Halperin J.L.
      Anticoagulation in women with non-valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials.
      • Hart R.G.
      • Pearce L.A.
      • McBride R.
      • Rothbart R.M.
      • Asinger R.W.
      Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III Clinical Trials.
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      • Zamba G.
      • Lip G.Y.H.
      • Olshansky B.
      Relation of gender-specific risk of ischemic stroke in patients with atrial fibrillation to differences in warfarin anticoagulation control (from AFFIRM).
      12 studies reported that female gender is not significant,
      • Ruigómez A.
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      • Wallander M.
      • Edvardsson N.
      • García Rodríguez L.A.
      Risk of cardiovascular and cerebrovascular events after atrial fibrillation diagnosis.
      • Lin L.Y.
      • Lee C.H.
      • Yu C.C.
      • Tsai C.T.
      • Lai L.P.
      • Hwang J.J.
      • Chen P.C.
      • Lin J.L.
      Risk factors and incidence of ischemic stroke in Taiwanese with nonvalvular atrial fibrillation–a nationwide database analysis.
      • Van Staa T.P.
      • Setakis E.
      • Di Tanna G.L.
      • Lane D.A.
      • Lip G.Y.
      A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice.
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      • Lip G.Y.
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      • Oleson J.B.
      Female sex as a risk factor for stroke in atrial fibrillation: a nationwide cohort study.
      • Potpara T.S.
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      • Stankovic G.R.
      • Seferovic P.M.
      • Ostojic M.C.
      • Lip G.Y.
      Gender-related differences in presentation, treatment, and long-term outcome in patients with first-diagnosed atrial fibrillation and structurally normal heart: the Belgrade Atrial Fibrillation Study.
      • Bosch R.F.
      • Pittrow D.
      • Beltzer A.
      • Kruck I.
      • Kirch W.
      • Kohlhaussen A.
      • Bonnemeier H.
      Gender differences in patients with atrial fibrillation.
      • Guo Y.
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      • Ma J.
      • Wang Y.
      • Lip G.Y.
      Relation of renal dysfunction to the increased risk of stroke and death in female patients with atrial fibrillation.
      • Poli D.
      • Antonucci E.
      • Testa S.
      • Ageno W.
      • Palareti G.
      Gender differences of bleeding and stroke risk in very old atrial fibrillation patients on VKA treatment: results of the EPICA study on the behalf of FCSA (Italian Federation of Anticoagulation Clinics).
      • Salam A.M.
      • AlBinali H.A.
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      • Asaad N.
      • Singh R.
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      • Al Suwaidi J.
      Women hospitalized with atrial fibrillation: gender differences, trends and outcome from a 20-year registry in a Middle Eastern country (1991-2010).
      • Inoue H.
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      • Yamashita T.
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      • Kumagai N.
      • Sakurai M.
      • Kawamura Y.
      • Kubota I.
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      • Okuyama Y.
      • Shimizu A.
      • Igawa O.
      • Bando S.
      • Fukatani M.
      • Saikawa T.
      • Chishaki A.
      Impact of gender on the prognosis of patients with nonvalvular atrial fibrillation.
      • Mant J.
      • Hobbs F.D.R.
      • Fletcher K.
      • Roalfe A.
      • Fitzmaurice D.
      • Lip G.Y.
      • Murray E.
      Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomized controlled trial.
      • Rienstra M.
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      • Ranchor A.V.
      • Veeger N.J.
      • Crijns H.J.
      • Van Gelder I.C.
      Gender-related differences in rhythm control treatment in persistent atrial fibrillation.
      and only 1 study reported that male gender is a significant risk factor.
      • Inoue H.
      • Atarashi H.
      Risk factors for thromboembolism in patients with paroxysmal atrial fibrillation.
      Four additional RCTs compared novel oral anticoagulant drugs (NOAC) and warfarin, providing further data on gender differences (Table 3).
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      Dabigatran versus warfarin in patients with atrial fibrillation.
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      • Munawar M.
      • O'Donnell M.
      • Lawrence J.
      • Lewis G.
      • Afzal R.
      • Yusuf S.
      Apixaban in patients with atrial fibrillation.
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      • Hermosillo A.G.
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      • Lopez-Sendon J.L.
      • Pais P.
      • Parkhomenko A.
      • Verheugt F.W.
      • Zhu J.
      • Wallentin L.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Patel M.R.
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      • Fox K.A.
      • Califf R.M.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      However, 1 RCT
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      • Wenger N.K.
      • Feyzi J.
      • Lengyel M.
      • Volgman A.S.
      • Petersen P.
      • Frison L.
      • Halperin J.L.
      Anticoagulation in women with non-valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials.
      and 1 observational study
      • Siu C.W.
      • Lip G.Y.H.
      • Lam K.F.
      • Tse H.F.
      Risk of stroke and intracranial hemorrhage in 9727 Chinese with atrial fibrillation in Hong Kong.
      no longer found a significant difference after multivariate analysis. Four studies, all reporting insignificant gender differences, only reported univariate risk estimates associated with female gender.
      • Lin L.Y.
      • Lee C.H.
      • Yu C.C.
      • Tsai C.T.
      • Lai L.P.
      • Hwang J.J.
      • Chen P.C.
      • Lin J.L.
      Risk factors and incidence of ischemic stroke in Taiwanese with nonvalvular atrial fibrillation–a nationwide database analysis.
      • Potpara T.S.
      • Marinkovic J.M.
      • Polovina M.M.
      • Stankovic G.R.
      • Seferovic P.M.
      • Ostojic M.C.
      • Lip G.Y.
      Gender-related differences in presentation, treatment, and long-term outcome in patients with first-diagnosed atrial fibrillation and structurally normal heart: the Belgrade Atrial Fibrillation Study.
      • Poli D.
      • Antonucci E.
      • Testa S.
      • Ageno W.
      • Palareti G.
      Gender differences of bleeding and stroke risk in very old atrial fibrillation patients on VKA treatment: results of the EPICA study on the behalf of FCSA (Italian Federation of Anticoagulation Clinics).
      • Inoue H.
      • Atarashi H.
      • Okumura K.
      • Yamashita T.
      • Origasa H.
      • Kumagai N.
      • Sakurai M.
      • Kawamura Y.
      • Kubota I.
      • Matsumoto K.
      • Kaneko Y.
      • Ogawa S.
      • Aizawa Y.
      • Chinushi M.
      • Kodama I.
      • Watanabe E.
      • Koretsune Y.
      • Okuyama Y.
      • Shimizu A.
      • Igawa O.
      • Bando S.
      • Fukatani M.
      • Saikawa T.
      • Chishaki A.
      Impact of gender on the prognosis of patients with nonvalvular atrial fibrillation.
      Table 1Observational studies addressing gender
      Publication

      (year)
      CohortTotal n# of

      females
      %

      female
      Age (years)Stroke (%)Relative Risk
      MalesFemalesp ValueMalesFemalesp ValueFemalesp Value
      Inoue (2000)
      • Inoue H.
      • Atarashi H.
      Risk factors for thromboembolism in patients with paroxysmal atrial fibrillation.
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      Japan74023431.656
      Gender-specific mean age not provided.
      NRNRNRNRRR 0.5 M0.0291
      Humphries (2001)
      • Humphries K.H.
      • Kerr C.R.
      • Connolly S.J.
      • Klein G.
      • Boone J.A.
      • Green M.
      • Sheldon R.
      • Talajic M.
      • Dorian P.
      • Newman D.
      New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome.
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      CARAF (Canada)109733930.960.5±0.665.4±0.7<0.0016.5
      Estimated from figure.
      7.8
      Estimated from figure.
      NSNRNR
      Wang (2003)
      • Wang T.J.
      • Massaro J.M.
      • Levy D.
      • Vasan R.S.
      • Wolf P.A.
      • D'Agostino R.B.
      • Larson M.G.
      • Kannel W.B.
      • Benjamin E.J.
      A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study.
      Framingham Heart Study (USA)70533647.775
      Gender-specific mean age not provided.
      NRNRNRNRHR 1.92 MNR
      Friberg (2004)
      • Friberg J.
      • Scharling H.
      • Gadsbøll N.
      • Truelsen T.
      • Jensen G.B.
      Comparison of the impact of atrial fibrillation on the risk of stroke and cardiovascular death in women versus men (the Copenhagen City Heart Study).
      Copenhagen City Heart Study27611039.967±8.469±6.8NR7.820NRHR 2.6 MNR
      4.7 years
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Dagres (2007)
      • Dagres N.
      • Nieuwlaat R.
      • Vardas P.E.
      • Andresen D.
      • Lévy S.
      • Cobbe S.
      • Kremastinos D.T.
      • Breithardt G.
      • Cokkinos D.V.
      • Crijns H.J.
      Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe.
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      Euro Heart Survey on AF5333224942.264±1370±12<0.0011.22.20.011OR 1.83 M0.019 M
      1 year
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Poli (2009)
      • Poli D.
      • Antonucci E.
      • Grifoni E.
      • Abbate R.
      • Gensini G.F.
      • Prisco D.
      Gender differences in stroke risk of atrial fibrillation patients on oral anticoagulant treatment.
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      University of Florence (Italy)78027535.37476<0.0011.2
      Events/100 patient-years.
      2.43
      Events/100 patient-years.
      0.042HR 2.3 M<0.01
      Ruigomez (2009)
      • Ruigómez A.
      • Johansson S.
      • Wallander M.
      • Edvardsson N.
      • García Rodríguez L.A.
      Risk of cardiovascular and cerebrovascular events after atrial fibrillation diagnosis.
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      UK General Practice Research83142651.361.2% subjects aged ≥70
      Gender-specific mean age not provided.
      NRNRNRNRRR 1.0 MNS
      Lin (2011)
      • Lin L.Y.
      • Lee C.H.
      • Yu C.C.
      • Tsai C.T.
      • Lai L.P.
      • Hwang J.J.
      • Chen P.C.
      • Lin J.L.
      Risk factors and incidence of ischemic stroke in Taiwanese with nonvalvular atrial fibrillation–a nationwide database analysis.
      Taiwan NHI research database7920363345.963.3% subjects aged ≥65
      Gender-specific mean age not provided.
      NRNRNRNROR 0.942 U0.512 U
      Oleson (2011)
      • Oleson J.B.
      • Lip G.Y.H.
      • Hansen M.L.
      • Hansen P.R.
      • Tolstrup J.S.
      • Lindhardsen J.
      • Selmer C.
      • Ahlehoff O.
      • Olsen A.M.
      • Gislason G.H.
      • Torp-Pedersen C.
      Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.
      Denmark national register735383765151.259.7% subjects aged ≥75
      Gender-specific mean age not provided.
      NRNRNRNRHR 1.6 M0.04 M
      van Staa (2011)
      • Van Staa T.P.
      • Setakis E.
      • Di Tanna G.L.
      • Lane D.A.
      • Lip G.Y.
      A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice.
      United Kingdom798443970449.773.3
      Gender-specific mean age not provided.
      NR1.21.9NRRR 1.05 MNS
      4 years
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Chao (2012)
      • Chao T.F.
      • Liu C.J.
      • Chen S.J.
      Atrial fibrillation and the risk of ischemic stroke: does it still matter in patients with a CHA2DS2-VASc score of 0 or 1?.
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      Taiwan NHI research database82932038.645.4 ± 12
      Gender-specific mean age not provided.
      11.64.40.014HR 2.48 M0.042 M
      57.4 ± 35.7 months
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Friberg (2012)
      • Friberg L.
      • Benson L.
      • Rosenqvist M.
      • Lip G.Y.H.
      Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study.
      Sweden1008025066750.374.780.9NR4.2
      Percent per year.
      6.2
      Percent per year.
      <0.0001HR 1.47 U; 1.18 M<0.001
      Mikkelsen (2012)
      • Mikkelsen A.P.
      • Lindhardsen J.
      • Lip G.Y.
      • Gislason G.H.
      • Torp-Pedersen C.
      • Oleson J.B.
      Female sex as a risk factor for stroke in atrial fibrillation: a nationwide cohort study.
      Denmark872024474451.37178.2<0.00013.7
      Events/100 patient-years.
      5.43
      Events/100 patient-years.
      NRHR 1.04 MNR
      Potpara (2012)
      • Potpara T.S.
      • Marinkovic J.M.
      • Polovina M.M.
      • Stankovic G.R.
      • Seferovic P.M.
      • Ostojic M.C.
      • Lip G.Y.
      Gender-related differences in presentation, treatment, and long-term outcome in patients with first-diagnosed atrial fibrillation and structurally normal heart: the Belgrade Atrial Fibrillation Study.
      Belgrade AF Study (Serbia)86231546.549.656.7<0.0016.970.579HR 1.11 U0.579 U
      10.1±6.1 years
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Tsadok (2012)
      • Avgil Tsadok M.
      • Jackevicius C.A.
      • Rahme E.
      • Humphries K.H.
      • Behlouli H.
      • Pilote L.
      Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation.
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      Quebec (Canada)835134411552.877.280.2NR4.35.8<0.001HR 1.14 M<0.001 M
      30, 90, 365 days
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Bosch (2013)
      • Bosch R.F.
      • Pittrow D.
      • Beltzer A.
      • Kruck I.
      • Kirch W.
      • Kohlhaussen A.
      • Bonnemeier H.
      Gender differences in patients with atrial fibrillation.
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      Germany2742102137.267.5±9.971.2±9.3<0.0013.43.60.74NRNR
      6, 12 months
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Disertori (2013)
      • Disertori M.
      • Franzosi M.G.
      • Barlera S.
      • Cosmi F.
      • Quintarelli S.
      • Favero C.
      • Cappellini G.
      • Fabbri G.
      • Maggioni A.P.
      • Staszewsky L.
      • Moroni L.A.
      • Latini R.
      Thromboembolic event rate in paroxysmal and persistent atrial fibrillation: data from the GISSI-AF trial.
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      GISSI-AF subset123448739.566.75 paroxysmal AF; 68.78 persistent AF
      Gender-specific mean age not provided.
      NR39NRNRNR
      1 year
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Guo (2013)
      • Guo Y.
      • Wang H.
      • Zhao X.
      • Zhang Y.
      • Zhang D.
      • Ma J.
      • Wang Y.
      • Lip G.Y.
      Relation of renal dysfunction to the increased risk of stroke and death in female patients with atrial fibrillation.
      Chinese PLA General Hospital103428127.27871<0.00018.16.050.267NRNR
      1.9 years
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Poli (2013)
      • Poli D.
      • Antonucci E.
      • Testa S.
      • Ageno W.
      • Palareti G.
      Gender differences of bleeding and stroke risk in very old atrial fibrillation patients on VKA treatment: results of the EPICA study on the behalf of FCSA (Italian Federation of Anticoagulation Clinics).
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      EPICA study (Italy)3015165454.982.6
      Median age.
      83.1
      Median age.
      0.0011.3
      Events/100 patient-years.
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      1.6
      Events/100 patient-years.
      0.25OR 1.2 U0.3 U
      Salam (2013)
      • Salam A.M.
      • AlBinali H.A.
      • Al-Mulla A.W.
      • Asaad N.
      • Singh R.
      • Al-Qahtani A.
      • Al Suwaidi J.
      Women hospitalized with atrial fibrillation: gender differences, trends and outcome from a 20-year registry in a Middle Eastern country (1991-2010).
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      Hamad General Hospital (Qatar)3849141736.854.5 ± 15.759 ± 150.0010.40.40.8NRNR
      20 years
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Aakre (2014)
      • Aakre C.A.
      • McLeod C.J.
      • Cha S.S.
      • Tsang T.S.
      • Lip G.Y.
      • Gersh B.J.
      Comparison of clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation.
      Olmsted County, Minnesota (USA)2720132048.573.33±14.57
      Gender-specific mean age not provided.
      NRNRNRNRHR 1.45 M0.0015 M
      Inoue (2014)
      • Inoue H.
      • Atarashi H.
      • Okumura K.
      • Yamashita T.
      • Origasa H.
      • Kumagai N.
      • Sakurai M.
      • Kawamura Y.
      • Kubota I.
      • Matsumoto K.
      • Kaneko Y.
      • Ogawa S.
      • Aizawa Y.
      • Chinushi M.
      • Kodama I.
      • Watanabe E.
      • Koretsune Y.
      • Okuyama Y.
      • Shimizu A.
      • Igawa O.
      • Bando S.
      • Fukatani M.
      • Saikawa T.
      • Chishaki A.
      Impact of gender on the prognosis of patients with nonvalvular atrial fibrillation.
      J-RHYTHM7406216529.269±1073±9<0.0011.81.60.576OR 0.89 U0.576 U
      2 years
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Shroff (2014)
      • Shroff G.R.
      • Solid C.A.
      • Herzog C.A.
      Atrial fibrillation, stroke, and anticoagulation in Medicare beneficiaries: trends by age, sex, and race, 1992-2010.
      US Medicare patients 2010803144087950.9NRNRNR1.4
      Estimated from figure.
      1.9
      Estimated from figure.
      NRNRNR
      Siu (2014)
      • Siu C.W.
      • Lip G.Y.H.
      • Lam K.F.
      • Tse H.F.
      Risk of stroke and intracranial hemorrhage in 9727 Chinese with atrial fibrillation in Hong Kong.
      Queen Mary Hospital, Hong Kong9727506452.176.9±12.5
      Gender-specific mean age not provided.
      NRNRNRNRHR 1.16 U; 1.03 M0.026 U; 0.723 M
      Yang (2014)
      • Yang Y.M.
      • Shao X.H.
      • Zhu J.
      • Zhang H.
      • Liu Y.
      • Gao X.
      • Liu L.S.
      • Yu L.T.
      • Zhao L.
      • Yu P.H.
      • Zhang H.
      • He Q.
      • Gu X.D.
      Risk factors and incidence of stroke and MACE in Chinese atrial fibrillation patients presenting to emergency departments: a national wide database analysis.
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      Chinese AF registry2016110454.868.5NRNRNRNRHR 1.359 U; 1.419 M0.073 U; 0.048 M
      GISSI-AF = Gruppo Italiano Studio Sopravvivenza Insufficienza; HR = hazard ratio; J-RHYTHM = Japanese Rhythm Management Trial for AF; M = multivariate analysis; NHI = National Health Insurance; OR = odds ratio; PLA = People's Liberation Army; RR = relative risk; U = univariate analysis.
      Study does not explicitly state whether patients with valvular AF were excluded. All unmarked studies recruited patients with nonvalvular AF.
      Gender-specific mean age not provided.
      Estimated from figure.
      § Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Events/100 patient-years.
      Percent per year.
      ∗∗ Median age.
      Table 2Randomized controlled trials (RCTs) addressing gender
      Publication

      (year)
      CohortTotal

      n
      # of

      females
      %

      female
      Age (years)Stroke (%)Relative Risk
      MalesFemalesp ValueMalesFemalesp

      Value
      Femalesp Value
      Hart (1999)
      • Hart R.G.
      • Pearce L.A.
      • McBride R.
      • Rothbart R.M.
      • Asinger R.W.
      Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III Clinical Trials.
      SPAF I-III185351427.76871NR2.1
      Percentage per year.
      4.4
      Percentage per year.
      NRRR 1.8 U; 1.6 M0.03 U; 0.01 M
      Fang (2005)
      • Fang M.C.
      • Singer D.E.
      • Chang Y.
      • Hylek E.M.
      • Henault L.E.
      • Jensvold N.G.
      • Go A.S.
      Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors in Atrial fibrillation (ATRIA) study.
      ATRIA cohort13559579542.7NRNRNR1.8
      Percentage per year.
      3.5
      Percentage per year.
      NRRR 1.6 MNR
      Rienstra (2005)
      • Rienstra M.
      • Van Veldhuisen D.J.
      • Hagens V.E.
      • Ranchor A.V.
      • Veeger N.J.
      • Crijns H.J.
      • Van Gelder I.C.
      Gender-related differences in rhythm control treatment in persistent atrial fibrillation.
      Additional therapies examined calcium channel blockers, β blockers, electrocardioversions, antiarrhythmic drugs.
      RACE substudy52219236.867±971±8<0.0016.76.8NSNRNR
      2.3 years
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Gomberg-Maitland (2006)
      • Gomberg-Maitland M.
      • Wenger N.K.
      • Feyzi J.
      • Lengyel M.
      • Volgman A.S.
      • Petersen P.
      • Frison L.
      • Halperin J.L.
      Anticoagulation in women with non-valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials.
      SPORTIF III and V7329225730.869.8±973.4±8<0.00011.44
      Percentage per year.
      2.08
      Percentage per year.
      0.016HR 1.44 U; 1.27 M0.0161 U; 0.16 M
      Sullivan (2012)
      • Sullivan R.M.
      • Zhang J.
      • Zamba G.
      • Lip G.Y.H.
      • Olshansky B.
      Relation of gender-specific risk of ischemic stroke in patients with atrial fibrillation to differences in warfarin anticoagulation control (from AFFIRM).
      AFFIRM substudy4060159439.368.3±8.371.3±7.5<0.0001350.002OR 1.6 M0.002 M
      2000 days
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      All studies recruited patients with nonvalvular AF.
      AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; HR = hazard ratio; M = multivariate analysis; OR = odds ratio; RR = relative risk; U = univariate analysis.
      Percentage per year.
      Additional therapies examined calcium channel blockers, β blockers, electrocardioversions, antiarrhythmic drugs.
      Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.
      Table 3NOAC drug studies addressing gender
      Publication

      (year)
      CohortArm of

      Study
      Total n# of

      females
      %

      female
      Age (years)Stroke (%)
      MalesFemalesp ValueMalesFemalesp Value
      Connolly (2009)
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • Eikelboom J.
      • Oldgren J.
      • Parekh A.
      • Pogue J.
      • Reilly P.A.
      • Themeles E.
      • Varrone J.
      • Wang S.
      • Alings M.
      • Xavier D.
      • Zhu J.
      • Diaz R.
      • Lewis B.S.
      • Darius H.
      • Diener H.C.
      • Joyner C.D.
      • Wallentin L.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      RE-LYDabigatran 110 mg6015215035.771.4±8.6
      Gender-specific mean age not provided.
      NR1.35
      P per year.
      1.86
      P per year.
      0.96
      Dabigatran 150 mg6076223636.871.5±8.8
      Gender-specific mean age not provided.
      NR1.10
      P per year.
      1.14
      P per year.
      0.24
      Warfarin6022221336.771.6±8.6
      Gender-specific mean age not provided.
      NR1.49
      P per year.
      2.03
      P per year.
      NR
      Connolly (2011)
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • Diener H.C.
      • Hart R.
      • Golitsyn S.
      • Flaker G.
      • Avezum A.
      • Hohnloser S.H.
      • Diaz R.
      • Talajic M.
      • Zhu J.
      • Pais P.
      • Budaj A.
      • Parkhomenko A.
      • Jansky P.
      • Commerford P.
      • Tan R.S.
      • Sim K.H.
      • Lewis B.S.
      • Mieghem W.V.
      • Lip G.Y.H.
      • Kim J.H.
      • Lanas-Zanetti F.
      • Gonzalez-Hermosillo A.
      • Dans A.L.
      • Munawar M.
      • O'Donnell M.
      • Lawrence J.
      • Lewis G.
      • Afzal R.
      • Yusuf S.
      Apixaban in patients with atrial fibrillation.
      AVERROESApixaban2808114840.968.671.4NR1.4
      P per year.
      1.9
      P per year.
      0.42
      Aspirin2791117442.168.871.8NR2.7
      P per year.
      4.9
      P per year.
      0.42
      Granger (2011)
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • Lopes R.D.
      • Hylek E.M.
      • Hanna M.
      • Al-Khalidi H.R.
      • Ansell J.
      • Atar D.
      • Avezum A.
      • Bahit M.C.
      • Diaz R.
      • Easton J.D.
      • Ezekowitz J.A.
      • Flaker G.
      • Garcia D.
      • Geraldes M.
      • Gersh B.J.
      • Golitsyn S.
      • Goto S.
      • Hermosillo A.G.
      • Hohnloser S.H.
      • Horowitz J.
      • Mohan P.
      • Jansky P.
      • Lewis B.S.
      • Lopez-Sendon J.L.
      • Pais P.
      • Parkhomenko A.
      • Verheugt F.W.
      • Zhu J.
      • Wallentin L.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ARISTOTLEApixaban9120323435.570
      Median age.
      Gender-specific mean age not provided.
      NR1.2
      P per year.
      1.4
      P per year.
      0.6
      Warfarin908131823570
      Median age.
      Gender-specific mean age not provided.
      NR1.5
      P per year.
      1.8
      P per year.
      0.6
      Patel (2011)
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • Pan G.
      • Singer D.E.
      • Hacke W.
      • Breithardt G.
      • Halperin J.L.
      • Hankey G.J.
      • Piccini J.P.
      • Becker R.C.
      • Nessel C.C.
      • Paolini J.F.
      • Berkowitz S.D.
      • Fox K.A.
      • Califf R.M.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ROCKET-AFRivaroxaban7131283139.773
      Median age.
      Gender-specific mean age not provided.
      NRNRNRNR
      Warfarin7133283239.773
      Median age.
      Gender-specific mean age not provided.
      NR2.02
      Events/100 patient-years.
      2.67
      Events/100 patient-years.
      <0.001
      All studies recruited patients with nonvalvular AF.
      ARISTOTLE = Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF; AVERROES = Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in AF Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; RE-LY = Randomized Evaluation of Long-Term Anticoagulation Therapy; ROCKET-AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in AF.
      Gender-specific mean age not provided.
      P per year.
      Median age.
      § Events/100 patient-years.
      Although only 13 of the 25 observational studies reported female gender as significant, 2 of the 12 observational studies that reported no significant gender differences had abnormal age distributions, which may have skewed the data. The Elderly Patients followed by Italian Centres for Anticoagulation (EPICA) study only included patients over 80 years old,
      • Wang T.J.
      • Massaro J.M.
      • Levy D.
      • Vasan R.S.
      • Wolf P.A.
      • D'Agostino R.B.
      • Larson M.G.
      • Kannel W.B.
      • Benjamin E.J.
      A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study.
      and a Beijing hospital study reported that the lack of significant gender differences may be because the female patients were younger and had fewer co-morbidities.
      • Oleson J.B.
      • Lip G.Y.H.
      • Hansen M.L.
      • Hansen P.R.
      • Tolstrup J.S.
      • Lindhardsen J.
      • Selmer C.
      • Ahlehoff O.
      • Olsen A.M.
      • Gislason G.H.
      • Torp-Pedersen C.
      Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.
      The Stroke Prevention in Atrial Fibrillation (SPAF) trials of the 1990s provided early data on gender differences.
      • Hart R.G.
      • Pearce L.A.
      • McBride R.
      • Rothbart R.M.
      • Asinger R.W.
      Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III Clinical Trials.
      These studies reported that women with AF have a greater risk of stroke than men (RR 1.6, p = 0.01), and this difference in stroke rate was substantially greater in patients aged >75 years. The largest RCT was the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study with a cohort of 13,559 adults with AF.
      • Fang M.C.
      • Singer D.E.
      • Chang Y.
      • Hylek E.M.
      • Henault L.E.
      • Jensvold N.G.
      • Go A.S.
      Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors in Atrial fibrillation (ATRIA) study.
      This was the first RCT with enough end points to examine the influence of gender on stroke risk. The study reported that the annual incidence rates of thromboembolism off warfarin were 3.5% for women versus 1.8% for men (RR 1.9, 95% CI 1.6 to 2.4). The difference between the RR of thromboembolism for women versus men for those aged ≤75 years (RR 1.6, 95% CI 1.0 to 2.3) and those aged >75 years (RR 1.8, 95% CI 1.4 to 2.3) was not statistically different.

       Gender as an Independent Stroke Risk Factor

      Interestingly, the balance of evidence suggests that female gender is an independent thromboembolic risk factor. Several meta-analyses have also found that women appear to have an increased stroke risk compared with their male counterparts. One meta-analysis of 17 studies reported a 1.31-fold (95% CI 1.18 to 1.46) increased stroke risk in women with AF, especially those aged ≥75 years, regardless of oral anticoagulation (OAC) therapy.
      • Wagstaff A.J.
      • Overvad T.F.
      • Lip G.Y.
      • Lane D.A.
      Is female sex a risk factor for stroke and thromboembolism in patients with atrial fibrillation? A systematic review and meta-analysis.
      Another meta-analysis reported that women with AF have a significantly greater residual risk of cerebrovascular accident/systemic embolism compared with men with AF (odds ratio 1.279, 95% CI 1.111 to 1.473, p = 0.001) while on warfarin, but there was no significant gender difference in residual risk of cerebrovascular accident/systemic embolism in patients with AF on novel OACs (odds ratio 1.146, 95% CI 0.97 to 1.354, p = 0.109).
      • Pancholy S.B.
      • Sharma P.S.
      • Pancholy D.S.
      • Patel T.M.
      • Callans D.J.
      • Marchlinski F.E.
      Meta-analysis of gender differences in residual stroke risk and major bleeding in patients with nonvalvular atrial fibrillation treated with oral anticoagulants.
      A meta-analysis analyzing the warfarin arm of 6 studies found that women with AF treated with OAC therapy still had higher stroke rates than men (RR 1.30, 95% CI 1.15 to 1.49, p <0.001).
      • Albertsen I.E.
      • Rasmussen L.H.
      • Overvad T.F.
      • Graungaard T.
      • Larsen T.B.
      • Lip G.Y.
      Risk of stroke or systemic embolism in atrial fibrillation patients treated with warfarin: a systematic review and meta-analysis.
      Likewise, there have been several systematic reviews of contemporary data on stroke in women with AF that have found female gender to be an independent predictor of stroke in AF with reported average RRs of 1.5 to 1.9.
      • Madias C.
      • Trohman R.G.
      The link between atrial fibrillation and stroke in women.
      • Hart R.G.
      • Eikelboom J.W.
      • Pearce L.A.
      Sex, stroke, and atrial fibrillation.
      • Pisters R.
      • Lane D.A.
      • Marin F.
      • Camm A.J.
      • Lip G.Y.
      Stroke and thromboembolism in atrial fibrillation: systematic review of stroke risk factors and risk stratification schema.

       Comparison of Stroke Risk Stratification Models Regarding Gender

      Female gender is increasingly recognized as a stroke risk factor in AF (Table 4). A previously commonly used stroke risk stratification model, CHADS2 (1 point each for congestive heart failure, hypertension, age ≥75 years, and diabetes mellitus and 2 points for previous stroke/transient ischemic attack) does not include gender.
      • Gage B.F.
      • Waterman A.D.
      • Shannon W.
      • Boechler M.
      • Rich M.W.
      • Radford M.J.
      Validation of clinical classification schemes for predicting stroke.
      A large Swedish cohort study found that at each CHADS2 score, the stroke rate was higher in women than in men.
      • Friberg L.
      • Benson L.
      • Rosenqvist M.
      • Lip G.Y.H.
      Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study.
      In light of the mounting evidence suggesting increased thromboembolic risk in women compared with men, the CHA2DS2-VASc (CHA2DS2 and 1 point each for vascular disease, age 65 to 74 years, and gender category) model was developed to complement CHADS2 by considering additional stroke risk factors, including female gender, age 65 to 74, and vascular disease.
      Table 4Recent evolution of risk stratification models
      YearRisk Stratification ModelGender as Risk Factor
      2001CHADS2Female gender not included
      2003Framingham stroke risk scoreFemale gender incorporated as risk factor
      2006ACC/AHA/ESC guidelinesRecognized female gender as one of the “less validated or weaker risk factors”
      2009CHA2DS2-VAScFemale gender incorporated as risk factor
      2010/2012ESC guidelinesUpgraded female gender from a “less validated or weaker risk factor” to a “clinically relevant non-major risk factor”
      2012Canadian Cardiovascular Society guidelines updateRecommended use of CHADS2 in 2010. In 2012, guidelines updated to consider CHA2DS2-VASc if CHADS2 = 0 and addressed single point for female
      ACC/AHA/ESC = American College of Cardiology/American Heart Association/European Society of Cardiology.
      Several studies support the use of CHA2DS2-VASc score, particularly for its additional predictive value for patients with low CHADS2 scores.
      • Aakre C.A.
      • McLeod C.J.
      • Cha S.S.
      • Tsang T.S.
      • Lip G.Y.
      • Gersh B.J.
      Comparison of clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation.
      • Palm F.
      • Kleemann T.
      • Dos Santos M.
      • Urbanek C.
      • Buggle F.
      • Safer A.
      • Hennerici M.G.
      • Becker H.
      • Zahn R.
      • Grau A.J.
      Stroke due to atrial fibrillation in a population-based stroke registry (Ludwigshafen Stroke Study) CHADS2, CHA2DS2-VASc score, underuse of oral anticoagulation, and implications for preventive measures.
      A Danish cohort study reported that CHA2DS2-VASc performed better than CHADS2 in identifying patients at high risk and at truly low risk.
      • Oleson J.B.
      • Lip G.Y.H.
      • Hansen M.L.
      • Hansen P.R.
      • Tolstrup J.S.
      • Lindhardsen J.
      • Selmer C.
      • Ahlehoff O.
      • Olsen A.M.
      • Gislason G.H.
      • Torp-Pedersen C.
      Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.
      Likewise, a Chinese AF cohort study found that the 3 new components of CHA2DS2-VASc, including age 65 to 74 years, female gender, and a history of other vascular disease, were predictive of stroke in their cohort.
      • Siu C.W.
      • Lip G.Y.H.
      • Lam K.F.
      • Tse H.F.
      Risk of stroke and intracranial hemorrhage in 9727 Chinese with atrial fibrillation in Hong Kong.
      A study on postmenopausal women with AF found that for CHADS2 <2, stroke risk almost doubles with each additional CHA2DS2-VASc point.
      • Abraham J.M.
      • Larson J.
      • Chung M.K.
      • Curtis A.B.
      • Lakshminarayan K.
      • Newman J.D.
      • Perez M.
      • Rexrode K.
      • Shara N.M.
      • Solomon A.J.
      • Stefanick M.L.
      • Torner J.C.
      • Wilkoff B.L.
      • Wassertheil-Smoller S.
      Does CHA2DS2-VASc improve stroke risk stratification in postmenopausal women with atrial fibrillation?.
      A Taiwanese study reported that women with AF with a CHA2DS2-VASc score of 1 (no risk factors other than gender) had a 2.5-fold stroke risk compared with men with AF with a score of 0, further validating the additional point for female gender.
      • Chao T.F.
      • Liu C.J.
      • Chen S.J.
      Atrial fibrillation and the risk of ischemic stroke: does it still matter in patients with a CHA2DS2-VASc score of 0 or 1?.
      That women with AF are at higher risk for thromboembolic events has been highlighted by the recognition and inclusion of female gender as an independent risk factor in newer stroke risk prediction models. However, although there are data to suggest that women with AF are more likely to suffer a thromboembolic event and tend to suffer worse clinical outcomes poststroke than their male counterparts, it has been noted that the more recent the study of excess female risk for thromboembolic events in AF, the lower this risk appears to be. In the 2003 Framingham study,
      • Wang T.J.
      • Massaro J.M.
      • Levy D.
      • Vasan R.S.
      • Wolf P.A.
      • D'Agostino R.B.
      • Larson M.G.
      • Kannel W.B.
      • Benjamin E.J.
      A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study.
      the risk for women was increased by 90%; by 80% in the 2007 Euro Heart Survey
      • Dagres N.
      • Nieuwlaat R.
      • Vardas P.E.
      • Andresen D.
      • Lévy S.
      • Cobbe S.
      • Kremastinos D.T.
      • Breithardt G.
      • Cokkinos D.V.
      • Crijns H.J.
      Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe.
      ; by 50% in the 2005 ATRIA study
      • Fang M.C.
      • Singer D.E.
      • Chang Y.
      • Hylek E.M.
      • Henault L.E.
      • Jensvold N.G.
      • Go A.S.
      Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors in Atrial fibrillation (ATRIA) study.
      ; and by 47% in the large Swedish cohort study
      • Friberg L.
      • Benson L.
      • Rosenqvist M.
      • Lip G.Y.H.
      Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study.
      in 2012. This is reflected in the 2012 ESC guidelines stating that women aged <65 years with lone AF are considered low risk and thus, no antithrombotic therapy should be considered. A female patient with AF can have 0 or 2 to 9 points with the CHA2DS2-VASc scoring system, as female gender is currently only recognized as a risk factor in the presence of at least one other risk factor.

       Reasons Why Stroke Risk in Women May Be Increased

      Many reasons have been hypothesized to account for the apparent increased thrombogenicity in women with AF. Differences in baseline patient characteristics involving AF presentation, medical co-morbidities, and stroke risk profiles may contribute to the increased stroke risk in women.
      • Lane D.A.
      • Lip G.Y.
      Female gender is a risk factor for stroke and thromboembolism in atrial fibrillation patients.
      Age is a well-known risk factor for stroke, and female patients in most studies were older, in the large Swedish cohort study, the mean age was 6 years higher in women than men,
      • Friberg L.
      • Benson L.
      • Rosenqvist M.
      • Lip G.Y.H.
      Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study.
      and it has been argued that this could account for the increase in thromboembolic risk. One study reported significantly larger left atrial dimensions in women (44.0 ± 6.5 vs 40.6 ± 6.3, p = 0.0026); however, another study found no difference in atrial size.
      • Poli D.
      • Antonucci E.
      • Grifoni E.
      • Abbate R.
      • Gensini G.F.
      • Prisco D.
      Gender differences in stroke risk of atrial fibrillation patients on oral anticoagulant treatment.
      Women with AF are also more likely to have preexisting hypertension,
      • Humphries K.H.
      • Kerr C.R.
      • Connolly S.J.
      • Klein G.
      • Boone J.A.
      • Green M.
      • Sheldon R.
      • Talajic M.
      • Dorian P.
      • Newman D.
      New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome.
      • Dagres N.
      • Nieuwlaat R.
      • Vardas P.E.
      • Andresen D.
      • Lévy S.
      • Cobbe S.
      • Kremastinos D.T.
      • Breithardt G.
      • Cokkinos D.V.
      • Crijns H.J.
      Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe.
      • Friberg L.
      • Benson L.
      • Rosenqvist M.
      • Lip G.Y.H.
      Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study.
      • Avgil Tsadok M.
      • Jackevicius C.A.
      • Rahme E.
      • Humphries K.H.
      • Behlouli H.
      • Pilote L.
      Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation.
      • Gomberg-Maitland M.
      • Wenger N.K.
      • Feyzi J.
      • Lengyel M.
      • Volgman A.S.
      • Petersen P.
      • Frison L.
      • Halperin J.L.
      Anticoagulation in women with non-valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials.
      • Rienstra M.
      • Van Veldhuisen D.J.
      • Hagens V.E.
      • Ranchor A.V.
      • Veeger N.J.
      • Crijns H.J.
      • Van Gelder I.C.
      Gender-related differences in rhythm control treatment in persistent atrial fibrillation.
      valvular heart disease,
      • Benjamin E.J.
      • Levy D.
      • Vaziri S.M.
      • D'Agostino R.B.
      • Belanger A.J.
      • Wolf P.A.
      Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study.
      • Dagres N.
      • Nieuwlaat R.
      • Vardas P.E.
      • Andresen D.
      • Lévy S.
      • Cobbe S.
      • Kremastinos D.T.
      • Breithardt G.
      • Cokkinos D.V.
      • Crijns H.J.
      Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe.
      and heart failure with preserved left ventricular function,
      • Dagres N.
      • Nieuwlaat R.
      • Vardas P.E.
      • Andresen D.
      • Lévy S.
      • Cobbe S.
      • Kremastinos D.T.
      • Breithardt G.
      • Cokkinos D.V.
      • Crijns H.J.
      Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe.
      but less likely to have coronary artery disease than men.
      • Dagres N.
      • Nieuwlaat R.
      • Vardas P.E.
      • Andresen D.
      • Lévy S.
      • Cobbe S.
      • Kremastinos D.T.
      • Breithardt G.
      • Cokkinos D.V.
      • Crijns H.J.
      Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe.
      • Fang M.C.
      • Singer D.E.
      • Chang Y.
      • Hylek E.M.
      • Henault L.E.
      • Jensvold N.G.
      • Go A.S.
      Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors in Atrial fibrillation (ATRIA) study.
      Women are more likely to have preexisting thyroid abnormalities,
      • Dagres N.
      • Nieuwlaat R.
      • Vardas P.E.
      • Andresen D.
      • Lévy S.
      • Cobbe S.
      • Kremastinos D.T.
      • Breithardt G.
      • Cokkinos D.V.
      • Crijns H.J.
      Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe.
      • Madias C.
      • Trohman R.G.
      The link between atrial fibrillation and stroke in women.
      which may also contribute to their increased thromboembolic risk. A 2010 study found that hyperthyroidism contributed a 1.44-time greater risk of ischemic stroke (95% CI 1.01 to 2.12; p = 0.038), after adjusting for age, gender, and AF, among other factors.
      • Sheu J.J.
      • Kang J.H.
      • Lin H.C.
      • Lin H.C.
      Hyperthyroidism and risk of ischemic stroke in young adults: a 5-year follow-up study.
      In addition to these co-morbidities, in particular, women with AF are more likely than their male counterparts to have a history of previous stroke—the strongest independent predictor for stroke.
      • Friberg L.
      • Benson L.
      • Rosenqvist M.
      • Lip G.Y.H.
      Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study.
      • Avgil Tsadok M.
      • Jackevicius C.A.
      • Rahme E.
      • Humphries K.H.
      • Behlouli H.
      • Pilote L.
      Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation.
      • Fang M.C.
      • Singer D.E.
      • Chang Y.
      • Hylek E.M.
      • Henault L.E.
      • Jensvold N.G.
      • Go A.S.
      Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors in Atrial fibrillation (ATRIA) study.
      However, many of the larger cohort studies adjusted for these co-morbidities and yet still found that women have a higher stroke risk.
      • Wagstaff A.J.
      • Overvad T.F.
      • Lip G.Y.
      • Lane D.A.
      Is female sex a risk factor for stroke and thromboembolism in patients with atrial fibrillation? A systematic review and meta-analysis.
      Other reasons suggested for the increased stroke risk in women include the possibility that women may have increased hypercoagulable qualities, such as endothelial dysfunction and prothrombotic factors, including elevated fibrinogen levels,
      • Kaptoge S.
      • White I.R.
      • Thompson S.G.
      • Wood A.M.
      Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the Fibrinogen Studies Collaboration.
      von Willebrand factor,
      • Wieberdink R.G.
      • van Schie M.C.
      • Koudstaal P.J.
      • Hofman A.
      • Witteman J.C.
      • de Maat M.P.
      • Leebeek F.W.
      • Breteler M.M.
      High von Willebrand factor levels increase the risk of stroke: the Rotterdam Study.
      • Conway D.S.
      • Heeringa J.
      • Van Der Kuip D.A.
      • Chin B.S.
      • Hofman A.
      • Witteman J.C.
      • Lip G.Y.
      Atrial fibrillation and the prothrombotic state in the elderly: the Rotterdam Study.
      and increased platelet activation.
      • Lane D.A.
      • Lip G.Y.
      Female gender is a risk factor for stroke and thromboembolism in atrial fibrillation patients.
      • Rauch U.
      Gender differences in anticoagulation and antithrombotic therapy.
      • Breet N.J.
      • Sluman M.A.
      • van Berkel M.A.
      • van Werkum J.W.
      • Bouman H.J.
      • Harmsze A.M.
      • Kelder J.C.
      • Zijlstra F.
      • Hackeng C.M.
      • Ten Berg J.M.
      Effect of gender difference on platelet reactivity.
      In addition, hormone replacement therapy (HRT) has been posited as a potential reason for the difference in thrombogenicity. SPAF III reported that estrogen hormone replacement therapy was independently associated with significantly higher rates of ischemic stroke in women with AF,
      • Hart R.G.
      • Pearce L.A.
      • McBride R.
      • Rothbart R.M.
      • Asinger R.W.
      Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III Clinical Trials.
      whereas ATRIA and the Stroke Prevention using an Oral Thrombin Inhibitor (SPORTIF) study did not find a significant association.
      • Fang M.C.
      • Singer D.E.
      • Chang Y.
      • Hylek E.M.
      • Henault L.E.
      • Jensvold N.G.
      • Go A.S.
      Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors in Atrial fibrillation (ATRIA) study.
      • Gomberg-Maitland M.
      • Wenger N.K.
      • Feyzi J.
      • Lengyel M.
      • Volgman A.S.
      • Petersen P.
      • Frison L.
      • Halperin J.L.
      Anticoagulation in women with non-valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials.
      However, the mixed evidence and low percentages of women using estrogen HRT in these studies suggest that this may not be the sole factor for increased stroke risk.

       Clinical Relevance of Gender Differences in Thromboembolic Risk

      Compared with men, women tend to be more symptomatic—experiencing longer episodes, more frequent recurrences, and faster ventricular response rates during AF.
      • Humphries K.H.
      • Kerr C.R.
      • Connolly S.J.
      • Klein G.
      • Boone J.A.
      • Green M.
      • Sheldon R.
      • Talajic M.
      • Dorian P.
      • Newman D.
      New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome.
      • Volgman A.S.
      • Manankil M.F.
      • Mookherjee D.
      • Trohman R.G.
      Women with atrial fibrillation: greater risk, less attention.
      • Rienstra M.
      • Van Veldhuisen D.J.
      • Hagens V.E.
      • Ranchor A.V.
      • Veeger N.J.
      • Crijns H.J.
      • Van Gelder I.C.
      Gender-related differences in rhythm control treatment in persistent atrial fibrillation.
      • Madias C.
      • Trohman R.G.
      The link between atrial fibrillation and stroke in women.
      • Stewart S.
      • Hart C.L.
      • Hole D.J.
      • McMurray J.J.
      A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study.
      Women with AF also tend to have lower quality of life
      • Dagres N.
      • Nieuwlaat R.
      • Vardas P.E.
      • Andresen D.
      • Lévy S.
      • Cobbe S.
      • Kremastinos D.T.
      • Breithardt G.
      • Cokkinos D.V.
      • Crijns H.J.
      Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe.
      • Rienstra M.
      • Van Veldhuisen D.J.
      • Hagens V.E.
      • Ranchor A.V.
      • Veeger N.J.
      • Crijns H.J.
      • Van Gelder I.C.
      Gender-related differences in rhythm control treatment in persistent atrial fibrillation.
      • Stewart S.
      • Hart C.L.
      • Hole D.J.
      • McMurray J.J.
      A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study.
      • Paquette M.
      • Roy D.
      • Talajic M.
      • Newman D.
      • Couturier A.
      • Yang C.
      • Dorian P.
      Role of gender and personality on qualify-of-life impairment in intermittent atrial fibrillation.
      and are older than men at the time of presentation.
      • Humphries K.H.
      • Kerr C.R.
      • Connolly S.J.
      • Klein G.
      • Boone J.A.
      • Green M.
      • Sheldon R.
      • Talajic M.
      • Dorian P.
      • Newman D.
      New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome.
      • Glader E.L.
      • Stegmayr B.
      • Norrving B.
      • Terént A.
      • Hulter-Åsberg K.
      • Wester P.O.
      • Asplund K.
      Sex differences in management and outcome after stroke: a Swedish national perspective.
      • Dagres N.
      • Nieuwlaat R.
      • Vardas P.E.
      • Andresen D.
      • Lévy S.
      • Cobbe S.
      • Kremastinos D.T.
      • Breithardt G.
      • Cokkinos D.V.
      • Crijns H.J.
      Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe.
      • Avgil Tsadok M.
      • Jackevicius C.A.
      • Rahme E.
      • Humphries K.H.
      • Behlouli H.
      • Pilote L.
      Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation.
      • Salam A.M.
      • AlBinali H.A.
      • Al-Mulla A.W.
      • Asaad N.
      • Singh R.
      • Al-Qahtani A.
      • Al Suwaidi J.
      Women hospitalized with atrial fibrillation: gender differences, trends and outcome from a 20-year registry in a Middle Eastern country (1991-2010).
      • Gomberg-Maitland M.
      • Wenger N.K.
      • Feyzi J.
      • Lengyel M.
      • Volgman A.S.
      • Petersen P.
      • Frison L.
      • Halperin J.L.
      Anticoagulation in women with non-valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials.
      • Rienstra M.
      • Van Veldhuisen D.J.
      • Hagens V.E.
      • Ranchor A.V.
      • Veeger N.J.
      • Crijns H.J.
      • Van Gelder I.C.
      Gender-related differences in rhythm control treatment in persistent atrial fibrillation.
      • Lip G.Y.
      • Eikelboom J.
      • Yusuf S.
      • Shestakovska O.
      • Hart R.G.
      • Connolly S.
      Modification of outcomes with aspirin or apixaban in relation to female and male sex in patients with atrial fibrillation: a secondary analysis of the AVERROES Study.
      • Lip G.Y.
      • Laroche C.
      • Boriani G.
      • Cimaglia P.
      • Dan G.A.
      • Santini M.
      • Kalarus Z.
      • Rasmussen L.H.
      • Popescu M.I.
      • Tica O.
      • Hellum C.F.
      • Mortensen B.
      • Tavazzi L.
      • Maggioni A.P.
      Sex-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Observational Research Programme Pilot survey on Atrial Fibrillation.
      In addition to these clinical differences in presentation between men and women with AF, there are also disparities in the medical management of these patients. These gender differences in the medical management of AF may increase stroke risk differences in men and women. In patients with atypical or no AF symptoms in the Euro Heart Survey on Atrial Fibrillation, treatment was more conservative in women, with significantly less utilization of rhythm-control strategies than in men.
      • Dagres N.
      • Nieuwlaat R.
      • Vardas P.E.
      • Andresen D.
      • Lévy S.
      • Cobbe S.
      • Kremastinos D.T.
      • Breithardt G.
      • Cokkinos D.V.
      • Crijns H.J.
      Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe.
      In a Serbian study, men were more likely to undergo electrocardioversion or to be prescribed OAC (both p <0.001), whereas women were more likely to be prescribed β blockers and calcium channel blockers (both p <0.01).
      • Potpara T.S.
      • Marinkovic J.M.
      • Polovina M.M.
      • Stankovic G.R.
      • Seferovic P.M.
      • Ostojic M.C.
      • Lip G.Y.
      Gender-related differences in presentation, treatment, and long-term outcome in patients with first-diagnosed atrial fibrillation and structurally normal heart: the Belgrade Atrial Fibrillation Study.
      Similarly, a recent study in France found that women over the age of 75 years were 1/3 less likely to be treated with systemic anticoagulation than men of similar age.
      • Sabouret P.
      • Depret-Bixio L.
      • Cotte F.E.
      • Marie P.
      • Bedira N.
      • Blin P.
      Sex differences in stroke prevention in atrial fibrillation in French primary care. Results of the AFIGP (Atrial Fibrillation in General Practice) database.
      The Canadian Registry of Atrial Fibrillation (CARAF) study found that older women were half as likely to receive warfarin and twice as likely to receive aspirin compared with older men.
      • Humphries K.H.
      • Kerr C.R.
      • Connolly S.J.
      • Klein G.
      • Boone J.A.
      • Green M.
      • Sheldon R.
      • Talajic M.
      • Dorian P.
      • Newman D.
      New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome.
      When women are prescribed systemic anticoagulation, differences may also exist in terms of the quality of anticoagulation. According to the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study, women with AF on warfarin spent less time in therapeutic range (TTR) than men (40 ± 0.7% vs 37 ± 0.5%, p = 0.0001), with more time spent below TTR (29 ± 0.7% vs 26 ± 0.5%, p = 0.0002).
      • Sullivan R.M.
      • Zhang J.
      • Zamba G.
      • Lip G.Y.H.
      • Olshansky B.
      Relation of gender-specific risk of ischemic stroke in patients with atrial fibrillation to differences in warfarin anticoagulation control (from AFFIRM).
      Differences in TTR, an important predictor of thromboembolic outcomes in AF, could indicate lower quality of warfarin anticoagulation in females.
      The lower rates of anticoagulation prescription for female patients may be related to the perception of increased bleeding risk in women compared with men. The CARAF study reported a 3.35-fold increased risk of major bleeding in women on warfarin compared with men on warfarin.
      • Humphries K.H.
      • Kerr C.R.
      • Connolly S.J.
      • Klein G.
      • Boone J.A.
      • Green M.
      • Sheldon R.
      • Talajic M.
      • Dorian P.
      • Newman D.
      New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome.
      The SPORTIF trials found no difference in major bleeding rates (p = 0.766), but women experienced more overall bleeding (p <0.001) and were more prone to anticoagulant-related bleeding.
      • Gomberg-Maitland M.
      • Wenger N.K.
      • Feyzi J.
      • Lengyel M.
      • Volgman A.S.
      • Petersen P.
      • Frison L.
      • Halperin J.L.
      Anticoagulation in women with non-valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials.
      However, they also reported that the higher rate of thromboembolism in women was related to more frequent interruption of anticoagulant therapy. The ATRIA study found that the reduction in rates of thromboembolism with warfarin was larger in women than in men (p = 0.01 for interaction of gender and warfarin) and found no gender differences in rates of major hemorrhage while on warfarin.
      • Fang M.C.
      • Singer D.E.
      • Chang Y.
      • Hylek E.M.
      • Henault L.E.
      • Jensvold N.G.
      • Go A.S.
      Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors in Atrial fibrillation (ATRIA) study.
      The Rate Control versus Electrical Cardioversion (RACE) study reported a lower incidence of bleeding in women compared with men.
      • Rienstra M.
      • Van Veldhuisen D.J.
      • Hagens V.E.
      • Ranchor A.V.
      • Veeger N.J.
      • Crijns H.J.
      • Van Gelder I.C.
      Gender-related differences in rhythm control treatment in persistent atrial fibrillation.
      SPAF reported that women derived greater benefit from anticoagulation than did men.
      • Hart R.G.
      • Halperin J.L.
      • Pearce L.A.
      • Anderson D.C.
      • Kronmal R.A.
      • McBride R.
      • Nasco E.
      • Sherman D.G.
      • Talbert R.L.
      • Marler J.R.
      Lessons from the stroke prevention in atrial fibrillation trials.
      Thus, these gender differences become important because although women may derive more benefit from systemic anticoagulation than their male counterparts, they may be less likely to receive systemic anticoagulation and when they are anticoagulated, the quality of anticoagulation may be lower.

      Disclosures

      The authors have no conflicts of interest to disclose.

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