Title: Gender Differences of Thromboembolic Events in Atrial Fibrillation
Abstract: 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) 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 2050.1American Heart Association Statistics Committee and Stroke Statistics SubcommitteeHeart disease and stroke statistics—2014 update: a report from the American Heart Association.Circulation. 2014; 129: e28-e292Crossref PubMed Scopus (149) Google Scholar The prevalence of AF is 3.2% of the population aged ≥20 years and reaches 20% at age 80.2Björck S. Palaszewski B. Friberg L. Bergfeldt L. Atrial fibrillation, stroke risk, and warfarin therapy revisited.Stroke. 2013; 44: 3103-3108Crossref PubMed Scopus (231) Google Scholar Men have a greater risk of developing AF than women by a factor of 1.5 after adjusting for other risk factors.3Benjamin 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.JAMA. 1994; 271: 840-844Crossref PubMed Scopus (2589) Google Scholar However, the absolute numbers of men and women with AF are roughly equal because of the higher average life expectancy of women.4Feinberg W.M. Blackshear J.L. Laupacis A. Kronmal R. Hart R.G. Prevalence, age distribution, and gender of patients with atrial fibrillation: analysis and implications.Arch Intern Med. 1995; 155: 469-473Crossref PubMed Scopus (1965) Google Scholar, 5Humphries 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.Circulation. 2001; 103: 2365-2370Crossref PubMed Scopus (308) Google Scholar Women make up about 60% of the population with AF aged >75, the median age of AF onset.6Volgman A.S. Manankil M.F. Mookherjee D. Trohman R.G. Women with atrial fibrillation: greater risk, less attention.Gend Med. 2009; 6: 419-432Abstract Full Text PDF PubMed Scopus (62) Google Scholar AF is associated with a fivefold increased risk of stroke7Wolf P.A. Abbott R.D. Kannel W.B. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.Stroke. 1991; 22: 983-988Crossref PubMed Scopus (5764) Google Scholar and is attributed with at least 50% of strokes occurring in subjects aged 80 years and older.2Björck S. Palaszewski B. Friberg L. Bergfeldt L. Atrial fibrillation, stroke risk, and warfarin therapy revisited.Stroke. 2013; 44: 3103-3108Crossref PubMed Scopus (231) Google Scholar 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.8Bailey A.L. Scantlebury D.C. Smyth S.S. Go Red for Women: thrombosis and anti-thrombotic therapy in women.Arterioscler Thromb Vasc Biol. 2009; 29: 284-288Crossref PubMed Scopus (47) Google Scholar In addition, women have a worse poststroke outcome than men in terms of motor and cognitive function and activities of daily living.9Glader 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.Stroke. 2003; 34: 1970-1975Crossref PubMed Scopus (277) Google Scholar AF is an independent stroke predictor of in-hospital mortality for women but is not for men.10Roquer J. Rodríguez-Campello A. Gomis M. Ois A. Martínez-Rodríguez J.E. Munteis E. Conte J.J. Montaner J. Sabín J.A. Comparison of the impact of atrial fibrillation on the risk of early death after stroke in women versus men.J Neurol. 2006; 253: 1484-1489Crossref PubMed Scopus (30) Google Scholar 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.11Stroke Prevention in Atrial Fibrillation InvestigatorsAdjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: the Stroke Prevention in Atrial Fibrillation III randomised clinical trial.Lancet. 1996; 348: 633-638Abstract Full Text Full Text PDF PubMed Scopus (1098) Google Scholar 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. 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. 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). 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Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7203) Google Scholar However, 1 RCT37Gomberg-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.Eur Heart J. 2006; 27: 1947-1953Crossref PubMed Scopus (96) Google Scholar and 1 observational study34Siu 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.Heart Rhythm. 2014; 11: 1401-1408Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar 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.18Lin 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.Atherosclerosis. 2011; 217: 292-295Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 24Potpara 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.Int J Cardiol. 2012; 161: 39-44Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 29Poli 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).Thromb Res. 2013; 131: 12-16Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 32Inoue 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.Am J Cardiol. 2014; 113: 957-962Abstract Full Text Full Text PDF PubMed Scopus (50) Google ScholarTable 1Observational studies addressing genderPublication(year)CohortTotal n# offemales%femaleAge (years)Stroke (%)Relative RiskMalesFemalesp ValueMalesFemalesp ValueFemalesp ValueInoue (2000)12Inoue H. Atarashi H. Risk factors for thromboembolism in patients with paroxysmal atrial fibrillation.Am J Cardiol. 2000; 86: 852-855Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar∗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 M0.0291Humphries (2001)5Humphries 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.Circulation. 2001; 103: 2365-2370Crossref PubMed Scopus (308) Google Scholar∗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.NSNRNRWang (2003)13Wang 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.JAMA. 2003; 290: 1049-1056Crossref PubMed Scopus (664) Google ScholarFramingham Heart Study (USA)70533647.775 †Gender-specific mean age not provided.NRNRNRNRHR 1.92 MNRFriberg (2004)14Friberg 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).Am J Cardiol. 2004; 94: 889-894Abstract Full Text Full Text PDF PubMed Scopus (206) Google ScholarCopenhagen City Heart Study27611039.967±8.469±6.8NR7.820NRHR 2.6 MNR4.7 years§Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.Dagres (2007)15Dagres 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.J Am Coll Cardiol. 2007; 49: 572-577Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar∗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 M1 year§Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.Poli (2009)16Poli 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.Thromb Haemost. 2009; 101: 938-942PubMed Google Scholar∗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<0.01Ruigomez (2009)17Ruigómez A. Johansson S. Wallander M. Edvardsson N. García Rodríguez L.A. Risk of cardiovascular and cerebrovascular events after atrial fibrillation diagnosis.Int J Cardiol. 2009; 136: 186-192Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar∗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 MNSLin (2011)18Lin 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.Atherosclerosis. 2011; 217: 292-295Abstract Full Text Full Text PDF PubMed Scopus (103) Google ScholarTaiwan NHI research database7920363345.963.3% subjects aged ≥65†Gender-specific mean age not provided.NRNRNRNROR 0.942 U0.512 UOleson (2011)19Oleson 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.BMJ. 2011; 342: d124Crossref PubMed Scopus (1050) Google ScholarDenmark national register735383765151.259.7% subjects aged ≥75†Gender-specific mean age not provided.NRNRNRNRHR 1.6 M0.04 Mvan Staa (2011)20Van 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.J Thromb Haemost. 2011; 9: 39-48Crossref PubMed Scopus (227) Google ScholarUnited Kingdom798443970449.773.3 †Gender-specific mean age not provided.NR1.21.9NRRR 1.05 MNS4 years§Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.Chao (2012)21Chao 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?.Stroke. 2012; 43: 2551-2555Crossref PubMed Scopus (58) Google Scholar∗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 M57.4 ± 35.7 months§Mean follow-up duration provided for studies with stroke percentage incidence reported during study follow-up.Friberg (2012)22Friberg 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.Br Med J. 2012; 344: e3522Crossref PubMed Scopus (203) Google ScholarSweden1008025066750.374.780.9NR4.2‖Percent per year.6.2‖Percent per year.<0.0001HR 1.47 U; 1.18 M<0.001Mikkelsen (2012)23Mikkelsen A.P. Lindhardsen J. Lip G.Y. Gislason G.H. Torp-Pedersen C. Oleson J.B. 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