10. Sex Differences in Patients With AF
Recognition of sex differences offers an opportunity to improve outcomes in women with AF.[659]
10.1 Epidemiology and pathophysiology
Age and sex are the two most powerful predictors of incident AF. Although the prevalence of AF doubles with each decade of age (increasing from 1%-4% at 60 years to 6%-15% at 80 years), male sex is associated with a 1.5-fold risk of AF, even after adjusting for age and predisposing conditions. Although the age-adjusted prevalence of AF is consistently observed to be higher in men (eg, a sex-based prevalence of 9.2% for women vs 15.0% for men in a community-based, randomized, controlled AF screening study performed in Sweden)[31],[85] the absolute number of female patients with AF exceeds the number of male patients with AF because of the longer life span of female patients. Although the exact mechanism responsible for the reported sex-related differences in AF remains inadequately understood, several theories have been suggested. First, anthropomorphic differences between the sexes result in a larger LA dimension and volume in male patients.[660],[661] Second, female patients with AF have been shown to have a relatively greater burden of atrial fibrosis using delayed-enhancement MRI.[662] Third, male patients with AF have greater expression of repolarizing ion channel subunits, which could favour reentry.[660],[663] Fourth, the contribution of sex hormones has been explored in several studies, with testosterone deficiency having been linked to increased atrial arrhythmogenicity[664]; progesterone associated with shortened action potentials[665]; and estrogen has been postulated to play a central role in arrhythmogenesis due to prolongation in conduction time, action potential duration, and the atrial effective refractory period.[666]
10.2 Presentation
Female patients with AF are more likely to have underlying hypertension and valvular disease, whereas male patients with AF are more likely to have CAD and abnormal LV function. Female patients with AF report more atypical symptoms, with a relatively greater symptom burden and lower QOL compared with male patients.[667],[668] As a result, women are more likely to seek care for AF symptoms and are more likely to experience depression related to AF.[669]
10.3 Outcomes
Important sex-specific differences in cardiovascular outcomes have been described. AF in female patients is associated with a greater all-cause mortality relative to male patients (RR, 1.12; 95% CI, 1.07-1.17).[670] Compared with male patients with AF, strokes experienced by female patients tend to be larger, and are associated with poorer functional outcomes and greater need for institutionalization.[671]
10.4 Stroke prevention
Sex-specific differences in antithrombotic therapy have been observed: female patients with AF are more likely to be prescribed antiplatelet agents; when OACs are prescribed, they are more likely to receive a DOAC and, are more likely to be inappropriately prescribed the lower approved dose.[672]–[675] In terms of efficacy, female patients with AF have a greater residual risk of stroke despite VKA therapy, which might reflect sex-specific differences in VKA metabolism or underlying risk factor control.[676],[677] Although no sex-specific difference in DOAC efficacy has been observed, there is a significant reduction in major and clinically-relevant nonmajor bleeding in female patients with AF treated with a DOAC.[21]–[23],[25],[52],[677]
10.5 Rate and rhythm management
Female patients with AF are more likely to receive rate control, compared with male patients with AF.[678],[679] In those who receive rhythm control, female patients with AF are preferentially managed with pharmacologic antiarrhythmic therapy, and are less likely to undergo ablation (OR, 0.5-0.8 compared with men).[680],[681] Moreover, female patients who do undergo ablation tend to be older, have more comorbidities, have more advanced AF (eg, longer duration of AF, more likely to be persistent), and show that treatment with a larger number of antiarrhythmic agents have failed.[395],[663],[682],[683] Despite their more complex clinical profile before ablation, female patients who undergo ablation have comparable acute and longer-term success rates compared with male patients.[668],[682],[683]
References
658. Phan K, Xie A, Di Eusanio M, Yan TD. A meta-analysis of minimally invasive versus conventional sternotomy for aortic valve replacement. Ann Thorac Surg 2014;98:1499-511.
659. Andrade JG, Deyell MW, Lee AYK, Macle L. Sex differences in atrial fibrillation. Can J Cardiol 2018;34:429-36.
660. Liu XK, Jahangir A, Terzic A, et al. Age- and sex-related atrial electrophysiologic and structural changes. Am J Cardiol 2004;94:373-5.
661. Nattel S. Atrial fibrillation and body composition: is it fat or lean that ultimately determines the risk? J Am Coll Cardiol 2017;69:2498-501.
662. Cochet H, Mouries A, Nivet H, et al. Age, atrial fibrillation, and structural heart disease are the main determinants of left atrial fibrosis detected by delayed-enhanced magnetic resonance imaging in a general cardiology population. J Cardiovasc Electrophysiol 2015;26:484-92.
663. Tsai WC, Chen YC, Lin YK, Chen SA, Chen YJ. Sex differences in the electrophysiological characteristics of pulmonary veins and left atrium and their clinical implication in atrial fibrillation. Circ Arrhythm Electrophysiol 2011;4:550-9.
664. Magnani JW, Moser CB, Murabito JM, et al. Association of sex hormones, aging, and atrial fibrillation in men: the Framingham Heart Study. Circ Arrhythm Electrophysiol 2014;7:307-12.
665. Nakamura H, Kurokawa J, Bai CX, et al. Progesterone regulates cardiac repolarization through a nongenomic pathway: an in vitro patch-clamp and computational modeling study. Circulation 2007;116:2913-22.
666. Perez MV, Wang PJ, Larson JC, et al. Effects of postmenopausal hormone therapy on incident atrial fibrillation: the Women’s Health Initiative randomized controlled trials. Circ Arrhythm Electrophysiol 2012;5:1108-16.
667. Reynolds MR, Lavelle T, Essebag V, Cohen DJ, Zimetbaum P. Influence of age, sex, and atrial fibrillation recurrence on quality of life outcomes in a population of patients with new-onset atrial fibrillation: the Fibrillation Registry Assessing Costs, Therapies, Adverse events and Lifestyle (FRACTAL) study. Am Heart J 2006;152:1097-103.
668. Yao RJR, Macle L, Deyell MW, et al. Impact of female sex on clinical presentation and ablation outcomes in the CIRCA-DOSE study. JACC Clin Electrophysiol 2020;6:945-54.
669. Ball J, Carrington MJ, Wood KA, Stewart S; SAFETY Investigators. Women versus men with chronic atrial fibrillation: insights from the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY). PLoS One 2013;8:e65795.
670. Emdin CA, Wong CX, Hsiao AJ, et al. Atrial fibrillation as risk factor for cardiovascular disease and death in women compared with men: systematic review and meta-analysis of cohort studies. BMJ 2016;532:h7013.
671. Appelros P, Stegmayr B, Terent A. A review on sex differences in stroke treatment and outcome. Acta Neurol Scand 2010;121:359-69.
672. Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest 2005;127:2049-56.
673, Avgil Tsadok M, Jackevicius CA, Rahme E, Humphries KH, Pilote L. Sex differences in dabigatran use, safety, and effectiveness in a population-based cohort of patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2015;8:593-9.
674. Olesen JB, Sorensen R, Hansen ML, et al. Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naive atrial fibrillation patients: Danish nationwide descriptive data 2011-2013. Europace 2015;17:187-93.
675. Hsu JC, Maddox TM, Kennedy K, et al. Aspirin instead of oral anticoagulant prescription in atrial fibrillation patients at risk for stroke. J Am Coll Cardiol 2016;67:2913-23.
676. Avgil Tsadok M, Jackevicius CA, Rahme E, et al. Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation. JAMA 2012;307:1952-8.
677. Pancholy SB, Sharma PS, Pancholy DS, et al. Meta-analysis of gender differences in residual stroke risk and major bleeding in patients with nonvalvular atrial fibrillation treated with oral anticoagulants. Am J Cardiol 2014;113:485-90.
678. Dagres N, Nieuwlaat R, Vardas PE, et al. 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 2007;49:572-7.
679. Lip GY, Laroche C, Boriani G, et al. 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. Europace 2015;17:24-31.
680. Patel N, Deshmukh A, Thakkar B, et al. Gender, race, and health insurance status in patients undergoing catheter ablation for atrial fibrillation. Am J Cardiol 2016;117:1117-26.
681. Schnabel RB, Pecen L, Ojeda FM, et al. Gender differences in clinical presentation and 1-year outcomes in atrial fibrillation. Heart 2017;103:1024-30.
682. Forleo GB, Tondo C, De Luca L, et al. Gender-related differences in catheter ablation of atrial fibrillation. Europace 2007;9:613-20.
683. Takigawa M, Kuwahara T, Takahashi A, et al. Differences in catheter ablation of paroxysmal atrial fibrillation between males and females. Int J Cardiol 2013;168:1984-91.