Gender-specific aspects and contemporary assessment of thromboembolic complications in atrial fibrillation (literature review)

The article examines the evolution of risk assessment strategies for thromboembolic complications in patients with atrial fibrillation (AF), with a focus on the role of gender in the CHA₂DS₂-VASc score, which has long been the standard for stroke risk stratification. The analysis of historical approaches of various feasibility study risk assessment strategies, starting from the recommendations of 2001, when there was no single risk assessment, to the current international guidelines of 2024, led to the conclusion that special attention should be paid to the expediency of including female sex as an independent stroke risk. Current data indicate that gender identity has been leveling off over time in the incidence of strokes among patients with AF and suggest considering the female sex only as an age-dependent modifier of stroke risk. The results of studies from different countries (Finland, Denmark, Great Britain) confirm a decrease in the influence of the female sex as an independent stroke risk factor, discussing the expediency of switching to a simplified CHA₂DS₂-VA score (excluding gender). The authors emphasize the importance of individualized episodic re-evaluation of thromboembolic complications risk, particularly in patients with comorbidities, and also emphasize the need for caution when implementing changes in domestic practice, considering the unique characteristics of Russian healthcare and its disparities with systems in other countries.

1. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154(13):1449-57. DOI:10.1001/archinte.1994.00420130036007. Erratum in: Arch Intern Med 1994;154(19):2254.

2. Fuster V, Rydén LE, Asinger RW, et al; American College of Cardiology; American Heart Association; European Society of Cardiology; North American Society of Pacing and Electrophysiology. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation). Eur Heart J. 2001;22(20):1852-923. DOI:10.1053/euhj.2001.2983.

3. Brignole M, Gianfranchi L, Menozzi C, et al. Assessment of atrioventricular junction ablation and DDDR mode-switching pacemaker versus pharmacological treatment in patients with severely symptomatic paroxysmal atrial fibrillation: a randomized controlled study. Circulation. 1997;96(8):2617-24. DOI:10.1161/01.cir.96.8.2617.

4. Fihn SD, Callahan CM, Martin DC, et al. The risk for and severity of bleeding complications in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics. Ann Intern Med. 1996;124(11):970-9. DOI:10.7326/0003-4819-124-11-199606010-00004.

5. Petersen P, Kastrup J, Videbaek R, Boysen G. Cerebral blood flow before and after cardioversion of atrial fibrillation. J Cereb Blood Flow Metab. 1989;9(3):422-5. DOI:10.1038/jcbfm.1989.62.

6. Fuster V, Rydén LЕ, Cannom DS, et al; Task Force on Practice Guidelines, American College of Cardiology/American Heart Association; Committee for Practice Guidelines, European Society of Cardiology; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation-executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). Eur Heart J. 2006;27(16):1979- 2030. DOI:10.1093/eurheartj/ehl176.

7. Orchard JJ, Giskes K, Orchard JW, et al. In a large dataset of primary care patients, use of CHA2DS2-VA score leads to almost universal recommendation for anticoagulation in those aged 65 years and over with atrial fibrillation. Eur J Cardiovasc Nurs. 2023;22(8):769-72. DOI:10.1093/eurjcn/zvad002.

8. Hart RG, Pearce LA, McBride R, et al. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. Stroke. 1999;30(6):1223-9. DOI:10.1161/01.str.30.6.1223.

9. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery; Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31(19):2369-429. DOI:10.1093/eurheartj/ehq278.

10. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137(2):263-72. DOI:10.1378/chest.09-1584.

11. Stöllberger C, Chnupa P, Kronik G, et al. Transesophageal echocardiography to assess embolic risk in patients with atrial fibrillation. ELAT Study Group. Embolism in Left Atrial Thrombi. Ann Intern Med. 1998(8);128:630-8. DOI:10.7326/0003-4819-128-8-199804150-00004.

12. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study-2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1-2):1-13. DOI:10.1016/s0022-510x(96)00308-5.

13. Fang MC, Singer DE, Chang Y, et al. Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study. Circulation. 2005;112(12):1687-91. DOI:10.1161/CIRCULATIONAHA.105.553438.

14. Wann LS, Curtis AB, January CT, et al; ACCF/AHA/HRS. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011;57(2):223-42. DOI:10.1016/j.jacc.2010.10.001.

15. Camm AJ, Lip GY, De Caterina R, et al; ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33(21):2719-47. DOI:10.1093/eurheartj/ehs253.

16. January CT, Wann LS, Alpert JS, et al; ACC/AHA Task Force Members. 2014 AHA/ ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):e199-e267. DOI:10.1161/CIR.0000000000000041.

17. Kirchhof P, Benussi S, Kotecha D, et al; ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893-962. DOI:10.1093/eurheartj/ehw210.

18. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation. 2019;140(2):e125-e151. DOI:10.1161/CIR.0000000000000665.

19. Hindricks G, Potpara T, Dagres N, et al; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373-498. DOI:10.1093/eurheartj/ehaa612.

20. Joglar JA, Chung MK, Armbruster AL, et al; Peer Review Committee Members. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(1):e1-e156. DOI:10.1161/CIR.0000000000001193.

21. Corica B, Lobban T, Hills MТ, et al. Sex as a Risk Factor for Atrial Fibrillation-Related Stroke. Thromb Haemost. 2024;124(4):281-5. DOI:10.1055/s-0043-1776394.

22. Champsi А, Mobley AR, Subramanian A, et al. Gender and contemporary risk of adverse events in atrial fibrillation. Eur Heart J. 2024;45(36):3707-17. DOI:10.1093/eurheartj/ehae539.

23. Lip GYH, Teppo K, Nielsen PB. CHA2DS2-VASc or a non-sex score (CHA2DS2-VA) for stroke risk prediction in atrial fibrillation: contemporary insights and clinical implications, Eur Heart J. 2024;45(36):3718-20. DOI:10.1093/eurheartj/ehae540.

24. Wagstaff AJ, Overvad TF, Lip GY, Lane DA. Is female sex a risk factor for stroke and thromboembolism in patients with atrial fibrillation? A systematic review and meta-analysis. QJM. 2014;107(12):955-67. DOI:10.1093/qjmed/hcu054.

25. 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. DOI:10.1136/bmj.h7013.

26. Lang C, Seyfang L, Ferrari J, et al; Austrian Stroke Registry Collaborators. Do Women With Atrial Fibrillation Experience More Severe Strokes? Results From the Austrian Stroke Unit Registry. Stroke. 2017;48(3):778-80. DOI:10.1161/STROKEAHA.116.015900.

27. Nielsen PB, Skjøth F, Overvad TF, et al. Female Sex Is a Risk Modifier Rather Than a Risk Factor for Stroke in Atrial Fibrillation: Should We Use a CHA2DS2-VA Score Rather Than CHA2DS2-VASc? Circulation. 2018;137(8):832-40. DOI:10.1161/CIRCULATIONAHA.117.029081.

28. Arakelyan MG, Bockeria LA, Vasilieva EY, et al. 2020 Clinical guidelines for Atrial fibrillation and atrial flutter. Russian Journal of Cardiology. 2021;26(7):4594. (In Russ.) DOI:10.15829/1560-4071-2021-4594.

29. Van Gelder IС, Rienstra M, Bunting KV, et al; ESC Scientific Document Group.. 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2024;45(36):3314-414. DOI:10.1093/eurheartj/ehae176.

30. Mobley AR, Subramanian A, Champsi A, et al. Thromboembolic events and vascular dementia in patients with atrial fibrillation and low apparent stroke risk. Nat Med. 2024;30(8):2288-94. DOI:10.1038/s41591-024-03049-9.

31. Rubanenko AO. Evolution of CHA2DS2-VASc score for predicting risk of stroke development in patients with atrial fibrillation. Rational Pharmacotherapy in Cardiology. 2023;19(2):197-202. (In Russ.) DOI:10.20996/1819-6446-2023-03-05.

32. Nielsen PВ, Overvad TF. Female Sex as a Risk Modifier for Stroke Risk in Atrial Fibrillation: Using CHA2DS2-VASc versus CHA2DS2-VA for Stroke Risk Stratification in Atrial Fibrillation: A Note of Caution. Thromb Haemost. 2020;120(6):894-8. DOI:10.1055/s-0040-1710014.

33. Choi SY, Kim MH, Kim HB, et al. Validation of the CHA2DS2-VA Score (Excluding Female Sex) in Nonvalvular Atrial Fibrillation Patients: A Nationwide PopulationBased Study. J Clin Med. 2023;12(21):6770. DOI:10.3390/jcm12216770.

34. Tomasdottir M, Friberg L, Hijazi Z, et al. Risk of ischemic stroke and utility of CHA2DS2-VASc score in women and men with atrial fibrillation. Clin Cardiol. 2019;42(10):1003-9. DOI:10.1002/clc.23257.

35. Wu VC, Wu M, Aboyans V, et al. Female sex as a risk factor for ischaemic stroke varies with age in patients with atrial fibrillation. Heart. 2020;106(7):534-40. DOI:10.1136/heartjnl-2019-315065.

36. Teppo K, Airaksinen KEJ, Jaakkola J, et al. Ischaemic stroke in women with atrial fibrillation: temporal trends and clinical implications. Eur Heart J. 2024;45(20):1819-27. DOI:10.1093/eurheartj/ehae198.

37. Ding M, Ebeling M, Ziegler L, et al. Time trends in atrial fibrillation-related stroke during 2001-2020 in Sweden: a nationwide, observational study. Lancet Reg Health Eur. 2023;28:100596. DOI:10.1016/j.lanepe.2023.100596.

38. Teppo K, Airaksinen KEJ, Jaakkola J, et al. Temporal trends of gender disparities in oral anticoagulant use in patients with atrial fibrillation. Eur J Clin Invest. 2024;54(1):e14107. DOI:10.1111/eci.14107.

39. Teppo K, Lip GYH, Airaksinen KEJ, et al. Comparing CHA2DS2-VA and CHA2DS2- VASc scores for stroke risk stratification in patients with atrial fibrillation: a temporal trends analysis from the retrospective Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) cohort. Lancet Reg Health Eur. 2024;43:100967. DOI:10.1016/j.lanepe.2024.100967.

40. Nielsen PB, Brondum RF, Nøhr AK, et al. Risk of stroke in male and female patients with atrial fibrillation in a nationwide cohort. Nat Commun. 2024;15(1):6728. DOI:10.1038/s41467-024-51193-0.

41. Nielsen PB, Larsen TB, Skjøth F, et al. Stroke and thromboembolic event rates in atrial fibrillation according to different guideline treatment thresholds: A nationwide cohort study. Sci Rep. 2016;6:27410. DOI:10.1038/srep27410.

42. Hernan MA. The hazards of hazard ratios. Epidemiology. 2010;21(1):13-5. DOI:10.1097/EDE.0b013e3181c1ea43.