Cardiovascular research findings have consistently demonstrated a range of disparities in cardiovascular disease (CVD) risk factors, outcomes, and quality of care among women compared with men.1 Among the ongoing gaps in this area, numerous studies have highlighted various sex-based differences in patients with atrial fibrillation (AF).
In a 2022 retrospective cohort study of 327 patients who presented to the emergency department with AF¸ results showed several differences between women and men in terms of baseline characteristics, treatment strategies, and outcomes. Women were significantly older than men (mean age, 69.30±11.9 [27–91] vs 57.79±14.8 [21–87], respectively; P <.001) and had higher rates of thyroid dysfunction (18.3% vs 1.8%; P <.001) and several other comorbidities including valvular heart disease, hypertension, and diabetes.2
After adjusting for age and comorbidities, women showed higher rates of heart failure hospitalization (odds ratio [OR], 2.73; 95% CI, 1.04–5.89; P <.001) and recurrent AF (OR, 3.86; P =.02) compared with men.2
In terms of treatment differences, antiarrhythmic medications were used less often in women vs men (24.0% vs 42.8%; P <.001), rate control medications were used more often than antiarrhythmic medications in women (P <.001), and catheter ablation was performed at higher rates in men (63.6%) vs women (36.4%).2
For the overall sample, thyroid dysfunction (OR, 5.95; 95% CI, 3.15-9.73; P <.001) and lack of antiarrhythmic therapies (OR 3.42; 95% CI, 1.81-6.46; P <.001) were associated with an increased risk for AF.2
These results align with those of numerous other studies demonstrating greater morbidity and treatment disparities in women with AF, including less frequent use of cardioversion and catheter ablation and worse outcomes with stroke prevention measures.3,4 In addition, researchers have observed a higher risk for stroke (and more severe strokes) and death, as well as worse symptoms and quality of life, in women vs men with AF.3,5
Factors Linked to Sex-Based AF Disparities
“There might be biological differences in terms of the effect of AF on the heart—for example, it may cause more heart failure in women because of the combined risk of AF and heart failure associated with hypertension,” said Louise Pilote, MD, MPH, PhD, FRCPC, professor of medicine at McGill University in Montreal, deputy director of the Research Institute of the McGill University Health Centre, and co-author of a 2022 study regarding sex-based disparities in AF research and guidelines.4
Hormonal mechanisms, specifically the impact of changing estrogen levels throughout the reproductive lifespan, have also been implicated in sex-based AF disparities. In a 2022 population-based cohort study of 235,191 women without AF at baseline, the risk for new-onset AF was higher in those with a history of irregular menstrual cycle, early or late menarche, early or delayed menopause, no live births, and 7 or more live births, after adjustment for multiple confounding variables.6
“These results underscored the importance of taking into account the reproductive history of women when developing tailored screening strategies for AF prevention in women,” wrote the study authors.6
Dr Pilote added, “Gender-related factors such as caregiving responsibility also affect women more than men and prevent them from seeking the care they need or adhering to medications for AF.”
Regarding the stroke findings in particular, disparities likely stem from multiple factors. “Since women are older when they get AF, they tend to have more comorbidities such as hypertension, diabetes, and heart failure, which increases their risk for strokes,” explained Annabelle Santos Volgman, MD, FACC, FAHA, theMcMullan-Eybel Endowed Chair of Excellence in Clinical Cardiology and professor of medicine at the Rush University Medical College in Chicago, and medical director of the Rush Heart Center for Women.
Women are also not receiving anticoagulation therapy as often as men “for various reasons such as physicians not prescribing anticoagulants,4 perhaps due to fear of an increased bleeding risk,” she said in an interview with Cardiology Advisor.
Closing the Gap
An overarching factor driving some of the ongoing sex-based disparities in AF is the relative lack of research focused on women with AF. As Dr Pilote and colleagues noted in their study, women are significantly underrepresented in AF studies, especially randomized controlled trials, and thus the evidence that shapes clinical practice guidelines on AF management are insufficient to inform sex-specific recommendations.4
On a related note, Michos et al recently found that women are also underrepresented in clinical AF trial leadership, and they stated that increasing such representation could ultimately increase the number of women enrolled in these trials as well.7
There is a clear need to increase participation of women in AF research, Dr Pilote told Cardiology Advisor: “We need to enroll sufficient numbers of women in AF trials to know that results apply to women. For example, do women require a different dose of anticoagulants than men?”
On the clinical level, physicians should “explain the importance of using anticoagulants to decrease the risk of strokes, and they should refer patients to cardiac specialists who can keep them in a normal rhythm instead of letting them stay AF,” Dr Volgman advised. “Additionally, women need to be informed of the importance of measures to prevent AF, such as controlling their blood pressure, being on the right medications for heart failure, and having awareness of potential AF triggers such as alcohol and poor blood pressure control.”
Physician Q&A: Salvatore Savona, MD
To gain further insights into sex-based disparities in AF, we interviewed Salvatore Savona, MD, clinical assistant professor in cardiac electrophysiology at The Ohio State University Wexner Medical Center in Columbus.
What does the available evidence suggest about differences in AF in women compared with men?
AF is the most commonly encountered arrhythmia and can affect men and women differently. Prior studies have shown that women with valve disease may be more likely to develop AF, whereas coronary disease may be more prevalent in men.2 The previously published Women’s Health Study has also shown an increased risk of developing AF with the number of pregnancies.8 Prior large studies including the Euro Heart Study on Atrial Fibrillation and the ORBIT-AF Registries have found that women present with AF later in life, with worse quality of life, and may have less typical symptoms.9,10
Women in these and other studies were also less likely to have received a rhythm control strategy. In regards to stroke prevention, women had lower rates—up to 33% lower—of prescribed anticoagulation in the PINNACLE National Cardiovascular Data Registry.11 Additionally, women prescribed warfarin have higher rates of stroke compared to men, though the rates are similar with direct oral anticoagulation therapy. Regarding catheter ablation, early studies showed a higher rate of complications with procedures, though this seems to have improved with the use of ultrasound-guided access and transeptal puncture.4
What are some of the proposed mechanisms driving these differences?
There are many proposed mechanisms to explain the differences in AF between men and women. Prior MRI studies have shown that there is a high fibrotic burden in women compared to men.12 Additionally, there are QT differences in men and women at baseline, and studies have also shown QT differences on ECG based on hormone changes, such as during menopause. This may result in less utilization of anti-arrhythmic therapy.13
Additionally, women have been underrepresented in cardiology trials, therefore they may present later in the time course of their disease, with more advanced disease. Regarding higher stroke risk while on warfarin, it is theorized this may be related to less time being therapeutically anticoagulated. Additionally, women appear to have more nonpulmonary vein triggers for AF, which may result in more complicated procedures.12
What are implications for cardiologists in terms of special screening and treatment considerations for women with AF?
The most feared complication from AF is a stroke, and patients should be thoroughly assessed for stroke risk at the time of AF diagnosis. This should be guided by the CHA2DS2-VASc score as outlined in the current AF guidelines.14 Additionally, there should be an early assessment of symptoms, especially more atypical symptoms such as fatigue and shortness of breath. This may allow for early intervention to prevent adverse remodeling from persistent AF. More data is suggesting that an early rhythm control strategy is helpful to prevent progression to persistent and permanent AF, highlighting the importance of early intervention.
What additional measures are needed to improve the care of women with AF?
As ablation strategies evolve and new energy delivery techniques—such as pulsed field ablation, for example—become utilized, it will be paramount to ensure women are represented in trials and post-approval studies to ensure procedural risks are mitigated.15 More patient education is also necessary so that patients do not dismiss symptoms that may be related to AF. Additionally, ongoing research into the drivers and mechanisms for AF and fibrosis will continue to be important to understand previously reported sex differences in patients with AF.
- Wenger NK, Lloyd-Jones DM, Elkind MSV, et al; on behalf of the American Heart Association. Call to action for cardiovascular disease in women: Epidemiology, awareness, access, and delivery of equitable health care: a presidential advisory from the American Heart Association. Circulation. Published online May 9, 2022. doi:10.1161/CIR.0000000000001071
- Israeli A, Gal D, Younis A, et al. Sex-differences in atrial fibrillation patients: bias or proper management? Vasc Health Risk Manag. 2022;18:347-358. doi:10.2147/VHRM.S366285
- Volgman AS, Benjamin EJ, Curtis AB, et al; American College of Cardiology Committee on Cardiovascular Disease in Women. Women and atrial fibrillation. J Cardiovasc Electrophysiol. Published online December 17, 2020. doi:10.1111/jce.14838
- Alipour P, Azizi Z, Norris CM, et al. Representation of women in atrial fibrillation clinical practice guidelines. Can J Cardiol. Published online January 6, 2022. doi:10.1016/j.cjca.2021.12.017
- Lang C, Seyfang L, Ferrari J, et al; on behalf of the Austrian Stroke Registry Collaborators. Do women with atrial fibrillation experience more severe strokes? Results from the Austrian Stroke Unit Registry. Stroke. Published online February 1, 2017. doi:10.1161/STROKEAHA.116.015900
- Lu Z, Aribas E, Geurts S, et al. Association between sex-specific risk factors and risk of new-onset atrial fibrillation among women. JAMA Netw Open. Published online September 1, doi:10.1001/jamanetworkopen.2022.29716
- Khan SU, Raghu Subramanian C, Khan MZ, et al. Association of women authors with women enrollment in clinical trials of atrial fibrillation. J Am Heart Assoc. Published online February 22, 2022. doi:10.1161/JAHA.121.024233
- Wong JA, Rexrode KM, Sandhu RK, Conen D, Albert CM. Number of pregnancies and atrial fibrillation risk: the Women’s Health Study. Circulation. 2017;135(6):622-624. doi:10.1161/CIRCULATIONAHA.116.026629
- 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. Published online January 22, 2007. doi:10.1016/j.jacc.2006.10.047
- Piccini JP, Simon DN, Steinberg BA, et al; on behalf of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators and Patients. Differences in clinical and functional outcomes of atrial fibrillation in women and men: two-year results from the ORBIT-AF Registry. JAMA Cardiol. Published online February 28, 2016. doi:10.1001/jamacardio.2016.0529
- Thompson LE, Maddox TM, Lei L, et al. Sex differences in the use of oral anticoagulants for atrial fibrillation: a report from the National Cardiovascular Data Registry (NCDR®) PINNACLE Registry. J Am Heart Assoc. 2017;6(7):e005801. doi:10.1161/JAHA.117.005801
- Yunus FN, Perino AC, Holmes DN, et al; on behalf of the GWTG-AFIB Working Group*. Sex differences in ablation strategy, lesion sets, and complications of catheter ablation for atrial fibrillation: an analysis from the GWTG-AFIB Registry. Circ Arrhythm Electrophysiol. Published online November 1, 2021. doi:10.1161/CIRCEP.121.009790
- Linde C, Bongiorni MG, Birgersdotter-Green U, et al; ESC Scientific Document Group. Sex differences in cardiac arrhythmia: a consensus document of the European Heart Rhythm Association, endorsed by the Heart Rhythm Society and Asia Pacific Heart Rhythm Society. Europace. Published online June 8, 2018. doi:10.1093/europace/euy067
- 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. J Am Coll Cardiol. Published online January 28, 2019. doi:10.1016/j.jacc.2019.01.011
- Verma A, Boersma L, Haines DE, et al. First-in-human experience and acute procedural outcomes using a novel pulsed field ablation system: the PULSED AF pilot trial. Circ Arrhythm Electrophysiol. Published online December 29, 2022. doi:10.1161/CIRCEP.121.010168