Author + information
- aDepartment of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- bDZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
- cBoston University and National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts
- dSections of Cardiovascular Medicine and Preventive Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts
- eDepartment of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Renate B. Schnabel, University Heart Center Hamburg-Eppendorf, Building O70, Martinistrasse 52, 20246 Hamburg, Germany.
“All men are created equal.”
—Thomas Jefferson, 1776 (1)
However, women with atrial fibrillation (AF) differ from men with the disease (2). In clinical practice, about one-half of the patients with AF are women. In general, women are older when AF manifests, have a higher prevalence of heart failure with preserved ejection fraction, and experience greater noncardiac comorbidities compared with men (3). Because stroke is the most-feared adverse event and its risk can be reduced significantly by oral anticoagulation (OAC), there has been a strong focus on potential sex differences in stroke risk. In particular, whether female sex is an independent risk factor for stroke incidence has been discussed intensively.
A recent meta-analysis of cohort studies examining sex differences in AF outcomes included 13 stroke studies. The authors reported a significant doubling in stroke risk in women compared with men (ratio of relative risks: 1.99; 95% confidence interval: 1.46 to 2.71). However, the meta-analysis identified significant heterogeneity across studies (I2 = 73%; p < .001), as well as indicators of potential publication bias (4); hence, the meta-analysis was not definitive regarding sex differences in stroke risk.
The study by Arnson et al. (5) in this issue of JACC: Clinical Electrophysiology adds contemporary evidence from a large Israeli health care provider database. In almost 90,000 patients with incident nonvalvular AF, the authors observed a significant interaction for stroke risk by sex and age group. Compared with men, women age ≥75 years revealed a higher risk of stroke; however, Arnson et al. (5) did not observe significant sex differences in stroke risk <75 years of age. In this respect, the Arnson et al. study (5) is largely confirmatory (6,7). In patients with age, sex, and history of congestive heart failure, hypertension, stroke/transient ischemic attack/thromboembolism, vascular disease, and diabetes (CHA2DS2-VASc) score of 0 or 1, the authors did not detect sex differences in stroke risk. Furthermore, the authors examined patients with and without each of the CHA2DS2-VASc risk factors separately. Although the details of the subgroup analyses were not shown, reportedly no sex differences in stroke risk were evident.
The increased stroke risk in women age ≥75 years demonstrated in the Arnson et al. study has been reported rather uniformly, even after adjustment for comorbidities and stroke risk factors (6,8,9). Despite vigorous accounting for potential confounders, however, as performed in the current and prior studies, residual confounding cannot be ruled out. In addition, sex differences in myocardial and vascular structure and function, systemic inflammation, and procoagulatory pathways, accentuated in postmenopausal women, offer many sources for pathophysiological differences in stroke risk (10).
In general, more comorbidities accumulate with advancing age that may differ by sex. Aging itself differs by sex. Because age is 1 of the strongest predictors of AF and its complication stroke, age-related changes also may contribute a significant proportion of the sex-related stroke risk differences in AF.
Observational studies of patients with AF, such as the Arnson et al. study (5), cannot exclude systematic sex differences and disparities in treatment and management that may be related to stroke risk. In the past, women showed a lower proportion of adequate OAC therapy, although women benefit similarly or even more from OAC compared with men (11). The potential for treatment biases explaining the observation of sex differences in stroke risk is lower today because of comparable anticoagulation rates by sex in more recent data (12). In the study by Arnson et al. (5), 40.4% of patients were on OAC, which is alarmingly low compared with other contemporary cohorts, but the percent of individuals on OAC was similar in both sexes. In the recent large direct oral anticoagulants trials, in which OAC was evenly distributed because of randomization, women showed a numerically higher incidence of stroke. Again, women were older on average at enrollment compared with their male counterparts.
In terms of clinical implications, the Arnson et al. study (5) and a large body of prior evidence reinforce current guidelines that female sex is counted as a score point in the CHA2DS2-VASc risk assessment in the presence of other stroke risk factors only. Female sex per se does not appear to be a risk factor at younger age or in the absence of other stroke risk factors; therefore, sex alone should not necessarily be a discriminator in anticoagulation decisions. In addition, the present study lamentably is consistent with global reports that anticoagulation is underused (13), which leaves much room for outcome improvement in both sexes.
Several research questions remain regarding whether women and men with AF are equal. Do truly sex-specific pathophysiologic mechanisms for stroke risk exist, in particular in older women, or does confounding, in particular comorbidities, fully explain observed differences in stroke incidence? Similarly, it needs to be clarified whether the higher residual stroke risk on OAC (14) from sex-specific pathophysiology, residual confounding, possible bias, or even disparities in patient management of women and men? Furthermore, the predominant role of age and aging in stroke risk needs to be dissected carefully from sex differences, in particular in older adults. And finally, how can we more effectively address patient, clinician, and system barriers to improve OAC use in women and men?
Future research will need to address sex and age differences and disparities to improve management and outcome of AF. Hence, the recent directives from the National Institutes of Health on addressing sex as a biological variable and enhancing inclusion of individuals across the lifespan are welcome and will improve the evidence base for sex differences in preclinical models and in older men and women with AF.
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Dr. Benjamin is supported in part by 1R01HL128914 and 2R01 HL092577. This project has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 648131), German Ministry of Research and Education (BMBF 01ZX1408A), and German Center for Cardiovascular Research (DZHK e.V.) (81Z1710103) (Dr. Schnabel).
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- 2018 American College of Cardiology Foundation
- ↵Brainyquote. Thomas Jefferson quotes. Available at: https://www.brainyquote.com/quotes/thomas_jefferson_157212. Accessed March 2, 2018.
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