Sex Differences in Stroke Risk Among Older Patients with Recently Diagnosed Atrial Fibrillation
Editor's Note: This Article of the Month is based on Avgil Tsadok M, Jackevicius CA, Rahme E, et al. Sex Differences in Stroke Risk Among Older Patients With Recently Diagnosed Atrial Fibrillation. JAMA 2012;307:1952-1958. doi:10.1001/jama.2012.3490.
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Patients with AF have a 5-fold increase in the risk of stroke. Some, but not all, prior AF studies have found that female sex is an independent risk factor for stroke.
A retrospective, inception cohort of administrative data elucidated patterns of warfarin use and stroke incidence in men and women with AF.
Tsadok et al. analyzed Canadian administrative data from January 1, 1998 to March 31, 2007. Patients were elderly (65 years or older) residents of Quebec, who were discharged from the hospital with a primary diagnosis of AF. Information on outpatient prescriptions, and inpatient and outpatient diagnostic and therapeutic procedures was available. Patients who developed AF as a post-admission complication, had perioperative AF, or had hyperthyroidism or thyrotoxicosis were excluded. Patients were also excluded if they were 105 years or older, or resided in chronic care facilities. The Med-Echo database was used to obtain information on patient characteristics in order to calculate the CHADS2 score (congestive heart failure, hypertension, age ≥ 75 diabetes, prior stroke or transient ischemic attack). The primary outcome was incident (ischemic) stroke; rates of transient ischemic attack and/or retinal infarct also were reported. Adherence to warfarin therapy was assessed by the medication possession ratio, which is defined as the number of days of tablets supplied divided by 365 days.
Continuous variables were compared using the t test or Mann-Whitney U test. Dichotomous variables were compared using the chi squared test. Incidence rates of stroke and mortality were calculated as the number of events per 100 person-years of follow-up. Cox proportional hazards regression were used to identity independent determinants of stroke. Follow-up was until the first diagnosis of stroke, death, or the end of the study period.
The cohort comprised of 39,398 (47.2%) men and 44,115 (52.8%) women. Women were on average 80.2 years old and men were 77.2 years old. The mean CHADS2 score in women was 1.99 (standard deviation (SD) 1.10) versus 1.74 (SD 1.13; p < .001) in men. Warfarin prescription rates were higher among men, but women tended to have more prescriptions filled for warfarin within 30 days post-discharge and had a greater medication possession ratio (indicating better compliance).
In both univariate and adjusted analyses, stroke incidence was greater in women, especially elderly women. The overall incidence (95% confidence interval [CI]) of stroke per 100 person-years was 2.02 (1.95-2.10) in women and 1.61 (95% CI, 1.54-1.69) in men (p < 0.001). Older women had significantly higher rates of stroke than older men, regardless of warfarin use or adherence level. Women had higher risk of stroke compared to men (hazard ratio 1.14 [95% CI, 1.07-1.22]), even after adjusting for comorbid conditions, CHADS2 score and warfarin treatment. The increased stroke risk from female gender was insignificant in patients younger than 75 years, but significant in older patients (p = 0.02 for interaction with age). There was no difference in rates of intracerebral hemorrhage between men and women.
Among elderly patients with AF, women have a higher risk of stroke than men. After controlling for comorbid conditions, women have 1.14-fold higher risk of stroke than men.
Some,5, 7, 8, 10, 13, 20, 22, 23, 27 but not all, prior studies (Table) have found female gender to be an independent risk factor for stroke in AF. Tsadok et al. have quantified this effect more precisely than prior studies. The significant interaction between female sex and age greater than 75, partially explains the inconsistencies between prior studies. The SPAF investigators first reported that among elderly (age > 75) patients with AF, females had higher risk of stroke than men.13 However, because the biological basis for this association remains speculative, validation of this relationship, as done in this study, was needed.
Overall, this study supports current ACCP15 recommendations to offer anticoagulant therapy to patients with a CHADS2 score of 1 or greater. Tsadok et al. found that the risk of stroke correlated with CHADS2 score among men and women and that the annual rate of stroke was too low (1% per year) in men and women with a CHADS2 score of 0 to justify routine prescription of anticoagulant therapy.
Variations in risk perception can lead to differences in the use of stroke prophylaxis. Women with AF tend to be older and have more hypertension and valvular heart disease, than their male counterparts.7 Other AF studies have shown that women are less likely than men to receive warfarin24, sometimes with devastating consequences.8, 21 Disparities in treatment of women may exist due to a misperception of low stroke risk in these patients.25 However, atrial remodeling, increased left atrial size, and thrombotic tendency (e.g. from estrogen replacement therapy) may elevate the risk of stroke in elderly women with AF.4, 27
In prior ACC/AHA/ESC guidelines11, female gender was included as a "less validated or weaker risk factor," for stroke in AF. That classification reflected those studies that have failed to demonstrate that female gender is an independent risk factor for stroke in AF.1, 2, 3, 9, 16, 17, 18, 19, 26 In contrast, the 2011 ESC guidelines6 feature the CHA2DS2-VASc score, which assigns an additional point to Vascular disease, Age > 75 years, and female Sex. However, in Tsadok et al, vascular disease was not an independent predictor of stroke and female sex was a relatively weak predictor of stroke.
Based on Tsadok et al. and other studies (Table), we conclude that female gender is a validated, but relatively weak risk factor for stroke in patients with AF unless their age is > 75 years. Because AF guidelines already recommend anticoagulant therapy to elderly patients with AF regardless of gender, and the association between female gender and stroke remains weak, the guidelines do not need to advocate anticoagulant therapy for all women.
Likewise, the present study does not support assigning a full point to female gender, as advocated by the CHA2DS2-VASc score, because its hazard ratio of 1.14 is less than a typical CHADS2 point, which has a hazard ratio of 1.4-1.5.1, 3, 12, 27
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- Hart et al. Factors Associated with Ischemic Stroke During Aspirin Therapy in AF: Analysis of 2012 Participants in the SPAF I-III Clinical Trials. Stroke 1999; 30:1223-29.
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- Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. CHEST 2012;141:e152S-184S
- Inoue, H. and Atarashi, H. Risk Factors for Thromboembolism in Patients with Paroxysmal AF. Am J Cardiol 2000; 86:852-55.
- Moulton, A.W., Singer, D.E., and Haas, J.S. Risk Factors for Stroke in Patients with Nonrheumatic AF: A Case Control Study. Am J Med 1991; 91:156-61.
- Petersen, P. and Godtfredsen, J. Risk Factors for Stroke in Chronic AF. Eur Heart J 1988; 9(3):291-94.
- Petersen, P. et al. Risk Factors for Thromboembolic Complications in Chronic AF. The Copenhagen AFASAK Study. Arch Intern Med 1990; 150:819-21.
- Poli et al. Gender Differences in Stroke Risk of AF Patients on Oral Anticoagulant Treatment. Thromb Haemost 2009; 101:938-942.
- Rietbrock, S., Heeley, E., Plumb, J., and van Staa, T. Chronic AF: Incidence, Prevalence, and Prediction of Stroke Using the Congestive Heart Failure, Hypertension, Age >75, Diabetes Mellitus, and Prior Stroke or Transient Ischemic Attack (CHADS2) Risk Stratification Scheme. Am Heart J 2008; 156(1):57-64.
- Shen et al. Racial/Ethnic Differences in Ischemic Stroke Rates and the Efficacy of Warfarin Among Patients with AF. Stroke 2008; 39:2736-43.
- Sherman et al. Occurrence and Characteristics of Stroke Events in the AF Follow-up Investigation of Sinus Rhythm Management (AFFIRM) Study. Arch Intern Med 2005; 165:1185-91.
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- Towfighi et al. A Midlife Stroke Surge among Women in the United States. Neurology 2007; 69:1898-1904.
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Keywords: Atrial Fibrillation, Atrial Remodeling, Cerebral Hemorrhage, Estrogen Replacement Therapy, Heart Failure, Hypertension, Hyperthyroidism, Quebec, Stroke, Thyrotoxicosis, Warfarin
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