By Carole Alison Chrvala, PhD
Reviewed by Philip Green, MD, Assistant in Clinical Medicine, Division of Cardiology, Department of Medicine, Columbia University Medical Center, NY
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Take Note
- A modest, statistically significant increase in the risk of atrial fibrillation (AF) was evident for women who had previously undergone hysterectomy and were treated with estrogen monotherapy compared with placebo.
- Notably, women who were obese or diagnosed with diabetes mellitus and treated with estrogen alone were at higher risk of AF, despite adjustment for incident cardiovascular disease.
The estimated prevalence of atrial fibrillation (AF) in the United States ranged between 2.7 million and 6.1 million cases in 2010, with diagnoses expected to double by 2050 to 5.6 million to 12 million.1 AF is the most common chronic arrhythmia diagnosed in women, increasing in prevalence from 0.1% among those younger than 55 to 9.1% in those 85 years or older. AF is associated with a 22% to 25% increase in risk of stroke among women older than 65 years and a 1.9- to 2.1-fold increased risk of death.2 While overall men are at a greater risk of developing AF, compared with men women with AF are more likely to have a stroke,2,3 are at increased risk of cardiovascular and all-cause mortality,1,3 and have a significantly lower quality of life4 following a diagnosis of AF.
While there is no accepted explanation for the sex differences in the impact of AF on clinical outcomes and mortality, there is growing evidence to suggest that sex hormones may play an important pathophysiologic role. The Women’s Health Initiative (WHI) postmenopausal hormone therapy (PHT) placebo-controlled trials randomized women who had not undergone hysterectomy to estrogen plus progestin (E+P trial) or estrogen only (E-alone trial) for women who had had a hysterectomy.2,5 Inclusion of new-onset AF as a secondary endpoint permitted analysis of the effects of E+P and E-alone on rates of AF.2
After an average follow-up of 5.6 years, 323 women were diagnosed with new-onset AF in the E+P group, compared with 288 cases in the placebo group. The risk of AF was comparable between the 2 treatment arms, with a hazard ratio (HR) of 1.07 (95% CI, 0.91-1.25; P=0.44). Among women in the E-alone trial, AF was diagnosed in a total of 360 and 323 women in the active treatment and comparison groups, respectively. Estrogen-alone therapy was associated with a significant increase in the diagnosis of new-onset AF, with a HR of 1.17 (95% CI, 1.00-1.36; P=0.045). Combined results from the E+P and E-alone trials revealed that postmenopausal women administered hormone therapy were at significantly increased risk of AF (HR, 1.12; 95% CI, 1.00-1.24; P=0.05).2 When the E+P and E-alone trials were combined, the rate of incident AF was significantly higher for women on hormone therapy who also had diabetes at baseline (HR, 1.49; 95% CI, 1.02-2.13; P=0.038), were age 70 to 79 years (HR, 1.25; 95% CI, 1.06-1.46; P=0.007), and had a body mass index ≥30 kg/m2 (HR, 1.25; 95% CI, 1.06-1.48; P=0.008).2
The E+P and E-alone trials are the first and largest placebo-controlled trials to examine the relationship between PHT and risk of AF and other cardiovascular events. Results from these trials demonstrate an increased risk of stroke and no decrease in risk of coronary heart disease as well as a modest, statistically significant increase in the risk of AF, primarily due to the effects of E-alone in women who had undergone a prior hysterectomy. The higher rate of incident AF was slightly diminished by adjustment for incident coronary heart disease or congestive heart failure, which suggests that the effect of exogenous estrogen on AF may be due, in part, to an overall increase in cardiovascular disease associated with hormone therapy.2
Perez and colleagues noted that the greater risk of AF among women in the E-alone trial might be due to a higher cardiovascular risk profile, which was evident for women in the E-alone versus the E+P trial. Alternatively, they suggested that the addition of progestin might diminish the effects of estrogen on arrhythmogenesis. However, the question of potential benefits associated with PHT for certain groups of women, such as those with diabetes, remains to be answered. Notably, the analysis of the WHI PHT trials suggests that women with obesity or diabetes mellitus who are treated with PHT may be at increased risk of AF, a finding to be validated in future studies but also one with potentially important clinical implications for decisions to administer PHT to specific patient subgroups.2
Published: 03/14/2013
References:
- Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127:e6-e245.
- Perez MV, Wang PJ, Larson JC, et al. Effects of postmenopausal hormone therapy on incident atrial fibrillation: the Women
- Friberg J, Scharling H, Gadsbøll N, et al; Copenhagen City Heart Study. Comparison of the impact of atrial fibrillation on the risk of stroke and cardiovascular death in women versus men (The Copenhagen City Heart Study). Am J Cardiol. 2004;94:889-894.
- Rienstra M, Van Veldhuisen DJ, Hagens VE, et al; RACE Investigators. Gender-related differences in rhythm control treatment in persistent atrial fibrillation: data of the Rate Control Versus Electrical Cardioversion (RACE) study. J Am Coll Cardiol. 2005;46:1298-1306.
- Stefanick ML, Cochrane BB, Hsia J, et al. The Women’s Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol. 2003;13(suppl 9):S78-S86.