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Invited Commentary
June 2016

Sex, Symptoms, and Atrial Fibrillation

Author Affiliations
  • 1Northwestern University Feinberg School of Medicine, Chicago Illinois
  • 2Bluhm Cardiovascular Institute, Northwestern University Hospital, Chicago Illinois
 

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Cardiol. 2016;1(3):292-293. doi:10.1001/jamacardio.2016.0545

You can observe a lot just by watching.

Yogi Berra, When You Come to a Fork in the Road, Take It!, 20011

Registries provide a unique opportunity to observe the contemporary practice of medicine for a defined disease state. Liberated from the strict inclusion/exclusion criteria of clinical trials and the agendas of study sponsors, these real-world cohort studies can provide valuable information about clinical practice, patient outcomes, safety, and comparative effectiveness. In this issue of JAMA Cardiology, the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) was used to examine the differential effect on symptoms, functional capacity, and quality of life that atrial fibrillation (AF) has on men and women and the variability in treatments and outcomes between the sexes.2 These issues, particularly those not related to stroke and death, are of particular interest when it comes to AF given the growing prevalence of the disease and a treatment approach frequently guided not by the burden of the disease in an individual inasmuch as by the burden of the disease on an individual.

Atrial fibrillation affects men and women differently. The prevalence of AF is lower for women across all age groups. Differential outcomes have been demonstrated, with most studies supporting female sex as an independent risk factor for stroke. Mortality is affected too, as the presence of the arrhythmia appears to negate the overall survival benefit observed in women.3 Treatment also varies, as women are less likely to undergo pulmonary vein isolation and less likely to receive anticoagulation in some studies despite the higher stroke risk.4,5 It is in this context that the current analysis of ORBIT-AF provides some potentially important contributions to our understanding of the interaction between sex and AF. The registry enrolled 10 135 patients with incident and prevalent AF (42% women) from 176 US sites including internal medicine, primary care, cardiology, and cardiac electrophysiology practices.2 Assessments were made for AF-related symptoms, functional status, quality of life, treatments, and outcomes. Enrollment occurred over a 14-month period beginning in mid-2010 and patients were followed up for a median of 2.3 years. Thus, ORBIT-AF represents a modern-day cohort study in the era of AF ablation, risk-stratification schemes for stroke, and a greater appreciation for the management of comorbidities.

Compared with men, women in ORBIT-AF had more severe symptoms, lower quality of life as measured by the Atrial Fibrillation Effects on Quality of Life questionnaire, and greater impairment in functional status when evaluated by European Heart Rhythm Association score.2 The greater negative effect of AF on women was observed despite their lower prevalence of permanent AF and a higher likelihood of being in sinus rhythm at the time of enrollment. Although more symptomatic, women were no more likely to be prescribed antiarrhythmic drugs, less likely to undergo cardioversion or AF ablation, and more likely to undergo atrioventricular nodal ablation. Despite similar rates of anticoagulation use between the sexes and similar time in therapeutic range, stroke risk was higher in women but risk-adjusted all-cause mortality was lower. These findings are important and interesting but raise several critical questions.

To date, randomized studies of rate vs rhythm control and guidelines based on these studies support the approach that symptoms serve as the major driver for adopting a rhythm-control strategy.6 However, symptoms are a poor marker for the presence or burden of the arrhythmia, with some patients feeling every premature beat and others totally oblivious to even chronic AF. The present study reveals that 32.1% of women and 42.5% of men had entirely asymptomatic AF,2 and prior studies of patients with implanted devices and a history of paroxysmal AF show that up to 94% of episodes have no associated symptoms.7 Further complicating the issue is that most self-reported symptoms actually occur during sinus rhythm. Additionally, many of the drugs used to treat AF may carry significant adverse effects, making the treatment worse than the disease for some patients. If symptom control is a major goal of AF therapy, it will be imperative to understand the extent to which the arrhythmia itself is responsible for the greater functional effect of AF in women as opposed to differences in underlying comorbidities, treatment concerns, and the adverse effects of therapies.

Independent of the differential effects of AF between the sexes, the ORBIT-AF registry exposes both our progress and stagnation when it comes to AF management. First, it appears that advancement has been made in prescribing anticoagulation as 80% of patients with CHADS2 (congestive heart failure, hypertension, age >75 years, diabetes mellitus, and stroke [doubled]) scores greater than 1 were receiving this therapy, a significant increase compared with older cohort studies but an achievement not mirrored in all cohort studies.4 Conversely, digoxin, a drug that neither maintains sinus rhythm nor adequately controls ventricular response, was still being used to treat almost a quarter of patients. The most effective treatment for maintaining sinus rhythm, AF ablation, still appears to be underused, while ablation of the atrioventricular node, the “last-ditch” effort of AF management, was being performed maybe more than is necessary.

While registries provide important contributions to our understanding of how medicine is practiced, they also have significant limitations that cannot be ignored. The ORBIT-AF registry accepted “all comers” and the mean age was significantly higher in women compared with men and higher overall compared with other US and European registries.4,8 Accordingly, CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age >75 years [doubled], diabetes mellitus, stroke [doubled]–vascular disease, age 65-74 years, and sex category [female]) scores were also greater in women, a factor that may have contributed to the observed differences in quality of life and functional status and may limit the generalizability of the findings to all populations. Furthermore, unlike clinical trials where randomization attempts to ensure that treatment arms are comparable, baseline differences in a registry may allow for residual or unmeasured confounders that cannot be fully accounted for with statistical methods. Indeed, the residual differences between men and women observed in ORBIT-AF cannot be explained by comorbidity burden alone and highlight an important avenue for future research. Data completeness and follow-up may also be problematic as evidenced by the fact that health status data were not available for all patients in ORBIT-AF and less than half the patients who reported health-related quality of life at baseline did so again at the 2-year mark. Overall, patient registries can demonstrate what issues are worthy of future exploration but the findings are usually more hypothesis generating than definitive. The ORBIT-AF registry shows us that “you can observe a lot just by watching,” but in medicine, watching is usually just the beginning.

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Article Information

Corresponding Author: Rod S. Passman, MD, MSCE, Northwestern University Feinberg School of Medicine, 676 N St Clair, Ste 600, Chicago, IL 60611 (r-passman@northwestern.edu).

Published Online: May 18, 2016. doi:10.1001/jamacardio.2016.0545.

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Passman reported serving as a consultant, research support, and speakers bureau member for Medtronic; serving as a consultant for Boehringer Ingelheim and Janssen Pharmaceuticals; and receiving royalties for UpToDate.

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