BREAKOUT SESSION

Sex- and Gender-specific Research Priorities for the Emergency Management of Heart Failure and Acute Arrhythmia: Proceedings from the 2014 Academic Emergency Medicine Consensus Conference Cardiovascular Research Workgroup Alyson J. McGregor, MD, MA, W. Frank Peacock, MD, Anna Marie Chang, MD, MSCE, Basmah Safdar, MD, MSc, and Deborah Diercks, MD, MSc

Abstract The emergency department (ED) is the point of first contact for patients with acute heart failure and arrhythmias, with 1 million annual ED visits in the United States. Although the total numbers of men and women living with heart failure are similar, female patients are underrepresented in clinical studies, with current knowledge predominantly based on data from male patients. This has led to an underappreciation of the sex-specific differences in clinical characteristics and pathophysiology-based management of heart failure. Similar disparities have been found in management of acute arrhythmias, especially atrial arrhythmias that lead to an increased risk of stroke in women. Additionally, peripartum and postpartum cardiomyopathy represent a diagnostic and treatment dilemma. This article is the result of a breakout session in the cardiovascular and resuscitation work group of the 2014 Academic Emergency Medicine consensus conference “Gender-Specific Research in Emergency Medicine: Investigate, Understand, and Translate How Gender Affects Patient Outcomes.” A nominal group technique was used to identify and prioritize themes and research questions using electronic mail, monthly conference calls, in-person meetings, and Web-based surveys between June 2013 and May 2014. Consensus was achieved through three rounds of nomination followed by the meeting on May 13, 2014, and resulted in seven priority themes that are essential to the common complex clinical syndrome of heart failure for both men and women and include the areas of pathophysiology; presentation and symptomatology; and diagnostic strategies using biomarkers, treatment, and mortality, with special consideration to arrhythmia management and pregnancy. ACADEMIC EMERGENCY MEDICINE 2014;21:1361–1369 © 2014 by the Society for Academic Emergency Medicine

From the Department of Emergency Medicine, Warren Alpert Medical School of Brown University (AJM), Providence, RI; the Department of Emergency Medicine, Baylor College of Medicine (WFP), Section of Emergency Medicine, Oregon Health and Science University (AMC), Portland, OR; the Department of Emergency Medicine, Yale University (BS), New Haven, CT; and the Department of Emergency Medicine, UC Davis Medical Center (DD), Davis, CA. Received June 15, 2014; revision received August 11, 2014; accepted August 29, 2014. Breakout session attendees: Blair Alden Parry, John Ashurst, Anise Ayodola, Kevin Barr, Lance Becker, Jeremy Brown, Robert Cannon, Anna Marie Chang, Alan Cherney, Ted Christopher, Laura Costelloe, Steven Deutsch, Holli DeVon, Gail D’Onofrio, Carole Douriez, Nina Gentile, Liz Goldberg, Brooke Harris, Erik Hess, Judd Hollander, Tami Kayea, Jennifer Kruse, Marianne Legato, Richard MacKenzie, Tracy Madsen, Alyson McGregor, Andrew Miller, Chris Moore, Bryan Mumma, Anthony Napoli, Katie O’Conor, Sarah Perman, Basmah Safdar, Jane Scott, Todd Sergel, Shameen Smamji, Howard Smithline, Danic Stone, Dorai Suprina, Deepak Vatti, Kevin Weaver, Michael Weigner, Jane Wigginton, Charles Wira, and Jennette Wolfe. The consensus conference was supported by grant 1R13NS087861-01 from the National Institute of Neurological Disorders and Stroke and the Office of Research on Women’s Health at the National Institutes of Health. Additional funding was provided by several organizational, institutional, and individual donors. Non-CME events were supported by Janssen Pharmaceuticals and Besins Critical Care/BH Pharma. See the executive summary elsewhere in this issue for full funding information. Dr. Chang is supported by NIH NHLBI award K12HL108974. Supervising Editor: James Miner, MD. Address for correspondence and reprints: Alyson J. McGregor, MD, MA; e-mail: [email protected].

© 2014 by the Society for Academic Emergency Medicine doi: 10.1111/acem.12526

ISSN 1069-6563 PII ISSN 1069-6563583

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eart failure, a major cause of cardiac death, is a complex clinical syndrome that can result from any cardiac disorder. Among older patients, heart failure represents the greatest health care burden in developed countries, affecting 5 million patients in the United States with the incidence steadily increasing in both men and women, with a slightly greater proportionality in men.1,2 The emergency department (ED) is often the point of first contact for these patients and has seen a 20% increase in visits over the last decade.3 It is a common discharge diagnosis, particularly in elderly women, and leads to a significant economic burden, with over 34.4 billion dollars spent in 2010.4,5 With underrepresentation of females in clinical studies,6 evidence relating to pathophysiology, etiology, clinical presentation, treatment, and outcome is predominantly based on data from male patients.7 This has led to differences in clinical characteristics between men and women being unrecognized or unknown. This article outlines the consensus recommendations made by the 2014 Academic Emergency Medicine (AEM) consensus conference for future research in the seven priority domains of heart failure, including pathophysiology, presentation and symptomatology, diagnosis using biomarkers, treatment, and mortality. Additional recommendations are presented for arrhythmias and concerns surrounding heart failure in pregnancy. METHODS The priority themes and research questions presented in this article were assembled through an iterative consensus-driven process using a nominal group technique (NGT) as described in the executive summary.8 The executive committee and conference leaders assembled a diverse group of stakeholders and experts who participated in the preconference monthly phone calls, which resulted in progressive refinement of surveys regarding themes and research questions using the NGT between June 2013 and May 2014. The method used to identify the participants is further described in the executive summary.8 Prior to the AEM consensus conference, a preconference survey eliciting open-ended feedback regarding the key themes and research questions identified was sent to all AEM peer reviewers. Responders’ demographics and a list of additional themes that did not qualify for the consensus process are summarized in the article from the emergency diagnosis and management of coronary artery disease breakout group from the cardiovascular research workgroup.9 On May 13, 2014, a total of 45 stakeholders participated in the final iteration of the consensus process (see list in footnote). The group composition is described further in the coronary artery disease breakout group.9 Anonymous voting was conducted with Poll Everywhere, with paper surveys as back-up. The process details are described elsewhere.8 Data were entered into an electronic spreadsheet (Microsoft Excel) and descriptive analyses were used to tabulate the results.

CONSENSUS RESULTS This article presents the results of both iterative electronic surveys as well as the in-person meeting on the day of the consensus conference. Seven major themes related to the emergency care of heart failure and arrhythmias were identified and are presented along with the research questions with high agreement on related importance. Questions that were related to the priority themes that underwent further voting at the consensus conference are presented in Table 1. Recommendation 1—Pathophysiology Heart failure is a clinical syndrome defined by characteristic symptoms and physical findings. It is characterized into two main entities based on echocardiographic findings: heart failure with reduced ejection fraction or with preserved ejection fraction, which is variably defined as a left ventricle ejection fraction (LVEF) greater than 40, 45, or 50%.10 The former is more common in men and is primarily related to coronary artery disease, while the latter is more common in women and less commonly associated with ischemia.11,12 There are a number of contributors to the sex discrepancy in heart failure with preserved ejection fraction pathophysiology and sex effects on cardiovascular aging. They are important to understand to devise sexspecific management for these patients. Beginning at puberty, left ventricular chamber size and mass are 15% to 40% lower in women than in men, and these differences persist even after adjustment for smaller body size in women.13 However, women are shown to have higher left ventricular systolic function independent of this ventricular volume.14 Despite having similar peripheral hemodynamics, there are significant sex differences in central hemodynamics. Left ventricular diastolic dysfunction significantly correlates with parameters representing arterial stiffness in women, but not in men.15 Also, there are fundamental differences between men and women in the left ventricular response to chronic load alteration. Males are more likely to develop eccentric left ventricular remodeling with stress, whereas females develop more concentric remodeling.16 Each of these sex dimorphisms becomes more pronounced after menopause. These data suggest that sex-specific maladaptions to hypertensive aging in women may underlie greater risk of heart failure with preserved ejection fraction. Priority Questions. 1. In patients presenting to the ED with heart failure, are there acute management therapies based on the known pathophysiologic differences in heart failure with preserved versus reduced ejection fraction that improve outcomes? Recommendation 2—Presentation and Symptomatology The presentations for women and men differ in heart failure, often due to the physiology of disease. In one study, women were more likely to present with “newonset” heart failure compared to men.17 Women tend to have different comorbidities and causes of heart failure.

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Table 1 Ranked Order of Consensus-driven Research Questions

Rank 1. 2. 3. 4. 5. 6.

Consensus-based Questions (Voted in Degree of Important From Highest to Lowest) In patients with heart failure are there interactions between comorbidities and gender impact mortality rates? How should we define heart failure with preserved ejection fraction by noninvasive methods for acute ED presentations? In patients with heart failure with preserved ejection fraction, are there risk factors that distinguish physiologic discomfort of pregnancy from heart failure with preserved ejection fraction? In patients presenting to the ED with heart failure, are there gender-specific clinical characteristics that can be identified in young patients at risk so that early referral and preventive management can be provided? In patients presenting to the ED with heart failure, are there new screening tests for heart failure with preserved ejection fraction that can be used to develop an ED-based registry? In patients with heart failure can sex-specific questionnaires be used to prognosticate genderspecific outcomes?

For example, hypertension, atrial fibrillation, and valvular heart disease are more common causes of acute heart failure in women; ischemic causes are common in men instead.18 Women more often have diabetes, anemia, and thyroid diseases as comorbidities. Women with heart failure tend to be older than men in most studies; it is unclear if this is due to a protective effect of estrogen. Women tend to have higher systolic blood pressures at presentation, more often present with orthopnea and rales but not edema, with other signs of congestion similar to men.19 This is likely due to higher prevalence of heart failure with preserved ejection fraction in this cohort. To assess the effect of heart failure on patient’s lives, it is necessary to survey the population. The Kansas City Cardiomyopathy Questionnaire has been found to be a validated measure in patients with reduced and preserved ejection fraction.20 Several studies have shown that even after controlling for ejection fraction, women have significantly worse general life satisfaction, physical function, and social and general quality of life scores compared to men.21,22 It is unclear why there is a difference in quality of life between men and women with heart failure. Despite these differences, men and women have similar 30-day readmission rates for heart failure.23 Priority Questions. 1. In patients with heart failure, are there the key biologic factors that account for sex-variable presentations? 2. In patients with heart failure, do sex-specific comorbidities affect the presentation and symptom management? Recommendation 3—Diagnosis Using Biomarkers B-type natriuretic peptide (BNP) levels are commonly used in the diagnosis and risk stratification of patients presenting with dyspnea that is concerning for heart failure. Prior studies have shown differences in BNP levels by sex. BNP is released and stored in secretory granules as proBNP in the ventricles and to a small extent the atria. It is activated by volume overload and

Mean Likert Score (Range 0–5) 4.28 3.92 3.78 3.65 3.33 2.83

myocardial stretch and released into the plasma in its active form BNP. When evaluating sex differences in BNP levels it is important to identify the patient population being evaluated. In population-based studies, BNP levels have been shown to be higher in women than men. In a study of 2,042 randomly selected residents of Olmstead County in Minnesota, plasma BNP was shown to be 32% higher in women than men (95% confidence interval [CI] = 15% to 51%), irrespective of the assay.24 The authors in part attribute this difference to the use of hormone replacement therapy (HRT), as those women on HRT after controlling for age show a 21% (95% CI = 6% to 40%) higher value than women not on HRT. These data provide some evidence that BNP levels are related to hormonal status.25 However, in studies that focus on patients with cardiomyopathy, men have higher circulating levels of natriuretic hormones than women.26 Despite the elevated BNP level found in women in general population studies, elevation of BNP levels after adjustment for other cardiac risk factors is a strong predictor of the development of heart failure, with a hazard ratios of 8.5.27 In patients presenting to the ED with symptoms suggestive of heart failure, measurement of BNP levels is often used as a diagnostic test. Despite differences in population studies, there are no differences in the diagnostic accuracy of BNP assays by sex.28,29 In the Breathing Not Properly study of 1,586 patients who presented to the ED with acute dyspnea, the areas under the curve were similar between women and men (0.870 and 0.918, respectively).29 These studies provide evidence that in the acute care setting the diagnostic accuracy of BNP does not vary by sex. BNP levels have also been used to assess the prognosis of patients presenting with heart failure. In the BASEL study, regression analyses of BNP levels > 500 pg/mL indicated a 5.1-fold increase in mortality for women (95% CI = 3.0 to 8.5, p < 0.001) versus a 1.8fold increase in men (95% CI = 1.2 to 2.6, p = 0.007).30 In another study that identified variables associated with prognosis in subjects with advanced heart failure, BNP was identified as a strong predictor in sex-based

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models.31 There appears to be an interaction between BNP levels, sex, and ejection fraction. A large registry study showed that for hospitalized heart failure patients with reduced ejection fraction, men had a higher in hospital mortality rate than women for any given BNP level between the values 500 to 3,000 pg/mL. However, among patients with preserved ejection fraction, sex differences did not exist when BNP levels were adjusted for confounders.32 Priority Questions. 1. In patients with acute heart failure, do sex-specific marker cutoffs for BNP improve diagnosis and prognosis of heart failure with preserved and reduced ejection fraction? Recommendation 4—Treatment Heart failure with reduced ejection fraction or with preserved ejection fraction has similar mortality (20% to 30% annual) and readmission rates (30% at 3 months), even though heart failure with preserved ejection fraction is less commonly associated with ischemic heart disease, the number one cause of mortality.33 This is because while clinical trials have shown a mortality benefit of angiotensin-converting enzyme (ACE) inhibitors, beta blockers, aldosterone antagonists, and resynchronization in cases with reduced ejection fraction, the same has not been demonstrated for those patients with preserved ejection fraction.34 Several key trials in patients with preserved ejection fraction have demonstrated improvement of diastolic function, neurohormonal changes, and readmission rates, but none have altered composite cardiac outcomes.35 Although women are diagnosed more often with heart failure with preserve ejection fraction, diuresed less intensely, and hospitalized longer and more often, more men die with this condition.36 The disparities by sex call for more collaborative trials for treatment of NY Class IV heart failure. The current guidelines recommend use of intravenous diuretics, nitrates, and ionotropes, as well as improving ventilation (intubation or biphasic positive pressure ventilation), in acute management of decompensated heart failure. The evidence is better studied for those with reduced ejection fraction, but same recommendations have been extrapolated to decompensation patients with preserved ejection fraction.34 The factors that promote fluid retention and precipitate heart failure are similar in patients with systolic heart failure and those with diastolic heart failure. These factors include tachycardia, uncontrolled hypertension, atrial fibrillation, noncompliance with medications, myocardial ischemia, anemia, renal insufficiency, and overindulgence in salty foods. The consensus is to treat the underlying causes such as hypertension, tachycardia, use of ACE inhibitors,37 aldosterone,38 or beta blockers39 and novel therapies such as phosphodiesterase inhibitors or late sodium channel blockers. Caution is advised for aggressive diuresis as preserved ejection fraction patients are more prone to hypotension, being dependent on higher left ventricular filling pressures. Not much is known about the sex variation in execution of these treatment recommendations including acute medication use in the ED,

use of noninvasive ventilation or intubation, and rates of intensive care unit admissions. A review of clinicaltrials.gov revealed other small experimental studies using inorganic nitrates, furosemide with dopamine, and ranolazine, but none are testing therapies for acute management of heart failure or are sex-specific. There is also lack of sex-specific reports of basic science results leading to a gap in translation in heart failure clinical trials.40 For end-stage heart failure, women are referred for destination therapy later, comprise 30% of the recipients, and have higher postprocedure complication rates compared to men. They also exhibit greater disability from heart failure as compared to men.41 Finally, there are no sex-specific guidelines for palliative care options for the patients with end stage cardiomyopathy. Priority Questions. 1. What are key sex-specific outcome measures for treatment of heart failure with preserved and reduced ejection fraction? 2. What are the sex-specific variations in acute management of heart failure that could influence shortterm prognosis as well as readmissions? 3. What is the role of acute diagnostics in tailored sexspecific treatment for heart failure in the ED (biomarkers, point-of-care ultrasound, right heart catheterization, etc.)? Recommendation 5—Mortality Differences The American Heart Association reported that in 2010 there were over 57,000 deaths from heart failure. Of these deaths the majority were in women.42 Studies have reported that there are differences in presentation and treatment of women with heart failure. Studies in chronic heart failure patients show that women have a lower mortality rate even after adjusting for ejection fraction.43 Although there have been studies examining mortality rates by sex in patients with chronic heart failure, fewer data are available to determine the risk of mortality by sex in acute heart failure patients. In a large trial of women hospitalized with acute heart failure and impaired renal function, age-adjusted 180day mortality was lower in women (hazard ratio [HR] = 0.74; 95% CI = 0.59 to 0.93), but this difference was negated in multivariable risk-adjusted models.44 These data are not consistent with the report of no difference in long-term mortality in women with reduced ejection fraction reported in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST; men 27% vs. women 24%, multivariate HR = 1.04, p = 0.61) or cardiovascular mortality plus heart failure hospitalization (men 42% vs. women 39%, multivariate HR = 1.11, p = 0.10).45 A large prospective cohort study of patients hospitalized with acute heart failure in Israel reported that women tended toward an increased risk for early (≤6 months) mortality (adjusted HR = 1.16, 95% CI = 0.96 to 1.41, p = 0.13), whereas men had significantly increased risk for late (>6 months) mortality (adjusted HR = 1.25, 95% CI = 1.09 to 1.43, p = 0.001).46 In an analysis of the Acute Decompensated Heart Failure National Registry (ADHERE), which includes patients hospitalized with acute heart failure,

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despite disparities in treatment, the risk-adjusted inhospital mortality (adjusted odds ratio [OR] = 0.974, 95% CI = 0.910 to 1.042, p = 0.4390) was similar in both sexes.47 Data regarding mortality rates in patients with acute heart failure are varied. Registry data that include the entire spectrum are not consistent in the risk of mortality by sex. Variations in conclusions may be based on risk-adjusted modeling strategies, the variation in populations being studied, and geographic variations in care. Recommendation 6—Arrhythmias Physiology. There are important sex differences in cardiac electrophysiology that alter the epidemiology, presentation, and prognosis of various arrhythmias. For example, women have higher resting heart rates and lower QRS voltage than men (even after adjustment for differences in left ventricular mass and body weight). There are also sex differences in the prevalence and presentation of various arrhythmias. Atrioventricular nodal reentrant tachycardia is twice as common in women, and atrioventricular reentrant tachycardia occurring in Wolff-Parkinson-White syndrome is more common in men. Further, atrial and ventricular fibrillation occurs more frequently in men with Wolff-Parkinson-White syndrome.48 Hormones may play a causal role in the sex differences of various arrhythmias. Women suffer more frequent and longer-lasting episodes of supraventricular tachycardia as well as an increased frequency of ventricular ectopic beats during the lacteal phase of the menstrual cycle.49 Electrocardiographically, women have longer QT intervals. This puts them at an increased risk for druginduced torsades de pointes (TdP), predisposing them to higher rates of drug induced TdP.50 Sex differences in ventricular tachyarrhythmia susceptibility likely result from the effects of several underlying characteristics that differ in males and females. This includes genetic differences for key repolarizing potassium channels and the effect of sex steroid hormones acutely modifying electrical activity. The implications of these differences may explain why before age 15 years, males with long QT syndrome suffer a higher risk of sudden cardiac death, but after age 15 years females suffer greater risk.51 Atrial Fibrillation. While men may more frequently suffer from atrial fibrillation, when it occurs women are at higher risk for both stroke and death, independent of other risk factors. Consequently, the Stroke Prevention in Atrial Fibrillation,52 Framingham risk,53 and the CHADS2-VACS54 scoring systems all include “female gender” as an important parameter for stroke risk assessment. Other sex-dependent differences exist. At hospital admission for atrial fibrillation, women tend to be older, and present with higher CHADS2 risk scores. They experience longer (>24 hours) and more symptomatic episodes of atrial fibrillation and they have more frequent recurrences, with significantly higher ventricular rates,55 and women with atrial fibrillation ultimately suffer a lower quality of life versus men.56 Overall, treatment for atrial fibrillation is more conservative in women. Despite these described risk pro-

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files, women are less likely to receive anticoagulation and ablation procedures compared to men. And while conversion to normal sinus rhythm is equally successful in both sexes, females receive significantly less rhythm control than men, with men being more likely to undergo electrical cardioversion than women.57 It is unclear whether these differences are related to variation in consent or communication of risk. If treated, women benefit from a greater reduction in thromboembolic events (adjusted relative risk 0.4 for women vs. 0.6 for men, p