Understanding the sex differences in cardiovascular disease presentation and outcomes remains a major research priority demonstrated by the record number of submissions for this year’s Go Red for Women® special issue of the American Heart Association’s flagship journal Circulation, published online today. Circulation editors said more than 100 manuscripts were submitted this year, the most ever in the five years in which the current editorial board has published the special issue.

“Undeniably, cardiovascular disease remains the number one killer of women around the world, taking the lives of 1 in 3 women. Even one life lost is too many, because we know much of heart disease and stroke is preventable and treatable,” said Circulation Editor-in-Chief Joseph A. Hill, MD, PhD. “Support for ongoing research, as well as female participation in pivotal clinical trials, are imperative to effectively address sex disparities in heart disease and stroke care as part of our effort to improve cardiovascular health for women. These are critical in our fight against heart disease and stroke in women.”

The first Go Red for Women Circulation special issue was published in February 2004. Since then, the journal has featured articles related to women and cardiovascular health most every February in recognition of American Heart Month. For the past five years, Hill and his editorial team have dedicated the February issue to the ongoing and unique challenges that face women in the fight against heart disease and stroke. This year’s Go Red for Women issue covers a broad array of topics specifically about cardiovascular disease in women, presented as original research articles, research letters, state of the art reviews, perspectives, editorials and a cardiology news story.

Below are highlights of some of the manuscripts in this issue, which can be accessed in full here.

Association between sex and treatment outcomes of atrial fibrillation ablation versus drug therapy: results from the CABANA Trial - Andrea M. Russo, et al.

Researchers in this clinical trial randomized 2,204 atrial fibrillation (AFib) patients (37% women) who were 65 or older or were under age 65 but had at least one risk factor for stroke to receive treatment with either catheter ablation or drug therapy to control heart rhythm.

There was no significant difference in the primary outcome of death, disabling stroke, serious bleeding or cardiac arrest in men versus women. Adverse events related to either therapy were low in both men and women, without significant sex differences. Catheter ablation compared with drug therapy reduced AFib recurrence in both men and women.

Whereas prior non-randomized data have suggested higher procedural complications in women compared with men, this was not seen in this randomized trial. Researchers said recommendations for ablation should not be discouraged based on concern for adverse events in women, and since ablation offers comparable benefits for women and men, sex should not be used as a basis for selecting a management strategy for treatment of AFib.

Comparison of the efficacy and safety outcomes of edoxaban in 8,040 women versus 13,065 men with atrial fibrillation in the ENGAGE AF TIMI 48 Trial – Robert Giugliano, et al.

In a secondary analysis of the ENGAGE AF TIMI 48 clinical trial, researchers set out to examine the efficacy and safety profile of the anticoagulant edoxaban in women versus men. The 21,105 patients (8,040 women) with AFib and an elevated risk for stroke in the trial were randomized to a higher-dose or a lower-dose of the newer anticoagulant edoxaban or to warfarin, which is an older anticoagulant that must be closely monitored and tends to carry some risks. Follow-up continued for about three years.

At baseline, women had a higher level of FXa activity, which is a critical protein in the clotting process, placing women at potentially increased risk of thrombosis relative to men. Treatment with high-dose edoxaban reduced FXa levels to a greater extent in women than in men, resulting in similar intensity of anticoagulation.

Compared with warfarin, the treatment effect of the higher dose of edoxaban on the risk of stroke or other major clotting events and on major bleeding was similar in women and men. However, the high-dose edoxaban reduced the risk of severe bleeding outcomes including hemorrhagic stroke to a greater extent in women than in men.

Researchers said the safety advantage of edoxaban in women is enhanced for multiple bleeding endpoints compared with men, suggesting that edoxaban is a particularly attractive option for the treatment of women with atrial fibrillation.

Gender based differences in outcomes among resuscitated patients with out-of-hospital cardiac arrest – Purav Mody, et al.

Researchers examined data for 20,508 patients in the Continuous Chest Compression trial to understand experiences of resuscitated, out-of-hospital, cardiac arrest patients. Of the 4,875 successfully resuscitated patients in the primary study cohort, 1,825 (37.4%) were women and 3,050 (62.6%) were men.

Overall, compared to men, women were older (67.5 vs. 65.3 years), received less bystander cardiopulmonary resuscitation (49.1% vs. 54.9%) and had a lower proportion of cardiac arrests that were witnessed (55.1% vs. 64.5%) or had a shockable rhythm (24.3% vs. 44.6%).

The EMS response time, epinephrine dose and amount of fluid administered during resuscitation were similar in men and women. Women had a marginally longer duration of resuscitation compared with men (14.6 minutes vs. 13.5 minutes). Discharge survival was significantly lower in women (22.5% vs. 36.3%).

Researchers said their study demonstrates the existence of gender disparities in post-resuscitation care and highlights the need for future qualitative studies focused on decision-making and care being provided in the post-resuscitation phase to narrow gender-based differences in cardiac arrest outcomes.

Trends in recurrent coronary heart disease following myocardial infarction among US women and men between 2008 and 2017 – Sanne A.E. Peters, et al.

In this study, data were collected from 770,408 women and 700,477 men in the U.S., <65 years of age with commercial health insurance through MarketScan, and ≥66 years of age with government health insurance through Medicare who had a myocardial infarction (MI) hospitalization between 2008 and 2017. Patients were followed for recurrent MI, recurrent coronary heart disease events (i.e., recurrent MI or coronary revascularization), heart failure hospitalization and all-cause mortality (Medicare only) in the 365 days post-MI.

Researchers found:

• From 2008 to 2017, age-standardized recurrent MI rates per 1,000 person-years decreased from 89.2 to 72.3 in women and from 94.2 to 81.3 in men.
• Recurrent coronary heart disease event rates decreased from 166.3 to 133.3 in women and from 198.1 to 176.8 in men.
• Heart failure hospitalization rates decreased from 177.4 to 158.1 in women and from 162.9 to 156.1 in men.
• All-cause mortality decreased from 403.2 to 389.5 in women and from 436.1 to 417.9 in men.

Researchers said rates of all tracked events in the first year after an MI declined considerably between 2008 and 2017 in both men and women, with proportionally greater reductions for women than men. However, rates remain very high and rates of everything except heart failure hospitalization continue to be higher among men than women.

Other studies in this special issue include:

• Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of MINOCA in women - Harmony Reynolds, et al. (Findings from this study were previously presented as Late-Breaking Science at the American Heart Association’s Scientific Sessions 2020.)
• Sex-stratified gene regulatory networks reveal female key-driver genes of atherosclerosis involved in smooth muscle cell phenotype switching - Hester den Ruijter, et al.
• Cardiac remodeling during pregnancy with metabolic syndrome: a prologue of pathological remodeling - Steven Houser, et al.
• Sex, permanent drug discontinuation and study retention in clinical trials: insights from the TIMI trials - Michelle O'Donoghue, et al. (This paper has an accompanying editorial: Adherence to study drugs - a matter of sex? - Sofia Sederholm Lawesson, et al.)
• Sex differences in blood pressure associations with cardiovascular outcomes - Susan Cheng, et al.
• Sudden cardiac arrest in young women - Eloi Marijon, et al.
• Temporal trends in the proportion of women physician speakers at major cardiovascular conferences - Celina Yong, et al.
• Regional heterogeneity in the coronary vascular response in women with chest pain and non-obstructive coronary artery disease - Malik Elharram, et al.
• Related differences in cardiac channelopathies: implications for clinical practice - Babken Asatryan, et al.
• Maternal stroke: A call for action - Islam Elgendy, et al.

• Efficacy of neprilysin inhibition in women with HFpEF: beyond phenotypes and natriuretic peptides - Christopher deFilippi, et al.
• The cascading effects of COVID-19 on women in cardiology - Nosheen Reza, et al.
• Transcatheter mitral valve edge-to-edge repair for secondary mitral regurgitation: why sex matters - Dharam Kumbhani, et al.
• Rising pre-pregnancy hypertension, preeclampsia disparities raise alarm - Bridget Kuehn

Authors’ disclosures and funding sources for all studies in the special issue are listed in the individual manuscripts.

“By publishing some of the best science on cardiovascular disease in women, our hope is that this issue of Circulation will catalyze the conduct of transformative and disruptive research in this area, enabling us to further our understanding of sex differences in CVD presentation and outcomes and effectively address sex disparities in cardiovascular care,” said Hill, who is a professor of internal medicine and molecular biology, Chief of Cardiology at UT Southwestern Medical Center and director of the Harry S. Moss Heart Center in Dallas, Texas

To raise awareness about how participation in research could further scientific understanding of cardiovascular health, the American Heart Association and Verily, Alphabet’s life sciences and health care arm, are collaborating on Research Goes Red™. Research Goes Red aims to empower women to contribute to health research. Learn more at http://www.goredforwomen.org/researchgoesred.