Sex Complicates Stroke Risk Scoring in AF

The European Society of Cardiology (ESC) caused a stir when they recommended in their latest atrial fibrillation (AF) management guideline that gender no longer be included in the decision to initiate oral anticoagulation therapy.

The move aims to level the playing field between men and women and follows a more nuanced understanding of stroke risk in patients with AF, say experts. It also acknowledges the lack of evidence in people receiving cross-sex hormone therapy.

In any case, the guidelines, developed in collaboration with the European Association
for Cardio-Thoracic Surgery and published by the European Heart Journal on August 30, simply follow last year’s US recommendations, they add.

One Size Does Not Fit All

So, what to the ESC guidelines actually say?

They underline that, if left untreated, the risk for ischemic stroke is increased fivefold in patients with AF, and the “default approach should therefore be to provide oral anticoagulation to all eligible AF patients, except those at low risk for incident stroke or thromboembolism.”

However, the authors note that there is a lack of strong evidence on how to apply the current risk scores to help inform that decision in real-world patients.

Dipak Kotecha, MBChB, PhD, Professor of Cardiology University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom, and senior author of the ESC guidelines, told Medscape Medical News that “the available scores have a relatively poor ability to accurately predict which patients will have a stroke or thromboembolic event.”

Instead, he said “a much better approach is for healthcare professionals to look at each patient’s individual risk factors, using the risk scores to identify those patients that might not benefit from oral anticoagulant therapy.”

For these guidelines, the authors therefore wanted to “move away from a one-size-fits-all” approach, Kotecha said, and instead ensure that more patients can benefit from the new range of direct oral anticoagulants (DOACs) that are easier to take and with much lower chance of side effects or major bleeding.

To achieve this, they separated their clinical recommendations from any particular risk score, and instead focused on the practicalities of implementation.

Risk Modifier Vs Risk Factor

To explain their decision the authors highlight that the “the most popular risk score” is the CHA₂DS₂–VASc, which gives a point for female sex, alongside factors such as congestive heart failure, hypertension, and diabetes mellitus, and a sliding scale of points for increasing age.

Kotecha pointed out the score was developed before the DOACs were available and may not account for how risk factors have changed in recent decades.

The result is that CHA₂DS₂–VASc gives the same number of points to an individual with heart failure or prior transient ischemic attack as to a woman aged less than 65 years of age, “but the magnitude of increased risk is not the same,” Usha Beth Tedrow, MD, Associate Professor of Medicine, Brigham and Women’s Hospital, Boston, told Medscape Medical News.

As far back as 2018, it was known that “female sex is a risk modifier, rather than a risk factor for stroke in atrial fibrillation,” noted Jose Joglar, MD, lead author of the 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation told Medscape Medical News.

A Danish national registry study involving 239,671 AF patients treated between 1997 and 2015, nearly half of whom were women, showed that, at a CHA₂DS₂–VASc score of 0, the “risk of stroke between men and women is absolutely the same,” he said

“It is not until after a CHA₂DS₂–VASc score of 2 that the curves start to separate,” Joglar, Program Director, Clinical Cardiac Electrophysiology Fellowship Program, The University of Texas Southwestern Medical Center, Dallas, Texas, continued, “but by then you have already made the decision to anticoagulate.”

More recently, Kotecha and colleagues conducted a population cohort study of the electronic healthcare records of UK primary care patients treated between 2005 and 2020, and identified 78,852 with AF; more than a third were women.

Their analysis, published on September 1, showed that women had a lower adjusted rate of the primary composite outcome of all-cause mortality, ischemic stroke, or arterial thromboembolism, driven by a reduced mortality rate.

“Removal of gender from clinical risk scoring could simplify the approach to which patients with AF should be offered oral anticoagulation,” Kotecha and colleagues concluded.

Joglar clarified that “women are at increased risk for stroke than men” overall, but by the time that risk “becomes manifest, other risk factors have come into play, and they have already met the criteria for anticoagulation.”

The authors of the latest ESC guideline therefore concluded that the “inclusion of gender complicates clinical practice both for healthcare professionals and patients.” Their solution was to remove the question of gender for decisions over initiating oral anticoagulant therapy in clinical practice altogether.

This includes individuals who identify as transgender or are undergoing sex hormone therapy, as all the experts interviewed by Medscape Medical News agreed that there is currently insufficient evidence to know if that affects stroke risk.

Instead, guidelines state that the drugs are “recommended in those with a CHA₂DS₂-VA score of 2 or more and should be considered in those with a CHA₂DS₂-VA score of 1, following a patient-centered and shared care approach.”

“Dropping the gender part of the risk score is not really a substantial change” from previous ESC or other guidelines, as different points were required in the past to recommend anticoagulants for women and men, Kotecha said, adding that “making the approach easier for clinicians may avoid penalizing women as well as non-binary and transgender patients.”

Anne B. Curtis, MD, SUNY Distinguished Professor, Department of Medicine, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, Buffalo, New York, agreed.

Putting aside the question of female sex, she said that there are not a lot of people under the age of 65 years with “absolutely no risk factors,” and so, “if the only reason you would anticoagulate” someone of that age is because they are a woman that “doesn’t make a lot of sense to me.”

The ESC guidelines are “trying to say, ‘look at the other risk factors, and if anything is there, go ahead and anticoagulate,” Curtis told Medscape Medical News.

“It’s actually a very thoughtful decision,” Tedrow said, and not “intended to discount risk in women.” Rather, it’s a statement that acknowledges the problem of recommending anticoagulation therapy in women “for whom it is not appropriate.”

Joglar pointed out that that recommendation, although not characterized in the same way, was in fact included in the 2023 US guidelines.

“We wanted to use a more nuanced approach,” he said, and move away from using CHA₂DS₂–VASc as the prime determinant of whether to start oral anticoagulation and towards a magnitude risk assessment, in which female sex is seen as a risk modifier.

“The Europeans and the Americans are looking at the same data, so we often reach the same conclusions,” Joglar said, although “we sometimes use different wordings.”

Overall, Kotecha expressed the hope that the move “will lead to better implementation of guidelines, at the end of the day.”

“That’s all we can hope for: Patients will be offered a more individualized approach, leading to more appropriate use of treatment in the right patients.”

The newer direct oral anticoagulation is “a much simpler therapy,” he added. “There is very little monitoring, a similar risk of bleeding as aspirin, and yet the ability to largely prevent the high rate of stroke and thromboembolism associated with atrial fibrillation.”

“So, it’s a big ticket item for our communities and public health, particularly as atrial fibrillation is expected to double in prevalence in the next few decades and evidence is building that it can lead to vascular dementia in the long-term.”

No funding was declared.

Kotecha declares relationships with Bayer, Protherics Medicines Development, Boston Scientific, Daiichi Sankyo, Boehringer Ingelheim, BMS-Pfizer Alliance, Amomed, MyoKardia. Curtis declared relationships with Janssen Pharmaceuticals, Medtronic, Abbott. Joglar declared no relevant relationships. Tedrow declared no relevant relationships.