VITAL Rhythm Data May Flip the Script on AF Screening in Women

A woman’s risk of developing atrial fibrillation (AF) may be masked by inadequate screening based on old assumptions, according to a new analysis of data from the VITAL Rhythm study.

“There is this long-held belief that men are more likely to get atrial fibrillation than women,” said Hasan K. Siddiqi, MD (Vanderbilt University Medical Center, Nashville, TN), the study’s lead author. “Large cohort studies that have looked at atrial fibrillation and risk have controlled for a variety of factors . . . , but often incorporate [body mass index] to control for body size.” Doing that in this data set led to the same outcome that others have found: namely, higher risk in women compared with men.

But, Siddiqi and colleagues considered the fact that body mass index (BMI) weight-to-height ratios can translate to drastically different body shapes and compositions in men and women. Going strictly by the BMI calculation, for example, superstar athletes like Tom Brady and Lebron James are categorized as obese, Siddiqi pointed out. So, the researchers decided to look further at individualized height and weight in the large VITAL Rhythm population. When they did, he added, everything “flipped.” At any given height, women were at higher risk for incident AF than men.

“We were shocked. We looked at the data multiple times to make sure we hadn’t calculated something incorrectly,” he told TCTMD. “Then we really started thinking about what could be going on here. “Truthfully, I don't think I know the answer quite yet, but based on what we're seeing, I think it's an important finding.”

Saima Karim, DO (Case Western Reserve University, Cleveland, OH), who commented on the study for TCTMD, said the higher prevalence of AF in women when accounting for height and body size instead of BMI in the multivariable model is “an unexpected finding” given the longstanding assumptions about women being at lower risk than men.

“The nuances of the various risk factors for atrial fibrillation were scrutinized by sex, and the findings are certainly a revelation,” she said in an email. “The other results in this study that were novel included that women were more symptomatic than men and more likely to have paroxysmal rather than persistent or permanent atrial fibrillation. The fact that women do have more frequent symptoms and present earlier with atrial fibrillation should lead to further investigation as to why they are less likely to get rhythm control, including therapies such as atrial fibrillation ablation.”

The greater frequency of symptoms in women versus men is in line with recent findings from a prespecified analysis of the EAST-AFNET 4 study of early rhythm control therapy, Siddiqi and colleagues observe.

The study was published online August 31, 2022 in JAMA Cardiology.

A Signal for Change

The main VITAL Rhythm study included men 50 years or older (n = 12,362) and women 55 years or older (n = 12,757) with no prior history of CVD or cancer (Black 20%; Hispanic 4%). Patients were randomized to placebo or daily vitamin D3 (2,000 IU) and omega-3 fatty acids (460 mg eicosapentaenoic acid and 460 mg docosahexaenoic acid) for the primary prevention of CVD and cancer.

For the purpose of the current prospective cohort analysis, the researchers looked at confirmed incident AF events over a median follow-up of 5.3 years. The rate of these events was 4% in men and 3.2% in women. The mean age at AF diagnosis was 74.4 in men and women. More than three-quarters of the women (77%) who developed incident AF had symptoms compared with 63% of men.

After adjustment for age and treatment assignment, the risk of incident AF was lower in women than men (HR 0.68; 95%CI 0.59-0.77). The findings also held true after further adjustment for race and ethnicity, smoking, alcohol intake, hypertension, diabetes, thyroid disease, exercise, and BMI (HR 0.73; 95%CI 0.63-0.85).

We need to start to [consider] that women are at equally or greater risk of atrial fibrillation, and so our screening programs need to change. Hasan Siddiqi

All body size parameters including height, weight, BMI, and body surface area were significantly different between men and women. When height and weight were substituted for BMI in the multivariable model, women were more likely than men to develop incident AF (HR 1.49; 95% CI 1.21-1.82). More specifically, height contributed the greatest risk (HR 1.39; 95% CI 1.14-1.70), with a nonsignificant contribution from weight (HR 1.05; 95% CI 0.90-1.23). Accounting for body surface area also put women at greater risk compared with men (HR 1.25; 95% CI 1.06-1.49). Sensitivity analyses, including various height-adjusted models, also showed greater risk of AF in women than men.

Siddiqi said the findings are important on a practical level in light of the greater emphasis on AF screening programs in elderly men.

“What this tells us is that we should be equally, if not more concerned, about [AF] in women as a potential cardiovascular risk that they carry, and that we need to [do] better in including women in screening programs,” he said. “We need to start to [consider] that women, particularly women who are perhaps taller, with other cardiovascular risk factors, are at equally or greater risk of atrial fibrillation, and so our screening programs need to change.”

Karim praised the efforts made by the researchers to ensure that the population was equally representative of both men and women (49% and 51%, respectively), unlike many AF studies that are generally biased towards men. She added that the study population also included ethnic and racial minorities proportionate to current US demographic patterns. Siddiqi agreed with Karim that there is a clear disparity in the guideline-directed treatment that women receive for AF, including antiarrhythmic therapies, anticoagulation, and ablation.

“Is there going to be a change in the guidelines from this? I think that's hard to say,” Siddiqi said. “This is certainly the kind of study that leads to more studies, I hope, and more investigation and understanding of the consequences of [these findings].”