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Researching sex-based differences to improve women’s health

May 9, 2019


By Samantha Noderer, MA, and Margot Walthall, MHA, OptumLabs, Patient Journeys and the Future of Health Care Series


Heart disease is the #1 killer in both women and men. Yet it affects each sex differently. 

Paula Johnson, MD, MPH, cardiologist and President of Wellesley College, has researched sex-based differences across many diseases over her career. At the 2018 OptumLabs Research & Translation Forum, she shared a story that illustrates the importance of doing so.

A middle-aged woman had a stent placed in one of the arteries going to her heart. When she had recurring symptoms, her doctor did the gold standard test ― a cardiac catheterization ― but saw no blockages. Nevertheless, her symptoms continued to the point she had to stop working. 

The patient went to the Connor’s Center for Women’s Health for another opinion. They did another cardiac catheterization and after looking more closely, found clues of a blockage. To confirm, they did an intracoronary ultrasound to look at the artery from the inside out. 

The issue was that coronary artery blockages look different in women compared to men. Yet care guidelines focus on the male standard, and that’s what the initial doctors were looking for. 

When heart disease evaluations consider sex-based differences from the start, there’s potential to identify and treat complications earlier and more effectively.

Have we really gotten as far as we should in medicine without making sex-based diagnoses and treatment decisions the norm?



Watch Now: “Women’s health and our opportunity to take
a life course approach” — Paula Johnson, Wellesley College


The research bias

Sex-based differences are often overlooked and under-evaluated in health care in part because of research shortcomings. Historically, health care research has focused on men as research subjects. 

Reasons for this include:

  • For decades, the vast majority of researchers were men. This can introduce an observer bias skewed towards male attitudes, design of research and interpretations.
  • Without evidence of sex-based differences from research, there were assumptions that women and men would have the same response to treatments.
  • Female sex may have been considered a “confounder” in certain research analyses given the need to consider the added complexity of monthly hormonal cycles and pregnancy. It was simply easier to study men only. 

In response to this systemic gap, the 1993 National Institutes of Health (NIH) Revitalization Act required NIH-funded clinical trials to include female sex in phase 3 clinical trials. 

While women generally are included as research subjects today, the potential sex-based distinctions in diagnosis, treatment and treatment response are still not always analyzed or reported. 

A recent meta-analysis―The More Things Change, the More They Stay the Same: A Study to Evaluate Compliance With Inclusion and Assessment of Women and Minorities in Randomized Controlled Trials―found only 28 of 107 (26%) NIH-funded clinical trials reported at least one outcome by sex or included sex as a covariate.

These evidence gaps can profoundly impact women’s health.

Instead of “leaving women’s health to chance,” Dr. Johnson advocates for science that considers “female sex as biologic variable, gender, and the complex nature of women’s health across the life course” to better understand risk, early warning signs of disease, and how to treat it. 

Sex-based differences in heart disease and stroke prevention

Just as diseases present differently, treatments can also have different risk/benefit profiles for women versus men.

Let’s take the use of direct oral anticoagulants (DOACs) ― alternatives to the long-time standard warfarin ― to prevent stroke in patients with an irregular heartbeat known as atrial fibrillation (A-fib).

A meta-analysis of DOAC treatment for A-fib, published in the American Journal of Cardiology, found that, compared with men, women treated with DOACs had a lower risk of major bleeding and women treated with warfarin had a higher risk of stroke and systemic embolism. 

This suggests a higher net clinical benefit of DOACs compared with warfarin in preventing stroke in women with A-fib. 

A recent study by OptumLabs partners at Johns Hopkins University―Trends and Variation in Oral Anticoagulant Choice in Patients with Atrial Fibrillation, 2010–2017―reveals more detailed uptake trends that support the meta-analysis. 

Researchers looked at 112,184 commercial and Medicare Advantage patients with A-fib who initiated a DOAC between 2010 and 2017. By 2013, women had higher odds of being prescribed a DOAC than men. 

This may be related to a slightly higher rate of apixaban uptake among women: the study found female sex (in addition to older age, higher stroke or bleeding risk, and more comorbidities) was associated with higher odds of an apixaban prescription. 

 By Q1 2017, over half (53.3%) of women with A-fib were prescribed apixaban compared to 47.4% of men. Apixaban has been the most frequently prescribed DOAC since Q3 2015.

While both men and women with A-fib can benefit from this class of stroke prevention drugs, there may be certain DOACs that are more effective in women (such as apixaban).  

A path forward

This is one example of an OptumLabs observational study that was designed to look at key sex-based differences in treating a relatively common health condition. 

With access to such a large and diverse data asset, OptumLabs and our partners have the opportunity to increase the impact of important studies through research designs that deeply explore potential sex-based differences in disease presentation, diagnosis, treatment and treatment response. 

This will enable us to better understand the intersection of biology, gender and life course of women’s health to ultimately improve health care and outcomes.


  • Margot Walthall, MHA, is vice president of integrated programs and translation at OptumLabs
  • Samantha Noderer, MA, is communications and translation manager at OptumLabs