Is it enough to have “enough” women in cardiac studies?

by Carolyn Thomas   ♥    @HeartSisters

Did you hear the one about the Harvard study on the effects of aspirin in preventing heart attack? Over 22,000 men participated, but the researchers did not recruit even one woman.¹

But that is not a joke.            .  .  

Based on the one-sided patient population studied, Harvard researchers reported that taking a daily aspirin would produce a “conclusive reduction in the risk of myocardial infarction” (heart attack).

Later studies however (ones that did include representative numbers of women) found that aspirin in men indeed reduced the risk of heart attack, but aspirin in women did not.²

The Harvard study was published back in 1989. Surely cardiac research is now far more inclusive than it was back then? It’s true that until 1993, many large cardiovascular trials (such as the Physicians’ Health Study cited above) included men only.

In most cases, in fact, even laboratory studies included male animals only.

After 1993, however, things began to improve, but only because major funding sources required researchers to include more women in their studies.²

Think about this for a moment.

Because women were excluded from cardiac research, white, middle-aged men were considered to be the “norm” for decades. 

And in the research lab, a type of observer bias – a male bias – in assuming a male’s attitude when conducting trials was another contributing factor, as described in this 2016 historical report:³

“At the same time, researchers often thought that women would have the same response as men from drugs in clinical trials.  They also viewed women as confounding and more expensive test subjects because of their fluctuating hormone levels. 

“Concerns of potential reproductive adverse effects led to policies and guidelines that considered pregnant women as a ‘vulnerable population’ and, subsequently, excluded these women from research and restricted the ability of women of child-bearing potential to enroll in studies.”

Why does this matter?

It matters to anybody who believes that women are NOT small men (coincidentally the title of a 2003 book written by cardiologist Dr. Nieca Goldberg, and renamed in 2006 as The Women’s Healthy Heart Program). 

For those who believed that women’s bodies are interchangeable with men’s bodies, it may have been easier to accept that the results of a study exclusively focused on 22,000 men would apply to all women as well.

But as Dr. Janine Austin Clayton, associate director for women’s health research at the National Institutes of Health, said in a 2014 New York Times interview: “We literally know less about every aspect of female biology compared to male biology.”

Dr. Goldberg recalls in her book feeling dismayed back in med school to learn that “all medical care was based on what was ‘normal’ for a 165-pound man”:

“During my residency, I heard a doctor say that women don’t get heart disease. I realized the field of women’s cardiology was lagging far behind that of men’s cardiology, and decided to specialize in it. It shocked me that coronary and cardiovascular issues in women were so poorly understood.”

So how many women are “enough” in a cardiac study?

It turns out that we do in fact have a simple way to tell if a research project has recruited enough women to be able to make accurate conclusions about that study’s findings. It’s called the Participation to Prevalence Ratio (PPR).⁴

Sounds like a mouthful, but the PPR is straightforward: imagine that women make up a certain percentage of a patient population diagnosed with a specific disease in the real world. An appropriate PPR score means that about the same percentage of the patients participating in any study on that specific disease will be female. A desirable range for an ideal ratio of female participation is between 0.8 and 1.2.

How are women doing when it comes to the PPR score in cardiac research?

In a study published last year in the Journal of the American College of Cardiology,  researchers found good news and bad news.

This study examined women’s participation numbers for 36 different cardiovascular disease pivotal drug trials submitted to the U.S. Food and Drug Administration (FDA) in order to get those heart drugs approved for marketing to the public. FDA researchers added that women were well represented in trials of drugs for hypertension (high blood pressure), pulmonary arterial hypertension (high blood pressure in the lungs caused by obstructed small arteries in the lung), and atrial fibrillation (an irregular rapid heart rate).

But representation of women fell below an acceptable PPR (under 0.8) for clinical trials that were studying:

• heart failure*
• coronary artery disease*
• acute coronary syndrome* 

By the way, the issue of appropriate patient representation in clinical trials reaches far beyond just counting males and females. For example, other studies suggest that older  patients (>age 65) and those from racial and ethnic minorities are significantly under-represented in heart research.²

Despite growing awareness (and even funding requirements) that women must be represented equitably across all areas of medical research, we still see that women’s participation “has been the lowest in cardiovascular trials”, as McGill University researchers Drs. Louise Pilote and Valeria Raparelli wrote about in 2018.

Even when women are actively recruited for participation in heart studies, however, there are often important sub-groups of women being missed entirely, and research results may not be analyzed for sex-specific differences in women. 

Yale University physicians Dr. Emily Bucholz and Dr. Harlan Krumholz believe that simply enrolling enough women into trials is not good enough.

Here’s what they wrote in Circulation, the journal of the American Heart Association:

“Women present with heart disease later in life compared with men, yet older women are often excluded from clinical trials.

“Women also have unique biological life events (e.g. menopause and pregnancy) which may alter both their risk of cardiovascular disease and response to treatment. However, these events have largely been ignored in cardiovascular research.

“Compared with men and older women, young women with myocardial infarction (heart attack) represent a higher risk population with higher rates of traditional and non-traditional risk factors, more atypical symptoms, and higher complication and mortality rates. And they more frequently experience atypical disease processes, including coronary microvascular disease and spontaneous coronary artery dissection (SCAD).

“It is not enough just to include more women in the studies, even though we should.

“It is not enough to publish more subgroup analyses by sex, even though we should.

“What is needed is to turn the spotlight on the imperative that studies be designed at the outset to address important differences between men and women, and among subgroups of women.”

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1. “Final Report on the Aspirin Component of the Ongoing Physicians’ Health Study.”  Steering Committee of the Physicians’ Health Study Research Group^. July 20, 1989. N Engl J Med 1989; 321:129-135

2. Downing N.S. , Shah ND, Neiman JH, Aminawung JA, Krumholz HM, Ross JS:  “Participation of the Elderly, Women, and Minorities in Pivotal Trials Supporting 2011-2013 U.S. Food and Drug Administration Approvals.”  Trials. 2016 Apr 14; 17:199.

3. Liu, K. A., & Mager, N. A.”Women’s Involvement in Clinical Trials: Historical Perspective and Future Implications.” Pharmacy Practice, 14(1), 2016. 708.

4. Pamela E. Scott, “Participation of Women in Clinical Trials Supporting FDA Approval of Cardiovascular Drugs”.  Journal of the American College of Cardiology. Volume 71, Issue 18, 8 May 2018. 1960-1969

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Q:  What do you think is behind the reluctance of researchers to design cardiac studies more representative of women?

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* DEFINITIONS (as found in my Patient-Friendly, Jargon-Free GLOSSARY OF CARDIOLOGY TERMS):

*Heart Failure (a really dreadful name that desperately needs to be changed): A chronic progressive condition that affects the pumping power of your heart muscle.

*Coronary Artery Disease: A narrowing of the arteries that supply blood to the heart. The condition results from a plaque rupture/blood clot or spasm, and greatly increases the risk of a heart attack.

*Acute Coronary Syndrome:  An emergency condition brought on by sudden reduced blood flow to the heart muscle, often a precursor to heart attack.

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See also:

–The book “Invisible Women: Data Bias in a World Designed for Men“ by Caroline Criado Perez, winner of the 2019 Royal Society Science Book Prize.

-My review of Maya Dusenbery’s book “Doing Harm: The Truth About How Bad Medicine and Lazy Science Leave Women Dismissed, Misdiagnosed, and Sick.  WARNING: Do NOT open this book before you have taken your blood pressure meds!

–Modern medicine is male-centric medicine, and that’s a problem for women.

-This is NOT what a woman’s heart attack looks like

-But what about the men?

-Women’s cardiac care: how do you think we’re doing? “

-A Typical Heart” – this documentary film pulls no punches

-Yentl’s bikini: Dr. Martha Gulati on women’s most deadly heart attacks

-Skin in the game: taking women’s cardiac misdiagnosis seriously

-How implicit bias in medicine hurts women and minorities

-Cardiac gender bias: we need less TALK and more WALK