It's time to close the gender gap in clinical trial research for heart failure

Linda developed heart failure after giving birth to her second child. When she became pregnant with her third child, she was sent to me for specialized care to help manage her condition throughout the pregnancy. She was terrified for both her health and the health of her baby; but, with the help of a multidisciplinary team, we delivered her baby successfully, and she was discharged. However, the significance of the disease in her and her family's life remained unchanged.

Linda not only had heart failure but also was morbidly obese. The heart failure symptoms were affecting her ability to work, care for her children, and enjoy an active, normal life. Managing Linda's heart failure with medication was more of an art, rather than guided by science. As a heart failure physician, I did not feel as confident as I would treating a man of the same age, BMI category, and symptom presentation.

Why? Because men and women have different physiology, pathophysiology and variations in underlying causes for their disease, which significantly impacts their treatment. But these differences are exacerbated by the failure of our clinical system to equally represent women as subjects of research, making it difficult to apply the findings of vital clinical trials to the female population. This gender gap is injurious to the health of women, and it is unacceptable.

The differences between genders in the prevalence, diagnosis, and treatment of heart failure are vast. For example, women tend to develop the most common form, with reduced injection fraction, later in life than men. They are also twice as likely to be diagnosed with the less common form of heart failure, with preserved ejection fraction, which also happens to be an understudied ailment. Overall, women may not be diagnosed with heart failure as often as men, possibly because their symptoms aren't as clear, even when they exhibit more symptom burden than men. Additionally, we know that women and men metabolize and absorb drugs differently, but the research doesn't provide enough data to know exactly how to adjust treatments for women.

Gender differences in treatment also emerge when it comes to mechanical circulatory support for advanced heart failure. Women are less likely to be implanted with an LVAD device and they live longer after a heart transplant than men. Also, men who are implanted with a woman's heart don't survive as long as they would if they received a man's heart. The reason is not established but we think this is because women's hearts are smaller.

Many of these differences can be attributed to physiology. Women tend to have more body fat, lower total body water content, slower gastrointestinal motility time, and less gastric secretion than men. So, the effect and distribution of drugs in their body differs from that of men. However, some differences, such as being diagnosed with heart failure less often, may be attributable to disparities in care.

Despite all of these underlying gender differences in heart failure, women are still woefully underrepresented in drug trials. Two recent major trials for heart failure drugs released at the American College of Cardiology Scientific Session--the VICTORIA trial and the PARADIGM trial--included only 20%-to-24% women. A study released earlier this year found that in 740 completed cardiovascular trials from 2010 to 2017, women made up only 38.2% of the more than 860,000 participants.

Gender disparities also persist in research related to mechanical circulatory support. In an analysis of the Intermacs Registry, which collected data in thousands of patients who were implanted with devices, women had increased risk for neurological complications, including stroke. However, this trial was not designed to pick up these events, so it yielded no data on how covariables, such as blood pressure or anticoagulation, played a role in this increased risk. The current recommendation is still to implant mechanical support devices in men and women equally while remaining mindful of the increased risk of neurological events in women.

How can we extrapolate the benefits of a clinical trial for women when they are underrepresented in the research? Compounding the problem, these studies typically don't examine gender differences or details such as how physiology impacts drug metabolization for the women who are included. So, in our medical practices, how can we be sure whether we can safely administer drugs or support devices to women if they were not included in appropriate numbers in a trial?

The reason why women are less likely to participate in trials is not well understood, but it's been hypothesized that men tend to take more risks and have more availability to participate. Women are often working full time and tend to be the caregivers for their families, which may hinder them from volunteering. Additionally, the majority of heart specialists are men, and questions arise about whether male investigators are more likely to approach men about participating in trials.

Gender differences matter and we must enroll more women in trials. We have enough data to show that we can't always use the same therapy in men and women and expect the same outcome. We need to break the barriers to enrolling women in clinical trials and even consider conducting separate trials specifically for women, so that we can truly get to the heart of the matter. 

Radha Gopalan, MD is the medical director for Advanced Heart Failure, Mechanical Circulatory Support and Heart Transplant at Banner – University Medicine Heart Institute.

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