Females’ historical underrepresentation in clinical trials, particularly studies of heart disease, is nearly as well recognized as the glass ceiling that’s traditionally kept women down in the business world. In response, Congress passed a law in the 1990s mandating that clinical trials be designed and conducted to allow analysis of whether the variables being studied affect women and men differently.
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Despite progress, women still being left out
Now a recent report from the federal Government Accountability Office (GAO) finds that the law has had mixed results. While NIH data show that more women than men were enrolled in NIH-funded clinical trials during 2005-2014, the report also notes that the NIH:
- Is limited in its ability to identify whether women are sufficiently represented in studies in specific areas (the report cites cardiovascular disease as an example).
- Does not track whether analysis of study outcomes by gender are planned or conducted.
“This is a disservice to women,” says Leslie Cho, MD, Director of the Women’s Cardiovascular Center at Cleveland Clinic. “We’ve extrapolated male data to females forever, yet we know there are fundamental differences in cardiac metabolism, bleeding and platelet aggregation. That’s why gender research is so important.”
The NIH is not alone in failing to take research in women seriously. Females represent only 25 to 30 percent of subjects in pharmaceutical trials, leaving a large knowledge gap in understanding how medications may affect women differently than men. “Women should be part of drug studies before the drugs are released,” says Dr. Cho.
How one center is taking up the challenge
As an academic medical center with a strong research emphasis and a long-standing cardiovascular information registry containing details on every cardiovascular patient it has treated since the late 1960s, Cleveland Clinic is uniquely positioned to conduct gender-based heart research.
The staff is also motivated. “My colleagues understand there are differences between men’s and women’s hearts,” notes Dr. Cho. “There’s a lot of interest in focusing on a gender-specific way to treat patients.”
This interest takes a number of forms. There are formal disease-specific programs that are designed for women or disproportionately attract female patients, providing fertile ground for research. These include programs for:
Additionally, Cleveland Clinic’s large volume of cardiovascular disease patients of both sexes enables researchers to evaluate how common diseases may affect men and women differently and determine how these differences should be treated. Important findings have led to improved care for women undergoing coronary artery bypass grafting and valve replacement, among other examples.
ICDs: Despite superior results, underused in women
One of the latest examples involves research from Cleveland Clinic electrophysiologist Niraj Varma, MD, PhD, that may shape how heart failure in women is treated.
Dr. Varma presented his newest findings as a late-breaking trial at the European Heart Rhythm Association’s EUROPACE-CARDIOSTIM 2015 meeting. In a database analysis of 270,000 U.S. patients who received various types of implantable cardiac devices (ICDs), he found that women receive fewer ICDs than men, yet those women who do receive a device fare as well as or better than men do. Moreover, women treated with cardiac resynchronization therapy (CRT) survive about 30 percent longer do than men who undergo CRT.
“It’s astounding,” says Dr. Varma. “These issues haven’t been examined properly because trials have enrolled few women.”
Dr. Varma is committed to closing these knowledge gaps through a series of related studies as discussed in this recent Consult QD post. One example, published in Heart Rhythm, is a 10-year analysis of Cleveland Clinic’s database to examine the effect of CRT in heart failure patients with left bundle branch block (LBBB) and nonischemic cardiomyopathy. Response to therapy was significantly better in women than in men — particularly among patients with QRS duration less than 150 msec.
“Current guidelines for CRT give a class IIa indication to LBBB patients with QRS duration of 120 to 149 msec,” Dr. Varma observes. “But our new data suggest the indication should be changed to class I for women to ensure that those who qualify are offered treatment.”
Gender and the ‘weight survival paradox’ in HF
Another area of active inquiry at Cleveland Clinic — one led by Dr. Cho — is how gender affects the impact of excess adiposity on survival in heart failure. Dr. Cho wondered whether females’ established survival advantage in heart failure might be related to overlap between two distinct concepts:
- The recently recognized association between extra weight and equal or improved survival in patients with a low ejection fraction (“overweight/obesity survival paradox”)
- The fact that women’s hearts utilize more fatty acids and less glucose compared with men’s hearts
To test the hypothesis, she led a review of 3,811 patients with advanced heart failure treated at Cleveland Clinic to determine the effect of BMI on mortality in both sexes. As reported in JACC Heart Failure and detailed in this recent Consult QD post, the analysis showed an overall weight survival paradox across the cohort, but this was attenuated by adjusting for confounding variables — except among overweight females. After adjustment, overweight and obese males had higher mortality than did normal-weight males, whereas overweight females (but not obese females) still retained a significant survival advantage over normal-weight females.
“A more favorable response to modest excess adiposity among females may partially explain these differing survival findings,” notes Dr. Cho.
More gender-specific studies needed (and underway)
In view of the new GAO report on women in health research, Cleveland Clinic’s Miller Family Heart & Vascular Institute is more committed than ever to exploring gender-related issues, starting with basic physiology. Among the work already underway is an investigation using echocardiography to identify differences in torsion that affect how women’s hearts contract and a study using MRI to see if gender-related differences in heart size may be a factor in heart failure activation.