Making the Case for Sex-Specific CVD Guidelines

A preponderance of evidence showing differences between men and women in CVD risk factors, response to treatment, and outcomes provides a compelling argument for moving toward sex-specific guidelines, the authors of a new paper contend.

“There's copious literature demonstrating that women have been underrepresented in trials in all areas of cardiology, whether that be heart failure, or interventional cardiology, or lipid-lowering therapy,” said Ersilia M. DeFilippis, MD (Columbia University Irving Medical Center, New York, NY), who co-authored the viewpoint with Harriette Van Spall, MD (McMaster University/Population Health Research Institute, Hamilton, Canada). While strides have been made in awareness of sex-specific differences and in increasing diversity in clinical trials, DeFilippis said it’s clear that there’s still a long way to go to get to a point where sex-specific recommendations, or sex-specific levels of evidence, become routinely discussed when looking at evidence in support of guidelines or position statements for CV-related conditions.

“We wanted to raise the point that there are certain areas where the differences in response by sex have been consistently demonstrated,” DeFilippis told TCTMD. One example is in heart failure with preserved ejection fraction, where the PARAGON-HF trial, though negative overall, found significantly lower rates of the primary composite outcome of first and recurrent HF hospitalizations and CV death with sacubitril/valsartan (Entresto; Novartis) versus valsartan alone in women but not men. Other data support the concept of sex-LVEF interactions in neurohormonal blockade where the upper LVEF threshold of benefit is higher in women than men.

“It is really important to make room in the guideline process for considering sex-specific data. We recognize that the level of evidence may not be of the highest class and there may be limitations to the data available,” DeFilippis said. “Still, whether it's coronary artery disease or heart failure, there should at least be some consideration by the [guideline] committee whether the level of evidence proposed should be modified depending on patient sex.”

In their paper, published this week in the Journal of the American College of Cardiology, DeFilippis and Van Spall urge the cardiology community to move toward assessing “plausible pathophysiologic differences between the sexes in the disease for which the guidelines are being considered.” If sex-specific factors are known to be involved in a given disease’s incidence or treatment response, they say, the evidence should be rigorously assessed with an eye toward adequate representation of women and inclusion of disaggregated data for men and women.

“We’re not saying that for each specific therapy and for each recommendation there's going to be a difference by sex,” DeFilippis said. “However, when we think about sex-specific data about digoxin or [cardiac resynchronization therapy] in the case of heart failure, maybe there should be.” She and Van Spall say that looking at things like neurohormonal blockade and dose tolerance separately in women and men represents a path toward informing and tailoring pharmacotherapy management better than a traditional “one-size-fits-all drug-dosing regimen.”

Patient-Centered Consent

A main stumbling block to good women-centric evidence is the underrepresentation of female patients in clinical trials, DeFilippis and Van Spall note. However, there is a laundry list of other deficits as well, such as lack of information-gathering on comorbidities unique to women that may influence their disease (ie, pregnancy-related disorders, polycystic ovary syndrome, and premature menopause, among others), lack of testing for sex-effect modification of therapies, and lack of reporting on adverse effects by sex. Data on differences in biology,  pharmacokinetics, pharmacodynamics, and psychosocial factors, they add, need to be assessed within the context of available evidence.

DeFilippis and Van Spall say some solutions for increasing the representation of women in trials include only using sex-specific eligibility criteria when it can be clearly justified, enrolling only women once a sufficient sample size of men has been reached, and increasing diversity among the clinical trial investigators. “We know that when we have more women in clinical trial leadership that more women are enrolled in the trials,” DeFilippis observed.

She and Van Spall add that patient-centered consent also may be a key to boosting female trial enrollment by ensuring that women “better understand the risks and benefits of trial participation, and remote follow-up processes may help them juggle the demands of caregiver responsibilities that can sometimes be a barrier to trial participation.”

Ultimately, DeFilippis said the primary concern for guideline or position statement committees should be to “think about the population of people who have the disease that the guideline is representing.” Even if preliminary sex-specific guidelines do not have the highest level of evidence that committees typically expect, she added, they may serve to highlight areas of further study and cause the guideline writers to lean into the evidence in subsequent iterations as emerging data allow.