by Gurkiran Dhuga&Glen Pyle

The fight for equality between the sexes has undoubtedly made significant advances recently. But a new meta-analysis examining sex differences in treatment for cardiovascular risk factors presents a depressing snapshot of the current state of medicine. In fact, it suggests that in order to make progress, we may need to go all the way back to the beginning. Back to primary care.

A Primary Deficiency

Researchers from the University of Oxford conducted a systematic review of 43 observational studies involving over 2.2 million patients in primary care settings. The data were examined for sex differences in the prescription of cardiovascular medications by primary care professionals. Researchers specifically looked at the rates of prescription for aspirin, statins, and common classes of antihypertensive medications including beta blockers, calcium channel blockers, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. All participants in the studies either had cardiovascular disease or were at high risk of developing cardiovascular disease and were guided by a primary care physician to help manage risk.

Across all studies the percent of women prescribed aspirin, statins, or antihypertensive medications were 41%, 60%, and 68%, respectively. In males, 56% were prescribed aspirin and 63% a statin, both of which were significantly higher than females. Of some additional concern, not only was there a sex difference in the prescription of statins, but the difference increased from 2000 to 2019. Women also had significant lower prescription rates for antihypertensive medications like beta-blockers and ACE inhibitors (ACEi) but were 27% more likely to be prescribed diuretics. Overall, this meta-analysis found significant sex differences in the prescription of cardiovascular medications in primary care, with women generally receiving less treatment than men.

Sex is Complicated

The significant differences in cardiovascular medication prescriptions begs the question of why are women less likely to be prescribed treatment to manage cardiovascular disease risks? One possible explanation is that women and men have different risk factors for cardiovascular disease. In the US, 7.2% of men have coronary artery disease (CAD) compared to only 4.2% of females. The higher rate of coronary artery disease may explain why men have higher rates of statin prescriptions. However, in the meta-analysis the mean age of participants from the various studies ranged from 51 to 76 years old. While women do experience lower rates of CAD prior to menopause, the difference narrows considerable after menopause. The average age of menopause is 51 years, meaning that the majority of women in the studies would have been post-menopausal and the risk for CAD would approach equality between the sexes.

Differences in disease rates cannot explain the discrepancy in antihypertensive treatments. Although the prevalence of hypertension in both sexes varies by age it is relatively similar overall with women accounting for 51% of hypertension patients. Before menopause women tend to have lower rates, but after menopause the risk doubles in women, and beyond age 65 women have higher rates of hypertension than age-matched men. Again, based on the participant ages in the studies, it is expected that risk for hypertension would not be lower in women.

Treatment Responses

Along with divergent comorbidities another possible explanation for the sex differences in prescription rates is that men and women have different responses to cardiovascular medications. For example, women experience more adverse side effects than men with the use of calcium channel blockers and ACEi. Furthermore, statin prescription could be low in women as female sex is a risk factor for the development of statin-associated muscle symptoms. Thus, sometimes women are prescribed ezetimibe, which can be used in place of statins. These side effects may explain why women have lower prescription rates for these classes of treatment.

By the Book

While there are potential explanations for why prescription rates and patterns for cardiovascular conditions are different between the sexes, left unanswered is whether these differences are clinically justifiable. Recently, a summary of recommendations for the prevention of cardiovascular disease in women was released. This guideline review lead by Dr. Leslie Cho from the Cleveland Clinic Foundation notes a variety of factors that may drive sex differences in treatment decisions, such as sex disparities in effectiveness, adverse reactions to medications, and sex-specific comorbidities like polycystic ovary syndrome. Even with these sex-specific elements, the authors recommend guidelines for statin therapy, aspirin use, and hypertension treatment that are largely the same for men and women, which suggests that the findings of large sex differences in prescription rates are problematic.

Why are primary care physicians less likely to follow guidelines and recommend statins, aspirin, and hypertensive treatments at similar rates for both sexes? One obstacle may be that current education on sex differences for cardiovascular disease is ineffective. Only 22% of primary care clinicians feel they are capable of assessing a women’s risk of cardiovascular disease. A significant reason for this uncertainty is that many clinical studies on cardiovascular disease have an underrepresentation of women, which results in less knowledge of the effects of cardiovascular medication on women. The knowledge gap fails to provide healthcare professionals with a solid body of evidence on which to base their decisions.

Back to the Future

The trend of lower levels of cardiovascular medication prescriptions for women is concerning, especially considering that preventative treatments such as aspirin are widely recommended for a variety of conditions including coronary heart disease, peripheral artery disease, and stroke for both sexes.

The systematic review by Oxford University researchers adds to the increasing number of studies showing that treatment of women for cardiovascular disease fails to follow guidelines. Unfortunately, the research provides no clear consensus as to whether sex differences in prescription rates are justified or disadvantageous. In order to gain further insight into this topic there must be an increase in the inclusion of women in clinical trials and more research on the sex differences of cardiovascular diseases and medications, including the impact on outcomes.

Gurkiran Dhuga is a student of Biomedical Sciences at the University of Guelph and an Undergraduate Research Assistant.

W. Glen Pyle is a Professor of Biomedical Sciences at the University of Guelph and an Associate Member of the IMPART Investigator Team Canada Network at Dalhousie Medicine. He is currently a Heart and Stroke Foundation of Canada Senior Career Investigator for Improving the Heart and Brain Health for Women in Canada.