Clinical practice is shaped by international guidelines that rely on randomised trials to inform recommendations where possible. However, a key challenge is the under-representation of women, both as participants and investigators, in the majority of these trials.¹ Figure 1, reproduced from Burgess et al,² illustrates the participation of women in cardiovascular (CV) trials relative to disease prevalence, revealing significant under-representation across most subspecialty areas. Furthermore, in clinical drug trials for acute coronary syndrome (ACS), coronary artery disease (CAD), and heart failure (HF) used for FDA approval, women accounted for only 24-28% of participants.³

Why does it matter that there are fewer females in clinical trials? 

Trial outcomes based predominantly on male participants introduce sex-related biases in the effectiveness of some treatments, leading to worse outcomes for many females.⁴ Potential differences may arise from significant variations in cardiovascular drug pharmacokinetics and pharmacodynamics between males and females.⁵ These differences include:

Absorption: Women have lower gastrointestinal motility and transit time, as well as fewer drug-metabolising enzymes and transporters, leading to reduced absorption rates

Distribution: Compared to men, women have lower body weight, reduced circulating blood volume, greater body fat, lower body water content, and lower cardiac output

Metabolism: Variations in hepatic influx transport and liver CYP enzyme activity impact drug metabolism

Excretion: Women have lower renal blood flow, slower clearance of renally excreted drugs and a longer elimination half-life.

For example, the same dose of ACE inhibitors (ACEi) or angiotensin receptor blockers (ARB) can result in up to 2.5 times higher plasma drug levels in females compared to males.⁶ This may contribute to the fact that women experience twice as many adverse drug reactions to CV medications. 

A recent study⁷ published in The Lancet demonstrated that women with heart failure with reduced ejection fraction (HFrEF) require lower doses of ACEi, ARB, and beta-blockers (BB) compared to men to achieve optimal cardiovascular risk reduction. The study found “In men, the lowest hazards of death or hospitalisation for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and beta blockers, but women showed approximately 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels.”

Similarly in interventional trials, the anatomy in women and men differs significantly. Extrapolation of techniques and results from trials enrolling largely men cause bias in effectiveness, which is then transferred to routine clinical practice. For example, in mitral valve regurgitation intervention, females have different morphological changes in the mitral valve apparatus, such as a larger corrected mitral annulus circumference and higher levels of annular calcification which can negatively affect outcomes of transcatheter edge-to-edge repair.⁸

Beyond biased treatments resulting from the under-representation of women in clinical trials, several additional factors may contribute to the disparities in outcomes among women. These factors include differences in socio-economic status, higher levels of depression and anxiety, financial barriers and behavioural differences, such as lower physical activity levels and risk aversion when considering trial participation. 

Screening for non-traditional CVD risk factors which includes a history of adverse pregnancy outcomes (including hypertensive disorders of pregnancy, gestational diabetes, pre-term labour, pregnancy loss) and premature menarche or menopause⁹ is recommended to up-classify cardiovascular risk, but is yet to be routinely implemented. 

Disparities in management of primary prevention of CVD using already established risk scores have also been highlighted over the last decade. Women are less likely to be managed appropriately with statin therapy or antihypertensive treatment. 

Ischaemic heart disease

Ischaemic heart disease (IHD), has historically been thought of as a disease that typically affects men. However, more women than men die from ischaemic heart disease in the developed world.^10,11 The risk of  acute coronary syndrome (ACS) for younger women is also increasing, which is not the case for any of the other age categories. 

A French study looking at the presentation of younger women with ACS demonstrated that the majority of women (92%) had chest pain; 60% had associated symptoms; and 10.5% had symptoms lasting longer than a week.¹² This study also reported that a third of women had a history of pregnancy complication, more than half a recent emotional stress and a large proportion (86%) were on an oestrogen containing contraceptive. These non-traditional female-specific risk factors may not be routinely asked about as part of the medical history. 

Historically, women have been described as experiencing more atypical symptoms of acute coronary syndrome (ACS). However, current ACS guidelines¹³ advise against using the term  ‘atypical’, as men and women share many common symptoms, and its use may contribute to treatment delays. Additionally, women are more likely to delay seeking medical assistance, which may lead to a reduction in the decision to proceed to coronary angiogram and/or angioplasty, which affects appropriate diagnosis and treatment.¹⁴

When women do present for care, the diagnostic threshold for ST-elevation myocardial infarction (STEMI) differs (≥ 1.5mm in women compared to ≥ 2mm in men over 40 years or ≥ 2.5mm in men under 40 years in leads V2-3). These more subtle ECG changes may be overlooked in women. Furthermore, the typically higher troponin elevations observed in men can obscure ACS diagnosis and treatment in women. This results in a longer ‘door to needle’ and ‘door to balloon’ time.¹⁵

Angiography can be more technically challenging in women, particularly in older women, due to more difficult arterial access and smaller coronary arteries. These factors may lead to treatment delays and worse outcomes. For patients requiring surgical revascularisation with CABG, a recent meta-analysis found women were more likely to have graft failure and an 84% higher risk of death.¹⁶ Raising awareness of delays in presentation, decision making and treatment, both among patients as well as healthcare professionals, is important to improve outcome differences.

Heart failure 

The aetiology of heart failure (HF) is often different between men and women. HFpEF affects women twice as much as men, and the pathophysiology is thought to be predominantly due to endothelial inflammation and coronary microvascular dysfunction.⁶

Recent work from the STOP-HF group in those at risk but yet to develop symptoms of HF also demonstrates that higher levels of cardiovascular stiffness and resistance is associated with higher observed rates of women developing HFpEF.^17,18 Women with HF tend to be more comorbid, more symptomatic and have a lower quality of life. 

The associated comorbidities also affect the risk of HF to a higher degree in women compared to men. For example, a woman with diabetes is five times more likely to develop HF than if they did not have diabetes, whereas the risk of diabetes increases a male’s risk by only two-fold.⁶ Men are more likely to be younger, to develop HFrEF and have myocardial ischaemia as the predominant risk factor, which leads to a macrovascular pathology involving myocyte necrosis and scar formation. 

Other important sex-specific risk factors are that men are more likely to have alcohol and illicit drug use as exposures, and in those with inherited cardiomyopathies, genetic penetrance is often more severe in men. Women have additional HF risk factors which include breast cancer treatments and hypertensive or metabolic disorders during pregnancy.

Atrial fibrillation

Men in general have a higher incidence of atrial fibrillation (AF) compared to women, but because women outlive men, the overall prevalence of AF is higher in women.¹⁹ The presentation of AF in women is very different compared to men, and outcomes are worse (although this might be obscured due to the higher age and comorbidity of women who have AF). 

Women are also more likely to have HFpEF, be more symptomatic and have a worse quality of life.²⁰ Despite being more symptomatic, women are less likely to have an AF ablation, even though anti-arrhythmic drug therapy seems to be more pro-arrhythmic in women.²⁰ This may be reflected in the differences in pharmacology of being older and female. 

Future directions

In 2024, The Irish Department of Health launched a Women’s Health Action Plan 2024-2025 (phase 2). This focuses on women’s views, investment (women’s health fund) and delivery of improvements in services for women’s health, especially cardiovascular health for women at midlife and older.²¹ This governmental initiative, which prioritises the patients’ voice, as well as involving experts with strong track records of service implementation, aims to reduce the disparity in cardiovascular outcomes in women. 

Another progressive initiative due to be implemented in 2025 is to include referrals for women with sex-specific cardiovascular risk factors, such as gestational hypertension or early menopause, to the STOP-HF unit at St Michael’s Hospital in Dublin. This highlights the commitment on the ground by cardiovascular healthcare professionals to enhance cardiovascular care for women. 

The service focuses on screening and optimising risk factors in individuals at higher risk of developing heart failure, while also increasing awareness among both patients and healthcare providers about the significance of sex-specific risk factors and improving preventive therapies for women.

Healthcare professionals involved in daily cardiovascular care can enhance treatment for women by recognising differences in presentation, treatment and management of cardiovascular conditions. Strengthening the evidence for CVD treatment in women also requires greater participation of women in clinical trials; not only as patients but also by increasing the representation of female researchers,⁴ investigators,^22,23 and leaders in clinical and guideline committees.²⁴

A note on language of this article: Female and women are used relatively interchangeably in this article as many studies use self-reported gender rather than sex. This article intends to describe all those who identify as women as well as those who share female biological realities and experiences.  

References

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