Gender Differences in Coronary Heart

Disease

Ramzi Y Khamis, Tareq Ammari, Ghada W Mikhail.

Department of Cardiovascular Medicine. Imperial College Healthcare NHS Trust. London.

UK.

Curriculum Sections

2.8 (Acute Coronary Syndromes) and 2.9 (Chronic Ischaemic Heart disease).

Learning Objectives.

Outline the differences in the presentation patterns, clinical characteristics, behavioural

characteristics and clinical outcomes relating to gender and coronary heart disease (CHD).

This will incorporate the following:

Knowledge: Understand the benefit of cardiovascular interventions in women in comparison

to men in both the acute and chronic presentations of CHD. Delineate the data reflecting the

need for more research into women and heart disease, coupled with more patient, and

physician education.

Skills: Learn the presentation patterns and gender-specific issues related to patients

presenting with CHD.

Behaviours and Attitudes: Discuss The Preconceived Ideas Around Gender And Heart

Disease, Emphasising The Need For Enhanced Assessment Of Women With Heart Disease.

Keywords: Gender, Coronary Heart Disease, and Women.

1

Introduction

The importance of CHD as a disease of both genders tends to be underappreciated, although

in 2014 CHD claimed almost three times more lives than breast cancer. Just below one in five

male deaths and one in ten female deaths were attributed to CHD. The British Heart

Foundation’s report in that same year states that CHD by itself is the biggest single cause of

death in the UK [1].

In general, women with CHD have worse outcomes than their male counterparts when no

adjustments are made for other characteristics and co-morbidities. Women tend to present

with coronary artery disease later in life, and even when they present young they tend to

receive less evidence based treatment than their male counterparts [2].

An important question is whether gender per se predisposes to higher cardiovascular risk.

Much of the research in this field has been in the setting of acute myocardial infarction (AMI)

with conflicting evidence from different studies. Some studies reported that gender is an

independent risk factor for worse outcomes [3] whilst others attributed the increased risk to

other characteristics, some of which may be gender related, such as vessel size [4].

The goal of this review is to highlight the differences in CHD outcomes between genders in

both the acute and chronic settings. It will also explore major factors that may lead to these

differences in particular pathological, physiological, presentation patterns, differences in

diagnosis and management as well as benefit gained from pharmacological therapies and

interventional procedures.

Differences in Outcomes: Is gender an independent prognostic factor of

worse clinical outcomes in CHD?

This section will explore the differences in outcomes between men and women focusing on

the common clinical scenarios, where gender is considered to be a possible prognostic factor

Chronic Stable Angina (CSA)

Most data in the field of CSA and gender has been extrapolated from sub-studies or registries,

which all resulted in similar conclusions. Daly et al. reported a significant gender bias in the

use of investigations and medical therapy in stable angina and also described less

revascularisation in women [5]. This was echoed by the large prospeCtive observational

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LongitudinAl RegIstry oF patients with stable coronary arterY disease (CLARIFY) study that

reported in 2012 that women with CSA were more likely to be older, have hypertension and

diabetes [6]. Lower rates of revascularisation were also noted in women. Interestingly one-

year outcomes were the same between the genders but this may be as a result of the short

follow up period.

Acute Coronary Syndromes (ACS)

Most historical studies have shown that women with AMI have an unfavourable outcome

compared to their male counterparts [4, 7]. Mortality rates after AMI have been shown to be

higher amongst women than men both in-hospital and at one year [8]. In addition, serious

complications of AMI, such as cardiogenic shock, congestive cardiac failure, and re-

infarction are more frequent in women [9]. Increased risk appears to be highest in young

women, whose in-hospital mortality is almost twice that of men. In a study from Newcastle,

although women presenting with AMI were more likely to present in cardiogenic shock

(11.6% vs 8.3%, p = 0.01) and were older (69.9 years vs 64.2 years, p = 0.02), there was no

gender difference in in-hospital mortality [10].

The type of presentation, whether ST elevation myocardial infarction (STEMI) or Non-ST

elevation myocardial infarction (NSTEMI), also has an impact on gender-based outcomes. A

large database analysis of nearly 140,000 patients presenting with both STEMI and NSTEMI

demonstrated that the overall 30-day mortality in women was almost double that of men [11].

However, this difference did not survive the multivariate analysis model. Interestingly, the

mode of presentation affected the differences in mortality. In STEMI, 30-day mortality was

higher amongst women than men whereas in NSTEMI and unstable angina, mortality was

lower amongst women. This adds to the question of whether women are treated as well as

men when presenting with STEMI [11].

A large American study attempted to answer the question on gender inequality in ACS.

TRANSLATE-ACS (Treatment with ADP Receptor Inhibitors: Longitudinal Assessment of

Treatment Patterns and Events after Acute Coronary Syndrome) concluded that women

presenting with AMI had higher unadjusted cumulative incidence of 1-year major adverse

cardiac events (MACE) than men (15.7% versus 13.6%, P=0.02). One-year MACE included

composite of all‐cause death, MI, stroke, or unplanned revascularisation. However, Female

sex was no longer associated with higher incidence of MACE after multivariable adjustment

(hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.83 to 1.15) [12]. Whilst in contrast, a

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European analysis including 74,389 patients from the French Nationwide Hospitals Database

showed that a 30% mortality excess persists amongst women even after age and co-

morbidities are taken into account [3]Error: Reference source not found.

Schiele et al undertook a propensity score-matched analysis study of the effects of clinical

characteristics and treatments on gender difference in outcomes after AMI. This included

more than 3,000 patients from France, a third of whom were women. The study concluded

that women admitted with AMI received fewer effective treatments, as defined by the study,

and have a 2-fold higher 30-day mortality. When adjusting for both baseline characteristics

and treatment (medical treatment, angiography and reperfusion) there was a similar in-

hospital and 30-day mortality between genders, suggesting that a higher use of invasive

procedures and reperfusion strategy could reduce the difference in mortality [13]. A large

multi-centre registry from Poland also showed similar results. It concluded that despite poor

baseline characteristics, less satisfactory management and a worse prognosis in women

undergoing STEMI, female gender by itself was not a risk factor for 12 month mortality [14].

To emphasise the gender inequality in AMI survival, data from Sweden showed that young

male survivors of AMI have low absolute long-term mortality rates, with these rates

remaining two fold to four fold that of the general population. On the other hand, women had

higher absolute mortality than men and a six to fourteen fold risk of death compared to that of

the general population [15]. This suggests that the gender imbalance still exists even in an

advanced Scandinavian healthcare model.

The factors that result in unadjusted worse outcomes for women are summarised in Figure 1.

However, as discussed above, most studies tend to point towards gender not being an

independent predictor of worse outcomes but is rather associated with the presence of co-

morbid factors that lead to adverse events.

Chest Pain With Unobstructed Coronary Arteries:

It was previously assumed that women who presented with chest pain but apparently

‘normal’ coronary arteries on catheterisation are at a lower risk of serious cardiovascular

events. The evidence suggests otherwise. A study comparing one cohort of women with

symptoms and signs suggestive of ischaemia but without obstructive coronary artery disease

with a second cohort of asymptomatic women demonstrated that symptomatic women with

unobstructed coronaries were at a significantly higher risk of myocardial infarction, stroke, or

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hospitalization for heart failure (7.9% vs 2.4% risk in asymptomatic women) [16]. This may

be explained by microvascular or endothelial dysfunction, a factor that has been a focus of

study [17].

Therefore it is clear that having symptoms without obstructed coronaries may need more

detailed investigation if they persist and almost certainly should prompt the physician to

address cardiovascular risk factors.

Gender- factors that may affect outcome in CHD.

This section will focus on specific pathological, physiological, clinical and management

factors that relate to CHD and have been highlighted in the literature to be different between

genders.

Pathological differences in ACS: Plaque erosion versus plaque rupture

Most AMIs are caused by thrombosis following plaque rupture. Plaque erosion is less

common and represents less than 50% of the pathology on autopsy studies. However, recent

data suggests that younger women have more plaque erosion and the ratio of rupture to

erosion increases with age [18]. The difference is significant, as ruptured plaques often

display expansive remodelling and have the characteristic properties of large necrotic core,

thin fibrous cap and foam cell infiltration. Plaque erosion, however, displays more negative

remodelling with the plaque rich in smooth muscle cells and proteoglycans. There are less

inflammatory components in eroded plaques, thus pointing to a somehow different

pathophysiological process[19]. This may challenge the classical definitions of plaque

vulnerability and therefore may impact on clinical judgement when assessing coronary

lesions with intravascular ultrasound (IVUS) or optical coherence tomography (OCT) in

female patients with ACS.

Physiological factors: Pregnancy and the menopause

Pregnancy is a unique risk factor for women. Pre-eclampsia in pregnancy may be an early

indicator of CHD risk. A large meta-analysis showed that women with pre-eclampsia have

twice the risk of CHD between five and fifteen years following pregnancy. Thus, it is

appropriate to follow up women who have suffered from pre-eclampsia for CHD risk factor

management [20]. Furthermore, spontaneous coronary artery dissection in pregnant women

represents an uncommon but devastating event in usually fit and healthy women [21]. There

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are postulated hormonal and physiological factors that may lead to dissection in pregnancy

including increased cardiac output, arterial sheer stress, alterations in collagen biology, as

well as increased hormonal levels.

The effect of menopause on CHD risk remains uncertain. In the Study of Women’s Health

across the Nation (SWAN) analysis [22], some risk factors such as total cholesterol were

driven by ovarian ageing whereas others were driven by chronological ageing emphasising

the need for a ‘tailored’ risk stratification strategy.

Following extensive review of evidence, Banks et al found that hormone replacement therapy

(HRT) in post-menopausal women does not reduce the risk of ischaemic heart disease (IHD)

[23]. More recently, a hypothesis that early rather than delayed initiation of oestrogen therapy

would be beneficial in preventing CHD was tested in the Women Health Initiative study [24].

The conclusion was that there was no positive effect on CHD risk from starting early

oestrogen therapy. This is in line with current Food and Drug Administration and British

guidelines that HRT should only be used for the short term relief of post-menopausal

symptoms [23].

Differences in presentation:

The symptomatic conundrum in women and the delay in seeking help in both stable

angina and ACS.

Women present with different symptoms than men. Commonly, in the chronic situation,

symptoms that women describe are often referred to as ‘atypical’, which may lead to the

under appreciation of risk associated with this presentation [25]. In ACS, a typical

presentation for a man tends to be chest or arm pain. Although most women present in a

similar fashion, they are more likely to present with less well-defined symptoms and without

chest pain [26]. ‘Atypical’ symptoms commonly include stomach pain, breathlessness as well

as constitutional symptoms such as nausea and fatigue [27].

This ‘symptomatic conundrum’ which may lead to missing important coronary disease, may

also lead to late presentation in STEMI which in turn delays effective reperfusion therapy

including primary percutaneous coronary intervention (PPCI) [28]. Analysis from one large

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registry demonstrated that age may play a part. Younger women tend to present with absence

of chest pain and suffer worse outcomes in comparison to their male counterparts. But, this is

attenuated by age with the difference between genders in the absence of chest pain narrowing

or disappearing as age advances [29].

Some of the delay in presentation can be partly explained by a relative lack of awareness

amongst women about the importance of CHD and the importance of urgent care. A detailed

descriptive behavioural study that investigated 53 American women presenting with AMI

found that a large proportion of the women in this study managed their symptoms by either

attributing them to an alternative cause, or by minimising their importance [30]. The other

key factor that contributes to either delay or lack of presentation is the recently demonstrated

underestimation of own cardiovascular risk. The Berlin Female Risk Evaluation (BEFRI)

Study, a randomised cross-sectional study elegantly demonstrated that less than half of urban

women correctly estimate their cardiovascular risk mainly attributed to age being the

strongest predictor of risk underestimation [31].

Thus the suggestion that women tend to present later than men, and with different symptoms,

sacrificing the valuable prognostic benefit of presenting early is important and should be

considered when assessing women presenting with chest pain and other ‘atypical’ symptoms.

Differences in diagnosis and management:

The ‘gender gap’ in the diagnosis and clinical management of patients presenting with

‘chest pain’.

There is increasing evidence that women presenting with chest pain are not as thoroughly

investigated as men. Registry data from the Euro Heart Survey in the management and

clinical outcomes of stable angina investigated 3,779 patients of which 42% were women

[5]Error: Reference source not found. This showed that women were less likely to undergo an

exercise ECG ( odds ratio [OR] 0.81; 95% CI 0.69 to 0.95) and less likely to be referred for

coronary angiography (OR 0.59; 95% CI, 0.48 to 0.72). A cross-sectional survey of 1,162

angina patients in Liverpool showed there was a gender-based hierarchy. General

practitioners were more likely to note the risk factors in male patients and refer them for

specialist investigation [25].

However, an Italian study investigating the use of cardiac procedures in relation to age and

sex found there was an age bias but no gender bias in referral to cardiac catheterisation

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[32]Error: Reference source not found. Although this may not be the case for older women, a

report from the Euro Heart Survey revealed that women above 60 years of age were less

likely than men to be treated with coronary artery bypass grafting (CABG) and more likely to

be treated with PCI [33]. This age-dependant gender disparity persisted after adjustment of

severity of disease, co-morbidities and other relevant clinical characteristics.

Interestingly in another cohort study, which included 50,000 with ACS, it was suggested that

under-treatment leading to morbidity may not be of significant importance [34]. The study

concluded that although women are less intensively treated, they have better long-term

outcomes than men after adjustment for differences in background characteristics. Thus, the

impact of the ‘under-treatment’ in ACS remains unclear. This will be partly addressed in the

outcomes section by discussing whether women benefit as much as men from coronary

intervention.

Recent work conducted in Edinburgh showed that the use of a high-sensitivity troponin assay

is better at diagnosing women with ACS than the standard assay. This may well be due to the

use of a ‘normal’ threshold that is too high for women. Therefore future direction of having

thresholds that are different for women and men using high-sensitivity assays are underway

and may improve the clinical diagnosis of ACS in women [35].

Coronary Intervention

Early studies suggested that women might not benefit as much as men from bare metal stent

(BMS) implantation[36]. Extensive registry data from the American National Heart, Lung

and Blood institute demonstrated that the use of drug eluting stents (DES) in both men and

women is safe and beneficial [37]. The TAXUS IV study suggested that safety and benefits

of the paclitaxel eluting stent (PES) in reducing clinical and angiographic restenosis are

generalizable to women [38]. Following this, a comprehensive gender analysis of the TAXUS

trials was undertaken. ‘Taxus Woman’ included around 10,000 patients of whom >3,000

were women. It concluded that despite their higher risk profile, women have comparable

benefits to men from PCI with PES except for a slightly higher revascularisation rate in the

high-risk cohort [39].

When studying sirolimus eluting stents (SES), when compared to BMS, there were reductions

in both in-stent restenosis and one-year MACE in men and women [40]. This reduction, as

excepted, was driven by a lower incidence of target lesion revascularisation and target vessel

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revascularisation in both genders. Furthermore, female gender was not found to be an

independent predictor of negative outcome in multivariate analyses.

Data from ‘second generation’ DES use is now emerging. In the Clinical Evaluation of the

XIENCE V Everolimus-Eluting Coronary Stent System in the Treatment of Patients With De

Novo Coronary Artery Lesions (SPIRIT) Women study, which was the first prospective

analysis of an‘ all-comers’ female population with a considerably high patient and lesion risk

profile, the Xience V stent was shown to be safe and effective [41]. There was a low rate of

TLR (2.4%) and stent thrombosis (0.59%), which is consistent with the data shown in

previous all comer studies containing both male and female patients.

Furthermore, a large analysis from the USAError: Reference source not found including

nearly 23,000 subjects has demonstrated that in the modern era of stenting, differences in

mortality and MACE between men and women no longer exist after coronary angioplasty.

There was a persistence of risk in other more minor complications, leading to the conclusion

that technological advances have not completely eliminated the gender gap, but narrowed it

significantly [42].

The safety of DES in women was further confirmed in a pooled analysis of 11,557 female

patients from 26 randomised trials. This not only showed safety of DES in women, but also

confirmed that newer generation DES have a more favourable safety profile than early DES

and thus should be the treatment of choice in women [43].

As interventional techniques are being developed, new gender gaps are appearing. A recent

study from the Mayo Clinic demonstrated that long-term outcome differs between women

and men undergoing fractional flow reserve (FFR) guided intervention. There was a clear

signal that women suffered more events whether they were treated medically or with PCI as

per FFR guidance [44]. There is also a suggestion that IVUS-based measures of both ‘culprit’

and non-culprit’ lesions is different in both genders[45]. One study suggested that thin-cap

fibroatheromas (TCFA) are a stronger marker of plaque vulnerability in women than men

[46]. This suggests the need for future gender-based approaches when determining

physiology or imaging based cut-off values in interventional cardiology.

Another example of a significant advance in interventional techniques that may narrow the

gap further is radial access, which may improve outcomes, as bleeding risk seems to be a

major aspect of female gender-specific risk. However, SAFE-PCI for Women (Study of

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Access Site for Enhancement of PCI for Women) showed no significant difference in the

primary efficacy endpoint of Academic Research Consortium type two, three, or five

bleeding or vascular complications between radial or femoral access in women requiring

intervention [47]. However, amongst women undergoing cardiac catheterisation or PCI,

radial access significantly reduced bleeding and vascular complications (0.6% vs. 1.7%; OR:

0.32; 95% CI: 0.12 to 0.90). Access site crossover was significantly higher amongst women

assigned to radial access PCI cohort, but more women preferred radial access [47].

There is now a growing body of evidence that discrepancies seen in worse outcome for

women receiving stents in different circumstances are either no longer present or are

significantly reduced when correcting for confounders. As the area of interventional

cardiology evolves, gender-based strategies need to be considered. This would be important

to address when designing new trials for new stent technologies such as bioresorbable

scaffolds.

Pharmacological therapy: a focus on antiplatelet agents and statins

Women have been shown to have a different response to antiplatelet agents than men[48].

Despite the use of dual antiplatelet therapy in patients undergoing coronary angioplasty,

women tend to have a higher residual platelet activity than their male counterparts [49].

The Controlled Abciximab and Device Investigation to Lower Late Angioplasty

Complications (CADILLAC) trial [50] demonstrated that women have comparable outcomes

to men when using abciximab in the context of ACS. This was strengthened by the findings

of the EArly discharge after Stenting of coronarY arteries (EASY) trial which showed that

when using radial approach, maximal antiplatelet therapy including abciximab, female gender

does not convey more risk of bleeding than male gender. [51].

Statins on the other hand have historically been suggested to have a less significant effect on

the reduction of cardiovascular events in primary prevention trials in women. The

Management of Elevated cholesterol in the primary prevention  Group of Adult Japanese

(MEGA) study showed that the reduction in events was significant only in men (The primary

composite end point was the first occurrence of CHD, comprising fatal and nonfatal

myocardial infarction, cardiac and sudden death, coronary revascularisation, and angina)

[52]. This notion has recently been challenged for the first time by the JUPITER trial in

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which 6,801 women were randomised to Rosuvastatin versus placebo compared with 11,001

men [53]. Statin treatment of apparently healthy women with elevated hsCRP  and non-

elevated low density lipoprotein (LDL) cholesterol resulted in similar and

significant proportional reductions in CHD compared with men. There is little data in

secondary prevention, although recent IVUS-based study showed greater coronary

atherosclerosis regression in women compared with men when using high intensity statins,

particularly in the context of lower achieved LDL levels [54].

Behavioural and psychological factors.

Younger women have a significantly higher rate of depression following cardiac events [55].

This generally puts women in an overall higher risk category, as they suffer worse physical

and psychological outcomes. It is therefore important to pay special attention to the

psychological sequelae of CHD in women.

The prevalence of tobacco smoking in women is on the increase. This has been linked to

gender empowerment [56]. In developed countries, the female-to-male ratio in smoking

prevalence is higher than other countries, thus emphasising the need for targeted education of

younger women in rising economies.

Research, Education and Future directionsWomen have been under-represented in research trials, approximately no more than 30% of

study populations being female [57] . This recruitment bias leads to a gap in the evidence,

with most data extracted from post-hoc analyses of trials, and meta-analyses rather than

gender-based randomised control studies. There are however encouraging examples from the

Transcatheter aortic valve implantation (TAVI) field that can be followed, where both men

and women were sufficiently represented in interventional cardiovascular registries and trials

[58, 59].

A number of international initiatives and campaigns have been set up to address both the

educational and research void. These initiatives aim to enhance research in women and heart

disease, increase physician and allied health professional education into the subject, as well

as raise the public awareness of the extent of heart disease in women.

Future directions should include research programmes focused on studying factors that are

unique to women that may affect outcome. Development of gender-specific technologies,

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pharmacological therapies, as well as more education and awareness amongst women and

physicians on the importance of CHD is needed.

Summary box 1 details suggested future actions to tackle the gender disparity in CHD.

Conclusion:

Women presenting with symptoms suggestive of CHD need to be treated appropriately and as

‘aggressively’ as their male counterparts. Atypical presentation patterns should not detract the

physician from tackling the risk factors appropriately and arranging further investigation if

there is a high-risk index of suspicion. More attention should be given to younger women as

they may suffer significantly worse outcomes. The field is in urgent need of specifically

designed trials that focus on women, collecting more gender tailored data, and development

of further technologies and techniques that may further close the gender gap.

Key messages:

1) Women may present late with ‘atypical symptoms’, which may delay investigations and

treatment for CHD. There is a referral bias where women are less intensively investigated and

treated than their male counterparts.

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Summary Box 1. Future actions to tackle the gender gap

Public awareness campaigns

addressing late presentation in

women

Focus on women-

specific risk factors

Physician education on

presentation of coronnary disease in

women

Gender-tailored

management e.g. different biomarkers, drugs and optimised

interventions

Research initiatives

focussing on gender

specific study design

2) Women have worse outcomes from both CSA and ACS which may be related to a worse

co-morbid profile as well as under-treatment when compared to men.

3) Women with CHD benefit as much from coronary intervention and drug eluting stents and

should be treated as intensively as men.

4) There are special factors that are gender related such as pregnancy, the menopause,

response to platelets as well as psychological factors that need to be considered when

assessing and treating women with suspected CHD.

5) More gender-based diagnostic criteria and gender- specific treatment protocols may help in

the future management of women presenting with CHD in order to close the gender gap in

outcomes.

The Corresponding Author has the right to grant on behalf of all authors and does grant on

behalf of all authors, an exclusive license (or non-exclusive for government employees) on a

worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if

accepted) to be published in HEART editions and any other BMJPGL products to exploit all

subsidiary rights.

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