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Acute coronary syndromes
Gender differences in coronary heart disease
  1. Ramzi Y Khamis1,2,
  2. Tareq Ammari1,
  3. Ghada W Mikhail1
  1. 1National Heart and Lung Institute, Imperial College, London, UK
  2. 2Department of Cardiovascular Medicine, Imperial College Healthcare NHS Trust, London, UK
  1. Correspondence to Dr Ramzi Y Khamis, National Heart and Lung Institute, Hammersmith Hospital Campus, Imperial College London, London, W12 0HN, UK; r.khamis{at}imperial.ac.uk

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Learning objectives

  • 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 with 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.

Introduction

The importance of coronary heart disease (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 comorbidities. 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 while 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

Most data in the field of chronic stable angina (CSA) and gender have been extrapolated from substudies or registries, which all resulted in similar conclusions. Daly et al5 reported a significant gender bias in the use of investigations and medical therapy in stable angina and also described less revascularisation in women. This was echoed by the large prospeCtive observational 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, 1-year outcomes were the same between the genders, but this may be as a result of the short follow-up period.

Acute coronary syndromes

Most historical studies have shown that women with AMI have an unfavourable outcome compared with their male counterparts.4 ,7 Mortality rates after AMI have been shown to be higher among women than men, both in hospital and at 1 year.8 In addition, serious complications of AMI, such as cardiogenic shock, congestive cardiac failure and reinfarction 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 inhospital 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 among women than men, whereas in NSTEMI and unstable angina, mortality was lower among 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 acute coronary syndromes (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% vs 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 ( HR 0.98, 95% CI 0.83 to 1.15).12 While in contrast, a European analysis including 74 389 patients from the French nationwide hospitals database showed that a 30% excess in mortality persists among women even after age and comorbidities are taken into account.3

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 3000 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 twofold 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 multicentre 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 twofold to fourfold that of the general population. On the other hand, women had higher absolute mortality than men and a 6-fold to 14-fold risk of death compared with 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 comorbid factors that lead to adverse events.

Figure 1

The multiple factors responsible for the observed ‘worse outcomes’ for women suffering from acute myocardial infarction.

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 hospitalisation 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 clinical judgement when assessing coronary lesions with intravascular ultrasound or optical coherence tomography in female patients with ACS.

Physiological factors: pregnancy and 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 5 and 15 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 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 al23 found that hormone replacement therapy (HRT) in postmenopausal women does not reduce the risk of ischaemic heart disease. More recently, a hypothesis that early, rather than delayed, initiation of oestrogen therapy would be beneficial in preventing CHD was tested in the Women's 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 the current Food and Drug Administration guidelines and British guidelines that HRT should only be used for the short-term relief of postmenopausal 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 underappreciation 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.28 Analysis from one large registry demonstrated that age may play a part. Younger women tend to present with absence of chest pain and suffer worse outcomes in comparison with 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 among 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 the 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 3779 patients of which 42% were women.5 This showed that women were less likely to undergo an exercise ECG (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 1162 patients with angina 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 that there was an age bias but no gender bias in referral to cardiac catheterisation.32 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 and more likely to be treated with PCI.33 This age-dependent gender disparity persisted after adjustment of severity of disease, comorbidities and other relevant clinical characteristics.

Interestingly in another cohort study, which included 50 000 with ACS, it was suggested that undertreatment 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 ‘undertreatment’ 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 generalisable to women.38 Following this, a comprehensive gender analysis of the TAXUS trials was undertaken. ‘Taxus Woman’ included around 10 000 patients of whom >3000 were women. It concluded that despite their high-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 with BMS, there were reductions in both in-stent restenosis and 1-year MACE in men and women.40 This reduction, as excepted, was driven by a lower incidence of target lesion revascularisation and target vessel 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 target lesion revascularisation (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 USA, 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 showed safety of DES in women and 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 intra-vascular ultrasound (IVUS)-based measures of both ‘culprit’ and non-culprit’ lesions are different in both genders.45 One study suggested that thin-cap fibroatheroma is 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 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, among 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 cross-over was significantly higher among 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) trial50 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 endpoint was the first occurrence of CHD, comprising fatal and non-fatal 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 which 6801 women were randomised to Rosuvastatin versus placebo, compared with 11 001 men.53 Statin treatment of apparently healthy women with elevated high sensitivity CRP (hsCRP) and non-elevated low-density lipoprotein (LDL) cholesterol resulted in similar and significant proportional reductions in CHD, when compared with men. There is little data on 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 LDL levels achieved.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 directions

Women 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, pharmacological therapies, as well as more education and awareness among women and physicians on the importance of CHD is needed.

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

  • Women may present late with ‘atypical symptoms’, which may delay investigations and treatment for coronary heart disease (CHD). There is a referral bias where women are less intensively investigated and treated than their male counterparts.

  • Women have worse outcomes from both chronic stable angina and acute coronary syndromes, which may be related to a worse comorbid profile as well as undertreatment when compared with men.

  • Women with CHD benefit as much from coronary intervention and drug-eluting stents, and should be treated as intensively as men.

  • 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.

  • 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.

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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 coronary disease in women

  • Gender-tailored management, eg, different biomarkers, drugs and optimised interventions

  • Research initiatives focusing on gender-specific study design

References

View Abstract

Footnotes

  • Contributors All authors have contributed to the writing, editing and revision of this Education in Heart article.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

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