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Learning objectives
Explore the impact of sex on morbidity and mortality from acute coronary syndrome.
Explore sex-based differences in pathophysiology, presentation and diagnosis of acute coronary syndrome.
Identify sex-based disparities in evidence-based treatment guidelines.
Recognise the need for sex-based research in acute coronary syndrome.
Introduction
Since 1984, more women than men have died annually in the USA from cardiovascular disease (CVD).1 Women with coronary artery disease (CAD) have worse outcomes when no adjustments are made for other characteristics and co-morbidities.2 Acute coronary syndrome (ACS) is a subset of CAD, characterised by an abrupt onset of signs and symptoms of myocardial ischaemia. It is associated with rupture or erosion of an atherosclerotic plaque that results in either the partial or complete occlusion of the infarct-related artery. ACS requires rapid assessment, diagnosis and treatment to achieve optimal outcomes.
Enormous advances have been made in ACS management; however, significant sex-related disparities persist resulting in suboptimal treatment of women. This inconsistency continues to be significant even when education, income and site of care are taken into consideration.3 Although many reasons have been elucidated to explain this disparity, much remains unclear. Differences could be explained in part by the pathophysiology of CAD in men and women. For example, women with ACS are less likely to have significant obstructive CAD but are more likely to have thrombus formation and plaque erosion when compared with men with similar symptoms.4 5
Additionally, differences exist regarding treatment and management leading to deferment of evidence-based therapies in women. Women continue to be under-represented in cardiovascular trials and on average comprise only 25% of clinical investigations in ACS.6 Fortunately, as awareness of this important issue increases, more research is being done to reveal sex-specific aspects of care. The goal of this review is to highlight differences in therapy and outcomes in ACS between sexes as well as strategy differences used in secondary prevention. A better understanding of the effectiveness of revascularisation therapies and medical treatment specifically in women is needed to reduce the high morbidity and mortality observed with ACS. Furthermore, sex-based differences in pathophysiology, clinical manifestations and diagnosis of CAD need to be understood in order to deliver appropriate and timely management.
CAD among women
Differences in pathophysiological mechanisms
The pathophysiological processes that lead to ischaemia differ significantly between sexes. Women with ischaemic heart disease less frequently have obstructive and extensive epicardial artery disease.7 Instead, they are more prone to thrombus formation and plaque erosion.4 Analysis shows that coronary vessels in women appear to contain more diffuse atherosclerosis with involvement of the entire circumference of the artery and therefore have fewer obstructive lesions in the setting of ACS.4 At the time of angiography, coronary arteries appear smooth-walled and ‘normal’ with no evidence of flow-limiting stenosis in nearly 50% of women.8 However, in such cases, intravascular ultrasound examination revealed that >80% of women with ‘normal angiograms’ have plaque lesions. Additionally, even when non-obstructive CAD by coronary angiogram has been documented, symptomatic women with persistent chest pain have a threefold higher rate of cardiovascular events when compared with asymptomatic women.9 This suggests that other mechanisms such as vasospasm, non-atherosclerotic coronary artery dissection, impaired coronary microcirculation and thrombophilia contribute to ischaemic syndromes in women more frequently than men. The National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation study group has highlighted microvascular and endothelial dysfunction as one potential theory for these findings.10 On average, females have coronary vessels 10% smaller than men, and functionally, their vessels frequently show impaired vasodilator response.11 Nonetheless, this hypothesis has been controversial as convincing evidence is lacking.12
Moreover, the coronary plaque itself seems to have some slight differences in the presentation of ACS in women and plaque erosion occurred in 44% of patients who died due to acute MI (AMI), with an increased prevalence in women.13 More recently, the advancements in intravascular imaging with optical coherence tomography has provided a tool for assessment of these atherosclerotic plaques. OCTAVIA study found plaque erosion to be the cause of ST-elevation MI (STEMI) in 25% of patients; however, no significant gender differences with plaque type were found.14 , 15
Disease presentation and diagnosis
Patient presentation can greatly influence the timely diagnosis and treatment of ACS. There is a large bulk of data available to show that women have longer delays to hospital presentation (figure 1). A meta-analysis of 42 studies from 1960 to 2008 showed that women have longer prehospital delays after development of symptoms suggestive of AMI than men (median range 1.8–7.2 hours for females vs 1.4–3.5 hours for men). Some patient-related factors associated with delay included advanced age, single marital status, history of myocardial infarction (MI) and being alone during symptom onset.16
The diagnosis of CAD presents a greater challenge in women. While chest pain is the most common symptom of ACS for both sexes, women tend to report more atypical symptoms including but not limited to nausea, vomiting, dyspnoea, fatigue and abnormal pain location.17 As a result, women and physicians are more likely to assume these symptoms have non-cardiac causes leading to delays in seeking and receiving aggressive medical care. In GENESIS-PRAXY study, female patients were less likely to receive a diagnosis of STEMI and more likely to have received the diagnosis of non-ST elevation MI (NSTEMI) or unstable angina (UA). The same study also found that females (aged ≤55 years) were more likely to present without chest pain.18 Furthermore, women tend to present with CAD about 10 years later than their male counterparts and are more likely to have coexisting chronic illnesses.19 In addition to the challenges, diagnosis and risk assessment of CAD has traditionally been more difficult in women. Cardiac biomarkers, sensitive markers of myocardial necrosis, are an important component in risk stratification and treatment strategies in ACS. One study demonstrated that men with UA or NSTEMI are more likely to have elevated creatine kinase MB and troponins, whereas women are more likely to have raised C reactive protein and brain natriuretic peptide.20 This suggests that a multimarker approach, including measurement of inflammatory markers, may aid in the initial risk assessment of UA/NSTEMI, particularly in women. A more recent study by Shah et al assessed the effect of using sex-specific diagnostic thresholds for high sensitivity troponin I assay on the incidence of myocardial infarction. This study demonstrated an increase in the diagnosis of MI in women (from 11% to 22%; p<0.001) when the reference range for troponin was adjusted with minimal effect in men (from 19% to 21%; p=0.002).21 This imparts that single diagnostic thresholds for high sensitivity troponin assays may lead to underdiagnosis and inequalities in treatment and outcomes of AMI in women.
Differences in prognosis and outcomes
Accumulated data have shown that women with ACS have an unfavourable outcome and overall worse prognosis.22 23 24 Although not an entirely consistent finding, mortality rates post-ACS have shown to be higher among women both in-hospital and at 1 year.25 Serious complications of ACS including cardiogenic shock, congestive heart failure and reinfarction are more frequent (figure 2).26 Of particular interest, increased risk appears to be highest in young women (<55 years) whose in-hospital mortality rate is approximately twice that of men.27 It is not clear why younger women with AMI carry a more unfavourable prognosis, and the complete explanation is far from elucidated. Factors including different symptomatology, delays in starting treatment and use of different therapeutic schemes depending on the patient’s sex are possible explanations.
Role of hormone replacement therapy (HRT)
Women are often older at presentation with their first AMI compared with men. This is thought to be due in part to the protective role of endogenous oestrogens on vascular endothelium in premenopausal women. The complex mechanisms are incompletely understood; however, direct effects of oestrogen on the vascular system include increased release of nitric oxide leading to vasodilation, regulation of prostaglandin production and inhibition of smooth muscle proliferation.28 29 Studies have shown that oestrogen depletion at menopause leads to increased endothelial dysfunction and lipid deposition, which lead to progression of atherosclerosis.30 31 Despite the cardioprotective effects of endogenous oestrogen, randomised controlled trials have not confirmed a cardioprotective benefit with exogenous oestrogen hormone therapy.32 33 34 In some trials, such as the Women’s Health Initiative, an increase in CAD risk was actually observed with HRT.35 36 Therefore, HRT is not routinely recommended for primary or secondary prevention of CAD in postmenopausal women at present.
Of note, while high circulating oestrogen has traditionally been thought to be cardioprotective, the use hormonal contraception and pregnancy are two unique risk factors for ACS in reproductive-aged women. The use of first-generation and second-generation oral contraceptive pills has been shown to double the risk of ACS, while pregnancy increased it further to 3–4 times higher.37 38 The risks were highest among women who smoked, had hypertension and diabetes mellitus. These findings suggest that the cardioprotective effects of oestrogen against ACS is negated by the strong association of potentially modifiable risk factors and comorbidities in reproductive-aged women.
Treatment disparity and outcomes among men and women
Reperfusion strategies
Percutaneous coronary intervention (PCI) is an early invasive catheter-based reperfusion strategy used to restore blood flow to ischaemic myocardial tissue in patients with ACS. It is the preferred method for patients with most forms of single-vessel disease. Studies have shown that appropriate cardiac catheterisation and PCI is associated with a well-established mortality benefit of reduced in-hospital deaths and recurrent MI.39 Risk-adjusted analyses of short-term and long-term mortality and outcomes have shown that in general women derive benefits similar to men from early reperfusion in ACS.40 41 42 In addition, men and women with STEMI have similar benefits from PCI relative to fibrinolytics.43 44 While the benefit of early-invasive strategy in NSTEMI is controversial, meta-analysis have shown that in the subgroup of patients with positive biomarkers, both sexes had improved outcomes with early-invasive strategy.19 45 Nonetheless women with ACS tend to receive less evidence-based pharmacotherapies and invasive procedures compared with their male counterparts.46 47–49
The AMIS Plus prospective cohort study demonstrated that females were less likely than men to undergo PCI.50 Similarly, a retrospective analysis by Kim et al showed women with ACS are 29% less likely than men to undergo PCI.51 There are likely to be multiple explanations as to why this sex disparity exists, including that women tend to have less typical symptoms at presentation leading to misdiagnoses and delays in effective treatment. Another study explains these disparities by women’s older age at presentation, greater risk profile and increased risk for adverse procedural outcomes.52 According to one meta-analysis of 12 PCI trials, vascular complications such as access-site haematomas or bleeding requiring transfusion occurred between 1.5 and 4 times more often in women than men.53 These findings encourage us to carefully assess the risk–benefit ratio for pursuing PCI in women. However, given the substantial benefit, there is a need to promote consistent application of evidence-based approaches irrespective of sex and rapid referral of both women and men for PCI when appropriate.
Early, rapid treatment of ACS is equally effective in both men and women with a decrease in mortality.54 Unfortunately, a number of studies indicate that women are more likely to expect a delay in PCI.55 56 According to results from VIRGO, which assessed 1465 patients with STEMI (57% men) aged 18–55 years, women were 1.7 times more likely to exceed recommended reperfusion time goals than men. They were also more likely to go untreated (9% vs 4%; p=0.002) after adjustment for age, transfer status, atypical symptoms and race.57 Another study found that on hospital arrival, female patients with STEMI had delays in door-to-balloon time.58 This again shows that women experience delays in the PCI process and in identification of STEMI that impact outcomes.
Coronary artery bypass grafting (CABG) is another viable revascularisation option for obstructive CAD, particularly in left main or severe triple-vessel disease. Women account for approximately one-third of patients undergoing CABG surgery in the USA annually. Similarly, like in primary PCI, women with ACS receive fewer bypass surgeries compared with men (47.6% vs 60%; p=0.0001).59
From a historical perspective coronary surgery has been associated with higher mortality in women. A 1975 study by Bolooki et al reported an operative mortality of 8% in women and 2% in men.60 However, women undergoing bypass surgery differed from men in baseline age, comorbid conditions, cardiovascular risk factors, left ventricular dysfunction and procedural characteristics. In the majority of studies that statistically adjusted for these confounders, sex was not an independent risk factor for death. Population studies such as the Coronary Artery Surgery Study (CASS) registry and the Bypass Angioplasty Revascularization Investigation (BARI) trial reported similar outcomes regarding graft patency and long-term survival in men and women.61 62 In fact, after adjusting for baseline differences, investigators concluded that female sex had a lower mortality at 5 years (RR of death 0.60; 95% CI 0.43 to 0.84; p=0.003).63 Thus, concerns about increased mortality in women should not influence referral for CABG when appropriate.
Pharmacological reperfusion using fibrinolytic agents are recommended by the AHA/ACC STEMI guidelines when there may be a delay to primary PCI. Both currently and in the past, women were less likely to undergo thrombolytic therapy than in men.64 One reason for why this may be is that when women did receive fibrinolysis they experienced a larger number of adverse outcomes compared with men—having greater rates of reinfarction, haemorrhagic stroke, major haemorrhage and long-term mortality.65
Bleeding complications
Understanding the pathophysiology of ACS has led to the development of highly successful antithrombotic strategies. Medicines such as aspirin, ticagrelor, prasugrel, clopidogrel and low-molecular-weight heparin (LMWH) used in the setting of early coronary revascularisation with PCI have reduced the risk of death, MI and recurrent ischaemia. As a result, however, a relative increase in the risk of bleeding complications has been observed. The bleeding risk is higher in women, which may in part be due to sex-based variation in platelet biology and response to antiplatelet strategies.66 Other literature proposes the increased risk is related to non-modifiable sex-associated factors such as lower body mass index, lower creatinine clearance and anatomic differences including small vessel size.67 Data from the CRUSADE registry demonstrated that excessive dosing of glycoprotein IIb/IIIa inhibitors (GPIs) was almost three times more common in women compared with men (46.6% vs 17.2%; p<0.0001). Bleeding was significantly lower for both sexes who received proper dosage adjustment.68 The current care of patients should therefore recognise the enhanced risk of bleeding in women and prioritise bleeding avoidance strategies. For instance, when PCI is planned, considerations should be given to anticoagulant dosing in women, especially with renally cleared agents such as GPIs and LMWH.
Female sex remains an independent high-risk factor for vascular access site complications. Radial access can help circumvent this risk. Major bleeding was not observed in women who underwent transradial access for PCI; however, it was observed that an alternative access site was used more frequently in women than men.69 Operators may be reluctant to use radial access in females due to smaller calibre vessels and increased rates of radial artery spasms, raising concerns for procedural failure.70 71 In the RIVAL randomised trial, the crossover rate from radial to femoral access or vice versa was higher in the group of patients assigned radial access compared with those assigned femoral access (women: 11.1% vs 1.9%; p<0.001; men: 6.3% vs 1.9%; p<0.0001). A higher crossover rate from radial to femoral access was further observed among women, mostly driven by a higher rate of radial artery spasm (women: 9.5%; men 3.5%; p<0.001). Despite these challenges, the RIVAL trial demonstrated a significant reduction in major vascular complications with radial access in women compared with femoral access with no difference in PCI success rates or complications.72 There is no doubt that the bleeding and vascular complications of ACS PCI are lower with the radial route. These complications are more common in women so radial access would mitigate for this.
Pharmacotherapy
Evidence-based cardiovascular drugs for secondary prevention can greatly reduce the risk of recurrent AMI and death, and the clear benefits of drug therapy are similar regardless of sex.73 74 Nevertheless, studies have shown that aspirin, beta blockers, statins and ACE inhibitors are underutilised in eligible patients, especially women who received different and often less intensive treatment than men (figure 3).75
In the AHA-Get With The Guideline CAD registry, women received lower prescription rates of evidence-based medicines.76 Data show that women are less likely to receive heparin, ACE inhibitor or GPIs at the time of admission and at the time of discharge– aspirin (87.5% vs 90.4% in men), beta blockers (80.5% vs 82.7% in men) and statins (55.9% vs 69.4% in men).77 Others have found lower rates of GPIs and clopidogrel at discharge.78 79 Yet another study revealed that 65% of women younger than 55 were started on cardioprotective medications versus 75% of men in the same age group.80 There was no significant difference in compliance rates between men and women.
It is unclear why evidence-based drug therapies in patients with ACS are not equally used. Sex differences may be related to variables including patient age, comorbidities such as heart failure and physician’s perception of risk. It has also been hypothesised that this may be due to lack of data specific to women for such therapies.81 82 This strongly suggests that in addition to greater utilisation of proven effective therapies in our female populations, more trials are needed specific to women.
Aspirin use in secondary prevention is associated with a significant reduction in cardiovascular events in high-risk patients.83 While the ACC/AHA 2014 guidelines recommend aspirin for treatment of ACS on arrival and maintaining therapy lifelong, aspirin use has not been fully investigated by stratifying according to sex. No single trial offers direct comparisons between male and female participants in substantial numbers.84 It is therefore concerning that aspirin remains underused for secondary prevention in the female subset given this lack of evidence.85 Aspirin therapy may be complicated by resistance, which is more prevalent in females than males. Women were less likely to respond to platelet inhibition therapy by aspirin and were more likely to have higher platelet aggregation at baseline compared with their male counterparts.86 Further studies on sex-based responsiveness to antiplatelet therapy are warranted.
The antiplatelet thienopyridine agents such as clopidogrel and ticagrelor have been shown to reduce ischaemic events in patients with ACS. When given in addition to aspirin, these agents decrease the rates of subacute stent thrombosis after stent implantation.87 88 In the CREDO trial, long-term treatment with clopidogrel was associated with a 26.9% relative risk reduction in adverse ischaemic events after elective PCI. Risk reduction rate of death, MI and stroke was 32.1% in women and 24.5% in men.89 Dual antiplatelet therapy with clopidogrel and aspirin raised major bleeding risk in both men and women without a sex differential and therefore should be utilised according to the benefit obtained.90
Unlike clopidogrel and prasugrel, ticagrelor is a reversible P2Y 12-receptor antagonist approved for use in ACS. According to PLATO trial, ticagrelor had a similar efficacy and safety profile in both sexes with no differences in the primary composite endpoint of death from vascular causes, MI or stroke for patients who were hospitalised for ACS.91
Cardiac rehabilitation
Cardiac rehabilitation is recognised as an integral part to the comprehensive care of patients following ACS. The rehabilitation service is designed to optimise physical, psychological and social functioning in cardiac patients as well as to slow or reverse progression of underlying CAD, thereby reducing morbidity and mortality. This secondary prevention programme is recommended as class I by the AHA/ACC in patients with CAD.
Despite evidence for improved prognosis and quality of life, several studies report that these structured programmes are underutilised, particularly in women. Fewer women are being referred to these programmes compared with men, and even when referrals are placed, women are less likely to use services.92 93 94
Recent research found that men may be benefiting more than women from current cardiac rehabilitation programmes.95 This sex-based difference may be related to the unique barriers to exercise encountered by women, such as social stigma against overexertion and higher comorbidities that can make it harder for women to participate in exercise. It is suggested that involving more targeted counselling and tailoring cardiac rehabilitation programmes to women may yield further improvement in functional capacity for female participants. Colbert et al demonstrated the importance of referral to and attendance at cardiac rehabilitation—this retrospective cohort study reported a significant reduction in mortality in women completing cardiac rehabilitation (HR 0.36; 95% CI 0.28 to 0.45) with a relative benefit greater than men (HR 0.51; 95% CI 0.46 to 0.56).96
ACS in developing countries
Sex-related disparities in ACS have predominantly been studied in major registries and clinical trials in Western populations. There is a paucity of data on sex-based differences in the treatment and outcomes of ACS in developing nations despite the increasing prevalence of CAD. Nonetheless, studies that are available have reported similar conclusions that women are managed more conservatively than their male counterparts, often contributing to a worse outcome in women. The Gulf RACE-2 registry demonstrated that women in the Middle East were less likely to undergo PCI and reperfusion than men and were less likely to be prescribed evidence-based pharmacotherapies at the time of discharge.97 Another registry, National Cardiovascular Disease-Acute Coronary Syndrome (NCVD-ACS), looked at sex differences in Malaysian populations, and again, found suboptimal treatments and interventions in women compared with men. This implies that the sex-related imbalance in ACS treatment exists on a global scale and more attention should be given to women in order to close this gap.
Conclusion
Biological differences exist between women and men with CAD. However, many of the adverse outcomes in women who present with ACS have been attributed to delays in symptom recognition and presentation as well as less aggressive therapeutic intervention as summarised in table 1. Women presenting with symptoms suggestive of CAD need to be treated appropriately and as ‘aggressively’ as their male counterparts if there is a high-risk index of suspicion. Furthermore, women have been largely under-represented in research trials with no more than 25%–30% of study populations being female. This recruitment bias leads to a gap in the evidence-based evaluation in randomised clinical trials. A number of international initiatives have been established to address this research void. Future directions should include research focused on answering the biological questions as well as identifying factors that are unique to female patients in order to address them. The management of women presenting with ACS needs to be studied continually in order to close the sex gap in outcomes.
Key points
Women with acute coronary syndrome (ACS) often have late presentation with atypical symptoms, which may delay diagnosis and treatment.
Women presenting with ACS respond to early reperfusion therapies just as well as men and therefore should be treated as intensively. Treatment should not be denied on the basis of diagnosis delays or sex bias.
There are special sex-related factors that need to be considered when assessing and treating women with suspected coronary artery disease (CAD) such as pregnancy, menopause and response to platelets.
Women tend to have more bleeding complications than men during percutaneous coronary interventions that may be circumvented by use of transradial access.
Women are less likely to receive guideline-indicated pharmacotherapies in secondary prevention.
Women are less likely to enrol in cardiac rehabilitation after a myocardial infarction or bypass surgery.
Continued emphasis on sex-specific clinical research and sex-specific treatment protocols offers a promising future for women with CAD and may help close the sex gap in outcomes.
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Footnotes
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.
Author note In the reference list papers with a * are highlighted as a key reference.