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Review
Evidence base for the management of women with non-ST elevation acute coronary syndrome
  1. James Jackson1,
  2. Mohammad Alkhalil1,2,
  3. Hanna Ratcovich1,
  4. Chris Wilkinson2,3,
  5. Roxana Mehran4,
  6. Vijay Kunadian1,2
  1. 1 Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
  2. 2 Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
  3. 3 Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
  4. 4 The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  1. Correspondence to Dr Vijay Kunadian, Translational and Clinical Research Institute, Newcastle University Faculty of Medical Sciences, Newcastle upon Tyne, Newcastle upon Tyne, UK; vijay.kunadian{at}ncl.ac.uk

Abstract

According to the Global Burden of Disease study, in 2019, there were an estimated 275.2 million cases of cardiovascular disease (CVD) in women worldwide. Although there was a decrease in the global age-standardised prevalence of CVD in women between 1990 and 2010 (–5.8%), there has been a slight increase (1.0%) since 2010. There were an estimated 6.10 million deaths from CVD in women in 1990, rising to 8.94 million in 2019. Hospital admissions of young women with acute myocardial infarction (AMI) steadily increased from 27% in 1995–1999 to 32% in 2010–2014. Women with AMI compared with men are less likely to receive guideline-indicated pharmacological (aspirin 93.4% vs 94.7%, P2Y12 inhibitors 79.3% vs 86.1% and statins 73.7% vs 77.5%) and revascularisation treatments (angiography (adjusted OR (aOR) 0.71), percutaneous coronary intervention (aOR 0.73)). Women represent <39% of clinical cardiovascular trial participants between 2010 and 2017. Major factors of under-representation in studies included concerns about the burden of participation on health and time. Women were more likely than men to document caring responsibilities as reasons for not participating in a clinical trial. Current clinical practice guidelines recommending risk stratification to guide the appropriateness of an invasive strategy in the context of acute coronary syndrome (ACS) may not be applicable to women given lack of studies specifically evaluating women using contemporary treatment strategies. In our review, we identify significant limitations in the evidence base for the best care of women with ACS, emphasising the need for well-designed clinical trials specifically recruiting women.

  • coronary angiography
  • coronary artery disease
  • acute coronary syndrome
  • atherosclerosis
  • myocardial infarction

https://doi.org/10.1136/heartjnl-2021-320533

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    Introduction

    Cardiovascular disease (CVD) is the leading cause of mortality in the world resulting in an estimated 17.8 million deaths in 2017, and around 35% of deaths in women worldwide in 2019. Although there was a decrease in the global age-standardised prevalence of CVD in women between 1990 and 2010, there has been a slight increase since 2010. The decrease in global cardiovascular mortality in women slowed down markedly over the last decade compared with previous years.1 2 There has been an increase in myocardial infarction (MI) in young women in recent years.3 4 Over 160 000 women annually are hospitalised with coronary heart disease (CHD) in the UK alone.5 Although men classically have been considered high risk for CHD, women tend to have relatively poorer outcomes and are less likely to receive guideline-indicated pharmacological and invasive coronary treatments during and after discharge following MI.6–13 There is also evidence that even when women do receive the current guideline recommended invasive treatments, they might not receive the same benefit as men and have a higher mortality rate.8 14–16 This may be due to differences in presentations and risks when compared with men, and potentially differing underlying disease mechanisms.

    Myocardial infarction with non-obstructive coronary artery disease (MINOCA) occurs up to 5 times more often in women than men.17 The data to guide optimal management of MINOCA are still emerging.18 19 This review summarises the clinical presentation, epidemiology, risk factors and management strategy of non-ST elevation acute coronary syndrome (NSTEACS) in women. It also synthesises the evidence behind the interventional management of women with NSTEACS.

    Age and comorbidities at the time of NSTEACS presentation

    According to recent Myocardial Ischaemia National Audit Project (MINAP) data, women diagnosed with a non-ST elevation myocardial infarction (NSTEMI) are on average 7 years older than men (69.0 years vs 76.0 years).20 21 In a further registry study (n=3887, 32.9% women), women were significantly older than men (70 years vs 65.1 years; p<0.001 in the routine medical therapy group and 65.4 years vs 60.0 years; p<0.001 in the invasive management group, respectively).22 This study also demonstrated that the prevalence of comorbidities such as diabetes and hypertension were higher in women than men. In the invasive management group, the prevalence of diabetes was 21.1% in men vs 29.0% in women (p=0.001) and the prevalence of hypertension was 71.3% in men and 82.1% in women (p<0.001).

    Signs and symptoms of NSTEACS in women

    While it has been suggested that women often present with other predominant symptoms of ischaemic heart disease such as breathlessness, nausea, weakness, fatigue and jaw pain,8 23 24 for women with suspected ACS, chest pain is still the most predominant symptom they would present with in likeness with men.25

    Differences in risk factors between men and women with CAD

    In addition to conventional risk factors for CVD such as obesity, diabetes, hypertension, dyslipidaemia, age, inactivity, family history and smoking, risk in women is further modified by pregnancy and hormonal factors26 (figure 1). Although some risk factors are more common in men, the prevalence of obesity in the USA is higher in women.27 Obesity also has been shown to increase women’s risk of CVD more than men (64% risk increase vs 46% risk increase).28 A retrospective study of 11 Spanish NSTEACS registries was conducted (n=7211, 2770 women) to assess the prognostic impact of diabetes mellitus in men and women over the age of 70 years.29 This study found that diabetes mellitus had a strong association with mortality in women (HR 1.45, 95% CI 1.18 to 1.78; p<0.001), but not in men (HR 0.98, 95% CI 0.84 to 1.14; p=0.787). Hypertension has also shown to have a greater population-adjusted risk of cardiovascular mortality in women than men (29.0% vs 14.9%).28 Oestrogen has a protective role in the development of CVD through improving lipid levels and reduced incidence of type 2 diabetes, but an individual’s risk profile alters with ageing and hormonal fluctuation.30

    Figure 1
    Figure 1

    Risk factors for women, categorised by age. Postmenopausal risks in older women include central adiposity, insulin resistance and a pro-atherogenic lipid profile. CVD, cardiovascular disease; PCOS, polycystic ovarian syndrome.

    At a young age, pregnancy-related risks such as pre-eclampsia and gestational diabetes are particularly important.31 Although the pathophysiology of why pre-eclampsia increases the risk of CVD remains unclear, in a meta-analysis of 116 175 women with pre-eclampsia/eclampsia compared with 2.3 million women who had uncomplicated pregnancies, the CVD and cardiovascular mortality was around 2 times greater, and increased alongside the severity of pre-eclampsia (mild: relative risk (RR) 2.00, 95% CI 1.83 to 2.19; moderate: 2.99, 95% CI 2.51 to 3.58; severe: 5.36, 95% CI 3.96 to 7.27, p<0.0001).32 Gestational diabetes has also been shown to increase the risk of CVD in a recent cohort study of 1 million women (67 356 with gestational diabetes). After adjusting for baseline characteristics, gestational diabetes was associated with a 2.1 times greater risk of MI (HR 2.14 95% CI 1.95 to 2.39) and 2.2 times greater risk of receiving a coronary angioplasty (HR 2.23 95% CI 1.87 to 2.65).33 Other factors such as polycystic ovarian syndrome, the use of the contraceptive pill and some autoimmune conditions are also associated with an increased cardiovascular risk in women.26

    Differences in care received by women following ACS

    A study of 28 985 people in Victoria, Australia found that women were less likely to receive coronary interventions compared with men (angiogram: adjusted OR (aOR) 0.71, 95% CI 0.66 to 0.75; percutaneous coronary intervention (PCI): aOR 0.73, 95% CI 0.66 to 0.80; coronary artery bypass surgery (CABG): aOR 0.58, 95% CI 0.53 to 0.64).34 These findings are corroborated in a further study including 16 861 patients presenting to an emergency department with NSTEMI, which found that women are less likely to receive angiography within 24 hours than men and spent on average 23 min longer in the emergency department. This study also showed there were higher unadjusted in-hospital mortality rates among women than men (4.8% vs 3.9%, p<0.001).12

    Medical therapy differences

    The current American Heart Association (AHA) guideline suggests that the medical therapies used for primary and secondary prevention of CAD are efficacious regardless of sex.35 Yet there are differences in the use of evidence-based medications between men and women. In a meta-analysis of 10 Thrombolysis In Myocardial Infarction (TIMI) trials of people with NSTEACS (n=68 730, 19 827 women), women were less likely to receive aspirin than men (93.4% vs 94.7% p<0.001), P2Y12 inhibitors (79.3% vs 86.1% p<0.001) and statins (73.7% vs 77.5% p<0.001).36 Registry data from Sweden show a similar pattern following ACS (n=180 368, 65 394 women) in which women were less likely than men to receive aspirin (85.7% vs 89.4%), beta-blockers (83.6% vs 86.0%), statins (67.8% vs 79.5%) and P2Y12 inhibitors (58.6% vs 66.8%).9 Discrepancies in the receipt of guideline-indicated therapy between men and women have been extensively reported elsewhere and is likely to be a contributing factor to the observed increased mortality in women following MI.4 10 11 Women have higher platelet reactivity and response to antiplatelet therapy with a higher bleeding risk at baseline (online supplemental file).

    Supplemental material

    Invasive management approach of NSTEACS

    Risk stratification

    The current guidelines suggest that individual risk stratification is required to determine which management pathway a patient undergoes.37 38 The National Institute for Health and Care Excellence (NICE) guidelines recommend using a 6-month predicted mortality score such as the Global Registry of Acute Cardiac Events (GRACE), which then informs the risk categories which have been derived from the MINAP database (figure 2).39 The European Society of Cardiology (ESC) and the AHA/American College of Cardiology (ACC) guidance both incorporate the use of the GRACE score within their stratification process.37 40

    Figure 2
    Figure 2

    Predicted 6-month mortality (%) with the National Institute for Health and Care Excellence cut-off for early invasive therapy in non-ST elevation acute coronary syndrome.

    The recommended management of NSTEACS is shown in figure 3, stratified by risk categories seen in table 1 (very high, high, intermediate and low).37 Neither NICE nor ESC guidelines suggest stratification on the basis of sex, whereas the AHA/ACC guidelines suggest that low-risk patients with troponin-negative ACS, and especially women, should be offered an ischaemia-guided (initial conservative) strategy. International guidelines suggest that patients at very high risk are likely to benefit from an immediate invasive therapy, whereas the decision in low-risk and intermediate-risk patients is more nuanced.37 39 40

    Figure 3
    Figure 3

    Current invasive treatment strategy for women. ACC, American College of Cardiology; AHA, American Heart Association; ESC, European Society of Cardiology; NICE, National Institute for Health and Care Excellence.

    View this table:
    Table 1

    Risk stratification of NSTEACS patients based on guidelines

    Evidence from randomised controlled trials on the management of NSTEACS in women

    The third Randomised Intervention Treatment of Angina (RITA 3) trial (n=1810 patients, women=682)8 16 investigators found that the incidence of death or MI after 1 year was higher in men allocated to conservative therapy than the intervention group (10.1% vs 7.0%; aOR 0.63, 95% CI 0.41 to 0.98), but in women the death and MI rate at 1 year were similar in the conservative and interventional groups (5.1% vs 8.6%; aOR 1.79, 95% CI 0.95 to 3.35; interaction p=0.007). For men and women in the low-risk group, both the interventional and conservative groups yielded similar results (6.1% vs 5.1% for men; 2.3% vs 3.8% for women, respectively). However, among moderate and higher risk patients, women in the invasive arm suffered a higher event rate of death or MI than those in the conservative arm (13.4% vs 3.4% for moderate risk and 11.7% vs 8.2% for high risk, respectively). These results differ from those in men who had a clear reduction in event rates when managed with the invasive strategy versus conservative (moderate risk: 5.4% vs 9.5%; high risk: 10.3% vs 17.9%). These results suggest that men with moderate and high risk may benefit more from the invasive strategy than women.

    The FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II, n=2457 patients; women=749), showed that an early invasive strategy did not reduce the risk of future cardiac events (death or MI at 12 months) among women (12.4% vs 10.5%, early invasive and non-invasive, respectively), in contrast to a clear benefit in men (9.6% vs 15.8%, p<0.001).14 The mortality rate at 12 months, although higher in women than men, was not statistically significant (4.0% vs 1.5%, respectively) in the group assigned to the early invasive strategy. However, there was an increased invasive procedure-related mortality in women than in men (1.8% vs 0.3%, p=0.002).

    The Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS, n=1200 patients; women=320) evaluated differences between the early invasive strategy and selective invasive strategy for high-risk patients defined by having elevated troponin showed no statistical difference of event rate for the primary end point (rehospitalisation for angina, recurrent MI or death within 1 year) between the early invasive strategy (22.7%) and the selective invasive strategy (21.2%) (RR 1.07; 95% CI 0.87 to 1.33; p=0.33).41

    The Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS TIMI-18) and its subanalysis of 757 women showed that sex was not an independent risk factor by treatment strategy, finding similar results in men and women with no difference between the conservative and invasive management groups.42 43 It also showed that higher risk women (as defined by the TIMI scoring system) with a raised troponin had better outcomes with a lower primary end point rate (rehospitalisation for ACS, MI and death) at 6 months when treated with an early invasive versus conservative strategy (19% vs 29%, OR 0.56; 95% CI 0.32 to 0.97; p=0.02) (table 2).

    View this table:
    Table 2

    Randomised control trials in NSTEACS female patients

    In the Organisation to Assess Strategies in Ischaemic Syndromes 5 (OASIS 5), a randomised trial of fondaparinux compared with enoxaparin in patients with NSTEACS, a substudy consisting of 184 women showed that there were significantly more deaths after 1 year in the routine invasive versus the selective invasive strategy (8.8% vs 1.1%; HR 9.01, 95% CI 1.11 to 72.90) and a higher rate of major bleeding at 30 days (8.8% vs 1.1%; HR 11.45, 95% CI 1.43 to 91.96).15 A meta-analysis including data from OASIS 5, FRISC II, RITA 3, TACTICS TIMI-18 and ICTUS showed that men saw a benefit from the routine invasive therapy (OR 0.78 95% CI 0.66 to 0.93), whereas women did not (OR 1.18, 95% CI 0.92 to 1.53, p interaction=0.01). The analysis also showed there was a higher mortality associated with a routine invasive strategy in women (OR 1.51, 95% CI 1.00 to 2.29).

    These studies, and in particular the final meta-analysis demonstrate that for women with NSTEACS, evidence to support the current treatment strategies used in those intermediate and high-risk women is not as clear cut as the guidance may suggest. Further evidence from meta-analyses and other studies on the management of NSTEACS in women is shown in the online supplemental file.

    Limitations of studies in women

    Representation of women in randomised controlled trials

    Many of the randomised controlled trials (RCTs) evaluating treatment strategies for the management of NSTEACS are dated, and women constitute a small minority of participants (table 3). A meta-analysis of RCTs of ACS trials between 1990 and 2000 found that, on average, women comprised 25% of the study population, and subsequent attempts at making cardiovascular RCTs more inclusive have had limited success.44 The risk stratification scores used in the current guidelines are therefore based on thresholds for male predominant populations and therefore may not be accurate in predicting risk for women. In CABG trials, women have been largely under-represented (prevalence 16.8%) over the last two decades and therefore their findings cannot be generalised given sex differences in biology and key operative aspects between men and women (online supplemental file).

    View this table:
    Table 3

    Representation of women in NSTEACS RCTs

    Much of the RCT evidence referenced so far precedes current techniques and technologies. Even without the controversy of results, the use of outdated techniques in the studies we rely on to inform our guidelines, warrants adequately powered up-to-date clinical trials of the best management approach for women with NSTEACS. The requirement for ‘adequately powered RCTs to identify potential sex differences in treatment strategies in patients presenting with NSTE-ACS’ has been highlighted as a gap in the evidence in the 2020 ESC NSTEACS guidelines.37

    The effect of baseline adjustments on women’s outcomes

    In a meta-analysis of 10 TIMI trials including 68 730 patients (19 827 women) presenting with NSTEACS, women were at higher risk of mortality than men regardless of treatment strategy (HR for all-cause death, men compared with women 1.12; 95% CI 1.01 to 1.24; p=0.03).36 However, after adjustment for baseline differences (age, BMI, smoking status, ethnicity, hypertension, hyperlipidaemia, diabetes mellitus, prior MI, prior PCI, prior heart failure, renal function and biomarkers) mortality rates were in fact lower in women than men (HR 0.84; 95% CI 0.78 to 0.90; p<0.0001). A retrospective analysis of patients (n=5686, 1572 women) with NSTEACS presenting to two Spanish University hospitals showed women had higher cardiovascular mortality when compared with men (OR 1.27; 95% CI 1.08 to 1.49).45 However, following propensity score matching, women had a similar risk of cardiovascular mortality when compared with men (OR 0.86; 95% CI 0.71 to 1.03). It is evident that women present with ACS at an older age and with greater comorbidity, which appears to account for differences in clinical outcome. These additional characteristics, which are integral representations of the female population with NSTEACS, cannot be overlooked or adjusted for when understanding the reasons behind poorer outcomes and subsequently for defining the optimal management strategy. These complex characteristics alongside reduced primary and secondary treatment provision and importantly diminished management strategy efficacy all contribute to a picture of poorer outcomes in women. Given women have traditionally been excluded from clinical trials with under-representation, it is unclear if the lack of benefit of invasive strategy among women is due to unmeasured confounders in women. This emphasises the need for further appropriately deigned clinical trials to understand and evaluate this better, taking into account all women-specific conditions including pre-eclampsia and other pregnancy-related disorders.

    Strategies for improving the care of women with NSTEACS

    There is scope for improvement at each stage of the clinical journey for women presenting with ACS. First, symptoms and signs must be accurately identified. After a diagnosis of ACS is made, then women should be offered guideline-indicated therapy for their acute presentation and any comorbidities. Appropriate secondary prevention, follow-up and access to cardiac rehabilitation should be offered. From a research perspective, there are uncertainties that remain unresolved. For example, do the existing recommendations represent contemporary risk assessments in a way that are applicable to, and do not disadvantage, women? MINOCA is more common in women, and the optimum clinical strategy is unclear. Ongoing studies have the potential to improve outcomes substantially for women with MINOCA. Finally, appropriate secondary prevention management in women is required. Some recommendations on how to correct this under-representation of women in clinical trials are to adjust the exclusion criteria, such as upper and lower age limits, and address economic and structural barriers such as providing access to childcare.46 All of these strategies need to be implemented to reduce the global burden of heart disease in women (figure 4).

    Figure 4
    Figure 4

    Women and cardiovascular disease. CHD, coronary heart disease; MINOCA, myocardial infarction with non-obstructive coronary artery; NSTEACS, non-ST elevation acute coronary syndrome.

    Myocardial infarction with non-obstructive coronary artery

    Ischaemia with non-obstructive coronary arteries (INOCA) and MINOCA conditions that occur more frequently in women compared with men require further diagnostic evaluation using functional angiography to clinch the final diagnosis. Functional coronary angiography represents the combination of coronary angiography with adjunctive tests including physiology (to diagnose coronary microvascular dysfunction), vasoreactivity (to diagnose coronary artery spasm) and intracoronary imaging (to diagnose plaque rupture, erosion, dissection).38 47 MINOCA is diagnosed using the following criteria: (1) raised cardiac biomarkers and clinical evidence of MI with symptoms, changes on ECG or evidence on imaging; (2) presence of non-obstructive coronary artery disease (<50% stenosis).48 MINOCA can include type 1 or type 2 MI and encompasses a range of disease mechanisms including coronary artery spasm, spontaneous coronary dissection, microvascular spasm, coronary embolism.18 37 Women older than 55 years have a 5-fold greater risk of developing Takotsubo syndrome than women younger than 55 years and a 10-fold greater risk than men. A large meta-analysis of 28 studies of patients with MI undergoing imaging to find the cause of disease showed that the prevalence of MINOCA was 6% (95% CI 5.0% to 7.0%).18 19 The variation in recovery: role of gender on outcomes of young patients with AMI (VIRGO) study showed that women have a fivefold higher chance of being diagnosed with MINOCA than men (14.9% vs 3.5%; OR 4.84; 95% CI 3.29 to 7.13).17 The optimal management of MINOCA is not yet known, although there are studies underway.49

    Conclusion

    Women currently have worse outcomes for ACS, have a different risk factor profile and have a much higher prevalence of MINOCA. It is possible that a different management approach is needed for women compared with men. This review demonstrates that the conflicting evidence contributing to the current treatment strategies is not as clearly defined as the guidelines might suggest. The evidence shows distinct benefits that are seen in men that may not be seen in women. Higher mortality rates are also associated with an invasive strategy in high-risk women which highlight the need for appropriate risk stratification before selection for the catheterisation lab. Further studies are needed to more accurately risk stratify women in order to guide treatment strategies.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study does not involve human participants.

    Acknowledgments

    The authors would like to thank Daniell Edward Raharjo for creating Figure 4.

    References

    1. ↵
      1. Global Burden of Disease Collaborative Network
      . Global burden of disease study 2019 (GBD 2019) results. Seattle, WA: Institute for Health Metrics and Evaluation, 2020. http://ghdx.healthdata.org/gbd-results-tool
    2. ↵
      1. GBD 2017 Causes of Death Collaborators
      . Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the global burden of disease study 2017. Lancet 2018;392:1736–88.doi:10.1016/S0140-6736(18)32203-7 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30496103
    3. ↵
      2. Gabet A ,
      3. Danchin N ,
      4. Juillière Y , et al
      . Acute coronary syndrome in women: rising hospitalizations in middle-aged French women, 2004-14. Eur Heart J 2017;38:1060–5.doi:10.1093/eurheartj/ehx097 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28329052
    4. ↵
      2. Arora S ,
      3. Stouffer GA ,
      4. Kucharska-Newton AM , et al
      . Twenty year trends and sex differences in young adults hospitalized with acute myocardial infarction. Circulation 2019;139:1047–56.doi:10.1161/CIRCULATIONAHA.118.037137 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30586725
    5. ↵
      Heart and circulatory disease statistics 2019 BHF in collaboration with the Institute of applied health research at the University of Birmingham, 2019. Available: https://www.bhf.org.uk/what-we-do/our-research/heart-statistics/heart-statistics-publications/cardiovascular-disease-statistics-2019
    6. ↵
      2. Tan YC ,
      3. Sinclair H ,
      4. Ghoorah K , et al
      . Gender differences in outcomes in patients with acute coronary syndrome in the current era: a review. Eur Heart J Acute Cardiovasc Care 2016;5:51–60.doi:10.1177/2048872615610886 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26450783
    7. ↵
      2. Kunadian V ,
      3. Qiu W ,
      4. Lagerqvist B , et al
      . Gender differences in outcomes and predictors of all-cause mortality after percutaneous coronary intervention (data from United Kingdom and Sweden). Am J Cardiol 2017;119:210–6.doi:10.1016/j.amjcard.2016.09.052 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27816119
    8. ↵
      2. Clayton TC ,
      3. Pocock SJ ,
      4. Henderson RA , et al
      . Do men benefit more than women from an interventional strategy in patients with unstable angina or non-ST-elevation myocardial infarction? the impact of gender in the RITA 3 trial. Eur Heart J 2004;25:1641–50.doi:10.1016/j.ehj.2004.07.032 pmid:http://www.ncbi.nlm.nih.gov/pubmed/15351164
    9. ↵
      2. Alabas OA ,
      3. Gale CP ,
      4. Hall M , et al
      . Sex differences in treatments, relative survival, and excess mortality following acute myocardial infarction: national cohort study using the SWEDEHEART registry. J Am Heart Assoc 2017;6. doi:doi:10.1161/JAHA.117.007123. [Epub ahead of print: 14 Dec 2017].pmid:http://www.ncbi.nlm.nih.gov/pubmed/29242184
    10. ↵
      2. Gudnadottir GS ,
      3. Andersen K ,
      4. Thrainsdottir IS , et al
      . Gender differences in coronary angiography, subsequent interventions, and outcomes among patients with acute coronary syndromes. Am Heart J 2017;191:65–74.doi:10.1016/j.ahj.2017.06.014 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28888272
    11. ↵
      2. Araújo C ,
      3. Pereira M ,
      4. Laszczyńska O , et al
      . Sex-related inequalities in management of patients with acute coronary syndrome-results from the EURHOBOP study. Int J Clin Pract 2018;72. doi:doi:10.1111/ijcp.13049. [Epub ahead of print: 22 Dec 2017].pmid:http://www.ncbi.nlm.nih.gov/pubmed/29271543
    12. ↵
      2. Langabeer JR ,
      3. Champagne-Langabeer T ,
      4. Fowler R , et al
      . Gender-based outcome differences for emergency department presentation ofnon-STEMI acute coronary syndrome. Am J Emerg Med 2019;37:179–82.doi:10.1016/j.ajem.2018.05.005 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29754965
    13. ↵
      2. Bavry AA ,
      3. Kumbhani DJ ,
      4. Rassi AN , et al
      . Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials. J Am Coll Cardiol 2006;48:1319–25.doi:10.1016/j.jacc.2006.06.050 pmid:http://www.ncbi.nlm.nih.gov/pubmed/17010789
    14. ↵
      2. Lagerqvist B ,
      3. Säfström K ,
      4. Ståhle E , et al
      . Is early invasive treatment of unstable coronary artery disease equally effective for both women and men? FRISC II study Group Investigators. J Am Coll Cardiol 2001;38:41–8.doi:10.1016/s0735-1097(01)01308-0 pmid:http://www.ncbi.nlm.nih.gov/pubmed/11451294
    15. ↵
      2. Swahn E ,
      3. Alfredsson J ,
      4. Afzal R , et al
      . Early invasive compared with a selective invasive strategy in women with non-ST-elevation acute coronary syndromes: a substudy of the OASIS 5 trial and a meta-analysis of previous randomized trials. Eur Heart J 2012;33:51–60.doi:10.1093/eurheartj/ehp009 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19202154
    16. ↵
      2. Fox KAA ,
      3. Poole-Wilson PA ,
      4. Henderson RA , et al
      . Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British heart Foundation RITA 3 randomised trial. randomized intervention trial of unstable angina. Lancet 2002;360:743–51.doi:10.1016/s0140-6736(02)09894-x pmid:http://www.ncbi.nlm.nih.gov/pubmed/12241831
    17. ↵
      2. Safdar B ,
      3. Spatz ES ,
      4. Dreyer RP , et al
      . Presentation, clinical profile, and prognosis of young patients with myocardial infarction with nonobstructive coronary arteries (MINOCA): results from the VIRGO study. J Am Heart Assoc 2018;7. doi:doi:10.1161/JAHA.118.009174. [Epub ahead of print: 28 Jun 2018].pmid:http://www.ncbi.nlm.nih.gov/pubmed/29954744
    18. ↵
      2. Ibánez B ,
      3. James S ,
      4. Agewall S , et al
      . 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Rev Esp Cardiol 2017;70:1082.doi:10.1016/j.rec.2017.11.010 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29198432
    19. ↵
      2. Pasupathy S ,
      3. Air T ,
      4. Dreyer RP , et al
      . Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation 2015;131:861–70.doi:10.1161/CIRCULATIONAHA.114.011201 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25587100
    20. ↵
      Myocardial ischaemia national audit project 2019 summary report (2017/2018 data): National Institute for cardiovascular outcomes research; 2019, 2021. Available: https://www.nicor.org.uk/wp-content/uploads/2019/09/MINAP-2019-Summary-Report-final.pdf [Accessed 20 May 2021].
    21. ↵
      2. Wilkinson C ,
      3. Weston C ,
      4. Timmis A , et al
      . The myocardial ischaemia national audit project (MINAP). Eur Heart J Qual Care Clin Outcomes 2020;6:19–22.doi:10.1093/ehjqcco/qcz052 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31511861
    22. ↵
      2. Cenko E ,
      3. Ricci B ,
      4. Kedev S , et al
      . Invasive versus conservative strategy in acute coronary syndromes: the paradox in women's outcomes. Int J Cardiol 2016;222:1110–5.doi:10.1016/j.ijcard.2016.07.211 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27514628
    23. ↵
      2. Culić V ,
      3. Eterović D ,
      4. Mirić D , et al
      . Symptom presentation of acute myocardial infarction: influence of sex, age, and risk factors. Am Heart J 2002;144:1012–7.doi:10.1067/mhj.2002.125625 pmid:http://www.ncbi.nlm.nih.gov/pubmed/12486425
    24. ↵
      2. Varghese T ,
      3. Wenger NK
      . Non-St elevation acute coronary syndrome in women and the elderly: recent updates and stones still left unturned. F1000Res 2018;7. doi:doi:10.12688/f1000research.16492.1. [Epub ahead of print: 29 Nov 2018].pmid:http://www.ncbi.nlm.nih.gov/pubmed/30631426
    25. ↵
      2. Gulati M ,
      3. Levy PD ,
      4. Mukherjee D
      . AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: Executive summary: a report of the American College of Cardiology/American heart association joint Committee on clinical practice guidelines. Circulation 2021;2021:CIR0000000000001030..
    26. ↵
      2. Maas AHEM ,
      3. Rosano G ,
      4. Cifkova R , et al
      . Cardiovascular health after menopause transition, pregnancy disorders, and other gynaecologic conditions: a consensus document from European cardiologists, gynaecologists, and endocrinologists. Eur Heart J 2021;42:967–84.doi:10.1093/eurheartj/ehaa1044 pmid:http://www.ncbi.nlm.nih.gov/pubmed/33495787
    27. ↵
      2. Flegal KM ,
      3. Kruszon-Moran D ,
      4. Carroll MD , et al
      . Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016;315:2284–91.doi:10.1001/jama.2016.6458 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27272580
    28. ↵
      2. Wenger N
      . Tailoring cardiovascular risk assessment and prevention for women: one size does not fit all. Glob Cardiol Sci Pract 2017;2017:e201701.doi:10.21542/gcsp.2017.1 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28971101
    29. ↵
      2. Díez-Villanueva P ,
      3. García-Acuña JM ,
      4. Raposeiras-Roubin S , et al
      . Prognosis impact of diabetes in elderly women and men with non-ST elevation acute coronary syndrome. J Clin Med 2021;10. doi:doi:10.3390/jcm10194403. [Epub ahead of print: 26 Sep 2021].pmid:http://www.ncbi.nlm.nih.gov/pubmed/34640420
    30. ↵
      2. Murphy E
      . Estrogen signaling and cardiovascular disease. Circ Res 2011;109:687–96.doi:10.1161/CIRCRESAHA.110.236687 pmid:http://www.ncbi.nlm.nih.gov/pubmed/21885836
    31. ↵
      2. Young L ,
      3. Cho L
      . Unique cardiovascular risk factors in women. Heart 2019;105:1656–60.doi:10.1136/heartjnl-2018-314268 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31315936
    32. ↵
      2. McDonald SD ,
      3. Malinowski A ,
      4. Zhou Q , et al
      . Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J 2008;156:918–30.doi:10.1016/j.ahj.2008.06.042 pmid:http://www.ncbi.nlm.nih.gov/pubmed/19061708
    33. ↵
      2. McKenzie-Sampson S ,
      3. Paradis G ,
      4. Healy-Profitós J , et al
      . Gestational diabetes and risk of cardiovascular disease up to 25 years after pregnancy: a retrospective cohort study. Acta Diabetol 2018;55:315–22.doi:10.1007/s00592-017-1099-2 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29327149
    34. ↵
      2. Worrall-Carter L ,
      3. McEvedy S ,
      4. Wilson A , et al
      . Gender differences in presentation, coronary intervention, and outcomes of 28,985 acute coronary syndrome patients in Victoria, Australia. Womens Health Issues 2016;26:14–20.doi:10.1016/j.whi.2015.09.002 pmid:http://www.ncbi.nlm.nih.gov/pubmed/26701204
    35. ↵
      2. Mosca L ,
      3. Benjamin EJ ,
      4. Berra K , et al
      . Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association. Circulation 2011;123:1243–62.doi:10.1161/CIR.0b013e31820faaf8 pmid:http://www.ncbi.nlm.nih.gov/pubmed/21325087
    36. ↵
      2. Sarma AA ,
      3. Braunwald E ,
      4. Cannon CP , et al
      . Outcomes of Women Compared With Men After Non-ST-Segment Elevation Acute Coronary Syndromes. J Am Coll Cardiol 2019;74:3013–22.doi:10.1016/j.jacc.2019.09.065 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31865968
      OpenUrlFREE Full Text
    37. ↵
      2. Collet J-P ,
      3. Thiele H ,
      4. Barbato E , et al
      . 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021;42:1289–367.doi:10.1093/eurheartj/ehaa575 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32860058
    38. ↵
      2. Kunadian V ,
      3. Chieffo A ,
      4. Camici PG , et al
      . An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group. Eur Heart J 2020;41:3504–20.doi:10.1093/eurheartj/ehaa503 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32626906
    39. ↵
      1. National Institute for Health and Care Excellence
      . Acute Coronary syndromes : NSTEMI and unstable angina – early management [NG185] [Internet]: NICE Guidelines, 2020. Available: https://www.nice.org.uk/guidance/ng185/chapter/Recommendations#nstemi-and-unstable-angina-early-management [Accessed 20 May 2021].
    40. ↵
      2. Amsterdam EA ,
      3. Wenger NK ,
      4. Brindis RG , et al
      . 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: Executive summary: a report of the American College of Cardiology/American heart association Task force on practice guidelines. Circulation 2014;130:2354–94.doi:10.1161/CIR.0000000000000133 pmid:http://www.ncbi.nlm.nih.gov/pubmed/25249586
    41. ↵
      2. de Winter RJ ,
      3. Windhausen F ,
      4. Cornel JH , et al
      . Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005;353:1095–104.doi:10.1056/NEJMoa044259 pmid:http://www.ncbi.nlm.nih.gov/pubmed/16162880
    42. ↵
      2. Glaser R ,
      3. Herrmann HC ,
      4. Murphy SA , et al
      . Benefit of an early invasive management strategy in women with acute coronary syndromes. JAMA 2002;288:3124–9.doi:10.1001/jama.288.24.3124 pmid:http://www.ncbi.nlm.nih.gov/pubmed/12495392
    43. ↵
      2. Cannon CP ,
      3. Weintraub WS ,
      4. Demopoulos LA , et al
      . Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879–87.doi:10.1056/NEJM200106213442501 pmid:http://www.ncbi.nlm.nih.gov/pubmed/11419424
    44. ↵
      2. Lee PY ,
      3. Alexander KP ,
      4. Hammill BG , et al
      . Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA 2001;286:708–13.doi:10.1001/jama.286.6.708 pmid:http://www.ncbi.nlm.nih.gov/pubmed/11495621
    45. ↵
      2. Álvarez Álvarez B ,
      3. Abou Jokh Casas C ,
      4. Agra Bermejo R , et al
      . Sex-Related differences in long-term mortality and heart failure in a contemporary cohort of patients with NSTEACS. The cardiochus-HSUJ registry. Eur J Intern Med 2020;81:26–31.doi:10.1016/j.ejim.2020.06.011 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32563689
    46. ↵
      2. Vogel B ,
      3. Acevedo M ,
      4. Appelman Y , et al
      . The Lancet women and cardiovascular disease Commission: reducing the global burden by 2030. Lancet 2021;397:2385-2438.doi:10.1016/S0140-6736(21)00684-X pmid:http://www.ncbi.nlm.nih.gov/pubmed/34010613
    47. ↵
      2. Reynolds HR ,
      3. Maehara A ,
      4. Kwong RY , et al
      . Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of myocardial infarction with nonobstructive coronary arteries in women. Circulation 2021;143:624–40.doi:10.1161/CIRCULATIONAHA.120.052008 pmid:http://www.ncbi.nlm.nih.gov/pubmed/33191769
    48. ↵
      2. Agewall S ,
      3. Beltrame JF ,
      4. Reynolds HR , et al
      . ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J 2017;38:143–53.doi:10.1093/eurheartj/ehw149 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28158518
    49. ↵
      1. Uppsala University KI
      2. Göteborg University
      3. University of Leeds
      4. University of Adelaide
      5. Oslo University Hospital
      6. New York University
      . Randomized Evaluation of Beta Blocker and ACEI/ARB Treatment in MINOCA Patients - MINOCA-BAT (MINOCA-BAT) Internet: Clinical Trials.gov 2020, 2021. Available: https://clinicaltrials.gov/ct2/show/NCT03686696 [Accessed 16 Jun 2021].

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    Footnotes

    • Contributors VK: conceived the idea, undertook multiple revisions. JJ: wrote the initial draft and undertook multiple revisions. MA, CW, HR and RM provided critical review.

    • Funding VK is supported by the British Heart Foundation Clinical Study Grant (CS/15/7/316), Newcastle NIHR Biomedical Research Centre and Institutional Research Grant from AstraZeneca (ISSBRIL0303).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.