Women Have a Worse Prognosis Than Men Following STEMI: CON

Editor's Note: This is the Con article of a two-part Pro/Con Expert Analysis. Click here for the Pro article.

Women with ST-segment elevation myocardial infarction (STEMI) have worse mortality than men with STEMI, but multiple factors contribute to this sex difference, including older age at presentation, increased cardiovascular risk profile, differences in reperfusion time and therapy, and differences in STEMI pathophysiology in women. If all these factors are controlled for, is female sex a true predictor of worse outcomes post-STEMI?

Women with STEMI tend to be older at presentation, with worse cardiovascular risk profiles, including higher rates of hypertension, diabetes, and dyslipidemia.1,2 Multiple prior studies have demonstrated that sex differences in long-term mortality are no longer present when adjusted for age and cardiovascular risk profile.1-4 Although this suggests that female sex is not an independent predictor of long-term mortality, there is still a sex discrepancy in survival for young women <65 years when compared with similarly aged men.3 This vulnerable population was the target of investigation in the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young Acute Myocardial Infarction Patients) study, which found that nearly all men and women in the study aged 15-55 years with acute myocardial infarction had at least 1 cardiovascular risk factor, but women were less likely than men to be told they were at risk or have a provider discuss risk modification.5 If the cardiovascular risk profile in young women can be improved by early detection and prevention, we may be able to influence sex differences in STEMI outcomes in the younger population.

In addition to sex differences in baseline cardiovascular risk factors, differences in STEMI management contribute to sex disparities in STEMI mortality. Although there have been increases in percutaneous coronary intervention (PCI) rates for STEMI and hospitals providing STEMI-related PCI in the United States,6 sex differences in reperfusion management persist. The Nationwide Inpatient Sample Database study of young adults (age < 60 years) with STEMI from 2004 to 2011 in the United States found that young women with STEMI were less likely to undergo coronary angiography, were less likely to receive revascularization, and experienced more delays in reperfusion than young men; these differences remained despite adjustment for socio-demographics, comorbidities, and clinical factors.7 More recently, the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry—Get With The Guidelines demonstrated that from 2008 to 2014, contact-to-device time remained longer in women than men, and longer reperfusion time was associated with increased mortality for both women and men.8 This is consistent with the VIRGO analysis, which found that short-term and long-term mortality rate was higher in young patients who exceeded the recommended reperfusion goals (particularly for the PCI transfer patients) compared with patients who met the recommended perfusion guidelines.9 Thus, improvements in emergency service recognition of STEMI and protocols to facilitate rapid transfer to a PCI-capable center are essential in maximizing STEMI outcomes for both men and women. In addition, prescriptions of guidelines-based pharmacotherapies at discharge are lower in women compared with men post-myocardial infarction.2,4 In a regional PCI-based STEMI system database with a standardized STEMI protocol, no sex differences in in-hospital or long-term (5-year) age-adjusted mortality were present, suggesting that STEMI treatment disparities and mortality in women can be improved using STEMI protocols and systems (Figure 1).4

Figure 1: Age-Adjusted Mortality to 5 Years Stratified by Sex

Figure 1
The 5-year follow-up demonstrated an absence of a sex disparity in survival post-STEMI in a regional PCI-based STEMI system using a standardized STEMI protocol. Reprinted with permission from Wei et al.4

Sex differences in the pathophysiology of STEMI may also lead to differences in administration of and response to guidelines-based STEMI therapy. For example, compared with men, women are less likely to have a culprit lesion identified at the time of angiography and more likely to have non-obstructive coronary artery disease.3,4 Myocardial infarction with non-obstructive coronary arteries (MINOCA) is more common in women than men and is associated with a 4.7% all-cause mortality at 1 year.10,11 Mechanisms of MINOCA include plaque rupture, plaque ulceration, coronary vasospasm, embolism, spontaneous coronary artery dissection, and Takotsubo cardiomyopathy.10 There are currently no national guidelines for the diagnosis and management of MINOCA. The VIRGO investigators found that approximately 1 in 8 young women with acute myocardial infarction are unclassified by the universal definition of myocardial infarction and proposed a new taxonomy for acute myocardial infarction to better phenotype patients and to ultimately determine optimal treatment strategies.12 The American Heart Association scientific statement on acute myocardial infarction in women also recognized this knowledge gap and recommended sex-specific examination of coronary pathophysiology and optimal diagnostic strategies to close the gap in sex disparities.13

One may hypothesize that women should actually have lower STEMI mortality than men because Thrombolysis in Myocardial Infarction flow pre-PCI is higher in women and because peak cardiac enzymes are lower in women compared with men.4 In addition, in a study of patients who underwent reperfusion with primary PCI post-STEMI and cardiac magnetic resonance imaging, higher myocardial salvage, smaller percent infarct size, and microvascular damage were observed in women compared with men, suggesting sex-based differences in myocardial response to ischemic injury and reperfusion, possibly due to ischemic preconditioning.14 However, a recent pooled analysis of patients with STEMI demonstrated that percent infarct size does not appear to contribute to long-term prognosis in women versus men after STEMI.15 Thus, application of guideline therapy after STEMI may be particularly essential in women to protect their higher amount of salvaged myocardium in the acute phase.

Although women with STEMI overall do have worse mortality compared with men, this worse outcome appears to be driven by multiple factors, including higher baseline age and worse cardiovascular risk profile, longer reperfusion times and fewer guideline-based pharmacotherapies, and differences in STEMI pathophysiology. We need to take advantage of our knowledge of these sex differences to improve STEMI outcomes in women. Using a standardized PCI-based STEMI protocol, age-adjusted survival is the same in women and men. Early cardiovascular risk factor identification and optimal guideline-based therapy are essential to improve STEMI outcomes in younger women, as is further investigation into the recognition, evaluation, and treatment of MINOCA.

References

  1. Pancholy SB, Shantha GP, Patel T, Cheskin LJ. Sex differences in short-term and long-term all-cause mortality among patients with ST-segment elevation myocardial infarction treated by primary percutaneous intervention: a meta-analysis. JAMA Intern Med 2014;174:1822-30.
  2. Yu J, Mehran R, Grinfeld L, et al. Sex-based differences in bleeding and long term adverse events after percutaneous coronary intervention for acute myocardial infarction: three year results from the HORIZONS-AMI trial. Catheter Cardiovasc Interv 2015;85:359-68.
  3. Otten AM, Maas AH, Ottervanger JP, et al. Is the difference in outcome between men and women treated by primary percutaneous coronary intervention age dependent? Gender difference in STEMI stratified on age. Eur Heart J Acute Cardiovasc Care 2013;2:334-41.
  4. Wei J, Mehta PK, Grey E, et al. Sex-based differences in quality of care and outcomes in a health system using a standardized STEMI protocol. Am Heart J 2017;191:30-36.
  5. Leifheit-Limson EC, D'Onofrio G, Daneshvar M, et al. Sex Differences in Cardiac Risk Factors, Perceived Risk, and Health Care Provider Discussion of Risk and Risk Modification Among Young Patients With Acute Myocardial Infarction: The VIRGO Study. J Am Coll Cardiol 2015;66:1949-57.
  6. Shah RU, Henry TD, Rutten-Ramos S, Garberich RF, Tighiouart M, Bairey Merz CN. Increasing percutaneous coronary interventions for ST-segment elevation myocardial infarction in the United States: progress and opportunity. JACC Cardiovasc Interv 2015;8:139-46.
  7. Khera S, Kolte D, Gupta T, et al. Temporal Trends and Sex Differences in Revascularization and Outcomes of ST-Segment Elevation Myocardial Infarction in Younger Adults in the United States. J Am Coll Cardiol 2015;66:1961-72.
  8. Roswell RO, Kunkes J, Chen AY, et al. Impact of Sex and Contact-to-Device Time on Clinical Outcomes in Acute ST-Segment Elevation Myocardial Infarction-Findings From the National Cardiovascular Data Registry. J Am Heart Assoc 2017;6:e004521.
  9. D'Onofrio G, Safdar B, Lichtman JH, et al. Sex differences in reperfusion in young patients with ST-segment-elevation myocardial infarction: results from the VIRGO study. Circulation 2015;131:1324-32.
  10. Pasupathy S, Tavella R, Beltrame JF. The What, When, Who, Why, How and Where of Myocardial Infarction With Non-Obstructive Coronary Arteries (MINOCA). Circ J 2016;80:11-6.
  11. Agewall S, Beltrame JF, Reynolds HR, et al. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J 2017;38:143-53.
  12. Spatz ES, Curry LA, Masoudi FA, et al. The Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) Classification System: A Taxonomy for Young Women With Acute Myocardial Infarction. Circulation 2015;132:1710-8.
  13. Mehta LS, Beckie TM, DeVon HA, et al. Acute Myocardial Infarction in Women: A Scientific Statement From the American Heart Association. Circulation 2016;133:916-47.
  14. Canali E, Masci P, Bogaert J, et al. Impact of gender differences on myocardial salvage and post-ischaemic left ventricular remodelling after primary coronary angioplasty: new insights from cardiovascular magnetic resonance. Eur Heart J Cardiovasc Imaging 2012;13:948-53.
  15. Kosmidou I, Redfors B, Selker HP, et al. Infarct size, left ventricular function, and prognosis in women compared to men after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: results from an individual patient-level pooled analysis of 10 randomized trials. Eur Heart J 2017;38:1656-63.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Stable Ischemic Heart Disease, Aortic Surgery, Cardiac Surgery and CHD & Pediatrics, Cardiac Surgery and Heart Failure, Cardiac Surgery and SIHD, Congenital Heart Disease, CHD & Pediatrics and Imaging, CHD & Pediatrics and Interventions, CHD & Pediatrics and Prevention, CHD & Pediatrics and Quality Improvement, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Structural Heart Disease, Angiography, Magnetic Resonance Imaging, Nuclear Imaging, Hypertension, Chronic Angina

Keywords: Acute Coronary Syndrome, Angina, Unstable, Cardiovascular Diseases, Chest Pain, Comorbidity, Confidence Intervals, Coronary Angiography, Coronary Artery Disease, Coronary Disease, Coronary Vasospasm, Coronary Vessel Anomalies, Demography, Diabetes Mellitus, Dyslipidemias, Embolism, Factor VII, Female, Follow-Up Studies, Goals, Hospital Mortality, Hypertension, Incidence, Inpatients, Ischemic Preconditioning, Life Expectancy, Magnetic Resonance Imaging, Myocardial Infarction, Myocardium, Percutaneous Coronary Intervention, Phenotype, Prognosis, Prospective Studies, Registries, Research Personnel, Retrospective Studies, Risk Factors, Sex Characteristics, Takotsubo Cardiomyopathy, Vulnerable Populations, Young Adult


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