In the United States and globally, cardiovascular disease (CVD) is the leading cause of mortality for women. Despite considerable improvements in cardiovascular mortality for women and men over the last 3 decades, a significant gap is still evident. Coronary heart disease remains understudied and undertreated in women. According to Mehta et al, the CVD mortality rate has been greater for women than men since 1985.¹

Since 1979, the CVD mortality rate has dropped dramatically in the developed world; however, more recent studies reveal that the coronary heart disease incidence and mortality among younger women has plateaued. Wilmot et al. analyzed coronary heart disease mortality data between 1979 and 2011 for U.S. adults older than 25 years. The results showed consistent mortality declines in adults over age 65. In stark contrast, men and women younger than 55 years initially showed a decline in mortality from 1979 to 1989, followed by subsequent stagnation over the next 2 decades. Young women, specifically, showed no improvements between 1990 and 1999.²

Overall outcomes for acute coronary syndromes (ACS) remain worse for women, providing a strong foundation for further research of sex-based differences. Berger et al. investigated the relationship between sex and 30-day mortality in ACS, comparing ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina (UA). The data for 136,247 patients (28% women) were collected from 11 independent, global randomized ACS clinical trials between 1993 and 2006.³ The most prominent finding relates to the relationship among mortality, sex, and type of ACS. Results revealed that in STEMI patients, 30-day mortality was higher among women yet diminished after adjustment (unadjusted odds ratio [OR] 2.29, 95% confidence interval [CI] 2.18-2.40; adjusted OR 1.15, 95% CI 1.06-1.24).³ For NSTEMI patients, the unadjusted risk was greater in women than men but after adjustment became lower (unadjusted OR 1.50, 95% CI 1.28-1.75; adjusted OR 0.77, 95% CI 0.63-0.95).³ For UA, both women and men had comparable unadjusted risk, yet after adjustment, women had a significantly lower 30-day mortality (unadjusted OR 0.86, 95% CI 0.72-1.03; adjusted OR 0.64, 95% CI 0.51-0.80).³ Overall, Berger et al. found a significant interaction between type of ACS and sex. The 30-day mortality risk among women was higher than men for patients with STEMI (p < 0.001). In NSTEMI and UA, the adjusted 30-day mortality risk was lower for women compared with men.³

Studies have also evaluated the mortality rates among men and women for different ACS. In a retrospective cohort study, Champney et al. evaluated the joint effects of sex, age, and type of myocardial infarction (MI). The study used patient data from 1,057 U.S. hospitals encompassing a total of 361,429 patients (35% women) from the National Registry of Myocardial Infarction (NRMI). They found that sex-related differences in mortality are age-dependent in STEMI and NSTEMI cases. Younger women had a higher in-hospital mortality rate than younger men, regardless of type of MI. In a risk-adjusted model, comorbidities and cardiovascular risk factors were shown to account for the majority of the sex-related mortality difference in younger patients. Still, after adjusting for comorbidities and risk factors, mortality stayed about 15-20% higher in younger women than in younger men. Champney et al. concluded that sex-related in-hospital mortality was dependent on age in both STEMI and NSTEMI patients. One possible factor explaining the higher in-hospital mortality of younger women compared with men was absence of chest pain.⁴

Women are typically older than men when hospitalized for MI and frequently present with less chest pain/discomfort. One study examined the relationship between lack of chest pain and higher mortality observed in younger women with MI. Canto et al. used the NRMI to analyze data from 1,143,513 patients (42% women). The overall proportion of MI patients who presented without chest pain/discomfort was significantly higher for women than men (42 vs. 30.7%; 95% CI; 41.8-42.1% vs. 30.6-30.8%; p < .001).⁵ Additionally, separate models were made for each age-stratum, and results showed that the absence of chest pain is more common in younger women. The same study found the in-hospital mortality rate was 14.6% for women and 10.3% for men. Younger women presenting without chest pain/discomfort had greater hospital mortality rates than men. This trend reversed with increasing age (Table 1). This study suggests that a key predictor of mortality in younger women could be the absence of chest pain. The three-way interaction between sex, age, and chest pain on mortality was statistically significant (p < 0.001).⁵

Table 1: Absence of Chest Pain is More Common in Younger Women With MI and Predicts Higher Mortality⁵

Age (years)	Hospital Mortality Adjusted OR (95% CI)
<45	1.18 (1-1.39)
45-54	1.13 (1.02-1.26)
55-64	1.02 (0.96-1.09)
65-74	0.91 (0.88-0.95)
>75	0.81 (0.79-0.83)

Clinical guidelines recommend that the time from hospital arrival to mechanical reperfusion—the door-to-balloon (D2B) time—should be as short as possible and within 90 minutes. Krumholz et al. analyzed data from the Centers for Medicare and Medicaid Services and reported on the D2B time in the United States during 2005-2010 stratified by sex, age, and race. The analysis found that median patient D2B times decreased from 96 minutes to 64 minutes over the period: more than a 30% decline. With data from 51,062 patients, results show a significant improvement in D2B time in both men and women, yet women continue to lag behind men each year.⁶

One study dove in further and investigated mortality trend sex differences from 1994 to 2006. Data were collected from the NRMI on 916,380 acute MI patients. Over the 12 years, in-hospital mortality decreased drastically in all patients, specifically more in women than men. Vaccarino et al. observed that in patients younger than 55 years, the decrease in mortality was 3 times larger in women than men. In contrast, the sex difference in mortality decrease became lower in older patients (p = 0.004 for the relationship among sex, age, and year). This concludes that the in-hospital mortality of young women less than 55 years has significantly improved over time. This study also found that 93% of the improved mortality of younger women is explained by improved risk factors: comorbidity and clinical characteristics on admission.⁷

Although long-term mortality outcomes are generally reported to be similar between men and women, outcomes do not account for differences in life expectancy. Bucholz et al. researched the impact of gender on life expectancy and the years of potential life lost following acute MI. This prospective cohort study used data from the Cooperative Cardiovascular Project of 146,743 patients (48.1% women) from 1994 to 1995.⁸ The unadjusted results showed that women lost approximately 10.5% more of their expected life than men after acute MI. After acute MI, men lost 41.8% of their remaining life, and women lost 52.3%.⁸ Bucholz et al. showed that even after adjusting for clinical presentation, medical history, treatment, and demographics, women still lost about 7.8% (standard error 0.3%) more remaining life than men.⁸ This difference in years of potential life lost between women and men indicates a need for further research into biological and psychosocial factors and barriers to care.⁸

According to the World Health Organization, there are 17.3 million deaths per year from CVD globally.⁹ Women account for over 50% of these deaths worldwide. Additional evidence that women have worse prognosis than men after STEMI comes from a global meta-analysis. An international research team conducted a global meta-analysis of STEMI care and outcomes, representing 29 countries, and included over 700,000 patients (32% women). The meta-analysis evaluated gender disparities in patient characteristics, mortality, and treatment times at several different time points: in-hospital, 30 days, and 1 year after the MI. Women in all countries had greater delays in D2B time. The results show a consistently higher mortality in women compared with men in hospital (OR 2.09 [1.91-2.28]) and at 12 months (OR 1.76 [1.63-1.90]).¹⁰ This research clearly highlights the gender discrepancy in mortality outcomes after STEMI. The study noted that some causes of the gender gap might include barriers to care and differences in women's risk factors, such as older age at the time of heart attack, and co-morbidities, such as diabetes.¹⁰

Despite the recent advancements in prevention and treatment of CVD, a significant gap remains. In the United States, although there has been a 30-40% overall decline in coronary heart disease mortality due to improved risk factor management, better systems of care, and improved D2B times, excess mortality in women with STEMI persists. Looking to the future, we need to be cognizant as a community to mitigate barriers and delayed diagnoses, include more women in clinical trials, and continue promoting the prevention of CVD worldwide.

References

1. 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.
2. Wilmot KA, O'Flaherty M, Capewell S, Ford ES, Vaccarino V. Coronary Heart Disease Mortality Declines in the United States From 1979 Through 2011: Evidence for Stagnation in Young Adults, Especially Women. Circulation 2015;132:997-1002.
3. Berger JS, Elliott L, Gallup D, et al. Sex differences in mortality following acute coronary syndromes. JAMA 2009;302:874-82.
4. Champney KP, Frederick PD, Bueno H, et al. The joint contribution of sex, age and type of myocardial infarction on hospital mortality following acute myocardial infarction. Heart 2009;95:895-9.
5. Canto JG, Rogers WJ, Goldberg RJ, et al. Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA 2012;307:813-22.
6. Krumholz HM, Herrin J, Miller LE, et al. Improvements in door-to-balloon time in the United States, 2005 to 2010. Circulation 2011;124:1038-45.
7. Vaccarino V, Parsons L, Peterson ED, Rogers WJ, Kiefe CI, Canto J. Sex differences in mortality after acute myocardial infarction: changes from 1994 to 2006. Arch Intern Med 2009;169:1767-74.
8. Bucholz EM, Normand SL, Wang Y, Ma S, Lin H, Krumholz HM. Life Expectancy and Years of Potential Life Lost After Acute Myocardial Infarction by Sex and Race: A Cohort-Based Study of Medicare Beneficiaries. J Am Coll Cardiol 2015;66:645-55.
9. World Health Statistics 2015 (World Health Organization website). 2017. Available at: http://www.who.int/gho/publications/world_health_statistics/2015/en/. Accessed 12/19/2017.
10. Jae Lee H, Lansky A, Mehta S, et al. Gender Disparities in ST-Elevation Myocardial Infarction Care and Outcomes in Emerging Countries: A Global Lumen Organization for Women (GLOW) Initiative and Call to Action. J Am Coll Cardiol 2016;67:2356.

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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