Acute Coronary Syndrome: The Risk to Young Women

The ISACS‐TC (International Survey of Acute Coronary Syndromes in Transitional Countries) is a large observational and multinational registry.^{12, 13, 14, 15, 16} Data were collected from 41 centers. Among these centers, there were 22 tertiary healthcare services providing advanced medical investigation and treatment, including percutaneous coronary intervention (PCI) and/or cardiac surgery, and 19 secondary healthcare services providing intensive care in critical coronary care units. The data coordinating center has been established at the University of Bologna (Bologna, Italy). The study was approved by the local research ethics committee from each hospital. Because patient information is collected anonymously, institutional review boards waive the need for individual informed consent.

The study population consisted of 14 931 eligible patients with ACS enrolled between October 2010 and April 2016. Appropriateness of inclusion was adjudicated by a cardiology specialist, considering clinical history, physical examination findings, ECG, and cardiac biomarkers.¹⁷ Patients included in the analysis were categorized into 2 groups: young patients, aged ≤45 years; and old patients, aged >45 years.

The angiographic substudy of ISACS‐TC was performed in the 22 tertiary healthcare services providing PCI and/or cardiac surgery, and it included 7723 angiograms. All angiograms were reviewed for complete 3‐vessel assessment of extent and burden of CAD. The presence of significant coronary disease was defined as a stenosis of at least 50% in a major epicardial vessel. Coronary thrombus was defined as an intraluminal filling defect or an area of contrast staining noted within the stenosis. Multivessel disease was defined as at least 2 main branches of the epicardial coronary artery with ≥50% stenotic lesions or ≥50% stenosis in the left main coronary artery.

The primary end point was 30‐day all‐cause mortality. In‐hospital within 24 hours medication and the use of PCI or fibrinolysis was noted. Baseline risk was estimated using the TIMI (Thrombolysis in Myocardial Infarction) Risk Index score, which was calculated for each patient using the following equation: [heart rate×(age/10)²/systolic blood pressure].¹⁸ Patients were grouped into 2 simplified risk categories: low risk (range, <12.5) and medium‐high risk (range, ≥12.5).

We compared the baseline characteristics, management, angiographic findings, and clinical outcomes between young patients (aged ≤45 years) and old patients (aged >45 years). Baseline characteristics were reported as numbers and percentages for categorical variables and as mean±SD or median and interquartile percentile range for continuous variables. Comparisons between groups were made by either χ² test for baseline categorical variables and a 2‐sample t test or Kruskal‐Wallis rank‐sum test for continuous variables. Multivariable logistic‐regression analyses were performed to evaluate the relations between baseline characteristics and the occurrence of death at 30 days and clinical presentation of ACS at a young age. Fixed covariates included in the analyses were as follows: sex; cardiovascular risk factors (history of hypercholesterolemia, hypertension, and diabetes mellitus, smoking status, family history of CAD, and body mass index [BMI]); clinical history of ischemic heart disease (prior angina pectoris, prior myocardial infarction, prior PCI, and prior coronary artery bypass graft surgery); clinical history of cardiovascular disorders (prior peripheral artery disease, prior heart failure, and prior stroke); severity of clinical presentation (STEMI at index event, systolic blood pressure and heart rate at hospital admission, TIMI Risk Index, and chronic kidney disease); and time from symptom onset to hospital admission of ≤12 hours. Covariates introduced in the secondary analyses, as categorical variables, were as follows: in‐hospital within 24 hours medication (specifically aspirin, clopidogrel, heparins, β blockers, and angiotensin‐converting enzyme inhibitors) and reperfusion therapy, which included PCI and fibrinolysis. Further analyses were performed to evaluate sex differences in the severity of CAD (significant versus nonobstructive) and the extent of the disease (number of diseased vessels with significant stenosis).

We had complete data on age, sex, and 30‐day mortality. Some patients had missing data on other variables. We imputed the missing values of the clinical variables whose missing rate was <10% using STATA software. For the clinical features, whose missing rate was >10%, we performed a Pearson χ² statistical test for independence between those features and mortality. Only the variable “hypercholesterolemia” had missing rates of >10%, and it was statistically dependent on the end point of mortality. We, therefore, did not dismiss this variable from the predictive model of mortality, and we kept it as missing.¹⁹

For all analysis, statistical significance was defined as P<0.05, and STATA 11 (StataCorp, College Station, TX) was used.

Table 1 lists the characteristics of patients based on age. Young patients were more commonly men and more likely to be smokers compared with old patients. Young patients also had fewer comorbidities: they less commonly had diabetes mellitus, hypercholesterolemia, and hypertension. More young patients had a family history of CAD and had a higher BMI.

Baseline angiographic data in the young population ranged from 3‐vessel disease in 7.2% to no significant stenoses in 11.4% of patients. Younger patients had a higher incidence of single‐vessel disease (62.7% versus 46.6%). Conversely, 3‐vessel disease was less common (7.2% versus 15.9%) in the young patients. Young patients had significantly less calcification. There was a predilection for the presence of significant CAD in the left anterior descending artery in the young group. There was a trend toward more nonobstructive disease in young women versus young men, although this did not reach statistical significance (15% versus 10.7%). The specific coronary arteries with disease are delineated for each population in Table 2.

The distribution of STEMI and non–ST‐segment–elevation ACS was significantly different between young and old patients: STEMI was the most common clinical manifestation of ACS in the young cases (Table 1). Young patients were at lower risk, as assessed by the TIMI Risk Index. More young patients reached the hospital before 12 hours from symptom onset. Multivariate analysis showed 3 clinical variables that were identified as independent risk factors for the occurrence of ACS in the young population: male sex, smoking habit, and higher BMI (Figure 1).

Initial management of ACS in young patients differed slightly from the standard management in the old group. The rate of administration of aspirin and clopidogrel was higher in young patients. In contrast, young patients less frequently received angiotensin‐converting enzyme inhibitors. More young patients received PCI, both for STEMI and non–ST‐segment–elevation ACS (Table 1).

When all of the clinical baseline variables were assessed simultaneously in multivariable analysis (Table 3), there were 7 factors positively associated with 30‐day all‐cause mortality: female sex, history of diabetes mellitus, greater TIMI Risk Index, STEMI as the index event, chronic kidney disease, clinical presentation with a higher heart rate, and clinical history of cardiovascular disorders. Age of ≤45 years had a significant protective effect on mortality (odds ratio [OR], 0.44; 95% confidence interval, 0.23–0.82). Multiple regression analysis was then repeated separately for men and women (Table 3). Interestingly, young age remained a factor associated with survival in men (OR, 0.24; 95% confidence interval, 0.10–0.58), but not in women (OR, 1.35; 95% confidence interval, 0.50–3.62). The adjusted OR for mortality associated with younger age did not change when controlling for medications used at hospital admission and reperfusion therapy (Figure 2).

Regression analysis in the young patients revealed that the only variable associated with 30‐day mortality was female sex: younger women had worse outcomes than men of a similar age (OR, 6.03; 95% confidence interval, 2.07–17.53), even after adjusting for use of guideline‐recommended medications and reperfusion therapy (Table 4 and Figure 3).

The demographic and clinical profiles of the young patients enrolled in the ISACS‐TC registry are comparable with those of young patients in other large studies of patients with ACS.^{3, 7, 26} The present study showed that ≈8% of all patients hospitalized with ACS were aged ≤45 years. In the GRACE (Global Registry of Acute Coronary Events) study, the frequency of young patients with ACS was 6.3%⁷; in the Thai ACS Registry and the ACS Spain Registry, the proportion of young people with ACS was 5.8% and 7%, respectively.^{3, 26} The mean age of our young ACS cohort was 40.3±6 years, which is consistent with prior work.^{1, 3, 7} Sex distribution also followed a pattern already observed in previous studies, with a lower percentage of women in the young‐age group.^{1, 3, 7}

In the current study, smoking and a higher BMI were independent predictors of ACS in the young population. One potential explanation for these findings could be a lack of awareness and poorer control of risk factors among the young population. This is consistent with population‐based estimates. The National Health and Nutrition Examination Survey reported that, although significant reductions were observed in the proportion of the US elderly population having traditional risk factors from 1999 to 2010, no significant declines were observed for women <60 years and men <40 years.²⁷ Our results are concordant with previous findings in which a high BMI was most predictive of death from cardiovascular disease among men and women in all age groups, but the relative increase in risk associated with a high BMI declined with increasing age.²⁸ Our data are also in keeping with recent data showing that smokers who were <50 years had the worst discrepancy in risk of STEMI: >8 times that of former and never smokers.²⁹ Overall, these findings suggest inadequacy of screening and risk factor control efforts among young people.

To our knowledge, we are the first to demonstrate that young age is independently predictive of lower 30‐day mortality after multivariate analysis among men, but not women, with ACS. When multivariate regression was performed on outcomes from the Get With the Guidelines‐Coronary Artery Disease registry, consistent with our data, the sex difference in short‐term mortality was greater in the younger cohort than in the older cohort. However, differences across sexes (young versus old women or young versus old men) were not examined.¹ Differences between the results of that study and ours may be also attributable to inclusion of only patients with STEMI and lack of angiographic data on the severity and extent of CAD. Other studies have demonstrated that young age is associated with an increased relative risk of cardiovascular death^{30, 31} in women who present with acute myocardial infarction. However, these results are derived from long‐term follow‐up data rather than the early 30‐day mortality that we present, and they are not specifically representative of the overall spectrum of patients with ACS. The definition of what constitutes a young patients often differs in such studies and may constitute a further barrier for comparison with our study.

Atherosclerosis of the coronary arteries is known to have an impact on the development and severity of ACS.³² Given that young patients with ACS presented an average of 2 decades earlier than old patients and with fewer risk factors, it is conceivable that we observed less multivessel disease, less calcification, and fewer ostial lesions in young people compared with old people. There was a predilection for the presence of significant CAD in the left anterior descending artery in the young group, as previously documented.^{33, 34} An interesting observation is that the proportion of nonobstructive CAD was similar in the young women and men (15% versus 10%), but the mortality rate was higher in women. Thus, sex differences in 30‐day mortality in young people are not explained by the difference in the severity of angiographically documented disease. Other aspects may account for the difference in outcomes between young women and men and may be related to vascular biological factors, such as lower coronary flow reserve, more vascular stiffness, and functional differences of smooth muscle cells in the vessel wall.^{35, 36} The issue of menopause is not thoroughly defined. The Framingham Heart Study reported a higher risk of cardiovascular disease in postmenopausal women that was even more pronounced in women aged 40 to 44 years,³⁷ whereas the Nurses’ Health Study found no significant association with time since natural menopause.³⁸ Socioeconomic status and level of depression may also play an important role in ACS prognosis in women.^{39, 40}

There are some limitations that must be noted. The current analysis is an observational study; therefore, we cannot excluded possible confounding variables that were not controlled. An ACS diagnosis in young patients could be problematic because myocarditis can mimic acute myocardial infarction. Thus, the prevalence of ACS at a young age might be influenced by an overdiagnosis or a misdiagnosis. We have no data about the use of substances in our patients, especially marijuana and sympathomimetic amines, which have been found to correlate with ACS at a younger age.⁴¹ Furthermore, the lack of a universal definition of “young” patients made the comparison among the few studies performed on this issue hard.