Abstract
Background
Studies have reported that women with ST elevation myocardial infarction (STEMI) have worse short- and long-term outcomes than men. It has not yet been confirmed whether these differences reflect differences in age between men and women.
Methods
We retrospectively enrolled 1035 consecutive STEMI patients treated with primary percutaneous coronary intervention (PCI). Baseline clinical characteristics, coronary anatomy, and outcome were compared between young (< 65 years old) and older patients (≥ 65 years old) of both sexes.
Results
Younger women presented with a lower incidence of typical angina (83% vs. 93%, p = 0.03), single-vessel disease (21% vs. 35%, p = 0.03), and total occlusion of infarct-related artery (65% vs. 83%, p = 0.001) than younger men, with no gender difference noted in the older group. Younger women in the study had a higher incidence of reinfarction, heart failure requiring admission, or mortality (23% vs. 6%, p < 0.001) during follow-up, compared with younger men, with no gender difference in the older group. Using the Kaplan-Meier analysis, younger women had lower rates of event-free survival (p < 0.001 by log-rank test) than younger men, with no gender difference in the older group. In multivariate analysis, age could predict long-term outcome in men (Hazard ratio 4.43, 95% confidence interval: 2.89-6.78, p < 0.001) but not in women.
Conclusions
In STEMI patients receiving primary PCI, sex-related long-term outcome differences were age-dependent, with younger women likely to have a worse long-term outcome when compared with younger men.
Keywords: Coronary heart disease, Gender, Myocardial infarction
INTRODUCTION
Acute myocardial infarction (MI) is the leading cause of morbidity and mortality among both women and men in substantial areas of the world, but there are several clinically important differences between how MI impacts the two sexes. Although the incidence of acute MI increases with age, women are less prone to developing acute MI than men at any given age, with a lag of approximately 10 years between the sexes.1-5 Compared with men, women with acute MI have higher incidences of associated diabetes, hypertension, hypertriglyceridemia, and metabolic syndrome, and a higher mortality rate after acute MI.2,6-15 Some studies have suggested a link to less aggressive hospital care of female patients, including the possible underuse of revascularization, as an explanation for their increased mortality.16 Other studies have indicated that age and comorbidity are the primary factors leading to mortality differences.17 Recent clinical trials of patients with ST-segment elevation MI (STEMI) showed no significant mortality variation in women compared with men, across all age ranges.18-20 A selection bias due to differential enrollment by gender and the low levels of younger patients in clinical trials might explain the failure of these studies to demonstrate excess mortality among younger women. Currently, it is unknown whether mortality among younger women gives rise to the excess mortality rates found in female patients with STEMI.
Because men and women differ in clinical presentation and prognostic factors, examining the relationship between sex and mortality according to patient age should shed light into the potential reasons for sex-related differences in short- and long-term outcomes after STEMI. Therefore, the aim of the present study was to examine the relationship between sex and age on short- and long-term outcomes in patients with STEMI receiving primary percutaneous coronary intervention (PCI).
METHODS
Patients
This retrospective study was approved by the local ethics committee; the informed consent requirement was waived because of the study’s retrospective design. To facilitate comparisons between men and women while striving to retain sufficient statistical power in each age group, we arbitrarily selected a cutoff point of 65 years to differentiate between younger and older patients. We analyzed the patients’ age- and sex-specific clinical characteristics, reperfusion therapy, angiographic findings, and short- and long-term clinical outcomes.
Definitions
STEMI was defined by the following criteria: (1) a typical chest pain lasting at least 20 minutes; (2) elevated serum cardiac biomarkers at least twice the upper limit of normal; (3) ST segment elevation of 1 mm or more with subsequent evolution of negative T-waves with a depth of 1 mm or more, development of new Q-waves of ≥ 0.04 seconds in duration, or deeper than one fourth of the following R wave in voltage.21 All the patients had complete occlusion or critical stenosis of infarct-related arteries confirmed by coronary angiography. Current smoking was defined as smoking up to 1 month before admission. Hyperlipidemia was defined as a previous diagnosis by a physician, receiving lipid-lowering therapy, or either total cholesterol over 200 mg/dl or serum triglycerides over 150 mg/dl. Hypertension was defined as a previous diagnosis by a physician, receiving anti-hypertensive therapy, or known blood pressure values of ≥ 140 mmHg systolic or ≥ 90 mmHg diastolic on 2 or more occasions. Diabetes was defined as previous diagnosis by a physician. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate (eGFR) less than 60 ml·min-1 1.73 m-2, and eGFR was measured using the Modification of Diet in Renal Disease (MDRD) study group equation developed in 1999.22 For evaluation of the peak serum cardiac biomarker activity, blood samples were obtained every 6 hours for 48 hours or until the activity returned to normal. The reference values for creatine kinase (CK) and CK-MB were 26-192 IU/L and 7-25 IU/L, respectively. Blood samples for the lipid profile were drawn after an 8-hour fast during the index hospitalization.
Coronary angiography
After providing written informed consent, all patients received coronary artery angiography. Judgment of vessel flow was based on the Thrombolysis in Myocardial Infarction (TIMI) flow grade. Angiographic stenosis was defined as a diameter reduction of ≥ 50%. Critical stenosis was defined as ≥ 70% narrowing of the coronary artery luminal diameter. Complete coronary occlusion was defined as the total absence of anterograde flow of contrast media or TIMI flow grade 0 in the infarct-related coronary artery. The infarct-related lesion was identified based on morphology including complete occlusion, thrombus, and ulcerative stenosis, or assumed to be the tightest stenosis if these features were absent.
Endpoints
The following clinical outcomes were analyzed: length of hospital stay, in-hospital mortality and morbidity, repeated PCI, reinfarction, and mortality during follow-up. Repeated PCI was defined as unstable angina that required repeated revascularization during follow-up. Clinical follow-up variables, including repeated PCI, reinfarction, heart failure requiring admission, and mortality were obtained at clinic visits, and by telephone conversation and chart review. For those patients without follow-up in our outpatient department, we followed the patients by telephone conversation by our research assistant.
Statistics
All analyses were performed using PASW software, version 18.0, and quantitative data are expressed as mean ± SD. The chi-square test or Fisher’s exact test was used to analyze the non-normal data. If the expected value of any cell was < 5, then a Fisher’s exact test was used. A p value of < 0.05 was considered statistically significant. A multivariable analysis with a Cox regression model was conducted separately for the 2 age groups, to identify the baseline variables independently associated with in-hospital morbidity and mortality. The selection of variables was restricted to variables that were identified a priori as relevant on the basis of clinical experience and variables with a p value less than .05 in the univariate model. The variables that were independently associated with in-hospital morbidity and mortality are presented as odds ratios followed by 95% confidence interval (CI). A significant hazard ratio was obtained if the 95% CI did not contain 1, and the p value was less than 0.05. The event-free (defined as free of reinfarction, heart failure requiring admission, or mortality) survival curves were constructed using the Kaplan-Meier method. The significance of the difference between the curves was assessed by the log-rank test.
RESULTS
Between April 1992 and December 2008, 1035 patients were admitted for STEMI and primary PCI in this institution. Of these 1035 patients, 850 patients (82%) were male, and 185 (18%) were female.
During this period, the mean age in men declined from 63.5 years in 1992 to 56.6 years in 2008 (slope -0.42), and in women it declined from 74.0 years in 1992 to 66.8 years in 2008 (slope -0.32) (Figure 1). The mean age of women was consistently older than men. Overall, the mean age was 60 ± 7.6 years, (range 26 to 98 years old), and women were older than men (69 ± 12 vs. 59 ± 12 years, p < 0.001).
Figure 1.
Trends in mean age of study patients by gender, year 1992-2008.
Of the 1035 study patients, 618 patients were < 65 years old, including 57 (9%) women and 561 (91%) men, and 417 were ≥ 65 years old, including 128 (31%) women and 289 (69%) men.
Coronary risk factors and prior disease
Among the younger men, 67% were smokers, compared with 16% (p < 0.001) among the younger women, and 55% and 10% (p < 0.001), respectively, among the older men and women (Table 1). Diabetes, hypertension, and hyperlipidemia were more common in women than men, irrespective of age. Women and men had similar BMI, prevalence of CKD, heart failure, and previous coronary artery disease, and history of cerebral vascular accident, also irrespective of age.
Table 1. Comparison of patient characteristics and clinical presentation between women and men according to age.
| < 65 years | ≥ 65 years | |||||
| Age groups | Women (n = 57) | Men (n = 561) | p value | Women (n = 128) | Men (n = 289) | p value |
| Age | 55 ± 8 | 52 ± 8 | 0.008 | 76 ± 8 | 73 ± 6 | < 0.001 |
| Body mass index (kg/m2) | 27 ± 4 | 26 ± 3 | 0.35 | 25 ± 4 | 24 ± 3 | 0.58 |
| Smoking | 9 (16) | 375 (67) | < 0.001 | 13 (10) | 159 (55) | < 0.001 |
| Diabetes mellitus | 35 (61) | 141 (25) | < 0.001 | 61 (48) | 88 (30) | 0.001 |
| Hypertension | 35 (61) | 260 (46) | 0.007 | 82 (64) | 149 (52) | 0.01 |
| Hyperlipidemia | 22 (39) | 141 (25) | 0.03 | 30 (23) | 37 (13) | 0.006 |
| Chronic kidney disease | 12 (21) | 107 (19) | 0.72 | 43 (33) | 98 (34) | 0.95 |
| Heart failure | 0 (0) | 10 (2) | 0.31 | 10 (8) | 10 (4) | 0.06 |
| Previous coronary artery disease | 4 (7) | 30 (5) | 0.6 | 14 (11) | 27 (9) | 0.62 |
| History of cerebral vascular accident | 3 (5) | 16 (3) | 0.32 | 10 (8) | 31 (11) | 0.36 |
| Presentation at emergency department | ||||||
| Typical angina | 47 (83) | 519 (93) | 0.03 | 105 (82) | 249 (86) | 0.28 |
| Killip class ≥ III | 20 (35) | 131 (23) | 0.09 | 49 (38) | 105 (36) | 0.7 |
| Laboratory analysis | ||||||
| Anemia (hemoglobin < 10 mg/dl) | 5 (9) | 9 (2) | 0.001 | 19 (15) | 14 (5) | 0.001 |
| CK (IU/L) | 2398 ± 1974 | 3286 ± 2778 | 0.02 | 2066 ± 2037 | 2824 ± 2732 | 0.005 |
| CK-MB (IU/L) | 211 ± 180 | 277 ± 254 | 0.06 | 197 ± 158 | 266 ± 284 | 0.01 |
| Cholesterol (mg/dl) | 201 ± 51 | 190 ± 42 | 0.08 | 189 ± 52 | 171 ± 38 | < 0.001 |
| Triglyceride (mg/dl) | 226 ± 203 | 159 ± 147 | 0.003 | 130 ± 89 | 111 ± 93 | 0.07 |
| High-density lipoprotein (mg/dl) | 44 ± 14 | 41 ± 13 | 0.17 | 48 ± 18 | 43 ± 13 | 0.03 |
| Low-density lipoprotein (mg/dl) | 124 ± 42 | 121 ± 38 | 0.77 | 121 ± 45 | 109 ± 33 | 0.02 |
| Door to balloon time, min | 91.4 ± 14.9 | 93.3 ± 34.9 | 0.9 | 85.4 ± 32.4 | 96.4 ± 36.1 | 0.05 |
| LVEF, by heart echo | 55 ± 5 | 57 ± 13 | 0.69 | 42 ± 26 | 41 ± 25 | 0.8 |
Values are presented as number (%) and mean ± SD.
CK, creatine kinase; CK-MD, creatine kinase-MB; LVEF, left ventricular ejection fraction.
Clinical presentation
Younger women were significantly less likely to present with typical angina on admission (83% vs. 93%, p = 0.03) than younger men (Table 1). There was no difference with respect to Killip classification, initial vital signs on arrival, door-to-balloon time and left ventricular ejection fraction among men and women, irrespective of age. More women presented with anemia compared with men, irrespective of age (9% vs. 2%, p = 0.02 in the younger group; 15% vs. 5%, p = 0.001 in the older group). Younger women had lower levels of CK activity (2398 ± 1974 IU/L vs. 3286 ± 2778 IU/L, p = 0.02) and triglyceride (159 ± 147 mg/dl vs. 226 ± 203 mg/dl, p = 0.003) than younger men. Older women had lower levels of CK activity (2066 ± 2037 IU/L vs. 2824 ± 2732 IU/L, p = 0.005) and C K-MB activity (266 ± 284 IU/L vs. 197 ± 158 IU/L, p = 0.01), and higher level of cholesterol (189 ± 52 mg/dl vs. 171 ± 38 mg/dl, p < 0.001), high-density lipoprotein (48 ± 18 mg/dl vs. 43 ± 13 mg/dl, p = 0.03), and low-density lipoprotein (121 ± 45 mg/dl vs. 109 ± 33 mg/dl, p = 0.02) than older men.
Coronary angiographic data and interventional therapy
Younger women had a higher prevalence of multi-vessel disease (79% vs. 65%, p = 0.03; Table 2) compared with younger men. Analysis of coronary angiogram data also showed that the left anterior descending artery was the most commonly involved infarct-related artery, followed by the right coronary artery and left circumflex artery in both men and women, irrespective of age. Younger women were less likely to have total occlusion of infarct-related artery than younger men (65% vs. 83%, p = 0.001). In both age groups, women had smaller stent diameter than men (3.0 ± 0.5 mm vs. 3.2 ± 0.5 mm, p = 0.001 in the younger group; 2.9 ± 0.3 mm vs. 3.1 ± 0.5 mm, p < 0.001 in the older group). In addition, women had similar stent number, stent length, post-PCI TIMI flow grade, and incidence of successful primary PCI, irrespective of age.
Table 2. Comparison of coronary angiographic features between women and men according to age.
| < 65 years | ≥ 65 years | |||||
| Age group | Women (n = 57) | Men (n = 561) | p value | Women (n = 128) | Men (n = 289) | p value |
| Number of diseased vessels | 0.03 | 0.28 | ||||
| Single-vessel disease | 12 (21) | 197 (35) | 29 (23) | 80 (28) | ||
| Multiple-vessel disease | 45 (79) | 364 (65) | 99 (77) | 209 (72) | ||
| Infarct-related artery | 0.85 | 0.64 | ||||
| Left main artery | 0 (0) | 5 (1) | 2 (2) | 12 (4) | ||
| Left anterior descending artery | 33 (58) | 292 (52) | 66 (52) | 153 (53) | ||
| Left circumflex artery | 5 (9) | 48 (9) | 12 (9) | 25 (9) | ||
| Right coronary artery | 19 (33) | 214 (38) | 47 (37) | 98 (34) | ||
| Intermediate artery | 0 (0) | 2 (0.4) | 0 (0) | 1 (1) | ||
| Total occlusion of infarct-related artery | 37 (65) | 463 (83) | 0.001 | 99 (77) | 217 (75) | 0.66 |
| Number of stents | 0.8 ± 0.5 | 0.8 ± 0.5 | 0.61 | 0.61 ± 0.64 | 0.76 ± 0.61 | 0.1 |
| Stent length (mm) | 20 ± 5 | 22 ± 7 | 0.17 | 21 ± 9 | 21 ± 8 | 0.9 |
| Stent diameter (mm) | 3.0 ± 0.5 | 3.2 ± 0.5 | 0.001 | 2.9 ± 0.3 | 3.1 ± 0.5 | < 0.001 |
| Post-PCI TIMI flow grade | 2.8 ± 0.8 | 2.7 ± 0.8 | 0.84 | 2.6 ± 1.0 | 2.6 ± 1.0 | 0.95 |
| Success of primary PCI | 52 (91) | 514 (92) | 0.92 | 110 (86) | 252 (87) | 0.72 |
| Intra-aortic balloon pump | 12 (21) | 100 (18) | 0.55 | 24 (19) | 75 (26) | 0.11 |
Values are presented as number (%) and mean ± SD.
PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.
Pharmacological treatment
Compared with men, women received similar in-hospital medical treatment as well as medication at follow-up, such as aspirin, clopidogrel, ticlopidine, angiotensin-converting enzyme inhibitors or angiotensin receptor blocker, beta-blocker, statin therapy and diuretic agents, irrespective of age (Table 3).
Table 3. Comparison of medical therapy at discharge between women and men according to age.
| < 65 years | ≥ 65 years | |||||
| Age group | Women (n = 57) | Men (n = 561) | p value | Women (n = 128) | Men (n = 289) | p value |
| Medication, at discharge, n (%) | ||||||
| Aspirin | 48 (84.2) | 503 (89.7) | 0.21 | 108 (84.4) | 252 (87.2) | 0.44 |
| Clopidogrel | 45 (79.0) | 397 (70.8) | 0.19 | 85 (66.4) | 213 (73.7) | 0.13 |
| Ticlopidin | 9 (15.8) | 91 (16.2) | 0.93 | 23 (18.0) | 54 (18.7) | 0.87 |
| Dual anti-platelet therapy | 48 (84.2) | 475 (84.7) | 0.93 | 96 (75.0) | 230 (79.6) | 0.3 |
| ACEi/ARB | 32 (56.1) | 307 (54.8) | 0.84 | 66 (51.6) | 162 (56.1) | 0.4 |
| Beta-blockers | 25 (43.9) | 264 (47.1) | 0.65 | 55 (43.0) | 119 (41.2) | 0.73 |
| Statin | 33 (57.9) | 262 (46.7) | 0.11 | 59 (46.1) | 131 (45.3) | 0.89 |
| Medication, at 6 months, n (%) | ||||||
| Aspirin | 46 (80.7) | 472 (84.1) | 0.5 | 102 (79.7) | 244 (84.4) | 0.24 |
| Clopidogrel | 40 (70.2) | 373 (66.5) | 0.57 | 82 (64.1) | 184 (53.7) | 0.24 |
| Ticlopidin | 12 (21.1) | 93 (16.6) | 0.39 | 19 (14.84) | 43 (14.9) | 0.99 |
| Dual anti-platelet therapy | 41 (71.9) | 405 (72.2) | 0.97 | 79 (61.7) | 201 (69.6) | 0.12 |
| ACEi/ARB | 36 (63.2) | 385 (68.6) | 0.4 | 81 (63.3) | 185 (64.0) | 0.89 |
| Beta-blockers | 31 (54.4) | 324 (57.8) | 0.62 | 66 (51.6) | 154 (53.3) | 0.75 |
| Statin | 36 (63.2) | 329 (58.6) | 0.51 | 70 (54.7) | 175 (60.6) | 0.26 |
Values are presented as number (%) and mean ± SD.
ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.
Prognosis
Older women experienced longer total hospital stays (11 ± 11 days vs. 9 ± 7 days, p = 0.01, Table 4) than older men. Older women also had a lower incidence of ventricular arrhythmia requiring defibrillation (6% vs. 13%, p = 0.03), and greater incidence of gastrointestinal bleeding requiring blood transfusion (20% vs. 8%, p < 0.001) than older men. There were no differences between men and women with respect to length of intensive care unit stay, in-hospital mortality, in-hospital morbidity rate (including cardiogenic shock, sepsis, cardiac rupture or tamponade, acute renal failure requiring hemodialysis, or intracranial hemorrhage), or in-hospital morbidity or mortality (all p > 0.05).
Both younger and older groups had similar follow-up periods (Table 4). The younger women had a higher incidence of heart failure requiring admission (12% vs. 1%, p < 0.001), and a higher incidence of reinfarction, heart failure requiring admission or mortality (23% vs. 6%, p < 0.001) than younger men, with no sex difference among older patients.
Table 4. Short- and long-term outcomes between women and men with STEMI according to age.
| < 65 years | ≥ 65 years | |||||
| Age group | Women (n = 57) | Men (n = 561) | p value | Women (n = 128) | Men (n = 289) | p value |
| Short-term outcome | ||||||
| Length of intensive care unit stay (day) | 4 ± 4 | 4 ± 3 | 0.36 | 5 ± 8 | 4 ± 4 | 0.23 |
| Length of total hospital stay (day) | 9 ± 8 | 8 ± 9 | 0.14 | 11 ± 11 | 9 ± 7 | 0.01 |
| In-hospital morbidity | 6 (11) | 110 (20) | 0.1 | 34 (27) | 80 (28) | 0.41 |
| Cardiogenic shock | 16 (28) | 108 (19) | 0.11 | 33 (26) | 83 (29) | 0.54 |
| Ventricular arrhythmia requiring defibrillation | 3 (0.2) | 63 (11) | 0.17 | 7 (6) | 36 (13) | 0.03 |
| Sepsis | 3 (5) | 15 (3) | 0.27 | 10 (8) | 24 (8) | 0.87 |
| Bleeding complications requiring blood transfusion | 4 (7) | 20 (4) | 0.2 | 26 (20) | 23 (8) | < 0.001 |
| Cardiac rupture/tamponade | 1 (2) | 3 (1) | 0.28 | 1 (1) | 4 (1) | 0.6 |
| Acute renal failure requiring hemodialysis | 1 (2) | 6 (1) | 0.64 | 3 (2) | 5 (2) | 0.67 |
| Intracranial hemorrhage | 0 (0) | 2 (0.4) | 0.65 | 1 (1) | 1 (0.4) | 0.55 |
| In-hospital mortality | 7 (12) | 40 (7) | 0.16 | 23 (18) | 49 (17) | 0.8 |
| In-hospital morbidity or mortality | 10 (18) | 129 (23) | 0.35 | 56 (44) | 125 (43) | 0.45 |
| Long-term outcome | ||||||
| Repeat percutaneous coronary intervention | 28 (49) | 236 (42) | 0.31 | 48 (38) | 105 (36) | 0.82 |
| Reinfarction | 3 (5) | 13 (3) | 0.27 | 6 (6) | 9 (3) | 0.25 |
| Heart failure requiring admission | 7 (12) | 7 (1) | < 0.001 | 18 (14) | 35 (12) | 0.58 |
| Mortality on follow-up | 4 (7) | 14 (3) | 0.05 | 12 (9) | 31 (11) | 0.68 |
| Reinfarction or heart failure requiring admission or mortality | 13 (23) | 35 (6) | < 0.001 | 30 (23) | 60 (21) | 0.6 |
| Follow-up duration, months | 50.3 ± 42.9 | 56.1 ± 45.4 | 0.33 | 36.3 ± 37.4 | 36.7 ± 35.4 | 0.92 |
Values presented as number (%) and mean ± SD.
The resulting Kaplan-Meier curves for event-free survival (with events defined as reinfarction, hear failure requiring admission, or mortality) were considerably different between women and men. Women had consistently lower event-free survival rates during the whole follow-up period in all populations (p < 0.001 by log-rank test, Figure 2A), and in the population under 65 years of age (p < 0.001 by log-rank test, Figure 2B), with no gender difference in patients older than 65 years (p = 0.70 by log-rank test, Figure 2C). Furthermore, older men had lower event-free survival rates during follow-up compared with younger men (supplementary data, Figure S1A) with no difference between older and younger women (Figure S1B).
Figure 2.
Gender differences of cumulative event-free survival curves by Kaplan-Meier analysis in (A) all patients, (B) patients < 65 years and (C) ≥ 65 years during long-term follow-up.
Figure S1.
Cumulative event-free survival curves for patients < 65 years and ≥ 65 years in (A) women and (B) men.
In women, diabetes [Hazard ratio (HR) 3.18, 95% confidence internal (CI): 1.64-6.14, p < 0.001], Killip ≥ III (HR 2.64, 95% CI: 1.13-6.17, p = 0.02), and CKD (HR 3.18, 95% CI: 1.59-6.36, p = 0.001), but not age, could predict reinfarction, heart failure requiring admission, or mortality during follow-up (Table 5). In contrast, in men, age (HR 4.81, 95% CI: 3.17-7.30, p < 0.001), diabetes (HR 1.80, 95% CI: 1.19-2.72, p = 0.006), and Killip ≥ III (HR 2.92, 95% CI: 1.42-6.00, p = 0.004) could predict reinfarction, heart failure requiring admission, or mortality during follow-up. Multivariate analysis indicated that diabetes (HR 3.36, 95% CI: 1.61-6.98, p = 0.001), chronic kidney disease [odds ratio (OR) 2.23, 95% CI: 1.05-4.75, p = 0.04], and statin therapy (OR 0.33, 95% CI: 0.16-0.72, p = 0.005) were significantly associated with reinfarction, heart failure requiring admission, or mortality in women during follow-up. In contrast, in men, age (OR 1.07, 95% CI: 1.05-1.10, p < 0.001), diabetes (OR 1.60, 95% CI: 1.01-2.55, p = 0.04) and beta-blockers (OR 0.38, 95% CI: 0.23-0.63, p < 0.001) were significantly associated with reinfarction, heart failure requiring admission, or mortality during follow-up.
Table 5. Baseline variables associated with reinfarction, heart failure requiring admission and mortality during follow-up by univariate and multivariate analysis with a Cox regression model.
| Women | Men | |||||||
| Univariate analysis | Multivariate analysis | Univariate analysis | Multivariate analysis | |||||
| HR (95% CI) | p value | HR (95% CI) | p value | HR (95% CI) | p value | HR (95% CI) | p value | |
| Age | 1.90 (0.98-3.69) | 0.06 | 1.34 (0.62-2.93) | 0.46 | 4.81 (3.17-7.30) | < 0.001 | 4.43 (2.89-6.78) | < 0.001 |
| Smoking | 1.53 (0.68-3.48) | 0.31 | 1.15 (0.73-1.79) | 0.55 | ||||
| Diabetes | 3.18 (1.64-6.14) | < 0.001 | 3.36 (1.61-6.98) | 0.001 | 1.80 (1.19-2.72) | 0.005 | 1.63 (1.07-2.48) | 0.02 |
| Hypertension | 1.11 (0.59-2.09) | 0.75 | 1.10 (0.74-1.65) | 0.64 | ||||
| Hyperlipidemia | 0.70 (0.32-1.52) | 0.37 | 0.69 (0.38-1.25) | 0.22 | ||||
| Chronic kidney disease | 3.14 (1.26-7.82) | 0.01 | 3.18 (1.59-6.36) | 0.001 | 1.83 (1.19-2.81) | 0.006 | 1.52 (0.98-2.36) | 0.06 |
| Killip < III | 2.64 (1.13-6.17) | 0.02 | 2.13 (0.86-5.29) | 0.1 | 2.92 (1.42-6.00) | 0.004 | 2.37 (1.24-4.50) | 0.009 |
| Door to balloon time, min | 0.94 (0.33-2.68) | 0.91 | 1.31 (0.7-2.44) | 0.4 | ||||
| Single vessel disease | 0.75 (0.36-1.56) | 0.44 | 0.77 (0.50-1.21) | 0.26 | ||||
| Beta-blockers | 0.73 (0.39-1.34) | 0.31 | 0.92 (0.46-1.83) | 0.82 | 0.72 (0.47-1.10) | 0.13 | 0.79 (0.53-1.19) | 0.27 |
| ACEi/ARB | 0.55 (0.29-1.04) | 0.07 | 0.57 (0.27-1.22) | 0.15 | 1.22 (0.77-1.94) | 0.4 | 0.88 (0.56-1.38) | 0.58 |
| Statin therapy | 1.09 (0.59-1.99) | 0.79 | 0.75 (0.39-1.42) | 0.37 | 1.29 (1.29-2.00) | 0.26 | 1.13 (0.73-1.75) | 0.57 |
ACEi, angiotensin converting enzyme inhibitors; ARB, angiotension receptor blockers; CI, confidence interval; HR, Hazard ratio.
DISCUSSION
Major findings
Women with STEMI were more likely than men to be non-smokers with diabetes, hypertension, hyperlipidemia, or anemia, irrespective of age. Infarct size was demonstrated to be smaller in women than in men, regardless of age. When mortality comparisons between women and men are undertaken, separating the younger and older patients, it becomes clear that younger women have a particularly adverse long-term prognosis compared with younger men; in contrast, older women have similar survival rates to older men.
Incidence
In the present study, patients with STEMI were predominantly male, and female patients made up about 20% of the patients admitted annually for STEMI in this institution. The mean age of women with STEMI was consistently older than men. This result is in line with previous studies indicating that women are less prone to developing STEMI than men, with a lag of approximately 10 years between the sexes. These findings may reflect different pathophysiologic processes, with STEMI being secondary to occlusive thrombus, while non-ST elevation acute coronary syndrome (NSTE-ACS) may reflect subtotal occlusion. Furthermore, in the present study, younger female patients with STEMI had significantly higher incidence of non-obstructive infarct-related arteries compared with younger men. However, there was no difference in incidence of non-obstructive infarct-related arteries between older women and men. These differences seem to be confined to younger patients, with a significant correlation between age and sex.
Differences in clinical presentation and risk factors among men and women
The interpretation of previous studies with respect to clinical presentation in acute coronary syndrome (ACS) is complicated because the study populations involved have varied substantially in inclusion criteria.6,8,9,11,13 Some studies have included patients with a broader range of ACS,6,9,13 but most of these studies investigated only patients with acute MI.7,8,10-12 Several clinical studies investigated only patients eligible for certain treatments, for example thrombolytic therapy.7,8,11-13 Of these studies, some did not analyze the differences in long-term outcome between women and men.6,7,9,13 Moreover, most of the studies did not include the Asian population. It is obvious that the selection criteria used are critical to any analysis of sex differences. The present study included Asian patients with STEMI receiving primary PCI, who form an important subset of patients with ACS.
In the present study, younger women had a higher incidence of diabetes, hypertension, hyperlipidemia, anemia, and atypical symptoms at presentation. Each of these findings could be attributed to the worse long-term clinical outcome during follow-up among younger women with STEMI, as compared with younger men. This finding is in accordance with previous studies, suggesting that traditional risk factors account for most of the risk of MI in both younger men and women.11,23
In these data, younger women presenting with STEMI had more risk factors and were more critically ill when compared with younger men, which in part explains their inferior long-term outcome. Since symptomatic coronary artery disease is relatively rare in younger women, a greater number or severity of risk factors may be expected in this group. Studies also suggest that pathophysiology of coronary artery disease in middle-aged or premenopausal women differs from that of older women and men, possibly due to the estrogen milieu.7,24 Younger women are more prone to plaque erosion, whereas older women and men are more prone to plaque rupture.25 Consistent with this, in the present study, no total occlusion of the infarct-related artery was observed in around a third of the younger women with STEMI, while receiving emergency coronary angiography. In addition, atypical symptoms, delayed recognition of heart disease, and missed diagnosis of MI may also contribute to the higher unadjusted mortality among younger women.26 Consistent with this, only 83% of younger women presented with typical angina at an emergency department in the present study.
Also in the present study, older women had similar short- and long-term outcomes as older men receiving primary PCI for STEMI. This finding is in accordance with other studies suggesting that the clinical outcome for older women is similar to that for older men following STEMI,5-8,14 with a few exceptions.27
Medical treatment for STEMI
Given the evidence of the benefits of early use of beta-blockers and statin therapy in STEMI patients, those without contraindication should promptly receive oral beta-blocker and statin therapy,28 irrespective of the administration of thrombolytic therapy or the performance of primary PCI. However, prescriptions for beta-blockers and statins were somewhat low in the present study. The prescription of beta-blockers and statins is still underutilized in the real world.29-31 These findings could be explained by the fact that most of the study patients were treated before the benefits of beta-blockers and statins for the treatment of STEMI were more widely understood, and thus were not as frequently recommended.28,32-34 However, the low prescription rate of these drugs in the study patients may affect the analysis of prognosis during follow-up.
Predictor for short- and long-term outcome in patients with STEMI
With age, men had an increased risk of reinfarction, heart failure requiring admission, or mortality during follow-up. However, there was no significant difference in long-term outcome among women of different ages; this suggests that women with STEMI receiving primary PCI have a worse long-term outcome, irrespective of age.
Clinical implications
The current and previous studies showed a pattern of increased mortality in younger women with STEMI compared with younger men.35 This difference may be due to complexities in gender differences. However, the findings in the present study advance our knowledge base regarding sex-related differences in patients with STEMI.
Study limitations
First, this was a retrospective study, which may have inherent shortcomings. Second, prescriptions for beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and statin therapy were underused in the present study, which may have influenced the outcome of the patients. These findings could be explained if most of the study patients were included before the benefits of these medications were widely recommended in STEMI.32,33 Similar to the patterns seen from the present study, the use of these medications in Taiwanese ACS patients reported to the Taiwan Full Spectrum Registry was suboptimal.29 However, patients were treated individually according to the experience and judgment of their clinical physicians.
CONCLUSIONS
In STEMI patients receiving primary PCI, we found that sex-related long-term outcome differences were age-dependent, with younger women likely to have a worse long-term outcome compared with younger men. In contrast, older women with STEMI receiving primary PCI had similar long-term outcome compared with older men. The higher risk in long-term outcome in younger women was not associated with a difference in the use of therapeutic modalities or medical therapies, but it was in large part driven by the fact that younger women suffering STEMI have more risk factors.
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