Acute myocardial infarction in the young - National Trend Analysis with gender-based difference in outcomes

IJCA-28129; No of Pages 8 International Journal of Cardiology xxx (xxxx) xxx

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Acute myocardial infarction in the young - National Trend Analysis with gender-based difference in outcomes Dhrubajyoti Bandyopadhyay a,⁎,1, Sandipan Chakraborty b,1, Birendra Amgai b,1, Neelkumar Patel b, Adrija Hajra c, Lyndsey Heise h, Karan Sud a, Raktim K. Ghosh d, Eyal Herzog a, Wilbert S. Aronow e, Gregg C. Fonarow f, Carl J. Lavie g a

Icahn School of Medicine at Mount Sinai, Mount Sinai St Luke's Roosevelt Hospital, Manhattan, NY, United States of America Interfaith Medical Center, Brooklyn, NY, United States of America c Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NY, United States of America d Case Western Reserve University, Heart and Vascular Institute, MetroHealth Medical Center, Cleveland, OH, United States of America e New York Medical College, New York, United States of America f Ronald Reagan-UCLA Medical Center, Los Angeles, Los Angeles, CA, United States of America g John Ochsner Heart and Vascular Institute, Ochsner Clinical School, the University of Queensland School of Medicine, New Orleans, LA, United States of America h Northwestern Medicine, Chicago, IL, United States of America b

a r t i c l e

i n f o

Article history: Received 15 June 2019 Received in revised form 29 October 2019 Accepted 11 November 2019 Available online xxxx

a b s t r a c t Introduction: Although acute myocardial infarction (AMI) is a disease predominantly affecting adults N60 years of age, a significant proportion of the young population who have different risk profiles, are also affected. We undertook a retrospective analysis using National Inpatient Sample (NIS) 2010 to 2014 to evaluate gender differences in characteristics, treatments, and outcomes in the younger AMI population. Methods: The NIS 2010–2014 was used to identify all patient hospitalizations with AMI between 18 to b45 years using ICD-9-CM codes. We demonstrated a gender-based difference of in-hospital all-cause mortality, other complications, and revascularization strategies in the overall AMI population and other subgroups of AMI [anterior wall ST-segment elevation MI (STEMI), and non-anterior wall STEMI and non-STEMI (NSTEMI)]. Results: A total of 156,018 weighted records of AMI hospitalizations were identified, of which 111,894 were men and 44,124 were women. Young women had a higher prevalence of anemia, chronic lung disease, obesity, peripheral vascular disease, and diabetes. Conversely, young men had a higher prevalence of dyslipidemia, smoking, and alcohol. Among non-traditional risk factors, women had a higher prevalence of depression and rheumatologic/collagen vascular disease. There was no difference in all-cause in-hospital mortality in women compared to men [2.03% vs 1.48%; OR 1.04, CI (0.84–1.29); P = .68], including in subgroup analysis of NSTEMI, anterior wall STEMI, and non-anterior wall STEMI. Women with AMI were less likely to undergo percutaneous coronary intervention [47.13% vs 61.17%; OR 0.66, 95% CI (0.62–0.70; P b .001] and coronary artery bypass grafting [5.6% vs 6.0%; OR 0.73, 95% CI 0.64–0.83; P b .001] compared to men. Women were also less likely to undergo percutaneous coronary intervention within 24 h of presentation (38.47% vs 51.42%, P b .001). Conclusion: Despite higher baseline comorbidities in young women with AMI, there was no difference in inhospital mortality in women compared to men. Additional studies are needed to evaluate the impact of gender on clinical presentation, treatment patterns, and outcomes of AMI in young patients. Clinical significance 1) No gender difference in all-cause mortality in young with myocardial infarction. 2) Women had lower odds of getting revascularization with stent placement. 3) Lower odds of stent placement within 24 h of admission, and bypass in women. 4) Higher odds of mitral regurgitation and complete heart block in young women. © 2018 Elsevier B.V. All rights reserved.

⁎ Corresponding author. E-mail addresses: [email protected] (D. Bandyopadhyay), [email protected] (E. Herzog), [email protected] (W.S. Aronow), [email protected] (G.C. Fonarow), [email protected] (C.J. Lavie). 1 Authors had equal contribution

https://doi.org/10.1016/j.ijcard.2019.11.096 0167-5273/© 2018 Elsevier B.V. All rights reserved.

Please cite this article as: D. Bandyopadhyay, S. Chakraborty, B. Amgai, et al., Acute myocardial infarction in the young - National Trend Analysis with gender-based difference in..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.11.096

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1. Introduction

AMI hospitalizations. Details of the inclusion criteria are illustrated in Fig. 1 and the relevant ICD-9 codes we used are shown in Supplemental Table 1.

Recognition of coronary artery disease (CAD) in the young has been highlighted in literature since 1960 [1]. Though the mortality from CAD has decreased over the years, this favorable trend is lacking in the younger population, especially younger women [2,3]. Hospitalization following acute myocardial infarction (AMI) in the young has not decreased over the years, [2] highlighting the importance of studying this population whose mortality cannot be explained by traditional cardiovascular disease (CVD) risk factors and thus lacking a structured guideline for prevention. Since the prevalence of CAD in this population is low, most of the research has been focused on identifying the risk factors, presentations, and outcomes in the elderly population. However, existing research in the area of CAD reveals that young women are considered a vulnerable population with an adverse CVD risk profile, increased admission rate related to a CVD cause, and higher mortality following AMI [4–7]. In contemporary studies, 30-day mortality in women has been demonstrated to be higher than men following AMI in persons b55 years old. These findings are not explainable by traditional CVD risk factors [8,9]. The definition of young patients with AMI is varied in literature. Where some studies used 55 years as the cutoff for the young population, the ISACS-TC registry initially proposed 45 years as the upper limit of defining young adults with ACS [10,11] as also done by other studies [12,13]. It is unclear that the prevailing data hold true even in a much younger population. Therefore, we conducted a large population-based real-world data analysis to identify the sex-based difference in mortality following AMI in the younger population (18 to b45 years). Our aim of the study is to determine 1) the difference in sex-based mortality in patients aged 18 to b45 years with subgroup analysis into non-ST-segment elevation MI (NSTEMI), anterior wall and non-anterior wall ST-elevated myocardial infarction (STEMI) and 2) sex differences in in-hospital outcomes and complications.

The primary outcome was in-hospital mortality. Secondary outcomes were length of stay (LOS), total cost, cardiogenic shock, ventricular tachycardia, cardiac arrest, complete heart block, respiratory failure, mechanical ventilation, ischemic stroke, extracorporeal membrane oxygenation requirement, left ventricular assist device (LVAD) requirement, intra-aortic balloon pump (IABP) requirement, acute kidney injury (AKI), AKI requiring dialysis, percutaneous coronary angiography (PCI) with stent placement, coronary artery bypass graft (CABG), pacemaker insertion, major bleeding requiring blood transfusion, and cardiac complication post AMI (free wall rupture, ventricular septal defect, and mitral regurgitation). Total cost was measured using costto-charge ratio and was adjusted using the inflation ratio calculated from the CPI inflation index to Feb 2019.

2. Methods

2.5. Statistical analysis

2.1. Data source

All statistical analyses were conducted as per the recommended methods accounting for the complex survey design of the NIS database [14]. Demographic and baseline characteristics of young patients with AMI between 18 to b45 years of age with AMI based on gender was summarized using descriptive statistics. Categorical data are reported as frequency and percentage, and continuous data are expressed as mean with standard deviation and standard error. Categorical variables were analyzed using Pearson's Chi-square test, and continuous variables were analyzed using the Student's t-test. For the gender-related outcome, the unadjusted odds ratio for primary and secondary outcome was calculated using univariate logistic regression. Multivariate logistic regression was used to adjust for potential confounders (gender, race, insurance, Charlson category, hospital region, hospital location, teaching status of hospital, anemia, congestive heart failure, coagulation disorder, hypertension, electrolyte disorder, obesity, peripheral vascular disease, chronic kidney disease, dyslipidemia, smoking, valvular heart disease) in the final model. Statistical significance was set at a two-sided Pvalue of b0.05. STATA/MP 15.10 (Stata Corp LLC) was used for statistical analysis.

The National Inpatient Sample (NIS) 2010 to 2014 was used to derive information for our study with retrospective data analysis. The NIS database is sponsored by the Agency for Healthcare Research and Quality (AHRQ) as a part of the Healthcare Cost and Utilization Project (HCUP) and is the most extensive publicly available all-payer administrative claims-based database. It contains data on more than seven million (unweighted) hospital discharges each year. When weighted, it represents about 35 million hospitalizations nationally. It provides information on clinical and resource utilization with safeguards to protect data for individual patients, physicians, and hospitals. The data are stratified to identify a 20% sample representative nationally across different hospitals and geographic regions. Starting from the year 2012, the NIS is a sample of discharges from all hospitals participating in HCUP. 2.2. Study design and population We identified our study population with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for STEMI and NSTEMI and labeled these as AMI. We identified a total of 2,897,764 discharge records. We excluded all patients above 45 years and b18 years of age. The total discharge records of AMI between 18 to b45 years of age were 160,589. We excluded 4571 hospitalizations because of pre-existing mitral regurgitation. AMI was further divided into anterior wall STEMI, non-anterior wall STEMI and NSTEMI. After exclusion, our final study included total 156,018 weighted records of

2.3. Definition of variables We used NIS to identify patient-level variables such as age, sex, and race, hospital-level variables such as hospital bed size (small, medium, or large), and hospital region (Northeast, Midwest, South, or West). We defined the severity of comorbid conditions by using the Deyo modification of the Charlson Comorbidity Index. Hypertension (HTN), congestive heart failure (CHF), diabetes mellitus (DM), renal failure, coagulation disorder, electrolyte imbalance, alcohol, smoking, anemia, obesity, dyslipidemia, chronic lung disease, and peripheral vascular disease were all considered as comorbidities. Comorbidities associated with hospitalization for AMI in young patients were identified using AHRQ comorbidity measures. 2.4. Outcomes measured

3. Results 3.1. Baseline characteristics A total of 111,894 men and 44,124 women were identified with the primary discharge diagnosis of AMI in the age group of 18 to b45 years during this study period. Mean age was 39 ± 4.83 years for men and 39

Please cite this article as: D. Bandyopadhyay, S. Chakraborty, B. Amgai, et al., Acute myocardial infarction in the young - National Trend Analysis with gender-based difference in..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.11.096

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Total admissions with discharge diagnosis of AMI (2010-2014) N=289,7764

Excluded populaon <18 years or >45 years N=273,7175 N=4571 admissions excluded because of pre-exisng mitral regurgitaon Total admissions with acute MI (18 to < 45 years) N=156018 Female with acute MI N=44124

Male with acute MI N=111,894

Fig. 1. Details of inclusion criteria for patients aged 18 to b45 years with AMI (acute myocardial infarction).

± 4.75 years for women. The majority of patients were Caucasians, having private insurance as their primary payer and from an urban location. Admissions were distributed equally between teaching and nonteaching hospital. About one-third of patients were from a very lowincome group with the majority of patients discharged at home (Table 1A).

2.2%; P b .001). The prevalence of acquired immune deficiency syndrome was equal in both groups. Among non-traditional CVD risk factors, young women with AMI had a higher proportion of depression (12.7% vs 4.8%; P b .001) and rheumatologic/collagen vascular disease (3.9% vs 0.6%; P b .001) (Table 1B). 3.3. Revascularization

3.2. Distribution of comorbidities Young women with AMI had a higher prevalence of anemia (15% vs 5.3%; P b .001), chronic lung disease (15.6% vs 7.5%; P b .001), fluid and electrolyte disorder (18.5% vs 13%; P b .001), obesity (31% vs 21.6%; P b .001), peripheral vascular disease (4.6% vs 2.4%; P b .001), DM (35% vs 23.7%; P b .001), and renal failure (8.9% vs 6.6%; P b .001), whereas young men had higher prevalence of dyslipidemia (60% vs 50.7%; P b .001), smoking (52.7% vs 49.7%; P b .001), and alcohol abuse (6.2% vs Table 1A Baseline demographics of male and female patients admitted with acute myocardial infarction (AMI) in age group 18 to b45 years. Variable

Female

Male

Total population (N) Age in years ± SD Race, n (%) White Black Hispanic Asian Native American Others Insurance, n (%) Medicare Medicaid Private insurance Self-pay Urban location, n (%) Teaching hospitals, n (%) Hospital bed size, n (%) Small Medium Large Hospital region, n (%) Northeast Midwest South West Median household income, n (%) $1–$38,999 $39,000–$47,999 $48,000–$62,999 $63,000 or more Discharge, n (%) Home Skilled nursing facility

44,124 39 ± 4.75

111,894 39 ± 4.83

24,744 (79.4) 9701 (4.4) 3656 (5.4) 814 (2) 261 (0.65) 1235 [3]

64,864 (63.4) 16,410 (16) 11,727 (11.5) 3531 (3.5) 749 (0.73) 4987 (4.8)

5342 (12.8) 12,634 (30.3) 16,929 (40.5) 6857 (16.4) 40,012 (91.3) 23,427 (53.5)

8360 (8) 18,644 (18) 52,550 (50.6) 23,384 (23.5) 103,445 (93) 60,600 (54.5)

4469 (10.2) 10,638 (24.3) 28,723 (65.5)

10,971 (10) 27,293 (24.6) 72,876 (65.6)

5985 (13.6) 11,000 (25) 20,629 (46.8) 6511 (14.8)

16,388 (14.7) 27,206 (24.3) 48,735 (43.6) 19,566 (17.5)

P-value 0.45 b0.001

b0.001

Table 1B Baseline demographics of male and female patients admitted with acute myocardial infarction (AMI) in age group 18 to b45 years. CHF: congestive heart failure; HTN: hypertension; PVD: peripheral vascular disease; MI: myocardial infarction; PCI: percutaneous coronary intervention; CABG: coronary artery bypass surgery; AIDS: acquired immune deficiency syndrome. Chronic comorbidities, n (%)

Female

Male

P-Value

Anemia CHF Chronic lung disease Coagulopathy HTN

5889 (5.3) 337 (0.3) 8389 (7.5) 2669 (2.4) 62,747 (56)

b0.001 0.11 b0.001 0.02 0.19

Fluid and electrolyte disorder Obesity

6682 (15) 182 (0.4) 6891 (15.6) 1247 (2.8) 25,101 (56.9) 8178 (18.5) 13,652 (31)

b0.001 b0.001

PVD Renal failure Diabetes

2017 (4.6) 3915 (8.9) 22,358 (35)

Dyslipidemia

15,478 (50.7) 21,941 (49.7) 957 (2.2) 3657 (8.3) 4010 (9.1)

14,506 (13) 24,207 (21.6) 2672 (2.4) 7415 (6.6) 67,249 (23.7) 26,484 (60)

b0.001

864 (2) 150 (0.4) 5612 (12.7) 1707 (3.9)

58,927 (52.7) 6902 (6.2) 9712 (8.7) 11,659 (10.4) 2103 (1.9) 425 (0.4) 5393 (4.8) 682 (0.6)

16,974 (38.5) 0.53 ± 1.3 3.18 ± 3.26

57,535 (51.4) 0.40 ± 0.99 3.19 ± 3.02

b0.001

19,897 (45.1) 13,750 (31.2) 10,478 (23.8)

68,255 (61)

Smoking

b0.001 0.10 0.67

b0.001

b0.001 16,198 (37.5) 12,152 (28.2) 9218 (21.4) 5599 (13)

Young women with AMI were less likely to undergo PCI with stent placement [47.1% vs 61.2%; OR 0.66, 95% CI 0.62–0.70; P b .001] and

34,595 (31.7) 29,556 (27) 25,593 (23.4) 19,459 (17.8)

Alcohol abuse Prior MI Prior PCI Prior CABG AIDS Depression Rheumatological disease/collagen vascular disease PCI within 24 h. of admission Mean time to PCI (days) Mean time to CABG (days) Charlson category, n (%) 1 2

b0.001 35,889 (81.4) 821 (1.9)

94,989 (85) 1454 (1.3)

3 or more

b0.001 b0.001 b0.001 b0.001

b0.001 0.26 b0.001 0.66 0.75 b0.001 b0.001

b0.001 0.95 b0.001

27,864 (24.9) 15,776 (14.1)

Please cite this article as: D. Bandyopadhyay, S. Chakraborty, B. Amgai, et al., Acute myocardial infarction in the young - National Trend Analysis with gender-based difference in..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.11.096

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CABG [5.6% vs 6.0%; OR 0.73, 95% CI 0.64–0.83; P b .001] compared to men. This was also consistent in patients with STEMI and NSTEMI, except in anterior wall STEMI, where women had equal odds of having CABG as men. Women were also less likely to undergo PCI within first 24 h of presentation (38.5% vs 51.4%, P b .001). Mean time to PCI in men was 0.40 ± 0.99 days and in women was 0.53 ± 1.3 days (P b .001). Mean time to CABG were 3.19 ± 3.02 days in men and 3.18 ± 3.26 days in women (P = .95). 3.4. In-hospital outcomes There was no difference in all-cause in-hospital mortality in young women with AMI compared to men [2% vs 1.5%; OR 1.04, 95% CI 0.84–1.29; P = .68] which held true even after subgroup analysis of NSTEMI [1.1% vs 0.7%; OR 1.20, 95% CI 0.84–1.73; P = .30], STEMI [0.4% vs 0.24%; OR 1.2, 95% CI 0.9–1–56; P = .22], anterior wall STEMI [3.8% vs 2.8%; OR 1.07, 95% CI 0.70–1.62; P = .75], and non-anterior wall STEMI [3.6% vs 2.2%; OR 1.19, 95% CI 0.82–1.73; P = .33] (Tables 2, 3, 4, 5, 6). Young women with AMI had a lower odds of having cardiogenic shock [3.4% vs 3.6%; OR 0.67, 95% CI 0.56–0.78; P b .001], ventricular arrhythmia [7% vs 9.5%; OR 0.70, 95% CI 0.62–0.78; P b .001], AKI [4.9% vs 6%; OR 0.53, 95% CI 0.46–0.61; P b .001] and AKI requiring dialysis [0.3% vs 0.4%; OR 0.47, 95% CI 0.28–0.80; P b .01] and higher likelihood of having major bleeding requiring transfusion [6.5% vs 2.9%; OR 1.72, 95% CI 1.50–1.98; P b .001], mitral regurgitation [4.1% vs 2.5%; OR 1.36, 95% CI 1.16–1.60; P b .001] and respiratory failure [6.2% vs 5.3%; OR 1.19, 95% CI 1.06–1.32; P b .01] after AMI compared with young men. On subgroup analysis, young women who presented with STEMI or anterior wall STEMI or NSTEMI had lower odds of having cardiogenic shock, ventricular arrhythmia, and AKI compared to young men (Tables 3, 4, and 5). There were no significant differences in ventricular arrhythmia or in-hospital cardiogenic shock in young women and men who presented with non-anterior wall STEMI (Table 6). Young women with anterior wall STEMI or NSTEMI had higher odds of having mitral regurgitation and major bleeding requiring transfusion compared with young men. There was higher likelihood of complete heart block (2.3% vs 1.4%; OR 1.63, 95% CI 1.11–2.41; P = .013) and major bleeding requiring transfusion (6.5% vs 2.8%; OR 1.97, 95% CI 1.47–2.63; P b .001) in young women compared with young men with nonanterior wall STEMI.

4. Discussion Form this retrospective analysis of NIS from 2010 to 2014 involving young (between age 18 to b45 years) AMI patients, we observed that 1) young men were more than twice in number compared to women; 2) There was no difference in all-cause in-hospital mortality based on gender, which also held true in the subgroup analysis of anterior wall STEMI, non-anterior wall STEMI, and NSTEMI; 3) There were decreased odds of having PCI with stent placement and CABG in young women with AMI compared to young men, with women having higher comorbidity burden compared to men; 4) Women had lower odds of having cardiogenic shock, ventricular arrhythmia, mechanical ventilation, AKI, and AKI requiring dialysis with higher odds of having major bleeding requiring transfusion, respiratory failure, and mitral regurgitation; The increasing proportion of young patients hospitalized with AMI is noteworthy in the United States [15]. Identification of atherosclerotic risk factors and treatment towards addressing these risk factors should begin early in adolescence and young adulthood. Unfortunately, a wellvalidated tool to identify the risk factors in this age group is lacking [16]. Authors from the YOUNG-MI registry highlighted the importance of improving CVD risk assessment tools in the young, as only 12.5% of young adults are on statins at the time of AMI [17]. Another study characterizing young patients with AMI (VIRGO: Variation in Recovery, Role of Gender on Outcome of Young AMI patients) showed that only half of the young AMI patients are aware of their high-risk status for major CVD events despite an overall higher prevalence of CVD risk factors [18,19]. Understanding of the complex interplay of CVD and non-CVD risk factors, socioeconomic factors, health insurance, healthcare access, and utilization are imperative to appreciate the gender-difference in outcomes following AMI in young population. Traditionally recognized as “man's disease”, identification of cardiometabolic risk is far less in women than men, even with an identical risk profile. The risk for CAD in women is dependent on many nontraditional CVD risk factors that are unique to women, such as gestational DM, pre-eclampsia, eclampsia, early menopause or menarche [20,21]. In our study, we identified a greater proportion of young women having depression and rheumatologic/collagen vascular disease compared to young men. Prior studies have demonstrated that depression increases the risk of CVD by increasing inflammatory and atherosclerotic biomarkers and platelet activation [22]. Psychosocial stressors, depression, and poverty are also more prevalent in women, which also contributes to higher cardiometabolic disease burden

Table 2 In-hospital outcomes, revascularization, and mechanical complication in women with acute myocardial infarction (AMI) compared to men: LOS: length of stay; ECMO: extracorporeal membrane oxygenation; LVAD: left ventricular assist device; PCI: percutaneous coronary intervention; CABG: coronary artery bypass surgery; AKI: acute kidney injury; IABP: intra-aortic balloon pump; VSD: ventricular septal defect. Variables

Female; n (%)

Male; n (%)

Odds ratio (OR)

P-value

95% confidence interval

In-hospital mortality Mean cost LOS (days) Cardiogenic shock Ventricular arrhythmia Cardiac arrest Complete heart block Respiratory failure Mechanical ventilation Acute stroke LVAD PCI with stent placement CABG Pacemaker insertion Major bleeding requiring transfusion AKI AKI requiring dialysis IABP Mechanical complication (ventricular rupture, VSD) Mitral regurgitation

891(2) 21,926 3.57 ± 4.33 1505 (3.4) 3083 (7) 1399 (3.2) 315 (0.7) 2736 (6.2) 627 (1.4) 80 (0.2) 55 (0.1) 20,795 (47.1) 2499 (5.6) 62 (0.1) 2859 (6.5) 2144 (4.9) 126 (0.3) 55 (0.1) 98 (0.2) 1810 (4.1)

1658(1.5) 23,561 3.34 ± 4.2 4054 (3.6) 10,605 (9.5) 3313 (3) 726 (0.7) 5885 (5.3) 1515 (1.4) 189 (0.2) 61 (0.1) 68,448 (61.2) 6715 (6.0) 141 (0.1) 3282 (2.9) 6652 (6) 428 (0.4) 61 (0.006) 230 (0.2) 2751 (2.5)

1.04

0.68 b0.001 b0.001 b0.001 b0.001 0.16 0.68 0.0002 b0.01 0.15 0.38 b0.001 b0.001 0.52 b0.001 b0.001 b0.01 0.38 0.95 b0.001

0.84–1.29

0.67 0.70 0.89 1.06 1.19 0.68 0.63 1.49 0.66 0.73 0.77 1.72 0.53 0.47 1.49 0.98 1.36

0.56–0.78 0.62–0.78 0.75–1.04 0.77–1.47 1.06–1.32 0.52–0.88 0.33–1.18 0.60–3.71 0.62–0.70 0.64–0.83 0.35–1.69 1.50–1.98 0.46–0.61 0.28–0.80 0.60–3.71 0.52–1.85 1.16–1.60

Please cite this article as: D. Bandyopadhyay, S. Chakraborty, B. Amgai, et al., Acute myocardial infarction in the young - National Trend Analysis with gender-based difference in..., International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.11.096

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Table 3 In-hospital outcomes, revascularization, and mechanical complication in women with STEMI (ST-elevated myocardial infarction) compared to men: ECMO: extracorporeal membrane oxygenation; LVAD: left ventricular assist device; PCI: percutaneous coronary intervention; CABG: coronary artery bypass surgery; AKI: acute kidney injury; IABP: intra-aortic balloon pump; VSD: ventricular septal defect. Variables

Female; n (%)

Male, n (%)

Adjusted odds ratio (OR)

P-value

95% confidence interval

In-patient mortality Cardiogenic shock Ventricular arrhythmia Cardiac arrest Complete Heart block Respiratory failure Mechanical ventilation Acute stroke LVAD PCI with stent placement CABG Pacemaker insertion Major bleeding requiring transfusion AKI AKI requiring dialysis IABP Mechanical complication (Ventricular rupture, VSD) Mitral regurgitation

564 (0.36) 1072 (7.0) 2072(13.54) 1002 (6.54) 245 (1.6) 1475 (9.63) 370 (2.41) 20 (0.13) 50 (0.33) 10,655 (69.59) 632 (4.13) 23 (0.15) 1003 (6.55) 565 (3.69) 16 (0.10) 50 (0.33) 73 (0.48) 527 (3.44)

1248 (0.24) 3186 (6.19) 7901 (15.34) 2632 (5.11) 541 (1.05) 3566 (6.92) 1077 (2.09) 70 (0.14) 46 (0.08) 40,206 (78.04) 2002 (3.89) 64 (0.12) 1508 (2.93) 2490 (4.83) 111 (0.21) 46 (0.08) 165 (0.32) 1202 (2.33)

1.18 0.799 0.83 1.06 1.45 1.01 0.73 0.47 2.33 0.72 0.78 0.79 1.90 0.46 0.36 2.33 1.18 1.20

0.22 0.032 0.012 0.54 0.039 0.90 0.08 0.22 0.15 b0.001 0.047 0.73 b0.001 b0.001 0.15 0.15 0.65 0.17

0.89–1.56 0.65–0.98 0.73–0.96 0.87–1.29 1.01–2.07 0.83–1.22 0.51–1.03 0.14–1.58 0.73–7.43 0.65–0.80 0.61–0.99 0.22–2.86 1.52–2.38 0.35–0.59 0.09–1.45 0.73–7.43 0.57–2.43 0.92–1.58

[23,24]. Moreover, women with AMI have more atypical symptoms and delay in presentation and recognition of symptoms [25]. Centers for Medicare and Medicaid Services Inpatient Quality Improvement Program has emphasized the importance of identifying CVD risk profiles in the young population to improve management and outcomes following AMI, particularly in women [2]. Quality improvement initiatives as per the Centers for Medicare and Medicaid Services Inpatient Quality Reporting Program have led to an improved outcome for patients with AMI, irrespective of gender [26]. Certain studies also showed that young women were more likely to be insured, which may improve outcome through timely care-seeking behavior [27]. Analysis following ARIC Community surveillance study showed a higher prevalence of comorbidities in young women presenting with AMI and less likelihood of undergoing revascularization similar to our study findings [18,28]. Another study (VIRGO study) also reported a higher prevalence of DM, CHF, chronic obstructive pulmonary disease, chronic kidney disease, and morbid obesity in women compared to men [18,19]. Multiple registry data and administrative claims have highlighted the fact that young women are sicker on admission and are less likely to receive effective care during hospitalization [3,9,25,29–32]. The gender-based differences in the management of AMI in older adults is well known, [33,34] but similar differences in young adults have been shown only

in a limited number of studies [11]. Studies have shown higher odds of death in young women compared to men, which include both inhospital and 30-day mortality post-AMI [35]. There is some evidence that the increased mortality seen in young women is being attenuated in recent years and is due to improved awareness and better risk profile [36]. Our study also demonstrated no differences in mortality based on sex even after subgroup analysis of STEMI and NSTEMI. One of the possible explanations to our finding is the inclusion of much younger patients in our study and the fact that we did not exclude transferred patients who are likely sicker thus minimizing the gaps of mortality between different genders. Traditionally it was thought that estrogen is cardioprotective for young women, hence a higher burden of CVD risk factors is required to incur an AMI, which explains the more significant cardiometabolic disease burden in women at the time of clinical presentation [37]. Young women who develop CAD have a different physiology and pathology compared to older women and men [22]. Young women found to have atherosclerosis early in life often have an aggressive form of CAD [25]. Additionally, DM seems to have a more profound effect in women compared to men who have CAD [38]. One study demonstrated increased 30-day mortality in young women with DM, but not in the older population [39]. Autoimmune diseases have also been

Table 4 In-hospital outcomes, revascularization, and mechanical complication in women with non ST-elevated myocardial infarction (NSTEMI) compared to men: ECMO: extracorporeal membrane oxygenation; LVAD: left ventricular assist device; PCI: percutaneous coronary intervention; CABG: coronary artery bypass surgery; AKI: acute kidney injury; IABP: intra-aortic balloon pump; VSD: ventricular septal defect. Variables

Female; n (%)

Male; n (%)

Odds ratio (OR)

P-Value

95% confidence interval

In-hospital mortality Cardiogenic shock Ventricular arrhythmia Cardiac arrest Complete heart block Respiratory failure Mechanical ventilation Acute stroke LVAD PCI with stent placement CABG Pacemaker insertion Major bleeding requiring transfusion AKI AKI requiring dialysis IABP Mechanical complication (ventricular rupture, VSD) Mitral regurgitation

327 (1.1) 433 (1.5) 1010 (3.5) 397 (1.4) 70 (0.2) 1261 (4.4) 258 (0.9) 60 (0.2) 5 (0.02) 10,140 (35.2) 1868 (6.5) 39 (0.1) 1857 (6.4) 1579 (5.5) 110 (0.4) 5 (0.02) 24 (0.1) 1283 (4.5)

410 (0.7) 867 (1.4) 2704 (4.5) 681 (1.1) 186 (0.3) 2319 (3.8) 438 (0.7) 119 (0.2) 16 (0.03) 28,243 (46.8) 4712 (7.8) 77 (0.1) 1774 (2.9) 4162 (6.9) 317 (0.5) 16(0.03) 64 (0.1) 1549 (2.6)

1.20 0.69 0.74 0.97 0.70 1.14 0.83 0.78 0.32 0.71 0.68 1.02 1.76 0.58 0.46 0.32 0.69 1.49

0.30 0.01 0.001 0.84 0.28 0.09 0.32 0.49 0.39 b0.001 b0.001 0.95 b0.001 b0.001 0.005 0.39 0.55 b0.001

0.84–1.73 0.52–0.91 0.61–0.89 0.72–1.3 0.36–1.3 0.97–1.34 0.57–1.19 0.38–1.58 0.025–4.23 0.66–0.76 0.59–0.79 0.43–2.40 1.49–2.08 0.50–0.68 0.27–0.79 0.02–4.23 0.20–2.34 1.24–1.79

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Table 5 In-hospital outcomes, revascularization, and mechanical complication in women with anterior wall ST-elevated myocardial infarction (STEMI) compared to men: ECMO: extracorporeal membrane oxygenation; LVAD: left ventricular assist device; PCI: percutaneous coronary intervention; CABG: coronary artery bypass surgery; AKI: acute kidney injury; IABP: intra-aortic balloon pump; VSD: ventricular septal defect. Variables

Female; n (%)

Male; n (%)

Odds ratio (OR)

P-value

95% confidence interval

In-patient mortality Cardiogenic shock Ventricular arrhythmia Cardiac arrest Complete heart block Respiratory failure Mechanical ventilation Acute stroke LVAD PCI with stent placement CABG Pacemaker insertion Major bleeding requiring transfusion AKI AKI requiring dialysis IABP Mechanical complication (ventricular rupture, VSD) Mitral regurgitation

227 (3.8) 598 (10) 1059 (17.7) 511 (8.5) 28 (0.5) 791 (13.2) 199 (3.3) 15 (0.3) 40 (0.7) 4533 (75.8) 323 (5.4) 5 (0.1) 400 (6.7) 225 (3.8) 10 (0.2) 40 (0.7) 45 (0.7) 243 (4.1)

549 (2.8) 1541 (9.5) 3777 (19.4) 1376 (7.1) 84 (0.4) 1912 (9.8) 584 (3) 35 (0.2) 36 (0.2) 15,961 (82) 772 (4) 24 (0.1) 620 (3.2) 1122 (5.8) 51 (0.3) 36 (0.2) 95 (0.5) 372 (1.9)

1.07 0.69 0.79 0.97 0.78 0.92 0.67 0.67 2.37 0.75 0.99 0.50 1.70 0.40 0.60 2.37 0.96 1.61

0.75 b0.01 0.016 0.84 0.60 0.50 0.07 0.58 0.18 b0.001 0.90 0.46 0.001 b0.001 0.55 0.18 0.94 0.02

0.70–1.62 0.53–0.90 0.65–0.95 0.74–1.2 0.28–2.12 0.71–1.19 0.43–1.04 0.16–2.76 0.66–8.43 0.63–0.89 0.70–1.39 0.82–3.13 1.22–2.35 0.27–0.60 0.11–3.19 0.66–8.43 0.37–2.46 1.07–2.42

implicated in sex-difference in the outcome. In Framingham Offspring Study, women with systemic lupus erythematous aged under 45 had more risk of having acute coronary syndrome than women without autoimmune disease [40]. On angiography, young women showed diffuse CAD and fewer obstructive lesions with less narrowing of the coronary arteries [41–44]. Young women often develop the disease of coronary microvasculature [45]. This pathophysiologic difference can explain the lower odds of having revascularization in our study possibly because physicians are less likely to attribute symptoms to their coronary vasculature. In VIRGO study analysis, 44% of women reported nausea as their presenting symptoms of AMI [19]. We have witnessed higher rate of bleeding in the female cohort. Studies have shown that the diameter of common femoral artery and radial artery are smaller in women compared to men and thus predisposes to more bleeding in women [46,47]. In previous study, older age, renal failure, cardiogenic shock, and use of larger sheaths, have been specifically identified as predictors of bleeding risk in women [48]. In this analysis, we do not have the information regarding sheath size, type and duration of anticoagulation use in our study to comment on increased bleeding risk based on these parameters. Compared to VIRGO study which have N3 times female population compared to male, our study has more than double male population

compared to female. Our study is also unique in having patients who are b45 years old in comparison to VIRGO study which contains population b55 years. Non-traditional risk factors are more prevalent in young population. We also included more non-traditional risk factors known to influence CAD like depression, rheumatological conditions and HIV compared to other studies. Moreover, VIRGO study is not designed to identify in-hospital mortality based on sex and stratify according to AMI type which is demonstrated in our study [18]. Our study has many future implications for research. We showed that there was no difference in in-hospital mortality in women compared to men, but women had less likelihood of having in-hospital complications compared to men. Women had greater baseline cardiometabolic risk profile and were less likely to undergo PCI or CABG following AMI. Further research is needed to determine how these risk factors contribute to the onset, progression, and prognosis of AMI in young adults and the best way to address these risk factors very early in life to decrease the incidence of AMI. Studies are also needed to determine the difference of pathophysiology in AMI between men and women and how nontraditional risk factors contribute to CAD. Moreover, we need to determine whether physicians and cardiologists should have a lower threshold for diagnosing AMI in young women, given their atypical symptoms, so that early reperfusion can be considered.

Table 6 In-hospital outcomes, revascularization, and mechanical complication in women with non-anterior wall STEMI (ST-elevated myocardial infarction) compared to men: ECMO: extracorporeal membrane oxygenation; LVAD: left ventricular assist device; PCI: percutaneous coronary intervention; CABG: coronary artery bypass surgery; AKI: acute kidney injury; IABP: intra-aortic balloon pump; VSD: ventricular septal defect. Variables

Female; n (%)

Male; n (%)

Odds ratio (OR)

P-value

95% confidence interval

In-hospital mortality Cardiogenic shock Ventricular arrhythmia Cardiac arrest Complete heart block Respiratory failure Mechanical ventilation Acute stroke LVAD PCI with stent placement CABG Pacemaker insertion Major bleeding requiring transfusion AKI AKI requiring dialysis IABP Mechanical complication (ventricular rupture, VSD) Mitral regurgitation

665 (3.6) 907 (5.1) 2023 (10.9) 888 (5.3) 287 (2.3) 1945 (7.3) 428 (1.8) 65 (0.1) 15 (0.1) 16,261 (65.6) 2177 (3.3) 57 (0.2) 2459 (6.5) 1920 (3.7) 115 (0.1) 15 (0.1) 53 (0.3) 1567 [3]

1109 (2.2) 2213 (4.2) 6827 (12.9) 1937(3.9) 642 (1.4) 3973 (5.2) 931 (1.5) 155 (0.11) 26 (0.03) 52,487 (75.7) 5943 (3.8) 118 (0.1) 261 (2.8) 5530 (4.3) 377 (0.2) 26 (0.03) 135 (0.2) 2379 (2.6)

1.19 0.87 0.82 1.05 1.63 1.03 0.79 – 2.04 0.70 0.62 1.03 1.97 0.49 0.22 2.04 1.05 1.02

0.33 0.38 0.056 0.71 0.013 0.77 0.38 – 0.54 b0.001 b0.01 0.97 b0.001 b0.001 0.18 0.54 0.92 0.88

0.82–1.73 0.65–1.17 0.67–1.00 0.79–1.40 1.11–2.41 0.79–1.35 0.48–1.32 – 0.20–20.80 0.61–0.81 0.44–0.88 0.18–5.84 1.47–2.63 0.35–0.70 0.02–2.03 0.20–20.80 0.35–3.14 0.72–1.45

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Our study is not without limitations. The HCUP project is primarily based on billing codes and thus carries a risk of miscoding. The optimal timing of revascularization is not documented in the database and cannot be captured in this database, which can affect clinical outcomes. Because it is a claim-based administrative database, the information on logistics (medication used, type of stent used, nature of coronary occlusion, single vessel vs. multivessel disease, echocardiography and other imaging results, pre and post procedure hemodynamics data) are lacking which can affect study results. It is also not possible to identify the first AMI compared to subsequent AMIs, as the dataset is not linked. This dataset only includes hospitalizations not individual patients so single patients with multiple hospitalizations could be counted more than once. Some of the comorbidities are claim-based thus are not standardized. NIS focuses only on the in-hospital outcome. Long-term follow-up results after the procedures are not available. 5. Conclusion Young women represent a distinct, high-risk CAD population owing to a higher prevalence of traditional and non-traditional CVD risk factors, atypical presentations and delayed presentations after AMI, and lower probability of undergoing revascularization therapy. More research is needed to determine whether addressing those risk factors early in life will decrease the risk of CAD in women. Additional studies are also required to identify the pathophysiology of progression of CAD in young individuals to offer effective, timely care for this highrisk population. Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijcard.2019.11.096. References [1] R. Mulcahy, N. Hickey, B. Maurer, Coronary heart disease in women. Study of risk factors in 100 patients less than 60 years of age, Circulation. 36 (4) (1967) 577–586. [2] K.A. Wilmot, M. O'Flaherty, S. Capewell, E.S. Ford, V. Vaccarino, Coronary heart disease mortality declines in the United States from 1979 through 2011: evidence for stagnation in young adults, Especially Women. Circulation. 132 (11) (2015) 997–1002. [3] A. Gupta, Y. Wang, J.A. Spertus, M. Geda, N. Lorenze, C. Nkonde-Price, et al., Trends in acute myocardial infarction in young patients and differences by sex and race, 2001 to 2010, J. Am. Coll. Cardiol. 64 (4) (2014) 337–345. [4] J.V. Tu, L. Nardi, J. Fang, J. Liu, L. Khalid, H. Johansen, et al., National trends in rates of death and hospital admissions related to acute myocardial infarction, heart failure and stroke, 1994-2004, CMAJ. 180 (13) (2009) E118–E125. [5] A. Towfighi, L. Zheng, B. Ovbiagele, Sex-specific trends in midlife coronary heart disease risk and prevalence, Arch. Intern. Med. 169 (19) (2009) 1762–1766. [6] D.S. Lee, M. Chiu, D.G. Manuel, K. Tu, X. Wang, P.C. Austin, et al., Trends in risk factors for cardiovascular disease in Canada: temporal, socio-demographic and geographic factors, CMAJ. 181 (3–4) (2009) E55–E66. [7] E.S. Ford, S. Capewell, Coronary heart disease mortality among young adults in the U.S. from 1980 through 2002: concealed leveling of mortality rates, J. Am. Coll. Cardiol. 50 (22) (2007) 2128–2132. [8] V. Vaccarino, L. Parsons, Every NR, Barron HV, Krumholz HM. sex-based differences in early mortality after myocardial infarction. National Registry of myocardial infarction 2 participants, N. Engl. J. Med. 341 (4) (1999) 217–225. [9] K.P. Champney, P.D. Frederick, H. Bueno, S. Parashar, J. Foody, C.N. Merz, et al., The joint contribution of sex, age and type of myocardial infarction on hospital mortality following acute myocardial infarction, Heart. 95 (11) (2009) 895–899. [10] B. Ricci, E. Cenko, Z. Vasiljevic, G. Stankovic, S. Kedev, O. Kalpak, et al., Acute coronary syndrome: the risk to young women, J. Am. Heart Assoc. 6 (12) (2017). [11] S. Bangalore, G.C. Fonarow, E.D. Peterson, A.S. Hellkamp, A.F. Hernandez, W. Laskey, et al., Age and gender differences in quality of care and outcomes for patients with ST-segment elevation myocardial infarction, Am. J. Med. 125 (10) (2012) 1000–1009.

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