Prognostic Outcomes in Acute Coronary Syndrome Patients Without Standard Modifiable Risk Factors: A Multi-Ethnic Study Of 8680 Asian Patients

doi:10.21203/rs.3.rs-941766/v1

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Prognostic Outcomes in Acute Coronary Syndrome Patients Without Standard Modifiable Risk Factors: A Multi-Ethnic Study Of 8680 Asian Patients

https://doi.org/10.21203/rs.3.rs-941766/v1

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IMPORTANCE

There are growing concerns that patients suffering from acute coronary syndrome (ACS) without standard modifiable cardiovascular risk factors (SMuRFs), including hypertension, hypercholesterolemia, diabetes and smoking, have increased mortality.

OBJECTIVE

This study examined the outcomes of ACS in patients without SMuRFs (termed SMuRF-less) in a multi-ethnic Asian population which remains unknown.

DESIGN

This retrospective study was conducted from 1^st January 2011 to 31^st March 2021.

SETTING

This study was conducted in a tertiary healthcare institution in Singapore.

PARTICIPANTS

Consecutive patients presenting with ACS disease were recruited in the study.

EXPOSURE

The outcomes of SMuRF-less patients were compared with SMuRF patients.

MAIN OUTCOMES AND MEASURES

The primary outcome was cardiovascular mortality. Secondary outcomes were all-cause mortality, readmission, cardiogenic shock, stroke and heart failure. Multivariable regression analysis adjusted for covariates including age, sex, ethnicity, chronic kidney disease, ACS type, cardiac arrest, and left main and/or left anterior descending coronary

RESULTS

Of the 8680 patients studied, 8.6% were SMuRF-less patients. SMuRF-less patients were significantly younger and had fewer comorbidities including stroke and chronic kidney disease, but higher rates of ventricular arrhythmias and inotropic or invasive ventilation requirement compared to the SMuRF group. Multivariable analysis showed higher rates of cardiovascular mortality (HR 1.48, 95% CI 1.09–1.86, p=0.048), cardiogenic shock (RR: 1.31, 95% CI 1.09–1.52, p=0.015) and stroke (RR: 2.51, 95% CI 1.67–3.34, p=0.030) in SMuRF-less patients compared to SMuRF patients. Both groups had similar readmission (RR: 1.10, 95% CI 0.87–1.39, p=0.413) and heart failure (RR: 0.82, 95% CI 0.56–1.21, p=0.326) rates. Kaplan-Meier curve showed higher 30-day cardiovascular mortality in the SMuRF-less group compared to SMuRF group (HR: 1.84, 95% CI 1.45-2.33, p<0.001), with similar significant trends found in men, STEMI patients, and the three Asian ethnicities.

CONCLUSION AND RELEVANCE

Although the proportion of ACS patients without standard risk factors in our Asian population is lower than those reported in the West, they also have worse short-term mortality compared to those with SMuRF. This calls for a global focus on the management of this unexpectedly high-risk subgroup of patients.

Cardiac & Cardiovascular Systems

Acute Coronary Syndrome

standard modifiable cardiovascular risk factors

prognostic outcomes

Question: What are the outcomes of acute coronary syndrome (ACS) patients without standard modifiable risk factors (SMuRF) in a multi-ethnic Asian population?

Findings: In this cohort study of 8680 patients presenting with ACS, SMuRF-less patients made up 8.6% of the population. They had higher rates of cardiovascular mortality, stroke and cardiogenic shock compared to those with SMuRF. Excess mortality was demonstrated in SMuRF-less men, and patients with ST-segment elevation myocardial infarction.

Meaning: This calls for a global focus on the management of this unexpectedly high-risk subgroup of SMuRF-less patients.

The control of cardiovascular risk factors is paramount in the prevention of adverse cardiovascular outcomes including stroke and acute coronary syndrome (ACS)¹. Hence, early identification and intervention of standard modifiable risk factors (SMuRF), such as hypercholesterolemia², hypertension³, smoking⁴ and diabetes mellitus⁵, are essential in reducing the atherosclerotic cardiovascular disease risk of all individuals^6–9 and prevention of cardiovascular disease¹⁰. Recent studies have shown a growing proportion of patients without SMuRF (termed SMuRF-less¹¹) who were previously asymptomatic, presenting with ST-segment elevation myocardial infarction (STEMI)¹². Their prevalence among patients presenting with STEMI has increased over the past decade from 13% to approximately 27%^{13, 14}, and these patients have a higher in-hospital mortality compared to patients with at least one SMuRF¹⁴.

To date, there is a paucity of studies examining the outcomes of this pragmatically challenging group of SMuRF-less patients who present with ACS. They are often overlooked in large clinical trials which rarely report the absence of standard modifiable risk factors or are less often recruited into trials targeting at atherosclerotic cardiovascular risk intervention. Despite the increasing focus on this group of patients in the West^14–17, SMuRF-less cohort has not been described in Asia. In addition, most previous studies are only limited to the subgroup of SMuRF-less patients presenting with STEMI, with only few studies on patients with Non-STEMI (NSTEMI)^{15, 18, 19}. This study will be the first to describe the prevalence and characteristic of SMuRF-less patients, and compare their outcomes to those with SMuRF in a large diverse Asian population presenting with ACS.

2.1. Setting and Design

Consecutive patients presenting with ACS to a major tertiary academic percutaneous coronary intervention (PCI)-capable hospital in Singapore between 1st January 2011 and 31st March 2021 were retrospectively studied. The hospital is part of the Western network that provides PCI services, including round-the-clock primary PCI, to the western region in Singapore²⁰. This Western network is a hub-and-spoke system that consists of our hospital (hub) and two other spoke hospitals. The patients presented with either STEMI or NSTEMI via the Emergency Department at the hub hospital or via inter-hospital transfer from the two spoke hospitals.

Patients included in the study were at least 18 years of age and presented with ACS. Patients with previous ACS, percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) were excluded. SMuRFs^{6, 21} were defined as having at least one of the following cardiovascular risk factors: ex-smoker or current smoker, hypertension, diabetes mellitus, or hypercholesterolemia. Hypertension was defined as previously diagnosed hypertension, prescribed anti-hypertensives, or newly diagnosed hypertension during the index admission. Diabetes mellitus was defined as previously diagnosed type 1 or 2 diabetes, prescribed glucose lowering medications, or newly diagnosed diabetes during index admission. Hypercholesterolaemia was defined as previously diagnosed hypercholesterolaemia, prescribed lipid-lowering therapy, or newly diagnosed hypercholesterolaemia during index admission. As both fasting glucose and acute-phase blood pressure readings are influenced by neurohormonal response to acute myocardial infarction, these were not incorporated in the definitions.

Patients were allocated to 2 study groups according to their SMuRF status: (1) SMuRF, defined as having 1 or more SMuRFs, or (2) SMuRF-less, defined as the absence of SMuRF.

2.2. Data Collection

Data on baseline demographic and clinical characteristics, SMuRF status, previous medical history, clinical status at presentation, angiographic and procedural characteristics, echocardiographic characteristics and medications on discharge were retrospectively collected from the electronic clinical records. Information on in-hospital complications were also retrieved.

2.3. Study Outcomes

The follow-up period was 30 days and primary outcome was cardiovascular mortality. Secondary outcomes were in-hospital all-cause mortality, unplanned readmission, cardiogenic shock, heart failure, and stroke. Cardiovascular mortality was defined as any death due to any cardiovascular causes, and all-cause mortality was defined as death due to any or unexplained causes. Cardiogenic shock was defined by the presence of persistent hypotension defined as SBP < 90 mm Hg or mean arterial pressure (MAP) 30 mm Hg below the baseline, cardiac index (< 1.8 L/min/m2 without support or < 2.2 L/min/m2 with support) with adequate or elevated filling pressures (left ventricular end diastolic pressure > 18 mm Hg or right ventricular end diastolic pressure > 10 to 15 mm Hg)²². Heart failure was defined clinically based on development of typical signs and symptoms, with structural and functional cardiac abnormalities²³.

Statistical analysis was conducted on STATA 16.1 (Statacorp) and IBM SPSS Statistics 25 (SPSS Inc., Chicago, IL, USA). A p-value of ≤ 0.05 was considered statistically significant. To compare between baseline characteristics of included patients, either chi square analysis or fisher exact test was used to compare categorical and binary variables. Unpaired t-test was used in the analysis of continuous variables. Cardiovascular mortality was assessed in the Fine-Gray model with hazard ratio (HR) to account for competing risk. The issue of competing risk has been well described by Abdel-Qadir et al.²⁴ In the analysis of binary outcomes including 30-day myocardial infarction, stroke, cardiogenic shock, heart failure and readmission, a generalized linear regression with a log link, gaussian distribution, and robust variance estimator were used to compute the risk ratios (RR)²⁵. The risk ratio was preferred due to the ease of interpretation compared to an odds ratio²⁶. Multivariable adjustment was performed with age, sex, ethnicity, chronic kidney disease, ACS type (STEMI and NSTEMI), cardiac arrest and presence of left main coronary and/or left anterior descending coronary artery disease included in the model. The Kaplan-Meier survival curves for cardiovascular mortality was constructed from the date of admission up to 30 days. The survival curves were further stratified according to the sex, the three main Asian ethnicities (Chinese, Malay and Indian), and the ACS type (STEMI and NSTEMI). The study was approved by the local institutional review committee in accordance to the revised Declaration of Helsinki (NHG Research – DSRB: 2021/00089-AMD0001). As the study involved the retrospective analysis of clinically acquired data, the institutional review board waived the need for written patient consent.

3.1. Study Cohort Characteristics

Of the 8680 patients with ACS enrolled into the study, 7934 (91.4%) patients were in the SMuRF group and 746 (8.6%) in the SMuRF-less group. The follow-up time was 30 days. Between 2011 and 2021, the yearly prevalence of SMuRF-less patients presenting with ACS fluctuated little and ranged from 5.9–10.7% (Fig. 1).

A total of 4975 (57.3%) patients presented with STEMI and 3705 (42.7%) with NSTEMI. A larger proportion of SMuRF-less patients presented with STEMI as compared to SMuRF patients (482 [64.5%] versus 4493 [56.6%] respectively, p < 0.001). The mean age of SMuRF-less patients was significantly lower than that of SMuRF patients (57 ± 14 years versus 61 ± 13 years respectively, p < 0.001). SMuRF-less patients were also less likely to have history of stroke (1.9% versus 6.0% respectively, p < 0.001) and chronic kidney disease (2.3% versus 10.2% respectively, p < 0.001), compared to SMuRF patients. In the SMuRF group, the prevalence of hypertension (60.4%), hypercholesterolemia (58.8%), and diabetes mellitus (41.9%) was high. Among these SMuRF patients, 3161 (41.2%) were current smokers, 964 (12.6%) ex-smokers and 3548 (46.2%) non-smokers. The baseline characteristics of the patients are outlined in Table 1.

During the index hospitalisation, SMuRF-less patients experienced higher rates of PCI (83.0% versus 79.0% respectively, p = 0.018) and were more likely to have culprit vessel involving the left anterior descending artery (56.6% versus 50.9% respectively), or left main coronary artery (3.4% versus 1.9% respectively) compared to SMuRF patients (p = 0.012). Additionally, SMuRF-less patients had higher prevalence of multivessel disease (1.9% versus 0.9% respectively, p = 0.018). Both groups of patients did not differ in the number of vessels and stents involved in PCI, post-PCI Thrombolysis in Myocardial Infarction (TIMI) flow score, PCI success rate and need for CABG.

SMuRF-less patients also had significantly higher rates of ventricular arrhythmias, and inotropic and invasive ventilation support when compared to SMuRF patients. However, ischemic mitral regurgitation was less common in the SMuRF-less than SMuRF patients. The incidences of other in-hospital complications including sepsis, atrial fibrillation, bleeding events, and acute renal failure were similar between the two groups of patients; and so was the length of hospital stay. On discharge, the SMuRF-less group was less likely to be prescribed ACE-inhibitors (ACE-I) or angiotensin-II receptor blockers (ARBs), β-blockers, and statins compared to the SMuRF group.

3.2. Study Outcomes

The cardiovascular mortality (10.7% versus 6.1% respectively, p < 0.001), all-cause mortality (11.7% versus 6.9% respectively, p < 0.001) and cardiogenic shock (16.3% versus 8.6% respectively, p < 0.001) was significantly higher in SMuRF-less patients compared to SMuRF patients. The incidences of stroke, hospital readmission and heart failure were similar between both study groups.

The Kaplan-Meier curve of 30-day cardiovascular mortality are presented based on study cohort, sex, ACS type and ethnicity (Fig. 2). For the overall study cohort, the cumulative event curves diverged early from the day of ACS presentation indicating higher early mortality in the SMuRF-less group compared to the SMuRF group which was sustained over the 30-day follow-up period (HR 1.837, 95% CI 1.450–2.328, p < 0.001). Similar trend was found in the men (HR 2.043, 95% CI 1.557–2.680, p < 0.001), but not for women (HR 1.390, 95% CI 0.852–2.270, p = 0.187). For each of the ethnicities, such trend was observed in the Chinese (HR 1.672, 95% CI 1.222–2.289, p = 0.001), Malay (HR 2.904, 95% CI 1.656–5.094, p < 0.001) and Indian (HR 2.055, 95% CI 1.185–3.563, p = 0.010). This trend was also observed in the patients with STEMI (HR 1.947, 95% CI 1.501–2.527, p < 0.001) but not in patients with NSTEMI (HR 1.188, 95% CI 0.658–2.145, p = 0.567).

The multivariable analysis showed that SMuRF-less patients had higher risk of cardiovascular mortality (HR 1.48, 95% CI 1.09–1.86, p = 0.048), cardiogenic shock (RR: 1.31, 95% CI 1.09–1.52, p = 0.015) and stroke (RR: 2.51, 95% CI 1.67–3.34, p = 0.030) compared to the SMuRF patients despite adjusting for important confounders (Fig. 3). The risk of unplanned readmission (RR: 1.10, 95% CI 0.87– 1.39, p = 0.413) and heart failure (RR: 0.82, 95% CI 0.56–1.21, p = 0.326) was similar between both patient groups.

This study is the first to examine the prognostic outcomes of an often-overlooked subset of patients without standard modifiable risk factors, in a typically understudied Asian population presenting with ACS. It is also the first of such study to include both patients with NSTEMI and STEMI. The main findings of the study are: 1) The prevalence of SMuRF-less patients presenting with ACS in an Asian cohort was 8.6%, with its yearly prevalence relatively constant over the past decade; 2) SMuRF-less patients tend to present in a more critical state compared to SMuRF patients, with higher rates of ventricular arrhythmia, and requirement for inotropic and invasive ventilation support; 3) The adjusted risks of cardiovascular mortality, cardiogenic shock and stroke were significantly higher in the SMuRF-less patients compared to SMuRF patients; 4) The significantly higher cardiovascular mortality in SMuRF-less patients compared to SMuRF patients was apparent early from presentation and was sustained over the 30-day follow-up period. Such trend was observed in men and STEMI patients, but not in women or NSTEMI patients. Similar trend was also seen across all three Asian ethnicities.

Traditionally, both primary and secondary prevention of cardiovascular diseases have been focused on high risk individuals with cardiovascular risk factors^{18, 27}. As a result, the subgroup of patients without SMuRFs remains understudied. Recent studies on both STEMI and NSTEMI have demonstrated an increasing prevalence of patients without traditional risk factors¹³, with the prevalence of SMuRF-less patients being 10.5% in the United States of America¹⁹, 14.5% in Canada¹⁵, 14.9% in Sweden¹¹ and 19–25% in Australia^{13, 14}. Notably, the population of SMuRF-less patients in our Asian cohort was much lower with a prevalence of only 8.6%. The stark difference in the proportion of SMuRF-less patients across the globe might be partly explained by the differences in risk factor identification²⁸, genetic predisposition²⁹, lifestyle factors such as smoking and physical activity^{30, 31}, and individual country’s primary prevention programme^{28, 32}. Even with the presence of traditional cardiovascular risk factors, their impacts might vary across different ethnic groups, with stroke being more common among hypertensive patients in Asia and chronic heart disease more prevalent in the West³³. Despite relatively lower than that seen in the West, the prevalence of SMuRF-less patients in our Asian cohort remains sizeable and warrants further attention to address specific modifiable factors that might predispose Asians to various cardiovascular comorbidities.

Even though the SMuRF-less patients in our cohort were generally younger and had fewer baseline comorbidities, their cardiovascular mortality was higher than those with conventional risk factors. This is consistent with the findings from previous studies^{11, 14–16, 19} based in the West, and could be partly explained by multiple postulated reasons. Several cardiovascular risk factors, such as serum cholesterol or glycated haemoglobin A1c, have a linear relationship with the risk of cardiovascular morbidity and categorising the patients into binary groups using a standard diagnostic threshold can potentially introduce selection bias by missing out on patients with borderline measurements for certain risk factor that have not reached the diagnostic thresholds. As mentioned earlier, individuals with pre-disease state for various cardiovascular risk factors might also have a higher atherosclerotic cardiovascular risk. Moreover, the role of less well established risk factors such as body mass index, triglyceride concentrations, high-density lipoprotein concentration and sedentary lifestyle, which might also be the potential drivers of atherosclerosis but have not been concomitantly evaluated. Additionally, some recognised risk factors such as abdominal obesity, psychosocial factors, sedentary lifestyle, dietary factors and alcohol consumption are not easily quantified and hence their potential impact on the outcome of SMuRF-less patients is not well assessed³⁴. Furthermore, as patients with known risk factors are more likely to be on treatment, the ACS severity may have been modified by evidence-based therapy used in primary intervention¹⁶ leading to better outcome among the SMuRF patients.

The pathogenesis of atherosclerosis, especially its genetic basis, is also not fully understood. A recent study reported as many as 55 genetic loci that are associated with coronary artery disease, with more than 66% of them not linked to the traditional risk factors³⁵. Compared to the patients with SMuRF, more SMuRF-less patients in our study were of Indian ethnicity and had family history of premature coronary artery disease highly suggestive of a genetic predilection to develop atherosclerotic cardiovascular disease. It is plausible that these genetic factors might play a major role in the disease process among SMuRF-less patients leading to onset of disease at a younger age and more advanced disease at presentation with consequent worse prognosis. This raises the possibility that other unknown factors might be involved in the pathogenesis and presentation of ACS among the SMuRF-less patients.

Our study found an increased short-term cardiovascular mortality only in the male SMuRF-less patients, which is in contrary to the observation by Figtree et al¹¹ which showed that SMuRF-less women with STEMI had an excess of short-term mortality over their men counterparts. Such discrepancy in observation could be partly attributed to constitutional differences in study population including ethnic background and the inclusion of full spectrum of ACS patients in our study as opposed to the subgroup of STEMI patients in Figtree et al’s study. Other possible factors include varying extent of delay in patient presentation³⁶ and hormonal-mediated differences associated with atherosclerotic plaque characteristics³⁷. However, our study was not granular enough to explain such differences and future studies are warranted.

Moreover, significant mortality difference between our SMuRF and SMuRF-less patients was only observed in the STEMI, but not NSTEMI patients. This is in contrast to a prior study that showed increased mortality in SMuRF-less as compared to SMuRF patients with NSTEMI¹⁹. One possible reason for this discrepancy is the difference in PCI rates between SMuRF and SMuRF-less patients as described by Roe et al, such that the lower use of invasive procedures in SMuRF-less patients might have contributed to their higher mortality¹⁹. Hence, similar PCI rates between SMuRF-less and SMuRF patients (53.2% versus 48.9% respectively, p = 0.321) might partly explain the similar mortality between the two groups of NSTEMI patients. Another possible reason is the significantly lower mortality events in NSTEMI as compared to STEMI patients (4.1% versus 8.3% respectively, p < 0.001) which might lead to less apparent difference seen between SMuRF and SMuRF-less patients among our NSTEMI patients³⁸.

Similar to current literature^{11, 15, 16}, we found that SMuRF-less patients were less likely to be treated with guideline-directed medication including beta-blockers, statins and/or ACE-I or ARBs when compared to the SMuRF patients. Figtree et al¹¹ has shown that suboptimal prescription rate of ACE-I or ARBs and beta-blockers was directly correlated to a higher mortality among the SMuRF-less patients which is in line with other studies demonstrating the prognostic benefit of early initiation of beta-blocker and ACE-I in patients with ACS^39–41. The reason SMuRF-less patients were less likely to be prescribed with prognostically important medication was unclear but could be related to the false perception that they were of lower cardiac risk. The worse clinical status at presentation, lack of pre-existing hypertension and higher incidence of stroke among the SMuRF-less patients might lead to a poorer hemodynamics which precluded the use of beta-blockers or ACE-I or ARBs. Increased awareness of the paradoxical unfavorable outcome in SMuRF-less patients presenting with ACS should be widely promoted and early initiation of guideline-directed medical therapy among ACS patients remains crucial regardless of the cardiovascular risk factor status.

Clinical Implications

Our findings raise concerns regarding the unfavourable outcome in SMuRF-less patients presenting with ACS among the Asian population. Such patients are not uncommon and may present in an even worse clinical state than those with one or more standard cardiovascular risk factors. These ameliorate the general sense of complacency that significant coronary artery disease is an unlikely health concern in individuals without cardiovascular risk factors. Clinicians need to be aware of this unexplained paradoxical phenomenon, and effective lifestyle and pharmacological intervention need to be optimised in all patients regardless of their SMuRF status. Although lower than that reported in the West, the proportion of SMuRF-less patients in our Asian population remains sizeable indicating that this is a global phenomenon that warrant its due attention by all healthcare systems. More efforts are needed to understand the underlying pathophysiology of atherosclerotic cardiovascular risk factors in SMuRF-less patients, from the onset of atherosclerosis through to its progression and the occurrence of ACS, in order to identify such individuals so that appropriate and timely preventative intervention can be given. Currently, most published studies were limited to short-term outcomes and hence further studies are also needed in order to understand the long-term outcome of SMuRF-less patients with ACS.

Strengths and Limitations

This study is the first to examine the prognosis of SMuRF-less patients presenting with ACS in a large Asian cohort over a 10-year period. However, this study has its limitations. Firstly, this is a single-centre retrospective observational study which might be affected by unknown confounders and bias. Therefore, causality cannot be deduced from our results. However, such potential bias was mitigated by adjusting for important covariates in the multivariable models and using mortality as the primary study outcome. Secondly, the current method of categorizing patients into SMuRF and SMuRF-less groups might not be ideal, but it is the universal method used by all published studies, and based on local or international diagnostic threshold for each of the SMuRFs. Such thresholds are generally derived based on clinical evidence or expert consensus, and usually form the thresholds for guideline-directed treatment. Thirdly, some recognized atherosclerotic cardiovascular risk factors other than those universally considered as SMuRF are also beyond the scope for evaluation in this study. The retrospective nature of the study did not allow further evaluation of SMuRF-less patients for non-atherosclerotic cause of ACS such as protein C and S deficiency.

Patients presenting with ACS but without any standard modifiable risk factor are not uncommon in a multiethnic Asian population. They tend to present in a worse clinical state and have poorer short-term outcome, including higher cardiovascular mortality, compared to those with SMuRF.

Compliance with Ethical Standards:

The authors declare that they have no conflict of interest.

Funding/Support

None reported.

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Table 1. Demographic and Clinical Characteristics of Study Cohort Presenting with Acute Coronary Syndrome, Based on Standard Modifiable Cardiovascular Risk Factors.

	Overall (N=8680)	SMuRF (N=7934)	SMuRF-less (N=746)	P-Value
Age	61 (13)	61 (13)	57 (14)	<0.001
Male	6846 (78.9)	6254 (78.8)	592 (79.4)	0.734
Ethnicity				<0.001
Chinese	4889 (61.0)	4468 (60.9)	421 (62.7)
Malay	1697 (21.2)	1607 (21.9)	90 (13.4)
Indian	1367 (17.1)	1208 (16.5)	159 (23.7)
Caucasian	56 (0.7)	55 (0.7)	1 (0.1)
Previous Stroke	492 (5.7)	478 (6.0)	14 (1.9)	<0.001
Atrial fibrillation	201 (2.3)	189 (2.4)	12 (1.6)	0.177
Previous heart failure	151 (1.7)	147 (1.9)	4 (0.5)	0.009
Chronic kidney disease	826 (9.5)	809 (10.2)	17 (2.3)	<0.001
Family history of CAD	928 (10.7)	829 (10.5)	99 (13.3)	0.017
Diabetes Mellitus	3324 (38.3)	3324 (41.9)	0	<0.001
Hypercholesterolemia	4663 (53.7)	4663 (58.8)	0	<0.001
Hypertension	4793 (55.2)	4793 (60.4)	0	<0.001
Smoking Status				<0.001
Smoker	3161 (37.9)	3161 (41.2)	0
Ex-smoker	964 (11.5)	964 (12.6)	0
Non-smoker	4224 (50.6)	3548 (46.2)	677 (100.0)
Discharge Medication
ACE-I/ARB	5477 (63.3)	5084 (64.3)	393 (53.3)	<0.001
β-blocker	6849 (79.2)	6304 (79.7)	545 (74.0)	<0.001
Statin	7906 (91.3)	7268 (91.8)	638 (86.3)	<0.001
Aspirin	8233 (95.1)	7539 (95.2)	694 (93.9)	0.109
P2Y12 inhibitor	6559 (95.3)	6085 (95.3)	574 (94.6)	0.405
Warfarin	325 (4.7)	291 (4.6)	34 (5.7)	0.239
Direct oral anticoagulants	175 (2.5)	160 (2.5)	15 (2.5)	0.963
Laboratory variables
Peak Creatinine (mmol/L)	129 (141)	130 (145)	108 (89)	<0.001
Troponin I (ng/L)	9465 (18278)	9395 (18232)	10223 (18770)	0.251
Left ventricular ejection fraction (%)	49 (13)	49 (13)	49 (13)	0.862
In-hospital management
Presentation Route				0.867
Emergency Medical Services	2436 (37.3)	2215 (37.1)	221 (39.0)
Walk-in	3024 (46.3)	2773 (46.5)	251 (44.3)
Interhospital transfer	1034 (15.8)	943 (15.8)	91 (16.0)
Elective	10 (0.2)	9 (0.2)	1 (0.2)
Inpatient	27 (0.4)	24 (0.4)	3 (0.5)
ACS type				<0.001
STEMI	4975 (57.3)	4493 (56.6)	482 (64.5)
NSTEMI	3705 (42.7)	3441 (43.4)	264 (35.4)
Cardiac Arrest	252 (2.9)	197 (2.5)	55 (7.4)	<0.001
Underwent PCI	5560 (79.3)	5043 (79.0)	517 (83.0)	0.018
Door to balloon time for STEMI patients (min)	87 (406)	81 (321)	140 (855)	0.172
Multivessel CAD	62 (1.0)	51 (0.9)	11 (1.9)	0.018
Culprit vessel				0.002
Left Main	136 (2.0)	116 (1.9)	20 (3.4)
Left Anterior Descending	3422 (51.4)	3086 (50.9)	336 (56.6)
Circumflex	766 (11.5)	712 (11.8)	54 (9.1)
Right Coronary Artery	1817 (27.3)	1680 (27.7)	137 (23.1)
Others	512 (7.7)	465 (7.7)	47 (7.9)
Number of stents				0.104
1	3992 (63.8)	3610 (63.5)	382 (67.5)
2	1219 (19.5)	1130 (19.9)	89 (15.7)
³ 3	335 (5.4)	307 (5.4)	28 (4.9)
Number of vessels intervened				0.582
1	3972 (88.3)	3591 (88.4)	381 (87.0)
2	464 (10.3)	415 (10.2)	49 (11.2)
³ 3	63 (1.4)	55 (1.4)	8 (1.8)
Post-PCI TIMI				0.352
0	96 (1.6)	84 (1.5)	12 (2.1)
1	31 (0.5)	26 (0.5)	5 (0.9)
2	171 (2.8)	156 (2.8)	15 (2.7)
3	5859 (95.2)	5331 (95.2)	528 (94.3)
Procedural success	6217 (97.5)	5658 (97.5)	559 (96.7)	0.231
Coronary Artery Bypass Grafting	225 (2.7)	212 (2.8)	13 (1.8)	0.138
In-hospital complications
Length of hospital stay (days)	6.9 (9.0)	7.0 (9.0)	6.7 (9.0)	0.475
Sepsis	561 (6.6)	520 (6.7)	41 (5.6)	0.265
New onset atrial fibrillation	436 (5.1)	406 (5.2)	30 (4.1)	0.199
Major bleeding	664 (7.8)	613 (7.9)	51 (7.0)	0.397
Inotropic support	832 (9.8)	722 (9.3)	110 (15.1)	<0.001
Intubation	723 (19.9)	626 (18.8)	97 (31.7)	<0.001
Mitral regurgitation	820 (9.5)	768 (9.7)	52 (7.0)	0.018
Ventricular arrhythmia				0.009
Nonsustained ventricular tachycardia	413 (11.5)	370 (11.2)	43 (14.9)
Sustained ventricular tachycardia	188 (5.2)	165 (5.0)	23 (8.0)
Acute renal failure				0.183
Not requiring dialysis	828 (21.5)	774 (21.8)	54 (18.2)
Requiring dialysis	129 (3.4)	122 (3.4)	7 (2.4)
Outcomes
All-cause mortality	633 (7.3)	546 (6.9)	87 (11.7)	<0.001
Cardiac related mortality	564 (6.5)	484 (6.1)	80 (10.7)	<0.001
Cardiogenic shock	669 (9.3)	574 (8.6)	95 (16.3)	<0.001
Stroke	167 (2.0)	150 (1.9)	17 (2.4)	0.396
Heart failure	992 (11.6)	924 (11.8)	68 (9.3)	0.117
30-day readmission	1142 (13.8)	1047 (13.9)	95 (13.2)	0.629

CAD – Coronary Artery Disease; ACEI – Angiotensin Converting Enzyme Inhibitor; ARB – Angiotensin II Receptor Blocker; ACS – Acute Coronary Syndrome; PCI – Percutaneous Coronary Intervention; STEMI – ST Elevated Myocardial Infarction; NSTEMI – Non-ST Elevated Myocardial Infarction; TIMI – Thrombolysis in Myocardial Infarction

* Categorical variables are presented as n (%) and continuous variables are presented as Mean (Standard Deviation)

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Prognostic Outcomes in Acute Coronary Syndrome Patients Without Standard Modifiable Risk Factors: A Multi-Ethnic Study Of 8680 Asian Patients

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