Risk factor profile and outcomes of premature acute coronary syndrome after percutaneous coronary intervention: A 1‐year prospective design

Abstract Background The prevalence of acute coronary syndrome (ACS) among young adults (premature ACS) has dramatically increased in recent years, especially in developing countries. Yet, the data on these patients' attributed risk factors and outcomes are inconsistent. In this study, we aimed to investigate these data in a cohort of premature ACS cases who underwent percutaneous coronary intervention (PCI) compared to older patients. Hypothesis We hypothesize that premature ACS patients undergoing PCI will exhibit different risk factor profiles and outcomes compared to non‐premature patients. specifically, we anticipate that premature patients do not necessarily have better outcomes than non‐premature. Methods Overall, 3142 and 10 399 patients were included in premature and non‐premature groups, respectively. Patients' pre‐operative, post‐operative, and follow‐up data were retrieved retrospectively from the Tehran Heart Center PCI databank. Results The mean age of premature and non‐premature cohorts was 48.39 and 67 years, respectively. Patients were predominantly male in both groups. Family history of coronary artery disease (CAD), dyslipidemia, smoking, and opium addiction were more prevalent among the younger cohort. After adjustment, in‐hospital mortality in younger patients was considerably higher, with all‐cause mortality and major cardiovascular and cerebrovascular events (MACCE) exhibiting no noticeable difference among the two groups. Conclusions Risk factor profile is different in young patients, and traditional cardiovascular risk factors, such as hypertension and diabetes mellitus, are more prevalent among older adults. Younger age is not equivalent to a better prognosis; hence, similar or even more caution should be taken into consideration regarding secondary prevention for these patients.


| INTRODUCTION
Premature acute coronary syndrome (ACS) is defined as the first occurrence of clinical manifestation of atherosclerosis in men and women at a young age. 1 Studies show that the mean age of coronary artery disease occurrence has decreased in recent years especially in Iran, mainly due to an increase in urbanization and unhealthy lifestyles. 2,3[6] The prevalence of premature ACS varies from one country to another; all healthcare providers should, therefore, evaluate the associated risk factors and mortality and morbidity rates to improve the general health of the population.Risk factors, diabetes mellitus, family history of coronary artery disease, dyslipidemia, smoking, and hypertension were significantly and positively associated with coronary artery disease in young adults compared to healthy ageand sex-matched populations in Iran. 7ttle evidence exists regarding the association between age and adverse outcomes among patients with ACS undergoing percutaneous coronary intervention (PCI), 8 such information can help healthcare systems to achieve better planning and apply preventive strategies for improving clinical outcomes following PCI to plan and manage coronary artery disease more properly.Thus, we aimed to compare the outcomes among the patients with ACS who underwent PCI, 1 year after the procedure in both men and women; collected data from the PCI data bank at the Tehran Heart Center (THC) over a span of 4 years with reliable follow-ups.

| Study design
This study was a single-center, registry-based cohort study conducted at the THC. 9 Data regarding the patient's characteristics and procedural details were recorded prospectively at the time of the procedure and during each follow-up afterward.The THC ethical board approved the study (IR-THC-13 799).This study did not meet the criteria for informed consent; consequently, an "informed consent waiver" was obtained from the THC ethical board.

| Study population
The entire cohort included 15 809 patients who underwent coronary angiogram and PCI at the THC between April 2015 and December 2019.Our inclusion criteria were: (1) all patients with ACS (see after for definition); (2) adequate preprocedural characteristics; and (3) completion of 1-year follow-up visits.The main exclusion criteria were patients presenting with stable angina and incomplete followups.The patients' follow-up protocol was at the 4th, 6th, and 12th month after PCI and annually thereafter.Patients were stratified into two groups; Premature ACS (women ≤55 years; men ≤50 years) and nonpremature ACS (women >55 years; men >50 years), based on the time of the procedure.Patients did not switch groups if they passed the cut-off points during the follow-up period.

| Definition of variables
Data from the study population were retrieved from our center's angiography/PCI databank.ACS refers to a spectrum of clinical presentations ranging from those for ST-elevated myocardial infarction (STEMI) to presentations found in non-ST-elevated myocardial infarction (NSTEMI) or in unstable angina (UA).The definition of hypertension was based on the presence of at least one of the following conditions; minimum systolic blood pressure of 140 mmHg, minimum diastolic blood pressure of 90 mmHg, or a history of taking antihypertensive drugs. 10e definition of dyslipidemia was based on the presence of either a minimum total cholesterol of 240 mg/dL, a minimum triglyceride of 200 mg/dL, or high-density lipoprotein cholesterol <40 mg/dL in men and <50 mg/dL in women, a minimum low-density lipoprotein cholesterol level of 160 mg/dL, or a history of taking lipid-lowering drugs. 11,12We determined cigarette smoking and opium consumption based on the patient's self-reported status.A current smoker was a person who currently smokes and has ever smoked more than 100 cigarettes. 13Based on the American Diabetes Association, diabetes mellitus was defined as the presence of a definite history of diabetes with records of treatment or fasting blood sugar ≥126 mg/ dL or 2-h postprandial glucose ≥200 mg/dL. 14Positive family history was defined as a first-degree relative younger than 55 years (men) or 65 years (women) who had coronary artery disease.
We used thrombolysis in myocardial infarction (TIMI) flow grade to assess the coronary artery flow in ACS.It is classified as grade 0 (no flow), grade 1 (penetration without perfusion), grade 2 (partial perfusion), or grade 3 (complete perfusion).Left main (LM) stenosis refers to those with stenosis of the left main coronary artery >50% on angiogram.

| Procedural technique
The standard techniques with the femoral approach were applied for performing PCI procedures.According to our procedure routine, all patients received a 300-600 mg loading dose of clopidogrel plus 325 mg aspirin before the procedure.During the procedure, patients received 70-100 IU/kg intravenous unfractionated heparin.Clopidogrel (75 mg/day) and aspirin (81 mg/day) were maintained for at least 1-year after the procedure.

| Study endpoints
All-cause mortality is defined as the occurrence of death of any cause during the follow-up, in-hospital mortality is defined as the occurrence of death during the first 30 days after the procedure, and MACCE occurrence is defined as the occurrence of one of the following conditions (which has happened first): all-cause mortality, nonfatal ACS, nonfatal stroke or transient ischemic attack, and repeat coronary revascularization via PCI or Coronary artery bypass graft surgery were considered as main endpoints.

| Statistical analysis
Normally and skewed distributed continuous variables were presented as mean with standard deviation (SD) or median with 25th and 75th percentiles (interquartile range [IQR] boundaries), respectively.
Student's t-test and Mann-Whitney U-test were used to compare normally and skewed distributed variables, respectively.Discrete variables were presented as frequency and percentages and compared between groups using the χ² test.The unadjusted inhospital mortality was reported using logistic regression (odds ratio [OR]).The unadjusted all-cause mortality and MACCE were reported using Cox's proportional hazards model (hazard ratios [HR]).We used the R version 4.0.3 for all statistical analyses. 15| RESULTS

| Study population
In all, 15 809 patients were recruited in this study.After applying exclusion criteria, 13 541 patients remained in the final analysis (Figure 1).From these, 3142 were categorized as premature ACS, and the rest (10 399) as nonpremature ACS.
The mean age of premature and nonpremature ACS groups was 48.39 ± 9.13 and 67.00 ± 12.60 years, respectively.The patients were mainly male in both groups (92.6% in premature and 66.6% in nonpremature; p < .001).The main presentations of ACS were unstable angina and NSTEMI in both groups (57.2% in the premature F I G U R E 1 Cumulative hazard of (A) mortality and (B) major cardiovascular and cerebrovascular events (MACCE) in premature and nonpremature patients.group and 65.8% in the nonpremature group; p < .001).In the premature group, smoking and opium consumption were higher and also, and HTN and DM were lower compared to the nonpremature group.Baseline LDL was significantly higher in younger patients.
As expected, a positive family history of CAD was higher in the premature ACS group.Detailed baseline characteristics are described in Table 1.

| Based on gender (male vs. female)
In men, all-cause mortality and MACCE were statistically similar in the premature and nonpremature group however in-hospital mortality was higher in younger patients, HR 4.232 (3.284-5.521)(p < .001).

| DISCUSSION
Based on our definition, roughly a quarter of ACS patients were premature.Smoking habits, positive family history of CAD, Baseline LDL levels, and opium addiction were higher in the premature group.
However, other major traditional CAD risk factors, such as HTN and DM, were relatively lower.The adjusted in-hospital mortality was surprisingly higher in the young cohort, with all-cause mortality and MACCE exhibiting no difference among the two patient groups.
These findings suggest that younger age is not necessarily associated with better post-revascularization outcomes.

| Risk factor distribution
The significant implication of smoking in premature ACS has been shown in previous literature. 16About half of the young population were smokers, which was almost twice the percentage of older patients (24.4%).Our results were in line with previous studies. 17oking is considered the strongest modifiable factor associated with premature CAD and ACS. 16,18Moreover, Alberty et al. highlighted a 10-year reduction in the age at which cardiovascular events occur due to smoking. 19Hence, addressing such risk factors in young people and taking proper measures to promote their cessation would yield the maximum harvest.
A family history of CAD is another traditional risk factor that is more prevalent among young patients.It is mediated by genetic determinants and diseases such as heterozygote familial hypercholesterolemia, whose prevalence is shown to be as high as 1 in 11 patients with premature ACS. 20,21As well as this, a shared lifestyle has probably led parents to cardiovascular morbidities.The integral role that the family history of CAD plays warrants further gene identification and risk stratification in primary prevention for at-risk populations.
Although implicated in all age groups, dyslipidemia and high LDL level were more prevalent among young patients than their older counterparts.Lipid abnormalities enhance atherosclerotic plaque formation, which can subsequently destabilize, initiating myocardial infarction (MI) and stroke field. 22The incidence of MACCE is substantially higher among premature patients with familial hypercholesterolemia. 20 High levels of lipoprotein a (Lpa) are detected in young patients presenting with ACS, and its negative cardiovascular effects are shown to be aggravated in T A B L E 1 Baseline characteristics in premature and nonpremature acute coronary syndrome (ACS) patients.association with elevated LDL levels field. 23Previous studies have also demonstrated a strong association between LDL/HDL ratio and the rate of MI, especially among young patients, 16 necessitating relevant screening and utilizing lipid-lowering medications before cardiovascular events.
Consistent with previous studies, conventional risk factors, including HTN and DM, exhibited higher rates among the mature ACS cohort. 16,24Yet, part of this lower prevalence among younger patients could be due to the under-diagnosis of these conditions due to poor screening in younger age groups.Some studies have suggested utilizing HbA1C measurement as a complementary to the self-reported history of DM in ACS patients 25  occurrence concomitant with acute MI in these patients accompanies a higher rate of in-hospital mortality. 27Furthermore, an increased inhospital mortality rate is associated with arrhythmias, which are more prevalently seen among younger patients. 24In this regard, the differences in the pathogenesis of AMI between younger and older patients must also be taken into consideration.Although atherosclerotic plaque rupture accounts for the majority of events in both cohorts, etiologies such as plaque erosion, spontaneous coronary dissection, and vasospastic angina are more common among younger age groups and may contribute to the difference found in the inhospital mortality rate within groups. 28The higher risk of in-hospital mortality in our study may also be partly explained by the fact that all the in-hospital events in our study population occurred in men and those presenting with STEMI.This can be indicative of profound tissue ) were used to stabilize potential selection biases of treatment, weights were calculated from propensity score (PS), which was generated by predicted probabilities of logistic regression on identified potential confounders (gender, body mass index [BMI], hemoglobin [Hb], high-density lipoprotein [HDL], estimated glomerular filtration rate [eGFR], triglyceride [TG], low-density lipoprotein [LDL], ejection fraction [EF], presenting first diagnosis, total cholesterol [TCH], family history, dyslipidemia [DLP], diabetes mellitus [DM], hypertension [HTN], cigarette smoking [CS], opium, cerebrovascular disease, chronic obstructive pulmonary disease [COPD], pre-and postprocedural TIMI flow, vessel severity [SVD, 2VD, 3VD]).The C-statistic for the model was 0.81.Weights for each case (Wi) are calculated as 1/PS(Xi) for premature ACS, and 1/(1-PS(Xi)) for nonpremature ACS.
T A B L E 2 Rates of post-percutaneous coronary intervention (PCI) outcome in premature and nonpremature ACS groups.