Table 1. The impact of sex on CAD .

CAD: Coronary artery disease, CVD: Cardiovascular disease, CHD: Coronary heart disease, NSTEACS: Non-ST elevation acute coronary syndromes, ACS: Acute coronary syndrome, AMI: Acute myocardial infarction, CV: Cardiovascular, MI: Myocardial infarction, DM: Diabetes mellitus, HT: Hypertension, CHF: Congestive heart failure, CKD: Chronic kidney disease, PCI: Percutaneous coronary intervention, NSTEMI: Non-ST-elevation myocardial infarction, GDMT: Guideline-directed medical therapy, IHD: Ischemic heart disease, NIT: Noninvasive testing, RCT: Randomized controlled trials, CABG: Coronary artery bypass graft, MBF: Myocardial blood flow, CFR: Coronary flow reserve, MVD: Microvascular disease, LMD: Left main disease, SE: Socioeconomic status, MACE: Major adverse cardiovascular events

Identification and Year of Publication	Outcome Measures	Key Findings	Limitations
Li et al. (2022) [3]	This study aims to analyze how the frequency and death rates differ between males and females in different areas and regions of China.	Modifiable risk determinants include high blood pressure, diabetes, physical activity, smoking, alcohol, nutrition, obesity, education, emotional factors, and cholesterol levels. The death rate and risk of having CVD are greater in females than in males. High blood pressure is the risk determinant that mostly affects the Chinese population with CVD.	The population included in this study is not representative of the whole population in China because people from certain regions did not participate. There is a chance that misclassification of measurements reported by the population themselves occurred.
Nussbaum et al. (2022) [5]	This study focuses on the sex differences related to the symptoms' manifestation, treatment, and diagnosis of CAD.	Females manifest non-obstructive CAD more frequently than males. They usually present atypical symptoms, including back pain, palpitations, etc., which lead to delayed diagnosis of the disease and consequently increase the risk of morbidity and mortality.	The inability to give sex-specific instructions and recommendations is due to the low representation of females in clinical trials for CVD, and not enough information about females with CHD is available.
Negrea et al. (2022) [6]	The aim of this study is to analyze the sex disparities in individuals with non-ST elevation acute coronary syndromes (NSTEACS) in terms of risk determinants and management of the condition. Also, it provides an evaluation of the non-traditional manifestation of NSTEACS.	Compared to males, females were more hypertensive and had greater levels of high-density lipoprotein cholesterol; on the contrary, males smoked more and had greater creatinine levels.	The findings of this single-center study with a small sample size cannot be generalized because the sample was from a small geographical area composed mostly of White communities.
El-Menyar et al. (2011) [7]	This study focused on patients with ACS, the variety of symptoms that they manifest, and how they affect the prognosis and outcomes.	Patients who manifest mostly the non-traditional symptoms of CAD get less evidence-based treatment and have a higher mortality rate. Fewer diagnostic tests were performed on these patients, leading to a delayed diagnosis.	The information used for this study was taken from an observational study. The findings cannot be generalized because they were seen in only a particular ethnic group.
van Oosterhout et al. (2020) [8]	The meta-analysis evaluated gender-based discrepancies in the manifestation of symptoms in individuals diagnosed with ACS.	The odds of having nausea, pain between shoulder blades, exhaustion, jaw pain, dyspnea, and throwing up are greater in females than males. However, the odds for chest pain are inferior in the female gender compared to the other symptoms. Regarding right arm, epigastric, and left arm pain and indigestion, there were no discrepancies. It suggests that symptoms of CAD should not be labeled as “typical” or “atypical".	The information gathered by medical record retrieval might generate bias. There is no relation to age. Exclusion of articles that were in a different language. Restricted only to patients with confirmed ACS and not suspected ACS.
Hema et al. (2016) [9]	The RCT aimed to check if risk evaluation, manifestation, testing choices, and outcomes were different in different genders with stabilized symptoms of presumed CAD.	Chest pain is one of the principal manifestations in both genders. It is more probable that men have “aching/dull” pain and “burning/pins and needles”, and females are more likely to have "crushing/pressure/squeezing/tightness" pain. Women had higher comorbidities than men presenting with CAD. Women had more abnormal electrocardiographic changes than men with acute coronary syndrome.	The discoveries can’t be extrapolated to other populations because the study population was limited to outpatients with stable symptoms with presumed CAD and did not include invasive testing.
Coventry et al. (2011) [10]	The study aimed to analyze gender discrepancies in the symptom manifestations of AMI.	Females tend to exhibit inferior odds compared to men with chest pain. Instead, they exhibit more frequent non-traditional symptoms associated with CAD, such as back and neck pain, exhaustion, and palpitations.	Most studies did not include the location and type of infarction and were excluded from the majority of studies. Many research papers had age restrictions.
Khesroh et al. (2017) [11]	This study aims to analyse the influence of sex on the manifestation, treatment, and death of patients diagnosed with ACS.	At the time of diagnosis with ACS, females were older and had more comorbidities than males. They also tend to present with non-traditional symptoms, in contrast to males.	The study only includes citizens from the Gulf area and doesn’t take into account the expats, who make up a large proportion of the population in this geographical area.
Perdoncin et etal. (2017) [12]	The study aims to analyze the sex-specific discrepancies in the management of CAD and how they influence the results for women.	Women usually present with symptoms that are not typical of CAD, like exhaustion, pain in the jaw, and shortness of breath. Women frequently have more complications linked to MI than men; this includes shock, hemorrhage, and stroke. Also, the cardiovascular aftermath for females is worse than that for males.	Absence of acknowledging any limitations. Doesn't specify the inclusion and exclusion criteria.
Sarma et al. (2019) [13]	To analyze the association of sex with major adverse cardiovascular phenomena (CV death, stroke, and MI) as well as all-cause mortality, adjusting for relevant risk factors in individual trials	Women present with CAD at an older age and greater comorbidities (DM, HT, CHF, CKD) have more atypical symptoms and are less treated with GDMT. Women were more likely to have non-obstructive CAD.	Residual confounders that could explain the differences between sexes can’t be excluded. Trials differed in design, time, follow-up, etc. Even though it was multinational, it was predominately White patients.
Du et al. (2017) [14]	Test key performance indicators reflecting in-hospital control of ACS in both male and female patients (including the rate of coronary angiography, PCI, use of evidence-based medications, and major adverse CV events).	Females with NSTEMI had less treatment in contrast with males and received less GDMT. In comparison to males, females have more comorbidities and are older. A greater proportion of women were retired and had lower socioeconomic status and education.	The study did not record the hold-up in hospital presentation or relocation to a specialist. Residual confounding.  Although the scale of the study is large, the investigation of the intervention effect isn’t enough to rule out differences in performance and clinical results.
Vasiljevic-Pokrajcic et al. (2016) [15]	Evaluated how CAD differs between sexes in terms of prevalence, treatment received, comorbidities, and outcomes.	Women have a higher range of comorbidities compared to men. Women receive fewer adequate treatments for acute coronary syndrome (4% less than men).	It was performed using only three tertiary medical centers located in Serbia.
Ferrari et al. (2013) [16]	States the main differences between sexes regarding baseline comorbidities and treatment in patients who had stable CAD.	Females were shown to present with a higher burden of comorbidities and risk factors than men. Females had a lower probability of undergoing interventional treatment and receiving coadjutant medical treatment for CAD prevention. It was shown that women have a shorter duration of suffering from CAD than men.	The study did not investigate how sex influenced prognosis in a long-term evaluation. It also did not evaluate other possible confounders that might explain differences in the management of CAD.
Mega et al. (2010) [17]	The study evaluated the clinical, biomarker, angiographic, and continuous ECG characteristics and post-360-day results of females with unstable ischemic heart disease randomized to ranolazine or placebo in MERLIN-TIMI 36.	Troponin values were lower at baseline for women. Women had higher BNP levels at baseline. The ECG of females showed ST depression and higher concentrations of BNP. Women had a median duration of evidence that was longer than men (40 minutes on average). A study showed that women had higher odds of presenting angina than men. Women had higher odds of having more comorbidities when presenting with CAD.	Films of realized angiographic assessments and angiographic evaluations were not checked by an angiographic core laboratory.
Otaki et al. (2015) [18]	The prospective, multinational registry examined the frequency, severity, and composition of coronary artery disease (CAD) in young individuals undertaking coronary CT angiography (CCTA).	Men had a higher prevalence of any kind of CAD in comparison to women.	The study was conducted on individuals who were already suspected of having CAD, which could represent a selection bias.
Smaardijk et al. (2020) [19]	The study evaluated the risks of psychological determinants for IHD incidence in both sexes.	Women present more frequently with non-obstructive IHD, including spasms, takotsubo cardiomyopathy, and microvascular coronary dysfunction. Women showed a 21% and men a 37% elevation in the risk of psychological determinants for MACE.	Miscellaneous studies were encountered. Possible biased publications
Pagidipati et al. (2019) [20]	The RCT measured gender discrepancies in the results of noninvasive testing (NIT) and the medical treatment (aspirin or statin use) that follows in patients with stable symptoms indicative of CAD.	Women received fewer statins, it was more improbable for them to have adverse cardiovascular results in contrast to males, and they were indicated less often for catheterization than men.	Randomization wasn’t categorized by patient sex; nonetheless, within each sex, the two testing arms were alike.
Guo et al. (2018) [21]	Compared outcome differences in both sexes after PCI in a one-year follow-up.	Women had the worst outcome after PCI, and age was an important risk factor associated with it.	The studies included were not RCTs. Women were only 25% of all the patients analyzed, which increases the risk of bias. There was a lot of heterogeneity between the studies chosen. Studies eligible were only in English.
Al-Fiadh et al. (2011) [22]	The RCT aimed to identify if there is an early or medium-term risk in the recent period of PCI between females and males that exhibits ACS by making use of a big multi-center PCI registry based in Australia.	The frequency of coronary disease at angiography was inferior in males and females, and less than half of women who indicated an earlier therapy commencement got PCI.	Information for patients who went through CABG or did not have any procedure was not given. Extended follow-ups were initially part of the plan; nonetheless, this was restricted to 12 months only.
Mehta et al. (2012) [23]	The retrospective observation focused on analyzing discrepancies in risk among females and males and assessing connections between sexes, 365-day mortality, and bleeding rates in patients receiving fibrinolysis for STEMI.	Women experienced more bleeding than men. Invasive procedures were less commonly performed on women. Women had a higher incidence of in-hospital hurdles when experiencing bleeding. Once the occurrence of bleeding was considered in the death model, females had an inferior risk of death.	Possibly other factors or coincidence played a role in the discovery of a connection between bleeding and mortality in females and males. The study's results may not apply to those who undergo PCI intervention due to the lack of information about the timing of bleeding for many patients.
Lichtman et al. (2018) [24]	The clinical trial addressed the missing information regarding the recognition and manifestation of AMI signs in younger patients.	The manifestation of AMI signs does not vary much between genders. The most prominent sign is chest pain in both genders; however, females also manifested other symptoms such as pain in the neck, jaw, arms, and palpitations. In comparison with males, females with STEMI did not show signs of chest pain. NSTEMI was more frequently exhibited in females.	Patients who passed away before hospitalization and did not agree to it were excluded. The study was unable to determine the initial or main symptoms reported by the patients.
Tamis-Holland et al. (2013) [25]	The RCT measures were death, myocardial infarction, cerebrovascular accident, chest pain, and Duke Activity Status Index scores by doing a comparison using the variables, interventions performed, and outcomes between both sexes.	Women had higher odds of presenting with angina. Men tend to have higher rates of left ventricular dysfunction than women. Women had higher odds of presenting with chronic heart failure and having diabetes for a longer time than men, as well as hypertension.	The study did not assess the severity of symptoms, had some missing data, and did not evaluate certain factors such as transportation and the living situation of patients.
Diercks et al. (2010) [26]	The study aimed to show if the “National Women's Cardiovascular Awareness Campaign” had a beneficial effect in reducing the time taken between symptom onset and hospital arrival in women suffering from myocardial infarction.	The average time that women take to present to the hospital after the onset of symptoms is higher compared to men. Women tend to arrive at the hospital after 12 hours of symptom onset. Possible risk factors associated with a longer duration of the interval included older age (being older than 60 years), race, and comorbidities like diabetes and high blood pressure.	Some patients had missing information regarding the time of symptom onset and arrival at the hospital. The study did not perform an evaluation of other factors involved, like transportation, the hospital’s closeness, or other living situations that might affect the patient. Patients who showed up after 24 hours from symptom onset were not included in the study. The study did not show a link between mortality and delay.
Gimenez et al. (2014) [27]	The RCT was designed to show differences in the treatment of suspected myocardial infarction in women by addressing angina’s characteristics and variations between men and women.	Women had higher odds of presenting symptoms of pressure like pain, dyspnea, pain that increased with palpation, pain moving to the neck or the back, sudden onset of angina, or pain that lasted for longer than half an hour. Women had lower chances of having no pain radiation, radiation to the right side of the chest and neck, or pain lasting 2 to 30 minutes.	The study did not evaluate the accompanying symptoms. It presented a bias in favor of typical chest pain.
Serruys et al. (2018) [28]	The multinational trial analyzed death (all-cause), myocardial infarction, or cerebrovascular accidents over 3 years after invasive intervention in the context of the left main disease. Secondary endpoints included events happening between the first 30 days and 3 years after the intervention, as well as outcomes for each sex with left coronary disease.	The female sex had a higher risk profile than the male sex but showed less complexity in coronary anatomy. Women also had greater chances of completing revascularization after percutaneous coronary intervention. However, women who underwent percutaneous coronary intervention had a higher risk of complications, including ischemic and bleeding complications. Sex was not independently associated with the primary endpoints or death after 3 years.	The subgroup used in the study is not a significant sample. The results found should be used to generate a hypothesis regarding the differences.
Xi et al. (2022) [29]	This systematic review and meta-analysis aimed to analyze the existing evidence on how sex affected mortality (short- and long-term) in patients presenting with myocardial infarction with ST-segment elevation.	Mortality (short-term) was higher in women with myocardial infarction than in men. Mortality (long-term) had similar results for both sexes. Both results were shown after adjusting for baseline risk factors.	The study did not consider how sex change affected other outcomes, such as disability, quality of life, and functional status, and relied on previous data taken from observational studies, which may lead to bias.
Berry et al. (2018) [30]	This randomized controlled trial aimed to investigate major ischemic, cardiovascular, and cerebrovascular events such as myocardial infarction or stent thrombosis.	Women who were on dual antiplatelet therapy after one year had a similar risk of ischemia and bleeding complications when compared to men after coronary percutaneous intervention and angioplasty.	The comparisons between treatments in both sexes were posterior to intervention, and this might limit the statistical significance.
Chichareon et al. (2020) [31]	The randomized controlled trial assessed the effectiveness of the treatment by measuring all-cause mortality and new Q-wave myocardial infarction 2 years after PCI. Additionally, the trial evaluated the treatment's safety by monitoring incidents of Bleeding Academic Research Consortium type 3 or 5 bleeding.	The risk of death for any cause was the same for males and females, as was the appearance of new Q-wave MI during a two-year follow-up. Hemorrhagic complications occurred at a higher rate than in men. When analyzing the antiplatelet therapy, the use of ticagrelor monotherapy resulted in a lower risk of bleeding in men over a period of one year.	The study is limited by the lack of stratification by sex, as the female group was smaller than the male one. Also, for higher statistical significance, adjusted analyses should be done.
Lauet al (2017) [32]	This meta-analysis aimed to identify major adverse cardiovascular events, myocardial infarction, stent thrombosis, cardiovascular or all-cause mortality, and bleeding complications after P2Y 12 inhibitor administration.	The use of P2Y12 inhibitors was similar between male and female patients, and in both cases, it reduced the risk of major cardiovascular events, myocardial infarction, and stent thrombosis. The study also found that the use of P2Y12 inhibitors had a similar increased risk of bleeding complications in both sexes.	The study is limited by heterogeneity given by variation among the types of study designs and populations.
Firouzabadi et al. (2013) [33]	The case-control study from Iran investigated the relationship between six gene polymorphisms of renin-angiotensin system compound components and coronary disease.	It was found that there was an independent association between angiotensin-converting enzyme A-240T polymorphism and a higher risk of presenting CAD in Iranian women.	There might be heterogeneity in studies regarding sample inclusion and exclusion criteria, or it might be due to the different racial characteristics of the population taken.
Haas et al. (2019) [34]	This post hoc study examines if there are sex differences in myocardial blood flow (MBF) and coronary flow reserve (CFR) between patients with type 2 diabetes mellitus who do not present clinical indications of obstructive CAD.	In contrast with males, females have poorer blood flow through the myocardium and diastolic function. Rest MBF is related to poorer diastolic function in females; this might be due to the response to aldosterone.	The study is not large, and the initial research did not intend to evaluate the effects of gender. Sex hormones were not considered in this study.
Hokimoto et al. (2014) [35]	The case-control study analyzed the relationship between CYP2C19 polymorphism and the development of coronary artery disease (CAD) when dyslipidemia, diabetes, and chronic kidney disease are not present to reduce the impact of conventional coronary risk determinants.	CYP2C19 PM is a predictor of CAD risk in females alone, but not in males.	The study only investigated the association in a Japanese population and may not be generalizable to other populations. The study did not investigate the functional significance of the CYP2C19 polymorphism or its potential mechanisms of action in the development of CAD.
Gijsberts et al. (2015) [36]	The observational study explored the relationship between set biomarkers and the severity of CAD in stable patients who will undergo coronary angiography, taking into account sex.	The severity of CAD is inferior in females in contrast to males, based on coronary angiography. The relationship between biomarkers and CAD severity doesn’t change between the two sexes.	It was not possible to continue assessing patients for the occurrence of cardiovascular events.
Guimarães et al. (2017) [37]	The study objective is to analyze the relation between gender and clinical results, as well as the relation between sex psychosocial features and cardiovascular risk.	Regarding psychosocial determinants, results, and clinical features, females and males with stable CAD exhibit many discrepancies. Females have more comorbidities and a poorer quality of life. Women have better lasting clinical results; this may be due to the frequency of signs of depression; the more prevalent these symptoms were, the more chances the cardiovascular risk of women was similar to that of men.	The number of females that participated in this study is shorter than that of males. Rigorous inclusion criteria were used, so the pool of individuals might not be a full representation of subjects diagnosed with stable CAD. A strict psychological assessment wasn’t conducted.
Norris et al. (2008) [38]	To compare HRQOL results post-cardiac catheterization to verify if sex discrepancies persist following adjustment of set risk determinants, baseline HRQOL, symptoms of depression, and social assistance among CAD patients of both sexes. Also, this analysis evaluated whether these determinants explain sex differences in HRQOL.	Females with coronary artery disease presented a poorer quality of life associated with health 365 days after coronary angiography, in contrast with males. The Seattle Angina Questionnaire scores are considerably more elevated in males than females.	The study pool of individuals was restricted to patients catheterized for CAD and made a response to the baseline and the 365-day follow-up. Additionally, the study did not retain the medication that was given and utilized over the 365 days.
Dreyer et al. (2015) [39]	The goal of this study is to analyze sex discrepancies in health status through time with a baseline of up to one-year post-AMI. The study analyzed mental and physical functioning, quality of life, and angina. It also analyzed recovery time and the impact of sex on each health status.	They had unfavourable physical restrictions, quality of life, and mental performance. The recovery time was alike between both sexes; however, females in the same age range as males who had an episode of AMI had a lower score in the entire health status.	Patients did not provide a response for the follow-up interview, and a portion was lost. The study could not reach patients who were sick and couldn’t participate. The study was observational, and the discrepancies among both sexes in health status might be due to measurement errors.
Orth-Gomér et al. (2018) [40]	The study measured the effect of psychological, clinical, and social determinants concerning the social degree of CAD patients with depression in a Germany-based trial.	Social support varied by sex and education level. Women with low education received the least support, while men with academic backgrounds received the most. Depression was highest for both genders in the lowest socioeconomic group, but significant only for women.	The description and categorization of socioeconomic status (SES) should be considered while drawing conclusions. The grouping of SES is a delicate matter, and several proportions of SES are outlined, with education being the more frequently utilized criterion for SES.
Daoulah et al. (2017) [41]	The observational, multicenter study focused on establishing the relationship between divorce and the severity of CAD, MVD, and LMD in men and women.	Critical CAD, MVD, and LMD are related to various divorces in females but there is no relation with males.	The number of divorcees is not large enough, and the time between the separation and cardiac catheterization wasn’t recorded. Generalizations of findings to divorcees in an unaffected population cannot be made.