Archives of Academic Emergency Medicine. 2019; 7 (1): e26 OR I G I N A L RE S E A RC H Association of Admission Blood Glucose Level with Major Adverse Cardiac Events in Acute Coronary Syndrome; a Cohort Study Mostafa Alavi-Moghaddam1, Mohammad Parsa-Mahjoob2, Robabeh Ghodssi-Ghassemabadi3, Bita Bitazar1∗ 1. Emergency Medicine Department, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Cardiovascular Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Department of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Received: January 2019; Accepted: March 2019; Published online: 16 April 2019 Abstract: Introduction: Appropriate management of abnormal admission blood glucose level (ABGL) in acute coronary syndrome (ACS) patients still remains a common issue. This study aims to assess the influence of ABGL on development of 30-day major adverse cardiac events (MACEs) in patients with suspected ACS. Methods: This is a prospective cohort study based on analysis of data collected from patients suspected to acute coronary syndrome admitted to emergency department. ABGL of patients was measured and its association with de- velopment of MACEs (MI, CVA, mortality) within 30 days of follow-up was studied. Results: 814 participants with the mean age of 61.8±13.4 years were studied (58.1% male). MACE endpoints were developed in 166 (39.0%) hyperglycemic, 30 (46.9%) hypoglycemic, and 53 (16.4%) normoglycemic patients (p<0.001). Mean ad- mission blood glucose level of patients who developed MACE within 30 days was significantly higher than oth- ers (210.6±123.4 vs 157.4±86.6mg/dL; p<0.001; OR: 1.006 (1.005 to 1.008)). There was a significant correlation between male gender (p=0.027), abnormal admission blood glucose level (p<0.001), diabetes (p = 0.001), hyper- lipidemia (p=0.059), prior CABG (p=0.008), first and second blood troponin levels (p<0.001), first and second abnormal ECGs (p<0.001), and also ECG changes (p<0.001) with developing MACE. Abnormal ABGL, first and second blood troponin levels, and the history of diabetes were among independent risk factors of developing MACE within 30 days. Conclusion: It seems that abnormal admission blood glucose level in suspected ACS patients was an independent predictor of major adverse cardiac events within 30 days. Keywords: Blood glucose; acute coronary syndrome; myocardial infarction; stroke; death Cite this article as: Alavi-Moghaddam M, Parsa-Mahjoob M, Ghodssi-Ghassemabadi R, Bitazar B. Association of Admission Blood Glucose Level with Major Adverse Cardiac Events in Acute Coronary Syndrome; a Cohort Study. Arch Acad Emerg Med. 2019; 7(1): e26. 1. Introduction Associations between elevated admission blood glucose level (ABGL) and bigger infarct size in acute myocardial infarction (AMI) as well as inflammation in acute coronary syndrome (ACS) have been reported (1, 2). Many studies have argued about the possible direct impact of hyperglycemia on adverse outcomes of acute coronary syndrome patients through var- ious pathophysiological mechanisms. Recent studies have suggested that hyperglycemia has a detrimental effect on is- ∗Corresponding Author: Bita Bitazar; Emergency Medicine Department, Imam Hossein Hospital, Madani Avenue, Imam Hossein Square, Tehran, Iran. Email: md.bitazar@gmail.com Tel: +9821-77558001 chemic myocardium. It has been reported that acute hyper- glycemia abolishes ischemic preconditioning and promotes apoptosis (3, 4). Acute hyperglycemia also decreases nitric oxide bioavailability, impairs endothelial function, increases platelet aggregability and stimulates coagulation (5). These changes may cause microvascular dysfunction during reper- fusion and impaired left ventricular function after AMI (6). This theory has a measure of support from studies that have identified a stronger correlation between the risk of ACS in patients with hyperglycemia without a history of diabetes (7). There is a biological plausibility to this result as these pa- tients may have an undiagnosed, untreated diabetic state re- sulting in more glycolytic damage than someone known to have diabetes and actively receiving treatment. Similar find- ings were obtained by Petursson et al. when assessing 30-day This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Alavi-Moghaddam et al. 2 mortality risk of patients with confirmed ACS (8). This re- sult has also been reported in patients experiencing AMI (9). Some studies have suggested insulin administration in pa- tients with severe hyperglycemia at the time of admission in emergency department regardless of their diabetic state (10, 11). In a guideline published by National Health System of the Great Britain, insulin administration is recommended in patients with confirmed ACS with admission blood glucose level higher than 198 mg/dl (12). In a Japanese study, al- though they stated that hyperglycemia was observed in many patients with ACS, they emphasized that administrating in- sulin requires more researches (13). A number of large therapeutic studies have attempted to ex- plain the effect of hyperglycemia on post-ACS mortality, but the lack of a general consensus on the appropriate manage- ment strategy for abnormal glycemia still remains a common issue in emergency departments. In addition, adverse out- comes risk stratification in cardiac patients and early predic- tion of major adverse cardiac events (MACE) is a matter of importance. Based on above-mentioned points, this study aims to assess the influence of admission blood glucose level (ABGL) on development of 30-day MACE in patients with suspected ACS. 2. Methods 2.1. Study design and setting This is a prospective cohort study based on analysis of data collected from patients with suspected acute coro- nary syndrome admitted to emergency department of Imam- Hossein Hospital, Tehran, Iran, between June 21, 2016 and June 20, 2017. Presenting blood glucose level of pa- tients was measured and its association with development of MACE within 30 days of follow-up was studied. The pro- tocol of this study was approved by Ethics committee of Shahid Beheshti University of Medical Sciences (number: IR.SBMU.RETECH.REC.1397.519) and researchers adhered to principals of Helsinki protocol and confidentiality of pa- tients’ information. Informed consent was obtained from pa- tients or his/her relatives before enrollment to the study. 2.2. Participants Patients were included if they fulfilled all of the following cri- teria: ≥18 years of age; ≥5 minutes of symptoms suggestive of ACS; and the attending physician deciding to investigate with cardiac biomarkers. Patients with a clear cause other than suspected ACS for the symptoms (e.g. clinical finding of pan- creatitis), transfer from another hospital, pregnancy, previ- ous enrollment, and inability to be contacted after discharge were excluded. The American Heart Association (AHA) case definitions for symptoms suggestive of a cardiac condition were used, which include chest pain, epigastric, jaw or arm pain, or discomfort or pressure without an apparent non- cardiac source . 2.3. Measurements and outcome After careful history taking, physical examination, and do- ing initial assessments, eligible patients were selected. Non- fasting, on-admission blood glucose level was measured for all patients. Blood samples for measuring blood glucose were taken from patients’ finger tips. All measurements were done by the same glucometer and the same glucose test tape. All patients were evaluated regarding the development of MACE within the 30 days of follow-up. Acute myocardial in- farction (AMI), cerebrovascular accident (CVA), and all-cause mortality were considered as MACE in this study. Patients’ follow-up was done by a senior emergency medicine resident via phone calls. 2.4. Data gathering The baseline characteristics (such as age and gender), med- ical history, contact information, and ECG and laboratory findings as well as 30-day outcome were recorded in special paper sheets. Blood glucose level ≤90 mg/dL was consid- ered as hypoglycemia, 91 to 126 mg/dL as normalglycemia, and >126 mg/dL as hyperglycemia. All data were collected by a senior emergency medicine resident under direct supervi- sion of an emergency medicine specialist. 2.5. Statistical Analysis The statistical analyses were performed using R statistical (version 3.2.1) and SPSS 21 software. Continuous data were presented as mean and standard deviation, and categorical data were presented as frequency and percentage. Logistic regression analysis was done concerning the variables age, gender, hypertension, dyslipidemia, diabetes, family history of cardiac disease, smoking, prior AMI, prior CABG, cardiac troponin and ECG changes. The relationship between the three ABGL categories and MACE within 30 days was ana- lyzed. Area under the ROC curve (AUC) was calculated in order to calculate predictive accuracy of HEART score and model containing HEART score and ABGL. Significance level was set at 0.05. 3. Results 3.1. Baseline characteristics of studied patients 877 patients suspected to ACS were evaluated. 63 of whom were excluded (42 were missed to follow-up and 21 had in- complete data; figure 1). Finally, 814 participants with the mean age of 60.8 ±13.4 (23 – 91) years were entered to anal- ysis (58.1% male). The mean admission blood glucose level of patients was 173.7±102.2 (71 – 540) mg/dL. 64 (7.9%) pa- tients were hypoglycemic, 324 (39.8%) normoglycemic, and This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2019; 7 (1): e26 Figure 1: Flow diagram of participant recruitment. Figure 2: Area under the ROC curve of HEART score and a model containing HEART score plus blood glucose level in predicting the development of major adverse cardiac event (MACE) within 30-day follow-up of acute coronary syndrome patients. 426 (52.3%) hyperglycemic at the time of admission to emer- gency department. MACE endpoints were identified in 249 (30.6%) patients within the 30 days of follow-up (231 (28.4%) AMI, 12 (1.5%) CVA, and 62 (7.6%) death cases). Table 1 compared the base- line characteristics of studied patients based on the pres- ence or absence of MACE. MACE endpoints were developed in 166 (39.0%) hyperglycemic, 30 (46.9%) hypoglycemic, and 53 (16.4%) normoglycemic patients (p<0.001). The mean admission blood glucose level of patients who developed MACE within 30 days was significantly higher than others (210.6±123.4 vs 157.4±86.6mg/dL; p<0.001; OR: 1.006 (1.005 to 1.008)). The HEART score of patients with MACE was sig- nificantly higher (p < 0.001). 3.2. Correlations There were significant correlations between male gen- der (p=0.027), abnormal admission blood glucose level (p<0.001), diabetes (p = 0.001), hyperlipidemia (p=0.059), prior CABG (p=0.008), first and second blood troponin lev- els (p<0.001), first and second abnormal ECGs (p<0.001), and also ECG changes (p<0.001) with developing MACE. The re- sults of multiple logistic regression model demonstrated that abnormal ABGL, first and second blood troponin levels, and the history of diabetes were among the independent risk fac- tors of MACE within 30 days (Table 1). Figure 2 shows the area under the ROC curve of HEART score + ABGL and HEART score alone in predicting the development of MACE (0.770 vs. 0.767). 4. Discussion The present study has confirmed findings from previous re- ports that abnormal ABGL is associated with increased risk of developing MACE in ACS patients. The findings showed that ABGL could probably be an independent risk factor re- gardless of diabetic status or traditional risk factors of MACE; like a similar study done by Gardner et al. (14), where they demonstrated that within 30 days of follow-up, the odds of patients with ABGL higher than 7 mmol/L (126 mg/dL) de- veloping MACE were 1.5 times higher than patients with an ABGL<7 mmol/L. Capes et al. [8] demonstrated that the rel- ative risk of in-hospital mortality in non-diabetic MI patients with ABGL>6.1 mmol/L was 3.9 times higher than patients with normal glycemia. Among diabetic MI patients, those with ABGL≥10 mmol/L had a 70% increase in the risk of in-hospital mortality compared to normal glycemic diabetic patients. The largest retrospective study on this subject to date, which examined the outcomes of 141680 elderly pa- tients with MI, demonstrated a significant 13-77% increase in 30-day mortality and a 7-46% increase in 1-year mortality depending on the degree of hyperglycemia (9). In the present study, the frequency of AMI endpoint was higher than CVA. This probably happened due to entering ACS patients to the study, most of which were affected with AMI. 39.0% of hyperglycemic patients finally developed MACE within 30 days. Foo et al. (15) did a similar study in 3 east London hospitals over a 2-year period. They demon- strated a near-linear relationship between higher admission glucose levels and higher rates of cardiac death. Particu- larly in glucose groups, measures being near to or far from normal glycemia affected the risk of cardiac problems. Li Dong-bao et al. (16) demonstrated a U-shaped relation- ship between admission glycemia and in-hospital mortality in AMI patients, which means that hypoglycemic and hyper- glycemic patients were high-risk, which matches findings of the present study. In this study, elderly people and patients with a known his- tory of diabetes and hyperlipidemia were more at risk. In Gardner et al. (14) study, the predictors of MACE in addi- tion to admission glycemia were male gender, age, hyperten- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Alavi-Moghaddam et al. 4 Table 1: Baseline characteristics of studied patients based on development of major adverse cardiac events (MACE) Characteristics Total MACE P OR (95% CI)* P Yes n=249 No n=565 Sex Male 473 159 (33.6) 314 (66.4) 0.027 0.72(0.51-1.01) 0.065 Female 341 90 (26.4) 251 (73.6) Age Mean ± SD 60.83± 13.40 61.5± 13.4 60.6± 13.4 0.395 1.01 (0.97-1.02) > 0.05 Blood glucose level (mg/dl) On admission 173.7± 102.2 210.6± 123.4 157.4± 86.6 <0.001 1.01 (1.01-1.01) <0.001 Comorbid disease Hypertension 446 (54.8) 146 (32.7) 300 (67.3) 0.144 1.36 (1.01-1.82) > 0.05 Hyperlipidemia 113 (13.9) 26 (23.0) 87 (77.0) 0.059 0.67 (0.43-1.04) > 0.05 Diabetes 262 (32.2) 100 (38.2) 162 (61.8) 0.001 1.95 (1.43-2.64) 0.003 Cardiac disease 335 (41.2) 106 (31.6) 229 (68.4) 0.586 1.23 (0.92-1.66) > 0.05 Smoking 132 (16.2) 45 (34.1) 87 (65.9) 0.340 1.05 (0.71-1.56) > 0.05 History of MI 55 (6.8) 18 (32.7) 37 (67.3) 0.722 1.22 (0.69-2.15) > 0.05 Prior CABG 83 (10.2) 47 (56.6) 36 (43.4) 0.008 1.95 (1.24-3.08) > 0.05 Positive troponin 1s t 57 (7.0) 32 (56.1) 25 (43.9) <0.001 2.91 (1.68-5.03) 0.025 2n d 265 (32.6) 137 (51.7) 128 (48.3) <0.001 2.93 (2.16-3.99) 0.004 ECG abnormality 1s t 540 (66.3) 191 (35.4) 349 (64.6) <0.001 1.95 (1.41-2.70) > 0.05 2n d 545 (67.0) 196 (36.0) 349 (64.0) <0.001 2.16 (1.55-3.01) ECG changes Positive 294 (36.1) 132 (44.9) 162 (55.1) <0.001 2.76 (2.04-3.72) > 0.05 HEART score Mean ± SD 6.54 ± 2.24 5.94 ± 2.32 7.88 ± 1.27 <0.001 1.75 (1.59-1.92) <0.001 ∗ unadjusted odds ratio with 95% confidence interval (CI). Data are presented as mean ± standard deviation (SD) or number (%). MI: myocardial infarction; CABG: coronary artery bypass graft; ECG: electrocardiogram. sion, ischemic ECG, and positive troponin, which matches the present study; but there was a mismatch in diabetes and hypertension variables. In a study in Poland, diabetes his- tory, age, hypertension, and hypercholesterolemia had a sig- nificant relationship with MACE (17). The cause of non- identical results in various studies could be different sample sizes and the method of blood glucose assessment and study population classification. It has been debated that whether hyperglycemia has a pos- sible direct impact on adverse outcomes or is just a sec- ondary factor. There is a hypothesis that proposes elevated blood glucose level is a marker of illness severity (18). It has been suggested that hyperglycemia is representative of an induced stress response proportional to the ischemic my- ocardial damage (14). This has been found in earlier stud- ies where the size of an infarct was associated with a cor- responding degree of creatine kinase MB, cortisol and cate- cholamine release and an associated linear increase in glu- cose (19). Therefore, it has been speculated that glucose may not necessarily be the causative agent leading to an increased risk of a MACE; but instead may simply act as a marker in- dicating the extent of myocardial damage, the presence of which is necessary for a MACE (20). If association of ABGl with developing MACE is proved, there will be hope that with more researches, measuring blood glu- cose level in suspected cardiac patients admitted to emer- gency departments can be used as a diagnostic and predic- tive tool for MACE. 5. Limitation There were some limitations in the present study. Because of the large number of patients presenting to the emergency de- partment of Imam-Hossein Hospital, assessing all suspected ACS patients was impossible and some eligible patients were probably missed. Fasting status of patients was unknown and thus the results may be skewed by patients that had re- cently consumed a high glucose load. The main goal of treat- ment staff of the hospital was secure treatment of cardiac pa- tients and therefore, the patients were not under total con- trol of researchers. ACS was diagnosed using common clini- cal judgments and atypical symptoms without chest discom- fort were not used; this may result in missing some cases. Additionally, diabetic patients presenting with silent myocar- dial infarction were not included. In this study, three glucose groups were considered; however, since blood glucose is a continuous variable, a cut-off with optimum diagnostic and This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2019; 7 (1): e26 prognostic value in ACS should be found. 6. Conclusion It seems that abnormal admission blood glucose level in pa- tients with suspected ACS was an independent predictor of major adverse cardiac events within 30 days. Yet, additional studies with greater sample sizes in emergency departments all over the country are required before it is applied in exist- ing or future screening tools. 7. Appendix 7.1. Acknowledgements The outhors would like to appreciat the staff of the Clini- cal Research Development Unit at Imam Hossein Hospital, affiliated to shahid Beheshti University of Medical sciences, Tehran, Iran for their kind services to develop and release of the results of this research. 7.2. Author contribution The authors met the standard criteria for authorship based on the recommendations of the international committee of medical journal editors. Authors ORCIDs Mostafa Alavi-Moghaddam: 0000-0002-7176-023X Mohammad Parsa-Mahjoob: 0000-0003-1269-3134 Robabeh Ghodssi-Ghassemabad: 0000-0001-5394-5137 7.3. Funding/Support No fund has been received. 7.4. Conflict of interest The authors report no conflicts of interest. References 1. Timmer JR, Ottervanger JP, de Boer M-J, Dambrink J- HE, Hoorntje JC, Gosselink AM, et al. Hyperglycemia is an important predictor of impaired coronary flow before reperfusion therapy in ST-segment elevation myocardial infarction. 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This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitation Conclusion Appendix References