Is There A Role of Glycated Hemoglobin for Predicting Major Ad- verse Cardiac Event in ST-Elevation Myocardial Infarction?

Background : Coronary Artery Disease (CAD) especially ST-Elevation Myocardial Infarction (STEMI) is the leading cause of mortality worldwide. Hyperglycemia and diabetes mellitus are both prevalent among patients with STEMI admitted to the hospital. Glycated hemoglobin (HbA1c) is a marker of glucose control. Objectives : We aimed to investigate the role of HbA1c as the predictor of major adverse cardiovascular events in STEMI patients. Methods : This was a retrospective cohort study. STEMI patients visiting Saiful Anwar General Hospital were registered. Patients were divided into three groups based on the HbA1c level <6.5%; 6.5-8.4% and ≥8.5%; respectively. The primary endpoint was in-hospital Major Adverse Cardiovascular Events (MACE), including cardiac death, recurrent myocardial infarction (MI), recurrent revascularization, acute pulmonary edema, cardiogenic shock, malignant arrhythmia, and stroke. Results: A total of 118 STEMI patients were included in this study, with distribution of 61 patients with HbA1c <6.5%, 25 patients with HbA1c 6.5-8.4%, and 31 patients with HbA1c ≥8.5%; respectively. The HbA1C level was associated with the history of diabetes mellitus (3.2% vs 36% vs 71%; p =0.000) and random blood glucose level at hospital admission (140.71 ± 39.67 mg/dL vs 172.96 ± 53.43 mg/dL vs 366.61 ± 169.67 mg/dL; p = 0.000). The MACE among three groups was not significantly different (17.7% vs 20% vs 35.5%; p=0,149). Conclusion: Our study reveals that the HbA1c level at hospital admission is associated with the history of diabetes mellitus and random blood glucose at hospital admission. However, HbA1c could not predict MACE in STEMI patients


Introduction
Background : Coronary Artery Disease (CAD) especially ST-Elevation Myocardial Infarction (STEMI) is the leading cause of mortality worldwide. Hyperglycemia and diabetes mellitus are both prevalent among patients with STEMI admitted to the hospital. Glycated hemoglobin (HbA1c) is a marker of glucose control. Objectives : We aimed to investigate the role of HbA1c as the predictor of major adverse cardiovascular events in STEMI patients. Methods : This was a retrospective cohort study. STEMI patients visiting Saiful Anwar General Hospital were registered. Patients were divided into three groups based on the HbA1c level <6.5%; 6.5-8.4% and ≥8.5%; respectively. The primary endpoint was in-hospital Major Adverse Cardiovascular Events (MACE), including cardiac death, recurrent myocardial infarction (MI), recurrent revascularization, acute pulmonary edema, cardiogenic shock, malignant arrhythmia, and stroke. Results: A total of 118 STEMI patients were included in this study, with distribution of 61 patients with HbA1c <6.5%, 25 patients with HbA1c 6.5-8.4%, and 31 patients with HbA1c ≥8.5%; respectively. The HbA1C level was associated with the history of diabetes mellitus (3.2% vs 36% vs 71%; p =0.000) and random blood glucose level at hospital admission (140.71 ± 39.67 mg/dL vs 172.96 ± 53.43 mg/dL vs 366.61 ± 169.67 mg/dL; p = 0.000). The MACE among three groups was not significantly different (17.7% vs 20% vs 35.5%; p=0,149). Conclusion: Our study reveals that the HbA1c level at hospital admission is associated with the history of diabetes mellitus and random blood glucose at hospital admission. However, HbA1c could not predict MACE in STEMI patients

Keywords:
ST-elevation myocardial infarction; Glycated hemoglobin; Diabetes mellitus In the past decades, rapid and sustained increase of prevalence of cardiovascular disease (CVD), 1 leads to a tremendous disease burden around the world. Acute coronary syndrome (ACS), which consist of Unstable Angina (UA), STEMI, and non-STEMI, is responsible for almost half of the CVD-associated morbidity. 2 STEMI is associated with acute total occlusion of the coronary arteries. It is the most high-risk emergency condition and still be the highest cause of mortality and morbidity. Revascularization strategy, including primary percutaneous coronary intervention (PPCI) and thrombolysis, must be performed to open acute total occlusion in the culprit artery and ensure adequate myocardial perfusion to prevent further myocardial damage. 3 The mortality in STEMI patients can be affected by several factors, such as the history of previous MI, Killip class, advanced age, emergency medical system (EMS)-based STEMI networks presence, time delay to treatment, treatment strategy, left ventricular ejection fraction (LVEF), number of diseased coronary arteries, diabetes mellitus, and renal failure. 3,4 Diabetes mellitus is a systemic metabolic disease that causes complications in microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular (coronary artery disease, cerebrovascular disease, and peripheral artery disease,). 5 Adequate glycemic control, defined as HbA1c value ≤ 7% has an essential role in preventing those dreadful complications.6 HbA1c reflects the mean glycemia level over the previous 8 to 12 weeks period. 7 HbA1c levels also have a prognostic value for the onset of CVD in the future. 8 However, the role of the HbA1c level in predicting the outcome of ACS is still unclear and needs to be proven. Several reports have shown that in patients with STEMI, the HbA1c levels have a prognostic value. However, these reports data remain inconclusive. 9,10 This study is aimed to investigate the role of HbA1c as the predictor of MACE in STEMI patients.

Design
We conducted a retrospective cohort study in Saiful Anwar General Hospital Malang, Indonesia, from May to August 2017. The investigation was approved by the institutional review board of Saiful Anwar General Hospital and conformed with all the principles outlined in the Declaration of Helsinki.

Study population
All STEMI patients from April 2015 to August 2017 were registered and included in this retrospective cohort study. The data about age, gender, STEMI characteristics, CVD risk factors, past medical history, vital signs, laboratory finding, medication, revascularization strategy, Killip class, Global Registry of Acute Coronary Events (GRACE) risk score, thrombolysis in myocardial infarction (TIMI) risk score, and MACE were collected from the medical records. The additional information was obtained via a phone call interview. The exclusion criteria included (1) incomplete data, (2) chronic kidney disease (CKD), and (3) anemia.

Exposure and Outcome
The exposure was the HbA1c level at hospital admission. HbA1c was obtained from peripheral venous blood samples taken at hospital admission. According to the HbA1c level, Patients were divided into three groups; <6.5% (group 1); 6.5-8.4% (group 2), ≥8.5% (group 3). The outcome measure was in-hospital MACE. MACE was defined as the composite of total cardiac death, recurrent MI, recurrent revascularization, acute pulmonary edema, cardiogenic shock, malignant arrhythmia, and stroke ( Figure 1).

Statistical Analysis
Categorical data ware presented as number and its percentage. However, the numeric data were presented as mean and its standard deviation. Chi-square test was conducted for categorical data analysis. For normally distributed data, numeric data was analyzed using the analysis of variance (ANOVA) test.However, if the data abnormally distributed, the statistical analysis of numerical data was conducted using the Kruskal Wallis test. The analysis was conducted using IBM SPSS version 22 software.
Overall, medications given during in-hospital treatment were similar among the three groups. dual antiplatelet treatment (aspirin and P2Y12ADP inhibitor) and anticoagulant were given to all patients. The difference of angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), β-blocker, mineralocorticoid receptor antagonist (MRA), nitrate, and a statin administration among three groups were not significant (p ≥ 0.05). The medication during in-hospital treatment is summarized in table 2.

Discussion
Since introduced in 1980, HbA1c has become a cornerstone of diabetes mellitus diagnostic criteria and treatment goals.11 HbA1c reflects total blood glucose exposure to the red blood cells. The turnover of HbA1c depends on the red blood cell lifespan; therefore, it reflects the average plasma glucose over the previous 8 to 12 weeks.7,12 HbA1C level can be measured at any time. It does not need any specific preparation, such as fasting at least 8 hours before the blood sample is taken. 13 In this study, lower HbA1c level more common in male patient (88.7% vs 80% vs 58.1%; p =0.003). Our result did not support a previous study by Qinglin et al., which involved 18,265 patients. They revealed that in the general population, the HbA1c levels were influenced by sex and age. The HbA1c level in men was slightly higher than in women, and with increasing age, the levels would also increase gradually. 14 The possible explanations for this discrepancy were: (1) only STEMI patients were included, not the general population; and (2) smaller sample size.
This study found that the higher TIMI value was found in the group with higher HbA1c. It was because the TIMI value also contained components of (1) age; (2) Killip class; (3) anterior MI or left bundle branch block (LBBB); (4) systolic blood pressure; (5) heart rate; (6) weight; (7) prior angina; (8) diabetes mellitus; (9) hypertension, and (10) time to thrombolytic. 15 Therefore, higher levels of HbA1c were found to be correlated with high TIMI value.
In this study, the history of diabetes mellitus was associated with increased levels of HbA1c at admission due to STEMI. A study by Timmer et al.obtained a similar result that patients admitted because p of ACS and high HbA1c levels were found in patients with a previous history of diabetes mellitus. Blood glucose level control is essential in diabetic patients. Poor glucose control before the onset of STEMI, as illustrated by high levels of HbA1c at admission, can cause many complications in diabetic patients. 16 Pusuroglu et al. showed poor glucose control, as reflected by increased HbA1c levels, increased mortality, reinfarction, and stroke in diabetes mellitus patients in long-term monitoring. 17 A long-term study from Hwang et al. revealed that tight blood glucose level control assessed using controlled HbA1c levels could reduce mortality, MI,and stroke. 18 In this study, we found a close relationship between an increase in blood glucose and HbA1c levels. Hyperglycemia at hospital admission is a common comorbid in STEMI. 19 This condition can occur in patients with diabetes mellitus and patients with a history of diabetes mellitus. The prevalence of diabetes mellitus ranged from 12.4% to 25% of hyperglycemia patients at hospital admission. 20 Hyperglycemia on admission is a mortality predictor in MI patients. 21 During hyperglycemia, the cytokines level is increased, especially tumor necrosis factor-alpha (TNFα). These cytokines caused endothelial dysfunction and reduced myocardial contractility. 22,23 In patients with STEMI who are accompanied by hyperglycemia signs, it will be challenging to dig about the previous history of DM. In this study, blood glucose levels on admission to the hospital were not an independent predictor of mortality. It may be regarding the comprehensive management of hyperglycemia in STEMI patients, and multifactorial causes of mortality.
This study did not reveal a significant relationship between HbA1c levels on admission with clinical outcomes, although there was an increased rate of worsening clinical outcomes among three groups (17.7% vs. 20% vs. 35.5%; p = 0,149). Other studies by Timmer JR et al. and Cakmak et al. revealed that the HbA1c value failed to predict in-hospital mortality although data on higher mortality were found, after adjusting several cardiovascular risk factors. Therefore, it was concluded that HbA1c levels were not a strong predictor of increased long-term mortality. 16,24 A study, including a large population by Optimal Therapy in Myocardial Infarction With Angiotensin II Antagonist Losartan (OPTIMAAL), also concludes that HbA1c levels were not a predictor of mortality in patients with diabetes mellitus. 25 Our study had several limitations. First, the data in this study were obtained from the medical record, which may cause errors in recording. Second, data were obtained from a single-center; therefore, they could not represent the overall population. Third, our study involved a small number of samples. Fourth, we had several confounding factors that could not be managed, for example, revascularization strategy. Not all patients included in this study received revascularization. Some parameters in the previous studies that were considered to be the cause of mortality were not proven to cause mortality in this study. The possible explanation was the data obtained only described the initial conditions at hospital admission. Some patients also suffered from mechanical complications due to STEMI, which may have a more significant role in mortality than just the HbA1c level value. Some patients are also on a ventilator due to respiratory failure, which may have a more significant role in patient mortality than the initial HbA1c value.

Discussion
Our study revealed that the HbA1c level at hospital admission is associated with the history of diabetes mellitus and random blood glucose at hospital admission. However, the HbA1c level at hospital admission could not predict MACE in STEMI patients.

Ethics Approval and Consent to participate
This study was approved by local Institutional Review Board, and all participants have provided written informed consent prior to involve in the study.

Consent for publication
Not applicable.

Availability of data and materials
Data used in our study were presented in the main text.

Competing interests
Not applicable.
6.5. Funding source Not applicable.

Acknowledgements
We thank to Brawijaya Cardiovascular Research Center.