Glycosylated hemoglobin (HbA1c) is a stable marker of long term blood glucose control and reflects the average blood glucose concentrations over the previous 8–12weeks . Elevated HbA1c is associated with increased cardiovascular risk. It is more closely related to the risk of complications than the other single or episodic measures of glucose levels in diabetic patients [2–5]. In a recent large based population study, it was found that the small elevation in the level of HbA1c in non diabetic patients (i.e. HbA1c<6.5%), is associated with increased risk of coronary heart disease (CHD) in apparently healthy non diabetic patients irrespective of the fasting blood glucose level . According to the American Diabetes Association (ADA), HbA1c levels between 5.7% and 6.4% indicates prediabetic state .
Acute myocardial infarction (AMI) is associated with high risk mortality and morbidity even with the best reperfusion strategy . Stratification of high risk patients is important to improve the prognosis. Previous trials have shown that admission blood glucose had short and long term prognostic value in AMI patients [9,10]. However; the admission blood glucose can't reflect the true glycometabloic state as it is affected by catecholamine release, stress and the patient's last meal. Data on the prognostic role of HbA1c in patients with AMI are derived from studies which differ in patients' selection criteria and therapy (thrombolysis vs. mechanical revascularization). Primary percutaneous coronary intervention (PPCI) has shown significant beneficial protection against death or reinfarction within 6months AMI .
Therefore, we aimed in this study to investigate whether the glycometabolic state measured by the level of HbA1c at time of admission could have a prognostic value for the angiographic and short term clinical outcome in STEMI non diabetic patients undergoing PPCI and whether there is a difference between subgroups of non diabetic patients based on the level of HbA1c.
2. Material and methods
2.1. Patient population
This is a single center observational prospective study. The study included 208 consecutive patients presented by STEMI to the cardiology department of Tanta university hospital during the period from June 2012 to December 2014. All the patients underwent PPCI. The study included males and females aged between 18 and 75years who have the diagnostic criterion of STEMI i.e. persistent typical chest pain more than 30min and ≥2mm ST segment elevation in 2 contiguous ECG leads within 12h of symptom onset. Exclusion criteria included previous use of hypoglycemic drugs or insulin, admission HbA1c≥6.5%, symptoms more than 12h, carcinogenic shock and unsuitable coronary anatomy for PCI. The patients were divided into 2 groups based on the level of admission HbA1c according to the ADA guideline, group I (HbA1c≤5.6%) and group II (HbA1c 5.7–6.4%). A written informed consent was obtained from all participants. The protocol was approved by the local ethics committee.
2.2. Patients' data
Baseline characteristics and demographic data were obtained for all patients. Vital signs, laboratory data and previous disease history were recorded.
2.3. Glycated hemoglobin measurements
Blood samples (5μL of Capillary blood or anticoagulated venous blood) were obtained at the time of admission and tested with NycoCard Reader II manufactured by Axis-Shield that reports Diabetes Control and Complications Trial (DCCT) aligned values  and using National Glycohemoglobin Standardization Program (NGSP)-certified method .
All the patients received the following regimen before PPCI: (1) clopidogrel loading dose of 600mg orally, followed by a maintenance dose of 75mg/day; (2) Aspirin 300mg followed by 81–325mg/day; (3) During the procedure, intravenous unfractionated heparin (70IU/kg), the dose is increased to 100IU/kg in case glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors are not administrated; and (4) GPIIb/IIIa inhibitor (eptifibatide or tirofiban) unless contraindicated.
2.5. Angiographic procedure
Coronary angiography and PPCI were done through femoral approach. The use of aspiration thrombectomy device was left upon the operator's discretion and only infarct related artery was treated during the index procedure. Pain to balloon time; TIMI flow rate  before and after the procedure; and myocardial brush grade (MBG)  were assessed.
2.6. In hospital outcome and follow up
MACE was defined as cardiac death, acute myocardial infarction, stent thrombosis or target lesion revascularization (TLR). Academic Research Consortium definition was used to diagnose and grade stent thrombosis . TLR was defined as clinically indicated percutaneous or surgical revascularization of the index lesion during follow-up. Revascularization was considered clinically indicated if there was >70% diameter stenosis on angiography or >50% stenosis together with a positive stress test or ischemic symptoms.
Transthoracic echocardiography evaluations were performed after 48–72h of acute myocardial infarction. Echocardiographic measurements of the left ventricle volumes and ejection fraction (EF%)were performed according to recommendations of the American Society of echocardiography . Upon discharge, all patients were on optimal medical therapy including dual antiplatelet, beta blocker, statin and angiotensin converting enzyme inhibitors (ACEI). Clinical follow up was conducted through office visits and telephone contact during the 6month follow up period.
2.7. Statistical analysis
The data were analyzed statistically using SPSS version 16. Quantitative variables were presented in the form of mean and standard deviation and description of qualitative variables was presented in their absolute and relative frequencies. Comparison between quantitative variables was carried out by T test of two independent samples and Chi square test was used to compare qualitative variables with each other. A backward stepwise multivariate Cox regression analysis was performed to identify independent predictors of 6months MACE. The significance of the results was assessed in the form of p-value differentiated into: non significant when p-value >0.05, and significant when p-value ≤0.05.
3.1. Baseline characteristics and laboratory findings
Patients' characteristics in the study subgroups are summarized in Table 1. A total of 208 non diabetic patients with STEMI were enrolled (mean age: 55.9±7.12years, 149 were men). 112 patients with normal glucose metabolism (group 1) and 96 patients with prediabetes (group 2).
The baseline characteristics were generally similar in both groups. The peak troponin level was similar in both groups indicating that the infracted area was consistent.
3.2. Angiographic Data and interventional procedure outcome
Table 2 lists the baseline angiographic procedure and treatment on discharge details. There was no significant difference between the two groups regarding infarct related artery, presence of left main or three vessel disease, time to reperfusion, thrombus aspiration use, and GPIIb/IIIa infusion. Also there was no significant difference regarding stent deployment, DES usage, stent length (SL) and stent diameter (SD).
The final angiographic results in the infarct related artery were significantly better in group 1 as the achievement of final TIMI 3 flow in the infarct related artery was significantly higher in group 1 (87.5% vs 75%, p=0.016), better MBG (MBG II or III was 70.5% in group 1 vs 55% in group 2), p=0.003. On the other hand, angiographic no reflow was significantly higher in group 2 (19.7% vs 7.14%, p=0.006)
3.3. Medications at discharge
Dual antiplatelet therapy after PCI and prevalence of use of other medications were similar among both groups Table 3.
3.4. In hospital clinical outcomes
The in- hospital outcome is shown in Table 4. One patient in group 1 died due to post procedure cardiogenic shock because of extensive infarction. In group 2 one patient died because of extensive anterior STEMI, urgent coronary angiography showed acute stent thrombosis in LAD stent. Another patient had non STEMI during planned PCI for non culprit RCA lesion 72h after the index procedure due to abrupt closure of posterolateral branch.
3.5. Six months clinical outcome
After six months, the risk of MACE was higher for group 2 (p≤0.001). The rate of death, STEMI, non STEMI and stent thrombosis were similar in both groups. On the other hand, the rate of target lesion revascularization was significantly higher in group 2 (38 vs 16 p<0.001). Out of the 16 patients in group 1 who underwent TLR, 13 patients had exercise induced angina and 3 patients developed non STEMI, However in group 2, 34 patients had exercise induced angina and 4 patients had non STEMI Table 5.
After multivariate Cox regression analysis for baseline characteristics and angiographic findings, HbA1c was significantly associated with 6months clinical outcomes (hazard ratio 1.9; 95% confidence interval 1.2–3.4; p=0.022). Significant predictors are shown in Table 6.
In the present study, 208 non diabetic STEMI patients treated by PPCI were categorized into patients with normal glucose tolerance and prediabetes patients according to the HbA1c range recommended by ADA. The main findings of the present study were as follows.
- Non diabetic patients with higher HbA1c (prediabetics) had worse immediate angiographic outcome (TIMI flow, MBG) and a higher risk of total MACE compared with non diabetic patients with lower HbA1c level up to six months follow up after primary PCI.
- The increased MACE risk was mainly due to higher risk of target lesion revascularization (TLR) occurring within six months.
- The risk of MI and stent thrombosis was similar among non diabetic patients with low and high HbA1c level up to six months.
HbA1c is associated with CHD risk among apparently healthy, non diabetic women and men and it is an important early clinical marker of disease risk .
In patients with STEMI without previously known diabetes, the acute glycometabolic response to stress in the early phase was heterogeneous ranging from normal glucose level to increase insulin resistance and hyperglycemia . In previous studies hyperglycemia was associated with increased mortality in STEMI patients [19–21]. However, hyperglycemia in acute STEMI is not a reflection of previous glucose metabolism but it represents the stress response to acute myocardial injury and it is related to increased catecholamine release [22,23]. HbA1c is a stable marker and reflects glucose metabolism over the past 2–3months. So, it is more accurate in assessing the effect of abnormal glucose metabolism in non diabetics with acute STEMI. However, there are conflicting results from the available studies regarding the role of HbA1c in those patients.
In a recent study, Pusuroglu et al. prospectively enrolled 443 consecutive patients with STEMI who underwent primary PCI and they found a significant association between HbA1c level and 1-year primary clinical outcomes, including CV mortality, non-fatal reinfarction and stroke . In agreement with our results they found an increased rate of TLR and non fatal MI in higher HbA1c groups.
In another observational study, 4176 STEMI non diabetic patients treated by primary PCI by Timmer et al. , admission HbA1c was found to be associated with long-term mortality after adjusting for the other risk factors.
The authors of the 2 previous studies explained the increased MACE rate in patients with higher HbA1c by the increased baseline cardiovascular risks and worse angiographic findings in patients with higher HbA1c level. However this was not the case in our study as there was no significant difference between patients with normal glucose metabolism and those with prediabetes in baseline clinical characteristics and angiographic findings. So, the increased MACE rate in our patients, with elevated HbAIc, particularly TLR, might be due to the adverse effect of the chronic abnormal glucose metabolism in those patients.
Chronic hyperglycemia, even below the threshold for diagnosis of diabetes, has adverse effect on platelet function, coagulation cascade, endothelial function and is associated with increased fibrinogen levels . It also affects the ischemic cell metabolism, inflammation and apoptosis [27,28]. All these factors are associated with worse outcome and increased mortality in ACS patients as reported by Deedwania et al. . This could explain why patients with prediabetes in this study had worse immediate angiographic outcome regarding TIMI flow, MBG and angiographic no reflow.
On the other hand, different results were recently reported by Tian et al.  who prospectively enrolled 607 patients with STEMI treated by primary PCI and they stratified the patients according to HbA1c into 3 groups: (I) HbA1c 5.6% or less (n=262); (II), HbA1c 5.7–6.4% (n=182); and (III), HbA1c at least 6.5% (n=164). The 7-d mortality was similar (p=0.179) between groups I (1.9%), II (2.2%) and III (0.0%) as well as the 30-day mortality (p=0.241) between groups I (3.8%), II (2.2%), and III (1.2%). Major adverse cardiac events at the 7-day and 30-day follow-up were not significantly different between the three groups either (p>0.05). After adjusting the baseline characteristics, HbA1c was not an independent predictor of short-term outcomes (HR=0.431; 95% CI: 0.175–1.061, p=0.067). Similar results were reported in another 2 studies where HbA1c was shown not to be a prognostic factor associated with 30-day mortality [31,32].
The reason why these studies failed to show significant prognostic value for HbA1c may be due to the fact that short time MACE in STEMI patients is related to reperfusion time, infarct size and other short term complications, whereas the abnormal glucose metabolism, represented by higher HbA1c, needs a longer time to manifest.
4.1. Study limitation
This is a single center study with a relatively small number of patients. Another limitation is the probability that some of the patients in the prediabetes group may have progressed to overt clinical diabetes mellitus during the six month follow up period and this could affect the clinical follow up.
Abnormal glycometabolic state assessed by HbA1c at admission in non diabetic STEMI patients is associated with higher MACE incidence at 6months follow up mainly due to higher incidence of TLR. This finding could raise a question about the effect of elevation of blood glucose level below the detection limit of diabetes on the PPCI outcome and indicates that routine measures of admission HbA1c in STEMI patients could improve clinical outcome by early detection of patients who need close follow up and better glycometabolic control.
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