The association of the basal TIMI flow, post-PCI TIMI flow and thrombus grade with HbA1c levels in non-diabetic patients with acute ST segment elevation myocardial infarction undergoing primary PCI

Introduction

Myocardial infarction is the main leading cause of death worldwide. it is estimated that approximately more than 3 million people develop acute ST-elevation myocardial infarction (STEMI), and also 4 million people have a non ST-elevation myocardial infarction (NSTEMI) each year [1]. With this increased mortality rate among acute MI (AMI) patients, the epidemiology and basic sciences with clinical evidence have supported the new evolution of clinical management in AMI treatment. The main path to this success is the useful consolidation of antithrombotic treatment combined with convenient reperfusion, either primary percutaneous coronary intervention (PCI) or fibrinolysis for STEMI and examination and revascularization for NSTEMI, underpinned by risk stratification and optimized methods of care [2]. Statistics show that cardiovascular diseases, especially acute myocardial infarction, have increased increasingly in the last decade, accounting for approximately 46 % of all deaths in Iran [3], 4]. Diabetes mellitus is one of the important risk factors of coronary heart disease and chronic heart failure so the risk of death and severe cardiac complications increases in diabetic patients with acute myocardial infarction. The presence of cardiovascular disease in diabetics is estimated to be higher than in non-diabetics in the same age group [5], 6]. Hemoglobin A1c, or glycosylated hemoglobin, is known as a marker of long-term glycemic control in diabetic patients, and its increased level in these patients is associated with an increased risk of microvascular and macrovascular diseases. In addition to the fasting blood sugar (FBS) level, one of the important ways to evaluate blood sugar control in diabetic patients is to estimate the level of glycosylated hemoglobin (HbA1c) in blood [7], 8]. Recent reports have shown that HbA1c levels indicate glycometabolic disorders in predicting people with cardiovascular diseases and mortality in patients without diabetes mellitus [9]. The use of thrombolytic therapy is widely accepted for treatment of acute myocardial infarction. Despite the improvement in mortality, thrombolytic therapy may be contraindicated in many patients presenting with myocardial infarction and is associated with a small but significant risk of hemorrhagic sequel [10], 11]. The standard treatment for a patient suffering from an acute heart attack with STEMI is re-establishing blood flow in the coronary arteries, which is called primary coronary intervention through the primary PCI. Primary angioplasty is a special case of immediate or direct angioplasty to restore blood flow to a blocked artery [12]. Angioplasty can also be done immediately (as soon as possible) after thrombolytic therapy, a procedure called facilitated angioplasty, or a little later in the post-MI period. Angioplasty is usually performed following angiography and definitive diagnosis of blocked vessels. Primary coronary angioplasty is more successful in restoring coronary blood flow than fibrinolytic treatment, and on the other hand, the rate of bleeding events will be lower [13]. In salvage angioplasty, patients are catheterized only when thrombolysis is considered failed; typically, in these circumstances, patients are not challenged with thrombolysis and are “crossover” to angioplasty [14]. Different investigations have revealed an association between HbA1c rates and the incidence of coronary artery disease (CAD). In known diabetics, coronary heart disease (CHD) is detected at a late stage, but nothing is understood regarding non-diabetics diagnosed with AMI. It has been shown that fatality risk raised to 1.25-fold at 30 days and 1.45-fold in the long-term in STEMI patients with high levels of HbA1c [15], 16].

Because the role of hemoglobin A1c in the acute phase of STEMI, in patients without diabetes mellitus, has not been studied so far, in this study, we decided to investigate the role of hemoglobin A1c, which is an easy and accessible marker, in predicting optimal coronary blood flow before and after primary PCI and thrombus burden in the infarct-related artery in patients with myocardial infarction with ST-segment elevation myocardial infarction (STEMI) and no history of diabetes mellitus.

Patients and methods

Results

Angiographic and interventional features

Angiographic features are shown in Table 4. The number of diseased vessels was the same in three groups and LAD artery was found to be the most common infarct related artery.

Table 4:

Angiographic characteristics of patients in study groups.

Culprit vessel	A1c≤5 %	5.1 %─5.9 %	6 %─6.4 %	p-Value
LAD	92 (55 %)	40 (54 %)	12 (50 %)	0.509
LCX	22 (13 %)	15 (20 %)	3 (13 %)
RCA	52 (31 %)	18 (24 %)	8 (33 %)
LM	1 (1 %)	1 (1 %)	1 (4 %)

In order to investigate the effect of hemoglobin A1c on TIMI flow before PCI, TIMI values ​​of 0 and 1 were placed in one group (group one) and values ​​of 2 and 3 were placed in another group (group two); this division is to identify the number of patients who had spontaneous coronary recanalization which is TIMI flow equal to or more than 2 in the pre-intervention angiogram. The result of this investigation is given in Table 5; you can see that there is a non-significant trend to decrease the prevalence of pre-primary PCI 2–3 with increasing hemoglobin A1c.

Table 5:

TIMI flow results before angioplasty based on HbA1c level.

Pre- primary PCI TIMI flow grade					p-Value
	A1c≤5 % (n=167)	5.1 %─5.9 % (n=74)	6 %─6.4 % (n=24)
Group 1 TIMI: 0, 1	114 (68 %)	55 (74 %)	21 (87 %)	190
Group 2 TIMI: 2, 3	53 (32 %)	19 (26 %)	3 (13 %)	75	0.124
Total	167	74	24	265

In order to investigate the effect of hemoglobin A1c on post-primary PCI TIMI flow grade, values ​​of 0, 1 and 2 were placed in one group (group one) and 3 were placed in another group (group two); This division is to identify the number of patients who have suboptimal TIMI.The results of this study are given in Table 6.You can see that the amount of TIMI 3 after the intervention in group one (87 %) is higher than group two (78 %) and group three (63 %), which shows a significant difference between the different HbA1c groups in terms of the amount of successful reperfusion; in other words, with the increase of HbA1c, the probability of achieving TIMI 3 flow after angioplasty decreases (p<0.008) (Table 6) (Figures 1 and 2).

Table 6:

TIMI flow results after angioplasty based on HbA1c level.

Post-primary PCI TIMI flow grade	HbA1c			Total	p-Value
	A1c≤5 %	5.1 %─5.9 %	6 %─6.4 %
Group 1, TIMI: 0, 1,2	22 (13 %)	16 (22 %)	9 (37 %)	47	0.008
Group 2, TIMI: 3	145 (87 %)	58 (78 %)	15 (63 %)	218
Total	167	74	24	265

Figure 1:

Pre-primary PCI TIMI flow grade relationship with HbA1c groups.

Figure 2:

Post-primary PCI TIMI flow grade relationship with HbA1c groups.

To investigate the effect of hemoglobin A1c on thrombus grade, the values ​​of 0, 1, 2 and 3 were placed in one group (group 1) and values ​​of 4 and 5 (Large Thrombus Burden) were placed in another group (group 2). The purpose of this classification is to identify the number of patients with large thrombus burden (LTB). The results of this study are shown in Table 7.As you can see, the thrombus burden in group three (87 %) is higher than group two (70 %) and group one (60 %), which means that with the increase in hemoglobin A1c level, the amount of thrombus in the IRA increases (p=0.021) Table 5, Figure 3. Furthermore, there was a significant correlation between HbA1c level and thrombus grade (r=0.163; p=0.008).

Table 7:

Thrombus grade results based on HbA1c level.

Thrombus burden grade	HbA1c			Total	p-Value
	≤5 % (n=167)	5.1 %─5.9 % (n=74)	6 %─6.4 % (n=24)
Group1: Grade 0,1,2,3	66 (40 %)	22 (30 %)	3 (13 %)	91	0.021
Group2: Grade 4,5	101 (60 %)	52 (70 %)	21 (87 %)	174
Total	167	74	24	265

Figure 3:

The association of thrombus grade with HbA1c groups.

Multivariable logistic regression analysis showed a higher troponin level (95 % CI 0.949–0.877, p=<0.001) as an independent predictor of initial 0–1 TIMI flow before primary PCI (Table 8). Multivariable logistic regression analysis identified increased HbA1c as an independent predictor of TIMI flow grade less than 3 after primary PCI (p=0.004) (Table9).Similar findings introduced elevated hemoglobin A1c as an independent predictor of large thrombus burden (LTB) (p<0.005) (Table10).

Table 8:

Multivariate regression analysis to predict pre-PCI TIMI flow grade.

	Constant	Probability interval	95 % confidence rate	p-Value
Total ischemic time, h	−1.053	71.1	0.979–1.075	0.284
Troponin, U/L	0.253	77.1	0.877–0.949	<0.001
Blood glucose, mg/dL	0.017	71.5	0.982–1.002	0.106

Table 9:

Multivariate regression analysis to predict post-PCI TIMI flow grade.

	Constant	Probability interval	95 % confidence rate	p-Value
Total ischemic time	1.478	82.5	0.952–1.083	0.640
Troponin	1.847	81.9	0.950–1.013	0.241
Triglyceride	0.928	82.3	0.999–1.012	0.053
HbA1c	2.570	82.3	0.330–0.799	0.004
Smoking	1.134	80.7	0.999–3.986	0.046

Table 10:

Multivariate regression analysis to predict thrombus burden grade.

	Constant	Probability interval	95 % confidence rate	p-Value
Total ischemic time	0.747	65.4	0.938–1.028	0.435
Triglyceride, mg/dl	0.618	64.9	0.996–1.004	0.990
HbA1c, %	−0.200	65.7	1.177–2.816	0.005
Smoking	0.953	69.1	0.419–1.307	0.299

Discussion

Our study shows that in non-diabetic STEMI patients, higher HbA1c level during hospitalization, reduces the prevalence of TIMI 3 flow in the infarct-related artery (IRA) after primary PCI (P=0.008).The benefits of reperfusion therapy have been attributed to the rapid establishment of normal blood flow in the IRA, which is synonymous with TIMI 3 flow. Studies have found that inability to achieve successful coronary reperfusion, i.e. post-interventional TIMI flow grade ≤2 isstrongly associated with worse clinical outcome and NYHA class during hospitalization and 6 months after [17]. Prehospital thrombolytic therapy, cardiogenic shock, three-vessel disease and diabetes mellitus increase the risk of a post-PCITIMI of less than 3 [18]. In a large prospective multicenter trial in STEMI patients, 12.9 % of patients did not achieve TIMI 3 flow after primary PCI and failure to establish TIMI 3 flow was still recognized as a strong predictor of mortality after primary PCI [19]. Coronary flow less than TIMI 3 after PCI and removal of coronary artery obstruction, in the absence of artery spasm or dissection is one of the examples of no-reflow phenomenon. In one study, it was shown that no-reflow occurred in 25 % of STEMI patients treated with primary PCI and with older age, thrombus load ≥4 and delay in referral, were more likely to occur and in 12-month follow-up, it was associated with a higher risk of death [20]. A study on patients with anterior STEMI noted that post-PCI TIMI<3 was associated with higher 30-day mortality; advanced age, thrombus burden grade, systolic blood pressure, stent length and initial TIMI flow 0 or 1, have been mentioned as related factors [21]. Low hemoglobin and hematocrit have been associated with suboptimal TIMI and no-reflow after primary PCI [22]. In fact, there is no effective treatment for TIMI flow less than 3 after angioplasty, so it is important to be able to predict the possibility of its occurrence and prevent it. For patients at high risk for a TIMI less than 3 after primary PCI, such as those who are older, have a large thrombus (≥4) or higher hemoglobin A1c (≥6 %), or who presented late, the stenting strategy may be delayed and longer antithrombotic treatment should be considered.

Several studies have been conducted on biochemical and inflammatory markers as potential predictors of TIMI flow after PCI; blood glucose is one of them. In acute myocardial infarction (AMI), stress hyperglycemia usually occurs secondary to elevated catecholamine levels, so simply examining plasma glucose levels at the time of AMI cannot predict prognosis [20]. Hemoglobin A1cis minimally affected by acute hyperglycemia often observed in myocardial infarction. In STEMI patients, early measurement of HbA1c may be a screening tool for glucose intolerance, as it can be measured in a non-fasting state and reflects the average glucose concentration over the previous 2–3 months. Causes are commonly associated with high HbA1c include diabetes, being overweight/obese, smoking, severe anemia, some chronic conditions such as periodontal (gum) disease, H. pylori infection, and chronic kidney disease, sleep disorders, some genetic hemoglobin disorders, opiates, statins, alcoholism. The prognostic importance of hemoglobin A1c in STEMI patients has been proven in various studies. The study performed by Çiçek and co-workers on 796 patients with STEMI and primary PCI, indicated the prognostic role of HbA1c for short- and long-term mortality. Nowadays, with the help of meta-analyses, it is clear that HbA1c has a prognostic value in acute myocardial infarction and coronary artery disease not only in patients with diabetes mellitus but also in non-diabetic patients [23];and it is recommended that non-diabetic patients strictly control their HbA1c level after PCI, in order to reduce the possibility of adverse clinical outcomes in their future [24]. So far, few studies have been conducted regarding the role of HbA1c in predicting coronary blood flow in acute myocardial infarction. Therefore, in this study, we investigated the direct effect of HbA1c on the angiographic parameters of the acute stage of STEMI, including the TIMI flow and the thrombus grade in the infarcted artery. In this study, we observed that higher hemoglobin A1c on admission was associated with a lower frequency of TIMI 3 after primary PCI. Our data were consistent with what Timmer et al. showed that increased HbA1c levels was associated with both lower TIMI flow grade (<3), and higher in-hospital mortality rate [25]. In our study, no significant correlation was observed between HbA1c and the pre-primary PCI TIMI flow. In the HORIZONS-AMI trial, 3093 STEMI patients were divided into two groups: TIMI 0–1 or 2–3 according to the initial TIMI, and it was observed that early opening of the infarcted artery (TIMI 2–3) is associated with better TIMI flow and myocardial blush after PCI and lower 1-year mortality [24]. Shaaban et al. have concluded that there is a better outcome with initial TIMI flow I-III grade than TIMI 0 grade in patients with STEMI treated by primary-PCI [26]. Another finding of our study was the direct correlation between HbA1c level and thrombus size in the infarcted artery.In line with this finding, Shah et al. revealed that in diabetic and non-diabetic STEMI patients, elevated HbA1c on admission was directly related to thrombus size [27]. In the primary PCI method, accurate assessment of the thrombus load in the infarcted artery is necessary to identify lesions that may be at high risk of distal embolization, especially complete occlusion of the infarcted artery.Published reports emphasize the importance of thrombus burden and its proper management. In anterior (and not non-anterior) STEMI patients, large thrombus had a significant effect on mortality and major cardiac events over the next 10 years [28]. Recently, a risk score called HAKTT has been designed to predict no-reflow before primary PCI, which can be easily used in the clinic, because it does not use any laboratory indicators;its components include 4 clinical indicators (heart rate, age, Killip class, total ischemia time) and an angiographic index (thrombus load).In this study, large thrombus burden (LTB) had the strongest association with no-reflow [29]. Current guidelines do not routinely recommend thrombus aspiration during primary PCI and place it in class III.However, in cases of large thrombus, this method has reduced the length of hospitalization and one-month mortality, andimproved TIMI, myocardial blush grade, ST-segment resolution and left ventricular systolic function [30].

In conclusion, we presented that the TIMI flow grade and thrombus grade were associated with HbA1c levels in non-diabetic patients with STEMI undergoing primary PCI. The main limitations of the study were the small number of enrolled patients, uni-central localization, 30 % of non-diabetic patients with STEMI who were admitted during this study, were excluded because they had a hemoglobin A1c level equal to or higher than 6.5 %, therefore, it is possible that selection bias has affected the results and finally, the lack of assessment of parameters that can affect the level of HBA1c values. However, the main feature of this study is that it is the first time to assess the HbA1c correlation with both TIMI flow and thrombus grade in order to more accurate evaluation of non–diabetic STEMI patients’ outcomes and successful preventive interventions.