Efficacy of intravenous eptifibatide in primary percutaneous coronary intervention patients

Early and complete restoration of blood flow in closed coronary arteries is the main goal in treating patients with myocardial infarction. Primary angioplasty is not always successful in establishing myocardial blood flow. Although the strategy of adding eptifibatide leads to better blood flow, its value as part of a routine strategy is questionable. Therefore, this study was performed to evaluate the efficacy of intravenous eptifibatide in primary percutaneous coronary intervention (PCI) patients. This clinical, randomized, double-blind trial was performed on patients aged 20-80 years undergoing primary PCI. The patients were selected for study by convenience sampling and were randomly divided into two equal groups. The first group was treated with intravenous eptifibatide immediately before angioplasty with heparin. The second group received only coronary angioplasty with heparin. After data collection, statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software, version 16. A total of 104 patients were enrolled in the study, and there were no statistically significant differences in terms of age (P=0.188), gender (P=0.345), risk factor (P>0.05), or history of PCI (P=0.199). Mean thrombolysis in myocardial infarction (TIMI) score was not significant between the two groups after receiving the drug and performing angioplasty (P>0.05), and the rate of ejection fraction was 46.33±6.69 in patients receiving eptifibatide and 47.54±4.67 in the heparin group, which was not statistically significant (P=0.884). We found that eptifibatide improves clinical indexes in patients undergoing primary PCI, but these differences were not significant in the two groups.


INTRODUCTION
Coronary artery disease is one of the most common causes of death worldwide. Nearly one-third of Americans over the age of 35 die from this disease. Coronary artery disease refers to the pathological processes of atherosclerosis that affect the coronary arteries [1,2]. Treatment of these patients can be done through medication or invasive strategy, and decisions are made for each person according to personal circumstances [3,4]. Initially, complete and stable coronary blood flow is an essential criterion for standard treatment of patients suffering from myocardial infarction with ST-segment elevation. Fibrinolytic treatment will reduce mortality in patients immediately after the onset of symptoms [5], but there are some limitations. Fibrinolytic treatment normalizes coronary blood flow in JOURNAL of MEDICINE and LIFE only 60% of patients and has a high risk of bleeding and hemorrhagic events. The treatment of choice for patients with ST-Elevation Myocardial Infarction (STEMI) is primary percutaneous coronary intervention (PCI), in which the rate of bleeding is lower [6]. However, the movement of atherothrombotic material during primary PCI is very common in STEMI patients. This can lead to obstruction of the distal arteries and improper myocardial perfusion, which is associated with larger infarcts, impaired ventricular function, and increased mortality.
Thrombosis and vascular debris may move and form plaques in the microvascular system, causing myocardial dysfunction and necrosis [7]. There are many therapeutic strategies to improve microvascular perfusion after primary PCI, such as thrombus aspiration, GP2b/3a administration (intracoronary bolus), and others. Eptifibatide is an antiplatelet drug that reversibly inhibits the binding of fibrinogen, Von Willebrand factor, and other adhesive molecules to the platelet glycoprotein receptor IIb/IIIa; it is usually used in combination with aspirin and a p2y12 inhibitor and as an anti-coagulant treatment for acute coronary syndrome, myocardial infarction, and patients undergoing PCI. The half-life of the drug is about 2.5 hours, and about 25% of it can bind to plasma proteins. The drug metabolite is about 5% of the total body clearance, and it is excreted through urine [9]. Similar studies have investigated the long-term efficacy of eptifibatide on the ejection fraction (EF) and myocardial perfusion [5,6,10]. Therefore, this study was performed to evaluate the effectiveness of intravenous eptifibatide in improving EF and myocardial perfusion in primary PCI patients and to assess the rate of bleeding complications of this drug.

MATERIAL AND METHODS
This clinical, randomized, and double-blind trial was performed on patients aged 20-80 years referred to Mazandaran Heart Hospital, Iran, who underwent primary PCI with an acute STEMI clinical picture from July 2018 to April 2019. Patients were selected by convenience sampling and were randomly divided into one of two intervention groups by cardiovascular assistants. These patients did not know which group they were in; then, patients who met the inclusion criteria were included in the study.

Inclusion criteria
• Typical ischemic chest pain over 30 minutes; • ST-segment elevation greater than one millimeter in at least two leads; • All STEMI patients who were candidates for primary PCI; • Myocardial infarction that did not last more than 12 hours.

Sample size
The sample size of this research was calculated based on the following statistical formula: By considering a 20% of sample loss, mean EF before and after treatment, and reference results [10], the sample size was calculated to be 124 individuals. JOURNAL of MEDICINE and LIFE

Procedure
All patients received 300 mg of chewable aspirin and 600 mg of clopidogrel before the procedure. In all patients, a percutaneous femoral artery approach was used for catheterization. In both intervention groups, wiring of the caliper vessel was also performed, followed by balloon dottering. Predilation and thrombosuction were performed if necessary.
Group 1 included patients with TIMI 0-1; they received 100 units of heparin/kg and then underwent balloon dottering after wiring of the culprit vessel; if necessary, low-pressure balloon inflation was performed, then stenting was done. Patients in group 2 received 50 to 70 μg/kg of heparin and 180 μg/kg of eptifibatide by intravenous bolus were injected. Wiring of the culprit vessel and, if necessary, low-pressure balloon inflation were performed. Then, stenting was performed, and eptifibatide was continued as a 12-hour infusion. From all cardiac referrals, a 12-lead electrocardiogram (ECG) was taken at baseline and 90 minutes after PCI in the coronary care unit (CCU). Both electrocardiograms were examined by a blind observer. In all patients, echocardiography was performed by one person at the beginning of admission and 3-4 days after PCI. 2D and Doppler echo parameters were measured using the standard methods. All volumes were normalized based on the body surface index. Regional wall motion was performed using a 17-segment model approved by

Statistical analysis
Data were described based on the mean and standard deviation for quantitative variables, while numbers and percentages were considered for qualitative variables. The relative frequency of complications between the two groups was assessed by the Chi-Square test. Statistical analysis was performed after entering the data into the Statistical Package for the Social Sciences (SPSS) software, version 16. A significance level of 0.05 was considered.

RESULTS
A total of 104 patients were included in the study, of whom 59 were in the heparin group and 45 in the eptifibatide group. JOURNAL of MEDICINE and LIFE the intervention in two treatment groups. The study results showed that the mean wall motion index before the intervention was 1.18±0.19 in the heparin group and 1.22±0.21 in the eptifibatide group. After the intervention, the wall motion index was 1.5±0.23 in the heparin group and 1.22±0.21 in the eptifibatide group. There was no statistically significant difference between the results before and after the wall motion index (P=0.061, P=0.08).
Our findings showed that patients in the eptifibatide group had lower CK-MB values (average of 156.49±143.447) than the heparin group who had an average of 121.88±103.155, but the two groups did not show a statistically significant difference in CK-MB levels before and after the intervention (Table 1 and Figure 3; P>0.05).
Left ventricular ejection fraction (LVEF) before intervention in patients in the heparin group was 40.59±5.5. In the eptifibatide group, it was 39.56±8.5%. After the intervention, LVEF was 47.54±4.6 in the heparin group and 46.33±6.6 in the eptifibatide group. No significant difference was found between the two groups regarding LVEF before and after the intervention (P=0.948, P=0.884; Figure 4).
The results showed that sum ST resolution above 70% was seen in 74.5% cases in the heparin group and 73.3% cases in the eptifibatide group. Furthermore, a sum ST Resolution of 50% was found to be 88.1% and 91.1% in the heparin and eptifibatide groups, respectively, which was not statistically significant between the two groups (P=0.341; Table 2).
Participants were examined for mitral regurgitation before and after the intervention in two groups ( Table 3). The results revealed no statistically significant difference between the two groups in terms of MR before and after the intervention (P>0.05).
The results of Table 4 showed that there was no significant difference between the two groups in terms of TIMI flow before and after the intervention based on the territory.

DISCUSSION
Early and complete restoration of blood flow in closed coronary arteries is the main goal in treating patients with myocardial infarction. Primary angioplasty is not always successful in restoring myocardial blood flow, despite success in the opening of the epicardial coronary arteries. Eptifibatide is a glycoprotein IIb/IIIa receptor antagonist. Although the strategy of adding eptifibatide leads to better blood flow, its value as part of the routine strategy is questionable, according to the results of previous studies [11,12]. Therefore, this study aimed to evaluate the effectiveness of intravenous eptifibatide in improving myocardial perfusion and the rate of hemorrhagic complications in primary PCI patients. The results of the present study demonstrated that eptifibatide has no significant advantage in the coronary artery flow compared to the usual treatment of patients. In the present study, no significant difference was found in terms of TIMI flow between the eptifibatide and heparin treatment groups. However, Gibson et al. reported that early administration of eptifibatide was associated with improved

Heparin Eptifibatide
PCI CABG JOURNAL of MEDICINE and LIFE epicardial flow and increased myocardial perfusion in patients with acute myocardial infarction, which was not consistent with the results of the present study [5].
Contrary to the results of the present study, other studies have suggested that the administration of eptifibatide is associated with improved myocardial perfusion [5,13]. In other words, this drug is effective in correcting perfusion parameters and the results of laboratory studies, which show an increase in clot dissolution when increasing eptifibatide concentration. In 2011, Mahmoudi et al. reported that the eptifibatide group showed a 6-month benefit in terms of mortality compared to the adjuvant group at Washington Hospital [14].
In the current study, the percentage of ST-segment resolution after treatment in the eptifibatide group was higher than in the heparin group. This means that the effect was higher in the eptifibatide group, but no statistically significant difference was found between the two groups in this regard.
In fact, most of the variables in the intervention group were better, but their differences were not significant compared to the control group.
Zeymer et al. compared the effects of early and delayed injection of eptifibatide in patients with STEMI; out of a total of 102 patients, 2 in each group had bleeding complications, but no difference has been found between the two groups, which were consistent with the results of our study. Also, no statistical difference was found between the two groups in terms of ST-segment resolution rate, and TIMI flow rate was similar in both groups after angioplasty, results which are somewhat consistent with our findings [15].
The Joint Canada/United States Survey of Health (JCUSH) divided patients undergoing elective or emergency PCI into two groups, one receiving placebo and the other receiving eptifibatide along with aspirin and heparin. Eptifibatide infusion was continued for 24-28 hours after angioplasty or until the patient was discharged from the hospital. The results of the aforementioned study showed that the rate of major and minor bleeding was higher in the eptifibatide group, which was not consistent with the results of our study [16]. In the study of Le May et al., it was found that the rate and frequency of bleeding complications were significantly higher in the eptifibatide group than in the control group. The reasons for the low rate of bleeding in the present study include the accuracy and skill of the operator, the careful selection of patients based on stringent inclusion and exclusion criteria, and the infusion of eptifibatide with a shorter duration (12 hours) [17].
In another study by Soon et al., two groups of patients (who received intracoronary bolus and intravenous injection) were evaluated for myocardial infarction. Patients in the intervention group received an eptifibatide intracoronary bolus dose, and patients in the control group received an eptifibatide infusion for 18 hours after PCI. The results of the study revealed that both groups were in a favorable prognosis in terms of angiographic findings [18]. In addition, Gibson et al. compared the effect of intracoronary versus intravenous   JOURNAL of MEDICINE and LIFE eptifibatide during PCI. The results of their study showed that epicardial TIMI flow had a significant increase in patients receiving intravenous eptifibatide compared to the intracoronary route [5], indicating that eptifibatide increases myocardial perfusion.

CONCLUSION
Eptifibatide improves clinical indexes in patients undergoing primary PCI, but these rates were not found to be statistically significant. Thus, further studies are needed to confirm or refute these data.