Effect of different approach with intracoronary ...



Effect of intra-coronary administration of tirofiban through aspiration catheter on elderly patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention

Running title: Tirofiban and Myocardial Perfusion

Authors’ Names: Sigan Hu1, Jian Zhu1, Bi Tang1, Hui Li1, Xiaolong Qu1, Tianping Chen1, Dasheng Gao1, Heng Zhang1, Hongju Wang1

Affiliation of Authors:

1Department of Cardiology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China.

Correspondence author:

Hongju Wang , MD, PhD Department of Cardiology, The First Affiliated Hospital of Bengbu Medical College, No.287 Changhuai Road, Bengbu, 233004, Anhui, P.R. China. E-mail: docwhj1101@. Or. Sigan Hu, MD. The First Affiliated Hospital of Bengbu Medical College, No.287 Changhuai Road, Bengbu, 233004, Anhui, P.R. China. E-mail: siganhu@

Abstract

Objectives. The aim of this study was to compare the efficacy and safety of two approaches of intra-coronary administration of tirofiban (aspiration catheter versus guiding catheter) on elderly patients (≥60 years old) with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI).

Background. It has been suggested that the administration of tirofiban by intra-coronary injection could promote drug absorption in the diseased region and enhance the inhibition of platelet aggregation, decreasing bleeding rates. Little is known about efficiency and safety for the two methods, including guiding catheter and aspiration catheter.

Methods. 89 elderly STEMI patients treated with PCI were randomly divided into two groups [guiding catheter (n=41) and aspiration catheter (n=48)] according to the injection route receiving intracoronary administration of tirofiban. Baseline features, epicardial and myocardial perfusion, and major adverse cardiac and cerebrovascular events (MACCE) and bleeding rate were compared.

Results. There were no differences in age, gender, history of hypertension, hypercholesterolemia, diabetes, etc (P>0.05). The patients in the aspiration catheter group generally had a higher incidence of cerebral vascular disease. Compared with guiding catheter group, patients in aspiration catheter group obtained more favorable myocardial perfusion (P 30 min duration and ECG changes with ST segment elevation of >2 mm in at least 2 precordial and >1 mm in the limb leads. Patients were excluded who had contraindications for the use of GPIs (active internal bleeding, known bleeding diathesis, intracerebral mass, or aneurysm), as well as patients with cardiogenic shock at admission or patients with noncardiac conditions that could interfere with compliance with the protocol or require interruption of thienopyridine treatment. Informed consent was obtained from individual patient and the study protocol was approved by the Institutional Review Board on Human Research. Tirofiban were used intra-coronary administration according to the thrombus burden. 89 patients were randomly divided into two groups according to the method used to administer the loading dose of tirofiban: guiding catheter Group (n=41) and aspiration catheter Group (n=48). The patients received an intra-coronary injection of 10μg/kg tirofiban(Grand Pharmaceutical Group, Wuhan, China).

All the patients received 300 mg Aspirin and 300-600 mg Clopidogrel and 100u/kg UFH in the cathlab. PPCI was performed via the radial artery approach, using standard 6F or 7F guiding catheters. The patients received intra-coronary target injection of tirofiban in aspiration catheter group, using the Export aspiration catheter (Medtronic, Inc.). The patients continued to receive Aspirin 100mg daily and Clopidogrel 75 mg daily (for one year) and Atorvastatin 20mg daily at the physician’s discretion. Other drugs were prescribed according to the present guidelines and the patient’s condition, for example angiotensin converting enzyme inhibitors (ACEI) and beta blockers.

Observation indexes. TIMI Myocardial Perfusion Frame Count (TMPFC) was a standardize and quantify myocardial perfusion by timing the filling and clearance of contrast in the myocardium using cine-angiographic frame-counting [13-15]. The first frame of TMPFC was defined as the frame that clearly demonstrated the first appearance of myocardial blush beyond the IRA (F1). The last frame of TMPFC was then defined as the frame where contrast or myocardial blush disappeared (F2). TMPFC is therefore F2-F1 frame counts at filming rate of 15 frames/sec, or (F2 - F1) x2 frame counts at the corrected filming rate of 30 frames/sec.

TIMI grades were used to assess the forward blood flow and were graded as follows: Grade 0, no blood perfusion in the IRA and occlusion of distal vessels without blood flow; grade 1, distal stenosis of the coronary artery without blood flow; grade 2, distal stenosis of the coronary artery with blood flow, but complete filling is slow; grade 3, blood flow is similar to normal coronary artery blood flow.

The patients were followed up in the hospital and 6 months after PCI for mortality, myocardial infarction, cerebrovascular events, need for urgent revascularization, bleeding, heart failure and hematoma. Major bleeding was defined as > 5 g/dl decrease in the hemoglobin level or need for transfusion, medium bleeding was defined as 3-5g/ dl decrease in the hemoglobin level, and minor bleeding was defined as 5cm hematoma at the access site. Major adverse cardiac and cerebrovascular events (MACCE) included cardiovascular mortality, myocardial infarction, heart failure, cerebrovascular accident, and need for urgent revascularization.

Analysis of patient data

The statistical analyses were conducted using the statistical software SPSS version 16.0 for Windows (SPSS Inc., Chicago, IL). The data are presented as mean ± standard deviation for the numerical variables and raw numbers and percentages (%) for the categorical variables. The continuous variables were compared using the Student t-test or nonparametric Mann-Whitney U test whenever the data did not appear to have a normal distribution, and the categorical variables were compared using the Pearson chi-square or the Fisher exact test, as required. P values ≤ 0.05 were considered statistically significant.

Results

Clinical characteristics and coronary angiography.

There were 89 STEMI patients (43 males and 46 females) enrolled in this study with mean age of 69.9years (ranging from 60 to 82years). A total of 89 IRAs were analyzed: 47 in the LAD system, 27 in the RCA system, 12 in the LCX system and 3 in the LM system .Table 1 shows the baseline characteristics of patients between two groups, as defined in methodology. There were no differences in age, gender, history of hypertension, hypercholesterolemia, diabetes, etc. The patients in the aspiration catheter group generally had a higher incidence of cerebral vascular disease. Table 2 shows angiographic and intervention findings in two Groups. There were no differences in IRA, multiple vessel disease (MVD), and intervention path.

Myocardial perfusion. As shown in Table 3, the TIMI grades in two groups were no differences, including preoperative and after the operation (P>0.05). When compared with the patients with optimal myocardial perfusion assessed by TMFC. Patients with intracoronary administration of tirofiban through aspiration catheter had a lower level of TMPFC (87.95±12.39 vs. 94.36±15.87, P0.05). As shown in Table 4, no significant difference was found in the incidence of MACCE in-hospital and 3-months and 6-months follow up.

Discussion

Acute myocardial infarction (AMI) is a serious type of coronary heart disease, which has the characteristics of high incidence, acute onset and high mortality [17-21]. The goal of AMI therapy is to rapidly and successfully restore epicardial blood flow and myocardial perfusion. However, some patients cannot achieve the full reperfusion of myocardial tissue, even although the IRA flow grade TIMI 3. This leads to obviously increase in the incidence of re-infarction, malignant arrhythmia, heart failure, and mortality [22]. Therefore, how to improve the myocardial perfusion of AMI is one of the hot topics in the field of cardiovascular research.

Compared with the thrombolytic therapy, PPCI to open IRA for patients with STEMI had better outcomes. The slow flow or no-reflow after the opening of IRA was one of the major complications of PPCI, acute or subacute thrombosis was the main reason for the most serious complication and major adverse cardiac events (MACE) after PCI [23]. The incidence of slow flow in patients with MI treated by PCI has been reported to be about 10-30 % [24]. In our study, the TIMI grade showed no differences, including preoperative and after the operation. Therefore, according to the epicardial blood flow grade can not reflect the levels of myocardial perfusion. TMPFC is a quantitative index for the assessment of myocardial perfusion; it allows quantification of TIMI myocardial perfusion grading (TMPG). TMPFC was confirmed to be independent predictor of 30d and 6 months MACCE. The mean TMPFC in the normal arteries was 83.47±17.96 frames (95% CI: 78.07 frames ≤TMPFC≤88.86 frames) [25]. We found that patients with intracoronary administration of tirofiban through aspiration catheter had a lower level of TMPFC (87.95±12.39 vs. 94.36±15.87), suggesting that the administration of tirofiban through aspiration catheter would improve myocardial perfusion in elderly patients with STEMI undergoing PCI compared with intracoronary injection of tirofiban through guiding catheter. Improved myocardial perfusion was associated with improve survival stunning myocardium, which may contribute to the improved outcome.

Tirofiban belongs to the platelet glycoprotein IIb/ IIIa inhibitor. It is one of the most powerful anti platelet aggregation drugs after administration of 5min, the inhibition of platelet inhibition could reach to 96%, which can reduce the incidence of MACCE. Serbia STEMI Register study showed that tirofiban administered with primary PCI, following 600 mg clopidogrel pretreatment, improved primary efficacy outcome at 30 days and at 1 year follow up without an increase in major bleeding [26]. In addition, Sun et al. found that intracoronary injection of tirofiban prevents microcirculation dysfunction during delayed percutaneous coronary intervention in patients with acute myocardial infarction [27]. Moreover, meta-analysis showed that compared with intravenous administration of tirofiban, intracoronary administration of tirofiban significantly increased TIMI grade 3 flow (OR 2.11; 95% CI 1.02 to 4.37; P = 0.04) and TMP grade 3 (OR 2.67; 95% CI 1.09 to 6.49; P = 0.03, I2 = 64%) while reducing MACE (OR 0.46, 95% CI: 0.28 to 0.75; P = 0.002) in acute coronary syndrome patients [28]. Our study showed that the administration of tirofiban via the aspiration catheter could further improve the myocardial perfusion level in elderly patients with acute STEMI, without increasing the incidence of bleeding events. Elderly patients with coronary heart disease have complex clinical risk factors, more complications [29]. The incidence of bleeding was higher after strengthening anti platelet therapy, especially for the intravenous administration [30]. The intra-coronary administration of tirofiban can reduce the systemic effects of drugs, increasing of local drug concentration, may lead to better effect of anti platelet, and anti inflammation [31, 32]. Administration of tirofiban by aspiration catheter can increase the drug concentration of microcirculation blood vessels, inhibit the expression of the platelet surface more receptors, and can not be cross-linked with fibrinogen.

Study limitations

The study is limited because of the sample size; a larger study with adequate statistical power is required to validate this novel angiographic end point. In addition, as this is a single-center clinical study, larger prospective and multicenter studies for assessing the value of this conclusion are warranted. Moreover, more precise devices such as cardiac magnetic resonance imaging should be used to evaluate the myocardial perfusion and cardiac function in the future study.

Conclusion Intracoronary delivery of tirofiban through aspiration catheter might be improve myocardial perfusion and long term prognosis in elderly patients with STEMI undergoing PCI compared with intracoronary injection of tirofiban through guiding catheter.

Acknowledgements

The present study was supported by the Program of Bengbu science and technology development (grant no. 20150336), Fund Program of Higher Education Institutions of Anhui Province (grant no.SK2016A0595), Natural Science Foundation of Higher Education Institutions of Anhui Province (grant no. KJ2015ZD30).

Conflict of interest

None

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