Comparison of the curative effect of intracoronary retrograde thrombolysis and thrombus aspiration combined with stent implantation on STEMI patients

Yan-Zi Lin, Tian-Fa Li, Yu-Zhuo Zhang, Yi-Ting Chen, Ya-Ni Yan, Zhe-Zun Wang,Fu-Qing Guan

Department of Cardiovascular Medicine,the First Affiliated Hospital of Hainan Medical University,Haikou 570100,China

Keywords:ST-segment elevation acute myocardial infarction I n t r a c o r o n a r y r e t r o g r a d e thrombolysis Percutaneous coronary intervention

ABSTRACT Objective: To evaluate the short-term and long-term curative effects of precise intracoronary retrograde thrombolysis combined with stent implantation, thrombus aspiration combined with stent implantation, and traditional stent implantation in patients with acute ST-segment elevation myocardial infarction. Methods: From January 2018 to October 2019, 184 patients diagnosed with acute ST-segment elevation myocardial infarction and infarction-related arterial blood flow TIMI 0 grade in the First Affiliated Hospital of Hainan Medical College and percutaneous coronary intervention(PCI) were selected. According to different surgical methods, patients were divided into intracoronary retrograde thrombolysis combined with stent implantation group (thrombolysis group, n=57 cases), thrombus aspiration combined with stent implantation group (aspiration group, n=57 cases) ), traditional stent implantation group (traditional group, n=70 cases). Compare the incidence of no-reflow phenomenon after percutaneous coronary intervention, the rate of 1 hour ST_segment fall 50% in the ECG after PCI, and the main adverse cardiovascular events(MACE) during hospitalization; compare the left ventricular end-diastolic diameter(LVEDD) 、left ventricular ejection fraction(LVEF)and major adverse cardiovascular events at 1 year after PCI. Results: 1. The short-term effects:The incidence of no-reflow phenomenon in the thrombolytic group was lower than that of the aspiration group and the traditional group, and the rate of 1hSTR 50% was higher than that of the aspiration group and the traditional group, the difference was statistically significant(P＜0.05). 2. The long-term effects:1 year after percutaneous coronary intervention, the LVEDD of the thrombolytic group was lower than that of the aspiration group and the traditional group, while the LVEF was higher than the aspiration group and the traditional group,and the incidence of major adverse cardiovascular events in the thrombolytic group at was lowest,both the difference was statistically significant ( P＜0.05). Conclusion: The application of intracoronary retrograde thrombolysis combined with stent implantation in STEMI patients can reduce the occurrence of no-reflow, improve long-term cardiac function, and reduce the occurrence of major adverse cardiovascular events for short-term and long-term.

1. Introduction

Percutaneous coronary intervention is the most common and effective vascularization method for acute ST-segment elevation myocardial infarction [1].However, vascular openment don't represent effective myocardial perfusion. In the process of ischemia reperfusion of myocardial cells after coronary occlusion, 10%-30%of patients can't achieve blood perfusion in myocardial tissue after PCI [2], and coronary angiography shows TIMI blood flow 2, which is defined as no reflow phenomenon(NRP) [3].Currently,the main clinical treatment measures include intracoronary thrombolysis and thrombus aspiration[4].Thrombus aspiration can theoretically reduce the thrombus load in the coronary artery, but the Taste and Total experiments [5][6] found that conventional thrombus aspiration does not improve the long-term prognosis of patients with direct PCI.Some studies have shown that the phenomenon of no reflow is mainly related to microcirculation embolism [7]. Since Professor Jinwen Tian first reported in 2013 that Intracoronary retrograde thrombolysis combined with stent implantation successfully treated one patient with acute coronary occlusion,Jingguo Nong,Zitong Guo,Zhiyuan Liu et al[8-11]successively reported that intracoronary retrograde thrombolysis through microcatheter in coronary artery can reduce the incidence of NRP and improve cardiac function compared with thrombus aspiration.Before the beginning of this study, our research group has compared the efficacy of intracoronary retrograde thrombolysis and forward thrombolysis in coronary artery, and found that intracoronary retrograde thrombolysis can better improve STEMI blood flow perfusion, myocardial tissue perfusion and left ventricular ejection fraction, and reduce the occurrence of NRP [12].Based on this,this study compared with thrombus aspiration and traditional stent implantation to explore the effectiveness and safety of intracoronary retrograde thrombolysis.

2. Materials and methods

2.1 Subjects

A total of 184 patients diagnosed with acute STEMI in the First Affiliated Hospital of Hainan Medical University from January 2018 to October 2019 were selected for emergency PCI treatment with angiography indicating TIMI grade 0 of infarct related arterial blood flow. Three different surgical methods were selected.According to the different surgical methods, the patients were divided into intracoronary retrograde thrombolysis combined with stent implantation group (thrombolysis group, n=57 cases),thrombus aspiration combined with stent implantation group(aspiration group, n=57 cases), and traditional stent implantation group (traditional group, n=70 cases).This study is a single-center controlled experimental study and has been approved by the Ethics Committee of Hainan Medical University [No. : HYLL-2020-017].Inclusion criteria: ①The diagnosis met the criteria of the 2013(ACC/AHA) STEMI management guidelines[13], with indications of emergency PCI;②Emergency coronary angiography diagnosis of acute complete coronary occlusion, TIMI grade 0.Exclusion criteria: ①acute occlusion caused by spasm;② Patients who have received intravenous thrombolytic therapy;③ contraindications to thrombolysis;(4) Any other patients judged by the investigator to be unsuitable for participating in this clinical study or whose condition is not suitable for emergency PCI.Patients who could not complete the surgery due to their condition or other reasons during standard surgery and needed to delay stent implantation were excluded.

2.2 Preoperative and postoperative medication

Substents in line with STEMI diagnosis were given aspirin enteric coated tablets 300mg combined with ticagrelor tablets 180mg or clopidogrel 300mg before each treatment in this study.Intravenous injection of common heparin sodium injection (60U/kg) according to the patient's body weight[14].Aspirin 100mg/d, clopidogrel 75mg/d or ticagrelor 180mg/d were used after stent implantation without contraindications for drugs.Enoxaparin was subcutaneously injected with 1mg/kg once every 12h for a total course of 7 days.Statin,ACEI/ARB andβ-blocker were given according to the patient's blood pressure, heart rate and drugs tolerance.

2.3 Methods

2.3.1 Baseline dataThe general clinical characteristics and examination results of the patients were recorded by the two physicians participating in this study.

2.3.2 The relevant operation of PCI

Coronary angiography (CAG) : the Infarct related artery (IRA)was determined by two interventional physicians with experience in cardiology (more than five years of Coronary interventional work and title of attending physician or above).The Thrombolysis in myocardial infarction (TIMI) blood flow grade was recorded during the operation before and after PCI [15].Microcatheter intracoronary retrograde thrombolysis technology [16] :Urokinase for injection(1×105U) and 15ml normal saline were prepared into a solution,and 5ml Iodopriamine was added into the solution to act as a tracer.Thrombolysis and recovery of distal blood flow were dynamically observed by DSA machine through a microcatheter at a rate of 2ml/min.Adjust dissolving suppositories dosage (control within 100000 IU) and the injection rate, time (thrombolysis is not more than 10 minutes), disappear until the retention phenomenon of contrast agent, restore blood flow to the distal to TIMI grade 2 or above, again into the thread, withdraw the microcatheter, such as after the treatment, blood flow is still not recover, can according to the situation of coronary artery in the balloon expansion, after the stent placement,The operation was completed, as shown in Figure 1.Thrombosis aspiration: Using the principle of negative pressure,the catheter is pushed from the proximal end of the vascular lesion to the distal end of the catheter until the X-ray shows forward blood flow, and then the stent is implanted.If there is no anterior blood flow after repeated 3-5 times of aspiration, balloon dilation can be used to restore the anterior blood flow and then coronary stent implantation can be performed according to the patient's condition.In traditional PCI, the balloon was sent to the lesion site by guiding catheter along the finger guide wire, and then the suitable stent was implanted after balloon pre-dilation.

Table 1.3.1 Baseline data of the three groups of patients

Figure 1 The flow chart of intracoronary retrograde thrombolysis

2.3.3 Observation targetShort-term Outcome Measures: TIMI flow grade and incidence of NRP after stenting;1hSTR, LVEDD, LVEF, TIMI massive bleeding,TIMI minor bleeding, stroke, Major adverse cardiovascular events(MACE), and length of stay were recorded during hospitalization.Long-term outcomes: LVEDD, LVEF and MACE 1 year after surgery.

2.3.4 Statistical treatment

The statistical software used was SPSS22.0. The measurement data were normally distributed and expressed as mean ± standard deviation (x±s). The t-test was used for comparison between two groups, analysis of variance was used for comparison between multiple groups, and LSD test was used for comparison between two groups.Data did not follow normal distribution, and was represented by median (quad). Comparison between two groups was performed by Mann-Whitney U test, and comparison between multiple groups was performed by Kruskal Wails H test.Enumeration data were represented by the ratio or percentage (%), and the chi-square test was used for comparison between groups, which was considered to be statistically significant.

3. Results

In the thrombolysis group, 2 patients still did not see forward blood flow after intracoronary retrograde thrombolysis combined with balloon dilation, so delayed stent implantation was given, and the group was excluded.In the aspiration group, 1 patient did not see forward blood flow after thrombus aspiration combined with balloon dilation, and 1 patient had severe coronary artery calcification and could not be excluded from the thrombus aspiration group.The final thrombolysis group and aspiration group were 55 patients respectively.

3.1 There were no statistically significant differences in clinical characteristics

Number of coronary artery lesions, infarct related arteries, and preoperative TIMI blood flow grading among the three groups(P＞0.05 ), and patients were comparable among the three groups.

3.2 Intraoperative interventions for PCI

The proportion of using bivarudine in thrombus group and traditional group was higher than that in thrombolytic group (p＜0.05), and there was no statistical significance in other intraoperative intervention measures (p＞0.05 ).As shown in table 2.1.

3.3 Short-term efficacy

The incidence of NRP in the thrombolysis group was lower than that in the aspiration group and the traditional group(3.6%vs20%vs18.6%,P=0.023), and the difference was statistically significant (P＜0.05).In the thrombolytic group,the highest proportion of 1hSTR was greater than 50% after PCI (89.1%vs65.5%vs71.4%,P=0.011), and the difference was statistically significant (P＜0.05).As shown in table 2.3.

3.4 Bleeding events, MACE and length of stay during hospitalization

There were no significant differences in the incidence of small or large TIMI bleeding, stroke and length of hospitalization among the three groups (P ＞ 0.05).The incidence of total MACE in the thrombolytic group was lower than that in the aspiration group and the traditional group (3.6%vs18.2%vs17.1%,P=0.039),and the difference was statistically significant ((P＜0.05). The incidence of malignant arrhythmia in the thrombolytic group was lower than that in the aspiration group and the traditional group(1.8%vs14.5%vs12.9%,P= 0.049).The difference was statistically significant ((P＜0.05).There was no statistical significance in cardiac death, non-cardiac death, recurrent acute myocardial infarction or severe heart failure among the three groups during hospitalization (P＞ 0.05), as shown in Table 2.4.

Table 2 .2 Comparison of intraoperative intervention measures among the three groups

Table 2.3 Comparison of myocardial perfusion and incidence of NRP

Table 2.4 Comparison of indicators in the three groups during hospitalization

3.5 Long-term efficacy

3.5.1 LVEDD and LVEF at 1 year postoperativelyAs shown in Table 2.5, there was no statistical significance in LVEDD and LVEF of thrombolysis group, aspiration group and traditional group within 24 hours after PCI (P ＞ 0.05).the LVEDD of the thrombolytic group and aspiration group one year after surgery decreased (51.35±3.07mm) vs (54.42±4.39mm) and(53.42±3.02mm) vs (54.65±4.30mm) compared with that within 24 hours after admission, with statistical significance (P＜0.05).There was no statistical significance in the traditional group within 24 hours after admission and 1 year after operation (P＜0.05).The difference of LVEDD among the three groups one year after surgery was statistically significant (P＜0.05),Pair comparison indicated that LVEDD in the thrombolytic group was lower than that in the aspiration group and the stent group ((51.35±3.07mm)vs(53.42±3.02mm) vs(53.90±6.99mm), P=0.014), and the difference was statistically significant (P＜0.05).The LVEF of thrombolysis group, aspiration group and traditional group at 1 year after surgery was compared with that at 24h after admission (57.76±7.39)%vs 52.6±8.29)%, (54.74±8.02)%vs 52.6±9.52)%, (54.44±7.53)%vs 51.56±7.55)%, respectively.The difference was statistically significant (P＜0.05). One year after surgery, the LVEF of the thrombolytic group was higher than that of the aspiration group and the stent group ((57.76±7.39) %vs (54.74±8.02) %vs (54.44±7.53)%,P=0.037), and the difference was statistically significant (P＜0.05).

Table 2.5 Changes of LVEDD and LVEF after treatment among the three groups

3.6 The incidence of MACE one year after surgery in the three groups

One year after surgery, the incidence of MACE in the thrombolytic group was lower than that in the aspiration group and the traditional group, and the difference was statistically significant (P＜0.05).The incidence of recurrent angina in the thrombolytic group was significantly lower than that in the aspiration group and the traditional group (1.8%vs14.5%vs10%,P=0.032), and the difference was statistically significant (P＜0.05).There was no significant difference in the incidence of death, severe heart failure, recurrent myocardial infarction, target vessel re-revascularization and malignant arrhythmia among the three groups (P＞0.05).The data are shown in Table 2.6.

Table 2.6 Comparison of MACE one year after surgery

4. Discussion

NRP after emergency PCI seriously affects postoperative myocardial blood flow reperfusion in PCI patients and increases the risk of cardiogenic death in STEMI patients [17].The mechanism of NRP is complex, and currently there is no guideline to recommend a specific treatment to have a clear effect. The 2013 American College of Cardiology/American Heart Association STEMI management guideline considers that thrombotic pumping in direct PCI is reasonable, which has been rejected by several clinical studies in recent years [18]-[21].Routine thrombus aspiration before direct PCI does not improve the prognosis of patients [5][6].Based on this, this study applied intracoronary retrograde thrombolysis combined with PCI in STEMI patients that infarct-associated vessel with TIMI grade 0 blood flow, and compared it with thrombus aspiration and traditional stent group.The final results showed that compared with thrombus aspiration and balloon dilatation, intracoronary reverse thrombolysis before PCI could increase the proportion of TIMI grade 3 and ST segment drop 50% in 1h ECG after PCI,and there was no statistical significance in the difference of major and minor hemorrhage in TIMI among the three groups during hospitalization.In the 1-year follow-up after operation, it was found that the left ventricular ejection fraction increased significantly in the thrombolytic group compared with the aspiration group and the traditional group, and the left ventricular end-diastolic diameter decreased compared with the aspiration group and the traditional group, suggesting the advantage of reverse thrombolytic therapy in improving long-term cardiac function and inhibiting left ventricular remodeling.In addition, the incidence of MACE 1 year after PCI in the thrombolytic group was lower than that in the aspiration group and the conventional group, suggesting long-term benefits.In this study, the incidence of NRP after PCI was 3.6% in the thrombolytic group and 20% in the aspiration group. According to the results of Nong Jingguo [8] 's 1-year follow-up, the incidence of no reflux was 1.7% in the reverse thrombolytic group and 15% in the aspiration group. The incidence of MACE one year after PCI was lower in the thrombolytic group than in the aspiration group, while the left ventricular function was improved compared with the aspiration group, which was basically consistent with the results of this study.Moreover, for the population characteristics in Hainan (low weight,low height, and more elderly population), there was no increase in bleeding events.In conclusion, intracoronary thrombolysis can better improve the level of myocardial perfusion, reduce the incidence of NRP after emergency PCI, and reduce the incidence of MACE during hospitalization and 1 year after PCI, without increasing the bleeding events, stroke and length of stay during hospitalization.In conclusion, inverse thrombolysis combined with stent implantation is not only safe, but also can benefit patients in the near future and effectively improve the long-term prognosis of patients. Associated with thrombus suction stent implantation, traditional stent implantation, the fundamental reason of intracoronary retrograde thrombolysis present superiority is because the method to dissolve the infarction related artery within the micro thrombus, micro blood clots in coronary artery is closely related to the occurrence of no reflow phenomenon, thrombus suction does not take out all the blood clots, of coronary thrombosis cannot by examining the existing development. Combined with the pathophysiological characteristics of STEMI, reverse thrombolysis not only increases the concentration of local thrombolytic drugs at the acute occlusion,but also gradually releases drugs in a reverse way from the distal end to the proximal end of the occlusive coronary artery, avoiding the impact of positive blood flow, so that incomplete thrombus or small thrombus will not be flushed to the distal end of the blood stream and cause microcirculation embolism [22].At the same time, the ischemic myocardium can realize the gradual reperfusion process and reduce the degree of reperfusion injury caused by the sudden opening of occluded vessels. Therefore, the effect of thrombolysis group was significantly lower than that of the aspiration group and the traditional group without reperfusion. The method uses precise dosage and precise location, and the urokinase is in full contact with the thrombus, which can activate the plasminogen in vivo to convert to plasminogen, thus hydrolyzing fibrin to dissolve the thrombus of fresh size. After timely perfusion, the incidence of MACE in the near and long term can be reduced without increasing bleeding complications, and the dosage is controllable. Although the operation is added in the course of reverse thrombolysis, reverse thrombolysis can further improve the short-term and long-term prognosis of patients, which is worthy of popularization and development.

Author’s Contribution

Yanzi Lin , responsible for the implementation of the study, data collection, statistics, and paper writing.

Tianfa Li , performing surgical operations, to modify the paper.

Yuzhuo Zhang, the implementation of surgical operations,implementation of the project application, to ensure that the study is reasonable.

Chen Yiting, Statistics.

Yan Yani, followed up patients.

Zhezun Wang, Data collection.

Fuqing Guan, basic information of registered patients.