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. 2022 Nov 30;25(1):40. doi: 10.3892/etm.2022.11739

Safety and efficacy of intracoronary recombinant human prourokinase administration in patients with acute myocardial infarction and ST‑segment elevation: A meta‑analysis of randomized controlled trials

Gang Fan 1,✉, Xiang-Ge Wu 1, Wen-Ping Jiao 1, Hong-Kao Zhang 1, Dian-Long Guo 1,✉
PMCID: PMC9764045  PMID: 36569445

Abstract

Slow blood flow or no reflow following percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI) typically leads to an adverse prognosis. However, it is controversial whether to use prourokinase (Pro-UK) during PCI in patients with acute STEMI. The present meta-analysis compared the efficacy and safety of intracoronary Pro-UK administration in patients with acute STEMI. Published randomized controlled trials (RCTs) were analyzed to compare Pro-UK with non-Pro-UK treatment in patients with acute STEMI. PubMed, Cochrane Library and China National Knowledge Infrastructure were searched and meta-analysis was performed using Review Manager 5.3 software. A total of 13 RCTs were selected and 1,797 patients were considered in the meta-analysis, including 897 patients who received Pro-UK intervention and 900 patients who were in the control group. No significant heterogeneity was identified across these selected studies. Pro-UK therapy significantly decreased the incidence of major adverse cardiac events [risk ratio (RR), 0.68; 95% CI, 0.56-0.82, P<0.0001], left ventricular end-diastolic diameter [standardized mean difference (SMD), -0.26; 95% CI, -0.40 – -0.12; P=0.0003], corrected thrombolysis in myocardial infarction (TIMI) frame count [SMD, -0.45; 95% CI, -0.62 – -0.28; P<0.00001] and cardiac troponin I [SMD, -0.31; 95% CI, -0.46 – -0.17; P<0.0001]. In addition, Pro-UK administration increased TIMI grade 3 flow (RR, 1.16; 95% CI, 1.07-1.25; P=0.0003), TIMI myocardial perfusion grade 3 (RR: 1.39, 95% CI: 1.12-1.74, P=0.004), ST-segment resolution (RR, 1.23; 95% CI, 1.10-1.36; P=0.0002) and left ventricular ejection fraction (SMD, 0.38; 95% CI, 0.27-0.49; P<0.00001). No significant difference was identified in bleeding (RR, 1.12; 95% CI, 0.85-1.47; P=0.41). The present meta-analysis determined that intracoronary Pro-UK administration is efficacious and safe to decrease slow blood flow or no reflow phenomena following PCI and improve the prognosis of patients with acute STEMI.

Keywords: ST-segment elevation myocardial infarction, percutaneous coronary intervention, prourokinase, no reflow, slow blood flow, meta-analysis

Introduction

Coronary artery disease (CAD) is the most common cardiovascular disease and has a notable impact on global health (1). ST-segment elevation myocardial infarction (STEMI) is one of the most acute manifestations of CAD, which is typically characterized by acute onset and high mortality (2). The recanalization of infarct-associated arteries or culprit vessels and reestablishing myocardial perfusion is the primary treatment for STEMI (3). Percutaneous coronary intervention (PCI) is the most effective and widely used method for reopening occluded vessels (3). With the application of PCI, mortality of STEMI significantly decreased (4). However, a review revealed that certain patients may experience slow blood flow or no reflow following PCI, decreasing the benefits of PCI (5). It has been reported that the incidence of slow blood flow or no reflow after PCI in patients with STEMI is ~30%, which leads to an increase in infarct size, heart failure and mortality rate (6). Slow blood flow and no reflow following PCI in patients with STEMI are independent risk factors for short-time prognosis and long-time major adverse cardiovascular events (MACEs) (6).

High thrombus burden, prolonged reperfusion time, stent diameter and post-stent expansion are all potential factors verified to affect the incidence of slow blood flow and no reflow after PCI (7). Therefore, adequate anticoagulation before and during PCI is key for the prevention of slow blood flow and no reflow. However, anticoagulation may increase the risk of bleeding. How to properly balance decreased slow blood flow and no reflow and the potential increased risk of bleeding is an urgent cardiovascular problem for treatment of acute STEMI.

Recombinant human prourokinase (Pro-UK) is a fibrin-specific plasminogen activator that shares structural similarities with tissue plasminogen activator but functions via a different mechanism (8). Studies show that Pro-UK presents with fewer hemorrhagic complications and lower re-occlusion rate in patients with acute STEMI compared with conventional drugs (9,10). In addition, certain prospective study found that Pro-UK decreases MACEs whereas a retrospective study revealed that Pro-UK does not affect MACEs (11). To date, Pro-UK is not a frequent agent applied to patients for acute STEMI due to lack of evidence. To the best of our knowledge, there are limited studies investigating the efficacy and safety of Pro-UK in patients with acute STEMI (11,12). Therefore, further investigations are needed to assess intracoronary administration of Pro-UK and non-Pro-UK treatment in patients with acute STEMI.

Since Pro-UK is a coronary thrombolytic drug from China, most clinical trials on Pro-UK are led by Chinese scholars or conducted in China. In the present study, a meta-analysis of randomized controlled trials (RCTs) from China was performed to compare the safety and efficacy between Pro-UK and non-Pro-UK for treatment of acute STEMI. This analysis aimed to provide novel evidence-based medical information for the intracoronary application of Pro-UK in patients with acute STEMI.

Patients and methods

Search strategy

Studies published before June 2022 were retrieved from the following databases: PubMed (https://pubmed.ncbi.nlm.nih.gov/), Cochrane Library (https://www.cochranelibrary.com/) and China National Knowledge Infrastructure (CNKI) (https://www.cnki.net/). The terms ‘STEMI’ and ‘PCI’ or ‘Percutaneous coronary intervention’ and ‘Prourokinase’ or ‘Pro-UK’ were used as the key search words.

Selection criteria

Studies were included if the following criteria were met: i) RCT; ii) study subjects were patients with acute STEMI; iii) patients with acute STEMI received Pro-UK intracoronary therapy and iv) efficacy evaluation indicators included at least recanalization indicators, bleeding and MACEs. By contrast, studies were excluded if the following criteria were met: i) Non-RCT; ii) duplicate publication; iii) follow-up <30 days; iv) ongoing or unpublished study; v) the study did not contain the original data or statistical analysis could not be performed and vi) observational or cohort study.

Quality assessment

The included RCTs were assessed using the method of Jadad which is recommended by the Cochrane Library (13). The quality of RCTs was evaluated based on the following components: i) Randomized method; ii) allocation concealment; iii) blinding of participant personnel and outcome assessors; iv) complete outcome data; v) free of selective outcome reporting; and vi) clear causes for loss or quitting of the follow-up.

Data extraction

The data utilized in the present study were extracted by two independent authors (GF and DG) and not blinded. The information regarding first author, publication date, study design, baseline characteristics and endpoints was noted. The study method described in this article refers to previously published research by Fan et al (14). The endpoints included MACE, bleeding, ST-segment resolution (STR), corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC), TIMI grade 3 (TIMI-3), TIMI myocardial perfusion grade (TMPG), left ventricular ejection fraction LVEF, left ventricular end-diastolic diameter (LVEDd) and cardiac troponin I (cTnI). During extraction, a third reviewer was used to resolve any disagreement between the two authors.

Statistical analysis

The data were analyzed using Review Manager 5.3 software (Cochrane). Continuous effective outcomes are presented as standardized mean difference (SMD) while dichotomous effective outcomes were analyzed using risk ratio (RR). Continuous data were mean with SD in this study. The 95% CI was also calculated. The heterogeneity across studies was analyzed using Q-test. Values of P>0.10 and I2<50% were considered to indicate no significant heterogeneity and the pooled outcomes were estimated using the Mantel-Haenszel fixed-effects model. P≤0.10 and I2≥50% were considered to indicate significant heterogeneity and the pooled analyses were estimated using the Mantel-Haenszel random-effects model. P<0.05 was considered to indicate a statistically significant difference.

Results

Included studies

Studies were screened from PubMed (n=21), Cochrane Library (n=14) and CNKI (n=164) databases. After scanning the publications, 106 of 199 studies were excluded because of irrelevant or duplicate records. After further reading, 15 of the remaining 93 studies were excluded based on the abstract. Among the remaining 78 papers, 11 were review articles, 47 were retrospective studies, five were ongoing studies and two studies were excluded owing to lack of data. Finally, a total of 13 studies comprising 1,797 patients were included in this meta-analysis, including 897 patients who received Pro-UK and 900 patients who were in the control group. The procedure for use in the study is presented in Fig. 1.

Figure 1.

Figure 1

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Flow diagram of study inclusion procedure. After screening the title/abstract, and assessing the full-text article, 13 studies were included in the final meta-analyses. CNKI, China National Knowledge Infrastructure.

Quality assessment and baseline characteristics

The primary characteristics of the included studies are illustrated in Table I. Patient age ranged from 49.0 to 64.9 years. The bias condition of selected studies is illustrated in Fig. 2 and bias summary is indicated in Fig. 3. The quality and grading of the included articles is presented in Table II. The selected reports were RCTs from China. The Jadad scoring of the included studies ranged from 5 to 7, which indicated high quality.

Table I.

Characteristics of included studies.

  N Age, years (mean ± SD) Endpoint  
First author, year Setting Journal Pro-UK Control Pro-UK Control Primary Secondary Control therapy Follow-up days (Refs.)
Wu et al, 2020 Single-center BMC Cardiovascular Disorders 25 25 59.5±14.4 61.0±12.6 Coronary physiological indexes Angiographic/reperfusion assessment; infarct size; cardiac function Saline 90 (15)
Jiang et al, 2020 Single-center Coronary artery Disease 125 135 53.9±6.6 55.1±6.8 Infarct size; reperfusion assessment; Cardiac function; MACEs; Hemorrhagic complications Saline 180 (16)
Fu et al, 2019 Single-center Catheter Cardiovascular Intervention 20 19 62.6±11.1 63.2±11.2 TIMI flow grade; CTFC MACEs; Bleeding; Electrocardiogram features and myocardial necrosis markers Thrombus aspiration 90 (17)
Huang et al, 2021 Multi-center Frontiers in cardiovascular medicine 111 117 59.4±10.1 58.5±9.9 CTFC TIMI flow grade; MACEs; Myocardial necrosis markers Saline 30 (18)
Geng et al, 2018 Single-center Journal of international Cardiology 118 112 53.5±11.4 55.2±10.4 Markers of infarct size and myocardial reperfusion Indicators of cardiac functions; MACEs; bleeding Saline 180 (19)
Xiao et al, 2019 Single-center Coronary artery Disease 33 38 62.1±15.8 64.9±13 TMPG and IMR values Cardiac functions; MACEs Thrombus aspiration 90 (20)
Wang et al, 2020 Single-center Coronary artery Disease 92 90 61.1±11.3 58.8±11 Incidence of restored myocardial reperfusion TIMI flow grade; MACEs; CTFC Saline 180 (21)
Lin et al, 2021 Single-center Journal of Clinical Cardiology (China) 36 40 65.2±11.2 52.4±11.7 Incidence of restored myocardial reperfusion; CTFC Cardiac functions; MACEs Tirofiban 365 (22)
Wang et al, 2021 Single-center Evolution and analysis of drug-use in hospitals of China 30 30 62.3±9.4 61.4±11.5 TIMI flow grade Cardiac function; MACEs Sodium nitroprusside 30 (23)
Zhao et al, 2021 Single-center Medical Science Journal of central south China 50 50 49.6±3.5 49.9±3.9 TIMI flow grade MACEs; Bleeding Alteplase 180 (24)
Han et al, 2021 Single-center Chinese journal crit care medicine 60 60 64.7±5.9 62.9±6.6 TIMI flow grade; CTFC; TMPG; Incidence of restored myocardial reperfusion Cardiac functions; MACEs Sodium nitroprusside 180 (25)
Han et al, 2013 Single-center Cardiovascular Therapeutics 100 97 56.8.7±9.8 57.1±8.9 TIMI flow grade MACEs; Bleeding Anti-platelet 365 (26)
Zhao et al, 2021 Single-center PJCCPVD 92 92 61.9±8.2 62.9±8.2 TIMI flow grade Myocardial necrosis markers; MACEs Tirofiban 60 (27)
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Pro-UK, prourokinase; MACEs, major adverse cardiac events; CTFC, corrected TIMI frame count; TMPG, TIMI myocardial perfusion grade; PJCCPVD, Journal of Practical Cardiopulmonary Vascular Disease.

Figure 2.

Figure 2

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Risk bias of included studies.

Figure 3.

Figure 3

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Risk summary of included studies. Red colors indicate high risk, Yellow colors indicate unclear risk, Green colors indicate low risk.

Table II.

Quality of included studies.

First author, year Randomized method Allocation concealment Blinding Complete outcome data Free of selective outcome reporting Clear cause for loss or quitting of follow-up Jadad score (Refs.)
Wu et al, 2020 Yes Yes Single-blind Yes Yes Yes 7 (15)
Jiang et al, 2020 Yes Yes Unclear Yes Yes Yes 6 (16)
Fu et al, 2019 Yes Unclear Unclear Yes Yes Yes 6 (17)
Dong et al, 2021 Yes Yes Single-blind Yes Yes Yes 7 (18)
Wei et al, 2018 Unclear Unclear Single-blind Yes Yes Yes 6 (19)
Xiao et al, 2019 Yes Unclear Single-blind Yes Yes Yes 7 (20)
Wang et al, 2020 No Yes Single-blind Yes Yes Yes 6 (21)
Lin et al, 2021 Yes Unclear Single-blind Yes Yes Yes 6 (22)
Wang et al, 2021 Yes Unclear Unclear Yes Yes Yes 6 (23)
Zhao et al, 2021 Unclear Unclear Unclear Yes Yes Yes 5 (24)
Han et al, 2021 Yes No Unclear Yes Yes Yes 6 (25)
Han et al, 2013 Yes Yes Single-blind Yes Yes Yes 7 (26)
Zhao et al, 2021 Yes Unclear Unclear Yes Yes Yes 6 (27)
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Comparison of MACEs between groups

A total of 13 studies comprising 1,797 patients reported MACEs. There was no significant heterogeneity between studies (P=0.50; I2=0%). The effect size of the pooled RRs was calculated using the Mantel-Haenszel fixed effects model. The results revealed that the Pro-UK group presented a significantly lower incidence of MACEs compared with that in the control group (RR, 0.68; 95% CI, 0.56-0.82; P<0.0001; Fig. 4).

Figure 4.

Figure 4

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Meta-analysis of major adverse cardiac events. Pro-UK, prourokinase; M-H, Mantel-Haenszel.

Comparison of bleeding between two groups

A total of 13 studies reported bleeding, including 897 patients who received Pro-UK and 900 patients who in the control group. There was no significant heterogeneity between studies (P=0.83; I2=0%). The results showed that there was no significant difference in bleeding incidence between the two groups (RR, 1.12; 95% CI, 0.85-1.47; P=0.41; Fig. 5).

Figure 5.

Figure 5

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Meta-analysis of bleeding. Pro-UK, prourokinase; M-H, Mantel-Haenszel.

Comparison of TIMI-3 between groups

A total of 10 studies comprising 1,301 patients reported TIMI-3, including 618 patients who received Pro-UK and 613 patients who were in the control group. There was no significant heterogeneity between studies (P=0.003; I2=64%). The effect size of the pooled RRs was estimated using the random effects model. The Pro-UK group presented a significantly increased TIMI-3 rate compared with that in the control group (RR, 1.16; 95% CI, 1.07-1.25; P=0.0003; Fig. 6).

Figure 6.

Figure 6

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Meta-analysis of thrombolysis in myocardial infarction grade 3. Pro-UK, prourokinase; M-H, Mantel-Haenszel.

Comparison of TMPG-3 between groups

A total of five studies comprising 462 patients reported TMPG-3, including 235 patients who received Pro-UK and 227 patients who were in the control group. There was no significant heterogeneity between studies (P=0.02; I2=67%). The effect size of the pooled RRs was calculated using the random effects model. The Pro-UK group presented a significantly increased TMPG-3 rate compared with that in the control group (RR, 1.39; 95% CI, 1.12-1.74; P=0.004; Fig. 7).

Figure 7.

Figure 7

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Meta-analysis of TIMI myocardial perfusion grade 3. Pro-UK, prourokinase; M-H, Mantel-Haenszel.

Comparison of STR between two groups

A total of nine studies comprising 1,256 patients reported STR, including 625 patients who received Pro-UK and 631 patients who were in the control group. There was no significant heterogeneity between studies (P=0.05; I2=49%). The effect size of the pooled RRs was estimated using the Mantel-Haenszel random effects model. The Pro-UK group presented a significantly increased STR rate compared with that in the control group (RR, 1.23; 95% CI, 1.10-1.36; P=0.0002; Fig. 8).

Figure 8.

Figure 8

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Meta-analysis of ST-segment resolution. Pro-UK, prourokinase; M-H, Mantel-Haenszel.

Comparison of LVEF between groups

A total of 10 studies comprising 1,316 patients reported LVEF, including 655 patients who received Pro-UK and 661 patients who were in the control group. There was no significant heterogeneity between studies (P=0.08; I2=42%). The effect size of the pooled SMD was estimated using the Mantel-Haenszel fixed effects model. The Pro-UK group presented a significantly higher LVEF compared with the control group (SMD: 0.38, 95% CI: 0.27-0.49, P<0.00001, Fig. 9).

Figure 9.

Figure 9

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Meta-analysis of left ventricular ejection fraction.

Comparison of LVEDd between groups

A total of six studies comprising 796 patients reported LVEDd, including 304 patients who received Pro-UK and 402 patients who were in the control group. There was no significant heterogeneity between studies (P=0.36; I2=9%). The effect size of pooled SMD was estimated using the fixed effects model. The Pro-UK group presented a significantly decreased LVEDd compared with that in the control group (SMD, -0.26; 95% CI, -0.40 – -0.12; P=0.0003; Fig. 10).

Figure 10.

Figure 10

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Meta-analysis of left ventricular end-diastolic diameter.

Comparison of CTFC between groups

A total of five studies comprising 570 patients reported CTFC, including 286 patients who received Pro-UK and 284 patients who were in the control group. There was no significant heterogeneity between studies (P=0.76; I2=0%). The effect size of pooled SMD was estimated using Mantel-Haenszel fixed effects model. The Pro-UK group presented a significantly decreased CTFC compared with that in the Control group (SMD, -0.45; 95% CI, -0.62 – -0.28, P<0.00001; Fig. 11).

Figure 11.

Figure 11

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Meta-analysis of corrected TIMI frame count.

Comparison of cTnI between groups

A total of four studies comprising 722 patients reported cTnI, including 360 patients who received Pro-UK and 362 patients who were in the control group. There was no significant heterogeneity between studies (P=0.67; I2=0%). The effect size of pooled SMD was estimated using the fixed effects model. The Pro-UK group presented a significantly decreased cTnI level compared with that in the control group (SMD, -0.31; 95% CI, -0.46 – -0.17; P<0.0001; Fig. 12).

Figure 12.

Figure 12

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Meta-analysis of cardiac troponin I.

Discussion

Altogether, 13 RCTs were included in the present meta-analysis. The pooled data estimations revealed that intracoronary Pro-UK administration was associated with decreased MACEs, LVEDd, CTFC and cTnI levels in patients with acute STEMI. Additionally, there were increased TIMI-3, TMPG-3, STR rate and LVEF levels in the Pro-UK group compared with those in the control group. No significant difference was identified regarding the safety indexes (bleeding) between groups.

The primary aim for the treatment of acute STEMI is to restore effective perfusion of the myocardium and minimize ischemic damage. PCI is the first option to reopen infarct-associated arteries and restore coronary blood flow (28). Stent implantation in patients with acute STEMI is beneficial. However, the incidence of slow blood flow or no reflow after PCI in patients with STEMI is ~30%, which usually leads to worse prognosis (29). Patients with STEMI and slow blood flow or no reflow have higher MACE occurrence rate compared with those with optimal flow (30). Delayed reperfusion, high thrombosis burden, glucose levels and stent diameter are factors that contribute to slow blood flow or no reflow following PCI (31).

High-burden thrombosis is the most important risk factor for no reflow or slow blood flow phenomena following PCI (32). Thrombus aspiration (TA) is a common method used for treating intracoronary thrombus, but TA cannot completely remove the thrombus and no reflow rate is still high following emergency PCI (33). Moreover, TA may cause local micro-thrombosis, which leads to no reflow or slowed blood flow and affects myocardial perfusion, increasing the risk of recurrent myocardial infarction, cardiogenic shock and malignant arrhythmia (33). Evidence-based study have suggested that TA is not associated with a decrease in long-term mortality or clinical outcomes in patients with STEMI (34). Currently, drugs such as tirofiban, sodium nitroprusside, nicorandil and diltiazem are widely used to decrease coronary thrombus burden. However, the incidence of no reflow after PCI is still high, which affects the prognosis of acute STEMI (35,36).

Recombinant human Pro-UK is the precursor of urokinase. The activated plasminogen combines with the thrombus Y/E tablet segment. Pro-UK quickly reacts with kininase and selectively activates plasminogen in thrombus fibrin, but it does not activate free plasminogen. Therefore, Pro-UK may decrease or avoid cytotoxicity, coagulation system allergy and systemic hemorrhage and other adverse events (37).

In the current study, 13 relatively high-quality RCTs were included. The present results revealed that intracoronary administration of Pro-UK therapy was associated with a lower incidence of MACEs (RR 0.68; 95% CI, 0.56-0.82; P<0.0001), lower LVEDd (SMD, -0.26; 95% CI, -0.40 – -0.12; P=0.0003), CTFC (SMD, -0.45; 95% CI, -0.62 – -0.28; P<0.00001) and cTnI (SMD, -0.31; 95% CI, -0.46 – -0.17; P<0.0001) in treating patients with acute STEMI. Furthermore, Pro-UK treatment had higher TIMI-3 (RR, 1.16; 95% CI, 1.07-1.25; P=0.0003), TMPG-3 (RR, 1.39; 95% CI, 1.12-1.74; P=0.004), STR (RR, 1.23; 95% CI, 1.10-1.36; P=0.0002) and LVEF (SMD, 0.38; 95% CI, 0.27 – -0.49; P<0.00001). Bleeding incidence (RR, 1.12; 95% CI, 0.85-1.47; P=0.41) was comparable between groups. Based on the present meta-analysis, intracoronary administration of Pro-UK during PCI in treatment of patients with acute STEMI should be recommended in clinical practice.

Certain limitations of the present meta-analysis should be mentioned. First, the meta-analysis was based on published RCTs and some large-scale ongoing trials were not included. Second, the analysis was performed on the trial level, not on the patient level. Third, there was only one multicenter trial in our meta-analysis that evaluated the Pro-UK effect. Additionally, the follow-up duration in studies was not uniform. Use of additional databases (such as Web of Science (https://www.webofscience.com/) and European Molecular Biology Organization (http://www.embo.org/) is required to validate the present results.

Intracoronary administration of Pro-UK not only decreases MACE, LVEDd, and cTnI levels, but also increases TIMI-3, TMPG-3, STR, and LVEF levels in patients with acute STEMI. Pro-UK is safe and effective to combine with PCI in treating patients with acute STEMI. However, more large-scale multicenter RCTs comparing Pro-UK and non-Pro-UK studies are needed to confirm this conclusion.

Acknowledgements

Not applicable.

Funding Statement

Funding: No funding was received.

Availability of data and materials

All data generated and/or analyzed during this study are included in this published article.

Authors' contributions

GF and DG conceived and designed the study. GF, XW and WJ carried out literature search, study selection and quality assessment. WJ and HZ performed data extraction. GF and HZ confirm the authenticity of all the raw data. GF, XW, DG and WJ performed statistical analysis. GF wrote the manuscript. GF and DG interpreted the data and revised the manuscript. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing of interests

The authors declare that they have no competing interests.

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Associated Data

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Data Availability Statement

All data generated and/or analyzed during this study are included in this published article.

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