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.
Coronary artery disease (CAD) is the most common cardiovascular disease and has a notable impact on global health (
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 (
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 (
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.
Studies published before June 2022 were retrieved from the following databases: PubMed (
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.
The included RCTs were assessed using the method of Jadad which is recommended by the Cochrane Library (
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
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.
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
The primary characteristics of the included studies are illustrated in
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;
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;
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;
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;
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;
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,
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;
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;
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;
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 (
High-burden thrombosis is the most important risk factor for no reflow or slow blood flow phenomena following PCI (
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 (
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 (
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.
Not applicable.
All data generated and/or analyzed during this study are included in this published article.
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.
Not applicable.
Not applicable.
The authors declare that they have no competing interests.
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.
Risk bias of included studies.
Risk summary of included studies. Red colors indicate high risk, Yellow colors indicate unclear risk, Green colors indicate low risk.
Meta-analysis of major adverse cardiac events. Pro-UK, prourokinase; M-H, Mantel-Haenszel.
Meta-analysis of bleeding. Pro-UK, prourokinase; M-H, Mantel-Haenszel.
Meta-analysis of thrombolysis in myocardial infarction grade 3. Pro-UK, prourokinase; M-H, Mantel-Haenszel.
Meta-analysis of TIMI myocardial perfusion grade 3. Pro-UK, prourokinase; M-H, Mantel-Haenszel.
Meta-analysis of ST-segment resolution. Pro-UK, prourokinase; M-H, Mantel-Haenszel.
Meta-analysis of left ventricular ejection fraction.
Meta-analysis of left ventricular end-diastolic diameter.
Meta-analysis of corrected TIMI frame count.
Meta-analysis of cardiac troponin 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 |
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 | ( |
Jiang |
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 | ( |
Fu |
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 | ( |
Huang |
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 | ( |
Geng |
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 | ( |
Xiao |
Single-center | Coronary artery Disease | 33 | 38 | 62.1±15.8 | 64.9±13 | TMPG and IMR values | Cardiac functions; MACEs | Thrombus aspiration | 90 | ( |
Wang |
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 | ( |
Lin |
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 | ( |
Wang |
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 | ( |
Zhao |
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 | ( |
Han |
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 | ( |
Han |
Single-center | Cardiovascular Therapeutics | 100 | 97 | 56.8.7±9.8 | 57.1±8.9 | TIMI flow grade | MACEs; Bleeding | Anti-platelet | 365 | ( |
Zhao |
Single-center | PJCCPVD | 92 | 92 | 61.9±8.2 | 62.9±8.2 | TIMI flow grade | Myocardial necrosis markers; MACEs | Tirofiban | 60 | ( |
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.
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 |
Yes | Yes | Single-blind | Yes | Yes | Yes | 7 | ( |
Jiang |
Yes | Yes | Unclear | Yes | Yes | Yes | 6 | ( |
Fu |
Yes | Unclear | Unclear | Yes | Yes | Yes | 6 | ( |
Dong |
Yes | Yes | Single-blind | Yes | Yes | Yes | 7 | ( |
Wei |
Unclear | Unclear | Single-blind | Yes | Yes | Yes | 6 | ( |
Xiao |
Yes | Unclear | Single-blind | Yes | Yes | Yes | 7 | ( |
Wang |
No | Yes | Single-blind | Yes | Yes | Yes | 6 | ( |
Lin |
Yes | Unclear | Single-blind | Yes | Yes | Yes | 6 | ( |
Wang |
Yes | Unclear | Unclear | Yes | Yes | Yes | 6 | ( |
Zhao |
Unclear | Unclear | Unclear | Yes | Yes | Yes | 5 | ( |
Han |
Yes | No | Unclear | Yes | Yes | Yes | 6 | ( |
Han |
Yes | Yes | Single-blind | Yes | Yes | Yes | 7 | ( |
Zhao |
Yes | Unclear | Unclear | Yes | Yes | Yes | 6 | ( |