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This study explored 1-year follow-up of Parmaco-invasive strategy with half-dose recombinant human prourokinase (PHDP) in patients with acute ST-segment elevation myocardial infarction (STEMI). The follow-up endpoints were major adverse cardiovascular events (MACEs) occurring within 30 days and 1 year, as well as postoperative bleeding events. The study ultimately included 150 subjects, with 75 in the primary percutaneous coronary intervention (PPCI) group and 75 in the PHDP group. This study found that the PHDP group had a shorter FMC-reperfusion time (42.00 min vs 96.00 min, P < 0.001). During PCI, the PHDP group had a lower percutaneous transluminal coronary angioplasty (PTCA) (P = 0.021), intropin (P = 0.002) and tirofiban (P < 0.001) use. And the incidence of intraoperative arrhythmia, malignant arrhythmia, and slow flow/no-reflow was lower in the PHDP group (P < 0.001). At the 30-day follow-up, there was a significantly higher proportion of patients in the PPCI group who were readmitted due to unstable angina (P = 0.037). After 1 year of follow-up, there was no statistically significant difference in MACEs between the two groups (P = 0.500). The incidence of postoperative major bleeding, intracranial bleeding, and minor bleeding did not differ between the PHDP and PPCI groups (P > 0.05). The PHDP facilitates early treatment of infarct-related vessels, shortens FMC-reperfusion time, and does not increase the risk of MACEs.

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BACKGROUND: Recombinant prourokinase (rhPro-UK) is a specific plasmin activator, which has been approved to treat acute myocardial infarction in China. AIM: This phase 3 trial aimed to further demonstrate the efficacy and safety of rhPro-UK in patients with acute ischemic stroke (AIS) within 4.5 h of symptom onset. METHODS AND DESIGN: RhPro-UK in AIS within 4.5 h of stroke onset trial-2 (PROST-2) is a multicenter, prospective randomized, open-label, blinded end-point, non-inferiority, recombinant tissue plasmin activator (rt-PA)-controlled, phase 3 trial. A total of 1552 patients who are eligible for intravenous thrombolytic therapy from 72 clinical sites will be randomly assigned to receive either rhPro-UK 35 mg (15 mg bolus + 20 mg infusion/30 min) or rt-PA 0.9 mg/kg (10% bolus + 90% infusion/1 h). STUDY OUTCOMES: The primary outcome is the proportion of patients with a modified Rankin Scale (mRS) score of 0-1 at 90 days. Secondary efficacy outcomes include the proportion of patients with mRS score of 0-2, the distribution of mRS, self-care ability in daily life on the Barthel Index at 90 days, the proportion of subjects with ⩾ 4 points decrease in National Institutes of Health Stroke Scale (NIHSS) score or NIHSS score ⩽ 1 from baseline at 24 h and 7 days after treatment. Safety outcomes are symptomatic intracranial hemorrhage (sICH) and major systematic bleeding within 7 days as well as death from all causes within 90 days. DISCUSSION: The results from the PROST-2 trial will comprehensively elucidate the efficacy and safety profile of rhPro-UK as a potential alternative agent for stroke thrombolysis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT05700591.

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BACKGROUND: The efficacy and safety of low-pressure balloon pre-dilatation before intracoronary pro-urokinase (pro-UK) in preventing no-reflow during percutaneous coronary intervention (PCI) remains unknown. This study aimed to evaluate the clinical outcomes of intracoronary pro-UK combined with low-pressure balloon pre-dilatation in patients with anterior ST-segment-elevation myocardial infarction (STEMI). METHODS: This was a randomized, single-blind, investigator-initiated trial that included 179 patients diagnosed with acute anterior STEMI. All patients were eligible for PCI and were randomized into two groups: intracoronary pro-UK combined with (ICPpD group, n = 90) or without (ICP group, n = 89) low-pressure balloon pre-dilatation. The main efficacy endpoint was complete epicardial and myocardial reperfusion. The safety endpoints were major adverse cardiovascular events (MACEs), which were analyzed at 12 months follow-up. RESULTS: Patients in the ICPpD group presented significantly higher TIMI myocardial perfusion grade 3 (TMPG3) compared to those in the ICP group (77.78% versus 68.54%, P = 0.013), and STR ≥ 70% after PCI 30 min (34.44% versus 26.97%, P = 0.047) or after PCI 90 min (40.0% versus 31.46%, P = 0.044). MACEs occurred in 23 patients (25.56%) in the ICPpD group and in 32 patients (35.96%) in the ICP group. There was no difference in hemorrhagic complications during hospitalization between the groups. CONCLUSION: Patients with acute anterior STEMI presented more complete epicardial and myocardial reperfusion with adjunctive low-pressure balloon pre-dilatation before intracoronary pro-UK during PCI. TRIAL REGISTRATION: 2019xkj213.

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The synergistic advantage of combining tissue plasminogen activator (tPA) with pro-urokinase (proUK) for thrombolysis has been demonstrated in several in vitro experiments, and a single site proUK mutant (m-proUK) has been developed for better stability in plasma. Based on these studies, combination thrombolytic therapy with intravenous tPA and m-proUK has been suggested as a promising treatment for patients with ischemic stroke. This paper evaluates the efficacy and safety of the dual therapy by computational simulations of pharmacokinetics and pharmacodynamics coupled with a local fibrinolysis model. Seven dose regimens are simulated and compared with the standard intravenous tPA monotherapy. Our simulation results provide more insights into the complementary reaction mechanisms of tPA and m-proUK during clot lysis and demonstrate that the dual therapy can achieve a similar recanalization time (about 50 min) to tPA monotherapy, while keeping the circulating fibrinogen level within a normal range. Specifically, our results show that for all dual therapies with a 5 mg tPA bolus, the plasma concentration of fibrinogen remains stable at around 7.5 µM after a slow depletion over 50 min, whereas a rapid depletion of circulating fibrinogen (to 5 µM) is observed with the standard tPA therapy, indicating the potential advantage of dual therapy in reducing the risk of intracranial hemorrhage. Through simulations of varying dose combinations, it has been found that increasing tPA bolus can significantly affect fibrinogen level but only moderately improves recanalization time. Conversely, m-proUK doses and infusion duration exhibit a mild impact on fibrinogen level but significantly affect recanalization time. Therefore, future optimization of dose regimen should focus on limiting the tPA bolus while adjusting m-proUK dosage and infusion rate. Such adjustments could potentially maximize the therapeutic advantages of this combination therapy for ischemic stroke treatment.

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This study investigated the efficacy and safety of pharmaco-invasive strategy with half-dose recombinant human prourokinase (PHDP) during hospitalization for patients with ST-segment elevation myocardial infarction (STEMI) to provide references for the treatment of STEMI. Patients with STEMI who fulfilled the inclusion and exclusion criteria and attended Chengde Central Hospital, Hebei Province, China, between September 3, 2019, and December 28, 2021, were included in this study. The experimental group received PHDP and the control group underwent primary percutaneous coronary intervention (PPCI). This study enrolled 150 patients with STEMI, 75 in the experimental group and 75 in the control group. Coronary angiography revealed successful thrombolysis in 64 (85.33%) patients. Compared with the control group, the experimental group had shorter first medical contact-reperfusion time (P < 0.001), less slow flow/no-reflow (P < 0.001), and a lower utilization rate of Tirofiban (P < 0.001). Validity endpoints: no statistically significant differences between the two groups. Safety endpoints: no statistically significant differences between bleeding and major adverse cardiovascular and cerebrovascular events (MACCEs), but the experimental group was more prone to arrhythmias (P = 0.040), particularly premature ventricular beats (PVB) (P = 0.008). In conclusion, the efficacy and safety of PHDP in the treatment of patients with STEMI were positive. Complete epicardial and myocardial reperfusion rates, risk for bleeding during hospitalization, and incidence of MACCEs were similar to those of the PPCI strategy. Although the PHDP group has a higher incidence of PVB, it does not increase the incidence of malignant arrhythmia. This study aimed to provide a new therapeutic strategy for the treatment of STEMI in hospitals without adequate PPCI resources condition.

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BACKGROUND AND PURPOSE: Recombinant human prourokinase (rhPro-UK) is a new generation of specific plasminogen activator, that is non-inferior to alteplase in acute ischemic stroke. We aimed to investigate the efficacy and safety of rhPro-UK compared with standard medical treatment in acute mild ischemic stroke within 4.5 hours of symptom onset. METHODS AND DESIGN: Prourokinase in mild ischemic stroke is a multicentre, prospective, randomised, open-label, blinded-endpoint controlled trial. Patients who had an acute ischemic stroke within 4.5 hours from symptom onset and with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤ 5 will be recruited. Patients will be randomly assigned (1:1) to receive intravenous rhPro-UK (35 mg) or standard medical treatment. The follow-up duration will be 90 days. The calculated sample size is 1446. STUDY OUTCOMES: Primary efficacy outcome is an excellent functional outcome, defined as a modified Rankin Scale (mRS) score ≤ 1 at 90 days. Secondary efficacy outcomes include ordinal distribution of mRS at 90 days, mRS score ≤ 2 at 90 days, early neurological improvement at 24 hours (a decrease of NIHSS score ≥ 4 points compared with baseline or NIHSS score ≤ 1 point), Barthel index of 75-100 points at 90 days, quality of life at 90 days, and activities of daily living at 90 days. Safety outcomes are symptomatic intracranial haemorrhage within 36 hours, mortality at 90 days, moderate and severe systematic bleeding at 90 days, and adverse events/serious adverse events within 90 days. DISCUSSION: This large phase III randomised clinical trial will answer the question of whether thrombolysis is beneficial for acute mild ischemic stroke, and may provide evidence for rhPro-UK in patients had an acute mild ischemic stroke within 4.5 hours of symptom onset. TRIAL REGISTRATION NUMBER: NCT05507645.

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Objective:To investigate the effect of different administration methods of recombinant human prourokinase (rhPro-UK) during emergency percutaneous coronary intervention (PCI) on myocardial perfusion and prognosis of patients with acute ST segment elevation myocardial infarction (STEMI).Methods:The clinical data of 132 patients with STEMI who underwent emergency PCI in the Military Hospital of the 71st Army Group of the Chinese People′s Liberation Army from August 2017 to August 2022 were analyzed retrospectively. Among them, 66 patients treated with rhPro-UK injection after the guide wire passed through the coronary artery lesion, balloon dilation and stent placement were included in group A. The other 66 patients treated with rhPro-UK injection once after the guide wire passed through the coronary artery lesion were included in group B. The two groups were compared in terms of PCI conditions, target vessel perfusion status [corrected TIMI frame count (CTFC) and blood flow (thrombolysis in myocardial infarction, TIMI) grade], myocardial perfusion status [TIMI myocardial perfusion grade (TMPG), ST segment regression rate (STR) at 90 min after operation and the incidence of no reflow/slow flow (NR/SF)], cardiac function indicators [left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV) and left ventricular ejection fraction (LVEF)], the incidence of major adverse cardiovascular events (MACE), and the incidence of bleeding events.Results:There were no statistically significant differences between the two groups in terms of the distribution of culprit blood vessels, intubation methods, and number of stents implanted ( P>0.05). After treatment, the proportion of TIMI blood flow grade 3 in the group A was higher than that in the group B:99.97% (64/66) vs. 87.88% (58/66). CTFC of the two tgroups decreased, and CTFC of group A was lower than that of group B: (23.49 ± 4.27) frames vs. (27.14 ± 4.83) frames ( P<0.05). The proportion of TMPG grade 3 in group A was significantly higher than that in group B: 95.45% (63/66) vs. 83.33% (55/66)( P<0.05). STR in group A was significantly higher than that in group B: 95.45% (63/66) vs. 83.33% (55/66)( P<0.05). The incidence of NR/SF in group A was lower than that in group B: 3.03% (2/66) vs. 14.29% (10/66)( P<0.05). There were no statistically significant differences in LVEDV or LVESV between the two groups before and after treatment ( P>0.05). After 1 month of treatment, LVEF of the two groups increased, and LVEF of group A was higher than that of group B: (71.08 ± 6.38) % vs. (66.24 ± 6.49) % ( P<0.05). After treatment, the incidence of MACE in group A was lower than that in group B: 6.06%(4/66) vs. 13.64%(9/66) ( χ2 = 2.13, P = 0.144). There was no statistically significant difference in the incidence of bleeding events between the two groups ( P>0.05). Conclusions:For patients with STEMI undergoing PCI, fractional injection of rhPro-UK can better improve myocardial perfusion, reduce the incidence of MACE, and effectively improve the prognosis, compared with one-time injection of rhPro-UK.

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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.

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OBJECTIVE: To evaluate the efficacy and safety of low-dose prourokinase (pro-UK) administration during primary percutaneous coronary intervention (PCI) for the treatment of acute ST-segment elevation myocardial infarction (STEMI) in patients with a high thrombus burden. METHODS: A prospective, randomized controlled trial was conducted at the Inner Mongolia People's Hospital, China. Patients with STEMI and a high thrombus burden who underwent thrombus aspiration and primary PCI were randomly allocated to pro-UK administration or control groups. The primary endpoint was corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC). RESULTS: There were no significant differences in the baseline demographics or clinical characteristics of the two groups. The CTFC, tissue myocardial perfusion grade, ST-segment resolution, and myocardial blush grade of the pro-UK group were significantly better than those of the control group. In addition, after 30 days of follow-up, the pro-UK group had better cardiac function and perfusion than the control group. There were no differences in the clinical outcomes or incidence of hemorrhage. CONCLUSIONS: Intracoronary low-dose pro-UK improves myocardial perfusion and cardiac function in patients with a high thrombus burden. Major hemorrhages still occur in patients administered pro-UK, but are no more frequent.Study registration: Chinese Clinical Trial Registry (ChiCTR1900022290).

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BACKGROUND: The effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not deplete fibrinogen and lyses fibrin only after induction with alteplase. Therefore, this treatment has the potential to be safer and more efficacious than treatment with alteplase alone. The aim of this study is to assess the safety and efficacy of thrombolytic treatment consisting of a small bolus alteplase followed by m-proUK compared with standard thrombolytic treatment with alteplase in patients presenting with ischemic stroke. METHODS: DUMAS is a multicenter, phase II trial with a prospective randomized open-label blinded end-point (PROBE) design, and an adaptive design for dose optimization. Patients with ischemic stroke, who meet the criteria for treatment with intravenous (IV) alteplase can be included. Patients eligible for endovascular thrombectomy are excluded. Patients are randomly assigned (1:1) to receive a bolus of IV alteplase (5mg) followed by a continuous IV infusion of m-proUK (40 mg/h during 60 min) or usual care with alteplase (0.9 mg/kg). Depending on the results of interim analyses, the dose of m-proUK may be revised to a lower dose (30 mg/h during 60 min) or a higher dose (50 mg/h during 60 min). We aim to include 200 patients with a final diagnosis of ischemic stroke. The primary outcome is any post-intervention intracranial hemorrhage (ICH) on neuroimaging at 24 h according to the Heidelberg Bleeding Classification, analyzed with binary logistic regression. Efficacy outcomes include stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) at 24 h and 5-7 days, score on the modified Rankin scale (mRS) assessed at 30 days, change (pre-treatment vs. post-treatment) in abnormal perfusion volume, and blood biomarkers of thrombolysis at 24 h. Secondary safety endpoints include symptomatic intracranial hemorrhage, death, and major extracranial hemorrhage. This trial will use a deferred consent procedure. DISCUSSION: When dual thrombolytic therapy with a small bolus alteplase and m-proUK shows the anticipated effect on the outcome, this will lead to a 13% absolute reduction in the occurrence of ICH in patients with ischemic stroke. TRIAL REGISTRATION: NL7409 (November 26, 2018)/NCT04256473 (February 5, 2020).

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Recombinant human prourokinase (rhPro-UK) is a novel thrombolytic that has been approved to treat patients with acute myocardial infarction. However, the safety and efficacy of intravenous rhPro-UK in patients with acute ischemic stroke (AIS) has not been well established. We aimed to investigate the safety and preliminary efficacy of rhPro-UK in patients with AIS in a multi-center phase IIa trial setting. One hundred nineteen patients within 4.5 h of AIS onset were enrolled in this randomized, open-label, 23-center phase IIa clinical trial. Patients were randomly assigned to 35 mg (n = 40) or 50 mg (n = 39) intravenous rhPro-UK or 0.9 mg/kg recombinant tissue plasminogen activator (r-tPA; n = 40). The primary endpoint was functional independence defined as a modified Rankin scale (mRS) score of 0 or 1 at 90 days. The secondary outcome was early neurological improvement defined as a reduction of ≥ 4 points on the National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 h after drug administration. Safety endpoints included death due to any cause, symptomatic intracerebral hemorrhage (sICH), and other serious adverse events (SAEs). The proportion of patients with an mRS score of ≤ 1 at 90 days did not differ significantly among three groups (35 mg rhPro-UK: 55.56% vs. 50 mg rhPro-UK: 57.89% vs. vs. r-tPA: 52.63%; P = 0.92). The rates of treatment response, referring to early neurological improvement, were similar among these three groups (36.11% vs. 31.58% vs. 28.95%, respectively; P = 0.85). There was no difference in mortality at 90 days or in the rate of other SAEs among the three groups. One patient in the 50 mg rhPro-UK group suffered sICH. While neither the primary efficacy outcomes nor safety profile differed significantly among the low, high rhPro-UK and control groups, it is a logical step to further test the low-dose rhPro-UK group versus the control group in a well-powered phase III study.Trial Registration: http://www.chictr.org.cn . Identifier: ChiCTR1800016519. Date of registration: June 6 2018.

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BACKGROUND: Prourokinase is a single-chain plasminogen activator presenting with fewer hemorrhagic complications and reduced reocclusion rate compared with the conventional fibrinolytic agents in patients with coronary artery disease. However, prourokinase intracoronary injection during PCI for treating patients with ST-segment elevation myocardial infarction (STEMI) is rarely investigated. Therefore, this study aimed to evaluate the efficacy and safety of intracoronary prourokinase during the percutaneous coronary intervention (PCI) in treating STEMI patients. METHODS: Fifty STEMI patients who underwent primary PCI were consecutively enrolled and randomly assigned to intracoronary prourokinase group (N = 25) or control group (N = 25). During the primary PCI procedure, patients in the intracoronary prourokinase group received 10 ml prourokinase injection, while patients in control group received 10 ml saline injection as control. The primary endpoints were coronary physiological indexes, the secondary endpoints were angiographic assessments, myocardial infarct size/reperfusion assessment, cardiac function evaluations, major adverse coronary events (MACEs) and hemorrhagic complications. All patients were followed up for 3 months. RESULTS: Post PCI, the index of microcirculatory resistance (IMR) was decreased in intracoronary prourokinase group than that in control group (34.56 ± 7.48 vs. 49.00 ± 8.98, P < 0.001), while no difference of coronary flow reserve (CFR) (2.01 ± 0.32 vs. 1.88 ± 0.23, P = 0.267) or fractional flow reserve (FFR) (0.89 ± 0.05 vs. 0.87 ± 0.04, P = 0.121) was found between the two groups. The thrombolysis in myocardial infarction myocardial perfusion grade (TMPG) (P = 0.024), peak values of creatine kinase (CK) (P = 0.028), CK isoenzyme-MB (CK-MB) (P = 0.016), cardiac troponin I (cTnI) (P = 0.032) and complete ST-segment resolution (STR) (P = 0.005) were better in intracoronary prourokinase group compared with control group. At 3-months post PCI, left ventricular ejection fraction (LVEF) and wall motion score index (WMSI) were higher, while left ventricular end-diastolic diameter (LVEDd) was lower in intracoronary prourokinase group compared with control group (all P < 0.05). There was no difference in hemorrhagic complication or total MACE between the two groups. CONCLUSION: Intracoronary prourokinase during PCI is more efficient and equally tolerant compared with PCI alone in treating STEMI patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800016207 . Prospectively registered.

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