| ObjectivesTo investigate the efficacy and safety of low-dose urokinase in the treatment of progressive ischemic stroke(PIS),and to further investigate the factors influencing the poor outcome of PIS,in order to provide a reference for the treatment of PIS.MethodsThis paper includes two parts:a previous retrospective study and a prospective randomized controlled study.In the first part,a retrospective cohort study design was used to include patients with PIS who were hospitalized at Shandong Provincial Qianfoshan Hospital from January 2018 to January 2021,and patients were divided into urokinase and control groups according to whether they received low-dose urokinase treatment.To analyze the efficacy of low-dose urokinase on PIS,and compare the differences in the efficacy of different doses of urokinase for PIS.In the second part,an open,randomized controlled clinical trial design was used to include patients with PIS who met the nadir criteria admitted to Shandong Provincial Qianfoshan Hospital and Zaozhuang City Central District People’s Hospital from May 2021 to March 2022,and the patients were randomly divided into a test group(urokinase+standard treatment)and a control group(standard treatment)using a stratified blocked randomization.The standard treatment used in the control group consisted mainly of dual antiplatelet aggregation,improvement of circulation,scavenging of oxygen free radicals,lipid lowering,blood pressure management,blood glucose control,and rehabilitation training.The test group was treated with urokinase within 24 hours of stroke progression in addition to the standard treatment.Urokinase was administered at a dose of 0.75 million U/kg/d,up to a total dose of 750,000 U,pumped intravenously at 150,000 U/hour,lasting for 3 days.The Efficacy was determined according to the neurological deficit score and clinical efficacy assessment criteria,using the effective rates within 7 days post treatment as the primary efficacy index,the modified Rankin Scale(mRS)score 90 days post treatment as the secondary efficacy index,and symptomatic intracranial hemorrhage,severe bleeding in other systems within 7 days post treatment and death within 90 days post treatment as the safety index.The differences in the distribution of efficacy and safety indicators between the test and control groups after treatment were examined to assess the efficacy and safety of the treatment method in the test group.Results1.Results of retrospective study:(1)Total 129 patients were included in the retrospective study,including 76 in the urokinase group and 53 in the control group.No statistical difference in baseline information between the two groups.(2)The differences in NIHSS scores before treatment between the two groups were not statistically significant,and the NIHSS scores at discharge were lower in the urokinase group than in the control group(4.88±2.88 vs 6.30±3.87,P=0.026),with statistically significant differences.(3)The overall effective rate at discharge was higher in the urokinase group than in the control group(71.05%vs 43.40%,P=0.002),with statistically significant differences.(4)There was no statistically significant difference in the efficiency of different dose groups of urokinase.In the urokinase group,the effective rate was higher in the 0.66～0.85 million U/kg/d group than in the control group(77.27%vs 43.40%,P=0.007),with statistically significant differences;and the differences in effective rates between the 0.25～0.45 million U/kg/d group and the 0.46～0.65 million U/kg/d group and the control group were not statistically significant.2.Results of prospective study:(1)Total 60 patients were included in the prospective part of the study,including 31 patients in the test group and 29 patients in the control group.No statistical difference in baseline information between the two groups.(2)There were no significant differences between the test and control groups in NIHSS scores at 24 hours,48 hours,72 hours and 7 days post treatment,but the NIHSS scores improvements at 24 hours,48 hours,72 hours and 7 days post treatment in the test group were greater than those in the control group,with statistically significant differences(Ps<0.05).(3)The test group had a significantly higher effective rate at 24 hours(22.58%vs.3.45%,P=0.029)and 7 days(77.42%vs 31.03%,P<0.001)post treatment than those of the control group;the differences in effective rates between the two groups were not statistically significant at 48 hours and 72 hours post treatment(4)The mRS at 90 days post treatment was lower in the test group than in the control group[2.00(2.00,3.00)vs 3.00(2.00,4.00),P=0.042],21 patients(67.74%)in the test group had a favorable outcome and 10 patients(34.48%)in the control group had a favorable outcome,the difference was statistically significant(P=0.019).(5)The NIHSS scores increased by 3.76±2.40 and 3.74±2.24 within 72 hours in patients with anterior circulation infarction and posterior circulation infarction,respectively,the difference was not statistically significant;the time from stroke onset to progression was 28.81±18.85(h)and 43.57±18.90(h)in patients with anterior circulation infarction and posterior circulation infarction,respectively,with statistically significant differences(P=0.005).(6)The interaction of urokinase treatment with variables such as sex,age,stroke history,baseline mRS,time from stroke onset to progression,degree of neurological deterioration,and stroke infarct type was not significant(P value for interaction>0.05).(7)Binary logistic regression analysis showed that history of diabetes(P=0.003,OR:11.376,95%CI:2.276～56.858)was independently negatively associated with treatment outcomes and urokinase treatment was independently positively associated with treatment outcomes(P=0.005,OR:0.102,95%CI:0.021～0.494).(8)No symptomatic intracranial hemorrhage within 7 days of treatment and no death within 90 days occurred in either group.Within 7 days of treatment,one patient in the test group had upper gastrointestinal bleeding,and two patients had black stools;one patient in the control group had black stools.The incidence of serious adverse events was not statistically different between the two groups(P=0.355).Conclusion1.The retrospective study showed that the addition of low-dose urokinase intravenous thrombolytic therapy improved the neurological functions and increased the therapeutic efficiency in patients with PIS compared with conventional treatment.Conventional treatment combined with 0.66～0.85 million U/kg/d urokinase treatment showed significant efficacy advantages over conventional treatment alone.2.The prospective studies showed that(1)Standard therapy combined with low-dose urokinase therapy improves the effective rates of patients with PIS at 24 hours and 7 days post treatment;(2)Standard therapy combined with low-dose urokinase therapy improves independent living ability and treatment outcomes of patients with PIS at 90 days post treatment;(3)Stroke progression occurs earlier in patients with anterior circulation infarction than in patients with posterior circulation infarction;(4)A history of diabetes may be an independent risk factor for poor outcomes in PIS;(5)low-dose urokinase treatment of PIS does not increase the risk of symptomatic intracranial hemorrhage,other systemic serious bleeding and fatal events and has a good safety profile. |
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