Hui Chen 1,2, Guangming Zhu 1, Nan Liu 1,2 and Weiwei Zhang 1

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1 Send Orders for Reprints to 62 Current Neurovascular Research, 2014, 11, Low-dose Tissue Plasminogen Activator is as Effective as Standard Tissue Plasminogen Activator Administration for the Treatment of Acute Ischemic Stroke Hui Chen 1,2, Guangming Zhu 1, Nan Liu 1,2 and Weiwei Zhang 1 1 Department of Neurology, Military General Hospital of Beijing PLA, Beijing, China 2 Third Military Medical University, Chongqing, China Abstract: We compared the efficacy of intravenous (IV) combination of low-dose tissue plasminogen activator (tpa) and urokinase (UK) versus either classical IV tpa or UK alone for acute ischemic stroke (AIS) within 4.5 h of symptom onset. One-hundred fifty-three AIS patients were treated with 1 of 3 different IV thrombolytic therapies within a 4.5-h time window. Clinical data included age, gender, type of therapy, NIHSS score, time from onset to needle, ASPECTS, mrs at 90 days, and medical history. The outcomes were NIHSS-a (the difference between NIHSS scores at admission and 24 h); NIHSS-b (difference between NIHSS scores at admission and 7 days), and mrs at 90 days. Multivariate logistic regression (MLR) was used to determine if treatments or other variables could predict these outcomes. Of 153 patients, 60.1% had a good outcome and 39.9% had a poor outcome. The most important predictors of 90-day mrs were AF history (p < 0.001) and NIHSS score at admission (p = 0.001). Age (p = 0.004) and treatment type (p = 0.043) that were also significantly associated with 90-day mrs. IV tpa yielded the best outcome, compared to low-dose tpa/uk (OR = 1.17) and UK alone (OR = 1.42). Low-dose tpa/uk also resulted in better outcome than UK alone did (OR = 1.12). We conclude that low-dose IV tpa with UK administered within a 4.5-h time window was effective and likely comparable to classical IV tpa thrombolysis. Keywords: Outcome, Stroke, Thrombolysis, Time window, Tissue-type plasminogen activator, Urokinase. INTRODUCTION Although intra-artery (IA) thrombolysis with tissue plasminogen activator (tpa) for patients with acute ischemic stroke (AIS) has been getting considerable attention in recent years [1], intravenous (IV) thrombolysis with tpa, the efficiency of which has been proven in many clinical trials, and which could be conducted even in regional hospitals, is still the first choice for AIS in China [2]. However, the percentage of IV thrombolysis with tpa in China is still low [3], and there are several reasons. First, patients with AIS are typically taken to regional medical centers initially, which are the closest hospitals; however, most of these hospitals have neither tpa nor enough experience with the thrombolytic procedure. Moreover, even if patients are eventually transferred to downtown medical centers, which can conduct IV or IA thrombolysis with tpa, this usually happens beyond the thrombolysis time window. According to our records, only 56 patients with AIS have met the IV thrombolysis criterion of a 3-h time window in 3 years. However, if we could extend the time window to 4.5 h, the number would have been 198. Some studies have demonstrated the safety and efficacy of the 4.5-h time window for IV thrombolysis [4-6]. *Address correspondence to this author at the Professor of Neurology, Department of Neurology, Military General Hospital of Beijing PLA, 5 Nanmencang, Dongsi, Beijing , China; Phone: ; Fax: ; zhangvivian@vip.sina.com Received: September 25, 2013 Revised: November 18, 2013 Accepted: November 20, 2013 The second reason for the low use of this procedure is that the cost of tpa is too high to be affordable for many patients in China, especially in developing areas [3]. Even in metropolitan districts, such as Beijing and Shanghai, the cost of 50 mg tpa may be equal to 2 3 months wages for downtown residents, and even more for those living in the countryside. Some previous studies conducted in Korea have demonstrated the safety and efficacy of urokinase (UK). According to a study, the administration of IV UK within 24 h resulted in a significant improvement in the National Institutes of Health Stroke Scale (NIHSS) score [7]. The price of UK is also reasonable [3] and, therefore, most hospitals prefer to stock UK rather than 50 mg tpa, especially since the latter may expire before being used. Sometimes, hospitals prefer to use 20 mg tpa for IV or IA thrombolysis, because some studies in China and Japan have reported that the optimal dose of tpa is lower for Asian patients with acute myocardial infarction or AIS than for Caucasian patients [8]. In view of the above, we have developed an eclectic therapy consisting of IV thrombolysis with low dose tpa/uk administered within 4.5 h of onset, which could be used in more patients at a more affordable price, and evaluated its outcome. The goal of our study was to compare the outcomes of different IV thrombolytic therapies administered within the extended time window of 4.5 h. In particular, we wanted to determine: (a) whether IV thrombolysis with low dose tpa/uk could be an alternative for Chinese AIS candidates; (b) the safety and efficacy of this therapy /14 $ Bentham Science Publishers

2 Low-dose Tissue Plasminogen Activator is as Effective Current Neurovascular Research, 2014, Vol. 11, No MATERIALS AND METHODS Patients All patients gave their written informed consent, and the study protocols were approved by the institutional ethics review boards of the Military General Hospital of Beijing PLA. We identified all consecutive patients admitted to the Military General Hospital of Beijing PLA from January 2005 to December 2011 with signs and symptoms suggesting hemispheric stroke and who met the following inclusion criteria: 1) acute ischemic stroke in the region of the anterior circulation; 2) age from 18 to 80 years; 3) time from onset to needle within 4.5 h; 4) NIHSS on admission between 4 and 22; and 5) non-contrast computed tomography (NCCT) on admission showing no evidence of intracranial hemorrhage or significant early ischemic change (affecting more than one-third of the middle cerebral artery territory); 6) informed consents obtained from the patient or his/her legal representative. The exclusion criteria were same as in a previous study by the NINDS [9]: 1) another stroke or serious head trauma within the preceding 3 months; 2) major surgery within 14 days; 3) history of intracranial hemorrhage; 4) systolic blood pressure above 185 mmhg or diastolic blood pressure above 110 mmhg; 5) rapidly improving or minor symptoms; 6) symptoms suggestive of subarachnoid hemorrhage; 7) gastrointestinal hemorrhage or urinary tract hemorrhage within the previous 21 days; 8) arterial puncture at a noncompressible site within the previous 7 days; 9) a seizure at the onset of stroke. We also excluded patients in a comatose state and patients with gaze palsy, because gaze palsy is an important sign of cortical infarct that has a high risk for bleeding complications. The following demographic and clinical variables were recorded: age, gender, type of therapy, and time from onset to needle; blood pressure; glucose and lipid levels in the blood; NIHSS score at admission and 24 h and 7 days after admission; Alberta Stroke Program Early CT Score (ASPECTS) in NCCT; and modified Rankin Score (mrs) at 90 days (by clinical visit or over phone). Symptomatic intracranial hemorrhage (sich) within 36 h and medical history such as hypertension, diabetes, hyperlipidemia, atrial fibrillation, and cardiovascular disease were also recorded. Consent Protocol An emergency stroke team chose the candidates who needed thrombolysis. They obtained informed consent from these patients or their legal representatives, who would make the final decision. The individual mentioned in this manuscript has given written informed consent to divulge details of the case. The consent form included all of the following information: 1) treatment choices: no thrombolysis, IV UK alone, IV low-dose tpa with UK, IV tpa (0.9 mg/kg), and IA thrombolysis; 2) IV tpa (0.9 mg/kg) is the most popular treatment for AIS in most developed countries; 3) tpa is the only thrombolytic agent approved by the Food and Drug Administration (FDA) 4) IV UK has been shown to be effective by the findings of Chinese studies [3] but not by the international studies; 5) different methods may lead to different outcomes, different possibilities of sich, and different costs of treatment; 6) Some studies have proved the advantage of IA thrombolysis over IV; 7) if necessary (i.e., IV thrombolysis cannot prevent the deterioration), IA thrombolysis may be used as a backup; 8) no matter which therapy is chosen, patients would be treated equally. Patients who received IA thrombolysis were not included in the final analysis because IA thrombolysis could affect the accuracy of data analysis. Due to the low number of patients (only 9 cases) who did not perform thrombolysis, we also had to exclude those patients who did not receive thrombolytic therapy as revealed from our database. However, all cases were recorded. Treatment Protocol Thrombolysis with 0.9 mg/kg tpa (tpa group): patients received IV tpa (Actilyse; Boehringer Ingelheim, Germany) at a dose of 0.9 mg/kg (maximum, 90 mg). Ten percent of tpa was given as a bolus, followed by delivery of the remaining 90% as a constant infusion over 1 h. Thrombolysis with low-dose tpa and UK (tpa/uk group): The total dose of tpa was 20 mg. Bolus was the same as before. The remaining was administered as a constant infusion over 30 min. For example, if the weight of the patient was 60 kg, the bolus would be 5.4 mg (60 kg 0.9 mg/kg 10%) and the remaining would be 14.6 mg (20 mg 5.4 mg). The UK (Luoxin; Temple Biochemical Pharmaceutical Company, China) was administered intravenously with 0.3 mega-units over 3 h. Thrombolysis with UK alone (UK group): 2 unit/kg UK (maximum 1.5 mega-units) was administered intravenously over 1 h at a constant infusion rate without a bolus. Definitions of Outcomes Short-term outcome was defined as the difference in NIHSS score between baseline and follow-up. There were 2 short-term outcomes: NIHSS-a, defined as the difference between NIHSS scores at admission and 24 h; NIHSS-b, defined as the difference between NIHSS scores at admission and 7 days. Improvement was defined as NIHSS > 2, and decline as NIHSS 2. Long-term outcome was defined as the mrs at 90 days. A good was considered when an mrs at 90 days was 2 points. Poor outcome was defined as mrs > 2 points. Statistical Analysis Descriptive statistics: Continuous scaled data (e.g., age, time from onset to needle, DBP, SBP) were summarized by the mean ± SD and by the range of the measurement distribution. Frequency data (e.g., gender and mrs) were summarized by counts and percentages. Multivariate logistic regression (MLR) was used to determine if different treatments would lead to different outcomes. A binary variable, Y, which divided the patients into 2 groups according to whether the patient had a good outcome (i.e., Y = 1 if mrs = 0 2) or a poor outcome (i.e., Y = 0 if mrs > 2), represented the dependent variable (i.e., outcome variable) in the MLR analysis. The same procedures were followed for NIHSS-a and b. The following regression model predictor variables were included: demographics, NIHSS at admission, time from onset to needle, ASPECTS in baseline, medical history, treatment type, admission BP, and glucose. The hypothesis testing procedure was

3 64 Current Neurovascular Research, 2014, Vol. 11, No. 1 Chen et al. Fig. (1). The grouped status of the patients screened. conducted by likelihood ratio (LR) tests to determine if any of the aforementioned variables were uniquely associated with the clinical outcome. Calculations were performed using SAS (Version 9.1; SAS Institute, Cary, NC) statistical software package. A p value < 0.05 was considered as statistically significant. RESULTS Patient Population We identified 198 patients with AIS matching our inclusion and exclusion criteria. Thirty-one patients were excluded in the first step. Seventeen of them received IA thrombolysis as the initial therapy, 9 refused or withdrew the consents, and 5 were not eligible because of other reasons. After the IV thrombolysis procedure, 4 patients with tpa, 7 with low-dose tpa/uk, and 3 with UK alone received IA thrombolysis. These 14 patients were also excluded. Only 153 of 198 patients were included in our final analytical database (Fig. 1). PREDICTION OF LONG-TERM OUTCOME Female patients, 70/153 (45.8%); mean age 63.3 years; range, years. Average time from onset to needle was 1.9 ± 2.2 h and range, h. Mean NIHSS score at admission was 14.8 ± 5.4 and range, Forty out of 153 (26.2%) received tpa (0.9 mg/kg) IV thrombolysis, 62/153 (40.6%) with low-dose tpa/uk, and 51/153 (33.3%) with UK only. Other clinical characteristics such as medical history and ASPECTS were also reported (Table 1). Of all 153 patients, 92 (60.1%) had good outcome and 61 (39.9%) had poor outcome. Age (p = 0.004), admission NIHSS (p = 0.001), AF history (p < 0.001), and treatment type (p = 0.043) were significantly associated with 90-day mrs outcome. DM was only marginally associated with outcome (p = 0.055). None of the other variables such as gender (p = 0.218), time from onset to needle (p = 0.310), and admission ASPECTS (p = 0.587) could predict 90-day mrs outcome. The most important predictors were AF history (p < 0.001) and NIHSS score at admission (p = 0.001) (Table 1). Different therapies of IV thrombolysis led to different outcomes. IV tpa thrombolysis had the best outcome, compared to low-dose tpa/uk (OR = 1.17, 95% CI from 0.86 to 1.57) and UK (OR = 1.42, 95% CI from 1.06 to 2.11). Low-dose tpa/uk also had better outcome than UK alone (OR = 1.12, 95% CI from 0.92 to 1.43). All adjusted odds ratios for the significant predictor variables are provided in Table 2.

4 Low-dose Tissue Plasminogen Activator is as Effective Current Neurovascular Research, 2014, Vol. 11, No Table 1. Association Between 90-Day mrs and Admission Variables. Variables Total n = 153 Patients with 90-day mrs 0-2 n = 92 Patients with 90-day mrs > 2 n = 61 LR-Statistic p Age (years) 63.3 ± ± ± Female (%) 70(45.8%) 43(46.7%) 27(44.3%) Medical History Hypertension 107(69.9%) 65(70.1%) 42(68.8%) Diabetes 63(41.2%) 36(39.1%) 27(44.3%) Hyperlipidemia 79(51.6%) 47(51.1%) 32(52.4%) Atrial fibrillation 25(16.3%) 11(11.9%) 14(23.0%) <0.001 CAD 59(38.6%) 35(38.0%) 24(39.3%) Admission BP SBP (mmhg) 171 ± ± ± DBP (mmhg) 86 ± ± ± Admission Glucose (mmol/l) 10.2 ± ± ± Average time from onset to needle (h) 1.9 ± ± ± Admission NIHSS 14.8 ± ± ± Admission ASPECTS 8.0 ± ± ± Treatment type tpa 40(26.2%) 23(57.5%) 17(45.5%) Low dose tpa/uk 62(40.5%) 33(53.2%) 29(46.8%) UK 51(33.3%) 24(47.1%) 27(52.9%) Certain values are represented as mean ± SD. CAD: Cardiovascular disease; BP: Blood pressure; SBP: Systolic blood pressure; DBP: Diastolic blood pressure p represents the statistical significance of comparisons between groups. Table 2. Adjusted Odds Ratios Related to the Predictor Variables Determined to be Uniquely Associated with Patient Outcome in 90-day mrs. Variable Ratio Estimated Adjusted Odds Ratio [95% CI] Age X*:X [ ] Admission NIHSS X:X [ ] DM None:Yes 1.13 [ ] AF None:Yes 6.58 [ ] Treatment tpa:low-dose tpa/uk 1.17 [ ] tpa:uk 1.42 [ ] Low-dose tpa/uk:uk 1.12 [ ] X denotes the value of the predictor variable (e.g., Age = 60 years:65 years). PREDICTION OF SHORT-TERM OUTCOME Of the 40 patients who received IV tpa thrombolysis, average NIHSS at admission was 15.0 ± 7.2, and 3 (7.5%) had sich within 36 h. The average NIHSS score at admission for those with low-dose tpa/uk was 12.2 ± 9.3, and 2 patients had sich within 36 h. The average NIHSS score at admission was 17.8 ± 6.2 in patients treated with UK alone, and 3 had sich within 36 h. The different treatment modalities had no impact on both NIHSS-a and NIHSS-b, though the percentage of decline in patients in the UK group (49.0% and 39.2%) was higher than the other 2 groups (Table 3). The only variable that could predict the change in NIHSS score was NIHSS score at admission (p < 0.001). DISCUSSION Because of significant advances in the neuroimaging techniques over the last decade, the concept of time is brain [10, 11] in stroke reperfusion treatment has been challenged by the concepts of pathophysiology is brain [12] and

5 66 Current Neurovascular Research, 2014, Vol. 11, No. 1 Chen et al. Table 3. Treatment Type and the Changes of NIHSS. Treatment Type tpa (0.9 mg/kg) (n = 40) Low-dose tpa/uk (n = 62) UK alone (n = 51) Admission NIHSS 15.0 ± ± ± 6.2 sich in 36 h 3(7.5%) 2(3.2%) 3(5.9%) NIHSS-a Improved 17(42.5%) 26(41.9%) 20(39.2%) Declined 23(57.5%) 36(58.1%) 31(60.8%) NIHSS-b Improved 27(67.5%) 39(62.9%) 28(54.9%) Declined 13(32.5%) 18(27.1%) 20(45.1%) NIHSS-a: NIHSS baseline-nihss 24 h; NIHSS-b: NIHSS baseline-nihss 7 days; Improved: NIHSS > 2; Declined: NIHSS 2 imaging is brain [13]. Furthermore, recent studies have already demonstrated the advantages of IA thrombolysis over IV [14]. However, unfortunately, the percentage of stroke patients receiving thrombolysis in China is still minimal, although most of them are initially administered with IV UK alone guided by NCCT without the help of any multimodal neuroimaging technique [8]. The main reasons for this are the relatively exorbitant cost of tpa as compared to UK, limited time window, and poor medical conditions in the developing areas. We developed a new method of IV thrombolysis because the European Cooperative Acute Stroke Study (ECASS)-III showed evidence of the efficacy of thrombolysis for up to 4.5 h within stroke occurrence [4], the tpa bolus might play a key role in IV thrombolysis, and Chinese studies had demonstrated the efficacy of UK [15]. This method is characterized by the following: 1) the same bolus as 0.9 mg/kg tpa IV thrombolysis; 2) total dose of 20 mg tpa; 3) the bolus is followed by a mega-units of IV UK to serve as an anticoagulant; 4) an extended time window of 4.5 h. If this strategy becomes successful, the number of AIS candidates who could meet inclusion criteria might increase by 3 times. According to our study, this new method (low-dose IV tpa/uk) has benefits within 4.5 h of the onset of symptoms. Although it is still not as effective as classical IV thrombolysis, it has advantages over UK alone. The rate of sich in our study was acceptable and did not differ significantly from the 2 other thrombolysis methods (Table 3). Low-dose IV tpa/uk could also be used as a bridging therapy followed by IA thrombolysis [16]. Combined IV/IA treatment is feasible and provides better recanalization [17]. The time window in IA thrombolysis is up to 6 h, whereas in IV it is h [18-20]. The gap between the 2 time windows is critical. When eligible patients with AIS arrive within 4.5 h, we can administer low-dose IV tpa/uk and simultaneously prepare for the procedure of IA. This helps prevent excessive dosing of tpa and minimize the occurrence of sich. We did not include any IA thrombolysis data in this study because: 1) The main goal of our study was to find a feasible way to perform IV thrombolysis for more candidates who were initially admitted to regional or countryside hospitals within the specified time window, but were beyond of the time window when transferred to a downtown medical center. 2) IV thrombolysis, which could be performed in the emergency room (ER), was always the first step in our center. If no favorable effects were observed, IA would follow as a backup [21]; however, the outcomes might be totally different. 3) Furthermore, the agents that are used in the IA procedure can be UK or tpa, and the doses are also variable. In view of the above, we excluded all cases with IA thrombolysis, but still recorded the numbers in each group. We did not use a placebo group as control because: 1) it would have been unethical not using the thrombolytic treatment for the appropriate patients, since tpa was shown to be effective and used worldwide [22, 23]; 2) most patients consented to one of the thrombolytic procedures. In the past 5 years only 9 cases refused or withdrew any active treatment, which would have been too few to be used as a control group. Most Chinese regional hospitals can perform NCCT and diffusion-weighted magnetic resonance imaging (DW MRI), but it is still impossible to get vascular imaging in the ER [3]. Since we tried to find a way that could be used in these hospitals, we also decided not to use advanced imaging for the selection of potential candidates. As a single-center pilot study, which was neither random nor double-blind, it had several limitations. Though we tried to minimize patient selection biases in our center, clinical decisions are always influenced by patients and their legal representatives. The economic conditions might also influence not only the choice of the treatments, but also the prognosis. The exclusion of combining IV with IA might have resulted in the exclusion of more severe cases from our study. Due to the absence of advanced imaging at admission, such as vascular or perfusion imaging, we could not get precise information about the salvaged tissue and recanalization. Some of the patients did not have DWI at admission; therefore, we could not use the increasing infarct volume as an outcome [24, 25].

6 Low-dose Tissue Plasminogen Activator is as Effective Current Neurovascular Research, 2014, Vol. 11, No CONCLUSION Our study has demonstrated that low-dose IV tpa with UK administered within a 4.5-h time window is effective and possibly comparable to the classical IV tpa thrombolysis method. It can be used in patients with AIS in China who would have otherwise been excluded due to economic or medical reasons. CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest. ACKNOWLEDGEMENTS We thank Guolu Zhang for collecting and recording the data. REFERENCE [1] Park H, Hwang GJ, Jin SC, Bang JS, Oh CW, Kwon OK. Intraarterial thrombolysis using double devices: mechanicomechanical or chemicomechanical techniques. J Korean Neurosurg Soc 2012; 51(2): [2] Pan SM, Liu JF, Liu M, et al. Efficacy and Safety of a Modified Intravenous Recombinant Tissue Plasminogen Activator Regimen in Chinese Patients with Acute Ischemic Stroke. 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