It has been unclear whether thrombolytic-related asymptomatic hemorrhagic transformation (AHT) affects the clinical outcome. To answer this question, we examined whether thrombolytic-related AHT affect short-term and long-term clinical outcome.
All data were collected from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) registry. The patients were diagnosed as having AHT group and non- hemorrhagic transformation (HT) group based on clinical and imaging data. The patients with symptomatic hemorrhagic transformation were excluded from this study. Thrombolytic-related AHT was defined according to European-Australasian Acute Stroke Study (ECASS) II criteria. 90-day functional outcome, 7-day National Institutes of Health Stroke Scale (NIHSS) score, 7-day and 90-day mortalities were compared between two groups. Logistic regression analysis was used to evaluate the effects of AHT on a short-term and long-term clinical outcome.
904 of all 1440 patients in TIMS-China registry were enrolled. 89 (9.6%) patients presented with AHT after thrombolysis within 24-36h. These patients with AHT were more likely to be elder age, cardioembolic subtype, and to have higher National Institutes of Health Stroke Scale score before thrombolysis than patients without AHT. No significant difference was found on the odds of 7-day (95% CI:0.692 (0.218–2.195), (P = 0.532) or 90-day mortalities (95% CI:0.548 (0.237–1.268), P = 0.160) and modified Rankin Score(0–1) at 90-day (95% CI:0.798 (0.460–1.386), P = 0.423) or modified Rankin Score(0–2) at 90-day (95% CI:0.732 (0.429–1.253), P = 0.116) or modified Rankin Score(5–6) at 90-day (95% CI:0.375 (0.169–1.830), P = 0.116) between two groups.
Citation: Jia W, Liao X, Pan Y, Wang Y, Cui T, Zhou L, et al. (2015) Thrombolytic-Related Asymptomatic Hemorrhagic Transformation Does Not Deteriorate Clinical Outcome: Data from TIMS in China. PLoS ONE 10(11): e0142381. https://doi.org/10.1371/journal.pone.0142381
Editor: Kandiah Jeyaseelan, National University of Singapore, SINGAPORE
Received: June 16, 2015; Accepted: October 21, 2015; Published: November 30, 2015
Copyright: © 2015 Jia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: All data necessary to replicate the study findings are available within the paper and its Supporting Information files. The data are from the Thrombolysis Implementation and Monitor of acute ischemic Stroke in China (TIMS-China) registry. Please contact Dr. Liao (firstname.lastname@example.org) for additional information.
Funding: This study was funded by the National Science and Technology, Major Project of China (2011BAI08B02 and 2006BA101A11).
Competing interests: The authors have declared that no competing interests exist.
Intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator) is the most effective therapy for acute ischemic stroke [1,2]. However, the potential increased risk of thrombolytic-related hemorrhagic transformation (HT), including Asymptomatic Hemorrhagic Transformation (AHT), limits its application [3–6]. The incidence of AHT after intravenous thrombolysis was found to be 9.9% from combined CT-based data of the NINDS rt-PA trial and the ATLANTIS trial [2,7,8]. Thrombolytic-related symptomatic HT is associated with worse functional outcome. However, it is controversial whether AHT directly leads to negative prognosis. Some studies suggest that prognosis of patients with asymptomatic HT may be innocuous; some studies confirmed that patients with AHT compared with those without HT had a negative effect on functional outcome [9–12]. Therefore, we hypothesized that thrombolytic AHT might be associated with negative neurologic recovery. The aim of this study is to identify risk factors of thrombolytic-related AHT as well as to examine the influence of AHT on short-term and long-term clinical outcome with TIMS-China registry.
Materials and Methods
All of data were collected from the Thrombolysis Implementation and Monitor of acute ischemic Stroke in China (TIMS-China) registry , a national prospective stroke registry of thrombolytic therapy with intravenous alteplase in patients with acute ischemic stroke in China. In nationwide, 67 centers participated in this stroke registry between May 2007 and April 2012. Demographics on clinical characteristics, cranial CT scans, medical therapy and thrombolysis information were collected. All patients were followed up for 3 months.
Eligible patients received intravenous thrombolysis within 4.5-hour. Patients with incomplete data and thrombolysis time window>4.5h or unknown were excluded. Patients with NIHSS score ≥25were excluded. Patients with symptomatic HT were excluded from this study. Eligible patients were divided into two groups: the AHT group, which had asymptomatic hemorrhagic transformation; and the non-HT group, which had no thrombolytic-related hemorrhagic transformation (Fig 1).
The registry of TIMS-China was approved by ethics committee of Beijing Tiantan hospital in 2006. The data from the TIMS-China registry was anonymous before access and analysis by all researchers and patient treatment was assigned and determined independent of all researchers. All patients had written informed consent before being entered in the registry.
Follow-up CT scans for patients were collected at 24–36 hours and 7-day. The diagnosis of HT on brain images was determined independently by 2 neurologists blinded to clinical data. If there was a disagreement between 2 neurologists, a third neurologist was consulted, and a consensus decision was reached. Hemorrhagic transformation must be scored according to the ECASS II classification  during all follow-up CT scans: hemorrhagic infarcts (type 1 or 2) or parenchymal hematomas (type 1 or 2). HT was also often divided into symptomatic HT and AHT groups based on the deterioration in neurologic status. AHT, according to ECASS II criteria, was defined as NIHSS score less than 4 points worsening from baseline in neurological status in the first 24 hours after thrombolysis with the presence of hemorrhagic transformation on the follow-up CT scan at 24-36h . The primary outcome measure collected included functional outcome at 90-day (functional independence was defined as a modified Rankin Scale (mRS) score of 0 to 6), NIHSS at 7-day, and mortality at 7-day and 90-day.
Results were reported as mean ± SD or the frequency of categorical variables. Pearson chi-square (χ2) test was used for comparisons of categorical variables. Continuous variables were analyzed using t test or Mann-Whitney U test. Percentage proportions of outcome events were calculated by dividing the number of events by the total number of patients. For each outcome variable, a separate multivariable logistic regression was performed. Odds ratios (ORs) with its 95% confidence intervals (CI) were calculated by using non-HT group after thrombolysis as the reference group. Two-sided values of P less than .05 were considered statistically significant. All statistical analyses were performed using SAS software version 9.3 (SAS Institute Inc, Cary, NC).
904 patients (62.8%) were enrolled from a patient population of 1440 from 67 centers across TIMS-China. Our exclusion criteria were as follows: (1) incomplete neuroimaging workups (n = 40), (2) loss to follow-up (n = 36), (3) thrombolysis time window>4.5h or unknown (n = 312), (4) symptomatic HT (n = 24), (5) Patients with severe stroke with a NIHSS score >25(n = 93). It had been reported that 89(9.6%) patients were transformed to AHT in China (Fig 1), 24 (2.5%) patients had symptomatic HT. The characteristics of the patients with AHT group and non-HT group after intravenous thrombolysis are shown in Table 1, which indicates that more patients with the history of atrial fibrillation, high NIHSS score and elderly age are with AHT after thrombolytic therapy and fewer patients with a history of transient ischemic attack are with AHT. Proportion of patients transformed with asymptomatic hemorrhage after thrombolytic therapy were as follow: HT2 subtype highest proportion (38 cases) > followed HT1 subtype (30 cases) > PH1 subtypes (15 cases) > PH2 subtypes (6 cases). NIHSS score of asymptomatic patients with hemorrhagic transformation after thrombolysis (15.56±6.61) was higher than that of the patients without bleeding transformation after thrombolysis (11.96±6.90) (P<0.001).
The proportion of poor outcome in patients with AHT was 13.48% at 3 months after a stroke onset and the patients with non-HT was 11.04%. AHT deteriorated clinical outcomes of 90-day of follow-up (mRS score (0–1 grade) and mRS score (0–2) in patients after thrombolysis when we analyze the data without any adjustment for covariates. After adjustment for baseline relevant factors, no significant difference was found on the odds of 7-day (95% CI:0.692 (0.218–2.195), (P = 0.532) or 90-day mortalities (95% CI:0.548 (0.237–1.268), P = 0.160) and modified Rankin score(0–1) at 90-day (95% CI:0.798 (0.460–1.386), P = 0.423) or modified Rankin score(0–2) at 90-day (95% CI:0.732 (0.429–1.253), P = 0.116) or modified Rankin score(5–6) at 90-day (95% CI:0.375 (0.169–1.830), P = 0.116) between two groups (Table 2). In AHT subgroup analysis, there was a more favorable clinical outcome in HI1and HI2 subgroups than PH1 and PH2 subgroups (Fig 2).
AHT: asymptomatic hemorrhagic transformation; mRS, modified Rankin Scale; HI1:hemorrhagic infarcts type 1; HI2: hemorrhagic infarcts type 2; PH1: parenchymal hematomas type 1; PH2: parenchymal hematomas type 2.
There were remarkably low rates of asymptomatic hemorrhagic transformation (4.5%)  in the National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study. A large observation study of intravenous thrombolysis, the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), also showed low rates of asymptomatic hemorrhagic transformation (9.6%) . In TIMS-China, its rate was 9.5%. However, there were higher rates of asymptomatic hemorrhage (39.6%) in the European Cooperative Acute Stroke Study (ECASS-II) . Compared with ECASS-II, the earlier initiation of thrombolysis is the possible reason for the low asymptomatic hemorrhage rates in NINDS, SITS-MOST and TIMS-China. In addition, the direct comparison of the AHT rates among different studies may be hampered by variability in definitions, the earlier initiation of thrombolysis and different image examination time [14–19]. In non-HT group, more patients had TIA history compared with AHT group, which was mainly explained by recurrent TIA increasing collateral circulation. In Asia, many hospitals choose a low-dose intravenous alteplas(IV-tPA) regimens because they believe that racial differences need to reduce dose of treatment in order to decrease rate of hemorrhage transformation. The result of J-MARS showed that 0.6 mg/kg IV-tPA achieved low rates of HT . TIMS-china registry demonstrated the standard-dose IV-tPA therapy was safe for Chinese patients with stroke, without any increased rate of HT or mortality compared with the low-dose Group . In our study, there is no difference of the dose IV-tPA between AHT group and non-HT group.
Previous some studies have shown that thrombolytic-related AHT does not have a negative effect on the short-term or long-term functional outcome. AHT after thrombolysis has a suggestive of vascular recanalization and effective treatment . Moreover, it seems to be a beneficial treatment choice that antiplatelet agents are administered for AHT patients after intravenous thrombolysis . Our novel findings are that among patients who suffered acute ischemic stroke receiving intravenous thrombolysis, the risk of poor outcome for patients with AHT was 0.375-fold at 3 months than for patients without any HT; the risk of mortality for patients with AHT was 0.548-fold at 3 months than patients without any HT. These findings show that clinical outcomes after thrombolysis do not deteriorate in the presence of AHT. Moreover, there is a favorable trend in AHT group, which may be due to improved reperfusion after thrombolysis. Conversely, some studies suggest AHT may not be benign [9,10]. A recent study showed AHT maybe have a negative effect . This differential effect may be due to the AHT populations coming from all ischemic stroke patients, while the AHT patients in our study are from ischemic stroke patients receiving intravenous thrombolysis. Additionally, the use of antiplatelet agents is not prescribed to some patients with AHT in above-mentioned study, which results in increased risk of ischemic stroke one-year recurrence. Our study suggests that elderly, cerebral embolism and higher NIHSS score increase risk of AHT. Similarly, previous studies have linked the factors to increased risk of HT [3,7,8,23,24].
Different from mechanism of symptomatic HT, we speculate that AHT may link with small artery formation rather than large artery formation. It has been showed that thrombolysis after acute ischemic infarction may lead to artery reopening and collateral circulation reperfusion6 . Moreover, the formation of collateral circulation may also improve the functional outcome. There is a favorable trend after thrombolysis-related AHT in our study supports this suggestion.
Our study may have the following limitations. (1) Our sample size was relatively small, and our data exclude severe stroke(NIHSS> or = 25), which maybe have a subtle effect (either positive or negative) of AICH outcome. (2) Another limitation is that the study did not follow the randomized, double-blind principles. Despite these limitations, our results have implications that post-thrombolytic AHT in China does have not a negative effect on clinical prognosis.
S1 Table. Description and Difference Test of Demographics between Groups
Special thanks to the physicians as well as all other personnel who dedicated themselves to the TIMS-CHINA project. We thank all participating hospitals, relevant clinicians, statistician, and imaging and laboratory technicians. The TIMS-CHINA investigators include: Yongjun Wang (Principle investigator), Beijing Tiantan Hospital; Xingquan Zhao, Beijing Tiantan Hospital; Yilong Wang, Beijing Tiantan Hospital; Xiaoling Liao, Beijing Tiantan Hospital; Chunxue Wang, Beijing Tiantan Hospital; Liping Liu, Beijing Tiantan Hospital; Chunjuan Wang, Beijing Tiantan Hospital; Yuesong Pan, Beijing Tiantan Hospital; Qi Bi, Beijing Anzhen Hospital; Liying Cui, Peking Union Medical College Hospital of Peking University; Yuheng Sun, Beijing Jishuitan Hospital; Maolin He, Beijing Shijitan Hospital; Dongsheng Fan, Peking University Third Hospital; Xiaojun Zhang, Beijing Tongren Hospital; Yansheng Li, Shanghai Renji Hospital; Shaoshi Wang, Shanghai First Municipal People’s Branch hospital; Wei Fan, Zhongshan Hospital of Fudan University; Chuancheng Ren, The Fifth People’s Hodpital of Shanghai, Fudan University; Zhenguo Liu, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University; Xiaojiang Sun, The sixth People’s Hospital Affiliated to Shanghai JiaoTong University; Xu Chen, Shanghai 8th People’s Hospital; Qingke Bai, Pudong New Area People’s Hospital; Dexiang Gu, Shanghai Yangpu Area Shidong Hospital; Chunmei Hu, Shanghai Baoshan Area Center Hospital; Xin Li, Shanghai Yangpu Area Center Hospital; Qiang Dong, Huashan Hospital of Fudan University; Yan Cheng, Tianjin Medical University Gengeal Hospital; Bin Li, Dagang Oilfield Gengeal Hospital; Chen Li,Tianjin Fifth Center Hospital; Tongyu Wang, Bohai Oilfield Hospital; Liping Wang,Ninghe County People’s Hospital of Tianjin; Kun Zhao, Baodi District People’s Hospital of Tianjin; Dingbo Tao, The First Afflicated Hospital of Dlian Medical University; Fang Qu, Dalian Second People’s hospital; Jingbo Zhang, Dalian Third People’s hospital; Jianfeng Wang, Dalian Central hospital; Ying Lian, Dalian Economic and Technological Development District Hospital; Fang Qu, Shenying Military District General hospital of Chinese People’s Liberation Army; Ying Gao, National Traditional Chinese Medicine (TCM)Thrombus Treatment Center of Liaoning Province; Huashan Sun, Jilin Chemical Industrial Group General hopital; Jinying Li, Jilin Oilfield General Hospital; Guozhong Li, The First Clinical College of Harbin Medical University; Yulan Zhu, The Second Clinical College of Harbin Medical University; Zichao Yang, The Fourth Clinical College of Harbin Medical University; Jun Zhou, Mudan Jiang Second hospital; Minxia Guo, Shaanxi Provincial People’s Hospital; Qilin Ma, The First Hospital of Xiamen; Xiaoping Gao, Hunan Provincial People’s Hospital; Renbin Huang, Chenzhou First People’s Hospital; Bo Xiao, Xiangya Hospital of Centre-south University; Kangning Chen, Southwest Hospital; Li Gao, Chengdu Third Municipal People’s Hospital; Anding Xu, The First Affiliated Hospital of Jinan University; Ming Shao, The First Affiliated Hospital of Guangzhou Medical University; En Xu, The Second Affiliated Hospital of Guangzhou Medical University; Xiaoping Pan, Guangzhou First Municipal People’s Hospital; Yefeng Cai, Guangdong Provincial Hospital of Traditional Chinese Medicine; Yun Xu, Drum Tower Hospital Affiliated to Nanjing Medical University; KaiFu Ke, The Affiliated Hospital of Nantong University; Yuenan Kong,Wuxi Second People’s Hospital; Liangcai Ding, The Third Affiliated Hospital of Suzhou University; Yibin Cao, Tangshan Gongren Hospital; Yumin Liu, Zhongnan Hospital of Wuhan University; Kang Xu, Hubei Xinhua Hospital; Chengming Xing, Qingdao Municipal Hospital Group; Shaohua Su, Dezhou People’s Hospital; Guiru Zhang, Penglai People’s Hospital; Rongyuan Zheng, The First Affiliated Hospital of Wenzhou Medical University; Ming Zhai, First People’s Hospital of Yunnan Province; Yi Zhu, The Xinjiang Autonomous Region People’s Hospital; Yuanxin Liu, Autonomous Region TCM Hospital Affiliated to Xinjiang Medical University; Xiaoying Zhang, Hospital of Xinjiang Production & Construction Corps; Shizheng Wu, Qinghai Provincial People’s Hospital; Jinfeng Liu, Yangquan Coalmine Group General hospital.
Conceived and designed the experiments: YW WJ LZ. Performed the experiments: WJ XL TC. Analyzed the data: WJ YP YW. Contributed reagents/materials/analysis tools: YP. Wrote the paper: WJ XL.
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