A comparison of rt-PA thrombolysis guidelines between China and the USA: are changes needed? Jing Xu1, Yongjin Zhang1, Hongyu Wei2, Yan Xu1, Min Wang1, Zenglin Cai1, Xiaomin Li3 1
Department of Neurology, Affiliated Lianyungang Hospital of Xuzhou Medical College, China, 2Department of Neurosurgery, Second People’s Hospital of Lianyungang, China, 3Emergency Department, Affiliated Lianyungang Hospital of Xuzhou Medical College, China Background and purpose: Thrombolytic treatment criteria vary significantly between China and the USA. We reviewed current intravenous (IV) thrombolytic therapy practices in China and the USA to determine the most appropriate. Methods: We conducted a systematic review of studies that used IV recombinant tissue plasminogen activator (rt-PA) therapy in China and the USA published between January 1950 and April 2012. Results: Literature search identified 17 American and 9 Chinese studies with a total of 2545 subjects. We found a significantly lower mortality rate in the US data compared with China (8% versus 13%; Chi-square 5 24.412, P , 0.001). Our meta-regression analysis uncovered significant factors influencing mortality including male sex, hypertension, high cholesterol, smoking, and onset to treatment time (all P , 0.05). There were significantly more favorable outcomes in China than in the USA (61% versus 49%, Chi-square 5 19.159, P , 0.001). No prior history of stroke and shorter onset to IV time were also significantly associated with a favorable outcome (P , 0.05). Conclusions: Onset to IV time is critical for reducing mortality and improving favorable outcomes. We suggest Chinese acute ischemic stroke treatment guidelines be revised to include an increase in the age limit of 80 years, removing contraindications such as a history of previous sever heart, liver, and kidney dysfunction, and placing more emphasis on physician expertise.
Keywords: Intravenous thrombolysis, Acute ischemic stroke (AIS), Recombinant tissue plasminogen activator (rt-PA, alteplase), Meta-analysis
Introduction Acute ischemic stroke has a high rate of morbidity and mortality, with a serious impact on human health. Approximately 80–90% of acute ischemic strokes are caused by blood clots in cerebral arteries. Early recanalization of occluded cerebral blood vessels in ischemic tissue can prevent necrosis and restore normal blood supply.1 Tissue-type plasminogen activator thrombolytic therapy within 3 hours of onset is currently the only drug protocol approved by the US Food and Drug Administration for acute ischemic stroke treatment.2 The Paul Coverdell National Stroke Thrombolysis Register reported that the proportion of thrombolytic ratio fluctuated between 3.8% and 8.5% among US states.3 This is consistent with data from other foreign communities
Correspondence to: Z. L. Cai, Department of Neurology, Affiliated Lianyungang Hospital of Xuzhou Medical College, Lianyungang 222002, China. Email: [email protected]
ß W. S. Maney & Son Ltd 2015 DOI 10.1179/1743132814Y.0000000415
and multi-center reports showing thrombolysis proportion at approximately 8%.3 The China National Stroke Registry research suggests approximately one in five patients with stroke presenting within 3 hours received thrombolytic therapy. In China, the onsetto-needle time, door-to-needle time, and especially imaging-to-needle time were significantly longer than those in developed countries.4 This study offers a systematic evaluation of the current practices of thrombolytic therapy comparing China and the USA. Our findings suggest the need to update current practices in Chinese guidelines for acute ischemic stroke treatment.
Materials and Methods Search strategy and study criteria We identified all observational studies that reported recanalization or clinical outcomes in acute ischemic stroke patients treated by intravenous (IV) recombinant tissue plasminogen activator (rt-PA). We searched PubMed MEDLINE, China National Knowledge
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Information (CNKI), and Chinese Wan Fang databases for articles published between January 1950 and April 2012 using the following combination of terms and their corresponding terms in Chinese: thrombolysis, thrombolytic, fibrinolysis, tissue plasminogen activator, intravenous, and stroke. Searches were restricted to studies published in English or Chinese and conducted in humans. Title and abstract review of all searched articles was completed by two of the authors (ZYJ, XJ). Full reports were independently reviewed by two of the authors (ZYJ, CZL) to include the articles for the meta-analysis. We also searched the reference lists to ensure efficiency of the search. Studies that met each of the following criteria were considered eligible: (1) involved acute ischemic stroke patients aged 18 years or older; (2) reported numbers, or percentages of recanalization or clinical outcomes in acute ischemic stroke patients treated by IV rt-PA; (3) retrospective or prospective studies with §20 patients treated by rt-PA; (4) study location within China or the USA; and (5) published in English or Chinese. Exclusion criteria were: (1) clinical application of other thrombolytic agents such as urokinase or streptokinase; (2) patients treated by IV thrombolysis combined with IA approach or other neurointerventional treatment; or (3) those from non-original studies. If a study was reported in duplicate, the English version or earliest publication date was included in our analysis. Conflicts regarding eligibility were resolved through consensus.
Data abstraction We used the following strategies to search various databases: report characteristics (first author’s name, journal, year of publication); study design (country, study period, number of centers, retrospective/prospective analysis, IV agents, and dose); study sample [sample size, age, sex, admission National Institutes of Health Stroke Scale (NIHSS), time from symptom onset to IV treatment); and data on and definitions of outcomes [recanalization, favorable functional outcome, mortality, symptomatic intracranial hemorrhage (sICH)]. Clinical outcomes included a favorable functional outcome, mortality, and sICH. The preferred
definition was a modified Rankin score of 0–2 at 30–90 days for favorable functional outcome, death at 90 days for mortality outcome, and hemorrhage on the follow-up CT/MRI scan associated with an increase of §4 points in NIHSS score for sICH outcome. When the preferred definition was not available, the authors’ definition was adopted.
Statistical analysis We organized the literature, checked the data in accordance with the requirements of meta-analysis, and used Stata 12 software for statistical analysis. Studies included in this study were given quality assessment and qualitative systematic review. We analyzed factors including spontaneous intracerebral hemorrhage (SICH), mortality rate, and rate of patients with favorable outcome (modified Rankin Scale #2 follow-up after 1–3 months). Subgroup analyses were conducted on the differences between China and the United States in SICH rate, mortality rate, and rate of favorable outcome. The Peto Mantel–Haenszel fixedeffect model was used when studies showed no significant heterogeneity; the Dersimonian–Laird random effects model was used in cases of significant heterogeneity. If the number of included studies was sufficiently large, funnel plot analysis was used to test for the existence of publication bias. After the literature search, existing factors affecting result selectively were removed and subgroup meta-analysis was used to analyze the effects of different factors on the results. Because SICH rates, mortality and favorable outcomes are not distributed normally, logarithmic conversion was used, and meta-analysis for each subgroup was conducted. The impact of other factors was determined by meta-regression analysis. Statistical analysis was conducted using the twotailed level of 0.05. MATLAB6.5 software was used for graphics.
Results Search results Our literature search identified 1326 papers derived from PubMed, PaperszMaster’s and PhD thesesz
Table 1 Indicators from the USA, China, and combined study data Past history High Male Hyper- Atrial Dia- choleAverage ratio Stroke tension fibrillation betes sterol Smoking Base Sample age (%) (%) (%) (%) (%) (%) (%) NIHSS USA 1898 China 647 Total 2545
69.16 65.04 68.53
54 59 56
15 17 15
65 61 64
23 27 25
20 17 19
26 18 22
22 42 23
14.03 15.28 14.31
Time from Mortality Favorable onset to SICH rate outcome IV (minute) (%) (%) (%) 141.97 180
15 6 9
8 13 13
49 61 53
Note: The average onset to treatment time in the USA was 141.97 minutes; study from Wang et al.4 was single Chinese report of 180 minutes.
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Figure 1 Forest plots of SICH rates from the USA and Chinese studies. Note: owing to that the heterogeneity of the overall merger Q-test has P value less than 0.1, there is heterogeneity, thus using a random effects model to merge. Z-test showed significance (P , 0.01) after the USA and China data were merged according to the state subgroup analyses. The incidence of SICH between the USA and China has no significant differences. Chi-square 5 1.210, P 5 0.271 (df 5 1).
Conference Papers in CNKI databases: 109z15z 10 articles; PaperszMaster’s and PhD thesesz Conference Papers in Chinese Wanfang databases: 298z89z16 articles. After initial review of these titles and abstracts, and exclusion of duplicate studies we identified 17 USA-based5–21 and 9 China-based studies4,22–29 eligible for analysis. Meta-analysis of rates of SICH, mortality, and favorable outcomes We used meta-analysis to merge all analysis indicators, with the resulting values shown in Table 1. We found that the combined overall Q-test confirmed study heterogeneity. We used a random effects model to merge the data. There was no significant difference in SICH rates between the USA and China (Chisquare 5 1.210, P 5 0.271, df 5 1). We found no evidence of publication bias in the USA published literature using the Egger’s test (P . 0.05). However,
publications from China did show publication bias (P , 0.05). The combined USA and Chinese data did not contain publication bias (P . 0.05). For metaanalysis of mortality, Q-test results showed heterogeneity was significant (P , 0.1); a random effects model was used to merge data. National subgroup analysis showed that each combined Z-test of the USA and China was significant (P , 0.01), and the overall merger was meaningful (P , 0.001) (Fig. 1). In addition, differences in mortality between the two countries was significant (Chi-square 5 24.412, P , 0.001, df 5 1). Both USA and Chinese published literature did not show publication bias (P . 0.05). An Egger’s test showed combined USA and China data showed publication bias (P , 0.01). Meta-analysis of favorable outcome The overall favorable outcome Q-test showed heterogeneity (P , 0.1). Again, we merged data with a
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Figure 2 Forest plots of favorable outcomes from the USA and Chinese studies. Note: owing to that the heterogeneity of the overall merger Q-test has P value less than 0.1, there is heterogeneity, so using a random effects model to merge. Z-test showed significance (P , 0.01) after the USA and China data were merged according to the state subgroup analyses. The favorable outcome between the USA and China has significant differences. Chi-square 5 19.159, P , 0.001 (df 5 1).
Table 2 Meta-regression analysis associated with mortality Regression coefficient
95% CI
Standard coefficient
T
P
30.645 20.120 0.049 20.002 20.210 231.924 286.622 23.053 24.576 3.989 224.329 263.036 20.025 0.262
24.927–66.217 20.344–0.104 20.042–0.140 20.013–0.008 20.449–0.029 247.903–215.945 2202.460–29.217 7.404–38.702 220.413–11.261 220.155–28.133 239.621–29.036 2109.881–216.191 20.250–0.201 0.145–0.379
20.100 0.093 20.038 20.184 20.450 20.769 0.305 20.078 0.069 20.438 21.314 20.017 0.378
1.896 21.182 1.185 20.495 21.932 24.397 21.646 3.242 20.636 0.364 23.502 22.962 20.242 4.937
0.085 0.262 0.261 0.631 0.080 0.001** 0.128 0.008** 0.538 0.723 0.005** 0.013* 0.813 0.000**
Duration Centers Sample Mean age Male ratio stroke Hypertension Atrial fibrillation Diabetes Hyperlipidemia Smoking Mean baseline NIHSS Onset to IV time Note: *P , 0.05; **P , 0.01.
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random effects model. National subgroup analysis showed significance in each combined Z-test of the USA and China (P , 0.01), with an overall meaningful merger (P , 0.001) (Fig. 2). We found significant differences in favorable outcome between the two countries (Chi-square 5 19.159, P , 0.001, df 5 1). Our data also show publication bias in both the USA (P , 0.05) and China (P , 0.01). Further, data from an Egger’s test showed publication bias in the combined data (P , 0.01). Regression results associated with mortality and favorable outcome Meta-regression analysis of the influencing factors (hypertension, male ratio, high cholesterol, smoking, and onset to treatment time) was all significantly related to mortality (all P , 0.05) (Table 2). Analysis of influencing factors shows that previous history of stroke and onset to IV time was significantly related to favorable outcome (regression coefficients: 184.162 and 0.651, T values 2.211 and 2.582, respectively, all P , 0.05) (Table 3).
Discussion The global burden from stroke has gradually increased in recent years. However, after years of being the third leading cause of death, it has recently dropped to the fourth in the USA.30 Patients with acute stroke older than 85 years show a differential clinical profile, a different frequency of stroke subtypes, and a poorer outcome compared with stroke patients who were younger than 85 years.31 The primary reason for success is improvements in acute stroke treatment within the first hours of treatment.30 In contrast to the US trend, stroke has replaced heart disease as the leading cause of death in China.32 Indeed, the number of deaths every year due to stroke has risen to nearly 1.6 million, with medical treatment expenses eclipsing 40 billion each year.32 The rising incidence and high morbidity have imposed a heavy burden on the Chinese healthcare system.4,33–35
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rt-PA (alteplase) was approved in North America in 1996 for treating acute ischemic stroke. Protocol recommendations were based heavily on the clinical trial findings by the National Institute of Neurological Disorders and Stroke, showing optimal results when administered within 3 hours.2 IV rt-PA treatment for acute ischemic stroke was approved in 2001 by the State Food and Drug Administration of China. A Cochrane systematic review of thrombolysis with IV rt-PA for acute ischemic stroke showed that treatment was associated with a significant improvement in neurological outcome.36 Further data have shown that the earlier the IV rt-PA is given, the greater the chance of a favorable outcome.37 However, while the reported usage rate of IV rt-PA ranged from 1.2% to 9% in other countries, China’s thrombolytic therapy rate was only 1.6%.4 In our literature review of studies that used IV rtPA thrombolytic therapy alone for acute ischemic stroke since 1995, we found no significant difference in SICH rate between the USA and China (Chisquare 5 1.210, P 5 0.271). In addition, we found significant differences in mortality (the combined ratio for the USA 8%, China 13%) between the two countries (Chi-square 5 24.412, P , 0.001). The meta-regression analysis of influencing factors including male ratio, hypertension, high cholesterol, smoking, and onset to treatment time was significantly related to mortality (all P , 0.05, Table 2). Interestingly, the average onset to treatment time in USA was 141.97 minutes, compared to a single time point of 180 minutes noted in Wang et al. Moreover, we show favorable outcome rate between the two countries differed significantly (Chi-square 5 19.159, P, 0.001). Both of the factors, history of stroke and onset to IV time, were significantly related to favorable outcome rate (all P , 0.05) (Table 3). In support of improving China’s therapeutic practices, it is important to point out major differences in IV rt-PA thrombolytic therapy between China and the USA. First, the proportion of patients
Table 3 Meta-regression analysis associated with favorable outcome
Duration Centers Sample Mean age Male ratio Stroke Hypertension Atrial fibrillation Diabetes Hyperlipidemia Smoking Mean baseline NIHSS Onset to IV time
Regression coefficient
95% CI
Standard coefficient
T
P
256.559 20.048 0.034 20.021 20.565 0.404 184.162 51.027 237.692 22.744 238.017 63.836 20.384 0.651
2162.290–49.172 21.261–1.166 20.426–0.494 20.070–0.029 21.394–0.265 266.270–67.079 2.702–365.622 234.350–136.405 2104.547–29.162 253.120–98.608 284.050–8.015 215.831–143.503 21.363–0.595 0.102–1.200
20.010 0.020 20.114 20.238 0.002 0.496 0.207 20.250 0.126 20.246 0.363 20.099 0.333
21.166 20.085 0.162 20.911 21.484 0.013 2.211 1.302 21.228 0.653 21.799 1.746 20.855 2.582
0.266 0.933 0.874 0.380 0.164 0.990 0.047* 0.217 0.243 0.526 0.097 0.106 0.409 0.024*
Note: *P , 0.05.
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receiving rt-PA within the treatment time window varied between 3.8% and 8.5% in the USA,3 compared with only 2.4% in China.4 Second, the average age of patients was 69.16 years in the USA, which was higher than China’s average of 65.04 years. In addition, there are many reports of US patients older than 80 years given IV thrombolysis, which is a rarity in China. Third, the average time from onset to treatment was 141.97 minutes in the USA, far below the single report of 180 minutes from Wang et al.4 in China. Fourth, it is surprising that favorable outcome rates in China are higher than the USA. Perhaps the reason is a lower average age of patients in China, or a lack of rigor in Chinese research literature. At any rate, it is worthy of further exploration. We believe that IV thrombolysis in China can be improved given the following reasons. First, the Chinese stroke treatment network lacks sophisticated connectivity, which is demonstrated nicely by US institutions. Chinese hospital treatment units tend to be independent, without two-way referral mechanisms among departments and divisions. Second, China has not established a system for remote stroke (TELESTROKE) or remote medication (TELEME DICINE). Many Chinese patients reach the hospital after the critical 3-hour treatment window. For some that do arrive in time, many hospitals lack appropriate resources to properly treat. Third, comprehensive clinical training of the thrombolytic process is lacking. Doctors tend to lack confidence in the protocol and fear thrombolysis may cause excessive bleeding. Fourth, most hospitals lack emergency multi-mode imaging evaluation tools, reducing the implementation rate of IV thrombolysis. Fifth, China suffers from a general lack of public health education regarding early signs of stroke and the importance of thrombolysis on a healthy prognosis. Sixth, rt-PA thrombolytic treatment is expensive. Many cities and rural areas do not offer cost reimbursement, leaving most patients unable to cover the high cost. Finally, and we believe the most important point, the official Chinese guide of IV thrombolysis contains significant differences compared to the US protocol that severely limits patient prognosis. Therefore, we offer our study findings as evidence to update thrombolytic therapy guidelines in China in order to reduce mortality and morbidity. We suggest an expansion of medical insurance coverage for rt-PA therapy. Given that secondary hospital physicians tend to lack experience in IV thrombolysis, we need to strengthen the training of doctors, and equip them with access to thrombolytic drugs. Furthermore, health administrative departments can look to the USA as a model for remote stroke and remote pharmaceutical systems. Finally, we offer some detailed suggestions for modifying the Chinese acute ischemic stroke treatment
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guidelines. First, the 2010 guidelines strictly limits treatment to patients aged .18 years to ,80 years regardless of patient health status. Perhaps treatment guidelines can be modified to allow a well-trained and responsible physician to decide according to the patient’s physical condition. Second, according to indication C, treatment is prescribed if ‘signs of brain dysfunction persists over 1 hr, and appear more serious’. A useful definition of ‘serious’ is missing from the guidelines. Does it refer to an NIHSS score greater than two points, or greater than four points? Clear explanations should be given, or it should be modified to ‘Diagnosis of ischemic stroke causing measurable neurological deficit’ similar to the Guidelines for the Early Management of Patients with Acute Ischemic Stroke.30 Third, China Guidelines 2010 state ‘Contraindications C: serious heart, liver, or kidney dysfunction’. How should a physician determine whether the patient has a serious heart, liver, or kidney dysfunction? Confirming tests will extend the critical treatment window. A possible modification is to define a ‘History of previous severe heart, liver and kidney dysfunction’. Fourth, China Guidelines 2010 reads ‘Contraindications C: severe diabetes’. Again, how can a physician confirm severe diabetes within the treatment time window? Finally, Chinese acute ischemic stroke treatment guidelines must emphasize a physician’s role and their clinical experience to allow ‘A physician with expertise in acute stroke care to modify this list’.30 We acknowledge that our study has several potential limitations. First, compared with English publications, the quality of Chinese medical publications tends to lack academic rigor, negatively affecting analysis results. Second, we analyzed various non-randomized observational studies in which heterogeneity in the quality of data may be a problem, and may be subject to undetected bias. Third, because of the limitations of meta-regression analysis on aggregated data, the impact of influencing factors on mortality and favorable outcome rate should be interpreted cautiously, and should be replicated using the original data.
Conclusions The use of IV rt-PA thrombolysis treatment for acute stroke patients in China is much lower compared with the USA. Several reasons for a lower proportion of treatment include a lack of public awareness about rtPA availability and success rate, high treatment costs, lack of resources, and few quality trained physicians to properly administer the protocol. We urge the Chinese government and health authorities to improve acute ischemic stroke thrombolysis guidelines using the US system as a quality reference to support the overarching goal of improving patient care.
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Disclaimer Statements Contributors All authors have read and approved the submitted manuscript. The manuscript has not been submitted or published elsewhere in whole or in part. All authors have read and approved the manuscript. Funding This project was supported by the Jiangsu Health International Exchange Program, the natural science foundation of Jiangsu Province, the Jiangsu Province Postdoctoral Research Funding, the ‘333 highlevel personnel training project’ of Jiangsu Province, the ‘Revitalization Plan’ of Xuzhou Medical College, and the ‘Key Medical Personnel Project’ of Lianyungang City. Conflicts of interest None. Ethics approval This study was approved by the Xuzhou Medical College Ethics Committee.
Acknowledgements We thank David C. Tong for his help in the CPMC Comprehensive Stroke Care Center. We also thank Dr Austin Cape for careful reading and insightful suggestions.
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14 Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology. 2002;59:862–7. 15 Akins PT, Delemos C, Wentworth D, Byer J, Schorer SJ, Atkinson RP. Can emergency department physicians safely and effectively initiate thrombolysis for acute ischemic stroke. Neurology. 2000;55:1801–5. 16 Egan R, Lutsep HL, Clark WM, Quinn J, Kearns K, Lockfeld A, et al. Open label tissue plasminogen activator for stroke: the Oregon experience. J Stroke Cerebrovasc Dis. 1999;8:287–90. 17 Mateen FJ, Nasser M, Spencer BR, Freeman WD, Shuaib A, Demaerschalk BM, et al. Outcomes of intravenous tissue plasminogen activator for acute ischemic stroke in patients aged 90 years or older. Mayo Clin Proc. 2009;84:334–8. 18 Pervez MA, Silva G, Masrur S, Betensky RA, Furie KL, Hidalgo R, et al. Remote supervision of IV-tPA for acute ischemic stroke by telemedicine or telephone before transfer to a regional stroke center is feasible and safe. Stroke. 2010;41:e18–24. 19 Asimos AW, Norton HJ, Price MF, Cheek WM. Therapeutic yield and outcomes of a community teaching hospital code stroke protocol. Acad Emerg Med. 2004;11:361–70. 20 Katzan IL, Furlan AJ, Lloyd LE, Frank JI, Harper DL, Hinchey JA, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA. 2000;283:1151–8. 21 Hassan AE, Hassanzadeh B, Tohidi V, Kirmani JF. Very mild stroke patients benefit from intravenous tissue plasminogen activator without increase of intracranial hemorrhage. South Med J. 2010;103:398–402. 22 Zhang B, Sun XJ, Ju CH. Thrombolysis with alteplase 4.5– 6 hours after acute ischemic stroke. Eur Neurol. 2011;65:170–4. 23 Zhang YD. Study of individualized treatment under the guide of perfusion MR in the patients with infarction within 9 hours of symptom onset [dissertation]. Fuzhou: Fujian Medical University; 2008. 24 Jing FY, Zhang ZC. The observation of rt-PA thrombolytic therapy in 60 cases with ultra-early acute cerebral infarction. J Apoplexy Nerv Dis. 2010;27:745–6. 25 Li JY, Wu Y, Xu MY. Alteplase thrombolytic therapy of 63 cases with ultra-early cerebral infarction. J Chin Physician. 2008;10:1412–3. 26 Zhan YH. Study on the treatment of intravenous and intraarterial thrombolysis with rt-PA in patients with acute cerebral infarction under the guide of Multimodal MRI [dissertation]. Fuzhou: Fujian Medical University; 2009. 27 Zhang B. Thrombolysis for the acute ischemic stroke [dissertation]. Shanghai: Shanghai Jiaotong University; 2008. 28 Huang H, Yang Y, Pan XP, Cheng QS, Deng WH, Zhou J. Comparative study of treatment for acute cerebral infarction of internal carotid artery system with intraarterial and intravenous thrombolysis. Chin J Neuromed. 2010;7:711–4. 29 Shao ZQ, Jiao JS, Xue S, Gui DC. Clinical application of intravenous thrombolytic therapy of recombinant tissue plasminogen activator for super-early stage of cerebral infarction. Clin Med China. 2006;10:873–5. 30 Jauch EC, Saver JL, Adams HP, Jr, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:870–947. 31 Arboix A, Garcia-Eroles L, Massons J, Oliveres M, Targa C. Acute stroke in very old people: clinical features and predictors of in-hospital mortality. J Am Geriatr Soc. 2000;48:36–41. 32 Jiang Y, Li XY, Hu N, Huang ZJ, Wu F. [Epidemiologic characteristics of cerebrovascular disease mortality in China, 2004– 2005]. Zhonghua Yu Fang Yi Xue Za Zhi. 2010;44:293–7. 33 Liu M, Wu B, Wang WZ, Lee LM, Zhang SH, Kong LZ. Stroke in China: epidemiology, prevention, and management strategies. Lancet Neurol. 2007;6:456–64. 34 Wang YL, Wu D, Liao X, Zhang W, Zhao X, Wang YJ. Burden of stroke in China. Int J Stroke. 2007;2:211–3. 35 Liu L, Wang D, Wong KS, Wang Y. Stroke and stroke care in China: huge burden, significant workload, and a national priority. Stroke. 2011;42:3651–4. 36 Wardlaw JM, Murray V, Berge E, Del ZGJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2009;(4):CD000213. 37 Lees KR, Bluhmki E, von KR, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375:1695–703.
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Department of Neurology, Affiliated Lianyungang Hospital of Xuzhou Medical College, China, 2Department of Neurosurgery, Second People’s Hospital of Lianyungang, China, 3Emergency Department, Affiliated Lianyungang Hospital of Xuzhou Medical College, China Background and purpose: Thrombolytic treatment criteria vary significantly between China and the USA. We reviewed current intravenous (IV) thrombolytic therapy practices in China and the USA to determine the most appropriate. Methods: We conducted a systematic review of studies that used IV recombinant tissue plasminogen activator (rt-PA) therapy in China and the USA published between January 1950 and April 2012. Results: Literature search identified 17 American and 9 Chinese studies with a total of 2545 subjects. We found a significantly lower mortality rate in the US data compared with China (8% versus 13%; Chi-square 5 24.412, P , 0.001). Our meta-regression analysis uncovered significant factors influencing mortality including male sex, hypertension, high cholesterol, smoking, and onset to treatment time (all P , 0.05). There were significantly more favorable outcomes in China than in the USA (61% versus 49%, Chi-square 5 19.159, P , 0.001). No prior history of stroke and shorter onset to IV time were also significantly associated with a favorable outcome (P , 0.05). Conclusions: Onset to IV time is critical for reducing mortality and improving favorable outcomes. We suggest Chinese acute ischemic stroke treatment guidelines be revised to include an increase in the age limit of 80 years, removing contraindications such as a history of previous sever heart, liver, and kidney dysfunction, and placing more emphasis on physician expertise.
Keywords: Intravenous thrombolysis, Acute ischemic stroke (AIS), Recombinant tissue plasminogen activator (rt-PA, alteplase), Meta-analysis
Introduction Acute ischemic stroke has a high rate of morbidity and mortality, with a serious impact on human health. Approximately 80–90% of acute ischemic strokes are caused by blood clots in cerebral arteries. Early recanalization of occluded cerebral blood vessels in ischemic tissue can prevent necrosis and restore normal blood supply.1 Tissue-type plasminogen activator thrombolytic therapy within 3 hours of onset is currently the only drug protocol approved by the US Food and Drug Administration for acute ischemic stroke treatment.2 The Paul Coverdell National Stroke Thrombolysis Register reported that the proportion of thrombolytic ratio fluctuated between 3.8% and 8.5% among US states.3 This is consistent with data from other foreign communities
Correspondence to: Z. L. Cai, Department of Neurology, Affiliated Lianyungang Hospital of Xuzhou Medical College, Lianyungang 222002, China. Email: [email protected]
ß W. S. Maney & Son Ltd 2015 DOI 10.1179/1743132814Y.0000000415
and multi-center reports showing thrombolysis proportion at approximately 8%.3 The China National Stroke Registry research suggests approximately one in five patients with stroke presenting within 3 hours received thrombolytic therapy. In China, the onsetto-needle time, door-to-needle time, and especially imaging-to-needle time were significantly longer than those in developed countries.4 This study offers a systematic evaluation of the current practices of thrombolytic therapy comparing China and the USA. Our findings suggest the need to update current practices in Chinese guidelines for acute ischemic stroke treatment.
Materials and Methods Search strategy and study criteria We identified all observational studies that reported recanalization or clinical outcomes in acute ischemic stroke patients treated by intravenous (IV) recombinant tissue plasminogen activator (rt-PA). We searched PubMed MEDLINE, China National Knowledge
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Information (CNKI), and Chinese Wan Fang databases for articles published between January 1950 and April 2012 using the following combination of terms and their corresponding terms in Chinese: thrombolysis, thrombolytic, fibrinolysis, tissue plasminogen activator, intravenous, and stroke. Searches were restricted to studies published in English or Chinese and conducted in humans. Title and abstract review of all searched articles was completed by two of the authors (ZYJ, XJ). Full reports were independently reviewed by two of the authors (ZYJ, CZL) to include the articles for the meta-analysis. We also searched the reference lists to ensure efficiency of the search. Studies that met each of the following criteria were considered eligible: (1) involved acute ischemic stroke patients aged 18 years or older; (2) reported numbers, or percentages of recanalization or clinical outcomes in acute ischemic stroke patients treated by IV rt-PA; (3) retrospective or prospective studies with §20 patients treated by rt-PA; (4) study location within China or the USA; and (5) published in English or Chinese. Exclusion criteria were: (1) clinical application of other thrombolytic agents such as urokinase or streptokinase; (2) patients treated by IV thrombolysis combined with IA approach or other neurointerventional treatment; or (3) those from non-original studies. If a study was reported in duplicate, the English version or earliest publication date was included in our analysis. Conflicts regarding eligibility were resolved through consensus.
Data abstraction We used the following strategies to search various databases: report characteristics (first author’s name, journal, year of publication); study design (country, study period, number of centers, retrospective/prospective analysis, IV agents, and dose); study sample [sample size, age, sex, admission National Institutes of Health Stroke Scale (NIHSS), time from symptom onset to IV treatment); and data on and definitions of outcomes [recanalization, favorable functional outcome, mortality, symptomatic intracranial hemorrhage (sICH)]. Clinical outcomes included a favorable functional outcome, mortality, and sICH. The preferred
definition was a modified Rankin score of 0–2 at 30–90 days for favorable functional outcome, death at 90 days for mortality outcome, and hemorrhage on the follow-up CT/MRI scan associated with an increase of §4 points in NIHSS score for sICH outcome. When the preferred definition was not available, the authors’ definition was adopted.
Statistical analysis We organized the literature, checked the data in accordance with the requirements of meta-analysis, and used Stata 12 software for statistical analysis. Studies included in this study were given quality assessment and qualitative systematic review. We analyzed factors including spontaneous intracerebral hemorrhage (SICH), mortality rate, and rate of patients with favorable outcome (modified Rankin Scale #2 follow-up after 1–3 months). Subgroup analyses were conducted on the differences between China and the United States in SICH rate, mortality rate, and rate of favorable outcome. The Peto Mantel–Haenszel fixedeffect model was used when studies showed no significant heterogeneity; the Dersimonian–Laird random effects model was used in cases of significant heterogeneity. If the number of included studies was sufficiently large, funnel plot analysis was used to test for the existence of publication bias. After the literature search, existing factors affecting result selectively were removed and subgroup meta-analysis was used to analyze the effects of different factors on the results. Because SICH rates, mortality and favorable outcomes are not distributed normally, logarithmic conversion was used, and meta-analysis for each subgroup was conducted. The impact of other factors was determined by meta-regression analysis. Statistical analysis was conducted using the twotailed level of 0.05. MATLAB6.5 software was used for graphics.
Results Search results Our literature search identified 1326 papers derived from PubMed, PaperszMaster’s and PhD thesesz
Table 1 Indicators from the USA, China, and combined study data Past history High Male Hyper- Atrial Dia- choleAverage ratio Stroke tension fibrillation betes sterol Smoking Base Sample age (%) (%) (%) (%) (%) (%) (%) NIHSS USA 1898 China 647 Total 2545
69.16 65.04 68.53
54 59 56
15 17 15
65 61 64
23 27 25
20 17 19
26 18 22
22 42 23
14.03 15.28 14.31
Time from Mortality Favorable onset to SICH rate outcome IV (minute) (%) (%) (%) 141.97 180
15 6 9
8 13 13
49 61 53
Note: The average onset to treatment time in the USA was 141.97 minutes; study from Wang et al.4 was single Chinese report of 180 minutes.
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Figure 1 Forest plots of SICH rates from the USA and Chinese studies. Note: owing to that the heterogeneity of the overall merger Q-test has P value less than 0.1, there is heterogeneity, thus using a random effects model to merge. Z-test showed significance (P , 0.01) after the USA and China data were merged according to the state subgroup analyses. The incidence of SICH between the USA and China has no significant differences. Chi-square 5 1.210, P 5 0.271 (df 5 1).
Conference Papers in CNKI databases: 109z15z 10 articles; PaperszMaster’s and PhD thesesz Conference Papers in Chinese Wanfang databases: 298z89z16 articles. After initial review of these titles and abstracts, and exclusion of duplicate studies we identified 17 USA-based5–21 and 9 China-based studies4,22–29 eligible for analysis. Meta-analysis of rates of SICH, mortality, and favorable outcomes We used meta-analysis to merge all analysis indicators, with the resulting values shown in Table 1. We found that the combined overall Q-test confirmed study heterogeneity. We used a random effects model to merge the data. There was no significant difference in SICH rates between the USA and China (Chisquare 5 1.210, P 5 0.271, df 5 1). We found no evidence of publication bias in the USA published literature using the Egger’s test (P . 0.05). However,
publications from China did show publication bias (P , 0.05). The combined USA and Chinese data did not contain publication bias (P . 0.05). For metaanalysis of mortality, Q-test results showed heterogeneity was significant (P , 0.1); a random effects model was used to merge data. National subgroup analysis showed that each combined Z-test of the USA and China was significant (P , 0.01), and the overall merger was meaningful (P , 0.001) (Fig. 1). In addition, differences in mortality between the two countries was significant (Chi-square 5 24.412, P , 0.001, df 5 1). Both USA and Chinese published literature did not show publication bias (P . 0.05). An Egger’s test showed combined USA and China data showed publication bias (P , 0.01). Meta-analysis of favorable outcome The overall favorable outcome Q-test showed heterogeneity (P , 0.1). Again, we merged data with a
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Figure 2 Forest plots of favorable outcomes from the USA and Chinese studies. Note: owing to that the heterogeneity of the overall merger Q-test has P value less than 0.1, there is heterogeneity, so using a random effects model to merge. Z-test showed significance (P , 0.01) after the USA and China data were merged according to the state subgroup analyses. The favorable outcome between the USA and China has significant differences. Chi-square 5 19.159, P , 0.001 (df 5 1).
Table 2 Meta-regression analysis associated with mortality Regression coefficient
95% CI
Standard coefficient
T
P
30.645 20.120 0.049 20.002 20.210 231.924 286.622 23.053 24.576 3.989 224.329 263.036 20.025 0.262
24.927–66.217 20.344–0.104 20.042–0.140 20.013–0.008 20.449–0.029 247.903–215.945 2202.460–29.217 7.404–38.702 220.413–11.261 220.155–28.133 239.621–29.036 2109.881–216.191 20.250–0.201 0.145–0.379
20.100 0.093 20.038 20.184 20.450 20.769 0.305 20.078 0.069 20.438 21.314 20.017 0.378
1.896 21.182 1.185 20.495 21.932 24.397 21.646 3.242 20.636 0.364 23.502 22.962 20.242 4.937
0.085 0.262 0.261 0.631 0.080 0.001** 0.128 0.008** 0.538 0.723 0.005** 0.013* 0.813 0.000**
Duration Centers Sample Mean age Male ratio stroke Hypertension Atrial fibrillation Diabetes Hyperlipidemia Smoking Mean baseline NIHSS Onset to IV time Note: *P , 0.05; **P , 0.01.
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random effects model. National subgroup analysis showed significance in each combined Z-test of the USA and China (P , 0.01), with an overall meaningful merger (P , 0.001) (Fig. 2). We found significant differences in favorable outcome between the two countries (Chi-square 5 19.159, P , 0.001, df 5 1). Our data also show publication bias in both the USA (P , 0.05) and China (P , 0.01). Further, data from an Egger’s test showed publication bias in the combined data (P , 0.01). Regression results associated with mortality and favorable outcome Meta-regression analysis of the influencing factors (hypertension, male ratio, high cholesterol, smoking, and onset to treatment time) was all significantly related to mortality (all P , 0.05) (Table 2). Analysis of influencing factors shows that previous history of stroke and onset to IV time was significantly related to favorable outcome (regression coefficients: 184.162 and 0.651, T values 2.211 and 2.582, respectively, all P , 0.05) (Table 3).
Discussion The global burden from stroke has gradually increased in recent years. However, after years of being the third leading cause of death, it has recently dropped to the fourth in the USA.30 Patients with acute stroke older than 85 years show a differential clinical profile, a different frequency of stroke subtypes, and a poorer outcome compared with stroke patients who were younger than 85 years.31 The primary reason for success is improvements in acute stroke treatment within the first hours of treatment.30 In contrast to the US trend, stroke has replaced heart disease as the leading cause of death in China.32 Indeed, the number of deaths every year due to stroke has risen to nearly 1.6 million, with medical treatment expenses eclipsing 40 billion each year.32 The rising incidence and high morbidity have imposed a heavy burden on the Chinese healthcare system.4,33–35
The status of thrombolysis in China and the USA
rt-PA (alteplase) was approved in North America in 1996 for treating acute ischemic stroke. Protocol recommendations were based heavily on the clinical trial findings by the National Institute of Neurological Disorders and Stroke, showing optimal results when administered within 3 hours.2 IV rt-PA treatment for acute ischemic stroke was approved in 2001 by the State Food and Drug Administration of China. A Cochrane systematic review of thrombolysis with IV rt-PA for acute ischemic stroke showed that treatment was associated with a significant improvement in neurological outcome.36 Further data have shown that the earlier the IV rt-PA is given, the greater the chance of a favorable outcome.37 However, while the reported usage rate of IV rt-PA ranged from 1.2% to 9% in other countries, China’s thrombolytic therapy rate was only 1.6%.4 In our literature review of studies that used IV rtPA thrombolytic therapy alone for acute ischemic stroke since 1995, we found no significant difference in SICH rate between the USA and China (Chisquare 5 1.210, P 5 0.271). In addition, we found significant differences in mortality (the combined ratio for the USA 8%, China 13%) between the two countries (Chi-square 5 24.412, P , 0.001). The meta-regression analysis of influencing factors including male ratio, hypertension, high cholesterol, smoking, and onset to treatment time was significantly related to mortality (all P , 0.05, Table 2). Interestingly, the average onset to treatment time in USA was 141.97 minutes, compared to a single time point of 180 minutes noted in Wang et al. Moreover, we show favorable outcome rate between the two countries differed significantly (Chi-square 5 19.159, P, 0.001). Both of the factors, history of stroke and onset to IV time, were significantly related to favorable outcome rate (all P , 0.05) (Table 3). In support of improving China’s therapeutic practices, it is important to point out major differences in IV rt-PA thrombolytic therapy between China and the USA. First, the proportion of patients
Table 3 Meta-regression analysis associated with favorable outcome
Duration Centers Sample Mean age Male ratio Stroke Hypertension Atrial fibrillation Diabetes Hyperlipidemia Smoking Mean baseline NIHSS Onset to IV time
Regression coefficient
95% CI
Standard coefficient
T
P
256.559 20.048 0.034 20.021 20.565 0.404 184.162 51.027 237.692 22.744 238.017 63.836 20.384 0.651
2162.290–49.172 21.261–1.166 20.426–0.494 20.070–0.029 21.394–0.265 266.270–67.079 2.702–365.622 234.350–136.405 2104.547–29.162 253.120–98.608 284.050–8.015 215.831–143.503 21.363–0.595 0.102–1.200
20.010 0.020 20.114 20.238 0.002 0.496 0.207 20.250 0.126 20.246 0.363 20.099 0.333
21.166 20.085 0.162 20.911 21.484 0.013 2.211 1.302 21.228 0.653 21.799 1.746 20.855 2.582
0.266 0.933 0.874 0.380 0.164 0.990 0.047* 0.217 0.243 0.526 0.097 0.106 0.409 0.024*
Note: *P , 0.05.
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receiving rt-PA within the treatment time window varied between 3.8% and 8.5% in the USA,3 compared with only 2.4% in China.4 Second, the average age of patients was 69.16 years in the USA, which was higher than China’s average of 65.04 years. In addition, there are many reports of US patients older than 80 years given IV thrombolysis, which is a rarity in China. Third, the average time from onset to treatment was 141.97 minutes in the USA, far below the single report of 180 minutes from Wang et al.4 in China. Fourth, it is surprising that favorable outcome rates in China are higher than the USA. Perhaps the reason is a lower average age of patients in China, or a lack of rigor in Chinese research literature. At any rate, it is worthy of further exploration. We believe that IV thrombolysis in China can be improved given the following reasons. First, the Chinese stroke treatment network lacks sophisticated connectivity, which is demonstrated nicely by US institutions. Chinese hospital treatment units tend to be independent, without two-way referral mechanisms among departments and divisions. Second, China has not established a system for remote stroke (TELESTROKE) or remote medication (TELEME DICINE). Many Chinese patients reach the hospital after the critical 3-hour treatment window. For some that do arrive in time, many hospitals lack appropriate resources to properly treat. Third, comprehensive clinical training of the thrombolytic process is lacking. Doctors tend to lack confidence in the protocol and fear thrombolysis may cause excessive bleeding. Fourth, most hospitals lack emergency multi-mode imaging evaluation tools, reducing the implementation rate of IV thrombolysis. Fifth, China suffers from a general lack of public health education regarding early signs of stroke and the importance of thrombolysis on a healthy prognosis. Sixth, rt-PA thrombolytic treatment is expensive. Many cities and rural areas do not offer cost reimbursement, leaving most patients unable to cover the high cost. Finally, and we believe the most important point, the official Chinese guide of IV thrombolysis contains significant differences compared to the US protocol that severely limits patient prognosis. Therefore, we offer our study findings as evidence to update thrombolytic therapy guidelines in China in order to reduce mortality and morbidity. We suggest an expansion of medical insurance coverage for rt-PA therapy. Given that secondary hospital physicians tend to lack experience in IV thrombolysis, we need to strengthen the training of doctors, and equip them with access to thrombolytic drugs. Furthermore, health administrative departments can look to the USA as a model for remote stroke and remote pharmaceutical systems. Finally, we offer some detailed suggestions for modifying the Chinese acute ischemic stroke treatment
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guidelines. First, the 2010 guidelines strictly limits treatment to patients aged .18 years to ,80 years regardless of patient health status. Perhaps treatment guidelines can be modified to allow a well-trained and responsible physician to decide according to the patient’s physical condition. Second, according to indication C, treatment is prescribed if ‘signs of brain dysfunction persists over 1 hr, and appear more serious’. A useful definition of ‘serious’ is missing from the guidelines. Does it refer to an NIHSS score greater than two points, or greater than four points? Clear explanations should be given, or it should be modified to ‘Diagnosis of ischemic stroke causing measurable neurological deficit’ similar to the Guidelines for the Early Management of Patients with Acute Ischemic Stroke.30 Third, China Guidelines 2010 state ‘Contraindications C: serious heart, liver, or kidney dysfunction’. How should a physician determine whether the patient has a serious heart, liver, or kidney dysfunction? Confirming tests will extend the critical treatment window. A possible modification is to define a ‘History of previous severe heart, liver and kidney dysfunction’. Fourth, China Guidelines 2010 reads ‘Contraindications C: severe diabetes’. Again, how can a physician confirm severe diabetes within the treatment time window? Finally, Chinese acute ischemic stroke treatment guidelines must emphasize a physician’s role and their clinical experience to allow ‘A physician with expertise in acute stroke care to modify this list’.30 We acknowledge that our study has several potential limitations. First, compared with English publications, the quality of Chinese medical publications tends to lack academic rigor, negatively affecting analysis results. Second, we analyzed various non-randomized observational studies in which heterogeneity in the quality of data may be a problem, and may be subject to undetected bias. Third, because of the limitations of meta-regression analysis on aggregated data, the impact of influencing factors on mortality and favorable outcome rate should be interpreted cautiously, and should be replicated using the original data.
Conclusions The use of IV rt-PA thrombolysis treatment for acute stroke patients in China is much lower compared with the USA. Several reasons for a lower proportion of treatment include a lack of public awareness about rtPA availability and success rate, high treatment costs, lack of resources, and few quality trained physicians to properly administer the protocol. We urge the Chinese government and health authorities to improve acute ischemic stroke thrombolysis guidelines using the US system as a quality reference to support the overarching goal of improving patient care.
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Disclaimer Statements Contributors All authors have read and approved the submitted manuscript. The manuscript has not been submitted or published elsewhere in whole or in part. All authors have read and approved the manuscript. Funding This project was supported by the Jiangsu Health International Exchange Program, the natural science foundation of Jiangsu Province, the Jiangsu Province Postdoctoral Research Funding, the ‘333 highlevel personnel training project’ of Jiangsu Province, the ‘Revitalization Plan’ of Xuzhou Medical College, and the ‘Key Medical Personnel Project’ of Lianyungang City. Conflicts of interest None. Ethics approval This study was approved by the Xuzhou Medical College Ethics Committee.
Acknowledgements We thank David C. Tong for his help in the CPMC Comprehensive Stroke Care Center. We also thank Dr Austin Cape for careful reading and insightful suggestions.
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