# Substantial Improvement of Stroke Care in China

Originally publishedhttps://doi.org/10.1161/STROKEAHA.118.022618Stroke. 2018;49:3085–3091

China bears the biggest burden of stroke in the world. Since 2008, stroke has been the leading cause of death in China, causing an enormous healthcare and economic burden to the country. However, China has made substantial progress in stroke education, research, and stroke care in recent times. Consequentially, China is now capable of conducting high-quality clinical trials and has certified many levels of stroke centers throughout the country, and for the first time, there is now a trend of decreased mortality rate from stroke. In the last decade, China has conducted many studies on stroke epidemiology, pathogenesis, treatment, and quality care. Here, we summarize the current data on stroke care from recent years, review some of the influential academic achievements, and take a glimpse into the future for stroke management in China. The authors declare that all supporting data are available within the article.

### Stroke Burden in China

Stroke has been the leading cause of death in China in recent years. In 1990, stroke was listed as the second cause of death in China.1 By 2010, stroke has become the leading cause of death in 27 of 33 provinces in China,2 responsible for a total of ≈1.9 million deaths in the same year. Stroke has the highest single-disease disability rate and is a financial and social burden in China. From 1993 to 2003, the average growth rate of the direct cost of stroke care was 18.04% per year.3 In 2010, the average cost per capita of patients with a high risk of stroke was estimated to be US $517.8 per year.4 This estimation covered the direct medical costs of US$435.4 (50.1%), direct nonmedical costs of US $18.1, and indirect costs of US$64.3 resulting from a loss of productivity. This heavy financial burden to the Chinese healthcare system has a foreseeable increase in the next 20 years because of the aging population. On the other hand, the rapid sociodemographic change and healthcare transformation have had an impact on the prevalence of common stroke risk factors in the past 20 years. Although hypertension remains to be the most important risk factor for all types of stroke, smoking, obesity, and diabetes mellitus have become more prevalent and continue to influence the stroke burden in China.5,6 For the past decade, the Chinese Center for Disease Control and Prevention has made great effort to improve stroke care quality and declared it a national priority.

### Epidemiology Update

According to the National Epidemiological Survey of Stroke in China (NESS-China), a nationally representative door-to-door survey of 480 687 adults in 2013, the stroke incidence and mortality rates in China seemed to be the highest in the world.7 The age-standardized prevalence, incidence, and mortality rates for stroke in China in 2012 to 2013 were 1115 of 100 000 (95% CI, 997–1233), 247 of 100 000 (95% CI, 211–283), and 115 of 100 000 (95% CI, 96–133), respectively. The current stroke prevalence in China seems to be the highest among other low- to middle-income countries (ranging from 536 to 1040/100 000) but significantly lower than that observed in high-income countries (ranging from 2600 to 8000/100 000). Stroke incidence rates observed in 2017 were also greater when compared with those in previous surveys, varying between 76 and 205205 of 100 000 person-years,8 suggesting a noticeable increase of stroke incidence in China for the past 3 decades. Compared with the white population, the mean age of stroke onset of Chinese population is earlier (range, 66–70 versus 72–76), with a higher proportion of intracerebral hemorrhage (28.0%; 95% CI, 23.6%–32.6% versus 12.4%; 95% CI, 10.2%–14.7%).9

According to a systematic analysis of the Global Burden of Disease Study 2013, the top 5 stroke risk factors for Eastern Asia are high systolic blood pressure, diet low in fruits, high diet in sodium, smoking, and air pollution.5 One interesting phenomenon was that diet low in vegetables was ranked in the 5 most common risk factors in every region of the world except Eastern Asia, which ranked 11th. High body mass index was not a significant risk in Eastern Asia when compared with that globally. However, air pollution was a significantly higher element in Eastern Asia, especially in China, when compared with the global ranking.

The age-specific prevalence of stroke did not differ significantly between men and women (1222.2/100 000 [95% CI, 1094.8–1349.5]) and (1005.7/100 000 [95% CI, 884.2–1127.1], respectively).7 Although the overall incidence of stroke was numerically higher in men than women across all age groups, these differences did not reach a statistically significant level in the age-standardized incidence rates.10

The burden of stroke seems to be increasing particularly in rural areas. In rural areas, the age-standardized prevalence of stroke in all ages was 365 of 100 000 individuals in 1985 and 930 of 100 000 in 2013, demonstrating a 2.5-fold increase over the past 3 decades, whereas the prevalence rates were 789 of 100 000 and 668 of 100 000 in urban areas, respectively.7 However, the prevalence of diabetes mellitus, dyslipidemia, atrial fibrillation, and coronary heart disease seemed to be greater in the urban versus rural areas. The diverging trends in the rates of stroke prevalence between rural and urban areas may be associated with the difference in stroke awareness, quality of stroke primary prevention, and socioeconomic status of the population.

The study in 2017 also confirmed previously observed North-to-South stroke prevalence gradient in China. Age-standardized prevalence is highest in Central China (1549.5/100 000), second in Northeast (1450.3/100 000), and lowest (624.5/100 000) in South China (P<0.001).7 There were statistically significant differences in the prevalence of risk factors between the regions. The population prevalence of hypertension and overweight correlated significantly with regional stroke incidence. Geographic differences in stroke prevalence may also be related to differences in sociographical and other risk factors between the regions.

Though the incidence and prevalence of stroke has increased, the observed stroke mortality rates in China decreased. Compared with results of the studies in the 1980s, stroke mortality in China had decreased by 31.0% in urban areas and by 11.4% in rural areas. In men, the age-adjusted stroke mortality rate decreased by 18.9% and in women by 24.9% between 1994 and 2013. Such decreased rate of stroke-related mortality could be from improved healthcare coverage and environment, treatment options and medical technology, support of the government of stroke programs and improved public knowledge on stroke.11

### Initiative on Improving Quality of Stroke Care

In 2007, the Ministry of Health of China established the goal of improving the quality of stroke care throughout China and launched the enrollment of China National Stroke Registry (CNSR). CNSR is a prospective, nationwide, hospital-based registry of patients with acute cerebrovascular events, with a coverage of 1% of the total 13 372 general hospitals in China. It was designed to help develop strategies, based on the real-time practicing data collected through the registry, with the goal for continuous improvement of stroke care in China.

CNSR phase 1 consisted of data collected on 22 216 patients among 137 hospitals from August 2007 to July 2008.12 Data collected during this phase mostly focused on the status assessment of quality of stroke care in China, including demographic characteristics, patient medical history, outcome of patients with acute cerebrovascular events, and adherence to the guidelines on secondary stroke prevention.

CNSR phase 1 used an analytical approach to look into how stroke care was delivered in China, specifically the use of intravenous r-tPA (recombinant tissue-type plasminogen activator). The data showed that the rate of using intravenous r-tPA was lower than that in Europe.13 Among the factors accountable for this delay, imaging-to-needle time was the most prolonged phase, nearly twice as long as that in the developed countries.14 The reason why the overall low rate of using thrombolytics for acute ischemic stroke (AIS) was complex. It was related to barriers in the healthcare system, the level of awareness by the physicians and patients, and a low socioeconomic status as a whole.

CNSR phase 1 brought forward the attention on patients with transient ischemic attack (TIA) and minor stroke, together known as the High-Risk Nondisabling Ischemic Cerebrovascular Events. This group of patients accounted for about one-third of the ischemic cerebrovascular patients.15 The data showed a 3-month stroke recurrence rate of 9.8% in patients with a minor stroke, as well as a 3-month stroke disability of 14.5% in over 50% of the inpatients, most happened within the first 2 days.15 Individual predictors of early recurrent stroke included hypertension, diabetes mellitus, and previous stroke. Atrial fibrillation and coronary artery disease were also independent risk factors, which was not confirmed in population from western countries.16 Also, when combined with the findings of magnetic resonance angiography, the presence of multiple infarctions and intracranial arterial stenosis (ICAS) were both associated with an increased risk of 90-day ischemic stroke, whereas the presence of both imaging features had a striking 13-fold risk.17

In early 2000s, adherence to evidence-based stroke care has been suboptimal based on several national studies conducted before 2009. This has led to several quality improvement initiatives by the China Ministry of Health after 2008 for the purpose of adhering to evidence-based care. CNSR phase 2 was then launched during June 2012 to January 2013 and consisted of 219 hospitals nationwide.18 Combining subjects from phase 1, a total of 31 777 subjects were included in the analysis. This phase mainly focused on the improvement and development of quality care in China by comparing the adherence to guideline-recommended performance measures before 2009 with that after the implementation of these initiatives since 2009.

Overall, CNSR phase 2 observed a marked improvement in adherence to guideline-recommended performance measures after implementing several quality management initiatives nationwide in China. The improvement of individual performance measures (acute and during discharge) and the composite score during the 5 years between 2 time periods were apparent.2,19 Potential factors included implementation of quality management initiatives of stroke care, including the establishment of the National Center of Quality Improvement in Stroke Care, the national guidelines for acute treatment and secondary prevention of stroke, organizational stakeholder and opinion leader meetings, hospital recruitment, collaborative workshops for hospital teams, and hospital tool kits. In addition, the health insurance coverage was improved over time, which had a positive impact on the improvement of quality of stroke care. However, there are still challenges. Stroke rehabilitation is known to improve functional recovery among stroke patients. Studies show that early combination therapy as well as 4-channel functional electrical stimulation can improve long-term motor function and activities of daily living.20 In 2012, the Ministry of Health endorsed rehabilitation assessment as part of a national standard for acute stroke care. However, almost 40% of AIS patients included in the study were not properly assessed for stroke rehabilitation, and there was wide variation in practice across hospitals.21 This is partially related to the insufficient or imbalanced distribution of limited medical resources. The total amount of medical resources per capita is lower in China when compared with most developed countries.22 For example, the number of doctors and nurses per 1000 people in China is 1.75 and 1.39; however, the numbers are 2.6 and 8.4 in the United States, respectively. Furthermore, the study concluded that patients with atrial fibrillation tend to have more unfavorable outcomes, but less likely to receive rehabilitation treatment, because of the fear of embolism.

CNSR phase 3 is an ongoing multicenter, prospective, consecutive, hospital-based registry study, conducted in 2015. It aims at establishing a cohort of Chinese ischemic cerebrovascular disease study based on the standard diagnostic procedure for etiological diagnosis and identifying the relevant risk factors and clinical prognosis of ischemic cerebrovascular disease of different cause. Furthermore, it seeks to establish an individualized and accurate early warning model for recurrence of ischemic cerebrovascular disease and evaluate the status of medical services and socioeconomic benefits. In the wake of developments in multifunctional imaging, genetics, and precision therapy, research is more specifically aimed at detailed aspects of stroke. For example, clinical outcome associated with brain imaging, echocardiography and cardiac monitoring for cardiogenic stroke, and vascular ultrasound, angiography, and high-resolution magnetic resonance imaging for vascular analysis.

Parallel to CNSR, the CICAS study group (Chinese Intracranial Atherosclerosis) and the ACTUAL (Endovascular Treatment for Acute Anterior Circulation Ischemic Stroke) registry focused on the prevalence and outcomes associated with intracranial large artery stenosis and occlusion.23–25 The findings from CICAS showed that 46.6% patients with stroke had intracranial occlusive disease, which was in sharp contrast to western countries where extracranial carotid atherosclerotic stenosis was one of the main causes of stroke.23 Patients with severe intracranial large artery stenosis of 75% to 99% had a higher risk of recurrent stroke of 5%. More importantly, the degree of stenosis was not the only independent predictor for recurrent stroke. Other risk factors include high diastolic blood pressure, no use of antithrombotic drugs, and a history of stroke. The data from ACTUAL shows that Asian patients with AIS have a risk of symptomatic intracranial hemorrhage after endovascular treatment of 16.0%, significantly higher than that reported in randomized controlled trial studies (4.4%).25,26 Factors include stroke of cardioembolic type, poor collateral circulation, delay of treatment, multiple passes with retriever, lower Alberta Stroke Program Early CT Score, and higher neutrophil ratio at baseline. It was worth noting that multiple passes with retriever may be because of a higher proportion of atherosclerotic occlusion in Asian patients, which is usually accompanied with a severe stenosis.

### Impact of Clinical Trials Conducted in China

The successful completion of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) was a milestone for the Chinese clinical researchers. It demonstrated that large-scale, high-quality, multicenter stroke studies could be conducted well and effectively in China. Published in 2013, the CHANCE trial was specifically aimed at high-risk TIA or minor ischemic stroke patients in the acute phase and proved that for patients who can be treated within 24 hours after onset of symptoms, the dual combination of clopidogrel and aspirin was superior to aspirin alone in reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage.27,28 In 2015, a 1-year follow-up result showed that there was no additional risk of late stroke that would eliminate the efficacy gap between the 2 groups,29 providing solid data for long-term secondary prevention protocol. The recently published POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) has not only confirmed the findings of CHANCE but also pointed out that dual antiplatelet therapy could have more hemorrhagic risk if used beyond 21 days.30 The findings of CHANCE were included in the 2018 American Heart Association/American Stroke Association guideline.31

CYP2C19 loss-of-function carrier was a known factor to render clopidogrel ineffective. Data from a substudy of the CHANCE trial concluded that such genotype carrier had less protection from subsequent stroke compared with noncarrier status.32 Therefore, verifying the genotype would be necessary in patients using clopidogrel. Other subgroup analysis from CHANCE that impacted the clinical practice included multiple infarctions, high glucose level, elevated soluble CD40 ligand, decreased estimated glomerular filtration rate, and symptomatic ICAS with concomitant metabolic syndrome. Modification of these independent risk factors would have significant impact on patient’s outcome.

CLASS-China (Clopidogrel Loading Dose Versus Maintenance Dose to Treat Patients With Acute Ischemic Stroke in China) explored its efficacy in patients with noncardiogenic stroke during the 48 hours of the initial stroke.33 This trial showed no difference in primary outcome or safety between the loading dosage group 16.1% (24/149) and control group 14.9% (22/148, P=0.782). The rate of mortality and disability in loading dose group (19.6%) was slightly lower than that in controlled group (23.4%, P=0.444) within 90 days. Because the trial was stopped early because of slow enrollment, future studies are still needed to examine this hypothesis.

ICAS is a known common cause of stroke in Asians. In 2013, the SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) revealed negative results for the endovascular approach, largely because of an unexpectedly high rate of stroke and death in 30 days, as well has no benefit over a 5-year follow-up.34 The use of intracranial angioplasty and stenting to treat ICAS did not stop in China. The clinicians felt strongly that in selective patients, there was still the indication of being effective and safe. A 1-year outcome registry study to evaluate the long-term efficacy of individually tailored stenting for patients with severe symptomatic ICAS combined with poor collaterals showed that intracranial stenting may have a potential benefit in China. In this study, patients with symptomatic ICAS with 70% to 99% stenosis located at the intracranial internal carotid, middle cerebral, intracranial vertebral, or basilar arteries combined with poor collaterals were treated with balloon-mounted stent or balloon plus self-expanding stent. Of the 159 patients treated with balloon-mounted stent and 141 with balloon plus self-expanding stent, the chance of having a primary outcome at 1 year was about 8.1% (95% CI, 5.3%–11.7%). However, about 18.4% (14/76) had r-stenosis of ≥70%.35

Miao et al36 also reported that patients with severe ICAS and hypoperfusion symptoms could benefit from intracranial stenting and revascularization. Accurate patient selection for tailored treatments could be more beneficial, hence the need for precision medicine. From a medical management point of view, the CLAIR study (Clopidogrel Plus Aspirin Versus Aspirin Alone for Reducing Embolization in Patients With Acute Symptomatic Cerebral or Carotid Artery Stenosis) investigated the use of antithrombotic drugs for early secondary prevention of stroke or TIA in patients with ICAS.37 It is concluded that combination therapy was indeed more effective than aspirin alone in reducing microembolic signals in patients with ICAS, suggesting that it could reduce the risk of recurrent stroke.

Future studies will be needed to specify the dosage of r-tPA. The J-ACT (Japan Alteplase Clinical Trial) showed promising results for the low-dose alteplase in the Japanese population, but the trial had a lack of control group, and therefore was biased.38 The ENCHANTED trial (Enhanced Control of Hypertension and Thrombolysis Stroke Study) involving predominately Asian patients with AIS did not show noninferiority of low-dose alteplase, but with significantly fewer symptomatic intracranial hemorrhages.39 Further research should focus on which group of patients will benefit from low-dose alteplase.

Although the bridging therapy of intravenous r-tPA and intra-arterial thrombectomy within 6 hours of onset of stroke has been recommended in the US and European Guidelines because of the evidence provided by the 7 trials conducted in western countries, Chinese researchers are conducting their own bridging trial. The EAST (Endovascular Therapy for Acute Ischemic Stroke Trial) set out to evaluate the safety and efficacy of Solitaire thrombectomy in patients with moderate-to-severe stroke in the Chinese population. This multicenter prospective control study plans to enroll 300 patients with AIS because of large-vessel occlusion indicated for treatment with Solitaire stent retriever within 12 hours of symptom onset from 17 stroke centers in China. Modified Rankin Scale score of ≤2 at 90 days and rate of arterial and symptomatic intracranial hemorrhage within 24±3 hours will be the outcome measures.40

CARE II study (Chinese Atherosclerosis Risk Evaluation) is a novel cross-sectional, multicenter study of the prevalence of high-risk atherosclerotic carotid plaque in Chinese patients with ischemic cerebrovascular events. CARE II will enroll 1000 patients with recent ischemic stroke or TIA and carotid plaque from 13 hospitals and medical centers across China. All patients will undergo magnetic resonance imaging of bilateral carotid arteries and routine brain magnetic resonance imaging. The study is sufficiently powered to demonstrate the prevalence of high-risk carotid plaque and to explore regional differences in Chinese patients who suffered stroke.41

Chinese researchers have conducted a multicenter, prospective, randomized, open-label, blinded, controlled clinical trial of effect of Ginkgo biloba extract on poststroke cognition. One hundred seventy-nine participants received 450 mg ginkgo biloba extract with 100 mg aspirin daily were compared with 169 who had 100 mg aspirin daily for 6 months. A marked slower decline in Montreal Cognitive Assessment scores (−2.77±0.21 versus −1.99±0.23; P=0.0116 [30 days]; −3.34±0.24 versus −2.48±0.26; P=0.0165 [90 days]; −4.00±0.26 versus −2.71±0.26; P=0.0004 [180 days]) was seen in the ginkgo biloba extract group with improved National Institutes of Health Stroke Scale score, Barthel Index, and Mini-Metal State Examination scores. Large double-blind trials are being planned to prove these findings.42

### Status of Thrombolysis and Novel Therapeutic Options Explored

In China, thrombolysis with intravenous r-tPA has gained momentum in recent years. There are hospitals that have treated over 8000 patients with intravenous r-tPA alone. Because urokinase has been approved for stroke in China, its uses have been common among county hospitals. The outcome of urokinase at a national level is to be collected. The use of multimodal imaging to guide intravenous r-tPA therapy for patients with AIS beyond 6 hours has been done in 2013, long before the conduction of wake-up stroke trial.43

Chinese stroke doctors and interventionists have also ventured into the therapeutic areas that have hardly been tried in other countries. One group of interventional neurologists have reported the success of recanalizing occluded intracranial large arteries in 16 patients with subacute symptomatic ischemic stroke by PTA or PTAS. After the procedure, 12 were recanalized, 2 were partially recanalized and 2 failed to open. At 3 months, 8 patients achieved a modified Rankin Scale scores of 0 to 1. The perioperative adverse events were 6.25%. Their series offered the clue that selective PTA or PTAS could be performed in patients with a small infarct size and large area of hypoperfusion from an occluded large cerebral artery after the acute phase. The timing of reopening these occluded large arteries was between 4 and 90 days.44

For patients who developed carotid in-stent restenosis or occlusion, no further treatment is provided at most stroke centers around the world. A group of neurosurgeons reported their experience of surgical treatment of in-stent restenosis by standard carotid endarterectomy with stent removal. Of 10 patients operated, 7 had no complications. One developed asymptomatic dissecting aneurysm, 1 had a dissection distal to the site of the stent after stent removal and treated with another stent, and 1 had cerebral hyperperfusion syndrome but recovered at discharge. At 25 months (range, 11–54 months) follow-up, one died from rectal cancer and another one had recurrent symptomatic restenosis (90%) 1 year later. They concluded that carotid endarterectomy with stent removal is a reasonable choice for symptomatic in-stent restenosis with higher but acceptable complications.45

### Stroke Center Certification, Community Stroke Education, and Telestroke in China

Currently, there are 2 stroke center certification institutions in China. The Chinese Stroke Association has certified over 300 Comprehensive Stroke Centers within 31 provinces, and the Office of Stroke Prevention of the Commission of Health has certified over 1000 Tertiary Stroke Centers. A phenomenon unique to China is that many hospitals are certified by both certification agencies. Data on the performance of these centers are currently being collected.

Under the leadership of Chinese Stroke Association, Red Ribbon Volunteer program, an award-winning program recognized by the World Stroke Organization, has provided community stroke education to millions of population in China. Nearly every tertiary hospital in China has participated in stroke risk screening and education in its community as part of the Red Ribbon Program. The China Stroke Centre Alliance County Hospital Training Camp program has brought stroke experts from over 1000 county hospitals.

Telestroke is a relatively new process in China. The National Telestroke Center was established in 2014. It was designed to provide neurological coverage to 300 rural hospitals nationwide through the telestroke network platform. It was a hub and spoke model, providing stroke diagnosis and treatment advices to underserved areas in China.46

One unique national program gained momentum in China was the development of citywide stroke/thrombolytic maps. This project was supported by the local government and developed under the principle of National Health Ministry, unified standards, and 1 platform. Realizing that many centers now can offer thrombolytic therapy, cities are developing maps that label the hospital that can provide thrombolytic treatment. In addition, the emergency service triage center will have the authority to direct the ambulance to the nearest stroke center 24/7. Currently, there are over 30 cities with such map in place. Data on its usage and outcome are being collected.

### Welcome to a New Era for Stroke Management in China

In 2017, National Ministry of Science and Technology issued The 13th 5-Year Plan for the National Economic and Social Development of PRC, among which indicated that one of the primary missions is the implementation of comprehensive prevention and control of chronic diseases. This prompted many studies on stroke management, including the study on the critical technology and process for improvement of reperfusion in patients with AIS, Sino-US collaborative network for blood pressure management strategies, early standardized treatment of ruptured intracranial aneurysm and risk assessment of unruptured aneurysm, etc. From standardized templet and record, electronic data extraction and application, and professional imaging analysis to individual follow-up evaluation, all current clinical studies in China are now up to the international standard. On the basis of several large databases, big data analysis can be done now to accomplish multi-omics research, establish biobank for neurological research, and facilitate individualized and precise treatment in the near future.

China has been making substantial progress in applying artificial intelligence in medical practice and in stroke outcome analysis.47 Zhang et al48 proposed a model for predicting 3-month treatment outcome by analyzing physiological parameters during the first 48 hours after stroke using logistic regression. To predict the outcome of stroke treatment, Chen et al49 analyzed computed tomographic scan data via machine learning for evaluating the cerebral edema after hemispheric infarction. For the first time in stroke and neurology practice, AI will compete with neurologist in reading magnetic resonance imaging films in Beijing.

In 2018, the National Clinical Improvement System concluded that there has been substantial improvement made in stroke care quality in the past 5 years. However, much work still need to be done in areas such as reducing the time from the emergency room to receiving thrombolytic therapy, appropriate use of anticoagulation therapy for stroke patients with atrial fibrillation, as well as timely and proper assessment of stroke rehabilitation. The next step is to introduce the stroke care performance improvement navigation plan, which will facilitate the process of standardizing care process so that high-quality stroke care can be uniformly achieved.

### Conclusions

In conclusion, despite the trend of decreasing stroke mortality in China, stroke incidence is still rising. In the past decade, China has made significant process in stroke education, stroke care, and research. The next phase of challenge will be to invest more financial and human resources so that standardized quality stroke care can be provided throughout the country and the goals set forth by the national 13th 5-year plan can be achieved.

### Footnotes

*Drs L. Liu and J. Liu are joint first authors.

Correspondence to Yongjun Wang, MD, PhD, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing 100050, China. Email

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