Association between annual household income and adverse outcomes in patients who had ischaemic stroke.

BACKGROUND AND PURPOSE: The association between annual household income and prognosis of ischaemic stroke remains debatable. We aimed to prospectively investigate the relationship between annual household income and prognosis at 3 months after ischaemic stroke. METHODS: We included 3975 participants from the China Antihypertensive Trial in Acute Ischemic Stroke. All participants were categorised into three groups according to annual household income per capita: <¥10 000 (Chinese Yuan Renminbi (RMB)), ¥10 000-19 999 and ≥¥20 000. The primary outcome was a composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset, and secondary outcomes included major disability, death, and vascular events. A meta-analysis was conducted to incorporate the results of the current study and previous studies on the association of income level with outcomes after stroke. RESULTS: Within 3 months after ischaemic stroke, 1002 participants (25.20%) experienced primary outcome (880 major disabilities and 122 deaths). After multivariate adjustment, low annual household income level was associated with increased risk of the primary outcome (OR 1.60; 95% CI: 1.12 to 2.31; Ptrend=0.034) when two extreme groups were compared. The meta-analysis confirmed the significant association between income level and death or major disability after stroke (pooled relative risk for lowest vs highest income level, 1.31 (95% CI: 1.18 to 1.45)). CONCLUSIONS: Low annual household income per capita was significantly associated with increased risks of adverse clinical outcomes at 3 months after ischaemic stroke, independently of established risk factors. Further studies from other samples are needed to replicate our findings due to a reason for excluding some patients who had a severe stroke in this study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (http://wwwclinicaltrialsgov) Registry (NCT01840072).

Plasma osteopontin levels and adverse clinical outcomes after ischemic stroke.

BACKGROUND AND AIMS: Osteopontin is implicated in atherosclerosis, and its expression is upregulated in response to brain injury. The aim of this study was to prospectively investigate the associations between plasma osteopontin levels and adverse clinical outcomes in ischemic stroke patients. METHODS: We measured baseline plasma osteopontin levels in 3545 ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was the composite outcome of death and major disability (modified Rankin scale score ≥3) at 1 year after ischemic stroke, and secondary outcomes included major disability, death, and the composite outcome of death and vascular events. RESULTS: During 1 year of follow-up, patients in the fourth quartile of plasma osteopontin had the highest risks of primary outcome, major disability, death, and the composite outcome of death and vascular events. After multivariate adjustment, the odds ratios or hazard ratios (95 % confidence intervals) associated with each standard deviation increase in log-transformed osteopontin were 1.20 (1.09-1.33) for primary outcome, 1.11 (1.00-1.23) for major disability, 1.29 (1.10-1.52) for death, and 1.15 (1.01-1.30) for the composite outcome of death and vascular events. The addition of plasma osteopontin to conventional risk factors significantly improved the risk reclassification for the primary outcome (net reclassification improvement: 16.91%, p < 0.001; integrated discrimination improvement: 0.43%, p = 0.002). CONCLUSIONS: Elevated plasma osteopontin levels at baseline were associated with increased risks of adverse clinical outcomes at 1 year after ischemic stroke, suggesting that osteopontin is a promising prognostic biomarker for ischemic stroke.

Prevalence of pediatric Kashin-Beck disease in Tibet.

INTRODUCTION: To estimate the prevalence of Kashin-Beck disease (KBD) among children in 2017 in Changdu of Tibet. METHODS: We adopted a four-step recruitment to include children aged 7-12 years from seven identified historically endemic counties in Changdu. Posterior-anterior radiographs of right hand and wrist were taken and were graded at four sites (metaphysis, epiphysis, and bony end of phalanges and metacarpal and carpal bones). Two trained researchers independently read the films. Inter-rater reliability was assessed using weighted Kappa and percentage agreement. We fitted logistic regression model to examine the association of age, sex, and altitude of residential village with prevalence of KBD. We examined association between site involvement and severity of KBD using chi-square test. RESULTS: We recruited 13,573 children (mean age = 9.3 years, 48.40% girls) with a response rate of 95.81%. The overall prevalence of radiographic KBD was 0.26%. Luolong County had the highest prevalence (0.69%), followed by Bianba (0.26%), Basu (0.24%), Mangkang (0.14%), Zuogong (0.14%), Dingqing (0.07%), and Chaya (0.00%). A higher risk of radiographic KBD was associated with older age (P for trend <0.001) and girls (OR=1.86, 95% CI: 0.94, 3.70), but not the altitude of residential village (P for trend=0.957). Metaphysis was involved in all cases of KBD while lesions in epiphysis and bony end of phalanges and metacarpals were only observed in severe cases. CONCLUSIONS: The prevalence of radiographic KBD among children aged 7-12 years was low in Changdu compared with previous census data, suggesting the effectiveness of preventative measures. Key Points • In this study, 13,573 Tibetan children were taken X-ray films of their hands and wrists. • The prevalence of radiographic KBD among children aged 7-12 years was low in Changdu of Tibet. • The preventative measures against KBD launched by Chinese government were effective in decreasing new onsets of KBD among Tibetan children.

Prognostic Metrics Associated with Inflammation and Atherosclerosis Signaling Evaluate the Burden of Adverse Clinical Outcomes in Ischemic Stroke Patients.

BACKGROUND: Conventional prognostic risk factors can only partly explain the adverse clinical outcomes after ischemic stroke. We aimed to establish a set of prognostic metrics and evaluate its public health significance on the burden of adverse clinical outcomes of ischemic stroke. METHODS: All patients were from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). We established prognostic metrics of ischemic stroke from 20 potential biomarkers in a propensity-score-matched extreme case sample (n = 146). Pathway analysis was conducted using Ingenuity Pathway Analysis. In the whole CATIS population (n = 3575), we evaluated effectiveness of these prognostic metrics and estimated their population-attributable fractions (PAFs) related to the risk of clinical outcomes. The primary outcome was a composite outcome of death or major disability (modified Rankin Scale score ≥3) at 3 months after stroke. RESULTS: Matrix metalloproteinase-9 (MMP-9), S100A8/A9, high-sensitivity C-reactive protein (hsCRP), and growth differentiation factor-15 (GDF-15) were selected as prognostic metrics for ischemic stroke. Pathway analysis showed significant enrichment in inflammation and atherosclerosis signaling. All 4 prognostic metrics were independently associated with poor prognosis of ischemic stroke. Compared with patients having 1 or 0 high-level prognostic metrics, those with 4 had higher risk of primary outcome (OR: 3.84, 95%CI: 2.67-5.51; PAF: 37.4%, 95%CI: 19.5%-52.9%). CONCLUSION: The set of prognostic metrics, enriching in inflammation and atherosclerosis signaling, could effectively predict the prognosis at 3 months after ischemic stroke and would provide additional information for the burden of adverse clinical outcomes among patients with ischemic stroke.

Education Level and Long-term Mortality, Recurrent Stroke, and Cardiovascular Events in Patients With Ischemic Stroke.

Background Epidemiological studies have reported discrepant findings on the relationship between education level and outcomes after stroke. We aimed to prospectively investigate the relationship between education level and mortality, recurrent stroke, and cardiovascular events in Chinese patients with ischemic stroke. Methods and Results We included 3861 participants from the China Antihypertensive Trial in Acute Ischemic Stroke. Education level was categorized as illiteracy, primary school, middle school, and college. Study outcomes were all-cause mortality, stroke-specific mortality, recurrent stroke, and cardiovascular events within 2 years after ischemic stroke. A meta-analysis was conducted to incorporate the results of the current study and previous other studies on the association of education level with outcomes after stroke. Within 2 years after ischemic stroke, there were 327 (8.5%) all-cause deaths, 264 (6.8%) stroke-specific deaths, 303 (7.9%) recurrent strokes, and 364 (9.4%) cardiovascular events, respectively. The Kaplan-Meier curves showed that patients with the lowest education level had the highest cumulative incidence rates of all-cause mortality, stroke-specific mortality, and cardiovascular events (log-rank P≤0.01). After adjusted for covariates, hazard ratios and 95% CIs of illiteracy versus college education were 2.79 (1.32-5.87) for all-cause mortality, 3.68 (1.51-8.98) for stroke-specific mortality, 2.82 (1.20-6.60) for recurrent stroke, and 3.46 (1.50-7.95) for cardiovascular events. The meta-analysis confirmed the significant association between education status and mortality after stroke (pooled relative risk for lowest versus highest education level, 1.24 [95% CI, 1.05-1.46]). Conclusions Low education level was significantly associated with increased risk of mortality, recurrent stroke, and cardiovascular events after ischemic stroke, independently of established risk factors. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT01840072.

Plasma S100A8/A9 Concentrations and Clinical Outcomes of Ischemic Stroke in 2 Independent Multicenter Cohorts.

BACKGROUND: S100A8/A9 is implicated in inflammation mechanisms related to atherosclerosis and plaque vulnerability, but it remains unclear whether S100A8/A9 is associated with the prognosis of ischemic stroke. The aim of this study was to investigate these associations in 2 independent multicenter cohorts. METHODS: Plasma S100A8/A9 concentrations at baseline were measured among 4785 patients with ischemic stroke from 2 independent cohorts: Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke (IIPAIS) and China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a composite outcome of death or major disability at 3 months after ischemic stroke. Secondary outcomes were major disability, death, and a composite outcome of death or vascular events. RESULTS: Among the combined participants of IIPAIS and CATIS, the adjusted odds ratios associated with the highest quartile of plasma S100A8/A9 were 2.11 (95% CI, 1.66-2.68) for the primary outcome and 1.62 (95% CI, 1.27-2.07) for the secondary outcome of major disability; adjusted hazard ratios were 4.14 (95% CI, 2.10-8.15) for the secondary outcome of death and 2.08 (95% CI, 1.38-3.13) for the composite outcome of death or vascular events. Each SD increase of log-transformed S100A8/A9 was associated with 28% (95% CI, 18%-39%; P < 0.001) increased risk of the primary outcome. Multivariable-adjusted spline regression analyses showed a linear association between plasma S100A8/A9 concentrations and primary outcome (P < 0.001 for linearity). Subgroup analyses further confirmed these associations. CONCLUSIONS: High plasma S100A8/A9 concentrations at baseline were independently associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that S100A8/A9 might have a role as a prognostic marker of ischemic stroke.

Serum dickkopf-3 is associated with death and vascular events after ischemic stroke: an observational study from CATIS.

BACKGROUND: Dickkopf-3 (Dkk-3) is implicated in the progression of atherosclerosis. This study aimed to investigate the association between serum Dkk-3 and the prognosis of ischemic stroke. METHODS: We measured serum Dkk-3 levels in 3344 ischemic stroke patients from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). The primary outcome was a combination of death and vascular events within 3 months after ischemic stroke. RESULTS: During 3 months of follow-up, the cumulative incidence rates of primary outcome among ischemic stroke patients in five quintiles of serum Dkk-3 (from low to high) were 4.49%, 3.74%, 2.54%, 5.23%, and 6.73%, respectively (log-rank p = 0.004). Multivariable Cox proportional hazards regression analyses showed that compared with the third quintile of serum Dkk-3, the adjusted hazard ratios (95% confidence intervals) associated with the first and fifth quintile were 3.49 (1.46-8.34) and 4.23 (1.86-9.64) for primary outcome, 3.47 (1.06-11.36) and 5.30 (1.81-15.51) for death, and 2.66 (1.01-7.01) and 3.35 (1.33-8.40) for vascular events, respectively. Multivariable-adjusted Cox proportional hazards regression model with restricted cubic splines showed a U-shaped association between serum Dkk-3 and the risk of primary outcome (p for nonlinearity = 0.030). Moreover, adding serum Dkk-3 to conventional risk factors could improve the predictive power for primary outcome (net reclassification improvement 28.44%, p < 0.001; integrated discrimination improvement 0.48%, p = 0.001). CONCLUSIONS: Both low and high serum Dkk-3 levels are associated with increased risks of death and vascular events within 3 months after ischemic stroke, indicating that serum Dkk-3 may have a special effect on the prognosis of ischemic stroke. We also found that serum Dkk-3 might be a prognostic biomarker for ischemic stroke. Further studies are needed to replicate our findings and to determine the optimal levels of serum Dkk-3.

Endostatin as a novel prognostic biomarker in acute ischemic stroke.

BACKGROUND AND AIMS: Endostatin is implicated in the atherosclerosis process and serves as a promising cardiovascular biomarker, while its clinical significance in ischemic stroke patients remains unclear. We aimed to examine the association between endostatin and mortality and disability after ischemic stroke. METHODS: A total of 3463 acute ischemic stroke patients with measured plasma endostatin from the China Antihypertensive Trial in Acute Ischemic Stroke were included in this study. The primary outcome was death or severe disability (modified Rankin scale score of 4-6), and secondary outcomes included death and vascular events. RESULTS: After 3-month follow-up, 402 (11.61%) participants experienced severe disability or died. Compared with the lowest quartile of endostatin, odds ratios or hazard ratios (95% confidence intervals) for the highest quartile were 1.47 (1.04-2.09) for the primary outcome, and 2.36 (1.23-4.54) for death after adjustment for multiple covariates, including age, sex, admission NIH Stroke Scale score and systolic blood pressure. Each 1-SD higher log-transformed endostatin was associated with a 20% (6%-36%) increased risk for primary outcome. Adding plasma endostatin to the basic model constructed with conventional factors significantly improved risk stratification of primary outcome, as observed by the category-free net reclassification index of 20.5% (95% CI 10.1%-30.8%; p < 0.001) and integrated discrimination improvement of 0.3% (95% CI 0.01%-0.6%; p = 0.04). CONCLUSIONS: Increased baseline plasma endostatin levels in acute ischemic stroke were associated with increased risk of mortality and severe disability at 3 months. Plasma endostatin may serve as an important prognostic marker for risk stratification in patients with ischemic stroke.

Renal Function Affects Prognostic Role of Antiphosphatidylserine Antibodies for Acute Ischemic Stroke Patients.

BACKGROUND: Whether the renal function influences the association between antiphosphatidylserine antibodies (aPS) and prognosis of ischemic stroke remains unclear. We aimed to investigate the prognostic value of aPS after ischemic stroke stratified by renal function status. METHODS: This prospective study was based on China Antihypertensive Trial in Acute Ischemic Stroke, a randomized clinical trial in 26 hospitals across China from August 2009 to May 2013. A total of 2,874 ischemic stroke patients with blood samples or baseline records of estimated glomerular filtration rate (eGFR) were included in this study. Serum aPS levels were quantitatively measured at baseline, and abnormal renal function in this study was defined as eGFR <90 mL/min per 1.73 m2. The primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke. Secondary outcomes were death and major disability separately. RESULTS: The association between aPS and primary outcome was significantly modified by renal function status (p for interaction = 0.02). After adjustment for covariates, increased aPS were significantly associated with the primary outcome in the patients with abnormal renal function (OR 2.09; 95% CI 1.24-3.53; p for trend = 0.006), but not in those with normal renal function (OR 0.92; 95% CI 0.69-1.23; p for trend = 0.59), when 2 extreme tertiles were compared. Furthermore, multiple-adjusted spline regression model showed a linear association between aPS and risk of primary outcome in the patients with abnormal renal function (p for linearity = 0.02) but not in those with normal renal function (p for linearity = 0.71). CONCLUSIONS: Increased aPS were positively and independently associated with death or major disability after acute ischemic stroke in the patients with abnormal renal function.

Tissue inhibitor metalloproteinase-1 and clinical outcomes after acute ischemic stroke.

OBJECTIVE: To prospectively investigate the relationships between serum tissue inhibitor metalloproteinase-1 (TIMP-1) and clinical outcomes in patients with acute ischemic stroke. METHODS: We derived data from the China Antihypertensive Trial in Acute Ischemic Stroke. Baseline serum TIMP-1 concentrations were measured in 3,342 participants. The primary outcome was the combination of death and major disability (modified Rankin Scale score ≥3) at 3 months after ischemic stroke, and secondary outcomes included major disability, death, and vascular events. RESULTS: A total of 843 participants (25.2%) experienced major disability or died within 3 months. After adjustment for age, sex, admission NIH Stroke Scale score, and other important covariates, odds ratios or hazard ratios (95% confidence intervals) of 1-SD (0.17 ng/mL) higher log-TIMP-1 were 1.17 (1.06-1.29) for the primary outcome, 1.13 (1.02-1.25) for major disability, 1.49 (1.19-1.87) for death, and 1.34 (1.11-1.62) for the composite outcome of death and vascular events. The addition of serum TIMP-1 to conventional risk factors model significantly improved risk prediction of the primary outcome (net reclassification index 9.0%, p = 0.02; integrated discrimination improvement 0.2%, p = 0.03). Participants with both higher TIMP-1 and matrix metalloproteinase-9 levels simultaneously had the highest risk of all study outcomes. CONCLUSIONS: Higher TIMP-1 levels were associated with increased risk of mortality and major disability after acute ischemic stroke. Our findings provided evidence supporting the important prognostic role of extracellular matrix biomarkers after acute ischemic stroke.

Immediate Antihypertensive Treatment for Patients With Acute Ischemic Stroke With or Without History of Hypertension: A Secondary Analysis of the CATIS Randomized Clinical Trial.

Importance: Clinical trials have generally shown a neutral effect of early blood pressure (BP) decreases on clinical outcomes after acute ischemic stroke. Whether the effect of early antihypertensive therapy differs for patients with ischemic stroke with or without prior hypertension is unclear. Objective: To investigate the association between immediate antihypertensive treatment and patient outcomes according to the presence or absence of hypertension before stroke onset. Design, Setting, and Participants: This study was a prespecified subgroup analysis of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS), a multicenter, single-blind, blinded end-points randomized clinical trial of 4071 patients with acute ischemic stroke and elevated systolic BP. Patients were recruited from August 2009 to May 2013, and this statistical analysis was performed using the intention-to-treat population from January to October 2018. Interventions: Participants were randomly assigned to receive antihypertensive treatment (aimed at decreasing systolic BP by 10%-25% within the first 24 hours after randomization, achieving systolic BP <140 mm Hg and diastolic BP <90 mm Hg within 7 days, and maintaining this level during hospitalization) or to the control arm (discontinued all antihypertensive medications). Main Outcomes and Measures: Primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3; range 0-6, with higher values indicating greater disability) at 14 days or hospital discharge. Results: In total, 2038 patients were randomized to receive antihypertensive treatment, and 2033 patients were randomized to the control group. The mean (SD) age was 62.0 (10.9) years, and 2604 participants (64.0%) were men. At day 14 or hospital discharge, the primary outcome was not different between the treatment and control groups among patients with or without prior hypertension (P = .97 for homogeneity): odds ratios (ORs) associated with treatment were 1.00 (95% CI, 0.87-1.16) for patients with prior hypertension and 1.00 (95% CI, 0.75-1.32) for patients without. Early antihypertensive treatment was associated with different rates of 3-month recurrent stroke (patients with hypertension: OR, 0.44; 95% CI, 0.25-0.77 vs without hypertension: OR, 3.43; 95% CI, 0.94-12.55; P = .005 for homogeneity) and vascular events (patients with hypertension: OR, 0.66; 95% CI, 0.43-1.02 vs those without hypertension: OR, 1.91; 95% CI, 0.75-4.83; P = .04 for homogeneity) by hypertension history. Conclusions and Relevance: Among patients with acute ischemic stroke, early antihypertensive treatment was not associated with different death and major disability outcomes by hypertension history. However, early antihypertension therapy was associated with a decreased rate of recurrent stroke among patients with a history of hypertension and may inform future studies in the optimal approach to hypertension management in the setting of acute ischemic stroke. Trial Registration: ClinicalTrials.gov identifier: NCT01840072.

Co-Effect of Serum Galectin-3 and High-Density Lipoprotein Cholesterol on the Prognosis of Acute Ischemic Stroke.

GOAL: The association of combined galectin-3 and high-density lipoprotein cholesterol (HDL-C) with prognosis of acute ischemic stroke remains unknown. This study aimed to evaluate the coeffect of galectin-3 and HDL-C on death and vascular events within 1 year after ischemic stroke. MATERIALS AND METHODS: Based on China Antihypertensive Trial in Acute Ischemic Stroke, a prospective study was conducted among 2970 patients with acute ischemic stroke. The primary outcome was a combination of death and vascular events within 1 year after ischemic stroke. The secondary outcomes were separately those of recurrent stroke, vascular events, and death. FINDINGS: The multivariate adjusted hazard ratios (95% confidence intervals) of primary outcome, recurrent stroke, and vascular events were 1.54 (1.07-2.20), 1.78 (1.08-2.95), and 1.92 (1.26-2.94), respectively, in patients with both high galectin-3 and low HDL-C compared to those with both low galectin-3 and high HDL-C. The addition of galectin-3 and HDL-C to conventional factors significantly improved predictive value. Net reclassification index was 15.7% for primary outcome, 18.3% for recurrent stroke, and 20.5% for vascular events. CONCLUSION: Combination of high galectin-3 and low HDL-C was associated with primary outcome, recurrent stroke, and vascular events within 1 year after ischemic stroke, suggesting that the combination of galectin-3 and HDL-C may be used to identify the individuals at risk of poor prognosis after ischemic stroke.

Platelet counts affect the prognostic value of homocysteine in acute ischemic stroke patients.

BACKGROUND AND AIMS: The association between homocysteine and prognosis of ischemic stroke remains controversial, and the role of platelet count on the effects of homocysteine in the prognosis of ischemic stroke is still not elucidated. METHODS: A total of 3229 acute ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) with homocysteine and platelet measurements were included in this analysis. They were prospectively followed up for death, recurrent stroke and vascular events within 1 year after acute ischemic stroke. RESULTS: There was a significant interaction effect between platelet count and homocysteine level on death (p for interaction < 0.05) within 1 year after ischemic stroke. After multivariate adjustment, high homocysteine level was associated with increased risk of 1-year mortality in patients with low platelet level (hazard ratio, 1.70; 95% confidence interval, 1.01-2.88) but not in those with high platelet level (hazard ratio, 1.08; 95% confidence interval, 0.65-1.75). The addition of homocysteine to a model containing conventional risk factors improved risk prediction of 1-year death (net reclassification index 0.53%, p < 0.001; integrated discrimination improvement 0.07%, p < 0.001). CONCLUSIONS: High homocysteine may be merely an independent risk factor of death in ischemic stroke patients with low platelet levels. Further prospective studies from other populations and randomized clinical trials are needed to verify our findings and clarify the potential mechanisms.

Increased Serum Netrin-1 Is Associated With Improved Prognosis of Ischemic Stroke.

Background and Purpose- Previous experimental studies suggested that serum netrin-1 was associated with the progression of ischemic stroke. Knowledge about netrin-1 among ischemic stroke patients may provide new ideas for the prognostic assessment of ischemic stroke. The aim of this study was to investigate the association between serum netrin-1 and prognosis of ischemic stroke. Methods- Serum netrin-1 levels at baseline were measured for 3346 ischemic stroke patients from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke), and all patients were followed up at 3 months after stroke onset. The primary outcome was a combination of death and major disability (modified Rankin Scale score of ≥3) within 3 months after stroke onset. Results- Up to 3 months after stroke onset, 845 patients (25.25%) experienced death or major disability. After adjustment for baseline National Institutes of Health Stroke Scale score and other potential confounders, elevated serum netrin-1 was associated with a decreased risk of primary outcome (odds ratio, 0.65; 95% CI, 0.47-0.88; Ptrend=0.002) when 2 extreme quartiles were compared. Each SD increase of log-transformed netrin-1 was associated with 17% (95% CI, 7%-26%) decreased risk of primary outcome. Multivariable-adjusted spline regression models showed a negative linear dose-response relationship between serum netrin-1 and the risk of primary outcome ( Plinearity=0.003). Adding netrin-1 quartile to a model containing conventional risk factors improved risk prediction for primary outcome (net reclassification improvement index =14.74%; P=0.002; integrated discrimination improvement =0.40%; P=0.005). Conclusions- Elevated serum netrin-1 levels were associated with improved prognosis at 3 months after ischemic stroke, suggesting that serum netrin-1 may be a potential prognostic biomarker for ischemic stroke. Further studies from other samples of ischemic stroke patients are needed to replicate our findings and to clarify the potential mechanisms. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01840072.

Family history of stroke and death or vascular events within one year after ischemic stroke.

BACKGROUND AND AIMS: The association between family history of stroke and clinical outcomes after ischemic stroke remains unclear. METHODS: A total of 3878 acute ischemic stroke patients from CATIS were included. The participants with ischemic stroke were divided into groups according to types of family history of stroke, stroke onset age and stroke subtypes. The primary outcome was a composite outcome of death and vascular events within 1 year after stroke. Multivariable Cox proportional hazard models were used to analyze the association between family history of stroke and other variables and clinical outcomes. RESULTS: Among 3878 ischemic stroke patients, 708 (18.26%) had a history of stroke in their first-degree relatives and 399 experienced a composite outcome (172 patients died and 227 experienced vascular events) within 1 year after stroke. Overall family history was not associated with the primary outcome (HR, 1.08; 95% CI, 0.37-3.19). However, the patients with maternal stroke history (HR, 1.87; 95% CI, 1.31-2.97), stroke onset age<55 years with family history (HR, 2.02; 95% CI, 1.08-3.80) and thrombotic stroke in the patients with family history (HR, 1.46; 95% CI, 1.00-2.12) were associated with primary outcome, death and vascular events, respectively. CONCLUSION: This study suggests that maternal stroke history, age<55 years at stroke onset and thrombotic stroke in the patients with a family history are associated with poor outcomes after stroke. Further studies from other samples are needed to replicate our findings due to a reason for excluding some severe stroke patients in this study.

Serum Dkk-1 (Dickkopf-1) Is a Potential Biomarker in the Prediction of Clinical Outcomes Among Patients With Acute Ischemic Stroke.

Objective- Serum Dkk-1 (dickkopf-1) level has been shown to be elevated in patients with ischemic stroke, but its impact on clinical outcomes of ischemic stroke remains unclear. The aim of this study is to investigate the association between serum Dkk-1 and prognosis of ischemic stroke. Approach and Results- We measured serum Dkk-1 levels in 3178 patients with ischemic stroke from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). The primary outcome was a combination of all-cause mortality and major disability (modified Rankin scale score, ≥3) at 1 year after stroke. Secondary outcomes were stroke recurrence and vascular events. After multivariate adjustment, elevated Dkk-1 levels were associated with an increased risk of primary outcome (odds ratio, 1.40; 95% CI, 1.03-1.89; Ptrend=0.015) when 2 extreme quartiles were compared. Each SD increase of log-transformed Dkk-1 was associated with 12% (95% CI, 1%-24%) increased risk of primary outcome. Multiple-adjusted spline regression model showed a linear association between serum Dkk-1 and risk of primary outcome ( P for linearity, 0.039). Subgroup analyses further confirmed these associations. The addition of serum Dkk-1 to conventional risk factors improved the predictive power for primary outcome (net reclassification improvement: 10.11%, P=0.029; integrated discrimination improvement: 0.21%, P=0.028). Conclusions- High serum Dkk-1 levels at baseline were associated with poor prognosis at 1 year after ischemic stroke, suggesting that serum Dkk-1 may be a potential prognostic biomarker for ischemic stroke. Further studies from other samples of patients with ischemic stroke are needed to replicate our findings and to clarify the potential mechanisms.

Multiple biomarkers covering distinct pathways for predicting outcomes after ischemic stroke.

OBJECTIVE: To study the prognostic significance of multiple novel biomarkers in combination after ischemic stroke. METHODS: We derived data from the China Antihypertensive Trial in Acute Ischemic Stroke, and 12 informative biomarkers were measured. The primary outcome was the combination of death and major disability (modified Rankin Scale score ≥3) at 3 months after ischemic stroke, and secondary outcomes included major disability, death, and vascular events. RESULTS: In 3,405 participants, 866 participants (25.4%) experienced major disability or died within 3 months. In multivariable analyses, elevated high-sensitive C-reactive protein, complement C3, matrix metalloproteinase-9, hepatocyte growth factor, and antiphosphatidylserine antibodies were individually associated with the primary outcome. Participants with a larger number of elevated biomarkers had increased risk of all study outcomes. The adjusted odds ratios (95% confidence intervals) of participants with 5 elevated biomarkers were 3.88 (2.05-7.36) for the primary outcome, 2.81 (1.49-5.33) for major disability, 5.67 (1.09-29.52) for death, and 4.00 (1.22-13.14) for vascular events, compared to those with no elevated biomarkers. Simultaneously adding these 5 biomarkers to the basic model with traditional risk factors led to substantial reclassification for the combined outcome (net reclassification improvement 28.5%, p < 0.001; integrated discrimination improvement 2.2%, p < 0.001) and vascular events (net reclassification improvement 37.0%, p = 0.001; integrated discrimination improvement 0.8%, p = 0.001). CONCLUSION: We observed a clear gradient relationship between the numbers of elevated novel biomarkers and risk of major disability, mortality, and vascular events. Incorporation of a combination of multiple biomarkers observed substantially improved the risk stratification for adverse outcomes in ischemic stroke patients.

Systolic Blood Pressure Trajectories in the Acute Phase and Clinical Outcomes in 2-Year Follow-up Among Patients With Ischemic Stroke.

BACKGROUND: Optimal blood pressure (BP) levels during acute ischemic stroke have not been established. We studied associations between systolic BP trajectories during acute phase and subsequent clinical outcomes among patients with ischemic stroke. METHODS: A total of 4,036 patients with acute ischemic stroke and elevated BP from the China Antihypertensive Trial in Acute Ischemic Stroke trial were included in this analysis. Three BPs were measured every 2 hours in day 1, every 4 hours during days 2 and 3, and every 8 hours thereafter until hospital discharge or death. Clinical outcomes were assessed at 3, 12, and 24 months. Latent variable mixture modeling was used to identify subgroups that share a similar underlying trajectory of systolic BP during the first 7 days after stroke onset. Logistic regression and Cox proportional hazards models were used to examine the associations between systolic BP trajectories and clinical outcomes during follow-up. RESULTS: We identified 5 systolic BP trajectories of high, high-to-moderate-low, moderate-high, moderate-low, and low. Compared to participants in high trajectory, multiple-adjusted odds ratios (95% confidence interval) of all-cause mortality at 3 months for individuals in high-to-moderate-low, moderate-high, moderate-low, and low were 0.34 (0.15-0.77), 0.58 (0.32-1.04), 0.29 (0.15-0.56), and 0.56 (0.26-1.19), respectively. Likewise, the corresponding hazard ratios for all-cause mortality in 24 months were 0.66 (0.44-1.00), 0.74 (0.53-1.05), 0.45 (0.32-0.66), and 0.61 (0.40-0.93), respectively. Similar associations were observed for recurrent stroke and cardiovascular disease, and in both the intervention and control groups. CONCLUSIONS: Patients with moderate-low systolic BP during acute ischemic stroke had a lower risk of adverse clinical outcomes.

Elevated C-reactive Protein and Depressed High-density Lipoprotein Cholesterol are Associated with Poor Function Outcome After Ischemic Stroke.

AIMS: C-reactive protein is an established marker of inflammation that can impair the protective function of High Density Lipoprotein Cholesterol (HDL-C). The combined effect of Creactive protein and HDL-C on long-term outcomes in patients with stroke remains uncertain. METHODS: A total of 3124 acute ischemic stroke subjects from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) were included in this analysis. Participants were divided into four groups according to CRP and HDL-C levels on admission. The primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at one year after stroke. RESULTS: Compared to participants with low CRP/ high HDL-C, adjusted odd ratios for primary outcome for those with low CRP /low HDL-C, high CRP /high HDL-C and high CRP /low HDL-C were 1.06(0.81-1.39),1.78(1.31-2.41) and 2.03(1.46-2.80), respectively, after multiple adjustments. Adding serum CRP and HDL-C status to a model containing conventional stroke risk factors significantly improve risk reclassification for the combined outcome of death and major disability (NRI: 6.85%, P=0.005; IDI: 2.57%, P=0.002). Moreover, no interaction was observed between CRP and HDL-C in relation to stroke outcomes (P-interaction >0.05 for all). CONCLUSIONS: High CRP with low HDL-C levels was associated with death and major disability within one year after ischemic stroke. The findings suggest that the ischemic patients with both high CRP and low HDL-C should be treated with reducing CRP and promoting HDL-C levels.

Prognostic Value of White Blood Cell in Acute Ischemic Stroke Patients.

BACKGROUND AND AIMS: It is unclear whether white blood cell on admission has a prognosis value on ischemic stroke and whether its function is affected by other inflammation factors. We hypothesized that elevated white blood cell is associated with stroke severity and 3-month mortality after acute ischemic stroke. METHODS: A total of 3891 acute ischemic stroke subjects from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) were included in this analysis. Participants were divided into four groups according to quartiles of white blood cell on admission (cutoff points for the quintiles: 5.60×109/L,6.83×109/L,8.50×109/L). The primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at 3 months. Secondary outcomes were major disability, death, and vascular events, respectively. RESULTS: After adjustment for major conventional risk factors, elevated white blood cell on admission was associated with poor primary and secondary outcomes after acute ischemic stroke. Compared with the lowest quartile, the ORs (95% CIs) for the highest quartile were 1.79 (1.37-2.91) and 1.62 (1.21-3.55) for primary outcome in model 1 and model 2. In addition, there was a linear association between white blood cell and primary outcome at 3-months (P for linear trend = 0.001). CONCLUSION: This analysis indicated that elevated white blood cell on admission is associated with 3-months poor prognosis in ischemic stroke patients independently of other inflammation factors. The results emphasize the need for further research on the application of anti-inflammatory therapy.