Early versus delayed antihypertensive treatment in patients with acute ischaemic stroke: multicentre, open label, randomised, controlled trial.

OBJECTIVES: To compared the effect of early antihypertensive treatment started within 24-48 h of stroke onset versus delaying treatment until day eight on reducing dependency or death. DESIGN: Multicentre, randomised, open label trial. SETTING: 106 hospitals in China between 13 June 2018 and 10 July 2022. PARTICIPANTS: 4810 patients (≥40 years) were enrolled with acute ischaemic stroke within 24-48 h of symptom onset and elevated systolic blood pressure between 140 mm Hg and <220 mm Hg. INTERVENTIONS: Patients were randomly assigned to receive antihypertensive treatment immediately after randomisation (aimed at reducing systolic blood pressure by 10%-20% within the first 24 h and a mean blood pressure <140/90 mm Hg within seven days) or to discontinue antihypertensive medications for seven days if they were taking them, and then receive treatment on day 8 (aimed at achieving mean blood pressure <140/90 mm Hg). MAIN OUTCOME MEASURES: The primary outcome was the combination of functional dependency or death (modified Rankin scale score ≥3) at 90 days. Intention to treat analyses were conducted. RESULTS: 2413 patients were assigned to the early treatment group and 2397 were assigned to the delayed treatment group. Mean systolic blood pressure was reduced by 9.7% (from 162.9 mm Hg to 146.4 mm Hg) in the early treatment group and by 4.9% (from 162.8 mm Hg to 154.3 mm Hg) in the delayed treatment group within 24 h after randomisation (P for group difference <0.001). Mean systolic blood pressure was 139.1 mm Hg in the early treatment group and 150.9 mm Hg in the delayed treatment group on day seven (P for group difference <0.001). Additionally, 54.6% of patients in the early treatment group and 22.4% in the delayed treatment group had blood pressure of less than 140/90 mm Hg (P<0.001 for group difference) on day seven. At day 90, 289 trial participants (12.0%) in the early treatment group, compared with 250 (10.5%) in the delayed treatment group, had died or experienced a dependency (odds ratio 1.18 (95% confidence interval 0.98 to 1.41), P=0.08). No significant differences in recurrent stroke or adverse events were reported between the two groups. CONCLUSIONS: Among patients with mild-to-moderate acute ischaemic stroke and systolic blood pressure between 140 mm Hg and <220 mm Hg who did not receive intravenous thrombolytic treatment, early antihypertensive treatment did not reduce the odds of dependency or death at 90 days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03479554.

Effectiveness of a non-physician community health-care provider-led intensive blood pressure intervention versus usual care on cardiovascular disease (CRHCP): an open-label, blinded-endpoint, cluster-randomised trial.

BACKGROUND: Effectiveness of a non-physician community health-care provider-led intensive blood pressure intervention on cardiovascular disease has not been established. We aimed to test the effectiveness of such an intervention compared with usual care on risk of cardiovascular disease and all-cause death among individuals with hypertension. METHODS: In this open-label, blinded-endpoint, cluster-randomised trial, we recruited individuals aged at least 40 years with an untreated systolic blood pressure of at least 140 mm Hg or a diastolic blood pressure of at least 90 mm Hg (≥130 mm Hg and ≥80 mm Hg for those at high risk for cardiovascular disease or if currently taking antihypertensive medication). We randomly assigned (1:1) 326 villages to a non-physician community health-care provider-led intervention or usual care, stratified by provinces, counties, and townships. In the intervention group, trained non-physician community health-care providers initiated and titrated antihypertensive medications according to a simple stepped-care protocol to achieve a systolic blood pressure goal of less than 130 mm Hg and diastolic blood pressure goal of less than 80 mm Hg with supervision from primary care physicians. They also delivered discounted or free antihypertensive medications and health coaching for patients. The primary effectiveness outcome was a composite outcome of myocardial infarction, stroke, heart failure requiring hospitalisation, and cardiovascular disease death during the 36-month follow-up in the study participants. Safety was assessed every 6 months. This trial is registered with ClinicalTrials.gov, NCT03527719. FINDINGS: Between May 8 and Nov 28, 2018, we enrolled 163 villages per group with 33 995 participants. Over 36 months, the net group difference in systolic blood pressure reduction was -23·1 mm Hg (95% CI -24·4 to -21·9; p<0·0001) and in diastolic blood pressure reduction, it was -9·9 mm Hg (-10·6 to -9·3; p<0·0001). Fewer patients in the intervention group than the usual care group had a primary outcome (1·62% vs 2·40% per year; hazard ratio [HR] 0·67, 95% CI 0·61-0·73; p<0·0001). Secondary outcomes were also reduced in the intervention group: myocardial infarction (HR 0·77, 95% CI 0·60-0·98; p=0·037), stroke (0·66, 0·60-0·73; p<0·0001), heart failure (0·58, 0·42-0·81; p=0·0016), cardiovascular disease death (0·70, 0·58-0·83; p<0·0001), and all-cause death (0·85, 0·76-0·95; p=0·0037). The risk reduction of the primary outcome was consistent across subgroups of age, sex, education, antihypertensive medication use, and baseline cardiovascular disease risk. Hypotension was higher in the intervention than in the usual care group (1·75% vs 0·89%; p<0·0001). INTERPRETATION: The non-physician community health-care provider-led intensive blood pressure intervention is effective in reducing cardiovascular disease and death. FUNDING: The Ministry of Science and Technology of China and the Science and Technology Program of Liaoning Province, China.

Comparative Effectiveness of Team-Based Care With and Without a Clinical Decision Support System for Diabetes Management : A Cluster Randomized Trial.

BACKGROUND: Uncontrolled hyperglycemia, hypercholesterolemia, and hypertension are common in persons with diabetes. OBJECTIVE: To compare the effectiveness of team-based care with and without a clinical decision support system (CDSS) in controlling glycemia, lipids, and blood pressure (BP) among patients with type 2 diabetes. DESIGN: Cluster randomized trial. (ClinicalTrials.gov: NCT02835287). SETTING: 38 community health centers in Xiamen, China. PATIENTS: 11 132 persons aged 50 years or older with uncontrolled diabetes and comorbid conditions, 5475 receiving team-based care with a CDSS and 5657 receiving team-based care alone. INTERVENTION: Team-based care was delivered by primary care physicians, health coaches, and diabetes specialists in all centers. In addition, a computerized CDSS, which generated individualized treatment recommendations based on clinical guidelines, was implemented in 19 centers delivering team-based care with a CDSS. MEASUREMENTS: Coprimary outcomes were mean reductions in hemoglobin A1c (HbA1c) level, low-density lipoprotein cholesterol (LDL-C) level, and systolic BP over 18 months and the proportion of participants with all 3 risk factors controlled at 18 months. RESULTS: During the 18-month intervention, HbA1c levels, LDL-C levels, and systolic BP significantly decreased by -0.9 percentage point (95% CI, -0.9 to -0.8 percentage point), -0.49 mmol/L (CI, -0.53 to -0.45 mmol/L) (-19.0 mg/dL [CI, -20.4 to -17.5 mg/dL]), and -9.1 mm Hg (CI, -9.9 to -8.3 mm Hg), respectively, in team-based care with a CDSS and by -0.6 percentage point (CI, -0.7 to -0.5 percentage point), -0.32 mmol/L (CI, -0.35 to -0.29 mmol/L) (-12.5 mg/dL [CI, -13.6 to -11.3 mg/dL]), and -7.5 mm Hg (CI, -8.4 to -6.6 mm Hg), respectively, in team-based care alone. Net differences were -0.2 percentage point (CI, -0.3 to -0.1 percentage point) for HbA1c level, -0.17 mmol/L (CI, -0.21 to -0.12 mmol/L) (-6.5 mg/dL [CI, -8.3 to -4.6 mg/dL]) for LDL-C level, and -1.5 mm Hg (CI, -2.8 to -0.3 mm Hg) for systolic BP. The proportion of patients with controlled HbA1c, LDL-C, and systolic BP was 16.9% (CI, 15.7% to 18.2%) in team-based care with a CDSS and 13.0% (CI, 11.7% to 14.3%) in team-based care alone. LIMITATION: There was no usual care control, and clinical outcome assessors were unblinded; the analysis did not account for multiple comparisons. CONCLUSION: Compared with team-based care alone, team-based care with a CDSS significantly reduced cardiovascular risk factors in patients with diabetes, but the effect was modest. PRIMARY FUNDING SOURCE: Xiamen Municipal Health Commission.

Effects of a Low-Carbohydrate Dietary Intervention on Hemoglobin A1c: A Randomized Clinical Trial.

Importance: Low-carbohydrate diets decrease hemoglobin A1c (HbA1c) among patients with type 2 diabetes at least as much as low-fat diets. However, evidence on the effects of low-carbohydrate diets on HbA1c among individuals with HbA1c in the range of prediabetes to diabetes not treated by diabetes medications is limited. Objective: To study the effect of a behavioral intervention promoting a low-carbohydrate diet compared with usual diet on 6-month changes in HbA1c among individuals with elevated untreated HbA1c. Design, Setting, and Participants: This 6-month randomized clinical trial with 2 parallel groups was conducted from September 2018 to June 2021 at an academic medical center in New Orleans, Louisiana. Laboratory analysts were blinded to assignment. Participants were aged 40 to 70 years with untreated HbA1c of 6.0% to 6.9% (42-52 mmol/mol). Data analysis was performed from November 2021 to September 2022. Interventions: Participants were randomized to a low-carbohydrate diet intervention (target <40 net grams of carbohydrates during the first 3 months; <60 net grams for months 3 to 6) or usual diet. The low-carbohydrate diet group received dietary counseling. Main Outcomes and Measures: Six-month change in HbA1c was the primary outcome. Outcomes were measured at 0, 3, and 6 months. Results: Of 2722 prescreened participants, 962 underwent screening, and 150 were enrolled (mean [SD] age, 58.9 [7.9] years; 108 women [72%]; 88 Black participants [59%]) and randomized to either the low-carbohydrate diet intervention (75 participants) or usual diet (75 participants) group. Six-month data were collected on 142 participants (95%). Mean (SD) HbA1c was 6.16% (0.30%) at baseline. Compared with the usual diet group, the low-carbohydrate diet intervention group had significantly greater 6-month reductions in HbA1c (net difference, -0.23%; 95% CI, -0.32% to -0.14%; P < .001), fasting plasma glucose (-10.3 mg/dL; 95% CI, -15.6 to -4.9 mg/dL; P < .001), and body weight (-5.9 kg; 95% CI, -7.4 to -4.4 kg; P < .001). Conclusions and Relevance: In this randomized clinical trial, a low-carbohydrate dietary intervention led to improvements in glycemia in individuals with elevated HbA1c not taking glucose-lowering medication, but the study was unable to evaluate its effects independently of weight loss. This diet, if sustained, might be a useful dietary approach for preventing and treating type 2 diabetes, but more research is needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03675360.

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

A village doctor-led multifaceted intervention for blood pressure control in rural China: an open, cluster randomised trial.

BACKGROUND: The prevalence of uncontrolled hypertension is high and increasing in low-income and middle-income countries. We tested the effectiveness of a multifaceted intervention for blood pressure control in rural China led by village doctors (community health workers on the front line of primary health care). METHODS: In this open, cluster randomised trial (China Rural Hypertension Control Project), 326 villages that had a regular village doctor and participated in the China New Rural Cooperative Medical Scheme were randomly assigned (1:1) to either village doctor-led multifaceted intervention or enhanced usual care (control), with stratification by provinces, counties, and townships. We recruited individuals aged 40 years or older with an untreated blood pressure of 140/90 mm Hg or higher (≥130/80 mm Hg among those with a history of cardiovascular disease, diabetes, or chronic kidney disease) or a treated blood pressure of 130/80 mm Hg or higher. In the intervention group, trained village doctors initiated and titrated antihypertensive medications according to a standard protocol with supervision from primary care physicians. Village doctors also conducted health coaching on home blood pressure monitoring, lifestyle changes, and medication adherence. The primary outcome (reported here) was the proportion of patients with a blood pressure of less than 130/80 mm Hg at 18 months. The analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03527719, and is ongoing. FINDINGS: Between May 8 and November 28, 2018, we enrolled 33 995 individuals from 163 intervention and 163 control villages. At 18 months, 8865 (57·0%) of 15 414 patients in the intervention group and 2895 (19·9%) of 14 500 patients in the control group had a blood pressure of less than 130/80 mm Hg, with a group difference of 37·0% (95% CI 34·9 to 39·1%; p<0·0001). Mean systolic blood pressure decreased by -26·3 mm Hg (95% CI -27·1 to -25·4) from baseline to 18 months in the intervention group and by -11·8 mm Hg (-12·6 to -11·0) in the control group, with a group difference of -14·5 mm Hg (95% CI -15·7 to -13·3 mm Hg; p<0·0001). Mean diastolic blood pressure decreased by -14·6 mm Hg (-15·1 to -14·2) from baseline to 18 months in the intervention group and by -7·5 mm Hg (-7·9 to -7·2) in the control group, with a group difference of -7·1 mm Hg (-7·7 to -6·5 mm Hg; p<0·0001). No treatment-related serious adverse events were reported in either group. INTERPRETATION: Compared with enhanced usual care, village doctor-led intervention resulted in statistically significant improvements in blood pressure control among rural residents in China. This feasible, effective, and sustainable implementation strategy could be scaled up in rural China and other low-income and middle-income countries for hypertension control. FUNDING: Ministry of Science and Technology of China.

Accuracy of Ankle-Brachial Index, Toe-Brachial Index, and Risk Classification Score in Discriminating Peripheral Artery Disease in Patients With Chronic Kidney Disease.

The accuracy of ankle-brachial index (ABI) and toe-brachial index (TBI) in discriminating lower extremity peripheral artery disease (PAD) has not been evaluated in patients with chronic kidney disease (CKD). We measured ABI, TBI, and Doppler ultrasound in 100 predialysis patients with CKD without revascularization or amputation. Leg-specific ABI was calculated using higher systolic blood pressure (SBP) in posterior tibial or dorsalis pedis artery divided by higher brachial SBP; alternative ABI was calculated using lower SBP in posterior tibial or dorsalis pedis artery. PAD was defined as ≥50% stenosis detected by Doppler ultrasound. PAD risk classification score was calculated using cardiovascular disease risk factors. The area under the curve (AUC, 95% confidence interval [CI]) for discriminating ultrasound-diagnosed PAD was 0.78 (0.69 to 0.87) by ABI, 0.80 (0.71 to 0.89) by alternative ABI, and 0.74 (0.63 to 0.86) by TBI. Sensitivity and specificity were 25% and 97% for ABI ≤0.9, 41% and 95% for alternative ABI ≤0.9, and 45% and 93% for TBI ≤0.7, respectively. AUC (95% CI) of PAD risk classification score was 0.86 (0.78 to 0.94) with sensitivity and specificity of 95% and 60% for risk score ≥0.10, 76% and 76% for risk score ≥0.25, and 43% and 95% for risk score ≥0.55. Combining risk score with ABI, alternative ABI, and TBI increased AUC (95% CI) to 0.89 (0.82 to 0.96), 0.89 (0.80 to 0.98), and 0.87 (0.78 to 0.96), respectively. In conclusion, current ABI and TBI diagnostic criteria have high specificity but low sensitivity for classifying PAD in patients with CKD. PAD classification risk score based on cardiovascular disease risk factors improves the accuracy of PAD classification.

Comparative effectiveness of team-based care with a clinical decision support system versus team-based care alone on cardiovascular risk reduction among patients with diabetes: Rationale and design of the D4C trial.

BACKGROUND: Diabetes has become a major public health challenge worldwide, especially in low- and middle-income countries (LMICs). Uncontrolled hyperglycemia, hypertension, and dyslipidemia major risk factors for all-cause mortality and cardiovascular disease (CVD) are common in patients with diabetes in China. We propose to compare the effectiveness of team-based care plus a clinical decision support system (CDSS) with team-based care alone on glycemic, blood pressure (BP), and lipid control, and clinical CVD reduction among patients with type-2 diabetes and at high risk for CVD. METHODS: The Diabetes Complication Control in Community Clinics (D4C) study is a cluster-randomized trial conducted among 38 community health centers in Xiamen City, China. Nineteen clinics have been randomly assigned to team-based care plus CDSS and 19 to team-based care alone. Team-based care includes primary care providers, health coaches, and diabetes specialists working collaboratively with patients to achieve shared treatment goals for CVD risk factor reduction. The CDSS integrates guideline-based treatment algorithms for glycemic, BP, and lipid control, along with a patient's medical history and insurance policy, to recommend treatment and follow-up plans. In phase 1, the co-primary outcomes are mean reduction in glycated hemoglobin (HbA1c), systolic BP (SBP), and low-density lipoprotein (LDL)-cholesterol over 18 months, and the proportion of patients with controlled HbA1c, SBP, and LDL-cholesterol at 18 months' between the 2 comparison groups. In phase 2, the primary outcome is the difference in major CVD incidence (non-fatal stroke, non-fatal myocardial infarction, hospitalized heart failure, and CVD mortality) between the 2 comparison groups. Mean reduction in HbA1c, SBP, and LDL-cholesterol levels will be simultaneously modeled for a single overall treatment effect. CONCLUSION: The D4C trial will generate evidence on whether a CDSS will further reduce the CVD burden among patients with diabetes beyond team-based care at community clinics. If proven effective, this implementation strategy could be scaled up within primary care settings in China and other LMICs to reduce CVD incidence and mortality among patients with diabetes.

Sodium Sensitivity, Sodium Resistance, and Incidence of Hypertension: A Longitudinal Follow-Up Study of Dietary Sodium Intervention.

[Figure: see text].

Combination Treatment with Sodium Nitrite and Isoquercetin on Endothelial Dysfunction among Patients with CKD: A Randomized Phase 2 Pilot Trial.

BACKGROUND AND OBJECTIVES: Endothelial dysfunction is common among patients with CKD. We tested the efficacy and safety of combination treatment with sodium nitrite and isoquercetin on biomarkers of endothelial dysfunction in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This randomized, double-blind, placebo-controlled phase 2 pilot trial enrolled 70 patients with predialysis CKD. Thirty-five were randomly assigned to combination treatment with sodium nitrite (40 mg twice daily) and isoquercetin (225 mg once daily) for 12 weeks, and 35 were randomly assigned to placebo. The primary outcome was mean change in flow-mediated vasodilation over the 12-week intervention. Secondary and safety outcomes included biomarkers of endothelial dysfunction, inflammation, and oxidative stress as well as kidney function, methemoglobin, and adverse events. Intention-to-treat analysis was conducted. RESULTS: Baseline characteristics, including age, sex, race, cigarette smoking, history of hypertension and diabetes, use of renin-angiotensin system blockers, BP, fasting glucose, lipid profile, kidney function, urine albumin-creatinine ratio, and endothelial biomarkers, were comparable between groups. Over the 12-week intervention, flow-mediated vasodilation increased 1.1% (95% confidence interval, -0.1 to 2.3) in the treatment group and 0.3% (95% confidence interval, -0.9 to 1.5) in the placebo group, and net change was 0.8% (95% confidence interval, -0.9 to 2.5). In addition, changes in biomarkers of endothelial dysfunction (vascular adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, vWf, endostatin, and asymmetric dimethylarginine), inflammation (TNF-α, IL-6, C-reactive protein, IL-1 receptor antagonist, and monocyte chemoattractant protein-1), and oxidative stress (oxidized LDL and nitrotyrosines) were not significantly different between the two groups. Furthermore, changes in eGFR, urine albumin-creatinine ratio, methemoglobin, and adverse events were not significantly different between groups. CONCLUSIONS: This randomized phase 2 pilot trial suggests that combination treatment with sodium nitrite and isoquercetin did not significantly improve flow-mediated vasodilation or other endothelial function biomarkers but also did not increase adverse events compared with placebo among patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Nitrite, Isoquercetin, and Endothelial Dysfunction (NICE), NCT02552888.

Serum cystatin C levels are negatively correlated with post-stroke cognitive dysfunction.

Stroke is the leading cause of death and long-term disability worldwide, and cognitive impairment and dementia are major complications of ischemic stroke. Cystatin C (CysC) has been found to be a neuroprotective factor in animal studies. However, the relationship between CysC levels and cognitive dysfunction in previous studies has revealed different results. This prospective observational study investigated the correlation between serum CysC levels and post-stroke cognitive dysfunction at 3 months. Data from 638 patients were obtained from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). Cognitive dysfunction was assessed using the Mini-Mental State Examination (MMSE) at 3 months after stroke. According to the MMSE score, 308 patients (52.9%) had post-stroke cognitive dysfunction. After adjusting for potential confounding factors, the odds ratio (95% CI) of post-stroke cognitive dysfunction for the highest quartile of serum CysC levels was 0.54 (0.30-0.98), compared with the lowest quartile. The correlation between serum CysC and cognitive dysfunction was modified by renal function status. We observed a negative linear dose-response correlation between CysC and cognitive dysfunction in patients with normal renal function (Plinearity = 0.044), but not in those with abnormal renal function. Elevated serum CysC levels were correlated with a low risk of 3-month cognitive dysfunction in patients with acute ischemic stroke, especially in those with normal renal function. The current results suggest that CysC is a protective factor for post-stroke cognitive dysfunction, and could be used to treat post-stroke cognitive dysfunction. The CATIS study was approved by the Institutional Review Boards at Soochow University from China (approval No. 2012-02) on December 30, 2012, and was registered at ClinicalTrials.gov (identifier No. NCT01840072) on April 25, 2013.

Cluster Randomized Trial for Hypertension Control: Effect on Lifestyles and Body Weight.

INTRODUCTION: Lifestyle modification, such as healthy diet habits, regular physical activity, and maintaining a normal body weight, must be prescribed to all hypertensive individuals. This study aims to test whether a multicomponent intervention is effective in improving lifestyle and body weight among low-income families. STUDY DESIGN: Cluster randomized trial conducted between June 2013 and October 2016. SETTING/PARTICIPANTS: A total of 1,954 uninsured adult patients were recruited in the study within 18 public primary healthcare centers of Argentina. INTERVENTION: Components targeting the healthcare system, providers, and family groups were delivered by community health workers; tailored text messages were sent for 18 months. MAIN OUTCOME MEASURES: Changes in the proportion of behavioral risk factors and body weight from baseline to end of follow-up. Data were analyzed in 2017. RESULTS: Low fruit and vegetable consumption (fewer than 5 servings per day) decreased from 96.4% at baseline to 92.6% at 18 months in the intervention group, whereas in the control group it increased from 97.0% to 99.9% (p=0.0110). The proportion of low physical activity (<600 MET-minutes/week) decreased from 54.3% at baseline to 46.2% at 18 months in the intervention group and kept constant around 52% (p=0.0232) in the control group. The intervention had no effect on alcohol intake (p=0.7807), smoking (p=0.7607), addition of salt while cooking or at the table (p=0.7273), or body weight (p=0.4000). CONCLUSIONS: The multicomponent intervention was effective for increasing fruit and vegetable intake and physical activity with no effect on alcohol consumption, smoking, addition of salt, or body weight among low-income families in Argentina. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT01834131.

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.

Antiphospholipid antibodies predict post-stroke depression after acute ischemic stroke.

BACKGROUND: Antiphospholipid activity was reported to be increased in depressive patients, while the impact of antiphospholipid antibodies (aPLs) on post-stroke depression (PSD) is unclear. We aimed to investigate the associations of aPLs, including antiphosphatidylserine (aPS) and anticardiolipin (aCL) antibodies with depression after acute ischemic stroke. METHODS: aPS and aCL were measured in 497 ischemic stroke patients recruited from 7 of 26 participating hospitals of China Antihypertensive Trial in Acute Ischemic Stroke. 24-item Hamilton Depression Rating Scale was used to evaluate PSD status at 3 months after stroke. RESULTS: Compared with aPS-negative or aCL-negative, the adjusted odds ratios (ORs) [95% confidence intervals (CIs)] associated with aPS-positive or aCL-positive were 1.77 (1.07-2.92) or 2.06 (1.11-3.80) for risk of PSD. On continuous analyses, per 1-SD increment of aPS and aCL were associated with 29% (OR 1.29, 95% CI 1.06-1.58) and 30% (OR 1.30, 95% CI 1.06-1.60) increased risks for PSD, respectively. Adding aPLs to conventional risk factors models significantly improved risk reclassification for PSD (net reclassification improvement index = 21.87%, P = 0.016 for aPS; net reclassification improvement index = 32.24%, P = 0.0004 for aCL). LIMITATIONS: aPLs levels were tested only at baseline without serial measurements, and we were unable to detect the association between aPLs changes and PSD. CONCLUSIONS: Higher aPS and aCL levels in the acute phase of ischemic stroke were associated with increased risk of 3-month PSD, suggesting that aPLs may play an important role in post-stroke depression prediction.

Multiple biomarkers covering several pathways improve predictive ability for cognitive impairment among ischemic stroke patients with elevated blood pressure.

BACKGROUND AND AIMS: We aimed to evaluate the ability of multiple novel biomarkers representing several pathophysiological pathways to improve risk prediction of post-stroke cognitive impairment. METHODS: We conducted a prospective multicenter study in 638 ischemic stroke patients with elevated blood pressure based on a random subsample from China Antihypertensive Trial in Acute Ischemic Stroke and measured 12 circulating biomarkers in these participants. Cognitive impairment was assessed at 3 months after stroke with definitions of Mini-Mental State Examination (MMSE) score <27 or Montreal Cognitive Assessment (MoCA) score <25. RESULTS: According to MMSE score, 1 SD increase of rheumatoid factor (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.02-1.46), matrix metalloproteinase-9 (OR 1.47, 95% CI 1.22-1.77) and total homocysteine (OR 1.22, 95% CI 1.01-1.49) after log transformation was significantly associated with the risk of post-stroke cognitive impairment. The ORs associated with their simultaneously high levels were 4.89 (95% CI, 2.31-10.35; ptrend<0.001) and 3.09 (95% CI, 1.60-5.98; ptrend<0.001) for cognitive impairment and the severity of cognitive impairment, respectively. Adding these 3 biomarkers to conventional model significantly improved the risk prediction of cognitive impairment (C statistic 0.729 vs. 0.688, p = 0.004; net reclassification improvement = 33.67%, p < 0.001; integrated discrimination index = 4.61%; p < 0.001). Similar significant findings were observed when cognitive impairment was defined by MoCA score. CONCLUSIONS: Combination of rheumatoid factor, matrix metalloproteinase-9 and total homocysteine can improve the risk prediction of cognitive impairment among ischemic stroke patients with elevated blood pressure. Further studies are warranted to validate our findings and explore their roles as potential therapeutic targets.

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.

Increased Growth Differentiation Factor 15 Is Associated with Unfavorable Clinical Outcomes of Acute Ischemic Stroke.

BACKGROUND: Growth differentiation factor 15 (GDF-15), a stress-responsive biomarker, is known to be independently associated with mortality and cardiovascular events in different disease settings, but data on the prognostic value of GDF-15 after stroke are limited. METHODS: Baseline serum GDF-15 was measured in 3066 acute ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a composite of death and major disability within 3 months. Secondary outcomes included death, major disability, vascular events, and stroke recurrence. The associations between GDF-15 and clinical outcomes after stroke were assessed by multivariate logistic regression or Cox proportional hazards models. RESULTS: At 3 months' follow-up, 676 (22.05%), 86 (2.80%), 81 (2.64%), and 51 (1.66%) patients had experienced major disability, death, vascular events, or stroke recurrence, respectively. After adjusting for age, sex, current smoking, alcohol consumption, and baseline National Institutes of Health Stroke Scale score, the odds ratio/hazard ratio (95% CI) of 1 SD higher of base-10 log-transformed GDF-15 was 1.26 (1.15-1.39) for primary outcome, 1.13 (1.02-1.25) for major disability, 1.79 (1.48-2.16) for death, and 1.26 (1.00-1.58) for vascular events. The addition of GDF-15 to established risk factors improved risk prediction of the composite outcome of death and major disability (c-statistic, net reclassification index, and integrated discrimination improvement, all P < 0.05). CONCLUSIONS: High GDF-15 concentrations are independently associated with adverse clinical outcomes of acute ischemic stroke, suggesting that baseline serum GDF-15 could provide additional information to identify ischemic stroke patients at high risk of poor prognosis.

Serum Rheumatoid Factor Levels at Acute Phase of Ischemic Stroke are Associated with Poststroke Cognitive Impairment.

BACKGROUND: The effect of serum rheumatoid factor (RF) on poststroke cognitive impairment remains unknown. We aimed to investigate the association of serum RF in the acute phase with cognitive impairment at 3 months after ischemic stroke onset. METHODS: Our study was based on a random sample from the China Antihypertensive Trial in Acute Ischemic Stroke, a total of 582 patients from 7 of 26 participating sites of the trial with serum RF levels were included in this analysis. Cognitive impairment was defined as Mini-Mental State Examination less than 27 or Montreal Cognitive Assessment less than 25. RESULTS: According to Mini-Mental State Examination score, the multivariate-adjusted odds ratio and 95% confidence interval of cognitive impairment for the highest tertile of serum RF was 1.79 (1.08-2.99) compared with the lowest tertile. Each standard deviation increase of log-transformed RF was associated with 33% (95% confidence interval: 7%-66%) increased risk of cognitive impairment, and a linear association between serum RF and risk of poststroke cognitive impairment was observed (P for linearity < .01). Adding log-transformed RF to a model containing conventional risk factors improved the predictive power for poststroke cognitive impairment (net reclassification improvement: 26.21%, P < .01; integrated discrimination index: 1.24%, P = .02). Similar significant findings were observed when cognitive function was defined by Montreal Cognitive Assessment score. CONCLUSIONS: Elevated serum RF levels in the acute phase were independently associated with 3-month cognitive impairment among ischemic stroke patients. Further studies are needed to replicate our findings and to clarify the potential mechanisms.

Genetic variants of cGMP-dependent protein kinase genes and salt sensitivity of blood pressure: the GenSalt study.

Genetic mechanisms involved in the susceptibility to salt sensitivity have not been completely clarified. This study aimed to comprehensively examine the association between genetic variants in the cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG/PRKG) genes and blood pressure (BP) responses to dietary sodium intervention in a Chinese population. A 7-day low-sodium intervention followed by a 7-day high-sodium intervention was conducted among 1906 Han participants from rural areas of northern China. Nine BP measurements were obtained at baseline and each intervention using a random-zero sphygmomanometer. Linear mixed-effect models were used to assess the additive association of 213 tag single-nucleotide polymorphisms (SNPs) in two PRKG genes (PRKG1 and PRKG2) with salt sensitivity phenotypes. Gene-based analyses were conducted using the truncated product method. The Bonferroni method was used to adjust for multiple testing. Mean systolic BP response to low-sodium intervention significantly decreased with the number of minor T allele of marker rs10997916 in PRKG1 (P = 2.4 × 10-5). Mean systolic BP responses (95% confidence interval) among those with genotypes CC, CT, and TT were -5.6 (-6.0, -5.3), -3.7 (-4.7, -2.8), and -1.3 (-4.6, 2.0) mmHg, respectively, during the low-sodium intervention. Gene-based analyses demonstrated that PRKG1 was significantly associated with systolic BP response to low-sodium intervention (P = 1.2 × 10-3), whereas PRKG2 was nominally significantly associated with diastolic BP responses to high-sodium intervention (P = 2.6 × 10-2). The current study suggested a significant association of genetic variants in the PRKG genes with variation of BP response to dietary sodium intake in Han Chinese population. These novel findings merit further replication in future.

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.