The joint association of lipoprotein(a) and Lp-PLA2 with the risk of stroke recurrence.

BACKGROUND AND PURPOSE: Currently little is known about the joint association of lipoprotein (a) [Lp(a)] and Lipoprotein-associated phospholipase A2 (Lp-PLA2) with stroke recurrence. METHODS: In this prospective multicenter cohort study, 10,675 consecutive acute ischemic stroke (IS) and transient ischemic attack patients (TIA) with Lp(a) and Lp-PLA2 were enrolled. The association of stroke recurrence within 1 year with Lp(a) and Lp-PLA2 was assessed using Cox proportional hazards models and Kaplan-Meier curves. The interaction between Lp(a) and Lp-PLA2 with stroke recurrence was evaluated by multiplicative and additive scales. RESULTS: A significant joint association of Lp(a) and Lp-PLA2 with the risk of stroke recurrence was observed. Multivariate cox regression analysis demonstrated that the combination of elevated Lp(a) (≥ 50 mg/dL) and Lp-PLA2 (≥175.1 ng/ml) was independently associated with the risk of stroke recurrence (adjusted hazard ratio: 1.42; 95 % CI: 1.15-1.76). Both significant multiplicative [(exp(ß3):1.63, 95 % CI: 1.17-2.29, P = 0.004] and additive interaction (RERI:0.55, 95 % CI: 0.20-0.90, P = 0.002; AP: 0.39, 95 %CI, 0.24-0.53) were observed between Lp(a) and Lp-PLA2. CONCLUSIONS: Our results indicated that Lp(a) and Lp-PLA2 have a joint association with the risk of stroke recurrence in IS/TIA patients. Patients with concomitant presence of elevated Lp(a) and Lp-PLA2 have greater risk of stroke recurrence.

Colchicine in patients with acute ischaemic stroke or transient ischaemic attack (CHANCE-3): multicentre, double blind, randomised, placebo controlled trial.

OBJECTIVES: To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3). DESIGN: Multicentre, double blind, randomised, placebo controlled trial. SETTING: 244 hospitals in China between 11 August 2022 and 13 April 2023. PARTICIPANTS: 8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled. INTERVENTIONS: Patients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days. MAIN OUTCOME MEASURES: The primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat. RESULTS: 4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83). CONCLUSIONS: The study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05439356.

The Influence of Non-High-Density Lipoprotein Cholesterol on the Efficacy of Genotype-Guided Dual Antiplatelet Therapy in Preventing Stroke Recurrence.

BACKGROUND AND PURPOSE: Non-high-density lipoprotein cholesterol (non-HDL-C), which represents the total cholesterol content of all pro-atherogenic lipoproteins, has recently been included as a new target for lipid-lowering therapy in high-risk atherosclerotic patients in multiple guidelines. Herein, we aimed to explore the relationship between non-HDL-C level and the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in preventing stroke recurrence. METHODS: This study comprised a post hoc analysis of the CHANCE-2 (Ticagrelor or Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II) trial, from which 5,901 patients with complete data on non-HDL-C were included and categorized by median non-HDL-C levels, using a cutoff of 3.5 mmol/L. The primary efficacy and safety outcomes were recurrent stroke and severe or moderate bleeding within 90 days. RESULTS: Ticagrelor-aspirin significantly reduced the risk of recurrent stroke in patients with low non-HDL-C (71 [4.8%] vs. 119 [7.7%]; adjusted hazard ratio [HR] 0.54; 95% confidence interval [CI], 0.40-0.74), but not in those with high non-HDL-C (107 [7.3%] vs. 108 [7.6%]; adjusted HR, 0.88; 95% CI, 0.67-1.16), compared with clopidogrel-aspirin (P for interaction=0.010). When analyzed as a continuous variable, the benefit of ticagrelor-aspirin for recurrent stroke decreased as non-HDL-C levels increased. No significant differences in the treatment assignments across the non-HDL-C groups were observed in terms of the rate of severe or moderate bleeding (5 [0.3%] vs. 8 [0.5%] in the low non-HDL-C group; 4 [0.3%] vs. 2 [0.1%] in the high non-HDL-C group; P for interaction=0.425). CONCLUSION: CHANCE-2 participants with low non-HDL-C levels received more clinical benefit from ticagrelor-aspirin versus clopidogrel-aspirin compared to those with high non-HDL-C, following minor ischemic stroke or transient ischemic attack.

Immediate- or Delayed-Intensive Statin in Acute Cerebral Ischemia: The INSPIRES Randomized Clinical Trial.

Importance: Comparisons are limited for immediate-intensive and delayed-intensive statin for secondary stroke prevention and neuroprotection in patients with acute mild ischemic stroke or transient ischemic attack (TIA) from atherosclerosis. Objective: To estimate whether immediate-intensive statin therapy is safe and can lower the risk of recurrent stroke compared with delayed-intensive statin in patients with acute mild ischemic stroke or high-risk TIA from atherosclerosis. Design, Setting, and Participants: The Intensive Statin and Antiplatelet Therapy for High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial, a double-blind, placebo-controlled, 2 × 2 factorial, randomized clinical trial enrolled patients from September 2018 to October 2022. The trial was conducted at 222 hospitals in China. Patients aged 35 to 80 years with mild ischemic stroke or high-risk TIA of presumed atherosclerosis within 72 hours of symptom onset were assessed. Interventions: Patients were randomly assigned to receive immediate-intensive atorvastatin (80 mg daily on days 1-21; 40 mg daily on days 22-90) or 3-day delayed treatment (placebo for days 1-3, followed by placebo and atorvastatin, 40 mg daily on days 4-21, and then atorvastatin, 40 mg daily on days 22-90). Main Outcomes and Measures: The primary efficacy outcome was new stroke within 90 days, and a secondary efficacy outcome was poor functional outcome. Moderate to severe bleeding was the primary safety outcome. Results: A total of 11 431 patients were assessed for eligibility, and 6100 patients (median [IQR] age, 65 [57-71] years; 3915 men [64.2%]) were enrolled, with 3050 assigned to each treatment group. Within 90 days, new stroke occurred in 245 patients (8.1%) in the immediate-intensive statin group and 256 patients (8.4%) in the delayed group (hazard ratio, 0.95; 95% CI, 0.80-1.13). Poor functional outcome occurred in 299 patients (9.8%) and 348 patients (11.4%) in the immediate-intensive and delayed-intensive statin groups, respectively (odds ratio, 0.83; 95% CI, 0.71-0.98). Moderate to severe bleeding occurred in 23 of 3050 patients (0.8%) and 17 of 3050 patients (0.6%), in the immediate-intensive and delayed-intensive statin groups, respectively. Conclusions and Relevance: Immediate-intensive statin initiated within 72 hours did not reduce the risk of stroke within 90 days and may be associated with improved functional outcomes without significant difference in moderate to severe bleeding, compared with 3-day delayed-intensive statin in Chinese patients with acute mild ischemic stroke or TIA from atherosclerosis. Trial Registration: ClinicalTrials.gov Identifier: NCT03635749.

Efficacy and safety of Ferrous iron on the prevention of Vascular cOgnitive impaiRment among patients with cerebral Infarction/TIA (FAVORITE): rationale and design of a multicentre randomised trial.

BACKGROUND: The incidence of vascular cognitive impairment (VCI) is high in patients suffering from ischaemic stroke or transient ischaemic attack (TIA) or with vascular risk factors. Effective prevention strategies for VCI remain limited. Anaemia or low haemoglobin was found as an independent risk factor for adverse outcomes after acute stroke. Anaemia or low haemoglobin was possibly associated with an increased risk of poststroke cognitive impairment. Whether supplement of ferrous iron to correct anaemia reduces the risk of VCI and improves adverse outcomes in patients with ischaemic cerebrovascular disease remains uncertain. AIM: We aim to introduce the design and rationale of the safety and efficacy of Ferrous iron on the prevention of Vascular cOgnitive impaiRment in patients with cerebral Infarction or TIA (FAVORITE) trial. DESIGN: FAVORITE is a randomised, placebo-controlled, double-blind, multicentre trial that compares supplement of ferrous iron with placebo for recent minor stroke/TIA patients complicated with mild anaemia or iron deficiency: Ferrous succinate sustained-release tablet 0.2 g (corresponding to 70 mg of elemental iron) once daily after or during breakfast for 12 weeks or placebo with much the same colour, smell and size as ferrous iron once daily during or after breakfast for 12 weeks. All paticipants will be followed within the next year. STUDY OUTCOMES: The primary effective outcome is the incidence of VCI at 3 months after randomisation and the primary safety outcome includes any gastrointestinal adverse event during 3 months. DISCUSSION: The FAVORITE trial will clarify whether supplement of ferrous iron to correct low haemoglobin reduces the risk of VCI in patients with recent ischaemic stroke or TIA complicated with mild anaemia or iron deficiency compared with placebo. TRIAL REGISTRATION NUMBER: NCT03891277.

Elevated gut microbiota metabolite bile acids confer protective effects on clinical prognosis in ischemic stroke patients.

Background: There is evidence of an association between the gut microbiota and progression of stroke. However, the relationship between gut microbial metabolites, specifically bile acids (BAs), and post-ischemic stroke disability and poor functional outcomes remains unexplored. Methods: Patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) in the Third China National Stroke Registry were grouped according to total bile acid (TBA) quartile on admission. Association of TBA with disability and poor functional outcomes were evaluated using logistic regression models and restricted cubic splines. Results: Data for 9,536 patients were included. After adjusting for confounders, the risks of disability and poor functional outcomes were significantly lower in the highest TBA quartile than in the lowest TBA quartile at the 3-month follow-up, with respective odds ratios (ORs) of 0.65 (95% confidence interval [CI] 0.55-0.78; p < 0.001) and 0.66 (95% CI 0.55-0.78, p < 0.001). Each standard deviation increase in the TBA level reduced the risks of disability and poor functioning outcomes by 10% (adjusted ORs 0.9 [95% CI 0.83-0.98; p = 0.01] and 0.9 [95% CI 0.83-0.97; p < 0.001], respectively). This association remained similar at the 1-year follow-up. After stratification by TOAST subtype, the risk of disability or a poor functional outcome in patients with the large-artery atherosclerosis or "other" subtype was significantly lower in the highest quartile than in the lowest quartile (p < 0.05). Conclusion: Serum TBA is an independent risk factor for disability and poor functional outcomes after AIS or TIA, and exerts a protective effects on brain.

Plasma sACE-2 and risk of recurrent stroke: a nested case-control analysis.

Introduction The angiotensin-converting enzyme-2 (ACE-2) and its shedding product [soluble ACE-2 (sACE-2)] are implicated in adverse cardiovascular outcomes. However, the relationship between sACE-2 and stroke recurrence is unknown. Herein, we examined the relationship of sACE-2 with stroke recurrence in patients with ischemic stroke or transient ischemic attack (TIA). Methods Data were obtained from the Third China National Stroke Registry (CNSR-Ⅲ). Eligible cases consisted of 494 patients who developed recurrent stroke within 1-year follow-up, 494 controls were selected using age- and sex- matched with a 1:1 case-control ratio. Conditional logistic regressions were used to evaluate the association between sACE-2 and recurrent stroke. The main outcomes were recurrent stroke within 1 year. Results Among 988 patients included in this study, the median (interquartile range) of sACE-2 was 25.17 (12.29-45.56) ng/mL. After adjustment for conventional confounding factors, the odds ratio with 95% confidence interval in the highest quartile versus the lowest quartile was 1.68 (1.12-2.53) for recurrent stroke within 1-year follow-up. Subgroup analysis showed that the association between elevated plasma level of sACE-2 and stroke recurrence was significant in patients with higher systemic inflammation, as indicated by high sensitivity C reactive protein (hsCRP) ≥ 2 mg/L (adjusted OR: 2.33 [95% CI, 1.15-4.72]) and neutrophil (NEUT) counts ≥ median (adjusted OR: 2.66 [95% CI, 1.35-5.23]), but not significant in patients with lower systemic inflammation. Discussion Elevated plasma sACE-2 concentration was associated with increased risk of recurrent stroke.

LDL-C Levels and Bleeding Risk in Patients Taking DAPT After Minor Ischemic Stroke or TIA.

Importance: Evidence on the bleeding risk associated with low-density lipoprotein cholesterol (LDL-C) levels in patients receiving dual antiplatelet therapy (DAPT) remains sparse. Objective: To investigate the association of LDL-C levels with bleeding risk in patients with minor ischemic stroke (MIS) or high-risk transient ischemic attack (HRTIA) receiving DAPT. Design, Setting, and Participants: This cohort study was an analysis of pooled data from 2 randomized, double-blind, placebo-controlled clinical trials in China of patients with MIS or HRTIA who were receiving DAPT: the CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) trial enrolled patients at 114 sites from October 2009 to July 2012, and the CHANCE-2 enrolled patients at 202 centers from September 2019 to March 2021. Both sets of patients were followed up for 90 days. Data analysis was performed from August 2022 to May 2023. Exposures: Baseline LDL-C levels and receipt of ticagrelor-aspirin and clopidogrel-aspirin DAPT. Main Outcomes and Measures: The primary outcome was any bleeding, and the secondary outcome was severe or moderate bleeding within 3 months after randomization. The association of LDL-C levels and all outcomes was assessed by using the Cox proportional hazard model. Hazard ratios (HRs) with 95% CIs were calculated on univariable (unadjusted) Cox regression models. Adjusted HRs (aHRs) and their 95% CIs were calculated on multivariable Cox regression models. Results: In total, 8996 patients with acute MIS or HRTIA who were receiving DAPT were included in the 2 trials, of whom 1066 without serum specimens and 490 patients with missing baseline LDL-C value were excluded. Finally, 7440 patients with DAPT (4486 in the clopidogrel-aspirin group and 2954 in the ticagrelor-aspirin group) were included in this study. The median (IQR) age was 64.32 (56.56-71.30) years, and 2479 patients (33.32%) were women. A total of 270 (3.63%) bleeding events were reported at 3 months, and LDL-C less than 70 mg/dL was associated with an increased risk of both any bleeding (aHR, 1.48; 95% CI, 1.03-2.12), and severe or moderate bleeding (aHR, 2.78; 95% CI, 1.18-6.53). The risk of any bleeding was increased at lower LDL-C levels in the ticagrelor-aspirin group (aHR, 1.71; 95% CI, 1.08-2.72). However, an increased risk of any bleeding was not observed in the clopidogrel-aspirin group (aHR, 1.30; 95% CI, 0.73-2.30). There was no significant association between LDL-C levels and the risk of severe or moderate bleeding in either the ticagrelor-aspirin or clopidogrel-aspirin group. Conclusions and Relevance: These findings suggest that low LDL-C levels are associated with an increased bleeding risk within 3 months among patients with MIS or HRTIA receiving DAPT, especially those taking ticagrelor-aspirin. Weighing the risks and benefits is crucial when simultaneously considering the selection of LDL-C target strategies and DAPT regimens among these patients.

Differential effect of ticagrelor versus clopidogrel by homocysteine levels on risk of recurrent stroke: a post hoc analysis of the CHANCE-2 trial.

BACKGROUND: Elevated homocysteine levels are associated with increased blood coagulation and platelet activity and may modulate the response to antiplatelet therapies. We aimed to investigate the effects of homocysteine levels on the efficacy and safety of ticagrelor-acetylsalicylic acid (ASA) versus clopidogrel-ASA among patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles. METHODS: We conducted a post hoc analysis of the CHANCE-2 (The Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular Events-II) trial. Participants were randomly assigned to treatment with ticagrelor-ASA or clopidogrel-ASA. We categorized participants into groups with elevated and non-elevated homocysteine levels, based on the median level. The primary efficacy outcome was recurrent stroke within 90-day follow-up. The primary safety outcome was severe or moderate bleeding within 90 days. RESULTS: A total of 2740 participants were randomly assigned to receive ticagrelor-ASA and 2700 to receive clopidogrel-ASA. Use of ticagrelor-ASA was associated with a reduced risk of recurrent stroke among participants with elevated homocysteine levels (74 [5.3%] v. 119 [8.5%]; hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.45-0.81), but not among those with non-elevated levels (86 [6.4%] v. 87 [6.7%]; HR 0.97, 95% CI 0.71-1.32; p = 0.04 for interaction). When analyzed as a continuous variable, the benefits of ticagrelor-ASA with regard to recurrent stroke increased as homocysteine levels increased (p = 0.04 for interaction). No significant interaction between homocysteine levels and treatment with regard to severe or moderate bleeding was observed (p = 0.7 for interaction). We found a significant interaction between homocysteine levels and therapy with regard to recurrent stroke in females (p = 0.04 for interaction) but not males. INTERPRETATION: In comparison with clopidogrel-ASA, ticagrelor-ASA conferred more benefit to patients with elevated homocysteine levels, particularly to female patients, in this secondary analysis of a randomized controlled trial involving patients with minor ischemic stroke or TIA. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT04078737.

Impact of alkaline phosphatase on clinical outcomes in patients with ischemic stroke: a nationwide registry analysis.

Background: Data on the association between serum alkaline phosphatase (ALP) levels and clinical outcomes in patients with ischemic stroke (IS) are inconsistent and limited. Therefore, this study aimed to investigate the correlation between ALP and prognosis in patients with IS. Methods: Patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) from the Third China National Stroke Registry were divided into four groups according to the quartiles of serum ALP levels on admission. Cox proportional hazards and logistic regression models were used to evaluate the correlation between ALP and the risk of all-cause mortality, disability (modified Rankin Scale (mRS) score 3-5), and poor functional outcomes (mRS score 3-6). Results: A total of 11,405 patients were included in the study. Higher levels of ALP were associated with all-cause mortality at 3 months (adjusted hazard ratio [HR] per standard deviation [SD]: 1.16; 95% confidence interval (CI): 1.07-1.27; p = 0.001) and 1 year (adjusted HR: 1.11; 95% CI: 1.03-1.20; p = 0.010). At the 3-month follow-up, each SD increase of ALP was associated with a 12 and 14% higher risk of disability (adjusted odds ratio (OR): 1.12; 95% CI: 1.06-1.18; p < 0.001) and poor functional outcomes (adjusted OR: 1.14; 95% CI: 1.08-1.20; p < 0.001). Similar results were observed at the 1-year follow-up. Higher ALP levels were associated with an increased risk of all-cause mortality, disability, and poor functional outcomes in patients with "others" subtypes (including other determined etiology and undetermined etiology) (p < 0.05). Conclusion: Elevated ALP levels were associated with an increased risk of all-cause mortality, disability, and poor function outcomes in patients with IS. Heterogeneity was observed among the subtypes of different etiologies.

Blood Pressure Partially Mediated the Association of Insulin Resistance and Cerebral Small Vessel Disease: A Community-Based Study.

BACKGROUND: Insulin resistance as a significant vascular risk factor has been studied in relation to cerebral small vessel disease (SVD). Evidence suggests that insulin resistance might trigger high blood pressure (BP). Therefore, we aimed to investigate whether insulin resistance impacts SVD with a mediating effect of BP in nondiabetic subjects. METHODS AND RESULTS: PRECISE (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) study participants underwent brain and vascular imaging techniques and metabolomic risk factors measurements. Insulin resistance was evaluated by the insulin sensitivity index and the Homeostatic Model Assessment for Insulin Resistance based on the standard oral glucose tolerance test. On average, 2752 nondiabetic subjects (47.1% men) aged 60.9 years were included. The multivariable logistic regression model and linear regression model tested the association of insulin resistance with BP components (including systolic BP [SBP], diastolic BP (DBP), and pulse pressure [PP]) and SVD, and of BP components with SVD. In the mediation analysis, SBP, DBP, and PP were found to partially mediate the detrimental effect of insulin resistance (assessed by the insulin sensitivity index) on lacunes (mediation percentage: SBP, 31.15%; DBP, 34.21%; PP, 10.43%), white matter hyperintensity (mediation percentage: SBP, 37.34%; DBP, 44.15%; PP, 9.80%), and SVD total burden (mediation percentage: SBP, 42.07%; DBP, 49.29%; PP, 11.71%) (all P<0.05). The mediation analysis results were not significant when using the Homeostatic Model Assessment for Insulin Resistance to assess insulin resistance. CONCLUSIONS: Higher insulin resistance was associated with SVD in this community-dwelling population. The association of insulin resistance with lacunes, white matter hyperintensity, and SVD total burden was explained in part by BP. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03178448.

Efficacy and safety of dual antiplatelet therapy in the elderly for stroke prevention: a subgroup analysis of the CHANCE-2 trial.

OBJECTIVES: Evidence of the optimal antiplatelet therapy for elderly patients who had a stroke is limited, especially those elder than 80 years. This study aimed to explore the efficacy and safety of dual antiplatelet therapy (DAPT) in old-old patients compared with younger patients in the ticagrelor or Clopidogrel with aspirin in High-risk patients with Acute Non-disabling Cerebrovascular Events-II (CHANCE-2) trial. METHODS: CHANCE-2 was a randomised, double-blind, placebo-controlled trial in China involving patients with high-risk transient ischaemic attack or minor stroke with CYP2C19 loss-of-function alleles. In our substudy, all enrolled patients were stratified by age: old-old (≥80 years), young-old (65-80 years) and younger (<65 years). The primary outcomes were stroke recurrence and moderate to severe bleeding within 90 days, respectively. RESULTS: Of all the 6412 patients, 406 (6.3%) were old-old, 2755 (43.0%) were young-old and 3251 (50.7%) were younger. Old-old patients were associated with higher composite vascular events (HR 1.41, 95% CI 1.00 to 1.98, p=0.048), disabling stroke (OR 2.43, 95% CI 1.52 to 3.88, p=0.0002), severe or moderate bleeding (HR 8.40, 95% CI 1.95 to 36.21, p=0.004) and mortality (HR 7.56, 95% CI 2.23 to 25.70, p=0.001) within 90 days. Ticagrelor-aspirin group was associated with lower risks of stroke recurrence within 90 days in younger patients (HR 0.68, 95% CI 0.51 to 0.91, p=0.008), which was no differences in old-old patients. CONCLUSION: Elderly patients aged over 80 in CHANCE-2 trial had higher risks of composite vascular events, disabling stroke, severe or moderate bleeding and mortality within 90 days. Genotype-guided DAPT might not be as effective in old-old patients as in younger ones. TRIAL REGISTRATION NUMBER: NCT04078737.

One-Year Outcomes of Early Therapy With Ticagrelor vs Clopidogrel in CYP2C19 Loss-of-Function Carriers With Stroke or TIA Trial.

BACKGROUND AND OBJECTIVES: The Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II (CHANCE-2) trial showed that among Chinese patients with minor ischemic stroke or transient ischemic attack (TIA) who were carriers of CYP2C19 loss-of-function alleles, dual-antiplatelet therapy with ticagrelor-aspirin reduced the 90-day risk of stroke without increased severe or moderate bleeding compared with clopidogrel-aspirin. However, whether dual-antiplatelet therapy with ticagrelor was superior to clopidogrel beyond the 90 days of follow-up remained unclear. In this study, we reported 1-year follow-up outcomes of the CHANCE-2 trial. METHODS: The CHANCE-2 trial is a randomized, double-blind, placebo-controlled trial at 202 centers in China. Patients with a minor stroke or TIA who carried CYP2C19 loss-of-function alleles were randomized within 24 hours after symptom onset, in a 1:1 ratio, to receive ticagrelor and placebo clopidogrel or to receive clopidogrel and placebo ticagrelor for 90 days; both groups received aspirin for the first 21 days. After day 90, treatment was as per the choice of the clinician and the patient. RESULTS: Among 6,412 patients, the proportion of patients on ticagrelor plus aspirin, clopidogrel plus aspirin, ticagrelor alone, clopidogrel alone, aspirin alone, other antiplatelet, and no antiplatelet beyond month 3 to 1 year was 0.09%, 1.56%, 0.13%, 2.66%, 73.65%, 0.78%, and 21.13% in the ticagrelor-aspirin group and 0.03%, 1.63%, 0.19%, 2.60%, 72.83%, 0.66%, and 22.06% in the clopidogrel-aspirin group, respectively. The primary outcome of new stroke occurred in 252 patients (7.91%) in the ticagrelor-aspirin group and 310 patients (9.73%) in the clopidogrel-aspirin group by 1 year of follow-up (hazard ratio 0.80; 95% CI 0.68-0.95; p = 0.007); new stroke beyond 3 months to 1 year occurred in 61 patients (2.07%) and 67 patients (2.32%) (p = 0.48), respectively. Primary safety outcome of severe or moderate bleeding occurred in 17 patients (0.53%) in the ticagrelor-aspirin group and 20 patients (0.63%) in the clopidogrel-aspirin group (p = 0.61). DISCUSSION: For CYP2C19 loss-of-function allele carriers, early dual-antiplatelet therapy with ticagrelor is superior to clopidogrel at 1 year in reducing recurrent stroke. TRIAL REGISTRATION INFORMATION: URL: clinicaltrials.gov. Unique identifier: NCT04078737. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with minor stroke or TIA with TIACYP2C19 loss-of-function, ticagrelor plus aspirin for 21 days is superior to clopidogrel plus aspirin in reducing the 1-year risk of recurrent stroke.

High-Sensitivity C-reactive Protein and Intracranial Arterial Stenosis Predicted Recurrent Stroke and Dependence or Death in Minor Stroke or Transient Ischemic Attack.

AIMS: Inflammation is associated with vascular events. We aimed to investigate the relationship between high-sensitivity C-reactive protein (hsCRP) levels with and without intracranial arterial stenosis (ICAS) and the prognosis of patients with minor stroke or transient ischemic attack. METHODS: We used data from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events trial (derivation cohort) and the Third China National Stroke Registry (validation cohort). Patients were divided into four groups according to the dichotomy of hsCRP level and ICAS status. The primary outcome was new ischemic stroke within 90 days, and the secondary outcome was dependence or death (Modified Rankin Scale score of 3-6) at 90 days. The associations between hsCRP level with and without ICAS and risk of outcomes were analyzed using multivariate Cox regression and logistic regression models. RESULTS: In the derivation cohort, compared with patients with nonelevated hsCRP levels and no ICAS, those with both elevated hsCRP levels and ICAS had increased risk of recurrent stroke (adjusted hazard ratio [HR], 2.62; 95% confidence interval [CI], 1.28-5.34; p=0.008) and dependence or death (adjusted odds ratio [OR], 7.58; 95% CI, 1.30-44.13; p=0.02). Consistent relationships of elevated hsCRP levels and presence of ICAS with recurrent stroke (adjusted HR, 1.67; 95% CI, 1.13-2.45; p=0.009) and dependence or death (adjusted OR, 1.87; 95% CI, 1.23-2.84; p=0.003) were observed in the validation cohort. CONCLUSION: Concomitant presence of increased hsCRP levels and ICAS was associated with increased risk of stroke recurrence and dependence or death in patients with minor ischemic stroke or transient ischemic attack.

Effects of remnant cholesterol on the efficacy of genotype-guided dual antiplatelet in CYP2C19 loss-of -function carriers with minor stroke or transient ischaemic attack: a post-hoc analysis of the CHANCE-2 trial.

Background: The atherogenicity of remnant cholesterol (RC), a contributor to residual risk of cardiovascular events, has been underlined by recent guidelines. We aimed to evaluate the relationship between RC levels and the efficacy and safety of genotype-guided dual antiplatelet therapy in the CHANCE-2 trial. Methods: This post-hoc study used data from the CHANCE-2 trial, which was a randomised, double-blind, placebo-controlled trial of 6412 patients (aged >40 years) enrolled from 202 hospitals in China, between Sept 23, 2019, and March 22, 2021, who carried CYP2C19 loss-of-function alleles and had either an acute minor stroke or high-risk transient ischaemic attack (TIA), and could start treatment within 24 h of symptom onset. Participants received either (1:1) ticagrelor plus aspirin (control) or clopidogrel plus aspirin (intervention) and the effect of reducing the 3-month risk of any new stroke was assessed (ischemic or haemorrhagic, primary outcome). From the CHANCE-2 study population, we enrolled 5890 patients with complete data on RC. The cutoff point of RC for distinguishing patients with greater benefit from ticagrelor-aspirin versus clopidogrel-aspirin was determined with subpopulation treatment effect pattern plot. The primary efficacy and safety outcome was recurrent stroke and severe or moderate bleeding within 90 days, respectively. CHANCE-2 is registered with ClinicalTrials.gov, NCT04078737. Findings: The cutoff to define elevated RC was 0.91 mmol/L. Ticagrelor-aspirin versus clopidogrel-aspirin was associated with a reduced risk of recurrent stroke in patients with non-elevated RC levels (122 [5.3%] versus 179 [7.8%]; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.54-0.85), but this benefit was absent in those with elevated RC levels (58 [8.4%] versus 48 [7.3%]; HR, 1.10; 95% CI, 0.73-1.65; P-interaction = 0.03). When analyzed as a continuous variable, the benefit of ticagrelor-aspirin on recurrent stroke decreased as RC levels increased. The rates of severe or moderate bleeding between treatment groups were similar across RC categories (0.3% versus 0.3%, P-interaction = 0.95). Interpretation: Our post-hoc findings suggest that RC could be a potential biomarker to discriminate patients who received more benefits from ticagrelor-aspirin versus clopidogrel-aspirin therapy in CYP2C19 loss-of-function carriers with minor stroke or TIA. These findings need to be validated in an independent study. Funding: The National Key Research and Development Program of China, Beijing Natural Science Foundation Haidian original innovation joint fund, Fund for Young Talents of Beijing Medical Management Center, the high-level public health talents, Training Fund for Open Projects at Clinical Institutes and Departments of Capital Medical University; and Salubris.

Adipose tissue specific insulin resistance and prognosis of nondiabetic patients with ischemic stroke.

BACKGROUND: Insulin resistance is linked to atherosclerotic cardiovascular diseases and stroke, whereas less is known about adipose tissue specific insulin resistance and outcomes after ischemic stroke. This study aimed to estimate the association between adipose tissue specific insulin resistance and prognosis of nondiabetic patients with ischemic stroke. METHODS: Patients with ischemic stroke without a history of diabetes mellitus in the Third China National Stroke Registry were included. Adipose tissue specific insulin resistance index (Adipo-IR) was calculated by fasting serum insulin and free fatty acids and categorized into 5 groups according to the quintiles. Outcomes included stroke recurrence (ischemic or hemorrhagic), combined vascular events, all-cause death, and poor outcome (modified Rankin Scale, 3-6) at 12 months after stroke onset. We assessed the association between Adipo-IR and risk of prognosis by multivariable Cox/logistic regression models adjusted for potential covariates. RESULTS: Among 2,222 patients, 69.0% were men with a mean age of 62.5 years. At 12 months, 185 (8.3%) patients had recurrent stroke, 193 (8.7%) had combined vascular events, 58 (2.6%) died, and 250 (11.5%) had a poor outcome. Compared with patients with the lowest quintile, patients with the second, third, fourth, fifth quintiles of the Adipo-IR were associated with an increased risk of stroke recurrence (hazard ratio [HR], 1.77; 95% CI, 1.04-3.03; P = 0.04; HR, 2.19; 95% CI, 1.30-3.68; P = 0.003; HR, 1.84; 95% CI, 1.06-3.21; P = 0.03; HR, 2.11; 95% CI, 1.20-3.71; P = 0.01, respectively) and marginally associated with an increased risk of combined vascular events ( HR, 1.60; 95%CI, 0.97-2.64; P = 0.07; HR, 1.91; 95% CI, 1.17-3.13; P = 0.01; HR, 1.62; 95% CI, 0.96-2.75; P = 0.07; HR, 1.80; 95% CI, 1.05-3.09; P = 0.03, respectively) at 12 months after adjustment for potential covariates. Adipo-IR was not associated with mortality and poor outcome at 12 months. CONCLUSIONS: These findings suggest that adipose tissue specific insulin resistance is independently associated with recurrent stroke and combined vascular events after acute ischemic stroke in nondiabetic patients.

Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke.

BACKGROUND: Dual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (≤24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied. METHODS: In 222 hospitals in China, we conducted a double-blind, randomized, placebo-controlled, two-by-two factorial trial involving patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 21) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90). There was no interaction between this component of the factorial trial design and a second part that compared immediate with delayed statin treatment (not reported here). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding - both assessed within 90 days. RESULTS: A total of 6100 patients were enrolled, with 3050 assigned to each trial group. TIA was the qualifying event for enrollment in 13.1% of the patients. A total of 12.8% of the patients were assigned to a treatment group no more than 24 hours after stroke onset, and 87.2% were assigned after 24 hours and no more than 72 hours after stroke onset. A new stroke occurred in 222 patients (7.3%) in the clopidogrel-aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.008). Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel-aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P = 0.03). CONCLUSIONS: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel-aspirin therapy initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days than aspirin therapy alone but was associated with a low but higher risk of moderate-to-severe bleeding. (Funded by the National Natural Science Foundation of China and others; INSPIRES ClinicalTrials.gov number, NCT03635749.).

One-year direct and indirect costs of ischaemic stroke in China.

BACKGROUND: This is the first real-world study to estimate the direct costs and indirect costs of first-ever ischaemic stroke with 1-year follow-up in China, based on a nationally representative sample. METHODS: Patients were chosen from 20 geographically diverse sites from the nationally representative database China National Stroke Registry-III (CNSR-III). The inclusion criteria were surviving patients who were hospitalised with first-ever ischaemic stroke from February 2017 to February 2018 (the index event); aged 18-80 during the index event; no history of other stroke types. The primary endpoints were direct medical costs, direct non-medical costs, indirect costs and total cost (ie, the sum of all cost components). Patient characteristics and clinical data were extracted from CNSR-III. Stroke-related in-hospital direct medical costs were collected from hospital electronic medical records. The patient survey collected data related to out-of-hospital direct medical costs, direct non-medical costs and indirect costs. The secondary objective was to explore clinical factors associated with cost outcomes through univariate analysis and multiple regression. RESULTS: The study enrolled 520 patients. The total cost was 57 567.48 CNY, with 26 612.67 CNY direct medical costs, 2 787.56 CNY direct non-medical costs and 28 167.25 CNY indirect costs. Univariate analysis showed that longer lengths of stay during the index event, higher National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale scores were associated with higher costs in all categories. Conversely, EuroQol 5 Dimension utility scores were associated with decreased costs except direct non-medical costs. Multiple regressions showed that higher admission NIHSS scores were independently associated with higher direct medical costs, indirect costs and total cost. Higher 3-month utilities were associated with lower total cost. CONCLUSION: This real-world study showed substantial 1-year economic burden following first-ever ischaemic stroke in China, and that indirect costs are a non-negligible driver of costs.

Ticagrelor Versus Clopidogrel in Minor Stroke or Transient Ischemic Attack With Intracranial Artery Stenosis: A Post Hoc Analysis of CHANCE-2.

Background This study aimed to investigate the efficacy and safety of ticagrelor-aspirin versus clopidogrel-aspirin in Chinese patients by the presence and clinical presentation of intracranial artery stenosis (ICAS) using randomized trial data from the CHANCE-2 (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events-II) trial. Methods and Results A total of 6412 patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles were randomized to either the ticagrelor-aspirin or clopidogrel-aspirin group. Patients without imaging of the intracranial artery were excluded from the nonprespecified subgroup analysis of CHANCE-2. All patients included were classified into the following groups: without ICAS, symptomatic ICAS, or asymptomatic ICAS. The primary efficacy outcome was new strokes within 90 days. There were 5893 patients (median age, 64.8 years; 33.9% women) included, and 172 (4.9%), 171 (10.5%), and 57 (7.7%) cases of new strokes occurred within 90 days in the without ICAS, with symptomatic ICAS, and with asymptomatic ICAS groups, respectively. Ticagrelor-aspirin was associated with reduced risk of new stroke in patients without ICAS (62 [3.5%] versus 110 [6.3%]; hazard ratio [HR], 0.57 [95% CI, 0.41-0.78]) but not in those with symptomatic ICAS (HR, 0.77 [95% CI, 0.56-1.05]) or in those with asymptomatic ICAS (HR, 0.77 [95% CI, 0.43-1.38]) compared with clopidogrel-aspirin (P for interaction=0.14). There were no significant differences in the proportion of severe or moderate bleeding events among different ICAS groups. Conclusions Patients without ICAS received a significantly greater benefit from ticagrelor-aspirin than clopidogrel-aspirin after minor ischemic stroke or transient ischemic attack, and there was no statistically significant difference between treatments in patients with symptomatic ICAS or asymptomatic ICAS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737.

Neglected Mendelian causes of stroke in adult Chinese patients who had an ischaemic stroke or transient ischaemic attack.

BACKGROUND AND PURPOSE: Multiple factors play important roles in the occurrence and prognosis of stroke. However, the roles of monogenic variants in all-cause ischaemic stroke have not been systematically investigated. We aim to identify underdiagnosed monogenic stroke in an adult ischaemic stroke/transient ischaemic attack (TIA) cohort (the Third China National Stroke Registry, CNSR-III). METHODS: Targeted next-generation sequencing for 181 genes associated with stroke was conducted on DNA samples from 10 428 patients recruited through CNSR-III. The genetic and clinical data from electronic health records (EHRs) were reviewed for completion of the diagnostic process. We assessed the percentages of individuals with pathogenic or likely pathogenic (P/LP) variants, and the diagnostic yield of pathogenic variants in known monogenic disease genes with associated phenotypes. RESULTS: In total, 1953 individuals harboured at least one P/LP variant out of 10 428 patients. Then, 792 (7.6%) individuals (comprising 759 individuals harbouring one P/LP variant in one gene, 29 individuals harbouring two or more P/LP variants in different genes and 4 individuals with two P/LP variants in ABCC6) were predicted to be at risk for one or more monogenic diseases based on the inheritance pattern. Finally, 230 of 792 individuals manifested a clinical phenotype in the EHR data to support the diagnosis of stroke with a monogenic cause. The most diagnosed Mendelian cause of stroke in the cohort was cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. There were no relationships between age or family history and the incidence of first symptomatic monogenic stroke in patients. CONCLUSION: The rate of monogenic cause of stroke was 2.2% after reviewing the clinical phenotype. Possible reasons that Mendelian causes of stroke may be missed in adult patients who had an ischaemic stroke/TIA include a late onset of stroke symptoms, combination with common vascular risks and the absence of a prominent family history.