Background Stroke disproportionately affects socioeconomically deprived populations, which leads to poor outcomes in disadvantaged groups. This study aimed to assess associations of socioeconomic status (SES) and long‐ and short‐term functional outcome after stroke in Mongolia. Methods A prospective, population‐based incidence stroke study was performed in Ulaanbaatar, Mongolia, between 2019 and 2020. SES indicators were average household family income and highest level of education attainment. The primary outcome was an unfavorable change in functional outcome on the binary modified Rankin Scale (scores 3–6 versus 0–2) measured at 28, 90, and 365 days. Logistic regression was used to analyze the association of SES and outcomes. Generalized linear mixed‐effects models were used to assess associations according to repeated measures of modified Rankin Scale over 12 months, and a mediation analysis aimed to determine the mechanism by which SES affects outcome. Results A total of 2205 patients (mean age, 58.0±12.8 years; 1330 [60.3%] men) were included. Patients with high‐level family income were less likely to have unfavorable short‐term (adjusted odds ratio, 0.36 [95% CI, 0.26–0.49]) and long‐term (adjusted odds ratio, 0.41 [95% CI, 0.30–0.58]) outcomes. Patients with higher SES experience faster recovery from disability within 1 year, and patients with intracerebral hemorrhage have the slowest recovery rate among the stroke subtypes. Mediation analysis revealed that the impact of SES on functional outcome was mostly direct rather than through other mediators. Conclusions Patients with higher SES exhibit a better recovery pattern up to 1 year after stroke. SES directly and significantly influenced stroke outcome.

Aims This study aims to re-analyse the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial using the win ratio approach to better understand the relative contributions of individual outcomes in a composite endpoint.Methods and results We applied an unmatched win ratio analysis to the 11 140 participants of the ADVANCE trial, comparing intervention and control groups for blood pressure and glucose control. Outcomes were prioritized hierarchically by severity: cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, nephropathy, and retinopathy. The ADVANCE trial is registered with ClinicalTrials.gov, number NCT00145925. For blood pressure lowering, the perindopril-indapamide group had a win ratio of 1.11 [95% confidence interval (CI) 1.01-1.22, P = 0.028] compared to placebo and a net benefit of 1.5% (95% CI 0.2%-2.8%) for a number needed to treat (NNT) of 68 patients. For intensive glucose control, the win ratio was 1.10 (95% CI 1.01-1.20, P = 0.027) compared to standard glucose control with a net benefit of 1.6% (95% CI 0.2%-3.0%) for a NNT of 63 patients. When both interventions were combined, the win ratio increased to 1.19 (95% CI 1.04-1.35, P = 0.010) and the NNT decreased to 41 patients. Cardiovascular death and nephropathy were the main contributors to the observed benefits.Conclusion The win ratio approach confirms the robustness of the original ADVANCE findings while providing a more detailed understanding of the relative importance of individual outcomes. This method enhances the interpretation and communication of composite endpoint analyses.

Abstract Background and aims Aside from elevated mean systolic blood pressure (BP), additional measures such as variability, pulse pressure (PP), or mean-arterial pressure (MAP), could be important targets for dementia prevention. This study aimed to investigate these associations in participants with stroke or transient ischaemic attack from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial. Methods Logistic regression models were used to estimate associations of BP parameters with a composite of cognitive decline according to Mini-Mental State Examination scores and/or adjudicated dementia outcomes. Subgroup analysis was conducted by mild cognitive impairment (MCI) at baseline, sex and stroke subtype. Results After 4 (median) years of follow-up of 5,128 participants, 567 (11.1%) developed cognitive decline/dementia. For systolic BP (SBP), the mean, maximum, cumulative load and last measure were associated with higher odds of cognitive decline/dementia. Higher mean SBP conferred the highest odds (odds ratio [OR] 1.23, 95% confidence intervals [CI] 1.08-1.39). For diastolic BP, higher mean, maximum, variability, cumulative load, slope and last measure were associated, but the strongest association was for load (OR 1.29, 95% CI 1.15-1.45). Only the mean PP was associated (OR 1.14, 95% CI 1.00-1.30). For MAP, MAP load showed the strongest association (OR 1.26, 95% 1.13-1.41). Finally, systolic, diastolic and MAP variability showed higher odds in those without MCI (p interaction <0.001). Conclusions Besides higher mean SBP, alternative measures such as variability, cumulative load, slope and last measures of diastolic BP, PP and MAP were associated with cognitive decline/dementia and need further consideration in cognitive decline/dementia prevention. Conflict of interest Sultana Shajahan: nothing to disclose. Mark Woodward: nothing to disclose. Craig S Anderson has received grants from the NHMRC, the Medical Research Foundation (MRF) of the UK, and AstraZeneca paid to his institution; is a consultant to Auzone BioTech Shanghai; reports membership of data and safety monitoring boards for several investigator-initiated clinical trials, and is the Editor-in-Chief of Cerebrovascular Diseases and President-elect of the World Stroke Organisation. Cheryl Carcel is supported by an NHMRC Investigator Grant, Emerging Leadership 1 (APP2009726), Heart Foundation Vanguard grant, and receives research support from Bayer. Linan Chen: nothing to disclose. Ruth Peters is supported by funding from NHMRC paid to her institution. Karin Rådholm: nothing to disclose. Stephen Harrap: nothing to disclose. John Chalmers: nothing to disclose. Katie Harris: nothing to disclose.

BACKGROUND AND AIMS:Blood pressure (BP) lowering reduces cardiovascular disease (CVD) risk; however, the benefits of treating patients with normal systolic BP but elevated diastolic BP remain uncertain. METHODS:Data from 51 randomized controlled trials were pooled to compare BP-lowering effects in participants with and without isolated diastolic hypertension (IDH), defined as systolic BP < 130 mmHg and diastolic BP ≥ 80 mmHg. Treatment effects were stratified across baseline diastolic BP categories (range < 60 to ≥90 mmHg) among individuals with baseline systolic BP < 130 mmHg. Fixed-effect one-stage individual participant data meta-analyses were used, and Cox proportional hazard models, stratified by trial, were applied to analyse the data. RESULTS:Among 358 325 participants, 15 845 (4.4%) had IDH. At a median follow-up of 4.2 years, a 5 mmHg reduction in systolic BP reduced the risk of major cardiovascular events similarly in individuals with IDH [hazard ratio 0.91; 95% confidence interval (CI) 0.82-1.01] and those without IDH (hazard ratio 0.90; 95% CI 0.89-0.92; P for interaction = 1.00). Analyses by baseline diastolic BP showed no evidence of heterogeneity in treatment effects among individuals with baseline systolic BP < 130 mmHg (P for interaction = .26). Relative treatment effects were not statistically different by CVD history, age, prior medication use, and BP measurement methods. CONCLUSIONS:The study found no evidence to suggest that pharmacological BP-lowering therapy in individuals with IDH is less or more effective than in those without IDH. Relative risk reductions also did not diminish in those with lower diastolic BP, down to <60 mmHg at baseline. No meaningful differences across various clinical phenotypes were detected.

Background Besides elevated mean systolic blood pressure (BP), BP variability, pulse pressure (PP), or mean arterial pressure (MAP) could be important targets for dementia prevention. This study investigated these associations in participants with stroke or transient ischemic attack from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial.Methods BP parameters were calculated from measurements for 18 months on six occasions. Risk of cognitive decline according to Mini-Mental State Examination scores and/or adjudicated dementia outcomes per 1-standard deviation higher for each BP parameter was calculated using modified Poisson regression models with a log link. Subgroup analysis was conducted by mild cognitive impairment (MCI) at baseline, sex, and stroke subtype.Results Of 5128 participants recruited between May 1995 and November 1997, 567 (11.1%) developed cognitive decline/dementia after 4 (median) years of follow-up until 2001. For systolic BP (SBP), higher mean, maximum, cumulative load, and last measure were associated with higher risk of cognitive decline/dementia, but mean conferred the highest risk (relative risk 1.18, 95% confidence intervals [CIs] 1.06-1.31). For diastolic BP, higher mean, maximum, variability, cumulative load, slope, and last measure were associated, while load showed the strongest association (1.23, 95% CI 1.12-1.36). Only the mean PP was associated (1.11, 95% CI 1.00-1.24). For MAP, MAP load showed the strongest association (1.20, 95% CI 1.09-1.33). Systolic, diastolic, and MAP variability showed a higher risk in those without MCI.Conclusions Besides mean SBP, higher variability, cumulative load, slope, and last measures of diastolic BP, PP, and MAP were associated with increased risk of cognitive decline/dementia.Clinical Trial Registration This trial was not registered because enrollment began before July 1, 2005.

Abstract Background and aims Although blood pressure (BP) lowering is central to secondary prevention after spontaneous intracerebral hemorrhage (ICH), uncertainties persist regarding the balance of benefits and risks in relation to the intensity of treatment in particular patients, such as the elderly. Methods An individual participant data meta-analysis of RCT in ICH patients (ESPRIT, PROGRESS, RESPECT, and TRIDENT). Intention-to-treat analysis of the primary outcome - time to first recurrent stroke - was undertaken in a fitted one-stage Cox model with a random effect for trial and covariate adjustment. Heterogeneity of treatment in several predefined subgroups was performed by adding the subgroup variable and its interaction with the intervention as fixed effects to the main model. Results The IPDMA included 2944 patients (mean age 59.6 yrs, 33.0% females, and 75.0% Asians) at a median 81 days (IQR 34-256) post-ICH. For an overall mean between-group DBP of 11/5 mmHg over a mean of 40 months of follow-up, recurrent stroke occurred in 96 (7.1%) in the active group versus 152 (11.4%) in the control group (adjusted hazard ratio 0·61, 95%CI 0.48-0.79), with serious adverse events in 311 (20.9%) and 388 (26.6%) of the groups, respectively. There was not heterogeneity of the effect across subgroups. Conclusions Intensive long-term BP lowering after ICH in reducing recurrent stroke benefits all types of patients without serious harms. Conflict of interest

Abstract Background and aims Hypertension is a major risk factor for stroke. Observational studies suggest frailty modifies the impact of hypertension; thus, frail individuals may require different treatment approaches for stroke risk reduction than non-frail individuals. Methods A single-stage individual participant data (IPD) meta-analysis using data from four landmark randomized, double-blind, placebo-controlled antihypertensive trials. Baseline frailty in each trial was assessed using the Frailty Index (FI) as a continuous and binary (FI ≤ 0.21 vs > 0.21) variable. Effects of antihypertensive treatment on outcomes by FI were examined using Fine-Gray models (adjusted for age, sex, education) yielding subdistribution hazard ratios (sHRs) for non-fatal stroke, accounting for the competing risk of mortality, and Cox regression yielding hazard ratios for major cerebrovascular events. Results A total of 24122 participants (mean age 68.5 years; 44% female) were included, with a median follow-up of 4.3 years. The median (interquartile interval) FI was 0.16(0.11–0.23) and 29% had FI > 0.21. The protective effect of antihypertensive treatment on non-fatal stroke was stronger in participants with FI ≤ 0.21 (sHR 0.72, 95% CI:0.63-0.82), than FI > 0.21 (sHR 1.00, 95% CI:0.82–1.23) (interaction P = 0.008, Figure 1). Significant interactions were also observed for major cerebrovascular event (P = 0.015). Conclusions This original IPD meta-analysis examined frailty as a modifier of antihypertensive treatment efficacy and found treatment was less protective against stroke in participants with higher frailty levels. This finding underscoring the importance of incorporating frailty assessments into treatment decisions when initiating antihypertensive treatment to prevent stroke in hypertensive patients. Conflict of interest Linan Chen: nothing to disclose; Katie Harris: nothing to disclose; Xiaoying Chen: nothing to disclose; Craig Anderson: nothing to disclose; John Chalmers: nothing to disclose; Kenneth Rockwood: nothing to disclose; David Ward: nothing to disclose; Ruth Hubbard: nothing to disclose; Ruirui Wang: nothing to disclose; Christine Jenkins: nothing to disclose; Jeff Williamson: nothing to disclose; Mark Woodward: nothing to disclose; Ruth Peters: nothing to disclose. Figure 1 - belongs to Results

AIMS:To determine the association of insulin resistance, assessed using the estimated glucose disposal rate (eGDR), and the risk of adverse clinical outcomes, and determine any effect modification on the efficacy of glucose- and blood pressure (BP)-lowering treatments. MATERIALS AND METHODS:Briefly, 11 140 participants with type 2 diabetes (T2D) were recruited from 20 countries for the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. eGDR was derived from waist circumference, hypertension status and glycated haemoglobin, calculated in 11 081 participants. Multivariable Cox models were used to estimate hazard ratios (HRs) of the association of eGDR with clinical events. RESULTS:Over a median of 5 years of follow-up, 2117 participants (19.1%) experienced a major macrovascular or microvascular event. Compared with individuals in the lowest quarter of eGDR, those in the highest quarter had significantly lower risks of a composite major macrovascular and microvascular event (HR 0.72, 95% CI 0.62-0.84). Similar associations were seen for major macrovascular events (HR 0.68, 95% CI 0.55-0.85), major microvascular events (HR 0.78, 95% CI 0.63-0.96), all-cause mortality (HR 0.69, 95% CI 0.55-0.86), and cardiovascular mortality (HR 0.62, 95% CI 0.45-0.85). No significant effect modification was observed across eGDR quarters for the efficacy or safety of intensive glucose control (vs. standard control) or BP-lowering treatment (vs. placebo). CONCLUSION:These findings highlight the value of eGDR as a prognostic marker for T2D. Intensive glucose- and BP-lowering treatments remain beneficial regardless of insulin resistance status. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00145925.

ABSTRACT Background Frailty is a common syndrome in patients with cardiovascular disease (CVD). Whether frailty modifies the risk of recurrent cardiovascular events in patients with established CVD and obstructive sleep apnoea (OSA) is uncertain. We aimed to determine associations of frailty and the risk of recurrent cardiovascular events in adults with moderate–severe OSA and established CVD. Methods Post hoc analyses of the international Sleep Apnea Cardiovascular Endpoints (SAVE) trial where participants from 89 clinical centres in seven countries with moderate‐to‐severe OSA and established CVD were randomised to usual care plus continuous positive airway pressure (CPAP) treatment or usual care alone. Participants were categorised using the Rockwood frailty index (FI) into three groups: nonfrail (FI ≤ 0.210), moderately frail (FI 0.211–0.310) and severely frail (FI ≥ 0.311). Cox proportional hazards models were used to assess associations of FI and both composite and individual cardiovascular outcomes over an average follow‐up period of 3.7 years. Results There were 2653 OSA participants (mean age 61.3 [SD 7.8] years, and 507 [19.1%] were female) with established CVD included with a mean FI of 0.290 (SD 0.125). There were 783 (29.5%) and 1006 (37.9%) classified as moderately and severely frail, respectively. Compared to those without frailty, those with severe frailty had increased risks of the composite cardiovascular endpoint (hazard ratio [HR], 2.41; 95% confidence interval [CI], 1.88–3.11), and separately for stroke (HR, 2.40; 95% CI, 1.54–3.74), hospitalisation for unstable angina (HR, 2.94; 95% CI, 1.98–4.35), all‐cause mortality (HR, 1.77; 95% CI, 1.01–3.11) and CVD death (HR, 2.51; 95% CI, 1.13–5.60), during a mean 3.7 years of follow‐up. There was a similar level of adherence to CPAP treatment (p = 0.488) across baseline frailty groups and no heterogeneity in the effect of CPAP treatment on composite and separate cardiovascular events. Conclusions In the SAVE cohort of adults with co‐occurring OSA and CVD, a higher FI was associated with significantly higher risk of recurrent cardiovascular events. Frailty did not modify CPAP treatment adherence or the effect of CPAP on recurrent cardiovascular events. Trial Registration: ClinicalTrials.gov identifier: NCT00738179.

Abstract Background and aims The Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial (TRIDENT) was a multinational, double-blind, randomized, placebo-controlled trial involving intracerebral hemorrhage (ICH) patients comparing a single antihypertensive Triple-Pill (telmisartan 20mg, amlodipine 2.5mg, indapamide 1.25mg) with matching placebo. The Triple-Pill significantly prevented recurrent stroke in relation to a between-group blood pressure (BP) difference of 9/4 mmHg over a mean 3-years of follow-up. We aimed to assess the success of blinding of treatment in relation to BP reduction by the Triple-Pill. Methods 1670 adults with clinically-stable spontaneous ICH and mild–moderate hypertension (SBP 130-160mmHg) were randomized to Triple-Pill or placebo at 57 sites in 10 countries during 2017-2025. After database lock, and before un-blinding of treatment assignment, investigators were asked to guess the treatment allocation of each participant at their site. Results Investigators provided pre-unblinding treatment guesses for 1,293 (77%) participants. Overall accuracy was 55% (95%CI 52–57), and broadly similar for the Triple-Pill (56%, 95%CI 52–60) and placebo (53%, 95%CI 49–57) (p=0.29). The Bang Blinding Indices for the Triple-Pill and placebo were 0.12 (95%CI 0.05 to 0.20) and 0.06 (95%CI -0.02 to 0.14), respectively. Conclusions Investigators were scarcely better than chance in guessing whether TRIDENT participants were allocated to the Triple-Pill or placebo, supporting successful blinding in the trial. Clinical judgment of BP response is limited because of the large natural variability in BP. Conflict of interest Ruth Freed: nothing to disclose; Craig Anderson: Dr Anderson has received grants from the National Health and Medical Research Council (NHMRC), and the Medical Research Foundation (MRF) of the UK,. He is a consultant to Auzone Biotechnology Shanghai, a Chair of the data and safety monitoring boards for several trials, President-elect of the World Stroke Organization, and the Editor-in-Chief of Cerebrovascular Diseases; Anthony Rodgers: Professor Rodgers is employed by The George Institute for Global Health (TGI) and Imperial College London. He is seconded part-time as the Chief Medical Officer of George Medicines Pty Ltd (GM); GM reimburses TGI for this secondment. GM is owned by George Health Enterprises Pty Ltd, which is partly owned by TGI’s social enterprise arm, George Institute Ventures Pty Ltd. TGI has submitted patent applications and has been granted patents for low-dose combination products in hypertension, on which Professor Rodgers is listed as an inventor. TGI has granted GM a licence to the patents and GM has received investment to develop single-pill cardiovascular therapies based on them. Professor Rodgers holds no shares in any of the aforementioned companies and will not receive any royalties from the commercialisation of the patents or sale of the products. Asita de Silva: Nothing to disclose; Lili Song: Nothing to disclose; Catharina Klijn: Nothing to disclose; Kolawole Wahab: Nothing to disclose; Rustam Al-Shahi Salman: Nothing to disclose; John Chalmers: Nothing to disclose; Katie Harris: Nothing to disclose.

INTRODUCTION:The benefits of long-term blood pressure (BP) lowering for the prevention of recurrent stroke and other serious cardiovascular (CV) events in patients who suffer an acute spontaneous intracerebral hemorrhage (ICH) is well established. However, there is uncertainty as to whether the treatment effect varies according to certain patient characteristics and across various CV and non-CV outcomes, and the timing of when the benefits manifest over time. We aim to pool individual participant data (IPD) from randomised controlled trials (RCTs) that included patients with a history of ICH to determine the efficacy of BP lowering for the secondary prevention of major CV events. METHODS AND ANALYSIS:A systematic review was undertaken according to the Preferred Reporting Items for Systematic review and Meta-Analysis of Individual Participant Data (PRISMA-IPD) Statement. A search of multiple databases from inception to 25 January 2026 was conducted to identify RCTs of BP-lowering therapy for secondary prevention after ICH that enrolled at least 100 participants with ICH. We will undertake an IPD meta-analysis, with TRIDENT (Triple therapy prevention of Recurrent Intracerebral Disease EveNts Trial) serving as our anchor study, and three other major RCTs of BP lowering treatment for secondary prevention with a subgroup of at least 100 ICH patients: ESPRIT (Effects of Intensive Systolic Blood Pressure Lowering Treatment in Reducing Risk of Vascular Events) trial, PROGRESS (Perindopril Protection Against Recurrent Stroke Study), and RESPECT (Recurrent Stroke Prevention Clinical Outcome) Study. The primary CV outcome is the time to first recurrent stroke of any type. Secondary outcomes include major adverse cardiovascular events (MACE): non-fatal stroke, non-fatal myocardial infarction, or cardiovascular death; each component of MACE, stroke subtypes, and all-cause death. The safety outcome is any serious adverse event. All analyses will be performed on the intention-to-treat dataset from each trial using a one-stage approach. The effect of the intervention will be estimated as the cause-specific hazard ratio and 95% confidence intervals (CI) obtained from a Cox proportional hazard model, adjusting for age, sex, history of hypertension, and history of diabetes mellitus. A sensitivity analysis will treat death as a competing risk. The time to benefit of BP lowering will also be estimated according to specific absolute risk reduction thresholds.

BACKGROUND:Individuals with chronic kidney disease (CKD), particularly those at more advanced stages, have been systematically under-represented in randomised controlled trials (RCTs) of blood-pressure-lowering treatment due to safety concerns, leading to a persistent paucity of evidence for cardiovascular risk management in this high-risk group. We investigated the effect of blood-pressure-lowering treatment on the risk of major cardiovascular disease and death across the full spectrum of CKD stages and by key clinical subgroups. METHODS:We conducted a one-stage meta-analysis of individual-participant data from RCTs in which participants were randomly assigned to a blood-pressure-lowering therapy versus a comparator. We used RCTs collated in the Blood Pressure Lowering Treatment Trialists' Collaboration dataset, published at any time in any language, which were eligible for inclusion if they had at least 1000 person-years of follow-up per arm, baseline blood-pressure and creatinine measurements, and time-to-event outcomes; those with unclear randomisation procedures or restricted to heart failure or acute care settings were excluded. Participants with a documented history of heart failure or extreme creatinine values were excluded. No age criteria were applied. The primary outcome was major cardiovascular events, defined as a composite of fatal or non-fatal stroke, ischaemic heart disease, or hospitalisation for, or death from, heart failure. Relative treatment effects were estimated with a stratified Cox proportional hazards model. Heterogeneity of treatment effects was evaluated across prespecified subgroups defined by CKD status, CKD stage (1-5), diabetes, proteinuria, and baseline blood pressure. A stratified network meta-analysis was performed to examine whether treatment effects differed by defined subgroups within each of five principal antihypertensive drug classes. The systematic review was registered in PROSPERO (CRD42018099283). FINDINGS:From 52 RCTs (363 684 participants), a total of 285 124 participants from 46 randomised trials met the eligibility criteria; 116 145 (40·7%) were women, 168 979 (59·3%) were men, 59 185 (20·7%) had CKD at baseline, and 86 067 (30·2%) had type 2 diabetes. During a median follow-up of 4·4 years (IQR 3·2-5·1), a 5 mm Hg reduction in systolic blood pressure reduced the risk of major cardiovascular disease in individuals with CKD (hazard ratio [HR] 0·91 [95% CI 0·87-0·94]) and without CKD (0·90 [0·88-0·93]; pinteraction>0·99). Furthermore, these observed relative risk reductions were consistent across all CKD stages, including severe stages 4-5 (pinteraction>0·99). Similar treatment effects were observed by proteinuria status and across blood-pressure categories, down to <120/70 mm Hg. However, the relative treatment effect in individuals with CKD was notably attenuated among those with coexisting diabetes (HR 0·96 [95% CI 0·90-1·02]) compared with those without (0·88 [0·84-0·93]; pinteraction=0·044). The stratified analysis within each drug class showed that the class-specific effects of antihypertensive agents versus placebo on cardiovascular disease risk remained unchanged across the investigated subgroups. INTERPRETATION:In the context of cardiovascular risk reduction, the relative benefit of blood-pressure lowering in patients with CKD is similar to that in individuals without CKD, with consistent efficacy across all CKD stages, blood-pressure thresholds, and proteinuria status. However, notably, this relative benefit is attenuated in patients with CKD and concomitant diabetes, underscoring the requirement for adapted therapeutic strategies in this high-risk subgroup. Moreover, the class-specific effects of principal antihypertensives in CKD mirror those observed in the broader population, independent of CKD stage or proteinuria status. FUNDING:British Heart Foundation.

INTRODUCTION:The aim of the study was to examine early neurological deterioration (END) using different definitions according to the National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS) scores for their ability to predict 90-day unfavorable functional outcomes in acute ischemic stroke (AIS) patients from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS:ENCHANTED was an international, multicenter, 2 × 2 quasi-factorial, prospective, randomized open-trial of low-dose versus standard-dose intravenous alteplase, and intensive versus guideline-recommended blood pressure lowering in thrombolysis-eligible patients with AIS. Mild, moderate, and significant END_NIHSS were defined as an increase in the NIHSS score of ≥1, ≥2, and ≥4 points, respectively. Mild and moderate-significant END_GCS were defined as a decrease in the GCS score of ≥1 and ≥2 points, respectively. In all cases, END also included death within 24 h. Any END was defined as an increase of ≥1 point in the NIHSS score, a decrease of ≥1 point in the GCS score, or death within 24 h. Receiver operating characteristic curve analyses were used to assess the predictive performance of different definitions of END for death or major disability (modified Rankin scale scores: 3-6) and all-cause mortality. RESULTS:Among the 4,434 AIS patients, END ranged from 7.9% to 23.0% depending on definition, with the highest frequency for "any END." The discriminative ability of any END was superior to mild END_NIHSS and mild END_GCS for predicting 90-day death or major disability (area under the curve [AUC] 0.666 vs. 0.638 and 0.616; p < 0.001) and all-cause mortality (AUC 0.722 vs. 0.692 and 0.720; p = 0.001). Compared to patients without any END, those with any END had higher odds of 90-day death or major disability (odds ratio [OR]: 7.04, 95% confidence interval [CI]: 5.87-8.44) and all-cause mortality (OR: 6.27, 95% CI: 4.87-8.07). CONCLUSIONS:In thrombolysis-eligible AIS patients, a broad definition of END identifies more patients with underlying acute neurological deterioration and demonstrated the strongest discriminative ability for 90-day outcomes.

Blood pressure (BP)-lowering therapy reduces cardiovascular risk, but whether its proportional benefits increase with longer treatment duration remains unclear. We conducted an individual participant-level data meta-analysis of 51 randomized trials from the Blood Pressure Lowering Treatment Trialists' Collaboration (358,642 participants; median follow-up: 4.2 years). Using Cox proportional hazards models, we estimated time-stratified hazard ratios (HRs) for major cardiovascular events (MACE; fatal or non-fatal stroke, ischemic heart disease or heart failure) across annual follow-up intervals up to more than 5 years, standardized to a 5-mmHg systolic BP reduction. Network meta-analysis examined whether temporal patterns differed across antihypertensive drug classes. Annual MACE incidence was highest during year 1 (3.0% treatment versus 3.6% control), declined during years 1-5 and then rose at more than 5 years (3.1% versus 3.4%). BP lowering reduced MACE risk, with benefits established early and not progressively increasing over time. A 5-mmHg systolic BP reduction was associated with a 12% lower MACE risk in year 1 (HR = 0.88, 95% confidence interval (CI): 0.84-0.91), with modest attenuation thereafter: HRs were 0.88 (0.85-0.92) in years 1-2, 0.94 (0.90-0.98) in years 2-3, 0.87 (0.83-0.92) in years 3-4, 0.97 (0.91-1.03) in years 4-5 and 0.94 (0.87-1.01) at more than 5 years (P for trend = 0.006). Similar patterns occurred across five drug classes. These findings indicate that the relative cardiovascular benefits of BP lowering emerge within months and do not increase over time, suggesting that prioritizing higher-risk individuals for treatment yields greater clinical utility than prolonged treatment in low-risk individuals.

BACKGROUND:Blood pressure (BP) variability and cumulative BP load are significantly associated with cardiovascular disease risk beyond mean systolic BP, but less is known regarding their associations with cognitive decline/dementia and whether these associations differ by cognitive function at baseline or by sex. The aims of this study were to determine associations of different BP parameters with cognitive decline/dementia in patients with type 2 diabetes and explore differences by mild cognitive impairment at baseline and sex. METHODS:Using data from the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) study, BP parameters were calculated from an 18-month exposure window comprising measurements at 3, 4, 6, 12, and 18 months, after randomization. Logistic regression was used to estimate the odds ratio (OR) per SD higher and 95% CI for the associations of BP parameters with the composite outcome of cognitive decline (≥3 points from baseline on the Mini-Mental State Examination) or clinical diagnosis of dementia. RESULTS:Of the 11 140 ADVANCE participants, 9586 patients had 5 complete BP measurements within the 18-month exposure window. After a mean follow-up of 3.5 years, 1674 (17.5%) participants were diagnosed with cognitive decline and/or dementia. Overall, variability and baseline pulse pressure (PP), but not BP load, were associated with higher odds of cognitive decline/dementia (OR: variability in systolic BP, 1.11 [95% CI, 1.05-1.17]; diastolic BP, 1.11 [95% CI, 1.05-1.17]; PP, 1.05 [95% CI, 1.00-1.11]; mean arterial pressure, 1.13 [95% CI, 1.07-1.19]; and baseline PP, 1.19 [95% CI, 1.13-1.25]). There were no differences by mild cognitive impairment at baseline or sex. CONCLUSIONS:Higher BP variability and baseline PP, but not mean BP or BP load, were associated with higher odds of cognitive decline/dementia in patients with type 2 diabetes. BP variability and PP may be important therapeutic markers for the preservation of brain health. REGISTRATION:URL: https://clinicaltrials.gov; Unique Identifier: NCT00145925.

BACKGROUND:Blood-pressure reduction is the only proven treatment to prevent stroke. Whether a single pill that combines three antihypertensive drugs at low doses, in addition to standard antihypertensive treatment, can lower blood pressure more than standard care alone and reduce the risk of recurrent stroke after intracerebral hemorrhage is uncertain. METHODS:We conducted a multinational, double-blind, randomized, placebo-controlled trial involving patients with a history of intracerebral hemorrhage. Patients were eligible for the trial if they had a systolic blood pressure of 130 to 160 mm Hg at baseline and were in clinically stable condition. After a 2-week active run-in phase during which all the patients received a once-daily pill containing three antihypertensive agents at low doses (telmisartan at 20 mg, amlodipine at 2.5 mg, and indapamide at 1.25 mg; the triple pill), the patients were randomly assigned to continue receiving the triple pill or to receive matching placebo. The primary outcome was the first recurrent stroke. Secondary outcomes included blood-pressure control, major cardiovascular events, death from cardiovascular causes, and safety. RESULTS:Of 1670 patients who underwent randomization, 833 were assigned to receive the triple pill and 837 to receive placebo. The mean age of the patients was 58 years. At a median follow-up of 2.5 years, recurrent stroke had occurred in 38 patients (4.6%) in the triple-pill group and 62 (7.4%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.41 to 0.92; P = 0.02). The mean systolic blood pressure during follow-up was 127 mm Hg and 138 mm Hg, respectively. The incidence of major cardiovascular events was lower with the triple pill than with placebo (6.6% vs. 9.8%; P = 0.04). Serious adverse events occurred in 23.2% of the patients in the triple-pill group and 26.0% of those in the placebo group. Early discontinuation of the trial regimen due to an adverse event occurred in 13.6% and 6.0%, respectively. The most common adverse event leading to discontinuation was an increase of 20% or more in the serum creatinine level. CONCLUSIONS:Among patients with intracerebral hemorrhage, treatment with a combination of three low-dose antihypertensive agents in a single pill, in addition to standard care, was associated with a lower incidence of recurrent stroke and major cardiovascular events than placebo. (Funded by the National Health and Medical Research Council of Australia and the Brazilian Ministry of Health; TRIDENT ClinicalTrials.gov number, NCT02699645; Australian New Zealand Clinical Trials Registry number, ACTRN12616000327482.).

BACKGROUND:Early intensive blood pressure (BP) lowering improves outcome after acute intracerebral hemorrhage (ICH), but the optimal degree of early systolic blood pressure (SBP) reduction remains uncertain. AIMS:We aimed to identify relative SBP reduction thresholds associated with the most favorable functional outcome after ICH. METHODS:We performed an individual participant data meta-analysis of five randomized trials of acute BP lowering in ICH (INTERACT1-4 and ATACH-II). The relative reduction measurements in SBP were defined as the percentage decrease (a) from baseline SBP to the lowest SBP in 1 h (primary) and (b) from baseline SBP to the achieved mean of SBP between 1 and 24 h. Associations with functional outcome, assessed as an unfavorable shift in scores on the modified Rankin scale (mRS) at the end of follow-up (90 or 180 days), were examined in multivariable ordinal logistic regression models and tested for non-linearity using restricted cubic splines. Heterogeneity of associations between the 1-hrelative SBP reduction and functional outcome by age, sex, history of hypertension, history of diabetes, baseline SBP, and hematoma volume was further explored by including each interaction term into the models. RESULTS:Among 11,283 participants (mean age, 62.6 years; 36.0% female; mean baseline SBP, 176.9 mmHg), the association between 1-h relative SBP reduction and unfavorable functional outcome was U-shaped with an inflection nadir at around 20%. Associations differed by sex, baseline SBP, and history of diabetes (all p for interaction <0.05). A similar U-shaped association was also observed in relation to the relative SBP reduction from baseline to the achieved level in 1-24 h, with the greatest apparent benefit at approximately 30%. CONCLUSION:In acute ICH, a first-hour relative SBP reduction of around 20% and a 24-h reduction target of 30%, individualized to the presenting SBP, were associated with the most favorable functional outcome. Larger reductions may attenuate the benefit and should be applied cautiously, particularly in patients with very high baseline SBP.

BACKGROUND:Blood pressure-lowering treatment prevents stroke after spontaneous intracerebral haemorrhage. However, there is uncertainty over the consistency of the effects across clinically relevant subgroups as well as the time course over which benefits accrue. We aimed to pool individual-level data across diverse settings and treatment strategies to quantify the size, heterogeneity, and timing of the effects of blood pressure-lowering treatment for the secondary prevention of major cardiovascular endpoints in patients with a history of intracerebral haemorrhage. METHODS:We did a systematic review and meta-analysis of identified randomised controlled trials evaluating long-term blood pressure-lowering for secondary prevention in adults with a history of spontaneous intracerebral haemorrhage. We searched Embase and Ovid MEDLINE, from database inception to Jan 25, 2026, with two authors (YG and MJV) independently screening titles, abstracts, and full-text articles for eligibility. Trials were eligible if they enrolled adults (aged 18 years or older) with previous spontaneous intracerebral haemorrhage, randomly assigned participants to fixed-dose antihypertensive therapy or an intensive, titrated target-based blood pressure-lowering strategy versus placebo or standard blood pressure management, and reported clinical outcomes. Stroke trials had available individual participant data for subgroups of at least 100 participants with acute intracerebral haemorrhage. Methodological quality was assessed using the Cochrane Risk of Bias 2 tool. The primary outcome was first recurrent stroke of any type. We pooled individual participant data with a one-stage intention-to-treat meta-analysis using Cox proportional hazards models, incorporating a random effect for trial and adjustment for prespecified covariates. Prespecified subgroup analyses included demographic variables and baseline blood pressure, with formal tests for treatment-by-subgroup interaction. We estimated the time to benefit for a clinically meaningful absolute risk reduction, defined as 1% risk difference. The protocol is registered with PROSPERO (CRD420251274994). FINDINGS:Of 236 records screened, 37 trials were retrieved, 24 were assessed for eligibility after duplicates were removed, and four eligible trials provided individual participant data for analysis. 2944 participants were included in the meta-analysis. The mean age was 59·6 years (SD 10·6), 972 (33·0%) were female, 1972 (67·0%) were male, 2218 (75·3%) were Asian, and the median follow-up was 42·0 months (IQR 24·0-66·0). The mean systolic blood pressure difference between blood pressure-lowering treatment and control over follow-up was 11·2 mm Hg (95% CI 10·7-11·7). Intensive blood pressure-lowering reduced the hazard of first recurrent stroke of any type compared with control (96 [6·5%] of 1487 participants versus 152 [10·4%] of 1457 participants; adjusted hazard ratio [HR] 0·62, 95% CI 0·48-0·80; p=0·0002). This finding was driven by fewer recurrent intracerebral haemorrhage events (33 [2·2%] of 1487 participants on blood pressure lowering-treatment versus 81 [5·6%] of 1457 control participants; adjusted HR 0·39, 95% CI 0·26-0·59; p<0·0001). Serious adverse events occurred in 429 (28·9%) of 1487 patients in the intensive group and 481 (33·0%) of 1457 patients in the control group. Treatment effects were consistent across prespecified subgroups (eg, age, sex, region, background blood pressure-lowering treatment, baseline blood pressure, and time since index event). The time to achieve a 1% absolute benefit was estimated to be 6·1 months (95% CI 3·5-14·8). INTERPRETATION:Intensive blood pressure-lowering treatment after spontaneous intracerebral haemorrhage reduces recurrent stroke, mainly by preventing recurrent haemorrhage, without evidence of excess serious adverse events. Effects were consistent across patient characteristics, including time since the index event and baseline level of blood pressure. The early accrual and durability of benefit after treatment initiation strengthens the case for sustained long-term blood pressure control as the cornerstone of secondary prevention after intracerebral haemorrhage. FUNDING:None.

BACKGROUND:The prognostic significance of body weight in patients receiving thrombolysis for acute ischemic stroke remains uncertain. This study aimed to determine whether body weight modifies the comparative effects of low- versus standard-dose intravenous alteplase and to evaluate the associations of body weight and clinical outcomes in patients with acute ischemic stroke. METHODS:A post hoc analysis of the ENCHANTED trial (Enhanced Control of Hypertension and Thrombolysis Stroke Study), an international partial-factorial randomized controlled trial comparing low-dose (0.6 mg/kg) versus standard-dose (0.9 mg/kg) intravenous alteplase and intensive (target systolic blood pressure 130-140 mm Hg) versus guideline-recommended (target systolic blood pressure <180 mm Hg) treatment. The primary outcome was poor functional outcome at 90 days, defined as a modified Rankin Scale score of 2 to 6 (versus 0-1). For the first objective, the exposure was defined as alteplase dose and body weight, whereas for the second objective, body weight alone was considered as the exposure. Logistic regression models were performed to analyze the association between body weight and outcome. The association shape between treatment effect and body weight was evaluated using restricted cubic splines. RESULTS:Among 3206 patients (mean age, 66.6 years; female 37.9%) in the alteplase-dose arm, body weight did not significantly modify the comparative effects of low- versus standard-dose alteplase on functional recovery (Pinteraction=0.60), death (Pinteraction=0.56), or symptomatic intracerebral hemorrhage (Pinteraction=0.46). In the full cohort of 4458 patients (mean age 66.7 years; female 37.8%), a nonlinear relationship was observed between continuous body weight and 90-day modified Rankin Scale score, with an inflection point at ≈74 kg. Patients weighing <74 kg had a significantly higher likelihood of poor functional outcome (odds ratio, 1.41 [95% CI, 1.06-1.87]; P=0.017) and death (1.65 [95% CI, 1.04-2.61]; 0.03), but not an increase in symptomatic intracerebral hemorrhage. CONCLUSIONS:There was no evidence of effect modification by body weight on the effectiveness of low- versus standard-dose intravenous alteplase in patients with acute ischemic stroke. Low body weight predicts a poor outcome but not an increased risk of symptomatic intracerebral hemorrhage after thrombolysis treatment for acute ischemic stroke. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01422616. URL: https://anzctr.org.au; Unique identifier: ACTRN12611000236998.