Glucose Control and Risk of Symptomatic Intracerebral Hemorrhage Following Thrombolysis for Acute Ischemic Stroke: A SHINE Trial Analysis.

BACKGROUND AND OBJECTIVES: Baseline hyperglycemia is associated with worse outcomes in acute ischemic stroke (AIS), including higher risk of symptomatic intracerebral hemorrhage (sICH) following treatment with thrombolysis. Prospective data are lacking to inform management of post-thrombolysis hyperglycemia. In a prespecified analysis from the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial of hyperglycemic stroke management, we hypothesized that post-thrombolysis hyperglycemia is associated with a higher risk of sICH. METHODS: Hyperglycemic AIS patients <12 hours onset were randomized to intensive insulin (target range 80-130 mg/dL) vs standard sliding scale (80-179 mg/dL) over a 72-hour period, stratified by treatment with thrombolysis. Three board-certified vascular neurologists independently reviewed all sICH events occurring within 7 days, defined by neurologic deterioration of ≥4 points on the NIH Stroke Scale (NIHSS). Associations between blood glucose control and sICH were analyzed using logistic regression accounting for NIHSS, age, systolic blood pressure, onset to thrombolysis time, and endovascular therapy (odds ratios [OR], 95% CI). Additional analysis compared patients in a high-risk group (age older than 60 years and NIHSS ≥8) vs all others. Categorical variables and outcomes were compared using the χ2 test (p < 0.05). RESULTS: Of 1151 SHINE participants, 725 (63%) received thrombolysis (median age 65 years, 46% women, 29% Black, 18% Hispanic). The median NIHSS was 7, baseline blood glucose was 187 (interquartile range 153-247) mg/dL, and 80% were diabetic. Onset to thrombolysis time was 2.2 hours (1.6-2.9). Post-thrombolysis sICH occurred in 3.6% (3.0% intensive vs 4.3% standard glucose control, OR 1.10, 0.60-2.01, p = 0.697). In the first 12 hours, every 10 mg/dL higher glucose increased the odds of sICH (OR 1.08, 1.03-1.14, p = 0.004), and a greater proportion of glucose measures in the normal range (80-130 mg/dL) decreased the odds of sICH (0.89, 0.80-0.99, p = 0.030). These associations were strongest in the high-risk group (age older than 60 years and NIHSS ≥8). DISCUSSION: In this prespecified analysis from the SHINE trial, intensive insulin therapy was not associated with a reduced risk of post-thrombolysis sICH compared with standard sliding scale. However, early post-thrombolysis hyperglycemia was associated with a higher risk of sICH overall, particularly in older patients with more severe strokes. Further prospective research is warranted to address the risk of sICH in hyperglycemic stroke patients undergoing endovascular therapy. TRIAL REGISTRATION INFORMATION: NCT01369069.

Factors Associated With Premature Termination of Hyperacute Stroke Trials: A Review.

BACKGROUND: We performed a review of acute stroke trials to determine features associated with premature termination of trial enrollment, defined by the authors as not meeting preplanned sample size. METHODS AND RESULTS: MEDLINE was searched for randomized clinical stroke trials published in 9 major clinical journals between 2013 and 2022. We included randomized clinical trials that were phase 2 or 3 with a preplanned sample size ≥100 and a time-to-treatment within 24 hours of onset for transient ischemic attack, ischemic stroke, or intracerebral hemorrhage. Data were abstracted on trial features including trial design, inclusion criteria, imaging, location and number of sites, masking, treatment complexity, control group (standard therapy, placebo), industry involvement, and preplanned stopping rules (futility and efficacy). Least absolute shrinkage and selection operator regression was used to select the most important factors associated with premature termination; then, a multivariable logistic regression was fit including only the least absolute shrinkage and selection operator selected variables. Of 1475 studies assessed, 98 trials met eligibility criteria. Forty-five (46%) trials were prematurely terminated, of which 27% were stopped for benefit/efficacy, 20% for lack of money/slow enrollment, 18% for futility, 16% for newly available evidence, 17% for other reasons, and 4% due to harm. Complex trials (adjusted odds ratio [aOR], 2.76 [95% CI, 1.13-7.49]), presence of a futility rule (aOR, 4.43 [95% CI, 1.62-17.91]), and exclusion of prestroke dependency (none/slight disability only; aOR, 2.19 [95% CI, 0.84-6.72] versus dependency allowed) were identified as the strongest predictors. CONCLUSIONS: Nearly half of acute stroke trials were terminated prematurely. Broadening inclusion criteria and simplifying trial design may decrease the likelihood of unplanned termination, whereas planned futility analyses may appropriately terminate trials early, saving money and resources.

The association of CYP2C19 LoF alleles with adverse clinical outcomes in stroke patients taking clopidogrel: An updated meta-analysis.

The aggregated risk of recurrent stroke in stroke/transient ischemic attack (TIA) patients carrying CYP2C19 LoF alleles who take clopidogrel has not been investigated recently, and the available research is limited. This study aimed to perform an updated meta-analysis to assess the association between CYP2C19 LoF alleles and the risk of recurrent stroke in patients taking clopidogrel. Databases were searched for the literature on eligible studies. The end points were recurrent stroke, composite vascular events, and bleeding events. Odds ratios (ORs) were calculated using RevMan software, where p < 0.05 was considered statistically significant. Patients carrying CYP2C19 LoF alleles who were treated with clopidogrel had a significantly increased risk of recurrent ischemic stroke compared with non-carriers (OR 2.18, 96% CI 1.80-2.63; p < 0.00001). The risk of recurrent stroke was only significantly different in Asian patients (OR 2.29, 96% CI 1.88-2.80; p < 0.00001) but not in patients of other ethnicities; however, there were a limited number of studies in other ethnic groups. Both observational studies (OR 2.83, 96% CI 2.20-3.65; p < 0.00001) and RCTs (OR 1.48, 96% CI 1.10-1.98; p = 0.009) found associations with a significantly increased risk of recurrent ischemic stroke. Asian stroke patients or TIA patients carrying CYP2C19 LoF alleles and taking clopidogrel were at a significantly higher risk of recurrent ischemic stroke than non-carriers. Significantly increased risk of recurrent ischemic stroke was found in both observational studies and RCTs.

Revolutionizing Stroke Recovery: Unveiling the Promise of Stem Cell Therapy.

Stem cells, renowned for their unique regenerative capabilities, present significant hope in treating stroke, a major cause of disability globally. This review offers a detailed analysis of stem cell applications in stroke (ischemic and hemorrhagic) recovery. It examines therapies based on autologous (patient-derived), allogeneic (donor-derived), and Granulocyte-Colony Stimulating Factor (G-CSF) based stem cells, focusing on cell types such as Mesenchymal Stem/Stromal Cells (MSCs), Bone Marrow Mononuclear Stem Cells (BMMSCs), and Neural Stem/Progenitor Cells (NSCs). The paper compiles clinical trial data to evaluate their effectiveness and safety and addresses the ethical concerns of these innovative treatments. By explaining the mechanisms of stem cell-induced neurological repair, this review underscores stem cells' potential in revolutionizing stroke rehabilitation and suggests avenues for future research.

[Thrombolysis treatment and multi- disciplinary management of central retinal artery occlusion in comparison with traditional ophthalmological treatment options]. / Arteria centralis retinae elzáródás thrombolysiskezelése és multidiszciplináris ellátása a hagyományos szemészeti kezelési formákkal összehasonlítva.

Background and purpose:

The management of central retinal artery occlusion (CRAO) has long been conservative therapy with limited efficacy carried out in ophthalmology departments together with etiolo­gi­cal investigations lacking a standardised protocol. However, CRAO is analogous to ischemic central nervous system stroke and is associated with increased stroke risk, thus, systemic thrombolysis treatment and multidisciplinary management can be beneficial. Since May 2022, at Semmelweis University CRAO patients diagnosed within 4.5 hours are given intravenous thrombolysis therapy and undergo etiologic workup based on current stroke protocols. Here we report our experience with the multidisciplinary, protocol-based management of CRAO in comparison with former non-protocol based ophthalmological conservative treatment.

We reviewed CRAO patients’ data treated conservatively and with paracentesis within 6 hours at the Department of Ophthalmology between 2013 and 2022 including changes in visual acuity, neurolo­gical and cardiovascular findings compared to those in the thrombolysis project. 

Of the 78 patients receiving non-protocol care, visual improvement was seen in 37% with natural course, 47% with conservative treatment and 47% with paracentesis. Four patients had significant carotid stenosis (2 underwent endarterectomy), 1 carotid dissection, 6 cardioembolism and 1 giant cell arteritis. Of the 4 patients within 4,5 hours, 3 gave their consent to the clinical trial and were treated with thrombolysis and underwent a full etiological assessment. 
2 pa­tients had improved visual acuity, 2 pa­tients had significant carotid stenosis and underwent endarterectomy, 1 patient was started on anticoagulation for newly diagnosed atrial fibrillation.

CRAO patients presenting within 4,5 hours are rare and more patients are needed in our study to establish the efficacy of thrombolysis. However uniform protocollized evaluation helps identifying embolic sources thus, avoiding further and potentially more serious thromboembolic events.

Effects of Achieving Rapid, Intensive, and Sustained Blood Pressure Reduction in Intracerebral Hemorrhage Expansion and Functional Outcome.

BACKGROUND AND OBJECTIVES: The time taken to achieve blood pressure (BP) control could be pivotal in the benefits of reducing BP in acute intracerebral hemorrhage (ICH). We aimed to assess the relationship between the rapid achievement and sustained maintenance of an intensive systolic BP (SBP) target with radiologic, clinical, and functional outcomes. METHODS: Rapid, Intensive, and Sustained BP lowering in Acute ICH (RAINS) was a multicenter, prospective, observational cohort study of adult patients with ICH <6 hours and SBP ≥150 mm Hg at 4 Comprehensive Stroke Centers during a 4.5-year period. Patients underwent baseline and 24-hour CT scans and 24-hour noninvasive BP monitoring. BP was managed under a rapid (target achievement ≤60 minutes), intensive (target SBP <140 mm Hg), and sustained (target stability for 24 hours) BP protocol. SBP target achievement ≤60 minutes and 24-hour SBP variability were recorded. Outcomes included hematoma expansion (>6 mL or >33%) at 24 hours (primary outcome), early neurologic deterioration (END, 24-hour increase in NIH Stroke Scale score ≥4), and 90-day ordinal modified Rankin scale (mRS) score. Analyses were adjusted by age, sex, anticoagulation, onset-to-imaging time, ICH volume, and intraventricular extension. RESULTS: We included 312 patients (mean age 70.2 ± 13.3 years, 202 [64.7%] male). Hematoma expansion occurred in 70/274 (25.6%) patients, END in 58/291 (19.9%), and the median 90-day mRS score was 4 (interquartile range, 2-5). SBP target achievement ≤60 minutes (178/312 [57.1%]) associated with a lower risk of hematoma expansion (adjusted odds ratio [aOR] 0.43, 95% confidence interval [CI] 0.23-0.77), lower END rate (aOR 0.43, 95% CI 0.23-0.80), and lower 90-day mRS scores (aOR 0.48, 95% CI 0.32-0.74). The mean 24-hour SBP variability was 21.0 ± 7.6 mm Hg. Higher 24-hour SBP variability was not related to expansion (aOR 0.99, 95% CI 0.95-1.04) but associated with higher END rate (aOR 1.15, 95% CI 1.09-1.21) and 90-day mRS scores (aOR 1.06, 95% CI 1.04-1.10). DISCUSSION: Among patients with acute ICH, achieving an intensive SBP target within 60 minutes was associated with lower hematoma expansion risk. Rapid SBP reduction and stable sustention within 24 hours were related to improved clinical and functional outcomes. These findings warrant the design of randomized clinical trials examining the impact of effectively achieving rapid, intensive, and sustained BP control on hematoma expansion. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in adults with spontaneous ICH and initial SBP ≥150 mm Hg, lowering SBP to <140 mm Hg within the first hour and maintaining this for 24 hours is associated with decreased hematoma expansion.

Risk and benefit of reinitiating antiplatelet therapy after spontaneous intracerebral hemorrhage: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the risks and benefits of reinitiating antiplatelet therapy after spontaneous intracerebral hemorrhage (ICH) through a systematic review and meta-analysis. The reinitiation of antiplatelet therapy is commonly used to reduce major vascular events in patients with occlusive vascular diseases, but its use in ICH patients may increase the risk of bleeding. MATERIALS AND METHODS: A comprehensive search was conducted on databases including MEDLINE, Embase, Cochrane Library, clinicaltrials.gov, and the International Standard Randomized Controlled Trial Number Register (ISRCTN). Randomized controlled trials and cohort studies that investigated the use of reinitiation of antiplatelet therapy after hemorrhagic stroke were included. Data on ICH recurrence, major bleeding events, major occlusive cerebrovascular events, ischemic stroke, and all-cause mortality were extracted and analyzed using R software. RESULTS: The study included a total of 10 studies with 6,340 participants. The control group consisted of 2,964 patients who did not receive antiplatelet therapy, while the study group included 1,285 patients who received antiplatelet therapy without restrictions on the specific drug type. The meta-analysis showed that antiplatelet therapy significantly reduced the risk of ICH recurrence (RR=0.72, 95% CI: 0.59, 0.87), had no significant impact on the risk of severe bleeding events (RR=0.93, 95% CI: 0.80, 1.08), significantly lowered the risk of major occlusive cerebrovascular events (RR=0.59, 95% CI: 0.46, 0.77), had no significant effect on the risk of ischemic stroke (RR=0.77, 95% CI: 0.53, 1.12), and did not significantly influence the risk of all-cause mortality (RR=0.75, 95% CI: 0.45, 1.15). CONCLUSIONS: Based on the findings, reinitiating antiplatelet therapy after spontaneous ICH appears to be generally safe. However, the benefits in terms of reducing the risk of all-cause mortality are not evident and require confirmation through large-scale, long-term, prospective, randomized controlled trials.

Contrast extravasation mimicking intracerebral and intraventricular hemorrhage after intravenous thrombolytic treatment of ischemic stroke: a case report.

BACKGROUND: Although contrast extravasation on follow-up head computed tomography (CT) is frequently visualized after endovascular treatment, this phenomenon is rare after intravenous thrombolytic treatment in patients with acute ischemic stroke (AIS). Here, we report a case of contrast extravasation mimicking intracerebral hemorrhage (ICH) with intraventricular extension after intravenous thrombolytic treatment and computed tomography angiography (CTA). CASE PRESENTATION: A 52-year-old man presented with right-sided hemiparesis and hypoesthesia. Initial non-contrast head CT was negative for intracranial hemorrhage and acute ischemic changes. He received intravenous treatment with tenecteplase 3.8 h after the onset of stroke. CTA of the head and neck was performed at 4.3 h after stroke onset. It showed no stenosis or occlusion of the carotid and major intracranial arteries. At about 1.5 h after CTA, the right-sided hemiparesis deteriorated, accompanied by drowsiness, aphasia, and urinary incontinence. Immediate head CT showed hyperdense lesions with mild space-occupying effect in the left basal ganglia and both lateral ventricles. The hyperdense lesions were reduced in size on follow-up CT after 5 h. Two days later, CT showed that the hyperdense lesions in the lateral ventricles almost completely disappeared and only a small amount remained in the infarcted area. CONCLUSIONS: Contrast extravasation into the brain tissue and lateral ventricles, mimicking ICH with intraventricular extension, could occur after intravenous thrombolytic treatment and CTA in a patient with AIS, which might lead to misdiagnosis and wrong treatment of the patient. The rapid resolution of intracranial hyperdense lesions is key to differentiate contrast extravasation from ICH on serial non-enhanced CT.

Clinical study of tirofiban compared to low molecular weight heparin in the antithrombotic treatment of progressive pontine infarction.

OBJECTIVE: To investigate the efficacy and safety of tirofiban and low molecular weight heparin (LMWH) in the treatment of patients undergoing acute progressive pontine infarction. PATIENTS AND METHODS: Patients with acute progressive pontine infarction who were hospitalized in the Neurology Department from June 2021 to June 2023 were included in the study and randomly divided into two groups, namely the experimental group (tirofiban group) and the control group (LMWH group). All patients in both groups were required to receive conventional comprehensive treatment and dual antiplatelet therapy with aspirin + clopidogrel at the beginning of admission. The National Institutes of Health Stroke Scale (NIHSS) score and Barthel Index (BI) were used to evaluate the neurological deficits on the first day of admission, the next day with stroke progression, and at discharge after treatment with tirofiban and LMWH, respectively in the two groups. The modified Rankin Scale was employed to assess prognosis on the 90th day after treatment. Clinical adverse events were followed up for 90 days, comparing the clinical efficacy and safety of the two treatment methods. RESULTS: There was no statistical significance in NIHSS score and Barthel Index between the tirofiban group and the LMWH group on the first day of admission and the next day with stroke progression (p > 0.05). After stroke progression, tirofiban and LMWH were separately used for treatment in the two groups. We found that the NIHSS score of the tirofiban group was lower than that of the LMWH group, and the Barthel Index score was higher than that of the LMWH group at discharge (p < 0.05). After three months of follow-up, the mRS score of the tirofiban group was dramatically higher than that of the LMWH group (p < 0.05). No significant harmful or adverse reactions, such as bleeding events, were found in the two groups (p > 0.05). CONCLUSIONS: Tirofiban may be more effective and safer than LMWH in controlling the progression of acute pontine infarction, but further and large-sample studies are still needed to confirm this finding.

What does cognitive screening reveal about early cognitive performance following endovascular clot retrieval and intravenous thrombolysis in acute ischaemic stroke?

Background Little is known regarding cognitive outcomes following treatment with endovascular clot retrieval (ECR) and intravenous tissue plasminogen activator (t-PA). We aimed to determine if there were any differences on a measure of cognitive screening between patients treated with ECR, t-PA, and those who were managed conservatively. Methods The medical records of ischaemic stroke patients admitted to Monash Medical Centre between January 2019 and December 2019 were retrospectively reviewed. Information extracted from medical records included age, sex, National Institutes of Health Stroke Scale at presentation, location of occlusion, treatment type, medical history, and cognitive screening performance measured by the Montreal Cognitive Assessment (MoCA). Results Eighty-two patients met the inclusion criteria (mean age = 66.5 ± 13.9; 49 male, 33 female). Patients treated with ECR performed significantly better on the MoCA (n = 36, 24.1 ± 4.3) compared to those who were managed conservatively (n = 26, 20.7 ± 5.5). Performance for patients treated with t-PA (n = 20, 23.9 ± 3.5) fell between the ECR and conservative management groups, but they did not significantly differ from either. Conclusion Our retrospective chart review found that ischaemic stroke patients treated with ECR appear to perform better on cognitive screening compared to patients who are managed conservatively. We also found that patients treated with ECR and t-PA appear to have similar cognitive screening performances in the acute stages following ischaemic stroke, although this finding is likely to have been impacted by group differences in stroke characteristics and may reflect the possibility that the ECR group performed better than expected based on their stroke severity.

Remote Ischemic Conditioning With Medical Management or Reperfusion Therapy for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke are controversial. With the publication of several randomized controlled trials (RCTs) and the recent results of the RESIST trial, it may be possible to identify the patient population that may (or may not) benefit from RIC. This systematic review and meta-analysis aims to evaluate the effectiveness and safety of RIC in patients with ischemic stroke receiving different treatments by pooling data of all randomized controlled studies to date. METHODS: We searched the PubMed, Embase, Cochrane, Elsevier, and Web of Science databases to obtain articles in all languages from inception until May 25, 2023. The primary outcome was the modified Rankin Scale (mRS) score at the specified endpoint time in the trial. The secondary outcomes were change in NIH Stroke Scale (NIHSS) and recurrence of stroke events. The safety outcomes were cardiovascular events, cerebral hemorrhage, and mortality. The quality of articles was evaluated through the Cochrane risk assessment tool. This study was registered in PROSPERO (CRD42023430073). RESULTS: There were 7,657 patients from 22 RCTs included. Compared with the control group, patients who received RIC did not have improved mRS functional outcomes, regardless of whether they received medical management, reperfusion therapy with intravenous thrombolysis (IVT), or mechanical thrombectomy (MT). In the medical management group, patients who received RIC had decreased incidence of stroke recurrence (risk ratio 0.63, 95% CI 0.43-0.92, p = 0.02) and lower follow-up NIHSS score by 1.72 points compared with the control group (p < 0.00001). There was no increased risk of adverse events including death or cerebral hemorrhage in the IVT or medical management group. DISCUSSION: In patients with ischemic stroke who are not eligible for reperfusion therapy, RIC did not affect mRS functional outcomes but significantly improved the NIHSS score at the follow-up endpoint and reduced stroke recurrence, without increasing the risk of cerebral hemorrhage or death. In patients who received IVT or MT, the benefit of RIC was not observed.

Allopurinol and cardiovascular outcomes in patients with ischaemic heart disease: the ALL-HEART RCT and economic evaluation.

Background: Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested beneficial cardiovascular effects of allopurinol. Objective: To determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease. Design: Prospective, randomised, open-label, blinded endpoint multicentre clinical trial. Setting: Four hundred and twenty-four UK primary care practices. Participants: Aged 60 years and over with ischaemic heart disease but no gout. Interventions: Participants were randomised (1 : 1) using a central web-based randomisation system to receive allopurinol up to 600 mg daily that was added to usual care or to continue usual care. Main outcome measures: The primary outcome was the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes were non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, all-cause mortality, hospitalisation for heart failure, hospitalisation for acute coronary syndrome, coronary revascularisation, hospitalisation for acute coronary syndrome or coronary revascularisation, all cardiovascular hospitalisations, quality of life and cost-effectiveness. The hazard ratio (allopurinol vs. usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis. Results: From 7 February 2014 to 2 October 2017, 5937 participants were enrolled and randomised to the allopurinol arm (n = 2979) or the usual care arm (n = 2958). A total of 5721 randomised participants (2853 allopurinol; 2868 usual care) were included in the modified intention-to-treat analysis population (mean age 72.0 years; 75.5% male). There was no difference between the allopurinol and usual care arms in the primary endpoint, 314 (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years), hazard ratio 1.04 (95% confidence interval 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, hazard ratio 1.02 (95% confidence interval 0.87 to 1.20); p = 0.77. The pre-specified health economic analysis plan was to perform a 'within trial' cost-utility analysis if there was no statistically significant difference in the primary endpoint, so NHS costs and quality-adjusted life-years were estimated over a 5-year period. The difference in costs between treatment arms was +£115 higher for allopurinol (95% confidence interval £17 to £210) with no difference in quality-adjusted life-years (95% confidence interval -0.061 to +0.060). We conclude that there is no evidence that allopurinol used in line with the study protocol is cost-effective. Limitations: The results may not be generalisable to younger populations, other ethnic groups or patients with more acute ischaemic heart disease. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment, but an on-treatment analysis gave similar results to the main analysis. Conclusions: The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve cardiovascular outcomes compared to usual care in patients with ischaemic heart disease. We conclude that allopurinol should not be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease but no gout. Future work: The effects of allopurinol on cardiovascular outcomes in patients with ischaemic heart disease and co-existing hyperuricaemia or clinical gout could be explored in future studies. Trial registration: This trial is registered as EU Clinical Trials Register (EudraCT 2013-003559-39) and ISRCTN (ISRCTN 32017426). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in Health Technology Assessment; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information.

The purpose of the ALL-HEART study was to determine whether giving allopurinol to people with ischaemic heart disease (also commonly known as coronary heart disease) would reduce their risk of having a heart attack, stroke or of dying from cardiovascular disease. Allopurinol is a medication usually given to patients with gout to prevent acute gout flares. It is not currently used to treat ischaemic heart disease. We randomly allocated people aged over 60 years with ischaemic heart disease to take up to 600 mg of allopurinol daily (in addition to their usual care) or to continue with their usual care. We then monitored participants for several years and recorded any major health events such as heart attacks, strokes and deaths. We obtained most of the follow-up data from centrally held electronic hospital admissions and death records, making the study easier for participants and more cost-efficient. We asked participants in both groups to complete questionnaires to assess their quality of life during the study. We also collected data to determine whether there was any economic benefit to the NHS of using allopurinol in patients with ischaemic heart disease. There was no difference in the risk of heart attacks, strokes or death from cardiovascular disease between the participants given allopurinol and those in the group continuing their usual care. We also found no difference in the risks of other cardiovascular events, deaths from any cause or quality-of-life measurements between the allopurinol and usual care groups. The results of the ALL-HEART study suggest that we should not recommend that allopurinol be given to people with ischaemic heart disease to prevent further cardiovascular events or deaths.

Impact of dementia status on intravenous thrombolysis and endovascular treatment for acute ischemic stroke: Retrospective study.

INTRODUCTION: Individuals with dementia are underrepresented in interventional studies for acute ischemic stroke (AIS). This research gap creates a bias against their treatment in clinical practice. Our goal was to compare the safety and efficacy of intravenous-thrombolysis (t-PA) and endovascular treatment (EVT) in individuals with or without pre-AIS dementia. METHOD: A retrospective study of AIS patients receiving t-PA or EVT between 2019 and 2022. Patients were classified as dementia on a case-by-case review of baseline assessment. Additional variables included demographic, vascular risk factors, AIS severity and treatment. Outcomes of interest were intracerebral hemorrhage, mortality in 90-days, and the difference in modified rankin scale (mRS) before AIS and in 90-days follow-up. Outcomes were compared across non-matched groups and following propensity-score matching. RESULTS: Altogether, 628 patients were included, of which 68 had pre-AIS dementia. Compared to non-dementia group, dementia group were older, had a higher rate of vascular risk factors, higher pre-stroke mRS and higher baseline NIHSS. Individuals with dementia had higher rates of mortality (25% vs.11%,p < 0.01) on non-matched comparison. All cohort and restricted t-PA EVT matched analysis showed no difference in any outcome. Regression analysis confirmed that AIS severity at presentation and its treatment, not dementia, were the chief contributors to patients' outcomes. DISCUSSION: Our results indicate that pre-AIS dementia does not impact the efficacy or safety of EVT or t-PA for AIS. We thus call for more inclusive research on stroke therapy with regards to baseline cognitive status. Such studies are urgently required to inform stroke guidelines and enhance care.

Efficacy and safety of stem cells in the treatment of ischemic stroke: A meta-analysis.

BACKGROUND: Stem cell therapy on ischemic stroke has long been studied using animal experiments. The efficacy and safety of this treatment in ischemic stroke patients remain uncertain. METHODS: We searched for all clinical randomized controlled trials published before October 2023, on PubMed, EMBASE, and the Cochrane Library using predetermined search terms, and performed a meta-analysis of the efficacy of stem cell therapy in ischemic stroke patients. RESULTS: 13 studies that included 592 ischemic stroke patients were reviewed. The mRS (MD -0.32, 95% CI -0.64 to 0.00, I2 = 63%, P = .05), NIHSS (MD -1.63, 95% CI -2.69 to -0.57, I2 = 58%, P = .003), and BI (MD 14.22, 95% CI 3.95-24.48, I2 = 43%, P = .007) showed effective stem cell therapy. The mortality (OR 0.42, 95% CI 0.23-0.79, I2 = 0%, P = .007) showed improved prognosis and reduce mortality with stem cell therapy. CONCLUSION: Stem cell therapy reduces mortality and improves the neurological prognosis of ischemic stroke patients. However, due to the different types of stem cells used and the limited data in the reported studies, the safety of clinical applications of stem cells in patients with ischemic stroke must be carefully evaluated. Future randomized controlled trials with large sample sizes from controlled cell sources are warranted to validate this finding.

Cost-Effectiveness of Increased Use of Dual Antiplatelet Therapy After High-Risk Transient Ischemic Attack or Minor Stroke.

BACKGROUND: Rates of dual antiplatelet therapy (DAPT) after high-risk transient ischemic attack or minor ischemic stroke (TIAMIS) are suboptimal. We performed a cost-effectiveness analysis to characterize the parameters of a quality improvement (QI) intervention designed to increase DAPT use after TIAMIS. METHODS AND RESULTS: We constructed a decision tree model that compared current national rates of DAPT use after TIAMIS with rates after implementing a theoretical QI intervention designed to increase appropriate DAPT use. The base case assumed that a QI intervention increased the rate of DAPT use to 65% from 45%. Costs (payer and societal) and outcomes (stroke, myocardial infarction, major bleed, or death) were modeled using a lifetime horizon. An incremental cost-effectiveness ratio <$100 000 per quality-adjusted life year was considered cost-effective. Deterministic and probabilistic sensitivity analyses were performed. From the payer perspective, a QI intervention was associated with $9657 in lifetime cost savings and 0.18 more quality-adjusted life years compared with current national treatment rates. A QI intervention was cost-effective in 73% of probabilistic sensitivity analysis iterations. Results were similar from the societal perspective. The maximum acceptable, initial, 1-time payer cost of a QI intervention was $28 032 per patient. A QI intervention that increased DAPT use to at least 51% was cost-effective in the base case. CONCLUSIONS: Increasing DAPT use after TIAMIS with a QI intervention is cost-effective over a wide range of costs and proportion of patients with TIAMIS treated with DAPT after implementation of a QI intervention. Our results support the development of future interventions focused on increasing DAPT use after TIAMIS.

Baseline Uric Acid Levels and Intravenous Thrombolysis Outcomes in Patients With Acute Ischemic Stroke: A Prospective Cohort Study.

BACKGROUND: The study aimed to investigate the relationship between uric acid (UA) levels and functional outcomes at 3 months in patients with acute ischemic stroke (AIS) who underwent intravenous thrombolysis (IVT). METHODS AND RESULTS: This prospective cohort study included 1001 consecutive patients with AIS who underwent IVT. The correlation between UA levels and post-IVT AIS outcomes was examined. Any nonlinear relationship was assessed using a restricted cubic spline function. The nonlinear P value for the association of UA levels with favorable (modified Rankin Scale [mRS] score ≤2) and excellent (mRS score ≤1) outcomes at 3 months post-IVT were <0.001 and 0.001, respectively. However, for patients with and without hyperuricemia, no evident nonlinear relationship was observed between UA levels and favorable 3-month post-IVT outcomes, with nonlinear P values of 0.299 and 0.207, respectively. The corresponding interaction analysis yielded a P value of 0.001, indicating significant heterogeneity. Similar results were obtained for excellent outcomes at 3 months post-IVT. In the hyperuricemia group, increased UA levels by 50 µmol/L reduced the odds of a favorable 3-month post-AIS outcome (odds ratio [OR], 0.75 [95% CI, 0.57-0.97]). Conversely, in the nonhyperuricemia group, a similar UA increase was linked to higher favorable outcome odds (OR, 1.31 [95% CI, 1.15-1.50]). CONCLUSIONS: An inverted U-shaped nonlinear relationship was observed between UA levels and favorable and excellent outcomes at 3 months in patients with AIS who underwent IVT. Higher UA levels predict favorable outcomes in patients without hyperuricemia but unfavorable outcomes in those with hyperuricemia.

Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones.

The majority of approved therapies for many diseases are developed to target their underlying pathophysiology. Understanding disease pathophysiology has thus proven vital to the successful development of clinically useful medications. Stroke is generally accepted as the leading cause of adult disability globally and ischemic stroke accounts for the most common form of the two main stroke types. Despite its health and socioeconomic burden, there is still minimal availability of effective pharmacological therapies for its treatment. In this review, we take an in-depth look at the etiology and pathophysiology of ischemic stroke, including molecular and cellular changes. This is followed by a highlight of drugs, cellular therapies, and complementary medicines that are approved or undergoing clinical trials for the treatment and management of ischemic stroke. We also identify unexplored potential targets in stroke pathogenesis that can be exploited to increase the pool of effective anti-stroke and neuroprotective agents through de novo drug development and drug repurposing.