Reversible cerebral vasoconstriction syndrome post-cardiac transplantation: a therapeutic dilemma: case report.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by diffuse, multifocal segmental narrowing of cerebral arteries and can result in ischaemic stroke. Causal factors, identified in 60% of cases, include immunosuppressant pharmacotherapy. The few reports following heart transplantation are almost all in Asian recipients. We report on a Caucasian Australian patient with immunotherapy induced RCVS post heart transplantation to highlight the state of knowledge of the condition and the treatment dilemma it poses. CASE PRESENTATION: A 51-year-old female underwent orthotopic heart transplantation at our institution. Induction immunotherapy comprised basiliximab, mycophenolate mofetil and methylprednisolone. On day 6 post-transplantation the patient was transitioned to oral prednisolone and tacrolimus. On day 7 the patient began to experience bilateral, severe, transient occipital and temporal headaches. On day 9 tacrolimus dose was up-titrated. A non-contrast computed tomography brain (CTB) was normal. Endomyocardial biopsy on day 12 demonstrated moderate Acute Cellular Rejection (ACR), which was treated with intravenous methylprednisolone. That evening the patient experienced a 15-minute episode of expressive dysphasia. The following morning she became confused, aphasic, and demonstrated right sided neglect and right hemianopia. A CT cerebral perfusion scan demonstrated hypoperfusion in the left middle cerebral artery (MCA) territory and cerebral angiography revealed widespread, focal multi-segmental narrowing of the anterior and posterior circulations. A diagnosis of RCVS was made, and nimodipine was commenced. As both steroids and tacrolimus are potential triggers of RCVS, cyclosporin replaced tacrolimus and methylprednisolone dose was reduced. A further CTB demonstrated a large left MCA territory infarct with left M2 MCA occlusion. The patient made steady neurological improvement. She was discharged 34 days post-transplantation with mild residual right lower limb weakness and persistent visual field defect on verapamil, cyclosporine, everolimus, mycophenolate mofetil and prednisolone. CONCLUSION: Reversible cerebral vasoconstriction syndrome is rare after orthotopic heart transplantation. Until now, RCVS has been almost exclusively described in Asian recipients, and is typically caused by immunotherapy. The condition may lead to permanent neurological deficits, and in the absence of definitive treatments, early recognition and imaging based diagnosis is essential to provide the opportunity to remove the causal agent(s). Co-existent ACR, can pose unique treatment difficulties.

Hyper-Acute Stroke Systems of Care and Workflow.

PURPOSE OF REVIEW: Recent stroke treatment advances have necessitated agile, broad-scale healthcare system redesign, to achieve optimal patient outcomes and access equity. Optimised hyperacute stroke care requires integrated pre-hospital, emergency department, stroke specialist, radiology, neurosurgical and endovascular neurointervention services, guided by a population-wide needs analysis. In this review, we survey system integration efforts, providing case studies, and identify common elements of successful initiatives. RECENT FINDINGS: Different regions and nations have evolved varied acute stroke systems depending on geography, population density and workforce. However, common facilitators to these solutions have included stroke unit care as a foundation, government-clinician synergy, pre-hospital pathway coordination, service centralisation, and stroke data guiding system improvement. Further technological advantages will minimize the geographical distance disadvantages and facilitate virtual expertise redistribution to remote areas. Continued treatment advances necessitate an integrated, adaptable, population-wide trans-disciplinary approach. A well-designed clinician-led and government-supported system can facilitate hyperacute care and scaffold future system enhancements.

The impact of incident stroke on cognitive trajectories in later life.

BACKGROUND: Cognitive impairment is common after stroke, and a large proportion of stroke patients will develop dementia. However, there have been few large prospective studies which have assessed cognition both prior to and after stroke. This study aims to determine the extent to which incident stroke impacts different domains of cognitive function in a longitudinal cohort of older community-dwelling individuals. METHODS: 19,114 older individuals without cardiovascular disease or major cognitive impairment were recruited and followed over a maximum 11 years. Stroke included ischaemic and haemorrhagic stroke and was adjudicated by experts. Cognitive function was assessed regularly using Modified Mini-Mental State Examination (3MS), Hopkins Verbal Learning Test-Revised (HVLT-R), Symbol Digit Modalities Test (SDMT), and Controlled Oral Word Association Test (COWAT). Linear mixed models were used to investigate the change in cognition at the time of stroke and decline in cognitive trajectories following incident stroke. RESULTS: During a median follow-up period of 8.4 [IQR: 7.2, 9.6] years, 815 (4.3%) participants experienced a stroke. Over this time, there was a general decline observed in 3MS, HVLT-R delayed recall, and SDMT scores across participants. However, for individuals who experienced a stroke, there was a significantly greater decline across all cognitive domains immediately after the event immediately after the event (3MS: -1.03 [95%CI: -1.45, -0.60]; HVLT-R: -0.47 [-0.70, -0.24]; SDMT: -2.82 [-3.57, -2.08]; COWAT: -0.67 [-1.04, -0.29]) and a steeper long-term decline for three of these domains (3MS -0.62 [-0.88, -0.35]; COWAT: -0.30 [-0.46, -0.14]); HVLT-R: -0.12 [95%CI, -0.70, -0.24]). However individuals with stroke experienced no longer-term decline in SDMT compared to the rest of the participants. CONCLUSIONS: These findings highlight the need for comprehensive neuropsychology assessments for ongoing monitoring of cognition following incident stroke; and potential early intervention.

Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial.

BACKGROUND: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo. METHODS: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete. FINDINGS: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]). INTERPRETATION: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings. FUNDING: Australian Government Medical Research Future Fund.

Perispinal Etanercept to improve STroke Outcomes (PESTO): Protocol for a multicenter, international, randomized placebo-controlled trial.

RATIONALE: A large proportion of stroke survivors will have long-lasting, debilitating neurological impairments, yet few efficacious medical treatment options are available. Etanercept inhibits binding of tumor necrosis factor to its receptor and is used in the treatment of inflammatory conditions. Perispinal subcutaneous injection followed by a supine, head down position may bypass the blood brain barrier. In observational studies and one small randomized controlled trial the majority of patients showed improvement in multiple post stroke impairments. AIM: Perispinal Etanercept to improve STroke Outcomes (PESTO) investigates whether perispinal subcutaneous injection of etanercept improves quality of life and is safe in patients with chronic, disabling, effects of stroke. METHODS AND DESIGN: PESTO is a multicenter, international, randomized placebo-controlled trial. Adult participants with a history of stroke between 1 and 15 years before enrollment and a current modified Rankin scale between 2 and 5 who are otherwise eligible for etanercept are randomized 1:1 to single dose injection of etanercept or placebo. STUDY OUTCOMES: The primary efficacy outcome is quality of life as measured using the Short Form 36 Health Inventory at day 28 after first injection. Safety outcomes include serious adverse events. SAMPLE SIZE TARGET: A total of 168 participants assuming an improvement of the SF-36 in 11% of participants in the control arm and in 30% of participants in the intervention arm, 80% power and 5% alpha. DISCUSSION: PESTO aims to provide level 1 evidence on the safety and efficacy of perispinal etanercept in patients with long-term disabling effects of stroke.

Statistical analysis plan for the Recovery-focused Community support to Avoid readmissions and improve Participation after Stroke randomised controlled clinical trial.

BACKGROUND: Unplanned hospital presentations may occur post-stroke due to inadequate preparation for transitioning from hospital to home. The Recovery-focused Community support to Avoid readmissions and improve Participation after Stroke (ReCAPS) trial was designed to test the effectiveness of receiving a 12-week, self-management intervention, comprising personalised goal setting with a clinician and aligned educational/motivational electronic messages. Primary outcome is as follows: self-reported unplanned hospital presentations (emergency department/admission) within 90-day post-randomisation. We present the statistical analysis plan for this trial. METHODS/DESIGN: Participants are randomised 1:1 in variable block sizes, with stratification balancing by age and level of baseline disability. The sample size was 890 participants, calculated to detect a 10% absolute reduction in the proportion of participants reporting unplanned hospital presentations/admissions, with 80% power and 5% significance level (two sided). Recruitment will end in December 2023 when funding is expended, and the sample size achieved will be used. Logistic regression, adjusted for the stratification variables, will be used to determine the effectiveness of the intervention on the primary outcome. Secondary outcomes will be evaluated using appropriate regression models. The primary outcome analysis will be based on intention to treat. A p-value ≤ 0.05 will indicate statistical significance. An independent Data Safety and Monitoring Committee has routinely reviewed the progress and safety of the trial. CONCLUSIONS: This statistical analysis plan ensures transparency in reporting the trial outcomes. ReCAPS trial will provide novel evidence on the effectiveness of a digital health support package post-stroke. TRIAL REGISTRATION: ClinicalTrials.gov ACTRN12618001468213. Registered on August 31, 2018. SAP version 1.13 (October 12 2023) Protocol version 1.12 (October 12, 2022) SAP revisions Nil.

A Network of Sites and Upskilled Therapists to Deliver Best-Practice Stroke Rehabilitation of the Arm: Protocol for a Knowledge Translation Study.

Implementation of evidence-informed rehabilitation of the upper limb is variable, and outcomes for stroke survivors are often suboptimal. We established a national partnership of clinicians, survivors of stroke, researchers, healthcare organizations, and policy makers to facilitate change. The objectives of this study are to increase access to best-evidence rehabilitation of the upper limb and improve outcomes for stroke survivors. This prospective pragmatic, knowledge translation study involves four new specialist therapy centers to deliver best-evidence upper-limb sensory rehabilitation (known as SENSe therapy) for survivors of stroke in the community. A knowledge-transfer intervention will be used to upskill therapists and guide implementation. Specialist centers will deliver SENSe therapy, an effective and recommended therapy, to stroke survivors in the community. Outcomes include number of successful deliveries of SENSe therapy by credentialled therapists; improved somatosensory function for stroke survivors; improved performance in self-selected activities, arm use, and quality of life; treatment fidelity and confidence to deliver therapy; and for future implementation, expert therapist effect and cost-effectiveness. In summary, we will determine the effect of a national partnership to increase access to evidence-based upper-limb sensory rehabilitation following stroke. If effective, this knowledge-transfer intervention could be used to optimize the delivery of other complex, evidence-based rehabilitation interventions.

Management of Poststroke Hyperglycemia: Results of the TEXAIS Randomized Clinical Trial.

BACKGROUND: Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia. METHODS: The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event. RESULTS: From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88]; P=0.38). No differences in secondary outcomes were observed. The per-patient mean daily frequency of hyperglycemia was significantly less in the exenatide group across all quartiles. No episodes of hypoglycemia were recorded over the treatment period. Adverse events of mild nausea and vomiting occurred in 6 (3.5%) exenatide patients versus 0 (0%) standard care with no withdrawal. CONCLUSIONS: Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered. REGISTRATION: URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

Tranexamic acid for haemostasis and beyond: does dose matter?

Tranexamic acid (TXA) is a widely used antifibrinolytic agent that has been used since the 1960's to reduce blood loss in various conditions. TXA is a lysine analogue that competes for the lysine binding sites in plasminogen and tissue-type plasminogen activator impairing its interaction with the exposed lysine residues on the fibrin surface. The presence of TXA therefore, impairs the plasminogen and tPA engagement and subsequent plasmin generation on the fibrin surface, protecting fibrin clot from proteolytic degradation. However, critical lysine binding sites for plasmin(ogen) also exist on other proteins and on various cell-surface receptors allowing plasmin to exert potent effects on other targets that are unrelated to classical fibrinolysis, notably in relation to immunity and inflammation. Indeed, TXA was reported to significantly reduce post-surgical infection rates in patients after cardiac surgery unrelated to its haemostatic effects. This has provided an impetus to consider TXA in other indications beyond inhibition of fibrinolysis. While there is extensive literature on the optimal dosage of TXA to reduce bleeding rates and transfusion needs, it remains to be determined if these dosages also apply to blocking the non-canonical effects of plasmin.

Tranexamic acid in a mouse model of cerebral amyloid angiopathy: setting the stage for a novel stroke treatment approach.

Background: Symptomatic intracerebral hemorrhage (sICH) commonly occurs in patients with cerebral amyloid angiopathy (CAA). Amyloid also initiates plasminogen activation and might promote sICH. Objectives: As amyloid-driven plasmin formation can be blocked by tranexamic acid (TXA), we aimed to evaluate the biodistribution and long-term consequences of TXA on brain amyloid-beta (Aß) levels, inflammation, and neurologic function in APP/PS1 mice. Methods: APP/PS1 mice overexpressing the mutant human amyloid precursor protein and wild-type littermates were randomized to TXA (20 mg/mL) or placebo in the drinking water for 6 months. TXA in plasma and various organs was determined by liquid chromatography-mass spectrometry. Plasmin activity assays were performed to evaluate changes in fibrinolytic activity. Neurologic function was evaluated by Y-maze and parallel rod floor testing. Proximity ligation-based immunoassays were used to quantitate changes of 92 biomarkers of inflammation. Brain Aß levels were assessed by immunohistochemistry. Results: Long-term oral TXA administration inhibited fibrinolysis. TXA accumulated in the kidney (19.4 ± 11.2 µg/g) with 2- to 5-fold lower levels seen in the lung, spleen, and liver. TXA levels were lowest in the brain (0.28 ± 0.01 µg/g). Over 6 months, TXA had no discernible effect on motor coordination, novelty preference, or brain Aß levels. TXA reduced plasma levels of epithelial cell adhesion molecule and increased CCL20. Conclusion: Long-term TXA treatment does not alter brain Aß levels or impact neurologic behavior in mice predisposed to amyloid deposition and had minor effects on the levels of inflammatory mediators. This finding supports the safety of TXA and lays the foundation for TXA as a novel treatment to reduce sICH in patients with CAA.

Low-Dose Aspirin and the Risk of Stroke and Intracerebral Bleeding in Healthy Older People: Secondary Analysis of a Randomized Clinical Trial.

Importance: Low-dose aspirin has been widely used for primary and secondary prevention of stroke. The balance between potential reduction of ischemic stroke events and increased intracranial bleeding has not been established in older individuals. Objective: To establish the risks of ischemic stroke and intracranial bleeding among healthy older people receiving daily low-dose aspirin. Design, Setting, and Participants: This secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, double-blind, placebo-controlled trial of daily low-dose aspirin was conducted among community-dwelling people living in Australia or the US. Participants were older adults free of symptomatic cardiovascular disease. Recruitment took place between 2010 and 2014, and participants were followed up for a median (IQR) of 4.7 (3.6-5.7) years. This analysis was completed from August 2021 to March 2023. Interventions: Daily 100-mg enteric-coated aspirin or matching placebo. Main Outcomes and Measures: Stroke and stroke etiology were predetermined secondary outcomes and are presented with a focus on prevention of initial stroke or intracranial bleeding event. Outcomes were assessed by review of medical records. Results: Among 19 114 older adults (10 782 females [56.4%]; median [IQR] age, 74 [71.6-77.7] years), 9525 individuals received aspirin and 9589 individuals received placebo. Aspirin did not produce a statistically significant reduction in the incidence of ischemic stroke (hazard ratio [HR], 0.89; 95% CI, 0.71-1.11). However, a statistically significant increase in intracranial bleeding was observed among individuals assigned to aspirin (108 individuals [1.1%]) compared with those receiving placebo (79 individuals [0.8%]; HR, 1.38; 95% CI, 1.03-1.84). This occurred by an increase in a combination of subdural, extradural, and subarachnoid bleeding with aspirin compared with placebo (59 individuals [0.6%] vs 41 individuals [0.4%]; HR, 1.45; 95% CI, 0.98-2.16). Hemorrhagic stroke was recorded in 49 individuals (0.5%) assigned to aspirin compared with 37 individuals (0.4%) in the placebo group (HR, 1.33; 95% CI, 0.87-2.04). Conclusions and Relevance: This study found a significant increase in intracranial bleeding with daily low-dose aspirin but no significant reduction of ischemic stroke. These findings may have particular relevance to older individuals prone to developing intracranial bleeding after head trauma. Trial Registration: ISRCTN.org Identifier: ISRCTN83772183.

Assessing atrial myopathy with cardiac magnetic resonance imaging in embolic stroke of undetermined source.

BACKGROUND: Left atrial myopathy has been implicated in atrial fibrillation (AF)-related stroke and embolic stroke of undetermined source (ESUS). OBJECTIVE: To use advanced cardiac magnetic resonance (CMR) imaging techniques, including left atrial (LA) strain and 4D flow CMR, to identify atrial myopathy in patients with ESUS. METHODS: 20 patients with ESUS and no AF or other cause for stroke, and 20 age and sex-matched controls underwent CMR with 4D flow analysis. Markers of LA myopathy were assessed including LA size, volume, ejection fraction, and strain. 4D flow CMR was performed to measure novel markers of LA stasis such as LA velocities and the LA residence time distribution time constant (RTDtc). These markers of LA myopathy were compared between the two groups. RESULTS: There was no significant difference in: CMR-calculated LA velocities or LA total, passive or active ejection fractions between the groups. There was no significant difference in CMR-derived reservoir, conduit or contractile average longitudinal strain between the ESUS and control groups (22.9 vs 22.6%, p=0.379, 11.2 ± 3.5 vs 12.4 ± 2.6% p=0.224, 10.8 ± 3.2 vs 10.4 ± 2.3%, p=0.625 respectively). Similarly, RTDtc was not significantly longer in ESUS patients compared to controls (1.3 ± 0.2 vs 1.2 ± 0.2, p=0.1). CONCLUSIONS: There were no significant differences in any CMR marker of atrial myopathy in ESUS patients compared to healthy controls, likely reflecting the multiple possible aetiologies of ESUS suggesting that the role LA myopathy plays in ESUS is smaller than previously thought.

A feasibility and safety study of afamelanotide in acute stroke patients - an open label, proof of concept, phase iia clinical trial.

BACKGROUND: Neuroprotective agents have the potential to improve the outcomes of revascularisation therapies in acute ischemic stroke patients (AIS) and in those unable to receive revascularisation. Afamelanotide, a synthetic α-melanocyte stimulating hormone analogue, is a potential novel neuroprotective agent. We set out to assess the feasibility and safety of afamelanotide for the first time in AIS patients. METHODS: AIS patients within 24 h of onset, with perfusion abnormality on imaging (Tmax) and otherwise ineligible for revascularisation therapies were enrolled. Afamelanotide 16 mg implants were administered subcutaneously on Day 0 (D0, day of recruitment), D1 and repeated on D7 and D8, if not well recovered. Treatment emergent adverse events (TEAEs) and neurological assessments were recorded regularly up to D42. Magnetic resonance imaging (MRI) with FLAIR sequences were also performed on D3 and D9. RESULTS: Six patients (5 women, median age 81, median NIHSS 6) were recruited. Two patients received 4 doses and four patients received 2. One patient (who received 2 doses), suffered a fatal recurrent stroke on D9 due to a known complete acute internal carotid artery occlusion, assessed as unrelated to the study drug. There were no other local or major systemic TEAEs recorded. In all surviving patients, the median NIHSS improved from 6 to 2 on D7. The median Tmax volume on D0 was 23 mL which was reduced to a FLAIR volume of 10 mL on D3 and 4 mL on D9. CONCLUSIONS: Afamelanotide was well tolerated and safe in our small sample of AIS patients. It also appears to be associated with good recovery and radiological improvement of salvageable tissue which needs to be tested in randomized studies. GOV IDENTIFIER: NCT04962503, First posted 15/07/2021.

Association Between CKD and Major Hemorrhage in Older Persons: Data From the Aspirin in Reducing Events in the Elderly Randomized Trial.

Introduction: Data on the association between chronic kidney disease (CKD) and major hemorrhage in older adults are lacking. Methods: We used data from a double-blind randomized controlled trial of aspirin in persons aged ≥ 70 years with prospective capture of bleeding events, including hemorrhagic stroke and clinically significant bleeding. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m2 and/or urinary albumin-to-creatinine ratio (UACR) ≥ 3 mg/mmol (26.6 mg/g). We compared bleeding rates in those with and without CKD, undertook multivariable analyses, and explored effect modification with aspirin. Results: Of 19,114 participants, 17,976 (94.0%) had CKD status recorded, of whom 4952 (27.5%) had CKD. Participants with CKD had an increased rate of major bleeding events compared with those without CKD (10.4/1000 vs. 6.3/1000 person-years [py], respectively) and increased bleeding risk (risk ratio [RR] 1.60; 95% confidence interval [CI]: 1.40, 1.90 for eGFR < 60 ml/min per 1.73 m2) and RR (2.10; 95% CI: 1.70, 2.50) for albuminuria. In adjusted analyses, CKD was associated with a 35% increased risk of bleeding (hazard ratio [HR] 1.37; 95% CI: 1.15, 1.62; P < 0.001). Other risk factors were older age, hypertension, smoking, and aspirin use. There was no differential effect of aspirin on bleeding by CKD status (test of interaction P = 0.65). Conclusion: CKD is independently associated with an increased risk of major hemorrhage in older adults. Increased awareness of modifiable risk factors such as discontinuation of unnecessary aspirin, blood pressure control, and smoking cessation in this group is warranted.

Statins for extension of disability-free survival and primary prevention of cardiovascular events among older people: protocol for a randomised controlled trial in primary care (STAREE trial).

INTRODUCTION: The world is undergoing a demographic transition to an older population. Preventive healthcare has reduced the burden of chronic illness at younger ages but there is limited evidence that these advances can improve health at older ages. Statins are one class of drug with the potential to prevent or delay the onset of several causes of incapacity in older age, particularly major cardiovascular disease (CVD). This paper presents the protocol for the STAtins in Reducing Events in the Elderly (STAREE) trial, a randomised double-blind placebo-controlled trial examining the effects of statins in community dwelling older people without CVD, diabetes or dementia. METHODS AND ANALYSIS: We will conduct a double-blind, randomised placebo-controlled trial among people aged 70 years and over, recruited through Australian general practice and with no history of clinical CVD, diabetes or dementia. Participants will be randomly assigned to oral atorvastatin (40 mg daily) or matching placebo (1:1 ratio). The co-primary endpoints are disability-free survival defined as survival-free of dementia and persistent physical disability, and major cardiovascular events (cardiovascular death or non-fatal myocardial infarction or stroke). Secondary endpoints are all-cause death, dementia and other cognitive decline, persistent physical disability, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, heart failure, atrial fibrillation, fatal and non-fatal cancer, all-cause hospitalisation, need for permanent residential care and quality of life. Comparisons between assigned treatment arms will be on an intention-to-treat basis with each of the co-primary endpoints analysed separately in time-to-first-event analyses using Cox proportional hazards regression models. ETHICS AND DISSEMINATION: STAREE will address uncertainties about the preventive effects of statins on a range of clinical outcomes important to older people. Institutional ethics approval has been obtained. All research outputs will be disseminated to general practitioner co-investigators and participants, published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT02099123.

Safety and Efficacy of Tenecteplase and Alteplase in Patients With Tandem Lesion Stroke: A Post Hoc Analysis of the EXTEND-IA TNK Trials.

BACKGROUND AND OBJECTIVES: The safety and efficacy of tenecteplase (TNK) in patients with tandem lesion (TL) stroke is unknown. We performed a comparative analysis of TNK and alteplase in patients with TLs. METHODS: We first compared the treatment effect of TNK and alteplase in patients with TLs using individual patient data from the EXTEND-IA TNK trials. We evaluated intracranial reperfusion at initial angiographic assessment and 90-day modified Rankin scale (mRS) with ordinal logistic and Firth regression models. Because 2 key outcomes, mortality and symptomatic intracranial hemorrhage (sICH), were few in number among those who received alteplase in the EXTEND-IA TNK trials, we generated pooled estimates for these outcomes by supplementing trial data with estimates of incidence obtained through a meta-analysis of studies identified in a systematic review. We then calculated unadjusted risk differences to compare the pooled estimates for those receiving alteplase with the incidence observed in the trial among those receiving TNK. RESULTS: Seventy-one of 483 patients (15%) in the EXTEND-IA TNK trials possessed a TL. In patients with TLs, intracranial reperfusion was observed in 11/56 (20%) of TNK-treated patients vs 1/15 (7%) alteplase-treated patients (adjusted odds ratio 2.19; 95% CI 0.28-17.29). No significant difference in 90-day mRS was observed (adjusted common odds ratio 1.48; 95% CI 0.44-5.00). A pooled study-level proportion of alteplase-associated mortality and sICH was 0.14 (95% CI 0.08-0.21) and 0.09 (95% CI 0.04-0.16), respectively. Compared with a mortality rate of 0.09 (95% CI 0.03-0.20) and an sICH rate of 0.07 (95% CI 0.02-0.17) in TNK-treated patients, no significant difference was observed. DISCUSSION: Functional outcomes, mortality, and sICH did not significantly differ between patients with TLs treated with TNK and those treated with alteplase. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that TNK is associated with similar rates of intracranial reperfusion, functional outcome, mortality, and sICH compared with alteplase in patients with acute stroke due to TLs. However, the CIs do not rule out clinically important differences. TRIAL REGISTRATION INFORMATION: clinicaltrials.gov/ct2/show/NCT02388061; clinicaltrials.gov/ct2/show/NCT03340493.

Increasing Patient Complexity Is Associated With Longer In-Hospital Lengths of Stay and Higher Rates of Medical Complications Following Primary 1- to 2-Level Lumbar Fusion.

BACKGROUND: The Elixhauser Comorbidity Index (ECI) is a stratification tool to predict adverse surgical outcomes. No studies have explored the relationship between ECI and outcomes following primary 1- to 2-level lumbar fusion (1-2LF). The purpose was to determine whether an ECI score greater than 1 correlated with (1) longer in-hospital length of stay (LOS) and (2) greater odds of developing 90-day medical complications. METHODS: A retrospective review from 2004 to 2015 was performed using the Medicare Standard Analytical Files for patients undergoing primary LF. Patients with ECI scores from 2 to 5 served as the study cohorts (1 for each ECI score), and patients with an ECI score of 1 served as the control cohort. In-hospital LOS and 90-day medical complications were compared between cohorts. A P value of <0.001 was statistically significant. RESULTS: A total of 105,120 patients were equally distributed between the 5 cohorts. Patients with an ECI score of 2 (6.00 ± 4.51), ECI 3 (6.22 ± 4.67), ECI 4 (7.35 ± 5.05), or ECI 5 (8.99 ± 5.67) had longer in-hospital LOS compared with patients with an ECI score of 1 (4.28 ± 4.36) (all P < 0.001). Patients with an ECI score of 2 (OR: 1.17, 95% CI: 1.05-1.30, P = 0.003; 2.85% vs 2.45%), ECI 3 (OR: 1.22, 95% CI: 1.10-1.36, P < 0.001; 2.98% vs 2.45%), ECI 4 (OR: 1.26, 95% CI: 1.13-1.40, P < 0.001; 3.10% vs 2.45%), or ECI 5 (OR: 1.18, 95% CI: 1.06-1.31, P = 0.001; 2.89% vs 2.45%) had greater incidence and odds of 90-day medical complications such as pneumonia, deep vein thrombosis, cerebrovascular accidents, and myocardial infarctions than patients in the control group (all P < 0.0001). CONCLUSIONS: Increasing ECI score was associated with longer in-hospital LOS and increased 90-day medical complication rates following 1-2LF. This study is the first to establish a correlation between ECI score, in-hospital LOS, and complication rates following lumbar fusion. CLINICAL RELEVANCE: ECI score may assist physicians in adjusting pre- and postoperative care for complex patients undergoing 1-2LF.

A Tailored Occupational Therapist-Led Vocational Intervention for People With Stroke: Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: Resuming work after stroke is a common goal of working-age adults, yet there are few vocational rehabilitation programs designed to address the unique challenges faced following stroke. The Work intervention was developed to address these gaps. OBJECTIVE: This paper presents a protocol that outlines the steps that will be undertaken to pilot both the intervention and trial processes for the Work trial. METHODS: The Work trial is a 2-arm, prospective, randomized, blinded-assessor study with intention-to-treat analysis. A total of 54 adults of working age who have experienced a stroke <4 months prior will be randomized 1:1 to either (1) an experimental group who will receive a 12-week early vocational intervention (Work intervention) plus usual clinical rehabilitation or (2) a control group who will receive only their usual clinical rehabilitation. RESULTS: Outcomes include study and intervention feasibility and intervention benefit. In addition to evaluating the feasibility of delivering vocational intervention early after stroke, benefit will be assessed by measuring rates of vocational participation and quality-of-life improvements at the 3- and 6-month follow-ups. Process evaluation using data collected during the study, as well as postintervention individual interviews with participants and surveys with trial therapists, will complement quantitative data. CONCLUSIONS: The results of the trial will provide details on the feasibility of delivering the Work intervention embedded within the clinical rehabilitation context and inform future trial processes. Pilot data will enable a future definitive trial to determine the clinical effectiveness of vocational rehabilitation when delivered in the early subacute phase of stroke recovery. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001164189; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378112&isReview=true. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40548.

Development, implementation, and evaluation of the Australian Stroke Data Tool (AuSDaT): Comprehensive data capturing for multiple uses.

BACKGROUND: Historically, national programs for collecting stroke data in Australia required the use of multiple online tools. Clinicians were required to enter overlapping variables for the same patient in the different databases. From 2013 to 2016, the Australian Stroke Data Tool (AuSDaT) was built as an integrated data management solution. OBJECTIVE: In this article, we have described the development, implementation, and evaluation phases of establishing the AuSDaT. METHOD: In the development phase, a governance structure with representatives from different data collection programs was established. Harmonisation of data variables, drawn from six programs used in hospitals for monitoring stroke care, was facilitated through creating a National Stroke Data Dictionary. The implementation phase involved a staged deployment for two national programs over 12 months. The evaluation included an online survey of people who had used the AuSDaT between March 2018 and May 2018. RESULTS: By July 2016, data entered for an individual patient was, for the first time, shared between national programs. Overall, 119/422 users (90% female, 61% aged 30-49 years, 57% nurses) completed the online evaluation survey. The two most positive features reported about the AuSDaT were (i) accessibility of the system (including simultaneous user access), and (ii) the ability to download reports to benchmark local data against peer hospitals or national performance. More than three quarters of respondents (n = 92, 77%) reported overall satisfaction with the data collection tool. CONCLUSION: The AuSDaT reduces duplication and enables users from different national programs for stroke to enter standardised data into a single system. IMPLICATIONS: This example may assist others who seek to establish a harmonised data management solution for different disease areas where multiple programs of data collection exist. The importance of undertaking continuous evaluation of end-users to identify preferences and aspects of the tool that are not meeting current requirements were illustrated. We also highlighted the opportunities to increase interoperability, utility, and facilitate the exchange of accurate and meaningful data.