Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial.

BACKGROUND: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months. METHODS: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812. FINDINGS: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups. INTERPRETATION: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale. FUNDING: Fonds NutsOhra.

The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial.

BACKGROUND: In adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke. METHODS: In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176. FINDINGS: Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82-1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group. INTERPRETATION: Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke. FUNDING: Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.

Cerebral microbleeds are not associated with long-term cognitive outcome in patients with transient ischemic attack or minor stroke.

BACKGROUND: Cerebral microbleeds have been related to cerebrovascular disease and dementia. They occur more frequently in patients with ischemic stroke than in the general population, but their relation to cognition in these patients is uncertain, particularly in the long run. We examined the relationship between microbleeds in patients with a transient ischemic attack (TIA) or minor ischemic stroke, and cognitive performance 4 years later. METHODS: Participants were recruited from a prospective multicenter cohort of patients with a TIA or minor ischemic stroke (n=397). They underwent magnetic resonance imaging (MRI), including a T2*-weighted sequence, within 3 months after their ischemic event. Microbleeds, atrophy, lacunae and white matter hyperintensities (WMH) were rated visually. Cognitive status was examined in 94% of all patients who were still alive after a mean interval of 3.8 years by the Dutch version of the Telephone Interview for Cognitive Status (TICS; n=280) or by an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) obtained from a close relative if a TICS could not be obtained (n=48). The relationship between presence of microbleeds and TICS or IQCODE score was assessed with linear regression analyses adjusted for age, sex, educational level and time interval between MRI and cognitive evaluation. RESULTS: The mean age was 65±12 years at inclusion. The vascular event at inclusion was a TIA in 170 patients (52%) and a minor ischemic stroke in 155 patients (47%). Microbleeds were present in 11.6% of the patients. Patients with microbleeds were significantly older than patients without microbleeds (70±9 vs. 64±12 years), more often had hypertension, and had more cerebral atrophy, WMH and lacunae on MRI (all p<0.05). The mean TICS score was 35.3±5.9 for patients with microbleeds (n=29) and 34.6±5.2 for patients without microbleeds (n=251); the adjusted mean difference (95% CI) was 1.69 (-0.01 to 3.38). The total IQCODE score was 66.0±10.8 for patients with microbleeds (n=9) and 63.1±12.9 for patients without microbleeds (n=39); the adjusted mean difference was 2.43 (-7.55 to 12.41). The relative risk (adjusted for age) for abnormal cognitive performance when having microbleeds was 1.19 (95% CI: 0.63-2.26). Subcortical atrophy was associated with lower TICS score [standardized regression coefficient ß: -0.12 (-0.23 to 0.00); p=0.04] and with lower IQCODE score [0.51 (0.19-0.83); p=0.00]. The adjusted mean difference of IQCODE scores between patients with and those without a lacunar infarct was 0.39 (0.12-0.65; p=0.01). CONCLUSIONS: In this sample of patients with a recent TIA or minor ischemic stroke, microbleeds were not associated with cognitive performance 4 years later. Apparently, this association is different from other markers of small vessel disease.

Participation in daily life activities at two months after stroke predicts long-term health-related quality of life.

BACKGROUND: After stroke, many patients experience problems with participation in daily activities. Improving participation is the main goal in stroke rehabilitation. However, the longitudinal relationship between participation and health-related quality of life (HRQoL) remains unclear. OBJECTIVES: This study aimed to examine (1) the predictive value of participation at two months on long-term HRQoL and (2) the longitudinal relationship between participation and HRQoL. METHODS: In this multicenter, prospective cohort study, patients were assessed at two and 12 months after stroke. Participation was measured with the Restriction subscale of the Utrecht Scale for Evaluation of Rehabilitation - Participation. HRQoL was assessed with the three-level version of the EuroQoL five dimensions questionnaire index score. RESULTS: This study included 291 patients. Mean age was 66.6 ± 12.4 years, 64.3% were male and mean National Institutes of Health Stroke Scale (NIHSS) was 2.5 ± 2.9. Multivariable linear regression, adjusted for demographic characteristics, stroke characteristics, physical and cognitive impairment, showed that a higher level of participation at two months correlated with a higher HRQoL at one year (B = .004; 95% CI =.002-.005). Patients whose participation improved had a greater increase in HRQoL, compared to patients without improvement (0.080 ± .21 versus -.054 ± .21; p < .001). CONCLUSIONS: The level of participation at two months post-stroke predicts HRQoL at one year. Improvement in participation during the first year after stroke is associated with improvement in HRQoL. We recommend including the assessment of participation in daily activities at follow-up visits.

Ultra-Early and Short-Term Tranexamic Acid Treatment in Patients With Good- and Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND OBJECTIVES: The results of the ULTRA trial showed that ultra-early and short-term treatment with tranexamic acid (TXA) does not improve clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). Possibly, the lack of a beneficial effect in all patients with aSAH is masked by antagonistic effects of TXA in certain subgroups. In this post hoc subgroup analysis, we investigated the effect of TXA on clinical outcome in patients with good-grade and poor-grade aSAH. METHODS: The ULTRA trial was a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment. Participants received ultra-early and short-term TXA in addition to usual care or usual care only. This post hoc subgroup analysis included only ULTRA participants with confirmed aSAH and available World Federation of Neurosurgical Societies (WFNS) grade on admission. Patients were categorized into those with good-grade (WFNS 1-3) and poor-grade (WFNS 4-5) aSAH. The primary outcome was clinical outcome assessed by the modified Rankin scale (mRS). Odds ratios (ORs) and adjusted ORs (aORs) with 95% CIs were calculated using ordinal regression analyses. Analyses were performed using the as-treated principle. In all patients with aSAH, no significant effect modification of TXA on clinical outcome was observed for admission WFNS grade (p = 0.10). RESULTS: Of the 812 ULTRA participants, 473 patients had (58%; N = 232 TXA, N = 241 usual care) good-grade and 339 (42%; N = 162 TXA, N = 176 usual care) patients had poor-grade aSAH. In patients with good-grade aSAH, the TXA group had worse clinical outcomes (OR: 0.67, 95% CI 0.48-0.94, aOR 0.68, 95% CI 0.48-0.94) compared with the usual care group. In patients with poor-grade aSAH, clinical outcomes were comparable between treatment groups (OR: 1.04, 95% CI 0.70-1.55, aOR 1.05, 95% CI 0.70-1.56). DISCUSSION: This post hoc subgroup analysis provides another important argument against the use of TXA treatment in patients with aSAH, by showing worse clinical outcomes in patients with good-grade aSAH treated with TXA and no clinical benefit of TXA in patients with poor-grade aSAH, compared with patients treated with usual care. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24, 2013). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tranexamic acid, given for <24 hours within the first 24 hours, does not improve the 6-month outcome in good-grade or poor initial-grade aneurysmal SAH.

Subtle problems in activities of daily living after a transient ischemic attack or an apparently fully recovered non-disabling stroke.

Little is known about the effects on the performance of activities of daily living (ADL) and quality of life (QoL) of transient ischemic attack (TIA) or a nondisabling stroke (NDS) with a full recovery in 72 hours. The present study evaluated ADL performance and QoL, as well as symptoms of anxiety and depression, in patients at 1 and 6 months after a TIA or an NDS. Consecutive hospitalized TIA/NDS patients not requiring rehabilitation were assessed at 1 and 6 months after discharge from a hospital or emergency department. ADL performance was evaluated using the Assessment of Motor and Process Skills (AMPS), QoL was assessed with the Short Form 36 (SF-36), and depression and anxiety symptoms were assessed with the Hospital Anxiety and Depression Scale (HADS). A total of 45 patients completed the follow-up. At 1 month after TIA/NDS, all patients were independent in ADL performance but had AMPS and SF-36 scores below the norm. In addition, 12 patients (27%) had anxiety symptoms, and 9 patients (20%) had symptoms of depression. Although initially considered fully recovered, 23 patients (51%) required rehabilitation after the first follow-up. After 6 months, their AMPS, SF-36, and HADS scores were lower than those of the patients who did not require rehabilitation after the first screening. Half of the patients with a TIA or an NDS who were initially considered fully recovered exhibited ADL limitations, decreased QoL, and symptoms of anxiety or depression after 6 months.

Prehospital transdermal glyceryl trinitrate in patients with presumed acute stroke (MR ASAP): an ambulance-based, multicentre, randomised, open-label, blinded endpoint, phase 3 trial.

BACKGROUND: Pooled analyses of previous randomised studies have suggested that very early treatment with glyceryl trinitrate (also known as nitroglycerin) improves functional outcome in patients with acute ischaemic stroke or intracerebral haemorrhage, but this finding was not confirmed in a more recent trial (RIGHT-2). We aimed to assess whether patients with presumed acute stroke benefit from glyceryl tr initrate started within 3 h after symptom onset. METHODS: MR ASAP was a phase 3, randomised, open-label, blinded endpoint trial done at six ambulance services serving 18 hospitals in the Netherlands. Eligible participants (aged ≥18 years) had a probable diagnosis of acute stroke (as assessed by a paramedic), a face-arm-speech-time test score of 2 or 3, systolic blood pressure of at least 140 mm Hg, and could start treatment within 3 h of symptom onset. Participants were randomly assigned (1:1) by ambulance personnel, using a secure web-based electronic application with random block sizes stratified by ambulance service, to receive either transdermal glyceryl trinitrate 5 mg/day for 24 h plus standard care (glyceryl trinitrate group) or to standard care alone (control group) in the prehospital setting. Informed consent was deferred until after arrival at the hospital. The primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included death within 7 days, death within 90 days, and serious adverse events. Analyses were based on modified intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. We separately analysed the total population and the target population (ie, patients with intracerebral haemorrhage, ischaemic stroke, or transient ischaemic attack). The target sample size was 1400 patients. The trial is registered as ISRCTN99503308. FINDINGS: On June 24, 2021, the MR ASAP trial was prematurely terminated on the advice of the data and safety monitoring board, with recruitment stopped because of safety concerns in patients with intracerebral haemorrhage. Between April 4, 2018, and Feb 12, 2021, 380 patients were randomly allocated to a study group. 325 provided informed consent or died before consent could be obtained, of whom 170 were assigned to the glyceryl trinitrate group and 155 to the control group. These patients were included in the total population. 201 patients (62%) had ischaemic stroke, 34 (10%) transient ischaemic attack, 56 (17%) intracerebral haemorrhage, and 34 (10%) a stroke-mimicking condition. In the total population (n=325), the median mRS score at 90 days was 2 (IQR 1-4) in both the glyceryl trinitrate and control groups (adjusted common OR 0·97 [95% CI 0·65-1·47]). In the target population (n=291), the 90-day mRS score was 2 (2-4) in the glyceryl trinitrate group and 3 (1-4) in the control group (0·92 [0·59-1·43]). In the total population, there were no differences between the two study groups with respect to death within 90 days (adjusted OR 1·07 [0·53-2·14]) or serious adverse events (unadjusted OR 1·23 [0·76-1·99]). In patients with intracerebral haemorrhage, 12 (34%) of 35 patients allocated to glyceryl trinitrate versus two (10%) of 21 allocated to the control group died within 7 days (adjusted OR 5·91 [0·78-44·81]); death within 90 days occurred in 16 (46%) of 35 in the glyceryl trinitrate group and 11 (55%) of 20 in the control group (adjusted OR 0·87 [0·18-4·17]). INTERPRETATION: We found no sign of benefit of transdermal glyceryl trinitrate started within 3 h of symptom onset in the prehospital setting in patients with presumed acute stroke. The signal of potential early harm of glyceryl trinitrate in patients with intracerebral haemorrhage suggests that glyceryl trinitrate should be avoided in this setting. FUNDING: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial.

BACKGROUND AND OBJECTIVES: The ULTRA-trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at six months. An expected proportion of the included patients had non-aneurysmal subarachnoid hemorrhage In this post-hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at six months. METHODS: The ULTRA-trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013 and January 20, 2020. After confirmation of subarachnoid hemorrhage on non-contrast computer tomography, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care, or usual care only. In this post-hoc analysis, we included all ULTRA-participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. The primary endpoint was clinical outcome at six months, assessed by the modified Rankin Scale, dichotomized into good (0-3) and poor (4-6) outcome. RESULTS: Of the 813 ULTRA-trial patients who had an aneurysmal subarachnoid hemorrhage, 409 (50%) were assigned to the tranexamic acid group and 404 (50%) to the control group. In the intention-to-treat analysis, 233 of 405 (58%) patients in the tranexamic acid group and 238 of 399 (60%) patients in the control group had a good clinical outcome (adjusted odds ratio (aOR) 0·92; 95% confidence interval (C.I.) 0·69 to 1·24). None of the secondary outcomes showed significant differences between the treatment groups: excellent clinical outcome (mRS 0-2) aOR 0.76, 95% C.I. 0.57-1.03, all-cause mortality at 30 days aOR 0.91, 95% C.I. 0.65-1.28), all-cause mortality at six months aOR 1.10 (95% C.I. 0.80-1.52). DISCUSSION: Ultra-early and short-term tranexamic acid treatment did not improve clinical outcome at six months in patients with aneurysmal subarachnoid hemorrhage and therefore, cannot be recommended. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24th, 2013). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage.

Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised, open-label, phase 2 trial.

BACKGROUND: In patients with atrial fibrillation who survive an anticoagulation-associated intracerebral haemorrhage, a decision must be made as to whether restarting or permanently avoiding anticoagulation is the best long-term strategy to prevent recurrent stroke and other vascular events. In APACHE-AF, we aimed to estimate the rates of non-fatal stroke or vascular death in such patients when treated with apixaban compared with when anticoagulation was avoided, to inform the design of a larger trial. METHODS: APACHE-AF was a prospective, randomised, open-label, phase 2 trial with masked endpoint assessment, done at 16 hospitals in the Netherlands. Patients who survived intracerebral haemorrhage while treated with anticoagulation for atrial fibrillation were eligible for inclusion 7-90 days after the haemorrhage. Participants also had a CHA2DS2-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less. Participants were randomly assigned (1:1) to receive oral apixaban (5 mg twice daily or a reduced dose of 2·5 mg twice daily) or to avoid anticoagulation (oral antiplatelet agents could be prescribed at the discretion of the treating physician) by a central computerised randomisation system, stratified by the intention to start or withhold antiplatelet therapy in participants randomised to avoiding anticoagulation, and minimised for age and intracerebral haemorrhage location. The primary outcome was a composite of non-fatal stroke or vascular death, whichever came first, during a minimum follow-up of 6 months, analysed using Cox proportional hazards modelling in the intention-to-treat population. APACHE-AF is registered with ClinicalTrials.gov (NCT02565693) and the Netherlands Trial Register (NL4395), and the trial is closed to enrolment at all participating sites. FINDINGS: Between Jan 15, 2015, and July 6, 2020, we recruited 101 patients (median age 78 years [IQR 73-83]; 55 [54%] were men and 46 [46%] were women; 100 [99%] were White and one [1%] was Black) a median of 46 days (IQR 21-74) after intracerebral haemorrhage. 50 were assigned to apixaban and 51 to avoid anticoagulation (of whom 26 [51%] started antiplatelet therapy). None were lost to follow-up. Over a median follow-up of 1·9 years (IQR 1·0-3·1; 222 person-years), non-fatal stroke or vascular death occurred in 13 (26%) participants allocated to apixaban (annual event rate 12·6% [95% CI 6·7-21·5]) and in 12 (24%) allocated to avoid anticoagulation (11·9% [95% CI 6·2-20·8]; adjusted hazard ratio 1·05 [95% CI 0·48-2·31]; p=0·90). Serious adverse events that were not outcome events occurred in 29 (58%) of 50 participants assigned to apixaban and 29 (57%) of 51 assigned to avoid anticoagulation. INTERPRETATION: Patients with atrial fibrillation who had an intracerebral haemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomised controlled trials large enough to allow identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous. FUNDING: Dutch Heart Foundation (grant 2012T077).

Early cognitive and emotional outcome after stroke is independent of discharge destination.

BACKGROUND AND PURPOSE: Cognitive and emotional problems occur frequently after stroke. Patients with minor stroke are more likely to be discharged home. This paper compares early cognitive and emotional outcomes in patients discharged home after stroke versus patients discharged to inpatient rehabilitation, and examines the effect of cognitive and emotional outcomes on long-term participation. METHODS: In this multicenter prospective cohort study, patients with stroke were assessed at two months with the Hospital Anxiety and Depression Scale (HADS), the Checklist for Cognitive and Emotional Consequences following Stroke (CLCE-24) and the Montreal Cognitive Assessment (MoCA). One year post stroke, participation was assessed with the Restriction subscale of the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P Restriction). RESULTS: The study included 332 patients. Two months post stroke, anxiety and cognitive problems were equally prevalent among patients discharged home (n = 243; 73%) and patients discharged to inpatient rehabilitation (n = 89; 27%) (HADS-A = 4.8 ± 3.9 versus 4.6 ± 4.0, p = 0.747; MoCA < 26: 66.7% versus 70.8%, p = 0.477; CLCE-cognition = 3.0 ± 2.9 versus 3.3 ± 2.8, p = 0.499). Depressive symptoms were less severe in patients discharged home (HADS-D = 4.3 ± 3.9 versus 5.5 ± 3.8, p = 0.010). In patients discharged home, cognitive complaints were predictive of long-term participation (B = - 2.03; 95% CI - 3.15, - 0.90), while cognitive or emotional outcomes were not predictive in patients discharged to inpatient rehabilitation. CONCLUSIONS: Cognitive and emotional problems at two months post stroke were comparable between patients discharged home and those discharged to inpatient rehabilitation. For patients discharged home, cognitive complaints were predictive of long-term participation.

Predictors of quality of life 1 year after minor stroke or TIA: a prospective single-centre cohort study.

OBJECTIVES: In patients after a transient ischaemic attack (TIA) or minor stroke, dysfunction is often underestimated by clinical measures due to invisible symptoms, including cognitive and emotional problems. Many of these patients need stroke care programme, but others do not. In this study, we aim to identify potential predictors of quality of life (QoL) in patients with TIA or minor stroke 1 year poststroke to be able to select which of these patients will need aftercare. DESIGN: Prospective observational cohort study. SETTING: Single-centre hospital in the Netherlands. PARTICIPANTS: 120 patients, diagnosed with TIA or minor stroke and discharged without rehabilitation treatment, completed the study. PRIMARY AND SECONDARY OUTCOME MEASURES: QoL (RAND-36), anxiety and depressive symptoms (Hospital Anxiety and Depression scale), the degree of disability or functional dependence after stroke (modified Rankin Scale (mRS)) and symptoms of anxiety and depression specific to stroke (SSADQ) were assessed at baseline (2-6 weeks poststroke) and compared with follow-up at 1 year poststroke. RESULTS: Depression (B=-1.35, p<0.001) and anxiety (B=-0.57, p=0.041) at baseline predicted a worse mental component of QoL after 1 year. Depression (B=-1.100, p<0.001) at baseline, but also age (B=-0.261, p=0.002) and female sex (B=4.101, p=0.034) predicted a worse physical component of QoL after 1 year. CONCLUSION: With the identification of these predictors, we might be able to select more efficiently and timely the patients with TIA or minor stroke who need stroke aftercare.

Accelerated long-term forgetting after TIA or minor stroke: A more sensitive measure for detecting subtle memory dysfunction?

Cognitive changes after minor stroke or TIA have been reported, with studies describing a 'vascular' cognitive profile with spared episodic memory. Still, many patients also report memory complaints. Studies using long-term forgetting paradigms have detected memory impairment after prolonged intervals in contrast to standard delayed testing in other patient groups. This study examined whether accelerated long-term forgetting (ALF) is present in patients with minor stroke or TIA by comparing one-week delayed recall and recognition with the performance of a healthy control group. Results revealed that the patients' performance after one week was worse than the controls, in the absence of an impairment after a short delay. Patients did, however, not report more memory worries than controls. Possibly, reduced effort, attention or mnemonic strategies may contribute to subtle consolidation problems, which go undetected in daily functioning.

High satisfaction with an individualised stroke care programme after hospitalisation of patients with a TIA or minor stroke: a pilot study.

BACKGROUND: Many hospitalised patients with a transient ischaemic attack (TIA) or minor stroke develop subtle cognitive disorders and emotional problems a few weeks after discharge, and are dissatisfied with the care they have received, even with specialised stroke care programmes. Therefore, an individualised stroke care programme was developed to match the therapy with the personal care needs. In this pilot study we evaluated the feasibility of the rehabilitation programme, the satisfaction of stroke patients with this programme, and the factors associated with satisfaction. METHODS: Consecutive patients who were hospitalised with a TIA or minor stroke, with no apparent residual deficits, were eligible. Occupational and neuropsychological screening was applied 4-6 weeks after discharge, and therapy was provided when necessary. After 6 months, satisfaction with care (Satisfaction-With-Stroke-Care-19), was assessed as the primary outcome. Secondary outcomes were quality of life (QoL), disability, handicap, anxiety and depression. RESULTS: 42 patients with a TIA or minor stroke participated in the programme and the follow-up. Of all the participants, 71% were satisfied with the care they have received after discharge. Male patients were more satisfied than female patients. Dissatisfied patients were less able to perform the activities of daily living, had a lower QoL and more depressive symptoms. After regression analysis, only the Barthel Index was independently associated with satisfaction. CONCLUSIONS: In this pilot study, our individualised stroke care programme seems to have improved patient satisfaction. Ability to perform daily activities is associated with satisfaction. A randomised controlled trial is needed to confirm the effectiveness of this rehabilitation programme.

Validity of the PROMIS-10 Global Health assessed by telephone and on paper in minor stroke and transient ischaemic attack in the Netherlands.

OBJECTIVES: Dysfunction after transient ischaemic attack (TIA) and minor stroke is often underestimated by clinical measures. Patient-reported outcome measures used in value-based healthcare may help in detecting these problems. The Patient-Reported Outcomes Measurement Information System 10-Question Short Form (PROMIS-10 Global Health) is a concise patient-centred outcome measuring tool proposed for assessing health status in patients who had stroke. This study aims to address the validity of the Dutch PROMIS-10 in patients who had stroke in the Netherlands and also aims to compare telephone versus on-paper assessment. DESIGN: Observational cohort study. SETTING: Single-centre hospital in the Netherlands. PARTICIPANTS: 75 patients who were diagnosed with TIA or minor stroke and discharged without rehabilitation treatment 1 year ago (between December 2014 and January 2016) completed the study. PRIMARY AND SECONDARY OUTCOME MEASURES: PROMIS-10 physical (PH) and mental health (MH) scores assessed 1 year poststroke on paper (n=37) and by telephone (n=38) was compared with RAND-36 physical and mental component scores assessed on paper. RESULTS: PROMIS-10 and RAND-36 correlated significantly in PH, r=0.81 (95% CI 0.69 to 0.88), and MH, r=0.76 (95% CI 0.64 to 0.85). Paper-and-pencil assessed correlations were r=0.87 and 0.79 for PH and MH, respectively. Telephone assessed correlations were r=0.76 and 0.73 for PH and MH, respectively. Internal consistency analysis indicated high reliabilities for both health components of the PROMIS-10, all Cronbach's α>0.70. CONCLUSIONS: The Dutch PROMIS-10 was found to strongly correlate with the RAND-36. Paper-and-pencil assessment was found to have a higher correlation than telephone assessment. This study provides support for the use of the Dutch PROMIS-10 in assessing health status in patients after TIA and minor stroke.

Cerebral white matter lesions predict both ischemic strokes and myocardial infarctions in patients with established atherosclerotic disease.

BACKGROUND: Cerebral white matter lesions (WML) are regarded as manifestations of small vessel disease, but have also been associated with large vessel atherosclerosis. We investigated whether WML have a predictive value for future ischemic events. METHODS AND RESULTS: Two-hundred-thirty patients with proven atherosclerotic disease, recent ischemic stroke (IS, n=70), recent myocardial infarction (MI, n=71), or peripheral arterial disease (PAD, n=89) were included. The presence of periventricular lesions (PVL) and deep white matter lesions (DWML) on MRI at entry and ischemic events during follow-up were registered. During follow-up with a mean duration of 3.5+/-1.4 years 22 patients had a MI, 21 patients suffered an IS and 2 patients died suddenly. The frequency of ischemic events during follow-up was higher among patients with PVL than in those without PVL (IS: 18% versus 5%, p=0.001; MI: 15% versus 7%, p=0.03; any ischemic event: 36% versus 11%, p<0.001). DWML was associated only with the combined outcome any ischemic event (p=0.04). In multivariate regression analysis the presence of PVL was independently associated with IS (HR 3.2 (95%CI 1.3-8.4) and MI (HR 3.4 (95%CI 1.4-8.0)). CONCLUSION: We observed an association between WML, especially PVL, and future ischemic strokes and myocardial infarctions in patients with established atherosclerotic disease.

Recurrent stroke risk and cerebral microbleed burden in ischemic stroke and TIA: A meta-analysis.

OBJECTIVE: To determine associations between cerebral microbleed (CMB) burden with recurrent ischemic stroke (IS) and intracerebral hemorrhage (ICH) risk after IS or TIA. METHODS: We identified prospective studies of patients with IS or TIA that investigated CMBs and stroke (ICH and IS) risk during ≥3 months follow-up. Authors provided aggregate summary-level data on stroke outcomes, with CMBs categorized according to burden (single, 2-4, and ≥5 CMBs) and distribution. We calculated absolute event rates and pooled risk ratios (RR) using random-effects meta-analysis. RESULTS: We included 5,068 patients from 15 studies. There were 115/1,284 (9.6%) recurrent IS events in patients with CMBs vs 212/3,781 (5.6%) in patients without CMBs (pooled RR 1.8 for CMBs vs no CMBs; 95% confidence interval [CI] 1.4-2.5). There were 49/1,142 (4.3%) ICH events in those with CMBs vs 17/2,912 (0.58%) in those without CMBs (pooled RR 6.3 for CMBs vs no CMBs; 95% CI 3.5-11.4). Increasing CMB burden increased the risk of IS (pooled RR [95% CI] 1.8 [1.0-3.1], 2.4 [1.3-4.4], and 2.7 [1.5-4.9] for 1 CMB, 2-4 CMBs, and ≥5 CMBs, respectively) and ICH (pooled RR [95% CI] 4.6 [1.9-10.7], 5.6 [2.4-13.3], and 14.1 [6.9-29.0] for 1 CMB, 2-4 CMBs, and ≥5 CMBs, respectively). CONCLUSIONS: CMBs are associated with increased stroke risk after IS or TIA. With increasing CMB burden (compared to no CMBs), the risk of ICH increases more steeply than that of IS. However, IS absolute event rates remain higher than ICH absolute event rates in all CMB burden categories.

Association between i.v. thrombolysis volume and door-to-needle times in acute ischemic stroke.

Centralization of intravenous thrombolysis (IVT) for acute ischemic stroke in high-volume centers is believed to improve the door-to-needle times (DNT), but limited data support this assumption. We examined the association between DNT and IVT volume in a large Dutch province. We identified consecutive patients treated with IVT between January 2009 and 2013. Based on annualized IVT volume, hospitals were categorized as low-volume (≤ 24), medium-volume (25-49) or high-volume (≥ 50). In logistic regression analysis, low-volume hospitals were used as reference category. Of 17,332 stroke patients from 11 participating hospitals, 1962 received IVT (11.3 %). We excluded 140 patients because of unknown DNT (n = 86) or in-hospital stroke (n = 54). There were two low-volume (total 101 patients), five medium-volume (747 patients) and four high-volume hospitals (974 patients). Median DNT was shorter in high-volume hospitals (30 min) than in medium-volume (42 min, p < 0.001) and low-volume hospitals (38 min, p < 0.001). Patients admitted to high-volume hospitals had a higher chance of DNT < 30 min (adjusted OR 3.13, 95 % CI 1.70-5.75), lower risk of symptomatic intracerebral hemorrhage (adjusted OR 0.39, 95 % CI 0.16-0.92), and a lower mortality risk (adjusted OR 0.45, 95 % CI 0.21-1.01), compared to low-volume centers. There was no difference in DNT between low- and medium-volume hospitals. Onset-to-needle times (ONT) did not differ between the groups. Hospitals in this Dutch province generally achieved short DNTs. Despite this overall good performance, higher IVT volumes were associated with shorter DNTs and lower complication risks. The ONT was not associated with IVT volume.

CT within 6 hours of headache onset to rule out subarachnoid hemorrhage in nonacademic hospitals.

OBJECTIVE: To investigate whether staff radiologists working in nonacademic hospitals can adequately rule out subarachnoid hemorrhage (SAH) on head CT <6 hours after headache onset. METHODS: In a multicenter, retrospective study, we studied a consecutive series of patients presenting with acute headache to 11 nonacademic hospitals. Inclusion criteria were (1) normal level of consciousness without focal deficits, (2) head CT <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist, and (3) subsequent CSF spectrophotometry. Two neuroradiologists and one stroke neurologist from 2 academic tertiary care centers independently reviewed admission CTs of patients with CSF results that were considered positive for presence of bilirubin according to local criteria. We investigated the negative predictive value for detection of SAH by staff radiologists in nonacademic hospitals on head CT in patients scanned <6 hours after onset of acute headache. RESULTS: Of 760 included patients, CSF analysis was considered positive for bilirubin in 52 patients (7%). Independent review of these patients' CTs identified one patient (1/52; 2%) with a perimesencephalic nonaneurysmal SAH. Negative predictive value for detection of subarachnoid blood by staff radiologists working in a nonacademic hospital was 99.9% (95% confidence interval 99.3%-100.0%). CONCLUSIONS: Our results support a change of practice wherein a lumbar puncture can be withheld in patients with a head CT scan performed <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist in the described nonacademic setting.

Arterial wall thickness and the risk of recurrent ischemic events in carriers of the prothrombin G20210A mutation with clinical manifestations of atherosclerosis.

The G20210A mutation in the prothrombin gene is an established risk factor for venous thrombosis. There is controversy about the role of this mutation in arterial thrombotic disease and atherosclerosis. We determined the presence of the prothrombin mutation and examined its influence on carotid and femoral artery intima-media thickness (IMT) and the occurrence of new ischemic events during follow-up in 277 patients with clinically manifest atherosclerotic disease: ischemic stroke, myocardial infarction or peripheral arterial disease. The mean age at entry was 63 years. Mean IMT was significantly higher in carriers of the prothrombin mutation (1.17 (SD 0.29) mm versus 0.97 (SD 0.25) mm: (delta)IMT=0.20, P=0.02). The increase in IMT was not attributable to differences in age, type of arterial disease or cardiovascular risk factors between carriers and non-carriers. During a mean follow-up of 3.5 years, a strong trend for more ischemic events was observed: 4 of the 11 carriers suffered from a recurrent ischemic event, compared with 30 of the 164 male non-carriers (36 versus 18%; P=0.06). These results suggest that the G20210A mutation contributes to the process of arterial wall thickening and is associated with the occurrence of ischemic events in a cohort of elderly persons with established atherosclerosis.

Chlamydial LPS antibodies, intima-media thickness and ischemic events in patients with established atherosclerosis.

BACKGROUND: Chlamydia pneumoniae has been associated with cardiovascular disease. However, studies on the presence of chlamydial antibodies and intima-media thickness (IMT) or future ischemic events are inconclusive. We examined the relation between circulating antibodies to chlamydial lipopolysaccharide (cLPS Ab), IMT and the occurrence of ischemic events during follow-up in patients with manifest atherosclerotic disease. METHODS: IgG and IgA antibodies against cLPS were determined in 273 out of 307 consecutive patients with a recent ischemic stroke (IS, n=90), a recent myocardial infarction (MI, n=87) or peripheral arterial disease (PAD, n=96). B-mode ultrasound IMT measurement of carotid and femoral arteries was performed and ischemic events, IS or MI, during follow-up were registered. RESULTS: IgG and IgA were found in 66 and 46% of the patients, respectively. We did not detect any difference in IMT between patients with or without antibodies: IgA-0.97(0.28) mm versus IgA+0.95(0.26) mm, P=0.63, IgG-0.96(0.28) mm versus IgG+0.96(0.26) mm, P=0.98. During follow-up with a mean duration of 3.5 years the combined endpoint, MI or IS, was similar in patients with or without antibodies (IgA-24% vs. IgA+19%, IgG-23% vs. IgG+22%). However, a lower frequency of MI was observed in IgA positive patients (IgA-13% vs. IgA+8%). The number of ischemic events in the 12 patients who used anti-chlamydial antibiotics was similar compared with those who did not use antibiotics. CONCLUSION: In patients with manifest atherosclerotic disease no association between the presence of cLPS Ab and IMT could be detected. In addition, no influence of cLPS Ab on the number of ischemic events was observed, the frequency of MI during follow-up in IgA positive patients was even lower.