Background and purpose
Recurrent ischemic stroke (IS) or TIA is frequent with a considerable variation in incidence and mortality across populations. Current data on stroke recurrence and mortality ...are useful to examine trends, risk factors, and treatment effects. In this study, we calculated the incidence of recurrent IS or TIA in a hospital‐based stroke population in Western Norway, investigated recurrence factors, and estimated the effect of recurrence on all‐cause mortality.
Methods
This prospective cohort study registered recurrence and mortality among 1872 IS and TIA survivors admitted to the stroke unit at Haukeland University Hospital between July 2007 and December 2013. Recurrence and death until September 1, 2016, were identified by medical chart review. Cumulative incidences of recurrence were estimated with a competing risks Cox model. Multivariate Cox models were used to examine recurrence factors and mortality.
Results
During follow‐up, 220 patients had 277 recurrent IS or TIAs. The cumulative recurrence rate was 5.4% at 1 year, 11.3% at 5 years, and 14.2% at the end of follow‐up. Hypertension (HR = 1.65, 95% CI 1.21‐2.25), prior symptomatic stroke (HR = 1.63, 95% CI 1.18‐2.24), chronic infarcts on MRI (HR = 1.48, 95% CI 1.10‐1.99), and age (HR 1.02/year, 95% CI 1.00‐1.03) were independently associated with recurrence. A total of 668 (35.7%) patients died during follow‐up. Recurrence significantly increased the all‐cause mortality (HR = 2.55, 95% CI 2.04‐3.18).
Conclusions
The risk of recurrent IS stroke or TIA was modest in our population and was associated with previously established risk factors. Recurrence more than doubled the all‐cause mortality.
Tenecteplase is a modified tissue plasminogen activator with pharmacological and practical advantages over alteplase—which is currently the only approved thrombolytic drug for ischaemic stroke. The ...NOR-TEST trial showed that 0·4 mg/kg tenecteplase had an efficacy and safety profile similar to that of a standard dose (0·9 mg/kg) of alteplase, albeit in a patient population with a high prevalence of minor stroke. The aim of NOR-TEST 2 was to establish the non-inferiority of tenecteplase 0·4 mg/kg to alteplase 0·9 mg/kg for patients with moderate or severe ischaemic stroke.
This phase 3, randomised, open-label, blinded endpoint, non-inferiority trial was performed at 11 hospitals with stroke units in Norway. Patients with suspected acute ischaemic stroke with a National Institutes of Health Stroke Scale score of 6 or more who were eligible for thrombolysis and admitted within 4·5 h of symptom onset were consecutively included. Random assignment, done by a computer with a block size of 4 and with allocations placed into opaque envelopes to be opened consecutively, was 1:1 between intravenous tenecteplase (0·4 mg/kg) or standard dose alteplase (0·9 mg/kg). Doctors and nurses providing acute care were not masked to treatment, but primary outcome assessment at 3 months was masked. The primary outcome was favourable functional outcome defined as a modified Rankin Scale score of 0–1 at 3 months, assessed in the modified intention-to-treat analysis (excluding patients who did not qualify for thrombolysis after randomisation or who withdrew informed consent). The non-inferiority margin was 3%. This trial (NOR-TEST 2) is registered with EudraCT (number 2018–003090–95) and ClinicalTrials.gov (NCT03854500). The trial was stopped early for safety reasons and is designated part A for analysis. Part B is ongoing with a lower dose of tenecteplase (0·25 mg/kg).
Between Oct 28, 2019, and Sept 26, 2021, 216 patients were enrolled. Patient enrolment was stopped after a per-protocol safety review showed an imbalance in the rates of symptomatic intracranial haemorrhage between the treatment groups, which surpassed the prespecified criteria for stopping the trial. Of 204 patients entering the modified intention-to-treat analysis, 100 were randomly allocated tenecteplase and 104 were allocated alteplase. All patients were followed up within 14 days of the end of the 3-months' follow-up period. A favourable functional outcome was reported less frequently in patients receiving tenecteplase (31 32% of 96 patients) compared with alteplase (52 51% of 101 patients; unadjusted OR 0·45 95% CI 0·25–0·80; p=0·0064). Any intracranial haemorrhage was significantly more frequent with tenecteplase (21 21% of 100 patients) than with alteplase (seven 7% of 104 patients; unadjusted OR 3·68 95% CI 1·49–9·11; p=0·0031). Mortality at 3 months was also significantly higher with tenecteplase (15 16% of 96 patients) than with alteplase (five 5% of 101 patients; unadjusted OR 3·56 95% CI 1·24–10·21; p=0·013). Numerically more cases of symptomatic intracranial haemorrhage were reported with tenecteplase (six 6% of 100 patients) than with alteplase (one 1% of 104 patients; unadjusted OR 6·57 95% CI 0·78–55·62; p=0·061).
In this prematurely terminated study (terminated to fulfil the prespecified safety criteria), tenecteplase at a dose of 0·4 mg/kg yielded worse safety and functional outcomes compared with alteplase. Our study consequently could not show that 0·4 mg/kg tenecteplase is non-inferior to alteplase in moderate and severe ischaemic stroke. Future stroke trials should assess a lower dose of tenecteplase versus alteplase in patients with moderate or severe stroke.
The Norwegian National Programme for Clinical Therapy Research.
Tenecteplase is a newer thrombolytic agent with some pharmacological advantages over alteplase. Previous phase 2 trials of tenecteplase in acute ischaemic stroke have shown promising results. We ...aimed to investigate the safety and efficacy of tenecteplase versus alteplase in patients with acute stroke who were eligible for intravenous thrombolysis.
This phase 3, randomised, open-label, blinded endpoint, superiority trial was done in 13 stroke units in Norway. We enrolled adults with suspected acute ischaemic stroke who were eligible for thrombolysis and admitted within 4·5 h of symptom onset or within 4·5 h of awakening with symptoms, or who were eligible for bridging therapy before thrombectomy. Patients were randomly assigned (1:1) to receive intravenous tenecteplase 0·4 mg/kg (to a maximum of 40 mg) or alteplase 0·9 mg/kg (to a maximum of 90 mg), via a block randomisation schedule stratified by centre of inclusion. Patients were not informed of treatment allocation; treating physicians were aware of treatment allocation but those assessing the primary and secondary endpoints were not. The primary outcome was excellent functional outcome defined as modified Rankin Scale (mRS) score 0–1 at 3 months. The primary analysis was an unadjusted and non-stratified intention-to-treat analysis with last observation carried forward for imputation of missing data. This study is registered with ClinicalTrials.gov, number NCT01949948.
Between Sept 1, 2012, and Sept 30, 2016, 1107 patients met the inclusion criteria and seven patients were excluded because informed consent was withdrawn or eligibility for thrombolytic treatment was reconsidered. 1100 patients were randomly assigned to the tenecteplase (n=549) or alteplase (n=551) groups. The median age of participants was 77 years (IQR 64–79) and the median National Institutes of Health Stroke Scale score at baseline was 4 points (IQR 2–8). A final diagnosis other than ischaemic stroke or transient ischaemic attack was found in 99 (18%) patients in the tenecteplase group and 91 (17%) patients in the alteplase group. The primary outcome was achieved by 354 (64%) patients in the tenecteplase group and 345 (63%) patients in the alteplase group (odds ratio 1·08, 95% CI 0·84–1·38; p=0·52). By 3 months, 29 (5%) patients had died in the tenecteplase group compared with 26 (5%) in the alteplase group. The frequency of serious adverse events was similar between groups (145 26% in the tenecteplase group vs 141 26% in the alteplase group; p=0·74).
Tenecteplase was not superior to alteplase and showed a similar safety profile. Most patients enrolled in this study had mild stroke. Further trials are needed to establish the safety and efficacy in patients with severe stroke and whether tenecteplase is non-inferior to alteplase.
Research Council of Norway.
Motor and cognitive impairments are frequently observed following stroke, but are often managed as distinct entities, and there is little evidence regarding how they are related. The aim of this ...study was to describe the prevalence of concurrent motor and cognitive impairments 3 months after stroke and to examine how motor performance was associated with memory, executive function and global cognition.
The Norwegian Cognitive Impairment After Stroke (Nor-COAST) study is a prospective multicentre cohort study including patients hospitalized with acute stroke between May 2015 and March 2017. The National Institutes of Health Stroke Scale (NIHSS) was used to measure stroke severity at admission. Level of disability was assessed by the Modified Rankin Scale (mRS). Motor and cognitive functions were assessed 3 months post-stroke using the Montreal Cognitive Assessment (MoCA), Trail Making Test Part B (TMT-B), 10-Word List Recall (10WLR), Short Physical Performance Battery (SPPB), dual-task cost (DTC) and grip strength (Jamar®). Cut-offs were set according to current recommendations. Associations were examined using linear regression with cognitive tests as dependent variables and motor domains as covariates, adjusted for age, sex, education and stroke severity.
Of 567 participants included, 242 (43%) were women, mean (SD) age was 72.2 (11.7) years, 416 (75%) had an NIHSS score ≤ 4 and 475 (84%) had an mRS score of ≤2. Prevalence of concurrent motor and cognitive impairment ranged from 9.5% for DTC and 10WLR to 22.9% for grip strength and TMT-B. SPPB was associated with MoCA (regression coefficient B = 0.465, 95%CI 0.352, 0.578), TMT-B (B = -9.494, 95%CI - 11.726, - 7.925) and 10WLR (B = 0.132, 95%CI 0.054, 0.211). Grip strength was associated with MoCA (B = 0.075, 95%CI 0.039, 0.112), TMT-B (B = -1.972, 95%CI - 2.672, - 1.272) and 10WLR (B = 0.041, 95%CI 0.016, 0.066). Higher DTC was associated with more time needed to complete TMT-B (B = 0.475, 95%CI 0.075, 0.875) but not with MoCA or 10WLR.
Three months after suffering mainly minor strokes, 30-40% of participants had motor or cognitive impairments, while 20% had concurrent impairments. Motor performance was associated with memory, executive function and global cognition. The identification of concurrent impairments could be relevant for preventing functional decline.
ClinicalTrials.gov Identifier: NCT02650531 .
Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of ...B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients.
In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m(2) or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8-44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6-10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening.
The delayed responses starting from 2-7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future research efforts in CFS.
ClinicalTrials.gov NCT00848692.
Introduction. Nonmodifiable cardiovascular risk factors, like age and sex, are easily quantifiable. Due to immense technical progress in diagnostics and medical data storage, the aim of this study ...was to quantify, verify, and to compare parental cardiovascular events (CVE) as an additional nonmodifiable risk factor for young and middle-aged ischaemic stroke patients and controls. Methods. Information about parental CVE was first obtained by standardized questionnaires answered by 385 acute ischaemic stroke patients (15-60 years of age) and 260 controls. After consent to contact living and include deceased parents, patients and controls provided necessary personal identification of their parents. Thereafter, CVE were verified by standardized questionnaires answered by parents or medical records in case of deceased parents. Results. One hundred-and-nine (14.2%) of 770 patient parents vs. 128 (24.6%) of 520 control parents were not available for verification. Active participation was obtained for 229 (73.9%) of 310 patient parents vs.113 (58.2%) of 194 control parents. Medical record verification was obtained for 192 (54.7%) of 351 deceased patient parents, vs.103 (52.0%) of 198 deceased control parents. This study showed highest death rates of fathers (65.3% patient fathers and 57.6% control fathers) and highest numbers of CVE, especially myocardial infarction among patient fathers of patients aged 50-60 years. Discussion and Conclusion. Obtaining verified parental CVE as a nonmodifiable risk factor is still challenging, despite widely available digital medical information. To attain more accurate information on parental CVE, we recommend active involvement of family members in addition to medical record verification, especially for patients aged <50 years. Trial Registration. This trial is registered with NCT01597453
Objectives
The objective was to quantify temporal trends in stroke mimics (SM) admissions relative to cerebrovascular accidents (CVA), incidence of hospitalized SMs and characterize the SM case‐mix ...at a general hospital's stroke unit (SU).
Materials & Methods
All SU admissions (n = 11240) of patients aged 15 or older to Haukeland University Hospital between 2008–2017 were prospectively included and categorized as CVA or SM. Logistic regression was used to estimate time trends in the proportion of SMs among the admissions. Poisson regression was used to estimate time trends in age‐ and sex‐dependent SM incidence.
Results
SMs were on average younger thaan CVA patients (68.3 vs. 71.4 years) and had a higher proportion of females (53.6% vs. 44.5%). The total proportion of SM admissions was 51.0%. There was an increasing time trend in the proportion of SM admissions, odds ratio 1.150 per year (p < 0.001), but this trend appears flattening, represented by a significant quadratic time‐term, odds ratio 1.009 (p < 0.001). A higher SM proportion was also associated with the time period of a Mass Media Intervention (FAST campaign) in 2014. There was also an increasing trend in SM incidence, that remains after adjusting for age, sex, and population; also, for incidence the trend appears to be flattening.
Conclusions
SMs account for approximately half of the SU admissions, and the proportion has been increasing. A FAST campaign appears to have temporarily increased the SM proportion. The age‐ and sex‐dependent incidence of SM has been increasing but appears to flatten out.
Background: Underlying malignancy can cause ischemic stroke in some patients. Mechanisms include the affection of the coagulation cascade, tumor mucin secretion, infections and nonbacterial ...endocarditis. The release of necrotizing factor and interleukins may cause inflammation of the endothelial lining, creating a prothrombotic surface that triggers thromboembolic events, including stroke. The aims of this study were to assess the occurrence of cancer in patients who had recently suffered an ischemic stroke and to detect possible associations between stroke and cancer subtypes. Methods: All ischemic stroke patients registered in the Norwegian Stroke Research Registry (NORSTROKE) as part of the ongoing Bergen NORSTROKE study were included. Blood samples were obtained on admission. Stroke etiology was determined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, and the severity of stroke was defined according to the National Institute of Health Stroke Scale score. Information about cancer disease after stroke was obtained from patient medical records and The Cancer Registry of Norway. Results: From a total of 1,282 ischemic stroke patients with no history of cancer, 55 (4.3%) patients were diagnosed with cancer after stroke. The median time from stroke onset to cancer diagnosis was 14.0 months (interquartile range 6.2-24.5). Twenty-three (41.8%) patients were diagnosed with cancer within 1 year and 13 (23.6%) within 6 months. The most common cancer type was lung cancer (19.0%). By Cox regression analysis, cancer after stroke was associated with elevated D-dimer levels on admittance (p < 0.001), age (p = 0.01) and smoking (p = 0.04). Conclusions: Cancer-associated stroke is rare, and routine investigation for cancer seems unwarranted in acute ischemic stroke. However, in stroke patients with elevated levels of blood coagulation factors, C-reactive protein, higher age and a history of smoking, underlying malignancy should be considered. Our study suggests that an unknown stroke etiology does not predict malignancy.
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