Hemodynamic Stroke: Emerging Concepts, Risk Estimation, and Treatment.

Ischemic stroke can arise from the sudden occlusion of a brain-feeding artery by a clot (embolic), or local thrombosis. Hemodynamic stroke occurs when blood flow does not sufficiently meet the metabolic demand of a brain region at a certain time. This discrepancy between demand and supply can occur with cerebropetal arterial occlusion or high-grade stenosis but also arises with systemic conditions reducing blood pressure. Treatment of hemodynamic stroke is targeted toward increasing blood flow to the affected area by either systemically or locally enhancing perfusion. Thus, blood pressure is often maintained above normal values, and extra-intracranial flow augmentation bypass surgery is increasingly considered. Still, current evidence supporting the superiority of pressure or flow increase over conservative measures is limited. However, methods assessing hemodynamic impairment and identifying patients at risk of hemodynamic stroke are rapidly evolving. Sophisticated models incorporating clinical and imaging factors have been suggested to aid patient selection. In this narrative review, we provide current state-of-the-art knowledge about hemodynamic stroke, tools for assessment, and treatment options.

Association between heavy alcohol consumption and cryptogenic ischaemic stroke in young adults: a case-control study.

BACKGROUND: The underlying risk factors for young-onset cryptogenic ischaemic stroke (CIS) remain unclear. This multicentre study aimed to explore the association between heavy alcohol consumption and CIS with subgroup analyses stratified by sex and age. METHODS: Altogether, 540 patients aged 18-49 years (median age 41; 47.2% women) with a recent CIS and 540 sex-matched and age-matched stroke-free controls were included. Heavy alcohol consumption was defined as >7 (women) and >14 (men) units per week or at least an average of two times per month ≥5 (women) and ≥7 (men) units per instance (binge drinking). A conditional logistic regression adjusting for age, sex, education, hypertension, cardiovascular diseases, diabetes, hypercholesterolaemia, current smoking, obesity, diet and physical inactivity was used to assess the independent association between alcohol consumption and CIS. RESULTS: Patients were twice as more often heavy alcohol users compared with controls (13.7% vs 6.7%, p<0.001), were more likely to have hypertension and they were more often current smokers, overweight and physically inactive. In the entire study population, heavy alcohol consumption was independently associated with CIS (adjusted OR 2.11; 95% CI 1.22 to 3.63). In sex-specific analysis, heavy alcohol consumption was associated with CIS in men (2.72; 95% CI 1.25 to 5.92), but not in women (1.56; 95% CI 0.71 to 3.41). When exploring the association with binge drinking alone, a significant association was shown in the entire cohort (2.43; 95% CI 1.31 to 4.53) and in men (3.36; 95% CI 1.44 to 7.84), but not in women. CONCLUSIONS: Heavy alcohol consumption, particularly binge drinking, appears to be an independent risk factor in young men with CIS.

Prehospital identification of acute ischaemic stroke with large vessel occlusion: a retrospective study from western Norway.

BACKGROUND: In 2019, the emergency medical services (EMS) covering the western Norway Regional Health Authority area implemented its version of the prehospital clinical criteria G-FAST (Gaze deviation, Facial palsy, Arm weakness, Visual loss, Speech disturbance) to detect acute ischaemic stroke (AIS) with large vessel occlusion (LVO). For patients with gaze deviation and at least one other G-FAST symptom, a primary stroke centre (PSC) may be bypassed and the patient taken directly to a comprehensive stroke centre (CSC) for rapid endovascular treatment (EVT) evaluation. The study aim was to investigate the efficacy of the G-FAST criteria for LVO patient selection and direct transfer to a CSC. METHODS: This retrospective study included patients with code-red emergency medical communication centre (EMCC) stroke suspicion ambulance dispatch between August to December 2020. Stroke suspicion was defined as having at least one G-FAST symptom at EMS arrival. We obtained patient data from dispatches from EMCCs, EMS records and local EVT registries. Clinical features, CT images, and reperfusion treatment were recorded. The test characteristics for gaze deviation plus one other G-FAST symptom in detecting LVO were determined. RESULTS: Among 643 patients, 59 were diagnosed with LVO at hospital arrival. In this group, seven fulfilled the G-FAST criteria for direct transport to a CSC at EMS arrival on scene, resulting in a sensitivity of 12% (95% CI 5% to 23%). The specificity was 99.66% (95% CI 98.77% to 99.96%), the positive predictive value 78%, and the negative predictive value 92%. EVT was performed in 64% (38/59) of LVO cases. Median time from PSC arrival to start of EVT at a CSC was 163 min. CONCLUSION: The use of local G-FAST prehospital criteria by EMS personnel to identify patients with AIS with LVO is not suitable for selection of patients with LVO for direct transfer to a CSC.

Prolonged and repeated microemboli detection in acute ischemic stroke - The Norwegian Microemboli in Acute Stroke Study (NOR-MASS).

OBJECTIVES: Cerebral microemboli can be detected by transcranial Doppler monitoring (TCDM) and may elucidate stroke etiology, the effect of preventive therapy, and the risk of stroke recurrence. Microemboli detection is usually performed for up to 60 minutes, but due to temporal variability, microembolization may be missed if the monitoring time is too short. We aimed to assess the time course of microembolization in acute ischemic stroke and explore the utility of prolonged and repeated microemboli detection. MATERIALS AND METHODS: Patients with suspected ischemic stroke and symptom onset within 24 hours were examined with bilateral, stationary TCDM for one hour followed by unilateral, ambulatory TCDM for two hours. Unilateral TCDM was repeated for the following two days and after three months. RESULTS: We included 47 patients, of which 41 had ischemic stroke, five had transient ischemic attack, and one had amaurosis fugax. Microemboli were detected in 60 % of patients. The occurrence was highest within 24 hours after onset and significantly lower at three months. Prolonged and repeated microemboli detection yielded only one additional microemboli-positive patient. Hence, patients who initially were microemboli negative tended to remain negative. We could not demonstrate an association between microemboli occurrence and clinical outcome or stroke recurrence. CONCLUSIONS: Microembolic signals are frequent within 24 hours after ischemic stroke onset, but prolonged and repeated microemboli detection did not increase the yield of MES positive patients. CLINICAL TRIAL REGISTRATION-URL: http://www. CLINICALTRIALS: gov. Unique identifier: NCT03543319.

Obesity and the Risk of Cryptogenic Ischemic Stroke in Young Adults.

OBJECTIVES: We examined the association between obesity and early-onset cryptogenic ischemic stroke (CIS) and whether fat distribution or sex altered this association. MATERIALS AND METHODS: This prospective, multi-center, case-control study included 345 patients, aged 18-49 years, with first-ever, acute CIS. The control group included 345 age- and sex-matched stroke-free individuals. We measured height, weight, waist circumference, and hip circumference. Obesity metrics analyzed included body mass index (BMI), waist-to-hip ratio (WHR), waist-to-stature ratio (WSR), and a body shape index (ABSI). Models were adjusted for age, level of education, vascular risk factors, and migraine with aura. RESULTS: After adjusting for demographics, vascular risk factors, and migraine with aura, the highest tertile of WHR was associated with CIS (OR for highest versus lowest WHR tertile 2.81, 95%CI 1.43-5.51; P=0.003). In sex-specific analyses, WHR tertiles were not associated with CIS. However, using WHO WHR cutoff values (>0.85 for women, >0.90 for men), abdominally obese women were at increased risk of CIS (OR 2.09, 95%CI 1.02-4.27; P=0.045). After adjusting for confounders, WC, BMI, WSR, or ABSI were not associated with CIS. CONCLUSIONS: Abdominal obesity measured with WHR was an independent risk factor for CIS in young adults after rigorous adjustment for concomitant risk factors.

Brain monitoring in hospitals needs to be strengthened. / Hjerneovervåking i sykehusene må styrkes.

Careful brain monitoring saves lives and is beneficial to patients' health. Nevertheless, Norway lacks guidelines for brain monitoring in hospitals.

Short-Term Outcome and In-Hospital Complications After Acute Cerebral Infarcts in Multiple Arterial Territories.

Background and Purpose- Patients with acute cerebral infarcts in multiple arterial territories (MACI) represent a substantial portion of the stroke population. There are no data on short-term outcome and in-hospital complications in patients with MACI. We compared patients with MACI with patients having acute cerebral infarct(s) in a single arterial territory. Methods- We analyzed 3343 patients with diffusion-weighted imaging-confirmed acute cerebral infarcts. MACI was defined as at least 2 acute cerebral ischemic lesions in at least 2 arterial cerebral territories. Patients with MACI were compared with patients with acute cerebral infarct(s) in a single arterial territory for relevant in-hospital complications and short-term outcome, namely National Institutes of Health Stroke Scale and modified Rankin Scale at day 7 after admission or at discharge when earlier. Results- A total of 311 patients (9.3%) met the definition of MACI. Both median National Institutes of Health Stroke Scale (2 [1-7] versus 1 [0-4]) and modified Rankin Scale (3 [1-4] versus 2 [1-3]) were higher in patients with MACI. MACI was independently associated with higher National Institutes of Health Stroke Scale and modified Rankin Scale. Deep venous thrombosis, myocardial infarction, and any complications were more frequent in patients with MACI. Conclusions- In-hospital complications were more frequent in patients with MACI, which may adversely affect short-term clinical and functional outcome. Closer follow-up of patients with MACI during hospitalization may prevent such events and negative progression.

Prevalence and covariates of uncontrolled hypertension in ischemic stroke survivors: the Norwegian stroke in the young study.

PURPOSE: Hypertension is the most important modifiable risk factor for stroke. Few data are available on control of hypertension in younger ischemic stroke survivors. MATERIAL AND METHODS: We assessed clinic and ambulatory blood pressure (BP) measurements in 320 patients aged 15-60 years (mean 48 ± 10) included in the Norwegian Stroke in the Young Study during 3-months follow-up after the index stroke. Controlled hypertension was defined as ambulatory BP <130/80 mmHg. Carotid-femoral pulse wave velocity (PWV) was measured by applanation tonometry. Carotid plaque was considered present if focal intima-media thickness >1.5 mm. RESULTS: At hospital discharge, 58% of the patients were treated for hypertension. Another 9% of the total study population was diagnosed with new-onset hypertension during follow-up. At the 3-months follow-up visit, 56% of patients with treated hypertension were uncontrolled. Patients with uncontrolled treated hypertension were older, had higher body mass index (BMI) and PWV, and were more likely to have diabetes and carotid plaques compared to patients with normotension (p < .01). Compared to controlled treated hypertension, patients with uncontrolled treated hypertension had higher prevalence of carotid plaque (p < .01). In a multivariate logistic regression, uncontrolled treated hypertension was associated with higher PWV and BMI, and presence of carotid plaque, independent of the more intensified use of antihypertensive treatment (all p < .05). CONCLUSION: Uncontrolled hypertension was highly prevalent in ischemic stroke survivors <60 years and associated with co-presence of obesity and functional and structural arterial damage. Our results highlight the unmet potential and challenge of optimization of hypertension diagnosis and management in order to prevent recurrent vascular events in ischemic stroke survivors.

Monitoring following acute stroke should be improved. / Overvåkning etter akutt hjerneslag bør bli bedre.

Many serious complications following acute stroke can be prevented and treated. This requires close and systematic monitoring following stroke.

Covariates of non-dipping and elevated night-time blood pressure in ischemic stroke patients: the Norwegian Stroke in the Young Study.

Abnormal night-time blood pressure (BP) reduction is associated with increased cardiovascular risk in hypertension. Little is known about the prevalence and covariates of night-time BP reduction in ischemic stroke patients. Clinic and ambulatory BP measurements were recorded in 268 stroke survivors aged 15-60 years. The degree of night-time dipping was calculated from the difference between day-time and night-time mean BP, and defined as non-dipping if < 10%. Aortic stiffness was derived from carotid-femoral pulse-wave velocity (PWV) by applanation tonometry and carotid intima-media thickness (cIMT) by ultrasound. A non-dipping pattern was found in 38%. Non-dippers had higher PWV, mean cIMT and night-time BP, and included more patients with history of hypertension, diabetes and high for age PWV compared to dippers (all p < 0.05). In multivariate logistic regression analyses, non-dipping was associated with high for age PWV [odds ratio (OR) = 2.28; 95% confidence interval (CI) 1.06-4.92, p < 0.05] independent of history of hypertension and other confounders, while elevated night-time BP was associated with increased cIMT (OR = 3.83; 95% CI 1.01-14.50, p < 0.05) independent of non-dipping status, male gender, obesity, antihypertensive treatment and high for age PWV. In conclusion, in the Norwegian Stroke in the Young Study, non-dipping BP pattern was common and associated with increased aortic stiffness.

Atherosclerosis in Trial of Org 10172 in Acute Stroke Treatment Subtypes among Young and Middle-Aged Stroke Patients: The Norwegian Stroke in the Young Study.

BACKGROUND: Ischemic stroke patients subtyped as of undetermined cause (SUC) usually outnumber those with determined cause subtypes. Etiological stroke classifications may lead to neglect of parallel, noncausative findings. Atherosclerosis progresses over decades and is associated with high morbidity and mortality in young stroke patients in long-term follow-up studies. We compared the prevalence of carotid atherosclerosis in all TOAST subtypes among young patients with acute ischemic stroke. METHODS: We investigated 150 patients aged 15-60 years with documented acute ischemic stroke, and 84 controls free of cardiovascular disease. Stroke etiology was classified according to TOAST criteria. Carotid intima-media thickness (cIMT) measurements were obtained from 12 standardized multiangle measurements in the common carotid artery, carotid bifurcation, and internal carotid artery. RESULTS: The causes of stroke were 5.3% large-artery atherosclerosis (LAA), 26.7% cardioembolism, 21.3% small-artery occlusion (SAO), 10% stroke of other determined cause, and 36.7% stroke of undetermined cause (SUC). cIMT was increased in patients with LAA (1.56 mm, P = .002), SAO (1.11 mm, P = .006), and SUC (1.10 mm, P = .004) compared to controls (cIMT 0.86 mm). Segmental cIMT distribution differed across stroke subtypes, age groups, and sexes. CONCLUSIONS: Atherosclerotic disease is prevalent in the majority of young and middle-aged ischemic stroke patients, requiring determined investigation and aggressive treatment of modifiable risk factors.

Stroke patients' knowledge about cardiovascular family history - the Norwegian Stroke in the Young Study (NOR-SYS).

BACKGROUND: Family history (FH) is a risk factor for cardiovascular disease, especially coronary artery disease (CAD). The impact on risk of stroke is less clear. This study investigated young and middle-aged ischemic stroke patients' knowledge on FH of stroke, CAD, and peripheral artery disease (PAD) with a special regard to sex differences. METHODS: From September 2010 to February 2014, all ischemic stroke patients aged 15-60 years were prospectively included in the Norwegian Stroke in the Young Study (NOR-SYS). FH of stroke, CAD and PAD in offspring, siblings, parents, and grandparents was assessed using a standardized face-to-face interview. In addition to 'yes' and 'no', the optional reply 'don't know' was included to improve accuracy. McNemar's test was used to compare paired proportions, i.e. FH in male vs. female relatives. Multiple logistic regression analyses were used to test the influence of patient sex on FH reporting and to adjust for possible confounding factors. RESULTS: Altogether 257 patients were included. Mean age was 49.5 years and 68.1% were males. FH of cardiovascular disease was reported by 59% of patients. When asked about FH of stroke, 48 (18.7%) and 46 (17.9%) patients reported yes, whereas 17 (6.6%) and 9 (3.5%) reported 'don't know' regarding father and mother respectively, similarly patients reported 'don't know' regarding 117 (45.5%) paternal vs. 83 (32.4%) maternal grandmothers (p < 0.001). Female patients reported less 'don't know' and were more likely to report a positive cardiovascular FH than males (OR: 3.4; 95% CI: 1.5 to 7.7; p = 0.004). Patients had more detailed knowledge about CAD than stroke in fathers (p < 0.001), mothers (p < 0.001) and siblings (p = 0.01). CONCLUSIONS: Young and middle-aged stroke patients reported a high FH burden of cardiovascular disease. Females are more likely to report a positive FH than males. Detailed knowledge on FH was best for CAD. Our results suggest sex has a big impact on FH knowledge. Females have more knowledge of FH than males and knowledge is better for relatives with a female than male linkage. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov , unique identifier: NCT01597453 .

The Norwegian Stroke in the Young Study (NOR-SYS): rationale and design.

BACKGROUND: Ischemic stroke in young adults is a major health problem being associated with a higher vascular morbidity and mortality compared to controls, and a stroke recurrence rate of 25% during the first decade. The assumed cause of infarction and the detected risk factors determine the early- and long-term treatment. However, for many patients the cause of stroke remains unknown. Risk factor profile and etiology differ in young and elderly ischemic stroke patients, and atherosclerosis is the determined underlying condition in 10 to 15%. However, subclinical atherosclerosis is probably more prevalent and may go unrecognized. METHODS/DESIGN: NOR-SYS is a prospective long-term research program. Standardized methods are used for anamnestic, clinical, laboratory, imaging, and ultrasound data collection in ischemic stroke patients aged ≤60 years, their partners and joint adult offspring. The ultrasound protocol includes the assessment of intracranial, carotid and femoral arteries, abdominal aorta, and the estimation of VAT. To date, the study is a single centre study with approximately 400 patients, 250 partners and 350 adult offspring expected to be recruited at our site. DISCUSSION: NOR-SYS aims to increase our knowledge about heredity and the development of arterial vascular disease in young patients with ischemic stroke and their families. Moreover, optimization of diagnostics, prophylaxis and early intervention are major targets with the intention to reduce stroke recurrence and other clinical arterial events, physical disability, cognitive impairment and death.

Comparison Between First-Ever Ischemic Stroke in Young Adults in 1988-1997 and 2008-2017.

Aim: To compare incidence of first-ever acute cerebral infarction, etiology and traditional risk factors in young adults 15-49 years in 1988-1997 and 2008-2017 in Hordaland County, Norway. Methods: Case-finding of young adults with acute cerebral infarction in 1988-1997 was done retrospectively by computer research from hospital registries in Hordaland County. Young adults with acute cerebral infarction living in the Bergen region in 2008-2017 were prospectively included in a database at Haukeland University Hospital. Traditional risk factors, etiology and modified Rankin scale score on discharge were registered. Results: Crude average incidence of acute cerebral infarction was 11.4 per 100.000 per year in 1988-1997 and 13.2 per 100.000 per year in 2008-2017 (P=0.04). The prevalence of prior myocardial infarction, angina pectoris, and dyslipidemia were lower in the 2008-2017 cohort (all P<0.05). Atherosclerosis was less common in the 2008-2017 cohort (P<0.001). Conclusion: The observed incidence of acute cerebral infarction in young adults increased from 1988-1997 to 2008-2017 in Hordaland County. Atherosclerosis was less common in the 2008-2017 cohort.

Tenecteplase, 0.4 mg/kg, in Moderate and Severe Acute Ischemic Stroke: A Pooled Analysis of NOR-TEST and NOR-TEST 2A.

Background The optimal dose of tenecteplase in acute ischemic stroke remains to be defined. We present a pooled analysis of the 2 NOR-TESTs (Norwegian Tenecteplase Stroke Trials) exploring the efficacy and safety of tenecteplase, 0.4 mg/kg. Methods and Results We retrospectively reviewed 2 PROBE (Prospective Randomized Open, Blinded End-point) trials, NOR-TEST and NOR-TEST 2A. Patients were randomized to either tenecteplase, 0.4 mg/kg, or alteplase, 0.9 mg/kg. The primary end point was favorable functional outcome at 3 months (modified Rankin Scale score, 0-1) or return to baseline if prestroke modified Rankin Scale score was 2. Secondary end points included favorable functional and clinical outcome and safety data. The pooled analysis includes patients with National Institutes of Health Stroke Scale score ≥6 from both trials and an additional post hoc analysis of patients with National Institutes of Health Stroke Scale score ≤5 from NOR-TEST. The per-protocol analysis contains 483 patients, of whom 235 were assigned to tenecteplase and 248 were assigned to alteplase. In per-protocol analysis, functional outcome was better in the alteplase arm with cutoff modified Rankin Scale score of 2 (odds ratio [OR], 0.52 [95% CI, 0.33-0.80]; P=0.003) and expressed by ordinal shift analysis (OR, 1.64 [95% CI, 1.17-2.28]; P=0.004). Mortality at 3 months was higher in the tenecteplase arm (OR, 2.48 [95% CI, 1.20-5.10]; P=0.01). Mortality and intracranial hemorrhage rates were higher in the severe stroke group randomized to tenecteplase, whereas these rates were similar for alteplase and tenecteplase in moderate and mild stroke. Conclusions Tenecteplase, 0.4 mg/kg, is unsafe in moderate and severe stroke, and the risk of death and intracranial hemorrhage probably increases with stroke severity. A lower tenecteplase dose should be tested in future trials. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01949948, NCT03854500.

European Stroke Organisation (ESO) expedited recommendation on tenecteplase for acute ischaemic stroke.

Within the last year, four randomised-controlled clinical trials (RCTs) have been published comparing intravenous thrombolysis (IVT) with tenecteplase and alteplase in acute ischaemic stroke (AIS) patients with a non-inferiority design for three of them. An expedited recommendation process was initiated by the European Stroke Organisation (ESO) and conducted according to ESO standard operating procedure based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. We identified three relevant Population, Intervention, Comparator, Outcome (PICO) questions, performed systematic reviews of the literature and meta-analyses, assessed the quality of the available evidence, and wrote evidence-based recommendations. Expert consensus statements were provided if insufficient evidence was available to provide recommendations based on the GRADE approach. For patients with AIS of <4.5 h duration who are eligible for IVT, tenecteplase 0.25 mg/kg can be used as a safe and effective alternative to alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS of <4.5 h duration who are eligible for IVT, we recommend against using tenecteplase at a dose of 0.40 mg/kg (low evidence, strong recommendation). For patients with AIS of <4.5 h duration with prehospital management with a mobile stroke unit who are eligible for IVT, we suggest tenecteplase 0.25 mg/kg over alteplase 0.90 mg/kg (low evidence, weak recommendation). For patients with large vessel occlusion (LVO) AIS of <4.5 h duration who are eligible for IVT, we recommend tenecteplase 0.25 mg/kg over alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS on awakening from sleep or AIS of unknown onset who are selected with non-contrast CT, we recommend against IVT with tenecteplase 0.25 mg/kg (low evidence, strong recommendation). Expert consensus statements are also provided. Tenecteplase 0.25 mg/kg may be favoured over alteplase 0.9 mg/kg for patients with AIS of <4.5 h duration in view of comparable safety and efficacy data and easier administration. For patients with LVO AIS of <4.5 h duration who are IVT-eligible, IVT with tenecteplase 0.25 mg/kg is preferable over skipping IVT before MT, even in the setting of a direct admission to a thrombectomy-capable centre. IVT with tenecteplase 0.25 mg/kg may be a reasonable alternative to alteplase 0.9 mg/kg for patients with AIS on awakening from sleep or AIS of unknown onset and who are IVT-eligible after selection with advanced imaging.

Vascular risk factors and staging of atherosclerosis in patients and controls: The Norwegian Stroke in the Young Study.

Objectives: We studied the prevalence of vascular risk factors (RFs) among 385 ischaemic stroke patients ⩽60 years and 260 controls, and their association with atherosclerosis in seven vascular areas. Methods: History of cardiovascular events (CVE), hypertension, diabetes mellitus (DM), dyslipidaemia, pack-years of smoking (PYS), alcohol, and physical inactivity were noted. Blood pressure, body mass index (BMI), waist-hip ratio (WHR), lipid profile, epicardial adipose tissue (EAT), visceral abdominal adipose tissue (VAT), and subcutaneous abdominal adipose tissue were measured. Numeric staging of atherosclerosis was done by standardized examination of seven vascular areas by right and left carotid and femoral intima-media thickness, electrocardiogram, abdominal aorta plaques, and the ankle-arm index. All results were age and sex-adjusted. Poisson regression analysis was applied. Results: At age ⩽49 years at least one RF was present in 95.6% patients versus 90.0% controls. Compared to controls, male patients and middle-aged female patients showed no significant differences. Young female patients compared to young female controls had a higher burden of RFs (94.3% vs 88.6%, p = 0.049). Poisson regression analysis combined for patients and controls, adjusted for age and sex, showed numeric staging of atherosclerosis associated with age, prior CVE, hypertension, DM, dyslipidaemia, PYS, alcohol, BMI, WHR, EAT, VAT, and an increased number of risk factors. Adjusted for all risk factors, numeric staging of atherosclerosis was associated with increasing age, hypertension, DM, PYS, and BMI. Conclusion: Vascular risk factors are highly prevalent in young- and middle-aged patients and controls, and are predictors of established atherosclerosis at study inclusion. Focus on main modifiable vascular RFs in primary prevention, and early and aggressive secondary treatment of patients are necessary to reduce further progression of atherosclerosis.

Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial.

BACKGROUND: 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. METHODS: 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). FINDINGS: 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). INTERPRETATION: 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. FUNDING: The Norwegian National Programme for Clinical Therapy Research.