Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Sex-Based Analysis of Workflow and Outcomes in Acute Ischemic Stroke Patients Treated With Alteplase Versus Tenecteplase.

BACKGROUND: Understanding sex differences in stroke care is important in reducing potential disparities. Our objective was to explore sex differences in workflow efficiency, treatment efficacy, and safety in the AcT trial (Alteplase Compared to Tenecteplase). METHODS: AcT was a multicenter, registry-linked randomized noninferiority trial comparing tenecteplase (0.25 mg/kg) with alteplase (0.9 mg/kg) in acute ischemic stroke within 4.5 hours of onset. In this post hoc analysis, baseline characteristics, workflow times, successful reperfusion (extended Thrombolysis in Cerebral Infarction score ≥2b), symptomatic intracerebral hemorrhage, 90-day functional independence (modified Rankin Scale score, 0-1), and 90-day mortality were compared by sex. Mixed-effects regression analysis was used adjusting for age, stroke severity, and occlusion site for outcomes. RESULTS: Of 1577 patients treated with intravenous thrombolysis (2019-2022), 755 (47.9%) were women. Women were older (median, 77 [68-86] years in women versus 70 [59-79] years in men) and had a higher proportion of severe strokes (National Institutes of Health Stroke Scale score >15; 32.4% versus 24.9%) and large vessel occlusions (28.7% versus 21.5%) compared with men. All workflow times were comparable between sexes. Women were less likely to achieve functional independence (31.7% versus 39.8%; unadjusted relative risk, 0.80 [95% CI, 0.70-0.91]) and had higher mortality (17.7% versus 13.3%; unadjusted relative risk, 1.33 [95% CI, 1.06-1.69]). Adjusted analysis showed no difference in outcomes between sexes. CONCLUSIONS: Differences in prognostic factors of age, stroke severity, and occlusion site largely accounted for higher functional dependence and mortality in women. No sex disparities were apparent in workflow quality indicators. Given the integration of the AcT trial into clinical practice, these results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Canadian centers. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Quality of Life After Intravenous Thrombolysis for Acute Ischemic Stroke: Results From the AcT Randomized Controlled Trial.

BACKGROUND: Recent evidence from thrombolysis trials indicates the noninferiority of intravenous tenecteplase to intravenous alteplase with respect to good functional outcomes in patients with acute stroke. We examined whether the health-related quality of life (HRQOL) of patients with acute stroke differs by the type of thrombolysis treatment received. In addition, we examined the association between the modified Rankin Scale score 0 to 1 and HRQOL and patient-reported return to prebaseline stroke functioning at 90 days. METHODS: Data were from all patients included in the AcT trial (Alteplase Compared to Tenecteplase), a pragmatic, registry-linked randomized trial comparing tenecteplase with alteplase. HRQOL at 90-day post-randomization was assessed using the 5-item EuroQOL questionnaire (EQ5D), which consists of 5 items and a visual analog scale (VAS). EQ5D index values were estimated from the EQ5D items using the time tradeoff approach based on Canadian norms. Tobit regression and quantile regression models were used to evaluate the adjusted effect of tenecteplase versus alteplase treatment on the EQ5D index values and VAS score, respectively. The association between return to prebaseline stroke functioning and the modified Rankin Scale score 0 to 1 and HRQOL was quantified using correlation coefficient (r) with 95% CI. RESULTS: Of 1577 included in the intention-to-treat analysis patients, 1503 (95.3%) had complete data on the EQ5D. Of this, 769 (51.2%) were administered tenecteplase and 717 (47.7%) were female. The mean EQ5D VAS score and EQ5D index values were not significantly higher for those who received intravenous tenecteplase compared with those who received intravenous alteplase (P=0.10). Older age (P<0.01), more severe stroke assessed using the National Institutes of Health Stroke Scale (P<0.01), and longer stroke onset-to-needle time (P=0.004) were associated with lower EQ5D index and VAS scores. There was a strong association (r, 0.85 [95% CI, 0.81-0.89]) between patient-reported return to prebaseline functioning and modified Rankin Scale score 0 to 1 Similarly, there was a moderate association between return to prebaseline functioning and EQ5D index (r, 0.45 [95% CI, 0.40-0.49]) and EQ5D VAS scores (r, 0.42 [95% CI, 0.37-0.46]). CONCLUSIONS: Although there is no differential effect of thrombolysis type on patient-reported global HRQOL and EQ 5D-5L index values in patients with acute stroke, sex- and age-related differences in HRQOL were noted in this study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Walking net V ˙ O2 rises with advancing age in older women: where to go from here?

PURPOSE: Walking net V ˙ O2 tends to increase with advancing age; however, factors contributing to this relationship have not been widely described. The implications of such findings could inform targeted strategies to promote independent mobility in older adults. Herein, we evaluated the relationship between net V ˙ O2 and age at two submaximal workloads while exploring potential moderators of this relationship. METHODS: Secondary analyses were performed on 35 older (65 ± 3 years) women who completed a battery of physical assessments including fixed-speed, non-graded and graded (+ 2.5%) treadmill walking with indirect calorimetry to determine net V ˙ O2. Maximal oxygen uptake ( V ˙ O2max), knee extensor maximal isometric voluntary contraction (MVC), peak rate of torque development (RTD), and plantar flexor range-of-motion (PFROM) were also measured. RESULTS: Bivariate correlations showed non-graded (r = 0.403, p = 0.017) and graded (r = 0.413, p = 0.014) net V ˙ O2 were positively related to age. Notably, these relationships strengthened after adjusting for V ˙ O2max. Regression modeling showed age, RTD:MVC ratio (composite of muscle performance), and PFROM together explained 49% and 34% of the variance in non-graded and graded net V ˙ O2, respectively. Further analyses suggested knee extensor MVC moderates the relationship between non-graded net V ˙ O2 and age, accounting for 9% of the variance [ΔR2 = 0.090, F (1,31) = 4.13, p = 0.05]. CONCLUSION: These data support the premise that, in older women, walking net V ˙ O2 rises with advancing age, and additionally, the RTD:MVC ratio and PFROM are independent correlates of non-graded net V ˙ O2. Exercise interventions with a high degree of training specificity including explosive, velocity-based elements may promote independent mobility in older women.

A Randomized Trial of Healthy Weight Gain in Athletic Individuals.

PURPOSE: The purpose of this study is to evaluate the outcomes of a 10-wk diet and exercise regimen designed to promote healthy weight gain with excess energy from peanut-containing or high-carbohydrate foods. METHODS: Nineteen male and 13 female athletes were randomly assigned to receive an additional 500 kcal·d -1 above typical intake through provision of either peanut-based whole foods/snacks (PNT group) or a similar, high-carbohydrate, peanut-free snack (CHO group) along with supervised, whole-body RT (3 d·wk -1 for 60-120 min). Body composition was assessed by dual-energyx-ray absorptiometry at baseline and postintervention. RESULTS: Total body mass (TBM) increased 2.2 ± 1.3 kg with 1.5 ± 1.1 kg as LBM after week 10. The PNT group ( n = 16; 27 ± 7 yr; 10 men, 6 women) gained less TBM than the CHO group ( n = 16; 23 ± 3 yr; 9 men, 7 women) (1.6 ± 1.1 kg vs 2.7 ± 1.2 kg, respectively, P = 0.007) with no differences in LBM (1.2 ± 1.1 kg vs 1.9 ± 1.0 kg, P = 0.136). CONCLUSIONS: These results suggest that the addition of 500 kcal·d -1 from whole foods/snacks in combination with a rigorous RT program promotes a similar weight gain of ~0.22 kg·wk -1 , primarily as LBM, over 10 wk in both male and female athletes. However, snack macronutrient content may impact the effectiveness of this regimen.

Role of Gut Microbe Composition in Psychosocial Symptom Response to Exercise Training in Breast Cancer Survivors (ROME) study: protocol for a randomised controlled trial.

INTRODUCTION: Breast cancer survivors have an increased risk for chronic fatigue and altered gut microbiota composition, both with negative health and quality of life affects. Exercise modestly improves fatigue and is linked to gut microbial diversity and production of beneficial metabolites. Studies suggest that gut microbiota composition is a potential mechanism underlying fatigue response to exercise. Randomised controlled trials testing the effects of exercise on the gut microbiome are limited and there is a scarcity of findings specific to breast cancer survivors. The objective of this study is to determine if fitness-related modifications to gut microbiota occur and, if so, mediate the effects of aerobic exercise on fatigue response. METHODS AND ANALYSIS: The research is a randomised controlled trial among breast cancer survivors aged 18-74 with fatigue. The primary aim is to determine the effects of aerobic exercise training compared with an attention control on gut microbiota composition. The secondary study aims are to test if exercise training (1) affects the gut microbiota composition directly and/or indirectly through inflammation (serum cytokines), autonomic nervous system (heart rate variability) or hypothalamic-pituitary-adrenal axis mediators (hair cortisol assays), and (2) effects on fatigue are direct and/or indirect through changes in the gut microbiota composition. All participants receive a standardised controlled diet. Assessments occur at baseline, 5 weeks, 10 weeks and 15 weeks (5 weeks post intervention completion). Faecal samples collect the gut microbiome and 16S gene sequencing will identify the microbiome. Fatigue is measured by a 13-item multidimensional fatigue scale. ETHICS AND DISSEMINATION: The University of Alabama at Birmingham Institutional Review Board (IRB) approved this study on 15 May 2019, UAB IRB#30000320. A Data and Safety Monitoring Board convenes annually or more often if indicated. Findings will be disseminated in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT04088708.

Tenecteplase Versus Alteplase in Medium Vessel Occlusion Ischemic Stroke: A Secondary Analysis of the Alteplase Compared to Tenecteplase Randomized Trial.

BACKGROUND AND PURPOSE: The safety and efficacy of tenecteplase in patients with ischemic stroke due to medium vessel occlusion (MeVO) are not well studied. We aimed to compare tenecteplase with alteplase in stroke due to MeVO. METHODS: Patients with baseline M2-middle cerebral artery (MCA), M3/M4-MCA, P2/P3/P4-posterior cerebral artery (PCA), A2/A3/A4-anterior cerebral artery (ACA) occlusions from the Alteplase Compared to Tenecteplase (AcT) trial were included. Primary outcome was the proportion of 90-day modified Rankin Scale (mRS) 0-1. Secondary outcomes were 90-day mRS 0-2, ordinal mRS, mortality, quality of life measures (EuroQol 5-Dimension 5-Level, EuroQol visual analog scale), and symptomatic intracerebral hemorrhage (sICH). Initial and final successful reperfusion were reported in patients undergoing endovascular thrombectomy (EVT). RESULTS: Among 1,558 patients with available baseline computed tomography angiography; 455 (29.2%) had MeVO of which 27.5% (125/455) were proximal M2; 16.3% (74/455) were distal M2; 35.2% (160/455) were M3/M4; 7.5% (34/455) were A2/A3/A4; and 13.6% (62/455) were P2/P3/P4 occlusions. EVT was performed in 87/455 (19.1%) patients. mRS 0-1 at 90 days was achieved in 37.9% in the tenecteplase versus 34.7% in the alteplase group (adjusted risk ratio [aRR] 1.07; 95% confidence interval [CI] 0.91-1.25). Rates of 90-day mRS 0-2, sICH, and mortality were similar in both groups. No statistical difference was noted in initial successful reperfusion rates (13.0% vs. 7.5%) among the 87 patients who underwent endovascular thrombectomy. However, final successful reperfusion was higher in the tenecteplase group (71.7% vs. 60.0%, aRR 1.29, 95% CI 1.04-1.61). CONCLUSION: Intravenous tenecteplase had comparable safety, functional outcomes and quality of life compared to intravenous alteplase among patients with MeVO. Among those treated with EVT, tenecteplase was associated with higher successful reperfusion rates than alteplase.

Intravenous tenecteplase compared with alteplase for minor ischaemic stroke: a secondary analysis of the AcT randomised clinical trial.

BACKGROUND: In ischaemic stroke, minor deficits (National Institutes of Health Stroke Scale (NIHSS) ≤5) at presentation are common but often progress, leaving patients with significant disability. We compared the efficacy and safety of intravenous thrombolysis with tenecteplase versus alteplase in patients who had a minor stroke enrolled in the Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke (AcT) trial. METHODS: The AcT trial included individuals with ischaemic stroke, aged >18 years, who were eligible for standard-of-care intravenous thrombolysis. Participants were randomly assigned 1:1 to intravenous tenecteplase (0.25 mg/kg) or alteplase (0.9 mg/kg). Patients with minor deficits pre-thrombolysis were included in this post-hoc exploratory analysis. The primary efficacy outcome was the proportion of patients with a modified Rankin Score (mRS) of 0-1 at 90-120 days. Safety outcomes included mortality and symptomatic intracranial haemorrhage (sICH). RESULTS: Of the 378 patients enrolled in AcT with an NIHSS of ≤5, the median age was 71 years, 39.7% were women; 194 (51.3%) received tenecteplase and 184 (48.7%) alteplase. The primary outcome (mRS score 0-1) occurred in 100 participants (51.8%) in the tenecteplase group and 86 (47.5 %) in the alteplase group (adjusted risk ratio (RR) 1.14 (95% CI 0.92 to 1.40)). There were no significant differences in the rates of sICH (2.9% in tenecteplase vs 3.3% in alteplase group, unadjusted RR 0.79 (0.24 to 2.54)) and death within 90 days (5.5% in tenecteplase vs 11% in alteplase group, adjusted HR 0.99 (95% CI 0.96 to 1.02)). CONCLUSION: In this post-hoc analysis of patients with minor stroke enrolled in the AcT trial, safety and efficacy outcomes with tenecteplase 0.25 mg/kg were not different from alteplase 0.9 mg/kg.

The treatment effect across ASPECTS in acute ischemic stroke: Analysis from the AcT Trial.

BACKGROUND: Early ischemic changes on baseline imaging are commonly evaluated for acute stroke decision-making and prognostication. AIMS: We assess the association of early ischemic changes on clinical outcomes and whether it differs between intravenous tenecteplase versus Alteplase. METHODS: Data are from the phase 3, Alteplase compared to Tenecteplase (AcT) trial. Subjects with anterior circulation stroke were included. Early ischemic changes were assessed using the Alberta Stroke Program Early CT score (ASPECTS). Efficacy outcomes included modified Rankin scale (mRS) 0-1, mRS 0-2, and ordinal mRS at 90 days. Safety outcomes included 24-hour symptomatic intracerebral hemorrhage (sICH), any hemorrhage on follow-up scan, and 90-day mortality rate. Mixed effects logistic regression was used to assess the association of ASPECTS [continuous and categorical (0-4 vs. 5-7 vs. 8-10)] with outcomes and if these associations were modified by thrombolytic type after adjusting for age, sex, and baseline stroke severity. RESULTS: Of the 1577 patients in the trial, 901 patients (56.3%) (median age 75 years [IQR 65-84], 50.8% females, median NIHSS 14 [IQR 17-19]) with anterior circulation stroke were included. mRS 0-1 at 90d was achieved in 1/14 (0.3%), 43/160 (14.7%) and 252/726 (85.1%) in the ASPECTS 0-4, 5-7 and 8-10 groups respectively. Every 1-point decrease in ASPECTS was associated with 2.7% and 1.9% decrease in chances of mRS 0-1 and mRS 0-2 at 90 days, respectively, and 1.9% chances of increase in mortality at 90 days. Subgroup analysis in EVT treated population showed similar results. Thrombolytic type did not modify this association between ASPECTS and 90-day mRS 0-1 (P interaction 0.75). There was no significant interaction by thrombolytic type with any other outcome. CONCLUSIONS: Similar to prior studies, we found that every one-point decrease in ASPECTS was associated with poorer clinical and safety outcomes. This effect did not differ between alteplase and tenecteplase.

Exercise Oxygen Uptake in 3- through 6-Year-Old Children.

This study compared submaximal and maximal oxygen uptake (V̇O2 max) in children ages 3-4 and 5-6 years. Methods appropriate for this age group were developed to elicit maximal performance on the exercise tests. Subjects (N = 22) performed progressive treadmill walking tests. The criteria used to determine whether V̇O2 max was reached were a plateauing of oxygen uptake, HR > 195, and an R > 1.00. The V̇O2 max for the 3- and 4-year-olds (44.5 ml•kg-1•min-1) was not significantly different from that of the 5- and 6-year-olds (44.1 ml•kg-1•min-1). At submaximal levels, 5- and 6-year-olds had significantly lower relative oxygen uptake, indicating better economy in walking. A large proportion of children met testing criteria for V̇O2 max. Test-retest results indicated that the tests were reliable.