Intravenous Thrombolysis in Patients 90 years or Older with Moderate to Severe Acute Ischemic Stroke Increases Ambulation at Discharge and is Safe: A prospective cohort study from a single center in Santiago, Chile.

Introduction: The World Health Organization predicts that the global population aged 60 years and older will double by 2050, leading to a significant rise in the public health impact of acute ischemic stroke (AIS). Existing stroke guidelines do not specify an upper age limit for the administration of intravenous thrombolysis (IVT), although some suggest a relative exclusion criterion in patients aged ≥ 80 in the 3 – 4.5 hour window. Many physicians avoid treating these patients with IVT, argumenting high risk and little benefit. Our aim was to investigate the efficacy and safety of IVT treatment in patients with non-minor AIS aged ≥ 90, admitted to our institution. The primary efficacy endpoint was the ability to walk at discharge (mRS 0-3) and the primary safety endpoints were death and symptomatic intracerebral hemorrhagic transformation (sIHT) at discharge. Methods: Patients with AIS aged ≥ 90 admitted to our center from January 2003 to December 2022 were included. They were selected if had an NIHSS ≥ 5, were previously ambulatory (prestroke mRS score 3 or less) and arrived within 6 hours from symptom onset. Those treated or not with IVT were compared with univariate analysis. Results: The mean age was 93.2 (2.4) years and 51 (73.9%) were female. The admission mRS and NIHSS were 1 (IQR 0 – 2) and 14 (IQR 7 – 22), respectively. Thrombolysed patients had a shorter time from symptom onset to door and lower glycemia on admission. IVT was associated with a higher proportion of patients achieving mRS 0 – 3 at discharge (p=0.03) and at 90 days (p=0.04). There were no differences between groups in the risk of death (p=0.55) or sIHT (p=0.38). Conclusion: In this small sample, ambulatory patients aged ≥ 90 with moderate or severe AIS treated with IVT, had increased odds of being able to walk independently at discharge than those not treated, without safety concerns

Validation of the simplified modified Rankin scale for stroke trials: Experience from the ENCHANTED alteplase-dose arm

Background and aims The structured, simplified modified Rankin scale questionnaire (smRSq) may increase reliability over the interrogative approach to scoring the modified Rankin scale (mRS) in acute stroke research and practice. During the conduct of the alteplase-dose arm of the international ENhanced Control of Hypertension ANd Thrombolysis StrokE stuDy (ENCHANTED), we had an opportunity to compare each of these approaches to outcome measurement. Methods Baseline demographic data were recorded together with the National Institutes of Health Stroke Scale (NIHSS). Follow-up measures obtained at 90 days included mRS, smRSq, and the 5-Dimension European Quality of life scale (EQ-5D). Agreements between smRSq and mRS were assessed with the Kappa statistic. Multiple logistic regression was used to identify baseline predictors of Day 90 smRSq and mRS scores. Treatment effects, based on Day 90 smRSq/mRS scores, were tested in logistic and ordinal logistic regression models. Results SmRSq and mRS scores had good agreement (weighted Kappa 0.79, 95% confidence interval (CI) 0.78–0.81), while variables of age, atrial fibrillation, diabetes mellitus, pre-morbid mRS (1 vs. 0), baseline NIHSS scores, and imaging signs of cerebral ischemia, similarly predicted their scores. Odds ratios for death or disability, and ordinal shift, 90-day mRS scores using smRSq were 1.05 (95% CI 0.91–1.20; one-sided P = 0.23 for non-inferiority) and 0.98 (95% CI 0.87–1.11; P = 0.02 for non-inferiority), similar to those using mRS. Conclusions This study demonstrates the utility of the smRSq in a large, ethnically diverse clinical trial population. Scoring of the smRSq shows adequate agreement with the standard mRS, thus confirming it is a reliable, valid, and useful alternative measure of functional status after acute ischemic stroke. Clinical Trial registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01422616

Ethnicity and Other Determinants of Quality of Functional Outcome in Acute Ischemic Stroke: The ENCHANTED Trial

Background and Purpose- Patient-centered outcomes are important. We aimed to determine predictors of health-related quality of life (HRQoL) and develop utility-weighted modified Rankin Scale (mRS) scores in thrombolyzed acute ischemic stroke patients from both arms of ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). Methods- ENCHANTED was an international quasi-factorial clinical trial of different doses of intravenous alteplase and intensities of blood pressure control in acute ischemic stroke patients, with outcomes on the 5-Dimensional European Quality of Life Scale and mRS assessed at 90 days post-randomization. Logistic regression models were used to identify baseline predictors of poor HRQoL (≤mean 5-Dimensional European Quality of Life Scale utility scores). Ordinary least squares regression derived utility-weighted mRS scores. Results- In 4016 acute ischemic stroke patients with complete 5-Dimensional European Quality of Life Scale and mRS data, independent predictors of poor HRQoL were older age (odds ratio, 1.19 [95% CI, 1.12-1.27], per 10-year increase), non-Asian ethnicity (1.91 [1.61-2.27]), greater stroke severity on the National Institutes of Health Stroke Scale (1.11 [1.09-1.12]), diabetes mellitus (1.41 [1.18-1.69]), premorbid disability (mRS score 1 versus 0; 1.62 [1.33-1.97]), large vessel atheromatous pathogenesis (1.32 [1.12-1.54]), and proxy respondent (2.35 [2.01-2.74]). Sensitivity analyses indicate the ethnicity influence on HRQoL was driven by the high proportion of Chinese (62.9% of Asian) participants with better HRQoL compared with non-Chinese or other Asian groups. Derived utility values across mRS scores 0 to 5 were 0.977, 0.885, 0.748, 0.576, 0.194, and -0.174, respectively. Correlations between mRS and 5-Dimensional European Quality of Life Scale scores were stronger in Asians. Conclusions- HRQoL is worse after thrombolyzed acute ischemic stroke in the elderly, non-Asians, with greater initial severity, diabetes mellitus, premorbid disability, due to large vessel atheroma, and proxy assessment. The broader significance of better HRQoL in Asians is tempered by Chinese participants dominating analyses. From utility-weighted mRS scores indicating the greatest steps in mRS scores are between 5 and 3, treatments to avoid major disability provide the greatest benefits for patients. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616

Early Blood Pressure Lowering Does Not Reduce Growth of Intraventricular Hemorrhage following Acute Intracerebral Hemorrhage:Results of the INTERACT Studies

Background: Intraventricular hemorrhage (IVH) extension is common following acute intracerebral hemorrhage (ICH) and is associated with poor prognosis. Aim: To determine whether intensive blood pressure (BP)-lowering therapy reduces IVH growth. Methods: Pooled analyses of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials (INTERACT1 and INTERACT2) computed tomography (CT) substudies; multicenter, open, controlled, randomized trials of patients with acute spontaneous ICH and elevated systolic BP, randomly assigned to intensive (Results: There was no significant difference in adjusted mean IVH growth following intensive (n = 228) compared to guideline-recommended (n = 228) BP treatment (1.6 versus 2.2 ml, respectively; p = 0.56). Adjusted mean IVH growth was nonsignificantly greater in patients with a mean achieved systolic BP ≥160 mm Hg over 24 h (3.94 ml; p trend = 0.26). Conclusions: Early intensive BP-lowering treatment had no clear effect on IVH in acute ICH

No benefit of flat head positioning in early moderate-severe acute ischemic stroke: HeadPoST study subgroup analysis

Background Although the Head Positioning in acute Stroke Trial (HeadPoST) showed no effect of the flat head position (FP; vs sitting up head position (SUP)) on functional outcome, we hypothesised that it could still offer benefits if commenced early in those with acute ischaemic stroke (AIS) of at least moderate severity. Methods Subgroup analysis of HeadPoST in participants with National Institutes of Health Stroke Scale (NIHSS) scores ≥7, ≥10 and ≥14, randomised to FP or SUP <4.5 hours of AIS onset on functional outcomes defined by a shift in scores on the modified Rankin scale (mRS) and death/disability (mRS scores 3–6), and any cardiovascular serious adverse event. Logistic regression analyses were undertaken adjusted for study design and baseline risk factors. Results There was no significant differential treatment effect in patient subgroups defined by increasing baseline NIHSS scores: adjusted OR and 95% CI for ordinal shift and binary (3–6) mRS scores: for NIHSS ≥7 (n=867) 0.92 (0.67 to 1.25) and 0.74 (0.52 to 1.04); NIHSS ≥ 10 (n=606) 0.80 (0.58 to 1.10) and 0.77 (0.49 to 1.19); NIHSS ≥14 (n=378) 0.82 (0.54 to 1.24) and 1.22 (0.69 to 2.14). Conclusions Early FP had no significant effect in patients with moderate–severe AI

Prognostic significance of early urinary catheterization after acute stroke: Secondary analyses of the international HeadPoST trial

Background An indwelling urinary catheter (IUC) is often inserted to manage bladder dysfunction, but its impact on prognosis is uncertain. We aimed to determine the association of IUC use on clinical outcomes after acute stroke in the international, multi-center, cluster crossover, Head Positioning in Acute Stroke Trial (HeadPoST). Methods Data were analyzed on HeadPoST participants (n = 11,093) randomly allocated to the lying-flat or sitting-up head position. Binomial, logistic regression, hierarchical mixed models were used to determine associations of early insertion of IUC within seven days post-randomization and outcomes of death or disability (defined as “poor outcome,” scores 3–6 on the modified Rankin scale) and any urinary tract infection at 90 days with adjustment of baseline and post-randomization management covariates. Results Overall, 1167 (12%) patients had an IUC, but the frequency and duration of use varied widely across patients in different regions. IUC use was more frequent in older patients, and those with vascular comorbidity, greater initial neurological impairment (on the National Institutes of Health Stroke Scale), and intracerebral hemorrhage as the underlying stroke type. IUC use was independently associated with poor outcome (adjusted odds ratio (aOR): 1.40, 95% confidence interval (CI): 1.13–1.74), but not with urinary tract infection after adjustment for antibiotic treatment and stroke severity at hospital separation (aOR: 1.13, 95% CI: 0.59–2.18). The number exposed to IUC for poor outcome was 13. Conclusions IUC use is associated with a poor outcome after acute stroke. Further studies are required to inform appropriate use of IUC

Influence of including patients with pre-morbid disability in acute stroke trials : The HeadPoST experience

Background: Patients with premorbid functional impairment are generally excluded from acute stroke trials. We aimed to determine the impact of including such patients in the Head Positioning in acute Stroke Trial (HeadPoST) and early additional impairment on outcomes. Methods: Post hoc analyses of HeadPoST, an international, cluster-randomized crossover trial of lying-flat versus sitting-up head positioning in acute stroke. Associations of early additional impairment, defined as change in modified Rankin scale (mRS) scores from premorbid levels (estimated at baseline) to Day 7 (“early ΔmRS”), and poor outcome (mRS score 3–6) at Day 90 were determined with generalized linear mixed model. Heterogeneity of the trial treatment effect was tested according to premorbid mRS scores 0–1 versus 2–5. Results: Of 8,285 patients (38.9% female, mean age 68 ± 13 years) with complete data, there were 1,984 (23.9%) with premorbid functional impairment (mRS 2–5). A significant linear association was evident for early ∆mRS and poor outcome (per 1-point increase in ΔmRS, adjusted odds ratio 1.20, 95% confidence interval 1.14–1.27; p < 0.0001). Patients with greater premorbid functional impairment were less likely to develop additional impairment, but their risk of poor 90-day outcome significantly increased with increasing (worse) premorbid mRS scores (linear trend p < 0.0001). There was no heterogeneity of the trial treatment effect by level of premorbid function. Conclusions: Early poststroke functional impairment that exceeded premorbid levels was associated with worse 90-day outcome, and this association increased with greater premorbid functional impairment. Yet, including premorbid impaired patients in the HeadPoST did not materially affect the subsequent treatment effect. Clinical Trial Registration: HeadPoST is registered at http://www.ClinicalTrials.gov (NCT02162017)

Lipid-lowering pretreatment and outcome following intravenous thrombolysis for acute ischaemic stroke: a post hoc analysis of the enhanced control of hypertension and thrombolysis stroke study trial

Background: Debate exists as to whether statin pretreatment confers an increased risk of 90-day mortality and symptomatic intracranial haemorrhage (sICH) in acute ischaemic stroke (AIS) patients treated with intravenous thrombolysis. We assessed the effects of undifferentiated lipid-lowering pretreatment on outcomes and interaction with low-dose versus standard-dose alteplase in a post hoc subgroup ­analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study. Methods: In all, 3,284 thrombolysis-eligible AIS patients (mean age 66.6 years; 38% women), with information on lipid-lowering pretreatment, were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 h of symptom onset. Of the total number of patients, 615 (19%) received statin or other lipid-lowering pretreatment. The primary clinical outcome was combined endpoint of death or disability (modified Rankin Scale scores 2–6) at 90 days. Results: Compared with patients with no lipid-lowering pretreatment, those with lipid-lowering pretreatment were significantly older, more likely to be non-Asian and more likely to have a medical history including vascular co-morbidity. After propensity analysis assessment and adjustment for important baseline variables at the time of randomisation, as well as imbalances in management during the first 7 days of hospital admission, there were no significant differences in mortality (OR 0.85; 95% CI 0.58–1.25, p = 0.42), or in overall ­90-day death and disability (OR 0.85, 95% CI 0.67–1.09, p = 0.19), despite a significant decrease in sICH among those with ­lipid-lowering pretreatment according to the European Co-operative Acute Stroke Study 2 definition (OR 0.49, 95% CI 0.28–0.83, p = 0.009). No differences in key efficacy or safety outcomes were seen in patients with and without lipid-lowering pretreatment between low- and standard-dose alteplase arms. Conclusions: Lipid-lowering pretreatment is not associated with adverse outcome in AIS patients treated with intravenous alteplase, whether assessed by 90-day death and disability or death alone

Head Position in Stroke Trial (HeadPoST)- sitting-up vs lying-flat positioning of patients with acute stroke: study protocol for a cluster randomised controlled trial

Background Positioning a patient lying-flat in the acute phase of ischaemic stroke may improve recovery and reduce disability, but such a possibility has not been formally tested in a randomised trial. We therefore initiated the Head Position in Stroke Trial (HeadPoST) to determine the effects of lying-flat (0°) compared with sitting-up (≥30°) head positioning in the first 24 hours of hospital admission for patients with acute stroke. Methods/Design We plan to conduct an international, cluster randomised, crossover, open, blinded outcome-assessed clinical trial involving 140 study hospitals (clusters) with established acute stroke care programs. Each hospital will be randomly assigned to sequential policies of lying-flat (0°) or sitting-up (≥30°) head position as a ‘business as usual’ stroke care policy during the first 24 hours of admittance. Each hospital is required to recruit 60 consecutive patients with acute ischaemic stroke (AIS), and all patients with acute intracerebral haemorrhage (ICH) (an estimated average of 10), in the first randomised head position policy before crossing over to the second head position policy with a similar recruitment target. After collection of in-hospital clinical and management data and 7-day outcomes, central trained blinded assessors will conduct a telephone disability assessment with the modified Rankin Scale at 90 days. The primary outcome for analysis is a shift (defined as improvement) in death or disability on this scale. For a cluster size of 60 patients with AIS per intervention and with various assumptions including an intracluster correlation coefficient of 0.03, a sample size of 16,800 patients at 140 centres will provide 90 % power (α 0.05) to detect at least a 16 % relative improvement (shift) in an ordinal logistic regression analysis of the primary outcome. The treatment effect will also be assessed in all patients with ICH who are recruited during each treatment study period. Discussion HeadPoST is a large international clinical trial in which we will rigorously evaluate the effects of different head positioning in patients with acute stroke. Trial registration ClinicalTrials.gov identifier: NCT02162017 (date of registration: 27 April 2014); ANZCTR identifier: ACTRN12614000483651 (date of registration: 9 May 2014). Protocol version and date: version 2.2, 19 June 2014