AVERT2(a very early rehabilitation trial, a very effective reproductive trigger): retrospective observational analysis of the number of babies born to trial staff

Objective: To report the number of participants needed to recruit per baby born to trial staff during AVERT, a large international trial on acute stroke, and to describe trial management consequences. Design: Retrospective observational analysis. Setting: 56 acute stroke hospitals in eight countries. Participants: 1074 trial physiotherapists, nurses, and other clinicians. Outcome measures: Number of babies born during trial recruitment per trial participant recruited. Results: With 198 site recruitment years and 2104 patients recruited during AVERT, 120 babies were born to trial staff. Births led to an estimated 10% loss in time to achieve recruitment. Parental leave was linked to six trial site closures. The number of participants needed to recruit per baby born was 17.5 (95% confidence interval 14.7 to 21.0); additional trial costs associated with each birth were estimated at 5736 Australian dollars on average. Conclusion: The staff absences registered in AVERT owing to parental leave led to delayed trial recruitment and increased costs, and should be considered by trial investigators when planning research and estimating budgets. However, the celebration of new life became a highlight of the annual AVERT collaborators’ meetings and helped maintain a cohesive collaborative group

Treating and Preventing Influenza in Aged Care Facilities: A Cluster Randomised Controlled Trial

PMCID: PMC3474842This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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

Effect of IV alteplase on the ischemic brain lesion at 24-48 hours after ischemic stroke

OBJECTIVE: To determine whether alteplase alters the development of ischemic lesions on brain imaging after stroke. METHODS: The Third International Stroke Trial (IST-3) was a randomized controlled trial of IV alteplase for ischemic stroke. We assessed CT or brain MRI at baseline (pretreatment) and 24 to 48 hours posttreatment for acute lesion visibility, extent, and swelling, masked to all other data. We analyzed associations between treatment allocation, change in brain tissue appearances between baseline and follow-up imaging, and 6-month functional outcome in IST-3. We performed a meta-analysis of randomized trials of alteplase vs control with pre- and postrandomization imaging. RESULTS: Of 3,035 patients recruited in IST-3, 2,916 had baseline and follow-up brain imaging. Progression in either lesion extent or swelling independently predicted poorer 6-month outcome (adjusted odds ratio [OR] = 0.92, 95% confidence interval [CI] 0.88-0.96, p < 0.001; OR = 0.73, 95% CI 0.66-0.79, p < 0.001, respectively). Patients allocated alteplase were less likely than controls to develop increased lesion visibility at follow-up (OR = 0.77, 95% CI 0.67-0.89, p < 0.001), but there was no evidence that alteplase reduced progression of lesion extent or swelling. In meta-analysis of 6 trials including IST-3 (n = 4,757), allocation to alteplase was associated with a reduction in ischemic lesion extent on follow-up imaging (OR = 0.85, 95% CI 0.76-0.95, p = 0.004). CONCLUSION: Alteplase was associated with reduced short-term progression in lesion visibility. In meta-analysis, alteplase reduced lesion extent. These findings may indicate that alteplase improves functional outcome by reducing tissue damage. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IV alteplase impedes the progression of ischemic brain lesions on imaging after stroke

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease:Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (&lt;45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.</p

Early decompressive hemicraniectomy in thrombolyzed acute ischemic stroke patients from the international ENCHANTED trial

Abstract Decompressive hemicraniectomy (DHC) can improve outcomes for patients with severe forms of acute ischemic stroke (AIS), but the evidence is mainly derived from non-thrombolyzed patients. We aimed to determine the characteristics and outcomes of early DHC in thrombolyzed AIS participants of the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Post-hoc analyses of ENCHANTED, an international, partial-factorial, open, blinded outcome-assessed, controlled trial in 4557 thrombolysis-eligible AIS patients randomized to low- versus standard-dose intravenous alteplase (Arm A, n = 2350), intensive versus guideline-recommended blood pressure control (Arm B, n = 1280), or both (Arms A + B, n = 947). Logistic regression models were used to identify baseline variables associated with DHC, with inverse probability of treatment weights employed to eliminate baseline imbalances between those with and without DHC. Logistic regression was also used to determine associations of DHC and clinical outcomes of death/disability, major disability, and death (defined by scores 2–6, 3–5, and 6, respectively, on the modified Rankin scale) at 90 days post-randomization. There were 95 (2.1%) thrombolyzed AIS patients who underwent DHC, who were significantly younger, of non-Asian ethnicity, and more likely to have had prior lipid-lowering treatment and severe neurological impairment from large vessel occlusion than other patients. DHC patients were more likely to receive other management interventions and have poor functional outcomes than non-DHC patients, with no relation to different doses of intravenous alteplase. Compared to other thrombolyzed AIS patients, those who received DHC had a poor prognosis from more severe disease despite intensive in-hospital management

Community-based interventions to prevent serious complications following spinal cord injury in Bangladesh:the CIVIC trial statistical analysis plan

Background: People who sustain spinal cord injuries in low- and middle-income countries are vulnerable to life-threatening complications after discharge. The aim of this trial is to determine the effect on all-cause mortality of a sustainable model of community-based care provided over the first 2 years after discharge. Methods and analysis: The CIVIC trial is a single centre, parallel group trial with concealed and stratified randomisation. The protocol has been previously published (BMJ Open 2016;6:e010350). This paper provides the accompanying detailed statistical plan. In total, 410 people with recent spinal cord injury who are wheelchair dependent and about to be discharged from the Centre for the Rehabilitation of the Paralysed in Bangladesh are randomised to intervention or control groups. Participants assigned to the intervention group receive a model of community-based care in which a case manager provides ongoing telephone-based support and visits participants in their homes over a 2-year period. Participants assigned to the control group receive usual care which may involve a follow-up phone call or a home visit. The primary outcome is all-cause mortality at 2 years as determined by a blinded assessor (Bangladesh does not have a death registry). The primary effectiveness analysis will compare Kaplan-Meier survival curves (time from allocation to death) in the intervention and control groups using the log-rank test (two-tailed α = 0.05). Participants will be censored at the time they were last known to be alive or at the time of the follow-up assessment. Recruitment finished in March 2018 and the last assessment will be conducted in March 2020. Discussion: The CIVIC trial will provide unbiased and precise estimates of the effectiveness of a model of community-based care for people with spinal cord injuries in Bangladesh. The results will have implications for provision of health services for people with spinal cord injuries and other conditions that cause serious disability in low-income and middle-income countries. Trial registration: ANZCTR, ACTRN12615000630516, U1111-1171-1876. Registered on 17 June 2015