Stroke treatment academic industry roundtable recommendations for individual data pooling analyses in stroke

Pooled analysis of individual patient data from stroke trials can deliver more precise estimates of treatment effect, enhance power to examine prespecified subgroups, and facilitate exploration of treatment-modifying influences. Analysis plans should be declared, and preferably published, before trial results are known. For pooling trials that used diverse analytic approaches, an ordinal analysis is favored, with justification for considering deaths and severe disability jointly. Because trial pooling is an incremental process, analyses should follow a sequential approach, with statistical adjustment for iterations. Updated analyses should be published when revised conclusions have a clinical implication. However, caution is recommended in declaring pooled findings that may prejudice ongoing trials, unless clinical implications are compelling. All contributing trial teams should contribute to leadership, data verification, and authorship of pooled analyses. Development work is needed to enable reliable inferences to be drawn about individual drug or device effects that contribute to a pooled analysis, versus a class effect, if the treatment strategy combines ≥2 such drugs or devices. Despite the practical challenges, pooled analyses are powerful and essential tools in interpreting clinical trial findings and advancing clinical care

Letter by Scheitz et al regarding article, "Randomized controlled trial of early versus delayed statin therapy in patients with acute ischemic stroke: ASSORT trial (administration of statin on acute ischemic stroke patient)"

No abstract available

Studies of the Clinical Pharmacology of Perindopril: A New Inhibitor of Angiotensin Converting Enzyme

Over the last thirty years, effective and relatively safe control of hypertension has become possible. As a result, less severe forms of high blood pressure now warrant treatment. Such treatment needs to be acceptable to the patient and free from long-term toxicity. The angiotensin converting enzyme (ACE) inhibitors offer the possibility of improved tolerability and a novel mechanism of action. After review of the renin-angiotensin system, the clinical pharmacology of the two currently available ACE inhibitors is discussed. Captopril and enalapril have been demonstrated to be effective treatments in hypertension and cardiac failure. Both drugs may cause significant side effects and so there is justification for investigation of a similar compound which has an excellent safety profile in laboratory studies. The steps involved in the transfer of drugs from the animal laboratory to early clinical studies in man are then discussed. Perindopril is the esterified form of a potent and long-acting ACE inhibitor, S-9780: it is a prodrug which relies on bioactivation in vivo. The studies described in this thesis include some of the earliest administrations of perindopril to man and the first clinical trial involving S-9780. In the earliest dose-ranging study, 36 normotensive volunteers, in parallel groups of 6 subjects, were given perindopril (1 to 16 mg) orally for 7 consecutive days. The drug was well tolerated and no sign of toxicity was detected. Blood pressure was lowered by active treatment (14/11 mmHg 6 hours after 16 mg) with only a slight rise in heart rate (15 beats. min-1) after chronic treatment with 16 mg. Plasma ACE was inhibited and plasma renin activity was elevated in a dose-related pattern. Plasma aldosterone levels fell. The maximum effect occurred after 4-6 hours and 60% inhibition of plasma ACE persisted 24 hours after dosing with 8 and 16 mg. Plasma catecholamines were unchanged. A double blind crossover study in 8 normotensive volunteers demonstrated that intravenous administration of the active metabolite of perindopril, S-9780, was well tolerated and apparently safe. Maximal inhibition of plasma ACE occurred after only 1 mg. A dose-related rise in plasma renin activity occurred but no effect on plasma aldosterone was detected. Blood pressure was lowered by 8/14 mmHg 3 hours after 4 mg of S-9780 intravenously with no change in heart rate or plasma catecholamines. The effect of perindopril on autonomic function was assessed in a double blind, placebo controlled, crossover study in 10 normotensive males. Eight milligrammes given orally lowered blood pressure without a change in heart rate. Perindopril enhanced the vagally mediated heart rate variation with deep breathing. There was no impairment of the response to either bicycle exercise at 175 W for 5 minutes or isometric handgrip. The pressor response to cold and the response to the Valsalva manoeuvre were unaltered. These results suggested that the absence of tachycardia after perindopril might be in part related to enhanced parasympathetic tone. In a single blind, placebo controlled study in seven hypertensive patients treated for one month, tolerability was excellent. Blood pressure was lowered from 164/93 mmHg to 145/84 mmHg by 4 mg of perindopril and after one month remained 142/82 mmHg. Neither postural hypotension nor tachycardia occurred. The biochemical effects were comparable to those in the volunteers. Plasma S-9780 levels were determined by an enzyme inhibition assay following treatment with oral perindopril and intravenous S-9780. The kinetics were linear and were not altered by repeated dosing. The intravenous data showed triphasic decay with a terminal half-life of over 30 hours; despite this, the accumulation half-life after repeated dosing was under 9 hours. The controversy over the pharmacokinetics of ACE inhibitors is acknowledged. Bioavailability of S-9780 after perindopril given orally was 15%. The kinetics of S-9780 in man corresponded to the kinetics in the laboratory animals which were used for the preclinical studies. Plasma ACE inhibition was related to plasma drug concentrations following intravenously administered S-9780: a close correlation was obtained using the Hill equation to describe the relationship. The plasma concentration of S-9780 which produced 50% inhibition of plasma ACE was 1.8 + 0.9 ng. ml-1 After oral dosing, the peak effect on ACE lagged behind peak plasma S-9780 concentration by several hours. A concentration-effeet model allowed description of this relationship. Using the parameters of the model, it was shown that the sensitivity of plasma ACE to S-9780 diminished slightly with repeated dosing. (Abstract shortened by ProQuest.)

Design of the Intravenous Magnesium Efficacy in Acute Stroke (IMAGES) trial [ISRCTN19943732]

The Intravenous Magnesium Efficacy in Acute Stroke (IMAGES) trial is a multicentre,randomised, placebo-controlled trial of magnesium sulphate (MgSO(4)) funded by the UK Medical Research Council. When complete, it will be the largest single neuroprotective study undertaken to date. Conscious patients presenting within 12 h of acute stroke with limb weakness are eligible. The primary outcome measure is combined death and disability as measured using the Barthel Index at 90-day follow up. By randomizing 2700 patients, the study will have 84% power to detect a 5.5% absolute reduction in the primary end-point. By April 2000, 86 centres were participating, with representation in Canada, USA, Europe, South America, Singapore and Australia. So far, 1206 patients have been randomised, of whom 37% were treated within 6 h. Overall 3-month mortality was 20% and the primary outcome event rate was 43%. The study is ongoing and centres worldwide are encouraged to participate

Outcomes of Community-Based Infant/ Toddler Teacher Preparation: Tiered Supports for Pre-service early Childhood Education Teachers in Early Head Start

This study examined results associated with a field-based undergraduate early childhood teacher education program designed as a response to calls for enhanced field experiences and community-situated teacher education that narrows the preparation-to-practice gap. Specifically, classroom observations were used to assess undergraduates’ progress in developmentally appropriate adult-child interaction during a portion of a semester-long professional preparation sequence focused on infants and toddlers offered in an urban Early Head Start program serving low-income children. During the sequence, a model relying on guided apprenticeship with classroom teachers and continuous direct supervision from university faculty was employed. In addition, a tiered model including universal, targeted, and intensive supports was implemented in order to support candidates in identifying and developing specific areas of need. The participants in this study demonstrated greater responsivity and intentional engagement with infants and toddlers as a result of this intensive preparation sequence. Participants who did not show an initial increase in skills responded to targeted and and/or intensive intervention strategies. This model suggests that by refocusing early childhood teacher preparation through a lens of partnership between EHS teachers, university faculty, and early childhood special education (ECSE) teacher candidates, significant gains in developmentally appropriate practice can be achieved even for candidates early in a preparation program

Use of a 3-item short-form version of the Barthel Index for use in stroke: systematic review and external validation

Background and Purpose—There may be a potential to reduce the number of items assessed in the Barthel Index (BI), and shortened versions of the BI have been described. We sought to collate all existing short-form BI (SF-BI) and perform a comparative validation using clinical trial data. Methods—We performed a systematic review across multidisciplinary electronic databases to find all published SF-BI. Our validation used the VISTA (Virtual International Stroke Trials Archive) resource. We describe concurrent validity (agreement of each SF-BI with BI), convergent and divergent validity (agreement of each SF-BI with other outcome measures available in the data set), predictive validity (association of prognostic factors with SF-BI outcomes), and content validity (item correlation and exploratory factor analyses). Results—From 3546 titles, we found 8 articles describing 6 differing SF-BI. Using acute trial data (n=8852), internal reliability suggested redundancy in BI (Cronbach α, 0.96). Each SF-BI demonstrated a strong correlation with BI, modified Rankin Scale, National Institutes of Health Stroke Scale (all ρ≥0.83; P<0.001). Using rehabilitation trial data (n=332), SF-BI demonstrated modest correlation with quality of life measures Stroke Impact Scale and 5 domain EuroQOL (ρ≥0.50, P<0.001). Prespecified prognostic factors were associated with SF-BI outcomes (all P<0.001). Our factor analysis described a 3 factor structure, and item reduction suggested an optimal 3-item SF-BI comprising bladder control, transfer, and mobility items in keeping with 1 of the 3-item SF-BI previously described in the literature. Conclusions—There is redundancy in the original BI; we have demonstrated internal and external validity of a 3-item SF-BI that should be simple to use

Preparing Early Childhood Professionals for the Culturally and Linguistically Diverse Classrooms and Communities of Illinois

Recent Illinois state policies call for mandatory preparation of early childhood educators to address the needs of the large and growing population of young English language learners. University-based early childhood teacher preparation programs across Illinois have responded by integrating content related to cultural and linguistic diversity into existing programs. The authors discuss research and professional literature in support of teacher preparation programs that emphasize field-based experience, particularly clinical experience in culturally and linguistically diverse schools and community organizations. They describe the comprehensive field-based teacher education program at Loyola University of Chicago that was redesigned to address current Illinois policies related to early childhood teacher education. The program, Teaching, Learning, and Leading with Schools and Communities (TLLSC), collaborates with school and community partners in the area to equip teachers to meet the needs of young culturally and linguistically diverse children and their families. Four video vignettes provide examples of and perspectives on participation in the TLLSC program. In these vignettes, childhood administrators, educators, undergraduate students, and teacher preparation faculty discuss their experiences with Loyola’s field-based teacher preparation. The authors address implications of early childhood teacher preparation for cultural and linguistic diversity in Illinois

Acute stroke: we have the treatments and we have the evidence – we need to use them

Despite huge global burden, stroke disease has traditionally received little attention in the general medical press. We review a series of four acute stroke research articles published in a themed issue of the Lancet. Claiborne-Johnston and coworkers presented a scoring system to stratify risk of stroke following transient ischaemic attack. Chalela and colleagues demonstrated that magnetic resonance imaging is superior to computed tomography in detecting acute ischaemic stroke and that fears of missing intracranial haemorrhage are unfounded. The SITS-MOST (Safe Implementation of Thrombolysis in Stroke – Monitoring Study) group reported positive experience of translating acute stroke thrombolysis trials into routine clinical practice in Europe, and the PROSIT (Project on Stroke Services in Italy) group studied acute effects of admission to a dedicated stroke unit. The message from all of these reports is that evidence-based, successful management of acute stroke is possible, and that investment in health infrastructure and changing mind sets of health practitioners to improve stroke care will deliver benefits

Mismatch-based delayed thrombolysis: a meta-analysis

<p><b>Background and Purpose</b>: Clinical benefit from thrombolysis is reduced as stroke onset to treatment time increases. The use of "mismatch" imaging to identify patients for delayed treatment has face validity and has been used in case series and clinical trials. We undertook a meta-analysis of relevant trials to examine whether present evidence supports delayed thrombolysis among patients selected according to mismatch criteria.</p> <p><b>Methods</b>: We collated outcome data for patients who were enrolled after 3 hours of stroke onset in thrombolysis trials and had mismatch on pretreatment imaging. We selected the trials on the basis of a systematic search of the Web of Knowledge. We compared favorable outcome, reperfusion and/or recanalization, mortality, and symptomatic intracerebral hemorrhage between the thrombolyzed and nonthrombolyzed groups of patients and the probability of a favorable outcome among patients with successful reperfusion and clinical findings for 3 to 6 versus 6 to 9 hours from poststroke onset. Results are expressed as adjusted odds ratios (a-ORs) with 95% CIs. Heterogeneity was explored by test statistics for clinical heterogeneity, I2 (inconsistency), and L’Abbé plot.</p> <p><b>Results</b>: We identified articles describing the DIAS, DIAS II, DEDAS, DEFUSE, and EPITHET trials, giving a total of 502 mismatch patients thrombolyzed beyond 3 hours. The combined a-ORs for favorable outcomes were greater for patients who had successful reperfusion (a-OR=5.2; 95% CI, 3 to 9; I2=0%). Favorable clinical outcome was not significantly improved by thrombolysis (a-OR=1.3; 95% CI, 0.8 to 2.0; I2=20.9%). Odds for reperfusion/recanalization were increased among patients who received thrombolytic therapy (a-OR=3.0; 95% CI, 1.6 to 5.8; I2=25.7%). The combined data showed a significant increase in mortality after thrombolysis (a-OR=2.4; 95% CI, 1.2 to 4.9; I2=0%), but this was not confirmed when we excluded data from desmoteplase doses that were abandoned in clinical development (a-OR=1.6; 95% CI, 0.7 to 3.7; I2=0%). Symptomatic intracerebral hemorrhage was significantly increased after thrombolysis (a-OR=6.5; 95% CI, 1.2 to 35.4; I2=0%) but not significant after exclusion of abandoned doses of desmoteplase (a-OR=5.4; 95% CI, 0.9 to 31.8; I2=0%).</p> <p><b>Conclusions</b>: Delayed thrombolysis amongst patients selected according to mismatch imaging is associated with increased reperfusion/recanalization. Recanalization/reperfusion is associated with improved outcomes. However, delayed thrombolysis in mismatch patients was not confirmed to improve clinical outcome, although a useful clinical benefit remains possible. Thrombolysis carries a significant risk of symptomatic intracerebral hemorrhage and possibly increased mortality. Criteria to diagnose mismatch are still evolving. Validation of the mismatch selection paradigm is required with a phase III trial. Pending these results, delayed treatment, even according to mismatch selection, cannot be recommended as part of routine care.</p&gt