Karin Ernstrom

Idebenone treatment fails to slow cognitive decline in Alzheimer’s disease

Objective: To determine the effect of idebenone on the rate of decline in Alzheimer’s disease (AD). Methods: A 1-year, multicenter, double-blind, placebo-controlled, randomized trial was conducted. Subjects were over age 50 with a diagnosis of probable AD and had Mini-Mental State Examination (MMSE) scores between 12 and 25. Subjects were treated with idebenone 120, 240, or 360 mg tid, each of which was compared with placebo. Primary outcome measures were the Alzheimer’s Disease Assessment Scale–Cognitive Subcomponent (ADAS-Cog) and a Clinical Global Impression of Change (CGIC). Secondary outcome measures included measurements of activities of daily living, the Behavioral Pathology in Alzheimer’s Disease Rating Scale, and the MMSE. Results: Five hundred thirty-six subjects were enrolled and randomized to the four groups. Except for a slight difference in age, there were no differences in patient characteristics at baseline. For the primary outcome measures, there were no significant overall differences between the treatment groups in the prespecified four-group design. In an exploratory two-group analysis comparing all three treated groups combined with placebo, drug-treated patients performed better on the ADAS-Cog in both the intent-to-treat (ITT) and completers analyses. There were no differences in the CGIC scores for the ITT or completers analyses in either the four-group or the two-group analyses. There were no overall differences on any of the secondary outcome measures in any of the analyses. Conclusion: Idebenone failed to slow cognitive decline in AD that was of sufficient magnitude to be clinically significant.

Can comprehensive stroke centers erase the 'weekend effect'?

Background: Prior epidemiological work has shown higher mortality in ischemic stroke patients admitted on weekends, which has been termed the ‘weekend effect’. Our aim was to assess stroke patient outcomes in order to determine the significance of the ‘weekend effect’ at 2 comprehensive stroke centers. Methods: Consecutive stroke patients were identified using prospective databases. Patients were categorized into 4 groups: intracerebral hemorrhage (ICH group), ischemic strokes not treated with IV t-PA (intravenous tissue plasminogen activator; IS group), acute ischemic strokes treated with IV t-PA (AIS-TPA group), and transient ischemic attack (TIA group). Weekend admission was defined as the period from Friday, 17:01, to Monday, 08:59. Patients treated beyond the 3-hour window, receiving intra-arterial therapy, or enrolled in nonobservational clinical trials were excluded. Patient demographics, NIHSS scores, and admission glucose levels were examined. Adverse events, poor functional outcome (modified Rankin scale, mRS, 3–6), and mortality were compared. Results: A total of 2,211 patients were included (1,407 site 1, 804 site 2). Thirty-six percent (800/2,211) arrived on a weekend. No significant differences were found in the ICH, IS, AIS-TPA, or TIA groups with respect to the rate of symptomatic ICH, mRS on discharge, discharge disposition, 90-day mRS, or 90-day mortality when comparing weekend and weekday groups. Using multivariate logistic regression to adjust for site, age, admission NIHSS, and blood glucose, weekend admission was not a significant independent predictive factor for in-hospital mortality in all strokes (OR = 1.10, 95% CI 0.74–1.63, p = 0.631). Conclusions: Our results suggest that comprehensive stroke centers (CSC) may ameliorate the ‘weekend effect’ in stroke patients. These results may be due to 24/7 availability of stroke specialists, advanced neuroimaging, or ongoing training and surveillance of specialized nursing care available at CSC. While encouraging, these results require confirmation in prospective studies.

Efficacy of Telemedicine for Stroke: Pooled Analysis of the Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC) and STRokE DOC Arizona Telestroke Trials

BACKGROUND AND PURPOSE Telemedicine can disseminate vascular neurology expertise and optimize recombinant tissue plasminogen activator (rt-PA) use for acute ischemic stroke in rural underserved communities. The purpose of this study was to prospectively assess whether telemedicine or telephone was superior for decision-making. METHODS The study design is a pooled analysis of two identically designed randomized controlled trials conducted in a multistate hub and spoke telestroke network setting with acute stroke syndrome patients, comparing telemedicine versus telephone-only consultations. From each trial, common data elements were pooled to assess, principally, for correctness of thrombolysis decision-making. Secondary outcomes included rt-PA use rate, 90-day functional outcome, post-thrombolysis intracranial hemorrhage, and data completeness. RESULTS Two hundred seventy-six pooled patients were evaluated. Correct thrombolysis eligibility decisions were made more often with telemedicine (96% telemedicine, 83% telephone; odds ratio [OR] 4.2; 95% confidence interval [CI] 1.69-10.46; p=0.002). Intravenous rt-PA usage was 26% (29% telemedicine, 24% telephone; OR 1.27; 95% CI 0.71-2.25; p=0.41). Ninety-day outcomes were not different for Barthel Index, modified Rankin Scale, or mortality. There was no difference in post-thrombolysis intracranial hemorrhage (8% telemedicine, 6% telephone; p>0.999). CONCLUSIONS This pooled analysis supports the hypothesis that stroke telemedicine consultations, compared with telephone-only, result in more accurate decision-making. Together with high rt-PA utilization rate, low post-rt-PA intracranial hemorrhage rate, and acceptable patient outcome, the results confirm that telemedicine is a viable consultative tool for acute stroke. The replication of the hub and spoke network infrastructure supports the generalizability of telemedicine when used in broader settings.

Comprehensive stroke centers and the 'weekend effect': the SPOTRIAS experience.

Background and Purpose: Previous studies have found mortality among ischemic stroke patients to be higher on weekends. We sought to evaluate whether weekend admission was associated with worse outcomes in a large comprehensive stroke center (CSC) cohort. Methods: Consecutive ischemic stroke patients presenting within 6 h of symptom onset were identified using the 8 CSC SPOTRIAS (Specialized Programs of Translational Research in Acute Stroke) database. Patients who received intra-arterial therapy or who were enrolled in a nonobservational clinical trial were excluded. All patients meeting the inclusion criteria were then divided into two groups: weekday admissions or weekend admissions. Weekend admission was defined as Friday 17:01 to Monday 08:59. The remainder were classified as weekday admissions. Multivariate logistic regression was used, adjusting for age, stroke severity on admission [according to the National Institutes of Health Stroke Scale (NIHSS)] and admission glucose, in order to compare the outcomes of the weekend versus the weekday groups. Results: Eight thousand five hundred and eighty-one subjects from the combined SPOTRIAS database were screened from 2002 to 2009; 2,090 (24.4%) of these met the inclusion criteria. There was no significant difference in tissue plasminogen activator treatment rates between the weekday and weekend groups (58.5 vs. 60.4%, p = 0.397). Weekend admission was not a significant independent predictor of inhospital mortality (8.4 vs. 9.9%, p = 0.056), length of stay (4 vs. 5 days, p = 0.442), favorable discharge disposition (38.0 vs. 42.2%, p = 0.122), favorable functional outcome at discharge (41.6 vs. 43.4%, p = 0.805), favorable 90-day functional outcome (54.2 vs. 46.9%, p = 0.301), or 90-day mortality (18.2 vs. 19.8%, p = 0.680) when adjusting for age, NIHSS and admission glucose. Conclusions: In this large cohort of ischemic stroke patients treated at CSCs, we did not observe the ‘weekend effect.’ This may be due to access to stroke specialists 24 h a day on 365 days a year, nurses with stroke experience and the organized system for delivering care that is available at CSCs. These results suggest that EMS protocol should be reexamined regarding the preferential delivery of weekend stroke victims to hospitals that provide all levels of reperfusion therapy. This further highlights the importance of organized stroke care.

Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2)

Background and Purpose— Therapeutic hypothermia is a potent neuroprotectant approved for cerebral protection after neonatal hypoxia-ischemia and cardiac arrest. Therapeutic hypothermia for acute ischemic stroke is safe and feasible in pilot trials. We designed a study protocol to provide safer, faster therapeutic hypothermia in stroke patients. Methods— Safety procedures and 4°C saline infusions for faster cooling were added to the ICTuS trial (Intravascular Cooling in the Treatment of Stroke) protocol. A femoral venous intravascular cooling catheter after intravenous recombinant tissue-type plasminogen activator in eligible patients provided 24 hours cooling followed by a 12-hour rewarm. Serial safety assessments and imaging were performed. The primary end point was 3-month modified Rankin score 0,1. Results— Of the intended 1600 subjects, 120 were enrolled before the study was stopped. Randomly, 63 were to receive hypothermia plus antishivering treatment and 57 normothermia. Compared with previous studies, cooling rates were improved with a cold saline bolus, without fluid overload. The intention-to-treat primary outcome of 90-day modified Rankin Score 0,1 occurred in 33% hypothermia and 38% normothermia subjects, odds ratio (95% confidence interval) of 0.81 (0.36–1.85). Serious adverse events occurred equally. Mortality was 15.9% hypothermia and 8.8% normothermia subjects, odds ratio (95% confidence interval) of 1.95 (0.56–7.79). Pneumonia occurred in 19% hypothermia versus 10.5% in normothermia subjects, odds ratio (95% confidence interval) of 1.99 (0.63–6.98). Conclusions— Intravascular therapeutic hypothermia was confirmed to be safe and feasible in recombinant tissue-type plasminogen activator–treated acute ischemic stroke patients. Protocol changes designed to reduce pneumonia risk appeared to fail, although the sample is small. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01123161.

CT Interpretation in a Telestroke Network: Agreement Among a Spoke Radiologist, Hub Vascular Neurologist, and Hub Neuroradiologist

Background and Purpose— The American Stroke Association guidelines emphasized the need for further high-quality studies that assess agreement by radiologists and nonradiologists engaged in emergency telestroke assessments and decision-making. Therefore, the objective of this study was to determine the level of agreement of baseline brain CT scan interpretations of patients with acute stroke presenting to telestroke spoke hospitals between central reading committee neuroradiologists and each of 2 groups, spoke hospital radiologists and hub hospital vascular neurologists (telestrokologists). Methods— The Stroke Team Remote Evaluation Using a Digital Observation Camera Arizona trial was a prospective, urban single-hub, rural 2-spoke, randomized, blinded, controlled trial of a 2-way, site-independent, audiovisual telemedicine and teleradiology system designed for remote evaluation of adult patients with acute stroke versus telephone consultation to assess eligibility for treatment with intravenous thrombolysis. In the telemedicine arm, the subjects’ CT scans were interpreted by the hub telestrokologist and in the telephone arm by the spoke radiologist. All subjects’ CT scans were subsequently interpreted centrally, independently, and blindly by 2 hub neuroradiologists. The primary CT outcome was determination of a CT-based contraindication to thrombolytic treatment. Kappa statistics and exact agreement rates were used to analyze interobserver agreement. Results— Fifty-four subjects underwent random assignment. The overall agreement for the presence of radiological contraindications to thrombolysis was excellent (0.91) and did not differ substantially between the hub telestrokologist to neuroradiologist and spoke radiologist to neuroradiologist (0.92 and 0.89, respectively). Conclusions— In the context of a telestroke network designed to assess patients with acute stroke syndromes, agreement over the presence or absence of radiological contraindications to thrombolysis was excellent whether the comparisons were between a telestrokologist and neuroradiologist or between spoke radiologist and neuroradiologist. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00623350.

Assessment of Long-Term Outcomes for the STRokE DOC Telemedicine Trial

Telemedicine can provide stroke evaluations in locations with limited available expertise. The reliability of telestroke has been established. Decision making efficacy has been shown in the National Institutes of Healths STRokE DOC trial. No prospective trial has assessed long-term telestroke outcomes, however. In an institutional review board-approved trial (NCT00936455), we contacted patients originally enrolled in the STRokE DOC trial. A telephone script was used to verify consent. Patients were asked standardized questions regarding disposition, modified Rankin Scale (mRS) score, mortality, and recurrent stroke for 2 retrospective time points (6 and 12 months postevent) and one current time point. Blind was maintained. Primary outcome measures of mortality and percent mRS score of 0-1 [%mRS(0-1)] at 6 months are reported. Wilcoxons rank-sum test was used for continuous variables, and Fishers exact was used for categorical variables. Of the original 222 participants, 75 patients or surrogates could be contacted. Mean time from enrollment was 3.96 ± 1.0 years (range, 2.33-5.45 years). Mean National Institutes of Health Stroke Scale (NIHSS) score was 8 ± 7 (5 ± 8 for telephone; 12 ± 8 for telemedicine; P = .002). The rate of intravenous recombinant tissue plasminogen activator (rt-PA) use was 31%. Six-month %mRS(0-1) outcome was not different, at 42%. Mortality after imputation to the entire study sample also was not different, at 18%. There was no difference in the rate of recurrent stroke (P = .61). Some 85% of patients were home at 6 months. This study reports a good 6-month outcome for stroke patients evaluated by telemedicine or telephone. This design is limited by the time since original enrollment and resultant inability to contact participants. Although these findings can add to the limited data on telemedicine outcomes, a prospective trial is needed.

Effect of study partner on the conduct of Alzheimer disease clinical trials

Objective: Alzheimer disease (AD) dementia clinical trials require 2 participants: a patient and a study partner. We assessed the prevalence of study partner types and how these types associate with patient-related outcome measures. Methods: Retrospective analyses of 6 Alzheimer’s Disease Cooperative Study (ADCS) randomized clinical trials were conducted. Study partners were categorized as spouse, adult child, or other. Prevalence of study partner type and associations between study partner type and trial outcomes including study completion and placebo decline on the Mini-Mental State Examination, the Alzheimer’s Disease Assessment Scale–cognitive subscale, the Clinical Dementia Rating scale Sum of the Boxes score, and the ADCS–Activities of Daily Living were examined. Results: More participants (67%) enrolled with spouses than adult children (26%) or other study partners (7%). Participants with spouse partners had a lower dropout rate (25%) than those with adult child (32%) or other study partners (34%); only the difference vs others was statistically significant. Participants with adult child and other partners randomized to placebo performed worse at baseline than those with spouse partners on the ADCS–Activities of Daily Living (p = 0.04), but were not different at 18 months. There were no differences at baseline for the Mini-Mental State Examination, Clinical Dementia Rating scale Sum of the Boxes score, or Alzheimer’s Disease Assessment Scale–cognitive subscale. In multivariate models of the rates of change over time among placebo participants, no differences among study partner groups reached statistical significance. Conclusions: Patients with nonspouse caregivers less frequently participate in AD dementia trials. Increased enrollment of AD patients with nonspouse caregivers may require additional recruitment and retention strategies.

In vitro Sonothrombolysis with Duplex Ultrasound: First Results Using a Simplified Model

Background: The main aim was to study the effects of ultrasound (US) alone, in combination with an US contrast agent (UCA), tissue plasminogen activator (tPA), or the combination of both upon blood clots. Methods: In order to learn about sonothrombolysis with diagnostic duplex US, a simplified in vitro test model, using human whole blood clots in Petri dishes, was established. Results: A total of 286 blood clots were analyzed. Improved sonothrombolysis due to insonation with diagnostic duplex US could be achieved, whether it was used alone or in combination with tPA. Although already described, a beneficial effect of UCA microbubbles on sonothrombolysis could not be confirmed due to the study design. Conclusion: Diagnostic duplex US improves thrombolysis significantly, even when it is used without tPA. To study the effect of UCA microbubbles on sonothrombolysis appropriately, any experimental design should provide continuous replenishment of microbubbles at the target site.

Intravenous Tissue Plasminogen Activator for Patients with Minor Ischemic Stroke

BACKGROUND Patients with minor ischemic stroke (MIS) are frequently excluded from thrombolytic therapy. Denial of therapy to these patients, however, remains controversial. We compared outcomes in patients with MIS who received intravenous (IV) tissue plasminogen activator (t-PA) with those who were not treated. METHODS We selected adult patients with stroke onset within 3 hours from a prospectively collected stroke registry. MIS was defined as an admission National Institutes of Health Stroke Scale (NIHSS) score ≤ 5. The primary outcome was a 90-day modified Rankin scale (mRS) score of 0 to 1. Secondary outcomes were a Barthel index (BI) score ≥ 95 at 90 days, symptomatic intracranial hemorrhage (SICH), and death. Multivariable logistic regression was performed to determine the association between outcomes adjusting for age, history of diabetes, and NIHSS score at admission. Reasons for t-PA exclusion were obtained. RESULTS We identified 133 patients with MIS; 59 patients received IV t-PA. The NIHSS score (mean ± SD) at admission was higher in the t-PA treated group (3.4 ± 1.4 v 1.9 ± 1.3 in the untreated group; P < .0001). Other baseline characteristics were not significantly different between the 2 groups. At 90 days, 57.6% of patients in the t-PA group and 68.9% of patients in the untreated group had a mRS score of 0 to 1 (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.39-2.2; P = .87). A BI score of 95 to 100 was achieved in 75% of patients in the IV t-PA group versus 78.9% in the untreated group (OR 1.18, 95% CI 0.43-3.23; P = .74). There were 3 deaths (5.1%) in the IV t-PA group and 3 deaths (4.1%) in the control group. CONCLUSIONS In our sample, patients with MIS treated with IV t-PA have similar outcomes as patients not receiving thrombolysis. A randomized trial or larger observational study is needed confirm or reject these findings.