Functional Assessment for Acute Stroke Trials: Properties, Analysis, and Application.
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ABSTRACT:
SUBMITTER: Taylor-Rowan M
PROVIDER: S-EPMC5879151 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Functional Assessment for Acute Stroke Trials: Properties, Analysis, and Application.
Taylor-Rowan Martin M Wilson Alastair A Dawson Jesse J Quinn Terence J TJ
Frontiers in neurology 20180326
A measure of treatment effect is needed to assess the utility of any novel intervention in acute stroke. For a potentially disabling condition such as stroke, outcomes of interest should include some measure of functional recovery. There are many functional outcome assessments that can be used after stroke. In this narrative review, we discuss exemplars of assessments that describe impairment, activity, participation, and quality of life. We will consider the psychometric properties of assessmen ...[more]
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Project description:BackgroundThrombolytic therapy with intravenous alteplase within 4.5 hours of ischemic stroke onset increases the overall likelihood of an excellent outcome (no, or nondisabling, symptoms). Any improvement in functional outcome distribution has value, and herein we provide an assessment of the effect of alteplase on the distribution of the functional level by treatment delay, age, and stroke severity.MethodsPrespecified pooled analysis of 6756 patients from 9 randomized trials comparing alteplase versus placebo/open control. Ordinal logistic regression models assessed treatment differences after adjustment for treatment delay, age, stroke severity, and relevant interaction term(s).ResultsTreatment with alteplase was beneficial for a delay in treatment extending to 4.5 hours after stroke onset, with a greater benefit with earlier treatment. Neither age nor stroke severity significantly influenced the slope of the relationship between benefit and time to treatment initiation. For the observed case mix of patients treated within 4.5 hours of stroke onset (mean 3 hours and 20 minutes), the net absolute benefit from alteplase (ie, the difference between those who would do better if given alteplase and those who would do worse) was 55 patients per 1000 treated (95% confidence interval, 13-91; P=0.004).ConclusionsTreatment with intravenous alteplase initiated within 4.5 hours of stroke onset increases the chance of achieving an improved level of function for all patients across the age spectrum, including the over 80s and across all severities of stroke studied (top versus bottom fifth means: 22 versus 4); the earlier that treatment is initiated, the greater the benefit.
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Project description:Edaravone (Radicut) is a free radical scavenger marketed in Japan by Mitsubishi Tanabe Pharma Corp. to treat acute ischemic stroke (AIS) patients presenting within 24 h of the attack. Injectable edaravone ampoules (30 mg b.i.d., i.v., 14 days) were first approved on 23 May 2001. On 19 January 2010, as a new innovation, the Radicut BAG (Intravenous BAG) was approved by the Japanese Ministry of Health and Welfare. Efficacy of edaravone ranges from large significant clinical improvements to only modest improvements in clinical function measured using standard stroke scales when administered 6-72 h following an ischemic stroke. With almost 17 years of edaravone clinical experience, a few adverse events--including acute renal failure--have been noted.This is the only article to date to critically review available clinical efficacy and toxicology data published in the literature to ascertain whether edaravone should be further pursued as a candidate for development worldwide.This review covers clinical studies carried out over the period 1993-2008.Edaravone may be a useful neuroprotective agent to treat the > 15 million victims worldwide who are devastated by stroke annually. Additional clinical studies are necessary to verify the efficacy of edaravone.
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Project description:PurposeTo develop a statistical approach that compares patient selection strategies across clinical trials and apply this approach to acute ischemic stroke clinical trials to identify the optimal inclusion criteria.MethodsWe developed a statistical approach that compares the number needed to treat to achieve one success (NNT) along with the number needed to screen to achieve one success (NNS) and assesses if there are significant differences in inclusion criteria, treatment course, and clinical outcome among patients that may have been included/excluded in the trials. We applied this approach to the study population from four recent positive acute stroke clinical trials: MR CLEAN, EXTEND-IA, ESCAPE, and SWIFT PRIME, applying published trial criteria to an independent registry of 612 acute stroke patients, since we did not have access to the complete trial data.ResultsAlthough reported NNT were similar for EXTEND-IA, SWIFT PRIME and ESCAPE, and somewhat higher for MR CLEAN, NNS varied across the trials from 21 for EXTEND-IA, 27 for MR CLEAN, to 46 for ESCAPE and 64 for SWIFT PRIME, reflecting less and more stringent inclusion criteria, respectively. Although there were significant differences in imaging biomarkers and other clinical characteristics among patients that may have been included/excluded in the trials, these differences did not translate to significant differences in treatment course or clinical outcomes.ConclusionsOur study proposes a robust statistical approach that can be applied to a larger pooled trial dataset, if made available, to objectively compare across clinical trials and inform inclusion criteria of future trials. Pooled analysis of the acute stroke trial data is needed to determine which imaging biomarker inclusion criteria are critical and which may be relaxed. If this procedure were applied across the pooled trial data, it could decrease costs and refine the design of future trials to be the most efficacious for the greatest number of patients.
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Project description:BackgroundDespite the high incidence of acute stroke, only a minority of patients are enrolled in acute stroke treatment trials. We aimed to identify factors associated with participation in clinical trials of novel therapeutic agents for acute stroke.MethodsProspective survey of patients with acute stroke <72 hours from onset. A structured interview was administered to the patient or primary decision-maker. If offered participation in an actual acute treatment trial, questions focused on decisions about that trial; otherwise a similar mock trial was proposed. The primary outcome was whether the subject agreed to participate in the proposed trial.ResultsA total of 200 subjects (47% patients, 53% proxies) completed the survey: mean age 63 +/- 14 years, 47% women, 44% white, 50% black. A real acute trial was offered to 22%; others were offered a mock trial. Overall, 57% (95% confidence interval: 50%-64%) of respondents stated they would participate in the proposed acute treatment trial. There were no differences with respect to age, sex, race, educational level, self-assessed stroke severity or stroke type, vascular risk factors, or comorbidities. Misconceptions about key research concepts were found in 50% but did not impact participation. Participation was associated with the perceived risk of the proposed trial intervention (p < 0.001), prior general attitudes about research (p < 0.001), and influences attributed to family, religion, and other personal beliefs (p < 0.001). Patients were more likely to participate than proxy decision-makers (p = 0.04).ConclusionsDemographic factors, clinical factors, and prior knowledge about research have little impact on the decision to participate in acute stroke clinical trials. Preexisting negative attitudes and external influences about research strongly inhibit participation. Patients are more inclined to participate than their proxy decision-makers.
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Project description:Background and purposeRecent randomized clinical trials (RCTs) have demonstrated benefits of endovascular recanalization therapy (ERT) contrary to earlier trials. We aimed to estimate the benefits of ERT added to standard therapy in acute ischemic stroke.MethodsFrom a literature search of RCTs testing ERT, we performed a meta-analysis to estimate an overall efficacy and safety of ERT for all trials, stent-retriever trials, and RCTs comparing ERT and intravenous tissue plasminogen activator (IV-TPA).ResultsWe identified 15 relevant RCTs including 2,899 patients. For all trials, ERT was associated with increased good outcomes (odds ratio [OR] 1.79; 95% confidence interval [CI] 1.34, 2.40; P<0.001) compared to the control. ERT also increased no or minimal disability outcomes, good neurological recovery, good activity of daily living, and recanalization. ERT did not significantly increase symptomatic intracranial hemorrhage (SICH) (OR 1.19; 95% CI 0.83, 1.69; P=0.345) or death (OR 0.87; 95% CI 0.71, 1.05; P=0.151). In contrast, ERT significantly reduced extreme disability or death (OR 0.77; 95% CI 0.61, 0.97; P=0.025). Restricting to five stent-retriever trials comparing ERT plus IV-TPA vs. IV-TPA alone, the benefit was even greater for good outcome (OR 2.39; 95% CI 1.88, 3.04; P<0.001) and extreme disability or death (OR 0.57; 95% CI 0.41, 0.78; P=0.001). Restricting to eight RCTs comparing ERT (plus IV-TPA in six trials) with IV-TPA alone showed similar efficacy and safety.ConclusionsThis updated meta-analysis shows that ERT substantially improves clinical outcomes and reduces extreme disability or death without significantly increasing SICH compared to standard therapy.
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Project description:ObjectiveTo validate subgroups of cognitive impairment on the Montreal Cognitive Assessment (MoCA)-defined as normal (score of 25-30), mildly impaired (score of 20-24), and moderately impaired (score less than 19)-by determining whether they differ in rehabilitation gain during inpatient stroke rehabilitation.DesignObservational study. Linear regression models were conducted and predictors included MoCA subgroups and relevant baseline demographic and clinical covariates. Separate models included the cognitive subscale of the FIM instrument as a predictor.SettingInpatient rehabilitation facility of an urban, academic medical center.ParticipantsInpatients (N=334) with mild-moderate strokes who were administered the MoCA on admission.InterventionsNot applicable.Main outcome measuresThe mean relative functional gain (mRFG) and mean relative functional efficiency (mRFE, which adjusts for length of stay) on the FIM total.ResultsMoCA subgroups significantly predicted mRFG and mRFE after accounting for age, sex, education, stroke severity, and recurrent vs first stroke. The normal group exhibited greater mRFG and mRFE than the mildly impaired group, while the moderately impaired group had significantly worse mRFG and mRFE than the mildly impaired group. The moderately impaired group had a significantly smaller proportion of individuals who made a clinically meaningful change on the total-FIM than the mildly impaired and normal groups. MoCA subgroups better accounted for mRFG and mRFE than a standard-of-care cognitive assessment (cognitive-FIM).ConclusionsUse of MoCA-defined subgroups can assist providers in predicting functional gain in survivors of stroke being treated in inpatient rehabilitation.
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Project description:Despite improved treatment, a large portion of patients with acute ischemic stroke due to a large vessel occlusion have poor functional outcome. Further research exploring novel treatments and better patient selection has therefore been initiated. The feasibility of new treatments and optimized patient selection are commonly tested in extensive and expensive randomized clinical trials. in-silico trials, computer-based simulation of randomized clinical trials, have been proposed to aid clinical trials. In this white paper, we present our vision and approach to set up in-silico trials focusing on treatment and selection of patients with an acute ischemic stroke. The INSIST project (IN-Silico trials for treatment of acute Ischemic STroke, www.insist-h2020.eu) is a collaboration of multiple experts in computational science, cardiovascular biology, biophysics, biomedical engineering, epidemiology, radiology, and neurology. INSIST will generate virtual populations of acute ischemic stroke patients based on anonymized data from the recent stroke trials and registry, and build on the existing and emerging in-silico models for acute ischemic stroke, its treatment (thrombolysis and thrombectomy) and the resulting perfusion changes. These models will be used to design a platform for in-silico trials that will be validated with existing data and be used to provide a proof of concept of the potential efficacy of this emerging technology. The platform will be used for preliminary evaluation of the potential suitability and safety of medication, new thrombectomy device configurations and methods to select patient subpopulations for better treatment outcome. This could allow generating, exploring and refining relavant hypotheses on potential causal pathways (which may follow from the evidence obtained from clinical trials) and improving clinical trial design. Importantly, the findings of the in-silico trials will require validation under the controlled settings of randomized clinical trials.
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Project description:ImportanceThe underenrollment of women in randomized clinical trials represents a threat to the validity of the evidence supporting clinical guidelines and potential disparities in access to novel treatments.ObjectiveTo determine whether women were underenrolled in contemporary randomized clinical trials of acute stroke therapies published in 9 major journals after accounting for their representation in underlying stroke populations.Data sourcesMEDLINE was searched for acute stroke therapeutic trials published between January 1, 2010, and June 11, 2020.Study selectionEligible articles reported the results of a phase 2 or 3 randomized clinical trial that enrolled patients with stroke and/or transient ischemic attack and examined a therapeutic intervention initiated within 1 month of onset.Data extractionData extraction was performed by 2 independent authors in duplicate. Individual trials were matched to estimates of the proportion of women in underlying stroke populations using the Global Burden of Disease database.Main outcomes and measuresThe primary outcome was the enrollment disparity difference (EDD), the absolute difference between the proportion of trial participants who were women and the proportion of strokes in the underlying disease populations that occurred in women. Random-effects meta-analyses of the EDD were performed, and multivariable metaregression was used to explore the associations of trial eligibility criteria with disparity estimates.ResultsThe search returned 1529 results, and 115 trials (7.5%) met inclusion criteria. Of 121 105 randomized patients for whom sex was reported, 52 522 (43.4%) were women. The random-effects summary EDD was -0.053 (95% CI, -0.065 to -0.040), indicating that women were underenrolled by 5.3 percentage points. This disparity persisted across virtually all geographic regions, intervention types, and stroke types, apart from subarachnoid hemorrhage (0.117 [95% CI, 0.084 to 0.150]). When subarachnoid hemorrhage trials were excluded, the summary EDD was -0.067 (95% CI, -0.078 to -0.057). In the multivariable metaregression analysis, an upper age limit of 80 years as an eligibility criterion was associated with a 6-percentage point decrease in the enrollment of women.Conclusions and relevanceFurther research is needed to understand the causes of the underenrollment of women in acute stroke trials. However, to maximize representation, investigators should avoid imposing age limits on enrollment.
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Project description:Long non-coding RNAs (lncRNAs) have been evidenced to be associated with the development of multiple diseases. However, the expression pattern and function of lncRNAs in acute ischemic stroke remain unclear. To determine the differential expression of lncRNAs in acute ischemic stroke, we analyzed the expression profile of lncRNAs by high-throughput sequencing analysis. Gene Ontology (GO) and pathway analyses were employed to analyze the gene function and identify enriched pathways of the differentially expressed lncRNAs. We also built an lncRNA-mRNA expression correlation network and verified the interactions of selected lncRNAs in acute ischemic stroke. To further confirm the results of the expression profile, 6 differentially expressed lncRNAs were randomly selected and quantitative RT-PCR (qRT-PCR) performed. We identified 44,578 aberrantly expressed lncRNAs, including 228 upregulated and 16 downregulated lncRNAs. The qRT-PCR results showed that ENSG00000269900, ENSG00000196559, ENSG00000202198, ENSG00000226482, ENSG00000260539 (up), and XLOC_013994_2 (down) were abnormally expressed, which was consistent with the sequencing results. The upregulated expression of lncRNA ENSG00000226482 may activate the adipocytokine signaling pathway, resulting in acute ischemia stroke. In summary, we analyzed the lncRNAs expression profile in acute ischemic stroke patients and identified the functions and enriched metabolic pathways, proposing new insights into the diagnostic and therapeutic biomarkers for this disease.
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