How to establish the outer limits of reperfusion therapy

Reperfusion therapy with intravenous alteplase and endovascular therapy are effective treatments for selected patients with acute ischemic stroke. Guidelines for treatment are based upon randomized trials demonstrating substantial treatment effects for highly selected patients based on time from stroke onset and imaging features. However, patients beyond the current established guidelines might benefit with lesser but still clinically significant treatment effects. The STAIR (Stroke Treatment Academic Industry Roundtable) XI meeting convened a workgroup to consider the “outer limits” of reperfusion therapy by defining the current boundaries, and exploring optimal parameters and methodology for determining the outer limits. In addition to statistical significance, the minimum clinically important difference should be considered in exploring the limits of reperfusion therapy. Societal factors and quality of life considerations should be incorporated into assessment of treatment efficacy. The threshold for perception of benefit in the medical community may differ from that necessary for the Food and Drug Administration approval. Data from alternative sources such as platform trials, registries and large pragmatic trials should supplement randomized controlled trials to improve generalizability to routine clinical practice. Further interactions between industry and academic centers should be encouraged

Acute stroke imaging research roadmap IV : imaging selection and outcomes in acute stroke clinical trials and practice

Background and Purpose: The Stroke Treatment Academic Industry Roundtable (STAIR) sponsored an imaging session and workshop during the Stroke Treatment Academic Industry Roundtable XI via webinar on October 1 to 2, 2020, to develop consensus recommendations, particularly regarding optimal imaging at primary stroke centers. Methods: This forum brought together stroke neurologists, neuroradiologists, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke, industry representatives, and members of the US Food and Drug Administration to discuss imaging priorities in the light of developments in reperfusion therapies, particularly in an extended time window, and reinvigorated interest in brain cytoprotection trials. Results: The imaging session summarized and compared the imaging components of recent acute stroke trials and debated the optimal imaging strategy at primary stroke centers. The imaging workshop developed consensus recommendations for optimizing the acquisition, analysis, and interpretation of computed tomography and magnetic resonance acute stroke imaging, and also recommendations on imaging strategies for primary stroke centers. Conclusions: Recent positive acute stroke clinical trials have extended the treatment window for reperfusion therapies using imaging selection. Achieving rapid and high-quality stroke imaging is therefore critical at both primary and comprehensive stroke centers. Recommendations for enhancing stroke imaging research are provided

How often is occult atrial fibrillation in cryptogenic stroke causal vs. incidental? A meta-analysis

IntroductionLong-term cardiac monitoring studies have unveiled low-burden, occult atrial fibrillation (AF) in some patients with otherwise cryptogenic stroke (CS), but occult AF is also found in some individuals without a stroke history and in patients with stroke of a known cause (KS). Clinical management would be aided by estimates of how often occult AF in a patient with CS is causal vs. incidental.MethodsThrough a systematic search, we identified all case–control and cohort studies applying identical long-term monitoring techniques to both patients with CS and KS. We performed a random-effects meta-analysis across these studies to determine the best estimate of the differential frequency of occult AF in CS and KS among all patients and across age subgroups. We then applied Bayes' theorem to determine the probability that occult AF is causal or incidental.ResultsThe systematic search identified three case–control and cohort studies enrolling 560 patients (315 CS, 245 KS). Methods of long-term monitoring were implantable loop recorder in 31.0%, extended external monitoring in 67.9%, and both in 1.2%. Crude cumulative rates of AF detection were CS 47/315 (14.9%) vs. KS 23/246 (9.3%). In the formal meta-analysis, the summary odds ratio for occult AF in CS vs. KS in all patients was 1.80 (95% CI, 1.05–3.07), p = 0.03. With the application of Bayes' theorem, the corresponding probabilities indicated that, when present, occult AF in patients with CS is causal in 38.2% (95% CI, 0–63.6%) of patients. Analyses stratified by age suggested that detected occult AF in patients with CS was causal in 62.3% (95 CI, 0–87.1%) of patients under the age of 65 years and 28.5% (95 CI, 0–63.7%) of patients aged 65 years and older but estimates had limited precision.ConclusionCurrent evidence is preliminary, but it indicates that in cryptogenic stroke when occult AF is found, it is causal in about 38.2% of patients. These findings suggest that anticoagulation therapy may be beneficial to prevent recurrent stroke in a substantial proportion of patients with CS found to have occult AF

Data_Sheet_2_Staged use of ordinal and linear disability scales: a practical approach to granular assessment of acute stroke outcome.pdf

BackgroundThe modified Rankin Scale (mRS) assessment of global disability is the most common primary endpoint in acute stroke trials but lacks granularity (7 broad levels) and is ordinal (scale levels unknown distances apart), which constrains study power. Disability scales that are linear and continuous may better discriminate outcomes, but computerized administration in stroke patients is challenging. We, therefore, undertook to develop a staged use of an ordinal followed by a linear scale practical to use in multicenter trials.MethodsConsecutive patients undergoing 3-month final visits in the NIH FAST-MAG phase 3 trial were assessed with the mRS followed by 15 mRS level-specific yes–no items of the Academic Medical Center Linear Disability Score (ALDS), a linear disability scale derived using item response theory.ResultsAmong 55 patients, aged 71.2 (SD ± 14.2), 67% were men and the entry NIHSS was 10.7 (SD ± 9.5). At 90 days, the median mRS score was 3 (IQR, 1–4), and the median ALDS score was 78.8 (IQR, 3.3–100). ALDS scores correlated strongly with 90 days outcome measures, including the Barthel Index (r = 0.92), NIHSS (r = 0.87), and mRS (r = 0.94). ALDS scores also correlated modestly with entry NIHSS (r = 0.38). At 90 days, the ALDS showed greater scale granularity than the mRS, with fewer patients with identical values, 1.9 (SD ± 3.2) vs. 8.0 (SD ± 3.6), p ConclusionAmong patients enrolled in an acute neuroprotective stroke trial, the ALDS showed strong convergent validity and superior discrimination characteristics compared with the modified Rankin Scale and increased projected trial power to detect clinically meaningful treatment benefits.</p

Data_Sheet_1_Staged use of ordinal and linear disability scales: a practical approach to granular assessment of acute stroke outcome.pdf

BackgroundThe modified Rankin Scale (mRS) assessment of global disability is the most common primary endpoint in acute stroke trials but lacks granularity (7 broad levels) and is ordinal (scale levels unknown distances apart), which constrains study power. Disability scales that are linear and continuous may better discriminate outcomes, but computerized administration in stroke patients is challenging. We, therefore, undertook to develop a staged use of an ordinal followed by a linear scale practical to use in multicenter trials.MethodsConsecutive patients undergoing 3-month final visits in the NIH FAST-MAG phase 3 trial were assessed with the mRS followed by 15 mRS level-specific yes–no items of the Academic Medical Center Linear Disability Score (ALDS), a linear disability scale derived using item response theory.ResultsAmong 55 patients, aged 71.2 (SD ± 14.2), 67% were men and the entry NIHSS was 10.7 (SD ± 9.5). At 90 days, the median mRS score was 3 (IQR, 1–4), and the median ALDS score was 78.8 (IQR, 3.3–100). ALDS scores correlated strongly with 90 days outcome measures, including the Barthel Index (r = 0.92), NIHSS (r = 0.87), and mRS (r = 0.94). ALDS scores also correlated modestly with entry NIHSS (r = 0.38). At 90 days, the ALDS showed greater scale granularity than the mRS, with fewer patients with identical values, 1.9 (SD ± 3.2) vs. 8.0 (SD ± 3.6), p ConclusionAmong patients enrolled in an acute neuroprotective stroke trial, the ALDS showed strong convergent validity and superior discrimination characteristics compared with the modified Rankin Scale and increased projected trial power to detect clinically meaningful treatment benefits.</p

Adopting a Patient-Centered Approach to Primary Outcome Analysis of Acute Stroke Trials Using a Utility-Weighted Modified Rankin Scale.

Background and purposeAlthough the modified Rankin Scale (mRS) is the most commonly used primary end point in acute stroke trials, its power is limited when analyzed in dichotomized fashion and its indication of effect size challenging to interpret when analyzed ordinally. Weighting the 7 Rankin levels by utilities may improve scale interpretability while preserving statistical power.MethodsA utility-weighted mRS (UW-mRS) was derived by averaging values from time-tradeoff (patient centered) and person-tradeoff (clinician centered) studies. The UW-mRS, standard ordinal mRS, and dichotomized mRS were applied to 11 trials or meta-analyses of acute stroke treatments, including lytic, endovascular reperfusion, blood pressure moderation, and hemicraniectomy interventions.ResultsUtility values were 1.0 for mRS level 0; 0.91 for mRS level 1; 0.76 for mRS level 2; 0.65 for mRS level 3; 0.33 for mRS level 4; 0 for mRS level 5; and 0 for mRS level 6. For trials with unidirectional treatment effects, the UW-mRS paralleled the ordinal mRS and outperformed dichotomous mRS analyses. Both the UW-mRS and the ordinal mRS were statistically significant in 6 of 8 unidirectional effect trials, whereas dichotomous analyses were statistically significant in 2 to 4 of 8. In bidirectional effect trials, both the UW-mRS and ordinal tests captured the divergent treatment effects by showing neutral results, whereas some dichotomized analyses showed positive results. Mean utility differences in trials with statistically significant positive results ranged from 0.026 to 0.249.ConclusionsA UW-mRS performs similar to the standard ordinal mRS in detecting treatment effects in actual stroke trials and ensures the quantitative outcome is a valid reflection of patient-centered benefits

Adopting a Patient-Centered Approach to Primary Outcome Analysis of Acute Stroke Trials Using a Utility-Weighted Modified Rankin Scale

Background and purposeAlthough the modified Rankin Scale (mRS) is the most commonly used primary end point in acute stroke trials, its power is limited when analyzed in dichotomized fashion and its indication of effect size challenging to interpret when analyzed ordinally. Weighting the 7 Rankin levels by utilities may improve scale interpretability while preserving statistical power.MethodsA utility-weighted mRS (UW-mRS) was derived by averaging values from time-tradeoff (patient centered) and person-tradeoff (clinician centered) studies. The UW-mRS, standard ordinal mRS, and dichotomized mRS were applied to 11 trials or meta-analyses of acute stroke treatments, including lytic, endovascular reperfusion, blood pressure moderation, and hemicraniectomy interventions.ResultsUtility values were 1.0 for mRS level 0; 0.91 for mRS level 1; 0.76 for mRS level 2; 0.65 for mRS level 3; 0.33 for mRS level 4; 0 for mRS level 5; and 0 for mRS level 6. For trials with unidirectional treatment effects, the UW-mRS paralleled the ordinal mRS and outperformed dichotomous mRS analyses. Both the UW-mRS and the ordinal mRS were statistically significant in 6 of 8 unidirectional effect trials, whereas dichotomous analyses were statistically significant in 2 to 4 of 8. In bidirectional effect trials, both the UW-mRS and ordinal tests captured the divergent treatment effects by showing neutral results, whereas some dichotomized analyses showed positive results. Mean utility differences in trials with statistically significant positive results ranged from 0.026 to 0.249.ConclusionsA UW-mRS performs similar to the standard ordinal mRS in detecting treatment effects in actual stroke trials and ensures the quantitative outcome is a valid reflection of patient-centered benefits

Acute Stroke Imaging Research Roadmap IV: Imaging Selection and Outcomes in Acute Stroke Clinical Trials and Practice.

Background and purposeThe Stroke Treatment Academic Industry Roundtable (STAIR) sponsored an imaging session and workshop during the Stroke Treatment Academic Industry Roundtable XI via webinar on October 1 to 2, 2020, to develop consensus recommendations, particularly regarding optimal imaging at primary stroke centers.MethodsThis forum brought together stroke neurologists, neuroradiologists, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke, industry representatives, and members of the US Food and Drug Administration to discuss imaging priorities in the light of developments in reperfusion therapies, particularly in an extended time window, and reinvigorated interest in brain cytoprotection trials.ResultsThe imaging session summarized and compared the imaging components of recent acute stroke trials and debated the optimal imaging strategy at primary stroke centers. The imaging workshop developed consensus recommendations for optimizing the acquisition, analysis, and interpretation of computed tomography and magnetic resonance acute stroke imaging, and also recommendations on imaging strategies for primary stroke centers.ConclusionsRecent positive acute stroke clinical trials have extended the treatment window for reperfusion therapies using imaging selection. Achieving rapid and high-quality stroke imaging is therefore critical at both primary and comprehensive stroke centers. Recommendations for enhancing stroke imaging research are provided