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Despite years of basic research and pioneering clinical work, ischemic stroke remains a major public health concern. Prior STAIR (Stroke Treatment Academic Industry Roundtable) conferences identified both failures of clinical trial design and failures in preclinical assessment in developing putative ischemic stroke treatments. At STAIR XI, participants in workshop no. 1 Top Priorities for Neuroprotection sought to redefine the neuroprotection paradigm and given the paucity of evidence underlying preclinical assessment, offer consensus-based recommendations. STAIR proposes the term brain cytoprotection or cerebroprotection to replace the term neuroprotection when the intention of an investigation is to demonstrate that a new, candidate treatment benefits the entire brain. Although “time is still brain,” tissue imaging techniques have been developed to identify patients with both predicted core injury and penumbral, salvageable brain tissue, regardless of time after stroke symptom onset. STAIR XI workshop participants called this imaging approach a tissue window to select patients for recanalization. Elements of the neurovascular unit show differential vulnerability evolving over differing time scales in different brain regions. STAIR proposes the term target window to suggest therapies that target the different elements of the neurovascular unit at different times. Based on contemporary principles of rigor and transparency, the workshop updated, revised, and enhanced the STAIR preclinical recommendations for developing new treatments in 2 phases: an exploratory qualification phase and a definitive validation phase. For new, putative treatments, investigators should carefully characterize the mechanism of action, the pharmacokinetics/pharmacodynamics, demonstrate target engagement, and confirm penetration through the blood-brain barrier. Before clinical trials, testing of candidate molecules in stroke models could proceed in a comprehensive manner using animals of both sexes and to include significant variables such as age and comorbid conditions. Comprehensive preclinical assessment might include multicenter, collaborative testing, for example, network trials. In the absence of a proven cerebroprotective agent to use as a gold standard, however, it remains speculative whether such comprehensive preclinical assessment can effectively predict clinical outcome.

Introduction: Long-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 normal individuals and patients with stroke of known cause (KS). Clinical management would be aided by estimates of how often occult AF in a patient with CS is causal versus incidental. Methods: Through systematic search, we identified all case-control and cohort studies applying identical long-term monitoring techniques to both CS and KS patients. We performed a random-effects meta-analyses 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 (method of Alsheikh-Ali et al, Stroke 2009) to determine the probability that occult AF is causal or incidental. Results: The systematic search identified 3 case-control and cohort studies enrolling 575 patients (337 CS, 238 KS). Methods of long-term monitoring were implantable loop recorder in 191 (33.2%), extended mobile external cardiac monitor in 277 (48.2%), and patch/event/Holter monitoring in 107 (18.6%). In formal meta-analysis, the summary odds ratio for occult AF in CS vs KS in all patients was 1.72 (95%CI 0.91-3.25) (Figure). With application of Bayes theorem, the corresponding probabilities indicated that, when present, occult AF in CS patients is causal in 44.4% and incidental in 55.6%. Only one study reported age-specific subgroup data: these suggested occult AF in CS patients was causal in 93% of patients Conclusions: In patients with cryptogenic stroke, when occult AF is found, it is likely causal in about 44% of patients, who may benefit from anticoagulation, and likely incidental in about 56% of patients, who may not benefit from anticoagulation. Figure

The modified Rankin Scale (mRS), a 7-level, clinician-reported, measure of global disability, is the most widely employed outcome scale in acute stroke trials. The scale’s original development preceded the advent of modern clinimetrics, but substantial subsequent work has been performed to enable the mRS to meet robust contemporary scale standards. Prior research and consensus recommendations have focused on modernizing 2 aspects of the mRS: operationalized assignment of scale scores and statistical analysis of scale distributions. Another important characteristic of the mRS still requiring elaboration and specification to contemporary clinimetric standards is the Naming of scale outcomes. Recent clinical trials have used a bewildering variety, often mutually contradictory, of rubrics to describe scale states. Understanding of the meaning of mRS outcomes by clinicians, patients, and other clinical trial stakeholders would be greatly enhanced by use of a harmonized, uniform set of labels for the distinctive mRS outcomes that would be used consistently across trials. This statement advances such recommended rubrics, developed by the Stroke Therapy Academic Industry Roundtable collaboration using an iterative, mixed-methods process. Specific guidance is provided for health state terms (eg, Symptomatic but Nondisabled for mRS score 1; requires constant care for mRS score 5) and valence terms (eg, excellent for mRS score 1; very poor for mRS score 5) to employ for 23 distinct numeric mRS outcomes, including: all individual 7 mRS levels; all 12 positive and negative dichotomized mRS ranges, positive and negative sliding dichotomies; and utility-weighted analysis of the mRS.

Background: The modified Rankin scale, a 7-level, clinician-reported, measure of global disability, is the most widely employed outcome scale in acute stroke trials. As the meaning of technical mRS scores (e.g. mRS 1, mRS 4) is not well-known among general clinicians, patients, and policy-makers, trialists sometimes apply valence (e.g. “excellent”, “good”) and health-state (e.g. “disabled”, “dependent”) terms to convey the clinical meaning of trial findings. The terms employed have not been well-delineated. Methods: Systematic meta-analysis assessing mRS descriptive terms across all large (n ≥ 100) RCTs for acute ischemic or hemorrhagic stroke reported 2000 - 2020, following PRISMA guidelines. Results: Among the 60 RCTs meeting study entry criteria, patient populations were acute ischemic stroke (AIS) in 88%, intracerebral hemorrhage in 8%, both in 3%. Among the 55 AIS trials, tested agents included: antiplatelet - 28%, endovascular thrombectomy - 20%, IV lytics - 20%, neuroprotective - 11%. The mRS was a major endpoint measure in 82% of trials (primary in 60%, secondary in 22%). Table 1 shows frequency of different valence terms (1A) and health state terms (1B) for 9 types of mRS analysis. Trials often used mutually contradictory terms for particular mRS outcomes. e.g. “good outcome” was applied to outcomes mRS 0-1 (2 trials), mRS 0-2 (2 trials), mRS 0-3 (1 trial), and ordinal mRS (3 trials); “favorable” was applied to mRS 0-1 (5 trials), mRS 0-2 (6 trials), and ordinal mRS (6 trials). Also many trials provided no meaningful descriptor (no valence descriptor in 82%, no health state descriptor in 58%). Conclusion: Across major acute stroke trials of the past 20 years, the valence and health state terms for different mRS outcomes have been often mutually contradictory or not provided at all. A standardized nomenclature for mRS outcome description would improve clinician and policy-maker understanding of trial results

Background and Purpose— Although 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. Methods— A 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. Results— Utility 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. Conclusions— A 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.

Ischemic stroke is a multifactorial disease with strong genetic elements. The purpose of this case-control study was to find relationships between apolipoprotein E (APOE), angiotensin-converting enzyme (ACE), and methylenetetrahydrofolate reductase (MTHFR) genotypes and atherosclerosis of the extracranial internal carotid and intracranial arteries in the Thai population. Patients aged >45 years with significant intracranial stenosis (IC group) or extracranial carotid artery stenosis (EC group) diagnosed by duplex ultrasound and/or computed tomography angiography (CTA) or magnetic resonance angiography (MRA) were studied. The control group comprised volunteers with no history of stroke and no evidence of significant cervicocerebral artery stenosis by ultrasound. Genomic DNA was extracted and genotyped for APOE isoforms, ACE insertion/deletion (I/D) polymorphism, and MTHFR C677T polymorphisms. There were 141 cases (83 in the IC group and 58 in the EC group) and 167 controls. The APOE e3/e4 genotype and APOE e4 allele were significantly associated with extracranial carotid artery stenosis (odds ratio, 2.55; 95% confidence interval, 1.07-6.05 and odds ratio, 2.85; 95% confidence interval, 1.35-5.99, respectively). These associations were not observed in patients with intracranial atherosclerosis. There was no significant association between ACE and MTHFR polymorphisms and stenosis at any site. In a multivariate model, sex, diabetes mellitus, hypertension, ischemic heart disease, and APOE e4 allele remained predictive of extracranial atherosclerosis. In our Thai population, the e4 allele in the APOE gene contributes to the genetic susceptibility of extracranial internal carotid atherosclerosis. The low prevalence of extracranial carotid stenosis in this population might result from low frequencies of the APOE e4 allele.

Background: The most common primary endpoint in acute stroke trials is the modified Rankin Scale (mRS) assessment of global disability. However, the mRS lacks granularity (assigns patients among only 7 broad levels) and is ordinal (scale levels unknown distances apart), constraining study power. Instruments that evaluate disability along an interval, continuous scale theoretically should increase study power. The Academic Medical Center linear disability scale (ALDS) is one such scale, assigning patients to scores from 0-100. Methods: Consecutive patients undergoing 3 month final outcome visits in the NIH FAST-MAG phase 3 trial were assessed with the mRS and ALDS. Scale scores were compared using splines and linear regression. Model trial power was computed using 4000 random simulations. Results: Among 55 patients, mean age was 71.2 (SD±14.2), 67% were male, and entry NIHSS was 10.7 (SD±9.5). At 90d, the median mRS was 3 (IQR 1 - 4, range 0-5, lower better) and median ALDS score 78.8 (IQR 3.3-100, range 0-100, higher better). The mRS and ALDS logit score were highly correlated, r = 0.94. ALDS logit score also correlated strongly with 90d Barthel Index(r=0.92) and 90d NIHSS (r=0.87), as well as modestly with entry NIHSS (r = 0.38). The ALDS showed greater discriminant validity than the mRS, with a mean of only 1.9 (SD±3.2) patients sharing each ALDS logit value versus a mean of 8.0 (SD±3.6) patients sharing each mRS score value, p < 0.001. Over a broad range of treatment effect magnitudes, trial power was 25-30% higher when the ALDS rather than the mRS was used as the primary trial endpoint (Figure). Conclusion: Among patients enrolled in an acute neuroprotective stroke trial, the ALDS, a linear disability scale derived using item response theory, showed strong convergent validity and superior discrimination characteristics compared with the modified Rankin Scale, and considerably increased trial power to detect clinically meaningful treatment benefits.