Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

Endovascular Therapy for Basilar Artery Occlusion: Among the First to Conceptualize, Last to Prove.

In 1981, the dismal outcomes of patients with basilar artery occlusion (BAO) inspired the first reports of intra-arterial thrombolytic treatment in BAO. These reports were among the first to conceptualize that opening an artery could help patients with large vessel occlusion stroke. Whereas multiple anterior circulation LVO trials demonstrated the efficacy of endovascular therapy starting in 2014, proof of benefit for BAO was lacking until 2022. In this commentary, we reflect on how the BASICS (Basilar Artery International Cooperation Study) and BEST (Basilar Artery Occlusion: Endovascular Interventions vs Standard Medical Treatment) trials lay the foundations for clinical trials in BAO, subsequently leading to the positive results of the ATTENTION (Endovascular Treatment for Acute Basilar-Artery Occlusion) and BAOCHE (Basilar Artery Occlusion Chinese Endovascular) trials.

Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention.

BACKGROUND: Individuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding. Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets. METHODS: We began a phase II, double-blinded, randomized, placebo-controlled trial at 367 sites in 2019. Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD2 score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint. Participant follow-up will end in 2022. CONCLUSION: The AXIOMATIC-SSP trial will evaluate the dose-response of milvexian for ischemic stroke occurrence in participants with ischemic stroke or TIA.

Prevalence of Retinal Emboli and Acute Retinal Artery Occlusion in Acute Ischemic Stroke.

OBJECTIVE: In population-based studies asymptomatic retinal emboli occur in .32%-2.9% of people. Retinal artery occlusion (RAO) may occur concurrently with cerebral stroke but the frequency is unknown. No study has examined how commonly retinal emboli occur in the acute stroke population. We aimed to assess the prevalence of retinal emboli and RAO at the time of carotid territory ischemic stroke. METHODS: Patients were enrolled prospectively after onset of symptoms consistent with the diagnosis of carotid territory ischemic stroke. Every participant underwent pharmacologic dilation of both pupils and bedside funduscopic examination. Emboli were classified as cholesterol, calcific, platelet/fibrin, or other and categorized by the side of occurrence. Stroke was classified as atheroembolic, cardioembolic, embolic stroke of undetermined source, lacunar, or other. Acute RAO was diagnosed by direct visualization of ischemic retinal whitening. RESULTS: Sixty-five patients were enrolled with a mean age of 59.2 years; 23 were female (35.4%). Eleven of 65 subjects (16.9%) had retinal emboli visible on funduscopy; all were cholesterol emboli except a single platelet/fibrin embolus in a patient with atheroembolic source. Six patients (9%) had acute RAO and no RAO was seen in the lacunar or undetermined source subgroups. CONCLUSIONS: Retinal emboli occurred more than 10 times more frequently in the acute stroke patient than in large population-based studies. RAOs also occurred concurrently with ischemic stroke. Although emboli were seen in patients with atheroembolic and cardioembolic sources, all patients with carotid disease had emboli in the ipsilateral eye. Future studies are required to determine if the presence of retinal emboli or RAO may help elucidate an etiology in patients suffering from embolic stroke of undetermined source.

Time Course for Benefit and Risk of Clopidogrel and Aspirin After Acute Transient Ischemic Attack and Minor Ischemic Stroke.

BACKGROUND: In patients with acute minor ischemic stroke or high-risk transient ischemic attack enrolled in the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke [POINT] Trial), the combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage in comparison to aspirin alone. METHODS: In a secondary analysis of POINT (N=4881), we assessed the time course for benefit and risk from the combination of clopidogrel and aspirin. The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction, or ischemic vascular death. The primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left-truncated models. RESULTS: Through 90 days, the rate of major ischemic events was initially high then decreased markedly, whereas the rate of major hemorrhage remained low but relatively constant throughout. With the use of a model-based approach, the optimal change point for major ischemic events was 21 days (0-21 days hazard ratio 0.65 for clopidogrel-aspirin versus aspirin; 95% CI, 0.50-0.85; P=0.0015, in comparison to 22-90 days hazard ratio, 1.38; 95% CI, 0.81-2.35; P=0.24). Models showed benefits of clopidogrel-aspirin for treatment delayed as long as 3 days after symptom onset. CONCLUSIONS: The benefit of clopidogrel-aspirin occurs predominantly within the first 21 days, and outweighs the low, but ongoing risk of major hemorrhage. When considered with the results of the CHANCE trial (Clopidogrel in High-Risk Patients With Non-disabling Cerebrovascular Events), a similar trial treating with clopidogrel-aspirin for 21 days and showing no increase in major hemorrhage, these results suggest that limiting clopidogrel-aspirin use to 21 days may maximize benefit and reduce risk after high-risk transient ischemic attack or minor ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Thyroid cartilage compression causing stroke.

We describe the diagnostic workup and surgical treatment of a patient presenting with the unique case of vertebral artery (VA) occlusion subsequent to head flexion leading to compression of an aberrant VA by the ipsilateral superior cornu of the thyroid cartilage. Imaging revealed ischemic infarcts as well as the presence of an aberrant right VA, which was compressed by the ipsilateral superior cornu of the thyroid cartilage upon neck flexion. The patient was managed with laryngoplasty involving removal of the right superior cornu of the thyroid cartilage. Laryngoscope, 129:E445-E448, 2019.

SCAI expert consensus statement on operator and institutional requirements for PFO closure for secondary prevention of paradoxical embolic stroke: The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists.

Until recently, evidence to support Patent Foramen Ovale (PFO) closure for secondary prevention of recurrent stroke has been controversial. Publication of high-quality evidence from randomized clinical trials and the subsequent FDA approval of two devices for percutaneous PFO closure is expected to increase the volume of PFO closure procedures not only in the United States but worldwide. As this technology is disseminated broadly to the public, ensuring the safe and efficacious performance of PFO closure is essential to mitigate risk and avoid unnecessary procedures. This document, prepared by a multi-disciplinary writing group convened by the Society for Cardiovascular Angiography and Interventions and including representatives from the American Academy of Neurology, makes recommendations for institutional infrastructure and individual skills necessary to initiate and maintain an active PFO/stroke program, with emphasis on shared decision making and patient-centered care.

Cerebral amyloid angiopathy: diagnosis and potential therapies.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) is characterized by the pathologic deposition of amyloid-beta within cortical and leptomeningeal arteries, arterioles, capillaries and, in rare cases, the venules of the brain. It is often associated with the development of lobar intracerebral hemorrhages (ICHs) but may cause other neurologic symptoms or be asymptomatic. Magnetic resonance imaging characteristics, such as lobar microbleeds, support a diagnosis of CAA and assist with hemorrhage risk assessments. Immunosuppressants are used to treat rarer inflammatory forms of CAA. For the more common forms of CAA, the use of antihypertensive medications can prevent ICH recurrence while the use of antithrombotics may increase hemorrhage risk. Anti-amyloid approaches to treatment have not yet been investigated in phase 3 trials. Areas covered: A literature search was conducted using MEDLINE on the topics of imaging, biomarkers, ICH prevention and treatment trials in CAA, focusing on its current diagnosis and management and opportunities for future therapeutic approaches. Expert commentary: There is likely a significant unrecognized burden of CAA in the elderly population. Continued research efforts to discover biomarkers that allow the early diagnosis of CAA will enhance the opportunity to develop treatment interventions.

Impact of Stroke Call on the Stroke Neurology Workforce in the United States: Possible Challenges and Opportunities.

BACKGROUND: The Stroke & Vascular Neurology Section of the American Academy of Neurology was charged to identify challenges to the recruitment and retention of stroke neurologists and to make recommendations to address any identified problems. The Section initiated this effort by determining the impact of stroke on-call requirements as a barrier to the recruitment and retention of vascular neurologists. METHODS: This is a cross-sectional survey of a sample of US Neurologists providing acute stroke care. RESULTS: Of the 900 neurologists who were sent surveys, 313 (35%) responded. Of respondents from institutions providing stroke coverage, 71% indicated that general neurologists and 45% indicated that vascular neurologists provided that service. Of those taking stroke call, 36% agreed with the statement, "I spent too much time on stroke call," a perception that was less common among those who took less than 12-hour shifts (P < .0001); 21% who participated in stroke call were dissatisfied with their current job. Forty-six percent indicated that their stroke call duties contributed to their personal feeling of "burnout." CONCLUSIONS: Although the reasons are likely multifactorial, our survey of neurologists providing stroke care suggests that over-burdensome on-call responsibilities may be contributing to the vascular neurology workforce burnout and could be affecting recruitment and retention of vascular neurologists. Strategies to reduce the lifestyle impact of stroke call may help address this problem.

Periprocedural heparin use in acute ischemic stroke endovascular therapy: the TREVO 2 trial.

BACKGROUND: The use of periprocedural heparin has previously been reported to be safe and potentially beneficial during thrombectomy with older generation devices. We aimed to evaluate the safety and clinical outcomes of heparin use in the stent retriever era. METHODS: A post hoc analysis of the TREVO 2 trial was performed comparing baseline characteristics and clinical outcomes between patients who received (HEP+) and those who did not receive periprocedural heparin (HEP-) while undergoing MERCI or TREVO clot retrieval. RESULTS: Of 173 patients, 58 (34%) received periprocedural heparin including 40 who received one preprocedural bolus (median 3000 units). Baseline characteristics among HEP+ and HEP- patients were similar except HEP+ patients had a lower NIH Stroke Scale (NIHSS) score (17 vs 19; p=0.04), lower IV tissue plasminogen activator use (38% vs 64%; p<0.01), and a higher median ASPECTS score (8.0 vs 7.0; p=0.02). HEP+ patients were more likely to have vertebrobasilar and middle cerebral artery (MCA)-M1 occlusions but less likely to have internal carotid artery and MCA-M2 occlusions (p=0.04). Time from symptom onset to puncture was similar in the two groups while procedure duration was longer in HEP+ patients (99 vs 83 min; p<0.01). Thrombolysis In Cerebral Infarction (TICI) 2b-3 reperfusion rates, embolization to unaffected territories, access site complications, and intracranial hemorrhages were similar between the groups. In multivariable logistic regression, a good outcome (90-day modified Rankin Scale score 0-2) was independently associated with heparin bolus use (OR 5.30; 95% CI 1.70 to 16.48), TICI 2b-3 reperfusion (OR 6.56; 95% CI 2.29 to 18.83), stent retriever use (OR 3.54; 95% CI 1.38 to 9.03) and inversely associated with intubation (OR 0.10; 95% CI 0.03 to 0.33), diabetes (OR 0.11; 95% CI 0.03 to 0.39), NIHSS (OR 0.84; 95% CI 0.75 to 0.93), time from symptom onset to puncture (OR 0.64; 95% CI 0.45 to 0.89), and heart failure (OR 0.23; 95% CI 0.06 to 0.83). CONCLUSIONS: The use of periprocedural heparin in stent retriever thrombectomy is associated with a good clinical outcome at 90 days and similar rates of symptomatic intracranial hemorrhage. Further studies are warranted. CLINICAL TRIAL REGISTRATION: URL:http://www.clinicaltrials.gov. Unique identifier: NCT01270867;Post-results.

Management of Symptomatic Intracranial Stenosis.

Intracranial atherosclerotic disease is a common cause of stroke worldwide, causing approximately 10 % of strokes in the USA and up to 50 % in Asian populations. Recurrent stroke risks are particularly high in those with a stenosis of 70 % or more and a recent transient ischemic attack or stroke. Warfarin has been associated with higher major hemorrhage rates and no reduction of recurrent stroke compared to aspirin in patients with symptomatic intracranial stenosis. After early trials showed the feasibility of stenting, two randomized trials compared stenting plus medical management to medical management alone in symptomatic intracranial stenosis. Stenting was linked with increased risk and showed no benefit in any subpopulation of patients. Aggressive medical management in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial was associated with half the risk of stroke compared to that in similar patients in a previous symptomatic intracranial stenosis trial after adjustment of confounding characteristics. Aggressive medical management comprises risk factor control, including a target systolic blood pressure <140 mmHg, a low density lipoprotein <70 mg/dL, hemoglobin A1C <7.0 %, and lifestyle management that incorporates exercise, smoking cessation and weight management, and the use of antithrombotics.

Early arrival at the emergency department is associated with better collaterals, smaller established infarcts and better clinical outcomes with endovascular stroke therapy: SWIFT study.

BACKGROUND AND PURPOSE: Increasing time from symptom onset to emergency department arrival may incur greater ischemic injury and decreased likelihood of good outcomes after acute stroke therapy. The impact of time may be assessed bythe extent of acute CT changes, status of collateral vessels, and clinical outcomes. METHODS: The SOLITAIRE FR With the Intention For Thrombectomy (SWIFT) trial comparing two neurothrombectomy treatments was analyzed by time, Alberta Stroke Program Early CT Scores (ASPECTS), angiographic collaterals, and 90-day modified Rankin Scale outcomes. We determined the interaction of time with ASPECTS, collateral grade, reperfusion, and clinical outcomes, with established determinants of angiographic and clinical outcomes as covariates. RESULTS: 137 patients (52% female) of mean age 67±12 years and median pretreatment NIH Stroke Scale score 18 (range 8-28) were enrolled. Median onset to door (OTD) time was 180 min (IQR 95-250). Presentation within 3 h of last known well was associated with absence of any prestroke disability and presence of atrial fibrillation but was unrelated to age, sex, other vascular risk factors, deficit severity, glucose level, or blood pressure. Worse collaterals were noted with longer OTD intervals: collateral grade 0-1 (n=32): mean 232±84 min; grade 2 (n=48): 164±99 min; grade 3 (n=35): 155±104 min; grade 4 (n=4): 54±16 min (p<0.001). Later presentation was associated with more extensive early infarct imaging changes (median ASPECTS 8 (IQR 7-9) >3 h vs 9 (IQR 8-10) <3 h, p=0.015). Multivariable analyses identified time >3 h as the only predictor of extensive infarct on imaging (ASPECTS ≤7), p=0.003. Earlier presentation was strongly associated with better 90-day modified Rankin Scale outcomes (p<0.001). CONCLUSIONS: Time was a critical factor in successful clinical outcomes for neurothrombectomy in the SWIFT trial. Shorter times to presentation were associated with better collaterals, smaller established infarcts, and better clinical outcome after revascularization.

Epidural Electrical Stimulation for Stroke Rehabilitation: Results of the Prospective, Multicenter, Randomized, Single-Blinded Everest Trial.

BACKGROUND: This prospective, single-blinded, multicenter study assessed the safety and efficacy of electrical epidural motor cortex stimulation (EECS) in improving upper limb motor function of ischemic stroke patients with moderate to moderately severe hemiparesis. METHODS: Patients ≥ 4 months poststroke were randomized 2:1 to an investigational (n = 104) or control (n = 60) group, respectively. Investigational patients were implanted (n = 94) with an epidural 6-contact lead perpendicular to the primary motor cortex and a pulse generator. Both groups underwent 6 weeks of rehabilitation, but EECS was delivered to investigational patients during rehabilitation. The primary efficacy endpoint (PE) was defined as attaining a minimum improvement of 4.5 points in the upper extremity Fugl-Meyer (UEFM) scale as well as 0.21 points in the Arm Motor Ability Test (AMAT) 4 weeks postrehabilitation. Follow-up assessments were performed 1, 4, 12, and 24 weeks postrehabilitation. Safety was evaluated by monitoring adverse events (AEs) that occurred between enrollment and the end of rehabilitation. RESULTS: Primary intent-to-treat analysis showed no group differences at 4 weeks, with PE being met by 32% and 29% of investigational and control patients, respectively (P = .36). Repeated-measures secondary analyses revealed no significant treatment group differences in mean UEFM or AMAT scores. However, post hoc comparisons showed that a greater proportion of investigational (39%) than control (15%) patients maintained or achieved PE (P = .003) at 24 weeks postrehabilitation. Investigational group mean AMAT scores also improved significantly (P < .05) when compared to the control group at 24 weeks postrehabilitation. Post hoc analyses also showed that 69% (n = 9/13) of the investigational patients who elicited movement thresholds during stimulation testing met PE at 4 weeks, and mean UEFM and AMAT scores was also significantly higher (P < .05) in this subgroup at the 4-, 12-, and 24-week assessments when compared to the control group. Headache (19%), pain (13%), swelling (7%), and infection (7%) were the most commonly observed implant procedure-related AEs. Overall, there were 11 serious AEs in 9 investigational group patients (7 procedure related, 4 anesthesia related). CONCLUSIONS: The primary analysis pertaining to efficacy of EECS during upper limb motor rehabilitation in chronic stroke patients was negative at 4 weeks postrehabilitation. A better treatment response was observed in a subset of patients eliciting stimulation induced upper limb movements during motor threshold assessments performed prior to each rehabilitation session. Post hoc comparisons indicated treatment effect differences at 24 weeks, with the control group showing significant decline in the combined primary outcome measure relative to the investigational group. These results have the potential to inform future chronic stroke rehabilitation trial design.

Stroke recurrence rates among patients with symptomatic intracranial vertebrobasilar stenoses: systematic review and meta-analysis.

BACKGROUND: A recent randomized trial of patients with primarily anterior circulation intracranial artery stenosis showed that intensive medical therapy was superior to intracranial stenting in preventing recurrent stroke. The rate of stroke recurrence or death in symptomatic intracranial vertebrobasilar stenosis with medical therapy alone may be especially high, and rates compared with endovascular therapy need further study. METHODS: We conducted a systematic review and meta-analysis of studies reporting the rates of stroke recurrence or death (the primary outcome) in symptomatic intracranial vertebrobasilar stenosis with medical or endovascular treatment over a minimum follow-up period of 6 months. We included all studies in any language indexed in MEDLINE or EMBASE, supplemented by bibliography searches and by contacting the authors. The secondary endpoints were stroke recurrence, and basilar artery and vertebral artery stroke recurrence rates. RESULTS: 23 studies (592 medical treatment patients and 480 endovascular treatment patients) were included. The risk of combined stroke recurrence or death was 14.8 per 100 person-years (95% CI 9.5 to 20.1) in the medical group compared with 8.9 per 100 person-years (95% CI 6.9 to 11.0) in the endovascular group. The incidence rate ratio was 1.3 (95% CI 1.0 to 1.7). The stroke recurrence rate was 9.6 per 100 person-years (95% CI 5.1 to 14.1) in the medical group compared with 7.2 per 100 person-years (95% CI 5.5 to 9.0) in the endovascular group. CONCLUSIONS: Our results showed that the risk of stroke recurrence or death or the risk of stroke recurrence alone was comparable between the medical and endovascular therapy groups. A small preventive effect of endovascular therapy may exist, particularly if the 30 day postprocedural risk is reduced.

Does the Stenting Versus Aggressive Medical Therapy Trial Support Stenting for Subgroups With Intracranial Stenosis?

BACKGROUND AND PURPOSE: Although the Stenting Versus Aggressive Medical Therapy for Intracranial Arterial Stenosis (SAMMPRIS) trial showed that medical therapy alone was superior to stenting plus medical therapy for preventing recurrent strokes in patients with symptomatic intracranial stenosis, we determined whether SAMMPRIS supported the use of stenting in any subpopulations of patients with symptomatic intracranial arterial stenosis. METHODS: The primary outcome, 30-day stroke and death and later strokes in the territory of the qualifying artery, was compared in those with and without baseline factors in the 2 treatment arms, percutaneous transluminal angioplasty and stenting (PTAS) plus aggressive medical therapy versus aggressive medical therapy alone. Baseline factors included sex, age, race, diabetes mellitus, hypertension, lipid disorder, smoking status, type of qualifying event, qualifying event hypoperfusion symptoms, use of antithrombotic or proton pump inhibitor at baseline, days to enrollment, old infarcts in the same territory, percent stenosis, other artery stenosis, and location of the symptomatic artery. RESULTS: A total of 451 patients were enrolled, 227 randomized to aggressive medical therapy and 224 to PTAS. Of all variables evaluated, the observed 2-year event rates were higher with PTAS than with aggressive medical therapy in the vast majority and the interaction with treatment was not statistically significant for any of the factors. CONCLUSIONS: The SAMMPRIS results do not provide evidence to support the use of PTAS using the Wingspan stent system compared with medical treatment in any examined subpopulation of patients with symptomatic intracranial stenosis, including those with qualifying event hypoperfusion symptoms. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00576693.

Long-Term Follow-up to a Randomized Controlled Trial Comparing Peroneal Nerve Functional Electrical Stimulation to an Ankle Foot Orthosis for Patients With Chronic Stroke.

BACKGROUND: Evidence supports peroneal nerve functional electrical stimulation (FES) as an effective alternative to ankle foot orthoses (AFO) for treatment of foot drop poststroke, but few long-term, randomized controlled comparisons exist. OBJECTIVE: Compare changes in gait quality and function between FES and AFOs in individuals with foot drop poststroke over a 12-month period. METHODS: Follow-up analysis of an unblinded randomized controlled trial (ClinicalTrials.gov #NCT01087957) conducted at 30 rehabilitation centers comparing FES to AFOs over 6 months. Subjects continued to wear their randomized device for another 6 months to final 12-month assessments. Subjects used study devices for all home and community ambulation. Multiply imputed intention-to-treat analyses were utilized; primary endpoints were tested for noninferiority and secondary endpoints for superiority. Primary endpoints: 10 Meter Walk Test (10MWT) and device-related serious adverse event rate. Secondary endpoints: 6-Minute Walk Test (6MWT), GaitRite Functional Ambulation Profile, and Modified Emory Functional Ambulation Profile (mEFAP). RESULTS: A total of 495 subjects were randomized, and 384 completed the 12-month follow-up. FES proved noninferior to AFOs for all primary endpoints. Both FES and AFO groups showed statistically and clinically significant improvement for 10MWT compared with initial measurement. No statistically significant between-group differences were found for primary or secondary endpoints. The FES group demonstrated statistically significant improvements for 6MWT and mEFAP Stair-time subscore. CONCLUSIONS: At 12 months, both FES and AFOs continue to demonstrate equivalent gains in gait speed. Results suggest that long-term FES use may lead to additional improvements in walking endurance and functional ambulation; further research is needed to confirm these findings.

Outcome in patients previously on antithrombotic therapy in the SAMMPRIS trial: subgroup analysis.

BACKGROUND AND PURPOSE: Stenting has been used as a rescue therapy in patients with intracranial arterial stenosis and a transient ischemic attack or stroke when on antithrombotic therapy (AT). We determined whether the stenting versus aggressive medical therapy for intracranial arterial stenosis (SAMMPRIS) trial supported this approach by comparing the treatments within subgroups of patients whose qualifying event (QE) occurred on versus off of AT. METHODS: The primary outcome, 30-day stroke and death and later strokes in the territory of the qualifying artery, was compared between (1) percutaneous transluminal angioplasty and stenting plus aggressive medical therapy (PTAS) versus aggressive medical management therapy alone (AMM) for patients whose QE occurred on versus off AT and between (2) patients whose QE occurred on versus off AT separately for the treatment groups. RESULTS: Among the 284/451 (63%) patients who had their QE on AT, the 2-year primary end point rates were 15.6% for those randomized to AMM (n=140) and 21.6% for PTAS (n=144; P=0.043, log-rank test). In the 167 patients not on AT, the 2-year primary end point rates were 11.6% for AMM (n=87) and 18.8% for PTAS (n=80; P=0.31, log-rank test). Within both treatment groups, there was no difference in the time to the primary end point between patients who were on or off AT (AMM, P=0.96; PTAS, P=0.52; log-rank test). CONCLUSIONS: SAMMPRIS results indicate that the benefit of AMM over PTAS is similar in patients on versus off AT at the QE and that failure of AT is not a predictor of increased risk of a primary end point. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00576693.

Predictors of functional dependence despite successful revascularization in large-vessel occlusion strokes.

BACKGROUND AND PURPOSE: High revascularization rates in large-vessel occlusion strokes treated by mechanical thrombectomy are not always associated with good clinical outcomes. We evaluated predictors of functional dependence despite successful revascularization among patients with acute ischemic stroke treated with thrombectomy. METHODS: We analyzed the pooled data from the Multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI), Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke (TREVO), and TREVO 2 trials. Successful revascularization was defined as thrombolysis in cerebral infarction score 2b or 3. Functional dependence was defined as a score of 3 to 6 on the modified Rankin Scale at 3 months. We assessed relationship of demographic, clinical, angiographic characteristics, and hemorrhage with functional dependence despite successful revascularization. RESULTS: Two hundred and twenty-eight patients with successful revascularization had clinical outcome follow-up. The rates of functional dependence with endovascular success were 48.6% for Trevo thrombectomy and 58.0% for Merci thrombectomy. Age (odds ratio, 1.04; 95% confidence interval, 1.02-1.06 per 1-year increase), National Institutes of Health Stroke Scale score (odds ratio, 1.08; 95% confidence interval, 1.02-1.15 per 1-point increase), and symptom onset to endovascular treatment time (odds ratio, 1.11; 95% confidence interval, 1.01-1.22 per 30-minute delay) were predictors of functional dependence despite successful revascularization. Symptom onset to reperfusion time beyond 5 hours was associated with functional dependence. All subjects with symptomatic intracranial hemorrhage had functional dependence. CONCLUSIONS: One half of patients with successful mechanical thrombectomy do not have good outcomes. Age, severe neurological deficits, and delayed endovascular treatment were associated with functional dependence despite successful revascularization. Our data support efforts to minimize delays to endovascular therapy in patients with acute ischemic stroke to improve outcomes. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00318071, NCT01088672, and NCT01270867.

The effects of peroneal nerve functional electrical stimulation versus ankle-foot orthosis in patients with chronic stroke: a randomized controlled trial.

BACKGROUND: Evidence supports peroneal nerve functional electrical stimulation (FES) as an effective alternative to ankle-foot orthoses (AFO) for treatment of foot drop poststroke, but few randomized controlled comparisons exist. OBJECTIVE: To compare changes in gait and quality of life (QoL) between FES and an AFO in individuals with foot drop poststroke. METHODS: In a multicenter randomized controlled trial (ClinicalTrials.gov #NCT01087957) with unblinded outcome assessments, 495 Medicare-eligible individuals at least 6 months poststroke wore FES or an AFO for 6 months. Primary endpoints: 10-Meter Walk Test (10MWT), a composite of the Mobility, Activities of Daily Living/Instrumental Activities of Daily Living, and Social Participation subscores on the Stroke Impact Scale (SIS), and device-related serious adverse event rate. Secondary endpoints: 6-Minute Walk Test, GaitRite Functional Ambulation Profile (FAP), Modified Emory Functional Ambulation Profile (mEFAP), Berg Balance Scale (BBS), Timed Up and Go, individual SIS domains, and Stroke-Specific Quality of Life measures. Multiply imputed intention-to-treat analyses were used with primary endpoints tested for noninferiority and secondary endpoints tested for superiority. RESULTS: A total of 399 subjects completed the study. FES proved noninferior to the AFO for all primary endpoints. Both the FES and AFO groups improved significantly on the 10MWT. Within the FES group, significant improvements were found for SIS composite score, total mFEAP score, individual Floor and Obstacle course time scores of the mEFAP, FAP, and BBS, but again, no between-group differences were found. CONCLUSIONS: Use of FES is equivalent to the AFO. Further studies should examine whether FES enables better performance in tasks involving functional mobility, activities of daily living, and balance.

Serial Alberta Stroke Program early CT score from baseline to 24 hours in Solitaire Flow Restoration with the Intention for Thrombectomy study: a novel surrogate end point for revascularization in acute stroke.

BACKGROUND AND PURPOSE: The Alberta Stroke Program Early CT Score (ASPECTS) on baseline imaging is an established predictor of acute ischemic stroke outcomes. We analyzed change on serial ASPECTS at baseline and 24-hour imaging in the Solitaire Flow Restoration with the Intention for Thrombectomy (SWIFT) study to determine prognostic value and to identify subgroups with extensive injury after intervention. METHODS: ASPECTS at baseline and 24 hours was independently scored in all anterior circulation SWIFT cases, blinded to all other trial data. ASPECTS at baseline, at 24 hours, and serial changes were analyzed with univariate and multivariate approaches. RESULTS: One hundred thirty-nine patients (mean age, 67 [SD, 12] years; 52% women; median National Institutes of Health Stroke Scale, 18 [interquartile range, 8-28]) with complete data at both time points were studied. Multivariate analyses showed that higher 24-hour ASPECTS predicted good clinical outcome (day 90 modified Rankin Scale, 0-2; odds ratio, 1.67; P<0.001). Among patients with high baseline ASPECTS (8-10; n=109), dramatic infarct progression (decrease in ASPECTS ≥6 points at 24 hours) was noted in 31 of 109 (28%). Such serial ASPECTS change was predicted by higher baseline systolic blood pressure (P=0.019), higher baseline blood glucose (P=0.133), and failure to achieve Thrombolysis in Cerebral Infarction score of 2b/3 reperfusion (P<0.001), culminating in worse day 90 modified Rankin Scale outcomes (mean modified Rankin Scale, 4.4 versus 2.7; P<0.001). CONCLUSIONS: Twenty-four-hour ASPECTS provides better prognostic information compared with baseline ASPECTS. Predictors of dramatic infarct progression on ASPECTS are hyperglycemia, hypertension, and nonreperfusion. Serial ASPECTS change from baseline to 24 hours predicts clinical outcome, providing an early surrogate end point for thrombectomy trials. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01054560.