Statin Overuse in Cerebral Ischemia Without Indications: Systematic Review and Annual US Burden of Adverse Events.

BACKGROUND: Statin agents play a major role in secondary prevention after acute cerebral ischemia (ACI) events but are not indicated in all patients with ischemic stroke and transient ischemic attack. National guidelines recommend statins for patients with ACI of large or small vessel atherosclerotic origin and without these stroke mechanisms but coexisting coronary artery disease or primary prevention indications. The potential adverse effect burden of statin overuse in the remaining ACI patients have not been well delineated. METHODS: Per Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines, we performed systematic meta-analyses of: (1) statin randomized clinical trials to determine absolute risk increases for 6 major adverse events; (2) large clinical series to determine the proportion of ACI events due to large or small vessel atherosclerotic disease; and (3) the proportion of remaining patients with coronary artery disease/primary prevention statin indications. RESULTS: For adverse effects, data were available from 63 randomized clinical trials enrolling 155 107 patients. Statin therapy was associated with an increased risk of the occurrence of 6 conditions: diabetes, myalgia or muscle weakness, myopathy, liver disease, renal insufficiency, and eye disease. Across 55 large series enrolling 53 501 patients, the rate of ACI due to large and small artery atherosclerosis was 45.0% (large artery atherosclerosis 21.6%, small vessel disease 23.4%), the rate of remaining patients with coronary artery disease/primary prevention statin indications was 31.8%, and the rate of patients without statin indications was 23.2%. Data synthesis indicated that, in the United States, were all patients with ACI without statin indications treated with statins, a total of 5601 patients would develop needless adverse events each year, most commonly diabetes, myopathy, and eye disease. CONCLUSIONS: More than one-fifth of patients with ACI do not have an indication for statins, and statin overuse in these patients could annually lead to over 5600 adverse events each year in the United States, including diabetes, myopathy, and eye disease. These findings emphasize the importance of adhering to guideline indications for the start of statin therapy in ACI.

Baseline Stroke Risk and Efficacy of Dual-Antiplatelet Therapy: A Post Hoc Analysis of the POINT Trial.

BACKGROUND: High-risk transient ischemic attacks and minor ischemic strokes are followed by a variable risk of ischemic stroke. We aimed to determine how baseline stroke risk modified the efficacy of clopidogrel-aspirin (referred to here as dual-antiplatelet therapy [DAPT]) for transient ischemic attack and minor ischemic stroke. METHODS: We performed an unplanned secondary analysis of the POINT trial (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke). We first evaluated the associations of the CHA2DS2-VASc and stroke prognosis instrument II (SPI-II) scores with the risk of incident ischemic stroke and major hemorrhage (intracranial hemorrhage or major systemic hemorrhage). We then tested for heterogeneity of the relative and absolute treatment effect of DAPT relative to aspirin across low- and high-risk patient subgroups. RESULTS: A total of 4841 trial participants were included in this analysis, with 2400 participants assigned to treatment with short-term DAPT and 2430 participants to treatment with aspirin and placebo. The dichotomized SPI-II score, but not the CHA2DS2-VASc score (P=0.18), was associated with the risk of incident ischemic stroke. A high-risk SPI-II score (>3) was associated with greater risk of incident ischemic stroke (hazard ratio of incident ischemic stroke relative to low-risk SPI-II score of 1.84 [95% CI, 1.44-2.35]; P<0.001) and numerically greater risk of major hemorrhage though not meeting statistical significance (hazard ratio, 1.80 [95% CI, 0.90-3.57]; P=0.10). The relative risk reduction with DAPT was similar across SPI-II strata (Pinteraction=0.31). The absolute risk reduction for ischemic stroke with DAPT compared with aspirin was nearly 4-fold higher (2.80% versus 0.76%; number needed to treat, 31 versus 131) in the high-risk SPI-II stratum relative to the low-risk stratum. The absolute risk increase for major hemorrhage with DAPT compared with aspirin was 3-fold higher (0.84% versus 0.30%; number needed to harm, 119 versus 331) in the high-risk SPI-II stratum relative to the low-risk stratum. CONCLUSIONS: Stratification by baseline stroke risk identifies a patient subgroup that derives greater absolute benefit from treatment with DAPT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00991029.

Subtype-Specific Association of Mitochondrial DNA Copy Number With Poststroke/TIA Outcomes in 10†241 Patients in China.

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) is associated with the severity and mortality in patients with stroke, but the associations in different stroke subtypes remain unexplored. METHODS: We conducted an observational prospective cohort analysis on patients with ischemic stroke or transient ischemic attack enrolled in the Third China National Stroke Registry. We applied logistic models to assess the association of mtDNA-CN with functional outcome (modified Rankin Scale score, 3-6 versus 0-2) and Cox proportional hazard models to assess the association with stroke recurrence (treating mortality as a competing risk) and mortality during a 12-month follow-up, adjusting for sex, age, physical activity, National Institutes of Health Stroke Scale at admission, history of stroke and peripheral artery disease, small artery occlusion, and interleukin-6. Subgroup analyses stratified by age and stroke subtypes were conducted. RESULTS: The Third China National Stroke Registry enrolled 15 166 patients, of which 10 241 with whole-genome sequencing data were retained (mean age, 62.2 [SD, 11.2] years; 68.8% men). The associations between mtDNA-CN and poststroke/transient ischemic attack outcomes were specific to patients aged ≤65 years, with lower mtDNA-CN significantly associated with stroke recurrence in 12 months (subdistribution hazard ratio, 1.15 per SD lower mtDNA-CN [95% CI, 1.04-1.27]; P=5.2×10-3) and higher all-cause mortality in 3 months (hazard ratio, 2.19 [95% CI, 1.41-3.39]; P=5.0×10-4). Across subtypes, the associations of mtDNA-CN with stroke recurrence were specific to stroke of undetermined cause (subdistribution hazard ratio, 1.28 [95% CI, 1.11-1.48]; P=6.6×10-4). In particular, lower mtDNA-CN was associated with poorer functional outcomes in stroke of undetermined cause patients diagnosed with embolic stroke of undetermined source (odds ratio, 1.53 [95% CI, 1.20-1.94]; P=5.4×10-4), which remained significant after excluding patients with recurrent stroke (odds ratio, 1.49 [95% CI, 1.14-1.94]; P=3.0×10-3). CONCLUSIONS: Lower mtDNA-CN is associated with higher stroke recurrence rate and all-cause mortality, as well as poorer functional outcome at follow-up, among stroke of undetermined cause, embolic stroke of undetermined source, and younger patients.

Redefining Disability: Patient-Reported Outcome Measures After Minor Stroke and Transient Ischemic Attack.

BACKGROUND: Long-term outcome assessment patients with stroke is not fully captured by usual clinical scales such as the modified Rankin Scale (mRS). Patient-reported outcome measures (PROMs) are standardized and validated assessments that consider clinical outcomes from the patient perspective. We aim to analyze the added value of PROMs in patients with transient ischemic attack and minor stroke. METHODS: We included consecutive patients with minor stroke or transient ischemic attack (National Institutes of Health Stroke Scale score 0-5) from April 2020 to October 2021 that participated in the PROMs-through-App program (NORA, NoraHealth Barcelona Spain). Clinician and self-evaluated outcomes were assessed at 90 days: clinician-evaluated mRS, self-reported mRS, the 10-item patient-reported outcome measures questionnaire global health survey (v1.2), Hospital Anxiety and Depression Scale, and the Fatigue Assessment Scale. We evaluated the acceptability (response rate), reliability (internal consistency), and construct validity (correlation with mRS and between scales) of each questionnaire. RESULTS: We included 355 patients in the analysis, response rate was patient-reported outcome measures questionnaire 71.3% (253), Hospital Anxiety and Depression Scale 70.7% (251), Fatigue Assessment Scale 71.8% (255), and self-assessed mRS 66.8% (237). PROMS internal consistency was good or excellent, while agreement between clinician and self-reported mRS was fair (k=0.34). Rate of abnormal PROMS scores were as follows (all responders versus clinician-reported mRS score 0-2): patient-reported outcome measures questionnaire mental health (43.1% versus 36.3%), physical health (48.6% versus 43.6%); Hospital Anxiety and Depression Scale-anxiety (21.9% versus 17.7%) and depression (17.1% versus 13.3%); and Fatigue Assessment Scale (40.8% versus 36.4%). PROMs scores correlated with clinician and self-reported mRS at 90 days. CONCLUSIONS: Evaluation of PROMs using a mobile-app-based communication system is a reliable and valid strategy to assess the outcome of patients from their perspective after a mild stroke or transient ischemic attack.

The CASSISS Randomized Clinical Trial.

The CASSISS trial (China Angioplasty & Stenting for Symptomatic Intracranial Severe Stenosis), recently published in JAMA, is the most recent of several randomized controlled trials that have failed to show a benefit of percutaneous angioplasty and stenting over medical therapy for the prevention of stroke due to intracranial atherosclerotic stenosis. Current practice guidelines recommended that percutaneous angioplasty and stenting should not be performed routinely as a treatment for stroke prevention in patients with intracranial atherosclerotic stenosis. The CASSISS trial reinforces those recommendations and will not change practice, but it may provide some important lessons for future trial design.

Stroke Learning Health Systems: A Topical Narrative Review With Case Examples.

To our knowledge, the adoption of Learning Health System (LHS) concepts or approaches for improving stroke care, patient outcomes, and value have not previously been summarized. This topical review provides a summary of the published evidence about LHSs applied to stroke, and case examples applied to different aspects of stroke care from high and low-to-middle income countries. Our attempt to systematically identify the relevant literature and obtain real-world examples demonstrated the dissemination gaps, the lack of learning and action for many of the related LHS concepts across the continuum of care but also elucidated the opportunity for continued dialogue on how to study and scale LHS advances. In the field of stroke, we found only a few published examples of LHSs and health systems globally implementing some selected LHS concepts, but the term is not common. A major barrier to identifying relevant LHS examples in stroke may be the lack of an agreed taxonomy or terminology for classification. We acknowledge that health service delivery settings that leverage many of the LHS concepts do so operationally and the lessons learned are not shared in peer-reviewed literature. It is likely that this topical review will further stimulate the stroke community to disseminate related activities and use keywords such as learning health system so that the evidence base can be more readily identified.

Prospective Validation of Computed Tomography to Identify Patients at High Risk for Stroke After Transient Ischemic Attack or Minor Stroke.

BACKGROUND: Computed tomography (CT) findings of acute and chronic ischemia are associated with subsequent stroke risk in patients with transient ischemic attack. We sought to validate these associations in a large prospective cohort of patients with transient ischemic attack or minor stroke. METHODS: This prospective cohort study enrolled emergency department patients from 13 hospitals with transient ischemic attack who had CT imaging. Primary outcome was stroke within 90 days. Secondary outcomes were stroke within 2 or 7 days. CT findings were abstracted from radiology reports and classified for the presence of acute ischemia, chronic ischemia, or microangiopathy. Multivariable logistic regression was used to test associations with primary and secondary end points. RESULTS: From 8670 prospectively enrolled patients between May 2010 and May 2017, 8382 had a CT within 24 hours. From this total population, 4547 (54%) patients had evidence of acute ischemia, chronic ischemia, or microangiopathy on CT, of whom 175 had a subsequent stroke within 90 days (3.8% subsequent stroke rate; adjusted odds ratio [aOR], 2.33 [95% CI, 1.62-3.36]). This was in comparison to those with CT imaging without ischemia. Findings associated with an increased risk of stroke at 90 days were isolated acute ischemia (6.0%; aOR, 2.42 [95% CI, 1.03-5.66]), acute ischemia with microangiopathy (10.7%; aOR, 3.34 [95% CI, 1.57-7.14]), chronic ischemia with microangiopathy (5.2%; aOR, 1.83 [95% CI, 1.34-2.50]), and acute ischemia with chronic ischemia and microangiopathy (10.9%; aOR, 3.49 [95% CI, 1.54-7.91]). Acute ischemia with chronic ischemia and microangiopathy were most strongly associated with subsequent stroke within 2 days (aOR, 4.36 [95% CI, 1.31-14.54]) and 7 days (aOR, 4.50 [95% CI, 1.73-11.69]). CONCLUSIONS: In patients with transient ischemic attack or minor stroke, CT evidence of acute ischemia with chronic ischemia or microangiopathy significantly increases the risk of subsequent stroke within 90 days of index visit. The combination of all 3 findings results in the greatest early risk.

Association Between CYP2B6 Polymorphisms and Efficacy of Clopidogrel in Minor Stroke or Transient Ischemic Attack.

BACKGROUND: CYP2B6 (cytochrome P450 subfamily IIB polypeptide 6), encoded by the CYP2B6 gene, is a critical enzyme involved in clopidogrel metabolism. However, the association between CYP2B6 polymorphisms and the efficacy of clopidogrel in minor stroke or transient ischemic attack for secondary stroke prevention remains unclear. METHODS: Based on CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) randomized clinical trial of aspirin plus clopidogrel versus aspirin alone, we investigated the role of CYP2B6 polymorphisms and the efficacy of clopidogrel in patients with minor stroke or transient ischemic attack in China from October 2009 to July 2012. A total of 2853 patients were successfully genotyped for CYP2B6-516G>T, rs3745274 and CYP2B6-1456 T>C, rs2054675. The primary efficacy and safety outcomes were new stroke and any bleeding within 90 days. RESULTS: Among the 2853 patients, 32.8% were identified as the carriers of the CYP2B6-516 GT/TT or -1456 TC/CC genotype. The incidences of 90-day new stroke in aspirin plus clopidogrel and aspirin alone groups were 7.1% versus 11.3% among noncarriers, respectively; and 9.7% versus 12.2% among carriers, respectively. The efficacy of aspirin plus clopidogrel versus aspirin alone was not significantly different (P interaction=0.29) in noncarriers (adjusted hazard ratio, 0.61 [95% CI, 0.45-0.83]) compared to carriers (adjusted hazard ratio, 0.80 [95% CI, 0.54-1.18]). The incidence (n=51) of 90-day any bleeding in aspirin plus clopidogrel and aspirin alone groups were 2.2% (21 bleeds) versus 1.9% (18 bleeds) among noncarriers (adjusted hazard ratio, 1.11 [95% CI, 0.59-2.09]) and 1.9% (9 bleeds) versus 0.7% (3 bleeds) among carriers (adjusted hazard ratio, 3.23 [95% CI, 0.86-12.12]). Similar findings were observed during the 1-year follow-up. CONCLUSIONS: In this post hoc analysis of the CHANCE trial, we did not observe a significant difference in the efficacy of aspirin plus clopidogrel compared with aspirin in carriers versus noncarriers of CYP2B6-516 GT/TT or -1456 TC/CC genotype. Our results suggest that both carriers and noncarriers suffering from a minor stroke are likely to benefit from aspirin plus clopidogrel treatment over aspirin monotherapy for secondary prevention. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00979589.

Diagnosis, Workup, Risk Reduction of Transient Ischemic Attack in the Emergency Department Setting: A Scientific Statement From the American Heart Association.

At least 240 000 individuals experience a transient ischemic attack each year in the United States. Transient ischemic attack is a strong predictor of subsequent stroke. The 90-day stroke risk after transient ischemic attack can be as high as 17.8%, with almost half occurring within 2 days of the index event. Diagnosing transient ischemic attack can also be challenging given the transitory nature of symptoms, often reassuring neurological examination at the time of evaluation, and lack of confirmatory testing. Limited resources, such as imaging availability and access to specialists, can further exacerbate this challenge. This scientific statement focuses on the correct clinical diagnosis, risk assessment, and management decisions of patients with suspected transient ischemic attack. Identification of high-risk patients can be achieved through use of comprehensive protocols incorporating acute phase imaging of both the brain and cerebral vasculature, thoughtful use of risk stratification scales, and ancillary testing with the ultimate goal of determining who can be safely discharged home from the emergency department versus admitted to the hospital. We discuss various methods for rapid yet comprehensive evaluations, keeping resource-limited sites in mind. In addition, we discuss strategies for secondary prevention of future cerebrovascular events using maximal medical therapy and patient education.

Efficacy and Safety of Using Dual Versus Monotherapy Antiplatelet Agents in Secondary Stroke Prevention: Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.

BACKGROUND: Dual antiplatelet treatment (DAPT) with aspirin plus clopidogrel for a limited time is recommended after minor noncardioembolic stroke. METHODS: We performed a meta-analysis of all major studies that compared the efficacy and safety of DAPT versus monotherapy for the secondary prevention of recurrent stroke or transient ischemic attack. The primary outcomes were stroke and the composite of stroke, transient ischemic attack, acute coronary syndrome, and death from any cause. The safety outcome was major hemorrhage. Relative risk (RR) and 95% CIs were calculated. Heterogeneity was assessed by I2 and Cochrane Q statistics. RESULTS: The analysis included 27 358 patients, the quality of evidence was moderate to low, and the heterogeneity for all the comparisons was low (I2≤25%). Compared with monotherapy, DAPT reduced the risk of recurrent stroke (RR, 0.71 [95% CI, 0.63-0.81]) and composite outcome (RR, 0.76 [95% CI, 0.69-0.83]) but increased the risk of major bleeding (RR, 2.17 [95% CI, 1.45-3.25]). In the subgroup analysis, ≤30 days of DAPT increased the risk of hemorrhage relative to monotherapy (RR, 1.94 [95% CI, 1.08-3.52]). In the sensitivity analysis, the risk for hemorrhage with ≤30 days of DAPT after excluding the combination of aspirin plus ticagrelor was comparable to monotherapy (RR, 1.42 [95% CI, 0.77-2.60]). However, the risk for stroke recurrence and composite outcomes in the subgroup and sensitivity analyses remain decreased compared with monotherapy. CONCLUSIONS: DAPT decreases the risk of recurrent stroke and composite events compared with monotherapy. DAPT increases the risk of major hemorrhage, except if the treatment is limited to 30 days and does not include the combination of aspirin plus ticagrelor.

Long-Term Secondary Prevention: Management of Blood Pressure After a Transient Ischemic Attack or Stroke.

Reducing blood pressure (BP) is a highly effective strategy for long-term stroke prevention. Despite overwhelmingly clear evidence from randomized trials that antihypertensive therapy substantially reduces the risk of stroke in primary prevention, uncertainty still surrounds the issue of BP lowering after cerebrovascular events, and the risk of recurrent stroke, coronary events, and vascular death remains significant. Important questions in a secondary prevention setting include should everyone be treated regardless of their poststroke BP, how soon after a stroke should BP-lowering treatment be commenced, how intensively should BP be lowered, what drugs are best, and how should long-term BP control be optimized and monitored. We review the evidence on BP control after a transient ischemic attack or stroke to address these unanswered questions and draw attention to some recent developments that hold promise to improve management of BP in current practice.

Atrial Fibrillation Detected After Stroke and Transient Ischemic Attack: A Novel Clinical Concept Challenging Current Views.

Atrial fibrillation (AF) can be newly detected in approximately one-fourth of patients with ischemic stroke and transient ischemic attack without previously recognized AF. We present updated evidence supporting that AF detected after stroke or transient ischemic attack (AFDAS) may be a distinct clinical entity from AF known before stroke occurrence (known atrial fibrillation). Data suggest that AFDAS can arise from the interplay of cardiogenic and neurogenic forces. The embolic risk of AFDAS can be understood as a gradient defined by the prevalence of vascular comorbidities, the burden of AF, neurogenic autonomic changes, and the severity of atrial cardiopathy. The balance of existing data indicates that AFDAS has a lower prevalence of cardiovascular comorbidities, a lower degree of cardiac abnormalities than known atrial fibrillation, a high proportion (52%) of very brief (<30 seconds) AF paroxysms, and is more frequently associated with insular brain infarction. These distinctive features of AFDAS may explain its recently observed lower associated risk of stroke than known atrial fibrillation. We present an updated ad-hoc meta-analysis of randomized clinical trials in which the association between prolonged cardiac monitoring and reduced risk of ischemic stroke was nonsignificant (incidence rate ratio, 0.90 [95% CI, 0.71-1.15]). These findings highlight that larger and sufficiently powered randomized controlled trials of prolonged cardiac monitoring assessing the risk of stroke recurrence are needed. Meanwhile, we call for further research on AFDAS and stroke recurrence, and a tailored approach when using prolonged cardiac monitoring after ischemic stroke or transient ischemic attack, focusing on patients at higher risk of AFDAS and, more importantly, at higher risk of cardiac embolism.

Treatment-Relevant Findings in Transesophageal Echocardiography After Stroke: A Prospective Multicenter Cohort Study.

BACKGROUND AND PURPOSE: Cardiac ultrasound to identify sources of cardioembolism is part of the diagnostic workup of acute ischemic stroke. Recommendations on whether transesophageal echocardiography (TEE) should be performed in addition to transthoracic echocardiography (TTE) are controversial. We aimed to determine the incremental diagnostic yield of TEE in addition to TTE in patients with acute ischemic stroke with undetermined cause. METHODS: In a prospective, observational, pragmatic multicenter cohort study, patients with acute ischemic stroke or transient ischemic attack with undetermined cause before cardiac ultrasound were studied by TTE and TEE. The primary outcome was the rate of treatment-relevant findings in TTE and TEE as defined by a panel of experts based on current evidence. Further outcomes included the rate of changes in the assessment of stroke cause after TEE. RESULTS: Between July 1, 2017, and June 30, 2019, we enrolled 494 patients, of whom 492 (99.6%) received TTE and 454 (91.9%) received TEE. Mean age was 64.7 years, and 204 (41.3%) were women. TEE showed a higher rate of treatment-relevant findings than TTE (86 [18.9%] versus 64 [14.1%], P<0.001). TEE in addition to TTE resulted in 29 (6.4%) additional patients with treatment-relevant findings. Among 191 patients ≤60 years additional treatment-relevant findings by TEE were observed in 27 (14.1%) patients. Classification of stroke cause changed after TEE in 52 of 453 patients (11.5%), resulting in a significant difference in the distribution of stroke cause before and after TEE (P<0.001). CONCLUSIONS: In patients with undetermined cause of stroke, TEE yielded a higher number of treatment-relevant findings than TTE. TEE appears especially useful in younger patients with stroke, with treatment-relevant findings in one out of seven patients ≤60 years. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03411642.

SLEAP SMART (Sleep Apnea Screening Using Mobile Ambulatory Recorders After TIA/Stroke): A Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Poststroke/transient ischemic attack obstructive sleep apnea (OSA) is prevalent, linked with numerous unfavorable health consequences, but remains underdiagnosed. Reasons include patient inconvenience and costs associated with use of in-laboratory polysomnography (iPSG), the current standard tool. Fortunately, home sleep apnea testing (HSAT) can accurately diagnose OSA and is potentially more convenient and cost-effective compared with iPSG. Our objective was to assess whether screening for OSA in patients with stroke/transient ischemic attack using HSAT, compared with standard of care using iPSG, increased diagnosis and treatment of OSA, improved clinical outcomes and patient experiences with sleep testing, and was a cost-effective approach. METHODS: We consecutively recruited 250 patients who had sustained a stroke/transient ischemic attack within the past 6 months. Patients were randomized (1:1) to use of (1) HSAT versus (2) iPSG. Patients completed assessments and questionnaires at baseline and 6-month follow-up appointments. Patients diagnosed with OSA were offered continuous positive airway pressure. The primary outcome was compared between study arms via an intention-to-treat analysis. RESULTS: At 6 months, 94 patients completed HSAT and 71 patients completed iPSG. A significantly greater proportion of patients in the HSAT arm were diagnosed with OSA (48.8% versus 35.2%, P=0.04) compared with the iPSG arm. Furthermore, patients assigned to HSAT, compared with iPSG, were more likely to be prescribed continuous positive airway pressure (40.0% versus 27.2%), report significantly reduced sleepiness, and a greater ability to perform daily activities. Moreover, a significantly greater proportion of patients reported a positive experience with sleep testing in the HSAT arm compared with the iPSG arm (89.4% versus 31.1%). Finally, a cost-effectiveness analysis revealed that HSAT was economically attractive for the detection of OSA compared with iPSG. CONCLUSIONS: In patients with stroke/transient ischemic attack, use of HSAT compared with iPSG increases the rate of OSA diagnosis and treatment, reduces daytime sleepiness, improves functional outcomes and experiences with sleep testing, and could be an economically attractive approach. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02454023.

Patient-Centered Outcomes in a Randomized Trial Investigating a Multimodal Prevention Program After Transient Ischemic Attack or Minor Stroke: The INSPiRE-TMS Trial.

BACKGROUND: The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes. METHODS: In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up. RESULTS: Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5-43.5); 36.1 after 2 years (95% CI, 13.1-59.7) and 29.6 (95% CI, 2.0-57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03-1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96-1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95-1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up. CONCLUSIONS: Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01586702.

Cerebrovascular Ischemic Events in Patients With Takayasu Arteritis.

BACKGROUND: Takayasu arteritis (TA) is a large vessel vasculitis that may complicate with cerebrovascular ischemic events. The objective was to describe clinical and vascular features of TA patients with cerebrovascular ischemic events and to identify risk factors for these events. METHODS: We analyzed the prevalence and type of stroke/transient ischemic attack (TIA), factors associated with cerebrovascular ischemic events, and stroke-free survival in a large cohort fulfilling the American College of Rheumatology or Ishikawa criteria of TA. RESULTS: Among 320 patients with TA (median age at diagnosis, 36 [25-47] years; 261 [86%] women), 63 (20%) had a stroke (n=41; 65%) or TIA (n=22; 35%). Ischemic event localized in the carotid territory for 55 (87%) patients and the vertebral artery territory in 8 (13%) patients. Multiple stenosis were observed in 33 (52%) patients with a median number of stenosis of 2 (minimum, 0 to maximum, 11), and aneurysms were observed in 10 (16%) patients. A history of stroke or TIA before TA diagnosis (hazard ratio [HR], 4.50 [2.45-8.17]; P<0.0001), smoking (HR, 1.75 [1.01-3.02]; P=0.05), myocardial infarction history (HR, 0.21 [0.05-0.89]; P=0.039), thoracic aorta involvement (HR, 2.05 [1.30-3.75]; P=0.023), time from first symptoms to diagnosis >1 year (HR, 2.22 [1.30-3.80]; P=0.005), and aspirin treatment (HR, 1.82 [1.04-3.19]; P=0.035) were associated with cerebrovascular ischemic event. In multivariate analysis, time from first symptoms to TA diagnosis >1 year (HR, 2.16 [1.27-3.70]; P=0.007) was independently associated with cerebrovascular ischemic events in patients with TA. The HR for cerebrovascular ischemic event in patients who already experienced a stroke/TIA was 5.11 (2.91-8.99; P<0.0001), compared with those who had not. CONCLUSIONS: Carotid stroke/TIA is frequent in TA. We identified factors associated with cerebrovascular ischemic events.

Impact of Shunting Practice Patterns During Carotid Endarterectomy for Symptomatic Carotid Stenosis.

BACKGROUND: We aimed to assess the effect of surgeons' shunting practice and shunt use on the early outcomes of carotid endarterectomy (CEA) in recently symptomatic patients. METHODS: We conducted a retrospective observational study based on a multicenter national prospective database. The Vascular Quality Initiative database (2010-2019) was queried for CEAs performed within 14 days after an ipsilateral stroke or transient ischemic attack. Surgeons were gauged as routine shunters if they shunted in >95% of CEAs, otherwise were classified as selective shunters. In-hospital stroke and death rates were compared between routine and selective shunters, stratifying by type of index event (transient ischemic attack versus stroke) and timing of CEA (≤2 versus >2 days). RESULTS: Thirteen thousand four hundred sixty-nine CEAs were performed after a transient ischemic attack (43%) or stroke (57%), 3186 (24%) by routine shunters, and 10 283 (76%) by selective shunters. Comparing routine and selective shunters, in-hospital stroke (1.9% versus 2.4%; P=0.09) and death (0.4% versus 0.5%; P=0.73) rates were similar. A lower stroke rate (1.5% versus 4.2%; P=0.02) was achieved by routine shunters for CEA performed <2 days after an ischemic stroke. Among selective shunters, a higher stroke rate occurred in case of shunt use (2.9% versus 2.3%; P<0.01), mainly due to cases presenting with stroke (3.5% versus 2.4%; P<0.01) but not transient ischemic attack (1.8% versus 1.5%; P=0.57). Awake anesthesia was adopted in 7.8% of cases by selective shunters and in 0.8% by routine shunters, without impact on the perioperative stroke rate (1.8% versus 2.3%; P=0.349). CONCLUSIONS: In this large national cohort, the overall outcomes of CEA were similar between routine and selective shunters. A lower postoperative stroke rate was achieved by routine shunters in CEA performed <2 days after an ischemic stroke. Among selective shunters, intraoperatively indicated shunting determined an increased stroke rate, likely due to intraoperative hypoperfusion. These data may guide the decision regarding timing of CEA and shunting intention in symptomatic patients.

Frequency and Prognostic Significance of Clinical Fluctuations Before Hospital Arrival in Stroke.

BACKGROUND AND PURPOSE: Clinical fluctuations in ischemic stroke symptoms are common, but fluctuations before hospital arrival have not been previously characterized. METHODS: A standardized qualitative assessment of fluctuations before hospital arrival was obtained in an observational study that enrolled patients with mild ischemic stroke symptoms (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) present on arrival to hospital within 4.5 hours of onset, in a subset of 100 hospitals participating in the Get With The Guidelines-Stroke quality improvement program. The number of fluctuations, direction, and the overall improvement or worsening was recorded based on reports from the patient, family, or paramedics. Baseline NIHSS on arrival and at 72 hours (or discharge if before) and final diagnosis and stroke subtype were collected. Outcomes at 90 days included the modified Rankin Scale, Barthel Index, Stroke Impact Scale 16, and European Quality of Life. Prehospital fluctuations were examined in relation to hospital NIHSS change (admission to 72 hours or discharge) and 90-day outcomes. RESULTS: Among 1588 participants, prehospital fluctuations, consisting of improvement, worsening, or both were observed in 35.5%: 25.1% improved once, 5.3% worsened once, and 5.1% had more than 1 fluctuation. Those who improved were less likely and those who worsened were more likely to receive alteplase. Those who improved before hospital arrival had lower change in the hospital NIHSS than those who did not fluctuate. Better adjusted 90-day outcomes were noted in those with prehospital improvement compared to those without any fluctuations. CONCLUSIONS: Fluctuations in neurological symptoms and signs are common in the prehospital setting. Prehospital improvement was associated with better 90-day outcomes, controlling for admission NIHSS and alteplase treatment. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02072681.

Sex Differences in Presentation of Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Women have worse outcomes than men after stroke. Differences in presentation may lead to misdiagnosis and, in part, explain these disparities. We investigated whether there are sex differences in clinical presentation of acute stroke or transient ischemic attack. METHODS: We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Inclusion criteria were (1) cohort, cross-sectional, case-control, or randomized controlled trial design; (2) admission for (suspicion of) ischemic or hemorrhagic stroke or transient ischemic attack; and (3) comparisons possible between sexes in ≥1 nonfocal or focal acute stroke symptom(s). A random-effects model was used for our analyses. We performed sensitivity and subanalyses to help explain heterogeneity and used the Newcastle-Ottawa Scale to assess bias. RESULTS: We included 60 studies (n=582 844; 50% women). In women, headache (pooled odds ratio [OR], 1.24 [95% CI, 1.11-1.39]; I2=75.2%; 30 studies) occurred more frequently than in men with any type of stroke, as well as changes in consciousness/mental status (OR, 1.38 [95% CI, 1.19-1.61]; I2=95.0%; 17 studies) and coma/stupor (OR, 1.39 [95% CI, 1.25-1.55]; I2=27.0%; 13 studies). Aspecific or other neurological symptoms (nonrotatory dizziness and non-neurological symptoms) occurred less frequently in women (OR, 0.96 [95% CI, 0.94-0.97]; I2=0.1%; 5 studies). Overall, the presence of focal symptoms was not associated with sex (pooled OR, 1.03) although dysarthria (OR, 1.14 [95% CI, 1.04-1.24]; I2=48.6%; 11 studies) and vertigo (OR, 1.23 [95% CI, 1.13-1.34]; I2=44.0%; 8 studies) occurred more frequently, whereas symptoms of paresis/hemiparesis (OR, 0.73 [95% CI, 0.54-0.97]; I2=72.6%; 7 studies) and focal visual disturbances (OR, 0.83 [95% CI, 0.70-0.99]; I2=62.8%; 16 studies) occurred less frequently in women compared with men with any type of stroke. Most studies contained possible sources of bias. CONCLUSIONS: There may be substantive differences in nonfocal and focal stroke symptoms between men and women presenting with acute stroke or transient ischemic attack, but sufficiently high-quality studies are lacking. More studies are needed to address this because sex differences in presentation may lead to misdiagnosis and undertreatment.

Risk of Subsequent Events in Patients With Minor Ischemic Stroke or High-Risk Transient Ischemic Attack.

This study aimed to present the prognosis after minor acute ischemic stroke (AIS) or transient ischemic attack (TIA), using a definition of subsequent stroke in accordance with recent clinical trials. In total, 9,506 patients with minor AIS (National Institutes of Health Stroke Scale ≤ 5) or high-risk TIA (acute lesions or ≥ 50% cerebral artery steno-occlusion) admitted between November 2010 and October 2013 were included. The primary outcome was the composite of stroke (progression of initial event or a subsequent event) and all-cause mortality. The cumulative incidence of stroke or death was 11.2% at 1 month, 13.3% at 3 months and 16.7% at 1 year. Incidence rate of stroke or death in the first month was 12.5 per 100 person-months: highest in patients with large artery atherosclerosis (17.0). The risk of subsequent events shortly after a minor AIS or high-risk TIA was substantial, particularly in patients with large artery atherosclerosis.