Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke.

OBJECTIVE: Agonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurological injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. METHODS: The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 µg/kg of 3K3A-APC. After intravenous tissue plasminogen activator, intra-arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. RESULTS: Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest-dose 3K3A-APC tested, 540 µg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066). INTERPRETATION: RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 µg/kg for the PAR1 active cytoprotectant, 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136.

Optimal Medical Management Reduces Risk of Disease Progression and Ischemic Events in Asymptomatic Carotid Stenosis Patients: A Long-Term Follow-Up Study.

BACKGROUND AND PURPOSE: To assess the effect of optimal medical management including atherosclerotic risk factor control on ischemic stroke (IS), transient ischemic attack (TIA), carotid revascularization (CRV), and progression of severity of carotid stenosis (PSCS) in patients with asymptomatic carotid artery stenosis (ACAS). METHODS: We conducted a retrospective analysis of patients with ACAS (who had at least 3 serial carotid duplex ultrasounds) for incidence of IS, TIA, and PSCS. RESULTS: Eight hundred sixty-four patients with a mean follow-up duration of 79 ± 36 months were included. IS/TIA and CRV occurred in 12.2% of the patients and PCSS was observed in 21.5% vessels. On univariate analysis it was found that low-density lipoprotein (LDL) levels >100 mg/dL, no statin or low-potency statins, average systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg and history of smoking were predictors of the combined endpoint of IS/TIA/CRV and PSCS. On multivariate analysis, it was found that LDL >100 mg/dL, no statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, and Hx of smoking were independent predictors of PSCS. Similarly no statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, Hx of atrial fibrillation/flutter, Hx of chronic kidney disease, and PSCS were independent predictors of IS/TIA. No statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, diabetes mellitus, baseline carotid artery stenosis ≥70%, and PSCS were found to be independent predictors of combined endpoint IS/TIA and CRV. CONCLUSION: Intensive medical therapy in the patients with ACAS results in lower incidence of IS/TIA, CRV, and PSCS with a significant incremental beneficial effect.

The relationship of pro-inflammatory markers to vascular endothelial function after acute stroke.

Purpose/Aim: Data from chronic stroke studies have reported reduced blood flow and vascular endothelial function in the stroke-affected limb. It is unclear whether these differences are present early after stroke. First, we investigated whether vascular endothelial function in the stroke-affected limb would be different from healthy adults. Second, we examined whether between-limb differences in vascular endothelial function existed in the stroke-affected arm compared to the non-affected arm. Last, we tested whether reduced vascular endothelial function was related to pro-inflammatory markers that are present early after stroke. MATERIALS AND METHODS: Vascular endothelial function was assessed by flow-mediated dilation (FMD) in the brachial artery within 72 h post-stroke. All participants withheld medications from midnight until after the procedure. Ultrasound scans and blood draws for pro-inflammatory markers occurred on the same day between 7:30 am and 9:00 am. RESULTS: People with acute stroke had significantly lower FMD (4.2% ± 4.6%) than control participants (8.5% ± 5.2%, p = 0.037). Stroke participants had between-limb differences in FMD (4.2% ± 4.6% stroke-affected vs. 5.3% ± 4.4% non-affected, p = 0.02), whereas, the control participants did not. Of the pro-inflammatory markers, only vascular cell adhesion molecule-1(VCAM-1) had a significant relationship to FMD (stroke-affected limb, r = -0.62, p = 0.03; non-affected limb, r = -0.75, p = 0.005), but not tumor necrosis factor alpha nor interleukin-6. CONCLUSIONS: Vascular endothelial function is reduced starting in the early stage of stroke recovery. People with higher levels of VCAM-1 had a lower FMD response.

Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection.

BACKGROUND AND PURPOSE: The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial. METHODS: The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria. RESULTS: Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment. CONCLUSIONS: It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714.

Predictors for atrial fibrillation detection after cryptogenic stroke: Results from CRYSTAL AF.

OBJECTIVE: We assessed predictors of atrial fibrillation (AF) in cryptogenic stroke (CS) or transient ischemic attack (TIA) patients who received an insertable cardiac monitor (ICM). METHODS: We studied patients with CS/TIA who were randomized to ICM within the CRYSTAL AF study. We assessed whether age, sex, race, body mass index, type and severity of index ischemic event, CHADS2 score, PR interval, and presence of diabetes, hypertension, congestive heart failure, or patent foramen ovale and premature atrial contractions predicted AF development within the initial 12 and 36 months of follow-up using Cox proportional hazards models. RESULTS: Among 221 patients randomized to ICM (age 61.6 ± 11.4 years, 64% male), AF episodes were detected in 29 patients within 12 months and 42 patients at 36 months. Significant univariate predictors of AF at 12 months included age (hazard ratio [HR] per decade 2.0 [95% confidence interval 1.4-2.8], p = 0.002), CHADS2 score (HR 1.9 per one point [1.3-2.8], p = 0.008), PR interval (HR 1.3 per 10 milliseconds [1.2-1.4], p < 0.0001), premature atrial contractions (HR 3.9 for >123 vs 0 [1.3-12.0], p = 0.009 across quartiles), and diabetes (HR 2.3 [1.0-5.2], p < 0.05). In multivariate analysis, age (HR per decade 1.9 [1.3-2.8], p = 0.0009) and PR interval (HR 1.3 [1.2-1.4], p < 0.0001) remained significant and together yielded an area under the receiver operating characteristic curve of 0.78 (0.70-0.85). The same predictors were found at 36 months. CONCLUSION: Increasing age and a prolonged PR interval at enrollment were independently associated with an increased AF incidence in CS patients. However, they offered only moderate predictive ability in determining which CS patients had AF detected by the ICM.

Patient-Centered Decision Support in Acute Ischemic Stroke: Qualitative Study of Patients' and Providers' Perspectives.

BACKGROUND: National guidelines endorse recombinant tissue-type plasminogen activator (r-tPA) in eligible patients with acute ischemic stroke to improve patients' functional recovery. However, 23% to 40% of ideal candidates with acute ischemic stroke for reperfusion are not treated, perhaps because of the difficulty in explaining the benefits and risks of r-tPA within the frenetic pace of emergency department care. To support better knowledge transfer and creation of a shared decision-making tool, we conducted qualitative interviews to define the information needs and preferred presentation format for stroke survivors, caregivers, and clinicians considering r-tPA treatment. METHODS AND RESULTS: A multidisciplinary team used qualitative research methods to identify informational needs and strategies for describing the benefits and risks of r-tPA in a clinical setting. Through focus groups (n=10) of stroke survivors (n=39) and caregivers (n=24) and individual interviews with emergency physicians (n=23) and advanced practice nurses (n=20), several themes emerged. Survivors and caregivers preferred a broader definition of a good outcome (independence, rather than no significant disability), simpler graphs as compared with detailed pictographs, and presentation of both population and individualized benefits (framed positively) and risk of receiving r-tPA. Some physicians expressed skepticism with the data and the ability to present risk/benefit information emergently, whereas other physicians and most advanced practice nurses thought such information would improve care. Physicians stressed the importance of presenting the risk of thrombolytic-related intracranial hemorrhage. CONCLUSIONS: This study suggests that a positively framed risk-benefit tool with graphical presentations of general and patient-specific risk estimates could support patients and providers in considering r-tPA for acute ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01864928.

Infarct Topography and Detection of Atrial Fibrillation in Cryptogenic Stroke: Results from CRYSTAL AF.

BACKGROUND: Insertable cardiac monitors (ICM) have been shown to detect atrial fibrillation (AF) at a higher rate than routine monitoring methods in patients with cryptogenic stroke (CS). However, it is unknown whether there are topographic patterns of brain infarction in patients with CS that are particularly associated with underlying AF. If such patterns exist, these could be used to help decide whether or not CS patients would benefit from long-term monitoring with an ICM. METHODS: In this retrospective analysis, a neuro-radiologist blinded to clinical details reviewed brain images from 212 patients with CS who were enrolled in the ICM arm of the CRYptogenic STroke And underLying AF (CRYSTAL AF) trial. Kaplan-Meier estimates were used to describe rates of AF detection at 12 months in patients with and without pre-specified imaging characteristics. Hazard ratios (HRs), 95% confidence intervals (CIs), and p values were calculated using Cox regression. RESULTS: We did not find any pattern of acute brain infarction that was significantly associated with AF detection after CS. However, the presence of chronic brain infarctions (15.8 vs. 7.0%, HR 2.84, 95% CI 1.13-7.15, p = 0.02) or leukoaraiosis (18.2 vs. 7.9%, HR 2.94, 95% CI 1.28-6.71, p < 0.01) was associated with AF detection. There was a borderline significant association of AF detection with the presence of chronic territorial (defined as within the territory of a first or second degree branch of the circle of Willis) infarcts (20.9 vs. 10.0%, HR 2.37, 95% CI 0.98-5.72, p = 0.05). CONCLUSIONS: We found no evidence for an association between brain infarction pattern and AF detection using an ICM in patients with CS, although patients with coexisting chronic, as well as acute, brain infarcts had a higher rate of AF detection. Acute brain infarction topography does not reliably predict or exclude detection of underlying AF in patients with CS and should not be used to select patients for ICM after cryptogenic stroke.

A Comparison of Atrial Fibrillation Monitoring Strategies After Cryptogenic Stroke (from the Cryptogenic Stroke and Underlying AF Trial).

Ischemic stroke cause remains undetermined in 30% of cases, leading to a diagnosis of cryptogenic stroke. Paroxysmal atrial fibrillation (AF) is a major cause of ischemic stroke but may go undetected with short periods of ECG monitoring. The Cryptogenic Stroke and Underlying Atrial Fibrillation trial (CRYSTAL AF) demonstrated that long-term electrocardiographic monitoring with insertable cardiac monitors (ICM) is superior to conventional follow-up in detecting AF in the population with cryptogenic stroke. We evaluated the sensitivity and negative predictive value (NPV) of various external monitoring techniques within a cryptogenic stroke cohort. Simulated intermittent monitoring strategies were compared to continuous rhythm monitoring in 168 ICM patients of the CRYSTAL AF trial. Short-term monitoring included a single 24-hour, 48-hour, and 7-day Holter and 21-day and 30-day event recorders. Periodic monitoring consisted of quarterly monitoring through 24-hour, 48-hour, and 7-day Holters and monthly 24-hour Holters. For a single monitoring period, the sensitivity for AF diagnosis was lowest with a 24-hour Holter (1.3%) and highest with a 30-day event recorder (22.8%). The NPV ranged from 82.3% to 85.6% for all single external monitoring strategies. Quarterly monitoring with 24-hour Holters had a sensitivity of 3.1%, whereas quarterly 7-day monitors increased the sensitivity to 20.8%. The NPVs for repetitive periodic monitoring strategies were similar at 82.6% to 85.3%. Long-term continuous monitoring was superior in detecting AF compared to all intermittent monitoring strategies evaluated (p <0.001). Long-term continuous electrocardiographic monitoring with ICMs is significantly more effective than any of the simulated intermittent monitoring strategies for identifying AF in patients with previous cryptogenic stroke.

Use of Accelerometers to Examine Sedentary Time on an Acute Stroke Unit.

BACKGROUND AND PURPOSE: Observational studies demonstrate low levels of physical activity during inpatient stroke rehabilitation. There are no prior studies that have objectively measured sedentary time on the acute stroke unit and whether sedentary time is related to functional outcomes. The purpose of this study was to characterize sedentary time after acute stroke and determine whether there is a relationship to functional performance at discharge. METHODS: Thirty-two individuals (18 men; 56.5 ± 12.7 years) with acute stroke were enrolled within 48 hours of hospital admission. An accelerometer was placed on the stroke-affected ankle to measure 24-hour activity and was worn for 4 days or until discharge from the hospital. Performance of activities of daily living, walking endurance, and functional mobility were assessed using the Physical Performance Test, Six-Minute Walk Test, and Timed Up and Go, respectively. RESULTS: Mean percent time spent sedentary was 93.9 ± 4.1% and percent time in light activity was 5.1 ± 2.4%. When controlling for baseline performance, the mean time spent sedentary per day was significantly related to Physical Performance Test performance at discharge (r = -0.37; P = .05), but not the Six-Minute Walk Test or Timed Up and Go. DISCUSSION AND CONCLUSIONS: Patients with acute stroke were sedentary most of their hospital stay. To minimize the potential negative effects of inactivity, our data suggest that there should be greater emphasis on increasing physical activity during the hospital stay.Video Abstract Available for more insights from the authors (Supplemental Digital Content 1, http://links.lww.com/JNPT/A101).

Predictors and clinical relevance of hemorrhagic transformation after endovascular therapy for anterior circulation large vessel occlusion strokes: a multicenter retrospective analysis of 1122 patients.

BACKGROUND AND PURPOSE: Endovascular techniques are frequently employed to treat large artery occlusion in acute ischemic stroke (AIS). We sought to determine the predictors and clinical impact of intracranial hemorrhage (ICH) after endovascular therapy. METHODS: Retrospective analysis of consecutive patients presenting to 13 high volume stroke centers with AIS due to proximal occlusion in the anterior circulation who underwent endovascular treatment within 8 h from symptom onset. Logistic regression was performed to determine the variables associated with ICH, hemorrhagic infarction (HI), and parenchymal hematomas (PHs), as well as 90 day poor outcome (modified Rankin Scale score ≥3) and mortality. RESULTS: There were a total of 363 ICHs (overall rate 32.3%; HI=267, 24%; PH=96, 8.5%) among the 1122 study patients (mean age 67±15 years; median National Institutes of Health Stroke Scale score 17 (IQR 13-20)). Independent predictors for HI included diabetes mellitus (OR 2.27, 95% CI (1.58 to 3.26), p<0.0001), preprocedure IV tissue plasminogen activator (tPA) (1.43 (1.03 to 2.08), p<0.037), Merci thrombectomy (1.47 (1.02 to 2.12), p<0.032), and longer time to puncture (1.001 (1.00 to 1.002), p<0.026). Patients with atrial fibrillation (1.61 (1.01 to 2.55), p<0.045) had a higher risk of PH while the use of IA tPA (0.57 (0.35 to 0.90), p<0.008) was associated with lower chances of PH. Both the presence of HI (2.23 (1.53 to 3.25), p<0.0001) and PH (6.24 (3.06 to 12.75), p<0.0001) were associated with poor functional outcomes; however, only PH was associated with higher mortality (3.53 (2.19 to 5.68), p<0.0001). CONCLUSIONS: Greater understanding about the predictors and consequences of ICH post endovascular stroke therapy is essential to improve risk assessment, patient selection/clinical outcomes, and early prognostication. Our data suggest that patients with atrial fibrillation are particularly prone to severe ICH and question the 'benign' nature of HI suggested by earlier studies.

Cryptogenic stroke and underlying atrial fibrillation.

BACKGROUND: Current guidelines recommend at least 24 hours of electrocardiographic (ECG) monitoring after an ischemic stroke to rule out atrial fibrillation. However, the most effective duration and type of monitoring have not been established, and the cause of ischemic stroke remains uncertain despite a complete diagnostic evaluation in 20 to 40% of cases (cryptogenic stroke). Detection of atrial fibrillation after cryptogenic stroke has therapeutic implications. METHODS: We conducted a randomized, controlled study of 441 patients to assess whether long-term monitoring with an insertable cardiac monitor (ICM) is more effective than conventional follow-up (control) for detecting atrial fibrillation in patients with cryptogenic stroke. Patients 40 years of age or older with no evidence of atrial fibrillation during at least 24 hours of ECG monitoring underwent randomization within 90 days after the index event. The primary end point was the time to first detection of atrial fibrillation (lasting >30 seconds) within 6 months. Among the secondary end points was the time to first detection of atrial fibrillation within 12 months. Data were analyzed according to the intention-to-treat principle. RESULTS: By 6 months, atrial fibrillation had been detected in 8.9% of patients in the ICM group (19 patients) versus 1.4% of patients in the control group (3 patients) (hazard ratio, 6.4; 95% confidence interval [CI], 1.9 to 21.7; P<0.001). By 12 months, atrial fibrillation had been detected in 12.4% of patients in the ICM group (29 patients) versus 2.0% of patients in the control group (4 patients) (hazard ratio, 7.3; 95% CI, 2.6 to 20.8; P<0.001). CONCLUSIONS: ECG monitoring with an ICM was superior to conventional follow-up for detecting atrial fibrillation after cryptogenic stroke. (Funded by Medtronic; CRYSTAL AF ClinicalTrials.gov number, NCT00924638.).

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.

Analysis of the costs and payments of a coordinated stroke center and regional stroke network.

BACKGROUND AND PURPOSE: An earlier study demonstrated significantly improved access, treatment, and outcomes after the implementation of a progressive, comprehensive stroke program at a tertiary care community hospital, Saint Luke's Neuroscience Institute (SLNI). This study evaluated the costs associated with implementing such a program. METHODS: Retrospective analysis of total hospital costs and payments for treating patients with ischemic stroke at SLNI (n=1570) as program enhancement evolved over time (2005, 2007, and 2010) and compared with published national estimates. Analyses were stratified by patient demographic characteristics, patient outcomes, treatments, time, and comorbidities. RESULTS: Controlling for inflation, there was no difference in SLNI total costs between 2005 and either 2007 or 2010, suggesting that while SLNI provided an increased level of services, any additional expenditures were offset by efficiencies. SLNI total costs were slightly lower than published benchmarks. Consistent with previous stroke care cost estimates, the median overall differential between total hospital costs and payments for all ischemic stroke cases was negative. CONCLUSIONS: SLNI total costs remained consistent over time and were slightly lower than previously published estimates, suggesting that a focused, streamlined stroke program can be implemented without a significant economic impact. This finding further demonstrates that providing comprehensive stroke care with improved access and treatment may be financially feasible for other hospitals.

Analysis of a coordinated stroke center and regional stroke network on access to acute therapy and clinical outcomes.

BACKGROUND AND PURPOSE: Compare access and outcomes in a tertiary care community hospital (Saint Luke's Neuroscience Institute) and its stroke network to hospitals in 3 national databases. METHODS: Retrospective analysis of ischemic stroke patients (2005, 2007, 2010) in Saint Luke's (n=1576), Get With The Guidelines-Stroke (n=423 809), Premier (n=91 598), and Merci Registry (n=966). Study measures were use of computed tomography scans and tissue plasminogen activator (tPA), symptomatic intracranial hemorrhage, discharge disposition, discharge National Institutes of Health Stroke Scale scores, and 90-day modified Rankin Scores. RESULTS: Saint Luke's increased access to care with higher tPA use than other hospitals (17.2% received intravenous tPA therapy compared with 5.8% at Get With The Guidelines-Stroke hospitals, P<0.001; 22.1% of Saint Luke's patients received tPA by any route compared with 3.5% of Premier patients, P<0.001). Use of intravenous tPA within 4.5 hours of onset was associated with more discharges to home (odds ratio, 2.123; 95% confidence interval, 1.394-3.246) and improved National Institutes of Health Stroke Scale scores (P=0.001). Saint Luke's patients also were more likely than those in other hospitals to receive computed tomography scans (99.4% vs 58.6% at Premier hospitals). Embolectomy at Saint Luke's was associated with better outcomes than peer hospitals, and treatment at Saint Luke's was independently associated with more discharges to home (odds ratio, 3.92; 95% confidence interval, 1.84-8.32). In 2010, symptomatic intracranial hemorrhages after tPA therapy was similar for Saint Luke's patients and Premier patients (2.2% vs 1.5%; P=0.590). CONCLUSIONS: Regionally coordinated stroke programs can substantially improve access and patient outcomes.

Should all patients with mild ischemic stroke be excluded from therapeutic stroke trials?

We aimed to investigate stroke etiology in our cohort of patients with mild ischemic stroke (MIS) and to study the effect of stroke etiology on patient outcome. We also studied the effect of intravenous (IV) recombinant tissue plasminogen activator (rt-PA) in this cohort. We analyzed patients with MIS who were eligible for IV rt-PA presenting within 3 hours of symptom onset with a National Institutes of Health Stroke Scale (NIHSS) score ≤ 5 admitted from March 2006 through June 2009. Stroke etiology was determined using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Primary outcome was the discharge NIHSS score. We identified 110 patients with MIS with a male-to-female ratio of: 1.4:1 and a mean age of 69 ± 13 years. The mean admission NIHSS score was 2 ± 3. The stroke risk factors were identified as: hypertension, 82 patients (75%); previous stroke/transient ischemic attack, 36 patients (33%); and atrial fibrillation, 28 patients (26%). Stroke etiology was identified as: large vessel atherosclerosis (31 patients, 28%), cardioembolism (29, 26%), small vessel occlusion (seven, 6%) and those with other or undetermined conditions (43, 39%). IV rt-PA was administered to 25 patients (23%). Despite the use of IV rt-PA in only one patient with small vessel occlusion, patients in our study with this stroke etiology tended to have better outcomes compared to those with other stroke subtypes, although the difference was not statistically significant. The discharge NIHSS score did not show any statistically significant difference between the treated and untreated patients with MIS. Our study shows that MIS may be caused by non small vessel occlusion in more patients than previously reported and this subgroup of patients with MIS should not be excluded from trials of intravenous and endovascular therapies.

Imaging-based endovascular therapy for acute ischemic stroke due to proximal intracranial anterior circulation occlusion treated beyond 8 hours from time last seen well: retrospective multicenter analysis of 237 consecutive patients.

BACKGROUND AND PURPOSE: Current selection criteria for intra-arterial therapies in the anterior circulation use time windows of 8 hours. Modern neuroimaging techniques have identified individuals with salvageable penumbra who present beyond this timeframe. We sought to assess safety, procedural, and clinical outcomes of MRI or CT perfusion imaging-based endovascular therapy in patients with anterior circulation stroke treated beyond 8 hours from time last seen well. METHODS: We conducted a multicenter retrospective review of consecutive patients meeting the following criteria: (1) acute proximal intracranial anterior circulation occlusion; (2) endovascular treatment initiated >8 hours from time last seen well; and (3) treatment selection based on MRI or CT perfusion imaging. RESULTS: Two hundred thirty-seven patients were identified (mean age, 63.8 ± 16 years; mean baseline National Institutes of Health Stroke Scale, 15 ± 5.5; mean time last seen well to treatment, 15 ± 11.2 hours; male gender, 46%). Successful revascularization was achieved in 175 of 237 (73.84%) patients. Parenchymal hematoma occurred in 21 of 237 (8.86%) patients. The 90-day mortality rate was 21.5% (51 of 237). The rate of good outcomes was 45% (100 of 223) in the 223 patients with available modified Rankin Scale data at 90 days or time of hospital discharge. In multivariate analyses, age (OR, 0.96; 95% CI, 0.94 to 0.98; P=0.002), admission National Institutes of Health Stroke Scale (OR, 0.93; 0.87 to 0.98; P=0.016), and successful revascularization (OR, 4.32; 1.99 to 9.39; P<0.0001) were identified as independent predictors of good outcomes. CONCLUSIONS: Endovascular therapy can be instituted with acceptable safety beyond 8 hours from time last seen well when selection is based on advanced neuroimaging. Successful revascularization is significantly associated with higher rates of good outcomes. The benefit of this approach compared with standard medical therapy should be assessed in a prospective randomized trial.

Hemorrhagic stroke: aneurysmal subarachnoid hemorrhage.

Non-traumatic subarachnoid hemorrhage (SAH) represents approximately 5-6% of all strokes. Morbidity and mortality rates remain high, but accurate diagnosis using clinical assessment and neuroimaging, critical care management, and early treatment using either surgical or interventional techniques have improved overall outcomes. This, the fifth in a Missouri Medicine series on stroke, summarizes the clinical and imaging aspects of making the diagnosis of SAH, critical care management of the patient, treatment options, and factors important in prognosis.

Hemorrhagic stroke: intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a devastating event, carrying a very high morbidity and mortality rate. Hypertension and age-related amyloid angiopathy are the strongest risk factors for ICH, but smoking, anticoagulation with warfarin, excessive alcohol intake and cocaine also increase risk. This, the fourth in a Missouri Medicine series on stroke summarizes the clinical and imaging aspects of making the diagnosis of ICH. Current medical and surgical therapies are discussed as well as predictors of outcome and recommendations for secondary prevention.

Prediction of adverse outcomes by blood glucose level after endovascular therapy for acute ischemic stroke.

OBJECT: The authors evaluated the prognostic significance of blood glucose level at admission (BGA) and change in blood glucose at 48 hours from the baseline value (CG48) in nondiabetic and diabetic patients before and after endovascular therapy for acute ischemic stroke (AIS). METHODS: The BGA and CG48 data were analyzed in 614 patients with AIS who received endovascular therapy at 7 US centers between 2006 and 2009. Data reviewed included demographics, stroke risk factors, diabetic status, National Institutes of Health Stroke Scale (NIHSS) score at presentation, recanalization grade, intracranial hemorrhage (ICH) rate, and 90-day outcomes (mortality rate and modified Rankin Scale score of 3-6 [defined as poor outcome]). Variables with p values < 0.2 in univariate analysis were included in a binary logistic regression model for independent predictors of 90-day outcomes. RESULTS: The mean patient age was 67.3 years, the median NIHSS score was 16, and 27% of patients had diabetes. In nondiabetic patients, BGA ≥ 116 mg/dl (≥ 6.4 mmol/L) and failure of glucose level to drop > 30 mg/dl (> 1.7 mmol/L) from the admission value were both significant predictors of 90-day poor outcome and death (p < 0.001). In patients with diabetes, BGA ≥ 116 mg/dl (≥ 6.4 mmol/L) was an independent predictor of poor outcome (p = 0.001). The CG48 was not a predictor of outcome in diabetic patients. A simplified 6-point scale including BGA, Thrombolysis in Myocardial Infarction (TIMI) Grade 2-3 Reperfusion, Age, presentation NIHSS score, CG48, and symptomatic ICH (BRANCH) corresponded with poor outcomes at 90 days; the area under the curve value was > 0.79. CONCLUSIONS: Failure of blood glucose values to decrease in the first 48 hours after AIS intervention correlated with poor 90-day outcomes in nondiabetic patients. The BRANCH scale shows promise as a simple prognostication tool after endovascular therapy for AIS, and it merits prospective validation.