Sonothrombolysis in Patients With Acute Ischemic Stroke With Large Vessel Occlusion: An Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: Evidence about the utility of ultrasound-enhanced thrombolysis (sonothrombolysis) in patients with acute ischemic stroke (AIS) is conflicting. We aimed to evaluate the safety and efficacy of sonothrombolysis in patients with AIS with large vessel occlusion, by analyzing individual patient data of available randomized-controlled clinical trials. METHODS: We included all available randomized-controlled clinical trials comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in patients with AIS with large vessel occlusion. The primary outcome measure was the rate of complete recanalization at 1 to 36 hours following intravenous thrombolysis initiation. We present crude odds ratios (ORs) and ORs adjusted for the predefined variables of age, sex, baseline stroke severity, systolic blood pressure, and onset-to-treatment time. RESULTS: We included 7 randomized controlled clinical trials that enrolled 1102 patients with AIS. A total of 138 and 134 confirmed large vessel occlusion patients were randomized to treatment and control groups respectively. Patients randomized to sonothrombolysis had increased odds of complete recanalization compared with patients receiving intravenous thrombolysis alone (40.3% versus 22.4%; OR, 2.17 [95% CI, 1.03-4.54]; adjusted OR, 2.33 [95% CI, 1.02-5.34]). The likelihood of symptomatic intracranial hemorrhage was not significantly different between the 2 groups (7.3% versus 3.7%; OR, 2.03 [95% CI, 0.68-6.11]; adjusted OR, 2.55 [95% CI, 0.76-8.52]). No differences in the likelihood of asymptomatic intracranial hemorrhage, 3-month favorable functional and 3-month functional independence were documented. CONCLUSIONS: Sonothrombolysis was associated with a nearly 2-fold increase in the odds of complete recanalization compared with intravenous thrombolysis alone in patients with AIS with large vessel occlusions. Further study of the safety and efficacy of sonothrombolysis is warranted.

Incidence and Etiologies of Stroke Mimics After Incident Stroke or Transient Ischemic Attack.

Background and Purpose- Stroke mimics (SM) pose a common clinical challenge, but the burden of SM in patients with previous ischemic stroke (IS) or transient ischemic attack is unknown. The objective of this study was to calculate the incidence of SM in IS survivors, compare it with the incidence of recurrent stroke in the same population, and explore the time-dependent patterns of SM etiologies. Methods- This prospective cohort study registered SM events and etiologies among 1872 IS and transient ischemic attack survivors diagnosed with index stroke at Haukeland University Hospital stroke unit from 2007 to 2013 by review of medical records. Cumulative incidences of SM were estimated with a competing risks Cox model and compared with incidence of recurrent stroke in the same population. Results- During 8172 person-years of follow-up, 339 patients had 480 SM events. The cumulative incidence rate of SM during follow-up was 58.7 per 1.000 person-years (95% CI, 53.7-64.2) compared with 34.0 per 1.000 person-years (95% CI, 30.2-38.2) for recurrent stroke in the same time period. The risks of SM and recurrent stroke were highest the first year after index IS or transient ischemic attack. The most frequent SM diagnoses were sequelae of cerebral infarction (19.8%), medical observation, and evaluation for suspected cerebrovascular disease (15.6%) and infections (14.0%). The 2 most frequent and unspecific diagnoses (sequelae of cerebral infarction and medical observation) were clustered in the first months after index stroke. Conclusions- SM after IS or transient ischemic attack are more frequent than recurrent stroke and the risk is especially high in the early period. SMs are multietiological and unspecific diagnoses are most frequent early after index stroke.

One-year versus five-year hospital readmission after ischemic stroke and TIA.

BACKGROUND: The burden of hospital readmission after stroke is substantial, but little knowledge exists on factors associated with long-term readmission after stroke. In a cohort comprising patients with ischemic stroke and transient ischemic attack (TIA), we examined and compared factors associated with readmission within 1 year and first readmission during year 2-5. METHODS: Patients with ischemic stroke or TIA who were discharged alive between July 2007 and October 2012, were followed for 5 years by review of medical charts. The timing and primary cause of the first unplanned readmission were registered. Cox regression was used to identify independent risk factors for readmission within 1 year and first readmission during year 2-5 after discharge. RESULTS: The cohort included 1453 patients, of whom 568 (39.1%) were readmitted within 1 year. Of the 830 patients that were alive and without readmission 1 year after discharge, 439 (52.9%) were readmitted within 5 years. Patients readmitted within 1 year were older, had more severe strokes, poorer functional outcome, and a higher occurrence of complications during index admission than patients readmitted during year 2-5. Cardiovascular comorbidity and secondary preventive treatment did not differ between the two groups of readmitted patients. Higher age, poorer functional outcome, coronary artery disease and hypertension were independently associated with readmission within both 1 year and during year 2-5. Peripheral artery disease was independently associated with readmission within 1 year, and atrial fibrillation was associated with readmission during year 2-5. CONCLUSIONS: More than half of all patients who survived the first year after stroke without any readmissions were readmitted within 5 years. Patients readmitted within 1 year and between years 2-5 shared many risk factors for readmission, but they differed in age, functional outcome and occurrence of complications during the index admission.

Recurrent ischemic stroke: Incidence, predictors, and impact on mortality.

BACKGROUND AND PURPOSE: Recurrent ischemic stroke (IS) or TIA is frequent with a considerable variation in incidence and mortality across populations. Current data on stroke recurrence and mortality are useful to examine trends, risk factors, and treatment effects. In this study, we calculated the incidence of recurrent IS or TIA in a hospital-based stroke population in Western Norway, investigated recurrence factors, and estimated the effect of recurrence on all-cause mortality. METHODS: This prospective cohort study registered recurrence and mortality among 1872 IS and TIA survivors admitted to the stroke unit at Haukeland University Hospital between July 2007 and December 2013. Recurrence and death until September 1, 2016, were identified by medical chart review. Cumulative incidences of recurrence were estimated with a competing risks Cox model. Multivariate Cox models were used to examine recurrence factors and mortality. RESULTS: During follow-up, 220 patients had 277 recurrent IS or TIAs. The cumulative recurrence rate was 5.4% at 1 year, 11.3% at 5 years, and 14.2% at the end of follow-up. Hypertension (HR = 1.65, 95% CI 1.21-2.25), prior symptomatic stroke (HR = 1.63, 95% CI 1.18-2.24), chronic infarcts on MRI (HR = 1.48, 95% CI 1.10-1.99), and age (HR 1.02/year, 95% CI 1.00-1.03) were independently associated with recurrence. A total of 668 (35.7%) patients died during follow-up. Recurrence significantly increased the all-cause mortality (HR = 2.55, 95% CI 2.04-3.18). CONCLUSIONS: The risk of recurrent IS stroke or TIA was modest in our population and was associated with previously established risk factors. Recurrence more than doubled the all-cause mortality.

Tenecteplase, 0.4 mg/kg, in Moderate and Severe Acute Ischemic Stroke: A Pooled Analysis of NOR-TEST and NOR-TEST 2A.

Background The optimal dose of tenecteplase in acute ischemic stroke remains to be defined. We present a pooled analysis of the 2 NOR-TESTs (Norwegian Tenecteplase Stroke Trials) exploring the efficacy and safety of tenecteplase, 0.4 mg/kg. Methods and Results We retrospectively reviewed 2 PROBE (Prospective Randomized Open, Blinded End-point) trials, NOR-TEST and NOR-TEST 2A. Patients were randomized to either tenecteplase, 0.4 mg/kg, or alteplase, 0.9 mg/kg. The primary end point was favorable functional outcome at 3 months (modified Rankin Scale score, 0-1) or return to baseline if prestroke modified Rankin Scale score was 2. Secondary end points included favorable functional and clinical outcome and safety data. The pooled analysis includes patients with National Institutes of Health Stroke Scale score ≥6 from both trials and an additional post hoc analysis of patients with National Institutes of Health Stroke Scale score ≤5 from NOR-TEST. The per-protocol analysis contains 483 patients, of whom 235 were assigned to tenecteplase and 248 were assigned to alteplase. In per-protocol analysis, functional outcome was better in the alteplase arm with cutoff modified Rankin Scale score of 2 (odds ratio [OR], 0.52 [95% CI, 0.33-0.80]; P=0.003) and expressed by ordinal shift analysis (OR, 1.64 [95% CI, 1.17-2.28]; P=0.004). Mortality at 3 months was higher in the tenecteplase arm (OR, 2.48 [95% CI, 1.20-5.10]; P=0.01). Mortality and intracranial hemorrhage rates were higher in the severe stroke group randomized to tenecteplase, whereas these rates were similar for alteplase and tenecteplase in moderate and mild stroke. Conclusions Tenecteplase, 0.4 mg/kg, is unsafe in moderate and severe stroke, and the risk of death and intracranial hemorrhage probably increases with stroke severity. A lower tenecteplase dose should be tested in future trials. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01949948, NCT03854500.

Five-year readmission and mortality differ by ischemic stroke subtype.

BACKGROUND: Ischemic stroke subtype may influence the risk of readmission and mortality after ischemic stroke (IS) and transient ischemic attack (TIA) due to differences in comorbidity, risk factors, and stroke severity. We aimed to study the five-year incidence and risk of all-cause readmission, cause-specific readmission and mortality after IS or TIA by stroke subtype. METHODS: The medical records of 1453 patients admitted with IS or TIA to the stroke unit at Haukeland University Hospital, Norway, between 2007 and 2012 were reviewed for identification of unplanned readmissions within five years after discharge. Stroke etiology was classified as large-artery atherosclerosis (LAA), cardioembolism (CE), small vessel occlusion (SVO), stroke of other determined etiology (SOE), multiple etiologies (ME), or cryptogenic stroke (CS). Kaplan-Meier estimates and Cox regression analyses were used to determine incidences and risk of readmission and death. RESULTS: The five-year incidence of all-cause readmission was 72.6% (74% LAA, 81% CE, 65% SVO, 55% SOE, 71% ME, and 67% CS), with infections, cardiac disease, stroke-related events and fractures as the most frequent causes. Compared to patients with other subtypes, SVO subtype had a 21% lower risk of all-cause readmission and a 48% lower risk of death, whereas CE had a 25% higher risk of all cause readmission and a 34% higher risk of death. CE subtype also had a 75% higher risk of readmission due to cardiac disease, whereas CS subtype had a 44% lower risk of readmission with cardiac disease. CONCLUSION: The five-year incidence of readmission and mortality varied among the stroke subtypes. The risk of readmission and death are especially high in patients with CE subtype, and lowest for patients with SVO subtype.

Atrial fibrillation in cryptogenic stroke and transient ischaemic attack - The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study: Rationale and design.

PURPOSE: Paroxysmal atrial fibrillation is often suspected as a probable cause of cryptogenic stroke. Continuous long-term ECG monitoring using insertable cardiac monitors is a clinically effective technique to screen for atrial fibrillation and superior to conventional follow-up in cryptogenic stroke. However, more studies are needed to identify factors which can help selecting patients with the highest possibility of detecting atrial fibrillation with prolonged rhythm monitoring. The clinical relevance of short-term atrial fibrillation, the need for medical intervention and the evaluation as to whether intervention results in improved clinical outcomes should be assessed. METHOD: The Nordic Atrial Fibrillation and Stroke Study is an international, multicentre, prospective, observational trial evaluating the occurrence of occult atrial fibrillation in cryptogenic stroke and transient ischaemic attack. Patients with cryptogenic stroke or transient ischaemic attack from the Nordic countries are included and will have the Reveal LINQ® Insertable cardiac monitor system implanted for 12 months for atrial fibrillation detection. Biomarkers which can be used as predictors for atrial fibrillation and may identify patients, who could derive the most clinical benefit from the detection of atrial fibrillation by prolonged monitoring, are being studied. CONCLUSION: The primary endpoint is atrial fibrillation burden within 12 months of continuous rhythm monitoring. Secondary endpoints are atrial fibrillation burden within six months, levels of biomarkers predicting atrial fibrillation, CHA2DS2-VASc score, incidence of recurrent stroke or transient ischaemic attack, use of anticoagulation and antiarrhythmic drugs, and quality of life measurements. The clinical follow-up period is 12 months. The study started in 2017 and the completion is expected at the end of 2020.

Thirty-day readmission after spontaneous intracerebral hemorrhage.

Background: Intracerebral hemorrhage (ICH) is the most severe form of stroke, but data on readmission after ICH are sparse. We aimed to determine frequency, causes, and predictors of 30-day readmission after ICH. Materials and Methods: This retrospective cohort study includes all spontaneous ICH survivors admitted to the stroke unit at Haukeland University Hospital in Bergen in Norway from July 2007 to December 2013. Patients were followed by review of electronic medical charts, and the first unplanned readmission within 30 days after discharge was used as final outcome. Cox regression analysis was performed to identify predictors of 30-day readmission. Results: We identified 226 patients with spontaneous ICH, 70 (31.0%) of whom died before discharge or were discharged to palliative care. Of the remaining 156 ICH survivors, 28 (18.0%) were readmitted within 30 days. Median time to readmission was 12 days (IQR 4.5 - 18.5). Most patients were readmitted due to infections (N = 13). None of the patients were readmitted with recurrent stroke. Pneumonia and enteral feeding during the index hospitalization were associated with readmission for infections (both p < .01). Age was the only independent predictor of readmission (HR 1.06, 95% CI 1.02 - 1.11, p = .006). Conclusions: Almost one in five of our spontaneous ICH survivors was readmitted within 30 days, and most readmissions were caused by infections.

Thirty-day recurrence after ischemic stroke or TIA.

BACKGROUND: Incidence of recurrent stroke is highest within 30 days after the initial ischemic stroke (IS) or TIA, but knowledge about early recurrence is lacking. We aimed to identify etiological groups with highest risk of early recurrence and assess how the TOAST classification identified index stroke etiology. METHODS: Medical records of 1874 IS and TIA patients in the Bergen NORSTROKE registry were retrospectively reviewed for identification of recurrent IS or TIA within 30 days after index IS or TIA. Stroke etiology was determined by review of electronical medical journals. Logistic regression was used to calculate odds ratios (OR) for 30-day recurrence. RESULTS: Thirty-three patients (1.8%) were readmitted with recurrent IS or TIA within 30 days after index stroke. By using TOAST, 12 patients were initially classified with stroke of unknown etiology (SUE). Etiologies behind recurrent IS or TIA were after the recurrent episode identified as extracranial large artery atherosclerosis (LAA) in 14 patients (42.4%), intracranial arterial pathology in seven patients (21.2%), active malignancy in six patients (18.2%), and cardio embolism in four patients (12.1%). Small vessel occlusion and SUE were the causes in one patient each. Logistic regression showed that patients with stroke of other determined etiology (SOE) and LAA had increased risk of 30-day recurrence (OR = 9.72, 95% CI 1.84-51.3, p < 0.01 and OR = 4.36, 95% CI 2.01-9.47, p < 0.01, respectively). CONCLUSION: Patients with LAA and SOE had increased risk of recurrent IS or TIA within 30 days. TOAST was inadequate at identifying exact etiologies behind recurrent stroke at index event.

The Impact of Ischaemic Stroke Subtype on 30-day Hospital Readmissions.

BACKGROUND: Stroke aetiology may affect the risk and causes of readmission after ischaemic stroke (IS) and transient ischaemic attack (TIA) due to differences in risk factors, functional outcome, and treatment. We aimed to examine frequencies, causes, and risk of 30-day readmission by stroke subtype, determine predictors of 30-day readmission, and study the impact of 30-day readmissions on one-year mortality. METHODS: All surviving patients admitted with IS or TIA from July 2007 to December 2013 were followed by review of medical records for all unplanned readmissions within 30 days after discharge. Stroke subtype was classified as large-artery atherosclerosis (LAA), cardioembolism (CE), small vessel occlusion (SVO), stroke of other determined aetiology (SOE), or stroke of undetermined aetiology (SUE). Cox regression analyses were performed to assess the risk of 30-day readmission for the stroke subtypes and identify predictors of 30-day readmission, and its impact on one-year mortality. RESULTS: Of 1874 patients, 200 (10.7%) were readmitted within 30 days [LAA 42/244 (17.2%), CE 75/605 (12.4%), SVO 12/205 (5.9%), SOE 6/32 (18.8%), SUE 65/788 (8.3%)]. The most frequent causes of readmissions were stroke-related event, infection, recurrent stroke/ TIA, and cardiac disease. After adjusting for age, sex, functional outcome, length of stay, and the risk factor burden, patients with LAA and SOE subtype had significantly higher risks of readmission for any cause, recurrent stroke or TIA, and stroke-related events. Predictors of 30-day readmission were higher age, peripheral arterial disease, enteral feeding, and LAA subtype. Thirty-day readmission was an independent predictor of one-year mortality. CONCLUSIONS: Patients with LAA or SOE have a high risk of 30-day readmission, possibly caused by an increased risk of recurrent stroke and stroke-related events. Awareness of the risk of readmission for different causes and appropriate handling according to stroke subtype may be useful for preventing some readmissions after stroke.