Nicole R. Gonzales

Influence of sex on outcomes of stenting versus endarterectomy: a subgroup analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST)

BACKGROUNDnIn the randomised Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the primary endpoint did not differ between carotid artery stenting and carotid endarterectomy in patients with symptomatic and asymptomatic stenosis. A prespecified secondary aim was to examine differences by sex.nnnMETHODSnPatients who were asymptomatic or had had a stroke or transient ischaemic attack within 180 days before random allocation were enrolled in CREST at 117 clinical centres in the USA and Canada. The primary outcome was the composite of stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke within 4 years. We used standard survival methods including Kaplan-Meier survival curves and sex-by-treatment interaction term to assess the relation between patient factors and risk of reaching the primary outcome. Analyses were by intention to treat. CREST is registered with ClinicalTrials.gov, NCT00004732.nnnFINDINGSnBetween Dec 21, 2000, and July 18, 2008, 2502 patients were randomly assigned to carotid endarterectomy (n=1240) or carotid artery stenting (n=1262), 872 (34.9%) of whom were women. Rates of the primary endpoint for carotid artery stenting compared with carotid endarterectomy were 6.2% versus 6.8% in men (hazard ratio [HR] 0.99, 95% CI 0.66-1.46) and 8.9% versus 6.7% in women (1.35, 0.82-2.23). There was no significant interaction in the primary endpoint between sexes (interaction p=0.34). Periprocedural events occurred in 35 (4.3%) of 807 men assigned to carotid artery stenting compared with 40 (4.9%) of 823 assigned to carotid endarterectomy (HR 0.90, 95% CI 0.57-1.41) and 31 (6.8%) of 455 women assigned to carotid artery stenting compared with 16 (3.8%) of 417 assigned to carotid endarterectomy (1.84, 1.01-3.37; interaction p=0.064).nnnINTERPRETATIONnPeriprocedural risk of events seems to be higher in women who have carotid artery stenting than those who have carotid endarterectomy whereas there is little difference in men. Additional data are needed to confirm whether this differential risk should be taken into account in decisions for treatment of carotid disease in women.nnnFUNDINGnNational Institute of Neurological Disorders and Stroke and Abbott Vascular Solutions (formerly Guidant).

Intraventricular hemorrhage: Anatomic relationships and clinical implications

Background: Spontaneous intracerebral hemorrhage (ICH) is frequently associated with intraventricular hemorrhage (IVH), which is an independent predictor of poor outcome. The purpose of this study was to examine the relationship between ICH volume and anatomic location to IVH, and to determine if ICH decompression into the ventricle is truly beneficial. Methods: We retrospectively analyzed the CT scans and charts of all patients with ICH admitted to our stroke center over a 3-year period. Outcome data were collected using our prospective stroke registry. Results: We identified 406 patients with ICH. A total of 45% had IVH. Thalamic and caudate locations had the highest IVH frequency (69% and 100%). ICH volume and ICH location were predictors of IVH (p < 0.001). Within each location, decompression ranges (specific volume ranges where ventricular rupture tends to occur) were established. Patients with IVH were twice as likely to have a poor outcome (discharge modified Rankin scale of 4 to 6) (OR 2.25, p = 0.001) when compared to patients without IVH. Caudate location was associated with a good outcome despite 100% incidence of IVH. Spontaneous ventricular decompression was not associated with better outcome, regardless of parenchymal volume reduction (p = 0.72). Conclusions: Intraventricular hemorrhage (IVH) occurs in nearly half of patients with spontaneous intracerebral hemorrhage (ICH) and is related to ICH volume and location. IVH is likely to occur within the “decompression ranges” that take into account both ICH location and volume. Further, spontaneous ventricular decompression does not translate to better clinical outcome. This information may prove useful for future ICH trials, and to the clinician communicating with patients and families. GLOSSARY: ANOVA = analysis of variance; EVD = external ventricular drainage; HSD = honestly significant differences; ICC = interclass correlation coefficient; ICH = intracerebral hemorrhage; IVH = intraventricular hemorrhage; LOS = length of stay; mRS = modified Rankin Scale.

Thrombus Burden Is Associated With Clinical Outcome After Intra-Arterial Therapy for Acute Ischemic Stroke

Background and Purpose— Studies have established a relation between recanalization and improved clinical outcome in acute ischemic stroke patients; however, intra-arterial clot size has not been routinely assessed. The aim of the study was to determine the impact of intra-arterial thrombus burden on intra-arterial treatment (IAT) and clinical outcome. Methods— A retrospective review of our IAT stroke database included procedure time, recanalization, symptomatic intracranial hemorrhage, poor outcome (modified Rankin Scale score ≥4 at discharge), and mortality. The modified Thrombolysis in Myocardial Infarction thrombus grade was dichotomized into grades 0 to 3 (no clot or moderate thrombus, <2 vessel diameters) versus grade 4 (large thrombus, >2 vessel diameters). Results— Data were collected on 135 patients with thrombus grading. The baseline median National Institutes of Health Stroke Scale score was higher in patients of grade 4 compared with grades 0 to 3 (19 vs 17, P=0.012). Grade 4 thrombi required longer (median, range) times for IAT (113, 37 to 415 minutes vs 74, 22 to 215 minutes, respectively; P<0.001) and higher rates of mechanical clot disruption (wire, angioplasty, snare, stent, or Merci retriever) compared with grades 0 to 3 (76% vs 53%, P=0.005). There were no differences in rates of symptomatic intracranial hemorrhage (6.6% vs 4.1%, P=0.701) or recanalization (50% vs 61%, P=0.216) in grade 4 versus grades 0 to 3. Multivariate analysis adjusted for age, baseline National Institutes of Health Stroke Scale score, and artery of involvement showed that grade 4 thrombi were independently associated with poor outcome (odds ratio=2.4; 95% CI, 1.06 to 5.57; P=0.036) and mortality (odds ratio=4.0; 95% CI, 1.2 to 13.2; P=0.023). Conclusions— High thrombus grade as measured by the modified Thrombolysis in Myocardial Infarction criteria may be a risk factor that contributes to poor clinical outcome.

Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC).

Rationale Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. Aims The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. Study Design This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. Outcomes The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.

Pleiotropic Role of PPARγ in Intracerebral Hemorrhage: An Intricate System Involving Nrf2, RXR, and NF‐κB

Intracerebral hemorrhage (ICH) is a subtype of stroke involving formation of hematoma within brain parenchyma, which accounts for 8–15% of all strokes in Western societies and 20–30% among Asian populations, and has a 1‐year mortality rate >50%. The high mortality and severe morbidity make ICH a major public health problem. Only a few evidence‐based targeted treatments are used for ICH management, and interventions focus primarily on supportive care and comorbidity prevention. Even in patients who survive the ictus, extravasated blood (including plasma components) and subsequent intrahematoma hemolytic products trigger a series of adverse events within the brain parenchyma, leading to secondary brain injury, edema and severe neurological deficits or death. Although the hematoma in humans gradually resolves within months, full restoration of neurological function can be slow and often incomplete, leaving survivors with devastating neurological deficits. During past years, peroxisome proliferator‐activated receptor gamma (PPARγ) transcription factor and its agonists received recognition as important players in regulating not only glucose and lipid metabolism (which underlies its therapeutic effect in type 2 diabetes mellitus), and more recently, as an instrumental pleiotropic regulator of antiinflammation, antioxidative regulation, and phagocyte‐mediated cleanup processes. PPARγ agonists have emerged as potential therapeutic target for stroke. The use of PPARγ as a therapeutic target appears to have particularly strong compatibility toward pathogenic components of ICH. In addition to its direct genomic effect, PPARγ may interact with transcription factor, NF‐κB, which may underlie many aspects of the antiinflammatory effect of PPARγ. Furthermore, PPARγ appears to regulate expression of Nrf2, another transcription factor and master regulator of detoxification and antioxidative regulation. Finally, the synergistic costimulation of PPARγ and retinoid X receptor, RXR, may play an additional role in the therapeutic modulation of PPARγ function. In this article, we outline the main components of the role of PPARγ in ICH pathogenesis.

Racial and Gender Differences in Stroke Severity, Outcomes and Treatment in Patients with Acute Ischemic Stroke

BACKGROUNDnPrevious research has indicated that women and blacks have worse outcomes after acute ischemic stroke (AIS). Little research has been done to investigate the combined influence of race and gender in the presentation, treatment, and outcome of patients with AIS. We sought to determine the association of race and gender on initial stroke severity, thrombolysis, and functional outcome after AIS.nnnMETHODSnAIS patients who presented to 2 academic medical centers in the United States (2004-2011) were identified through prospective registries. In-hospital strokes were excluded. Stroke severity, measured by admission National Institutes of Health Stroke Scale (NIHSS) scores, treatment with tissue plasminogen activator (tPA), neurologic deterioration (defined by a ≥2-point increase in NIHSS score), and functional outcome at discharge, measured by the modified Rankin Scale, were investigated. These outcomes were compared across race/gender groups. A subanalysis was conducted to assess race/gender differences in exclusion criteria for tPA.nnnRESULTSnOf the 4925 patients included in this study, 2346 (47.6%) were women and 2310 (46.9%) were black. White women had the highest median NIHSS score on admission (8), whereas white men had the lowest median NIHSS score on admission (6). There were no differences in outcomes between black men and white men. A smaller percentage of black women than white women were treated with tPA (27.6% versus 36.6%, P < .0001), partially because of a greater proportion of white women presenting within 3 hours (51% versus 45.5%, P = .0005). Black women had decreased odds of poor functional outcome relative to white women (odds ratio [OR] = .85, 95% confidence interval [CI] .72-1.00), but after adjustment for baseline differences in age, NIHSS, and tPA use, this association was no longer significant (OR = 1.2, 95% CI .92-1.46, P = .22). Black women with an NIHSS score less than 7 on admission were at lower odds of receiving tPA than the other race/gender groups, even after adjusting for arriving within 3 hours and admission glucose (OR = .66, 95% CI .44-.99, P = .0433).nnnCONCLUSIONnRace and gender were not significantly associated with short-term outcome, although black women were significantly less likely to be treated with tPA. Black women had more tPA exclusions than any other group. The primary reason for tPA exclusion in this study was not arriving within 3 hours of stroke symptom onset. Given the growth in incident strokes projected in minority groups in the next 4 decades, identifying factors that contribute to black women not arriving to the emergency department in time are of great importance.

Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIIa

We report myocardial injury in 20 recombinant factor VIIa (rFVIIa) treated and 110 nontreated patients with intracerebral hemorrhage. Patients were treated or received standard medical management. All received EKG and cardiac enzyme testing. Elevated troponin occurred in 20% treated vs 3% nontreated (p = 0.02). Myocardial infarction occurred in 10% vs 1% (p = 0.01). We found a significant increase in myocardial injury in rFVIIa treated patients.

Treatment Targets in Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) imparts a higher mortality and morbidity than ischemic stroke. The therapeutic interventions that are currently available focus mainly on supportive care and secondary prevention. There is a paucity of evidence to support any one acute intervention that improves functional outcome. This chapter highlights current treatment targets for ICH based on the pathophysiology of the disease.

Polymorphonuclear neutrophil in brain parenchyma after experimental intracerebral hemorrhage.

Polymorphonuclear neutrophils (PMNs) infiltration into brain parenchyma after cerebrovascular accidents is viewed as a key component of secondary brain injury. Interestingly, a recent study of ischemic stroke suggests that after ischemic stroke, PMNs do not enter brain parenchyma and as such may cause no harm to the brain. Thus, the present study was designed to determine PMNs’ behavior after intracerebral hemorrhage (ICH). Using the autologous blood injection model of ICH in rats and immunohistochemistry for PMNs and vascular components, we evaluated the temporal and spatial PMNs distribution in the ICH-affected brain. We found that, similar to ischemia, there is a robust increase in presence of PMNs in the ICH-injured tissue that lasts for at least 1 to 2xa0weeks. However, in contrast to what was suggested for ischemia, besides PMNs that stay in association with the vasculature, after ICH, we found abundance of intraparenchymal PMNs (with no obvious association with vessels) in the ICH core and hematoma border, especially between 1 and 7xa0days after the ictus. Interestingly, the increased presence of intraparenchymal PMNs after ICH coincided with the massive loss of microvascular integrity, suggesting vascular disruption as a potential cause of PMNs presence in the brain parenchyma. Our study indicates that in contrast to ischemic stroke, after ICH, PMNs target not only vascular compartment but also brain parenchyma in the affected brain. As such, it is possible that the pathogenic role and therapeutic implications of targeting PMNs after ICH could be different from these after ischemic stroke. Our work suggests the needs for more studies addressing the role of PMNs in ICH.

Ongoing Clinical Trials in Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) accounts for 10% to 15% of all strokes. ICH continues to impart a considerable degree of morbidity and mortality, with 30-day mortality ranging from 44% to 50%.1–3 ICH remains a devastating disease, and current treatment options lag far behind those for ischemic stroke.nnThere are no approved therapies, which improve outcome, and treatment remains mainly supportive. Despite the lack of available acute treatment options for ICH, the past decade of clinical and preclinical research has identified important concepts in its pathophysiology and how this information might be used in developing treatment. Recent clinical trials in ICH have identified important considerations in patient selection, which have informed current and future trials evaluating treatment for ICH, and preclinical work in ICH has identified new treatment targets.nnAn understanding of the pathophysiology of the disease provides a starting point for identification of treatment targets. The pathophysiology of ICH begins with the predisposition of developing the disease, including genetics and risk factors that conspire to generate the initial hemorrhage. Once present, ICH causes both primary and secondary injury. The primary insult is attributable to disruption of adjacent tissue and mass effect.4 Secondary injury occurs with development of edema, free radical formation, inflammation, and direct cellular toxicity attributable to the deposited hematoma and subsequent degradation by-products. Each of these phases of disease provides a potential treatment target as shown in the Figure. The multiple steps along the path of disease also underscore the fact that successful treatment for ICH will most likely be multifaceted with different treatments at different time points.nnnnFigure. nTreatment targets for intracerebral hemorrhage (ICH).nnnnA complete discussion of treatment targets for ICH is beyond the scope of this brief summary and has been reported recently.5 Ongoing clinical trials in ICH are outlined in …