American Heart Association

Monthly Archives: January 2015

rt-PA plus Eptifibatide versus rt-PA

Abdel Salam R. Kaleel M.D, MSc

Adeoye O, Sucharew H, Khoury J, Tomsick T, Khatri P, Palesch Y, et al. Recombinant Tissue-Type Plasminogen Activator Plus Eptifibatide VersusRecombinant Tissue-Type Plasminogen Activator Alone in Acute Ischemic Stroke:Propensity Score-Matched Post Hoc Analysis. Stroke. 2015

This post-hoc propensity matched analysis of data gathered from the CLEAR-ER, IMS III, and ALIAS PART 2 trials attempted to shed some light on the potential efficacy of rt-PA plus eptifibatide and the need for phase III trials to further document its role in acute ischemic stroke. 

The CLEAR-ER trial was a randomized trial which treated patients with either 0.6 mg/kg IV rt-PA versus 0.6 mg/kg of rt-PA plus eptifibatide (135 mcg/kg bolus and two hour infusion at 0.75 mcg/kg/min). This study was able to demonstrate the safety profile and favorable tendency of combination therapy vs IV rt-PA alone- but what results would be obtained if the combination therapy patients of CLEAR-ER were compared to the IV rt-PA patients of the IMS III and ALIAS PART 2?

To help determine that, eighty-five combination arm CLEAR-ER patients and 169 patients from the IMS III and ALIAS PART 2 trials were included in this analysis by a propensity score matching approach based on age, gender, race, baseline mRS, baseline NIHSS, and time from stroke onset to rt-PA initiation.

The primary outcome was defined as 90 day severity adjusted mRS dichotomization based on baseline NIHSS (favorable outcome if mRS= 0 with NIHSS ≤ 7; mRS= 0 or 1 with NIHSS 8-14; mRS= 0-2 with NIHSS >14). Secondary outcomes included 90-day mRS dischotomization as “excellent” (mRS 0-1); favorable (mRS 0-2); an analysis of the ordinal mRS; and, NIHSS of 0 or 1 at 24 hours.

At 90 days, it was observed that the combination rt-PA and eptifibatide group from the CLEAR-ER group had a greater proportion of patients with favorable outcomes (45% vs 36%., p=0.18). Secondary outcomes were 52% vs 34 % for excellent outcomes and 60% vs 53% for favorable outcomes. While a favorable direction towards combination therapy was observed, the study itself, as pointed out by the authors, is inherently limited by its post-hoc analysis and the small number of combination therapy patients available for analysis. Further trials should be pursued to determine if this analysis has any bearing for clinical practice.

By |January 12th, 2015|treatment|0 Comments

DVT Prophylaxis after ICH: What do YOU do?!

Mark N. Rubin, MD

Prabhakaran S, Herbers P, Khoury J, Adeoye O, Khatri P, Ferioli S, and Kleindorfer DO. Is Prophylactic Anticoagulation for Deep Venous Thrombosis Common PracticeAfter Intracerebral Hemorrhage? Stroke. 2015

Intracerebral hemorrhage (ICH), as has been discussed and re-discussed, is not only a terrible neurologic illness with exceedingly high morbidity and mortality, but systemically trying as well. Among the myriad complications that arise in the early period after ICH, venous thromboembolism (VTE) is perhaps chief among them given the potential morbidity and mortality, with one study suggesting a nearly four-fold increase in incidence as compared to ischemic strokes (1.9% vs 0.5%). This makes for an ostensibly difficult clinical conundrum, given the appropriate reluctance to anticoagulate – the preferred means of VTE prophylaxis – in the setting of ICH. However, given the suggestion that most ICH hematoma growth is in the first 24-48 hours from ictus, there is a guideline-based recommendation (albeit with a low level of evidence supporting it) to initiate low-dose heparin or heparinoid once a patient is 24-96 hours from the event and there has been demonstration of cessation of bleeding. Given the clinical dilemma of anticoagulating in the setting of a hemorrhage and the lack of high-level evidence to guide therapy, the current investigators conducted a nationwide survey to ascertain a gestalt of pharmacologic VTE prophylaxis in this country in the setting of ICH.

The survey was conducted in a standardized and structured fashion via an ICD-9-code-based database that includes all payer types (to expand the generalizability past, say, the Medicare population only), screening for adult ICH patients from 2006-2010. They found 32,690 patients meeting their inclusion criteria and, based on pharmacy records, only 5,395 (16.5%) received any prophylactic anticoagulation during the hospital stay. Among these patients, 2,416 (44.8%) received a dose by hospital day 2 and the dominating agent was unfractionated heparin (71.1% of those patients). Of interest, there was a trend toward increasing use of VTE prophylaxis over the study period (14.3% to 18% of patients) and there was a large variation in use by region, with the Northeast leading the way with 23.2%, the South 19%, the Midwest 10.8% and the West 9.8% of patients. Geographic location was the only independent predictor of prophylactic anticoagulation in their study.

This study has interesting implications not only for ICH practice but guideline-based initiatives for any clinical situation. Why are less than 20% of patients receiving what should be a safe intervention to prevent a major, life-ending complication? Is it only because some practitioners cannot get past the use of anticoagulants in the setting of a hemorrhage, in spite of an (albeit lacking) evidence-base and guideline to support the practice? Are these data and guidelines broadly accessible? Should this practice be under the kind of scrutiny we all know of when we care for other types of stroke (acute ischemic stroke in particular)? How does batting 0.200 compare to other guideline-based recommendations in acute neurology? Or any other specialty?

Cortical Morphology and White Matter Hyperintensities

Rizwan Kalani, MD

Tuladhar AM, Reid AT, Shumskaya E, de Laat KF, van Norden AGW, van Dijk, et al EJ. Relationship Between White Matter Hyperintensities, Cortical Thickness, and Cognition. Stroke. 2015

White matter hyperintensities (WMH) seen on brain magnetic resonance imaging (MRI) of healthy, elderly patients have been associated with vascular risk factors. Potential mechanisms by which WMH lead to symptoms include atrophy of previously connected cortex and network dysfunction. In this study, Tuladhar et alevaluated the relationship between WMH, cortical morphology and cognition in older, non-demented patients with cerebral small vessel disease (e.g. WMH).

Data from 426 individuals, age 50-85 years, with WMH and/or lacunar infarct on MRI was analyzed from the Radbound University Nijmegen Diffusion Tensor MRI Prospective Cohort Study. Vascular risk factor assessment and detailed neuropsychological testing was completed on all enrolled. All subjects’ MRI was obtained on the same scanner. Two blinded raters calculated MRI WMH load and cortical thickness (CT) was measured by imaging analysis software.

WMH burden was negatively correlated with bilateral fronto-temporal region CT but positively correlated with paracentral region CT (even after adjusting for vascular risk factors) (p<0.05). WMH distribution was associated with regional CT – for example, the burden in the corpus callosum, internal capsule, corona radiata, posterior thalamic radiation, and superior longitudinal fasciculus was negatively correlated with CT in the fronto-temporal regions. The authors additionally demonstrated that thinner CT was related to worse cognitive performance (including mini-mental status exam, verbal memory, fluency, attention); this remained true after adjusting for age, gender, education, and also WMH. Though WMH was associated with the higher intellectual functions testing, the relationship was no longer significant when controlling for CT.

This report provides further evidence on how vascular disease may affect cognition. It is important to remember that the findings are cross-sectional, correlative, and hypothesis-generating. Future studies will have to elucidate the pathophysiology of cortical atrophy in those with WMH and determine what other factors contribute to it.

Acute Stroke Care in Europe

Ali Saad, MD

Wiedmann S, Hillmann S, Abilleira S, Dennis M, Hermanek P, Niewada M, et al. Variations in Acute Hospital Stroke Care and Factors Influencing Adherence to Quality Indicators in 6 European Audits. Stroke. 2015

This is a European study looking at risk factors that impact variations in acute hospital stroke care during 2007-2008. The authors used national databases from Germany, Poland, Scotland, Catalonia, Sweden, England/Wales/Northern-Ireland to look at demographic and clinical characteristics.

Key findings were that older patients were less likely to get thrombolysis, anticoagulation, and stroke unit care, but were more likely to be screened for dysphagia. Women were also less likely to receive anticoagulation/antiplatelet treatment or stroke unit treatment. aside from these trends, the study also found that there was great variation in stroke quality indicators like the delivery of thrombolytics, dysphagia screening, admission to a stroke unit for care, anticoagulant therapy, antiplatelet therapy etc. The use of thrombolytics alone varied from 1.3% to 9.1% among different audits.

Standardizing care in Europe would be more difficult compared to the US given hospitals’ different definitions of a stroke unit and the lack of a unifying governing body. Although the EU helps provide universal health care, it currently does not dictate best clinical practice for stroke. Joint Commission International does accredit hospitals as primary stroke centers, but no European countries have participated in this accreditation. I contacted the European stroke organization with the same question and am waiting to hear back from them. i’ll update this blog post with a comment if I do.

Some similarities the authors found compared to the US data include older patients being less likely to receive anticoagulation for Afib and more likely to receive dysphagia evals.

For those interested in the “weekend effect” on the delivery of stroke care, this study did not find one. the literature shows no consistent weekend effect and varies widely by country and hospital studied. Even different studies done of the same country, but at different hospitals or periods of time, show inconsistent findings.

Limitations of this study include no mention of a body (or lack thereof) that accredits stroke cares or enforces standard of care through hospital reimbursement like in the US. It is a retrospective study of several European countries so selection bias may have occurred. Although the authors showed a variation in stroke care, they did not present numbers comparing the same parameters measured in US counterparts, the data was also too limited to provide measures like functional outcome and mortality to show whether the lack of standardized care translated to worse morbidity and mortality. Lastly, there is no mention of a key stroke quality measure, post-stroke rehab, possibly due to the lack of data.

How does this study change my practice? It makes me more cognizant of biased treatment of women and the elderly. also makes me aware of the lack of standardized care for acute stroke in Europe.

Comprehensive evaluation of the relationship of abnormal brain lesions and cognitive function

Abnormal lesions in the brain will affect your cognition over time. This concept is rather intuitive but hard to prove because of our past limitations in performing good cognitive exams and mapping brain volume loss. This however has changed with the advent of newer technology. The authors of this paper studied a subset of patients from the Atherosclerosis risk in Communities (ARIC) population who underwent a brain MRI scan. Those with poor cognitive scores suggestive of dementia were excluded. Participants were additionally administered a battery of neuropsychological tests. Cognitive domains included: Memory (Delayed Word Recall Test, Logical Memory immediate and delayed recall, and incidental Learning from the Wechsler Memory Scale-III), Psychomotor Speed/Executive Function (PS/EF) (Digit Symbol Substitution Test, Trail Making Test parts A and B and WAIS-R Digits Span Backwards), and Language (Letter fluency, Boston Naming Test, and Animal Naming). Additionally all participants also underwent an extensive evaluation of vascular risk factors at each visit with detailed medical history and APOE genotyping performed.

A 3 Tesla MRI scan with all standard sequences was performed. White matter hyper intensity burden was calculated using total intracranial volume as a covariate. Cortical infarctions were counted and characterized on flair sequences as large or small and subcortical infarctions were also sub classified. Regions of Interest (ROI’s) were identified based on relevance to cognition and cortical volumes of the right and left hippocampus, posterior regions and frontal lobes were estimated. Primary analyses were conducted using general linear models. Potential nonlinear relationships were examined with lowess smooth curves and modeled using fractional polynomial and linear-spline formulations. Potential outlier effects were assessed with DFFITS for influential points, Cook’s D statistic, and graphical displays such as residual and added-variable plots. Several statistical modifications were undertaken for the cognitive scores, MRI results and brain volume measurement that are detailed in the manuscript. All models were adjusted for clinical and demographic variables including age, sex, race, education, and history of diabetes, history of hypertension, history of alcohol use, and history of smoking, APOE ε4 genotype and total intracranial volume. Interaction terms were examined to assess potential modifying effects of sex and/or race; none were supported. Sensitivity analyses to  for hippocampal ROIs, <60 mm3 for posterior cortical  for frontal cortical ROIs, and using fractional polynomial formulations for examine stability of estimates were conducted examining adjustment model, nonlinearity threshold and sampling weight incorporation; similar results were found throughout.

Cross-sectional mediation analyses showed the posterior cortical regions and a group of frontal regions moderately mediated associations between WMH burden and a cognitive composite representing psychomotor speed and executive function (PS/EF). The association between infarcts, the variable representing the presence of any infarct, and the PS/EF composite was also moderately mediated by the posterior cortical ROI. In bivariate analyses, both CVD imaging features – WMH and infarcts – were associated with posterior cortical ROI volume. Only WMH were associated with frontal ROI volume.
This study is a complex yet valiant effort in establishing the link between brain lesions, brain volume and cognitive function. It is certainly hypothesis generating and lends credence to the theory that loss of brain volume mediates the cognitive slowing in patients with cerebrovascular disease. 

Improving Stroke Education with High School Students

Rizwan Kalani, MD

Matsuzono K, Yokota C, Takekawa H, Okamura T, Miyamatsu N, Nakayama H, et al. Effects of Stroke Education of Junior High School Students on Stroke Knowledgeof Their Parents: Tochigi Project. Stroke. 2015

The Tochigi prefecture (district), with its 2 million inhabitants, has among the highest stroke mortality rates in Japan. In this study, Matsuzono et al evaluated if teaching high school students about stroke (signs/symptoms, appropriate action at onset, risk factors, and the FAST mnemonic) could improve their parents’ knowledge about stroke in a large, high-risk community.

1127 students (13-15 years old) were enrolled along with their parents. Baseline questionnaires assessed knowledge regarding stroke of both the students and their parents. Public health workers then gave students a stroke didactic, showed a brief cartoon, and read a comic to them. This was followed by having the students take the comic home and reviewing it with their parents. Follow-up questionnaires assessing knowledge regarding stroke were then completed.

Results from questionnaires were evaluated from 1125 students and 915 parents/guardians (of which 137 were medical professionals). The number of correct answers increased significantly for all questions in students, except that corresponding to headache as a stroke symptom (60.7% prior and 94.3% after, p<0.001). Similarly, the parents answered questions correctly with significantly increased frequency except recognition of headache and hemisensory loss as acute stroke symptoms and hypertension as a risk factor (83.0% vs 92.7%, p<0.001). 91% of students and 93% of parents understood the FAST mnemonic after being taught.

This study again demonstrates that young adults and children attending school can assist in improving stroke education to high risk populations. It shows that simple, culturally-tailored, population-based approaches to improving stroke outcomes can be effectively implemented. Future work will have to evaluate if such strategies can affect outcomes (improving vascular risk factor screening/control and health-related behaviors), be applied more broadly for public health education and stroke prevention, and be improved to maximize impact.

By |January 5th, 2015|prevention|0 Comments

Square the circle: CTP or DWI for hyperacute stroke decision-making?

Mark N. Rubin, MD

Schaefer PW, Souza L, Kamalian S, Hirsch JA, Yoo AJ, Kamalian S, et al. Limited Reliability of Computed Tomographic Perfusion Acute Infarct Volume Measurements Compared With Diffusion-Weighted Imaging in Anterior Circulation Stroke. Stroke. 2015

For anyone who was worried that acute stroke evaluation and management was getting too easy, square this circle: should we be making major decisions based on CT-based perfusion mapping or MRI-based restricted diffusion?

This question has major implications for clinical practice and acute stroke research. The broad availability and rapid acquisition of CT makes it an attractive means of inferring “physiologic data” during hyperacute stroke, and is the dominant mode of advanced imaging in acute stroke practice at large. That being the case, many patients are likely triaged for care, including endovascular reperfusion, based on the clinical scenario and CT perfusion data. Furthermore, CT perfusion thresholds have been used in several large-scale acute stroke treatment trials.

This contribution from Dr. Schaefer, et al calls these practices into question. The investigators designed their study around the practical questions, in their words: “Can CTP substitute for DWI in individual patient triage? And, can CTP replace DWI for stroke treatment trials?” They sought to answer these questions by recruiting consecutive acute stroke patients who were able to undergo CTA, CTP and MRI within hours of one another, a demonstrable proximal anterior circulation occlusion and a 3-month mRS score. They were able to analyze 55 cases meeting these criteria and scrutinized the correlation between CTP (more specifically, CBF and CBV maps) and DWI in terms of size and signal-to-noise ratio. Their results were clear if not surprising: visual inspection of perfusion abnormality (CBF better than CBV) correlated with DWI overall but not perfectly so, and the signal-to-noise was much higher with DWI, allowing for better delineation of the infarct volume.

As far as I’m concerned, these findings beg more questions than they answer, making this a very successful contribution! This puts data to that sense we all get when trying to digest Stroke and the Amazing Technicolor DreamCTP, but in practice and research design we have to seriously consider at what we are looking. The availability and rapidity of CT makes us hope and wish it is an acceptable surrogate for stroke lesion size, but these data suggest it is too imprecise a tool to make it the definitive approach as compared to MRI. I anticipate these data will positively inform future diagnostic and treatment trials for hyperacute stroke.