American Heart Association

Monthly Archives: February 2015

What’s Drip and Ship got to do with it?

Duy Le, MD

Sheth KN, Smith EE, Grau-Sepulveda MV, Kleindorfer D, Fonarow GC, and Lee H. Schwamm LH. Drip and Ship Thrombolytic Therapy for Acute Ischemic Stroke: Use, Temporal Trends, and Outcomes. Stroke. 2015

Finding ways to improve access to stroke care is of high priority. The next promising stroke treatment is rendered useless unless accessible to stroke patients. In light of this, drip and ship has been one of the many methods to increase IV-tPA access to the general population. Smaller hospitals that do not feel comfortable managing patients will often transfer to larger centers after initiating IV-tPA. Additionally, there is often transfer with the intention of potentially bridging with IA therapy. With the advent of the recent MR CLEAN results, we will definitely see this trend increase. While many places have already become knee deep in the drip and ship method, the questions that still loom at large include the following: 1) Is it a safe process? 2) Are there differences in the populations? 3) Are outcomes affected? 

Sheth et al evaluate these questions in a retrospective fashion using GWTG data from April 2003 to Oct 2010. They included patients who received IV-tPA under 3 hours. Excluded were sites with fewer than 30 IV-tPA patients, inpatient strokes, patients receiving experimental therapies. Ultimately, 44,667 patients were treated with IV-tPA. 10,475 (23.5%) were by way of drip and ship. Baseline characteristics were unbalanced with regards to stroke severity (first NIHSS median 12.9 for front-door patients and 11.0 for drip& ship [significant]), arrival between the hours of 7 am to 5 pm (47.2% vs. 28.7% significant), age 70.1 vs 67.3 years (significant), and sex (male 49.9% vs. 46.3% significant). With regards to outcomes adjusted for NIHSS, hospital mortality, sICH, independent ambulation and discharge home all favored front door patients; significant.

The flaw of this study lies in the fact that the baseline characteristics of the front door vs. drip and ship group are imbalanced in so many different categories. Statistically, Sheth et al attempt to adjust for these differences in their model. Due to the large number of subjects evaluated in the study, there is ultimately some credence to the results. It tells us that as a whole, drip and ship patients may do slightly poorer than their doorstep counterparts. However, their baseline NIHSS is lower than their front door counterparts, which although initially baffling, is explained by the fact that scales documented for drip & ship patients typically occur upon arrival to the second hospital. Thus the drip & ship patients have received the IV-tPA for some time already, and early responders may confound this comparison of baseline NIHSS.

There are many other instances that we can point out in terms of weaknesses due to the inherent nature of being a retrospective study. Nonetheless, the study still makes a powerful observation that drip and ship method for IV-tPA treatment is a definite reality. 25% of IV-tPA’s were given in a drip and ship manner. Although the data does appear to show that drip &ship patients do slightly worse with the above outcomes, compared to their front door counterparts, the retrospective nature of this study and baseline data capturing likely are confounding the results. I definitely agree with the encouragement of this paper to push for improvement of data capturing by targeting quality improvement projects and performance measures. After all, even if outcomes are not as good as front door patients, drip and ship still has the potential for better outcomes than no intervention at all.

By |February 11th, 2015|clinical|0 Comments

Biomarkers Predict Death After Stroke

Rizwan Kalani, MD

Greisenegger S, Segal HC, Burgess AI, Poole DL,  Mehta Z, and Rothwell PM. Biomarkers and Mortality After Transient Ischemic Attack and Minor IschemicStroke: Population-Based Study. Stroke. 2015

Premature death after stroke or TIA is more often a consequence of cardiac disease or malignancy than the cerebrovascular event itself. Prior studies evaluating various serologic biomarkers for predicting recurrent vascular events or death after stroke/TIA have shown mixed results. Greisenegger et al evaluated the association of several biomarkers with all-cause mortality (particularly cardiac or cancer death) in those with minor stroke or TIA.

The cohort studied came from an ongoing population based-study of vascular disease incidence and outcomes in Oxfordshire, UK (Oxford Vascular Study). TIA was defined according to the WHO definition (<24 hours of focal neurological deficit suspected to be of vascular cause – not imaging-based definition that excludes tissue injury) and minor stroke included those with NIHSS<3. Patient death was classified into vascular (stroke, cardiac, etc.) and non-vascular (cancer, other systems) causes. The panel of biomarkers collected are implicated in 1. the inflammatory response – IL-6, CRP, neutrophil-gelatinase associated lipocalin (NGAL), soluble tumor necrosis factor receptor-1 (sTNFR-1); 2. thrombosis – thrombomodulin (TM), fibrinogen, P-selectin, D-dimer, von Willebrand factor (vWF), protein-Z; 3. cardiac function – nt-proBNP; 4. cardiac/neuronal injury – neuron-specific enolase (NSE), heart-type fatty acid binding protein (HFABP); and 5. neural regeneration – BDNF.

929 patients with TIA (47%) and minor stroke (53%) were enrolled. The median age was 74 years and 51% were female. Biomarkers were drawn on average 5 days after the cerebrovascular event; the median follow-up of patients was 6.4 years. 39% (361/929) of patients died during the follow-up period – 151 of vascular cause, 184 non-vascular cause, and 26 unclear etiology. None of the biomarkers correlated with recurrent non-fatal stroke or MI. sTNFR-1, NGAL, CRP, IL-6, vWF, nt-proBNP, and hFABP were predictive of all-cause mortality after adjusting for demographics, risk factors, and prior medical therapy. The strongest associations were for sTNFR-1 (HR 1.45), nt-proBNP (HR 1.44), and hFABP (HR 1.37). sTNFR-1, NGAL, vWF, nt-proBNP, and hFABP were predictive of vascular death in multivariate analysis with the strongest association detected for nt-proBNP (HR 1.8). Among those, all but NGAL were predictive of cardiac death. Nt-proBNP was strongest predictor of stroke-related death. IL-6, CRP, NGAL, sTNFR-1, and hFABP were predictive of non-vascular death. The strongest associations were for hFABP (HR 1.5) and sTNFR-1 (HR 1.47); these two were also predictive of cancer-related death (hFABP HR 1.61, sTNFR-1 HR 1.41). Taken together, sTNFR-1, vWF, hFABP, and nt-proBNP added more prognostic information in comparison to outcome prediction models based on clinical risk factors. These four markers remained predictive of all-cause mortality at 2, 3, and 5 year follow-up.

This study demonstrates that biomarkers related to the inflammatory response, cardiac function, cardiac/neuronal injury, and thrombosis are independent predictors of death in patients with minor stroke or TIA. Those with highest predictive value were sTNFR-1, vWF, nt-proBNP and hFABP. The value of nt-proBNP was shown to be specifically predictive of vascular death and may assist in guiding further cardiac evaluation after stroke. hFABP may be of value for identifying occult malignancy after cerebrovascular ischemia, but this needs to be evaluated in independent cohorts. Future studies will have to validate this and assess the utility of incorporating these biomarkers in clinical care.

By |February 10th, 2015|prognosis|1 Comment

Location, Location, Location: Distance from Carotid Terminus to MCA Clot Predicts Outcome

Mark N. Rubin, MD

Friedrich B, Gawlitza M, Schob S, Hobohm C, Raviolo M, Hoffmann KT, and Lobsien D, Distance to Thrombus in Acute Middle Cerebral Artery Occlusion: A Predictor of Outcome After Intravenous Thrombolysis for Acute Ischemic Stroke. Stroke. 2015

It is well known to strokologists that patients with acute ischemic stroke from proximal occlusions tend to fare poorly as compared to those with distal occlusions. Several prospective and retrospective observational studies have confirmed this relationship. What has been lacking, however, is precision in the definition of “proximal occlusion,” as seen with the heterogeneity of definitions across trials and observational studies.

This interesting CTA-based imaging study sought to rigidly stratify occlusion location by distance from a single anatomical landmark: the middle of the “carotid T.” In a standardized fashion, the investigators looked back at CTA studies from 136 patients who received IV tPA and measured from the midpoint of the distal ICA to the proximal end of a clot and compared that distance to 7-day NIHSS and 90-day mRS. Overall, the main finding was the distance from the carotid T to the clot was an independent predictor of outcome, even when controlling for clot length. There was an exponential decline in likelihood of good outcome (mRS < or = 2) with distance to thrombus of <16mm. Short distance to thrombus also predicted long thrombus length as compared to more distal occlusions.

In addition to assisting in the definition of proximal occlusions with discrete measurements and a practical anatomical landmark for standardization, this investigation also suggests that perhaps we should pay more attention to clot location and length in our treatment trials and natural history studies, as evidence mounts that these data are quite relevant.

By |February 9th, 2015|prognosis|0 Comments

“Do You Understand The Words That Are Coming Out of My Mouth?”: Impact of Language Barriers on Stroke Care

Vikas Pandey, MD

Shah BR, Khan NA, O’Donnell MJ, and Kapral MK. Impact of Language Barriers on Stroke Care and Outcomes. Stroke. 2015

As a stroke fellow and previous neurology resident in Miami covering a county hospital where the majority of patients speak either Spanish or Haitian Creole exclusively (Spanish 70%, Creole 10%), the linked article regarding language barriers in stroke care is one I can definitely relate to. My high school level Spanish improved exponentially during residency and this enabled me to obtain accurate patient accounts and histories, pinpoint better time of onsets and allowed for better recognition of tPA contraindications when I was the first-responding resident. My Haitian Creole ability however is still essentially nonexistent (leading to an interaction similar to Chris Tucker and Jackie Chan referenced in the title). By not being able to communicate easily to a significant number of my patients, I personally felt the care I was delivering to be suboptimal as language is obviously the critical way to tell the patient what has happened to him/her, what disabilities this will lead to, what expectations to have in terms of recovery, and what things can be done for prevention. Even going through a translator without experience in the medical field may not be enough to relay this message properly.

The group out of Ontario, Canada decided to test whether the presence of a language barrier during delivery of care for ischemic stroke led to worsened mortality and clinical outcome. They selected patients from the Ontario Stroke Registry who were admitted with acute stroke (ischemic or hemorrhagic) or TIA seen in the emergency department or hospitalized in 12 stroke centers in Ontario Province. They determined that a language barrier was present if the patient’s preferred language was not English at most of the hospitals within the network except at one which operated mainly bilingually in which case the patient had a language barrier if they could not speak English or French. After excluding subarachnoid hemorrhages, the final cohort had 14,293 patients of which 1,506 (10.5%) had a language barrier. They found that 7 day mortality rate was 7% among those with a language barrier and 9.2% among those without one (p= 0.006). There was a similar and significant difference at 30 day and 1 year mortality. They also adjusted for other variables such as age, sex, ethnicity and socioeconomic status, stroke characteristics, and vascular risk factors and found no difference in the results. There was no difference in in-hospital complications. The rate of thrombolysis also did not differ.

The observation that patients with a language barrier conversely did better in regards to initial and out-of-hospital mortality is a somewhat surprising one. The authors did find, however, that this difference became less significant when taking into account the desire for aggressive versus supportive care. This lead to a higher percentage of language-barrier patients that left the hospital with a residual neurological deficit. Perhaps one explanation for this would be the presumption that not being able to fully explain the extent of the patient’s condition to the patient’s family (who may also have the language barrier present) may lead to maintenance of aggressive care and less early mortality. Another factor playing a role in this is the possibility of inefficacy of in-hospital rehab in patients with language barriers. The authors also noted that the impedance in communication may have led to more assessments and imaging during hospitalization that may have improved the mortality numbers. So while my feelings of inadequacy when treating Haitian patients at my hospital may be unsettling, there is a possibility that this barrier is leading to more frequent imaging and more in-depth patient assessment and examinations, hopefully leading to better outcome.


Another Crack at it for Candesartan and Acute Ischemic Stroke

Goals of blood pressure has been a hot topic in hemorrhagic strokes. The INTERACT trials have confirmed with evidence, that it is safe to lower blood pressure acutely in patients with intracerebral hemorrhages. The question of what blood pressure goals should be during acute ischemic strokes remains a question. While it is intuitive that permissive hypertension is beneficial for patients, there has never been any clear data to suggest what the actual goals should be. Additionally, as intuitive as it seems to increase perfusion by allowing for permissive hypertension, is there truly a benefit with permissive hypertension? The Scandinavian Candesartan Acute Stroke Trial (SCAST) done prior did not show benefit with regards to blood pressure lowering with candesartan in acute stroke. Sanset et al attempt to re-evaluate this same data to see if there is difference in outcome when looking at different stroke subtypes. 

The data was generated from the original SCAST trial which was a randomized, placebo controlled trial including 2029 patients presenting within 30 hours of ischemic or hemorrhagic stroke with systolic blood pressure greater than 140 mmHg. Acute ischemic stroke (AIS) subtype was determined using the Oxfordshire Community Stroke Project (OCSP) classification.

Results included 1733 patients with AIS. There was a trend towards better effect (mRS 0-2) of candesartan in patients with larger infarcts (Total anterior Circulation + Partial anterior circulation) than in patients with smaller infarcts (Lacunar Infarction). This is unfortunately only a trend, as confidence intervals for all stroke subtypes cross 1.0. Lastly, A composite vascular end point consisting of vascular death, myocardial infarction or stroke during the first 6 months did not show any difference between the two groups.

One thought to ponder (as this study insinuates) is that small vessel infarct patients may be harmed with acute blood pressure lowering. This is thought to be secondary to baseline elevated blood pressures which would be too low with goals such as <140 systolic. It is worthwhile to note that OCSP categories of “total anterior circulation,” “partial anterior circulation,” “posterior circulation,” and “lacunar infarct” were used. An actual measurement of infarct volume may have been more useful, although this parameter is not likely available due to using data from a prior study. Additionally, using TOAST category stroke subtypes may have been more useful in the clinical setting as TOAST imparts clinical relevance more so than the OCSP does. Ultimately this study shows that there was only a trend towards better effect of candesartan in patients with larger infarcts. I would argue however, it is not necessarily a function of infarct volume, rather it may be due to the mechanism of stroke, ie…large vessel infarct vs. lacunar infarct. In either case, this notion needs further studies to truly support such a notion.

By |February 5th, 2015|treatment|0 Comments

Genetic Study of Intracranial Aneurysms

Rajbeer Singh Sangha, MD

Yan J, Hitomi T, Takenaka K, Kato M, Kobayashi H, Okuda H, et al. Genetic Study of Intracranial Aneurysms. Stroke. 2015

The authors of this study delve into an interesting topic of determining the genetic predisposition of intracranial aneurysms (IA). Intracranial aneurysms when ruptured can lead to subarachnoid hemorrhage and can lead to devastating brain injury. Evaluation of the pathogenesis of aneurysms on the basis of luminal forces—such as high blood flow, shear stress and turbulence—alone may conceal other equally important abluminal factors, such as morphological or biological phenomena within the vessel wall, or the perianeurysmal environment.1-3 Microarray gene analyses of human tissue has found differential gene expression profiles between healthy arterial wall and aneurysm wall, with increased expression of genes related to infiltration of inflammatory cells, complement activation, apoptosis and inhibition of re-endothelialization in the aneurysm wall.4 Yan and colleagues attempted to determine the genetic component that contributes to the process of the development of intracranial aneurysms by performing whole exome sequencing of 42 cases with a definite phenotype of IA from 12 families. 

They approached this daunting task by first establishing a large cohort of familial and sporadic IA cases from hospitals located in the western part of Japan. Using complex genetic analysis, they were able to determine via replicate association studies that only p.E133Q in ADAMTS15 was aggregated in the familial IA cases [odds ratio, 5.96; 95% confidence interval: 2.40–14.82; P=0.0001, significant after the Bonferroni correction (P =0.05/78=0.0006)]. Furthermore, they found that silencing ADAMTS15 and overexpression of ADAMTS15 p.E133Q accelerated endothelial cell migration, suggesting that ADAMTS15 may have antiangiogenic activity.

The authors take an important step forward in the cumbersome process of identifying possible genetic links that exist for intracranial aneurysms and this warrants further studies as well as genetic testing on patients that present with a familial history of intracranial aneurysms. Through genetic analysis, future targeting of these genes will go a long ways in reducing the burden of disease. I believe we have only touched the tip of the iceberg and gene therapy shall soon be entering its infant stages as further research is conducted.


1. Schievink, W. I. Intracranial aneurysms. N. Engl. J. Med. 336, 28–40 (1997).
2. Wiebers, D. O. et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362, 103–110 (2003).
3. Hashimoto, T., Meng, H. & Young, W. L. Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling. Neurol. Res. 28, 372–380 (2006)
4. Burton, C. & Johnston, J. Multiple cerebral aneurysms and cardiac myxoma. N. Engl. J. Med. 282, 35–36 (1970).

Interleukin 23 levels are increased in carotid atherosclerosis – A possible role for the IL-23/IL-17 axis?

Michelle Christina Johansen, MD

Abbas A, Gregersen I, Holm S, Daissormont I, Bjerkeli V, Krohg-Sørensen K, et al. Interleukin 23 Levels Are Increased in Carotid Atherosclerosis: Possible Role for the Interleukin 23/Interleukin 17 Axis. Stroke. 2015

The world of immunology and elucidation of cytokine pathways is not usually the focus of the vascular neurologist, but perhaps our attention should be redirected. It is well established that atherosclerosis is a state of inflammation and prior studies have shown an increased expression of IL-23 in carotid lesions, with particularly high levels in symptomatic patients. Targeting of IL-23, a member of the IL-12 family of cytokines with pro-inflammatory properties, is already underway in other autoimmune diseases including psoriasis, inflammatory bowel disease and rheumatoid arthritis. How is this interleukin, with its role in producing IL-17 related to cerebrovascular disease?

Abbas et. al in their study reinvestigated the association of IL-23 to atherosclerosis and sought to better establish any relationship between expression and cerebrovascular disease. 177 patients with internal carotid stenosis (≥50%) were recruited and classified according to symptoms: 69 patients had a stroke/TIA/amaurosis fugax ipsilateral to the stenosed carotid artery in the prior 2 months and 108 patients either had symptoms >2 months or had no symptoms. The patients were compared to 24 healthy controls from the same area of Norway. Plasma samples were obtained by venipuncture. Plaque samples were obtained for examination from 68 of the patients with carotid atherosclerosis and compared to non-atherosclerotic control vessels of organ donors.

Those with carotid atherosclerosis (177) were found to have markedly raised plasma IL-23 levels compared to controls (24). Notably, the level of IL-23 increased in a step wise fashion with the highest plasma levels in those with the most recent symptoms (<1month). Even those without symptoms still had higher levels of IL-23 than healthy controls. When the plaque samples were evaluated, IL-23 as well as IL-23 receptors (R) were 18 fold higher in those with atherosclerosis. However, there was no association between levels of IL-23 and presence or absence of symptoms.

In order to better elucidate the role of IL-23, plasma dendritic cells, peripheral blood mononuclear cells and monocytes from patients with carotid atherosclerosis were evaluated. The investigators found those with carotid atherosclerosis had increased levels of IL-23/IL-23R in dendritic cells as well as increase release of IL-17 from mononuclear cells when stimulated with IL-23 in comparison to healthy controls. IL-23 promoted release of tumor necrosis factor (TNF) only in those with carotid atherosclerosis.

Recent data indicate that IL-23 is a dominant cytokine controlling inflammation in peripheral tissues and joints, but what role does it have to play in stoke? This study suggests that IL-23 plays a unique role in the patient with atherosclerosis compared to healthy controls. The study has limitations such as a small control sample size, but is it possible that the release of IL-23, the interaction with its receptor or the stimulation of IL-17 represent three potential targets for new therapies? Could we control some of the sequela of stroke by a modulation of this cascade? While other trials targeting the inflammatory response in stroke are underway using Methotrexate and Tysabri, perhaps further research should be directed at the IL-23/IL-17 cascade in hopes that in vivo trials could provide even more exciting results.