American Heart Association

Monthly Archives: June 2013

Risk of SAH and Early Case Fatality

Vasileios-Arsenios Lioutas, MD

  • Garbe E
  • Kreisel SH
  • and Behr S.
  • Risk of Subarachnoid Hemorrhage and Early Case Fatality Associated with Outpatient Antithrombotic Drug Use. Stroke. 2013

    Subarachnoid hemorrhage (SAH) constitutes a relatively small percentage of stroke but carries a high risk of morbidity and mortality. There are several well established risk factors, including cerebral artery aneurysms, polycystic kidney disease and hypertension. 

    In this population based, case-controlled study, Drs. Garbe, et al, broach the issue of outpatient antithrombotic use effect on SAH incidence and early (30-day) case fatality. Their study was performed in Germany from 2004-2006 and includes detailed data on hospitalizations for SAH along with outpatient prescriptions for antirhrombotic medications, including phenprocoumon (warfarin analogue used in Germany), unfractionated or low molecular weight heparins, clopidogrel/ticlopidine and low dose aspirin.

    In a multivariable model, phenprocoumon, aspirin and clopidogrel/ticlodipine were independently associated with increased risk for SAH (adjusted ORs 1.7, 1.5, 1.6 respectively). A similar trend was noted for heparin, but the sample was significantly underpowered, likely due to limited use of heparin in the outpatient setting. On the contrary, the early case fatality was not affected by antithrombotic drug use but rather by age (over 70) and hypertension.

    Interestingly the study does not include any information regarding smoking status, as it was impossible to gauge this by review of the epidemiologic data. Although it would be interesting to include this variable, the authors’ point that smoking status would be unlikely to significantly affect the question they attempt to answer is probably valid.

    In the contrary, one of the strengths of the study is that it represents a “real life scenario”. Those medications are widely used in most of the Western societies where cardiovascular disease predominates as major cause of mortality and morbidity. Besides their better studied bleeding complications, it seems that they also confer increased risk for subarachnoid hemorrhage as well, emphasizing the need to prescribe and use them cautiously.

    SLSR differences in outcome and predictors between ischaemic and haemorrhagic stroke

    Jose Gutierrez, MD, MPH

    Bhalla A,Yanzhong Y, Rudd A, and Wolfe, CDA. Differences in Outcome and Predictors Between Ischemic andIntracerebral Hemorrhage: The South London Stroke Register. Stroke. 2013

    Stroke is a devastating disease affecting millions of patients worldwide. Stroke outcomes are subject of great interest, especially for comparison of effective therapies and prognostication. In this article, investigators used a large, population-based cohort of patients with incident stroke and followed them over 10 years. Some of the information captured for this analysis included vascular risk factors, level of care and severity during the acute stroke episode, presence of dysphagia and urinary incontinence, stroke subtypes (Ischemic vs. hemorrhagic stroke) and measures of functionality as defined by the Barthel Index and life status. The authors used logistic regression to identify predictor of poor outcome defined as either dead or a Barthel Index of 14 or less.
    The authors included 3730 patient, 85% had ischemic stroke. Patient with ICH were more likely to be men, young, and African Blacks while ischemic stroke was more frequent in whites. Patients with ICH had a more severe presentation of acute stroke but were less likely to have prior disability compared to those with ischemic strokes. The predictors for poor outcome varied by stroke subtype and time to follow up. At 1 year, older age, a more severe clinical presentation (defined by Glasgow coma scale, urinary incontinence, dysphagia and Barthel index < 15), atrial fibrillation and diabetes were associated with worse outcome in patient with ischemic stroke while in those with ICH, female sex, Barthel index < 15 at presentation (not at baseline) and urinary incontinence were predictors of bad outcome. At 10 years, only increased age, urinary incontinence, Glasgow coma scale < 13, and atrial fibrillation were predictors of poor outcome while for ICH,  urinary incontinence and age reached statistical significance. Predictors of improvement in Barthel Index from 7 days to 3 months were the presence of ICH as the primary stroke subtype, Glasgow coma scale < 13 and presence of urinary incontinence while older age and female sex were negative predictors of improvement.

    These results confirm previous literature that suggests that although patients with ICH have greater short-term mortality that hose with ischemic stroke, if survival is achieved, the outcome might be better. Interestingly, incontinence and dysphagia seem to be good predictors of poor outcome. Whether these factors are surrogate of extent or localization of the injuries remains to be determined. A better understanding of factors promoting recovery and improved outcomes would certainly impact millions of people with stroke and lessen the societal burden of this disabling disease, enhancing the importance of these results.

    MRI T1 contrast permeability

    Osman Mir, MD


    Liu HS, Chung HW, Chou MC, Liou M, Wang CY, Kao HW. Effects of Microvascular Permeability Changes on Contrast-Enhanced T1and Pharmacokinetic MR Imagings After Ischemia. Stroke. 2013


    Liu et al explored the effects of microvascular permeability on T1 contrast enhancement on MRI after ischemic stroke and  its relationship with hemorrhagic transformation. 

    It has been previously shown that reperfusion in the setting of ischemia might be related to Hemmorhagic transformation(HT) of ischemic tissue. They wanted to further elucidate this finding with the help of contrast enhancement. Contrast enhancement in AIS(acute ischemic stroke) is typically in the sub-acute phase and associated with breakdown of Blood Brain Barrier(BBB). Liu et al have used contrast enhancement by doing multiple MRI’s of different patients at different time points to better assess breakdown of BBB and also to look at Microvascular Permeability.


    This is a retrospective study in which they looked at 26 patients getting MRI’s in hyperacute to chronic phases exploring the relationship. They found that Endothelial transfer constant ktran, an indirect measure of Microvascular permeability, is a better predictor of Parechymal enhancement in the ischemic tissue rather than Cerebral blood volume in hyperacute and acute settings. Parenchymal enhancement as seen on T1 images is related more to luxury perfusion in later stages.

    Also in patients with HT there was increase in ktran compared to patients with non HT. This probably needs further investigatation in a large patient population in a prospective fashion. However, it does raise interesting questions regarding application of perfusion imaging and ktran in hyperacute stroke patients going for reperfusion therapy.

    Validation of the SOAR stroke prognostic score

    Waimei Tai, MD

  • Kwok CS
  • Potter JF
  • Dalton G
  • George A
  • Metcalf AK
  • Ngeh, J.
  • The SOAR Stroke Score Predicts Inpatient and 7-Day Mortality in Acute Stroke. Stroke. 2013


    Kwok et. al recently wrote an interesting article that externally validates a predictor score of near term mortality for stroke (ischemic and hemorrhagic). The same group designed the predictor score using another cohort (unable to review the original paper as it is in press) and now they have externally validated the predictor using routinely collected data in NHS hospitals. The strength of the score is its simplicity. SOAR (0-7 scale) uses simple clinical data: stroke type (ischemic/hemorrhagic), stroke distribution (Oxford Community Stroke Project Classification), age, and pre-morbid Rankin.  For readers unfamiliar with OCSP, it was originally designed for ischemic stroke and classifies stroke as:  total anterior (TACI), partial anterior (PACI), lacunar (LACI), and posterior (POCI) circulation infarcts.

    The trouble I see with the intrinsic design of the score are two-fold: (1) as far as I’m aware, OCSP is not a routinely recorded variable in the clinical data in North America and (2) pre-morbid Rankin is also not routinely collected for clinical purposes although one may attempt to extrapolate pre-morbid Rankin based on function if that is recorded. The OCSP score maybe derived from review of imaging, so it maybe easy to score post-hoc, but given that it was initially designed for ischemic stroke alone, I am not sure of its applicability on hemorrhagic stroke.

    The simplicity of the SOAR score itself belies the hidden complexity of inputs that themselves need extrapolation from routine clinical data. For now, it is simple relative to other predictor scores available.

    The low positive predictive value of 23% for score > 3 is also concerning, as the authors mentioned even though the sensitivity (80%) and specificity (72%) seem reasonable. Eventually a score derived from more routine clinically collected information (similar to APACHE score used in intensive care) would seem more widely adoptable.

    CT perfusion aspects outcome

    Jose Gutierrez, MD, MPH

  • Psychogios MN
  • Schramm P
  • Frölich AM
  • Kallenberg K
  • Wasser K
  • Reinhardt L. 
  • Alberta Stroke Program Early CT Scale Evaluation of Multimodal Computed Tomography in Predicting Clinical Outcomes of StrokePatients Treated With Aspiration Thrombectomy. Stroke. 2013

    In a forthcoming paper in Stroke, Psychogios et al. investigate the usefulness of ASPECT score, cerebral blood flow (CBF)-ASPECTS and cerebral blood volume (CBV)-ASPECTS in predicting outcomes in 51 patients with M1 occlusion who underwent clot aspiration with the penumbra device. The authors also used the difference between CBV-CBF ASPECTS (Δ(CBV-CBF)-ASPECTS) as evidence of mismatch or area of penumbra. For example, if both the CBV-ASPECT and the CBF-ASPECT have a similar score, then the difference would be near to zero and would imply most of the tissue is already infarcted. On the contrary, a greater difference between these two scores would imply a small “infarct core” with a larger area of “salvageable tissue”. The majority of the patients achieved recanalization (61%) and less than a third had a favorable outcome (27%, defined as MRS ≤ 2) at 90 days. In multivariate analysis, the proportion of patient with favorable outcome was smaller with older age and greater with increasing Δ(CBV-CBF)-ASPECTS. In those who recanalized, only Δ (CBV-CBF)-ASPECTS predicted good outcome.

    Several issues arise from this study. First, when three randomized clinical trial have failed to show a benefit for endovascular intervention as adjunct to IV-TPA with or without imaging selection, how do we incorporate the results of this study? If used as hypothesis generator, how would this differ from MR-RESCUE selection process? Second, the proportion of patients with a good outcome in this study is close to what is the natural history of MCA occlusions (around a third of all MCA strokes [Kaste et al. Stroke] or 22% for large artery disease in the NINDS trial placebo arm using a more selective cutoff of MRS ≤ 1) which argues for the futility of the intervention. Finally, although recanalization rates have been associated with better outcomes and despite the greater recanalization rates obtained with devices in randomized clinical trials, achieving recanalization has not been enough to achieve significance compared to IV-TPA.

    Where do go from here? What features should the next trial have that incorporates the lessons learned with this and other studies about who might, if any, benefit from interventions other than IV-TPA?

    Diabetes, admission glucose, and outcomes after stroke thrombolysis. A registry and systematic review

    Diogo C. Haussen, MD

    Desilles JP, Meseguer E, Labreuche J, Lapergue B, Sirimarco G, Gonzalez-Valcarcel J. Diabetes Mellitus, Admission Glucose, and Outcomes After StrokeThrombolysis: A Registry and Systematic Review. Stroke. 2013

    Desilles J-P, Meseguer E, Labreuche J, Lapergue B, Sirimarco G, Gonzalez-Valcarcel J, et al. Diabetes, admission glucose, and outcomes after stroke thrombolysis. A registry and systematic review.

    The association between diabetes or post-stroke hyperglycemia and poor clinical outcomes after thrombolysis has not been clearly defined. Desilles et al. present data derived from their local prospective registry and a metaanalysis evaluating this relevant issue.

    The systematic review indicated that a history of diabetes and higher admission glucose level predicted worse functional outcomes and increased rates of symptomatic intracerebral hemorrhages. Interestingly, the data from their registry revealed that diabetes and initial glycemia did not influence endovascular recanalization rates.

    The authors discuss the potential inhibitory effect of hyperglycemia in the fibrinolytic system and the deleterious consequences of high glucose levels on the blood-brain barrier. However, they acknowledge that stress-hyperglycemia induced by the stroke may simply constitute a marker of a more severe disease given its reported correlation with higher NIH stroke scale and larger infarct core volumes. This would hypothetically explain why intensive glycemic control was not found to lead to improved outcomes in hyperacute ischemic strokes, and makes us wonder about the causal relationship between hyperglycemia and poor prognosis.

    Alcohol and Stroke Severity

    Tareq Kass-Hout, MD

    Ducroquet A, Leys D, Al Saabi A, Richard F, Cordonnier C, Girot M, et al. Influence of Chronic Ethanol Consumption on the Neurological Severity in Patients With Acute Cerebral Ischemia. Stroke. 2013

    Ducroquet and colleagues conducted a study, recently published online in Stroke, to test if excessive chronic ethanol consumption is associated with higher severity of the neurological deficit in acute ischemic stroke. Even though this phenomenon has been seen in animal studies, such effect has not been evaluated in humans.

    In this prospective observational cohort of a 436 patients with a median age of 70 years old, being classified as a heavy drinker was independently associated with more severe strokes (OR 2.26; 95%CI 1.06-4.82; p=0.034). There is not necessarily a causal relationship between ethanol consumption and stroke severity, but just a statistical association, which could be related to confounders that were not included in the analysis.

    In short, the link between chronic heavy alcohol consumption and neurological severity in patients with acute cerebral ischemia is yet to be understood. This study, however, showed that excessive chronic ethanol consumption is associated with higher baseline stroke severity. As an interventional study would not be feasible, this question can be answered only through experimental approaches in animals.


    Protamine and CAS

    Aaron Tansy, MD

  • McDonald JS
  • Kallmes DF
  • Lanzino G
  • and Cloft HJ. 
  • Protamine Does Not Increase Risk of Stroke in Patients With Elective Carotid Stenting. Stroke. 2013


    Still in its relative infancy, the neuroendovascular field has adopted many of its procedural methods from those within interventional cardiology and vascular surgery on the assumption that they have already been tested and deemed safe within these preceding domains. As a result, whether the safety and efficacy of many of these practices actually generalizes to the neuroendovascular field is still unproven. 

    In a paper published in Stroke, Jennifer McDonald and colleagues address the safety and efficacy of protamine to promote hemostasis and reduce femoral access site bleeding after elective carotid angioplasty and stenting. The group performed a retrospective analysis of patient data culled from a national, multi-center database comparing outcomes for carotid stenting patients who received protamine matched against those who did not. For both primary (ischemic stroke or TIA) and multiple secondary outcomes including mortality, ICH, and peripheral vascular complications, post-procedure protamine administration was not associated with significantly worse outcomes. Only blood transfusion incidence was significantly higher for those who received protamine compared to those who did not.

    Limited by its methodology including selection bias, urban-based hospital focus, unknown context for and non-standardized administration of protamine, this study does not provides any definite or readily generalizable conclusions. However, it does suggest that protamine’s use imparts no more danger than not using it after carotid stenting: in of itself, hardly a compelling reason for its use. Still, this finding provides a little fodder to evaluate further whether protamine’s post-procedural use may not only be no less safe, but also possibly safer.

    Famridine for Stroke

    Shruti Sonni, MD


  • Iaci JF
  • Parry TJ
  • Huang Z
  • Finklestein SP
  • Ren JM
  • Barrile DK. 
  • Dalfampridine Improves Sensorimotor Function in Rats With ChronicDeficits After Middle Cerebral Artery Occlusion. Stroke. 2013

    In this study funded by two biotechnology companies, Laci et al. studied the effects of dalfampridine on persistent sensorimotor deficits after stroke. Dalfampridine, commonly marketed under the trade name ‘Ampyra’, is a potassium channel blocker that has been used extensively in demyelinating neurological condition such as spinal cord injury and multiple sclerosis. In ischemic stroke, it is thought to enhance function in areas of myelin damage or by enabling activation of undamaged pathways.
    Rats underwent proximal MCA occlusions, and were administered Dalfampridine at 4 or 8 weeks after the ictus. Dalfampridine improved fore and hindlimb placing to stimuli, indicating recovery in sensorimotor systems and body swing symmetry indicating recovery in striatal function, both of which are affected by hemispheral infarcts.
    A subsequent proof-of-concept study was conducted in 83 human post-stroke patients by Acorda Therapeutics Inc., and preliminary results appear promising in improving walking. The next step is a clinic development program, to be discussed with the FDA. This is an exciting new pharmacological opportunity in this largely affected population.

    Silent Information Regulator 1 (SIRT1) and neuroprotection

    Nandakumar Nagaraja, MD

    Hernández-Jiménez M, Hurtado O, Cuartero MI, Ballesteros I, Moraga A, Pradillo JM. Silent Information Regulator 1 Protects the Brain Against Cerebral Ischemic Damage. Stroke. 2013


    Silent Information Regulator 1 (SIRT1), also known as Sirtuin 1 is a NAD+ dependent protein deacetylase implicated in aging, neurodegeneration and ischemic preconditioning in the heart and brain.

    In a recent article published in the journal Stroke, Hernandez-Jimenez and colleagues evaluated the role of SIRT1 in the mouse model of permanent MCA occlusion. The study showed that SIRT1 was found in the cytoplasm of neurons. Activation of SIRT1 resulted in decrease in infarct volume. Inhibition or genetic deletion of SIRT1 resulted in increase in infarct volume. They also found that SIRT1 played a role in inhibition of p53 and NFkB induced inflammatory and apoptotic pathways. Therapeutic agents that target SIRT1 and increase its activity could be potentially used for treatment of stroke to reduce the infarct volume.

    Several neuroprotective agents that were shown to be effective in the laboratory have failed to show significant benefit in phase III clinical trials. In an effort to effectively translate preclinical studies into clinical trials the STAIR (Stroke Therapy Academic Industry Roundtable) committee has provided recommendations for the preclinical studies in the laboratory. Some of the recommendations include establishing efficacy in two or more laboratories, replication in a second species, studies involving females, aged animals and animals with co-morbid conditions such as hypertension, diabetes and hypercholesterolemia etc. In the next few years it would be interesting to watch out for such preclinical studies targeting SIRT1 modulation as a mechanism for neuroprotection in cerebral ischemia and also delineating the molecular cascade of events that result in neuroprotection.