American Heart Association


The Complex Relationship Between Statins and Intracerebral Hemorrhage Outcomes

Mark R. Etherton, MD, PhD

Siddiqui FM, Langefeld CD, Moomaw CJ, Comeau MJ, Sekar P, Rosand J, et al. Use of Statins and Outcomes in Intracerebral Hemorrhage Patients. Stroke. 2017

In this entry, I discuss a recent publication by Fazeel Siddiqui and colleagues regarding the use of statins and outcomes after intracerebral hemorrhage (ICH).

The current evidence suggests a complex relationship between serum cholesterol levels, statin use, and outcomes after ICH. Low serum cholesterol levels have been associated with increased incidence of ICH, as well as hematoma expansion. However, a prior meta-analysis demonstrated antecedent statin use was associated with decreased risk of mortality and increased likelihood of a good outcome after ICH (Jung et al. Int J Stroke. 2015). The authors, therefore, set out to investigate the relationship of statin use with ICH outcomes by evaluating 3-month disability, mortality, and hematoma size/expansion.

Hematoma Shape, but not Density, is Predictive of Clinical Outcomes in ICH from the INTERACT2 Study

Peggy Nguyen, MD

Delcourt C, Zhang S, Arima H, Sato S, Al-Shahi Salman R, Wang X, et al. Significance of Hematoma Shape and Density in Intracerebral Hemorrhage: The Intensive Blood Pressure Reduction in Acute Intracerebral Hemorrhage Trial Study. Stroke. 2016

In patients with intracerebral hemorrhage (ICH), parameters such as hematoma volume has been shown to be predictive of hematoma growth and poor clinical outcomes; other characteristics, such as shape and density have been shown to be associated with growth, but evidence demonstrating its predictive value for clinical outcomes has been limited. Here, the authors used data from the INTERACT2 study and evaluated the association of hematoma shape (irregularity) and density (heterogeneity) on 90-day death or disability.

2066 subjects were included for analysis, with 946 subjects having irregular hematomas and 781 subjects having heterogenous hematomas. Of note, there were significant differences between patients with irregular versus regular hematomas, including older age, more severe neurological status, and lobar hemorrhages in the former group, among others. Similarly, patients with heterogenous hematomas, compared to those with homogenous hematomas, were more likely to have lobar hematomas and less likely to have intraventricular extension. Larger hematomas were more likely to be irregular and heterogenous, and this is likely reflected in the differences between each group and their comparators. In addition, the decision to withdraw treatment was more likely to be made among patients with irregular hematomas and among patients with heterogenous hematomas, when compared to their counterparts.

Nevertheless, when controlled for factors such as age, systolic blood pressure, NIHSS, prior use of antithrombotics, location and volume of baseline hematoma, IVH, and decision to withdraw active treatment, irregular hematomas were found to be independently associated with the primary outcome of risk of death or major disability at 90-days (OR 1.60) and major disability at 90 days (OR 1.60) although not with death alone. Heterogenous density did not predict the primary outcome, nor individually, the outcome of death nor disability.

This study is significant in providing some evidence for imaging markers which may be predictive of clinical outcomes in the emergent period, allowing clinicians to adjust decision making and provide better informed counseling to patients and their families.   

Administration of transdermal glycerol trinitrate does not affect functional outcomes in patients with ICH

Alexander E. Merkler, MD

Krishnan K, Scutt P, Woodhouse L, Adami A, Becker JL, Berge E, et al. Glyceryl Trinitrate for Acute Intracerebral Hemorrhage: Results From the Efficacy of Nitric Oxide in Stroke (ENOS) Trial, a Subgroup Analysis. Stroke. 2016

Outcomes in patients with intracerebral hemorrhage (ICH) are poor; more than two-thirds of survivors with ICH are left disabled at three months and less than half of patients with ICH are alive at 1 year. Ongoing research continues to address ways to improve outcomes – one such approach is acute blood pressure reduction. High blood pressure is common in acute ICH and is associated with worse outcomes, at least in part through hematoma expansion. Previous trials such as INTERACT have shown a trend towards improved functional outcomes using intensive BP lowering within the first 6 hours after ICH, but management of high BP in acute ICH remains uncertain.

The current subgroup analysis of the ENOS (Efficacy of Nitric Oxide in Stroke) trial evaluates the impact of transdermal glyceryl trinitrate (GTN) in patients with ICH. ENOS was a large multicenter trial that evaluated BP reduction in patients with both ischemic stroke and ICH using GTN. When GTN was given within 48 hours of stroke onset, BP was significantly reduced at day 1; however, functional outcome at 90 days was no different. When GTN was given within six hours of stroke though, functional outcomes were improved. In this current manuscript, the authors performed a pre-specified subgroup analysis, evaluating whether use of GTN in patients with ICH improved functional outcomes both overall, and within 6 hours of having an ICH.

629 patients with ICH presenting within 48 hours and initial SBP >140mmHg were included. Patients were randomized to receive GTN transdermally for one week versus no GTN. The mean time to randomization was 25 hours. 87% of hemorrhages were deep and 26% of patients had IVH. BP was significantly lower following the first dose of GTN versus no GTN (7.5/4.2 mmHg).

Overall, at 90 days, the median mRS was the same (3) in both the GTN and no GTN groups. In addition, there were no differences between secondary outcomes such as measures of disability, cognition, mood and quality of life. No differences in serious adverse events were seen.

Of the 61 (9.7%) patients randomized within 6 hours (and in whom the average time to treatment was 4.4 hours), patients randomized to GTN had an improved functional outcome as manifested by a positive shift on the mRS, improved mood and quality of life and reduced death.

GTN is a useful transdermal agent to acutely lower BP and does not seem to have serious adverse effects. The study adds further support that early BP lowering in patients with ICH may improve functional outcomes.

By |January 15th, 2016|hemorrhage|0 Comments

High risk of growth and rupture found in vertobrobasilar, non-sacular and dolichoectatic aneurysms

Alexander E. Merkler, MD

Nasr DM, Brinjikji W, Rouchaud A, Kadirvel R, Flemming KD, and Kallmes DF. Imaging Characteristics of Growing and Ruptured Vertebrobasilar Non-Saccular and Dolichoectatic Aneurysms. Stroke. 2016

Vertebrobasilar, non-sacular and dolichoectatic aneurysms (VBDAs) often represent a therapeutic challenge to clinicians – observe, serial image, or treat? The current study by Nasr et al adds further support to the pre-existing literature that VBDAs are generally associated with a poor natural history with high growth and rupture rates.

The authors performed a retrospective study on all VBDAs seen at their hospital. VBDAs were defined to include fusiform aneurysms (aneurysms with focal dilitations without a definable neck), dolichoectasia (uniform aneurysm dilitations), and transitional aneurysms (uniform aneurysm dilitations with superimposed dilitations of a focal portion of the involved artery). Dissecting aneuryms were excluded as the authors felt these lesions have a distinct natural history. 

152 patients with VBDAs were followed for a mean of 3.6 years. 30% of the aneurysms were fusiform, 49% were dolichoectatic, and 21% were transitional. The median diameter of the aneurysms was 7.2mm. 23% of aneurysms demonstrated growth (>2mm) during the course of the study, resulting in an annual aneurysm growth rate of 6.5%. 5.3% (8) of aneurysms ruptured during follow-up, yielding a rupture rate of 1.5%/year and 13.2% of patient with VBDAs had posterior circulation infarcts.

In univariate analyses, aneurysm type, large (>10mm) aneurysms, presence of T1 signal in the aneurysm rim (representing subacute thrombus), presence of thrombus, and presence of daughter aneurysm were also associated with aneurysm rupture. However, in multivariate analyses, only aneurysm type was associated with aneurysm growth and rupture: transitional aneurysms had significantly higher odds of growth/rupture than dolichoectatic, but not fusiform aneurysms

The main limitations include the lack of standardization of imaging modality and lack of pre-specified time of imaging follow-up.

Overall, this study confirms that VBRAs, and in particular transitional vertebrobasilar aneurysms, have high rates of growth and rupture and warrant close imaging follow-up. Further research will be needed to better distinguish which aneurysms are at highest risk for rupture and may potentially benefit from treatment.

By |January 6th, 2016|hemorrhage|0 Comments

Markers on non-contrast CT head that predict later hematoma expansion

Peggy Nguyen, MD

Blacquiere D, Demchuk AM, Al-Hazzaa M, Deshpande A, Petrcich W, Aviv RI, et al. Intracerebral Hematoma Morphologic Appearance on Noncontrast Computed Tomography Predicts Significant Hematoma Expansion. Stroke. 2015 

Hematoma expansion occurs in approximately one-third of patients with intracerebral hemorrhage (ICH), but markers for predicting expansion are not well defined. The PREDICT study, aimed at prospectively validating the spot sign on CT angiography, found the spot sign had a sensitivity of 51% for predicting expansion. Markers present on non-contrast CT head previously published elsewhere as associated with hematoma expansion or larger ICH include hematoma density, shape, presence of fluid-levels, and regularity, but predictive models utilizing these markers are not widely used. Here, the authors hypothesized that these non-contrast CT head markers (irregular margins, heterogeneous density, and fluid-blood levels) would predict expansion both independently and together with the spot sign on CTA, with the aim of identifying non-contrast measures which would be reliable markers of hematoma expansion and to create a more sensitive prediction model.

Analyzing a PREDICT cohort of 311 patients, the authors found a high inter-observer agreement for fluid levels, and relatively good agreement for scoring of heterogeneity and irregularity. All 3 non-contrast CT markers were significantly associated with hematoma expansion on follow up CT scan; in addition, all 3 non-contrast CT markers were significantly associated with the spot sign on CTA and with absolute hematoma growth at 24 hours. Margin irregularity was the most sensitive and fluid levels was the most specific, but the spot sign remained the most specific predictor of hematoma expansion, with the highest positive and negative predictive values of hematoma expansion. The predictive value of the spot sign was not altered when the non-contrast markers were added to the model, confirming the spot sign as the most reliable marker for hematoma expansion. However, given the ease of scoring, the relatively good inter-observer agreement, and the ease of obtaining a non-contrast CT scan, especially in situations where contrast may be contraindicated, it does appear that heterogeneity, irregularity, and fluid-blood levels might also be appropriate surrogate markers.

By |November 6th, 2015|hemorrhage|0 Comments

Cognitive Decline Occurs in More Than 1/3 of Long-Term Survivors of ICH

Alexander E. Merkler, MD

Benedictus MR, Hochart A, Rossi C, Boulouis G, Hénon H, van der Flier WM, and  Cordonnier C. Prognostic Factors for Cognitive Decline After Intracerebral Hemorrhage. Stroke. 2015

The association between stroke and cognitive decline is complex and, as Drs. Benedictus et al point out, pre-existing dementia is often present in patients with stroke, and post-stroke dementia is also highly prevalent. Furthermore, dementia increases the risk of stroke, and as a corollary, stroke also increases the risk of dementia. Disentangling this relationship poses a challenge.

In the present article, Drs. Benedictus and her colleagues evaluate the association and potential risk factors for cognitive decline after intracerebral hemorrhage (ICH). Although ICH accounts for only 10% of all strokes, the mortality rate is over 50% within the first year. Although various scores have been created to help predict which patients will survive and regain functional independence (ICH score and FUNC score), there has been a paucity of data on cognitive outcomes after ICH. 

In order to assess risk factors for cognitive decline after ICH, the authors evaluated a cohort of adult patients with ICH. MRI was used to evaluate for cortical atrophy, white matter hyperintensities, lacunes, and microbleeds. Patients were prospectively followed for cognitive decline using MMSEs at 6 months, 12 months, and then annually after ICH.

Out of a cohort of 560 patients, 167 were included in the final analysis. During a median follow-up of 4 years, 37% of patients developed cognitive decline. Perhaps not surprisingly, pre-existing cognitive impairment was the strongest predictor of cognitive decline after ICH. In addition, both previous stroke/TIA and severity of cortical atrophy (but not presence of white matter hyperintensities, microbleeds, or lacunes) were associated with cognitive decline after ICH. In a post-hoc sensitivity analysis evaluating risk factors of cognitive decline in patients without pre-existing cognitive decline, only severity of cortical atrophy remained associated with development of cognitive decline. Finally, ICH location (lobar or non-lobar) was not associated with development of cognitive decline.

Limitations include: 1) baseline demographics (age) and radiographic risk factors such as cortical atrophy were not equally distributed between patients who had cognitive data available for analysis; 2) cognitive decline was solely based on MMSE which made it impossible to perform in patients with certain neurological sequelae of stroke such as aphasia; and 3) cognitive status was only evaluated in patients who survived for at least 1 year after ICH (since patients needed 2 MMSE performed 6 months apart), which limits generalizability of this study.

Overall, what does this study tell us? First, more than 1/3 of patients with ICH will develop cognitive decline. Second, risk factors for the development of cognitive decline after ICH are already present before ICH occurs – baseline cognitive impairment, prior stroke/TIA, and baseline cortical atrophy. Third, the interaction between neurodegenerative and vascular pathology is complex, but this study emphasizes the need for better stroke prevention, which, in turn, may lead to decreased neurodegeneration and perhaps vice versa.

By |September 23rd, 2015|hemorrhage|1 Comment

The ABC/2 score is an accurate measurement for ICH

Peggy Nguyen, MD

Webb AJS, Ullman NL, Morgan TC, Muschelli J, Kornbluth J, Awad IA, et al. Accuracy of the ABC/2 Score for Intracerebral Hemorrhage: Systematic Review and Analysis of MISTIE, CLEAR-IVH, and CLEAR III. Stroke. 2015

The ABC/2 score is a simple method used by both clinicians and researchers to assess intracranial hemorrhage (ICH) size; however, the score has only been validated in small research cohorts. In this study, Webb et al. perform an analysis and systematic review of the validity of the ABC/2 score in three large clinical trials, MISTIE, CLEAR-IVH, and CLEAR III to address whether the ABC/2 score, in both a specialized reading center (RC) as well as a local research site, is an accurate and valid score for determining ICH volume as well as eligibility and clot resolution in trials for ICH.

In their analysis of 4369 scans, the authors found that, when compared to the reference-standard of CT-based planimetry (CTP), both RC-ABC/2 scores as well as site-ABC/2 scores were valid measures of ICH volume for eligibility and clot resolution in all trials. Specifically, RC-ABC/2 scores had good accuracy in defining ICH volume, and categorizing ICH volume as mild, moderate, or severe. Site-ABC/2 scores were less accurate, but still acceptable. ABC/2 scores tended to be less accurate with lobar hemorrhages, larger ICHs, and irregular or heterogenous clots, a conclusion also supported in part by their systematic review, which, although too heterogenous for quantitative analysis, did identify ten studies, of which 2 found greater errors with larger ICHs, and 2 found greater errors with more irregular ICHs.

This study is the largest validation of the ABC/2 score, providing good evidence that the ABC/2 score, which can be performed easily, is accurate and valid. Keeping in mind its possible limitations in certain types of ICH (lobar, larger and more irregular size), this gives clinicians and researchers greater confidence in using the ABC/2 score both in clinical practice and in research, especially in smaller settings where more accurate CT based measurements may not be quickly feasible.

By |August 12th, 2015|hemorrhage|0 Comments

VASOGRADE in DCI- Does it Scale?

Abdel Kaleel, MD, MSc

de Oliveira Manoel AL, Jaja BN, Germans MR, Yan H, Qian W, Kouzmina E, et al.The VASOGRADE: A Simple Grading Scale for Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage. Stroke. 2015

VASOGRADE, a grading scale mostly derived from the WFNS grade and modified Fisher scale, has been proposed for risk stratification after aneurysmal subarachnoid hemorrhage. The purpose of this study was to validate this scale, particularly its relationship with the development of Delayed Cerebral Ischemia (DCI). Consecutive patients between January 2012 and June 2013 at the St. Michael’s Hospital in Toronto, Canada were assessed, having been divided into three VASOGRADE categories: VASOGRADE-Green (modified Fisher scale 1 or 2 and World Federation of Neurosurgical Societies scale (WFNS) 1 or 2); VASOGRADE-Yellow (modified Fisher 3 or 4 and WFNS 1-3); and VASOGRADE-Red (WFNS 4 or 5, irrespective of modified Fisher grade. A total of 746 patients were included in the final analysis. The primary outcome was delayed cerebral ischemia (DCI). DCI was present in 151 patients with 15%, 9%, and 37% of VASOGRADES Green, Yellow, and Red groups having developed DCI, respectively. Patients who were identified as VASOGRADE Red had a significantly higher risk of development of DCI and patients who were classified as VASOGRADE Yellow had a tendency for a higher risk for DCI. Overall, DCI status was appropriately identified in almost 70% of patients. Multiple clinical applications of VASOGRADE’s use in DCI were proposed, including decision on disposition/length of stay and treatment aggressiveness, in addition to its ability to predict DCI risk.

Early Rehab – It leads to better outcomes!

Rajbeer Singh Sangha, MD

Liu N, Cadilhac DA, Andrew NE, Li Z, Li J, et al. Randomized Controlled Trial of Early Rehabilitation After Intracerebral Hemorrhage Stroke: Difference in Outcomes Within 6 Months of Stroke. Stroke. 2014

Current evidence suggests that early physical rehabilitation (VER) of stroke survivors in the acute stage may result in better motor recovery, reduced mental, functional and neurological disability, and improved quality of life. The previous studies that have been conducted regarding this topic have analyzed a small proportion of patients with ICH and there still remains a need for a larger phase three trial. According to the authors, the current general consensus that exists is that patients with ICH should be mobilized later than those with ischemic stroke, despite a lack of evidence to support this view. They aimed to compare Very Early Rehabilitation (VER) with standard care in patients with ICH and hypothesized that VER within 48 hours of ICH onset would result in reduced mortality, morbidity, and better quality of life outcomes compared to standard care at 3- and 6- months following stroke.

The study was a prospective, multi-centre, randomized controlled study, with 2 parallel groups followed for 6-months with blinded assessment of outcomes. Both groups received standard care, but participants in the VER group commenced rehabilitation as soon as practical after randomization but within 48 hours of ICH onset. In contrast, the standard care group commenced rehabilitation after 7 days. Out of 326 patients that were eligible, 243 patients were randomized (mean age 59 years; 56% male). At 6-months, patients receiving standard care were more likely to have died (aHR: 4.44, 95%CI: 1.24, 15.87). Further analysis of the morbidity outcomes showed a 6-point difference in the Physical Component Summary score of the SF-36 (95%CI 4.2, 8.7); a 7-point difference for the Mental Component Summary score (95%CI: 4.5, 9.5); a 13-point difference in Modified Barthel Index scores (95%CI: 6.8, 18.3), and a 6-point difference in SAS scores (95%CI: 4.4, 8.3) was reported in favor of the intervention groups.

The findings in this study point strongly towards ICH patients who were randomized to VER more likely to be alive at 6-months than those who received standard care alone. Patients who received VER also had a shorter length of hospital stay and reported significantly greater quality of life, independence with activities of daily living, and improved mental health outcomes at 6-months following stroke compared to those randomized to standard care. These results are in conjunction with previous smaller trials that have been conducted including the VERITAS trial in the UK and the AVERT phase II trial. While the authors could not account for the exact pathophysiological mechanism that lead to the improved outcomes, it should mean a significant change in the dogma towards rehabilitation in centers that wait for a period of 7 days or greater prior to starting. Further trials should focus on the specific techniques that would improve outcomes in a more efficient manner as well as more sensitive scales of measuring outcomes including the Neuro QOL which is a validated self-reported neurological assessment of quality of life.

By |November 19th, 2014|hemorrhage|1 Comment

Spotting the SPOT sign by using a delayed CT angiogram sequence

It is common knowledge amongst the stroke community that a spot sign seen on a CT angiogram predicts hematoma expansion in patients with Intracerebral hemorrhage (ICH).  Size of the hematoma is an independent predictor of poor outcome and all attempts are made to prevent the increase in size by use of hemostatic medications and blood pressure control. The authors of this study hypothesize that addition of a 90 second delayed CT would help capture additional ICH patients with the spot sign and increase the sensitivity for predicting hematoma expansion and poor outcome. Patients with spontaneous ICH were enrolled prospectively between February 2012 and August 2013 and underwent a non-contrast head CT, immediately followed by CTA of the head with a 90 second delayed acquisition through the hematoma volume.

All CTA studies were independently reviewed by two board-certified radiologists and the spot sign was identified as a focus of contrast pooling within the ICH with an attenuation ≥120 HU that was discontinuous from normal or abnormal vasculature adjacent to the ICH and was of any size and morphology. Hematoma expansion was considered significant if the volume increased by 6ml or by 33% from baseline. A multivariate logistic regression model was utilized to analyze data and sensitivity, specificity and positive/negative predictive values were calculated.

A total of 121 patients were enrolled in the study however only 74 had follow up CT scans and were included in the primary analysis. A total of 15 patients had a positive spot sign detected on any CTA and the overall rate of hematoma expansion was 15%. Hematoma expansion was predominantly seen in the spot sign positive group (47% vs. 7%). Accuracy measures for the spot sign on delayed CTA were: sensitivity 55%, specificity 87%, PPV 43%, NPV 92%, accuracy 82%. When the CT scans for all 121 patients were analyzed the spot sign was seen on 36 scans, with 15 detected exclusively on the delayed 90 second imaging. The presence of a spot sign and high blood glucose levels were independent predictors of mortality in the multivariate logistic regression model. Greater than 95% of these patients with a positive spot sign were dead at follow up.
This study re-enforces that spot sign is a predictor of hematoma expansion and poor outcome. The 90 second sequence is cost effective and time efficient however the numbers in the study are really small. The question arises – are we going to try everything to detect a spot sign? The authors conclude that the delayed 90 second sequence may help select patients eligible hemostatic intervention but we need to ask ourselves if it really changes clinical practice. Although the spot sign is predictive of expansion, it is only seen in a small percent of patients with ICH and a delayed CT has a sensitivity of 55% to detect a spot sign.  If a safe hemostatic medication is available and approved, I wonder if we would be so selective in its use.  Let’s reserve our judgement till the  SPOTLIGHT (spot sign selection of intracerebral hemorrhage to guide hemostatic therapy trial)  is on ICH treatment with hemostatic therapy. 
By |October 28th, 2014|hemorrhage|0 Comments