American Heart Association


Stroke Risk Stratification in Non-Valvular Atrial Fibrillation — Validating CHA2DS2-VASc in an Asian Cohort

Gurmeen Kaur, MBBS

Kim T, Yang P, Uhm J, Kim J, Pak H, Lee M, et al. CHA2DS2-VASc Score (Congestive Heart Failure, Hypertension, Age ≥75 [Doubled], Diabetes Mellitus, Prior Stroke or Transient Ischemic Attack [Doubled], Vascular Disease, Age 65–74, Female) for Stroke in Asian Patients With Atrial Fibrillation: A Korean Nationwide Sample Cohort Study. Stroke. 2017

Non-valvular atrial fibrillation (AF) is a cause of at least 15-20% of strokes in the U.S., with a 5-times increased risk when compared to patients with no atrial fibrillation. The safety, efficacy and availability of oral anticoagulants, in addition to Vitamin K antagonists like warfarin, have made strokes secondary to atrial fibrillation virtually preventable. This has created a need for accurate Stroke Risk Assessment and Stratification.

Various stroke risk schemas over the years have included AFI/ SPAF (1994), CHADS2 (2001), Framingham (2003), NICE (2006) and the relatively recent CHA2DS2-VASc Score, also referred to as Birmingham 2009, that accounts for congestive heart failure, hypertension, 75 years of age and older (2 points), diabetes mellitus, previous stroke or transient ischemic attack (2 points), vascular disease, 65 to 74 years of age, female sex.

Kim et al study a total of 5855 oral anticoagulant (OAC) naïve patients with AF to determine whether the CHA2DS2-VASc score could be reliably used for the Asian population, because the validation studies were performed in an all-Caucasian cohort and various Asian studies have previously reported ethnic differences in the conventional stroke risk factors.

By |August 14th, 2017|clinical, prognosis|0 Comments

As in adults, TIA heralds stroke in Children

Alexander E. Merkler, MD

Lehman LL, Watson CG, Kapur K, Danehy AR, and Rivkin MJ. Predictors of Stroke After Transient Ischemic Attack in Children. Stroke. 2015

Pediatric stroke is a leading cause of death and disability in children. In adults, stroke occurs in 10-15% of adults within 3 months of transient ischemic attack (TIA), but little is known about risk of stroke after TIA in children. In this manuscript, Dr. Lehman et al evaluate predictors of stroke after TIA in children.

63 children were identified as having a TIA at Boston Children’s Hospital. TIA was defined using the time-based definition: a focal neurological deficit that resolved within 24 hours. All patients were required to have an MRI within 3 months of TIA. Similar to adults, almost 80% of patients had motor symptoms. Headache accompanied TIA in 54% of children, but only 10% of patients carried a diagnosis of migraine.

After a median follow-up of 4.5 years, 10/63 children (16%) developed MRI evidence of stroke, 4 (6%) of whom had imaging evidence of stroke at the time of TIA, and 8 (13%) of whom developed new imaging evidence of ischemic injury not seen on the MRI done at the time of TIA.

Independent predictors for stroke after TIA included female sex (OR 11.3, 95% CI, 1.3-98.7), cerebral arteriopathy (OR 24.5, 95% CI, 4.0-149.8), and presence of autoimmune disorders (OR 26.5, 95% CI, 3.6-191.6).

Limitations included 1) small number of patients and therefore wide confidence intervals; 2) retrospective design; 3) use of a time-based definition of TIA thereby likely included cerebrovascular mimics such as migraine.

Overall, similar to adults, children with TIA seem to have a significant risk of developing a stroke. Risk factors for stroke after TIA include female sex, cerebral arteriopathy, and presence of an autoimmune disorder. Further research will be necessary to confirm these findings and help prevent the development of stroke in the pediatric population.

By |December 23rd, 2015|prognosis|0 Comments

Copeptin: a promising marker in risk stratification after ischemic stroke and TIA

Luciana Catanese, MD

Griesenegger S, Segal HC, Burgess AI, Poole DL, Mehta Z, Rothwell PM. Copeptin and Long-Term Risk of Recurrent Vascular Events after TIA and Ischemic Stroke: Population-Based Study. Stroke. 2015.

Copeptin is a stress hormone released in an equal proportion to vasopressin (AVP), and serves a surrogate marker for the hypothalamo-pituitary-adrenal axis. Prior literature has suggested that Copeptin is a promising prognostic biomarker in vascular diseases such as MI, CHF and ischemic stroke/TIA. However, the prognostic value of Copeptin in regard to long-term risk of vascular events after TIA and stroke remains uncertain.

In this issue of Stroke, Griesenegger et al. present a longitudinal population-based study with a mean follow–up of 5.7 years, to determine whether Copeptin levels could predict the long-term risk of vascular events in patients with TIA or ischemic stroke. The authors also contrasted Copeptin level amongst different etiological subtypes of stroke/TIA.

Of 92,728 individuals in the Oxford Vascular Study, 1076 eligible patients (mean age 75) with TIA, minor and major ischemic stroke recruited from 2002-2007, were included. Copeptin level was obtained at baseline (median time to sampling 5 days) and repeated in 384 patients after one year.

After about 6000 patient-years of follow-up, the cox regression analysis including age, sex, hypertension, diabetes, previous MI, stroke, peripheral vascular disease, smoking, CHF, atrial fibrillation, and treatment with antiplatelets, statins or antihypertensive agents, showed that Copeptin significantly predicted subsequent vascular events (HR 1.47), recurrent ischemic stroke (HR 1.22), vascular death (HR 1.85) and all cause death (HR 1.75). The predictive value of Copeptin was greatest following a cardioembolic cerebrovascular event. Moreover, Copeptin outperformed other circulating biomarkers of thrombosis, inflammation and neuronal/myocardial injury within this population.

Inclusion of Copeptin into a model containing the aforementioned vascular risk factors improved the model’s predictive ability for recurrent vascular events, vascular death, death and recurrent stroke by 32%, 55%, 66% and 16%, respectively.

Overall, Copeptin seems to be a promising biomarker in risk stratification after ischemic stroke and TIA, particularly in patients with cardiogenic strokes/TIA. One of the main limitations of the study is the lack of adjustment for other possible confounding factors, such as indices of cardiac function. Therefore, further validation of these findings with the inclusion of cardiac markers is warranted.

By |November 10th, 2015|prognosis|0 Comments

Poor collateral status independently predicts developing malignant anterior circulation infarction

Jay Shah, MD

Flores A, Rubiera M, Ribó M, Pagola J, Rodriguez-Luna D, Muchada M, et al. Poor Collateral Circulation Assessed by Multiphase Computed Tomographic Angiography Predicts Malignant Middle Cerebral Artery Evolution After Reperfusion Therapies. Stroke. 2015 

A potential fatal complication of ischemic stroke is malignant middle cereberal artery infarction (mMCAi) often requiring decompressive craniectomy. Therefore, early detection is paramount and several predictors have been evaluated. One such factor is leptomeningeal or pial collateral circulation (CC) status which has been associated with outcomes and infarct volume. Traditional single-phase CT angiogram (CTA) may lack temporal resolution to accurately detect collateral status but multi-phase CTA may improve CC evaluation. The relationship between CC and development of mMCAi is unknown and the authors predict that poor CC status may be an early predictor of malignant edema. 

The study was a prospective study that enrolled consecutive ischemic stroke patients who presented less than 4.5 hours from onset with proximal anterior circulation occlusion. Collaterals were measured with a multi-phase CTA and scored on a 5 point scale with scores 0-3 given “poor” designation while 4 and 5 were stratified as “good”. The primary outcome was presence of mMCAi. In total, 81 patients were enrolled. 15 developed mMCAi with 5 requiring surgery. mMCAi patients presented more often with ICA occlusion and expectedly, had significantly higher infarct volume. 38 patients were identified as poor CC and there was significant association with mMCAi evolution. In the multivariate analysis, poor CC status was the only independent predictor of mMCAi.

This study shows that poor collateral status is an independent predictor of developing malignant infarction, especially in patients who did not achieve recanalization. Multi-phase CTA can identify patients who may be at higher risk of developing malignant edema, potentially requiring decompressive surgery. Early surgery can potentially improve prognosis and outcome. A potential limitation to this study was the low number of patients, especially in the mMCAi group (n=15). Furthermore, obtaining multi-phase CTA and timely radiological interpretation may not be readily available which could limit its utilization. Any delay could preclude its use altogether as infarct volume can be calculated from follow-up imaging which also correlates with developing mMCAi.

By |October 30th, 2015|prognosis|0 Comments

Associations between metabolic risk factors and incidental MRI markers of small vessel disease: Results from the Atherosclerosis Risk in Communities Study

Danny R. Rose, Jr., MD

Increasing evidence indicates that small vessel-type intracranial disease is not a homogeneous entity. Pathologic studies demonstrate that the radiographic manifestations of small vessel disease such as white matter hyperintensities (WMHs) and lacunar infarctions have distinct histopathological appearances. Even for lacunar infarctions, the work of CM Fisher and others dating back several decades suggest a different pathogenesis for larger lacunes (i.e., microatheroma formation) versus smaller lacunes (i.e., lipohyalinosis). Given this, it is reasonable to hypothesize that the risk factors for these different processes also differ. Dearborn et al. sought to investigate these potential associations using the Atherosclerosis Risk in Communities (ARIC) study cohort, specifically evaluating radiographic progression of small vessel disease reflected by MRI over 10-years.

The ARIC study was designed to investigate the causes of atherosclerosis and its outcomes and includes a prospective cohort that began recruitment in 1987. The analytic population for the current analysis consisted of 934 participants without a prior history of stroke who had two brain MRI scans approximately 10-years apart that were analyzed for the presence and size of incident lacunar infarctions as well as the presence and extent of white matter hyperintensities using both a visual scale and volumetric measurements. Risk factor assessment included components of metabolic syndrome (i.e., abdominal girth, HDL, blood pressure, triglycerides, fasting glucose) as well as an ad-hoc Insulin Resistance score, which was intended to examine the clustering of metabolic risk factors. The IR score included seven variables selected to exclude highly correlated factors and included log-transformed values for insulin and homeostatic model analysis for insulin resistance (HOMA-IR), BMI, waist-to-hip ratio and waist circumference.

Elevated triglycerides and decreased HDL were associated with an increase incident of all lacunar infarction, but not WMHs. Systolic blood pressure was associated with WMH and incident lacunes in unadjusted models, but did not reach statistical significance for lacunes in adjusted models. No significant difference was observed comparing the progression of WMH in patients with and without metabolic syndrome, but patients with metabolic syndrome did have more incident lacunes, with the increase being predominantly due to an increase in the number of larger lacunes.

Higher insulin levels, HOMA-IR and BMI were not associated with either measure. Increasing HOMA-IR and BMI were associated with incident large lacunes, but only in unadjusted models. Abdominal obesity as measured by waist circumference and waist-to-hip ratio was associated with incident lacunes, with a larger effect size for larger lacunes. The IR score was associated with increased odds of incident lacunes, with increased effect size for larger lacunes.

The results of this cohort study reinforce previously held assumptions, provide suggestions of novel associations, and question some previously reported associations. Given the different histopathologic appearance of WMH, small lacunes and large lacunes, the different associations found in the study are not surprising. The association of WMHs with hypertension and not with other metabolic factors mirrors the pathophysiology of leukoaraiosis. The role of atherosclerosis in the presumed pathogenesis of larger lacunes seems to be supported by its association with dyslipidemia. The IR score may represent a useful measure of the metabolic sequelae of insulin resistance aside from the effects of hyperglycemia. 

The study does have limitations. It is based on an observational cohort, which limits statistical adjustment for potential cofounders. The categorization of lacune sizes established in prior ARIC studies is somewhat arbitrary, but reflects the pathologic spectrum of lacunar disease for separating what are probably distinct pathophysiologic mechanisms for Fisher’s two “types” of lacunar infarcts. Prospective studies focusing on interventions for these presumed causative factors would further support these associations and potentially provide novel therapeutic targets.

By |October 28th, 2015|prognosis|0 Comments

Blood pressure variability and acute stroke.

Russell Mitesh Cerejo, MD 

Manning LS, Rothwell PM, Potter JF, and Robinson TG. Prognostic Significance of Short-Term Blood Pressure Variability in Acute Stroke: Systematic Review. Stroke. 2015 

Appropriate management of blood pressure in acute stroke has always a moving target. In a meta-analysis of 18 studies, Dr. Manning and her group evaluated the effect of blood pressure variability within the first seven days after a stoke on short and long term outcomes. None of the studies were randomized controlled trials (RCT) but seven studies were of a prospective observational nature, five were observational analyses of prospective stroke registry data and six were observational analyses of previous RCT data. Seven studies were deemed suitable for the final meta-analysis of blood pressure variability on functional outcome. 

The group found that greater variability in blood pressure early after acute stroke might be associated with an increased risk of death and disability. Early on, systolic blood pressure variation was also associated with hemorrhagic complications after thrombolysis. However no effect was seen on short-term functional or neurological outcomes.

There was considerable heterogeneity in the studies that were reviewed by the group. The authors stress the importance of standardized practice for reporting of blood pressure measurements, blood pressure medications and timing with respect to the stroke onset. This will help draw robust conclusion in the future with regards to blood pressure management in acute stroke care.

By |August 28th, 2015|prognosis|0 Comments

CHA2DS2VASc score as a predictor of recurrent stroke in non-AF patients.

Jay Shah, MD 

Andersen SD, Gorst-Rasmussen A, Lip GYH, Bach FW, and Bjerregaard Larsen TB. Recurrent Stroke: The Value of the CHA2DS2VASc Score and the Essen Stroke Risk Score in a Nationwide Stroke Cohort. Stroke. 2015  

There is great interest in developing clinical scoring systems that stratify patients based upon ischemic stroke risk profiles. CHA2DS2VASc score is one such system where congestive heart failure, hypertension, age 65-74 years, diabetes, peripheral artery disease, and female gender earn a point while history of stroke or TIA and age >75 register 2 points. This score has been validated in patients with atrial fibrillation (AF) and is utilized to determine anticoagulation candidacy. It has also been shown to predict recurrent stroke in non-AF population but has not been adequately replicated. In this observational cohort study, the authors assessed the ability of CHA2DS2VASc score to predict recurrent stroke, death, and cardiovascular event using registry-based data of adults without AF and first-time stroke across a 10-year span. Essen Stroke Risk Score, a risk score specifically developed for the stroke population, was also calculated as a comparison. It allocates one point for age 65-75 years (2 for >75), hypertension, diabetes, myocardial infarction, other cardiovascular disease, peripheral arterial disease, smoking and previous stroke or TIA.

The cohort consisted of 42,182 patients. Patients were followed-up for an average of 3.5 years. Mean CHA2DS2VASc score was 4.3 and mean Essen Stroke Risk Score was 2.4. Increasing values of both scoring systems were associated with an increased risk of all three outcomes. One and five-year hazard ratios for CHA2DS2VASc score of > 7 were 1.56 and 1.90, respectively. Essen Stroke Risk Score had marginally better discriminatory performance in relation to stroke recurrence.

The difference in stroke recurrence rates between the lowest and highest risk scores were fairly modest, as reflected in the low hazard ratios (hazard ratio of 1.2 in CHA2DS2VASc score of 4 versus 1.56 in CHA2DS2VASc score of > 7). This implies that incremental addition of stroke risk factors only minimally increased stroke risk and prior ischemic infarct results in much higher baseline risk outweighing the impact of other risk factors. Overall, the CHA2DS2VASc score did correlate with increased risk of stroke, death, and cardiovascular events but further refinement is needed and clinical application and decision making based upon the score in this population may be premature. An area of further interest would be to determine mechanism of stroke recurrence and evaluate if there is correlation with clinical scoring systems. Finding such an association would help guide tailored therapy thereby decreasing stroke risk.

By |August 11th, 2015|prognosis|0 Comments

Seizures After Stroke in Young Adults Are Associated with Mortality

Mark N. Rubin, MD
Arntz RM, Rutten-Jacobs LCA, Maaijwee NAM, Schoonderwaldt HC, Dorresteijn LDA, van Dijk EJ, and de Leeuw FE. Poststroke Epilepsy Is Associated With a High Mortality After a Stroke at Young Age: Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation Study. Stroke. 2015 

As if decades of disability or premature death is not enough for young adults who suffer an ischemic stroke, the development of post-stroke epilepsy – which is not entirely rare – is associated with a dramatic climb in short- and long-term post-stroke mortality. 

The authors of this study bring us the results of a large Dutch cohort (631 patients) recruited over a 30 year period (1980-2010) with substantial follow up (mean 12.5 years) scrutinizing the association between post-stroke epilepsy and mortality in young adults (age 18-50 years). Overall 76 of the patients (~12%) developed epilepsy in their post-stroke course. The cumulative 30-day case fatality difference was astounding: 27.4% vs 2.1% in those with and without post-stroke epilepsy, respectively. After adjusting for confounders, the development of epilepsy remained independently associated with mortality (HR 4.8, 95% CI 1.7-14), with the index stroke being the major cause of death in these patients.

There are other data that provide nuance to the consideration of post-stroke epilepsy as a reason to raise the hairs on the back of a provider’s neck, but the punchline is thus: a stroke severe enough to cause a seizure is also severe enough to take a life. It’s a Biomarker of Badness, although not quite so bad being singled out by Oscar!

By |July 23rd, 2015|prognosis|0 Comments

White Matter Lesions Increase the Risk of Intracerebral Hemorrhage after Thrombolysis

Cerebral white matter lesions (WML), a manifestation of small vessel disease, has been associated with intracerebral hemorrhage (ICH). In this report, Curtze et al evaluated the risk of spontaneous ICH conferred by WML in ischemic stroke patients treated with intravenous thrombolysis (IVT). 

2485 consecutive patients treated with IVT over a 14 year period at the Helsinki University Central Hospital were evaluated. In addition to the baseline CT completed prior to IVT administration, a 24-hour post-IVT head CT scan was routinely done in this cohort (as well as when ICH was suspected). Symptomatic ICH (sICH) was defined per the ECASS-2 criteria; remote parenchymal hemorrhage was also assessed. WML grading (by four visual rating scales – Gorter scale, van Swieten scale, Blennow rating scale, and Wahlund rating scale) was completed from baseline CT scans by stroke neurologists blinded to patient data and outcomes.

124 patients developed sICH (5%). All of the rating scales (tested as continuous variables and dichotomized with different cut-off points) were associated with an increased risk of sICH (in univariate and multivariate models). A Wahlund scale score >1 (at least moderate focal WML) conferred a 2.7 (95% CI 1.87-3.90) higher odds of developing sICH in univariate analysis. This association remained (OR 2.64, 95% CI 1.71-4.02) even after adjusting for confounding variables. A Blennow score of 5 had the highest association with sICH (OR 3.59, 95% CI 1.72-7.5) in multivariate analysis. A Blennow score >4 (high burden of WML) also was associated with remote parenchymal hemorrhage (multivariable adjusted OR 4.11, 95% CI 2.38-7.1).

This study suggests that IVT-eligible patients with moderate-to-severe WML on baseline CT could have over two-fold higher risk of sICH. It the largest study on this topic; prior reports have evaluated smaller cohorts and demonstrated conflicting results. The notable limitations to this study are that it did not include a non-IVT treated stroke patient cohort and that it was a retrospective analysis. Though multiple factors contribute to sICH risk after IVT, this association should be kept in mind when discussing IVT with patients.

Early recurrence and cerebral bleeding in patients with acute ischemic stroke and AF

Rajbeer Singh Sangha, MD

Paciaroni M, Agnelli G, Falocci N, Caso V, Becattini C, Marcheselli S, et al. Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation: Effect of Anticoagulation and Its Timing: The RAF Study. Stroke. 2015 

The authors of this study tackled an important question and one that has always been a grey area for stroke neurologists. They looked to answer the question of when anticoagulation should be initiated following a cardioembolic stroke. This international prospective multicenter study looked at three main questions which included the risk of recurrent ischemic events and bleeding following a cardioembolic stroke, the risk factors which are associated with these events and finally what is the rate of recurrence and bleeding when anticoagulation has been initiated.

The study looked at 1029 patients out of which 123 had 128 events (12.6%): 77 (7.6%) ischemic stroke or TIA or systemic embolism, 37 (3.6%) symptomatic cerebral bleeding and 14 (1.4%) major extracranial bleeding. Primary study outcome looked at recurrent ischemic cerebrovascular events (stroke or TIA) and symptomatic systemic Embolisms and also symptomatic cerebral bleedings and major extra-cerebral bleeding at 90 days. At 90 days, 50% of the patients were either deceased or disabled (mRS≥3), and 10.9% were deceased. Factors predictive of the primary study outcomes included CHA2DS2-VASc score, high NIHSS, large ischemic lesion and type of anticoagulant. At adjusted Cox regression analysis, initiating anticoagulants 4 to 14 days from stroke onset was associated with a significant reduction in primary study outcome, compared to initiating treatment before the aforementioned time period. About 7% of the patients treated with oral anticoagulants alone had an outcome event compared to 16.8% and 12.3% of the patients treated with low molecular weight heparins (LMWHs) alone or followed by oral anticoagulants, respectively (p=0.003).

Patients who received a direct oral anticoagulant were found to have low risks for both
symptomatic intracranial bleeding (2.1%) and ischemic event (4.3%), suggesting the need for further testing the new class of novel anticoagulant drugs in the acute phase of ischemic stroke in patients with AF. The advent of the novel anticoagulants has allowed for a reduction not only in ischemic events secondary to AF but also reduced bleed rates and thus I ask how far can we push the boundaries of starting these medications before we run into greater risks than benefits. This topic continues to be one of contention as the point in time to start anticoagulation is likely to be stratified secondary to multiple factors; perhaps a composite score should be created and tested in future studies.