American Heart Association

Monthly Archives: December 2015

Antiplatelet use is associated with intraplaque hemorrhage. Is this clinically significant?

Jay Shah, MD

Liem MI, Schreuder Floris H.B.M., van Dijk AC, de Rotte A A.J., Truijman MT.B., Daemen Mat J.A.P., et al. Use of Antiplatelet Agents Is Associated With Intraplaque Hemorrhage on Carotid Magnetic Resonance Imaging: The Plaque at Risk Study. Stroke. 2015 
Carotid atherosclerosis is a major stroke risk factor and treatment has been predicated on degree of stenosis and ischemia within the ipsilateral territory. Plaque features, such as intraplaque hemorrhage (IPH), may also be important. Plaques with IPH have higher risk of rupture and embolization. IPH can be visualized using high-resolution carotid MRI but clinical characteristics have not been widely studied. In this study, the authors investigated the association between clinical patient characteristics and carotid IPH in setting of recently symptomatic mild to moderate carotid stenosis.

Baseline data from 100 patients were used. These patients were included in the Plaque At RISK (PARISK) study. In this study, inclusion criteria included of ischemic infarct or TIA within 3 months and ipsilateral stenos is of <70%. Risk factors, history, and use of anti-platelet or anti-coagulation were documented and high-resolution MRI of the carotid arteries was performed. IPH on the imaging was defined as a hyperintense signal in the plaque. Two independent observers scored the ipsilateral artery. In total, IPH was present in 45 patients with 31 exclusively on the symptomatic side. There was a higher prevalence of IPH among men and patients with anti-platelet use prior to the index event.

The results in this study suggest that previous use of antiplatelet agents is associated with carotid IPH. This conclusion is troubling as IPH is associated with increased risk of stroke. The counterintuitive conclusion, then, is that antiplatelet agents are associated with increased risk of stroke. However, as the authors point out, the stroke protective effect of antiplatelet agents are relatively small and certainly not full-proof. Patients do have recurrent ischemia following antiplatelet therapy and perhaps IPH can at least be a contributing factor but overall, the clinical significance of IPH remains unclear. This study had relatively low number of patients and there is no follow-up data on patients with IPH to determine if indeed there was a higher stroke recurrence rate in this population (PARISK trial will finish in 2016). Furthermore, antiplatelet use had largest effect on patients with bilateral IPH suggesting such agents cause a systemic effect. Therefore, it is premature to recommend carotid revascularization or antiplatelet discontinuation solely based on the presence of IPH.

CTP to recanalization time: the key for accurate determination of infarct core?

Luciana Catanese, MD

d’Esterre CD, Boesen ME, Ahn SH, Pordeli P, Najm M, Minhas P, et al. Time-Dependent Computed Tomographic Perfusion Thresholds for Patients With Acute Ischemic Stroke. Stroke. 2015

Appropriate patient selection and expedient treatment times have had a pivotal role in the success of endovascular thrombectomy in acute ischemic stroke (AIS). Perfusion imaging may be a tool in further refining optimal patient selection for endovascular acute stroke therapy and broadening current treatment boundaries. In this regard, the authors aimed to determine the computed tomographic perfusion (CTP) thresholds and accuracy for the prediction of irreversibly injured brain tissue at 24-48 hours in patients achieving early reperfusion (<90 minutes from CTP), reperfusion within 90-180 minutes and in those who did not reperfuse acutely.

AIS patients that received endovascular therapy as part of a prospective, multi-center study (Prove-IT) who were >18 years old, presented within 12 hours of a known symptom onset time, and with complete arterial occlusion were eligible. Recanalization was assessed on conventional or CT angiography. All patients underwent CTP on admission and a non-contrast head CT (NCCT) or MRI- diffusion weighted imaging (DWI) at 24-48 hours to establish the core of infarct. Cerebral blood flow (CBF), cerebral blood volume (CBV) and Tmax for both grey (GM) and white matter (WM) were calculated. Patient data was initially stratified in two groups (those who underwent CTP within 180 minutes and those who did it later), which were subsequently categorized into three sub-groups based on time from CTP to reperfusion (<90 minutes, 90-180 minutes and no acute reperfusion). The area under receiver operator characteristic (ROC) curve and Youden’s method were used to determine the most accurate thresholds for prediction of final infarct core along with the respective sensitivities and specificities for each threshold.

Overall, 132 out of 146 initial patients were included in the analysis after 14 patients were excluded due to inadequate CTP scans. When looking at the group who underwent CTP within 180 minutes from symptom onset, the Tmax thresholds (>16 s average for both GM and WM) had the highest accuracy for core infarct estimation (sensitivity 0.85 and specificity 0.81) if successful reperfusion [TICI 2b-3] was achieved early (<90 minutes), whereas CBF (< 8.15 ml.min-1 .100g-1 average for GM and WM) and CBV had moderate (average sensitivity 0.79 and specificity 0.82) and low (average sensitivity 0.5 and specificity 0.6) discriminative ability, respectively. For the rest of the groups and its corresponding subgroups, Tmax and CBF had similar accuracies and CBV had the least discriminative power. Interestingly, the time from stroke symptom onset to CTP had no significant impact on the CTP thresholds.

In summary, the authors showed that the discriminative ability of CTP in infarct core estimation at 24-48 hours laid mostly on the Tmax and CBF and was inversely correlated with the time from imaging to effective reperfusion. CBV did not prove to be a reliable parameter for this purpose.

Although perfusion imaging may ultimately prove to be useful in patient selection for endovascular thrombectomy, there still is quite a long road ahead. Perfusion imaging in acute ischemic stroke remains a snapshot of intricate and dynamic vascular pathophysiology. Validation of these results in future studies that employ systematic DWI for defining infarct core, concomitant penumbra measurements and much larger sample sizes, will aid in better understanding the applicability of these findings to clinical practice.

Something in the Air…Causing Stroke?

Ilana Spokoyny, MD

Sade MY, Novack V, Ifergane G, Horev A, and Kloog I. Air Pollution and Ischemic Stroke Among Young Adults. Stroke. 2015 

Air pollution is known to cause inflammation, and small particulate matter has been linked to cardiovascular disease. The proposed mechanisms of stroke caused by particulate matter is direct entry into the CNS via olfactory tract, and oxidative stress caused by inhalation of the particulate matter. The authors of this Israeli study hypothesized that exposure to small particulates is associated with increased stroke incidence in young adults. Young adults in particular have lower cardiovascular risk factors, and are more likely to have stroke due to metabolic or toxic causes. Previous studies connecting air pollution to stroke had mixed results, but as the authors point out, a major flaw was the method used to measure particulate matter. The typical manner of measuring the pollution level was based on centrally located monitoring stations, which were either inaccurate in representing rural populations not living near a monitoring station or did not represent them at all. The authors used an innovative method of estimating the concentration of particulate matter, using daily satellite remote sensing data with a 1km spatial resolution.

The study was done using data from the largest HMO in Southern Israel, and included patients admitted to the only acute neurological care center in the area. The average amount of pollution at a patient’s home address on the day of their stroke was calculated and adjusted for daily average temperature and humidity. The pollution data was used in a case-crossover design, such that a patient’s exposure on the day of his/her stroke was compared to the exposure in other time periods of that same patient, so each subject served as his/her own control.

Approximately 4800 patients were included, 90% of whom had ischemic stroke. An association was seen between ischemic stroke and both PM-10 (particulate matter smaller than 10μm, OR 1.11) and PM-2.5 (particulate matter smaller than 2.5μm, OR 1.10) calculated on day of stroke, but this association was only seen in patients under 55 years old and did not persist in the overall population or for hemorrhagic stroke. No association was found with the particulate matter concentration 1-4 days prior to the stroke. One hypothesis for this association only being seen in young adults is that atherosclerosis (seen more in older patients) makes the vessels less reactive, and thereby less susceptible to the vascular effects of air pollution.

Interestingly, there was a higher stroke risk associated with increases in the particulate matter at lower ranges of overall pollution (i.e an increase in PM-10 from 30 to 48 μm/m3 was associated with a higher odds ratio than an increase in PM-10 from 160 to 178 μm/m3. The lower range of particulate matter is more likely to be associated with traffic (compared to higher levels which are typically due to natural pollutants such as dust). Additionally, a stronger association between pollution and stroke was seen in patients whose homes were within 75 meters of a main road, again implicating traffic pollution.

Several limitations of the study are noted by the authors, include incomplete data on smoking as well as traffic noise and gaseous air pollution. We should also consider that the patients may not have been home on the day of their stroke, so the pollution measure at their house, however accurate, may be irrelevant. If workplace location were known, and traffic pollution is implicated, it would be interesting to estimate the exposure by combining data on the patient’s commute as well as home and workplace particulate matter measurements. Additionally, it is likely that chronic exposure to particulate matter increases the cardiovascular and stroke risk, and we see some evidence of this in the current paper (increased risk of stroke in patients living in proximity to a major road). While the pollution measure in the 1-4 days preceding the day of stroke presentation did not correlate with stroke risk, obtaining a longer-term estimate of the cumulative exposure may be useful to study in the future. Overall, the increased risk of stroke associated with increased particulate matter (likely traffic related) is critical information which may help influence policy surrounding air pollution standards.

Prevalence of Cerebellar Cortical Infarct Cavities: Correlation with Risk Factors and MRI Markers of Cerebrovascular Disease

Russell Mitesh Cerejo, MD

De Cocker LJL, Kloppenborg RP, van der Graaf Y, Luijten PR, Hendrikse J, Geerlings MI. Cerebellar Cortical Infarct Cavities: Correlation With Risk Factors and MRI Markers of Cerebrovascular Disease. Stroke. 2015

This Dutch Study by by Laurens JL et al. set out to answer a very crucial question in this age of advanced imaging. They looked at the prevalence of cerebellar cortical infarcts in a population with vascular risk factors. This was a subset study of the Second Manifestations of ARTerial disease-Memory depression and aging (SMART-Medea) study. In the span of 5 years they identified 636 patient that met their imaging and clinical criteria. One of more cerebellar cortical cavities were seen in 61 (~10%) of patients while cerebellar infarcts and cortical cavities were seen in 11%. The presence of cavities was significantly associated with age, intimal media thickening, hyperhomocysteinemia, cerebral infarct and brain atrophy. Interestingly no significant association was found between white matter hyperintensities or white matter lacunes of presumed vascular origin. 

They also evaluated physical and mental functioning and found that cerebellar cavities were associated with a decrease in physical but not mental functioning. The authors suggest that cerebellar cortical cavities may be due to a large vessel disease since they were associated with surrogate markers of atherosclerosis (high IMT and hyperhomocysteinemia). Their study also suggested that most cerebellar infarcts could be small and escape clinical attention during acute stage of infarction.

New multimodal imaging technique may lead to one-stop-shop for treatment of acute large vessel occlusion

Allison E. Arch, MD

Yang P, Niu K, Wu Y, Struffert T, Dorfler A, Schafer S, et al. Time-Resolved C-Arm Computed Tomographic Angiography Derived From Computed Tomographic Perfusion Acquisition: New Capability for One-Stop-Shop Acute Ischemic Stroke Treatment in the Angiosuite. Stroke. 2015

Outcomes are typically poor for patients with acute large vessel occlusions and ischemic stroke. Rapid endovascular recanalization is currently the best chance for meaningful neurologic recovery. Getting these patients into the endovascular suite quickly is a top priority. To minimize the delay that often occurs in the ED, a one-stop-shop has been proposed by Yang and colleagues, in which multimodal diagnostic imaging followed by endovascular clot retrieval would both occur in the same suite. To do this, the authors evaluated a non-enhanced C-arm cone beam CT system to obtain a non-enhanced cone beam CT, time-resolved CTA, and CT perfusion. They acquired dynamic perfusion parameters instead of using a steady state technique, and they used novel image processing algorithms. They hypothesized that if the image quality and diagnostic value of these reconstructed images were accurate, then patients may have a rapid one-stop-shop option for stroke treatment.
Twenty-one patients were included in the study, and 20 of them had successful reconstructed images. Two independent physicians interpreted the images, and they reached excellent agreement in making a diagnosis of large vessel occlusion using time-resolved C-arm cone beam CTA. The images were high quality with accurate detection of large vessel occlusions – both in the anterior and posterior circulations. The authors concluded that, “full head, subtracted, volume rendered, time-resolved C-arm cone beam CTAs can be reconstructed from C-arm cone beam CT dynamic perfusion measurements acquired in the angiography suite at the time of diagnostic or therapeutic interventions.”

Does this mean that patients with suspected large vessel occlusions will soon skip the ED and head directly into angiography suites? Only time will tell.

Modafinil may improve post-stroke fatigue – results from a small randomized placebo-controlled trial

Danny R. Rose, Jr., MD 

Bang Poulsen MB, Damgaard B, Zerahn B, Overgaard K, and Rasmussen RS. Modafinil May Alleviate Poststroke Fatigue: A Randomized, Placebo-Controlled, Double-Blinded Trial. Stroke. 2015 

Fatigue is a common but relatively unstudied consequence of stroke that can have significant negative effects on quality of life. Various pharmacologic and non-pharmacologic interventions have been proposed and investigated in limited studies, but there is no clear consensus on the best strategy for clinical intervention. Poulsen et al. sought to investigate the potential for modafinil, a wakefulness promoting agent that is efficacious in various sleep disorders, to improve post-stroke fatigue in a randomized controlled trial.

The investigators conducted a phase three, single-center, randomized double-blind, placebo-controlled trial in which patients were assigned to modafinil or placebo at a 1:1 ratio. The primary endpoint was a reduction of fatigue at 90 days as measured by the general fatigue domain on the Multidimensional Fatigue Inventory-20 (MFI-20 GF), with additional secondary endpoints that included other measures of fatigue, quality of life, cognition, mood, neurological outcome, bone density, and muscle mass at 30, 90 and 180 days. In an attempt to isolate post-stroke fatigue from other medical or pharmacologic factors, the investigators used relatively stringent inclusion and exclusion criteria, resulting in the randomization of just 41 subjects from an initial pool of 1121. Included patients had a stroke within the prior 14 days (this was later increased to 6 months due to low recruitment) and had post-stroke fatigue, defined as a score of 12 or greater on the MFI-20 GF. Patients with cognitive impairments that precluded assessment by questionnaire were excluded, as were patients with comorbid medical conditions associated with lethargy, those receiving treatment with benzodiazepines or antiepileptic agents, and those with contraindications to modafinil therapy. Baseline characteristics did not differ significantly between the placebo and modafinil group. Subjects were treated with 400mg of modafinil (reduced to 200mg if the patient was 65 years of age or older) in a single daily dose administrated in the morning for 90 days.

Analysis at 90 days revealed a nonsignificant 27% decrease in the median score of the MFI-20 GF in the modafinil group as compared to placebo (p=0.31), resulting in a neutral outcome for the trial’s primary endpoint. The Fatigue Severity Scale (FSS), another validated tool for assessment of fatigue in stroke and other disorders, did show significant improvement from randomization to 90 days and significantly lower overall scores at 90 days. There were also significant improvements with treatment in multiple domains of the Stroke Specific Quality of life scale (SS-QoL), including language, work and productivity at 30 and 90 days. Although adverse events were relatively common, no serious side effects were reported in the study—three patients stopped medication before 90 days due to presumed adverse effects. Two of these patients discontinued the medication due to dizziness and one due to rash, all of which were in the modafinil group. There was no difference in blood pressure from randomization to 90 days between the two groups.

This trial represents the first randomized, double-blind, placebo-controlled study of post-stroke fatigue treated with modafinil. The investigators’ attempt at isolating a specific patient population that limited confounding factors unfortunately led to the study being under-powered to properly evaluate the primary endpoint. These issues reflect the current knowledge gap in our understanding of the precise cause of post-stroke fatigue (which may not be a homogenous entity from a pathophysiological standpoint) and how it interacts with comorbid medical conditions and other sequelae of stroke. The trend towards improvement in the primary endpoint and significant improvements in FSS scores despite low statistical power presents a promising opportunity for follow-up study with a larger patient population. Given these preliminary findings of potential efficacy coupled with a reassuring safety profile, specifically with regard to adverse reactions related to its sympathomimetic effects, there may be a role for modafinil as an off-label treatment for post-stroke fatigue in carefully selected patients.

By |December 9th, 2015|treatment|1 Comment

Red Meat and Processed Meat Consumption Associated with Increased Risk of Stroke

Alexander E. Merkler, MD

Haring B, Misialek JR, Rebholz CM, Petruski-Ivleva N, Gottesman RF, Mosley TH, and Alonso A. Association of Dietary Protein Consumption With Incident Silent Cerebral Infarcts and Stroke: The Atherosclerosis Risk in Communities (ARIC) Stud
y. Stroke. 2015

Diet is an increasingly important topic in the field of cerebrovascular disease. The current study adds to the growing body of evidence that red and processed meat consumption increases the risk of stroke.

Dr. Haring et al evaluated the relationship between dietary protein consumption and stroke using the Atherosclerosis Risk in Communities Study (ARIC). More than 11,000 patients were enrolled in ARIC, a prospective study of middle aged adults, performed at four socioeconomically diverse locations in the United States. Patients included had no history of prior stroke and had no history of diabetes or cardiovascular disease so as to exclude patients that may lead to changes in diet. Dietary protein consumption use was assessed using questionnaires at the initial enrollment visit and then again six to eight years later.

Patients were followed for a median of 22 years. Overall, neither total protein intake nor animal protein consumption was associated with total, ischemic, or hemorrhagic stroke. On the other hand, higher intake of processed meat or red meat was significantly associated with an increased risk of stroke. Furthermore, only red meat consumption was associated with the development of ischemic stroke. No association was found between fish, nut, or low-fat dairy consumption and overall stroke risk.

Limitations include 1) Dietary protein was assessed at only one or two visits early on in the study and dietary habits may have changed over the ensuing years; 2) lack of adjustment for typical vascular risk factors; 3) lack of information regarding the etiology of stroke.

Overall, diet is an extremely important and modifiable stroke risk factor. Further research is warranted to help guide dietary modifications for both primary and secondary stroke counseling.

Can inclusion criteria for endovascular therapy be broadened? Implications from a stroke registry in Catalonia

Recent trials have shown that endovascular treatment improves outcomes in patients with ischemic strokes secondary to proximal arterial occlusion. REVASCAT trial investigated the benefit of endovascular therapy versus best medical therapy alone. This study was undertaken in Catalonia, Spain where a mandatory registry (SONIIA) was initiated to monitor reperfusion therapy quality. This registry, since 2011, captured clinical data and outcomes on all ischemic stroke patients undergoing reperfusion therapy (IV TPA and/or endovascular treatment), including those in the REVASCAT trial. In this study, the authors used data from the registry and the trial to assess endovascular treatment and compared outcomes of patients treated within and outside of the trial.

In the 2 years of REVASCAT enrollment, 17596 ischemic strokes occurred; of which, 206 were included in the trial (103 in each arm). Of the 2576 patients receiving reperfusion therapies, 21% underwent endovascular therapy (n=540). Therefore, 437 endovascular treatments were performed outside of REVASCAT. 340 patients were ineligible for the trial due to various reasons: treatment later than 8 hours, age, M2 occlusion, and basilar artery occlusion. Of the 97 eligible patients, 67 were treated at REVASCAT hospitals and had other exclusions not captured by the registry. Procedural results were similar between eligible and ineligible patients. The 3-month functional outcomes were similar and superior compared to the medical arm of REVASCAT trial.

Outcome was similar within ineligible patients, which substantiates the value of endovascular treatment on a wide range of stroke patients and not just to those included in the recent trials. This data suggests that the current inclusion criteria for endovascular treatment may be too stringent and patients who would otherwise be deemed ineligible may potentially benefit. This is important to remember as our experience and expertise with endovascular treatment expands, additional patients could be considered. To truly determine efficacy, prospective trials would need to be conducted. Furthermore, this study has implications on healthcare systems. The utilization rate of endovascular treatment in Catalonia was 4.3/100,000 which correlated to 4% of all ischemic strokes during a 2 year period. If the scope of endovascular treatment were to broaden, stroke systems of care would need to be become more coordinated and efficient to allow for an increase in volume.

By |December 7th, 2015|treatment|0 Comments

Motivational Interviewing for secondary stroke prevention adherence

Population-level recurrent stroke rates remain high, and recurrent strokes are associated with substantial morbidity and mortality. In this issue of Stroke Dr. Barker-Collo and colleagues test the effectiveness of motivational interviewing (MI) in ultimately reducing the risk of recurrent stroke in patients with stroke in New Zealand.

The trial was designed as a single-blind, prospective trial of 386 patients with stroke assigned to MI versus usual care. The MI treatment consisted of 4 sessions at 1, 3, 6 and 9 months after stroke. These outcomes were assessed at the same interval: change in systolic blood pressure, change in LDL, self-reported adherence, recurrent stroke/MI risk, quality of life and mood.

193 patients were in each group. The age of patients is not reported. Otherwise, the patients were similar at baseline. Notably, ~80% had completed high school.

The rate of blood pressure and cholesterol medication prescription was >97% at all time points. Unfortunately, anti-thrombotic prescription rates are not reported. The self-reported adherence rates were very high and marginally better in the MI group at only the 9 month time-point. Otherwise, there were no differences in rate of death, stroke, TIA, MI. Blood pressure and cholesterol changes were not significantly different, either.

The bottom line
Cerebrovascular outcome rates are low in contemporary stroke trials that ensure optimal vascular risk factor management in both arms. Efforts, such as this trial, to help real-world populations realize the benefits of secondary prevention research are important. Motivational interviewing may be a fruitful way to improve secondary prevention adherence.

However, it is difficult to generalize this study to other countries (such as the United States), where secondary prevention prescription rates are far lower than the 97% reported in this study. In most parts of the world, first educating physicians to prescribe adequate secondary prevention drugs may be an easier and more effective approach.
By |December 4th, 2015|clinical|0 Comments

Prophylactic AEDs following intracerebral hemorrhage not necessarily associated with increased morbidity

Peggy Nguyen, MD
The most recent AHA/ASA guidelines recommend against the use of routine antiepileptic prophylaxis in patients with intracerebral hemorrhage due to studies suggesting AED use in ICH patients lead to more functional and cognitive dysfunction; however, these studies were done primarily with the use of older antiepiletics such as phenytoin.

Here, the authors identified a subgroup of consecutive patients (n=744) in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study enrolled between 10/13/2010 and 10/30/2012, who were not already on antiepileptics at presentation and did not have a seizure on presentation in order to characterize outcomes of those who received AED prophylaxis and those who did not. Of the 744 patients, 39% received an antiepileptic for prophylaxis, of which 89% received leviteracetam. In addition to racial and ethnic differences in the baseline characteristics among patients, there were also important differences between those who received AED prophylaxis and those who did not; namely, (1) AED use was more frequent in those with larger hematomas and lobar hemorrhages. Craniotomies were more common in patients who received AEDs but this was not significantly associated on stepwise regression. Prophylactic AED use was associated with worse outcomes on the unadjusted model for 3-month outcomes, but after adjusting for GCS, age, race/ethnicity, sex, hematoma volume, presence of IH, and craniotomy, prophylactic AED use was no longer associated with 3-month outcome.

This suggests that the association of poor outcomes associated with AED prophylaxis in ICH may be erroneously attributed to the AED, when it may actually be a function of the larger hematoma volumes and ICH characteristics of the population receiving AEDs. In addition, with leviteracetam being prescribed more often in lieu of the older antiepileptics, a poor outcome which may have been associated with the older antiepileptics might no longer be sufficient reason to recommend against the use of AED prophylaxis in the ICH population. The AHA/ASA recommendation is cautious, to be certain, but it may be time to revisit this issue, and a larger study may be warranted.

By |December 3rd, 2015|treatment|0 Comments