American Heart Association

Monthly Archives: August 2014

Who gets higher rates of thrombolytic therapy? A retrospective study from a Swedish registry.

Duy Le, MD

Stecksén A, Glader EL, Asplund K, Norrving B, and Eriksson M. Education Level and Inequalities in Stroke Reperfusion Therapy:Observations in the Swedish Stroke Register. Stroke. 2014

An essential mantra of vascular neurology has been that time is tissue. While many studies have evaluated what systems within the hospital help to expedite thrombolytic times, this study aims to evaluate what underlying patient factors, including education level, affect thrombolytic therapy (either IV-tPA or IA). Stecksen et al conducted a retrospective study, evaluating over 85,000 patients with ischemic stroke between the ages of 18-80 years between 2003-2009 from the Swedish registry, Riksstroke. Of the 85,885 patients evaluated, only 2.3% had an unknown level of education.  3,649 (4.2%) of patients received reperfusion therapy. As a whole, university educated patients (4.6%) were more likely to be treated with thrombolysis, as opposed to secondary or primary education patients (3.6%), (p<0.001). If a hospital was deemed “specialized,” which was not clearly defined by the paper, there was more likely a higher rate or reperfusion attempted. The study also attempted to evaluate if hospital settings themselves were responsible for differing rates of thrombolytic treatment. They did not find this to be the case in both community hospitals and Academic hospitals. In stratified multivariable analyses by hospital type, significant differences by education level with regards to receiving IV-tPA existed only among large non-university hospitals (university education OR 1.20 vs. secondary education 1.14).

Weaknesses of the study, which are specified by the authors, include a lack of data for delays, distance to the hospital, and reperfusion that may have been given outside of protocol. Surely these factors would influence the timing or reperfusion therapy. Additionally, there was no evaluation and separation of IV-tPA vs. IA intervention as individual categories. Nonetheless, this study does highlight for us that as much as we can control in the hospital to streamline IV-tPA processes to increase the rate and administration time, much work remains to be done outside of the hospital, before the patient ever arrives to the ED. Targeting those and educating those in the community with secondary and primary level of education may be of great benefit.   

Mind Your ‘P’s & ‘Q’s: P-Wave Morphology & Incident Stroke

Mark N Rubin, MD

Kamel H, Soliman E, Heckbert S, Kronmal R, Longstreth WT, Jr, Nazarian S, Peter Okin P. P-Wave Morphology and the Risk of Incident Ischemic Stroke in the Multi-Ethnic Study of Atherosclerosis. Stroke. 2014

The Atherosclerosis Risk in Communities (ARIC) study group, already an important contributor of some of our most fundamental knowledge in cerebrovascular epidemiology, has provided us with an interesting piece of evidence that suggests a previously overlooked feature of a 12-lead electrocardiogram (ECG) called P-wave Terminal Force in V1 (PTFV1) may inform incident stroke risk. This follows on their previous work, which suggested an association between PTFV1 and incident stroke but did not control for atrial fibrillation (AF) in the cohort; a focus of this particular investigation is the role of PTFV1 after controlling for AF.

To start, what is PTFV1?!

My understanding is that PTFV1 is the degree of deflection of the terminal (or latter) aspect of a biphasic P wave. I see it most typically defined as a deflection of >40 mm2. It is a marker of morphologic and/or electrophysiologic dysfunction of the atria, related to P-wave dispersion and duration (other markers with the same implications). A better description of the relationship between these ECG markers and the cardiologic implications can be read here.

In brief, the investigators built on their previous findings of an association between PTFV1, a marker of atrial abnormality, and incident ischemic stroke. A major (and fair) criticism of their previous work is that those findings were not controlled for the presence of AF. This study, in a large cohort of > 6700 patients, was specifically designed to address this interaction, at least to the degree possible, so as to screen for an independent association between PTFV1 and incident ischemic stroke beyond the risk AF confers.

The event rate was fairly low, with only 121 strokes (1.8%) in a median of 8.5 years. AF was noted in 541 (8%) participants. However, after “adjusting for baseline confounders,” PTFV1 positivity was more strongly associated with stroke (hazard ratio [HR] per 1-SD increase, 1.21; 95% confidence interval [CI], 1.02-1.44) than AF (HR per 1-SD, 1.11; 95% CI, 1.03-1.21).

Although there are certainly some limitations to this investigation, as outlined in their discussion, this finding has interesting implications. The frustration of making a diagnosis of “cryptogenic stroke” in a patient with multiple cortical infarcts of varying ages, a morphologically abnormal left atrium and a swing-and-a-miss on prolonged outpatient telemetry is real and frequent, and the idea that any atrial abnormality – manifesting in AF or otherwise – confers ischemic stroke risk and may require treatment for risk reduction is an attractive premise for future research.

For sure, as regards incident stroke risk and ECGs, we should mind our ‘p’s and ‘q’s.

The Obese Prince and the Smoking Pauper: the interaction between smoking, hypertension and socioeconomic status on stroke risk

Vikas Pandey, MD

“Rich people diseases” have stereotypically been defined as obesity, diabetes, hypertension, and gout, while “poor people diseases” have classically been diseases such as dysentery, malaria, and typhoid. This class struggle has always been a point of philosophical intrigue given the irony that poor people can avoid diseases of the poor by obtaining wealth, only to suffer from a different subset of medical illnesses that affect the wealthy. Education, another measure of socioeconomic status, has previously been linked to increased incidence of both ischemic and hemorrhagic strokes given the increased exposure to risk factors and inability to address these risk factors.  Knowing which groups are most at risk for stroke is important from the public health standpoint given that specified intervention in these subgroups can potentially prevent the most cases.

The authors were testing the hypothesis that while there is a clear link to smoking and stroke risk, as well as hypertension and stroke risk, there is limited data on the interplay between socioeconomic position, smoking and hypertension and their combined effect on ischemic and hemorrhagic stroke incidence. The authors used a pooled cohort study with 68,643 participants from Denmark aged 30-70 and included information on socioeconomic position based on their highest attained education level. Qualitative smoking data and categorized hypertension data was also obtained. The authors analyzed this data using an additive hazards model that is used for assessing additive interactions in survival analyses. They found that smoking was clearly more frequent in those with low education and level of blood pressure was only slightly higher in the low education group. Out of 100,000 person years, low education was deemed to cause 181 extra cases of ischemic stroke in men and 93 extra cases in women. This difference was less marked in hemorrhagic stroke. The combined effect of exposure to all three risk factors was associated with 566 extra cases among men and 438 extra cases among women compared to no exposure. This result was more than what would be expected as a sum of their separate effects demonstrating a synergistic effect of the risk factors with one another.

The article demonstrated an additive effect between the three risk factors specifically studied as well as numerous synergistic links between subgroups of the risk factors.  While some of the data may contain flaws such as underreporting (i.e. incorrect smoking reporting due to low education level) and confounding variables that are difficult to control for, the end message is still convincing in showing that legislation and public health campaigns may be more beneficial if aimed toward the lower socioeconomic classes as the same reductions in risk factors in both groups would reduce a larger number of cases in the lower socioeconomic class. Though the intention of this conclusion is well-guided, I feel that it is equally plausible that such a campaign toward the lower socioeconomic classes would have less of an impact. From personal experience in Miami-Dade county (approximately 20% living below the poverty line), stroke prevention measures do not seem to spur a change in health decisions for those of lower socioeconomic status as they do for aware and educated patients in a higher socioeconomic class. This aspect may be a little lost in the cohort studied from Denmark given the adjusted poverty rate is approximately 6% in the country, one of the lowest for any developed nation. For this reason, I feel future studies in evaluating the reception and comprehension of different stroke prevention policies as well as cultural differences in viewpoints toward personal health may further allow us to pinpoint more accurately the subgroup of patients for which our public health measures may be of the most benefit.


Cryptogenic stroke in elderly: Is heart where the answer lies?

Chirantan Banerjee, MD

Seo JY, Lee KB, Lee JG, Kim JS, Roh H, Ahn MY, et al. Implication of Left Ventricular Diastolic Dysfunction in Cryptogenic Ischemic Stroke. Stroke. 2014

Despite technological progress, about 1 in 3 ischemic strokes remains cryptogenic. More than 30% of these patients will have a recurrent stroke in the next 5 years. Several studies in the last few years have brought into focus atrial fibrillation (AF) as the underlying etiology in a sizeable proportion of these patients, especially those above 60 years. The longer we look for atrial fibrillation, the more likely we are to find it. In the recently published CRYSTAL – AF trial, 12.4% patients had atrial fibrillation detected when monitored for 1 year. This is especially important, as the therapeutic implications are major.

Clinical, electrocardiographic and echocardiographic markers of atrial fibrillation may be especially important to assess in cryptogenic stroke patients, as they may point out which patients are more likely to have occult atrial fibrillation, and thus may need to be monitored longer. Left ventricular diastolic dysfunction (LVDD) is thought to be a marker of paroxysmal non-valvular AF.

In the current study, Seo et al. compared the prevalence of left ventricular diastolic dysfunction (LVDD) in cryptogenic stroke (CS) v/s  stroke with AF and stroke without AF (lacunar strokes, and strokes with >50% referable large artery stenosis). Also, they compared the proportion of severe LVDD between CS  patients with cardioembolism (CE)-mimic DWI pattern and non CE-mimic DWI pattern, with the aim to delineate if LVDD can be used as a marker to predict occult AF in CS patients with CE-mimic pattern on MRI. The study cohort consists of 1901 patients with acute stroke enrolled into a prospective registry at the Soonchunhyang University Hospital in Seoul, Korea between January 2004 to March 2013, with a mean age of 58 years. After excluding patients with missing workup, and patients with known sources for cardioembolism which may affect LVDD such as mechanical valve, mitral stenosis, atrial myxoma etc, 55 CS patients, 310 strokes with AF and 969 strokes without AF were included in analysis. LVDD was ascertained by 2 cardiologists and assigned grades I-III based on accepted parameters.  When dichotomized at grade III, severe LVDD was much more prevalent in CS than stroke without AF, and almost comparable to stroke with AF.  Moreover, among the CS patients, the presence of LVDD was much higher in CE-mimic patients than non-mimics. On the contrary, although left atrial enlargement (LAE) was predominantly detected in stroke with AF, its frequency was not different between CS and stroke without AF. In a multivariable model, LVDD was associated with stroke with AF, despite controlling for hypertension, LAE and PFO.

These findings are significant, as they validate LVDD being a marker for AF in a stroke population, despite controlling for hypertension. The fact that most of our current AF detection techniques including ambulatory cardiac telemetry or implantable devices are contingent on timing, more permanent markers are needed that precede or predict AF to save time and money. Also, in this study, LVDD proved to be a good, if not a more sensitive marker than LAE for AF.  The higher prevalence of LVDD in CS with CE-mimic lesion distribution suggests that these patients likely have underlying AF as a cause for the CS. However, being a retrospective single center study, the findings cannot be generalizable to our stroke patients. Also, there may be an inherent selection bias because a significant proportion of patients, who did not have a full workup were excluded. Despite these limitations, it makes a strong argument for patients that suffer CS with CE mimic lesion patterns and have LVDD to undergo longer cardiac monitoring, as their risk of having AF is very high. In our aging population, where the prevalence of AF is predicted to double by 2050 to 5.5 million, tools to increase pre-test probability of detecting AF will help us tailor stroke care to individual stroke patients, while saving resources by avoiding unnecessary testing on others.

INTRAVENTRICULAR FIBRINOLYSIS: Removing the clog and restoring drainage

Prachi Mehndiratta, MD

Khan NR, Tsivgoulis G, Lee SL, Jones GM, Green CS, Katsanos AH, et al. Fibrinolysis for Intraventricular Hemorrhage: An Updated Meta-Analysis and Systematic Review of the Literature. Stroke. 2014

Intraventricular hemorrhage (IVH) results when parenchymal blood dissects or breaks the lining of the fluid filled cavities within the brain. IVH is associated with Intracerebral hemorrhage (ICH) in about 40% of cases and results in a varying but high mortality rate of 40-80%. When present, it requires placement of external ventricular drains to avoid complications such as hydrocephalus. The placement of such a drain for prolonged periods of time carries its own risks of infections such as ventricultis. Recently several studies such as the CLEAR IVH trial have been randomizing patients to receive intraventricular tissue plasminogen activator to decrease clot burden. The authors of this Meta analyses describe the pooled results of studies till date that have explored the use of intraventricular fibrinolysis (IVF).  

A total of 24 retrospective cohort, prospective cohort and randomized controlled studies that met the inclusion criteria of patients’ age >18years, non-traumatic IVH treated with IVF and provided control data were studied. Total sample size, number of patients in each arm, dosage and method of fibrinolysis, IVF complications and outcomes were carefully evaluated. The primary outcome was all cause mortality until one year after treatment whereas secondary outcome was defined as a good functional outcome (modified Rankin score 0-3), as well as lower rates of rehemorrhage, ventriculitis and shunt placement.

The pooled results were starkly in favor of IVF. There was a significantly decreased likelihood of mortality (RR= 0.55, 95%CI: 0.42-0.71; p<0.00001) with IVF and significantly increased likelihood of good functional outcome in the pooled analyses ((RR: 1.66, 95%CI: 1.27-2.19; p=0.0003). These results were primarily driven by the prospective and retrospective studies and only a trend towards significance was noted amongst randomized trials. There was no increase in the rates of ventriculitis, rehemorrhage or shunt requirement associated with IVF use.

These are promising results but should be understood with caution. The decreased relative risk for mortality and increased relative rate of good outcome were not observed in randomized studies. Additionally this Meta analyses represented a widely heterogeneous population with studies utilizing different fibrinolytics in varied doses. A well conducted randomized controlled trial would certainly provide some answers. Let us hope that our doubts about IVF are soon CLEARed.

A Smashing Success? Another look at the etiologic classification of intracerebral hemorrhage

Michelle Christina Johansen, MD

Yeh SJ, Tang SC, Tsai LK, and Jeng JS. Pathogenetical Subtypes of Recurrent Intracerebral Hemorrhage: Designations by SMASH-U Classification System. Stroke. 2014

Intracerebral hemorrhage (ICH) composes a high percentage of admissions to neurointensive care units and they remain a major cause of mortality. Not all hemorrhages are created equal and Dr. Yeh investigate the data surrounding different bleed subtypes in an effort to offer insight into functional outcomes and mortality. Their study employed the SMASH-U classification method which separates ICH etiologies into Structural, Medication related, Amyloid Angiopathy, Systemic Disease, Hypertension and Undetermined. They focused much discussion on the two most common etiologies, Hypertension and Amyloid. They state that the approaches to these distinct patient populations differs and that other classification systems, such as those that use location of bleed are not sufficient to distinguish between these two groups.

The researchers took advantage of their access to the National Taiwan University Hospital Stroke Registry which documents all patients who had a stroke (based on head CT and ICD codes) within two weeks of admission. They obtained data from 4,578 acute ICH patients, classified the patients into the six SMASH-U types and then analyzed the outcomes of first ever ICH cases versus recurrent ICH cases similarly stratified. They excluded trauma or tumor related, subdural/epidural/subarachnoid hemorrhage and stroke hemorrhagic transformation resulting in thorough examination of 3,785 cases. Two raters independently assigned classifications and if after discussion no consensus was reached, they were labeled Undetermined. The bleed was designated Structural if there were vascular lesions in the area of ICH; Medication related if INR≥2, new oral anticoagulant within three days or use of heparin/thrombolytic agent; Amyloid related if the ICH met Boston Criteria; Systemic disease related if there were evidence of thrombocytopenia, liver cirrhosis or non-medication induced coagulopathy and Hypertension induced according to guidelines laid out by the original SMASH-U paper. Notably the investigators added renal failure in consideration of systemic disease. 

The most common etiologies were hypertension and amyloid followed by systemic disease, undetermined, structural and medication related. Of the 185 cases of recurrent ICH classified, the etiology was different in 34. Among the 44 amyloid cases, 31 recurred with the same etiology but 10 were classified as hypertension related. Seventy eight of the 93 recurrent hypertension classified ICH were the same etiology but 7 were re-classified as amyloid related. The main reason for reclassification appears to be the location of the bleed (lobar versus deep structures). The authors appropriately point out that location alone is not sufficient to determine etiology and that amyloid angiopathy can occur in younger patients calling into question the Boston classification scheme. 

The importance of accurate classification is not only deciding treatment but also reflects patient survival.  In evaluation of results, those with Systemic Disease related (51-62%) or Medication induced (49-60%) had worse survival while those with Structural etiology (5-6%) had the best survival.  Interestingly, this article suggests that those with amyloid related hemorrhages (17-27%) fared worse than those with hypertension induced ICH (12-18%) as contrasted to the similar survival curve demonstrated in the SMASH-U study by Meretoja et al. 

While confounders such as the addition of renal failure to systemic disease must be acknowledged, there are many considerations raised for the treating neurologist when assessing this data. Our first year of training is usually dedicated to learning general medicine and it is all too easy to forget this realm with increasing specialization. The importance of appropriate recognition and treatment of comorbid illness such as ITP or cirrhosis is only confirmed by this data. The worse survival curve in patients with amyloid is also something to ponder. How does one decide the appropriate treatment for a patient with Afib and suspected amyloid angiopathy? In the era of rapid expansion and development of oral anticoagulants, many with unestablished methods of reversal, does this preclude the above patients from these medications? While ICH unfortunately remains a staple admission to neurologic intensive units, perhaps consideration of etiology will lead to appropriate and more accurate therapy and assessment of risk.

Restarting Antithrombotics after ICH

Abdel Salam R. Kaleel M.D, MSc

Pasquini M, Charidimou A, van Asch CJJ, Baharoglu MI, Samarasekera N, Werring DJ, et al. Variation in Restarting Antithrombotic Drugs at Hospital Discharge After Intracerebral Hemorrhage. Stroke. 2014

Restarting antithrombotic therapy following an intracerebral hemorrhage (ICH) has been the subject of much controversy and debate over the years. This is especially true as an increasing number of patients are prescribed antithrombotics for atrial fibrillation or thrombo-embolic disease. However, little data is currently available to support the establishment of definitive guidelines for these patients with most recommendations suggesting an individualized approach for each patient. 

With that in mind, this study was designed to assess the variation in restarting antithrombotic drugs by comparing the characteristics and proportions of patients taking antithrombotic drugs at ICH onset and discharge in four hospital-based cohorts in France, the Netherlands, and in the United Kingdom using bivariate and multivariable logistic regression analysis.A total of 2138 patients, median age 72 years, 53% male) were reviewed in this study, 942 of whom were taking antithrombotics at presentation- 559 of them taking antiplatelets prior to ICH, 333 taking Vitamin K antagonists, and 50 taking both. Exclusion criteria included patients with purely extra-axial hemorrhage, patients treated with heparin, or patients with a secondary cause of ICH such as vascular malformation. 

Data was collected on each patient, a study investigator with stroke expertise analyzed the images for classification into the various groups (lobar, non-lobar, unclassifiable, or multiple), and antithrombotic drug was categorized by type (antiplatelet, antithrombotic, or both). Case fatality rate was recorded at 30 days. Patients taking antithrombotic drugs had higher case fatality rate at 30 days, overall, when compared to patients not taking antithrombotics. Bivariate analysis revealed that restarting antithrombotics was more likely in younger patients, but median ICH volume was not found to differ between survivors who restarted or stopped antithrombotic agents. The proportion of patients restarting was also highest in those who were taking vitamin K antagonists before ICH. The strengths of the study included the large sample size and inclusion of multiple cohorts representing different settings. The variation between patients suggested that the cohort of origin played a role and the authors recommended that further studies be carried out to determine the best approach to guide future treatment plans.

By |August 6th, 2014|prevention|0 Comments

Flow Diversion Versus Conventional Treatment for Carotid Cavernous Aneurysms

Rajbeer Singh Sangha, MD

Zanaty M, Chalouhi N, Starke R, Guiherme B, Saigh M, Schwartz E, et al. Flow Diversion Versus Conventional Treatment for Carotid Cavernous Aneurysms. Stroke. 2014

With continuing advances in technology and healthcare, several endovascular options have emerged for the treatment of cavernous carotid aneurysms (CCA). These strategies include balloon-assisted coiling (BAC), stent-assisted coiling (SAC), carotid vessel destruction (CVD) and flow diversion. The reported recurrence rate and incomplete angiographic occlusion after treatment with conventional endovascular technique remains high, discouraging their use in complex aneurysms. Recently, Flow-diversion has been emerging as a novel treatment, however there is currently not enough data to establish its superiority over the conventional modalities.  The authors of this study compared the above treatment modalities looking at morbidity, mortality, evolution of mass symptoms and aneurysm occlusion/rate of retreatment. 

Analysis of 157 patients showed no difference in age, gender, and mean aneurysm size between those treated with PED and those treated with conventional endovascular procedures. The patients treated with PED had a significantly lower proportion of small size aneurysms (<10mm), significantly higher rate of improvement (92.16%) and a shorter follow-up duration. The rate of complete occlusion was 81.36% (48/59) for PED, 42.25% (39/71) for SAC, 27.27% (6/22) for coiling and 73.33% (11/15) for CVD.  The rate of major complications was 6.6% (11/167). Patients that were treated with PED or SAC had 3.84 lower odds to develop complications (OR= 0.26 p<0.05).

The authors make a compelling case through this study for the use of flow diversion (PED) technique for treatment of symptomatic CCA. The results of this study certainly do provide merit to the argument and given the low rate of complications, it is difficult to see why such a technique should not be aggressively studied further. Given the retrospective nature of the study and the possible biases which are acknowledged by the authors, a large multicenter trial would provide the power and validity required to show that PED is likely superior versus traditional endovascular methods that have been employed. It is refreshing to see an endovascular procedure which has lower rates of complication and less requirements for retreatment given the discouraging news that has been surrounding the field with recent studies the past few years.

Atrial Fibrillation, Subclinical Infarcts, and Cognitive Decline

Rizwan Kalani, MD

Chen LY, Lopez FL, Gottesman RF, Huxley RR, Agarwal SK, Loehr L, et al. Atrial Fibrillation and Cognitive Decline−The Role of Subclinical Cerebral Infarcts: The Atherosclerosis Risk in Communities Study. Stroke. 2014

Atrial Fibrillation (AF) is the most common cardiac arrhythmia, with increasing prevalence, incidence, and associated mortality worldwide. The increased risk of stroke is well known to all of us, but more recent studies have demonstrated an association of AF with cognitive impairment or dementia. Large epidemiologic series have shown that patients with AF have both an increased risk of dementia and faster cognitive decline, even without a clinical history of symptomatic stroke. We all probably have seen patients with a history of AF with clinically silent infarcts (SI) on neuroimaging; the authors of this study hypothesized that these lesions are associated with greater cognitive impairment in AF patients.

Chen et al evaluated data from the Atherosclerosis Risk in Communities (ARIC) biracial, multicenter, population-based study. The 935 patient cohort analyzed completed study visits that included three serial cognitive assessments (between 1993-1995, 1996-1998, and 2004-2006) and brain MRI at two points in time (between 1993-1995 and 2004-2006). AF diagnosis was obtained from ECG’s at study visits and hospital records, with cardiologist confirmation; patients were also clinically monitored for incident clinical stroke. Attention, executive function, and recent memory were assessed using the digit symbol substitution (DSS), word fluency (WF), and delayed word recall (DWR) tests, respectively. SI were defined as asymptomatic T2/PD hyperintense, T1 hypodense, focal, >3mm non-mass lesions on MRI.
The main novel findings were that patients who developed AF had significantly greater annual average rate of decline in DSS (-0.77) and WF (-0.80) in a linear model compared to those who did not develop AF, after adjusting for demographics/education/vascular risk factors. In subgroup analysis, patients who had more prevalent SI’s on baseline imaging who developed AF had greater decline in WF (-2.65) than those who didn’t develop AF during follow-up. In those that were found to have new SI’s on serial imaging during the study period, the ones that developed AF had greater decline in DSS (-1.51) than those who did not develop AF. Furthermore, in patients with incident AF, the proportion that developed SI’s was nearly twice that of those without new AF. In individuals without SI’s, incident AF was not associated with cognitive testing scores.
This study suggests that the association between incident AF and cognitive decline is mediated by SI’s. Most of these lesions turned out to be in the deep grey nuclei or deep supratentorial white matter; though not classic AF-related ischemia, up to 15% of patients with lacunar infarction have demonstrated an embolic source in prior reports. It is important to note that the role of shared vascular risk factors (HTN, DM, APO-e4 genotype, etc) contributing to cognitive decline cannot be excluded in this study.

The implications and questions raised by the results are important given the global epidemics of stroke, dementia, and AF. Future studies will need to evaluate risk of SI in those with low CHA2DS2-VASc scores and if anticoagulation reduces risk of cognitive decline in AF patients. Other questions raised are if we should be looking for occult AF in patients with SI’s or should we treat them with anticoagulants without documented AF?