American Heart Association

Monthly Archives: January 2016

The CARS Study: Encouraging Results for Stroke Recovery with Cerebrolysin

Ilana Spokoyny, MD

Muresanu DF, Heiss WD, Hoemberg V, Bajenaru O, Popescu CD, Vester JC et al. Cerebrolysin and Recovery After Stroke (CARS): A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial. Stroke. 2016

The data on neuroprotectants has been quite discouraging so far. Often, an agent will prove effective at reducing stroke size or improving patient outcome in laboratory models of ischemia, but this effect does not always translate to clinical trials. The authors of the CARS study point out that this disconnect may be attributed to inappropriate animal models, and the simplistic design of human clinical trials which have not taken into account the complex parallel pathways which contribute to cerebral ischemia. Previous agents have targeted one pathophysiologic pathway, but the authors suggest that a multi-targeted therapy is necessary. Cerebrolysin, a porcine-derived neuropeptide combination, may in fact be an exception to the notion that neuroprotectants do not work, based on this phase II randomized controlled clinical trial conducted in Romania, Ukraine, and Poland.

Cerebrolysin has been previously shown to be effective in animal models, even when started up to 48 hours post-stroke. It has also been studied in several small clinical trials, and as a subgroup of a larger clinical trial, in which it was shown to improve outcome and reduce mortality after severe stroke. However, the effects did not persist over time, and had disappeared by day 90. In these previous trials, Cerebrolysin was given in the acute phase and for a short duration. The authors comment that the potential neurotrophic and neuroplastic effects may have been overlooked.

The CARS study compared arm motor recovery at 90 days among patients receiving Cerebrolysin or placebo. The trial included 205 patients between 18-80 years old, with supratentorial ischemic strokes at least 4 cc in volume, with baseline mRS 0-1, moderate or minimal aphasia, and minimal to severe arm weakness. The mean baseline NIHSS was 9.2. Patients were treated with IV Cerebrolysin or placebo daily for 21 days, beginning at 24-72 hours post-stroke. All patients also received early aggressive rehabilitation for 21 days, which was started within 72 hours of stroke onset and consisted of exercise 2 hours per day, five days per week. The patients then continued to exercise for 30 minutes per day, 3 days a week post-discharge.

The primary outcome was arm motor function, measured by the Action Research Arm Test score at 90 days. The ARAT score ranges from 0 (no function) to 57 (no limitation). Patients with post-stroke baseline score 0-50 were included. The primary outcome showed a large superiority of Cerebrolysin (increased ARAT in 92%, an average of 30.7 points) over placebo (increased ARAT in 84%, an average of 15.9 points). A good functional outcome (mRS 0-1) was seen in 42% of Cerebrolysin-treated patients compared with 15% of placebo-treated patients. The secondary outcome was a composite of twelve outcome scales, including gait velocity, fine motor function, ADL independence, aphasia, neglect, quality of life, cognition, and depression. The composite outcome showed a small superiority of Cerebrolysin. The safety of Cerebrolysin was equivalent to placebo. The most common adverse effects were UTI, depression, and cytolytic hepatitis in the Cerebrolysin group, and UTI, hypertension, and depression in the placebo group.

A larger-scale phase III randomized trial is needed to ensure that effects were not exaggerated by poor outcomes in the placebo group, small sample size, or the fact that both groups engaged in early and sustained rehabilitation therapy. However, this phase II trial is quite encouraging for the prospect of an effective neuroprotective and neuroplastic agent on the horizon.

Clinical outcome beyond 6 hours in acute infarction may depend on degree of ischemia

Jay Shah, MD

An H, Ford AL, Eldeniz C, Chen Y, Vo KD, Zhu H, et al. Reperfusion Beyond 6 Hours Reduces Infarct Probability in Moderately Ischemic Brain Tissue. Stroke. 2016

Time has been considered to be the prime factor in determining cerebral tissue fate after ischemia. However, severity of ischemia is also an important determinant that may be under appreciated. Animal models have shown that tissue with severely reduced cerebral blood flow (CBF) died while tissues with mild to moderate CBF, defined as 12-18 ml/100g/min, survived. This suggests that the therapeutic window is dependent on the degree of ischemia. This concept has not been examined in humans following ischemic stroke.

The authors conducted a prospective MRI study in acute ischemic stroke patients. Patients were enrolled within 4.5 hours of stroke onset. Acute endovascular intervention was an exclusion criteria. Patients underwent MRI scans at various times: within 4.5 hours, 6 hours, 24 hours, and 1 month following stroke onset. This scan included dynamic susceptibility contrast (DSC) perfusion image which allowed for CBF and CBV calculations. FLAIR sequence at one month was used to determine final tissue fate. 

In total, 27 patients were included in the study. 18 patients were treated with IV tPA. 23 patients had perfusion improvement. Perfusion change during the hyperacute phase (3-6 hours) significantly influenced tissue fate regardless of the degrees of ischemia but perfusion change during the acute phase (6-24 hours) impacted tissue outcome only in tissue with mild to moderate ischemia.

An important finding of this study is that perfusion improvement was associated with reduced infarct probability for tissue with mild to moderate ischemia beyond 6 hours suggesting such patients may have a prolonged therapeutic window. The etiology for differing degrees of ischemia was not provided within the study but presumably this was related to collateral circulation. In patients that present later within the 6 hour window for endovascular treatment, CT angiogram and perfusion studies are frequently ordered in order to determine similar parameters as this study. Important limitations of this study include lack of vascular imaging and exclusion of patients with endovascular intervention. Future studies should evaluate outcomes of patients that undergo endovascular treatment beyond 6 hours based on degree of ischemia.

Problem solving group therapy after stroke may improve coping abilities and quality of life

Neal S. Parikh, MD 

Visser MM, Heijenbrok-Kal MH, van‘t Spijker A, Lannoo E, Busschbach JJV, and Ribbers GM. ProblemSolving Therapy During Outpatient Stroke Rehabilitation Improves Coping and Health-Related Quality of Life: Randomized Controlled Trial. Stroke. 2016   

Marieke Visser and colleagues sought to assess the utility of group-based problem solving therapy (PST) after stroke for improving coping strategies and health-related quality of life (HRQoL). 

The authors begin by summarizing the body of evidence regarding reduced HRQoL after stroke. One possible mediator of HRQoL is coping strategy. Problem-solving refers to an active process by which the stroke survivor finds specific solutions to specific problems, as opposed to the less active process of coping, by which the survivor simply learns to accept obstacles. The authors cite evidence suggesting that PST may be helpful for reducing depression. 

166 patients undergoing out-patient rehabilitation after stroke (including subarachnoid hemorrhage) who were deemed able to participate in group therapy were randomized to standard rehabilitation or standard rehabilitation plus PST. The PST module consisted of 8 weekly group sessions lasting 1.5 hours each during which participants were coached in positive problem solving techniques. Participants randomized to PST attended an average of 6.5 sessions.

Patients were assessed within 3 weeks prior to intervention, 10 days post-intervention, and 6 and 12 months post-intervention. The outcome measures were: 1. Coping Inventory for Stressful Situations, 2. Social Problem Solving Inventory-Revised and 3. Psychological, stroke-specific HRQoL scales. A secondary outcome was depression as measured by the Center for Epidemiologic Studies Depression Scale. Approximately 10% of subjects dropped out, roughly equally between the two groups.

At the 6 month post-intervention evaluation, PST was associated with increases in coping strategies deemed positive by the authors in addition to increases in general measures of HRQoL. These benefits were not apparent at 12 months post-intervention. There were no measurable, durable differences in problem-solving skills, psychological HRQoL, or depression between the two groups.

The results of the study are challenging to interpret. Unfortunately, the study did not utilize an active control group. Therefore, it is unclear whether the transient benefits of PST seen at the 6 month post-intervention evaluation were due to PST itself or simply the additional attention received by participants as compared to the control group.

This study demonstrates the feasibility of rigorous assessment of rehabilitative methods. Targeting specific cognitive rehabilitative approaches to patients with specific anatomically-based deficits may yield more convincing data. Advances in rehabilitation science may eventually allow clinicians to recommend individualized, high-yield programs for their patients.

By |January 11th, 2016|treatment|1 Comment

Antithrombotic therapy for recurrent ischemic stroke: Two may be better than one

Peggy Nguyen, MD

Kim JT, Park MS, Choi KH, Cho KH, Kim BJ, Han, et al. Different Antiplatelet Strategies in Patients With New Ischemic Stroke While Taking Aspirin. Stroke. 2016

Despite the multitude of clinical trials evaluating anti-platelet therapies for recurrent stroke, there are still no clear answers on the optimal regimen for patients who have “failed aspirin.” Here, the authors use a nationwide stroke registry to analyze outcomes of patients who have suffered a non-cardioembolic stroke while on aspirin, looking at three different arms: (1) those who were maintained on aspirin after their stroke, (2) those who were switched to a different anti-platelet agent, the most common being clopidogrel and (3) those who had a second anti-platelet agent added on to aspirin, again, commonly clopidogrel.

Of note, baseline characteristics were different among the three groups. For example, index large artery atherosclerosis strokes were much more common in the dual anti-platelet therapy group compared to the mono-aspirin group, while other etiologies and undetermined causes were much more common in the mono-aspirin group. In general, however, results were suggestive of benefit with alternative antiplatelet therapies when someone has had an aspirin failure, more so for dual antiplatelet therapy. Patients had less composite events (combination of stroke, MI, and all-cause mortality) when they were switched to dual-antiplatelet therapy compared to the other regimens; similarly, those who were switched to a different anti-platelet therapy did better than those maintained on aspirin. In respect to ischemic stroke recurrence alone, however, switching to another antiplatelet agent did not reduce stroke recurrence, although the addition of another antiplatelet therapy did.

Does this mean patients should be switched to dual antiplatelet therapy if they have failed aspirin monotherapy? Perhaps. The CHANCE trial (NEJM, 2013) showed benefit of short-term dual antiplatelet therapy in certain patients and patients in the SAMMPRIS trial (NEJM, 2011) did quite well on dual antiplatelet therapy (although antiplatelet regimen was not the focus of that trial). Although clopidogrel was the most common alternative antiplatelet medication used, some patients were on cilostazol, a medication which is more widely used in Asian countries than in the United States, so there was not uniformity in the regimens chosen. A randomized controlled trial may be the way to go to provide more definitive answers.

By |January 8th, 2016|treatment|0 Comments

Low socioeconomic status across age spectrum associated with higher incidence of stroke in adulthood

Low socioeconomic status is associated with a higher incidence risk of stroke in multiple populations worldwide. Although differences in the prevalence and severity of vascular risk factors likely contribute to this disparity, these risks may also be modified by negative socioeconomically driven influences throughout an individual’s lifespan. Becher et al. sought to investigate this further by conducting a case-control study to investigate the contribution of socioeconomic, genetic, and infectious risk factors during childhood, adolescence, and adulthood with respect to the risk of ischemic stroke in adulthood.
The study was nested in a population-based stroke registry in the city of Ludwigshafen, a city in South-West Germany with about 160,000 inhabitants. Patients of Caucasian race-ethnicity ages 18-80 with first-ever ischemic stroke treated at the only stroke unit within the city were compared to age and sex matched controls who were randomly selected from the general population. Patients with prior stroke, myocardial infarction within the last 90 days, dementia or severe communication barriers were excluded. 

Variables that were studied included anthropometric measures, medical history, smoking status, alcohol intake, diet, physical activity and medications. Socioeconomic measures were separated by age group (childhood, up to age 14; adolescence, age 15-25; adulthood,> age 25). Childhood socioeconomic conditions included parents’ occupation (divided into academic, non-academic white collar, blue collar and unskilled labor) during subjects’ childhood as well as living, familial, material and self-estimated financial conditions. For adolescence, highest school degree and professional education was used.  Last, profession, marital status and periods of unemployment were used as conditions for adulthood. Risk scores were calculated prior to analysis by summing scores according to weights chosen a priori based on previous work. Principal component analysis was also performed, as well as classification into tertiles of the summed scores based on distribution in controls. Odds ratio estimates were determined using both univariate and multivariate analyses, with the latter adjusted for known risk factors for stroke and the other life periods. 

A total of 470 subjects agreed to participate in the study and were compared to 809 controls. For childhood conditions, a higher number of siblings (OR=1.48[1.12-1.96]), lack of an own toilet (OR=1.52[1.12-2.05]), and estimated lower family income (OR=2.9[2.18-3.87]) were independently  associated with stroke in multivariate analysis. Lack of vocational training in adolescence (OR=1.93[1.03-3.63]) was independently associated with stroke.  In adulthood, single, divorced or windowed persons (OR=1.63[1.20-2.22]), greater than 6 months of unemployment (OR=1.52[1.05-2.19]) and unskilled last profession (OR=1.99[1.11-3.60]) were independently associated with stroke. In the fully adjusted model (adjusting for age, sex, medical and lifestyle risk factors, and the other life stages), low socioeconomic conditions during childhood (OR=1.77[1.20-2.60]) and adulthood (OR=1.74[1.16-2.60]) were independently associated with stroke risk. Interestingly, adjustment for medical risk factors attenuated the socioeconomic effect in childhood whereas lifestyle risk factors reduced the effect during adolescence and adulthood. When analyzed by stroke subtype, less favorable childhood socioeconomic conditions were associated with a strong risk of large artery stroke (OR=2.13[1.24-3.67]) that was not found for other etiologies of stroke or life stages. 

This study provides an intriguing insight into the impact of various socioeconomic conditions during each stage of life on stroke risk during adulthood. The relatively large number of patients and variety of factors assessed contribute to the strength of the study, although the lack of knowledge about the precise way that socioeconomic conditions affect health makes confounding factors difficult to assess and control. The attenuation of childhood risk after adjustment for medical factors suggests that factors in childhood may be causally linked to the development of known medical risk factors for stroke later in life, and the attenuation of adult risk after adjustment for lifestyle factors suggests that their effects may be independent of medical risk factors. Further study looking at associations with childhood socioeconomic conditions and medical risk factors for stroke could provide further clarity on this issue. The association of low socioeconomic conditions in childhood with large artery strokes may be related to this relationship, as there are many commonalities between medical risk factors for atherogenesis and stroke. The authors’ hypothesis related to chronic systemic inflammation could be further investigated using high-sensitivity CRP values either in a similarly designed study or, ideally, a longitudinal cohort that would track these values over time.   

The racial and geographical homogeneity of the study population limits its generalizability.  Conducting and reviewing similar studies with racially diverse populations in a variety of locations could be helpful in identifying common factors, as there is likely important variation in diet and environmental exposures between low socioeconomic status groups in different regions worldwide. This study and similar studies will be vital in expanding our understanding of how social conditions contribute to stroke risk.

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

Severe leukoaraiosis attenuates classic NIHSS-bias of dominant hemispheric infarction.

Jay Shah, MD

Helenius J, Goddeau RP, Moonis M, and Henninger N. Impact of Leukoaraiosis Burden on Hemispheric Lateralization of the National Institutes of Health Stroke Scale Deficit in Acute Ischemic Stroke. Stroke. 2016

The National Institute of Health Stroke Scale (NIHSS) is biased toward dominant hemisphere infarcts, demonstrating greater functional deficits. This lateralization of the NIHSS deficit has been shown to adversely affect stroke recognition and outcome. Therefore, understanding factors that modify the association between infarct laterality and NIHSS severity is important. Age has been shown to be a factor in lateralization of brain function but it’s unclear if age affects lateralization of the NIHSS deficit. Leukoaraiosis commonly presents in the elderly and can be used as a marker for age. In this study, the authors hypothesized that leukoaraiosis modifies the association between infarct laterality and NIHSS severity. 

Authors retrospectively analyzed consecutive patients with acute supratentorial ischemic strokes over a one year span. Baseline characteristics, including NIHSS, and modified rankin scale (mRS) at 90 days were recorded. Leukoaraiosis was defined as white matter hypoattenuation on FLAIR sequences and graded according to the Fazekas scale within periventricular and subcortical regions. Degree of leukoaraiosis was dichotomized to non-to-mild (score of 0-2) and severe (score of 3-6).

In total, 238 patients were included for analysis. Patients with left hemispheric infarcts had significantly greater NIHSS scores than right hemispheric infarcts. Hemispheric lateralization of NIHSS was only present in patients with non-to-mild leukoaraiosis. Severe leukoaraiosis attenuated the hemispheric lateralization of NIHSS. In multivariable linear regression models, leukoaraiosis, not chronological age, predicted NIHSS-deficit severity.

This study found that severe leukoaraiosis is associated with a remarkable attenuation of NIHSS-bias. The leukoaraiotic brain, due to loss of white matter tract, relies on recruitment of additional functional domains thereby becoming more susceptible for functional deficits after an ischemic stroke irrespective of laterality. This study serves as a reminder to not exclude patients for thrombolytics and endovascular therapy based solely on a low NIHSS as this scale is biased toward usually left hemispheric infarcts. This study provides insight into how leukoaraiosis affects cerebral functioning.

Peri-menopausal vasomotor symptom trajectories and carotid intima media thickness

Neal S. Parikh, MD

Thurston RC, El Khoudary SR, Tepper PG, Jackson EA, Joffe H, Chen HY, and Matthews KA. Trajectories of Vasomotor Symptoms and Carotid Intima Media Thickness in the Study of Women’s Health Across the Nation. Stroke. 2016

Thurston and colleagues sought to assess the relationship between trajectories of menopause-related vasomotor symptoms (VMS) (such as hot flashes and night sweats) and carotid intima media thickness (IMT).
The authors note that the patterns of VMS vary substantially among women; symptoms can occur prior to menopause, during or for long periods after. Temporal variations and differences in patterns are hypothesized to have different physiologic underpinnings and sequela, including for cardiovascular disease. 

The Study of Women’s Health Across the Nation (SWAN) – a multiethnic, longitudinal cohort of peri-menopausal women between the ages of 42-52 not using oral contraceptive or hormone therapy, served as the study cohort. The cohort enrollment assessments occurred in 1996-1997. After up to 13 annual visits, women underwent carotid ultrasound imaging.

811 of 1512 women with IMT data were ultimately included. They were required to have had at least 3 visits during which they completed questionnaires regarding VMS and to be notably free of a history of stroke or myocardial infarction. IMT was measured at the common carotid artery. The mean and maximal IMT were used for analyses. Covariates were site, age, ethnicity, education, BMI, blood pressure, lipid profile, diabetes, smoking status, use of cardiovascular medications and anxiety.

A statistical approach termed “group based growth trajectory modeling” was used to identify four distinct trends: consistently low VMS burden, consistently high VMS burden, early-onset (self-limited) VMS and late-onset VMS. At baseline, high VMS burden and early onset VMS were associated with cardiovascular disease risk factors.

Unadjusted, consistently high VMS burden was associated with increased IMT. Of the four trajectories, early onset VMS (onset up to 10 years prior to final menstrual period and subsiding over several years) was associated with increased mean and maximal IMT in linear regression adjusted for demographics and cardiovascular disease risk factors.

It seems, then, that early-onset VMS is independently associated with carotid IMT, a marker of cardiovascular disease. These findings may help future studies target women with early-onset VMS, in whom these symptoms may be most relevant to the pathophysiology of cardiovascular disease.