Practical use of dabigatran etexilate for stroke prevention in atrial fibrillation

Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug-drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice.

Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene.

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8 x 10(-5)), establishing a novel phenotype for this genetic variant.

Risk of incident stroke in patients with Alzheimer disease or vascular dementia

OBJECTIVE To explore the risk of ischemic stroke, hemorrhagic stroke, or TIA in patients with Alzheimer disease (AD) or vascular dementia (VD). METHODS We conducted a follow-up study with a nested case-control analysis using the UK-based General Practice Research Database. We included patients aged 65 years and older with an incident diagnosis of AD or VD between 1998 and 2008 and a comparison group of dementia-free patients. We estimated incidence rates of ischemic stroke, hemorrhagic stroke, or TIA in patients with AD, VD, or without dementia, and we calculated odds ratios with 95% confidence intervals (CIs) of developing such an outcome in patients with AD or VD, stratified by use of antipsychotic drugs. RESULTS We followed 6,443 cases with AD, 2,302 with VD, and 9,984 dementia-free patients over time and identified 281 cases with incident ischemic stroke, 139 with hemorrhagic stroke, and 379 with TIA. The incidence rates of ischemic stroke for patients with AD, VD, or no dementia were 4.7/1,000 person-years (PYs) (95% CI 3.8-5.9), 12.8/1,000 PYs (95% CI 9.8-16.8), and 5.1/1,000 PYs (95% CI 4.3-5.9), respectively. Compared with dementia-free patients, the odds ratio of developing a TIA for patients with AD treated with atypical antipsychotic drugs was 4.5 (95% CI 2.1-9.2). CONCLUSIONS Patients with VD, but not AD, have a markedly higher risk of developing an ischemic stroke than those without dementia. In patients with AD, but not VD, use of atypical antipsychotic drugs was associated with an increased risk of TIA.

Impact of changes in haematocrit level and platelet count on thromboelastometry parameters

INTRODUCTION To what extent haematocrit levels (Hct) and platelet counts (PLT) influence the measurement of parameters of thromboelastometry when assessed with the ROTEM® device is unclear. We investigated to what extent thromboelastometry measurements depend on Hct and PLT. MATERIALS AND METHODS Whole blood samples were taken for in-vitro preparations of mixtures with three different levels of PLT and a varying Hct. Maximum clot firmness (MCF), clotting time (CT), clot formation time (CFT) and alpha angle (α) for INTEM, EXTEM, FIBTEM and APTEM was recorded. RESULTS Measurements depended substantially on Hct and PLT. MCF readings were systematically lower with increasing Hct (0.2 vs. 0.4: -7.8 (-8.3 to -7.2); p<0.001, 0.2 vs. 0.55: -14.5 (-17.3 to -14.3); p<0.001) but higher with increasing PLT (50 vs. 125×10(9)/l: 8.2 (4.2 to 12.3); p=0.005, 50 vs. 250×10(9)/l: 12.0 (7.2 to 16.8); p=0.002). CT readings were systematically higher with increasing Hct (0.2 vs. 0.4: 9.2 (6.2 to 12.1); p=0.001, 0.2 vs. 0.55: 38.2 (21.5 to 54.9); p=0.003) while increasing PLT had no influence. CFT readings were also systematically higher with increasing Hct (0.2 vs. 0.4: 83.8 (40.2 to 127.6); p=0.006, 0.2 vs. 0.55: 226.2 (110.7 to 341.7); p=0.006) but systematically lower with increasing PLT (50 vs. 125×10(9)/l: -144.0 (-272.3 to -15.6); p=0.036, 50 vs. 250×10(9)/l: -189.2 (-330.4 to -48.0); p=0.02); readings of the alpha angle showed a similar pattern. CONCLUSIONS Our results suggest that readings of thromboelastometry parameters need to be adjusted by Hct and PLT to avoid potential confounding and miss-interpretations in clinical practice.

Three-dimensional, task-specific robot therapy of the arm after stroke: a multicentre, parallel-group randomised trial

BACKGROUND: Arm hemiparesis secondary to stroke is common and disabling. We aimed to assess whether robotic training of an affected arm with ARMin--an exoskeleton robot that allows task-specific training in three dimensions-reduces motor impairment more effectively than does conventional therapy. METHODS: In a prospective, multicentre, parallel-group randomised trial, we enrolled patients who had had motor impairment for more than 6 months and moderate-to-severe arm paresis after a cerebrovascular accident who met our eligibility criteria from four centres in Switzerland. Eligible patients were randomly assigned (1:1) to receive robotic or conventional therapy using a centre-stratified randomisation procedure. For both groups, therapy was given for at least 45 min three times a week for 8 weeks (total 24 sessions). The primary outcome was change in score on the arm (upper extremity) section of the Fugl-Meyer assessment (FMA-UE). Assessors tested patients immediately before therapy, after 4 weeks of therapy, at the end of therapy, and 16 weeks and 34 weeks after start of therapy. Assessors were masked to treatment allocation, but patients, therapists, and data analysts were unmasked. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00719433. FINDINGS: Between May 4, 2009, and Sept 3, 2012, 143 individuals were tested for eligibility, of whom 77 were eligible and agreed to participate. 38 patients assigned to robotic therapy and 35 assigned to conventional therapy were included in analyses. Patients assigned to robotic therapy had significantly greater improvements in motor function in the affected arm over the course of the study as measured by FMA-UE than did those assigned to conventional therapy (F=4.1, p=0.041; mean difference in score 0.78 points, 95% CI 0.03-1.53). No serious adverse events related to the study occurred. INTERPRETATION: Neurorehabilitation therapy including task-oriented training with an exoskeleton robot can enhance improvement of motor function in a chronically impaired paretic arm after stroke more effectively than conventional therapy. However, the absolute difference between effects of robotic and conventional therapy in our study was small and of weak significance, which leaves the clinical relevance in question.

Effects of arm training with the robotic device ARMin I in chronic stroke: three single cases

BACKGROUND: Several clinical studies on chronic stroke conducted with end-effector-based robots showed improvement of the motor function in the affected arm. Compared to end-effector-based robots, exoskeleton robots provide improved guidance of the human limb and are better suited to train task-oriented movements with a large range of motions. OBJECTIVE: To test whether intensive arm training with the arm exoskeleton ARMin I is feasible with chronic-stroke patients and whether it improves motor function in the paretic arm. METHODS: Three single cases with chronic hemiparesis resulting from unilateral stroke (at least 14 months after stroke). A-B design with 2 weeks of multiple baseline measurements (A), 8 weeks of training (B) with repetitive measurements and a follow-up measurement 8 weeks after training. The training included shoulder and elbow movements with the robotic rehabilitation device ARMin I. Two subjects had three 1-hour sessions per week and 1 subject received five 1-hour sessions per week. The main outcome measurement was the upper-limb part of the Fugl-Meyer Assessment (FMA). RESULTS: The ARMin training was well tolerated by the patients, and the FMA showed moderate, but significant improvements for all 3 subjects (p < 0.05). Most improvements were maintained 8 weeks after discharge. CONCLUSIONS: This study indicates that intensive training with an arm exoskeleton is feasible with chronic-stroke patients. Moderate improvements were found in all 3 subjects, thus further clinical investigations are justified.

Effects of intensive arm training with the rehabilitation robot ARMin II in chronic stroke patients: four single-cases

BACKGROUND: Robot-assisted therapy offers a promising approach to neurorehabilitation, particularly for severely to moderately impaired stroke patients. The objective of this study was to investigate the effects of intensive arm training on motor performance in four chronic stroke patients using the robot ARMin II. METHODS: ARMin II is an exoskeleton robot with six degrees of freedom (DOF) moving shoulder, elbow and wrist joints. Four volunteers with chronic (>or= 12 months post-stroke) left side hemi-paresis and different levels of motor severity were enrolled in the study. They received robot-assisted therapy over a period of eight weeks, three to four therapy sessions per week, each session of one hour.Patients 1 and 4 had four one-hour training sessions per week and patients 2 and 3 had three one-hour training sessions per week. Primary outcome variable was the Fugl-Meyer Score of the upper extremity Assessment (FMA), secondary outcomes were the Wolf Motor Function Test (WMFT), the Catherine Bergego Scale (CBS), the Maximal Voluntary Torques (MVTs) and a questionnaire about ADL-tasks, progress, changes, motivation etc. RESULTS: Three out of four patients showed significant improvements (p < 0.05) in the main outcome. The improvements in the FMA scores were aligned with the objective results of MVTs. Most improvements were maintained or even increased from discharge to the six-month follow-up. CONCLUSION: Data clearly indicate that intensive arm therapy with the robot ARMin II can significantly improve motor function of the paretic arm in some stroke patients, even those in a chronic state. The findings of the study provide a basis for a subsequent controlled randomized clinical trial.

New Technologies and Concepts for Rehabilitation in the Acute Phase of Stroke: A Collaborative Matrix

The process of developing a successful stroke rehabilitation methodology requires four key components: a good understanding of the pathophysiological mechanisms underlying this brain disease, clear neuroscientific hypotheses to guide therapy, adequate clinical assessments of its efficacy on multiple timescales, and a systematic approach to the application of modern technologies to assist in the everyday work of therapists. Achieving this goal requires collaboration between neuroscientists, technologists and clinicians to develop well-founded systems and clinical protocols that are able to provide quantitatively validated improvements in patient rehabilitation outcomes. In this article we present three new applications of complementary technologies developed in an interdisciplinary matrix for acute-phase upper limb stroke rehabilitation – functional electrical stimulation, arm robot-assisted therapy and virtual reality-based cognitive therapy. We also outline the neuroscientific basis of our approach, present our detailed clinical assessment protocol and provide preliminary results from patient testing of each of the three systems showing their viability for patient use.

Insular and caudate lesions release abnormal yawning in stroke patients.

Abnormal yawning is an underappreciated phenomenon in patients with ischemic stroke. We aimed at identifying frequently affected core regions in the supratentorial brain of stroke patients with abnormal yawning and contributing to the anatomical network concept of yawning control. Ten patients with acute anterior circulation stroke and ≥3 yawns/15 min without obvious cause were analyzed. The NIH stroke scale (NIHSS), Glasgow Coma Scale (GCS), symptom onset, period with abnormal yawning, blood oxygen saturation, glucose, body temperature, blood pressure, heart rate, and modified Rankin scale (mRS) were assessed for all patients. MRI lesion maps were segmented on diffusion-weighted images, spatially normalized, and the extent of overlap between the different stroke patterns was determined. Correlations between the period with abnormal yawning and the apparent diffusion coefficient (ADC) in the overlapping regions, total stroke volume, NIHSS and mRS were performed. Periods in which patients presented with episodes of abnormal yawning lasted on average for 58 h. Average GCS, NIHSS, and mRS scores were 12.6, 11.6, and 3.5, respectively. Clinical parameters were within normal limits. Ischemic brain lesions overlapped in nine out of ten patients: in seven patients in the insula and in seven in the caudate nucleus. The decrease of the ADC within the lesions correlated with the period with abnormal yawing (r = -0.76, Bonferroni-corrected p = 0.02). The stroke lesion intensity of the common overlapping regions in the insula and the caudate nucleus correlates with the period with abnormal yawning. The insula might be the long sought-after brain region for serotonin-mediated yawning.

Prospective, multicenter, single-arm study of mechanical thrombectomy using Solitaire Flow Restoration in acute ischemic stroke

BACKGROUND AND PURPOSE Mechanical thrombectomy using stent retriever devices have been advocated to increase revascularization in intracranial vessel occlusion. We present the results of a large prospective study on the use of the Solitaire Flow Restoration in patients with acute ischemic stroke. METHODS Solitaire Flow Restoration Thrombectomy for Acute Revascularization was an international, multicenter, prospective, single-arm study of Solitaire Flow Restoration thrombectomy in patients with large vessel anterior circulation strokes treated within 8 hours of symptom onset. Strict criteria for site selection were applied. The primary end point was the revascularization rate (thrombolysis in cerebral infarction ≥2b) of the occluded vessel as determined by an independent core laboratory. The secondary end point was the rate of good functional outcome (defined as 90-day modified Rankin scale, 0-2). RESULTS A total of 202 patients were enrolled across 14 comprehensive stroke centers in Europe, Canada, and Australia. The median age was 72 years, 60% were female patients. The median National Institute of Health Stroke Scale was 17. Most proximal intracranial occlusion was the internal carotid artery in 18%, and the middle cerebral artery in 82%. Successful revascularization was achieved in 79.2% of patients. Device and procedure-related severe adverse events were found in 7.4%. Favorable neurological outcome was found in 57.9%. The mortality rate was 6.9%. Any intracranial hemorrhagic transformation was found in 18.8% of patients, 1.5% were symptomatic. CONCLUSIONS In this single-arm study, treatment with the Solitaire Flow Restoration device in intracranial anterior circulation occlusions results in high rates of revascularization, low risk of clinically relevant procedural complications, and good clinical outcomes in combination with low mortality at 90 days. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov. Unique identifier: NCT01327989.

Stent-retriever thrombectomy: impact on the future of interventional stroke treatment

Endovascular treatment for acute ischemic stroke has evolved in the past years. The current development of stent-retriever thrombectomy is a landmark in the clinical treatment and study results of acute ischemic stroke. This review summarizes the recent study results, elucidates the shortcomings of endovascular stroke treatment, and takes the opportunity for an outlook on the role of stroke interventions in the future.

Outcome of standard and high-risk patients with acute anterior circulation stroke after stent retriever thrombectomy.

BACKGROUND AND PURPOSE Stent retrievers have become an important tool for the treatment of acute ischemic stroke. The aim of this study was to analyze outcome and complications in a large cohort of patients with stroke treated with the Solitaire stent retriever. The study also included patients who did not meet standard inclusion criteria for endovascular treatment: low or high baseline National Institutes of Health Stroke Scale score, ≥80 years of age, extensive ischemic signs in middle cerebral artery territory, and time from symptom onset to endovascular intervention>8 hours. METHODS Consecutive patients with acute anterior circulation stroke treated with the Solitaire FR were analyzed. Data on characteristics of endovascular interventions, complications, and clinical outcome were collected prospectively. Patients who met standard inclusion criteria were compared with those who did not. RESULTS A total of 227 patients were included. Mean age was 68.2±14.7 years, and median National Institutes of Health Stroke Scale score on admission was 16 (range, 2-36). Reperfusion was successful (thrombolysis in cerebral infarction, 2b-3) in 70.9%. Outcome was favorable (modified Rankin Scale, 0-2) in 57.7% of patients who met standard inclusion criteria and 30.3% of those who did not. The rates for symptomatic intracranial hemorrhage were 3.7% and 13.1%, for death 11.4% and 33.8%, and for symptomatic intraprocedural complications 2.5% and 4.8%, respectively. CONCLUSIONS Patients<80 years of age, without extensive pretreatment ischemic signs, and baseline National Institutes of Health Stroke Scale score≤30 had high rates of favorable outcome and low periprocedural complication rates after Solitaire thrombectomy. Successful reperfusion was also common in patients not fulfilling standard inclusion criteria, but worse clinical outcomes warrant further research with a special focus on optimal patient selection.

Impact of Age and Baseline NIHSS Scores on Clinical Outcomes in the Mechanical Thrombectomy Using Solitaire FR in Acute Ischemic Stroke Study

BACKGROUND AND PURPOSE Age and stroke severity are inversely correlated with the odds of favorable outcome after ischemic stroke. A previously proposed score for Stroke Prognostication Using Age and NIHSS Stroke Scale (SPAN) indicated that SPAN-100-positive patients (ie, age + NIHSS score = 100 or more) do not benefit from IV-tPA. If this finding holds true for endovascular therapy, this score can impact patient selection for such interventions. This study investigated whether a score combining age and NIHSS score can improve patients' selection for endovascular stroke therapy. MATERIALS AND METHODS The SPAN index was calculated for patients in the prospective Solitaire FR Thrombectomy for Acute Revascularization study: an international single-arm multicenter cohort for anterior circulation stroke treatment by using the Solitaire FR. The proportion with favorable outcome (90-day mRS score ≤2) was compared between SPAN-100-positive versus-negative patients. RESULTS Of the 202 patients enrolled, 196 had baseline NIHSS scores. Fifteen (7.7%) patients were SPAN-100-positive. There was no difference in the rate of successful reperfusion (Thrombolysis In Cerebral Infarction 2b or 3) between SPAN-100-positive versus -negative groups (93.3% versus 82.8%, respectively; P = .3). Stroke SPAN-100-positive patients had a significantly lower proportion of favorable clinical outcomes (26.7% versus 60.8% in SPAN-100-negative, P = .01). In a multivariable analysis, SPAN-100-positive status was associated with lower odds of favorable outcome (OR, 0.3; 95% CI, 0.1-0.9; P = .04). A higher baseline Alberta Stroke Program Early CT Score and a short onset to revascularization time also predicted favorable outcome in the multivariable analysis. CONCLUSIONS A significantly lower proportion of patients with a positive SPAN-100 achieved favorable outcome in this cohort. SPAN-100 was an independent predictor of favorable outcome after adjusting for time to treatment and the extent of preintervention tissue damage according to the Alberta Stroke Program Early CT Score.

Factors that determine penumbral tissue loss in acute ischaemic stroke

The goal of acute stroke treatment with intravenous thrombolysis or endovascular recanalization techniques is to rescue the penumbral tissue. Therefore, knowing the factors that influence the loss of penumbral tissue is of major interest. In this study we aimed to identify factors that determine the evolution of the penumbra in patients with proximal (M1 or M2) middle cerebral artery occlusion. Among these factors collaterals as seen on angiography were of special interest. Forty-four patients were included in this analysis. They had all received endovascular therapy and at least minimal reperfusion was achieved. Their penumbra was assessed with perfusion- and diffusion-weighted imaging. Perfusion-weighted imaging volumes were defined by circular singular value decomposition deconvolution maps (Tmax > 6 s) and results were compared with volumes obtained with non-deconvolved maps (time to peak > 4 s). Loss of penumbral volume was defined as difference of post- minus pretreatment diffusion-weighted imaging volumes and calculated in per cent of pretreatment penumbral volume. Correlations between baseline characteristics, reperfusion, collaterals, time to reperfusion and penumbral volume loss were assessed using analysis of covariance. Collaterals (P = 0.021), reperfusion (P = 0.003) and their interaction (P = 0.031) independently influenced penumbral tissue loss, but not time from magnetic resonance (P = 0.254) or from symptom onset (P = 0.360) to reperfusion. Good collaterals markedly slowed down and reduced the penumbra loss: in patients with thrombolysis in cerebral infarction 2 b-3 reperfusion and without any haemorrhage, 27% of the penumbra was lost with 8.9 ml/h with grade 0 collaterals, whereas 11% with 3.4 ml/h were lost with grade 1 collaterals. With grade 2 collaterals the penumbral volume change was -2% with -1.5 ml/h, indicating an overall diffusion-weighted imaging lesion reversal. We conclude that collaterals and reperfusion are the main factors determining loss of penumbral tissue in patients with middle cerebral artery occlusions. Collaterals markedly reduce and slow down penumbra loss. In patients with good collaterals, time to successful reperfusion accounts only for a minor fraction of penumbra loss. These results support the hypothesis that good collaterals extend the time window for acute stroke treatment.