Aktuelle Aspekte der Sekundärprophylaxe des ischämischen Schlaganfalls

Secondary prevention including lifestyle modulation and medical interventions remain the basic principle in our therapeutic challenge to reduce the risk of recurrent subsequent ischemic stroke. The substantial number of randomized clinical trials published in the past 2 years was broadened our evidence-based therapeutic armament in the field of secondary prevention of ischemic stroke. An update of current knowledge in secondary stroke prevention is presented in this review on the basis of the 2007 revised guidelines of the German Neurological Society and the German Stroke Society. Special emphasis is given to medical and nonmedical modulation of cardiovascular risk factors (treatment of hypertension, hypercholesterolemia, and diabetes mellitus), prophylactic vitamin supplementation, and the use of platelet inhibitors and treatment of symptomatic intracranial stenosis.     

Management of the neurological manifestations of APS--what do the trials tell us?

Purpose: To systematically review evidence from clinical trials about the management of neurological manifestations of Antiphospholipid Syndrome (APS). Methods: Articles reporting case-control, cohort and prospective studies and treatment trials of primary or secondary stroke prevention in patients with aPL were identified in an OVID literature search from 1966 to 2004, using the keywords: APS, aPL and cerebrovascular disease. Articles were evaluated according to the standard system for assessing medical evidence to answer the following questions: (1) What is the role of aPL and recurrent stroke risk in both primary and secondary APS populations? (2) What is the evidence to support specific treatment strategies for secondary prevention of aPL-associated stroke? (3) What is the evidence to support specific treatment strategies for primary prevention of aPL-associated stroke? Conclusions: (1) aPL are a risk factor for incident stroke (Grade A, established as useful for the given condition in the specified population). (2) The evidence to support the role of aPL in recurrent stroke is conflicting and, therefore, inconclusive. (3) Warfarin at moderate-intensity doses is equally effective in preventing a recurrent thrombotic event as warfarin at high-intensity doses in patients with APS (Grade A evidence, established as useful for the given condition in the specified population). (4) Warfarin, at moderate-intensity doses is as effective as aspirin (at a dose of 325 mg/day) in preventing recurrent thrombotic events in patients who are aPL-positive at the time of an initial stroke (Grade B evidence, probably useful for the given condition in the given population). (5) Currently there are no data to support the use of any prophylactic therapy in patients with aPL and no clinical manifestations for the purposes of preventing an incident stroke.     

The role of intima-media-thickness, ankle-brachial-index and inflammatory biochemical parameters for stroke risk prediction: a systematic review

Background: Despite important advances in therapeutic approaches in stroke, the options of acute treatment are still limited. Primary prevention represents another potentially highly efficient strategy. For effective prevention the early detection of subjects at risk is of utmost importance. Coinciding with a change in current understanding of atherosclerosis as an inflammatory, cross‐organ disease, new parameters to assess the individual risk are emerging. Methods: Systematic review of the potential of selected parameters for prediction of cerebrovascular events beyond detection of traditional risk factors that might expand the repertoire of primary prevention programs in stroke. Results: An absolute carotid intima‐media thickness difference of 0.1 mm increases the future risk of stroke by 13–18%. An ankle‐brachial index <0.9 was associated with a relative risk of 2.33 (95% CI 2.02–2.68) for stroke. In patients with acute stroke and ABI values < 0.9 the risk for a new vascular event is significantly increased (HR 2.1; 95% CI 1.6–2.8). Measurements of several molecular biomarkers may be used to predict future vascular events independently of traditional risk factors. Conclusions: Based on the data presented, there is clear evidence that measurement of the ankle‐brachial index identifies subjects of increased stroke risk in primary and secondary care settings as well as of stroke recurrence in acute stroke.     

Using measures of sarcopenia to predict recurrent cerebrovascular events in stroke and TIA patients

PurposeSarcopenia is associated with poor outcomes, and evidence suggests an inverse relationship between skeletal muscle mass and cardiovascular risk. Sarcopenia has been studied after stroke, but its value as a risk factor for stroke has not been examined. This prospective cohort study measured sarcopenia in stroke/TIA patients at baseline to explore its role in predicting recurrent events.MethodThe Arterial Stiffness In lacunar Stroke and TIA (ASIST) study included 96 patients with TIA/lacunar stroke, of which 82 patients (mean age 71.2±10.8 years) had bioimpedance analysis to assess body composition. Skeletal Mass Index (SMI) was calculated and parameters of sarcopenia assessed using Davison (1) and Janssen (2) criteria. Recurrent cerebrovascular events were monitored over 5 years.ResultsEighteen patients had recurrent events. On independent samples t test there were significantly more participants with sarcopenia in the recurrent events group (89% vs 56%, p<0.001) using Davison (1) criteria, as well as lower mean SMI, significantly more participants with diabetes and higher arterial stiffness. On binary logistic regression, the only significant predictors of recurrent events were SMI (p=0.036, hazard ratio=0.414, 95% confidence interval 0.195-0.948) and diabetes (p=0.004, hazard ratio=9.06, 95% confidence interval 2.009-40.860) when corrected for age, sex and cardiovascular risk factors. Using Janssen (2) criteria in the regression, severe sarcopenia was a significant predictor of recurrent events (p=0.028). There was a significant association between sarcopenia and recurrent events on Chi square based on Davison (p=0.02) and Janssen (p=0.034) definitions.ConclusionsThe presence of baseline sarcopenia in stroke and TIA patients is an independent predictor of recurrent events.     

Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke

Recurrent stroke is a major public health concern and new treatment strategies are needed. While modulation of the renin angiotensin aldosterone system (RAAS) has proven effective in reducing recurrent cardiac events, its role in preventing recurrent cerebrovascular events remains unclear. RAAS is both a circulating and tissue based hormonal system that regulates homeostasis and tissue responses to injury in both the CNS and the periphery, via the activity of angiotensin II (Ang II). Vascular and hematologic effects induced by Ang II including endothelial dysfunction, vascular structural changes, inflammation, hemostasis, and fibrinolysis are increasingly linked to the occurrence of cerebrovascular events. Animal models have shown that RAAS modulation may be protective in cerebrovascular disease. The HOPE and LIFE trials support the role of blood pressure independent mechanisms of RAAS modulation for improving outcomes in a broad range of patients with cardiovascular disease but do not specifically address recurrent stroke prevention. PROGRESS, a trial of secondary stroke prevention, demonstrates that blood pressure reduction with a combination strategy including the routine use of ACE inhibitors prevents recurrent stroke. Current evidence suggests that the RAAS plays an important role in the development and progression of cerebrovascular disease. Modulation of the RAAS holds promise for the secondary prevention of stroke, however, ongoing clinical trials will better define the exact role of ACE inhibitor and angiotensin II Type 1 receptor blocker therapy in stroke survivors.     

Hyperhomocyst(e)inemia is a risk factor of secondary vascular events in stroke patients

OBJECTIVE: Moderate hyperhomocyst(e)inemia is an independent risk factor for stroke, but it is unclear whether it also would be a risk factor for secondary vascular events after stroke. METHODS: Longitudinal study of 137 consecutive ischemic stroke patients (age 45-91 years) who were prospectively studied with a standard clinical protocol. Vascular events (stroke recurrence, ischemic heart disease, deep venous thrombosis or peripheral arterial disease) were identified during 2 years of follow-up. Serum homocyst(e)ine was determined 3 months after the stroke. The cumulative proportion of patients with homocyst(e)ine above or below the 75th percentile who survived free of vascular events was determined by Kaplan-Meier analysis. Cox models were used to estimate the relative risk of vascular events after controlling for other confounding factors. RESULTS: Serum homocyst(e)ine was significantly higher in patients with vascular events (26.2 versus 19.4 micromol/l; p = 0.016). The cumulative proportion of patients with vascular events was 46.5% in the group with homocyst(e)ine over the 75th percentile (>30 micromol/l) and 20.2% in the other group (log-rank test 7.5; p = 0.0062). After adjustment for age, sex, high blood pressure, diabetes, heart disease, previous cerebrovascular disease, smoking and serum cholesterol, the relative risk of vascular event for patients above compared with those below the 75th percentile of serum homocyst(e)ine was 2.8 (CI 95% 1.3-6; p = 0.01). CONCLUSION: Hyperhomocyst(e)inemia is a significant risk factor for vascular events after ischemic stroke. This finding is independent of other risk factors such as hypertension, and may have therapeutic relevance in the secondary prevention of vascular diseases in stroke patients.     

Prevention of stroke in patients with diabetes mellitus and the metabolic syndrome

The basic principles of stroke prevention are the same in patients with diabetes and/or the metabolic syndrome as in those without. Blood-pressure lowering is highly effective in both primary and secondary prevention of stroke in diabetics, and there is no evidence to suggest that the benefits of lipid-lowering therapy are any less. Antiplatelet agents are effective in secondary prevention and may be indicated in asymptomatic diabetic patients, who have a substantially increased risk of acute vascular events. Uncertainty over optimal management of patients with diabetes, and possibly of those with metabolic syndrome, relates more to the thresholds for initiation of treatment. The decision to initiate treatment should depend on the balance between the absolute risk of potentially preventable events and the risks of any complications of treatment. The absolute risks of ischaemic stroke and acute coronary events are significantly increased in diabetics in population-based cohort studies and the recommended thresholds for instigating blood pressure lowering and lipid lowering are therefore lower than in the general population. Optimization of strategies to prevent vascular complications must be a priority, given the rapid rises in the incidence and prevalence of type 2 diabetes and the metabolic syndrome in most populations across the globe.     

Current strategies for ischemic stroke prevention: role of multimodal combination therapies

Stroke remains a global leading cause of death and long-term disability, highlighting the need for more effective treatment approaches. The majority of strokes are of ischemic origin, often caused by large- or small-artery atherothrombosis, or cardioembolism. Considering the systemic nature of the atherothrombotic disease process, stroke patients are at increased risk for ischemic events in several vascular territories: cerebral, coronary and peripheral. Due to the limited options for acute stroke therapies, stroke prevention is an important therapeutic approach. In addition to the management of modifiable risk factors such as hypertension, dyslipidemia and smoking through pharmacotherapy or lifestyle adjustments, anticoagulants, surgical and perhaps endovascular approaches are indicated in certain patients. Antiplatelet therapies using various agents are a cornerstone of secondary stroke prevention. To ensure the appropriate continuum of care after hospitalization for ischemic stroke, some interventions for the prevention of recurrent ischemic stroke should be initiated during the acute hospitalization setting and maintained in the out-patient setting.     

Prevención de ictus en pacientes con diabetes mellitus tipo 2 o prediabetes. Recomendaciones del Grupo de Estudio de Enfermedades Cerebrovasculares de la Sociedad Española de Neurología

ObjectiveTo update the Spanish Society of Neurology's guidelines for stroke prevention in patients with type 2 diabetes or prediabetes, analysing the available evidence on the effect of metabolic control and the potential benefit of antidiabetic drugs with known vascular benefits in addition to conventional antidiabetic treatments in stroke prevention.DevelopmentPICO-type questions (Patient, Intervention, Comparison, Outcome) were developed to identify practical issues in the management of stroke patients and to establish specific recommendations for each of them. Subsequently, we conducted systematic reviews of the PubMed database and selected those randomised clinical trials evaluating stroke as an independent variable (primary or secondary). Finally, for each of the PICO questions we developed a meta-analysis to support the final recommendations.ConclusionsWhile there is no evidence that metabolic control reduces the risk of stroke, some families of antidiabetic drugs with vascular benefits have been shown to reduce these effects when added to conventional treatments, both in the field of primary prevention in patients presenting type 2 diabetes and high vascular risk or established atherosclerosis (GLP-1 agonists) and in secondary stroke prevention in patients with type 2 diabetes or prediabetes (pioglitazone).     

Current Status of Antiplatelet Agents to Prevent Stroke

Stroke is one of the leading causes of disability; most are due to atherothrombotic mechanisms. About one third of ischemic strokes are preceded by other stroke or transient ischemic attacks. Stroke survivors are at high risk for vascular events (i.e., cerebrovascular and cardiovascular). Prevention of recurrent stroke and other major vascular events can be accomplished by control of risk factors. Nonetheless, the use of antiplatelet agents remains the fundamental component of secondary stroke prevention strategy in patients with noncardioembolic disease. Currently, the uses of aspirin, clopidogrel, or aspirin plus extended-release dipyridamole are valid alternatives for stroke or transient ischemic attack patients. To maximize the beneficial effects of these agents, the treatment should be initiated as early as possible and continue on a lifelong basis.     

Risk factors for arterial ischemic stroke in children

Since early recurrence occurs in at least 10% of patients presenting with their first stroke in childhood in the reported series, the search for modifiable risk factors should be a priority. Risk factors for stroke in adults include hypertension, diabetes, and smoking, as well as cardiac disease and sickle cell anemia; asymptomatic cerebrovascular disease and transient ischemic events may predict stroke in this age group. The investigation of a child with a stroke has traditionally focused on finding a single cause rather than looking for risk factors to which the patient may be exposed life long. Approximately half of children presenting with stroke have a known predisposing condition, but some have unexpected pathologies such as primary cerebrovascular disease associated with congenital heart anomalies, or may have modifiable risk factors such as hypertension associated with sickle cell disease. The literature on children presenting with initially unexplained (cryptogenic) stroke suggests that there is a daunting list of possible causes, but since the series have mainly been small, it has been difficult to evaluate the relative importance of the reported associations. This paper reviews the literature on congenital, genetic, and acquired risk factors for stroke in childhood, and includes data from the large series of patients seen at Great Ormond Street Hospital over the past 10 years. The majority have arteriographic abnormalities and there is little evidence for asymptomatic cardiac disease. Genetic predisposition, trauma, infection, and nutritional deficiencies appear to be important, although case-control studies will be required to prove causation. Appropriate screening for modifiable risk factors may lead to prevention of recurrence in some patients. In the long term, an understanding of the multiple etiologies of childhood cerebrovascular disease and ischemic stroke may lead to primary prevention in this age group, and perhaps in adults.     

The BC genotype of the VNTR polymorphism of platelet glycoprotein Ibalpha is overrepresented in patients with recurrent stroke regardless of aspirin therapy

BACKGROUND: The contribution of genetic factors to aspirin treatment failure (ATF) for secondary prevention is not settled in patients with ischemic stroke. METHODS: We assessed the polymorphisms VNTR (A, B, C, D) of glycoprotein (GP) Ibalpha, 807C/T of GP Ia/IIa, and Pl(A1/A2) of GP IIb/IIIa, and the 5-year incidence of major recurrent events in 82 stroke patients with no major sources of cardioembolism (mean age 70, SD 9.0 years; female gender 23%). Using a structured interview, all participants confirmed good compliance with aspirin (100-300 mg/day) for secondary prevention. Demographics and atherothrombotic risk factors assessed included diabetes, hypertension, dyslipemia, smoking, and coronary heart disease. RESULTS: Thirty-one stroke patients had one recurrent stroke or myocardial infarction within 33 (7-48) months of aspirin onset, while 51 patients demonstrated an uneventful clinical course. Female gender (p < 0.05), diabetes (p < 0.05), dyslipemia (p < 0.05), and the BC genotype of VNTR (25.8 vs. 7.8%, p < 0.05) were more prevalent in patients in whom aspirin failed to prevent clinical events than in those in whom it did not. The BC genotype of VNTR was the only factor that remained associated with ATF in an age-, sex-, and risk factor-adjusted logistic regression analysis (OR 9.6, 95% CI 1.5-61.0). CONCLUSION: The BC genotype of the VNTR polymorphism of GP Ibalpha is an independent predictor of recurrent events in stroke patients treated with aspirin. This finding suggests that high shear-induced platelet activation mediated by GP Ibalpha and von Willebrand factor is an important contributor to ATF in the stroke population.     

The role of antiplatelet therapy in the management of ischemic stroke: implementation of guidelines in current practice

Abstract

Objective: To review and discuss evidence-based guideline recommendations for the use of antiplatelet agents for secondary prevention in patients with ischemic stroke or TIA.

Methods: A literature search was conducted on PubMed through August 2007 using combinations of the following search terms: aspirin, clopidogrel, dipyridamole plus aspirin, transient ischemic attack, secondary prevention, stroke and guidelines.

Results: Modification of risk factors such as hypertension, diabetes, hypercholesterolemia, cigarette smoking and obesity are fundamental to stroke management. Antiplatelet therapy is highly effective in reducing the risk of recurrent vascular events and is recommended over oral anticoagulants for non-cardioembolic stroke. Evidence from head-to-head comparative clinical trials versus aspirin monotherapy has shown that clopidogrel and the combination of aspirin plus dipyridamole are safe and effective therapeutic options.

Discussion: Despite the availability of evidence-based guidelines, recommended interventions are largely underutilized. Quality improvement initiatives such as the ASA's Get with the Guidelines – Stroke and the UCLA stroke PROTECT Program have demonstrated effectiveness in increasing adherence to recommended therapies and thereby improving patient outcomes.     

The role of blood pressure lowering before and after stroke

PURPOSE OF REVIEW: Elevated blood pressure is one of the most potent risk factors for first ever and recurrent stroke as well as influencing early outcome after acute stroke. There have been a number of significant randomized controlled trials which may influence management in each of these three categories. RECENT FINDINGS: For primary prevention, the recent information from the Heart Outcomes Prevention Evaluation, Losartan Intervention for Endpoint Reduction to Hypertension, Study on Cognition and Prognosis in the Elderly and Australian National Blood Pressure Study support the view that blood pressure lowering protects against stroke regardless of baseline blood pressure level. There is some evidence that blockade of the angiotensin system may give additional protection. For secondary prevention, evidence from the Perindopril Protection against Recurrent Stroke Study shows that blood pressure lowering with perindopril based therapy reduces fatal or non-fatal stroke events, again in hypertensive or normotensive individuals. There is uncertainty about blood pressure lowering in acute stroke, although presentation of the recent Acute Candesartan Cilexetil Evaluation in Stroke Survivors trial in which there was significant protection against vascular events using candesartan suggests that further studies should be undertaken. SUMMARY: Blood pressure lowering for primary prevention of stroke should be undertaken using a variety of therapeutic agents. For secondary stroke prevention perindopril based therapy should be used based on current evidence. Uncertainty still exists as to whether blood pressure lowering in the acute stroke setting is safe or improves outcomes.     

非心房颤动缺血性卒中患者卒中复发的预测模型——Essen卒中风险评分量表

卒中复发风险预测评分是一种重要的工具,可以根脑血管事件复发的风险将患者分层,从而指导预防性治疗措施。Essen卒中风险评分量表（Essen Stroke Risk Score,ESRS）是一个简便、易于临床操作的9分量表,已在大量卒中人群中证实ESRS对于卒中再发和复合心血管事件的发生具有有效、可行的预测价值。因此,ESRS可以预测卒中患者的卒中或复合心血管事件的复发风险;评估患者危险分层并指导用药。     

Transient ischemic attack: A neurologic emergency

Classically, a transient ischemic attack (TIA) has been defined as an acute episode of neurologic symptoms lasting less than 24 hours attributed to focal ischemia in a vascular distribution of the brain or retina. Stroke and TIA share similar risk factors, evaluation, and secondary prevention. However, evaluation of patients with TIA has traditionally lacked the same urgency that has been directed to acute stroke, probably because patients with TIA are at baseline neurologically when the diagnosis is made. Recently, several studies have found a high risk of stroke shortly after TIA. Furthermore, recent evidence suggests that early recovery from ischemia actually is associated with greater instability. Identifying patients with the highest risk of recurrent ischemic events for urgent evaluation and intervention is key in secondary stroke prevention. This article reviews the current literature on new concepts about TIA, subsequent risk of stroke, and guidelines on evaluation and treatment.     

The relationships between atherosclerosis,heart disease,type 2 diabetes and dementia

Abstract

Type 2 diabetes in the elderly is associated with increased incidence of vascular disease, particularly, atherosclerosis of large blood vessels. Together with other risk factors such as dyslipidemia, atherosclerosis increases the risk for coronary heart disease and stroke. Most studies that have examined the impact of type 2 diabetes and other heart disease risk factors on cognitive functions do not provide evidence that heart disease risk factors (with the possible exception of triglycerides) further increase the likelihood of observing cognitive deficits in diabetic patients. However, none of these studies used imaging techniques to evaluate atherosclerosis or evidence of cerebrovascular disease, such as infarctions. The few studies that have included brain imaging suggest that evidence of cerebrovascular disease further increases the risk for dementia in diabetic patients. The results of longitudinal studies suggest that diabetes is an independent risk factor for cognitive decline and dementia. The pattern of neuropsychological performance observed in type 2 diabetic patients appears to be the result of multiple interacting processes developing over time. In addition to the detrimental effects of protracted impaired glucose regulation on the central nervous system, type 2 diabetes pathology also encompasses the detrimental effects of associated complications such as cerebrovascular disease, which is likely the main cause of the observed processing speed/reaction time decrements.     

Inhibidores de la proproteína convertasa subtilisina/kexina tipo 9 (iPCSK9) en la prevención secundaria de episodios vasculares en pacientes con ictus isquémico: Documento de consenso y aplicaciones prácticas

IntroductionPatients with history of stroke or transient ischaemic attack present considerable risk of future vascular events. Reducing levels of low-density lipoprotein (LDL) cholesterol decreases the incidence of new vascular events, although in a substantial number of patients, the currently available lipid-lowering therapies fail to achieve the therapeutic goals recommended in clinical guidelines. The aim of this consensus statement is to provide updated information on the role of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab in the secondary prevention of vascular events in patients with history of ischaemic stroke.MethodsA literature review was performed to identify the main evidence on the use of PCSK9 inhibitors in these patients and the recommended therapeutic targets of LDL cholesterol. The results were discussed in 2 consensus meetings that constituted the basis for the drafting of the document.ConclusionsPCSK9 inhibitors are effective in reducing vascular risk in secondary prevention; evolocumab specifically has achieved this reduction in patients with history of ischaemic stroke. Moreover, both alirocumab and evolocumab present good safety profiles, even in patients achieving LDL cholesterol levels < 20 mg/dL, and no signs of cognitive impairment have been observed in patients treated with evolocumab who achieved very low levels of LDL cholesterol. In the light of this evidence, we provide practical recommendations about the use of PCSK9 inhibitors in secondary prevention of vascular events in patients with history of ischaemic stroke and follow-up of these patients.     

缺血性脑卒中再发风险预测的现况

卒中是全球严重的公共健康问题，缺血性卒中占其中的60％-80％。众所皆知，缺血性卒中拥有高复发的特性，且复发事件的危害更严重于首发事件，目前研究已证实卒中二级预防治疗的药物和措施能有效减少脑卒中复发事件的发生，但是由于每个患者的病睛和卒中类型不同，每个患者间的卒中复发危险程度也存在差异，因此根据不同的预测量表来预测卒中患者的复发风险，临床上分层管理患者，更好地指导患者进行有效的二级预防是非常有价值的。     

The relationships between atherosclerosis, heart disease, type 2 diabetes and dementia

Type 2 diabetes in the elderly is associated with increased incidence of vascular disease, particularly, atherosclerosis of large blood vessels. Together with other risk factors such as dyslipidemia, atherosclerosis increases the risk for coronary heart disease and stroke. Most studies that have examined the impact of type 2 diabetes and other heart disease risk factors on cognitive functions do not provide evidence that heart disease risk factors (with the possible exception of triglycerides) further increase the likelihood of observing cognitive deficits in diabetic patients. However, none of these studies used imaging techniques to evaluate atherosclerosis or evidence of cerebrovascular disease, such as infarctions. The few studies that have included brain imaging suggest that evidence of cerebrovascular disease further increases the risk for dementia in diabetic patients. The results of longitudinal studies suggest that diabetes is an independent risk factor for cognitive decline and dementia. The pattern of neuropsychological performance observed in type 2 diabetic patients appears to be the result of multiple interacting processes developing over time. In addition to the detrimental effects of protracted impaired glucose regulation on the central nervous system, type 2 diabetes pathology also encompasses the detrimental effects of associated complications such as cerebrovascular disease, which is likely the main cause of the observed processing speed/reaction time decrements.