Secondary prevention of ischemic stroke

Stroke strikes often suddenly, causes long-term disability and death, and is a huge economical burden for the society, not to mention the human tragedy for the patient and the family. At least 15% of stroke survivors will have a second stroke during the next five years, quarter of which prove out to be fatal within four weeks. Secondary prevention of ischemic stroke (IS) targets at reducing stroke recurrence by means of 1) detection and modification of risk factors, 2) antithrombotic or anticoagulant treatment, and 3) surgical interventions for selected patient subgroups. In this review we will discuss these issues in detail and also offer our personal suggestions for treatment choices. Detecting and treating the modifiable risk factors is the major challenge of secondary prevention of IS.     

Secondary prevention of stroke: a practical guide to drug treatment

Stroke is a disease of the elderly and, as a result of the expected demographic changes in many industrialised countries, its incidence is likely to increase in the future. A first-ever stroke significantly increases the likelihood of further events; thus, secondary prevention is of major importance. Only a minority of recurrent strokes can be prevented by surgical or other invasive methods, meaning that most secondary preventive measures involve drug treatment, which has become increasingly sophisticated in recent years. Ischaemic stroke constitutes the vast majority of all strokes; effective secondary prevention depends on a variety of factors, of which the correct classification in terms of subtypes and aetiological mechanisms is a pivotal prerequisite, as is the assessment of the patient's cardiovascular risk profile. In addition to the evaluation of pathomechanisms, stratification of subtypes of brain infarction is mainly based on morphology seen with brain imaging techniques, which provides additional evidence for the presumed cause of the stroke. Inhibitors of platelet function and anticoagulants are the two major groups of antithrombotic drugs used for the secondary prevention of stroke. Antiplatelet agents are still indicated in the majority of patients after ischaemic stroke, especially if an arterial origin is presumed. In addition to aspirin (acetylsalicylic acid), the position of which as the first-line antiplatelet drug is increasingly being questioned, other compounds with antiplatelet activity have been developed and have proven effective in secondary stroke prevention, including ticlopidine, clopidogrel and dipyridamole. Anticoagulants are principally indicated after cardioembolic ischaemic stroke; however, their inherent bleeding risks render their use in many cases rather difficult, in particular for elderly patients. Patient compliance with the recommended treatment is of major importance, given the somewhat limited efficacy of antithrombotic agents in stroke prevention. Since 'real world' experience does not match the circumstances under which clinical trials are conducted, this article will also deal with problems not covered by specific studies, such as risk stratification for anticoagulant treatment and how to proceed in cases of unknown stroke aetiology. The management of major cardiovascular risk factors is the other mainstay of secondary stroke prevention. Recent evidence indicates that antihypertensive treatment may be as effective as antithrombotic drugs for secondary prevention of stroke. This still needs to be proven for the treatment of other cardiovascular risk factors, such as diabetes mellitus and hypercholesterolemia. Nevertheless, the results of recent studies investigating the effect of HMG-CoA reductase inhibitors ('statins') on cardiovascular events strongly suggest a stroke-preventive effect.     

Secondary prevention of stroke in patients with nonvalvular atrial fibrillation: optimal intensity of anticoagulation

Nonvalvular atrial fibrillation (NVAF) is frequently seen in elderly people and has become a main cause of cardioembolic stroke. The efficacy of anticoagulation for primary prevention of stroke or transient ischaemic attacks (TIAs) in patients with NVAF has been established by prospective, randomised and controlled trials. Warfarin decreased the frequency of all strokes by 68% and the rate of the combined outcome of stroke, systemic embolism or death by 48%. Anticoagulation with warfarin using international normalised ratios (INRs) ranging from 2.0 to 3.0 is recommended for patients with NVAF, who have any of the risk factors identified by the Atrial Fibrillation Investigators (AFI) [previous stroke or TIA, history of hypertension, diabetes mellitus, advanced age (> or = 65 years old), congestive heart failure and coronary artery disease], the American College of Chest Physicians (ACCP) [increased age (> 75 years old), prior stroke, hypertension and heart failure], or the Stroke Prevention in Atrial Fibrillation (SPAF) investigators [women > 75 years old, prior stroke, systolic blood pressure > 160mm Hg, recent heart failure, and fractional shortening < 25% on echocardiography]. For the secondary prevention of stroke, the efficacy of adjusted-dose warfarin therapy has been demonstrated by 2 major randomised trials. SPAF III (INR 2.0 to 3.0) demonstrated a lower incidence of ischaemic stroke or systemic embolism (3.4 %/year) compared with low fixed-dose warfarin plus aspirin (acetylsalicylic acid) [11.9%]. The European Atrial Fibrillation Trial [EAFT] (INR 2.5 to 4.0) showed a lower incidence of all stroke (4.0 %/year) with adjusted-dose warfarin compared with placebo (12.0 %/year). The incidence of major bleeding in the adjusted-dose warfarin group in SPAF III and EAFT was 2.4 and 2.8 %/year, respectively. EAFT incidence rates for the occurrence of a first ischaemic or haemorrhagic complication analysed by INR range indicated that the rate was lowest at INRs of 2.0 to 2.9, and higher with INRs of 3.0 to 3.9. Therefore, the optimal intensity of anticoagulation for prevention of recurrent stroke seems to be an INR of between 2.0 and 3.0, as for primary prevention. Retrospective and prospective studies from Japan reported that in the elderly, haemorrhagic complications occur frequently with INRs above 2.6 and major ischaemic events cannot be prevented at INRs below 1.6. Therefore, an INR target between 1.6 and 2.6 may be an alternative for secondary prevention of stroke in elderly patients with NVAF who have a potential risk of bleeding, to avoid both major ischaemic and haemorrhagic events. Antiplatelets may be administered in patients who are unable to manage taking warfarin properly or who have a high risk of falling and subsequently sustaining a head injury, although the efficacy of antiplatelets for secondary prevention of stroke in NVAF has not yet been established.     

Antiplatelet drugs in cardiovascular prevention: coronary events and stroke: primary prevention

(1) Aspirin reduces the risk of myocardial infarction in men over 40 with no history of cardiovascular disease, and in hypertensive patients of both sexes over that age. But it does not seem to reduce overall mortality, and its risk-benefit ratio is not very favourable because of its gastrointestinal adverse effects. (2) In patients with symptomatic lower-limb arterial disease, ticlopidine and clopidogrel reduce the risk of coronary events.     

Antiplatelet drugs in cardiovascular prevention: stroke: acute phase and secondary prevention

(1) In the acute phase of ischaemic stroke in patients free of thrombogenic heart disease, combined treatment with aspirin + moderate-dose unfractionated heparin reduces the risk of relapse and death. Unfractionated heparin at higher anticoagulant doses has an unfavourable risk-benefit ratio. Treatment is controversial in patients with events associated with atrial fibrillation. (2) After ischaemic stroke in patients free of thrombogenic heart disease, aspirin reduces the risk of relapse and death. Other antiplatelet drugs, the aspirin + dipyridamole combination, ticlopidine and clopidogrel have similar efficacy to aspirin. (3) The risk-benefit ratio of oral anticoagulant is favourable after ischaemic stroke associated with atrial fibrillation; but it is unfavourable after stroke without thrombogenic heart disease.     

Arterial stiffness and stroke in hypertension: therapeutic implications for stroke prevention

Stroke is the second leading cause of mortality worldwide, and the leading cause of death in China and Japan. Its prevention represents a major goal. Identification of primary stroke risk, particularly through newly individualised risk factors including biomarkers of large artery damage such as arterial stiffening, is necessary for determining the appropriate level of intervention. The purpose of this review is to focus on the pathophysiology of arterial stiffness, its predictive value for stroke and the therapeutic implications of this risk factor for stroke prevention. The predictive value of arterial stiffness for stroke was demonstrated in a longitudinal study that included 1715 patients with essential hypertension and measurements of carotid-femoral pulse wave velocity (PWV) [an indicator of arterial stiffness] at entry. Over a mean follow-up period of 7.9 years, during which 25 fatal strokes occurred, PWV significantly predicted stroke (relative risk = 1.39 [(95% CI 1.08, 1.72]; p = 0.02 for each 4 m/sec increase) independently of classical cardiovascular risk factors, including age, cholesterol level, diabetes mellitus, smoking and mean blood pressure. Additional longitudinal studies are needed to confirm the predictive value of aortic stiffness on primary and secondary events, in low- and high-risk populations, in various countries, and using different methodologies of arterial stiffness measurement. Drug treatment could prevent stroke through a reduction in arterial stiffness in parallel with correction of cardiovascular risk factors such as hypertension, dyslipidaemia, diabetes mellitus and smoking, all of which are associated with arterial stiffening. In view of the important local actions of angiotensin II on arterial stiffening, drugs interfering with the renin-angiotensin-aldosterone system should be particularly effective. Promising therapeutic strategies to reduce arterial stiffness include taking advantage of the non-lipid-lowering effects of statins and directly targeting the molecular events leading to arterial stiffening, such as formation of advanced glycation end products.     

Pertussis resurgence: diagnosis, treatment, prevention, and beyond

The introduction of routine vaccination against Bordetella pertussis more than a half century ago led to a drastic decline in the number of reported cases of pertussis. It was originally believed that lifelong immunity was afforded after vaccination. Unfortunately, this belief is flawed, as the highest number of pertussis cases since 1959 was reported in 2004. This significant increase has led to additional research on immunity, vaccination, and treatment of B. pertussis in all age groups. We performed a MEDLINE search of literature from 1966-2006 to evaluate and review the existing data on immunity to and prevention or treatment of B. pertussis infections. Additional articles were identified from the bibliographies of reviewed literature. Numerous articles pertaining to these topics have been published recently. The most significant changes in the management of this infectious disease surround the new recommendations by the Advisory Committee on Immunization Practices for adult and adolescent immunizations to assist in preventing outbreaks of B. pertussis. The Centers for Disease Control and Prevention recently published guidelines updating the recommended pharmacologic agents for treatment or prevention of B. pertussis. Despite decades of successful vaccination programs, pertussis continues to be a problematic disease. Fortunately, data and vaccines are now available that make development of a pertussis booster vaccination campaign reasonable. However, until widespread compliance with such programs is achieved, clinicians need to maintain vigilance against pertussis.     

评价脑苷肌肽治疗急性脑梗死的疗效和安全性

随着社会人口老龄化问题加重, 脑卒中发病率逐年上升, 其中缺血性脑卒中占大多数。近年来, 缺血性脑卒中的主要临床治疗方法为溶栓治疗以及机械取栓, 但疗效有限, 许多患者治疗后仍出现严重残疾, 且不能有效地防治缺血造成的脑组织损伤以及神经功能障碍, 其原因可能是缺乏有效的神经保护剂辅助治疗。目前, 大多数神经保护剂在临床试验中疗效结果均不明显。简述近年来针对脑缺血损伤和脑缺血再灌注损伤的神经保护剂的种类, 讨论其出现应用缺陷的原因, 以促进神经保护剂在临床上成功应用, 为未来缺血性脑卒中的治疗研究提供参考。

     

Cost-effectiveness of stroke prevention

Stroke is a preventable disease and there are several interventions that might have an important role in reducing the burden of disease. Economic appraisal of these different interventions is essential as resources are scarce and it is logical to attempt to obtain the greatest reduction in disease for the lowest cost. Anticoagulation for non-rheumatic atrial fibrillation is highly effective, but is expensive and cost-effectiveness analyses show that use of aspirin alone would prevent almost as many strokes at much lower cost. Antiplatelet drugs are both effective and inexpensive and their use in secondary prevention would potentially save the NHS about 900 Pounds per life year gained. Carotid endarterectomy and the associated screening costs are poor value for money but recent attempts to use predictive models to determine which patients will benefit from surgery may improve its cost-effectiveness. Current evidence is dominated by pharmacological interventions and much less good evidence is available for life-style modifications such as dietary change and physical exercise. Modification of major cardiovascular risk factors (blood cholesterol, high blood pressure and smoking) is very cost-effective but needs to be better targeted if potential health gain is to be realised.     

Stenting and prevention of ischemic stroke

Stenting for the prevention of atherosclerosis related ischemic strokes is a recent option in the therapeutic armamentarium. For extracranial carotid artery stenosis, stenting has proven its benefit in patients defined as "high-risk" for surgery, but beyond this specific population, surgery remains the gold standard. Based on recent prospective randomized trials, carotid endarterectomy (CEA) and carotid artery stenting (CAS) seem to share equivalent peri-procedural stroke risks, but the significantly higher rates of local nerve injury and myocardial infarction related to the surgical approach should favor the endovascular intervention in the future. In other locations, such as extracranial vertebral artery or intracranial stenoses, the current practice of care is not defined and the benefit of stenting is under investigation. However, in patients with symptomatic lesions despite appropriate antithrombotic therapy, stenting is considered to have a better benefit/risk profile in comparison to intracranial bypass surgery. In-stent restenosis (ISR), a major concern after stenting in coronary arteries, is an infrequent event following cervical internal carotid stenting but is relatively common and may worsen outcomes following treatment of extracranial vertebral and intracranial arterial stenoses. Drug eluting stents have proven their efficacy to control ISR and have changed dramatically the landscape of interventional cardiology, for this purpose their evaluation is now starting in the cerebral vasculature. The field of endovascular interventions is rapidly evolving and the development of devices dedicated to the cerebral vasculature is without any doubt going to extend the spectrum of treatable lesions.     

Medical prevention of stroke and stroke recurrence in patients with TIA and minor stroke

Background: Secondary stroke prevention after transient ischemic stroke (TIA) or minor stroke is of major importance in order to avoid recurrent cerebrovascular events and decrease morbidity and mortality. Objective/methods: Systematically review of recently published, high-quality studies emphasizing the need for emergency assessment and treatment of patients with TIA and minor stroke and to give a comprehensive and distinct overview over medical secondary stroke prevention trials performed in these patients. Results/conclusions: Evaluation and implementation of preventive stroke therapy has to be immediate in patients with TIA and stroke. For patients with non-cardioembolic stroke, antiplatelet agents are the treatment of choice. Aspirin plus extended-release dipyridamole and clopidogrel are more effective than aspirin and should be used in patients with a high risk of recurrent stroke. Oral anticoagulation is highly effective in patients with a cardiac source of embolism. Treatment of risk factors such as arterial hypertension and high cholesterol is even more important in secondary stroke prevention than in primary prevention. Vitamin supplementation and lowering of elevated levels of homocysteine are not effective in stroke prevention.     

Novel therapies for the prevention of stroke

The health and economic burden of stroke to society is enormous. Pharmacological therapies remain the primary stroke prevention strategy for the vast majority. Several existing and newer pharmacological agents aimed at the treatment of hypertension and lowering cholesterol are proving to be effective. For example, the antiplatelet agent clopidogrel has reduced end points in the secondary prevention of stroke, as have combinations of aspirin with traditional therapies, including dipyramidole. The direct oral thrombin inhibitor ximelagatran is a novel oral anticoagulant that has shown significant potential as a possible replacement to warfarin therapy, for the prevention of stroke for patients with non-valvular atrial fibrillation. Additional novel agents with hypothetical, although not yet proven, benefits in stroke prevention include fish oils, homocysteine-lowering therapy and anti-inflammatory agents. Finally, a controversial novel polypill, which would include fixed combinations of several pharmacological agents, may yet become a realistic and promising stroke prevention option.     

New strategies for the prevention of stroke

1. Stroke is a major cause of disability and death worldwide. It is preferable to prevent stroke rather than to treat it and, for the prevention of stroke, all risk factors relating to stroke need to be understood. The present paper reviews potential new strategies for the prevention of stroke based on findings of new risk factors, as well as classical risk factors. 2. Recently, new risk factors related to stroke were reported, including dysfunction of the arterial baroreflex, pro‐inflammatory cytokines, vitamins and hormone deficiency. Correspondingly, therapies targeting these risk factors where shown to significantly reduce the incidence and/or severity of stroke. 3. Because the genesis of stroke is multifactorial, the prevention of stroke should not target one risk factor only. Combination therapies with drugs acting on different risk factors may be more effective in the prevention of stroke.     

Clopidogrel for the secondary prevention of stroke

Patients suffering a transient ischaemic attack (TIA) or ischaemic stroke (IS) have a high risk of recurrence. The inhibition of platelet function is effective in the reduction of secondary vascular events in patients with TIA or stroke. This is true for acetylsalicylic acid (ASA), clopidogrel, ticlopidine and the combination of ASA plus slow-release dipyridamole. This overview analyses the results of recent trials and presents ongoing or future trials with clopidogrel as well as the combination of clopidogrel plus ASA. Clopidogrel is superior to ASA in the prevention of vascular events in patients with IS, myocardial infarction (MI) or peripheral arterial disease (PAD). The difference is highest for high-risk patients such as diabetics, patients who underwent coronary bypass surgery and patients with a remote prior history of ischaemic events. A prediction model is presented which allows the identification of patients in whom clopidogrel is superior to ASA for the secondary prevention of stroke. The combination of clopidogrel and ASA is better than ASA alone in patients undergoing coronary stent implantations and patients with unstable angina or non-Q-wave MI. In high-risk patients with TIA or stroke, the addition of ASA to clopidogrel is not superior to ASA monotherapy but results in a higher rate of bleeding complications. The long-term combination therapy is currently investigated in several large trials in > 30,000 patients, with a large number of stroke patients.