Progress in clinical neurosciences: pharmacotherapies for the secondary prevention of stroke

Stroke is a leading cause of mortality and long-term disability worldwide. Survivors of a previous stroke or transient ischemic attack are vulnerable to further cerebrovascular events, as well as myocardial infarction, peripheral vascular disease, congestive heart failure and vascular death. Traditional approaches to the secondary prevention of stroke have included aspirin after ischemic stroke, warfarin for stroke associated with cardioembolic sources, and carotid endarterectomy for eligible candidates with significant carotid artery stenosis. In recent years, much evidence has emerged to support a broader array of pharmacotherapies, including newer antiplatelet agents, lipid lowering drugs, and several classes of blood pressure lowering therapies. Also under study are B vitamins for patients with cerebrovascular disease and hyper-homocysteinemia, and oral direct thrombin inhibitors for high-risk patients with atrial fibrillation. We review the literature to determine the clinical significance of these therapies, and provide recommendations regarding their use in the prevention of recurrent stroke.     

Antiplatelet Agents for Stroke Prevention

Stroke is one of the leading causes of disability and death. Ischemic stroke is a syndrome with heterogeneous mechanisms and multiple etiologies, rather than a singularly defined disease. Approximately one third of ischemic strokes are preceded by another cerebrovascular ischemic event. Stroke survivors are at high risk of vascular events (i.e., cerebrovascular and cardiovascular events), particularly during the first several months after the ischemic event. The use of antiplatelet agents remains the fundamental component of secondary stroke prevention. Based on the available data, antiplatelet agents should be used for patients with noncardioembolic stroke. The use of combination therapy (aspirin plus clopidogrel) has not been proven to be effective or safe to use for prevention of early stroke recurrence or in long-term treatment. There is no convincing evidence that any of the available antiplatelet agents are superior for a given stroke subtype. Currently, the uses of aspirin, clopidogrel, or aspirin combined with extended release dipyridamole are all valid alternatives after an ischemic stroke or transient ischemic attack. However, to maximize the effects of these agents, the treatment should be initiated as early as possible and be continued on a lifelong basis.     

Long-term prevention of ischaemic stroke and stroke recurrence

Stroke is the third most important cause of mortality, but the leading cause of severe handicap, dependency, and loss of social competence. Because of the high recurrence rate, active secondary prevention is mandatory once a stroke has occurred. Secondary prevention of stroke implies the primary prevention of cardiovascular disorders as well. Among the modifiable risk factors hypertension is worst and should be normalized according to recent WHO criteria, also in the elderly. Smoking is another major risk factor and hard to delete. Diabetes mellitus and hyperlipidaemia are also important risk factors and should be treated consequently by diet and medication. Moderate alcohol intake, normalization of body weight and regular physical activity also contribute considerably to prevention of stroke. Whether hyperhomocysteinaemia should be normalized has not yet been clarified. Cardiovascular disorders are an important source of ischemic strokes, particularly atrial fibrillation. Low dose anticoagulation can dramatically reduce stroke risk. Carotid endarterectomy in symptomatic stenoses is the most expensive means of stroke prevention. In less severe stenoses, or ICA occlusions, antiplatelet agents are the treatment of choice. Composite drugs with ASS and other antiplatelet agents seem to be superior to either compound alone. Dissections of the cervical arteries should not be operated on but may be treated by anticoagulation or antiplatelet agents in the acute and subacute phase. The potency of a consequent and comprehensive stroke prevention in preventing disability and death is much greater than any sophisticated acute stroke treatment.     

复发性缺血性脑卒中患者二级预防措施执行情况调查

目的分析复发性缺血性脑卒中患者二级预防措施依从性,总结二级预防失败患者药物治疗不当的原因和教训。方法登记2008年5月至2011年6月因再发脑梗死入院患者,按改良TOAST分型进行基线资料以及二级预防执行情况分析,从抗血小板药物使用、血压控制、他汀药物使用情况、糖尿病、吸烟等5个方面调查二级预防措施长期执行情况。结果急性缺血性脑卒中638例,其中复发性缺血性脑卒中106例,动脉粥样硬化血栓形成是最主要的病因类型(78.3%),其两次卒中事件时间间隔小于小血管病变(P<0.05)。二级预防措施执行情况分析显示69.4%患者未规律服用抗血小板药物,54.5%高血压患者血压控制不达标,87.7%高脂血症患者未达到血脂控制目标,76.5%糖尿病患者血糖不达标,86.7%吸烟患者未戒除吸烟。结论二级预防各项措施与指南之间均存在较大差距,迫切需要在基层医务人员和患者中强化二级预防的教育。     

Multifunctional actions of approved and candidate stroke drugs

Ischemic stroke causes brain damage by multiple pathways. Previous stroke trials have demonstrated that drugs targeting one or only a few of these pathways fail to improve clinical outcome after stroke. Drugs with multimodal actions have been suggested to overcome this challenge. In this review, we describe the mechanisms of action of agents approved for secondary prevention of ischemic stroke, such as antiplatelet, antihypertensive, and lipid-lowering drugs. These drugs exhibit considerable properties beyond their classical mechanisms, including neuroprotective and neuroregenerative properties. In addition, candidate stroke drugs currently studied in clinical phase III trials are described. Among these, albumin, hematopoietic growth factors, and citicoline have been identified as promising agents with multiple mechanisms. These drugs offer hope that additional treatment options for the acute phase after a stroke will become available in the near future.     

Clinical consequences of aspirin and clopidogrel resistance: an overview

The aim of this review is to introduce the concept of personalized medicine in secondary stroke prevention with antiplatelet medication. In the last years, many studies have been conducted regarding aspirin resistance and genotyping of clopidogrel metabolism. A review of the currently published data on this issue emphasizes the importance of focusing on the individualizing approach in antiplatelet therapy to achieve maximal therapeutic beneficial effect. However, many authors suggest that, before new information from ongoing trials become available, good clinical practice should dictate the use of low dose of aspirin that was shown to be effective in the prevention of stroke and death in patients with ischemic cerebrovascular disease, because higher doses do not have significantly better efficacy than lower doses in secondary stroke prevention, but lower‐dose aspirin is associated with less side effects. On the other hand, many factors are associated with clopidogrel resistance, and recent genetic studies showed that the CYP2C19*2 genotype (loss‐of‐function allele) is related to poor metabolism of clopidogrel, but larger studies are needed to definitively confirm or rule out the clinical significance of this genetic effect. The aim of personalized approach in secondary stroke prevention is to take the most appropriate medicine in the right dose in accordance with the clinical condition of the patient and associated risk factors.     

Choices in medical management for prevention of acute ischemic stroke

Stroke is a leading cause of death and disability. Although advances are being made in the treatment of acute ischemic stroke, its prevention is equally as important. Identification and management of risk factors are essential. Medical therapy is also helpful in the secondary prevention of ischemic stroke. There are currently four plateletantiaggregating agents used to prevent ischemic stroke: aspirin, aspirin plus dipyridamole, clopidogrel, and ticlopidine. The relevant studies proving their efficacy are noted, as are some of their similarities and differences. The use of warfarin is also discussed.     

Antiplatelet therapy in acute cerebral ischemia

BACKGROUND: Improved recognition of stroke signs and symptoms has paralleled the development of pharmacological strategies that may be examined to reduce stroke mortality and morbidity. Presently, tissue plasminogen activator is the only therapy that significantly improves outcome in acute stroke, with no agent demonstrating a significant reduction in mortality. SUMMARY OF REVIEW: Antiplatelet agents are a heterogenous class of drugs that have been successfully used for more than 2 decades in secondary stroke prevention. These agents include aspirin, with or without dipyridamole, and more recently, the adenosine antagonists ticlopidine and clopidogrel. However, studies of the use of antiplatelet agents within 48 hours of the ictus have examined only aspirin. Only 1 study, the Multicentre Acute Stroke Trial-Italy (MAST-I), entered patients within 6 hours of the ictus. These data suggest that an improvement in mortality may be related to the speed of administration. No significant adverse events were noted with early antiplatelet monotherapy. However, MAST-I did note a significant increase in early mortality in patients receiving aspirin plus streptokinase, a finding not adequately explained by an increase in the intracranial hemorrhage rate. CONCLUSIONS: The use of antiplatelet therapy in acute stroke, clinical or experimental, has only recently received attention. It is likely that the use of antiplatelet agents for acute stroke therapy will be less restrictive than that currently seen for thrombolytics. Future studies should include an examination of those agents that have previously demonstrated efficacy in secondary stroke prevention, most notably, aspirin. The recognition that all platelet stimuli share a final common pathway that is dependent on the surface glycoprotein IIb/IIIa (fibrinogen) receptor has resulted in the development of various agents which block this receptor and are currently the focus for clinical trials. The role of nitric oxide in stroke therapy will depend on minimizing the hypotensive side effects of this agent. Stroke models are needed to provide preliminary data on the efficacy of antiplatelet therapy, especially as relates to the interaction of antiplatelet agents with thrombolytics.     

Secondary prevention of stroke

Stroke is a common disorder and a leading cause of disability and death. Ischaemia is a more common cause than haemorrhage and radiological imaging is required to accurately differentiate these. Some specific risk factors for stroke are non-modifiable--these include age, gender, racial and hereditary factors. Certain risk factors for ischaemic stroke can be identified and modification of these can be used for secondary prevention--examples include hypertension, heart diseases, atrial fibrillation, diabetes mellitus, dyslipidaemia, smoking, excessive alcohol consumption and carotid stenosis. Carotid endarterectomy is valuable in selected patients. In ischaemic stroke and transient ischaemic attack antithrombotic therapy is an option used in secondary prevention. In atrial fibrillation, warfarin should be used where possible in secondary prevention. When warfarin is contraindicated aspirin should be used. In other patients, an antiplatelet regime is appropriate--aspirin is commonly used and is the least expensive regime. Other antiplatelet agents such as dipyridamole, ticlopidine and clopidogrel may have a place. Younger patients with ischaemic stroke may have a thrombophilia state and should be appropriately investigated.     

Regional differences in incidence and management of stroke - is there any difference between Western and Japanese guidelines on antiplatelet therapy?

PURPOSE: There have not been many discussions on the differences between the guidelines for the management of stroke used in eastern and western countries. The purpose of this paper was to examine whether or not there are substantial differences between western countries and Japan in the prevalence of stroke and the frequencies of stroke subtypes, as well as in the recommended therapy for secondary prevention of ischemic stroke. RESULTS AND CONCLUSIONS: Although there are racial differences and differences in approved drugs between the East and West, the prevalence of stroke and the frequencies of stroke subtypes tend to converge throughout the world. However, the ratio of stroke to ischemic heart disease is still different between the East and West. Comparison of various countries' guidelines shows that recommendations on antiplatelet therapy for secondary prevention of ischemic stroke are fundamentally similar in the East and West, but the recommended doses of antiplatelets, especially aspirin and ticlopidine, are smaller in Japan. Furthermore, Japanese guidelines only recommend the use of antiplatelets (particularly cilostazol) for patients with lacunar infarction with evidence.     

Antiplatelet therapy is effective in the prevention of stroke or death in women: subgroup analysis of the European stroke prevention study (ESPS)

Previous stroke prevention studies have suggested that the efficacy of antiplatelet therapy may be less in women than in men. This however, could be due to the small number of women in these trials and the low incidence of cases among female subjects. The European Stroke Prevention Study was a multicenter trial comparing the effect of a combination of dipyridamole 75 mg t.i.d and acetylsalicylic acid 330 mg t.i.d. to placebo in the secondary prevention of stroke or death after one or more recent attacks of TIA (transient ischemic attack), RIND (reversible ischemic neurological deficit) or stroke of atherothrombotic origin. From the 2500 patients recruited, 1307 patients were from a single center, Kuopio, East Finland. Forty-five percent of the patients were women. The number of end-point events (stroke or death from any cause) in women was one-third lower than that in men. End-point reduction in the treatment group was about 50% in women and about 40% in men, significantly lower than in the placebo group in both sexes. Thus, in the relatively randomly selected patient population from one Finnish center, a combination of dipyridamole and acetylsalicylic acid is as effective in women as in men in the prevention of stroke or death. It is unclear, however, whether this beneficial effect in both sexes is due to aspirin only or to the combination therapy of aspirin and dipyridamole.     

Stroke prevention: anti-platelet and anti-thrombolytic therapy

In patients with TIA or ischemic stroke of noncardiac origin antiplatelet drugs are able to decrease the risk of stroke by 11-15%, and the risk of stroke, MI, and vascular death by 15-22%, but not mortality. Low doses of aspirin (50-325 mg) are as effective as high doses and cause less gastrointestinal side effects. Severe bleeding complications are not dose-dependent. The combination of aspirin with slow release dipyridamole is superior to aspirin alone for stroke prevention. Ticlopidine is superior to aspirin but has slightly more serious adverse effects (neutropenia). It will be replaced by clopidgrel which has a better safety profile. Anticoagulation with an INR between 3.0 and 4.5 is too dangerous. Whether anticoagulation with lower INR is safe and effective is not yet known.     

Atherothrombosis: a major health burden

Atherosclerosis involves structural change to the intima and media of medium- and large-sized arteries. Although an atherosclerotic plaque may remain clinically silent, it is prone to disruption, leading to local platelet activation and aggregation. Therefore, the major complication of atherosclerosis is thrombosis, with local occlusion or distal embolism - a generalized disease process known as atherothrombosis. The three main clinical manifestations of atherothrombosis are coronary heart disease (myocardial infarction and angina), peripheral arterial disease and cerebral ischaemia. Atherothrombosis is a leading cause of mortality, and stroke is the leading cause of disability in adults, the second most important cause of dementia and the third most common cause of death in Western countries. Ischaemic stroke accounts for 80% of strokes and atherothrombosis accounts for approximately 20% of all strokes. Criteria for atherothrombotic stroke are evidence of a 50% (or greater) stenosis of a cervical artery and exclusion of other potential causes. The incidence of cerebrovascular events is 2,900 per million inhabitants per year, consisting of 500 transient ischaemic attacks and 2,400 strokes, of which 75% are first-ever stroke. The prevalence of stroke in the same population is 12,000, of which 800 patients (7%) per year have recurrences. The risk of ipsilateral stroke is 5% per year and the risk of a cardiac event is higher at 7%. Besides optimal management of risk factors for atherothrombosis and carotid surgery, antiplatelet therapy is the cornerstone of vascular prevention. In secondary prevention, antiplatelet agents are effective in reducing the risk of further ischaemic events in patients with atherothrombosis. Clopidogrel, a newly licensed ADP receptor antagonist, is the only antiplatelet agent to have demonstrated its superiority versus aspirin for the reduction of major ischaemic events (myocardial infarction, ischaemic stroke, vascular death) in patients whose initial manifestation of atherothrombosis was one of the three main clinical manifestations of the disease (recent ischaemic stroke, myocardial infarction, established peripheral arterial disease).     

叶酸与缺血性卒中关系的研究进展

缺血性卒中是我国人口的首位死亡原因,高同型半胱氨酸血症是缺血性卒中的独立危险因素之一,补充叶酸能降低血浆同型半胱氨酸水平。本文就叶酸对缺血性卒中的一级预防和二级预防的作用、影响因素及补充叶酸的建议等研究进行综述,为卒中的预防提供新的治疗方法与思路。     

Results of the management of atherothrombosis with clopidogrel in high-risk patients trial: implications for the neurologist

The secondary prevention of ischemic stroke is aided by the use of antiplatelet therapy, and the predominant current choices are aspirin, aspirin plus extended-release dipyridamole, and clopidogrel. The potential utility of combining platelet antiaggregants with different mechanisms of action proved successful with aspirin plus extended-release dipyridamole, and this approach has been explored with the combination of clopidogrel and aspirin. In the Management of Atherothrombosis With Clopidogrel in High-Risk Patients trial, this combination was compared with clopidogrel alone for secondary prevention in patients with transient ischemic attack and stroke in a high-risk population with a high prevalence of other vascular risk factors. A nonsignificant trend for a reduction of the combined endpoint of ischemic stroke, myocardial infarction, vascular death, and rehospitalization was observed in the combination therapy group (P = .24). The frequency of serious, life-threatening bleeding adverse effects was almost doubled in the combination arm. Neurologists need to be aware of these results and avoid the use of clopidogrel plus aspirin in patients with stroke or transient ischemic attack until evidence that the combination is safe in this population is provided. Neurologists faced with patients who have had a stroke or transient ischemic attack and are receiving this combination of antiplatelet agents after coronary stenting should inform their cardiology colleagues of the reported bleeding risk, and they should encourage the use of the combination for as short a time period as possible after such coronary intervention.     

从东西方种族差异看缺血性卒中抗血小板治疗策略选择

全球卒中的疾病负担沉重,抗血小板治疗是缺血性卒中二级预防的必要手段,然而东西 方人群的疾病特点存在差异,可能对抗血小板治疗的选择产生影响。本综述从卒中发病特点、患者复 发和出血风险差异以及抗血小板治疗反应多样性等多角度出发,探讨适合亚洲人群的缺血性卒中抗 血小板治疗方案。     

899例缺血性脑卒中二级预防干预调查

目的 了解缺血性脑卒中患者住院期间二级预防药物的应用情况,为改进缺血性脑卒中二级预防工作提供依据.方法 回顾性调查899例缺血性脑卒中患者住院期间二级预防药物的服药率.结果 在899例缺血性脑卒中患者中,合并高血压者有632例,合并糖尿病者有220例,既合并有高血压又合并糖尿病者有177例.入选的899例患者中,服用抗血小板药物者占91.9％ (826例),在短暂性脑缺血发作组和脑梗死组间差异有统计学意义(P＜0.01);服用调脂药物者占77.2％(694例),在短暂性脑缺血发作组和脑梗死组间差异无统计学意义;632例缺血性脑卒中合并高血压患者中服用降压药者占95.4％(603例);220例缺血性脑卒中合并糖尿病患者中服用降糖药者(包括使用胰岛素)占84.5％(186例);177例既合并有高血压又合并有糖尿病的脑卒中患者中均用药者占83.1％(147例).结论 住院期间脑梗死患者抗栓药物服用率较短暂性脑缺血发作高,缺血性脑卒中二级预防用药尚不令人满意,临床医生应对脑卒中的二级预防治疗给予重视.     

缺血性脑卒中二级预防中的抗血小板治疗及其研究进展

抗血小板治疗是缺血性脑卒中二级预防中影响脑卒中再发率的重要因素。阿司匹林和氯吡格雷是临床常用的抗血小板药物。缺血性脑卒中二级预防中抗血小板药物的联合应用以及新药的研究已成为时下热点。由于缺血性脑卒中发病后早期再发率较高,因此早期以及长期二级预防中的抗血小板治疗方式不尽相同。     

非心源性缺血性卒中及短暂性脑缺血发作患者的抗血小板治疗

在脑血管病患者中,约80%为缺血性卒中患者,多伴有多种危险因素,是卒中复发的高危人群。在非心源性缺血性卒中/短暂性脑缺血发作（transient ischemic attack,TIA）的二级预防中,抗血小板治疗的疗效已被大量临床研究证实,并被各国的指南所推荐。本文结合新近发表的指南以及经典的临床试验,对非心源性缺血性卒中/TIA的抗血小板治疗模式做一综述。     

Antiplatelet therapy in children

Platelets are essential for the maintenance of vascular integrity and control of bleeding at sites of injury, but they are also implicated in the progression of atherosclerotic lesions and arterial vascular thrombosis. The use of antiplatelet drugs for the primary and secondary prevention of cardiovascular and cerebrovascular thromboses in adult populations has been extensively evaluated, resulting in defined management strategies. Much less is known about the appropriate use of antiplatelet drugs (primarily aspirin) in infants and children for secondary prevention in ischemic stroke, for prevention of coronary artery thrombosis in Kawasaki disease, or for prevention of thromboembolism following surgery for congenital cardiac disease. Additional studies will be required to evaluate the relative benefits of aspirin and anticoagulants in these settings. A role for newer antiplatelet drugs in the management of pediatric arterial thrombosis is as yet unexplored.