Antiplatelet therapy in ischemic stroke

Stroke is the third leading cause of death and the leading cause of disability in the developed world. Atherothrombosis is the underlying condition that results in events leading to ischemic stroke and vascular death. Antiplatelet therapy is commonly used for both acute stroke and in secondary prevention. Numerous trials and meta-analyses have left little doubt that antiplatelet therapy effectively reduces stroke risk in patients with prior stroke or transient ischemic attack. Current antiplatelet agents include acetylsalicylic acid, clopidogrel, ticlopidine and extended release dipyridamole with low doses of acetylsalicyclic acid (aspirin). The optimum doses of antiplatelet drugs depend upon several variables, such as genetic and environmental factors, so that clinical and laboratory response for dosage varies for each patient. Recently, the correlation between the laboratory-measurable effect of antiplatelet agents and the clinical effectiveness on the mortality of ischemic stroke and cardiovascular patients has been documented. Due to the side effect of bleeding with different antithrombotic drugs, their future employment will be determined in combination with low dosages of each component. Laboratory-controlled, tailored drug therapy will be needed for long-lasting secondary prevention of ischemic stroke.     

Use of antiplatelet agents to prevent stroke: What is the role for combinations of medications?

Antiplatelet agents are the medications of choice for preventing non-cardioembolic strokes. The diverse pathways involved in platelet function suggest the possibility of synergistic effects by combining various agents. In heart disease and in the setting of coronary artery stents, antiplatelet therapy with clopidogrel and aspirin has established benefits. Although it is tempting to extrapolate the benefits of this combination for stroke prevention, recent clinical trials have not borne this out. Unacceptable bleeding risks without additional efficacy weigh against the routine use of clopidogrel with aspirin for stroke prophylaxis. The combination of aspirin and extended-release dipyridamole has demonstrated superiority over aspirin in two large secondary stroke prevention trials.     

强化抗血小板治疗在缺血性脑卒中复发高危患者二级预防中的临床研究

目的观察强化抗血小板药物氯吡格雷在缺血性脑卒中复发高危患者二级预防中的长期疗效及安全性。方法采用艾森卒中风险评分（ESRS）量表筛选住院的急性非心源性缺血性脑卒中复发高危患者100例,随机分为氯吡格雷组和阿司匹林组,每组50例。两组均给予脑卒中常规治疗,氯吡格雷组予氯吡格雷75mg及阿司匹林100mg口服,1周后仅予氯吡格雷75mg,口服。阿司匹林组予阿司匹林200mg,口服,1周后改为100mg,口服。随访3个月和1年,观察两组缺血性脑卒中复发率及药物不良反应发生率。结果随访3个月时,脑卒中复发率：阿司匹林组为6．3％,氯吡格雷组为2．0％,差异无统计学意义（P〉0．05）;药物不良反应发生率：阿司匹林组为14％,氯吡格雷组为2％,差异有统计学意义（P〈0．05）。随访1年时,脑卒中复发率：阿司匹林组为13％,氯吡格雷组为2％,差异有统计学意义（P〈0．05）;药物不良反应发生率：阿司匹林组为38％,氯吡格雷组为6％,差异有统计学意义（P〈0．01）。结论缺血性脑卒中复发高危患者二级预防中强化抗血小板治疗可降低脑卒中复发风险,长期应用获益较高,安全性好。     

个体化抗血小板治疗对缺血性卒中二级预防的效果研究

目的 研究个体化抗血小板治疗在缺血性卒中二级预防的效果。 方法 选择2013年3月-2014年5月于陕西省人民医院就诊的急性缺血性卒中患者207例,随机分为 常规治疗组与个体化治疗组。常规治疗组应用阿司匹林100 mg/d抗血小板治疗。个体化治疗组应用 Essen卒中风险评分量表（Essen Stroke Risk Score,ESRS）将高危组给予氯吡格雷75 mg/d,低危组给 予阿司匹林100 mg/d抗血小板治疗。7 d后进行血栓弹力图（thromboela stogram,TEG）及CYP2C19基因型 检测,结合TEG及CYP2C19基因型结果,决定抗血小板治疗方案。随访1年,比较个体化治疗组和常规 治疗组患者终点事件发生率。 结果 CYP2C19快代谢基因型、中间代谢基因型患者应用氯吡格雷的血小板抑制率明显高于慢代谢 型,结果差异有显著性（P =0.018,P =0.015）。个体化治疗组（112例）和常规治疗组组（95例）终点事 件发生率差异无显著性（P＞0.01）。 结论 CYP2C19快代谢基因型、中间代谢基因型患者应用氯吡格雷的血小板抑制率明显高于慢代谢 型。与阿司匹林常规治疗方案相比,利用CYP2C19基因多态性与TEG检测指导下的个体化抗血小板方 案未显示降低缺血性卒中后终点事件发生率,可能需要更大规模、随访时间更长的研究。     

Antiplatelet drugs for prevention of cerebral ischemic accidents]

Antiplatelet (AP) drugs play a major role in stroke prevention. Aspirin (50-1300 mg), ticlopidine (500 mg), clopidogrel (75 mg) and dipyridamole (400 mg) are effective in secondary prevention of atherothrombotic brain infarcts. Aspirin has been the most extensively studied drug and remains the most cost-effective one. The optimal dose is still debated; doses between 100 and 300 mg are the most widely used. The preventive efficacy of aspirin is already present at the acute phase of cerebral infarct. In primary prevention, aspirin nearly halves the risk of myocardial infarction but does not reduce that of stroke. Cardiac diseases with a high embolic risk require the use of oral anticoagulation. In non valvular atrial fibrillation, the choice of antithrombotic drugs depends on risk stratification: oral anticoagulants are indicated in high risk subjects whereas aspirin is recommended in low risk subjects and when oral anticoagulants are contraindicated. Studies with new associations of AP and with new drugs are required to increase the yield of the antiplatelet approach in high risk subjects; this should be done in parallel with efforts to detect and to treat the vascular risk factors associated with the development of a mass approach for stroke primary prevention.     

Antiplatelet agents and randomized trials

Patients who have transient ischemic attack (TIA) or ischemic stroke are at a high risk of having a first or recurrent stroke. The annual risk is between 5% and 15%; the risk is highest in the first 48 hours following a TIA and highest in the first 7 days following an ischemic stroke. Secondary prevention includes antithrombotic therapy, treatment of risk factors, and interventional treatment of carotid stenosis. Antithrombotic options can include antiplatelet drugs such as aspirin, aspirin plus extended-release dipyridamole (ER-DP), clopidogrel, or clopidogrel plus aspirin. Oral anticoagulation is used in patients with a cardiac source of embolism such as atrial fibrillation. Aspirin monotherapy offers a modest risk reduction for recurrent stroke and for the combined endpoint of nonfatal stroke, myocardial infarction (MI), and vascular death. The combination of ER-DP and aspirin was shown to be superior to aspirin monotherapy in several trials. Clopidogrel is superior to aspirin in high-risk patients suffering from stroke, MI, or peripheral arterial disease. The combination of clopidogrel plus aspirin is not superior to aspirin or clopidogrel monotherapy and carries a significantly higher bleeding risk. The combination might offer benefit in short-term secondary prevention after TIA or stroke. Another ongoing trial is currently investigating the possible benefit and side effects of aspirin plus ER-DP versus clopidogrel in secondary stroke prevention.     

Future perspectives for optimizing oral antiplatelet therapy

Secondary prevention of stroke and other manifestations of atherothrombosis is essential if the burden of disease associated with these events is to be reduced. Therefore, it is important to identify patients most likely to benefit from antiplatelet therapy. There is a good rationale for combining antiplatelet agents with different modes of action, since different signalling pathways contribute to platelet activation. Based on the promising results obtained with an adenosine diphosphate receptor antagonist-aspirin combination in coronary stenting, several additional trials with clopidogrel plus aspirin are ongoing. They include CURE (Clopidogrel in Unstable angina to prevent Recurrent Events, in unstable angina and non-Q-wave myocardial infarction) and COMMIT (in acute myocardial infarction), which compare clopidogrel with placebo in patients receiving aspirin, and CREDO (Clopidogrel for Reduction of Events During extended Observation), a 1-year treatment follow-up to the clopidogrel arms of the CLASSICS trial (Clopidogrel Aspirin Stent International Cooperative Study). Planned trials with clopidogrel in neurology include SPS3 (Secondary Prevention of Small Subcortical Strokes, in patients with symptomatic lacunar stroke), and MATCH (Management of Atherothrombosis with Clopidogrel in High-risk patients, in patients with stroke or transient ischaemic attack plus one additional risk factor), which will compare the efficacy of clopidogrel plus aspirin versus clopidogrel in reducing important ischaemic events. Combination therapy with an oral glycoprotein (GP) IIb/IIIa receptor antagonist plus aspirin has so far been less promising. Trials of three compounds--orbofiban, xemilofiban and sibrafiban--in combination with aspirin for secondary prevention in cardiac patients have reported increased mortality compared with aspirin alone. A similar effect was seen when sibrafiban monotherapy was compared directly with aspirin alone. Trials of newer oral GP IIb/IIIa inhibitors are under way or are planned. The combination of dipyridamole plus aspirin appears to be superior to aspirin alone for the prevention of stroke in patients with stroke or transient ischaemic attack; the effectiveness of this combination is being further investigated in ESPRIT (European/Australian Stroke Prevention in Reversible Ischaemia Trial).     

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.     

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.     

Dual Antiplatelet Therapy of Clopidogrel and Aspirin in Secondary Prevention of Ischemic Stroke: Evidence and Indications

Nowadays the dual antiplatelet therapy (DAPT) becomes more widely used in patients with ischemic stroke. Nevertheless, controversies exist for indications of DAPT. In view of evidence‐based medicine analysis, patients with high‐risk transient ischemic attack and minor stroke, severe symptomatic intracranial artery stenosis, symptomatic intracranial and extracranial artery stenosis causing artery‐to‐artery embolism, ischemic stroke attributed to aortic arch plaques, high‐risk atrial fibrillation not suitable for oral anticoagulants, intracranial and extracranial stent implantation, and ischemic stroke with acute coronary syndrome may gain great benefit from DAPT of clopidogrel and aspirin. In clinical practice, individualized antiplatelet therapy strategies should be taken by weighing risks of ischemia and hemorrhage.     

Antiplatelet resistance in stroke

Although the exact prevalence of antiplatelet resistance in ischemic stroke is not known, estimates about the two most widely used antiplatelet agents - aspirin and clopidogrel - suggest that the resistance rate is high, irrespective of the definition used and parameters measured. Inadequate antiplatelet responsiveness correlates with an increased risk of recurrent ischemic vascular events in patients with stroke and acute coronary syndrome. It is not currently known whether tailoring antiplatelet therapy based on platelet function test results translates into a more effective strategy to prevent secondary vascular events after stroke. Large-scale clinical trials using a universally accepted definition and standardized measurement techniques for antiplatelet resistance are needed to demonstrate whether a 'platelet-function test-guided antiplatelet treatment' strategy translates into improved stroke care. This article gives an overview of the clinical importance of laboratory antiplatelet resistance, describes the challenges for platelet-function test-guided antiplatelet treatment and discusses practical issues about the management of patients with aspirin and/or clopidogrel resistance.     

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.     

Antithrombotics for secondary prevention of noncardioembolic ischaemic stroke

Antiplatelet therapy is more effective than anticoagulation for the prevention of noncardioembolic ischaemic stroke. The choice of antiplatelet regimen, however, remains contentious. Recent controversies regarding aspirin resistance and the optimal dosing of aspirin, as well as recognition of the variable bioactivation of clopidogrel, have added further confusion to the debate. The American Heart Association (AHA) and American Stroke Association (ASA) recently released their third joint guideline in the past 5 years on secondary stroke prevention. The European Stroke Organisation has published three guidelines on this issue since 2000. These frequent updates have been necessary because of rapidly accumulating data from clinical trials. Careful consideration of the sometimes confusing trial results reveals that the 2011 AHA-ASA guidelines are correct in no longer specifying a 'preferred' antiplatelet regimen from among the choices recently studied. This recommendation does not, however, mean that all antiplatelet regimens should be considered equal. This Review discusses the various antiplatelet regimens, and the trials that led to the rapid evolution of the guidelines for secondary prevention of ischaemic stroke.     

Antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke: a critical review

For patients with ischemic stroke or transient ischemic attack caused by atherothromboembolism, immediate and long-term aspirin reduces the relative risk of recurrent stroke, MI, and death attributable to vascular causes. Oral anticoagulation is not more effective than aspirin. Long-term clopidogrel reduces the relative risk of stroke, MI, or vascular death by about 9% (0.3% to 16.5%) compared with aspirin. Any long-term benefits of clopidogrel combined with aspirin, compared with aspirin or clopidogrel alone, appear to be offset by increased major bleeding. The combination of aspirin and extended-release dipyridamole reduces the relative odds of stroke, MI, or vascular death by about 18% (odds ratio 0.82, 0.74 to 0.91) compared with aspirin alone without causing more bleeding. Cilostazole reduces the risk of stroke, MI, or vascular death by 39% compared to placebo. A large clinical trial comparing clopidogrel with the combination of aspirin and dipyridamole, in >20 000 patients with recent (<120 days) atherothrombotic ischemic stroke, is expected to report in 2008. Emerging antiplatelet therapies presently being evaluated for secondary prevention of atherothromboembolism include other P(2)Y(12) ADP receptor antagonists (prasugrel, cangrelor, AZD 6140), thromboxane receptor antagonists (eg, S18886 - terutroban), and thrombin receptor (PAR-1) antagonists (eg, SCH530348).     

阿加曲班治疗急性缺血性卒中的临床应用

阿加曲班是一种直接凝血酶抑制剂,具有起效较快、作用时间短、出血倾向小、无免疫源性等优点,能够有效阻止血栓进展,防止继发微血栓形成。国内外多项研究证实,阿加曲班能有效改善急性缺血性卒中患者的神经系统症状和日常活动能力,且对急性动脉粥样硬化性卒中和心源性卒中均有治疗作用,此外,阿加曲班与阿司匹林、奥扎格雷等抗血小板药物以及肝素相比疗效更显著,具有较高的安全性,同时由于作用机制不同,阿加曲班与阿司匹林、氯吡格雷等抗血小板药物、重组组织型纤溶酶原激活物(recombinant tissue plasminogen activator,rt-PA)联合治疗可能发挥协同作用。本文就阿加曲班在急性缺血性卒中的临床应用做一系统性综述。     

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.     

Clopidogrel resistance?

Clopidogrel is an effective inhibitor of platelet activation and aggregation due to its selective and irreversible blockade of the P2Y(12) receptor. Combination antiplatelet therapy with clopidogrel and aspirin is an important strategy for patients with acute coronary syndromes and those undergoing percutaneous interventions. Despite significant benefits demonstrated with combination antiplatelet treatment in large clinical trials, the occurrence of adverse ischemic events, including stent thrombosis, remains a serious clinical problem. Recent studies have demonstrated distinct response variability and nonresponsiveness to clopidogrel therapy based on ex vivo platelet function measurements. Small scale investigations have suggested that nonresponsiveness may be associated with a heightened risk for adverse clinical events. The above findings have stimulated a close examination of clopidogrel metabolism.     

Suboptimal response to clopidogrel: A genetic risk factor for recurrent ischaemic stroke

Anti-platelet agents (APA) are widely used in the secondary prevention of ischaemic stroke but about 30% of patients derive suboptimal platelet inhibition from APA. An underlying cause for suboptimal platelet inhibition is varying response to clopidogrel, which is linked to polymorphisms in the CYP2C19 gene responsible for the metabolism and activation of clopidogrel. CYP2C19 polymorphism influences clinical outcomes in patients with coronary artery disease, particularly among those treated with percutaneous transluminal coronary artery stenting. Randomized controlled trials have shown that high doses of clopidogrel can overcome suboptimal platelet response in carriers of the CYP2C19¹2 allele. The United States Food and Drug Administration has issued a boxed warning advising clinicians to consider genotyping patients prior to prescribing clopidogrel. There are ongoing studies investigating the clinical utility of genotyping to inform management decisions in stroke prevention.     

Clopidogrel withdrawal: is there a "rebound" phenomenon?

Dual antiplatelet therapy with aspirin and clopidogrel is routinely indicated in patients with acute coronary syndromes and following percutaneous coronary intervention to reduce the risk of cardiovascular mortality and ischaemic events. Although clinical guidelines recommend aspirin lifelong and clopidogrel for between one and 12 months, depending upon the indication, the optimal duration of clopidogrel therapy actually remains contentious. Premature cessation of clopidogrel in patients receiving drug-eluting stents is a clear risk factor for stent thrombosis, but recent clinical studies have also demonstrated a link between "appropriate" cessation of clopidogrel and clustering of adverse clinical events. It has been suggested that this may be due to a "rebound" prothrombotic and/ or proinflammatory response associated with clopidogrel withdrawal. This review will examine the definition and concept of a "rebound" phenomenon associated with clopidogrel cessation as well as the likely mechanisms behind this effect. Within the context of clinical event clustering after clopidogrel cessation, we will also discuss (i) the clinical importance of clopidogrel and the increasing uncertainty surrounding optimal duration of therapy, (ii) the antiplatelet and anti-inflammatory properties of clopidogrel and, in particular, its influence on arachidonic acid pathways traditionally thought to be mediated predominantly by aspirin and (iii) the role of newer, more potent antiplatelet agents and potential changes to antiplatelet therapy prescribing guidelines in the future.