Role of antiplatelet agents in cerebrovascular disease.

It is now generally accepted by neurologists that most transient ischaemic attacks, particularly in the carotid artery territory, have a thromboembolic basis. These emboli are, for the most part, fibrin-platelet aggregates. Others which contain atheromatous debris are more likely to produce longer lasting neurological deficits. If one assumes this hypothesis then it is reasonable to employ drugs which interfere with platelet aggregation in order to prevent cerebrovascular symptoms and signs. Acetylsalicylic acid (aspirin) prevents aggregation by inhibiting the 'release reaction' initiated by thromboxane A2. This inhibition lasts for the life of the affected platelets. Recent trials in the United States and Canada have demonstrated a positive clinical benefit from the employment of aspirin in patients suffering from transient cerebral ischaemic attacks and amaurosis fugax. There was a reduction or cessation of the attacks in both males and females and a 50% reduction of stroke morbidity and mortality in males.     

Combination antiplatelet agents for secondary prevention of ischemic stroke

Stroke is a leading cause of death and the primary cause of serious, long-term disability in the United States. Joint guidelines from the American Heart Association (AHA) and American Stroke Association (ASA), as well as recent guidelines from the Eighth American College of Chest Physicians (ACCP) Conference on Antithrombotic and Antiplatelet Therapy, recommend aspirin, clopidogrel, or extended-release dipyridamole plus aspirin as acceptable first-line options for secondary prevention of ischemic events in patients with a history of ischemic stroke or transient ischemic attack (TIA). The ACCP strongly recommends the combination of extended-release dipyridamole plus aspirin over aspirin monotherapy (highest level of evidence) and suggests clopidogrel monotherapy over aspirin monotherapy (lower level of evidence). The AHA-ASA guidelines suggest that either extended-release dipyridamole plus aspirin or clopidogrel monotherapy should be used over aspirin monotherapy. Both guidelines recommend avoiding the combination of clopidogrel and aspirin for most patients with previous stroke or TIA. Results from recent trials evaluating combination antiplatelet therapy have been published that enhance the AHA-ASA recommendations and provide the foundation for the updated ACCP guideline. To identify pertinent combination antiplatelet trials, a MEDLINE search of the literature from 1967-2007 was performed. Two trials were identified--the European-Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA). The ESPRIT compared aspirin monotherapy with the combination of aspirin plus extended-release dipyridamole for prevention of secondary ischemic events in patients with a history of TIA or minor stroke. The CHARISMA trial compared aspirin plus clopidogrel with aspirin alone in a population at high risk for atherothrombotic events using the composite outcome of myocardial infarction, stroke, and death from cardiovascular causes. Data from ESPRIT add to evidence that the combination of aspirin plus extended-release dipyridamole is superior to aspirin alone. The findings of the CHARISMA trial reinforce recommendations from both AHA-ASA and ACCP that the combination of aspirin and clopidogrel be reserved for special populations requiring this antiplatelet combination (e.g., those who have had coronary artery stenting).     

Clinical pharmacokinetics of antiplatelet agents used in the secondary prevention of stroke

Stroke is one of the leading causes of death and debilitation. Several million stroke survivors are alive throughout the world today. Prevention of recurrent stroke is of major importance to stroke survivors. Several pharmacological agents are currently available for use in secondary stroke prevention.Clopidogrel, the combination of immediate-release aspirin and extended-release dipyridamole and aspirin alone are the most widely recommended agents for use in the secondary prevention of strokes. Clopidogrel has shown superiority over aspirin in the combined endpoints of stroke, death and myocardial infarction. The immediate-release aspirin/extended-release dipyridamole combination has shown superiority to aspirin alone in the secondary prevention of stroke.Dipyridamole has been studied as an antiplatelet agent for several decades. Early trials to prove its efficacy compared with aspirin were not favourable, and patients often experienced many adverse effects. Researchers began developing an extended-release formulation in an effort to maintain therapeutic blood concentrations with less frequent daily administration and better adverse effect profile. Pharmacokinetic analysis of this new product showed it to have a more consistent and reproducible absorption compared with immediate-release dipyridamole. The rate of absorption of extended-release dipyridamole is considerably slower than that of immediate-release dipyridamole, while similar plasma concentrations are maintained to optimise antiplatelet efficacy. This allows extended-release dipyridamole to be administered twice daily rather than four times daily.A large-scale randomised trial was conducted with extended-release dipyridamole 200mg in combination with immediate-release aspirin 25mg given twice daily. The combination product showed a greater efficacy at preventing a recurring stroke then either agent administered alone. Indirect comparisons with clopidogrel show that the combination of immediate-release aspirin/extended-release dipyridamole may be more effective than clopidogrel at preventing a recurring stroke.     

Role of antiplatelet therapy in cardiovascular disease II: Ischemic stroke

The etiology of cerebrovascular disease is heterogeneous, with the majority of strokes being of ischemic origin. Transient ischemic attack is now considered to be an important precursor and long-term risk factor for ischemic stroke. Given the lack of acute therapies for ischemic stroke, current treatments focus on secondary prevention through risk-factor management, pharmacotherapy and interventional approaches. As illustrated in this paper, antiplatelet agents (e.g. clopidogrel, aspirin, dipyridamole) are the cornerstone of therapy for prevention of recurrent ischemic stroke.     

Role of antiplatelet therapy in cardiovascular disease II: Ischemic stroke

The etiology of cerebrovascular disease is heterogeneous, with the majority of strokes being of ischemic origin. Transient ischemic attack is now considered to be an important precursor and long-term risk factor for ischemic stroke. Given the lack of acute therapies for ischemic stroke, current

treatments focus on secondary prevention through risk-factor management, pharmacotherapy and interventional approaches. As illustrated in this paper, antiplatelet agents (e.g. clopidogrel, aspirin, dipyridamole) are the cornerstone of therapy for prevention of recurrent ischemic stroke.     

Recent advances in antiplatelet agents

Platelet aggregation plays a key role in the pathogenesis of thromboembolic diseases such as myocardial infarction, stroke, unstable angina and peripheral artery disease. Until recently, aspirin was the only antiplatelet agent available to prevent or treat these events. Over the past several years, there has been a substantial expansion in the antiplatelet armamentarium as well as in the understanding of the clinical importance of antiplatelet therapy in limiting the complications of thrombosis. Aspirin was one of the first agents to be adopted and it remains as the standard therapy with the higher amount of available clinical information. Following aspirin, ADP receptor antagonists like ticlopidine and clopidogrel as well as phosphodiesterase inhibitors dipyridamole and cilostazol have been introduced. Glycoprotein (GP) IIb/IIIa receptor antagonists like eptifibatide, tirofiban and abciximab are the newer antiplatelet agents which act at the end of the common pathway of platelet aggregation. Although results of clinical studies with the first oral GPIIb/IIIa antagonists were disappointing, agents of the new generation might expand the potential application of GPIIb/IIIa targeted therapy. This review will highlight recent advances in the development of aspirin, phosphodiesterase inhibitors, ADP receptor antagonists and the platelet glycoprotein IIb/IIIa inhibitors. The emphasis of this paper has been placed on the chemical aspects of these agents.     

Novel situations of endothelial injury in stroke--mechanisms of stroke and strategy of drug development: protective effects of antiplatelet agents against stroke

Stroke is the second cause of mortality worldwide, and intravenous administration of tissue plasminogen activator (t-PA) within 3 h of symptom onset is the only treatment proven effective for re-establishment of cerebral blood flow following acute ischemic stroke. However, its widespread application remains limited by its narrow therapeutic time window and the related risks of intracranial hemorrhage. On the other hand, in patients with atherothrombotic risk, antiplatelet agents are widely used to decrease the risk of occlusive arterial events. All of these drugs are used during coronary interventions and in the medical management of acute coronary syndromes. In contrast, only aspirin, cilostazol, and thienopyridine derivatives (ticlopidine and clopidogrel) are used in the long-term prevention of cerebrovascular events in patients with risk of recurrence. In this paper, we introduce recent clinical findings on antiplatelet therapies for secondary prevention after ischemic stroke and describe basic research that has focused on cerebrovascular protection by cilostazol, which has a unique pharmacological profile.     

Combination antiplatelet agents in ischemic cerebrovascular disease

Combination antiplatelet agents with multiple mechanisms of action are being used with increasing frequency for vascular disorders, including cerebrovascular disease. Limited data exist regarding the efficacy of combination antiplatelet therapy in the primary or secondary prevention of cerebral ischemia, and combination therapies are often used without adequate evidence of efficacy. However, over the last few years, several cerebrovascular and cardiovascular trials have provided some preliminary information on the effectiveness of various combination therapies in preventing cerebral ischemic disease. This article reviews recently completed cerebrovascular and cardiovascular trials that tested a combination antiplatelet regimen against aspirin alone, and that assessed cerebral ischemia as an outcome measure. Controversies pertaining to these trials and to the use of the various combination antiplatelet regimens are discussed. Based on cardiovascular studies, clopidogrel in combination with aspirin has not been proven superior to aspirin alone for the primary prevention of cerebral ischemia. No data exists regarding the combination of clopidogrel and aspirin for the secondary prevention of cerebrovascular disease. The combination of aspirin plus extended-release dipyridamole (xrDP) appears to be superior to aspirin alone in the secondary prevention of cerebral ischemia, but may compromise cardiovascular protection in patients with coexisting coronary artery disease. Combination therapy with aspirin and clopidogrel seems to increase the risk of major hemorrhages, whereas aspirin plus xrDP does not. Ongoing trials are expected to clarify the role of various combination antiplatelet regimens.     

抗血小板药物联合治疗在缺血性脑血管病中的应用

抗血小板药物具有不同的作用机制,用于治疗频发性动脉疾病,包括脑血管疾病。近期的脑血管及心血管试验表明,联合治疗可以有效的预防缺血性脑血管病。预防血栓形成的药物氯吡格雷,曾被誉为超级阿斯匹林,与阿斯匹林联合治疗脑缺血显示出比单独使用阿斯匹林更突出的功效。阿斯匹林与防治心绞痛控释药双嘧达莫联合治疗效果较为突出。尽管如此,缺血性脑血管病的抗血小板药物联合治疗仍然存在着某些争议。目前的研究旨在区分不同抗血小板联合剂的作用。     

Combining antiplatelet and thrombolytic therapies for stroke

Pharmacological therapy for acute nonhaemorrhagic stroke has become a reality over the last 5 years. Mechanistically, both thrombolytic (tissue plasminogen activator and urokinase) and antiplatelet (aspirin) monotherapy have demonstrated efficacy. However, unintended actions limit the extent of clinical improvement in each circumstance. For example, in addition to excess bleeding, tissue plasminogen activator therapy has been associated with complement activation, neuronal toxicity and laminin degradation, while aspirin may reduce nitric oxide synthase activity and cerebral blood flow. Attention is now directed toward improving the therapeutic index for each class of agents. Generally, while thrombolytic therapy is focused on developing agents with greater fibrin specificity and safety (that is, a reduction in intracranial haemorrhage rate), the development of antiplatelet agents is primarily focused on achieving greater potency. The latter is being investigated by combining agents with different mechanisms (aspirin and dipyridamole, aspirin and clopidogrel) as well as agents designed to block the glycoprotein IIb/IIIa receptor, the final common pathway for platelet aggregation. Thus, combination therapy using both thrombolytic and antiplatelet agents will further attempt to improve the therapeutic index by increasing potency and improving the safety profile. Anecdotal case studies support the merits of this approach and are consistent with the data reported for myocardial ischaemia and interventional strategies. It is anticipated that drug therapy directed at both thrombolytic and antiplatelet targets will ultimately result in a widened therapeutic window that will allow acute stroke therapy to be administrated to a much greater number of patients than is currently possible.     

Combining antiplatelet and thrombolytic therapies for stroke

Pharmacological therapy for acute nonhaemorrhagic stroke has become a reality over the last 5 years. Mechanistically, both thrombolytic (tissue plasminogen activator and urokinase) and antiplatelet (aspirin) monotherapy have demonstrated efficacy. However, unintended actions limit the extent of clinical improvement in each circumstance. For example, in addition to excess bleeding, tissue plasminogen activator therapy has been associated with complement activation, neuronal toxicity and laminin degradation, while aspirin may reduce nitric oxide synthase activity and cerebral blood flow. Attention is now directed toward improving the therapeutic index for each class of agents. Generally, while thrombolytic therapy is focused on developing agents with greater fibrin specificity and safety (that is, a reduction in intracranial haemorrhage rate), the development of antiplatelet agents is primarily focused on achieving greater potency. The latter is being investigated by combining agents with different mechanisms (aspirin and dipyridamole, aspirin and clopidogrel) as well as agents designed to block the glycoprotein IIb/IIIa receptor, the final common pathway for platelet aggregation. Thus, combination therapy using both thrombolytic and antiplatelet agents will further attempt to improve the therapeutic index by increasing potency and improving the safety profile. Anecdotal case studies support the merits of this approach and are consistent with the data reported for myocardial ischaemia and interventional strategies. It is anticipated that drug therapy directed at both thrombolytic and antiplatelet targets will ultimately result in a widened therapeutic window that will allow acute stroke therapy to be administrated to a much greater number of patients than is currently possible.     

基因检测在氯吡格雷抗血小板治疗中的意义

氯吡格雷通过抑制ADP介导的血小板活化和聚集,能够有效地预防动脉粥样硬化血栓形成事件.然而,氯吡格雷的抗血小板疗效具有明显的个体差异,遗传因素是其中的重要原因.将基因检测应用于服用氯吡格雷的患者,是指导个体化治疗的可行途径.     

Effects of antiplatelet agents on platelet-induced thrombin generation

OBJECTIVES: The influence of antiplatelet agents on platelet-induced thrombin generation may increase the risk of bleeding. Assessment of the endogenous thrombin potential (ETP), is therefore a parameter deserving attention in early pharmacodynamic studies with antiplatelet drugs. The aim ofthis study was to assess whether an automated ETP-assay can be used to determine possible inhibitory effects of antiplatelet drugs on platelet-associated thrombin generation. METHODS: We first characterized the in vitro dose-response relationship of several platelet agonists (ADP, collagen, U46619, TRAP (amino acid sequence: SFLLRNP) and tissue factor (TF) using the generation of ETP. One submaximal concentration of each agonist was then used to assess the influence of in vivo treatment with aspirin (single oral dose of 500 mg as inhibitor of thromboxane synthesis) and clopidogrel (given orally for 6 days, as an inhibitor of the purinergic P2Y12-receptor on platelets) and in vitro treatment with abciximab (which inhibits the platelet glycoprotein IIb/IIIa-receptor for fibrinogen), on the ETP. RESULTS: The effect of TF and the other platelet inducers on thrombin generation was dose-dependent. Repeat measurements on samples from the same subject, with the same inducer concentration on 2 different occasions showed a variability of approx. 22% (absolute difference between 2 measurements as % of mean). The coefficient on variation of repeat measurements of one sample varied between 7% and 17%, depending on the inducer. After a single dose of aspirin, ETP was reduced by 25-40%, depending on the platelet activating agent used. The reduction in ETP with abciximab in vitro was more pronounced. In contrast, TF-induced ETP was not influenced by aspirin or abciximab. Clopidogrel, administered for 6 days, reduced the ETP by 60% when platelets were stimulated using 20 microM ADP, whereas collagen-induced ETP and TF-induced ETP remained unchanged. CONCLUSIONS: The ETP-method is a sensitive and reproducible method for the detection of drug effects on platelet-induced thrombin generation of high throughput, and can be recommended for studies on the pharmacodynamic profile of drugs interfering with platelet function.     

Primary and secondary stroke prevention with antiplatelet drugs

Aspirin is not effective in the primary prevention of stroke. Patients with TIA or ischemic stroke carry a risk of recurrent stroke between 5 and 20% per year. 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%. Aspirin is the most widely used drug. It is affordable and effective. Low doses of 50-325 mg aspirin are as effective as high doses and cause less gastrointestinal side effects. Severe bleeding complications are dose-dependent. The combination of aspirin with slow release dipyridamole is superior to aspirin alone for stroke prevention. Clopidgrel is superior to aspirin in patients at high risk of recurrence. The combination of aspirin plus clopidogrel is not more effective than clopidogrel alone but carries a higher bleeding risk. None of the antiplatelet agents is able to reduce mortality.     

Primary prevention of ischaemic cardiovascular disorders with antiplatelet agents

In those who have already survived myocardial infarction (MI) or stroke, or have had a transient ischaemic episode (TIA), daily low dose aspirin (ASA) reduces the risk of recurrences by an amount that greatly exceeds the risk of serious bleeding (secondary prevention). ASA is therefore recommended for these people. However, in primary prevention-reducing risk in those so far free of clinically manifest episodes-pthe benefit is of the same order as the bleeding hazard, (which is much the same in both primary and secondary prevention contexts). The use of other effective agents such as statins further emphasises the even balance between benefit and hazard in primary prevention. Six primary prevention trials are reviewed, first singly and then in a meta-analysis based on individual patient data. ASA reduced non-fatal myocardial infarction by about 25%. However, death from coronary heart disease (CHD) was not significantly reduced (by 5%), nor was any vascular death (3%). There was a non- significant reduction in strokes of 5%, this being the net result of an 8% reduction in non-fatal stroke and a 21% increase in stroke death (mainly from haemorrhagic events), both effects being non-significant. Serious vascular events (MI, stroke or vascular death) were significantly reduced by 12%, mainly due to the large effect on non-fatal MI. About 1650 people would need to be treated with ASA for a year to avoid one serious vascular event, which contrasts with the 10-20 events avoided in secondary prevention by treating 1,000 patients for a year. Other primary prevention trials not included in the meta-analysis have also reported no benefits in MI or stroke, but the findings of still unpublished trials are awaited. Recently, however, encouraging results have come from meta-analyses of the effects of ASA on cancer incidence and mortality and on its effects on cancer metastasis, particularly for adenocarcinomas. Typically, reductions in these measures have been around 30% following treatment for four or five years, but more in several instances. These results alter the balance in primary prevention between benefit and hazard as it appears for arterial events alone, tipping it towards the use of ASA. Consequently, new guidelines on advice and decisions on ASA in primary prevention are now needed. Low dose ASA, eg. 75 mg daily is as effective as higher doses for all the vascular and cancer benefits established in the meta-analyses, and it causes less serious bleeding than higher doses.     

Synthesis of 2,3-disubstituted 1,4-naphthoquinones as antiplatelet agents

In continuing search for novel antiplatelet agents, the highly potent agent 2-chloro-3-methoxycarbonylethylcarboxamido-1,4-naphthoquinone 2 was selected as lead compound. Structure-activity relationships in this series were examined. Some of these compounds showed significant antiplatelet activities. Further studies on the action mechanism showed that 2-acetamido-3-chloro-1,4-naphthoquinone 4 has a direct inhibitory action on cytosolic phospholipase A(2) (cPLA(2)) activity in platelets.     

阿托伐他汀联合抗血小板药治疗缺血性脑卒中的研究进展

目的探讨阿托伐他汀联合抗血小板药治疗缺血性脑卒中患者的疗效与安全性。方法查阅文献,综合论点。结果我国人群中脑卒中患者以缺血性为主,他汀类药物和抗血小板药根据不同的药理机制与脑卒中的一、二级预防有着紧密的联系,结论两者在缺血性脑卒患者中联合使用取得了比单一使用更好的疗效,本文就该种疗法的应用进行综述。     

Chalcones as potent antiplatelet agents and calcium channel blockers

In an effort to continually develop potent antiplatelet agents with vasorelaxing and antiinflammatory actions, a novel series of antiinflammatory chalcones was continually screened to evaluate their antiplatelet and vasorelaxing effects. Their structure–activity relationships and mode of action were discussed and characterized. A novel series of antiinflammatory chalcones was studied on antiplatelet effect in rabbit washed platelets and human platelet‐rich plasma (PRP) and vasorelaxing effect in rat thoracic aorta. Arachidonic acid‐induced platelet aggregation was potently inhibited by almost all the chalcone derivatives and 13–15 also had a potent inhibitory effect on cyclooxygenase. The selective chalcones 12–16 tested in human PRP significantly inhibited secondary aggregation induced by adrenaline. In rat thoracic aorta, most of chalcones at high concentration significantly depressed the contractions induced by Ca²⁺ (1.9 mM) in high K⁺ (80 mM) medium and the phasic and tonic contractions caused by norepinephrine (3 μM). In the rat thoracic aorta, the phenylephrine‐ and high K⁺‐induced ⁴⁵Ca²⁺ influx were both inhibited by a selective chalcone derivative, 14 . These results indicate that the antiplatelet actions of chalcones are mainly mediated through the suppression of cyclooxygenase activity and reduced thromboxane formation and their inhibitory effects on the contractile response caused by high K⁺ and norepinephrine in rat thoracic aorta are mainly due to inhibition of Ca²⁺ influx through both voltage‐dependent and receptor‐operated Ca²⁺ channels. Drug Dev. Res. 53:9–14, 2001. © 2001 Wiley‐Liss, Inc.     

Risk reduction strategies in ischaemic stroke : the role of antiplatelet therapy

Stroke is a common and serious disorder, and is a leading cause of disability and death in adults. Transient ischaemic attacks are now recognised as being common precursors of stroke, with a high risk of subsequent vascular events. The majority of strokes are ischaemic in origin, and are typically due to athero-thrombosis/microatheromatosis involving a large or small cerebral blood vessel or to an embolic event. Owing to the diffuse nature of atherothrombosis, these patients are at risk of ischaemic events in other vascular beds. Options for treating patients with acute ischaemic stroke are very limited; therefore prevention is a key strategy for reducing the risk of recurrent stroke and other vascular events. Treatment of risk factors such as hypertension, diabetes mellitus, smoking and obesity is an important approach for stroke prevention. Platelets are involved in the development of thrombi and emboli, making antiplatelet therapy an important preventive strategy. Antiplatelet agents are effective in preventing recurrent ischaemic stroke and other vascular ischaemic events, such as myocardial infarction and vascular death. In some cases, anticoagulants may be effective in preventing ischaemic stroke recurrence. Carotid endarterectomy can reduce stroke risk in patients with moderate- or high-grade carotid artery stenosis. Choosing the most appropriate therapy for the individual patient is key to optimising stroke prevention.