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.     

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).     

新型减肥药物和心血管疾患

重度肥胖患者需应用减肥药物,利拉鲁肽、纳曲酮和安非他酮、苯丁胺和托吡酯是新型减肥药物。利拉鲁肽有减轻体重、改善糖代谢和脂代谢、降低血压等作用,对心血管事件发生率无不利影响。纳曲酮和安非他酮可减轻体重。苯丁胺和托吡酯有减轻体重、改善糖代谢等作用。纳曲酮和安非他酮、苯丁胺和托吡酯对心血管事件的影响尚有待研究。     

Antiplatelet therapy in atherothrombotic cardiovascular diseases for primary and secondary prevention: a focus on old and new antiplatelet agents

Aspirin has long been the mainstay of primary and secondary prevention against myocardial infarction and ischemic cerebrovascular events. However, the incremental value of aspirin for primary prevention has recently been subject to debate given data from recent large clinical trials, as the net clinical benefit is small. In secondary prevention, aspirin is still strongly recommended. Efforts in obtaining more efficient antiplatelet agents and to reduce cardiovascular morbidity and mortality have led to the development of new adenosine diphosphate (ADP) receptor antagonists, which are superior to clopidogrel. New generation antiplatelet drugs i.e. prasugrel and ticagrelor aim to reduce atherothrombotic events, mortality and stent thrombosis, as well as overcome low- or non-response to clopidogrel. Further agents with antiplatelet properties are being investigated at present. This overview aims to give insights into the rapidly changing field of antiplatelet strategies in cardiovascular diseases.     

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.     

The risk of bleeding with the use of antiplatelet agents for the treatment of cardiovascular disease

Introduction: In the presence of injured coronary vascular endothelium, platelets become activated to form hemostatic plugs. While this represents a normal healing response to disrupted vascular endothelium, occlusive cardiovascular disease, as a result of maladaptive thrombus formation, is a major cause of morbidity and mortality. Due to the platelet predominance of arterial thrombi, antiplatelet agents are the mainstay of therapy for arterial cardiovascular disease, though come with a significantly increased risk of bleeding.

Areas covered: This review will provide a comprehensive overview of available antiplatelet agents used to treat coronary artery cardiovascular disease. The risks of bleeding with each agent will be considered.

Expert opinion: Available antiplatelet therapies are effective in treating acute thrombotic events and preventing recurrent events, however, they also carry significant bleeding risks. The decision to use or continue antiplatelet agents remains challenging for physicians and necessitates a thorough understanding of the future risk of thrombotic risks of thrombotic or bleeding events in a patient. Clinical prediction rules and risk scores may be useful to support physician decision-making.     

Oral antiplatelet agents and bleeding risk in relation to major cardiovascular surgery

INTRODUCTION: Patients requiring major cardiovascular surgery are likely to be prescribed antiplatelet agents either alone or in combination. By virtue of antiplatelet agent effect, they can potentially increase bleeding complications, especially if used in combination. This article aims to review the evidence and make appropriate recommendations regarding these agents. ASPIRIN: 16 papers are reviewed which concern surgery whilst taking aspirin. The bulk of the evidence is from the coronary bypass setting. CLOPIDOGREL: 14 papers are reviewed which concern surgery whilst taking clopidogrel. DIPYRIDAMOLE: 2 papers are reviewed concerning dipyridamole. CILOSTAZOL: No trials are available concerning surgery and cilostazol. Several relevant publications are reviewed. CONCLUSION: It is the recommendation of the authors that aspirin should usually be continued perioperatively, whilst clopidogrel should be stopped for seven days prior to surgery if at all possible.     

抗血小板药物致胃肠道出血的防治进展

抗血小板聚集是血栓栓塞性疾病防治的重要措施,但由抗血小板药物引发的胃肠道损害临床常见。本文就阿司匹林与氯吡格雷等抗血小板药物导致胃肠道出血的研究现状及其防治的研究进展作一综述。     

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.     

Current issues in thrombosis prevention with antiplatelet drugs

In this review, the major current problems related to the pharmacology and clinical use of antiplatelet drugs are discussed in relation to the physiopathology of the platelet-vessel wall interaction and arterial thrombus formation. Although platelet adhesion to injured vessels is a crucial step in thrombogenesis, none of the currently used antiaggregating drugs prevents this phenomenon. Why the normal endothelium does not react with platelets is not known. Thus we are unable to pharmacologically restore endothelial 'non-thrombogenicity' when lost by single or repeated injury. In contrast, more information is available on the mechanisms controlling and amplifying platelet activation by physiological stimuli (such as collagen and thrombin), and on their pharmacological modulation. The 3 main amplification loops involve arachidonic acid metabolism, ADP release and possibly the availability of a phospholipid platelet activating factor. These pathways are in turn activated by the phosphatidylinositol cycle. The most widely used antiaggregating drug is aspirin. It prevents the formation of arachidonic acid metabolites both in platelets and in vascular cells. The use of low-dose aspirin, thromboxane-synthase inhibitors, thromboxane receptor antagonists, epoprostenol (prostacyclin) and its stable analogues, and ticlopidine all appear to be promising pharmacological approaches, but none has so far been tested in clinical trials for thrombosis prevention. On the other hand, aspirin (in relatively large doses of 300 to 1500 mg daily), sulphinpyrazone and dipyridamole have been tested alone or in combination in the secondary prevention of thromboembolic complications. Aspirin has significantly reduced both the occurrence of myocardial infarction and mortality rate in patients with unstable angina and/or previous myocardial infarction; it has also proved beneficial in cerebrovascular disease. The beneficial effect of aspirin was dose-independent. In some of these trials aspirin was combined with either dipyridamole or sulphinpyrazone. When used alone, the latter compound has reduced sudden death or thromboembolic complications in patients with myocardial infarction. It remains to be established whether antiplatelet therapy may prevent or stop the progression of atherosclerosis.     

Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke

Stroke is the third most common cause of death in the US. Primary prevention of stroke can be achieved by control of risk factors including hypertension, diabetes mellitus, elevated cholesterol levels and smoking. Approximately one-third of all ischaemic strokes occur in patients with a history of stroke or transient ischaemic attack (TIA). The mainstay of secondary prevention of ischaemic stroke is the addition of medical therapy with antithrombotic agents to control the risk factors for stroke. Antithrombotic therapy is associated with significant medical complications, particularly bleeding.Low-dose aspirin (acetylsalicylic acid) has been shown to be as effective as high-dose aspirin in the prevention of stroke, with fewer adverse bleeding events. Aspirin has been shown to be as effective as warfarin in the prevention of noncardioembolic ischaemic stroke, with significantly fewer bleeding complications. Ticlopidine may be more effective in preventing stroke than aspirin, but is associated with unacceptable haematological complications. Clopidogrel may have some benefit over aspirin in preventing myocardial infarction, but has not been shown to be superior to aspirin in the prevention of stroke. The combination of clopidogrel and aspirin may be more effective than aspirin alone in acute coronary syndromes, but the incidence of adverse bleeding is significantly higher. Furthermore, the combination of aspirin with clopidogrel has not been shown to be more effective for prevention of recurrent stroke than clopidogrel alone, while the rate of bleeding complications was significantly higher with combination therapy. The combination of aspirin and extended-release dipyridamole has been demonstrated to be more effective than aspirin alone, with the same rate of adverse bleeding complications as low-dose aspirin. When selecting the appropriate antithrombotic agent for secondary prevention of stroke, the adverse event profile of the drug must be taken into account when assessing the overall efficacy of the treatment plan.     

Oral antiplatelet therapy in secondary prevention of cardiovascular events: an assessment from the payer's perspective

BACKGROUND: A wide variety of oral antiplatelet trials have been carried out, and a large number of cost-effectiveness estimates based on them have been published. OBJECTIVE: To assess the cost effectiveness of oral antiplatelet treatments in the prevention of cardiovascular events. METHODS: A comprehensive literature search was carried out in PubMed and the Cochrane Library and the data reviewed. Cost-effectiveness or cost-utility studies of oral antiplatelets published since 2000 were selected. Cost-effectiveness analyses from the perspective of the UK NHS were then carried out using a Markov model with a 6-month cycle length and a lifetime horizon. Inputs from the CAPRIE, CHARISMA, (PCI)-CURE, CREDO, COMMIT, CLARITY, ESPS 2 and ESPRIT trials were included. All estimates of cost found (per event avoided, per QALY gained or per life-year gained) were included. Results were analysed in light of the National Institute for Health and Clinical Excellence (NICE) guidelines for the use of antiplatelets for the prevention of cardiovascular events and all estimates were updated to pound (year 2006 values) for easy comparison. RESULTS: Of the initial 141 studies found, 21 were included in the initial review. The literature and the Markov model subsequently used suggest that aspirin (acetylsalicylic acid) dominates placebo for the secondary prevention of cardiovascular events, as it is effective, is also less costly and is as well tolerated as placebo. Additionally, in periods or patients with elevated risk, more intensive treatment with clopidogrel (alone or together with aspirin) is cost effective compared with aspirin alone for the secondary prevention of ischaemic events. For secondary stroke prevention, combination therapy with aspirin and dipyridamole has a favourable incremental cost-effectiveness ratio (ICER) when compared with aspirin alone and, based on an indirect comparison, also when compared with clopidogrel. CONCLUSIONS: The cost-effectiveness estimates presented in this article support the NICE guidelines for the use of antiplatelets for the prevention of cardiovascular events. Based on these pharmacoeconomic data alone, aspirin should be prescribed for primary or secondary prevention among patients at high risk of cardiovascular events, dipyridamole for the secondary prevention of stroke (for a maximum of 5 years), and clopidogrel for the treatment of symptomatic cardiovascular disease or acute coronary syndrome (for a maximum of 2 years). The cost effectiveness of antiplatelets hinges on the patient's initial risk, the risk reduction associated with treatment, and the price of the treatment. Evidence suggests that the cost effectiveness of antiplatelets can be optimized by individualising the treatment decision based on patient risk and expected risk reduction.     

Endothelin receptor antagonists. Promising new agents in the management of cardiovascular disorders

Since its discovery in 1988, endothelin (ET) has been widely implicated in the pathophysiology of cardiovascular disease. ET antagonists have favourable effects in experimental models of these conditions and have proved useful in elucidating the role of the ET system. Orally acting ET antagonists appear very promising in clinical trials, particularly in patients with chronic heart failure and hypertension, but more information on the roles of the ET receptor subtypes in health and disease is required so that an informed choice can be made between the use of endothelin-A (ET-A) receptor-selective and nonselective receptor antagonists.