The value of clopidogrel versus aspirin in reducing atherothrombotic events: the CAPRIE study

Atherothrombotic disease is a growing health problem, and is increasingly more costly to manage. Clopidogrel is an advanced, specific adenosine diphosphate receptor antagonist, which has been shown to be a highly potent antiplatelet agent. Data from the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study have demonstrated the significantly superior clinical benefit of clopidogrel over aspirin for secondary prevention of atherothrombotic disease, with a relative risk reduction in myocardial infarction, stroke or vascular death of 8.7% (95% confidence interval 0.3, 16.5; P = 0.043). Moreover, clopidogrel demonstrated an amplified clinical benefit versus aspirin in patients at high risk of atherothrombotic events, such as those with a previous history of symptomatic atherothrombotic disease or with major risk factors such as diabetes mellitus or hypercholesterolaemia. On the basis of commonly accepted threshold criteria (Euros 20000 per life-year gained; LYG), clopidogrel in comparison with aspirin is cost-effective for the secondary prevention of atherothrombotic disease (cost per LYG ranging from Euros 19462 to Euros 3256). Economic analyses have demonstrated consistent cost-effectiveness results with clopidogrel in different countries. Moreover, in high-risk patient subgroups the cost-effectiveness of clopidogrel in comparison with aspirin was evenbetter (cost per LYG ranging from Euros 5900 to Euros 6310). Compared with other treatment strategies used for the prevention of ischaemic or atherothrombotic events, the cost-effectiveness of clopidogrel in comparison with aspirin based on CAPRIE is favourable, with most analyses in the intermediate range of cost-effectiveness. The available data thus support the use of clopidogrel as a clinically efficient and cost-effective option for secondary prevention of atherothrombotic disease, particularly in high-risk patients.     

Prevention of coronary heart disease with aspirin and clopidogrel: efficacy, safety, costs and cost-effectiveness

Atherothrombotic coronary artery disease is the single most common cause of death worldwide and a growing public health problem. Platelets play a central role in the pathogenesis of atherothrombosis and are therefore commonly targeted by one or more antiplatelet drugs as part of primary and secondary atherothrombosis prevention strategies. Aspirin reduces the risk of serious vascular events (myocardial infarction, stroke or cardiovascular death) by approximately 20% in a broad range of high-risk patients and remains the first-line antiplatelet drug because of its relative safety, low cost and cost-effectiveness. Compared with aspirin alone, clopidogrel reduces the risk of serious vascular events by approximately 10% and the combination of aspirin and clopidogrel reduces the risk by approximately 20% in patients with non-ST-segment elevation acute coronary syndrome. Clopidogrel has a similar safety profile to aspirin but clopidogrel tablets are substantially more expensive. However, the incremental cost-effectiveness ratio of clopidogrel compared with aspirin is favourable, particularly in high-risk patients and is intermediate compared with a range of other effective therapeutic strategies for the treatment of coronary heart disease. Clopidogrel should be considered as a replacement for aspirin in patients who are allergic to aspirin, cannot tolerate aspirin, have experienced a recurrent atherothrombotic vascular event whilst taking aspirin and are at very high absolute risk of a serious vascular event (e.g., > 20%/year). The combination of clopidogrel and aspirin should be considered in patients with non-ST-segment elevation acute coronary syndrome or undergoing percutaneous coronary intervention.     

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).     

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.     

Prevention of ischaemic stroke--antiplatelets

Aspirin is the treatment of first choice for long-term secondary prevention of vascular events in patients with confirmed non-cardioembolic ischaemic stroke or TIA. However, there is no good evidence that it is of benefit in primary stroke prevention. If aspirin is contra-indicated, dipyridamole monotherapy is a relatively cheap, but slightly less effective, alternative. Aspirin and dipyridamole have an additive effect in secondary stroke prevention, but there is a high incidence of side effects and subsequent discontinuation of treatment with combination therapy. It is reasonable to consider clopidogrel for secondary prevention of vascular events in patients with ischaemic stroke who are intolerant of aspirin or dipyridamole, or who have a history of ischaemic heart disease. However, its cost is considerable. Over the next decade, oral antiplatelet agents directed against specific platelet receptors, or a combination of antiplatelet drugs inhibiting different aspects of platelet function, may improve secondary prevention of stroke.     

The value of clopidogrel in addition to standard therapy in reducing atherothrombotic events

The recent multinational, randomised, prospective studies Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Percutaneous Coronary Intervention substudy of CURE (PCI-CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO) have demonstrated the clinical efficacy and safety of clopidogrel for the treatment of patients with non-ST-segment elevation acute coronary syndromes (ACS), including those undergoing percutaneous coronary intervention. In these settings, clopidogrel significantly reduces the risk of atherothrombotic events, with relative risk reductions of 20-30% (absolute risk reduction 1.9-3.0%). Health economic evaluations based on data from these studies conducted in Europe and the United States have clearly demonstrated the cost-effectiveness of clopidogrel in combination with aspirin compared with aspirin alone for the management of ACS. Within-trial evaluations based on CURE and PCI-CURE data showed that treatment with clopidogrel on top of standard therapy reduced the cost of initial hospitalisation as well as the total cost associated with hospitalisations. Long-term economic analyses based on the CURE study demonstrate that clopidogrel is cost saving in the Netherlands and that the cost per life-year gained (LYG) in other European countries is between Euros 549 and Euros 5048. In the United States, the cost per LYG for clopidogrel has been assessed at US dollars 6173 on the basis of CURE, US dollars 5910 for PCI-CURE and US dollars 3685 for CREDO, all of which are considerably lower than that associated with common cardiovascular benchmarks. The results are robust and consistent across different countries using varying costing strategies and estimates of survival. In conclusion, these data demonstrate that clopidogrel in combination with aspirin for the management of ACS is both clinically effective and cost-effective in this setting.     

Clopidogrel: a pharmacoeconomic review of its use in patients with non-ST elevation acute coronary syndromes

Clopidogrel (Plavix) is a selective inhibitor of adenosine diphosphate-induced platelet aggregation. In patients with acute coronary syndromes (ACS) [unstable angina or non-ST-segment elevation myocardial infarction], clopidogrel plus aspirin (acetylsalicylic acid) for up to 1 year significantly reduced the risk of cardiovascular events relative to placebo plus aspirin in the well designed clinical trial CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) and its substudy in patients undergoing percutaneous coronary intervention (PCI) [PCI-CURE]. In pharmacoeconomic evaluations based on data from these trials conducted in a number of countries that used a variety of models, methods and/or type of costs, clopidogrel plus aspirin was consistently predicted to be cost effective relative to aspirin alone in the management of patients with ACS, including those undergoing PCI. Clopidogrel plus aspirin in patients with ACS reduced the incremental cost per cardiovascular event prevented and/or life-year gained (LYG) relative to aspirin alone in analyses using within-trial data (including longer-term analyses incorporating life-expectancy estimates) from the CURE or PCI-CURE studies. In Markov models of cost effectiveness with a lifetime horizon from a healthcare payer perspective based on the CURE trial, relative to aspirin alone, clopidogrel plus aspirin for 1 year was predicted to have incremental costs per LYG of 8132Euro in Spain (2003 values) and 1365Euro in Sweden (2000 values). In similar Swedish analyses from a healthcare payer perspective, clopidogrel plus aspirin for 1 year was predicted to have incremental costs per LYG of 10,993Euro (2004 values) relative to aspirin alone based on data from the PCI-CURE substudy. Broadly similar results have also been reported in modelled analyses from other countries. Cost-utility analyses based on the CURE trial suggest that, relative to lifelong aspirin alone, clopidogrel plus aspirin for 1 year followed by aspirin alone is associated with incremental costs per QALY gained that are below the traditional threshold of cost utility in Spain, the UK and the US. In patients with ACS, including those undergoing PCI, the addition of clopidogrel to standard therapy with aspirin is clinically effective in preventing cardiovascular events. Available pharmacoeconomic data from several countries, despite some inherent limitations, support the use of clopidogrel plus aspirin for up to 1 year as a cost-effective treatment relative to aspirin alone in this patient population.     

Safety of clopidogrel and aspirin for stroke prevention: implications of the CHARISMA trial.

Antiplatelet therapy is universally recommended for the prevention of recurrent events in patients with noncardioembolic ischaemic stroke or transient ischaemic attack (TIA), acute and chronic coronary artery disease, or peripheral arterial disease. However, choosing which antiplatelet agents to use in these situations remains controversial. The use of aspirin, aspirin plus extended-release dipyridamole, or clopidogrel is recommended as initial therapy in patients with noncardioembolic ischaemic stroke or TIA to reduce the risk of recurrent stroke and other cardiovascular events. Based on the results of the MATCH trial, combination therapy with aspirin plus clopidogrel is not recommended for patients with ischaemic stroke or TIA due to the increased risk of haemorrhage.The results of the CHARISMA trial support this recommendation; despite previous data demonstrating a favourable benefit-risk profile of aspirin plus clopidogrel in patients with acute coronary syndrome, this combination should not be used in patients at high risk for atherothrombosis and those with previous stroke or TIA. In these patients, the CHARISMA trial demonstrated a lack of significant clinical efficacy and an increased risk of bleeding with clopidogrel plus aspirin compared with aspirin alone.Further research is needed to assess the benefit-risk ratio of clopidogrel plus aspirin in specific subpopulations of patients at high risk for atherothrombotic events, and to determine the role of clopidogrel plus aspirin in preventing cardioembolic stroke or early recurrent stroke after symptomatic large-vessel atherostenosis. Recent and ongoing studies are seeking to better define the roles of different antiplatelet regimens in preventing recurrent stroke.     

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 the Secondary Prevention of Atherothrombotic Events

Atherothrombosis is the leading cause of death worldwide and has a large economic impact. It is a pathologic process related to atherosclerosis, which leads to adverse clinical manifestations, including acute coronary syndrome, cerebrovascular disease, and peripheral arterial disease. Patients with atherothrombosis are at heightened risk for recurrent ischemic events or death, and therefore, secondary prevention is an important goal in the treatment of these patients. Antiplatelet therapies available for long-term secondary prevention include aspirin (acetylsalicylic acid), extended-release dipyridamole plus aspirin, and clopidogrel. A number of clinical trials have demonstrated the benefit of combined antiplatelet therapy in secondary prevention, supporting the recommendations made in current published guidelines. Although the efficacy and safety of antiplatelet agents is well established and supported by clinical trials, their utilization rate in patients with atherothrombosis remains suboptimal. Quality improvement initiatives have demonstrated effectiveness in promoting the awareness and implementation of treatment guidelines. This article reviews the benefits and risks of antiplatelet therapy in patients with cardiovascular disease with the aim of spurring greater adherence to treatment recommendations and, thereby, better patient outcomes.     

Antiplatelet therapy for the prevention of recurrent stroke and other serious vascular events: a review of the clinical trial data and guidelines

ABSTRACT

Background: One strategy of reducing the burden of stroke is the prevention of recurrent stroke, following an initial ischaemic stroke or transient ischaemic attack (TIA) of arterial origin, by means of antiplatelet therapy.

Scope: This review article surveys and discusses the current clinical trial data and guidelines for the use of antiplatelet therapy in the prevention of recurrent stroke/TIA of arterial origin (not stroke due to atrial fibrillation). Based on the latest available evidence, a new antiplatelet treatment algorithm for the long-term treatment of patients following atherothromboembolic ischaemic stroke or TIA is proposed.

Findings: Meta-analyses of randomised clinical trials in patients with TIA and ischaemic stroke of arterial origin indicate that, compared with control, the relative risk reduction (RRR) for recurrent stroke and other serious vascular events is 13% (95% confidence interval [CI] 6% to 19%) with aspirin, 13% (4% to 21%; p = 0.046) with dipyridamole and 34% (24% to 43%) with the combination of aspirin and dipyridamole. Compared with aspirin, the relative risk of recurrent stroke and other serious vascular events is reduced by 7.3% (95% CI –5.7% to 18.7%) with clopidogrel and 18% (9% to 26%; p = 0.0003) with the combination of aspirin and dipyridamole. The combination of aspirin and clopidogrel is not significantly more effective in preventing serious vascular events than clopidogrel alone (RRR 6.4%; –4.6% to 16.3%) in the long-term treatment of patients with previous ischaemic stroke and TIA, mainly because of a cumulative excess of bleeding complications. The relative risks and benefits of long-term treatment with clopidogrel and the combination of aspirin and dipyridamole are being compared in an ongoing large clinical trial (PRoFESS). Current Australian therapeutic guidelines for antiplatelet therapy among patients with TIA and ischaemic stroke of arterial origin have incorporated important new findings from recently published clinical trials and recommend aspirin or the combination of dipyridamole plus aspirin as the preferred long-term antiplatelet therapy.

Conclusion: Whilst awaiting the results of the PRoFESS trial, the combination of dipyridamole plus aspirin is the preferred antiplatelet regimen to reduce the risk of recurrent vascular events among patients with TIA and ischaemic stroke of arterial origin.     

Efficacy and costs of secondary prevention with antiplatelets after ischaemic stroke

Ischaemic stroke and other atherothrombotic events substantially increase the medico-economic burden because of their high treatment costs and long-lasting disabilities with need for chronic care. Studies have shown that the cost of stroke represents approximately 3 - 5% of the annual health budget. Antiplatelet agents play a major role in secondary stroke prevention. Acetylsalicylic acid (ASA), ASA combined with extended-release dipyridamole (ER-Dip), and clopidogrel are all acceptable choices for first-line treatment in the secondary prevention of stroke. The newer antiplatelets, however, are more expensive than ASA, and their cost-effectiveness is not easily estimated. ASA has to be given to 33 stroke patients to prevent one future stroke, myocardial infarction (MI) or vascular death compared with placebo. Adding ER-Dip to ASA increases the benefit for the patients. A total of 33 stroke patients had to be treated with this combination, instead of ASA, to prevent one stroke. However, the combination of ASA plus ER-Dip does not prevent MI, vascular death or the combined end point of either stroke or death. Clopidogrel is more effective than ASA in preventing a combined end point of ischaemic stroke, MI, or vascular death, but it has not been shown to be superior to ASA in preventing recurrent stroke in transient ischaemic attack or stroke patients. Several subgroups, such as stroke patients with additional peripheral artery disease, patients with prior coronary artery bypass, patients with insulin-dependent diabetes, and patients with recurrent vascular events, were identified, in whom the benefit of clopidogrel is amplified. Taking economical aspects into account, the fixed combination of ASA and ER-Dip can be recommended for secondary stroke prevention as a first-line alternative to ASA in patients without major comorbidity. In patients with higher comorbidity, clopidogrel may be more effective for the individual patient compared with ASA, and might also be cost-effective. Furthermore, in patients with ASA intolerance clopidogrel is a useful, but expensive, alternative.     

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。     

CYP2C19基因导向的抗血小板药物治疗方案在急性冠状动脉综合征患者中的经济学评价

目的： 从药物经济学角度评价拟行介入手术的急性冠脉综合征患者依据CYP2C19基因指导抗血小板药物应用的可行性。方法： 采用回顾性分析,选取皖南医学院弋矶山医院2018年4月至2020年4月收治的513例采用氯吡格雷联合阿司匹林或替格瑞洛联合阿司匹林进行抗血小板治疗的急性冠脉综合征住院患者,根据是否进行CYP2C19基因检测及个体化用药指导,非随机分为个体化治疗组和采用氯吡格雷标准剂量的常规治疗组。成本仅包括直接医疗成本,效果指标采用患者1年内发生主要心血管不良事件次数,进行增量成本效果分析和敏感性分析。结果： 个体化治疗组（n=312）的人均总治疗费用为49 319元,常规治疗组（n=201）为51 820元;1年内再入院率个体化治疗组为12.18%,常规治疗组为21.89%,具有统计学差异（P<0.05）。增量成本效果比为257.5元/%,相比常规治疗组,个体化治疗组每使100个患者中减少1例因发生主要心血管不良事件再入院,可少花费25 750元,表明个体化治疗策略具有明显的成本-效果优势。敏感性分析表明,提高用药效果对增量成本效果比的改变并不十分显著,提示医疗费用才是影响基因检测经济性的关键因素。结论： 通过CYP2C19基因检测指导的抗血小板治疗方案对急性冠脉综合征患者经皮冠状动脉介入术后预防主要心血管不良事件具有良好效果,并具有明显成本-效果收益,更具有药物经济学优势。     

Economic assessment of the secondary prevention of ischaemic stroke with dipyridamole plus aspirin (Aggrenox/Asasantin) in France

OBJECTIVE: To assess the cost effectiveness of aspirin 25 mg plus dipyridamole 200 mg twice daily in the secondary prevention of ischaemic stroke, according to the French social security perspective, using efficacy data from the second European Stroke Prevention Study (ESPS-2). The ESPS-2 was a double-blind, placebo-controlled clinical trial which assessed the efficacy of four secondary prevention strategies: (i) placebo; (ii) aspirin (acetylsalicylic acid) 25 mg twice daily; (iii) dipyridamole 200 mg twice daily; and (iv) aspirin 25 mg plus dipyridamole 200 mg twice daily. METHOD: We performed a cost-effectiveness analysis with Monte Carlo simulations to compute confidence intervals. We combined data from various sources including the Dijon Stroke Registry, Institut National de la Statistique et des Etudes Economiques, Etude du Co?t de l'Infarctus Cérébral (Study of the Cost of Cerebral Infarction [ECIC]) study and the ESPS-2 trial. RESULTS: According to our findings, a preventive strategy with aspirin 25 mg plus dipyridamole 200 mg twice daily is associated with net benefits per avoided stroke recurrence amounting to USD 23,932 (95% CI -USD 32,609, USD 35,772) compared with aspirin 25 mg twice daily alone, and USD 31,555 (95% CI USD 4921, USD 74,515) compared with dipyridamole alone (1997 values). Sensitivity analysis demonstrated that dipyridamole plus aspirin was still cost effective when the average cost of adverse effects per episode (ignored in the original estimation of the cost-effectiveness ratios due to a lack of data) was assumed to be USD 8600 (50,000 French francs); this cost is unlikely as most of the adverse effects associated with aspirin plus dipyridamole are only slight to moderate in severity. CONCLUSIONS: In the secondary prevention of stroke in France, this study suggests, given its underlying assumptions and data, that aspirin 25 mg plus dipyridamole 200 mg twice daily is likely to be a cost-effective strategy from the social security perspective, when compared with other relevant strategies that were evaluated in the ESPS-2 trial.     

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.     

Aspirin and Platelet Adenosine Diphosphate Receptor Antagonists in Acute Coronary Syndromes and Percutaneous Coronary Intervention

Platelet activation and aggregation are key components in the cascade of events causing thrombosis following plaque rupture. Antiplatelet therapy is essential in the treatment of patients with acute coronary syndromes (ACS) and for those requiring percutaneous coronary intervention (PCI). Aspirin (acetylsalicylic acid) is a well established antiplatelet therapy and is mandated for secondary prevention of cardiovascular events following ACS. In patients with ACS, the addition of clopidogrel to aspirin is more effective than aspirin alone. For patients undergoing PCI, dual antiplatelet therapy with aspirin and clopidogrel is warranted. Aspirin should be continued indefinitely after PCI. Pretreatment of patients with clopidogrel prior to PCI lowers the incidence of cardiovascular events, yet the optimum timing of drug administration and dose are still being investigated, as is the duration of therapy following PCI. Late-stent thrombosis with drug-eluting stents has pushed the recommendation for duration of clopidogrel therapy up to 1 year and perhaps beyond, in patients without risks for bleeding. The concepts of aspirin and clopidogrel resistance are important clinical questions. No uniform definition exists for aspirin or clopidogrel resistance. Measurements of resistance are often highly variable and do not necessarily correlate with clinical resistance. Noncompliance remains the most prominent mode of resistance. Screening of selected patient populations for resistance or pharmacologic intervention of those patients termed 'resistant' warrants further study.     

Antithrombotic drugs for secondary stroke prophylaxis

Stroke is the third most common cause of adult mortality in the United States. Antithrombotic agents form the mainstay of stroke prevention. Aspirin produces a modest reduction in the risk of second stroke and is widely recommended for initial therapy. The thienopyridines ticlopidine and clopidogrel are alternatives for secondary prevention in patients who do not respond to or cannot take aspirin. They are no more effective than aspirin and have been associated with thrombotic thrombocytopenic purpura. The combination of aspirin and extended-release dipyridamole has several mechanisms of action and an additive effect on reducing stroke risk compared with either agent alone. A 2-fold increase in risk reduction and favorable safety profile suggest that the combination can serve as first-line prophylaxis against a second stroke.     

Antiplatelet therapy in cerebrovascular disorders

Antiplatelet treatment is a mainstay in acute and long-term secondary stroke prevention. Aspirin is still most widely used worldwide, however, there is increasing evidence from small randomised trials that dual antiplatelet therapy combining aspirin with dipyridamole or clopidogrel might be more effective in the acute and early chronic post-ischemic phase (i.e. first 90 days). Both clopidogrel and the combination of aspirin and extended-release dipyridamole are recommended by current guidelines in long-term secondary stroke prevention in patients who are at high risk for a recurrent ischemic stroke, since they are more effective compared with aspirin monotherapy.Antiplatelet agents are the therapy of choice in patients with ischemic stroke due to intracranial stenosis and patent foramen ovale. In contrast, oral anticoagulation is clearly superior to single or double antiplatelet therapy in patients with cardioembolic stroke, mainly caused by atrial fibrillation.Concerning newer antiplatelet agents, only cilostazol appears to be a promising therapeutic option in patients with ischemic stroke in the near future, but so far, only studies in Asian stroke patients have been performed.     

Clopidogrel hydrogen sulphate for atrial fibrillation

INTRODUCTION: Atrial fibrillation is a common cardiac rhythm abnormality with a considerable cardiovascular disease burden worldwide. It is an independent major risk factor for stroke. Stroke prevention with anticoagulation or antiplatelet agents has been an important area of clinical research. Warfarin is the most widely used antithrombotic therapy for stroke prophylaxis for last several years, and now dabigatran (150 mg b.i.d.) is more effective than warfarin in stroke prevention in individuals at increased of stroke. In addition, several studies have evaluated the efficacy of clopidogrel for stroke prophylaxis either alone or in combination with aspirin. AREAS COVERED: This review summarizes the key findings of the trials looking at the efficacy of clopidogrel in stroke prevention. A literature search was performed using PubMed and Google Scholar. The trials that evaluated the efficacy of clopidogrel in preventing atherothrombotic events or stroke were also included. EXPERT OPINION: Clopidogrel prevents more vascular events, including stroke, in patients with a recent myocardial infarction, stroke or peripheral vascular disease than aspirin. Combination of clopidogrel and aspirin provides a greater reduction of stroke than aspirin or clopidogrel monotherapy, but at an increased risk of bleeding. Dual antiplatelet therapy (clopidogrel and aspirin) is inferior to warfarin in primary stroke prevention for patient with atrial fibrillation and thus should be considered for stroke prophylaxis only in patients ineligible for warfarin. However, with the advent of newer agents, like direct thrombin inhibitors and Factor Xa inhibitors, the role of antiplatelet therapy for stroke prevention in atrial fibrillation remains unclear.