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).     

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.     

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.     

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.     

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.     

Current Management of Transient Ischemic Attack

Transient ischemic attack (TIA) is a precursor to ischemic stroke. At least half of patients with TIA have a new, small ischemic lesion demonstrable on magnetic resonance imaging using a diffusion weighted sequence. The risk of subsequent major stroke is 10-20% in the next 3 months with much of that risk front-loaded in the first week. Strategies to identify and treat high-risk patients need to be defined. The optimal treatment approach and the timing of interventions, both medical and surgical, remains unknown. In general, aspirin is the first line of treatment to prevent further stroke. Other antiplatelet agents such as clopidogrel alone or in combination with aspirin and the combination aspirin/extended-release dipyridamole may be administered. Endarterectomy or carotid stenting is of great benefit to patients with TIA secondary to stenosis in the extracranial carotid artery.     

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.     

Medical prevention of stroke and stroke recurrence in patients with TIA and minor stroke

Background: Secondary stroke prevention after transient ischemic stroke (TIA) or minor stroke is of major importance in order to avoid recurrent cerebrovascular events and decrease morbidity and mortality. Objective/methods: Systematically review of recently published, high-quality studies emphasizing the need for emergency assessment and treatment of patients with TIA and minor stroke and to give a comprehensive and distinct overview over medical secondary stroke prevention trials performed in these patients. Results/conclusions: Evaluation and implementation of preventive stroke therapy has to be immediate in patients with TIA and stroke. For patients with non-cardioembolic stroke, antiplatelet agents are the treatment of choice. Aspirin plus extended-release dipyridamole and clopidogrel are more effective than aspirin and should be used in patients with a high risk of recurrent stroke. Oral anticoagulation is highly effective in patients with a cardiac source of embolism. Treatment of risk factors such as arterial hypertension and high cholesterol is even more important in secondary stroke prevention than in primary prevention. Vitamin supplementation and lowering of elevated levels of homocysteine are not effective in stroke prevention.     

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.     

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.     

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.     

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。     

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.     

阿司匹林联合双嘧达莫用于缺血性脑卒中二级预防的Meta分析

目的以阿司匹林为对照组,系统评价阿司匹林双嘧达莫联合用药,对缺血性脑卒中二级预防的有效性和安全性。方法通过卒中、非致死性卒中、各种原因引起的死亡及非致死性卒中与各种原因引起的死亡联合事件发生的相对危险度,分析联合用药的有效性,通过出血性并发症及脑出血发生的相对危险度,分析联合用药的安全性。结果 a.与阿司匹林相比较,联合用药能更有效的预防卒中的发生(RR=0.86 95%CI[0.74,1.00]),使非致死性卒中的发生率降低22%(RR=0.78 95%CI[0.67,0.90]),也能明显降低非致死性卒中与各种原因引起的死亡联合事件的发生率(RR=0.87 95%CI[0.79,0.96])。但是,联合用药对各种原因引起的死亡无效(RR=0.98,95%CI[0.85,1.13])。b.与阿司匹林相比较,联合用药不会增加出血性并发症的发生率(RR=0.95,95%CI[0.80,1.12]),但可以使脑出血的发生率增加14%(RR=1.14,95%CI[0.54,2.42]),尽管这一结果无明显统计学意义。结论与阿司匹林相比较,联合用药对卒中、非致死性卒中及非致死性卒中与各种原因引起的死亡联合事件的预防更有效,联合用药不会增加出血性并发症的发生率,但能轻微增加脑出血的发生率。     

High prevalence of previous antiplatelet drug use in patients with new or recurrent ischemic stroke: Buffalo metropolitan area and Erie County stroke study

STUDY OBJECTIVE: To determine the proportion of patients in a large metropolitan population who developed ischemic stroke despite having received antiplatelet drug therapy, and their associated characteristics and in-hospital outcomes. DESIGN: Retrospective, cross-sectional study. SETTING: Eleven hospitals in western New York State. PATIENTS: One thousand five hundred eighty-two patients with new or recurrent ischemic stroke who were admitted to one of the 11 study hospitals between January 1 and December 31, 2000, and for whom data were available regarding previous drug therapy. MEASUREMENTS AND MAIN RESULTS: The proportion of patients taking antiplatelet drugs before the onset of stroke was determined. Demographic and clinical characteristics, stroke subtypes, in-hospital bleeding complications, mortality, and discharge drugs were compared between patients with and those without previous antiplatelet drug use. Previous use of antiplatelet drugs was observed in 642 (41%) of the 1582 patients admitted with ischemic stroke. The antiplatelet drugs were aspirin alone (494 patients), clopidogrel alone (70), aspirin and clopidogrel (36), aspirin in combination with other antiplatelet drugs (20), and others (22). Patients with previous use of antiplatelet drugs were older and more likely to have hypertension, diabetes mellitus, hyperlipidemia, and a history of cardiovascular disease. The proportion of patients with large-vessel disease was greater among patients with previous use of antiplatelet drugs. Patients with previous use of antiplatelet drugs were more likely to be discharged with aspirin, clopidogrel, and an aspirin-dipyridamole combination. CONCLUSION: The relatively high proportion of patients who developed ischemic stroke despite taking antiplatelet drugs observed in this regional hospital-based study mandates clinical trials specifically addressing therapeutic intervention for this group of patients.     

Clopidogrel for the secondary prevention of stroke

Patients suffering a transient ischaemic attack (TIA) or ischaemic stroke (IS) have a high risk of recurrence. The inhibition of platelet function is effective in the reduction of secondary vascular events in patients with TIA or stroke. This is true for acetylsalicylic acid (ASA), clopidogrel, ticlopidine and the combination of ASA plus slow-release dipyridamole. This overview analyses the results of recent trials and presents ongoing or future trials with clopidogrel as well as the combination of clopidogrel plus ASA. Clopidogrel is superior to ASA in the prevention of vascular events in patients with IS, myocardial infarction (MI) or peripheral arterial disease (PAD). The difference is highest for high-risk patients such as diabetics, patients who underwent coronary bypass surgery and patients with a remote prior history of ischaemic events. A prediction model is presented which allows the identification of patients in whom clopidogrel is superior to ASA for the secondary prevention of stroke. The combination of clopidogrel and ASA is better than ASA alone in patients undergoing coronary stent implantations and patients with unstable angina or non-Q-wave MI. In high-risk patients with TIA or stroke, the addition of ASA to clopidogrel is not superior to ASA monotherapy but results in a higher rate of bleeding complications. The long-term combination therapy is currently investigated in several large trials in > 30,000 patients, with a large number of stroke patients.     

Drug evaluation of clopidogrel in patients with ischemic stroke

Clopidogrel is an effective antiplatelet medication used for the secondary prevention of ischemic events in patients with various cardiovascular, cerebrovascular and peripheral vascular disease conditions. The objective of this paper is to discuss the role of clopidogrel in ischemic stroke patients and to review the existing data from randomized trials supplemented by pilot and mechanistic studies that supports these indications for its use. An analysis of the mechanism of action and pharmacology of clopidogrel is provided. After Phase III trials, such as the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) and MATCH (Management of Atherothrombosis with Clopidogrel in High-risk patients) trials, the role of clopidogrel in secondary prevention is well defined. The role of clopidogrel in acute ischemic stroke and neurointerventional procedures is evolving based on new pilot trials. At present, there is insufficient data to recommend the use of clopidogrel in acute ischemic stroke. Clopidogrel may be a valuable alternative to aspirin. However, more studies are required to assess the role of clopidogrel in selected patient groups with respect to acute ischemic stroke.     

Warfarin and aspirin give more benefit than aspirin alone but also more bleeding after myocardial infarction

The anticoagulant, warfarin, and the antiplatelet agent, aspirin, have been shown to have similar benefits after myocardial infarction. As these agents have different mechanisms of action, the beneficial effects of warfarin and aspirin may be additive after myocardial infarction. In the Warfarin, Aspirin, Reinfarction Study (WARIS II), the main outcome was a composite of death, non-fatal reinfarction or thromboembolic stroke, whichever came first over 4 years. Compared to aspirin alone (160 mg/day), the risk reduction was 19% (p = 0.03) with warfarin alone (INR of 2.8 IU) and 29% (p = 0.001) with the combination of aspirin and warfarin (aspirin, 75 mg/day; warfarin, INR of 2.2 IU). This difference in the first event with warfarin alone or the combination, represented a reduction in reinfarction and thromboembolic stroke rather than death. For reinfarction, compared to aspirin alone (117 of 1206), there was a reduction with warfarin alone (90 of 1216) and a further reduction with the combination (69 of 1208). For thromboembolic stroke, compared to aspirin (32 of 1206), there were similar reductions with warfarin and the combination. There were more major and minor bleeding in the warfarin groups than the aspirin group, with major bleeding occurring in 8, 33 and 28 patients taking aspirin, warfarin and aspirin and warfarin, respectively. In conclusion, as compared with aspirin alone, therapy with moderate-intensity warfarin combined with aspirin and high-intensity warfarin alone, resulted in a reduced risk of reinfarction and ischemic stroke but a higher risk of bleeding.     

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.     

Drug evaluation of clopidogrel in patients with ischemic stroke

Clopidogrel is an effective antiplatelet medication used for the secondary prevention of ischemic events in patients with various cardiovascular, cerebrovascular and peripheral vascular disease conditions. The objective of this paper is to discuss the role of clopidogrel in ischemic stroke patients and to review the existing data from randomized trials supplemented by pilot and mechanistic studies that supports these indications for its use. An analysis of the mechanism of action and pharmacology of clopidogrel is provided. After Phase III trials, such as the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) and MATCH (Management of Atherothrombosis with Clopidogrel in High-risk patients) trials, the role of clopidogrel in secondary prevention is well defined. The role of clopidogrel in acute ischemic stroke and neurointerventional procedures is evolving based on new pilot trials. At present, there is insufficient data to recommend the use of clopidogrel in acute ischemic stroke. Clopidogrel may be a valuable alternative to aspirin. However, more studies are required to assess the role of clopidogrel in selected patient groups with respect to acute ischemic stroke.