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.     

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.     

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.     

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.     

Editorial Commentary

Thrombotic events of the arterial circulation continue to be the major cause of cardiovascular death in spite of great efforts to prevent and treat thrombosis. Current antithrombotic strategies in clinical use are primarily based on aspirin (antiplatelet), heparin (anticoagulant) and coumadins (chronic anticoagulants). Recently, ReoPro®, an antibody blocking the platelet fibrinogen receptor, GpIIb/IIIa, has been introduced for limited acute use for prevention of ischaemic complications of coronary balloon angioplasty. Clopidogrel is a novel antiplatelet agent that has demonstrated antithrombotic efficacy beyond aspirin in preclinical studies and is now in clinical (Phase II) development for secondary prevention of broad ischaemic cardiovascular events including death. Clopidogrel is an ADP receptor antagonist with additional properties that produce effective and long-lasting antithrombotic actions. Clopidogrel seems to be free of the adverse side-effects that flawed ticlopidine, a closely related thieno-derivative, and is at least six-fold more potent. It is expected that clopidogrel will add significantly to the antichrombotic arsenal and reduce cardiovascular morbidity and mortality above and beyond currently available therapy.     

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.     

Clopidogrel: a review of its use in the prevention of atherothrombosis

Clopidogrel is an ADP receptor antagonist that is indicated for the reduction of atherosclerotic events including myocardial infarction, ischaemic stroke and vascular death in patients with atherosclerosis manifested by recent stroke, myocardial infarction or established peripheral vascular disease. In the 19 185 patients enrolled in the multicentre, randomised double-blind CAPRIE study, the annual risk of the combined end-point of ischaemic stroke, myocardial infarction and death from vascular disease (vascular death) was significantly lower during treatment with clopidogrel 75 mg/day than aspirin 325 mg/day [5.3 vs 5.8%/year, respectively; relative risk reduction (RRR) 8.7%, p = 0.043] after a mean follow-up of 1.9 years. Clopidogrel provided even greater reductions in the risk of recurrent ischaemic events than aspirin in patients with a history of coronary artery bypass surgery, diabetes mellitus and in those receiving concomitant lipid-lowering therapy. Moreover there was a significant reduction in the incidence of hospitalisation in patients treated with clopidogrel. In a patient population (Saskatchewan, Canada) with a greater risk of ischaemic events than the CAPRIE study population, the number of patients needed to be treated with clopidogrel to prevent 1 ischaemic event was estimated to be 70 (vs 200 in the CAPRIE study). In randomised trials and registry surveys, clopidogrel 75 mg/day plus aspirin had similar efficacy (as measured by adverse cardiac outcomes) to ticlopidine 250mg twice daily plus aspirin during the 30 days after placement of intracoronary stents. Tolerability of clopidogrel was significantly better than ticlopidine in the randomised, double-blind CLASSICS study. Among patients treated with clopidogrel or aspirin in the CAPRIE study, the overall gastrointestinal tolerability of clopidogrel was generally better than that of aspirin; the frequency of gastrointestinal haemorrhage was significantly lower among patients treated with clopidogrel than aspirin. Diarrhoea, rash and pruritis were significantly more common with clopidogrel than aspirin. CONCLUSION: Clopidogrel was significantly more effective than aspirin in the prevention of vascular events (ischaemic stroke, myocardial infarction or vascular death) [corrected] in patients with atherothrombotic disease manifested by recent myocardial infarction, recent ischaemic stroke or symptomatic peripheral arterial occlusive disease [corrected] in the CAPRIE study. The overall tolerability profile of the drug was similar to that of aspirin, although gastrointestinal haemorrhage occurred significantly less often in clopidogrel recipients. The drug is widely used in combination with aspirin for the prevention of atherothrombosis after placement of intravascular stents, and available data suggest that this combination is as effective as ticlopidine plus aspirin for this indication.     

Aspirin and esomeprazole are superior to clopidogrel in preventing recurrent ulcer bleeding

Although low-dose aspirin is commonly used as the antiplatelet agent to prevent ischaemic events such as myocardial infarction and stroke, clopidogrel is probably superior at preventing ischaemic events. For patients who cannot tolerate aspirin, adding a proton pump inhibitor or substituting clopidogrel are options. Patients with endoscopy-confirmed ulcer healing were assigned to clopidogrel 75 mg/day or aspirin 80 mg/day and esomeprazole 20 mg b.i.d. for 12 months. There were 14 confirmed cases of recurrent ulcer bleeding, with 13 being from the 161 patients taking clopidogrel and 1 from the 159 patients taking aspirin plus esomeprazole. This trial has clearly shown that the combination of aspirin and esomeprazole is superior to clopidogrel in preventing recurrent ulcer bleeding. A more interesting study may have been to compare the effects of aspirin and clopidogrel in the presence of esomeprazole in patients with a history of ulcers.     

Guidelines for stroke prevention in patients with atrial fibrillation

Atrial fibrillation (AF) is a major independent risk factor for stroke. AF is most commonly associated with nonvalvular cardiovascular disease and is especially frequent among the elderly. The annual risk for stroke in patients with AF is approximately 5% with a wide range depending on the presence of additional risk factors. For patients who cannot successfully be converted and maintained in normal sinus rhythm (NSR), antithrombotic therapy is an effective method for preventing stroke. The 2 drugs which are indicated for stroke prophylaxis in patients with AF are warfarin and aspirin. For primary prevention, warfarin reduces the risk of stroke approximately 68%. Aspirin therapy is less effective, resulting in a 20 to 30% risk reduction. Combination therapy with aspirin and low intensity warfarin adjusted to an International Normalised Ratio (INR) of 1.2 to 1.5 has not been shown to be superior to standard intensity warfarin with a target INR of 2.0 to 3.0. In patients with AF and a prior history of stroke or transient ischaemic attack (TIA), the absolute risk reduction with warfarin is even greater because of the high risk of stroke in this population. In contrast, aspirin has not been shown to significantly reduce the risk of stroke in patients with AF when used for secondary prevention. When appropriately managed, warfarin is associated with a low risk of major bleeding. In controlled trials of highly selected patients, the annual rate of intracranial haemorrhage (ICH) with warfarin was approximately 0.3%. Studies have shown that specialty anticoagulation clinics can achieve similar low rates of major bleeding. However, these results cannot be extrapolated to the general population. Factors which have been identified as predictors of bleeding include advanced age, number of medications and most importantly, the intensity of anticoagulation. INR values above 4.0 have been associated with an increased risk of major bleeding while values below 2.0 have been associated with thrombosis. Slow careful dosage titration, regular laboratory monitoring and patient education can substantially reduce the risk of complications. In patients with AF, antithrombotic therapy has been shown to be cost effective. For high risk patients, warfarin is the most cost-effective therapy, provided the risks for bleeding are minimised. In contrast, aspirin is the most cost-effective agent for low risk patients. Current practice guidelines for stroke prophylaxis recommend warfarin (target INR 2.5: range 2.0 to 3.0) for AF patients at high risk for stroke including those over 75 years of age or younger patients with additional risk factors. Aspirin should be reserved for low risk patients or those unable to take warfarin. Although these recommendations are strongly supported by the clinical trial evidence, studies show that many patients are not receiving appropriate antithrombotic therapy. In particular, warfarin is underutilised in high risk elderly patients. Additional studies are needed to identify barriers that prevent implementation of the clinical trial findings into clinical practice.     

Aspirin and esomeprazole are superior to clopidogrel in preventing recurrent ulcer bleeding

Although low-dose aspirin is commonly used as the antiplatelet agent to prevent ischaemic events such as myocardial infarction and stroke, clopidogrel is probably superior at preventing ischaemic events. For patients who cannot tolerate aspirin, adding a proton pump inhibitor or substituting clopidogrel are options. Patients with endoscopy-confirmed ulcer healing were assigned to clopidogrel 75 mg/day or aspirin 80 mg/day and esomeprazole 20 mg b.i.d. for 12 months. There were 14 confirmed cases of recurrent ulcer bleeding, with 13 being from the 161 patients taking clopidogrel and 1 from the 159 patients taking aspirin plus esomeprazole. This trial has clearly shown that the combination of aspirin and esomeprazole is superior to clopidogrel in preventing recurrent ulcer bleeding. A more interesting study may have been to compare the effects of aspirin and clopidogrel in the presence of esomeprazole in patients with a history of ulcers.     

Ticagrelor. Acute coronary syndromes: nothing new

Several revascularisation methods are effective in patients with acute coronary syndromes. Standard antithrombotic treatment combines heparin and aspirin during the acute phase, followed by long-term aspirin therapy. The only proven advantage of adding clopidogrel is for patients who undergo angioplasty with stenting. Ticagrelor is an antiplatelet drug belonging to a different chemical class than clopidogrel. Its chemical structure resembles that of adenosine. Ticagrelor has been authorised in the European Union for patients with acute coronary syndromes, in combination with aspirin. Clinical evaluation is mainly based on a double-blind randomised trial comparing ticagrelor + aspirin versus clopidogrel + aspirin in 18 624 patients who underwent angioplasty (64% of patients), coronary artery bypass grafting (10%), or who received medical treatment only. Half of the patients were treated for at least 9 months. After 12 months of treatment, compared to the clopidogrel group, overall mortality appeared to be significantly lower in the ticagrelor group (4.5% versus 5.9%), along with cardiovascular mortality (4.0% versus 5.1%). Symptomatic myocardial infarction was also less frequent (5.8% versus 6.9%), but not stroke (about 1.4% in both groups). Ticagrelor did not statistically significantly reduce overall mortality in patients who had angioplasty with stenting, but stent thrombosis was less frequent than with clopidogrel (2.9% versus 3.8%). In combination with aspirin, ticagrelor provoked more bleeding than clopidogrel, based on the definition used in the trial (16.1% versus 14.6%). In contrast, the rate of major bleeding was similar in the two groups (11.5%), including fatal bleeding (0.3%). The adverse effect profile of ticagrelor resembles that of adenosine in certain respects. For example, dyspnoea was more frequent with ticagrelor than with clopidogrel (13.8% versus 7.8%), as were conduction disorders and ventricular pauses at the beginning of treatment (5.8% versus 3.6%). There were also more cases of hyperuricaemia and elevated creatinine levels with ticagrelor. Ticagrelor and its active metabolite are substrates and inhibitors of cytochrome P450 isoenzymes and P-glycoprotein, creating a risk of multiple pharmacokinetic interactions. Pharmacodynamic interactions are also likely to occur, especially with antithrombotic agents and heart-rate-lowering drugs. In practice, in patients with an acute coronary syndrome treated with angioplasty and stenting, and who are also receiving aspirin, it remains to be shown whether the harm-benefit balance of ticagrelor is clearly better than that of clopidogrel. In other settings, there is no firm evidence that ticagrelor is better than aspirin alone.     

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.     

Clopidogrel: new preparation. An alternative to aspirin

(1) Clopidogrel, an antiplatelet drug chemically similar to ticlopidine, is marketed in France for secondary prevention of thrombotic complications in patients with a history of myocardial infarction, ischaemic stroke or peripheral arterial disease. (2) Marketing authorisation was based mainly on the CAPRIE trial, a study that involved 19,815 patients. In this trial of secondary cardiovascular prevention, clopidogrel was slightly more effective than aspirin (325 mg/day) according to a statistical analysis of a combined end point (ischaemic stroke, or myocardial infarction, or death of vascular causes). The difference was more marked in the subgroup of patients with obstructive arterial disease of the lower limbs. (3) Clopidogrel was well tolerated in this trial. The only adverse effects more frequent on clopidogrel than on aspirin were rash and diarrhoea. (4) Clopidogrel showed no haematological toxicity, an adverse effect that restricts the use of ticlopidine. (5) The lack of long-term follow-up in real clinical settings prevents any meaningful estimation of the safety profile or of the risk of drug interactions.     

Secondary stroke prevention: inside the vessels and beyond

Cerebral ischaemic stroke is frequently a relapsing, if not chronic, disease. Its incidence is age-dependent, and with the ageing of society the need for effective therapies increases.This review considers current and alternative hypotheses underlying secondary prevention of stroke. Currently, secondary stroke prevention is widely practiced with aspirin (acetylsalicylic acid), a drug that has been in use for more than 100 years. Newer drugs such as ticlopidine and clopidogrel have subsequently been developed, but their efficacy barely surpasses that of aspirin. Other drugs used in secondary stroke prevention include HMG-CoA reductase inhibitors and antihypertensive agents.The endovascular paradigm has shaped the thinking of secondary stroke prevention, and aspirin, ticlopidine and clopidogrel are known as 'platelet inhibitors'; however, their pharmacological and clinical effects are not fully explained within the platelet paradigm. Moreover, in recent years, reduction of stroke incidence has also been observed with HMG-CoA reductase inhibitors, regardless of their lipid-lowering effects. Hence, current understanding needs to be supplemented by considering mechanisms beyond platelet inhibition. Evidence has shown that aspirin, ticlopidine and clopidogrel share neuroprotective properties not explained by the platelet paradigm and that are reminiscent of a preconditioning effect. This neuroprotective mechanism is also shared with HMG-CoA reductase inhibitors.     

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.     

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.     

A benefit-risk assessment of agents used in the secondary prevention of stroke.

Stroke is a major cause of morbidity and mortality. Full assessment of stroke or transient ischaemic attack (TIA) patients is required to identify all risk factors and apply appropriate secondary preventative strategies. Antiplatelet therapies are effective in the secondary prevention of ischaemic stroke and can be justified despite adverse effects such as gastrointestinal haemorrhage. Aspirin (acetylsalicylic acid), aspirin plus dipyridamole, ticlopidine and clopidogrel are all of value but their adverse effect profiles vary significantly. Combinations of antiplatelet agents may offer additional benefit but not all combinations have been studied in stroke patients. Anticoagulation with agents such as warfarin is effective with coexisting atrial fibrillation and other conditions predisposing to cardioembolic stroke. Antihypertensive agents have been extensively studied in the primary prevention of stroke; however, relatively few trials of antihypertensive agents in the secondary prevention of stroke are available. The incidence of adverse effects of antihypertensive agents is relatively low and the benefit-risk profile would tend to favour their use in the secondary prevention of stroke. Recent studies of ACE inhibitors have identified an important role for these agents in the secondary prevention of stroke even in those who are normotensive and in those who have had a haemorrhagic stroke. The incidence of serious adverse effects with ACE inhibitors appears relatively low. Lipid-lowering agents may have a role to play in certain groups of patients with stroke. The incidence of adverse effects is relatively low with HMG-CoA reductase inhibitors. Cigarette smoking is an important risk factor for stroke and evidence is available that smoking cessation does reduce the individual's risk of stroke. Pharmacological agents are available to help smoking cessation. In patients with diabetes mellitus, intensive regimens with insulin and oral hypoglycaemic agents have so far not definitively been shown to reduce the incidence of macrovascular complications such as stroke. Tight glycaemic control has been shown to improve microvascular complications such as retinopathy, nephropathy and neuropathy and hence this is reason enough to advocate the use of these agents. Future developments in the treatment of diabetes may help. Secondary prevention of stroke has improved greatly over the past decade and hopefully will continue to improve. The use of pharmacological agents available currently and in the future will be clarified and refined as further clinical trials report.     

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。     

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.