Clopidogrel

Dual antiplatelet therapy with acetylsalicylic acid (aspirin) and clopidogrel is a guideline-recommended standard of care for patients with acute coronary syndromes (ACS) and those who undergo percutaneous coronary intervention (PCI). Despite a large body of clinical evidence obtained from randomized clinical trials and patient registries supporting the efficacy and safety of aspirin plus clopidogrel therapy in these patients, questions concerning the optimal use of dual antiplatelet therapy remain. Widely debated topics pertaining to dual antiplatelet therapy in patients with ACS or undergoing PCI include (i) the appropriate clopidogrel loading dose; (ii) the optimal time to initiate the clopidogrel loading dose; (iii) the optimal duration of dual antiplatelet therapy following ACS or PCI; (iv) impact of variability of platelet response on patient outcomes; and (v) the role of other recommended and emerging P2Y₁₂ antagonists. This review discusses these ongoing controversies regarding the optimal use of dual antiplatelet therapy with aspirin and clopidogrel in patients with ACS or those undergoing PCI.     

Platelet P2Y12 receptor inhibition by thienopyridines: status and future

Thienopyridines have a well-established role in the treatment of coronary artery disease, especially in the setting of acute coronary syndromes and percutaneous coronary interventions. Ticlopidine, the first FDA-approved thienopyridine, was shown to be effective in reducing coronary events in high risk patients, but the original enthusiasm was hampered by concerns about its serious bone marrow toxicity. Clopidogrel a second generation thienopyridine with lesser side effects, is not only at least as effective as ticlopidine, but in combination with a low dose of aspirin, has been demonstrated to reduce the risk of major cardiovascular events in acute coronary syndrome patients in large-scale, randomised trials. Recent studies have highlighted major flaws in clopidogrel pharmacokinetics due to its delayed onset of action, and much attention has been devoted to the phenomenon of clopidogrel ‘resistance’. Among the novel, third generation thienopyridines, prasugrel as compared to clopidogrel has demonstrated lower inter-patient response variability and a reduced incidence of ischaemic events, but at an increased risk of major bleeding. Currently, several studies are continuing to test new direct P2Y12 receptor antagonists, such as cangrelor and AZD6140, characterised by a faster reversal of platelet inhibition.     

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.     

Clopidogrel

? Clopidogrel is a selective inhibitor of ADP-induced platelet aggregation.

? A large, multicenter, randomized study in 12562 patients with acute coronary syndromes without ST-segment elevation demonstrated that treatment with clopidogrel (loading dose of 300mg followed by once daily treatment with 75mg) in addition to standard therapy including aspirin (75 to 325 mg/day) significantly reduced the risk of the combined endpoint of cardiovascular death, myocardial infarction or stroke compared with treatment with standard therapy. Furthermore, the composite risk of these outcomes or refractory ischemia was also significantly reduced in patients treated with clopidogrel plus aspirin. The effects of clopidogrel were independent of background treatment with cardiovascular medications and/or interventions.

? The risk of severe ischemia, recurrent angina or heart failure was also significantly reduced in patients receiving clopidogrel plus aspirin. There was also a significant reduction in the need for coronary revascularization during the initial period of hospitalization.

? In patients undergoing percutaneous coronary intervention (PCI), the relative risk of the combined endpoint of cardiovascular death, myocardial infarction or urgent target-vessel revascularization within 30 days of the intervention was significantly reduced. Moreover, the relative risk of the single endpoint of myocardial infarction within 30 days of PCI was significantly in favor of clopidogrel-treated patients.

? Hemorrhagic events (both major and minor) were significantly more frequent in patients with acute coronary syndromes receiving treatment with clopidogrel plus aspirin than in patients treated with aspirin alone. This was largely attributable to an increased incidence in the rate of gastrointestinal hemorrhage and bleeding at the site of arterial puncture. However, there was no difference between the two groups in the incidence of bleeding episodes that were considered to be life-threatening.

     

Clopidogrel: an updated and comprehensive review

The risk of adverse events in patients with acute coronary syndrome remains substantial despite the use of regular aspirin. The addition of clopidogrel to regular aspirin therapy has been shown to be associated with significantly better outcomes in a variety of clinical settings within the spectrum of acute coronary syndromes. In this article, the evidence and therapeutic implications for the use of clopidogrel in patients with non-ST-elevation and ST elevation acute coronary syndromes is discussed, and also in those undergoing percutaneous coronary intervention. The use of clopidogrel in combination with other antithrombotics in the acute setting is considered, including glycoprotein IIb/IIIa receptor antagonists and direct thrombin inhibitors. Clopidogrel has changed the way in which patients with non-ST-elevation and, more recently, ST elevation acute coronary syndromes are treated.     

Prasugrel

Clinical trials have demonstrated the superior clinical efficacy of dual antiplatelet therapy with a thienopyridine (a P2Y(12) receptor blocker) and aspirin (COX-1 inhibitor) in patients undergoing stenting as well as patients with acute coronary syndromes. However, clopidogrel treatment is associated with a wide response variability and non-responsiveness in selected patients. The latter phenomenon is linked to the occurrence of recurrent ischaemic events including stent thrombosis in the recent studies. Prasugrel is a new thienopyridine derivative that produces more potent platelet inhibition and a rapid onset of action that is associated with irreversible P2Y(12) receptor blockade. The latter properties of prasugrel may provide a superior alternative to clopidogrel, with less response variability and a decreased prevalence of non-responsiveness.     

Prasugrel

Clinical trials have demonstrated the superior clinical efficacy of dual antiplatelet therapy with a thienopyridine (a P2Y₁₂ receptor blocker) and aspirin (COX-1 inhibitor) in patients undergoing stenting as well as patients with acute coronary syndromes. However, clopidogrel treatment is associated with a wide response variability and non-responsiveness in selected patients. The latter phenomenon is linked to the occurrence of recurrent ischaemic events including stent thrombosis in the recent studies. Prasugrel is a new thienopyridine derivative that produces more potent platelet inhibition and a rapid onset of action that is associated with irreversible P2Y₁₂ receptor blockade. The latter properties of prasugrel may provide a superior alternative to clopidogrel, with less response variability and a decreased prevalence of non-responsiveness.     

Incremental Effect of Clopidogrel on Important Outcomes in Patients with Cardiovascular Disease

OBJECTIVES: To quantify the impact of clopidogrel plus aspirin on the individual outcomes of death, myocardial infarction, or stroke in patients with established cardiovascular disease, or in patients with multiple risk factors for vascular disease. BACKGROUND: Randomized trials have demonstrated a reduction in composite outcomes when clopidogrel is added to aspirin therapy in patients with coronary artery disease; however, the magnitude of benefit on individual outcomes is unknown. METHODS: We conducted a meta-analysis on randomized, controlled trials that compared aspirin plus clopidogrel with aspirin plus placebo for the treatment of coronary artery disease. RESULTS: This analysis included five randomized trials (CURE, CREDO, CLARITY, COMMIT, and CHARISMA) in 79 624 patients. The incidence of all-cause mortality was 6.3% in the aspirin plus clopidogrel group versus 6.7% in the aspirin group (odds ratio [OR] 0.94; 95% CI 0.89, 0.99; p = 0.026). The incidence of myocardial infarction was 2.7% and 3.3% (OR 0.82; 95% CI 0.75, 0.89; p < 0.0001), and stroke was 1.2% and 1.4% (OR 0.82; 95% CI 0.73, 0.93; p = 0.002). Similarly, the incidence of major bleeding was 1.6% and 1.3% (OR 1.26; 95% CI 1.11, 1.41; p < 0.0001), and fatal bleeding was 0.28% and 0.27% (OR 1.04; 95% CI 0.76, 1.43; p = 0.79). CONCLUSION: The addition of clopidogrel to aspirin results in a small reduction in all-cause mortality in patients with ST-elevation myocardial infarction and a modest reduction in myocardial infarction and stroke in patients with cardiovascular disease. The overall incidence of major bleeding however is increased, although there is no excess of fatal bleeds or hemorrhagic strokes.     

Antiplatelet Drug Resistance and Drug-Drug Interactions: Role of Cytochrome P450 3A4

Antiplatelet therapy provided pivotal advances in the treatment of cardiovascular disease. Aspirin and thienopyridine, clopidogrel, is currently the treatment of choice in acute coronary syndromes and the prevention of thrombosis after coronary stent implantation. Despite the efficacy of this dual antiplatelet therapy in reduction of adverse coronary events in patients with acute coronary syndromes, complications persist in a subgroup of these patients. Emerging causes of aspirin and clopidogrel resistance may translate to increase risk for recurrent myocardial infarction, stroke, or cardiac related mortality. However, the mechanism of antiplatelet drug resistance remains incompletely characterized, and a sensitive and specific assay of aspirin and clopidogrel effect that reliably predicts treatment failure has not emerged. To date, evidence supporting antiplatelet drug resistance are pharmacokinetic response variability, drug-drug interaction through competitive inhibition a specific enzymatic pathway, genetic variability, and variability in the induction of enzymatic pathway in metabolic activation of prodrugs, like clopidogrel. Further investigation or guidelines are needed to optimize antiplatelet treatment strategies to identify and treat patients resistant to aspirin and/or clopidogrel.     

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.     

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.     

The safety and efficacy of aspirin and clopidogrel as a combination treatment in patients with coronary heart disease

The use of aspirin and clopidogrel in combination has become part of the standard clinical care of patients with coronary artery disease. The use of this combination provides significant benefits compared with the use of aspirin alone in patients with acute coronary syndromes, and in patients treated with percutaneous coronary intervention with stent placement (both bare metal and drug-eluting stents). Clinical trials have demonstrated significant efficacy of this dual therapy; however, there is the potential for significant bleeding complications from the synergistic antiplatelet effects. In total, it appears that when there is vessel injury (mechanical from perctutaneous coronary intervention or a ruptured plaque), dual antiplatelet therapy with aspirin and clopidogrel results in improved outcomes, albeit with a small but significant inherent risk of increased bleeding.     

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.     

Genetics of platelet inhibitor treatment

Dual antiplatelet therapy with aspirin and a P2Y₁₂ receptor antagonist is the standard of care in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes (ACS) because this regimen has markedly decreased the rate of cardiovascular events. The substantial variability in pharmacodynamic response as well as the moderate antiplatelet efficacy of clopidogrel has raised major concerns, since high on-clopidogrel platelet reactivity has consistently been associated with increased risk for ischaemic events in PCI patients. Baseline demographic and clinical variables contributing to the observed variability have been identified. Besides this, research within the past decade has focused on the impact of genetic polymorphisms encoding transport systems or enzymes involved in the absorption and metabolism of these drugs. Loss-of-function polymorphisms in CYP2C19 are the strongest individual variables affecting pharmacokinetics and antiplatelet response to clopidogrel, but explain no more than 5 to 12% of the variability in adenosine diphosphate-induced platelet aggregation on clopidogrel. No genetic variables contributing to clinical outcomes of patients treated with the newer P2Y₁₂ receptor antagonists, prasugrel or ticagrelor, have been identified so far. This review aims to provide an update on the current status of genotype-based personalized therapy with clopidogrel.     

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.     

Defining the optimal dose of aspirin and clopidogrel in acute coronary syndromes. Evaluation of ‘Dose comparisons of clopidogrel and aspirin in acute coronary syndromes’, N Engl J Med 2010;363:930-42

Platelet inhibition is integral to the contemporary management of acute coronary syndromes. While aspirin and clopidogrel are used almost universally in patients treated with an early invasive strategy, the optimal dosing strategy for these drugs remains unknown. In a large randomized trial, the OASIS-CURRENT 7, investigators demonstrated no benefit of a higher dose of aspirin. There was no overall benefit of a higher dose of clopidogrel, although in patients treated with percutaneous coronary intervention a double-dose strategy was associated with a reduction in stent thrombosis and other ischemic events at the cost of an increased risk of bleeding events.     

Antiplatelet therapy with clopidogrel and aspirin in vascular diseases: clinical evidence for and against the combination

The focus of this review is to discuss the hypothesis that justifies the use of dual antiplatelet therapy of aspirin and clopidogrel versus monotherapy with aspirin in arterial vascular disease. By analyzing the CLARITY-TIMI and COMMIT trials, the authors discuss the appropriate use of aspirin plus clopidogrel for patients suffering acute myocardial infarction. In contrast, in the CHARISMA trial, the combination was not justified in stable high-risk patients with documented coronary disease, cerebrovascular disease or symptomatic peripheral artery disease. In two additional cardiovascular studies, the CURE and the PCI-CURE trials, the benefit of the drug combination was evident in those patients who underwent percutaneous coronary intervention and coronary artery bypass grafting. Finally, two focused cerebrovascular studies, the CARESS and the MATCH trials, were analyzed. The CARESS trial demonstrated the clinical benefit of this combination in an acute clinical setting. However, the combination proved to be ineffective in the longer-term MATCH trial. It appears from these large clinical trials that the risk-benefit of dual antiplatelet therapy with aspirin and clopidogrel is justified in high-risk symptomatic patients but not in asymptomatic patients. The exact dose regimen and duration of combination therapy await definition and require careful assessment to optimize the anticoagulant benefit, while minimizing the hemorrhagic risk.     

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: a CURE in acute coronary syndromes?

The standard approach to preventing acute coronary syndromes (ACSs)has been to inhibit platelet aggregation with aspirin and to inhibit blood coagulation with low molecular-weight heparin (LMWH). Even with this combination there is still a substantial short and long-term cardiovascular risk. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial [1] compared clopidogrel plus aspirin against aspirin alone in patients with ACSs. The clopidogrel regimen was a loading dose of 300 mg p.o. followed by 75 mg/day and the recommended dose of aspirin was 75 - 325 mg/day. The first primary outcome was a composite of death from cardiovascular causes, non-fatal myocardial infarction (MI) or stroke and this occurred significantly less often in the clopidogrel than the placebo group (9.3 vs. 11.4%). Although there were more clopidogrel patients with life-threatening bleeding (clopidogrel 2.2%, placebo 1.8%), this represented GI haemorrhages and bleeding at sites of arterial puncture rather than fatal bleeding. This trial suggests a role for clopidogrel in the long-term treatment of ACSs.     

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.