The basis of platelets: platelets and atherothrombosis: an understanding of the lack of efficacy of aspirin in peripheral arterial disease (PAD) and diabetic patients

Platelet activation subsequent to the adhesion of platelets to the vascular wall results in the release of mediators that promote platelet aggregation, which plays a pivotal role in the development of the polyvascular atherosclerotic disease that can be referred to by the acronym 'ATIS' (AtheroThrombosIS). The currently available antiplatelet drugs used to prevent vascular events in patients with cardiovascular disease, including peripheral arterial disease (PAD), include aspirin and thienopyridines such as clopidogrel. These drugs decrease platelet aggregability, each of them by inhibiting a different pathway of platelet activation and recruitment. Aspirin acts by inhibiting thromboxane A2 (TXA2) formation through the inhibition (acetylation) of cyclo-oxygenase. On the other hand, thienopyridines suppress the platelet aggregation adenosine diphosphate (ADP) pathway by inhibiting the platelet P2Y12 subtype of the ADP receptor. The results of the large ATT (Antithrombotic Trialists' Collaboration) meta-analysis of published clinical studies on aspirin, reported in 2002, confirmed the previous meta-analysis and major trials that treatment with aspirin (mixed with other antiplatelet agents in these large meta-analyses) can prevent vascular events in high-risk patients with cardiovascular disease. However, it must be stressed that specifically in PAD patients no significant effect of aspirin was demonstrated in a more recent meta-analysis. This was also the case for primary and secondary prevention in diabetic patients. In keeping with these observations, neither a five-year follow-up study of Japanese diabetic patients in the JPAD (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes) study, a seven-year follow-up study of UK diabetic patients with PAD in the POPADAD (Prevention of Progression of Arterial Disease and Diabetes) study, nor a very recent Scottish study in the same population of diabetics with PAD revealed a significant beneficial effect for aspirin in preventing ischaemic events. This failure may be a consequence of more rapid recovery of platelet aggregability following each dose of aspirin in these PAD or diabetic populations, with the accelerated platelet turnover resulting in a condition of aspirin resistance. Results of the large scale CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) trial that evaluated clopidogrel in patients with cerebral infarction, myocardial infarction or PAD have found clopidogrel to be significantly more effective than aspirin in preventing ischaemic events in patients with PAD. Furthermore, a subgroup analysis of the study has confirmed the efficacy of clopidogrel in diabetic patients with PAD, showing a significant reduction of events in clopidogrel-treated, compared with aspirin-treated, diabetic patients. These results are also likely to be attributable to the greater frequency of aspirin resistance in aspirin-treated patients in these populations (diabetics and/or PAD). Platelets, through activation and aggregation, have an important role in ATIS. However, although antiplatelet therapy with low-dose aspirin has been reported to prevent vascular events in high-risk patients with cardiovascular disease, recent studies in patients with PAD or diabetes mellitus have failed to support the efficacy of aspirin in preventing vascular events in these patient populations. In contrast, clopidogrel appears to be a useful antiplatelet agent in the prevention of vascular events in patients with PAD or diabetes.     

ADP Receptor Antagonism

ADP is one of the most important mediators of both physiologic hemostasis and thrombosis. Development and utilization of agents that block ADP receptors on the platelet membrane, namely thienopyridines, has represented a major advancement for treatment of patients undergoing percutaneous coronary interventions and those with acute coronary syndromes. Currently, clopidogrel, a second-generation thienopyridine that inhibits the ADP P2Y(12) receptor, represents the treatment of choice, in addition to aspirin, for the prevention of stent thrombosis. Further, long-term adjunctive use of this ADP P2Y(12) receptor antagonist is also associated with improved clinical outcomes in high-risk patients, and represents the standard of care for these patients. Despite the unambiguous clinical benefit associated with clopidogrel, accumulating experience with this drug has also led to identification of some of its drawbacks, which are related to inadequate platelet inhibition with standard dosage regimens as well as to its irreversible antiplatelet effects. This has led to the questioning of currently recommended clopidogrel dosage regimens as well as to the development of novel and more potent ADP P2Y(12) receptor antagonists, some of which are also reversible agents. Numerous studies are currently ongoing with the objective of demonstrating how more potent platelet inhibition using higher loading and maintenance dose regimens of clopidogrel or novel ADP P2Y(12) receptor antagonists - such as prasugrel, ticagrelor (AZD 6140) and cangrelor - will affect clinical outcomes. This article reviews the current knowledge of platelet ADP P2Y(12) receptor antagonism and the projected developments in this field.     

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.     

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.     

Resistance to antiplatelet drugs: what progress has been made?

Introduction: Despite well-documented efficacy, recurrent thrombotic event occurrences, particularly stent thrombosis, have been repeatedly demonstrated in stented patients treated with aspirin and clopidogrel. The latter observation stimulated the close scrutiny of the pharmacodynamic effects of clopidogrel and revealed the ‘wide variability’ and the phenomenon of ‘antiplatelet resistance’. High on-treatment platelet reactivity to ADP (HPR) during clopidogrel therapy is an independent risk factor for ischemic event occurrences in post-percutaneous coronary intervention (post-PCI) patients. Recent observational studies demonstrated a link between low on-treatment platelet reactivity to bleeding. The concept of a ‘therapeutic window’ of P2Y₁₂ receptor reactivity associated with both ischemic event occurrence (upper threshold) and bleeding risk (lower threshold) has been proposed.

Areas covered: An update on and a brief review of the current knowledge on antiplatelet resistance were presented. Evidence available from studies evaluating aspirin resistance and high and low on-treatment platelet reactivity to ADP during P2Y₁₂ receptor blocker therapy was collected from a selective literature search.

Expert opinion: The available evidence indicates that HPR is an independent risk factor for post-PCI ischemic event occurrences. The therapeutic window concept for the P2Y₁₂ receptor blocker therapy may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome.     

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.     

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.     

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

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

Failure of Aspirin to Prevent Atherothrombosis

Aspirin (acetylsalicylic acid) reduces the odds of serious atherothrombotic vascular events and death in a broad category of high risk patients by about one-quarter. The mechanism is believed to be inhibition of thromboxane biosynthesis by inactivation of platelet cyclo-oxygenase-1 enzyme. However, aspirin is not that effective; it still fails to prevent the majority of serious vascular events. Mechanisms that may account for the failure of aspirin to prevent vascular events include non-atherothrombotic causes of vascular disease, non-adherence to aspirin therapy, an inadequate dosage, alternative ‘upstream’ pathways of platelet activation (e.g. via stimulation of the ADP, collagen or thrombin receptors on platelets), aspirin-insensitive thromboxane biosynthesis (e.g. via monocyte cyclo-oxygenase-2), or drugs that interfere with the antiplatelet effects of aspirin. Genetic or acquired factors may further modify the inhibitory effects of aspirin on platelets (e.g. polymorphisms involving platelet-associated proteins, increased platelet turnover states). Identification and treatment of the potential causes of aspirin failure could prevent at least another 20% of serious vascular events (i.e. over and above those that are currently prevented by aspirin). There is currently no role for routine laboratory testing to measure the antiplatelet effects of aspirin. Clinicians should ensure that patients at high risk of atherothrombosis (>3% risk over 5 years) are compliant with aspirin therapy and are taking the correct dosage (75–150 mg/day). Patients who cannot tolerate aspirin, are allergic to aspirin, or have experienced recurrent serious atherothrombotic events whilst taking aspirin, should be treated with clopidogrel, and patients with acute coronary syndromes benefit from the combination of clopidogrel plus aspirin. Future research is required to standardize and validate laboratory testing of the antiplatelet effects of aspirin and to identify treatments that can both improve these laboratory measures and reduce the risk of future atherothrombotic events.     

Antiplatelet Agents for the Prevention of Cardiovascular Disease in Diabetes Mellitus

Patients with diabetes mellitus (DM) have accelerated atherothrombotic disease of coronary, cerebral, leg, and other vessels. The major cause of death is cardiovascular, and the risk for a myocardial infarction (MI) in a patient with DM who has never had a MI is the same as a nondiabetic individual who has already had one. In this paper, we review the major reasons for a prothrombotic state in patients with DM: alterations in the intrinsic coagulation and fibrinolytic systems and many abnormalities of platelet function. Increased platelet thromboxane production as well as activation of platelet receptors for fibrinogen and or adenosine diphosphate (ADP) are often present, and can be treated with aspirin (acetylsalicylic acid) and/or receptor blockers. Review of the major primary prevention trials in DM indicates that a significantly reduced risk for MI or major cardiovascular events may be obtained by enteric-coated aspirin, 81–325 mg/day. There is emerging consensus that this is recommended strategy in adult (aged >30 years) patients with DM who are at high vascular risk. Surveys suggest that this includes virtually every patient with type 2 DM in the US, as well as many patients with complicated type 1 DM. These recommendations are also appropriate for secondary prevention. Data supporting the use of clopidogrel as an alternative drug in the case of aspirin allergy or other contraindications are reviewed. Evidence is presented in support of using aspirin plus clopidogrel in acute coronary syndromes (ACS), and a meta-analysis of six trials of platelet glycoprotein (GP) IIb/IIIa inhibitors and aspirin in diabetic patients with ACS establishes this regimen as an effective choice. Although bleeding episodes are more common with combined antiplatelet therapy for ACS than for aspirin alone, the benefit of a significant reduction in 30-day mortality appears to outweigh the risk of major bleeding. It is concluded that major advances in our understanding of the prothrombotic state in DM have been made. Evidence from controlled clinical trials supports the use of enteric-coated aspirin, 81–325 mg/day, as a primary and a secondary prevention strategy in adults with DM with high vascular risk. In ACS, combination therapy with aspirin plus clopidogrel or alternatively, aspirin plus a platelet GP IIb/IIIa inhibitor is supported by prospective trial data. These approaches should be added to the other multifactorial preventive strategies directed at lowering the risk for major vascular events in patients with DM.     

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。     

Dual antiplatelet therapy for prevention of recurrent ischemic events.

The advantages of dual antiplatelet therapy over monotherapy in preventing recurrent ischemic events are examined. Atherosclerosis is an insidious systemic process involving multiple vascular beds, including the cerebral, coronary, and peripheral arteries. Atherosclerotic plaque rupture is one of the inciting events in the progression of platelet activation, aggregation, and thrombus formation. Patients with any clinical manifestation of atherosclerosis are vulnerable to others in different vascular beds since the disease develops throughout the vasculature, and different vascular events have common predisposing risk factors. Ischemic coronary heart disease and cerebrovascular disease are two of the three most frequent causes of death in the United States. The efficacy of aspirin in the secondary prevention of myocardial infarction (MI) and stroke has been demonstrated in numerous trials. While dipyridamole has not been linked with a greater odds reduction than aspirin in the development of MI, stroke, and vascular death, ticlopidine and clopidogrel have been associated with a greater reduction in the development of acute MI, stroke, and vascular death than aspirin. Clinical trials evaluating the efficacy and safety of combination antiplatelet therapy in the prevention of recurrent ischemic events are ongoing. The rationale for using a combination of two mechanistically different antiplatelet agents is supported by ex vivo and clinical studies. Inhibition of platelet aggregation and thrombus formation is enhanced with dual antiplatelet therapy. Combination antiplatelet regimens with different mechanisms of action to inhibit multiple sites in the thrombotic pathway may further improve long-term clinical outcomes. Dual antiplatelet therapy may have advantages over monotherapy in the prevention of recurrent ischemic events.     

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.     

Significance of aspirin and clopidogrel resistance in patients undergoing percutaneous coronary interventions

Dual antiplatelet therapy (aspirin plus clopidogrel) is mandatory in patients treated with coronary stent implantation. This strategy is highly effective in prevention of stent thrombosis until its struts are covered with endothelium. However, a substantial number of patients still suffer from recurrent ischemic coronary events despite adequate antiplatelet therapy. These events fall into three categories: stent thrombosis, in stent restenosis and events related to other non-stented coronary lesions. Some data suggest that beside other local and systemic factors resistance to aspirin and clopidogrel may be a possible cause of stent thrombosis and ischemic events in patients after coronary interventions. Several mechanisms of antiplatelet drug resistance have been reported including poor compliance, interactions with other drugs, genetic polymorphism or increased platelet turnover. More research is needed to adequately assess the clinical significance and prognostic value of antiplatelet drug resistance detected by laboratory tests in patients undergoing percutaneous intervention. We review published data on mechanisms and the clinical significance of aspirin and clopidogrel resistance in patients after coronary interventions.     

Interactions between clopidogrel and proton pump inhibitors: a review of evidence

Clopidogrel is a thienopyridine, which inhibits the platelet P2Y adenosine diphosphate (ADP) receptor termed P2Y(12). It is taken as a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) isoenzymes. In addition, esterases shunt the majority of clopidogrel to an inactive pathway, whilst the remaining prodrug requires two separate CYP-dependent oxidative steps. PPIs might diminish the antiplatelet effects and the clinical effectiveness of clopidogrel possibly through inhibition of CYP2C19 and CYP3A4 isoenzymes. Treatment with clopidogrel and aspirin decreases recurrent cardiovascular events after an acute coronary syndrome. However, an inherent increment of major bleeding is also associated with antiplatelet therapy, as well as dyspepsia with aspirin. Also, major bleeding has been associated with high risk for ischemic events and mortality. For this reason, a proton pump inhibitor (PPI) is often co-prescribed to reduce the risk of gastrointestinal tract bleeding, but its concomitant use might reduce the inhibitory effect of clopidogrel on platelet aggregation. Nevertheless, doubts exist about the possible interaction of concomitant PPI use that may reduce the inhibitory effect of clopidogrel on platelet aggregation. Indeed, there is some controversy with regard to the true risk of cardiovascular adverse events arising from a potential drug-drug interaction between clopidogrel and PPI. In this article, we will review the current status and controversies in relation to a possible interaction between clopidogrel and PPIs.     

Antiplatelet therapy in cerebrovascular disorders

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

Clopidogrel hydrogen sulphate for atrial fibrillation

Introduction: Atrial fibrillation is a common cardiac rhythm abnormality with a considerable cardiovascular disease burden worldwide. It is an independent major risk factor for stroke. Stroke prevention with anticoagulation or antiplatelet agents has been an important area of clinical research. Warfarin is the most widely used antithrombotic therapy for stroke prophylaxis for last several years, and now dabigatran (150 mg b.i.d.) is more effective than warfarin in stroke prevention in individuals at increased of stroke. In addition, several studies have evaluated the efficacy of clopidogrel for stroke prophylaxis either alone or in combination with aspirin.

Areas covered: This review summarizes the key findings of the trials looking at the efficacy of clopidogrel in stroke prevention. A literature search was performed using PubMed and Google Scholar. The trials that evaluated the efficacy of clopidogrel in preventing atherothrombotic events or stroke were also included.

Expert opinion: Clopidogrel prevents more vascular events, including stroke, in patients with a recent myocardial infarction, stroke or peripheral vascular disease than aspirin. Combination of clopidogrel and aspirin provides a greater reduction of stroke than aspirin or clopidogrel monotherapy, but at an increased risk of bleeding. Dual antiplatelet therapy (clopidogrel and aspirin) is inferior to warfarin in primary stroke prevention for patient with atrial fibrillation and thus should be considered for stroke prophylaxis only in patients ineligible for warfarin. However, with the advent of newer agents, like direct thrombin inhibitors and Factor Xa inhibitors, the role of antiplatelet therapy for stroke prevention in atrial fibrillation remains unclear.     

氯吡格雷联合阿司匹林治疗短暂性脑缺血发作的疗效及安全性研究

目的探讨氯吡格雷联合阿司匹林在短暂性脑缺血发作中的疗效及安全性。方法选取60例TIA患者,随机分为两组,对照组予小剂量阿司匹林,观察组则在对照组予氯比格雷,比较两组的疗效及用药安全性。结果观察组总有效率达90.0%,与对照组的总有效率73.3%比较,差异有统计学意义(P<0.05)。观察组治疗后发作时间均较治疗前及对照组缩短更明显,差异有统计学意义(P<0.05)。结论氯吡格雷联合阿司匹林治疗短暂性脑缺血发作能明显减少发作时间,改善患者的临床症状,安全性好,值得推广和应用。     

Anti-platelet therapy and aspirin resistance - clinically and chemically relevant?

Platelets play a central role in the pathogenesis of the atherothrombosis which ultimately causes myocardial infarction, stroke and peripheral vascular disease. Commonly used oral anti-platelet drugs include aspirin (an irreversible inhibitor of cyclo-oxygenase), clopidogrel (an ADP receptor antagonist), other thienopyridines such as ticlopidine and prasgruel, and dipyridamole (an inhibitor of adenosine reuptake and platelet phosphodiesterase). Newer agents are in development and one, ticagrelor, a reversible ADP receptor antagonist has shown promise. Despite their proven benefit, recurrent vascular events still occur in those taking anti-platelet drugs. This has led to the concept of anti-platelet resistance, most commonly aspirin resistance as this drug is the cornerstone of most regimens. The causes of aspirin resistance are numerous but potential mechanisms include lack of patient adherence, non COX-1 mediated thromboxane A2 synthesis, increased activity of alternate platelet activation pathways, interference of aspirin action by other drugs and probably pharmacogenetic factors. Measurement of platelet response to aspirin is made possible using a number of in-vitro laboratory assays of platelet function which include measurement of thromboxane A2 metabolites as well as newer point-of-care assays of platelet aggregation. The phenomenon of aspirin resistance is important as it raises the possibility of developing strategies to identify those who respond best to a particular anti-platelet regimen, or to development of newer anti-platelet therapies to which more patients respond. This review discusses important aspects of aspirin resistance both in terms of clinical medicine, alternative anti-platelet strategies, and the potential to overcome its various causes.     

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.