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.     

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

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

Aspirin in Cardiovascular Disorders

Clinical trials of aspirin (acetylsalicylic acid) for cardiovascular disorders have employed doses defined for other pharmacological effects of the drug (such as analgesic effects). Antioxidant and anti-inflammatory mechanisms with different dose-response relationships may contribute to the clinical effect of aspirin in cardiovascular disease. The optimal aspirin dose remains uncertain. Although the difference between 325 mg/day and 81 mg/day of aspirin sounds trivial, finding an optimal aspirin dose has enormous potential to reduce ischemic events. Large aspirin doses have not been associated with proportionally greater benefit. For patients with ischemic heart disease, overall consensus defines a range between 75 and 160 mg/day for the secondary prevention of myocardial infarction, stroke, and vascular death. Any benefit of aspirin must be measured against its adverse effects, principally gastrointestinal hemorrhage. The potential for adverse bleeding events may be lower with a 81mg dose, while maintaining clinical benefit. Although current aggregate data is reassuring about aspirin administration, it is increasingly clear that existing aspirin studies are insufficient to conclusively determine an optimal aspirin dose. Platelets can be activated by pathways that are not blocked by aspirin, and the dose of aspirin needed to fully suppress platelet aggregation may be higher in some patients as a result. Higher doses of aspirin than are currently used (75-325 mg/day) may be required in these patients to achieve desired antithrombotic effects. Better understanding of aspirin-resistant populations will facilitate identification of patients who require higher aspirin doses or alternative forms of antiplatelet therapy.     

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

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

Clopidogrel: 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.     

Cardioprotective effects and gastrointestinal risks of aspirin: Maintaining the delicate balance

Aspirin is a very useful medication for the prevention of cardiovascular thrombotic events in patients with or those at risk for cardiovascular disease (CVD). Aspirin, however, carries an increased risk for gastrointestinal (GI) injury (e.g., ulceration) and its complications (e.g., hemorrhage), which may be caused by its antiplatelet and gastric mucosal effects. In those with established CVD, aspirin use has been documented to decrease the risk of a first myocardial infarction (MI). Its effects on stroke and vascular death are less conclusive. The use of aspirin in these individuals is recommended only for those whose risk for cardiovascular events (based on coronary risk assessment tools) is sufficiently high that it outweighs the risk for GI complications. Secondary prevention refers to the use of aspirin to prevent cardiovascular events in patients with established CVD such as an MI, stroke, or angina. The use of aspirin in these individuals is recommended based on a documented decrease in future cardiovascular events and mortality. The risk for GI events with aspirin is at least additive to the risk for these events in those who also are receiving therapy with a nonsteroidal anti-inflammatory drug. Patients being treated with aspirin, even at 81 mg/day for cardioprotection, should be assessed for factors that increase the risk for GI injury. Studies have confirmed that co-therapy with a proton pump inhibitor (PPI) or misoprostol decreases the risk for GI injury and complications. Although both classes of such gastroprotective agents are effective, treatment with a PPI is tolerated better, with fewer patients discontinuing the drug because of side effects such as diarrhea.     

Thromboxane Receptors Antagonists and/or Synthase Inhibitors

Atherothrombosis is the major cause of mortality and morbidity in Western countries. Several clinical conditions are characterized by increased incidence of cardiovascular events and enhanced thromboxane (TX)-dependent platelet activation. Enhanced TX generation may be explained by mechanisms relatively insensitive to aspirin. More potent drugs possibly overcoming aspirin efficacy may be desirable. Thromboxane synthase inhibitors (TXSI) and thromboxane receptor antagonists (TXRA) have the potential to prove more effective than aspirin due to their different mechanism of action along the pathway of TXA(2). TXSI prevent the conversion of PGH(2) to TXA(2), reducing TXA(2) synthesis mainly in platelets, whereas TXRA block the downstream consequences of TXA(2) receptors (TP) activation.TXA(2) is a potent inducer of platelet activation through its interaction with TP on platelets. TP are activated not only by TXA(2), but also by prostaglandin (PG) D(2), PGE(2), PGF(2α), PGH(2), PG endoperoxides (i.e., 20-HETE), and isoprostanes, all representing aspirin-insensitive mechanisms of TP activation. Moreover, TP are also expressed on several cell types such as macrophages or monocytes, and vascular endothelial cells, and exert antiatherosclerotic, antivasoconstrictive, and antithrombotic effects, depending on the cellular target.Thus, targeting TP receptor, a common downstream pathway for both platelet and extraplatelet TXA(2) as well as for endoperoxides and isoprostanes, may be a useful antiatherosclerotic and a more powerful antithrombotic intervention in clinical settings, such as diabetes mellitus, characterized by persistently enhanced thromboxane (TX)-dependent platelet activation through isoprostane formation and low-grade inflammation, leading to extraplatelet sources of TXA(2). Among TXRA, terutroban is an orally active drug in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. Despite great expectations on this drug supported by a large body of preclinical and clinical evidence and pathophysiological rationale, the PERFORM trial failed to demonstrate the superiority of terutroban over aspirin in secondary prevention of cerebrovascular and cardiovascular events among ~20,000 patients with stroke. However, the clinical setting and the design of the study in which the drug has been challenged may explain, at least in part, this unexpected finding.Drugs with dual action, such as dual TXS inhibitors/TP antagonist and dual COXIB/TP antagonists are currently in clinical development. The theoretical rationale for their benefit and the ongoing clinical studies are herein discussed.     

Aspirin resistance: disparities and clinical implications

Abstract Aspirin is one of the most widely prescribed drugs for the prevention of thrombosis in patients with vascular disease. Yet, aspirin is unable to prevent thrombosis in all patients. The term "aspirin resistance" has been used to broadly define the failure of aspirin to prevent a thrombotic event. Whether this is directly related to aspirin itself through biochemical aspirin resistance or treatment failure, or if it is because of aspirin's inability to overcome the thrombogenic aspects of the disease process itself, has not been elucidated. This can have dramatic clinical implications for a variety of vascular disease subsets and is cause for concern, considering the high prevalence of aspirin use for both primary and secondary prevention. Disparities exist in the rates of aspirin resistance among certain patient populations, such as women, patients with diabetes mellitus, and those with heart failure, and across clinical conditions, such as cardiovascular and cerebrovascular disease. Clinical trial data from studies observing resistance have revealed that regardless of study size, dose of aspirin, control for drug interactions and adherence, or assay used to measure platelet function, aspirin resistance is associated with an increased risk for adverse events. Although the evidence is mounting, there has yet to be a consensus on the appropriate clinical response to aspirin resistance.     

Aspirin and antiplatelet agent resistance: implications for prevention of secondary stroke

Oral antiplatelet drugs, including aspirin, clopidogrel and extended-release dipyridamole, are widely prescribed for the secondary prevention of vascular events, including stroke. Despite the benefits of antiplatelet therapy, 10?20% of patients experience a recurrent vascular event while taking antiplatelet medication. This article discusses the concept of antiplatelet resistance in general, focusing on aspirin resistance in particular, as a poorly defined cause of recurrent vascular events. Factors such as the lack of a standardized method to diagnose aspirin resistance and a poor clinical correlation with laboratory assays make the treatment of aspirin nonresponders difficult. In addition, there are confounding conditions such as diabetes mellitus that can affect aspirin resistance and determine a different course of treatment for these patients. Other antiplatelet options may also have resistant subpopulations; thus, alternative strategies for the secondary stroke patient must be explored.     

The Role of Oral Antiplatelet Agents in Atherothrombotic Disease

Atherothrombosis involves the mutually interactive dual mechanistic processes of atherosclerotic plaque progression and thrombus formation. In the setting of acute plaque rupture, resultant thrombus formation precipitates acute ischemic events such as acute coronary syndromes (ACS), stroke, and transient ischemic attack. Peripheral arterial disease is also a manifestation of atherothrombotic disease, and occurs both acutely and as a result of underlying disease progression. Atherothrombotic disease is highly prevalent and imposes a substantial burden on the community. For example, coronary artery disease was the single greatest cause of mortality among men and women in the US and accounted for an estimated US dollars 142.1 billion in health costs in 2005. Activated platelets are the prime mediators of arterial thrombus formation. This review discusses the evidence supporting the use of oral antiplatelet agents with other risk prevention strategies in the long-term secondary prevention of atherothrombotic disease. The most widely used oral antiplatelet agent is aspirin (acetylsalicylic acid), and both aspirin and clopidogrel have proven roles in the management of atherothrombotic disease. Clopidogrel should also be used in combination with aspirin in patients with non-ST-segment elevation ACS and those undergoing percutaneous coronary intervention. Recent data suggest that clopidogrel may have a significant role, with or without fibrinolytic therapy, in the immediate management of ST-segment elevation ACS.     

Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders

Ticlopidine inhibits platelet aggregation induced by adenosine diphosphate (ADP) and most other platelet agonists in ex vivo studies of human platelets. The drug also improves other abnormalities of platelet function seen in patients with cerebrovascular disease, peripheral arterial disease, ischaemic heart disease or other conditions involving platelet hyperaggregation. Abnormal platelet activity has been implicated in a variety of clinical conditions in which patients are at high risk of thromboembolic events, and thus the effectiveness of ticlopidine has been investigated in such patients. Since the initial review of the drug appeared in the Journal, data from several large multicentre studies have shown that ticlopidine has a substantial benefit to offer patients who have experienced transient ischaemic attacks or stroke, and in those with peripheral arterial disease or ischaemic heart disease. Ticlopidine reduces the incidence of further stroke, myocardial infarction or vascular death, and is superior to placebo and aspirin in this regard in studies of patients with recent stroke or transient ischaemic attacks, or intermittent claudication. Ticlopidine is equally effective in both men and women and also improves symptoms of claudication in patients with peripheral arterial disease, and appears to reduce anginal pain. Patients with subarachnoid haemorrhage and sickle cell disease have shown some improvement with ticlopidine administration. The drug reduces thromboembolic events and re-stenosis in patients undergoing haemodialysis and cardiac surgery, and appears to prevent the progression of nonproliferative diabetic retinopathy. Ticlopidine in large clinical trials is associated with a higher incidence of adverse effects than placebo and an overall incidence similar to aspirin. Most adverse effects do not require withdrawal of treatment. Gastrointestinal symptoms (particularly diarrhoea) are most common, occurring almost twice as frequently with ticlopidine as with aspirin. Other adverse effects associated with ticlopidine include skin rash, haemorrhagic disorders, and haematological effects; these latter effects require careful monitoring of patients during the initial weeks of therapy. In conclusion, ticlopidine is a valuable addition to the prophylactic treatments available for the management of patients with cerebrovascular disease, peripheral arterial disease or ischaemic heart disease, who present a high risk of thromboembolic events. Although tolerability may be a problem for some patients, the overall benefit conferred by the drug would appear to outweigh this potential disadvantage. Because of its antiplatelet activity, ticlopidine has a promising role in other disorders mediated by platelet dysfunction. However, the precise role of the drug in these additional therapeutic indications awaits clarification with wider clinical experience.     

Antiplatelet and Anticoagulant Therapy for Atherothrombotic Disease: The Role of Current and Emerging Agents

Coronary atherothrombotic disease, including chronic stable angina and acute coronary syndromes (ACS), is associated with significant global burden. The acute clinical manifestations of atherothrombotic disease are mediated by occlusive arterial thrombi that impair tissue perfusion and are composed of a core of aggregated platelets, generated by platelet activation, and a superimposed fibrin mesh produced by the coagulation cascade. Long-term antithrombotic therapies, namely oral antiplatelet agents and anticoagulants, have demonstrated variable clinical effects. Aspirin and P2Y₁₂ adenosine diphosphate (ADP) receptor antagonists have been shown to reduce the risk for thrombosis and ischaemic events by blocking the thromboxane (Tx) A₂ and platelet P2Y₁₂ activation pathways, respectively, whereas the benefits of oral anticoagulants have not been consistently documented. However, even in the presence of aspirin and a P2Y₁₂ receptor antagonist, the risk for ischaemic events remains substantial because platelet activation continues via pathways independent of TxA₂ and ADP, most notably the protease-activated receptor (PAR)-1 platelet activation pathway stimulated by thrombin. Emerging antithrombotic therapies include those targeting the platelet, such as the new P2Y₁₂ antagonists and a novel class of oral PAR-1 antagonists, and those inhibiting the coagulation cascade, such as the new direct factor Xa antagonists, the direct thrombin inhibitors, and a novel class of factor IX inhibitors. The role of emerging antiplatelet agents and anticoagulants in the long-term management of patients with atherothrombotic disease will be determined by the balance of efficacy and safety in large ongoing clinical trials.     

Clopidogrel: a selective inhibitor of platelet ADP receptors

Platelets play a key role in the development of ischemic complications in the arterial circulation. Antiplatelet therapy has proven effective in the treatment and prevention of ischemic events. Numerous clinical studies have confirmed the therapeutic efficacy of aspirin to such a point that this antiplatelet agent has become the gold standard in clinical practice. Clopidogrel is a thienopyridine compound that inhibits platelet aggregation by selectively binding to adenylate cyclase-coupled ADP receptors. Results of a large, double-blind, randomized study (CAPRIE) confirm that administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction or vascular death. The present article highlights the importance of activation of platelets through ADP receptors and reviews the pharmacology and clinical studies of clopidogrel, a selective inhibitor of these mechanisms.     

阿司匹林抵抗机制及防治研究进展

阿司匹林是预防心血管事件的常用药物,但并不是所有服用阿司匹林的患者均能获得满意的疗效,这一现象称之为阿司匹林抵抗。对于它的发生机制及防治方法说法众多,该文根据已有文献报道,进行了综述。     

Aspirin resistance: definitions, mechanisms, prevalence, and clinical significance

Aspirin is the most commonly used therapeutic agent in prevention of vascular ischemic events. Aspirin exerts its antithrombotic effect primarily by interfering with the biosynthesis of thromboxane A2 (TXA2) and inhibition of TXA2 -dependent platelet aggregation. A meta-analysis of secondary prevention trials indicated that aspirin reduced major cardiovascular or cerebral events by 25%. This led to the widespread use of aspirin for prevention of cardiovascular events. However, it appears that aspirin antiplatelet effect is not uniform in all patients and previous studies estimated that 8-45% of the population were aspirin resistant. Furthermore, (i) the optimal dosage of aspirin for complete inhibition of platelet aggregation by physiological agonists (i.e arachidonic acid) is subject to great interindividual variability, (ii) the tests to detect aspirin resistance in vitro are subject to debate and (iii) the mechanisms by which some patients are resistant to aspirin in vitro remain to be determined. Despite these unresolved questions, recent clinical studies provide the reliable evidence that aspirin resistance correlates with confirmed clinical unresponsiveness, highlighting the clinical interest of determining the aspirin inhibitory effects on patients' platelets. In conclusion, discovery of aspirin resistance in individuals might be important in order to devise better anti-platelet strategies and improve our ability to prevent acute thrombotic complication.     

Prothrombotic potential of NSAID in ischemic heart disease

Non-steroidal anti-inflammatory drugs (NSAID) target the enzyme cyclooxygenase (COX) thus affording relieve from pain, inflammation or fever. As COX-dependently formed prostanoids not only mediate signals involved in inflammation and pain, but also regulate important physiological cardiovascular functions, some NSAID have recently been reported to be associated with arterial thrombosis or hypertension. This is in contrast to the well-known antiplatelet effects of low-dose aspirin, but in coherence with the specific effects of some NSAID on prostanoid formation in the vasculature. A correlation between the intake of selective inhibitors of the cyclooxygenase 2 (COX-2) isoform and atherothrombotic events has recently been established. Large retrospective analyses of clinical data have repeatedly shown this effect and in some cases have also observed potential hazards for other, rather non-selective NSAID. This review evaluates potential prothrombotic effects of NSAID in vascular ischemic disease in comparison to low-dose aspirin and selective COX-2 inhibitors and discusses pathophysiological backgrounds for such observations.     

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.     

Resveratrol inhibits aggregation of platelets from high-risk cardiac patients with aspirin resistance

Up to 20% of serious vascular events in high-risk vascular patients is attributable to a failure of aspirin (ASA) to suppress platelet aggregation. Resveratrol is a cardioprotective phytoestrogen that can inhibit platelet aggregation in animal models. We hypothesized that resveratrol can also inhibit aggregation of platelets from ASA-resistant (ASA-R) patients. Thus, platelet-rich plasma was isolated from ASA-sensitive (ASA-S) and ASA-R patients (aspirin resistance was defined as higher-than-expected aggregation to collagen and epinephrine [>/=40%] after oral treatment with 100 mg/d ASA). Aggregation to adenosine diphosphate (ADP; 5 and 10 mumol/L), collagen (2 mug/mL), and epinephrine (10 mumol/L) in the absence and presence of resveratrol (10 mol/L) was measured by optical aggregometry. Maximal aggregation to 5 mumol/L ADP was only slightly affected by resveratrol. Similar results were obtained using 10 mumol/L ADP. Maximal aggregation of ASA-R platelets to collagen was significantly decreased by resveratrol, whereas resveratrol had only marginal effects in ASA-S platelets. Similar results were obtained with epinephrine as well. Collectively, resveratrol effectively inhibited collagen- and epinephrine-induced aggregation of platelets from ASA-R patients, which may contribute to its cardioprotective effects in high-risk cardiac patients.     

1例甲氨蝶呤治疗银屑病合并脑梗塞患者的病例分析

目的 通过对1例甲氨蝶呤治疗银屑病合并脑梗塞患者的病例进行分析,为临床治疗过程中药物相互作用、不良事件的判断和治疗提供思路。方法 临床药师参与1例给予甲氨蝶呤治疗后出现严重黏膜炎、骨髓抑制的银屑病合并脑梗塞患者的治疗过程,临床药师建议暂停服抗血小板药阿司匹林,密切监测血常规、凝血功能等情况。结果 医师采纳临床药师建议,嘱患者暂停服阿司匹林,使用白介素-11升血小板的同时,密切监测血常规、凝血功能、血压控制情况。10 d后,病情基本恢复,血象正常,安排出院。结论 临床药师在临床工作中,应积极发挥应有作用,与临床医师通力协作,积极开展药品不良事件监测工作,详细询问患者既往用药史,采取有效的干预措施,共同促进合理用药,提升治疗效果。     

Indobufen: an updated review of its use in the management of atherothrombosis

Indobufen inhibits platelet aggregation by reversibly inhibiting the platelet cyclooxygenase enzyme thereby suppressing thromboxane synthesis. Clinical trials have evaluated the efficacy of oral indobufen in the secondary prevention of thromboembolic complications in patients with or without atrial fibrillation, in the prevention of graft occlusion after coronary artery bypass graft (CABG) surgery and in the treatment of intermittent claudication. In the secondary prevention of thromboembolic events indobufen 200 mg once or twice daily was significantly more effective than no treatment although not as effective as ticlopidine 250 mg once or twice daily, during 1-year nonblind clinical trials. Compared with placebo, indobufen 100 mg twice daily significantly reduced the risk of stroke in a small 28-month trial of patients at increased risk of systemic embolism (50% had atrial fibrillation). Furthermore, in patients with nonrheumatic atrial fibrillation and a recent cerebrovascular event enrolled in the 1-year Studio Italiano Fibrillazione Atriale (SIFA) trial, indobufen 100 or 200 mg twice daily was as effective as warfarin (titrated to produce an international normalised ratio of 2.0 to 3.5) in the secondary prevention of thromboembolic events; the incidences of the composite end-point of major vascular events (10.6 vs 9.0%) and recurrent stroke (5 vs 4%) were similar between treatments. In 2 large 12-month trials, the Studio Indobufene nel Bypass Aortocoronarico (SINBA) and the UK study, indobufen 200 mg twice daily was as effective as aspirin (acetylsalicylic acid) 300 or 325 mg plus dipyridamole 75 mg 3 times daily in the prevention of early and late occlusion of saphenous grafts in patients after CABG surgery. Indobufen 200 mg twice daily for 6 months significantly improved walking capacity compared with placebo, and caused a more pronounced improvement in both pain-free and total walking distance than either pentoxifylline 300 mg or aspirin 500 mg twice daily in separate 6- and 12-month studies of patients with intermittent claudication. Oral indobufen up to 200 mg twice daily was generally well tolerated in >5000 patients with atherosclerotic disease. Adverse events (predominantly gastrointestinal), reported by 3.9% of patients, rarely required withdrawal from treatment. In the SINBA and UK studies, fewer adverse events and less gastrointestinal bleeding were seen with indobufen than with aspirin plus dipyridamole treatment, while in the SIFA trial, noncerebral bleeding events occurred significantly less frequently in indobufen than warfarin recipients (0.6 vs 5.1%) and major bleeding events occurred only in the warfarin group. Conclusion: Indobufen is as effective as warfarin in the prophylaxis of thromboembolic events in at risk patients with nonrheumatic atrial fibrillation, as aspirin plus dipyridamole in the prevention of CABG occlusion and may be more effective than aspirin or pentoxifylline in improving walking capacity in patients with intermittent claudication. The improved tolerability profile of indobufen (favourable gastric tolerance and reduced haemorrhagic complications) compared with aspirin 300 to 325 mg 3 times daily or warfarin, in addition to a similar antiplatelet effect, suggests indobufen can be considered a drug with a definite role in the management of atherothrombotic events. In particular, indobufen may be an effective alternative for at risk patients with nonrheumatic atrial fibrillation in whom anticoagulant therapy is contraindicated or who are at higher risk of bleeding.