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.     

Monitoring of the antiplatelet drugs effect in patients with coronary artery disease: what is the real clinical impact?

Antiplatelet therapy is used to reduce the risk of ischemic events in patients with cardiovascular disease. The balance of benefits and risks of antiplatelet drugs in coronary artery disease has been evaluated in large-scale randomised trials, however the absolute benefit for an individual patient and a specific platelet-active drug need further evaluation. Several well-conducted studies have demonstrated a substantial inter-individual variability in the platelet responsiveness to drugs. The historical "gold standard" test of platelet function (optical aggregation) has well established limitations for measuring the effect of antiplatelet drugs. Other new tests developed (i.e. PFA-100, VerifyNow) may overcome some of these limitations but they do not correlate well with each other. Despite these unresolved methodological questions, several recent clinical studies, but not all, suggest a significant correlation between antiplatelet resistance status and serious vascular events. In these conditions, laboratory monitoring for antiplatelet therapies raises several questions: (i) the necessity for a consensus on the definition of resistance and on the best test for evaluation of the condition, (ii) the demonstration that biological resistance has clinical significance, and (iii) the clinical impact of adapting the antiplatelet therapy. Therefore, it is not currently appropriate to test patients or to change therapy on the basis of such tests, other than in prospective and adequately powered clinical trials.     

糖尿病状态下阿司匹林抵抗的研究进展

阿司匹林作为抗血小板聚集治疗的“金标准”,在预防心脑血管栓塞性疾病方面起着重要的作用。然而在服用阿司匹林后,并非所有的患者均能获得一致的抗血小板聚集效益。临床上,服用治疗剂量的阿司匹林后仍出现心血管事件的现象被称为“阿司匹林抵抗（aspirinresistance,AR）”。发生阿司匹林抵抗的患者中有相当一部分是糖尿病患者。尽管很多糖尿病患者服用阿司匹林进行心血管疾病的一级预防,但获益很低。对于非糖尿病患者,阿司匹林可以降低41％的心血管事件。而在糖尿病患者中心血管事件发生率仅降低了10％。虽然研究显示糖尿病同阿司匹林抵抗高度相关,然而糖尿病患者中高阿司匹林抵抗发生率的原因还不清楚。本文拟就糖尿病患者的阿司匹林抵抗机制及其逆转方法进行探讨。     

Heterogeneity of Efficacy and Safety of Antiplatelet Therapy in Cardiovascular and Cerebrovascular Disease

The beneficial effects of antiplatelet therapy for secondary prevention in patients with prior cardiovascular or cerebrovascular events, including stroke, transient ischemic attack, and myocardial infarction, have been demonstrated repeatedly over the past decade. It is increasingly apparent that pathophysiologic differences between patients with different types of prior vascular events have an important effect on treatment outcomes. Several large, important trials of antiplatelet therapies, including MATCH, CHARISMA, ESPRIT, and TRITON-TIMI 38, underscore the heterogeneity of the efficacy and safety of antiplatelet agents in patients with recent cerebrovascular disease, compared with patients with recent acute coronary syndromes. Trial data therefore support an individualized approach to antithrombotic therapy for secondary vascular-event prevention that is appropriate for any probable future vascular events and actively reduces the impact of modifiable risk factors common to all vascular events. The potential for benefit in reducing recurrent vascular events must be weighed against the increased risk of bleeding and of patient non-responsiveness to treatment. A number of other factors also need to be considered, including drug interactions, patient compliance, and adverse-effect profiles. Overall, there is now a substantial body of clinical trial evidence that supports the need to carefully individualize antiplatelet therapy and other risk-reducing strategies on the basis of each patient’s pathology and specific needs.     

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.     

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.     

Effects of diabetes on murine lipoproteins and vascular disease

The creation of mouse models that recapitulate human diabetic cardiovascular disease remains a significant challenge. Part of the problem relates to the lack of a clear understanding of the human phenotype. Although improved insulin-treat of hyperglycemia reduces cardiovascular events in patients with type 1 diabetes, similar data are not available in type 2 diabetes. Moreover, whether human vascular disease is increased by hyperglycemia, defective insulin actions, or other factors is not known. Significant progress has been made in developing models of both type 1 and type 2 diabetes in mouse that can be used to study the relationship between hyperglycemia and atherosclerosis. This review describes mouse models that recapitulate specific aspects of diabetic dyslipidemia, hyperglycemia/insulin resistance, and diabetic vascular disease. Overall, the studies have clearly demonstrated that hyperlipidemia is a major driver of atherosclerotic vascular disease in the mouse. The effects of hyperglycemia and insulin resistance on murine atherosclerosis remain uncertain.     

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.     

Acute and long-term antiplatelet therapy

Clinical presentations of atherothrombotic vascular disease, i.e., acute coronary syndromes, cerebrovascular events and events associated with peripheral arterial disease, are the major causes of mortality and morbidity worldwide. Platelet activation and aggregation play an important role in the progression and clinical presentation of atherothrombotic disease, and antiplatelet therapy improves outcome in patients with atherothrombotic vascular disease. Aspirin has been the cornerstone of antiplatelet therapy for many decades, but in recent years, adenosine diphosphate (ADP) receptor antagonists, mainly clopidogrel and ticlopidine, and glycoprotein (GP) IIb/IIIa (integrin alpha IIb beta 3) inhibitors have also shown similar effectiveness. This review briefly summarizes the major clinical trials and recommendations for the efficacy and safety of antiplatelet therapy in patients with established atherothrombotic disease.     

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.     

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.     

新型抗血小板药坎格瑞洛的国外研究现状

新型抗血小板药物坎格瑞洛是首个速效、静脉使用的抗血小板药物,可逆性地与P2Y12受体结合,发挥抗血小板作用,与传统的抗血小板药物氯吡格雷相比,其起效迅速、半衰期短,已广泛应用于需要进行冠脉介入治疗(PCI)的急性冠脉综合征(ACS)患者和心源性休克患者中.CHAMPION试验以患者死亡、心肌梗死和心肌缺血导致的血管重建...     

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.     

Old and New Molecular Mechanisms Associated with Platelet Resistance to Antithrombotics

Current available data show that about 5 to 40% of coronary patients treated with conventional doses of antithrombotic drugs do not display adequate antiplatelet response. Nowadays, aspirin remains the main antiplatelet therapy. However, a significant number of patients show platelet resistance to aspirin therapy, and recurrent thrombotic events occur. Combined antithrombotic therapies with thienopyridines, such as clopidogrel have been used to resolve this problem. However, clopidogrel treatment has been also associated with wide response variability, and non-responsiveness to clopidogrel also occurs in some patients. Therefore, the main question arising about the antithrombotic therapy is why particular patients do not benefit from the therapy and how they might be identified to improve their treatment. Different hypotheses have been suggested, including genetic factors, platelet heterogeneity, non-compliance and others. However, it is probably that many molecular mechanisms involved in platelet resistance to antithrombotic therapies still remains unknown. New technologies, such as proteomics and genetic, are beginning to show new unknown biological biomarkers and molecular mechanisms which may be associated with platelet antithrombotic drug resistance.     

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.     

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.     

PHARMAC and lack of funding for clopidogrel

Clopidogrel is an antiplatelet drug that has been shown in several trials to reduce clinical events such as cardiovascular death, stroke, and myocardial infarction when compared to aspirin in a broad range of patients with atherosclerotic vascular disease. Clopidogrel has also been shown to reduce the same events by 20% when added to aspirin in patients with unstable angina and also in patients undergoing coronary artery stenting. Despite this information being available for 5 to 10 years, guideline recommendations, and the knowledge that 5% of patients have major allergy to aspirin, New Zealand patients have only been able to receive funded clopidogrel for a short period, typically 3 weeks, after coronary artery stenting. We believe this is an example where New Zealanders have been denied treatments, despite a strong evidence-base, by PHARMAC's actions of delaying the funding of new drugs. We need to have a better process whereby New Zealanders can rapidly access new treatments.     

氯吡格雷抵抗原因及对策的研究进展

众所周知,血小板在动脉血栓形成中起到了关键的作用,抗血小板治疗已成为急性冠脉综合征患者预防和治疗动脉血栓的基石。氯吡格雷作为一种新型抗血小板药物,对心血管病的重要辅助治疗作用已得到证实。但研究发现,大约有11%～44%患者对氯吡咯雷表现为低反应甚至无反应,定义为氯吡格雷抵抗。而导致此种抵抗现象的可能原因是氯吡格雷给药剂量不足,个体的基因多态性和药物之间的相互作用等。其主要对策有提高氯吡格雷的给药剂量,联用其它抗血小板药物,减少药物的不良相互作用和采用新型药物等。     

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.     

Is there a role for oral anticoagulant therapy in patients with peripheral arterial disease?

Peripheral arterial disease (PAD) is an index of systemic atherosclerotic disease and is associated with a high incidence of atherothrombotic complications in coronary, cerebral and peripheral arteries. While antiplatelet agents have been extensively evaluated and shown to be effective in reducing the risk of ischemic vascular complications in PAD, few randomised controlled trials have compared the effects of antiplatelet agents with oral anticoagulants in PAD. Oral anticoagulants have been shown to be superior to aspirin only for the prevention of infrainguinal bypass occlusion of venous grafts in case the bypass is at high risk for occlusion. The effectiveness of oral anticoagulants in reducing vascular morbidity and mortality is still uncertain. However, the reduction of ischemic events by oral anticoagulants is associated with an increased risk of bleeding. As a result, oral anticoagulants have a limited role in patients with symptomatic PAD.