Triple antithrombotic therapy in patients with atrial fibrillation undergoing coronary artery stenting: hovering among bleeding risk, thromboembolic events, and stent thrombosis

Dual antiplatelet treatment with aspirin and clopidogrel is the antithrombotic treatment recommended after an acute coronary syndrome and/or coronary artery stenting. The evidence for optimal antiplatelet therapy for patients, in whom long-term treatment oral anticoagulation is mandatory, is however scarce. To evaluate the safety and efficacy of the various antithrombotic strategies adopted in this population, we reviewed the available evidence on the management of patients receiving oral anticoagulation, such as a vitamin-k-antagonists, referred for coronary artery stenting. Atrial fibrillation is the most frequent indication for oral anticoagulation. The need of starting antiplatelet therapy in this clinical scenario raises concerns about the combination to choose: triple therapy with warfarin, aspirin, and a thienopyridine being the most frequent and advised. The safety of this regimen appeared suboptimal because of an increased risk in hemorrhagic complications. On the other hand, the combination of oral anticoagulation and an antiplatelet agent is suboptimal in preventing thromboembolic events and stent thrombosis; dual antiplatelet therapy may be considered only when a high hemorrhagic risk and low thromboembolic risk are perceived. Indeed, the need for prolonged multiple-drug antithrombotic therapy increases the bleeding risks when drug eluting stents are used. Since current evidence derives mainly from small, single-center and retrospective studies, large-scale prospective multicenter studies are urgently needed.     

Antithrombotic therapy in patients treated with oral anticoagulation undergoing coronary artery stenting. An expert consensus document with focus on atrial fibrillation

Dual antiplatelet treatment with aspirin and clopidogrel is recommended after coronary stenting (PCI-S). There is scant evidence defining optimal post-PCI-S antithrombotic therapy in patients with atrial fibrillation (AF) in whom oral anticoagulation (OAC) is mandated. To evaluate the safety and efficacy of the antithrombotic strategies for this population, we conducted a systematic review of the available evidence in patients treated with OAC undergoing PCI-S. AF was the most frequent indication for OAC. Post-PCI-S management was highly variable, and triple therapy with warfarin, aspirin, and clopidogrel was the most frequent and effective combination. Warfarin plus aspirin alone was not sufficiently effective in the early period after PCI-S and should not be prescribed. While acknowledging that the optimal antithrombotic treatment for patients with AF at medium or high thromboembolic risk undergoing PCI-S is currently undefined, triple therapy of warfarin, aspirin, and clopidogrel is currently recommended, although associated with an increased risk of major bleeding. Restrictive use of drug-eluting stent is also recommended, due to the need for prolonged multiple-drug antithrombotic therapy which may increase the bleeding risk. Whether the combination of warfarin and clopidogrel (without aspirin) will preserve efficacy and produce less bleeding is an important issue still needing to be addressed.     

Rivaroxaban (Xarelto) for acute coronary syndrome

The standard antithrombotic therapy for treatment of patients with acute coronary syndrome (ACS) is dual antiplatelet therapy with aspirin and clopidogrel (Plavix) or another thienopyridine, plus a parenteral anticoagulant while the patient is hospitalized, followed by antiplatelet therapy alone after discharge. The addition of the oral anticoagulant warfarin (Coumadin, and others) to dual antiplatelet therapy is generally not recommended for this indication because of fluctuations in its anticoagulant effect and the risk of bleeding. A recently published trial found that addition of a low dose of the oral anticoagulant rivaroxaban (Xarelto) to antiplatelet therapy after discharge reduced the risk of major cardiovascular events without increasing the incidence of fatal bleeding.     

房颤合并冠状动脉粥样硬化性心脏病的抗栓治疗策略

房颤和冠状动脉粥样硬化性心脏病均为常见疾病。缺血性卒中和系统性血栓栓塞是房颤患者的主要不良预后,抗栓治疗可显著减少血栓栓塞事件风险;另一方面,抗血小板治疗又是冠状动脉粥样硬化性心脏病治疗的关键。当房颤患者合并冠状动脉粥样硬化性心脏病时,需要通过抗凝联合抗血小板治疗以减少卒中及缺血性心脏事件的发生。然而,联合抗栓策略会增加出血并发症的风险。如何平衡出血和血栓风险,以及如何在不同口服抗凝药物和抗血小板药物中进行选择,制定最优的抗栓方案是临床工作面临的挑战。     

Potential role of oral anticoagulants in the treatment of patients with coronary artery disease: focus on dabigatran

The pharmacologic management of patients with high-risk coronary artery disease consists of aspirin and a P2Y₁₂ receptor inhibitor. Chronic oral anticoagulation with warfarin is the major treatment strategy to attenuate thromboembolism or stroke in patients with deep vein thrombosis, pulmonary embolism, heart failure and atrial fibrillation. A substantial percentage of the latter group of patients have coronary artery disease and may require stenting with long-term dual antiplatelet therapy in addition to therapy with warfarin to reduce arterial ischemic events in addition to stroke. These new oral anticoagulants have been developed for long-term therapy to overcome the limitations of warfarin. Dabigatran is a direct thrombin inhibitor and its role in patients with acute coronary syndrome is being explored.     

Antithrombotic medication for stroke prevention

This article provides the reader with an overview and an update on antithrombotic stroke-prevention strategies. Relevant journals were hand-searched by the authors to compile a broad, but not comprehensive, summary of innovative and clinically relevant studies. These findings were then summarized to provide an expert opinion on selected fields of medical stroke prevention. We conclude that aspirin, clopidogrel or dipyridamol–aspirin are the cornerstone therapies in patients with noncardioembolic stroke. More potent antiplatelet drugs or the combination of aspirin and clopidogrel prevent more ischemic events but also lead to more bleeding complications. For secondary stroke prevention in patients with atrial fibrillation, oral anticoagulation is more effective than aspirin or the combination of aspirin and clopidogrel.     

Combination of clopidogrel and aspirin for reduction of vascular events in patients with atrial fibrillation

Evaluation of: The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N. Engl. J. Med. 360(20), 2066–2078 (2009).

Atrial fibrillation (AF) is the most common heart rhythm disorder and increases the risk for stroke by fivefold. Therefore, antithrombotic pharmacological agents are recommended and commonly used to prevent stroke and thromboembolic vascular events in patients with AF. Although, aspirin is an effective and acceptable agent for low-risk patients, oral vitamin K antagonists anticoagulants have superiority over aspirin in patients with AF who are at high risk for complications. However, given several practical impediments, vitamin K antagonists may not be suitable for certain high-risk patients with AF. It is not unusual for clinicians to encounter situations where selection of appropriate pharmacotherapy options for stroke prevention may be quite challenging in high-risk patients with AF who are deemed to be unsuitable candidates for oral anticoagulants. It may be hypothesized that, in such a situation, a combination of clopidogrel with aspirin, possibly by their additive effect in the prevention of platelet-mediated thrombosis may be used effectively instead of oral anticoagulants. In this article, we have discussed this issue and review one of the recently published Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) studies, the ACTIVE-A trial, in which the treatment strategies utilizing ‘clopidogrel plus aspirin’ and ‘aspirin alone’ in patients with AF who were at increased risk for stroke and for whom therapy with a vitamin K antagonist was considered unsuitable were compared.     

Apixaban: an Oral Direct Factor-Xa Inhibitor

Apixaban is a highly selective, reversible, direct factor Xa inhibitor that inhibits both free factor Xa and prothrombinase activity, and clot-bound factor Xa activity. A predictable pharmacokinetic profile, multiple pathways of elimination, an improved bleeding profile relative to warfarin with a lack of other significant adverse events, and no need for routine anticoagulation monitoring make apixaban appealing. Apixaban is currently approved for venous thromboembolism (VTE) prophylaxis in total hip replacement and total knee replacement in Europe, Brazil, Australia, and New Zealand, and has been pre-approved in Indonesia and the Philippines. Completed phase 3 trials suggest that apixaban has promise as an alternative to aspirin and warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. Results of a large phase 3 trial were the first to show a survival benefit for this new class of oral anticoagulants in patients with atrial fibrillation. In patients with acute coronary syndrome, apixaban added to dual antiplatelet therapy with aspirin and clopidogrel resulted in unacceptably high rates of major bleeding. In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin, and was associated with significantly more major bleeding events than enoxaparin. Ongoing phase 3 trials will provide data regarding the efficacy and safety of apixaban for treatment of acute deep vein thrombosis and pulmonary embolism.     

Long-term care after percutaneous coronary intervention: focus on the role of antiplatelet therapy

Arterial wall injury caused by percutaneous coronary intervention (PCI) triggers transient platelet activation and mural thrombosis; these effects are superimposed on the preexisting platelet hyperreactivity associated with underlying atherothrombosis. Platelet activation has been implicated in the major complications of PCI: acute and subacute thrombosis and restenosis. Antithrombotic and anticoagulant therapy minimizes thrombotic complications after PCI. Aspirin plus a thienopyridine (ticlopidine or clopidogrel) is more effective than aspirin plus heparin and extended warfarin therapy in preventing periprocedural ischemic events and subsequent stent thrombosis and results in less major and minor bleeding. Dual antiplatelet therapy with aspirin and clopidogrel (the preferred thienopyridine because of its superior hematologic safety) is recommended for at least 4 weeks to prevent subacute stent thrombosis with bare-metal stents and 3 to 6 months to prevent late-stent thrombosis with drug-eluting stents. Coronary atherothrombosis is a diffuse vascular disease, and reduction of the risk of future ischemic events requires strategies that extend beyond the focal treatment of stenotic lesions. Optimal long-term care after PCI requires aggressive systemic pharmacotherapy (antiplatelet agents, statins, beta-blockers, and angiotensin-converting enzyme Inhibitors) in conjunction with therapeutic lifestyle changes (smoking cessation, weight reduction, dietary measures, and exercise). In this context, dual antiplatelet therapy (aspirin plus clopidogrel) is recommended for at least 12 months after PCI for prophylaxis of future atherothrombotic events.     

口服抗凝剂在非瓣膜性房颤伴慢性肾功能不全患者中的应用进展

口服抗凝剂可有效降低房颤患者的卒中风险, 但房颤伴慢性肾功能不全患者的卒中和出血风险却明显升高, 给抗凝治疗带来困难。非维生素K拮抗剂类口服抗凝剂疗效和安全性不劣于传统的抗凝剂华法林, 无需定期监测国际标准化比值, 患者依从性更好。然而, 非维生素K拮抗剂类口服抗凝剂均不同程度地通过肾脏代谢, 其在非瓣膜性房颤伴慢性肾功能不全患者中的应用尚存在争议。本文对非瓣膜性房颤伴慢性肾功能不全患者口服抗凝剂的应用进展进行综述, 以期为临床实践提供参考。     

Anticoagulation and antiaggregation in cardiac patients

Aspirin treatment for primary prevention is safe and useful at an annual coronary event risk > or = 1.5%. Both aspirin and clopidogrel reduce the rate of cardiovascular events in patients with coronary disease. Clopidogrel in addition to aspirin further reduces cardiovascular events, but is associated with and increased bleeding risk. Recent studies in patients with myocardial infarction suggest that treatment with either coumadin or with coumadin and aspirin are both at least as effective than treatment with aspirin alone. Thromboembolism and bleeding during therapeutic anticoagulation are the major chronic risks for patients with native valvular heart disease and mechanical prosthetic valves. The recommendations for the prevention of thromboembolic events and bleeding complications are discussed and recommended intensity of antithrombotic therapy are outlined. Key points of the guidelines for managing patients with atrial fibrillation are summarised.     

Managing Antithrombotic Therapy in Patients With Both Atrial Fibrillation and Coronary Heart Disease

Purpose

Atrial fibrillation (AF) and coronary heart disease (CHD) commonly occur together. Previous consensus guidelines were published before the wide availability of novel oral anticoagulants (NOACs) and newer P2Y₁₂ antiplatelet agents. We examine recent evidence to guide management in 3 categories of patients with AF and CHD: patients with stable CHD, nonstented patients with recent acute coronary syndrome, and patients with a coronary stent requiring dual-antiplatelet therapy.

Methods

We conducted a literature search by evaluation of PubMed and other data sources including international meeting reports. We critically reviewed recent clinical trial and relevant registry evidence to update European and US consensus documents.

Findings

Oral anticoagulation with warfarin or NOACs is required to prevent embolic stroke in AF, and antiplatelet therapy is insufficient for this purpose. Antiplatelet therapy using monotherapy with aspirin is the standard of care in stable CHD. Dual-antiplatelet therapy with aspirin and clopidogrel or a new P2Y₁₂ inhibitor (dual-antiplatelet therapy) is needed to reduce coronary events after an acute coronary syndrome or after percutaneous coronary intervention. Combinations of these agents increase the risk of bleeding, and limited clinical trial evidence suggests that withdrawal of aspirin may reduce bleeding without increasing coronary events.

Implications

Available clinical trials and registries provide remarkably little evidence to guide difficult clinical decision making in patients with combined AF and CHD. In patients on triple antithrombotic therapy with vitamin K antagonists, aspirin, and clopidogrel, a single clinical trial indicates that withdrawal of aspirin may reduce bleeding risk without increasing the risk of coronary thrombosis. It is unclear whether this evidence applies to combinations of NOACs and newer P2Y₁₂ inhibitors. Clinical trials of combinations of the newer antithrombotic agents are urgently needed to guide clinical care.     

Antiplatelet therapy for secondary prevention of acute coronary syndrome, transient ischemic attack, and noncardioembolic stroke in an era of cost containment

Physicians are aware of the profound impact of oral antiplatelet therapy for secondary prevention of acute coronary syndrome (ACS), transient ischemic attack, and noncardioembolic stroke. Numerous clinical studies have compared the benefits of aspirin (ASA) alone with those of combination therapy with extended-release dipyridamole or with those of clopidogrel, with or without ASA, for secondary stroke prevention; and of ASA monotherapy compared with ASA plus clopidogrel combination therapy for secondary prevention in various ACS populations. More recently, ASA plus prasugrel has been compared with ASA plus clopidogrel in a high-risk ACS population. However, given the different treatment modalities and methods used in the various trials, it is difficult to make generalizations as to which therapy is most effective with the lowest risk of bleeding. Further complicating physician's decision making are cost considerations, particularly with the newer oral antiplatelet agents, which are considerably more expensive than ASA. This review provides a brief overview of the clinical data on each of the currently marketed oral antiplatelet agents and the available data on cost-effectiveness for the secondary prevention of ACS, transient ischemic attack, and noncardioembolic stroke.     

肠溶阿司匹林和氯吡格雷在抗血小板治疗中上消化道出血的相关危险因素分析

[目的]分析肠溶阿司匹林和氯吡格雷在抗血小板治疗中导致上消化道出血的相关危险因素.[方法]回顾性分析2009年2月至2013年5月冠状动脉硬化性心脏病患者98例的临床资料,其中58例患者采用肠溶阿司匹林联合氯吡格雷抗血小板治疗（观察组）;其余40例患者则单独采用肠溶阿司匹林或氯吡格雷抗血小板治疗（对照组）,比较两组患者的上消化道出血发生率并分析统计导致患者上消化道出血的相关危险因素.[结果]观察组上消化道出血发生率8.6％明显高于对照组2.5％（P＜0.05）;Logistic回归分析发现高龄（＞60岁）、服用时间超过3个月、有既往消化道出血病史和抗血小板药物联合使用是抗血小板治疗中增加上消化道出血的危险因素.[结论]抗血小板药物联合使用增加患者上消化道出血的几率,同时对高龄、服药时间较久及既往有上消化道出血史的患者应高度警惕上消化道出血的可能.     

Antiplatelet therapy in acute coronary syndromes: the emergency physician's perspective

The platelet plays a central role in the pathogenesis of coronary thrombosis after atherosclerotic plaque rupture, and its active inhibition forms a cornerstone of the management of acute coronary syndromes (ACS). Early treatment with clopidogrel in addition to aspirin is more effective than aspirin alone in reducing recurrent ischemic events in patients presenting with ACS, and is a useful adjunct to percutaneous coronary intervention, especially with stenting. There is a potential for increased bleeding complications in patients on clopidogrel therapy who subsequently undergo urgent coronary artery bypass graft surgery. Consequently, many emergency physicians withhold clopidogrel treatment until it is clear that urgent coronary artery bypass graft surgery will not be required. The potential untoward effects seem to be minimized by withholding antiplatelet therapy 3-5 days before surgery. Intravenous glycoprotein (GP) IIb/IIIa receptors inhibitors are also particularly useful in patients who undergo percutaneous coronary intervention, and may have some utility in the medical management of patients with high-risk non-ST-segment elevation ACS, starting in the emergency department. For patients presenting to the emergency department with ACS, the benefits and risks of initiating clopidogrel or GP IIb/IIIa inhibitor therapy need to be considered on an individual basis.     

Preventing ischemic stroke. Current approaches to primary and secondary prevention

Preventing stroke is the most important strategy for reducing the cost of this disease. Management of modifiable risk factors, especially hypertension and Oral anticoagulation with warfarin for selected high-risk patients with nonvalvular atrial fibrillation. Carotid endarterectomy for selected patients with carotid artery stenosis greater than 60%. Regular physical exercise. Treatment with statin medications for patients who have coronary artery disease with or without hyperlipidemia. Routine use of antiplatelet medication has no proven role in primary stroke prevention, although aspirin is often prescribed for patients with vascular risk factors who have not yet had symptoms of either stroke or ischemic heart disease. The major strategies for secondary stroke prevention are: Appropriate evaluation to identify the mechanism of the initial stroke. Carotid endarterectomy for patients with symptomatic carotid artery stenosis of 50% or more. Oral anticoagulation with warfarin for patients with nonvalvular atrial fibrillation. Use of various antiplatelet agents, including aspirin, ticlopidine, clopidogrel, and the combination of aspirin and slow-release dipyridamole. Whether treatment of risk factors reduces the risk of secondary stroke is currently being evaluated in clinical trials.     

Dual antiplatelet therapy in patients with diabetes mellitus: special considerations

Diabetes mellitus (DM) is associated with higher rates of ischemic events in patients suffering from an acute coronary syndrome and/or undergoing percutaneous coronary intervention, thereby underscoring the need to develop more effective and specific strategies toward mitigation of the cardiovascular burden associated with DM. Platelet hyper-reactivity associated with DM is a central contributor to this high risk, since platelets are the key players in the processes underpinning atherothrombotic complications, thereby representing a specific therapeutic target. Oral dual antiplatelet therapy comprising the combination of aspirin (75–100 mg) and clopidogrel (75 mg) has been, for years, the standard antithrombotic treatment for patients with acute coronary syndrome and/or undergoing percutaneous coronary intervention. However, despite the use of this therapy, high rates of cardiovascular events continue to occur, especially within the cohort of patients with DM. These observations could be in part explained by an inadequate clopidogrel-induced platelet inhibition, which has been associated with impaired clinical outcomes. In particular, DM is associated with a higher prevalence of reduced responsiveness to standard dual antiplatelet therapy, which may contribute to the higher rates of ischemic events seen in this population. These findings have prompted the identification of alternative dual antiplatelet treatment regimens to optimize platelet inhibition. The present review aims to describe benefits and limitations of oral dual antiplatelet therapy with aspirin and clopidogrel (75 mg) and to appraise the evidence regarding alternative oral dual antiplatelet therapy regimens, which include higher doses of aspirin and clopidogrel or the combination of prasugrel or ticagrelor with aspirin, focusing on patients with DM.     

Anti-thrombotic therapy for non-rheumatic atrial fibrillation

Recent randomized trials of antithrombotic therapy in non-rheumatic atrial fibrillation have helped to clarify the benefits of warfarin and aspirin. Low-risk patients (normotensives aged <60 with normal left ventricular function) have a small risk of thromboembolic events and are unlikely to benefit significantly from anticoagulants, but may benefit from aspirin with little increase in risk of bleeding. High-risk patients (>75 years, impaired left ventricular function, previous thromboembolism and/or associated conditions such as hypertension and diabetes mellitus) have an increased risk of thromboembolism, and benefit from long-term anticoagulant therapy to a greater degree than with aspirin, although at a risk of increased bleeding complications.      

Acute ischemic coronary artery disease and ischemic stroke: similarities and differences

Although acute myocardial infarction (MI) and acute ischemic stroke share similarities, physicians need to recognize important differences in pathophysiology and how these differences affect acute treatment and prevention to provide optimal patient care. Potential causes of acute ischemic stroke are substantially more heterogeneous than for acute MI, and available acute therapies are substantially more limited. In acute ischemic stroke patients, diagnostic evaluation is paramount in determining eligibility for treatment with the only approved therapy, which must be administered within 3 hours after stroke onset. For patients having acute MI, reperfusion therapy by percutaneous intervention or thrombolytic drug therapy is well established. Because atherosclerosis is a common pathway to acute MI and acute ischemic stroke, modifying associated known risk factors is required for primary and secondary prevention of both conditions. Pharmacologic therapies recommended for secondary prevention include beta-blockers and angiotensin-converting enzyme inhibitors for MI, oral anticoagulants for stroke, and statins and antiplatelet agents for both conditions. Aspirin is recommended for preventing recurrence of both MI and stroke; agents inhibiting the adenosine diphosphate pathway of platelet activation, such as ticlopidine and clopidogrel, are also beneficial. Recent studies suggest the benefits associated with adding aspirin to clopidogrel do not outweigh the significant increase in bleeding risk. The synergistic effects of aspirin plus extended-release dipyridamole make this combination twice as effective than aspirin alone in secondary prevention of ischemic stroke. An ongoing study is directly comparing the combination of aspirin plus extended-release dipyridamole with clopidogrel for the prevention of recurrent stroke.