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。     

Ximelagatran for stroke prevention in atrial fibrillation

Atrial fibrillation is the most common sustained cardiac arrhythmia and the most frequently encountered cause of embolic stroke. Vitamin K antagonists (such as warfarin) have represented the cornerstone of anticoagulation practice for the last 60 years. Although highly effective in preventing thromboembolic events among patients with atrial fibrillation, warfarin therapy is limited by a multitude of potential problems. Hence, warfarin is significantly underused in clinical practice, with only half of warfarin-treated patients actually achieving therapeutic anticoagulation in routine clinical practice. Consequently, there is an overwhelming need for an alternative oral anticoagulant for patients with atrial fibrillation that is safer, more practical and effective. Ximelagatran (Exanta, AstraZeneca) is a novel oral direct thrombin inhibitor that is rapidly converted to the active compound melagatran after oral absorption. It has a low potential for drug interactions, anticoagulation monitoring is not required, and it is administered at a fixed twice-daily dose. The Stroke Prevention using the ORal Thrombin Inhibitor in patients with nonvalvular atrial Fibrillation (SPORTIF) III and V trials have together demonstrated the noninferiority of ximelagatran relative to warfarin for the prevention of stroke and embolic events in atrial fibrillation. Unfortunately, initial optimism has been tempered by serious concerns over its safety data in view of its propensity to cause elevation in liver enzymes.     

Ximelagatran for stroke prevention in atrial fibrillation

Atrial fibrillation is the most common sustained cardiac arrhythmia and the most frequently encountered cause of embolic stroke. Vitamin K antagonists (such as warfarin) have represented the cornerstone of anticoagulation practice for the last 60 years. Although highly effective in preventing thromboembolic events among patients with atrial fibrillation, warfarin therapy is limited by a multitude of potential problems. Hence, warfarin is significantly underused in clinical practice, with only half of warfarin-treated patients actually achieving therapeutic anticoagulation in routine clinical practice. Consequently, there is an overwhelming need for an alternative oral anticoagulant for patients with atrial fibrillation that is safer, more practical and effective. Ximelagatran (Exanta®, AstraZeneca) is a novel oral direct thrombin inhibitor that is rapidly converted to the active compound melagatran after oral absorption. It has a low potential for drug interactions, anticoagulation monitoring is not required, and it is administered at a fixed twice-daily dose. The Stroke Prevention using the ORal Thrombin Inhibitor in patients with nonvalvular atrial Fibrillation (SPORTIF) III and V trials have together demonstrated the noninferiority of ximelagatran relative to warfarin for the prevention of stroke and embolic events in atrial fibrillation. Unfortunately, initial optimism has been tempered by serious concerns over its safety data in view of its propensity to cause elevation in liver enzymes.     

Anticoagulant therapy for atrial fibrillation. Recommendations from major studies.

The role of antithrombotic therapy in reducing thromboembolic complications in patients with chronic atrial fibrillation has been clarified by the results of four major randomized and placebo-controlled trials. Patients with rheumatic heart disease complicated by atrial fibrillation should receive long-term warfarin therapy to reduce the risk of stroke unless an absolute contraindication exists. Patients with nonrheumatic atrial fibrillation should also be treated with low-dose warfarin therapy, especially if high-risk features for thromboembolism exist. In patients who have contraindications to warfarin therapy and in young patients with lone atrial fibrillation or paroxysmal atrial fibrillation, therapy with 325 mg of aspirin a day is preferred. Ongoing trials directly comparing aspirin and warfarin will provide additional insight into the optimal role of these antithrombotic agents in patients with atrial fibrillation.     

老年人房颤与NT-ProBNP、左房大小的关系及抗凝现状分析

目的观察老年人房颤与N-末端脑钠肽前体(NT-proBNP)及左房大小的关系,并分析其抗凝现状。方法对120例老年房颤患者的临床资料进行回顾性分析,包括初发、阵发、持续性、持久性、长期持续性房颤患者的NT-proBNP水平、左房内径和抗凝方法。结果 120例老年房颤患者中,初诊房颤占15.0%,阵发性房颤占30.0%,持续性房颤、持久性房颤、长期持续性房颤占55.0%。使用华法林抗凝治疗占41%,房颤发生脑栓塞占9.1%。持续性房颤、持久性房颤、长期持续性老年房颤的患者NT-proBNP明显高于阵发性、初诊房颤患者,其左房内径明显大于阵发性、初诊房颤患者的左房内径。抗凝治疗中华法林组栓塞事件发生率(2.08%)低于阿司匹林组(13.89%),而两组出血事件发生率无显著差异。结论持续性房颤、永久性房颤、长期持续性房颤在老年患者中占主导地位。房颤时间越长,左房内径越大,NT-proBNP也越高。华法林抗凝效果优于阿司匹林,且获益超过出血风险。     

Ximelagatran: a new antithrombotic option in atrial fibrillation

Treatment strategies in patients with atrial fibrillation typically involve pharmacologic or interventional invasive therapies to suppress the rhythm, control ventricular contraction rates, or prevent thromboembolic complications. Current therapies used for rhythm conversion in atrial fibrillation may have undesirable risks or side effects that limit this approach. Lifelong anticoagulation may be necessary to prevent the formation of thrombus in the left atrial chamber that can travel into the cerebral circulation to cause a stroke. Currently, warfarin is the most commonly prescribed anticoagulant for this purpose. Unfortunately, many patients with atrial fibrillation may not receive warfarin because of the difficulties in dosing and maintaining desirable target goals. The oral direct thrombin inhibitor ximelagatran has several pharmacologic properties that provide a unique and potentially desirable treatment option. Clinical studies have demonstrated that ximelagatran, administered in twice-daily doses of 36 mg, is non-inferior to warfarin for thromboprophylaxis against stroke or systemic embolism in atrial fibrillation. The pharmacology of ximelagatran and clinical trials with its use in atrial fibrillation is reviewed.     

Old and new anticoagulant drugs: a minireview

Abstract The limits of traditional anticoagulants, such as heparin and warfarin, have prompted the search for new agents for prophylaxis and treatment of arterial and venous thromboembolism, including factor Xa and thrombin inhibitors. These agents can be given orally, and their most significant advantage is that no laboratory monitoring is needed. The anti-Xa inhibitor rivaroxaban and the direct thrombin inhibitor dabigatran etexilate are licensed for prophylaxis of venous thromboembolism (VTE) in high-risk orthopedic surgery. They are at least as safe and effective as heparins but much more expensive. Dabigatran, rivaroxaban, and other agents currently in the pipeline of clinical development have the potential to replace warfarin in the two most frequent indications for anticoagulation, i.e. secondary prophylaxis of VTE and atrial fibrillation. Prevention and treatment of coronary artery thrombosis in patients with ischemic heart disease is another area of investigation for the role of new anticoagulants. These drugs have the potential to meet some currently unmet needs of traditional anticoagulants, but available clinical data warrant confirmation and expansion. Lack of specific antidotes for anticoagulation reversal and the high cost are important limitations of their use.     

Acute anticoagulation adjustment in patients with atrial fibrillation at risk for stroke: approaches,strategies, risks and benefits

The acute management of anticoagulation in patients with atrial fibrillation to prevent stroke and other thromboembolic complications includes the use of individualized strategies tailored to the patient and based on the situation (cardioversion, surgeries, dental procedures, cardiac interventions, other invasive procedures and initiation of, or adjustment to, warfarin dosing). The vast range of choices can cause confusion and few randomized controlled clinical trials in this area provide adequate guidance. Chronic anticoagulation management is more straightforward since clinical evidence is ample, randomized clinical trial data provides cogent informaiton and guidelines have been established. Acute management of anticoagulation in patients with atrial fibrillation to prevent thromboembolic complications is often unrecognized but is emerging as a crucial, but challenging, and increasingly complex aspect of the care of patients with atrial fibrillation. This review addresses issues regarding such patients who may be at risk for stroke and require acute adjustments of anticoagulation (in light of, or in lieu of, chronic anticoagulation). Several promising new strategies are considered in light of established medical care. This analysis provides practical recommendations based on available data and presents results from recent investigations that may provide insight into future strategies.     

Acute anticoagulation adjustment in patients with atrial fibrillation at risk for stroke: approaches, strategies, risks and benefits

The acute management of anticoagulation in patients with atrial fibrillation to prevent stroke and other thromboembolic complications includes the use of individualized strategies tailored to the patient and based on the situation (cardioversion, surgeries, dental procedures, cardiac interventions, other invasive procedures and initiation of, or adjustment to, warfarin dosing). The vast range of choices can cause confusion and few randomized controlled clinical trials in this area provide adequate guidance. Chronic anticoagulation management is more straightforward since clinical evidence is ample, randomized clinical trial data provides cogent informaiton and guidelines have been established. Acute management of anticoagulation in patients with atrial fibrillation to prevent thromboembolic complications is often unrecognized but is emerging as a crucial, but challenging, and increasingly complex aspect of the care of patients with atrial fibrillation. This review addresses issues regarding such patients who may be at risk for stroke and require acute adjustments of anticoagulation (in light of, or in lieu of, chronic anticoagulation). Several promising new strategies are considered in light of established medical care. This analysis provides practical recommendations based on available data and presents results from recent investigations that may provide insight into future strategies.     

The Importance of Atrial Fibrillation Burden and the Origin of Device‐Tailored Anticoagulation

The current paradigm for anticoagulation in patients with atrial fibrillation is based upon clinical risk factors for stroke without reference to the frequency or duration (i.e., burden) of atrial fibrillation episodes. In the last decade, increasing evidence derived from device‐based surveillance of atrial fibrillation has suggested that in some patients the burden of atrial fibrillation may be associated with thromboembolic risk. The development of rapidly acting oral anticoagulants and devices with remote monitoring capability has allowed the testing of a strategy of tailored or “pill‐in‐the‐pocket” anticoagulation based upon atrial fibrillation burden.     

心房颤动抗凝治疗进展

心房颤动是临床上最常见的心律失常,增加卒中风险。华法林抗凝效果虽已受到广泛的肯定,但同时存在出血风险、治疗窗狭窄、需要长期监测国际标准化比率以调整药量等缺点。新型口服抗凝药的应用如达比加群、利伐沙班、阿哌沙班可有效预防卒中及血栓栓塞。经皮左心耳封堵术亦可成为预防心房颤动血栓事件的有效替代治疗方式。     

New oral anticoagulants: An emergency department overview

As of September 2013, three new oral anticoagulants (NOACs) are now available for clinical use on the Pharmaceutical Benefits Scheme in Australia. All three are for stroke prevention in atrial fibrillation, and one will also be available for the treatment of deep venous thrombosis and pulmonary embolism. All have been evaluated in large, multicentre randomised clinical trials. These drugs show at least equivalent efficacy to the current standard of care, the vitamin K antagonist warfarin. Major bleeding rates are overall comparable with warfarin, but there is an important reduction in intracranial bleeding of approximately 50% with all NOAC agents. The NOACs are administered in a simple, fixed dose regimen. There are a few clinically important interactions with other medications or diet. Concerns exist about the potential for irreversible bleeding in the small number of patients in which that occurs. This short report will discuss the pharmacology of these agents, the indications for use, aspects of laboratory monitoring and the management of bleeding with these agents.     

Composite end point analyses of non-vitamin K antagonist oral anticoagulants compared with warfarin in patients with atrial fibrillation

Objective: Non-vitamin K antagonist oral anticoagulants (NOACs) have been proposed as alternatives to vitamin K antagonists (VKAs). The aim of this study is to examine the efficacy and safety of NOACs compared with warfarin with composite end points in patients with atrial fibrillation. Methods: This semi-systematic review performed a study of Phase III randomized controlled trials comparing NOACs with vitamin K antagonists (VKAs) in patient with atrial fibrillation using composite end points (combination of various clinical events). The use of composite end points allowed for combining efficacy and safety outcomes, thereby comparing the differences between NOAC and warfarin therapy from a clinical perspective. Results: Treatment with NOAC compared with warfarin was associated with a significant reduction in the sum of stroke or non-CNS, systemic embolism and major bleeding (odds ratio 0.87; 95% CI: 0.82–0.91). Conclusion: Generally, NOACs were associated with a more favorable efficacy and safety profile compared with warfarin with regard to composite end points.     

Atrial fibrillation: New drugs, devices, and procedures

The way atrial fibrillation is managed has changed in recent years. Although new anticoagulants are available and more are coming, they offer only marginal benefit over warfarin (Coumadin) and have the disadvantages that their levels cannot be monitored and that their effect cannot be reversed rapidly if bleeding develops. Attempts should be made To Whom It May Concern: control symptomatic atrial fibrillation, first with antiarrhythmic drugs, then with radiofrequency ablation or with a combination. Ablation can be repeated for fibrillation that persists after the first few months.     

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.      

Combined antiplatelet and anticoagulant therapy: clinical benefits and risks

Summary.  The combination of anticoagulant and antiplatelet therapy is more effective than antiplatelet therapy alone for the initial and long-term management of acute coronary syndromes but increases the risk of bleeding. Antiplatelet therapy is often combined with oral anticoagulants in patients with an indication for warfarin therapy (e.g. atrial fibrillation) who also have an indication for antiplatelet therapy (e.g. coronary artery disease) but the appropriateness of such an approach is unresolved. Anticoagulation appears to be as effective as antiplatelet therapy for long-term management of acute coronary syndrome and stroke, and possibly peripheral artery disease, but causes more bleeding. Therefore, in such patients who develop atrial fibrillation, switching from antiplatelet therapy to anticoagulants might be all that is required. The combination of anticoagulant and antiplatelet therapy has only been proven to provide additional benefit over anticoagulants alone in patients with prosthetic heart valves. The combination of aspirin and clopidogrel is not as effective as oral anticoagulants in patients with atrial fibrillation, whereas the combination of aspirin and clopidogrel is more effective than oral anticoagulants in patients with coronary stents. Whether the benefits of triple therapy outweigh the risks in patients with atrial fibrillation and coronary stents requires evaluation in randomized trials.     

EMILIN2 (Elastin microfibril interface located protein), potential modifier of thrombosis

Warfarin has a long history of benefit and has become the gold standard medication for the prevention of ischemic stroke in patients with atrial fibrillation. Nevertheless, it is far from perfect and there is no doubt that new drugs must be found to replace warfarin. The new oral anticoagulants that are on the market or awaiting approval or under research offer some benefits but not enough to replace warfarin until results of additional studies can show an adequate balance between effectiveness/safety and cost/benefit. There are several issues concerning the new oral anticoagulants. It is essential that the effect of any anticoagulant can be measured in plasma. But to date, there is no test to assess the effect or therapeutic range for the new oral anticoagulants. There is no antidote to neutralize the action of the new drugs in cases of bleeding or when acute surgical intervention is necessary. Dabigatran requires dose adjustment in patients with moderate renal impairment and is contraindicated in patients with severe renal failure. Rivaroxaban should be used with caution in patients with severe renal impairment. Apixaban excretion is also partly dependent on renal function, although the impact of renal insufficiency has not yet been determined. How anticoagulant bridging can be done before surgery has not yet been established. In conclusion, although thousands of patients have been treated in phase III studies, additional data are necessary before conclusions can be drawn on the potential for these new anticoagulant drugs to replace warfarin in patients with atrial fibrillation.     

Anticoagulation for heart failure in sinus rhythm: a Cochrane systematic review

BACKGROUND: Patients with chronic heart failure (heart failure) are at risk of thromboembolic events, and coronary ischaemic events also contribute to the progression of heart failure. Long-term oral anticoagulation is established in certain groups, including patients with heart failure and atrial fibrillation, but there is wide variation in the use of oral anticoagulation in the broader heart failure population. OBJECTIVE: To determine whether long-term oral anticoagulation reduces total deaths and/or major thromboembolic events in patients with heart failure. DESIGN:Systematic review. DATA SOURCES: Reference lists of papers resulting from this search, electronic database searching (MEDLINE, EMBASE, DARE), and abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. Relevant authors of these studies were contacted to obtain further data. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing oral anticoagulants with control or placebo. Non-randomized studies were included, as they may help in assessing side-effects. Other inclusion criteria included duration of treatment > or =1 month, and adults with heart failure due to any underlying cause. Inclusion decisions were duplicated, and disagreement resolved by discussion or a third party. RESULTS: One recent pilot RCT compared warfarin, aspirin and no antithrombotic therapy, but no definitive data have yet been published. Three small prospective studies of warfarin in heart failure were also identified, but were over 50 years old, with methods considered unreliable today: in these, anticoagulation was more efficacious than control in reducing all-cause death (OR 0.64; 95%CI 0.45-0.90) and cardiovascular events (OR 0.26; 95%CI 0.16-0.43). Four retrospective non-randomized cohort analyses and three small observational studies of oral anticoagulation in heart failure included differing populations of heart failure patients, and reported contradictory results. CONCLUSIONS: Limited evidence from randomized trials and observational studies found a reduction in mortality and cardiovascular events with anticoagulants compared to controls. This evidence should be interpreted with caution. Although oral anticoagulation is indicated in certain groups of patients with heart failure (e.g. atrial fibrillation), the available data do not support its routine use in heart failure patients who remain in sinus rhythm.     

Pharmacologic and nonpharmacologic therapies for stroke prevention in nonvalvular atrial fibrillation

Thromboembolism is the crucial cause of ischemic stroke in patients with atrial fibrillation (AF). Anticoagulation therapy with vitamin K antagonists, such as warfarin, have been proven to be effective for stroke prevention in AF. Nonetheless, the use of warfarin may be limited due to increased risk of bleeding, the potential interaction with multiple foods and drugs, and the need for routine coagulation monitoring. Over the last decade anticoagulants, such as dabigatran and rivaroxaban, have been developed and have shown superiority compared to warfarin for preventing stroke in patients with nonvalvular AF in large randomized trials. In addition, on account of the risk of thrombus formation in the left atrial appendage (LAA), many nonpharmacologic approaches have been developed to reduce stroke risk in patients with AF who are not candidates for anticoagulant therapy. Surgical, epicardial, and endovascular techniques for LAA closure are being investigated currently. Both novel pharmacotherapy and nonpharmacologic approaches for stroke prevention will be detailed in this review.     

Recommendations for thromboprophylaxis in the 2012 focused update of the ESC guidelines on atrial fibrillation: a commentary

The objective of this article is to provide a commentary on the recommendations for stroke prevention from the 2012 focused update of the European Society of Cardiology guidelines on the management of atrial fibrillation and the evidence (or lack of it) supporting these recommendations. These guidelines strongly advocate a major clinical practice shift towards initially focusing on the identification of ‘truly low risk’ patients who do not need any antithrombotic therapy. After this initial decision‐making step, effective stroke prevention – that is, oral anticoagulation therapy (whether as well‐controlled adjusted dose warfarin or with one of the novel oral anticoagulants) – could be offered to patients with atrial fibrillation with ≥ 1 stroke risk factors. The 2012 focused update guideline also provides additional guidance on advances in stroke and bleeding risk assessment that are evident since publication of the 2010 guideline, as well as recommendations on the use of the novel oral anticoagulants and the left atrial appendage occlusion devices that have been increasingly used in European clinical practice over the last 2 years.