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.     

房颤患者华法林抗凝治疗177例

目的回顾性分析心房颤动（房颤）患者的抗凝治疗与卒中情况。 方法调查2015年8月1日至2017年6月30日苏北人民医院住院房颤患者301例的病例资料,记录性别、年龄、主要诊断、合并疾病情况、CHA2DS2-VASc评分、HAS-BLED评分、INR值、华法林剂量、新型口服抗凝剂（NOAC）、阿司匹林使用情况、血栓栓塞事件、出血事件情况,分析抗凝治疗的规范性及其与临床后果的关系。 结果住院房颤患者平均年龄（72±11）岁,房颤类型以非瓣膜型房颤为主,占93.7%（282/301）,58.8%的房颤患者采用口服华法林抗凝治疗,4%接受NOAC抗凝治疗。华法林抗凝治疗组缺血性卒中发生率显著低于未抗凝治疗组差异具有统计学意义（13.0% vs 20.5%,P=0.025）。瓣膜型和非瓣膜型房颤患者华法林抗凝治疗后INR达标（INR 2.0~3.0）的比率分别为15.8%和7.1%。 结论为了达到更好的房颤患者卒中预防效果,需进一步加强华法林抗凝治疗的教育和监测。     

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.     

A review of anticoagulation with warfarin in patients with nonvalvular atrial fibrillation

BACKGROUND: Warfarin therapy has proved safe and effective in a number of randomized controlled trials of stroke prophylaxis in patients with nonvalvular atrial fibrillation (NVAF), reducing the risk of stroke in these patients by two thirds. However, participants in the clinical trials were carefully selected and younger than patients in actual clinical practice. OBJECTIVE: This analysis sought to determine whether the results of clinical trials in patients with NV can be extrapolated to the general population seen in clinical practice. METHODS: A MEDLINE search from 1966 to the present was used to identify observational trials of anticoagulation in patients with NVAF that addressed warfarin use, anticoagulation control, efficacy, and complications. The search terms used were atrial fibrillation and anticoagulation. RESULTS: Although warfarin prophylaxis against stroke in patients with NVAF appeared to be as well tolerated and effective in clinical practice as in clinical trials, it was generally underused, particularly in the elderly. Anticoagulation control was not as good in clinical practice as in clinical trials, although the rates of stroke and major bleeding were comparable. CONCLUSIONS: Judicious use of warfarin, tailored to individual stroke risk, seems to be a reasonable policy. Warfarin therapy increases quality-adjusted survival in patients at high risk for stroke, and it is recommended for medium-risk patients unless their risk of bleeding is high or their quality of life while taking warfarin would be poor. Patients at a low risk for stroke will have equivalent health outcomes and incur lower costs if treated with aspirin. Despite the increased risk of hemorrhage in elderly patients, the net benefit of warfarin therapy is greater in this age group because of the higher risk of stroke. Active involvement of patients and their caregivers in an anticoagulation service setting may improve outcomes of anticoagulation therapy.     

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.     

Left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation

The most severe consequence of atrial fibrillation (AF) is a cardioembolic stroke. The incidence of cardioembolic stroke increases significantly in patients with AF. Although warfarin has been the mainstay of the prevention of cardioembolic stroke, there are several limitations to the use of warfarin that hinder its effectiveness. This article provides the historical development of devices that exclude the left atrial appendage, their effectiveness and potential patient selection, as an alternative to warfarin and the novel oral anticoagulation therapy for the prevention of cardioembolic stroke in patients with AF.     

Novel drugs for oral anticoagulation pharmacotherapy

Long-term anticoagulation with warfarin is the mainstay of treatment in patients with diseases with high thromboembolic potential, such as atrial fibrillation. However, warfarin therapy carries a number of inherent limitations, including slow onset and offset of action, interindividual variability, food and drug interactions, lack of selectivity and a narrow therapeutic window. Recently developed oral anticoagulants that selectively block key factors in the coagulation cascade, with no need for monitoring or dose adjustment, have the potential to replace warfarin in clinical practice. The safety and efficacy of these agents in patients with atrial fibrillation, venous thromboembolisms and acute coronary syndromes have been the object of numerous recent large-scale clinical investigations. This article provides an overview of the evidence currently available on the use of novel, orally available, selective anticoagulants in patients at risk for thromboembolic events.     

Atrial fibrillation: current therapeutic approaches.

Atrial fibrillation is associated with potentially life-threatening strokes. Anticoagulation with warfarin or aspirin reduces the risk of embolic events in patients with chronic atrial fibrillation and mitral valve stenosis or other underlying heart disease. In patients with acute onset of atrial fibrillation, anticoagulation is not necessary before cardioversion. However, in patients with chronic atrial fibrillation, anticoagulation should be started three weeks before cardioversion and continued for four weeks after the return of normal sinus rhythm. Quinidine remains the agent most commonly used for medical cardioversion in patients who are hemodynamically stable. If a patient is hemodynamically unstable or the atrial fibrillation is not corrected with drug therapy, direct-current electrical cardioversion has a high success rate. Antiarrhythmic (quinidine) therapy is often continued indefinitely to help maintain sinus rhythm.     

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。     

A review of the literature on atrial fibrillation: rate reversion or control?

Aims. The aim of this paper is to review the current literature describing the aetiology of atrial fibrillation and to examine the evidence for rate reversion and rate control. Background. Atrial fibrillation is the most commonly seen arrhythmia within the clinical setting. Treatment depends on severity of symptoms, which are predominantly palpitations and shortness of breath. The primary complications from atrial fibrillation are thrombo‐embolic events (such as a pulmonary embolus or stroke). Objectives and methods. A comprehensive literature review on atrial fibrillation, rate reversion and rate control was undertaken to examine the incidence of atrial fibrillation, to review research on management of atrial fibrillation and to determine if rate reversion was superior to rate control in the treatment of atrial fibrillation. Results. Many studies have been carried out to determine the best treatment for this condition. The choices are currently pharmacological and electrical cardioversion in conjunction with anticoagulant therapy. Drug therapies are not without their problems, especially toxicity and the need for close clinical monitoring. Transaesophageal echocardiography has been used to establish the presence of left atrial thrombi and aims to reduce the anticoagulation time and reduce the risk of thrombo‐embolic events. A randomized comparative study of transaesophageal echocardiography and conventional anticoagulation therapy prior to cardioversion demonstrated statistically significant reduction in haemorrhagic events and a shorter time to cardioversion in those in the transaesophageal echocardiography group compared with the conventional group. For those with persistent atrial fibrillation, surgery is an option with valve repair or replacement carried out in conjunction with a bi‐atrial surgical ablation. Conclusions. The management of atrial fibrillation is dependent on many factors and to date there are no proven clinical rationale for rate control or reversion. Relevance to clinical practice. Atrial fibrillation requires immediate attention in order to avoid thrombo‐embolic complications and the use of transaesophageal echocardiography and conventional anticoagulation therapy can significantly reduce these complications.     

Cost-effectiveness of genotype-guided warfarin therapy for anticoagulation in elderly patients with atrial fibrillation

Background: In patients with atrial fibrillation (AF), anticoagulation with warfarin decreases the risk of embolic stroke by >50%. Identification of genetic polymorphisms in enzymes involved in the metabolism of warfarin can partially predict the maintenance dose and thus potentially decrease the incidence of bleeding episodes secondary to warfarin overdose.Objectives: The objectives of this study were to evaluate the potential clinical and economic outcomes of genotype-guided warfarin therapy in elderly patients newly diagnosed with AF and to identify a threshold in bleeding risk at which such therapy may be cost-effective.Methods: A decision tree was designed to represent the medical decision (pharmacogenetic testing or not) and the main clinical outcomes (embolic stroke, bleeding). Event rates of embolic stroke and bleeding complications were based on data from previously published clinical trials and an observational study, respectively; costs were from a third-party payer perspective; and utilities were from the patient perspective. It was assumed that use of pharma-cogenetic testing would not lead the clinician to make any potentially harmful modifications to the regimen.Results: This analysis found that any reduction in major bleeding as a result of pharmacogenetic testing would lead to improved utility. The higher costs of pharmacogenetic testing compared with no testing would be immediately offset by any reduction in major bleeding.Conclusions: In this decision analysis, genotype-guided warfarin therapy for anticoagulation in elderly patients with AF was potentially cost-effective, and its benefits were closely related to efficacy in preventing bleeding events. Clinical trials testing the efficacy of genotype-guided warfarin therapy are warranted.     

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。     

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.     

Should nursing home residents with atrial fibrillation be anticoagulated?

Most long-term care residents with atrial fibrillation would be at high risk for embolic stroke based on age and comorbidities according to the criteria presented here. Additionally, they are theoretically excellent candidates for adjusted-dose warfarin treatment for atrial fibrillation. They are accessible for monitoring and tend to have less dietary variability, a controlled medication list, and supervised medication administration. Balancing these features is at least a moderate risk of severe bleeding from anticoagulation based on age, comorbidities, and polypharmacy. However, studies suggest that even those long-term care residents identified as ideal candidates for anticoagulation may not receive warfarin. Those residents who do receive warfarin may not be anticoagulated within the therapeutic range much of the time. This treatment pattern may expose older adults with a high stroke risk to dying from a cardioembolic stroke or to acquiring functional deficits that make them more dependent and lower their quality of life.     

Case-Based Discussion Regarding Challenges in Patient Selection and Procedural Planning in Left Atrial Appendage Occlusion

Atrial fibrillation (AF) accounts for most embolic strokes, especially in elderly individuals. Although anticoagulation is known to reduce the risk of embolic stroke, a significant proportion of patients have relative or absolute contraindications to anticoagulation. The left atrial appendage has been implicated as the major source of emboli in more than 90% of ischemic strokes in nonvalvular AF. Left atrial appendage occlusion offers an alternative for stroke prevention in patients with an elevated stroke risk (CHADS₂ score ≥2 or CHA₂DS₂-VASc score ≥3) who have a rationale for avoiding long-term oral anticoagulation after a shared decision-making process. However, there remain significant challenges in left atrial appendage occlusion therapy related to patient selection, the procedure itself, and postprocedural patient management decisions. In this review article, we discuss some of these challenges in a case discussion–based approach.     

Personalizing oral anticoagulant treatment in patients with atrial fibrillation

For decades, warfarin has remained the standard oral anticoagulation for stroke prevention in atrial fibrillation (AF). Three novel oral anticoagulants (NOACs) have been recently approved for stroke prevention in non-valvular AF: dabigatran, rivaroxaban and apixaban. Better pharmacological and clinical profiles make these newcomers a preferable alternative over warfarin. Current AF guidelines do not endorse NOACs over warfarin, or one NOAC over another. Indeed, choice of the anticoagulation regimen should be personalized based on the relative efficacy and safety of different agents across subgroups stratified by thrombotic and bleeding risk, as well as on other clinical factors, including anticoagulation control on warfarin, drug interactions, compliance and need for coagulation monitoring. This review appraises i) the randomized evidence on approved NOACs versus warfarin in AF across subgroups stratified by risk factors of stroke and bleeding and by the anticoagulation level reached on warfarin; and ii) clinical factors impacting on the anticoagulation regimen selection.     

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: stroke prevention in patients with atrial fibrillation

It is well recognized that during atrial fibrillation (AF), clots may form in the left atrium. This, in turn, may lead to embolization of the clot, with resulting ischemic stroke or systemic embolism. Also, the presence of AF confers a fivefold increased risk for stroke. AF is the most common and important cause of stroke resulting from any cause. This article considers the risks for and anticoagulation prophylaxis against embolic stroke in patients with AF.     

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.