新型口服抗凝药在非瓣膜性房颤合并脑血管病中的研究进展

抗凝治疗被认为是非瓣膜性心房颤动(房颤)患者缺血性卒中预防策略的基石。新型口服抗凝药相较于传统口服抗凝药华法林, 具有起效快、半衰期短、药物相互作用少以及无需频繁监测凝血指标等优点, 被普遍应用于预防治疗中, 大幅降低了非瓣膜性房颤患者缺血性卒中的发生风险。但对于合并颅内动脉粥样硬化狭窄、急性缺血性卒中、颅内出血、颅内微出血等增加卒中及出血风险的非瓣膜性房颤患者, 临床抗凝治疗及启动时间的选择无疑是个挑战。本文将对新型口服抗凝药在合并常见脑血管病的非瓣膜性房颤患者中的应用进行综述, 为临床治疗与预防提供参考。     

新型口服抗凝药在伴有慢性肾脏疾病的非瓣膜性房颤患者中抗凝的研究进展

心房颤动是常见的心律失常疾病,持续48 h即可形成血栓,血栓脱落可导致动脉栓塞,其中90%是缺血性脑卒中,而慢性肾脏疾病可进一步增加房颤患者的卒中和出血风险。因此,在伴有慢性肾脏疾病的非瓣膜性房颤患者中的抗凝尤为重要。华法林用于肾功能不全的房颤患者虽可减少血栓栓塞的发生率,但是随着肾功能的恶化,华法林可增加出血的风险,且维持国际标准化比值（INR）在目标范围的时间非常困难。与华法林相比,新型口服抗凝药物能显著地降低卒中、颅内出血和死亡风险。然而新型口服抗凝药物在轻度、中度、重度,甚至血液透析房颤患者的应用仍存在争议。     

牛国栋:房颤消融围手术期抗凝策略怎么选?为你支招!

正导管消融给房颤患者带来获益的同时,也增加了卒中等栓塞事件的风险,为减少血管栓塞事件进行抗凝治疗又会导致患者出血风险增加。因此,对房颤消融患者如何进行围手术期抗凝管理,一直是目前临床上十分棘手的重点难点问题,随着非维生素K拮抗剂口服抗凝药(NOACs)在非瓣膜性房颤患者抗凝治疗应用的逐渐增多,其与传统抗凝药物的对比性研究进展如何?该如何看待两者的优势和劣势?中华医学会心电生理与起搏分会青年委员会副主任委员、阜外医     

口服抗凝药在心房颤动合并慢性肾脏病患者应用的研究进展

慢性肾脏病(CKD)在房颤患者中非常普遍,是卒中和死亡的危险因素,其发病机制十分复杂。无论是房颤还是CKD,均与脑卒中、心血管疾病发病率和病死率增加相关。两者亦具有密切的双向关系,且常常同时存在。相较于单独的房颤或CKD患者,同时患有两种疾病的患者脑卒中风险、血栓栓塞风险和病死率较高[1]。因此,如何有效治疗该类人群一直是当今医学界关注的热点。目前华法林用于肾功能不全的房颤患者虽可减少血栓栓塞的发生率,但其起效慢、出血风险高及需频繁监测INR等缺点限制了其使用。新型口服抗凝药物(NOACs)的出现克服了传统口服抗凝药(OACs)的弊端,但该类药物均经过肾脏代谢,肾功能不全使药物在体内蓄积导致出血风险增加。近年来,对于NOACs治疗该类人群的研究也越来越多。现将OACs在伴有CKD的非瓣膜性房颤患者中抗凝的有效性和安全性综述如下。     

新型口服抗凝药利伐沙班在房颤患者中的应用

心房颤动(简称房颤)是临床常见的心律失常,房颤是卒中的独立危险因素,会增加脑卒中的风险,因此需对房颤患者进行长期的抗凝治疗。新型口服抗凝药物(NOAC)在减少血栓栓塞事件的同时可改善患者的预后,提高患者的生活质量。本文介绍了新型口服抗凝药利伐沙班的药理作用及作用机制,并介绍了利伐沙班在特殊人群房颤中的应用,为临床医护人员在房颤患者中如何合理使用抗凝药物提供指导。     

口服抗凝药对房颤患者的卒中预防作用

口服抗凝药是预防房颤患者卒中的有效措施,而房颤患者在伴随其他疾病等特殊情况下,将影响口服抗凝药的作用从而增大卒中或出血风险。本文将对比新型口服抗凝药及华法林对房颤患者卒中预防过程中的获益与风险,旨在为不同房颤患者的抗凝药物选择提供参考。     

非瓣膜性心房颤动患者新型口服抗凝药物研究进展

心房颤动(简称房颤)是临床常见的持续性心律失常之一。房颤最严重的后果是栓子脱落导致脑卒中,因此对于房颤患者治疗关键在于预防脑卒中的发生[1]。经现有的风险评估,房颤患者长期应用口服抗凝药物可降低卒中或系统性栓塞的风险[2]。因华法林研究证据较充分,目前临床应用较为普遍,但因其存在一些不足,例如剂量个体差异大及频繁监测凝血指标等,限制了华法林的应用[3-4]。新型口服抗凝药物弥补了华法林的     

艾多沙班用于非瓣膜性心房颤动抗凝治疗的研究进展

口服抗凝药物是非瓣膜性房颤患者降低血栓栓塞和卒中风险的有效治疗方法。既往临床长期应用的口服抗凝药为维生素K拮抗剂及肝素,近年来新型口服抗凝剂逐渐得到广泛应用,包括直接凝血酶抑制剂达比加群和Xa因子抑制剂如利伐沙班、阿哌沙班及艾多沙班,均可用于非瓣膜性心房颤动患者的卒中预防。艾多沙班作为新型口服抗凝剂,为房颤患者提供了更多的用药选择。本研究对艾多沙班在房颤患者抗凝预防和临床治疗中的作用进行综述。     

新型口服抗凝剂利伐沙班在心房颤动抗凝治疗中的研究进展

<正>心房颤动(房颤)是临床上最常见的心律失常,其发病率随年龄增长而增加,血栓栓塞性并发症是其导致人类致残、致死的重要原因之一,临床研究证实房颤使脑卒中的发病率增加5倍以上,大约25%的缺血性卒中来源于心房颤动[1],脑卒中的病死率是20%,而存活的患者中有60%最终发展成严重瘫痪。药物抗凝治疗是房颤治疗中能够改善预后的重要措施,可以有效降低血栓栓塞性事件的危险性,华法林是传统的、能够长期口服的抗凝血药物,然而,华法林抗凝作用的个体差异很大,部分患者服用常规剂量也可以发生出血性并发症,需要频繁监测凝     

慢性肾功能不全合并非瓣膜房颤患者抗血栓药物治疗的有效性和安全性概述

摘 要约1/3的房颤（AF）患者伴发慢性肾脏疾病（CKD）。AF患者存在全身性栓塞风险,因抗凝药物的使用存在出血的风险。CKD,尤其是终末期CKD,增加了AF患者血栓栓塞以及大出血的风险。许多研究已评估了华法林在AF合并CKD,尤其是终末期CKD患者（包括血液透析患者）缺血性卒中,全身栓塞和大出血风险的影响,但研究结果不一致。新型口服抗凝药物（NOACs）已在Ⅲ期（中度）CKD患者中进行了研究,研究提示,经剂量调整后,NOACs可获得与华法林相近的预防血栓栓塞的疗效,并可明显减少致命性出血的风险。本文就CKD合并非瓣膜性AF患者使用华法林和NOACs的有效性和安全性做一综述。     

New pharmacologic approaches to prevent thromboembolism in patients with atrial fibrillation

Atrial fibrillation (AF) is associated with a 6 fold increased risk for ischemic stroke. Observational studies suggest that one in four to five strokes is due to AF. Depending on the risk profile of an individual patient, the yearly risk for ischemic stroke is between 2% and 14%. AF is accompanied by an increased propensity for atrial clot formation due to a combination of decreased atrial blood flow, increased activity of the platelet/plasmatic coagulation system and prothrombotic changes at the atrial endocardium. This review summarizes the current guidelines for thromboembolic prevention in patients with AF. In many cases, continuous oral anticoagulation therapy (OAT) with vitamin K antagonists (VitKAs) is indicated if AF is accompanied by more than one additional risk factor for thromboembolic complications. However, therapeutic range of VitKAs (Phenprocoumon, Warfarin, and others), the most commonly used oral anticoagulants, is narrow and their use requires regular anticoagulation monitoring. Possibly due to these limitations, about one third of eligible patients are not treated with VitKAs. Furthermore, in many treated patients OAT is not well controlled. Thus, in clinical practice anticoagulation therapy in AF is suboptimal. Therefore, new and more convenient pharmacologic approaches to prevent thromboembolism with i.e. direct thrombin inhibitors (DTI), synthetic polysaccharides (factor Xa Inhibitors), and others are discussed, and their possible future role in the treatment of AF is evaluated.     

Timing of Initiation of Oral Anticoagulation after Acute Ischemic Stroke in Patients with Atrial Fibrillation

Patients with atrial fibrillation (AF) who suffer an acute ischemic stroke are at risk for both hemorrhagic transformation and recurrent ischemic stroke in the acute post-stroke period. Oral anticoagulants are recommended for secondary stroke prevention in patients with AF. The optimal time to initiate anticoagulant therapy after acute ischemic stroke in patients with AF is uncertain. There is concern that early initiation increases the risk of hemorrhagic transformation, whereas delayed initiation leaves the patient at risk for recurrent ischemic stroke. In this article, we provide a review of the risk of hemorrhagic transformation of acute ischemic stroke as well as review the literature and major guidelines addressing the timing of anticoagulation initiation after an acute ischemic stroke in patients with AF. Relevant articles published from 1990 to the present were identified using the PubMed and Embase databases. The majority of available literature is observational data. Large ischemic lesions, cerebral microbleeds, thrombolytic therapy, and other clinical factors may increase the risk of hemorrhagic transformation of an acute ischemic stroke. Parenteral anticoagulation within 48 hours is associated with an increased risk of hemorrhagic transformation and is not recommended. Insufficient data exist to support the safety of routine oral anticoagulant (direct oral anticoagulants or warfarin) initiation within 48 hours of an acute ischemic stroke. Direct oral anticoagulant initiation within 2 days of an acute ischemic stroke is associated with a 5% rate of hemorrhagic transformation. Infarct size and presence of hemorrhage are important factors in identifying the optimal time to initiation and should guide decisions when available. A recommended framework for patient decision making is provided. Randomized controlled trials in this area are needed to identify the optimal timing of anticoagulation initiation, and such trials are under way.     

Evaluation and management of atrial fibrillation

Atrial fibrillation (AF) is the most common clinically encountered arrhythmia affecting 0.4% of the general population. Its prevalence increases with age, affecting more than 6% of people over 80 years of age. The annual risk of ischemic stroke in patients with lone AF is approximately 1.3%. This annual risk increases up to 10% -12% in patients with a prior stroke or transient ischemic attack. Randomized clinical trials (RCT) comparing adjusted-dose oral anticoagulation and placebo showed a risk reduction of 61% (95% CI 47% to 71%). The absolute risk reduction for stroke with oral anticoagulants is about 3% per year. Aspirin has been shown in meta-analyses to have on average a 20-25% relative risk reduction, and is inferior to oral anticoagulants. In high risk patients with AF warfarin is a class I ACC/AHA indication unless there is a contraindication for anticoagulation. Unfortunately, this therapy requires frequent monitoring with blood samples and the interaction with food and several medications makes its use difficult and sometimes unreliable. It requires strict patient compliance and its use is also linked to potentially serious bleeding complications. In clinical practice, less than 60% of patients who do not have contraindications to oral anticoagulation are actually receiving them. Additionally, of those that receive oral anticoagulation, less than 50% are consistently within therapeutic targets. As such, the "real world" efficacy of a strategy towards prescribing oral anticoagulants is likely significantly lower than that demonstrated in clinical trials. As such, the need to discover other methods of anticoagulation with oral bioavailability, predictable pharmacokinetics, and minimal interactions with diet and other pharmacological agents is imperative. Low molecular weight heparin has a more predictable bioavailability and a longer half-life, but its subcutaneous mode of administration and long-term risks, in particular, osteoporosis makes the chronic use of this medication non-feasible. Antiplatelet agents such as clopidogrel have proven efficacy and superiority compared to aspirin to prevent systemic vascular events in at-risk patient populations, but currently they do not play an important role in the prevention of AF related thromboembolic events. The ACTIVE study is a randomized trial comparing the combination of clopidogrel and aspirin therapy to oral anticoagulation with warfarin in patients with AF, and was unfortunately terminated prematurely by the data safety and monitoring board because of increased events in the antiplatelet arm. Direct thrombin inhibitors, such as ximelagatran, may be as effective as warfarin for stroke-risk reduction in patients with AF. No anticoagulation monitoring is needed and it has excellent bioavailability, with a twice-daily oral dose. Elevation of liver enzymes was an initial concern regarding the use of this new drug, which is not available for general use. Ongoing pharmacological research and future clinical trials may one day leave the "warfarin days" behind. Unfortunately, the new therapies that are being tested seem to be at least several years away from being available on a widespread basis. In this review, we discuss the underlying pathophysiology of AF and stroke. We also provide a comprehensive discussion regarding various available therapies to treat AF.     

New evidences for old concerns with oral anticoagulation in atrial fibrillation: focus on dabigatran

Introduction: Nonvalvular atrial fibrillation (NVAF) is associated with a fivefold excess risk of stroke. Antithrombotic therapy is crucial to reduce the risk of stroke. During past decades, vitamin K antagonists (warfarin or acenocoumarol) have been widely used for this purpose. However, they have several disadvantages that limit their daily use in clinical practice.

Areas covered: In patients with NVAF at risk of stroke, the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial demonstrated that, compared with warfarin, dabigatran 150 mg b.i.d. was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage, whereas dabigatran 110 mg b.i.d. exhibited similar rates of stroke and systemic embolism, but lower rates of major hemorrhage. Fortunately, data about dabigatran are not limited to RE-LY trial. In fact, many substudies have been drawn, providing new and important evidences about the benefits of dabigatran.

Expert opinion: The most recent evidences about efficacy and safety of dabigatran in patients with NVAF, focusing on different substudies of RE-LY trial, are reviewed. In summary, dabigatran is beneficial not only in general population with NVAF but also in different subgroups of patients or different clinical settings (i.e., CHADS2 score, INR control, type of AF, elderly, previous transient ischemic attack or stroke, cardioversion and so on).     

New and emerging anticoagulant therapy for atrial fibrillation and acute coronary syndrome

Abstract Thrombosis is an underlying cause of many cardiovascular disorders, and generation of thrombi in the arterial circulation can lead to unstable angina, myocardial infarction, or ischemic stroke. Antithrombotic therapy is widely used, with proven benefit to prevent ischemic stroke and thromboembolic events in patients with atrial fibrillation (AF) or to prevent further ischemic complications in patients with acute coronary syndrome (ACS). Traditional anticoagulants (including unfractionated heparin, low-molecular-weight heparin, and warfarin) and antiplatelet agents (including aspirin, clopidogrel, and prasugrel) are typically used for these indications. Limitations to their use include variable pharmacokinetic and pharmacodynamic profiles, inability to inhibit fibrin-bound thrombin, risk of heparin-induced thrombocytopenia, delayed onset of action, numerous drug interactions, need for substantial laboratory monitoring and dosage titrations, hyporesponsiveness or resistance, hypersensitivity, adverse events, and bleeding. To overcome some of the limitations of traditional agents, new antithrombotic agents under development are highly selective for specific coagulation factors blocking the synthesis of thrombin. Clinicians must have an understanding of the new anticoagulants to aid in the selection of appropriate therapies for patients. We describe the most relevant phases II and III clinical trials that evaluated several recent emerging anticoagulant drugs for use in patients with AF or ACS. The advantages of many new agents include predictable pharmaco-dynamic response and pharmacokinetic parameters, allowing for fixed oral dosing with no need for laboratory monitoring. For patients with AF, dabigatran is already approved for the prevention of stroke and systemic embolism, rivaroxaban appears to be an effective alternative to warfarin in high-risk patients, and apixaban may also be an effective alternative to aspirin in patients unable to take warfarin. Otamixaban shows promise as an intravenous alternative for patients with ACS in the acute care setting. Likewise, rivaroxaban, dabigatran, and darexaban with or without dual antiplatelet therapy may be beneficial for secondary prevention of ischemic events in patients with ACS.     

Oral IIa and Xa inhibitors for prevention of stroke in atrial fibrillation: clinical studies and regulatory considerations

Atrial fibrillation (AF), the most common, clinically significant, cardiac arrhythmia affects 1% of the general population and has important hemodynamic and thromboembolic complications that contribute to elevated morbidity and mortality. AF increases the overall risk of stroke five-fold, accounting for approximately 15% of all strokes and is associated with particularly severe stroke. For the last 50 years, long-term anticoagulation with vitamin K antagonists has been the most effective therapy for preventing stroke and systemic embolism in patients with AF and other risk factors, but their use has a lot of limitations and drawbacks (frequent monitoring and dose adjustment, food and drug interactions, delayed onset of action etc). Nowadays, new oral anticoagulants have emerged that seem to overcome those limitations. Direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban have proven, in large, multicenter, randomized, phase III, clinical studies, to be at least as efficient as warfarin in stroke prevention in patients with AF. RELY and ROCKET AF trials have contributed to market approval of dabigatran and rivaroxaban, respectively and made them available to clinical practice. Another factor Xa inhibitor, edoxaban, is under evaluation in an ongoing phase III clinical trial and others such as AZD0837, betrixaban and darexaban are still in safety and tolerability phase II studies. The oral anticoagulation landscape is changing rapidly and these new agents seem to be very promising. However future post-marketing studies and registries will help clarify their efficacy and safety.     

Dabigatran etexilate: a pharmacoeconomic review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation

This article provides an overview of the clinical profile of oral dabigatran etexilate (Pradaxa?, Pradax?) [hereafter referred to as dabigatran] when used for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF), followed by a review of cost-utility analyses of dabigatran in this patient population. Dabigatran (110 or 150?mg twice daily) demonstrated noninferiority versus adjusted-dose warfarin with regard to the prevention of stroke and systemic embolism (primary endpoint) in patients with AF in the RE-LY trial, and the 150?mg twice-daily dosage was significantly more effective than warfarin for this endpoint, as well as most other efficacy endpoints. The incidence of major bleeding was generally similar in patients receiving dabigatran 150?mg twice daily or warfarin, but was lower in patients receiving dabigatran 110?mg twice daily. With regard to other bleeding endpoints, dabigatran was generally associated with lower rates than warfarin, except for gastrointestinal major bleeding. Dabigatran (both dosages) was associated with a higher incidence of dyspepsia than warfarin. Results of modelled cost-utility analyses from several countries from the perspective of a healthcare payer over a lifetime (or 20-year) time horizon and primarily based on data from the RE-LY trial were generally consistent. All but one analysis demonstrated that twice-daily dabigatran 150?mg (or age-adjusted, sequential dosing) was cost effective with regard to the incremental cost per QALY gained relative to adjusted-dose warfarin in the prevention of stroke and systemic embolism in AF patients, as the results were below generally accepted cost-effectiveness thresholds. In contrast, the incremental cost per QALY gained for dabigatran 110?mg twice daily versus warfarin exceeded cost-effectiveness thresholds in all studies except one. Sensitivity analyses suggested that the cost utility of dabigatran versus warfarin was generally robust to variations in the majority of parameters. However, the incremental cost per QALY gained for dabigatran versus warfarin improved when levels of international normalized ratio control in warfarin recipients decreased and when the baseline level of risk of stroke increased.     

Role of Emerging Antithrombotic Therapy in the Prevention of Cardioembolic Complications in Patients with Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is an independent risk factor of potentially catastrophic cardioembolic strokes. AF patients are categorized into high-, intermediate-, and low-risk for thromboembolic complications using the CHADS₂ or CHA₂DS₂-VASc scoring system. Oral anticoagulation using warfarin has been the standard therapy for stroke prevention in intermediate- to high-risk AF patients. However, warfarin use has been limited by several factors such as narrow therapeutic windows, drug-drug and drug-food interactions, and hemorrhagic complications. Rigorous research evaluated dual antiplatelet therapy of clopidogrel and aspirin (acetylsalicylic acid) as a potential alternative to warfarin in the ACTIVE W trial. Dual antiplatelet therapy of clopidogrel and aspirin was found to be inferior to warfarin in preventing stroke and systemic embolism with increased bleeding risk. Other extensive research has led to the development of new antithrombotic agents. Recently, dabigatran etexilate 150 mg twice daily, a direct thrombin inhibitor, was approved by the US FDA for stroke prevention in patients with non-valvular AF after it was found to be superior to warfarin in preventing thromboembolic events and associated with less bleeding in the RE-LY trial. It was also cost effective when compared with warfarin. Dabigatran can be considered in high-risk AF patients who are unable or unwilling to comply with the frequent laboratory and clinic visits that are required when receiving treatment with warfarin. Factor Xa inhibitors are another class of new anticoagulants that have been developed. Oral rivaroxaban was non-inferior to warfarin in thromboprophylaxis and with similar bleeding in the ROCKET-AF trial (HR 0.88; p=0.117). Apixaban, another factor Xa inhibitor, was superior to aspirin in reducing stroke and systemic embolism in patients with AF in the AVERROES trial (HR 0.45; p<0.001). The results of the ARISTOTLE trial, which is evaluating apixaban against warfarin in ～18 000 patients with AF, are expected to be available later this year. Edoxaban, another oral factor Xa inhibitor, is currently being evaluated against warfarin in the ENGAGE AF-TIMI 48 trial in ～20 000 patients with AF. With these new developments, there is a necessity for the clinical practitioner to become familiar with these new and upcoming therapies and guidelines. This review provides an overview of the available data regarding the clinical usefulness of these agents.     

经皮左心耳封堵装置预防心房颤动血栓新进展

心房颤动是临床上最常见的心律失常之一,造成血流动力学紊乱后易在左心耳处形成血栓,是脑卒中的独立危险因素.目前心房颤动的主要治疗策略是消除心房颤动和预防脑卒中,经皮左心耳封堵术是在传统药物、电复律、射频消融、口服抗凝药之外近年来发展的通过微创导管术封堵左心耳以达到预防心房颤动病人血栓栓塞的新技术,帮助有抗凝治疗禁忌的非瓣膜性心房颤动病人安全有效地预防脑卒中的发生.该研究就经皮左心耳封堵术在心房颤动中的应用进展进行综述.     

心房颤动抗栓药物治疗进展

心房颤动(房颤)是导致卒中和外周栓塞的重要独立预测因素,华法林抗凝治疗可降低卒中率,但目前华法林临床应用不足。正在研究或已经上市的新型抗栓药物包括达比加群酯、利伐沙班和阿派沙班等可能革命性的改变这一现状。