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。     

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.     

心房颤动患者左心耳封堵术后抗栓策略

心房颤动可引起血栓栓塞,甚至脑卒中.大多数房颤患者血栓主要形成于左心耳.左心耳封堵术(LAAO)通过对左心耳进行介入封堵,以替代长期口服抗凝药预防血栓栓塞,其安全性和有效性已在众多临床研究中得到证实.LAAO后抗栓治疗对患者的康复及减少不良反应的发生至关重要.目前LAAO后抗栓治疗策略主要有抗凝+抗血小板联合治疗、双联...     

Striking a balance between the risks and benefits of anticoagulation bridge therapy in patients with atrial fibrillation: clinical updates and remaining controversies

Long-term anticoagulation with a vitamin K antagonist (VKA) or the new agent dabigatran is recommended to decrease stroke risk in patients with atrial fibrillation. When patients with atrial fibrillation undergo initiation or interruption of VKA therapy, or experience an isolated subtherapeutic international normalized ratio (INR), bridge therapy with a parenteral anticoagulant may be considered. To describe the literature for anticoagulation bridge therapy in patients with atrial fibrillation, we conducted a MEDLINE search (1966-February 2011) of the English-language literature to identify related studies. Ongoing clinical trials were identified through a search of the ClinicalTrials.gov registry. Major national and international guidelines were gathered and evaluated. Additional literature was obtained through review of relevant references of the identified articles. Bridging is not supported by guidelines or clinical trials for patients starting VKA therapy for atrial fibrillation. A subtherapeutic INR value during long-term VKA therapy may be associated with increased thromboembolic events, but the benefit of bridging has not been demonstrated. When VKA therapy is interrupted for procedures, retrospective and cohort data suggest that the decision to bridge should be based on a patient's thromboembolic and bleeding risks associated with the procedure. Typically, it is recommended to use bridge therapy in patients with atrial fibrillation at high risk for thromboembolism, but the benefit of bridging is less clear in patients at low risk. Not all procedures necessitate anticoagulation interruption. Recent trials suggest that VKAs can be continued when patients are undergoing cardiac device procedures and some types of radiofrequency ablation. Several clinical trials are ongoing that will provide more definitive guidance for perioperative anticoagulation management of patients with atrial fibrillation. Patients taking dabigatran are unlikely to require bridge therapy because of a predictable anticoagulant effect and rapid onset of action. However, evidence for optimal perioperative management of dabigatran is needed.     

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.     

房颤合并肝硬化患者的口服抗凝药物选择及抗栓策略研究

目的 探讨房颤合并肝硬化患者临床治疗中口服抗凝药物的选择及安全性。方法 在1例房颤合并乙型肝炎肝硬化患者房间隔修补术后抗栓方案的制定中,通过查阅指南和文献,总结、分析房颤合并肝硬化患者口服抗凝药物的疗效及安全性评价现状。结果 通过综合评估患者情况,停用华法林,予达比加群酯110 mg,bid,联合氯吡格雷75 mg,qd抗栓6个月,之后达比加群酯110 mg,bid长期抗凝治疗。结论 房颤合并肝硬化患者抗栓治疗,应充分评估血栓及出血风险,制定个体化的抗栓策略。房颤合并Child-Pugh A级肝硬化,新型口服抗凝药均可使用;合并Child-Pugh C级肝硬化,口服抗凝剂均不建议使用;合并Child-Pugh B级肝硬化,出血风险高的患者长期抗凝治疗中可选用小剂量达比加群酯。     

Direct oral anticoagulants and cardiovascular prevention in patients with nonvalvular atrial fibrillation

Introduction: Patients with atrial fibrillation have an increased risk for stroke, systemic embolism and cardiovascular events, including myocardial infarction and cardiovascular death. However, the majority of studies that have analyzed the efficacy of anticoagulants have been focused only on their effects on the risk of stroke.

Areas covered: The available evidence about the association between atrial fibrillation and cardiovascular disease as well as the effects of oral anticoagulation on cardiovascular death and myocardial infarction, with a particular focus on direct oral anticoagulants, was updated in this review.

Expert opinion: The management of patients with atrial fibrillation should not be limited to the prevention of stroke, but should also include the prevention of cardiovascular events. Despite treatment with vitamin K antagonists, many patients with atrial fibrillation still develop cardiovascular complications, particularly individuals whose anticoagulation is difficult to control. Direct oral anticoagulants overcome the majority of limitations of vitamin K antagonists and compared with warfarin, they lead to a greater reduction in the risk of stroke or systemic embolism, all-cause mortality, and intracranial hemorrhage. Although these drugs can only be compared indirectly, it seems that not all direct oral anticoagulants are equal with regard to the prevention of myocardial infarction.     

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。     

Antiplatelet drugs in cardiovascular prevention: stroke prevention in patients with thrombogenic heart disease

(1) In patients with atrial fibrillation and a moderate embolic risk, aspirin reduces the risk of stroke and has a comparable risk-benefit ratio to oral anticoagulants. (2) Oral anticoagulants are superior to aspirin in patients with atrial fibrillation and a history of stroke. (3) In patients with a mechanical valve prosthesis and a high embolic risk, the oral anticoagulant + aspirin combination has a better risk-benefit ratio than oral anticoagulant alone.     

新型口服抗凝药在非瓣膜性房颤中的应用进展

目的:对新型口服抗凝药(NOACs)在非瓣膜性房颤抗凝治疗中的临床应用和发展进行探讨。方法:收集最新发表的相关文章,对新型口服抗凝药的药理学特性、临床试验结果和临床应用进行分析总结。结果与结论:房颤是临床中最常见的心律失常,对于CHA_2DS_2-VASc评分≥2或既往曾有一过性脑缺血发作(TIA)或有卒中史的患者,应该使用抗凝药物。新型口服抗凝药,与维生素K拮抗剂(VKA)相比,有相似甚至更好的抗凝效果、安全性和便利性。它们具有快速起效,更多可预测的药动学特征,与其他药物相互作用少,饮食对其无明显影响,比华法林导致颅内出血的风险更低。     

Prevention of embolic complications in nonvalvular atrial fibrillation in the elderly.

Atrial fibrillation is common in elderly subjects, usually with coexistent underlying heart disease. Nonvalvular atrial fibrillation is associated with increased morbidity and mortality, especially due to embolic complications: it carries a 5.6-fold increased risk of stroke, compared with age-matched controls. Three recent trials have demonstrated that prophylactic anticoagulation (either 'full' or 'partial') decreases the rate of stroke significantly, with an acceptably low rate of complications. The benefits of aspirin prophylaxis are less clear, and currently there is no evidence for a beneficial effect in the elderly patient. At present, no factor apart from a previous symptomatic embolism predicts those who are at risk of embolism. The risk of stroke appears to continue for a long time and, until data are provided, therapy should be continued indefinitely in the absence of contraindications. All patients with nonvalvular atrial fibrillation should be considered for prophylactic anticoagulants. Further work is required to identify those at highest risk, and to clarify how long therapy should be continued and whether there are subgroups in whom full or partial anticoagulation would be preferable.     

Will warfarin soon be passé? New approaches to stroke prevention in atrial fibrillation

Atrial fibrillation (AF) is the most common cause for thromboembolic stroke. Oral anticoagulation with warfarin is still the most effective therapy in patients with AF, who are at an increased risk for stroke. Nevertheless, warfarin therapy has several limitations; therefore, new anticoagulants like warfarin analogs, thrombin inhibitors, or factor Xa inhibitors have been developed. Some of them are currently being tested in phase III trials in patients with AF. Furthermore, the pathophysiology of prothrombotic endocardial remodeling in fibrillating atria suggests that angiotensin II increases prothrombotic expression of vascular adhesion molecules at the atrial endocardium. Thus, novel anticoagulants or hybrid therapy with a combination of anticoagulants with inhibitors of endocardial remodelling like angiotensin II receptor blockers appear to be attractive future perspective approaches.     

Novel Oral Anticoagulants for Stroke Prevention in the Geriatric Population

Prior to the availability of several newer anticoagulant medications, there had been no new advances in anticoagulation management for stroke prevention since the advent of warfarin in the 1950s. The availability of the novel oral anticoagulants (NOACs) dabigatran, rivaroxaban, and apixaban represent improvements over warfarin in many respects, including the elimination of the need for therapeutic drug monitoring, fewer drug and food interactions, and favorable efficacy; however, these agents are not without risk. Specifically, the use of the NOACs in the geriatric population, who are more likely to have an increased risk of stroke due to atrial fibrillation and other medical comorbidities, is not without risk. The objective of this review is to update the clinician on the use of the NOACs in the geriatric population and introduce the controversies and risks surrounding these newer therapies.     

Challenges and Treatment for Stroke Prophylaxis in Patients with Atrial Fibrillation in Mexico: A Review

Atrial fibrillation (AF) is associated with an increased risk of stroke. AF-related strokes cause greater disability and mortality than those in patients without AF, and are associated with a significant clinical and economic burden in Mexico. Antithrombotic therapy reduces stroke risk in patients with AF and is recommended for all patients except those classified as having a low stroke risk. However, its use is suboptimal all around the world; one study showed that only 4 % of Mexican patients with AF who presented with ischemic stroke were in the therapeutic range for anticoagulation. Vitamin K antagonists (VKAs) such as warfarin or acenocoumarin have long been the only oral anticoagulants for stroke prevention in AF. Although effective, VKAs have disadvantages, including the need for regular coagulation monitoring and dose adjustment. Interactions with numerous common medications and foods contribute to the risk of serious bleeding and thrombotic events in VKA-treated patients. Thus novel oral anticoagulants (NOACs), more properly called direct oral anticoagulants (DOACs), such as dabigatran etexilate, rivaroxaban, apixaban, and edoxaban (not available in Mexico), have been developed. These offer the convenience of fixed-dose treatment without the need for monitoring, and have few drug or food interactions. Pivotal phase III trials have demonstrated that these agents are at least as effective as warfarin in preventing stroke and are associated with a reduced risk of intracranial hemorrhage. With apixaban approved in Mexico in April 2013, clinicians now have the choice of three novel DOACs as alternatives to warfarin. However, it is yet to be established which of these agents should be the first choice, and treatment decisions are likely to depend on the individual patient’s characteristics.     

Dietary implications for patients receiving long-term oral anticoagulation therapy for treatment and prevention of thromboembolic disease

Introduction: The effectiveness of oral anticoagulation therapy with warfarin (a vitamin K antagonist) in the treatment of thromboembolic disease, including stroke prophylaxis in patients with atrial fibrillation is well recognised. However, warfarin has a narrow therapeutic window and an unpredictable anticoagulation response, which make it difficult to achieve and maintain optimal anticoagulation. Various dietary factors, including sudden changes in eating patterns, can significantly alter anticoagulation control, thereby potentially exposing patients to the risk of bleeding or thromboembolic complications. Dietary vitamin K intake is a particularly important factor, given the mechanism of action of warfarin.

Areas covered: In this article, we cover the sources of vitamin K and their potential effect of dietary vitamin K on anticoagulation response to warfarin. We also discuss the results of studies on the effect of vitamin K supplementation on anticoagulation stability.

Expert commentary: A stable dietary vitamin K, promoted by daily oral vitamin K supplementation, can improve anticoagulation stability in patients on warfarin therapy. There is experimental evidence in animals that dietary vitamin K affects anticoagulation response to the direct thrombin inhibitor, ximelagatran. Whether dietary vitamin K affects anticoagulation response to the currently licensed direct oral anticoagulants (DOACs) in man remains to be investigated.     

Suboptimal Use of Oral Anticoagulants in Atrial Fibrillation: Has the Introduction of Direct Oral Anticoagulants Improved Prescribing Practices?

Background and Objectives

Atrial fibrillation (AF) and the associated risk of stroke are emerging epidemics throughout the world. Suboptimal use of oral anticoagulants for stroke prevention has been widely reported from observational studies. In recent years, direct oral anticoagulants (DOACs) have been introduced for thromboprophylaxis. We conducted a systematic literature review to evaluate current practices of anticoagulation in AF, pharmacologic features and adoption patterns of DOACs, their impacts on proportion of eligible patients with AF who receive oral anticoagulants, persisting challenges and future prospects for optimal anticoagulation.

Literature Source and Selection Criteria

In conducting this review, we considered the results of relevant prospective and retrospective observational studies from real-world practice settings. PubMed (MEDLINE), Scopus (RIS), Google Scholar, EMBASE and Web of Science were used to source relevant literature. There were no date limitations, while language was limited to English. Selection was limited to articles from peer reviewed journals and related to our topic.

Results

Most studies identified in this review indicated suboptimal use of anticoagulants is a persisting challenge despite the availability of DOACs. Underuse of oral anticoagulants is apparent particularly in patients with a high risk of stroke. DOAC adoption trends are quite variable, with slow integration into clinical practice reported in most countries; there has been limited impact to date on prescribing practice.

Conclusion

Available data from clinical practice suggest that suboptimal oral anticoagulant use in patients with AF and poor compliance with guidelines still remain commonplace despite transition to a new era of anticoagulation featuring DOACs.

     

Current anticoagulant safety

INTRODUCTION: Currently used anticoagulants such as unfractionated heparin, low-molecular-weight heparin and vitamin K antagonists, have several drawbacks, mostly related to safety. In this review, we will briefly discuss and compare the safety of anticoagulation therapy with 'old' and new agents. AREAS COVERED: Safety issues with anticoagulation therapy are mostly related to bleeding. The intensity of anticoagulation is related to the risk of bleeding and thus, for the efficacy not to be affected, must be maintained at the lower effective intensity. Several improvements have been made in the management of anticoagulation therapy; these include monitoring, pathology-based treatment schemes taking into account patient characteristics, patient education and the introduction of anticoagulation centers. Safety of novel anticoagulants is encouraging. EXPERT OPINION: Novel agents have the potential to compete with existing therapy for thromboprophylaxis, treatment and stroke prevention in atrial fibrillation. Promising results have emerged from trials comparing them with existing treatment. Not long from now we will see these new agents in the armamentarium of antithrombotic drugs.     

临床药师对长期抗凝的心房纤颤患者的药学监护*

目的：探讨临床药师对长期抗凝治疗的心房纤颤患者进行药学监护的切入点和要点。方法：从传统口服抗凝药与新型口服抗凝药之间的转换、药物相互作用、围手术期抗凝策略、抗凝药物的不良反应、出院用药教育五个角度,临床药师提供个体化药学监护和指导。结果：临床药师通过参与对房颤患者的药学监护,有助于保障患者的用药安全性、合理性和延续性。结论：临床药师应积极参与房颤患者的抗凝治疗,并提出合理化建议。     

临床药师对长期抗凝的心房纤颤患者的药学监护*

目的：探讨临床药师对长期抗凝治疗的心房纤颤患者进行药学监护的切入点和要点。方法：从传统口服抗凝药与新型口服抗凝药之间的转换、药物相互作用、围手术期抗凝策略、抗凝药物的不良反应、出院用药教育五个角度,临床药师提供个体化药学监护和指导。结果：临床药师通过参与对房颤患者的药学监护,有助于保障患者的用药安全性、合理性和延续性。结论：临床药师应积极参与房颤患者的抗凝治疗,并提出合理化建议。     

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.