Challenges of stroke prevention in patients with atrial fibrillation in clinical practice

Strokes and transient ischaemic attacks in patients with atrial fibrillation (AF) can be largely prevented. Risk stratification and appropriate prophylactic regimens help to alleviate the burden of AF-related thromboembolism. Guidelines recommend routine anticoagulation with oral vitamin K antagonists (VKAs) for patients at moderate-to-high risk of stroke, and acetylsalicylic acid (ASA) for those at low risk of stroke. ASA is less effective at reducing the risk of stroke than VKAs; however, ASA does not require monitoring or dose adjustment. Trials of anticoagulants show consistent benefits of oral VKAs for primary and secondary stroke prevention in patients with AF. Nevertheless, VKAs do require frequent coagulation monitoring and dose adjustment because of their variable dose-response profile, narrow therapeutic window, increased risk for bleeding complications and numerous food and drug interactions. This review aims to provide an overview of the clinical challenges of anticoagulant therapy for the prevention of stroke in patients with AF.     

Decision-Making in Clinical Practice: Oral Anticoagulant Therapy in Patients with Non-valvular Atrial Fibrillation and a Single Additional Stroke Risk Factor

Approximately 1 in 3–4 patients presenting with an ischemic stroke will also have atrial fibrillation (AF), and AF-related strokes can be effectively prevented using oral anticoagulant therapy (OAC), either with well-controlled vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs). In addition, OAC use (both VKAs and NOACs) is associated with a 26% reduction in all-cause mortality (VKAs) or an additional 10% mortality reduction with NOACs relative to VKAs. The decision to use OAC in individual AF patient is based on the estimated balance of the benefit from ischemic stroke reduction against the risk of major OAC-related bleeding [essentially intracranial hemorrhage (ICH)]. Better appreciation of the importance of VKAs’ anticoagulation quality [a target time in therapeutic range (TTR) of ≥70%] and the availability of NOACs (which offer better safety compared to VKAs) have decreased the estimated threshold for OAC treatment in AF patients towards lower stroke risk levels. Still, contemporary registry-based data show that OAC is often underused in AF patients at increased risk of stroke. The uncertainty whether to use OAC may be particularly pronounced in AF patients with a single additional stroke risk factor, who are often (mis)perceived as having a “borderline” or insufficient stroke risk to trigger the use of OAC. However, observational data from real-world AF cohorts show that the annual stroke rates in such patients are higher than in patients with no additional stroke risk factors, and OAC use has been associated with reduction in stroke, systemic embolism, or death in comparison to no therapy or aspirin, with no increase in the risk of bleeding relative to aspirin. In this review article, we summarize the basic principles of stroke risk stratification in AF patients and discuss contemporary real-world evidence on OAC use and outcomes of OAC treatment in AF patients with a single additional stroke risk factor in various real-world AF cohorts.     

Impact of bariatric surgery on oral anticoagulants pharmacology,and consequences for clinical practice: a narrative review

The prevalence of obesity has been steadily increasing in recent years worldwide. At the same time bariatric surgery, the best therapeutic strategy to date in terms of sustainable weight loss and improvement of associated comorbidities has been also increasing. However, these surgeries, whether primarily restrictive or malabsorptive, raise questions about the pharmacology of oral drugs. Among widely used drugs, anticoagulants are the referent therapy to treat some cardiovascular diseases such as atrial fibrillation and venous thromboembolism. How bariatric surgery may impact pharmacological properties of oral anticoagulants, and more specifically, direct oral anticoagulants (DOACs) are difficult to anticipate. In this review, we describe available data concerning the potential impact of bariatric surgery on the pharmacology of oral anticoagulants. The vitamin K antagonists (VKAs) requirements for the same international normalized ratio target are reduced after bariatric surgery. Limited data available for dabigatran 150 mg twice daily indicate a risk of insufficient efficacy in atrial fibrillation after gastric bypass due to probable impaired absorption. Data for rivaroxaban at the prophylactic dose of 10 mg per day suggest no impact of bariatric surgery from 3 days to 8 months post‐surgery. However, no conclusive data are available for other anticoagulants or the use of DOACs at therapeutic doses. To date, DOACs are not recommended in patients who have undergone bariatric surgery, because of limited available data. Pending new studies to confirm the predictable pharmacokinetics and safety of DOACs in this population, especially at therapeutic doses, VKAs remain the first option for chronic anticoagulation.     

Pharmacological and Non-pharmacological Treatments for Stroke Prevention in Patients with Atrial Fibrillation

Atrial fibrillation (AF) is associated with significant risk of stroke and other thromboembolic events, which can be effectively prevented using oral anticoagulation (OAC) with either vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, or edoxaban. Until recently, VKAs were the only available means for OAC treatment. NOACs had similar efficacy and were safer than or as safe as warfarin with respect to reduced rates of hemorrhagic stroke or other intracranial bleeding in the respective pivotal randomized clinical trials (RCTs) of stroke prevention in non-valvular AF patients. Increasing “real-world” evidence on NOACs broadly confirms the results of the RCTs. However, individual patient characteristics including renal function, age, or prior bleeding should be taken into account when choosing the OAC with best risk–benefit profile. In patients ineligible for OACs, surgical or interventional stroke prevention strategies should be considered. In patients undergoing cardiac surgery for other reasons, the left atrial appendage excision, ligation, or amputation may be the best option. Importantly, residual stumps or insufficient ligation may result in even higher stroke risk than without intervention. Percutaneous left atrial appendage occlusion, although requiring minimally invasive access, failed to demonstrate reduced ischemic stroke events compared to warfarin. In this review article, we summarize current treatment options and discuss the strengths and major limitations of the therapies for stroke risk reduction 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.     

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.     

Efficacy and Safety of Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation Undergoing Elective Surgical Procedures: A Meta-analysis

Objective: The study objective was to determine if peri-operative bridging anticoagulation in patients with atrial fibrillation is beneficial or harmful.Design: Systematic review and meta-analysis.Setting: Inpatient or in-hospital setting.Participants: Adults with atrial fibrillation having a CHADS2 score >1 undergoing elective surgical procedure on anticoagulation.Methods: A systemic search of multiple databases (Cochrane, Medline, PubMed) was performed regarding studies conducted on efficacy and safety of perioperative bridging anticoagulation in patients with atrial fibrillation. Studies identified were reviewed by two authors individually before inclusion. The results were then pooled using Review Manager to determine the combined effect. Stroke/systemic embolism was considered as the primary efficacy outcome. Major bleeding was the primary safety outcome.Results: The systematic search revealed 108 potential articles. The full texts of 28 articles were retrieved for assessment of eligibility. After full text review, 25 articles were excluded. Three articles met inclusion criteria. No significant difference in stroke/systemic embolism with bridging anticoagulation was noted (risk ratio, 1.25-95% confidence interval [CI], 0.55–2.85). Bridging was associated with significantly higher risk of major bleeding (risk ratio, 3.29-95% CI, 2.25–4.81).Conclusion: An individualized approach is required when initiating peri-operative bridging anticoagulation. There is certainly a higher risk of bleeding with bridging anticoagulation and no difference in stroke/systemic embolism. However, the results cannot be extrapolated to patients who have valvular atrial fibrillation or CHADS2 score of 5 or greater.     

非瓣膜病性心房颤动患者血栓栓塞危险分层及抗血栓治疗现状

目的分析非瓣膜病性心房纤颤(NVAF)患者抗血栓药物治疗现状。方法调查无抗凝治疗禁忌证的NVAF患者104例,对其病因、血栓栓塞危险因素、抗血栓药物应用情况及未应用华法林抗凝治疗原因进行分析。应用ACC/AHA/ESC心房颤动指南血栓栓塞危险分层标准对NVAF患者进行血栓栓塞危险评估。结果对104例NVAF患者进行血栓栓塞危险评估,符合抗凝指征的NVAF患者75例(72.1%),其中仅27例(36.0%)抗凝治疗,而NVAF呈阵发性者共22例,仅有1例(4.5%)抗凝治疗。应用华法林平均剂量(2.6±0.8)mg/d,平均INR值2.1±0.5;阿司匹林平均剂量(86.1±15.4)mg/d。未能抗凝治疗48例,其中严重出血1例(1.3%);不能做好凝血监测2例(2.7%);拒绝应用8例(10.7%);阵发性心房纤颤而未行抗凝治疗21例(28.0%);冠脉支架术后患者应用氯吡格雷和阿司匹林抗血小板治疗而未应用华法林抗凝治疗者3例(4.0%);原因不明12例(16.0%)。结论NVAF患者抗栓治疗欠规范,依从性差,抗栓治疗的教育和管理有待加强。     

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.     

Management of paroxysmal atrial fibrillation

Paroxysmal atrial fibrillation is a common, poorly understoodand difficult-to-treat arrhythmia. Although it tends to betreated in a similar fashion to chronic atrial fibrillation,its pathophysiology is different, and drugs commonly used forchronic atrial fibrillation may have only limited value in treating paroxysmal atrial fibrillation. A broad range of presentingclinical symptoms may be associated with this arrhythmia, andeven in the asymptomatic patient, there may be a risk of seriousthromboembolic events. In symptomatic patients, effective controlof paroxysms with anti-arrhythmic therapy can often be difficult,and the role of anticoagulation remains controversial. Thisreview attempts to clarify these issues, by surveying the rangeof therapies available.     

Antithrombotic therapy for heart failure in sinus rhythm

Although the risk of thromboembolism in chronic heart failure is high even in the absence of atrial fibrillation, the risk to benefit ratio of anticoagulation vs. antiplatelet therapy or no antithrombotic therapy is poorly defined in this population. Post hoc analysis of large therapeutic heart failure trials has estimated the risk of thromboembolism to be between 1 and 4.5%. However, most of these studies have included some patients with atrial fibrillation, and thromboembolism was not a predefined endpoint. At present, the evidence for either anticoagulation or antiplatelet therapy is limited and the results from current large-scale randomized studies are awaited. From the randomized studies carried out thus far, there is a beneficial trend in favour of anticoagulation therapy, with less hospitalization for heart failure compared with patients taking aspirin.     

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.     

缺血性卒中的抗凝治疗

几个大规模、多中心、随机试验发现,天然肝素(UFH)或低分子肝素(LMWH)并不能改善急性缺血性卒中患者的总体预后。紧急抗凝可预防长期卧床急性缺血性卒中患者深静脉血栓的形成。伴房颤及附加危险因素,如附壁血栓和(或)新发心肌梗死的心源性栓塞性卒中患者具有较高复发性卒中危险,若无显著出血可紧急抗凝。华法令抗凝可作为伴心房纤颤卒中患者的初级和二级预防。颅内静脉窦栓塞形成、颈动脉夹层和抗磷脂抗体综合征患者可常规抗凝,而非心源性栓塞性卒中或症状性颅内动脉狭窄综合征患者长期抗凝治疗证据不足。     

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.     

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.     

Treatment options for multivessel coronary artery disease

Until recently, pharmaceutical options for stroke prevention in atrial fibrillation were restricted to aspirin or vitamin K antagonist therapy. In recent years development has been underway for alternatives. Apixaban, a direct Factor Xa inhibitor, is orally dosed, target selective and has few known drug or food interactions. As such, it is a member of a new generation of anticoagulants expected to revolutionize the way we approach anticoagulation for stroke prevention in atrial fibrillation. Apixaban has been studied in Phase II and Phase III trials for a variety of indications. The AVERROES trial established apixaban as superior to aspirin for stroke reduction in patients with atrial fibrillation for whom vitamin K antagonist therapy is unsuitable. The recent ARISTOTLE trial found apixaban to be superior to warfarin for stroke prevention in a wide range of patients with atrial fibrillation, with significantly lower bleeding risk, and lower risk of all-cause mortality.     

Apixaban for the prevention of stroke in atrial fibrillation

Until recently, pharmaceutical options for stroke prevention in atrial fibrillation were restricted to aspirin or vitamin K antagonist therapy. In recent years development has been underway for alternatives. Apixaban, a direct Factor Xa inhibitor, is orally dosed, target selective and has few known drug or food interactions. As such, it is a member of a new generation of anticoagulants expected to revolutionize the way we approach anticoagulation for stroke prevention in atrial fibrillation. Apixaban has been studied in Phase II and Phase III trials for a variety of indications. The AVERROES trial established apixaban as superior to aspirin for stroke reduction in patients with atrial fibrillation for whom vitamin K antagonist therapy is unsuitable. The recent ARISTOTLE trial found apixaban to be superior to warfarin for stroke prevention in a wide range of patients with atrial fibrillation, with significantly lower bleeding risk, and lower risk of all-cause mortality.     

Non-Vitamin K Oral Anticoagulants for Stroke Prevention in Special Populations with Atrial Fibrillation

Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke or systemic embolism compared with normal sinus rhythm. These strokes may efficiently be prevented in patients with risk factors using oral anticoagulant therapy, with either vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) (i.e., direct thrombin inhibitors or direct factor Xa inhibitors). Owing to their specific risk profiles, some AF populations may have increased risks of both thromboembolic and bleeding events. These AF patients may be denied oral anticoagulants, whilst evidence shows that the absolute benefits of oral anticoagulants are greatest in patients at highest risk. NOACs are an alternative to VKAs to prevent stroke in patients with “non-valvular AF”, and NOACs may offer a greater net clinical benefit compared with VKAs, particularly in these high-risk patients. Physicians have to learn how to use these drugs optimally in specific settings. We review concrete clinical scenarios for which practical answers are currently proposed for use of NOACs based on available evidence for patients with kidney disease, elderly patients, women, patients with diabetes, patients with low or high body weight, and those with valve disease.