Pharmacology,benefits, unaddressed questions,and pragmatic issues of the newer oral anticoagulants for stroke prophylaxis in non-valvular atrial fibrillation and proposal of a management algorithm

This systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral direct thrombin and factor Xa inhibitors, which have emerged for the first time in ~ 60 years as cogent alternatives to warfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most common clinical scenarios with several unsolved questions and areas of uncertainty that may play a role in physicians' reluctance to prescribe the newer oral anticoagulants such as 1) patients with renal failure; 2) the elderly; 3) patients presenting with atrial fibrillation and acute coronary syndromes and/or undergoing coronary stenting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspects presented in current guidelines are covered and we also propose an evidence-based anticoagulation management algorithm.     

Dabigatran,rivaroxaban, and apixaban are superior to warfarin in Asian patients with non-valvular atrial fibrillation: An updated meta-analysis

BACKGROUNDMost of the randomized clinical trials that led to the wide use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation (AF) originated from western countries. AIMTo systematically review and quantitatively synthesize the real-world data regarding the efficacy and safety of dabigatran, rivaroxaban, and apixaban compared to warfarin for stroke prevention in Asian patients with non-valvular AF.METHODSMedline, Cochrane, and ClinicalTrial.gov databases were reviewed. A random-effect model meta-analysis was used and I-square was utilized to assess the heterogeneity. The primary outcome was ischemic stroke. The secondary outcomes were all-cause mortality, major bleeding, intracranial hemorrhage, and gastrointestinal bleeding.RESULTSTwelve studies from East Asia or Southeast Asia and 441450 patients were included. Dabigatran, rivaroxaban, and apixaban were associated with a significant reduction in the incidence of ischemic stroke [hazard ratio (HR) = 0.78, 95% confidence interval (CI): 0.65-0.94; HR = 0.79, 95%CI: 0.74-0.85, HR = 0.70, 95%CI: 0.62-0.78; respectively], all-cause mortality (HR = 0.68, 95%CI: 0.56-0.83; HR = 0.66, 95%CI: 0.52-0.84; HR = 0.66, 95%CI: 0.49-0.90; respectively), and major bleeding (HR = 0.61, 95%CI: 0.54-0.69; HR = 0.70, 95%CI: 0.54-0.90; HR = 0.58, 95%CI: 0.43-0.78; respectively) compared to warfarin.CONCLUSIONDabigatran, rivaroxaban, and apixaban appear to be superior to warfarin in both efficacy and safety in Asians with non-valvular AF.     

Non-vitamin K antagonist oral anticoagulants in elderly patients with atrial fibrillation: A systematic review with meta-analysis and trial sequential analysis

Background: Elderly population is known to be associated with polymedication, comorbidities and altered drug pharmacokinetics. However, the most adequate oral anticoagulant, attending to its relative efficacy and safety, remains unclear.Methods: We searched for phase III randomized controlled trials (MEDLINE, Cochrane Library, SciELO collection and Web of Science) comparing novel non-vitamin K antagonist oral anticoagulants (NOACs) with Vitamin K antagonists (VKA) in the elderly population (≥75 years-old) in atrial fibrillation (AF). Risk ratios (RR) were calculated using a random effects model. Trial sequential analysis (TSA) was performed in statistically significant results to evaluate whether cumulative sample size was powered.Results: Four trials rendered data about elderly (≥75 years-old) and younger patients (<75 years-old) with AF. NOACs demonstrated a 30% significant risk reduction (RR 0.70, 95% CI: 0.61 to 0.80) in elderly patients compared to VKA, without heterogeneity across studies (I² = 0%). The TSA showed that cumulative evidence of this subgroup exceeded the minimum information size required for the risk reduction. In younger patients, VKA and NOACs shared a similar risk of stroke and systemic embolism (RR 0.97, 95% CI: 0.79 to 1.18). Regarding major bleeding risk in the elderly, the overall comparative risk of NOACs was not different from VKA (RR 0.91, 95% CI: 0.72 to 1.16; I² = 86%).Conclusions: NOACs reduce significantly the risk of stroke and systemic embolism in elderly patients without increasing major bleeding events. The dimension of stroke risk reduction was significantly higher in the elderly than in younger adults.     

新型口服抗凝药治疗70岁以上老年心房颤动患者疗效及安全性的Meta分析

目的:系统评价新型口服抗凝药(NOACs)治疗70岁以上老年心房颤动(房颤)患者疗效及安全性。方法:计算机检索PubMed、Embase、Cochrane library等数据库,检索时间均从建库至2021年3月,收集其中收录的公开发表的关于NOACs(达比加群、利伐沙班、阿哌沙班、西美加群、艾多沙班)与华法林治疗70...     

Atrial fibrillation,oral anticoagulants and health related quality of life

IntroductionAtrial fibrillation (AFib) is a disease that can influence the health related quality of life. Also oral anticoagulants can influence it both because of its therapeutic benefits or complications as well as how the anticoagulant usage influence the person's life style by regular laboratory test necessity or diet restrictions.AimDetermine and analyze whether there is a statistically significant difference comparing health related quality of life between K vitamin antagonist, warfarin, users, novel anticoagulant (NOAC), rivaroxaban, dabigatran, users and patients, who do not use any kind of oral anticoagulant.Materials and methodsA cross-sectional analytic research was made in Pauls Stradins Clinical university hospital, Center of Cardiology in Riga, Latvia during the time period from October 2016 till June 2017. Persons with high-risk non-valvular atrial fibrillation were offered to participate in this research. If the person agreed, an oral interview with questions about disease anamnesis, demographic data, laboratory test results, echocardiography results, modified SF-36 survey, used oral anticoagulant type was held. Data were precised with the help of the case anamnesis information. For statistical data analysis was used SPSS Statistics database.ResultsAltogether 218 patients were enrolled, of which 56.9% were female and 43.1% – male, mean age – 70.4 years, mean CHA₂D₂-VASc score – 4.4. Warfarin used 37.6%, 33.0% – novel oral anticoagulants, but 29.4% did not use any kind of oral anticoagulant. A statistically significant difference was discovered between the mean ranks in physical functioning sections comparing warfarin (mean rank 95.85) with NOACs (mean rank 124.57); p = 0.012. Also a statistically significant difference was in social functioning comparing warfarin (mean rank 96.16) with NOACs (mean rank 119.08); p = 0.026. Age had low negative correlation (r = −0.23) with physical functioning. Duration of atrial fibrillation diagnosis did not have correlations with the results.ConclusionNOAC usage correlates with the best health related quality of life scores, gaining a statistically significant difference compared to warfarin users in physical functioning (warfarin – 95.85, NOACs – 124.57; p = 0.012) and social functioning mean ranks (warfarin – 95.16, NOACs – 119.08; p = 0.026). Age had low negative correlation with physical functioning scores.     

Balancing Efficacy and Bleeding Risk in the Prevention of Stroke Due to Atrial Fibrillation with Newer Oral Anticoagulants

With the evaluation and approval of newer oral anticoagulants such as the factor IIa inhibitor, dabigatran etexilate and the factor Xa inhibitors, rivaroxaban and apixaban, strategies for stroke prevention in atrial fibrillation need a thorough re-evaluation of current options. Clinicians are naturally excited about the imminent introduction of these newer drugs that do not need international normalized ratio (INR) monitoring, besides having no drug–food and minimal drug–drug interactions. However, as with all new drugs, it is always prudent to use these judiciously so that they stay in our therapeutic armamentarium for a long time. More than 56 years after the introduction of warfarin we now have three drugs, viz., dabigatran 150 mg bid, rivaroxaban 20 mg od, and apixaban 5 mg bid which were effective in comparison with warfarin in reducing the risk of stroke and bleeding in the landmark trials, RE-LY, ROCKET-AF, and ARISTOTLE respectively. There is a thin dividing line between physiological hemostasis and pathological thrombosis. Routine INR monitoring may not be required but in special situations, such as prior to major surgery, overdose, non-compliance or stroke while on the anticoagulant, one may wish to know whether there are any laboratory measures of efficacy or means of reversal of over anticoagulation. Similar questions may be raised about other situations such as renal dysfunction, cardioversion, ablation procedures, post-stenting, or switch to and from warfarin, heparin or LMWH? This document is an attempt to address these concerns based on available evidence and give physicians a perspective and practice guidelines on how best to use these agents, both old and new, for optimal patient outcomes, maximizing efficacy and minimizing risk.     

口服抗凝药物预防心房颤动患者脑卒中的研究进展

<正>心房颤动是临床常见的心律失常,我国拥有心房颤动患者超过800万。脑卒中是心房颤动的严重并发症,与年龄和血压匹配的对照人群相比,无潜在瓣膜性心脏病的心房颤动患者发生脑卒中可能性是对照人群的5倍以上,有瓣膜性心     

华法令在心房颤动患者的应用研究

目的　探讨简化的抗凝指标检测法及低抗凝强度的华法令应用于心房颤动 (简称房颤 )的可行性。方法　 115例房颤患者随机分为低抗凝强度组 (INR 1 5～ 2 0 )和标准抗凝强度组 (INR 2 1～ 3 0 ) ,在服华法令后第4日采血检测INR ,以后每周 1次至每月检测 1次。结果　 95 7%病例第 4日检测的INR≤ 3 0 ,只有 1例INR达4 0伴皮肤出血 (占 0 9% ) ;平均随访 3.4年 ,低抗凝强度组栓塞年发生率 0 98% ,标准抗凝强度组未发生栓塞 ,但两组比较差异无显著意义 (P >0 0 5 ) ;出血年发生率分别为 0 4 9%和 3 74 % ,两组比较差异有显著意义 (P <0 0 5 )。结论　简化的抗凝指标检测法是可行的 ;对非瓣膜性房颤可考虑应用低抗凝强度的华法令 ,瓣膜性房颤仍需标准抗凝强度的华法令治疗。     

华法林在慢性心房颤动抗凝治疗中的应用

目的:探讨华法林在慢性心房颤动(CAf)抗凝治疗中的合理应用。方法:共入选234例具有血栓栓塞高风险的CAf患者,给予华法林抗疑治疗,监测国际标准化比值(INR)以调整华法林用量,随访观察华法林的不同起始剂量、不同的抗凝强度以及高龄(≥65岁)等因素对INR达标时间、INR稳定值、华法林维持量、出血率及栓塞率的影响。结果:分别采用开始剂量为普通剂量(2．5mg／d)与小剂量(1．25 mg／d)2种方式,两者最终获得稳定的INR、华法林维持量及出血率均差异无统计学意义,但前者能明显缩短INR首次达标时间及获得INR 稳定值的时间(均P<0．01),并有降低栓塞率的趋势;与低强度抗凝相比,中强度抗凝能显著降低栓塞率(P< 0．05),虽然伴出血率明显升高(P<0．05),但无严重出血发生;在相同的目标INR内,高龄患者出血率并不增加,但所需的华法林维持量有所降低(P<0．01)。结论:以普通量的华法林开始CAf抗凝治疗是安全的,抗栓塞效果优于小剂量;对具有栓塞高风险的CAf需保持中强度抗凝水平;华法林抗凝治疗并不增加高龄患者的出血风险。     

华法林对老年持续性房颤患者的疗效

目的:探讨华法林对老年房颤(AF)患者的疗效和安全性。方法:选择2014年1月至2016年12月于我院治疗的老年AF患者100例。按照随机对照原则,患者被分为华法林组(51例)和阿司匹林组(49例),两组均随访治疗1年。观察比较两组终点事件发生率和不良反应发生率。结果:阿司匹林组失访1例。终点事件:华法林组:脑梗死2例;阿司匹林组:脑梗死7例、外周血管栓塞2例、死亡1例。华法林组终点事件总发生率显著低于阿司匹林组(3.92%比20.83%,P=0.010)。不良反应:华法林组:皮肤瘀斑3例、牙龈出血1例;阿司匹林组:黑便3例,两组总不良反应发生率无显著差异(P=0.934)。结论:华法林能显著降低老年AF患者终点事件的发生率,值得推广应用。     

Practical Considerations in the Use of Novel Oral Anticoagulants for Stroke Prevention in Nonvalvular Atrial Fibrillation

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia associated with an increased risk of stroke. The role of anticoagulation therapy in the prevention of thrombosis and stroke is of critical importance for patients with AF. Limitations with vitamin K antagonists (VKAs), the current standard of care, have led to the development of novel oral anticoagulants (NOACs) that target either thrombin (dabigatran etexilate) or activated factor X (rivaroxaban, apixaban, and edoxaban). In comparison with traditional VKAs such as warfarin, these NOACs offer several pharmacologic advantages, including rapid onset of action, no significant food interactions, low potential for drug–drug interactions, and no requirement for routine coagulation monitoring. Completed phase‐III clinical trials have demonstrated the therapeutic potential of dabigatran, rivaroxaban, and apixaban in comparison with warfarin for stroke prevention in patients with nonvalvular AF (NVAF). While the future utility of NOACs in preventing stroke in patients with NVAF looks promising, several practical issues, including the current lack of a reversal strategy and use of these agents in older patients with renal dysfunction, must be considered. Clinician and patient understanding of such issues will be important for the safe and effective use of NOACs.     

高龄非瓣膜性房颤的华法林治疗11例体会

目的:探讨华法林治疗高龄非瓣膜性房颤患者安全有效的抗凝强度。方法:对11例高龄非瓣膜房颤有抗凝适应证者予华法林治疗,将抗凝强度控制在INR为1.5~2.0,观察疗效和出血并发症。结果:观察期间11例患者无致命性出血,仅1例皮肤出血且未停药。7例患者反复发作的短暂性脑缺血发作和脑梗塞症状得到控制。3例有2种以上危险因素的患者未出现栓塞并发症。结论:低抗凝强度(INR1.5~2.0)抗凝对高龄非瓣膜性房颤患者安全有效。     

城郊高龄老年房颤患者华法林治疗的安全性

目的：探讨城郊高龄老年房颤患者应用华法林的安全性.方法：选择100例资料完整的老年房颤患者,按照数字表法,被随机分为华法林组（51例）：华法林起始剂量1.25 mg,1次/d.每隔3d测定血浆凝血酶原时间国际标准化比值（INR）1次.2～4周达到目标范围,如INR未达标,每隔1周增加华法林0.625 mg,直到INR控制在2.0～3.0.INR稳定前门诊随访每周监测1次,INR稳定后每4周监测1次;阿司匹林组（49例）：阿司匹林,100 mg,1次/d.结果：与阿司匹林组比较,华法林组血栓栓塞等终点事件发生率明显降低（19.15％比3.92％,P=0.017）,出血等不良反应发生率无显著差异（4.25％比5.88％,P＞0.05）.结论：高龄老年房颤患者应用华法林,能显著降低栓塞发生率,而且是安全的.     

Apixaban in patients with atrial fibrillation and prior coronary artery disease: Insights from the ARISTOTLE trial

Background

A substantial portion of patients with atrial fibrillation (AF) also have coronary artery disease (CAD) and are at risk for coronary events. Warfarin is known to reduce these events, but increase the risk of bleeding. We assessed the effects of apixaban compared with warfarin in AF patients with and without prior CAD.

Methods and results

In ARISTOTLE, 18,201 patients with AF were randomized to apixaban or warfarin. History of CAD was defined as documented CAD, prior myocardial infarction, and/or history of coronary revascularization. We analyzed baseline characteristics and clinical outcomes of patients with and without prior CAD and compared outcomes by randomized treatment using Cox models. A total of 6639 (36.5%) patients had prior CAD. These patients were more often male, more likely to have prior stroke, diabetes, and hypertension, and more often received aspirin at baseline (42.2% vs. 24.5%). The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism and death from any cause (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.71–1.27, P for interaction = 0.12; HR 0.96, 95% CI 0.81–1.13, P for interaction = 0.28). Rates of myocardial infarction were numerically lower with apixaban than warfarin among patients with and without prior CAD. The effect of apixaban on reducing major bleeding and intracranial hemorrhage was consistent in patients with and without CAD.

Conclusions

In patients with AF, apixaban more often prevented stroke or systemic embolism and death and caused less bleeding than warfarin, regardless of the presence of prior CAD. Given the common occurrence of AF and CAD and the higher rates of cardiovascular events and death, our results indicate that apixaban may be a better treatment option than warfarin for these high-risk patients.