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。     

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。     

伴有慢性肾脏疾病的心房颤动患者的抗凝治疗

慢性肾脏疾病是心房颤动的一个独立危险因素,伴有慢性肾脏疾病的心房颤动患者更易发生血栓栓塞疾病;但慢性肾脏疾病患者行抗凝治疗时,出血并发症的发生率增加。华法林在伴有慢性肾脏疾病的心房颤动患者抗凝治疗中对出血并发症的影响仍有争议,采用华法林抗凝应充分考虑药物的风险-效益比,进行个体化治疗,明确指征,避免用于高出血风险患者,并加强国际标准化比率监测。新型抗凝药物和左心耳封堵术在伴有慢性肾脏疾病的心房颤动患者的疗效还有待研究。     

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。     

一例口服华法林引起出血的病例分析

华法林是最古老的口服抗凝药物,目前仍是长期抗凝治疗中最常用的药物。华法林能有效减少房颤患者发生脑卒中的危险,是目前唯一可以降低房颤患者卒中和栓塞风险、降低病死率的药物。华法林是双香豆素的衍生物,可以抑制新的血栓形成,减少血栓扩大和进展,抑制血栓脱落预防栓塞,有利于清除形成的血栓。华法林抑制凝血因子羧基化,使凝血因子不能与磷脂表面结合,破坏其加速血液凝固[1]。出血风险增高是华法林最常见的不良反应。也是临床医生不能积极使用的主要原因。     

慢性肾脏病静脉血栓栓塞症抗凝治疗新进展

慢性肾脏病静脉血栓栓塞症抗凝治疗需平衡出血和血栓风险,本文根据各类抗凝药物特点,结合抗凝药物在慢性肾脏病中的研究进展、国内外最新抗凝、抗栓指南,综述了肾功能不同阶段选择的抗凝药物及剂量。新型直接口服抗凝药的使用是抗凝治疗的新进展,对于轻至中度肾功能不全者,新型直接口服抗凝药是一个合理的选择,阿哌沙班或可成为中重度肾功能不全伴静脉血栓栓塞症治疗药物华法林的替代。     

新型口服抗凝药物在房颤治疗及预后方面的研究进展

华法林是防治房颤卒中最有效抗凝药物。出血、频繁监测INR值等缺点限制了华法林临床使用率。新近一些新型口服抗凝药物的研究不断涌现,许多研究结果表明这些新型口服抗凝药物在预防卒中的作用中不劣于华法林,且出血风险可能较华法林低,故有望取代华法林这一传统抗凝药。本文系统回顾近年有关口服抗凝药的相关研究,并将这些研究进展综述如下。     

房颤患者预防栓塞性疾病临床治疗分析

目的：心房纤颤患者通过口服抗凝药物华法林治疗预防血栓栓塞并发症的临床分析。方法持续心房颤动(房颤)患者共120例,根据临床用药分为两组：阿司匹林组60例口服阿司匹林,华法林组60例口服华法林,进行临床观察,发生血栓栓塞疾病情况进行疗效评估。结果循环栓塞疾病并发症发生率,接受口服华法林抗凝治疗组明显低于口服阿司匹林抗血小板聚集治疗组。结论华法林能有效预防房颤患者血栓栓塞并发症。     

心房颤动合并慢性肾脏病患者口服抗凝药物治疗的研究进展

慢性肾病与心房颤动(房颤)密切相关并常常共存.慢性肾病和房颤均是血栓发生的危险因素,因此房颤合并慢性肾病人群其缺血性卒中及体循环栓塞的风险显著增加.对于普通的房颤人群,口服抗凝药物治疗是预防缺血性卒中和体循环栓塞发生的有效干预手段,并且慢性肾病还会增加出血风险,因此合并慢性肾病的房颤人群进行口服抗凝药物治疗可能并不具有...     

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。     

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。     

新型口服抗凝血药预防心房颤动患者发生卒中的疗效和安全性的Meta分析

目的采用Meta分析方法,评价新型口服抗凝血药预防心房颤动患者发生卒中的疗效和安全性。方法制定原始文献的纳人标准、排除标准及检索策略,用检索词“新型口服抗凝血药、心房颤动、卒中、栓塞”,通过对MEDLINE、EMBASE、Cochrane数据库和中国期刊全文数据库（CNKI）、万方数据资源系统等检索,获得新型口服抗凝血药预防心房颤动患者发生卒中的研究文献。使用国际Cochrane中心推荐的方法进行文献质量评价,采用RevMan5．2软件对满足纳入标准的有关新型口服抗凝血药预防心房颤动患者发生卒中的大样本随机对照研究（RCTs）进行Meta分析。选取卒中或全身性栓塞、任何原因导致的死亡作为主要疗效指标,出血性卒中和大出血作为主要安全指标,得出合并后的风险比（RR）及其95％可信区间（95％CI）进行定量综合评估。结果共检索出192篇文献,其中4篇RCT研究符合纳入标准,进行Meta分析。纳入研究的偏倚风险较小,研究间异质性较小。Meta分析结果显示,与华法林比较,新型口服抗凝血药显著降低心房颤动患者发生卒中或全身性栓塞（RR=0．83,95％CI：0．76～0．91,P〈0．0001）;显著降低发生任何原因导致的死亡（RR=0．89,95％CI：0．85～0．94,P〈0．0001）;显著降低发生出血性卒中（RR=0．47,95％CI：0．35～0．63,P〈0．00001）;降低发生大出血（RR=0．79,95％CI：0．65～0．97,P=0．02）。结论新型口服抗凝血药在预防心房颤动患者发生卒中的疗效和安全性方面,优于华法林。     

Renal profiles of anticoagulants

Anticoagulants are widely used to prevent and treat venous thromboembolism, prevent stroke in atrial fibrillation, and manage acute coronary syndrome. These drugs are often used in elderly patients, who commonly have renal impairment, comorbidities, and polypharmacy. Renal impairment is a risk factor for bleeding and thrombosis during anticoagulant therapy and can influence the balance between the safety and efficacy of such agents. Some of the more established anticoagulants, such as the low-molecular-weight heparins, warfarin, and fondaparinux, are contraindicated for use in patients with severe renal impairment. Of the new oral anticoagulants, dabigatran etexilate, rivaroxaban, and apixaban are at the most advanced stages of development. Dabigatran requires dose adjustment in patients with moderate renal impairment and is contraindicated in patients with severe renal impairment. Rivaroxaban can be administered as a fixed dose for the prevention of venous thromboembolism in patients with moderate renal impairment and should be used with caution in patients with severe renal impairment. Apixaban excretion is also partly dependent on renal function, although the impact of renal insufficiency has not been determined. Additional data on the safety of chronic dosing of the newer oral anticoagulants in renal impairment are awaited.     

Risk of major bleeding and thromboembolism in Asian patients with nonvalvular atrial fibrillation using direct oral anticoagulants versus warfarin

Background Bleeding and thromboembolism prevention is important in patients with nonvalvular atrial fibrillation receiving anticoagulants, including direct oral anticoagulants and warfarin. Asians have higher risks of bleeding complications when taking anticoagulants. However, evidence that considers laboratory parameters is lacking. Objective We aimed to compare the safety and effectiveness between direct oral anticoagulants and warfarin in Asian patients with nonvalvular atrial fibrillation. Setting Retrospective design using hospital-based data. Method This propensity score-matched cohort study included data extracted from the electronic medical records of the En Chu Kong Hospital Research Database. Main outcome measure Outcome measures were major bleeding and thromboembolism. Cox proportional hazard models were applied for evaluating hazard ratios with 95% confidence intervals. Results Among 1075 patients with nonvalvular atrial fibrillation, 687 and 388 were administered direct oral anticoagulants and warfarin, respectively. After propensity score matching, 264 patient pairs were selected. Compared with warfarin use, direct oral anticoagulant use was associated with similar risks for major bleeding and thromboembolism; however, the latter was associated with increased gastrointestinal bleeding risks (adjusted hazard ratio 3.59; 95% confidence interval, 1.31–11.39). Notably, an approximately 10 fold increased risk of gastrointestinal bleeding was observed in 0–6 month direct oral anticoagulant users (adjusted hazard ratio 10.13, 95% confidence interval 1.27–80.89). Conclusion Direct oral anticoagulant use was not associated with major bleeding and thromboembolism occurrence in Asian patients with nonvalvular atrial fibrillation. However, direct oral anticoagulant use was associated with increased gastrointestinal bleeding risks, especially when used within 0–6 months of direct oral anticoagulant use.

     

新型口服抗凝药物的安全性

新型抗凝药物主要包括直接凝血酶抑制剂和Xa因子抑制剂。其中,直接凝血酶抑制剂达比加群酯口服制剂、直接Xa因子抑制剂利伐沙班和阿哌沙班口服制剂已在我国上市;另外一种直接Xa因子抑制剂贝曲沙班口服制剂也正在进行Ⅲ期临床研究;而直接Xa因子抑制剂爱多沙班口服制剂已在日本上市。达比加群酯致颅内出血发生风险低于华法林,但该药可能增加急性冠状动脉综合征患者严重出血和具有临床意义轻度出血的发生率,以及心肌梗死或急性冠状动脉综合征的发生风险。利伐沙班在预防非瓣膜性心房颤动所致脑卒中和栓塞方面优于华法林,预防骨科术后血栓效果优于依诺肝素,大出血事件发生风险与两药相似,而颅内出血发生风险低于华法林。阿哌沙班在降低心房颤动患者脑卒中或全身性栓塞发生率及病死率方面优于华法林,颅内出血发生率低于华法林,大出血发生率与华法林相似或降低;阿哌沙班的安全性与用药剂量相关。爱多沙班的主要不良反应为出血,用于心房颤动患者的有效性及安全性均优于华法林。贝曲沙班用于全膝关节置换术后预防血栓效果与依诺肝素相似,出血发生率低于依诺肝素。     

More light at the end of the tunnel - apixaban in atrial fibrillation

INTRODUCTION: Subjects with atrial fibrillation are at risk of thromboembolic events. The vitamin K antagonists (e.g., warfarin) are useful at preventing coagulation in atrial fibrillation, but are difficult to use. One of the FXa inhibitors, oral apixaban, has been tested as an anticoagulant in atrial fibrillation. AREAS COVERED: In ARISTOTLE (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) apixaban was compared to warfarin in subjects with atrial fibrillation, and shown to cause a lower rate of stroke or systemic embolism and of major bleeding, than warfarin. In the AVERROES (Apixaban versus acetylsalicylic acid [ASA] to prevent stroke in atrial fibrillations patients who have failed or are unsuitable for vitamin K antagonist treatment) trial, stroke or systemic embolism occurred less often with apixaban than aspirin, whereas the occurrence of major bleeding was similar in the groups. EXPERT OPINION: Apixaban is much easier for subjects with atrial fibrillation to use than warfarin, as it does not require regular monitoring by a health professional, with dosage adjustment. In addition to replacing warfarin in subjects with atrial fibrillation who are unable or not prepared to use warfarin, apixaban has the potential to replace warfarin more widely in the prevention of thromboembolism in subjects with atrial fibrillation.     

Review of Challenges in Optimizing Oral Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation

Oral anticoagulant therapy is the mainstay of stroke prevention in patients with atrial fibrillation; it is highly effective at reducing stroke risk, but its use can be limited by increased risk of bleeding. As new oral anticoagulants are available, barriers to optimal use of oral anticoagulation therapy warrant consideration by healthcare professionals and administrators who are seeking to optimize the quality of care for patients with atrial fibrillation. Suboptimal use of oral anticoagulation therapy constitutes an important health problem with significant humanistic and economic consequences. Based on a review of the medical literature published between 2000 and 2011, this article summarizes the literature on the barriers to optimal use of oral anticoagulation therapy, describes the clinical and economic burdens that these barriers add to the burden of atrial fibrillation, and discusses how well the new oral anticoagulants may address some of these issues.     

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.     

我院心房颤动合并慢性肾脏病患者抗凝治疗状况的分析

目的：回顾性分析我院心房颤动（房颤）合并慢性肾脏病（CKD）患者的抗凝治疗状况,为提高抗凝治疗的合理性、安全性提供参考。方法：随机收集南通市第一人民医院2014年1月～2015年12月房颤合并CKD患者90例以及房颤但肾功能正常者90例的病历资料。对患者华法林使用率、抗血小板药使用率、抗栓药物的出血不良反应等情况进行分析,并分析年龄、合并慢性疾病、既往脑血管事件、出血风险评分等单因素对华法林使用率的影响。结果：房颤合并CKD患者的抗栓比例为68.9%,其中华法林抗凝比例为10.0%,低于肾功能正常患者;合并CKD患者的抗栓药物出血不良反应发生率为6.45%, CKD并未增加抗栓药物的出血不良反应发生率。华法林使用单因素分析提示高龄、冠心病、CKD对其影响较大。结论：我院房颤合并CKD患者的抗凝治疗严重不足。临床药师应加强药学服务,协助医师制定个体化用药方案,开展药学跟踪随访工作,确保抗凝治疗的延续性以及安全性。