New anticoagulants for venous thromboembolism and atrial fibrillation: what the future holds

Introduction: The field of anticoagulation has seen impressive progress over the last decade. The introduction of the Non Vitamin K Oral Anticoagulants (NOACs) has revolutionized practice surrounding thromboprophylaxis, treatment of thromboembolic disease and stroke prevention in atrial fibrillation (AF). However, the search for the ‘holy grail’ of anticoagulation, an agent that combines optimal efficacy with minimal bleeding diathesis, continues.

Areas covered: In this paper we aim to summarize the current evidence from pre-clinical studies and early phase clinical trials, presenting the pharmacodynamic and pharmacokinetic properties as well as the safety and efficacy profiles of the most important antithrombotic agents in development.

Expert opinion: Research focused on the development of new anticoagulation agents is rapidly expanding. Although the exploration of antithrombotic agents that act on well-established targets such factor Xa and thrombin remains the mainstay, attention has also shifted to other factors in the coagulation cascade. The evidence emerging from clinical research is growing, generating exciting possibilities in the field of anticoagulation.     

Thromboembolic and bleeding risks in patients undergoing atrial fibrillation ablation: oral anticoagulation perspectives

Introduction: Atrial fibrillation (AF) is a cause of significant morbidity and mortality. Catheter ablation for AF (CAAF) has emerged as an effective treatment option of rhythm control for patients with symptomatic AF. However, the risk of thromboembolism and bleeding in the periprocedural period represent a worrisome complication of this therapy. The reported incidence of thromboembolic and bleeding events associated with CAAF varies from 0.9% to 5% depending on the CAAF strategy and the anticoagulation regimen used in the periprocedural period.

Areas covered: The different anticoagulation regimens used prior to, during, and after CAAF to minimize the risk of thromboembolic and bleeding events are reviewed. The use of uninterrupted oral anticoagulation and appropriate heparin dosing to achieve safe activated clotting time levels are also detailed. A comprehensive approach with assessment of individual risk for thromboembolic and bleeding complications, and understanding the pharmacokinetics of the anticoagulant agents available is also reviewed.

Expert opinion: The key advances done in the periprocedural anticoagulation field include the use of uninterrupted anticoagulation strategies in patients undergoing AF ablation and efforts to simplify the selection of patients who need LAA thrombus screening prior to ablation.     

慢性房颤华法令抗凝治疗的理想INR值探讨

目的:探讨慢性房颤华法令抗凝治疗的理想国际标准化比值(INR)。方法:对115例有血栓栓塞高危因素的慢性房颤患者给予华法令抗凝治疗,定期随访INR,同时观察治疗中发生的血栓栓塞和出血事件。结果:115例患者中有8例共10次发生血栓栓塞事件,7例7次发生与抗凝有关的出血事件,10次血栓栓塞事件中9次发生在INR<1.7,而所有的出血事件都发生在INR>3.5,INR 1.7～3.5时栓塞或出血发生率均较低。结论:INR 1.7～3.5是慢性房颤华法令抗凝治疗较理想的抗凝强度。     

老年心房颤动并发脑栓塞及抗凝治疗临床研究

目的探讨老年房颤患者并发脑栓塞的危险因素以及抗凝治疗的现状。方法我们对2007年1月至2012年1月106例老年房颤患者的危险因素、超声心动图心脏附壁血栓发现率、抗凝治疗及脑梗死发生情况,同时观察心脏病无房颤患者及非心脏病无房颤患者脑梗死发生情况。结果 106例房颤患者中,病因以冠心病（59.43%）、高心病（11.32%）、心肌病（包括扩张性和肥厚性心肌病）5.66%为常见;超声心动图检查,于左心房发现附壁血栓3例;房颤组脑梗死发生率为35.8%,心脏病无房颤组脑梗死发生率为15.3%,而非心脏病无房颤组脑梗死发生率为3.8%;持续性房颤患者中未用或偶尔使用抗凝剂者和长期使用者脑梗死发生率分别为53.3%和35.7%。结论房颤是老年人脑梗死发生的危险因素之一,抗凝治疗能够降低这种危险。     

住院心房颤动患者抗凝治疗现状分析

目的了解住院心房颤动（房颤）患者抗凝治疗中存在的问题,为更加安全的抗凝治疗提供依据。方法收集2013年1月1日至8月31日在江苏省苏北人民医院心内科住院治疗的所有非瓣膜性房颤患者病历资料进行回顾性分析。根据2010年《欧洲心脏病学会（ESC）心房颤动治疗指南》,采用CHADS2-VASc评分和HAS—BLED评分分别对患者进行血栓栓塞危险程度分层和出血风险评估。主要分析指标为接受不同房颤治疗方案（室率控制,节律控制）患者的血栓栓塞危险分层,出血风险评分,抗凝药物应用情况、国际标准化比值（INR）、出血合并症、血栓栓塞事件、患者用药依从性等。结果纳入分析的患者共134例,男性69例,女性67例;年龄20～91岁,平均（67±14）岁,CHA2DS2-VASe评分为0、1和≥2分者分别为11、23和100例,HAS—BELD评分≥3分者13例。接受室率控制和节律控制治疗者分别为85和49例。接受室率控制治疗的85例患者中CHA2DS2-VASe评分为0、1、≥2分者分别为1、12、72例。0分者1例使用阿司匹林。1分者12例中2例应用华法林,2例未行抗凝治疗（1例有禁忌证）,8例使用抗血小板药物（阿司匹林、氯吡格雷单用或二药联用）,其中2例单用氯吡格雷患者头颅CT检查均有多发性缺血灶。≥2分者72例中33例应用华法林,35例应用抗血小板药物,4例未行抗凝治疗。接受华法林抗凝治疗的患者出院时25例INR〈2．0,7例INR为2．0～3．0,1例INR〉3．0。接受节律控制治疗的49例患者CHA2DS2-VASe评分平均为（2．3±1．8）,HAS—BLED评分平均为（1．3±1．1）,其中25例应用华法林,出院时17例INR〈2．0,5例INR为2．0～3．0,2例INR〉3．0。1例患者未监测INR。134例患者中有15例（11．2％）出现脑梗死,其中8例（53．3％）应用华法林抗凝治疗,患者出院时INR均未达标。结论住院房颤患者抗凝治疗中存在的主要问题是采用华法林抗凝的比例较低,采用华法林治疗的部分患者抗凝强度不足。临床医师过分担心发生出血合并症是抗凝治疗不规范的主要原因。     

200例非瓣膜性心房颤动住院病人抗凝治疗现状及影响因素分析

目的 了解非瓣膜性心房颤动(NVAF)住院病人抗凝治疗的现状并探讨其影响因素。方法 回顾性分析2017年1—5月南京医科大学附属南京医院200例NVAF住院病人的临床特征及抗凝治疗方案,应用CHA₂DS₂-VASc和HAS-BLED评分对卒中风险和出血风险进行评估;根据危险分层分析抗凝药物的临床应用情况;并运用logistic回归分析讨论抗栓治疗的影响因素。结果 入选病人CHA₂DS₂-VASc评分平均(4.55±2.01)分,卒中高危组189例(94.5%),卒中中危组11例(5.5%);HAS-BLED评分平均(2.04±1.26)分,高出血风险组69例(34.5%),低出血风险组131例(65.5%)。仅36.0%病人接受抗凝治疗,抗凝治疗率随卒中风险的增加呈先升后降的趋势,卒中高危组抗凝治疗率(36.5%)高于卒中中危组(27.3%),差异无统计学意义(χ²=1.305,P=0.521);抗凝治疗率随着出血评分的增加而降低,低出血风险组的抗凝治疗率(44.3%)高于高出血风险组(20.3%),且差异有统计学意义(χ²=11.350,P=0.003)。抗凝亚组中,高出血风险组较低出血风险组倾向于选择新型口服抗凝药(P=0.031)。logistic回归分析表明合并血管疾病(OR=0.867)、药物(OR=2.182)、PCI术后(OR=3.557)、房颤消融术后(OR=0.255)及病人因素(OR=4.504)均影响抗凝方案的选择,且PCI术后和病人因素的影响差异有统计学意义(P＜0.05)。结论 目前南京医科大学附属南京医院对NVAF的抗凝治疗与指南推荐有一定的差距,未按危险分层标准抗凝且整体的抗凝治疗率低。     

高风险冠心病合并房颤用抗凝和双联抗栓治疗的疗效及安全性观察

目的观察冠心病合并房颤患者抗栓与抗凝治疗的疗效及安全性。方法将67例栓塞风险评分（CHADS2）为3-6分,出血风险评分（HEMORR2HAGES）〉2分的冠心病合并房颤患者随机分为抗凝组与抗栓组,抗凝组使用华法林钠,抗栓组使用阿司匹林和氢氯吡格雷,随访观察4年,比较两组栓塞事件及出血事件的发生情况,并重新使用2010版血栓栓塞风险评估评分法（CHA2DS2-VASC）和出血风险评估法（HAS—BLED）进行回顾性评分。结果抗凝组栓塞事件发生较抗栓组明显减少,两组差异有统计学意义;而出血风险抗凝组较抗栓组有增高趋势．但差异无统计学意义。结论抗凝治疗可以减少高卒中高出血风险冠心病合并房颤患者栓塞风险。     

静脉血栓栓塞患者凝血与抗凝血因子活性或含量的测定

目的观察静脉血栓栓塞患者血浆凝血因子和抗凝血因子活性或含量变化。方法95例静脉血栓栓塞患者和95名正常对照,用定量乳胶凝集试验行D-二聚体含量检测;一期法检测血浆凝血因子Ⅱ活性(FⅡ∶C)、凝血因子Ⅴ活性(FⅤ∶C)、凝血因子Ⅷ活性(FⅧ∶C)和凝血因子Ⅸ活性(FⅨ∶C);发色法底物检测蛋白C活性(PC∶A)和抗凝血酶活性(AT∶A)。结果与对照组相比,静脉血栓栓塞组血浆纤维蛋白原(Fg)含量、D-二聚体含量、FⅡ∶C、FⅤ∶C和FⅧ∶C水平均明显增高,FⅨ∶C与对照组比较差异无统计学意义(P>0.05);而PC∶A和AT∶A水平在静脉血栓栓塞组虽有降低,但与对照组比较差异无统计学意义(P>0.05)。结论凝血因子联合作用在静脉血栓栓塞发病中起主要作用。     

Cost effectiveness of rivaroxaban versus warfarin among nonvalvular atrial fibrillation patients in Saudi Arabia: A Single–Center retrospective cohort study

BackgroundRivaroxaban is a novel oral anticoagulant (NOAC) that is commonly used for stroke prevention among patients with atrial fibrillation (AF). However, its cost effectiveness in reducing the risk of hospitalization and mortality in comparison to warfarin among nonvalvular AF patients in Saudi Arabia is largely unknown.MethodsThis was a single-center retrospective chart review of adult patients (≥18 years) with nonvalvular AF who were treated with warfarin or rivaroxaban for at least 12 months. Patients with mitral valve stenosis were excluded from the study. Multiple logistic regression was conducted to examine the risk of hospitalization and mortality as a composite outcome, and all annual healthcare costs were captured. Inverse probability treatment weighting with bootstrapping was conducted to determine the mean costs and effectiveness rates.ResultsTwo-hundred and twenty-six patients (142 on rivaroxaban and 84 on warfarin) met the inclusion criteria and were included in the analysis. Most of the patients were females (65.91 %), had diabetes (50.57 %) and hypertension (73.76 %), and with a mean age of 68.95 ± 12.55 years. No significant difference in the odds of the composite outcome for rivaroxaban versus warfarin was found (OR = 0.785, 95 % CI = [0.427–1.446], p = 0.443). Rivaroxaban resulted in a mean annual cost saving of $13,260.79 with an 87.65 % confidence level that it would be more effective than warfarin with a mean difference in effectiveness rate of 0.168 % (95 % CI [-5.210–18.36]).ConclusionRivaroxaban was associated with lower direct medical costs and non-inferior effectiveness among nonvalvular AF patients in comparison to warfarin.     

心房颤动188例临床分析

目的探讨心房颤动（房颤）的基础疾病、并发症及抗凝治疗情况。方法选取1993年1月到2006年12月期间在我院住院的房颤患者188例，采用回顾性分析方法对其进行研究。结果与房颤相关的病因谱发生明显变化：风湿性瓣膜疾病已由第1位下降，而高血压、冠心病等心血管疾病成为房颤的主要相关疾病；栓塞性疾病是房颤的严重并发症；华法林使用比率很低。结论房颤的防治应引起临床关注，尤其应加强对房颤诱因的监测和治疗，以及房颤的抗凝治疗。     

肺癌并静脉血栓栓塞症的危险因素分析

目的 总结我院38例肺癌合并静脉血栓患者的临床资料,探讨其发生的危险因素.方法 对2010年4月至2015年7月本院38例肺癌合并静脉血栓患者(血栓组)与同期76例不存在静脉血栓的肺癌患者(非血栓组)的临床资料进行回顾性病例-对照分析.单因素分析后,对有可能有意义的因素进行多因素Logistic回归分析,查找肺癌合并静脉血栓的危险因素.结果 单因素分析显示腺癌、ⅢB～Ⅳ期、D二聚体增高、中心静脉置管、CEA增高是发生静脉血栓的危险因素(P＜0.05).多因素回归分析显示腺癌、ⅢB～Ⅳ期、D二聚体增高是肺癌发生静脉血栓的独立危险因素(P＜0.05).结论 肺腺癌、肿瘤晚期、D二聚体增高是肺癌合并静脉血栓的高危因素.     

心房纤颤并发血栓栓塞危险因素分析

目的：研究分析心房纤颤并发血栓栓塞危险因素。方法：选用中山医科大学附一院就诊的患者90例,随机分为A、B组,所有患者入院时经胸超声采用HP5500型彩超仪,探头频率为3.5MHz。准确测量LA内径,并仔细探察左房,尤其是左心耳有无附壁血栓。患者于清晨、空腹、仰卧状态下,用抽取肘静脉血,经过一定的处理过程,采用酶联免疫吸附双抗体夹心法测定血管性假血友病因子（vWF）,血浆凝血酶-抗凝血酶复合物（TAT）,D-二聚体（D-D）及P-选择素（GMP-140）。结果：A组的LA内径明显高于B组,差异有统计学意义（P〈0.05）。A组患者的血浆vWF、TAT、D-D也明显高于B组,差异有统计学意义,而两组的P-选择素差别不大。房颤患者血栓栓塞的独立危险因素为,D-D浓度增高、LA内径增大、TAT浓度增大,且D-D浓度增高的相对危险度（OR值）较大。结论：房颤患者血栓栓塞的独立危险因素是vWF、D-D浓度增高、LA内径增大,且D-D浓度增高的危险因素高于其他因素,结合多个危险因素,可提高诊断房颤血栓栓塞的特异性,更可靠地分析血栓栓塞危险性。     

Quality measures for anticoagulation care

Objective: To systematically identify and assess current quality measures for anticoagulation in atrial fibrillation (AF), venous thromboembolism (VTE) treatment and surgical VTE prophylaxis.

Research design and methods: Fifteen quality measure websites were searched as were bibliographic databases (January 2000–February 2016). Quality measures were included if developed in the United States and incorporating an aspect of anticoagulation for the aforementioned indications or if applicable but not indication specific (non-disease specific measure). Two reviewers independently extracted data regarding the characteristics of each quality measure.

Results: Thirty-five measures were identified, mostly in VTE treatment (48.6%), followed by non-disease specific measures (25.7%), AF (17.6%) and surgical VTE prophylaxis (8.8%). Process measures predominated (82.9%). A majority of quality measures (65.7%) were focused on parenteral anticoagulants or warfarin and not applicable to novel oral anticoagulants (NOACs). Ten (28.6%) measures are used by the Centers for Medicare and Medicaid Services or as a core measure of The Joint Commission. Limitations include the inability to statistically pool data and possible publication bias given the nature of databases for quality measures.

Conclusions: Quality measures are recognized in anticoagulation care. Areas for improvement include expanding beyond process measures and capturing adverse events and the advantages offered by NOACs.     

Anticoagulant effects of Idraparinux after termination of therapy for prevention of recurrent venous thromboembolism: observations from the van Gogh trials

Aim To gather information on anticoagulant effects after the termination of long-term therapy with idraparinux. Methods The anticoagulant effects of idraparinux, a synthetic polymethylated analogue of its pentasaccharide, were analysed in 23 patients after termination of a 6- or 12-month therapy period for the prevention of recurrent venous thromboembolism (VTE). Plasma samples of patients initially randomized to 2.5 mg idraparinux (normal creatinine clearance) or 1.5 mg idraparinux (creatinine clearance <30 ml/min) were investigated in the van Gogh trials. At 3-month intervals for up to 15 months following the termination of the therapy, the factor Xa-specific S2222 chromogenic substrate (aXa) assay and Heptest were used to determine various pharmacokinetic parameters and prothrombin-induced clotting time (PiCT), activated partial thromboplastin time (aPTT) and prothrombin time (PT) were determined. Results Based on the aXa assay and Heptest, the half lives (t1/2) were 60.2 days and 107.7 days (p < 0.0001), maximum drug concentrations (Cmax) were 0.30 and 0.39 μg/l (p = 0.0016), areas under the activity time curve (AUC) were 33.7 and 38.0 μg/l per day (p = 0.0002), plasma clearances were 0.09 and 0.06 ml/min (p < 0.0001), mean residence times (MRT) were 75.4 and 121.9 (p < 0.0001) and volumes of distribution (Vdiss) were 7.4 and 8.6 l (p = 0.1336), respectively. After 12 months of treatment (n = 18), the S2222 and Heptest results showed significantly higher Cmax and AUC, lower Vdiss and clearance and unchanged t1/2 and MRT values compared to 6 months of treatment (n = 5). The PiCT was prolonged for a period of 9 months. Coagulation times of aPTT and PT were not influenced. The results of these parameters did not differ between 12 and 6 months of treatment. Conclusion The data support reports on a non-ionic binding of idraparinux to antithrombin and other proteins. We suggest that these findings may explain some of the findings of the van Gogh Extension trial.     

典型房扑射频消融术后部分患者发生房颤的危险因素分析

目的 分析典型房扑射频消融术后部分患者发生房颤的危险因素。方法 选择2015年2月至2018年2月六安市人民医院体表心电图提示典型房扑、电生理检查均证实为三尖瓣环峡部依赖性房扑并成功给予三尖瓣峡部线性消融（CTIA）手术的患者68例,随访6～34个月。根据术后随访是否发生房颤分为两组,其中发生房颤组23例,未发生房颤组45例,比较两组患者年龄、基础疾病、P波宽度及离散度、左房内径（LAD）、左室舒张末内径（LVEDD）、左室射血分数（LVEF）及口服药物的差异。结果 两组患者的P波宽度、P波离散度、LAD、LVEDD、LVEF进行比较,差异有统计学意义（P<0.05）。logistic回归分析显示,LAD、P波宽度及离散度是典型房扑射频消融术后发生房颤的独立危险因素。结论 LAD、P波宽度及离散度是预测典型房扑射频消融术后发生房颤的重要指标。     

房颤患者不同评分方法对危险分层后预防性抗凝治疗的影响

目的 探讨房颤患者预防缺血性脑卒中评分方法的适宜性.方法 选择房颤患者80例随机分为两组,A组患者采用CHADS2评分,B组采用CHA2DS2-VAS评分,分别建立随访档案,了解是否有缺血性脑卒中、死亡及主要出血事件的发生.结果 A组发生缺血性脑卒中7例,B组1例,差异有统计学意义(P＜0.05).结论 用CHA2DS2-VAS评分进行危险分层,对高危患者采用抗凝预防治疗,安全有效.     

Quality of oral anticoagulation control in Chinese patients with non-valvular atrial fibrillation: a prospective controlled study

Abstract

Objective

The sex, age, medical history, treatment, tobacco use, race risk (SAMe-TT₂R₂) Score; the sex, age, medical history, treatment, tobacco use, genotype combination (SAMe-TT₂G₂) Score; and the so-called modified SAMe-TT₂R₂ scores have been proposed to predict the anticoagulation quality for patients with non-valvular atrial fibrillation (NVAF). The data from a prospective controlled study is used to validate the SAMe-TT₂R₂ and SAMe-TT₂G₂ scores in Chinese NVAF patients treated with warfarin and to evaluate the association of factors with time in therapeutic range (TTR) to predict the quality of oral anticoagulation control.     

观察华法林及阿司匹林分别对非瓣膜性心房颤动患者血栓栓塞的影响

目的观察华法林及阿司匹林对非瓣膜性心房颤动患者血栓栓塞事件的影响。方法80例非瓣膜性心房颤动患者分为华法林组及阿司匹林组,阿司匹林组每天服用阿司匹林100 mg,华法林组根据国际标准化比值(INR)调整华法林用量,随访时间为2 a。结果阿司匹林组死亡2例,1例为缺血性卒中,另1例为心力衰竭;华法林组1例为猝死。阿司匹林组发生栓塞事件共8例,出血并发症3例;华法林组发生栓塞事件共3例,出血并发症7例。结论华法林可明显降低非瓣膜性房颤患者血栓栓塞事件,但出血并发症稍增多,关键是要严密随访INR。