Comparison of effectiveness and safety of treatment with apixaban vs. other oral anticoagulants among elderly nonvalvular atrial fibrillation patients

Objective: To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) of elderly (≥65 years of age) nonvalvular atrial fibrillation (NVAF) patients initiating apixaban vs. rivaroxaban, dabigatran, or warfarin.

Methods: NVAF patients with Medicare Advantage coverage in the US initiating oral anticoagulants (OACs, index event) were identified from the Humana database (1 January 2013–30 September 2015) and grouped into cohorts depending on OAC initiated. Propensity score matching (PSM), 1:1, was conducted among patients treated with apixaban vs. each other OAC, separately. Rates of S/SE and MB were evaluated in the follow-up. Cox regressions were used to compare the risk of S/SE and MB between apixaban and each of the other OACs during the follow-up.

Results: The matched pairs of apixaban vs. rivaroxaban (n?=?13,620), apixaban vs. dabigatran (n?=?4654), and apixaban vs. warfarin (n?=?14,214) were well balanced for key patient characteristics. Adjusted risks for S/SE (hazard ratio [HR] vs. rivaroxaban: 0.72, p?=?.003; vs. warfarin: 0.65, p?p?p?p?=?.27) and MB (HR: 0.82, p?=?.23) of NVAF patients treated with apixaban vs. dabigatran trended to be lower, but did not reach statistical significance.

Conclusions: In the real-world setting after controlling for differences in patient characteristics, apixaban is associated with significantly lower risk of S/SE and MB than rivaroxaban and warfarin, and a trend towards better outcomes vs. dabigatran among elderly NVAF patients in the US.     

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。     

阿哌沙班预防心房颤动患者的卒中

阿哌沙班是激活Ⅹ因子(Ⅹa)抑制剂,具有快速吸收、线性药代动力学、较少药物相互作用的特点。在不适合接受华法林治疗的心房颤动人群中所进行的随机对照试验证实,阿哌沙班在减少卒中和系统栓塞方面的疗效优于阿司匹林,安全性相似;在至少有1个危险因素的心房颤动人群中进行的与华法林的对照试验中,阿哌沙班可减少卒中和栓塞事件,主要是减少出血性卒中,同时减少重要出血和全因死亡。     

新型抗凝药与华法林用于非瓣膜性房颤患者卒中防治的成本效果分析

目的:评估中国非瓣膜性房颤患者使用新型抗凝药预防卒中的成本效果,为中国房颤患者抗凝治疗药物的合理选用提供理论依据。方法:基于全球性临床试验ARISTOTLE、RE-LY及ROCKET-AF的研究数据及我国目前医疗成本,建立一年期决策树及长期外推Markov模型的方法,通过分别计算3种新型口服抗凝药物阿哌沙班(5 mg bid)、达比加群(150 mg bid、110 mg bid)、利伐沙班(20 mg qd)和华法林的调整质量生命年(QLAYs)及治疗成本,对新型抗凝药物用于中国房颤患者卒中预防的成本效果进行了分析和研究。结果:NOACs治疗的总成本为163586~582710元,使用NOACs患者可获得的质量调整生命年为6.812~7.010。以华法林为参考的增效成本效果分析显示,成本效果比(ICER)为177271~739480元/QLAY,ICER_利伐沙班> ICER_阿哌沙班> ICER_{达比加群150 mg}> ICER_{达比加群110 mg}。3种抗凝药物与华法林比较的ICER均大于我国人均国民生产总值(GDP)的3倍,但小于部分城市人均GDP的3倍。一维敏感度分析显示该成本效果分析结果稳定可靠。结论:目前在我国,与华法林相比,使用新型抗凝药物预防非瓣膜性房颤患者卒中不具备成本效果优势。目前仅在我国经济发达的某些城市,可推荐阿哌沙班或达比加群用于房颤卒中的治疗。     

中国非瓣膜性心房颤动患者华法林使用不足的相关因素分析

目的:评估中国首发缺血性卒中或短暂性脑缺血发作(TIA)的已知非瓣膜性心房颤动(NVAF)患者华法林的使用情况及使用不足的相关因素。方法:从中国国家卒中登记数据库(CNSR)中连续筛选首发缺血性卒中或TIA的NVAF患者,筛选已知心房颤动和新发心房颤动患者,评估华法林在适合抗凝治疗的已知心房颤动患者中的使用比例。采用多变量logistic回归模型评估华法林使用不足的相关因素。结果:在筛选出的11 080例首发缺血性卒中或TIA患者中,有996例(9.7%)患者存在NVAF且无抗凝治疗禁忌症,其中有592例既往已知存在心房颤动。在这些患者中,只有96例(16.2%)发病前服用了华法林,496例(83.8%)发病前未服用华法林。在服用华法林的患者中,只有1例患者入院时的国际标准化比值(INR)在治疗范围(2.0～3.0)内。依据CHADS2卒中风险评分,在卒中发生前的低危心房颤动患者中,有近20.2%的患者服用了华法林,而在中危及高危患者中,华法林的服用比例分别只有15.2%和16.4%。年老的和既往存在冠心病病史的患者服用华法林的可能性较小,而发病前服用抗血小板药物的患者更有可能服用华法林。结论:CNSR中首发缺血性卒中或TIA的NVAF患者中,适宜抗凝治疗的患者存在严重的华法林使用不足,即使接受抗凝治疗,达标率也极低。如果发病前给予合适的抗凝治疗并监测,许多由心房颤动导致的卒中和TIA就可避免。     

An early evaluation of bleeding-related hospital readmissions among hospitalized patients with nonvalvular atrial fibrillation treated with direct oral anticoagulants

Objective:

Clinical trials have demonstrated that direct oral anticoagulants (DOACs) are efficacious in reducing stroke risk among patients with nonvalvular atrial fibrillation (NVAF) with differences in the reduction of bleeding risks vs. warfarin. The objective of this study was to assess bleeding-related hospital readmissions among hospitalized NVAF patients treated with dabigatran, rivaroxaban, and apixaban in the US.

Research design and methods:

Patients (≥18 years) with a discharge diagnosis of NVAF who received apixaban, dabigatran, or rivaroxaban during hospitalization were identified from the Premier Hospital database (1 January 2012–31 March 2014) and the Cerner Health Facts hospital database (1 January 2012–31 August 2014). Patients identified from each database were analyzed separately and grouped into three cohorts depending on which DOAC was received. Patient characteristics, hospital resource use and costs, and frequency of readmissions within 1 month were evaluated.

Results:

Among study populations identified from the Premier database (N?=?74,730) and the Cerner database (N?=?14,201), patients who received apixaban were older, had greater comorbidity, and had higher stroke and bleeding risks. After controlling for patient characteristics, including comorbidity and stroke and bleeding risks, compared with patients who received apixaban during their index hospitalizations, the odds of bleeding-related hospital readmissions were significantly greater by 1.4-fold (p?<?0.01) for patients who received rivaroxaban and 1.2-fold (p?=?0.16) numerically greater for patients who received dabigatran among patients identified from the Premier Hospital database. Among patients in the Cerner Health Facts hospital database, bleeding-related hospital readmissions were significantly greater by 1.6-fold (p?=?0.04) for patients who received rivaroxaban and 1.3-fold (p?=?0.30) numerically greater for patients who received dabigatran compared to patients who received apixaban.

Limitations:

No causal relationship between treatment and outcomes can be concluded.

Conclusions:

NVAF patients using different DOACs had different characteristics, including stroke and bleeding risks. Use of rivaroxaban, compared to apixaban was associated with significantly greater risk of bleeding-related readmissions across two database claims analyses.     

Risk of stroke/systemic embolism,major bleeding and associated costs in non-valvular atrial fibrillation patients who initiated apixaban,dabigatran or rivaroxaban compared with warfarin in the United States Medicare population

Objective: To compare the risk and cost of stroke/systemic embolism (SE) and major bleeding between each direct oral anticoagulant (DOAC) and warfarin among non-valvular atrial fibrillation (NVAF) patients.

Methods: Patients (≥65 years) initiating warfarin or DOACs (apixaban, rivaroxaban, and dabigatran) were selected from the Medicare database from 1 January 2013 to 31 December 2014. Patients initiating each DOAC were matched 1:1 to warfarin patients using propensity score matching to balance demographics and clinical characteristics. Cox proportional hazards models were used to estimate the risks of stroke/SE and major bleeding of each DOAC vs. warfarin. Two-part models were used to compare the stroke/SE- and major-bleeding-related medical costs between matched cohorts.

Results: Of the 186,132 eligible patients, 20,803 apixaban–warfarin pairs, 52,476 rivaroxaban–warfarin pairs, and 16,731 dabigatran–warfarin pairs were matched. Apixaban (hazard ratio [HR]?=?0.40; 95% confidence interval [CI] 0.31, 0.53) and rivaroxaban (HR?=?0.72; 95% CI 0.63, 0.83) were significantly associated with lower risk of stroke/SE compared to warfarin. Apixaban (HR?=?0.51; 95% CI 0.44, 0.58) and dabigatran (HR?=?0.79; 95% CI 0.69, 0.91) were significantly associated with lower risk of major bleeding; rivaroxaban (HR?=?1.17; 95% CI 1.10, 1.26) was significantly associated with higher risk of major bleeding compared to warfarin. Compared to warfarin, apixaban ($63 vs. $131) and rivaroxaban ($93 vs. $139) had significantly lower stroke/SE-related medical costs; apixaban ($292 vs. $529) and dabigatran ($369 vs. $450) had significantly lower major bleeding-related medical costs.

Conclusions: Among the DOACs in the study, only apixaban is associated with a significantly lower risk of stroke/SE and major bleeding and lower related medical costs compared to warfarin.     

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.     

Stroke prevention in atrial fibrillation patients

Importance of the field: Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and is associated with an increased risk of stroke, mortality and significant morbidity. Given the rapidly increasing incidence and prevalence of AF, and the resulting public health burden of the consequences associated with this arrhythmia, stroke prevention is an extremely important topic.

Areas covered in this review: This review covers the epidemiology of AF, the pathophysiology of ischemic stroke in AF and current antithrombotic therapy choices for stroke prevention in this condition. In addition, this article discusses important topics such as the assessment of stroke risk stratification and bleeding risk assessment, which are key issues in deciding upon thromboprophylaxis for AF patients. Finally, the review highlights the advent of new anticoagulant therapies and discusses the future challenges for researchers in this area.

What the reader will gain: This review summarizes all of the major antithrombotic trials conducted in AF patients over the last twenty years and highlights the importance of anticoagulation therapy for the prevention of stroke, after appropriate individual stroke and bleeding risk assessment.

Take home message: Assessment of individual stroke risk and bleeding risk is key in determining appropriate thromboprophylaxis for AF patients, given the associated thromboembolic and hemorrhagic complications. The availability of newer, safer and more convenient drugs will mean that oral anticoagulation is available for a larger proportion of AF patients who may benefit from it.     

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。     

Impact of renal function on ischemic stroke and major bleeding rates in nonvalvular atrial fibrillation patients treated with warfarin or rivaroxaban: a retrospective cohort study using real-world evidence

Objectives: Renal dysfunction is associated with increased risk of cardiovascular disease and is an independent predictor of stroke and systemic embolism. Nonvalvular atrial fibrillation (NVAF) patients with renal dysfunction may face a particularly high risk of thromboembolism and bleeding. The current retrospective cohort study was designed to assess the impact of renal function on ischemic stroke and major bleeding rates in NVAF patients in the real-world setting (outside a clinical trial).

Methods: Medical claims and Electronic Health Records were retrieved retrospectively from Optum’s Integrated Claims–Clinical de-identified dataset from May 2011 to August 2014. Patients with NVAF treated with warfarin (2468) or rivaroxaban (1290) were selected. Each treatment cohort was stratified by baseline estimated creatinine clearance (eCrCl) levels. Confounding adjustments were made using inverse probability of treatment weights (IPTWs). Incidence rates and hazard ratios of ischemic stroke and major bleeding events were calculated for both cohorts.

Results: Overall, patients treated with rivaroxaban had an ischemic stroke incidence rate of 1.9 per 100 person-years (PY) while patients treated with warfarin had a rate of 4.2 per 100 PY (HR?=?0.41 [0.21–0.80], p?=?.009). Rivaroxaban patients with an eCrCl below 50?mL/min (N?=?229) had an ischemic stroke rate of 0.8 per 100 PY, while the rate for the warfarin cohort (N?=?647) was 6.0 per 100 PY (HR?=?0.09 [0.01–0.72], p?=?.02). For the other renal function levels (i.e. eCrCl 50–80 and ≥80?mL/min) HRs indicated no statistically significant differences in ischemic stroke risks. Bleeding events did not differ significantly between cohorts stratified by renal function.

Conclusions: Ischemic stroke rates were significantly lower in the overall NVAF population for rivaroxaban vs. warfarin users, including patients with eCrCl below 50?mL/min. For all renal function groups, major bleeding risks were not statistically different between treatment groups.     

Safety and efficacy of non-vitamin K oral anticoagulants in non-valvular atrial fibrillation: a Bayesian meta-analysis approach

Introduction: Choosing between different non-vitamin K antagonist oral anticoagulants (NOACs) in non-valvular atrial fibrillation (NVAF) is difficult due to the absence of head to head comparative studies. We performed a Bayesian meta-analysis to explore similarities and differences between different NOACs and to rank treatments overall for safety and efficacy outcomes.

Areas covered: Through a systematic literature search we identified randomized controlled Phase III trials of dabigatran, rivaroxaban, apixaban, and edoxaban versus adjusted-dose warfarin in patients with NVAF.

Expert opinion: Warfarin ranked worst for all-cause mortality and intracranial bleedings and had a nil probability of ranking first for any outcome. The risk of major bleeding versus warfarin was lower with apixaban, dabigatran 110 mg, and both doses of edoxaban. All agents reduced the risk of intracranial bleeding versus warfarin. Edoxaban 30 mg was the best among the treatments being compared for major and gastrointestinal bleeding. Dabigatran 150 mg was the best for stroke and systemic embolism. This study suggests that NOACs are generally preferable to warfarin in patients with NVAF. However, safety and efficacy differences do exist among NOACs, which might drive their use in specific subsets of AF patients, allowing prescribers to tailor treatment to distinct patient profiles.     

达比加群酯预防房颤患者卒中的临床研究

目的 观察达比加群酯预防房颤患者卒中的疗效及安全性。方法 纳入房颤患者80例均符合抗凝治疗指征。按照奇偶数法随机分为观察组（n=40）和对照组（n=40）。观察组给予达比加群酯110 mg,2次/d;对照组给予华法林2.5 mg/d,并定期测定国际标准化比值（INR）,根据INR调整剂量。两组疗程均为6个月。记录两组患者卒中、全身性栓塞和大出血发生情况。两组患者出院时检查凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）、纤维蛋白原（FIB）和D-二聚体等凝血指标。结果 观察组患者卒中/全身性栓塞的发生率为17.5%,对照组为37.5%,两组患者卒中/全身性栓塞发生率有统计学差异（P<0.05）;观察组患者大出血发生率显著低于对照组,差异有统计学意义（P<0.05）。两组患者凝血功能指标差异均无统计学意义。治疗后,两组血脂水平均较治疗前显著改善,同组治疗前后比较差异有统计学意义（P<0.05）;且观察组血脂水平改善更为明显,组间差异有统计学意义（P<0.05）。结论 与华法林比较,对有房颤患者行抗凝治疗达比加群酯具备同等疗效,且安全性更高。     

非瓣膜性房颤患者应用达比加群相关出血事件的危险因素分析

目的:分析非瓣膜性房颤患者服用达比加群发生出血的危险因素。方法:本研究是一个单中心、回顾性研究,旨在探索达比加群相关出血事件的危险因素。应用某院电子病历管理系统,收集于2014年11月-2016年7月期间517例接受达比加群抗凝治疗的非瓣膜性房颤患者资料,包括患者年龄、性别、体质量、血常规、血脂、血糖、肝肾功能、合并疾病以及治疗药物等。结果:所有纳入研究的患者住院期间共有49例(9.5%)发生了出血,468例(90.5%)未发生出血。2组患者在性别、体质量、用药前红细胞压积、血小板计数、肝功能、血脂、空腹血糖、凝血指标以及合并高血脂症、肝功能不全和心功能不全方面的差异无显著性。然而,出血事件往往倾向发生于老年以及合并高血压和糖尿病的患者。肾功能不全是导致达比加群出血的重要危险因素之一,其中肌酐>115μmol·L^-1、估测肾小球滤过率<60mL/(min·1.73m^2)会显著增加房颤患者服用达比加群发生出血不良反应的风险。此外,联合应用抗血小板药物可增加房颤患者服用达比加群的出血风险,当联合应用双联抗血小板药物时出血风险显著升高(OR=4.16,95%CI 2.07~8.37)。结论:非瓣膜性房颤患者使用达比加群发生出血事件的危险因素有高龄,合并高血压、糖尿病,肌酐>115μmol·L^-1,肾小球滤过率<60mL/(min·1.73m^2)以及联合应用抗血小板药物。     

低剂量华法林对心房颤动患者脑卒中和凝血指标的影响

目的 探讨心房颤动患者低剂量长期使用华法林对患者脑卒中和凝血指标的影响。方法 选择2016年1月—2018年12月喀什地区第一人民医院收治的心房颤动患者213例作为研究对象,按照随机数字表法将患者分为3组,每组各71例。对照组患者使用阿司匹林肠溶片,200 mg/d。华法林高剂量组患者在使用华法林钠片前测定抗凝强度国际化标准比率（INR）作为基础值,初始剂量为2.5 mg/d,每隔3~5 d复查IRN,根据IRN调整使用剂量,每次增加0.625 mg,直至复查INR达标,达标时IRN值为2.1~3.0。华法林低剂量组患者使用华法林初始量为1.25 mg/d,每隔3~5 d复查IRN,达标时IRN值为1.5~2.0。根据IRN调整使用剂量,如果INR<1.5,每次增加0.625 mg,直至复查INR达标;如果INR>2.1,将华法林剂量减少0.625 mg。INR不稳定时,连续达标2次后以该剂量作为维持剂量,每月复查1次,直至INR达标。3组均治疗随访18个月。观察并比较两组患者的脑卒中发生情况、凝血指标、华法林用量、达INR标准时间和不良反应发生情况。结果 随访后,华法林高剂量组脑卒中发生率为2.82%,华法林低剂量组为4.23%,均明显低于对照组的14.08%,组间差异具有统计学意义（P<0.05）。治疗后,3组活化部分凝血活酶时间（APTT）、凝血酶原时间（PT）均明显延长（P<0.05）,华法林高剂量和低剂量APTT、PT显著优于对照组,组间差异具有统计学意义（P<0.05）。华法林低剂量组华法林使用量和INR达标准值时间均明显低于华法林高剂量组（P<0.05）。治疗期间,华法林高剂量组出血、腹部不适等不良反应发生率为9.86%,华法林低剂量组为5.63%,均明显低于对照组的29.58%（P<0.05）。结论 心房颤动患者长期使用低剂量华法林能够有效的达到预防脑卒中的效果,其疗效与标准抗凝强度相当,且明显优于阿司匹林,具有较高的临床应用价值,可推广使用。     

The hidden costs of anticoagulation in hospitalized patients with non-valvular atrial fibrillation

Introduction: Non-valvular atrial fibrillation (NVAF) and ischemic stroke are collectively associated with annual hospital costs of tens of billions of dollars in the USA. Oral anticoagulant (OAC) treatment with warfarin reduces the risk of stroke in patients with NVAF. Unfortunately, because of the complexity of warfarin therapy and potential for adverse events (AEs), many patients who might benefit go untreated or receive suboptimal therapy, increasing their stroke and/or bleeding risk.

Areas covered: This review explores current hospital costs and resource utilization for NVAF patients on warfarin therapy and the potential impact of newer OACs in this area.

Expert opinion: Many ischemic strokes could be prevented through wider use of OACs. Further, admissions due to anticoagulant-associated AEs could be reduced by optimizing OAC therapy. In the hospital, specialized anticoagulation services can decrease costs by improving the effectiveness of warfarin management, empowering patients through education and optimizing care transitions. With fewer interactions and no dose titration or monitoring required, the novel OACs (NOACs) have the potential to further decrease inpatient resource utilization and costs. It is important that, as data become available, inpatient costs are included in cost–benefit comparisons between warfarin and the NOACs.