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.     

Changing anticoagulant paradigms for atrial fibrillation: dabigatran,apixaban and rivaroxaban

Introduction: Vitamin K antagonists (VKAs) are the main therapeutic agents used to prevent embolic events in patients with atrial fibrillation (AF). Despite their proven efficacy, VKAs are underused and have several limitations. In recent years, there has been great interest in the development of new oral anticoagulants with a more efficient pharmacological profile, first tested in venous thromboembolism prevention and later in AF.

Areas covered: The authors review the pharmacological differences between dabigatran, rivaroxaban and apixaban, and potential subgroups of patients in whom these new drugs would constitute a possible alternative to VKA therapy. Pharmacodynamic and pharmacokinetic data from each compound are analyzed in respect to their potential use in AF. This article provides an exhaustive review of the current status of this topic and the controversies still regarding each drug.

Expert opinion: Apixaban and rivaroxaban are under evaluation for thromboembolic prevention in AF; dabigatran was recently approved for this indication. Therefore, it is important to know the characteristics of these drugs as a potential alternative to VKAs.     

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.     

新型口服抗凝药在非瓣膜性房颤中的应用进展

目的:对新型口服抗凝药(NOACs)在非瓣膜性房颤抗凝治疗中的临床应用和发展进行探讨。方法:收集最新发表的相关文章,对新型口服抗凝药的药理学特性、临床试验结果和临床应用进行分析总结。结果与结论:房颤是临床中最常见的心律失常,对于CHA_2DS_2-VASc评分≥2或既往曾有一过性脑缺血发作(TIA)或有卒中史的患者,应该使用抗凝药物。新型口服抗凝药,与维生素K拮抗剂(VKA)相比,有相似甚至更好的抗凝效果、安全性和便利性。它们具有快速起效,更多可预测的药动学特征,与其他药物相互作用少,饮食对其无明显影响,比华法林导致颅内出血的风险更低。     

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。     

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.     

Comparative coronary risks of apixaban,rivaroxaban and dabigatran: a meta-analysis and adjusted indirect comparison

Aims

There are concerns regarding increased risk of acute coronary syndrome with dabigatran. We aimed to assess whether alternative treatment options such as rivaroxaban or apixaban carry a similar risk as compared with dabigatran.

Methods

We searched MEDLINE and EMBASE for randomized controlled trials of apixaban, dabigatran or rivaroxaban against control (placebo, heparin or vitamin K antagonist). We pooled odds ratios (OR) for adverse coronary events (acute coronary syndrome or myocardial infarction) using fixed effect meta-analysis and assessed heterogeneity with I². We conducted adjusted indirect comparisons to compare risk of adverse coronary events with apixaban or rivaroxaban vs. dabigatran.

Results

Twenty-seven randomized controlled trials met the inclusion criteria. Dabigatran was associated with a significantly increased risk of adverse coronary events in pooled analysis of nine trials (OR 1.45, 95% CI 1.14, 1.86). There was no signal for coronary risk with apixaban from nine trials (pooled OR 0.89, 95% CI 0.78, 1.03) or rivaroxaban from nine trials (pooled OR 0.81, 95% CI 0.72, 0.93). Overall, adjusted indirect comparison suggested that both apixaban (OR 0.61, 95% CI 0.44, 0.85) and rivaroxaban (OR 0.54; 95% CI 0.39, 0.76) were associated with lower coronary risk than dabigatran.Restricting the indirect comparison to a vitamin K antagonist as a common control, yielded similar findings, OR 0.57 (95% CI 0.39, 0.85) for apixaban vs. dabigatran and 0.53 (95% CI 0.37, 0.77) for rivaroxaban vs. dabigatran.

Conclusions

There are significant differences in the comparative safety of apixaban, rivaroxaban and dabigatran with regards to acute coronary adverse events.     

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。     

Cost-effectiveness analysis of dabigatran versus rivaroxaban for stroke prevention in patients with non-valvular atrial fibrillation using real-world evidence in elderly US Medicare beneficiaries

Objective: Dabigatran and rivaroxaban have been approved by the US FDA to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) patients. Newly published real-world evidence based on the US population found that elderly Medicare patients with NVAF treated with rivaroxaban experienced statistically significant increases in intracranial hemorrhage (ICH) and major extracranial bleeding, and statistically nonsignificant decreases in thromboembolic stroke and acute myocardial infarction (AMI) compared with dabigatran. This study assessed the cost-effectiveness of dabigatran vs. rivaroxaban for the treatment of US Medicare NVAF patients.

Methods: A previously published Markov model was adapted to compare dabigatran and rivaroxaban. The model considered thromboembolic stroke, bleeding events, and AMI based on the published real-world event risks. Model outputs included clinical event rates, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).

Results: Dabigatran patients experienced fewer ICH and major extracranial bleeding events than rivaroxaban patients, but more stroke and AMI events. Dabigatran was found to yield lower costs and higher QALYs than rivaroxaban, with incremental costs of ?$3534 and incremental QALYs of 0.004. Results remained consistent in sensitivity analyses, with a positive net monetary benefit (willingness-to-pay thresholds of $50,000 and $100,000 per QALY) for dabigatran over rivaroxaban for all model inputs tested.

Conclusions: In this study using US Medicare real-world data, dabigatran was found to dominate rivaroxaban. The analyses were limited by the short follow-up period of the real-world data and results may not be generalizable to other patient populations.     

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.     

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。     

Minor bleeding in patients with atrial fibrillation using a non-vitamin-K antagonist oral anticoagulant

Abstract

Aims

We sought to investigate the magnitude of minor bleeding and identify risk factors for minor bleeds during non-vitamin-K antagonist oral anticoagulant (NOAC) therapy.     

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。     

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.     

利伐沙班用于超高龄非瓣膜性房颤患者的安全性评价

目的:观察超高龄非瓣膜性房颤(non-valvular fibrillation,NVAF)患者临床特点和抗凝治疗安全性。方法:回顾性分析武汉市第三医院2020年5月至2021年4月接受利伐沙班抗凝治疗的NVAF患者,根据年龄分为观察组(年龄≥80岁)和对照组(<80岁)。观察2组患者发生缺血性脑卒中、心肌梗死、全身性栓塞、大出血及死亡事件的风险。结果:116人完成随访,观察组59人,对照组57人。所有患者至少合并1种慢性疾病,低体质量和肾功能不全是超高龄NVAF患者的生理特点。93.2%患者服用低于标准剂量的利伐沙班,52.5%患者有高或中等依从性。随访结束,2组患者缺血事件、大出血、临床相关非大出血和死亡事件的发生率相似。结论:对于超高龄NVAF患者应充分评估卒中风险和出血风险,低于标准剂量利伐沙班能否达到预期效果需进一步研究。     

Warfarin versus dabigatran etexilate: an assessment of efficacy and safety in patients with atrial fibrillation

Introduction: Oral anticoagulation is the mainstay for stroke and thromboembolic event prevention in patients with atrial fibrillation (AF). Given limitations of warfarin therapy, non-vitamin K oral anticoagulants have been developed including direct thrombin inhibitors (i.e., dabigatran etexilate). Dabigatran etexilate has been tested thoroughly in terms of efficacy and safety in clinical trials and studies, involving ‘real-world’ cohorts. In this review, currently available evidence in patients with non-valvular AF is discussed.

Areas covered: The pharmacology, efficacy and safety, and current aspects of use of dabigatran etexilate in patients with non-valvular AF are reviewed in a comparative manner to warfarin both for chronic anticoagulation and in different clinical settings.

Expert opinion: Dabigatran etexilate appeared to have several pharmacokinetic and pharmacodynamic advantages over warfarin, as well as a favorable efficacy and safety profile being at least noninferior and often superior to warfarin in patients with non-valvular AF. The latter was shown in the clinical trials, meta-analyses and studies with ‘real-world’ data. Currently ongoing trials will expand the body of evidence on warfarin and will aid decision making in currently controversial areas. Important limitations of dabigatran etexilate include contraindications for its use in patients with prosthetic heart valves and end-stage chronic kidney disease.     

利伐沙班在非瓣膜性房颤患者中的临床应用分析及建议

目的：制定利伐沙班在临床非瓣膜性房颤患者中应用的合理性评价标准和用药建议,为规范其临床合理应用提供依据。方法：汇总国内外利伐沙班相关指南、专家共识和文献,形成利伐沙班在非瓣膜性房颤患者中应用的合理性评价标准,回顾性调查某院2018年下半年非瓣膜性房颤住院患者中使用利伐沙班病例,通过纳入标准,将符合要求的病例按照评价标准进行合理性分析;通过发放调查问卷汇总医生和患者在使用利伐沙班过程中的关注点,针对性制定合理化用药建议。结果：2018年下半年,利伐沙班在非瓣膜性房颤住院患者中使用例数共计217例,实际统计分析病例106例,利伐沙班使用不合理率为19.81%（21/106）,以低剂量人群和特殊病理状态患者给药剂量和围手术期用药时机错误为主要原因,不良反应发生率为6.60%（7/106）,均为出血性不良反应;医生和患者在使用利伐沙班中的关注点多集中在监护指标、出血事件处理和用药注意事项等方面。结论：利伐沙班在临床非瓣膜性房颤患者中应用较广泛,其疗效良好,但仍然存在不合理用药情况,特别是在给药剂量和围手术期用药方面,临床药师应密切关注利伐沙班临床应用指南等的更新,制定合理性评价标准和用药建议,积极与医生和患者沟通,促进利伐沙班合理使用。     

Secondary adherence to non-vitamin-K antagonist oral anticoagulants in patients with atrial fibrillation in Sweden and the Netherlands

Objective: There is limited evidence on patients’ adherence and the impact of the prescribed dosing regimen in non-vitamin-K oral anticoagulants (NOACs). We aimed to assess secondary adherence to NOACs and to determine the impact of the dosing regimen in patients with atrial fibrillation.

Methods: Patients using a NOAC between 2009 and 2013 were identified from the nation-wide Swedish Prescribed Drug Register and the Dutch regional IADB.nl database. Patients using a consistent dosage for at least 180 consecutive days were included. Adherence was calculated using the medication possession ratio (MPR) and adjusted for overlapping dates. Adherence was defined as a MPR ≥0.8. Sensitivity analyses were performed using a MPR ≥0.9. Logistic regression was performed to compare secondary adherence and to explore the influence of the dosing regimen.

Results: A total of 5254 Swedish and 430 Dutch NOAC users were included. The mean MPR was 96.0% (SD 7.8%) in Sweden and 95.1% (SD 10.1%) in the Netherlands. Multivariable logistic regression analysis showed that a twice daily regimen had a lower likelihood of being secondary adherent compared to a once daily regimen in Sweden (odds ratio [OR] 0.21 [95% CI 0.12–0.35]).

Limitations: The influence of selection bias introduced by the inclusion criterion of ≥2 dispensations covering at least 180 days could not be excluded.

Conclusions: This study demonstrated that secondary adherence was high in this specific setting among patients with at least two initial dispensations of a NOAC covering a minimum of 180 days. The use of NOACs in a once daily regimen showed higher adherence compared to a twice daily regimen.     

Novel anticoagulants for stroke prevention in atrial fibrillation: safety issues in the elderly

Vitamin K antagonists (VKAs) are the most widely used anticoagulants for stroke prevention in patients with atrial fibrillation (AF). Recently, the US FDA approved three novel anticoagulants that work through inhibition of coagulation cascade independent of Vitamin K-dependent enzymatic reactions and, therefore, should have less food–drug interactions. Since AF is a disease of the aging heart, it is important to assess safety and efficacy of these new anticoagulants in elderly patients. We reviewed age-related changes in pharmacokinetics and pharmacodynamics observed with senescence and the effects of these changes on novel anticoagulants, known and anticipated drug and food interactions, and challenges related to bleeding complications and temporary discontinuation prior to surgery or interventional procedure. Although advantageous to VKA in age groups represented in trials, there are lack of data on VKA usage in older–elderly patients; additional research and post-marketing analysis in older–elderly patients are needed.