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.     

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.     

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.     

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。     

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.     

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.     

Risk of major bleeding in patients with non-valvular atrial fibrillation treated with oral anticoagulants: a systematic review of real-world observational studies

Objective: To conduct a systematic review of real-world (RWD) studies comparing the risk of major bleeding (MB) among patients with non-valvular atrial fibrillation (NVAF) on direct oral anticoagulants (DOACs) or warfarin.

Methods: MEDLINE, Embase, NHS-EED, and EconLit were searched for RWD studies published between January 2003 and November 2016 comparing MB risk among DOACs and warfarin. Proceedings of clinical conferences from 2012 to 2016 were reviewed.

Results: A total of 4218 citations were identified, 26 of which met eligibility criteria. Most studies were retrospective analyses of administrative claims databases and patient registries (n?=?23 of 26); about half were based in the United States (n?=?15). Apixaban showed a significantly lower risk of MB versus warfarin in all eight included studies. MB risk was either significantly lower (n?=?9 of 16) or not significantly different (n?=?7 of 16) between dabigatran and warfarin; there was no significant difference between rivaroxaban and warfarin in all seven included studies. The risk was significantly lower with apixaban versus rivaroxaban (n?=?7 of 7) but not significantly different from dabigatran (n?=?6 of 7). MB risk was significantly lower (n?=?3 of 4) or not significantly different (n?=?1 of 4) with dabigatran versus rivaroxaban. No evidence was identified for edoxaban.

Conclusion: DOACs were associated with similar or lower risks of MB versus warfarin. A lower MB risk was consistently observed for apixaban, but less consistently for dabigatran; MB risk was similar between rivaroxaban and warfarin. Among DOACs, the risk of MB with apixaban was consistently lower than with rivaroxaban, but similar to dabigatran.     

Edoxaban for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation

Introduction: Oral anticoagulation is central to the management of patients with atrial fibrillation (AF) and at least one additional stroke risk factor. For decades, the vitamin K antagonists (e.g. warfarin) remained the only oral anticoagulant available for stroke prevention in AF. The non-vitamin K oral anticoagulants (NOACs) are now available, and these drugs include the direct thrombin inhibitors and factor Xa inhibitors. The latter class includes edoxaban, which has recently been approved for stroke prevention in AF by the United States Food and Drug Administration and the European Medicine Agency. In line with other NOACs, edoxaban avoids the many limitations of warfarin associated with variability of anticoagulation effect and multiple food and drug interactions.

Areas covered: In this review, the currently available evidence on edoxaban in patients with non-valvular AF is discussed. The pharmacology, efficacy and safety, and current aspects of use of edoxaban in patients with non-valvular AF for stroke and thromboembolism prevention are reviewed.

Expert opinion: Phase III trials on edoxaban for stroke prevention in non-valvular AF confirms non-inferiority of edoxaban compared to well-managed warfarin both in terms of efficacy and safety. Currently ongoing and future trials as well as real-world data are warranted to confirm its effectiveness and safety for chronic anticoagulation and improve evidence in other areas which are lacking evidence where NOAC use remains controversial.     

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.     

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。     

Long-term outcome in patients with non-valvular atrial fibrillation on dabigatran: a prospective cohort study

ABSTRACT

Introduction: Most studies on thromboembolic and bleeding risk in patients with non-valvular atrial fibrillation (NVAF) exposed to non-vitamin K oral anticoagulants stem from interrogation of insurance databases.

Areas covered: We studied 742 consecutive patients with NVAF who started treatment with dabigatran in three hospitals in Italy. Average follow-up was 1.80 years.

Mean age was 76.2 years. CHA₂DS₂VASc score was 0–1 in 37 (5%), 2 in 97 (13%) and ≥ 3 in 604 (82%) patients. NVAF was permanent in 349 (48%). Overall, 76% of patients remained on treatment over the entire follow-up period. Among 180 patients who discontinued permanently, the most frequent reasons were dyspepsia (33.9%), bleeding (17.8%), and renal worsening (12.1%). About 48% and 74% of permanent discontinuations occurred during the first 6 and 12 months of treatment, respectively. Rates of major events (per 100 patient-years) were 0.75 for stroke, 0.31 for myocardial infarction, 1.50 for all-cause death, and 1.80 for major bleedings. The rate of intracranial bleedings was 0.45 and that of major gastrointestinal bleedings was 0.75.

Expert opinion: This prospective cohort study confirms the low incidence of stroke, major bleeding and intracranial bleeding, and a 76% persistence with treatment, in patients with NVAF treated with dabigatran over about 2 years.     

New advances in the treatment of atrial fibrillation: focus on stroke prevention

Introduction: Atrial fibrillation (AF) is the most common arrhythmia and brings about significant mortality and morbidity as a result of heart failure and ischemic stroke. Besides vitamin K antagonists (VKA), several new pharmacological agents (nonvitamin K antagonist oral anticoagulants [NOACs]) and procedures have since been developed to improve stroke prevention efforts in AF.

Areas covered: This paper will discuss the antiplatelet agents, VKA and NOACs, and their efficacy and safety for stroke prevention in AF. Focus will be placed on the NOACs, their limitations and special considerations. A short assessment of other nonpharmacological antithrombotic procedures will also be made. An extensive PubMed search was used to identify suitable papers.

Expert opinion: Despite the advent of NOACs, the VKAs will remain as an important oral anticoagulant due to its versatility. However, convenience and limited food or drug interactions will make NOACs attractive options. The choice between various NOACs will depend on several important factors as illustrated below. Over time, the role for antiplatelet agents will gradually diminish. Left atrial appendage occlusion devices have shown promising results and may have the potential to change the way clinicians manage thromboembolism risks related to AF.     

Pharmacokinetics of anticoagulants apixaban,dabigatran, edoxaban and rivaroxaban in elderly Japanese patients with atrial fibrillation treated in one general hospital

1. Steady-state plasma concentrations of anticoagulants and the time since the previous administration in mainly outpatients with atrial fibrillation administered standard or reduced doses were analyzed for 110 elderly Japanese subjects (mean age, 76?years) treated with apixaban (2.5 or 5.0?mg twice daily), dabigatran etexilate (110 or 150?mg twice daily), edoxaban (30 or 60?mg once daily) or rivaroxaban (10 or 15?mg once daily) at one general hospital.

2. The pharmacokinetics in patients treated with standard and reduced doses of the four anticoagulants using liquid chromatography-tandem mass spectrometry was compared with the concentration ranges estimated using physiologically based pharmacokinetic modeling. Reduced doses of anticoagulants resulted in relatively small pharmacokinetic variations compared with the standard dose.

3. Statistical analyses revealed that renal impairment is likely not the sole determinant factor for high plasma concentrations of apixaban, dabigatran, edoxaban and rivaroxaban.

4. Patients with atrial fibrillation should be treated with the correct doses of oral anticoagulants as specified in the package inserts (e.g. reduced doses for elderly patients, patients with low body weights and in combination with P-glycoprotein inhibitor drugs) to avoid excessive or insufficient doses of direct oral anticoagulants.

     

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.