Novel Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: Focus on Apixaban

Stroke prevention in atrial fibrillation (AF) has been challenging over decades, mostly due to a number of difficulties associated with oral vitamin K antagonists (VKAs), which have been the most effective stroke prevention treatment for a long time. The oral direct thrombin inhibitors (e.g., dabigatran) and oral direct inhibitors of factor Xa (e.g., rivaroxaban, apixaban) have emerged recently as an alternative to VKAs for stroke prevention in AF. These drugs act rapidly, and have a predictable and stable dose-related anticoagulant effect with a few clinically relevant drug-drug interactions. The novel oral anticoagulants are used in fixed doses with no need for regular laboratory monitoring of anticoagulation intensity. However, each of these drugs has distinct pharmacological properties that could influence optimal use in clinical practice. The following phase 3 randomized trials with novel oral anticoagulants versus warfarin for stroke prevention in AF have been completed: the Randomized Evaluation of Long-term Anticoagulant therapy (RE-LY) trial with dabigatran, the Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial with rivaroxaban, and the Apixaban for Reduction of Stroke and Other Thromboembolism Events in Atrial Fibrillation (ARISTOTLE) trial with apixaban. Moreover, the Apixaban Versus Acetylsalicylic Acid to prevent Strokes (AVERROES) trial included patients with AF who have failed or were unsuitable for warfarin, and compared apixaban versus aspirin for stroke prevention in AF. Overall, apixaban has two large trials for stroke prevention in AF showing benefits not only over warfarin, but also over aspirin among those patients who have failed or refused warfarin. In the ARISTOTLE trial, apixaban was superior to warfarin in the reduction of stroke or systemic embolism, major bleeding, intracranial hemorrhage, and all-cause mortality, with a similar reduction in the rate of ischemic stroke and better tolerability. When compared with aspirin in the AVERROES trial, apixaban was associated with more effective reduction of stroke, a similar risk of major bleeding, and better tolerability. In this review article, the authors summarize the current knowledge on novel oral anticoagulants and discuss the clinical aspects of their use for stroke prevention in AF, with particular emphasis on apixaban.     

Cost-Effectiveness of Apixaban Versus Other New Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation

Background

Apixaban (5 mg BID), dabigatran (available as 150 mg and 110 mg BID in Europe), and rivaroxaban (20 mg once daily) are 3 novel oral anticoagulants (NOACs) currently approved for stroke prevention in patients with atrial fibrillation (AF).

Objective

The objective of this study was to evaluate the cost-effectiveness of apixaban against other NOACs from the perspective of the United Kingdom National Health Services.

Methods

A Markov model was developed to evaluate the pharmacoeconomic impact of apixaban versus other NOACs over a lifetime. Pair-wise indirect treatment comparisons were conducted against other NOACs by using ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), and ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial results for the following end points: ischemic stroke, hemorrhagic stroke, intracranial hemorrhage, other major bleeds, clinically relevant nonmajor bleeds, myocardial infarction, and treatment discontinuations. Outcomes were life-years, quality-adjusted life years gained, direct health care costs, and incremental cost-effectiveness ratios.

Results

Apixaban was projected to increase life expectancy versus other NOACs, including dabigatran (both doses) and rivaroxaban. A small increase in therapeutic management costs was observed with apixaban due to projected gains in life expectancy and lower discontinuation rates anticipated on apixaban versus other NOACs through lifetime. The estimated incremental cost-effectiveness ratio was £9611, £4497, and £5305 per quality-adjusted life-year gained with apixaban compared with dabigatran 150 mg BID, dabigatran 110 mg BID, and rivaroxaban 20 mg once daily, respectively. Sensitivity analyses indicated that results were robust over a wide range of inputs.

Conclusions

Although our analysis was limited by the absence of head-to-head trials, based on the indirect comparison data available, our model projects that apixaban may be a cost-effective alternative to dabigatran 150 mg BID, dabigatran 110 mg BID, and rivaroxaban 20 mg once daily for stroke prevention in AF patients from the perspective of the United Kingdom National Health Services.     

Comparison of the Cost-effectiveness of New Oral Anticoagulants for the Prevention of Stroke and Systemic Embolism in Atrial Fibrillation in a UK Setting

PurposeThree new oral anticoagulants (NOACs) have recently become available in the United Kingdom as an alternative to warfarin in the prevention of stroke and systemic embolism in atrial fibrillation. This study examines the relative cost-effectiveness of dabigatran (BID dosing of 150 mg or 110 mg based on patient age), rivaroxaban, and apixaban from a UK payer perspective.MethodsA previously published model that follows up patients through treatment of atrial fibrillation during a lifetime was adapted to allow comparison of the 3 NOACs and warfarin. Acute thromboembolic and bleeding events, as well as long-term consequences of stroke, intracranial hemorrhage, and acute myocardial infarction, were tracked. Relative efficacy was calculated from a formal indirect treatment comparison using data from the 3 key trials (Randomized Evaluation of Long-Term Anticoagulation Therapy, Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation, and Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) of the NOACs. Data from the rivaroxaban trial were adjusted for the difference in international normalized ratio control among warfarin patients versus the other 2 trials. Model outputs included total costs, event rates, and quality-adjusted life-years.FindingsAmong the patients taking NOACs, those taking dabigatran had the highest total QALYs (7.68 QALYs), followed by apixaban (7.63 QALYs) and rivaroxaban (7.47 QALYs). Patients taking dabigatran had the lowest total lifetime costs (£23,342), followed by apixaban (£24,014) and rivaroxaban (£25,220). The differences between dabigatran and apixaban were modest but consistent in sensitivity analyses, with the directionality only changing at the limits of the CIs for the relative risks of ischemic stroke or intracranial hemorrhage or when assuming that both treatment discontinuation and post-event disability rates differ by drug.ImplicationsDabigatran was found to be economically dominant over rivaroxaban and apixaban in the UK setting. These economic findings are based on relative clinical efficacy from an indirect treatment comparison and would benefit from any data of direct comparisons of the NOACs in the future.     

Pharmacological and Non-pharmacological Treatments for Stroke Prevention in Patients with Atrial Fibrillation

Atrial fibrillation (AF) is associated with significant risk of stroke and other thromboembolic events, which can be effectively prevented using oral anticoagulation (OAC) with either vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, or edoxaban. Until recently, VKAs were the only available means for OAC treatment. NOACs had similar efficacy and were safer than or as safe as warfarin with respect to reduced rates of hemorrhagic stroke or other intracranial bleeding in the respective pivotal randomized clinical trials (RCTs) of stroke prevention in non-valvular AF patients. Increasing “real-world” evidence on NOACs broadly confirms the results of the RCTs. However, individual patient characteristics including renal function, age, or prior bleeding should be taken into account when choosing the OAC with best risk–benefit profile. In patients ineligible for OACs, surgical or interventional stroke prevention strategies should be considered. In patients undergoing cardiac surgery for other reasons, the left atrial appendage excision, ligation, or amputation may be the best option. Importantly, residual stumps or insufficient ligation may result in even higher stroke risk than without intervention. Percutaneous left atrial appendage occlusion, although requiring minimally invasive access, failed to demonstrate reduced ischemic stroke events compared to warfarin. In this review article, we summarize current treatment options and discuss the strengths and major limitations of the therapies for stroke risk reduction in patients with AF.     

Clinical Benefit of Direct Oral Anticoagulants Versus Vitamin K Antagonists in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves

PurposeThe use of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) and bioprosthetic heart valve is still controversial. The aim of this study was to compare the tolerability and effectiveness of treatment with DOACs versus vitamin K antagonists (VKAs) in patients with AF and a bioprosthetic heart valve in clinical practice.MethodsData for this study were sourced from the multicenter, prospectively maintained AF Research Database (NCT03760874), which includes all patients with AF undergoing follow-up at participating centers through outpatient visits every 3–6 months. The rates of occurrence of thromboembolic events (ischemic stroke, transient ischemic attack, systemic embolism), major bleed, and intracranial hemorrhage (ICH) were assessed. These data were used for quantifying the net clinical benefit (NCB) of DOACs versus VKAs, in accordance with the following formula: (Thromboembolic events incidence rate with VKAs – Thromboembolic events incidence rate with DOACs) – Weighting factor × (ICH rate with DOACs – ICH incidence rate with VKAs). The database was retrospectively queried for patients with AF who were prescribed a DOAC or VKA and had a history of bioprosthetic heart valve replacement.FindingsA total of 434 patients with AF (DOACs, n = 211; VKAs, n = 223) were identified. Propensity score matching identified 130 patients prescribed DOACs (apixaban, 55.4%; rivaroxaban, 30.0%; dabigatran, 13.1%; edoxaban, 1.4%) and the same number of VKA recipients (warfarin, 89.2%; acenocoumarol, 10.8%). The mean (SD) duration of follow-up was 26.8 (2.3) months. The incidence rates of thromboembolic events were 1.3 per 100 person-years in the DOAC group versus 2.0 per 100 person-years in the VKA group (P = 0.14). The incidence rates of major bleed events were 2.6 per 100 person-years in the DOAC group versus 4.9 per 100 person-years in the VKA group (P = 0.47). The incidence rates of ICH were 0.38 per 100 person-years in the DOAC group versus 1.16 in the VKA group (hazard ratio = 0.33; 95% CI, 0.05–2.34; P = 0.3). A positive NCB of DOACs over VKAs of +1.87 was found.ImplicationsAccording to these data from clinical practice, DOACs seem to be associated with a greater NCB versus VKAs in patients with AF with a bioprosthetic heart valve, primarily due to lower rates of both major bleeds and thromboembolic events.     

Mixed Treatment Comparison Meta-Analysis of Aspirin,Warfarin, and New Anticoagulants for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation

Background

Warfarin and aspirin are used to prevent stroke in patients with atrial fibrillation (AF). There are inherent challenges with both treatments, including variable and inconsistent benefit and increased bleeding risks. The availability of new anticoagulants offers some alternatives.

Objective

A mixed treatment comparison meta-analysis to evaluate direct and indirect treatment data including aspirin, warfarin apixaban, dabigatran, edoxaban, and rivaroxaban for the prevention of primary or secondary stroke in patients with AF.

Methods

A comprehensive, systematic literature search was conducted to identify randomized trials comparing aspirin, warfarin, apixaban, dabigatran, edoxaban, and rivaroxaban in patients with AF requiring treatment for stroke prevention. Open-label and blinded designs were included if they evaluated any stroke or any bleeding event. Data on stroke and bleeding events were abstracted, verified, evaluated, scored, and entered into Aggregate Data Drug Information System version 1.16 to generate a mixed treatment comparison meta-analysis. Direct and indirect comparisons were evaluated, and we looked for inconsistency in closed loop structures. Data are reported as rate ratios with 95% credible intervals. In addition, we reviewed variance statistics and explored variance with node-splitting models.

Results

Our literature search yielded 30 articles, 21 of which were included. All treatments except aspirin reduced the risk of any stroke compared with placebo. Warfarin (0.43 [0.33–0.57]), apixaban (0.37 [0.27–0.54]), dabigatran (0.34 [0.21–0.57]), rivaroxaban (0.36 [0.22–0.60]), and aspirin with clopidogrel (0.73 [0.53–0.99]) were more protective than aspirin alone. Warfarin and the new anticoagulants were similar in the reduction of stroke, vascular death, and mortality. There was no difference in major bleeding between any treatment group. There were more nonmajor bleeding events when comparing warfarin and apixaban (1.83 [1.05–4.03]); no other differences between warfarin and the other new anticoagulants were found.

Conclusions

This mixed treatment comparison meta-analysis found similarity between warfarin and the new anticoagulants with the exception of one comparison, in which warfarin was associated with more non-major bleeding than apixaban. Thus, the new anticoagulants are therapeutically comparable when warfarin is inappropriate.     

Pharmacokinetics of Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Extreme Obesity

PurposeDirect oral anticoagulants (DOACs) are recommended in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF) eligible for oral anticoagulation therapy; however, data and clinical experiences supporting the use of DOACs in patients with a body mass index ≥40 kg/m² or weight >120 kg remain limited. The aim of this study was to evaluate the pharmacokinetic properties of DOACs in patients with AF and extreme obesity.MethodsWe enrolled all consecutive patients with AF and extreme obesity undergoing treatment with DOACs followed up at Monaldi Hospital, Naples, Italy. To determine peak plasma and trough levels of DOACs, plasma samples were collected at 2nd, 4th, 6th, and 12th hours from the last dose intake in patients receiving apixaban and dabigatran and at the 2nd, 4th, 6th, and 24th hours in those receiving edoxaban and rivaroxaban. The DOACs’ peak and trough plasma levels obtained from our study population were compared with those sourced from pharmacokinetic studies among patients without obesity, defined as a normal reference range in the literature. If at least 1 peak or trough plasma level was found ​​below or above the normal reference ranges, the patients were classified as having out-of-range DOAC plasma levels. Study population was then divided into in-range and out-of-range groups. Baseline characteristics, including DOAC treatment, were compared between the 2 groups. Univariate and multivariate logistic regression analysis were performed to identify baseline variables associated with DOACs’ plasma concentration out of the expected range.FindingsA total of 58 patients (mean [SD] age, 70.93 [8.73] years; 40% female) with extreme obesity (mean [SD] body mass index. 44.43 [3.54] kg/m²) and AF while undergoing DOAC treatment were included in the present study. In 9 patients (15.5 %), the DOAC plasma concentrations were out of the expected ranges (out-of-range group);, indicating a greater likelihood of edoxaban 30 mg treatment (33% vs 2%; P < 0.01) and inappropriate DOAC underdosing (56% vs 4%; P < 0.005) compared with the in-range group. According to the multivariate logistic analysis (P = 0.0011), the inappropriate DOAC underdosing (hazard ratio = 29.37; P = 0.0002) was an independent predictor of DOAC plasma levels out of the expected ranges.ImplicationsPatients with extreme obesity and AF who were receiving DOAC therapy had DOAC plasma concentrations in the expected range. The inappropriate DOAC underdosing seems to be the only independent clinical factor associated with a plasma concentration of the drug out of the expected range.     

Atrial Fibrillation and Anticoagulation in Patients with Permanent Pacemakers: Implications for Stroke Prevention

Several large prospective randomized trials have demonstrated that anticoagulation with warfarin reduces the risk of thromboembolic stroke in high risk patients with chronic AF by approximately 70%. Large numbers of patients with permanent pacemakers have AF, and anticoagulation rates in this population have not been described. In a prospective analysis of 110 consecutive patients attending the pacemaker clinic of a large university hospital, we assessed the number of patients with AF and the proportion of these patients who were receiving anticoagulation to prevent thromboembolic stroke. Where necessary, temporary pacemaker reprogramming to low ventricular rates was utilized to facilitate the diagnosis of AF. Fifty-three of the 110 patients (48%) were diagnosed with AF, all of whom (100%) had accepted high risk factors for thromboembolic stroke. Only eight of the 53 (15%) had been anticoagulated with warfarin. Thirty-six of the 53 patients (68%) diagnosed with AF had no prior documented diagnosis of chronic AF, and the majority had no symptoms suggesting AF. A single lead II ECG was insufficient in 67 of the 110 patients (61%) to diagnose the underlying atrial rhythm; the remainder required 12-lead ECGs or temporary pacemaker reprogramming to low ventricular rates to diagnose the underlying atrial rhythm. AF is common in patients with permanent pacemakers. It is commonly asymptomatic, and anticoagulation is markedly underutilized in reducing stroke risk in these patients. Attention to the possibility of AF in paced patients should allow prompt diagnosis and allow both the initiation of anticoagulation in order to reduce thromboembolic stroke risk and consideration for cardioversion of AF to sinus rhythm.     

口服抗凝剂在非瓣膜性房颤伴慢性肾功能不全患者中的应用进展

口服抗凝剂可有效降低房颤患者的卒中风险,但房颤伴慢性肾功能不全患者的卒中和出血风险却明显升高,给抗凝治疗带来困难。非维生素K拮抗剂类口服抗凝剂疗效和安全性不劣于传统的抗凝剂华法林,无需定期监测国际标准化比值,患者依从性更好。然而,非维生素K拮抗剂类口服抗凝剂均不同程度地通过肾脏代谢,其在非瓣膜性房颤伴慢性肾功能不全患者中的应用尚存在争议。本文对非瓣膜性房颤伴慢性肾功能不全患者口服抗凝剂的应用进展进行综述,以期为临床实践提供参考。     

Left Atrial Appendage Occlusion for The Unmet Clinical Needs of Stroke Prevention in Nonvalvular Atrial Fibrillation

Oral anticoagulation is the dominant strategy for stroke prevention in patients with nonvalvular atrial fibrillation. However, lifelong oral anticoagulation is associated with major issues including inappropriate dosing, nonadherence, and adverse effects. Therefore, efforts have been made to develop site-specific therapy aimed to occlude the left atrial appendage, the anatomical site accountable for more than 90% of nonvalvular atrial fibrillation–related ischemic strokes. This review focuses on the growing literature to put into perspective the risk-balance ratio of left atrial appendage occlusion.     

An Endovascular Approach to Cardioembolic Stroke Prevention in Atrial Fibrillation Patients

This report is of a 62-year-old woman presenting with a 3-year history of chronic atrial fibrillation (AF) and unable to tolerate chronic warfarin therapy due to bleeding episodes and unstable INR values. Additional high risk factors for stroke are a history of congestive heart failure and previous embolic stroke. Percutaneous left atrial appendage transcatheter occlusion (PLAATO™) was performed to seal the LAA. A transesophageal echocardiography (TEE) at the 1- and 6-month follow-up showed no device migration and no new thrombus related to the implant. The patient has been doing well on postprocedure aspirin with no embolic events. (PACE 2003; 26[Pt. II]:1604–1606)     

非瓣膜病性房颤伴缺血性中风的二级预防

目的：观察应用阿司匹林预防非瓣膜病性房颤伴缺血性中风患者复发的疗效。方法：选取89例非瓣膜病性房颤伴缺血性中风的患者,随机分为两组,其中阿司匹林组47例,丹参对照组42例,随访1年,观察阿司匹林及丹参片对其复发率病死率及其他血管事件发生率的影响。结果：对照组中风后1年的复发率高于阿司匹林组（P〈0.05）;对照组中风后1年的病死率与其他血管事件的发生率高于阿司匹林组,但差异无统计学意义（P〉0.05）。结论：阿司匹林对非瓣膜病性房颤伴缺血性中风患者有预防复发的作用。     

Long-Term Risk of Major Adverse Cardiac Events in Atrial Fibrillation Patients on Direct Oral Anticoagulants

ObjectiveTo determine the association between direct oral anticoagulant (DOAC) use and risk of major adverse cardiac events (MACEs) in patients with atrial fibrillation (AF).Patients and MethodsThis study is a single-center prospective observational cohort study including 2366 outpatients with non-valvular AF on treatment with DOACs or vitamin K antagonists (VKAs) from February 2008 for patients on VKA and September 2013 for patients on novel oral anticoagulants. The primary endpoint was the incidence of MACE including fatal and non-fatal myocardial infarction (MI), cardiac revascularization, and cardiovascular death.ResultsThe mean age was 75.1±9.0 years; 44.7% were women. During a mean follow-up of 33.3±21.9 months (6567 patients/years) 133 MACEs occurred (2.03%/year): 79 MI/cardiac revascularization and 54 cardiovascular deaths. Of these, 101 were on VKAs (2.42%/year) and 32 on DOACs (1.34%/year; log-rank test P=.040). This difference was evident also considering MI alone (1.53%/year and 0.63%/year in the VKA and DOAC group, respectively, log-rank test P=.009). At multivariable Cox proportional hazard regression analysis, use of DOACs was associated with a lower risk of MACE (hazard ratio, 0.636; 95% CI, 0.417 to 0.970; P=.036) and MI (hazard ratio, 0.497; 95% CI, 0.276 to 0.896; p=.020). Sensitivity analysis showed that this association was consistent in younger patients (<75 years), in patients with anemia, and in those without chronic obstructive pulmonary disease and heart failure. We also found that both dabigatran and apixaban/rivaroxaban were associated with a lower rate of MACE, with similar efficacy between full and low doses.ConclusionDOACs are associated with a lower risk of MACE in patients with AF independently from dosage.     

房颤与缺血性中风

以往大多数学者认为颅外血管病变是脑栓塞的一个重要病因 ,随着食道超声等检查的临床广泛应用 ,人们逐渐认识到心脏病变是脑中风的一个重要因素 ,在原因不明的年轻的中风病人中 ,心脏结构的异常可能是大脑中风栓子的主要来源 ,这些病人并没有明显的动脉粥样硬化 ,另一方面 ,甚至在有明显颅外血管病变的老年病人中亦可能隐藏心脏来源的栓子。动脉造影证实的外周血管狭窄大于 6 0 %的病人中 ,约 15 %～ 35 %的病人也可能有心源性栓子。腔隙性脑梗死是由长期高血压引起的脑部小动脉穿支血管病变 ,但其中 5 0 %隐匿的栓子可能与心脏病变有关[1] …     

Perception of the Risk of Stroke and the Risks and Benefits of Oral Anticoagulation for Stroke Prevention in Patients With Atrial Fibrillation: A Cross-Sectional Study

ObjectiveTo assess the perception of the risk of stroke and the risks and benefits of oral anticoagulation (OAC) in patients with atrial fibrillation (AF).Patients and MethodsConsecutive patients with chronic AF who presented for an outpatient cardiology visit or were admitted to a noncritical care cardiology ward service from September 15 through December 20, 2017, were invited to participate in this survey. Participants were asked to estimate their stroke risk without OAC and bleeding risk with OAC using a quantitative risk scale. The reported values were compared with subjectively estimated risks derived from the CHA₂DS₂-VASc and HAS-BLED scores. Similarly, we compared patient perception of the stroke risk reduction afforded with OAC compared with what is reported in the literature.ResultsA total of 227 patients were included in the analysis. The mean ± SD CHA₂DS₂-VASc score was 4.3±1.6, and HAS-BLED score was 2.3±1.2. Atrial fibrillation was paroxysmal in 53.3% and persistent/permanent in 46.7%. There was a negligible correlation between patient perceived and estimated risk of stroke (r=0.07; P=.32), and bleeding (r=0.16; P=.02). Most patients overestimated their risks of stroke and bleeding: 120 patients (52.9%) perceived an annual stroke risk greater than 20%, and 115 (53.5%) perceived an annual bleeding risk with OAC greater than 10%. Most patients (n=204; 89.9%) perceived that OAC would reduce their annual stroke risk by at least 50%.ConclusionPerceived risks of stroke and bleeding are markedly overestimated in most patients with AF. Further research is needed to discern the root causes and to identify effective methods of bridging this alarming disparity.