An evidence-based review of edoxaban and its role in stroke prevention in patients with nonvalvular atrial fibrillation.

Atrial fibrillation is the most common arrhythmia in the elderly. It is responsible for significant morbidity and mortality from cardioembolic complications like stroke. As a result, atrial fibrillation patients are risk-stratified using the CHADS2 or CHA2DS2-VASc scoring systems. Those at intermediate-to-high risk have traditionally been treated with therapeutic anticoagulation with warfarin for stroke prevention. Although effective, warfarin use is fraught with multiple concerns, such as a narrow therapeutic window, drug-drug and drug-food interactions, and excessive bleeding. Novel oral anticoagulant agents have recently become available as viable alternatives for warfarin therapy. Direct thrombin inhibitor dabigatran and factor Xa inhibitors like rivaroxaban and apixaban have already been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation. Edoxaban is the latest oral direct factor Xa inhibitor studied in the largest novel oral anticoagulant trial so far: ENGAGE AF-TIMI 48. Treatment with a 30 mg or 60 mg daily dose of edoxaban was found to be noninferior to dose-adjusted warfarin in reducing the rate of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, with a lower incidence of bleeding complications and cardiovascular deaths. Edoxaban was recently reviewed by an FDA advisory committee and recommended as a stroke-prophylaxis agent. Once approved, it promises to provide another useful alternative to warfarin therapy

The relation of serum GGT level in patients with non valvular atrial fibrillation and normal sinus rhythm

Background: The primary objective of the study was to assess and compare the relation of serum GGT level in patients with non valvular atrial fibrillation and normal sinus rhythm. The fundamental mechanisms underlying AF remains poorly understood. Oxidative stress is hypothesized to induce and maintain nonvalvular atrial fibrillation particularly in elderly patients. GGT levels are increased in patients with chronic inflammation. Increased serum levels of GGT are found in chronic nonvalvular atrial fibrillation (AF) patients as compared with patients in sinus rhythm.Methods: We included 75 patients of nonvalvular atrial fibrillation and 75 patients of sinus rhythm after applying exclusion criteria. Serum level of gamma glutamyl transrerase (GGT) of both the groups was compared.Results: Presence of coronary artery disease, hypertension, gender, hyperlipidemia, diabetes mellitus and smoking status were comparable between the 2 groups (P > 0.05 for all). Serum gamma glutamyl transferase activity in 75 cases was 71.45±26.21 with maximum being 147 IU/L more than the normal range for age, whereas in controls it was 19.68±5.53 i.e. much within the normal range for age.Conclusions: At the end of the study we concluded that serum GGT levels were significantly higher in patients with chronic nonvalvular atrial fibrillation (AF) patients as compared with patients in sinus rhythm

XANTUS: rationale and design of a noninterventional study of rivaroxaban for the prevention of stroke in patients with atrial fibrillation.

Atrial fibrillation (AF) is associated with a fivefold increase in the risk of stroke. The Phase III 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 showed that rivaroxaban, an oral, direct Factor Xa inhibitor, was noninferior to warfarin for the reduction of stroke or systemic embolism in patients with AF. Compared with warfarin, rivaroxaban significantly reduced rates of intracranial and fatal hemorrhages, although not rates of bleeding overall. XANTUS (Xarelto(®) for Prevention of Stroke in Patients with Atrial Fibrillation) is a prospective, international, observational, postauthorization, noninterventional study designed to collect safety and efficacy data on the use of rivaroxaban for stroke prevention in AF in routine clinical practice. The key goal is to determine whether the safety profile of rivaroxaban established in ROCKET AF is also observed in routine clinical practice. XANTUS is designed as a single-arm cohort study to minimize selection bias, and will enroll approximately 6,000 patients (mostly from Europe) with nonvalvular AF prescribed rivaroxaban, irrespective of their level of stroke risk. Overall duration of follow-up will be 1 year; the first patient was enrolled in June 2012. Similar studies (XANTUS-EL [Xarelto(®) for Prevention of Stroke in Patients with Nonvalvular Atrial Fibrillation, Eastern Europe, Middle East, Africa and Latin America] and XANAP [Xarelto(®) for Prevention of Stroke in Patients with Atrial Fibrillation in Asia-Pacific]) are ongoing in Latin America and Asia-Pacific. Data from these studies will supplement those from ROCKET AF and provide practical information concerning the use of rivaroxaban for stroke prevention in AF

Major Outcomes in Atrial Fibrillation Patients with One Risk Factor: Impact of Time in Therapeutic Range

BACKGROUND: The benefits and harms of oral anticoagulation (OAC) therapy in patients with only one stroke risk factor (i.e. CHA2DS2-VASc= 1 in males, or 2 in females) has been subject of debate. METHODS: We analysed all patients with only one stroke risk factor from the merged datasets of SPORTIF III and V trials. Anticoagulation control was defined according to time in therapeutic range (TTR). RESULTS: Of the original trial cohort, 1,097 patients had only one stroke risk factor. Stroke/systemic thromboembolic event had an incidence of 0.9 per 100 patient-years, with an incidence of 1.6 per 100 patient-years for all-cause death and 2.3%/patient-years for the composite outcome of stroke/systemic thromboembolic event/all-cause death. There were no significant differences in the risk for stroke/systemic thromboembolic event between sexes, nor between the different stroke risk factors amongst these atrial fibrillation patients with only one stroke risk factor. Cox regression analysis in patients treated with warfarin only found TTR to be inversely associated with stroke/systemic thromboembolic event (p=0.034) and all-cause death (p=0.015). Chronic heart failure was significantly associated with the outcome of all-cause death (p=0.0019) and the composite outcome of stroke/systemic thromboembolic event/all-cause death (p=0.021). There was a significant inverse linear association between TTR and the cumulative risk for both stroke/systemic thromboembolic event and all-cause death (both p<0.001). CONCLUSIONS: In atrial fibrillation patients with only one additional stroke risk factor (i.e. CHA2DS2-VASc= 1 in males or 2 in females), rates of major adverse events (stroke/systemic thromboembolic event, mortality) were high, despite anticoagulation. TTR in warfarin-treated patients was inversely associated with the occurrence of both stroke/systemic thromboembolic event and all-cause death

Study protocol: The DESPATCH study: Delivering stroke prevention for patients with atrial fibrillation - a cluster randomised controlled trial in primary healthcare

Background: Compelling evidence shows that appropriate use of anticoagulation in patients with nonvalvular atrial fibrillation reduces the risk of ischaemic stroke by 67% and all-cause mortality by 26%. Despite this evidence, anticoagulation is substantially underused, resulting in avoidable fatal and disabling strokes.Methods: DESPATCH is a cluster randomised controlled trial with concealed allocation and blinded outcome assessment designed to evaluate a multifaceted and tailored implementation strategy for improving the uptake of anticoagulation in primary care. We have recruited general practices in South Western Sydney, Australia, and randomly allocated practices to receive the DESPATCH intervention or evidence-based guidelines (control). The intervention comprises specialist decisional support via written feedback about patient-specific cases, three academic detailing sessions (delivered via telephone), practice resources, and evidence-based information. Data for outcome assessment will be obtained from a blinded, independent medical record audit. Our primary endpoint is the proportion of nonvalvular atrial fibrillation patients, over 65 years of age, receiving oral anticoagulation at any time during the 12-month posttest period.Discussion: Successful translation of evidence into clinical practice can reduce avoidable stroke, death, and disability due to nonvalvular atrial fibrillation. If successful, DESPATCH will inform public policy, providing quality evidence for an effective implementation strategy to improve management of nonvalvular atrial fibrillation, to close an important evidence-practice gap.Trial registration: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12608000074392. 2011 Gattellari et al; licensee BioMed Central Ltd

Healthcare resources and costs associated with nonvalvular atrial fibrillation in Spain: apixaban versus acenocoumarol

Aim: Healthcare resources usage and costs associated to nonvalvular atrial fibrillation (NVAF) were analyzed in Spain. Methods: This is an observational and retrospective study on patients with NVAF who started their treatment with apixaban or acenocoumarol between 1 January 2015 and 31 December 2017. Results: 2160 patients treated with apixaban were paired (1:1) with patients treated with acenocoumarol (propensity score matching). Apixaban reduced the incidence of strokes and systemic embolisms, minor and major bleedings and deaths, versus acenocoumarol. Apixaban led to reductions of 80, 55 and 43% in costs related to nursing visits, hospitalizations, and emergency visits, respectively, leading to annual cost savings of euro274/patient, from the perspective of society. Conclusion: Our results suggested that apixaban is a cost-effective alternative for patients with NVAF

A review of the real-world incidence of major bleeding after anticoagulant use in atrial fibrillation patients in the United States

OBJECTIVE: To comprehensively review real-world database studies in the United States that assess the risk of major bleeding among direct oral anticoagulant (DOAC) therapies or warfarin in a nonvalvular atrial fibrillation (NVAF) population. BACKGROUND: NVAF patients receiving anticoagulant therapy to reduce the risk of stroke or blood clots are at a higher risk of serious bleeding complications with the use of warfarin or other anticoagulant agents. METHODS: Reviewed MEDLINE (via Pubmed) and bibliographies of identified literature for publications and conference abstracts of retrospective observational studies using U.S. data sources from the first available date to June 15th, 2018. RESULTS: A total of 26 real-world database studies were identified and fully reviewed. Most studies utilized data from administrative claims or forms of patient registries (n = 25). Patient populations assessed were generally older and male. Apixaban resulted in statistically significant reductions in bleeding risk compared to warfarin in most studies that assessed the relationship (n = 11). Dabigatran was less consistently shown to exhibit a lower bleeding risk compared to warfarin; nine studies reported lower risk, though only three studies were statistically significant. In a head-to-head comparison, however, apixaban and dabigatran generally showed no significant difference. Bleeding risk for rivaroxaban was similar to warfarin. No studies were found that evaluated the bleeding risk of edoxaban. CONCLUSIONS: Overall, DOACs exhibit a lower risk of major bleeding compared to warfarin, although with significantly different rates. Apixaban most consistently shows reduced risk of bleeding in the real-world compared to warfarin, followed by dabigatran. More evidence is needed to evaluate the recently approved agent edoxaban

Role of rivaroxaban in the management of atrial fibrillation: insights from clinical practice.

© 2018 Vimalesvaran et al. This work is published and licensed by Dove Medical Press Limited.Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and it leads to significant morbidity and mortality, predominantly from ischemic stroke. Vitamin K antagonists, mainly warfarin, have been used for decades to prevent ischemic stroke in AF, but their use is limited due to interactions with food and other drugs, as well as the requirement for regular monitoring of the international normalized ratio. Rivaroxaban, a direct factor Xa inhibitor and the most commonly used non-vitamin K oral anticoagulant, avoids many of these challenges and is being prescribed with increasing frequency for stroke prevention in non-valvular AF. Randomized controlled trial (RCT) data from the 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 have shown rivaroxaban to be non-inferior to warfarin in preventing ischemic stroke and systemic embolism and to have comparable overall bleeding rates. Applicability of the RCT data to real-world practice can sometimes be limited by complex clinical scenarios or multiple comorbidities not adequately represented in the trials. Available real-world evidence in non-valvular AF patients with comorbidities - including renal impairment, acute coronary syndrome, diabetes mellitus, malignancy, or old age - supports the use of rivaroxaban as safe and effective in preventing ischemic stroke in these subgroups, though with some important considerations required to reduce bleeding risk. Patient perspectives on rivaroxaban use are also considered. Real-world evidence indicates superior rates of drug adherence with rivaroxaban when compared with vitamin K antagonists and with alternative non-vitamin K oral anticoagulants - perhaps, in part, due to its once-daily dosing regimen. Furthermore, self-reported quality of life scores are highest among patients compliant with rivaroxaban therapy. The generally high levels of patient satisfaction with rivaroxaban therapy contribute to overall favorable clinical outcomes.Peer reviewedFinal Published versio

Current clinician perspective on non-vitamin K antagonist oral anticoagulant use in challenging clinical cases.

OBJECTIVE: The evolution of non-vitamin K antagonist anticoagulants (NOACs) has changed the horizon of stroke prevention in atrial fibrillation (SPAF). All 4 NOACs have been tested against dose-adjusted warfarin in well-designed, pivotal, phase III, randomized, controlled trials (RCTs) and were approved by regulatory authorities for an SPAF indication. However, as traditional RCTs, these trials have important weaknesses, largely related to their complex structure and patient participation, which was limited by strict inclusion and extensive exclusion criteria. In the real world, however, clinicians are often faced with complex, multimorbid patients who are underrepresented in these RCTs. This article is based on a meeting report authored by 12 scientists studying atrial fibrillation (AF) in diverse ways who discussed the management of challenging AF cases that are underrepresented in pivotal NOAC trials. METHODS: An advisory board panel was convened to confer on management strategies for challenging AF cases. The article is derived from a summary of case presentations and the collaborative discussions at the meeting. CONCLUSION: This expert consensus of cardiologists aimed to define management strategies for challenging cases with patients who underrepresented in pivotal trials using case examples from their routine practice. Although strong evidence is lacking, exploratory subgroup analysis of phase III pivotal trials partially informs the management of these patients. Clinical trials with higher external validity are needed to clarify areas of uncertainty. The lack of clear evidence about complex AF cases has pushed clinicians to manage patients based on clinical experience, including rare situations of off-label prescriptions