Stroke/systemic Embolic Events Research Articles

Edoxaban dose, frailty, and outcomes in patients with atrial fibrillation: the ETNA-AF-Europe 4-year follow-up

Abstract Background Frailty is a common reason to choose non-recommended (non-rec) doses of non-vitamin-K-antagonist oral anticoagulants in patients with atrial fibrillation (AF); however, it is not known how this practice affects stroke and bleeding outcomes. Purpose To assess clinical outcomes in frail patients with AF receiving non-rec vs recommended (rec) doses of edoxaban using 4-yr follow-up data from ETNA-AF-Europe. Methods The prospective, observational ETNA-AF-Europe study followed patients with AF receiving edoxaban for up to 4 yrs. In ETNA-AF-Europe, perceived frailty was based on investigators’ own clinical binary judgement in each patient. Objective frailty was determined using a simplified adaptation of the Rockwood’s Frailty Index. For objective frailty, patients with missing index were categorised as non-frail. Patients with perceived or objective frailty were combined for this analysis. Baseline characteristics and hazard ratios (HRs) with 95% confidence intervals (CIs) assessing risk of outcomes in frail patients prescribed non-rec vs rec edoxaban doses (i.e., non-rec 60mg vs rec 30mg and non-rec 30mg vs rec 60mg) are presented. Data were adjusted for age, sex, and derived versions of the CHA2DS2-VASc and HAS-BLED scores. Net clinical benefit was defined as any stroke/systemic embolic event (SEE), transient ischaemic attack, venous thromboembolic event, major bleeding, or cardiovascular death, whichever came first. Results Of 13164 patients, 1786 were frail (13.6%; perceived frailty [n=1410], age [IQR]: 82.0 [78.0-86.0] yrs, women: 57.9%; objective frailty [n=540], age [IQR]: 77.0 [71.0-82.0] yrs, women: 31.9%; both, n=164). Baseline characteristics are reported in Table 1. Risk of all-cause death was higher in frail patients treated with non-rec 30mg vs rec 60mg (HR [95% CI]: 1.44 [1.06,1.96]). The annualised rate [CI] of any stroke/SEE was non-significantly higher (HR [95% CI]:1.60 [0.80,3.20]) with non-rec 30mg (n=169; 2.25 [1.25,4.06]) vs rec 60mg (n=622; 1.54 [1.08,2.20]). There was, however, no association between treatment received and risk (HR [95% CI]) of major bleeding (1.19 [0.58,2.43]) or net clinical benefit (1.26 [0.84,1.87]) (Figure 1). In frail patients who received non-rec 60mg (n=183) vs rec 30mg (n=695), risk of any stroke/SEE (HR [95% CI]) was higher (2.15 [1.03,4.49]), but there were no significant differences in the risk (HR [95% CI]) of major bleeding (1.03 [0.52,2.01]), net clinical benefit (1.15 [0.78,1.71]), or all-cause death (0.79 [0.59,1.05]) (Figure 1). Conclusions In this large European AF registry, the presence of frailty should not drive dosing recommendations for edoxaban. In particular, when compared with the rec 60mg dose, the non-rec 30mg (reduced) dose, was associated with more all-cause death and no benefits on major bleeding.Baseline Characteristics

Clinical outcomes of edoxaban treatment in atrial fibrillation patients with high bleeding risk: insights from the ETNA-AF-China 1-year follow-up

Abstract Background In China and many other countries, anticoagulated atrial fibrillation (AF) patients with high bleeding risk often raises clinical concern; the optimal dose of direct oral anticoagulants (DOACs) preventing stroke/systemic embolic events (SEE) in those population remains unclear. Purpose To assess the effectiveness and safety of edoxaban treatment in Chinese AF patients with high bleeding risk, and to compare 60 mg vs 30 mg dose in this real-world registry. Methods ETNA-AF-China is a prospective, observational study conducted in 89 centres across Chinese Mainland enrolling AF patients receiving edoxaban. This subgroup analysis was based on 1-year follow-up data. Patients were categorized to high bleeding risk group who had a DOAC score ≥6 (age, creatinine clearance, underweight, history of stroke/TIA/SEE, diabetes, hypertension, antiplatelet use, NSAIDs use, history of major/critical bleeding, liver disease) at baseline, or moderate-to-low bleeding risk group meeting criteria of DOAC score <6. The safety, effectiveness, and composite outcomes were reported by comparison between patient subgroups using Cox proportional hazards models. Results Of 4883 patients with 1-year follow-up, 1534 (31.4%, 60 mg: n=518, 30 mg: n=1016) were identified as high bleeding risk and 3349 (68.6%) as moderate-to-low bleeding risk. As expected, patients with high bleeding risk were more often elderly (48.2% ≥80 years), had lower body weight, worse renal function, higher CHA2DS2-VASc score than those with moderate-to-low risk (Figure 1). In both high risk and moderate-to-low risk subgroups, patients receiving 60 mg edoxaban were younger, with better renal function, lower CHA2DS2-VASc score compared with 30 mg. Annualised event rates of major bleeding (HR 2.95, 95%CI 1.62–5.36), all cause death (3.42, 2.29–5.09), CV death (3.27, 1.52–7.04), major adverse cardiac events (MACE, 2.61, 1.69–4.02) and all NCOs were significant higher in patients with high bleeding risk compared with moderate-to-low risk (Figure 2). After multivariable adjustment, edoxaban dose of 60 mg other than 30 mg were associated with significantly lower rates of all cause death (adjusted HR 0.41, 0.18–0.90) and lower trend of NCO3 (0.51, 0.28–0.92) and NCO4 (0.51, 0.30–0.88) by composite of stroke/SEE, major bleeding and death events in high risk subgroup; no significant difference between edoxaban doses and stroke or bleeding outcomes with cumulative low event rates were observed. Conclusion In routine clinical care, AF patients at high bleeding risk faces worse outcomes of death events, MACE, as well as the composite outcomes over moderate-to-low risk patients. Among patients with high bleeding risk, edoxaban use showed effectiveness and safety with overall low incidence, and potential better survival, composite endpoint benefit could be associated with 60mg. Further investigation is ongoing.

Clinical outcomes in >10,000 Asian vs >61,000 Non-Asian race patients with AF randomized to Warfarin vs DOACs: a patient-level meta-analyses from COMBINE AF

Abstract Background Randomized data comparing clinical outcomes of atrial fibrillation (AF) patients with Asian vs non-Asian races are limited. Methods Using the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database (data from RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48), we performed an individual patient-level meta-analysis to investigate and compare clinical outcomes of AF patients with self-defined Asian and non-Asian races adjusted for baseline characteristics. Standard-dose direct oral anticoagulants (SD DOAC) were defined as dabigatran 150mg bid; rivaroxaban 20mg (15mg) QD, apixaban 5 mg (2.5 mg) bid, or edoxaban 60 mg (30 mg) QD. Low-dose DOACs (DOACs [LD]) were defined as dabigatran 110 mg bid or edoxaban 30 mg (15mg) QD. Results There were 10,212 pts of Asian race and 61,471 non-Asian races in the COMBINE AF database. Compared with non-Asians, Asians were on average 3.2 yrs younger, 20 kg lighter, had worse renal function (mean CrCl 64.9 vs. 77.3 mL/min), and higher rates of prior stroke/transient ischemic attack (37.2% vs 26.6%), P<0.001 for each. The median value of time in therapeutic range of patients randomized to warfarin was lower in Asians than non-Asians (57.7% vs. 66.2%, P<0.001). In the warfarin arm, Asians had a higher adjusted risk of stroke/systemic embolic events (SEE), major bleeding (MB), ICH, GI bleeding (GIB), and net clinical outcome (NCO: stroke/SEE, MB, or death)(Figure; Upper panel). Compared to warfarin, SD DOACs significantly reduced the risks of stroke/SEE, MB, and NCO to a greater degree in Asians than non-Asians (HR stroke/SEE: Asians 0.65 vs Non-Asians 0.86; HR MB: Asians 0.62 vs Non-Asians 0.91; HR NCO: Asians 0.76 vs non-Asians 0.94; Pint <0.02 for each), while SD DOACs increased GIB only in non-Asians (Asian HR 0.92 [0.69-1.23] vs Non-Asians HR 1.41 [1.25-1.58], Pint 0.009; Figure Lower panel). Conclusions The adjusted risks of stroke/SEE and major bleeding with warfarin were higher in Asians compared to non-Asians. The benefits of DOACs over warfarin in preventing stroke/SEE, MB, and net clinical outcomes were significantly greater in Asians than non-Asians.

Patient Outcomes in Very Elderly Patients With Non-Valvular Atrial Fibrillation - ANAFIE Registry.

The All Nippon Atrial Fibrillation In the Elderly Registry provides real-world insights into non-valvular atrial fibrillation (NVAF) in >30,000 elderly Japanese patients (aged ≥75 years), including >2,000 nonagenarians. We aimed to investigate outcomes in these patients by age and oral anticoagulant (OAC) type. This prospective, multicenter, observational, cohort, 2-year follow-up study included elderly patients with NVAF who were able to attend hospital visits. The incidences of stroke/systemic embolic events (SEE), major bleeding, intracranial hemorrhage (ICH), cardiovascular death, all-cause death, and major adverse cardiovascular or neurological events (MACNE) were evaluated by age. Incidence rates increased significantly with age. Stroke/SEE, major bleeding, and ICH incidences plateaued in patients aged ≥90 years. Direct OACs (DOACs) yielded a numerically lower event incidence vs. warfarin in all age groups and endpoints, except for major bleeding in patients aged ≥90 years. DOACs (vs. warfarin) were significantly associated with a lower risk of stroke/SEE, major bleeding, and ICH in the ≥80-<85 years group, and reduced cardiovascular and all-cause death in the ≥75-<80 years group. In the ≥90 years subgroup, major bleeding history was a risk factor for all-cause death. Although DOAC vs. warfarin offers potential benefits for stroke prevention, limitations occurred in reducing major bleeding among those aged ≥90 years, indicating a potential benefit of very-low-dose DOAC for this demographic.

The predictive role of N-terminal pro-B-type natriuretic peptide in assessing outcomes for atrial fibrillation patients, with or without heart failure: a comprehensive systematic review and meta-analysis

Background and purpose: Brain natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are commonly used to predict clinical outcomes in patients with heart failure (HF). The prognostic role of BNP/NT-proBNP in patients with atrial fibrillation (AF) and comorbid HF is controversial. The current study aimed to understand the clinical importance of BNP/NT-proBNP measurement in predicting the outcomes of AF patients regardless of HF status. Methods: This is a systematic review and meta-analysis. A comprehensive literature search was conducted using PubMed, EBSCOHost, Cochrane, ScienceDirect, and ClinicalKey. Studies that reported all-cause mortality, stroke/systemic embolic events (SEE)/thromboembolic events (TE), major adverse cardiovascular events (MACE), and major bleeding were included in this study. All-cause mortality was the primary outcome. Studies that reported BNP data but not NT-proBNP were also included. BNP/NT-proBNP is categorized as high and low level based on the highest and lowest groups compared in the included studies. Results: Sixteen studies (n = 45,400) were included in data synthesis: six were post hoc analysis of randomized controlled trials and the remaining were prospective cohort studies. The included studies were published between 2011 and 2022. The follow-up duration ranged from 1.0 to 5.2 years. High level of BNP/NT-proBNP was associated with a significantly increased risk of all-cause mortality (pooled hazard ratio [HR]: 2.26, 95% confidence interval [95% CI]: 1.98–2.56), stroke/SEE/TE (pooled HR: 2.45, 95% CI: 2.07–2.90), and MACE (pooled HR: 2.38, 95% CI: 1.90–2.99) in patients with AF; the pooled HR of major bleeding was 1.17 (95% CI: 1.01–1.36). Sensitivity analysis in patients with AF and HF produced similar results. Conclusions: BNP and NT-proBNP are strong predictors of clinical outcomes in patients with AF regardless of HF.

Anticoagulant therapy and home blood pressure-associated risk for stroke/bleeding events in elderly patients with non-valvular atrial fibrillation: the sub-cohort study of ANAFIE registry

The benefits of direct oral anticoagulants (DOACs) and warfarin in elderly Japanese patients with non-valvular atrial fibrillation (NVAF) and high home systolic blood pressure (H-SBP) are unclear. This sub-cohort study of the ANAFIE Registry estimated the incidence of clinical outcomes in patients receiving anticoagulant therapy (warfarin and DOACs) stratified by H-SBP levels (<125 mmHg, ≥125–<135 mmHg, ≥135–<145 mmHg and ≥145 mmHg). Of the overall ANAFIE population, 4933 patients who underwent home blood pressure (H-BP) measurements were analyzed; 93% received OACs (DOACs: 3494, 70.8%; warfarin: 1092, 22.1%). In the warfarin group, at <125 mmHg and ≥145 mmHg, the respective incidence rates (per 100 person-years) were 1.91 and 5.89 for net cardiovascular outcome (a composite of stroke/systemic embolic events (SEE) and major bleeding), 1.31 and 3.39 for stroke/SEE, 0.59 and 3.91 for major bleeding, 0.59 and 3.43 for intracranial hemorrhage (ICH), and 4.01 and 6.24 for all-cause death. Corresponding incidence rates in the DOACs group were 1.64 and 2.65, 1.00 and 1.88, 0.78 and 1.69, 0.55 and 1.31, and 3.43 and 3.51. In warfarin-treated patients, the incidence rates of net cardiovascular outcome, stroke/SEE, major bleeding, and ICH were significantly increased at H-SBP ≥ 145 mmHg versus <125 mmHg. In the DOAC group, although there was no significant difference between H-SBP < 125 mmHg and ≥145 mmHg, the incidence rates of these events tended to increase at ≥145 mmHg. These results suggest that strict BP control guided by H-BP is required in elderly NVAF patients receiving anticoagulant therapy.

Risks of Heart Failure, Stroke, and Bleeding in Atrial Fibrillation According to Heart Failure Phenotypes

BackgroundThe risks of heart failure (HF) events compared with stroke/systemic embolic events (SEE) or major bleeding (MB) in heart failure with reduced ejection fraction (HFrEF) vs heart failure with preserved ejection fraction (HFpEF) in a large atrial fibrillation (AF) population have not been well-studied. ObjectivesThis study sought to assess HF outcomes, according to HF history and HF phenotypes (HFrEF vs HFpEF), and compare these events with SEE and MB, among patients with AF. MethodsWe analyzed patients enrolled in the ENGAGE-AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48) trial. Cumulative incidence of heart failure hospitalization (HHF) or HF death was assessed and compared with the rates of fatal and nonfatal stroke/SEE and MB over a median follow-up of 2.8 years. ResultsOverall, 12,124 (57.4%) had a history of HF (37.7% HFrEF, 40.1% HFpEF, 22.1% with unknown ejection fraction). The rate per 100 person-years (py) of HHF or HF death (4.95; 95% CI: 4.70-5.20) was higher than of fatal and nonfatal stroke/SEE (1.77; 95% CI: 1.63-1.92) and MB (2.66; 95% CI: 2.47-2.86) among patients with HF history. HFrEF patients experienced a higher rate of HHF or HF death compared with HFpEF patients (7.15 vs 3.65; P < 0.001), while the rates of fatal and nonfatal stroke/SEE and MB were similar by HF phenotype. Patients with HF history had a higher rate of mortality after a HHF (1.29; 95% CI: 1.17-1.42) than after a stroke/SEE (0.69; 95% CI: 0.60-0.78) or after MB (0.61; 95% CI: 0.53-0.70). Overall, patients with nonparoxysmal AF had a higher rate of HF and stroke/SEE events regardless of HF history. ConclusionsPatients with AF and HF, regardless of ejection fraction, are at a higher risk of HF events with higher subsequent mortality rates than of stroke/SEE or MB. While HFrEF is associated with a higher risk of HF events than HFpEF, the risk of stroke/SEE and MB is similar between HFrEF and HFpEF.

Impact of cognitive impairment on clinical outcomes in elderly patients with atrial fibrillation: ANAFIE Registry

BackgroundThis subcohort study of All Nippon AF In the Elderly (ANAFIE) Registry based on 33 275 elderly patients (aged ≥75 years) with non-valvular atrial fibrillation (NVAF) investigated the relationship between...

Value of N-Terminal Pro-Brain Natriuretic Peptide for Embolic Events Risk Prediction in Patients with Atrial Fibrillation; a Systematic Review and Meta-Analysis.

A comprehensive conclusion has yet to be made about the predictive value of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) for stroke/systemic embolic events (SEE) in patients with atrial fibrillation (AF). This study aims to review the evidence for evaluating the value of NT-proBNP in predicting the risk of stroke/SEE in patients with AF through a systematic review and meta-analysis. Two independent reviewers screened all relevant studies that were retrieved from the database of Medline, Embase, Scopus, and Web of Science until December 7th, 2021. The predictive value of NT-proBNP in the prediction of stroke/SEE was recorded as hazard ratio (HR) and 95% confidence interval (95% CI). Nine articles (38,093 patients, 3.10% stroke/SEE) were included in our analysis. There was no publication bias in these studies (P=0.320). Our analysis showed that NT-proBNP can be a good predictor of stroke/SEE risk in AF patients, even at different cut-off values (HR=1.76; 95% CI: 1.51, 2.02; P < 0.001). Subgroup analysis showed that diabetes could have a possible effect on the predictive value of NT-proBNP (meta-regression coefficient = 0.042; P = 0.037). Measurement of NT-proBNP during the first admission could be used to assess the short- or long-term risk of stroke/SEE in patients with AF. Further studies are needed to evaluate the possible applicability of serum NT-proBNP measurement in the settings in which stroke is the sole outcome of the investigation.

Prognostic impact of heart rate during atrial fibrillation on clinical outcomes in elderly non-valvular atrial fibrillation patients: ANAFIE Registry sub-cohort study

BackgroundElderly patients with atrial fibrillation (AF) are at a higher risk for all-cause mortality and heart failure. Rate control is an essential component in AF management. This exploratory study assessed the relationship between resting heart rate during AF at baseline and clinical outcomes in Japanese elderly non-valvular AF (NVAF) patients, using the All Nippon AF In the Elderly Registry (ANAFIE) dataset. MethodsThis sub-cohort included patients who agreed to participate and presented with AF at enrollment in the ANAFIE study. They were categorized into six groups according to the resting heart rate during AF. Outcomes included 2-year cumulative incidences of stroke/systemic embolic events (SEE), ischemic stroke, major bleeding, cardiovascular (CV) events, CV death, all-cause death, and net clinical outcome, a composite of stroke/SEE, major bleeding, and all-cause death. ResultsOf the 8292 patients included in this sub-cohort (paroxysmal, 1496; non-paroxysmal, 6796), 90 % of patients were using anticoagulants. Higher heart rate was more frequently reported in women and in patients with paroxysmal AF and was associated with increased use of direct oral anticoagulants (DOACs) and antiarrhythmic drugs. Heart rate ≥110 beats per minute (bpm) was associated with a significantly higher incidence of cardiac events and numerically higher incidences of CV death and all-cause death compared with a heart rate of 60 to <80 bpm, all of which were driven by an increased risk in patients with non-paroxysmal AF. Hazard ratios by the type of anticoagulant for each clinical outcome were comparable across all heart rate categories, indicating no significant interactions. ConclusionsElderly Japanese patients with non-paroxysmal NVAF and a heart rate ≥110 bpm have an increased risk of cardiac events. There was no interaction between heart rate category and the relative risk of adverse clinical events in patients taking DOACs compared with those taking warfarin.

Home Blood Pressure Can Predict the Risk for Stroke/Bleeding Events in Elderly Patients With Nonvalvular Atrial Fibrillation From the ANAFIE Registry.

Blood pressure (BP) fluctuates significantly in patients with atrial fibrillation (AF); office BP measurements seem insufficient to assess AF patient risk accurately. We hypothesized that home BP could better predict the risk of stroke/systemic embolic events (SEE) and major bleeding in patients with AF than office BP. In this prespecified subcohort study of the ANAFIE (All Nippon AF in the Elderly) Registry, we evaluated the impact of home BP on the risk of stroke/SEE, major bleeding, intracranial hemorrhage, all-cause death, and net cardiovascular outcome (a composite of stroke/SEE and major bleeding). At enrollment, home BP was measured twice in the morning and evening for 7 days. In total, 4933 elderly patients (aged ≥75 years) with nonvalvular AF participated. Incidences of net cardiovascular outcome, stroke/SEE, major bleeding, and intracranial hemorrhage increased significantly with increasing home systolic BP (H-SBP). Compared with H-SBP <125 mm Hg, ≥145 mm Hg was associated with increased risk of these events. The association between H-SBP and the events was observed only in patients with ≥20 H-SBP measurements. In elderly patients with nonvalvular AF, high H-SBP (≥145 mm Hg) was a significant predictor of stroke/SEE, major bleeding, and intracranial hemorrhage risk. Strict BP control guided by the increasing number of home BP measurements may provide an accurate clinical outcome risk assessment. URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000024006.

Clinical outcomes in patients with atrial fibrillation with or without concomitant diabetes after two years of edoxaban treatment: ETNA-AF-Europe registry

Abstract Background/Introduction Concomitant diabetes mellitus (DM) in patients with atrial fibrillation (AF) has been associated with a higher risk of stroke/systemic embolic events (SEE), and higher mortality. Purpose To evaluate effectiveness and safety outcomes in AF patients with different types of concomitant DM vs those without concomitant DM after 2 years of edoxaban treatment in a sub-analysis of the prospective ETNA-AF-Europe registry. Methods Patients with AF who received edoxaban once daily were enrolled across 825 centres in 10 European countries. This sub-analysis is based on a data snapshot from 26th October 2020. Patients were grouped by DM status (with or without DM; insulin-treated or non-insulin-treated DM). Baseline characteristics are summarised descriptively. Kaplan-Meier (KM) survival curves of outcomes were constructed; annualised event rates (AERs; %/year) and comparisons between patients with or without DM by univariate analysis are presented. Comparisons of patients with insulin- vs non-insulin-treated DM were made by multivariate analysis adjusted for HbA1c. Results Patients' demographics and baseline characteristics are shown in Table 1. Of 13,133 patients with AF, 2885 (22.0%) had DM. Among patients with DM, 2756 (95.6%) received treatment: 605 (22.0%) with insulin and 2151 (78.0%) with non-insulin treatments. KM curves for effectiveness and safety outcomes are shown in Figure 1. AERs (%/year) of ischaemic stroke/transient ischaemic attack (TIA)/SEE were 0.86% in patients with AF and no DM, 0.87% with non-insulin-treated DM (p=0.9216 vs no DM) and 1.81% with insulin-treated DM (p=0.0022 vs no DM; p=0.0014 vs non-insulin-treated DM). AERs of myocardial infarction (MI) were 0.40%, 0.43% (p=0.7454 vs no DM), and 1.04% (p=0.0033 vs no DM) respectively; of major bleeding were 0.90%, 1.10% (p=0.2427 vs no DM), and 1.71% (p=0.0106 vs no DM), respectively; and of all-cause death were 3.36%, 5.02% (p&amp;lt;0.0001 vs no DM), and 8.91% (p&amp;lt;0.0001 vs no DM) respectively. In a multivariate analysis of DM patients adjusted for HbA1c (patients with AF and DM with HbA1c measured, n=1869), patients with AF and insulin-treated DM had a higher risk of stroke/TIA/SEE (HbA1c adjusted HR [95% CI]: 2.13 [1.12–4.05], p=0.0205) and all-cause death (1.83 [1.35–2.49], p=0.0001) vs those with non-insulin-treated DM; no significant difference in the risk of MI (2.10 [0.78–5.66], p=0.1448) or major bleeding (1.81 [0.95–3.44], p=0.0706) was detected between the groups. Conclusion In patients with AF and DM, risk of stroke/TIA/SEE, MI and major bleeding was confined to insulin-treated DM patients only. These patients also had poorer survival rates vs those without DM and those with non-insulin-treated DM, reinforcing previously published data showing a strong association between insulin treatment and poorer outcomes, and a mild/absent association between non-insulin treatments and poorer outcomes in patients with AF and DM. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was funded by Daiichi Sankyo Europe.

Effect of Cancer on Clinical Outcomes in Elderly Patients With Non-Valvular Atrial Fibrillation - Substudy of the ANAFIE Registry.

Data on outcomes for patients with atrial fibrillation (AF) and active cancer are scarce. The effect of active cancer on thrombosis and bleeding risks in elderly (≥75 years) patients with non-valvular AF (NVAF) enrolled in the All Nippon AF In the Elderly (ANAFIE) Registry were prospectively analyzed. In this subanalysis of the ANAFIE Registry, a prospective, multicenter, observational study conducted in Japan, we compared the incidence rates of clinical outcomes between active cancer and non-cancer groups. Relationships between primary outcomes and anticoagulation status were evaluated. Of the 32,725 patients enrolled in the Registry, 3,569 had active cancer at baseline; 92.0% of active cancer patients received anticoagulants (23.7%, warfarin; 68.2%, direct oral anticoagulants [DOACs]). Two-year probabilities of stroke/systemic embolic events (SEE) were similar in the cancer (3.33%) and non-cancer (3.16%) groups. Patients with cancer had greater incidences of major bleeding (2.86% vs. 2.04%), all-cause death (10.95% vs. 6.77%), and net clinical outcomes (14.63% vs. 10.00%) than those without cancer. In patients without cancer, DOACs were associated with a decreased risk of stroke/SEE, major bleeding, all-cause death, and net clinical outcome compared with warfarin. No between-treatment differences were observed in patients with active cancer. Active cancer had no effect on stroke/SEE incidence in elderly NVAF patients, but those with cancer had higher incidences of major bleeding events and all-cause death than those without cancer.

Anticoagulant treatment status and outcomes of elderly non-valvular atrial fibrillation patients with a history of catheter ablation in Japan: subanalysis of the ANAFIE registry

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Co., Ltd. OnBehalf ANAFIE Registry Group Backgrounds Benefits of catheter ablation (CA) have been shown for patients with atrial fibrillation (AF). However, data in elderly patients aged ≥75 years who have undergone CA for non-valvular AF (NVAF) are insufficient. Purpose The All Nippon Atrial Fibrillation In the Elderly (ANAFIE) Registry is a prospective, multicenter, observational study, which was designed to collect the real-world data on the clinical status and prognosis in 30,000 over Japanese patients (aged ≥75 years) with NVAF. This cross-sectional subanalysis of the ANAFIE registry assessed the 2-year outcomes and anticoagulant treatment in elderly NVAF patients with a history of CA. Methods A total of the 32,275 patients from the ANAFIE registry were divided into two groups by a history of CA: the CA and No-CA groups. Kaplan-Meier analysis was used to evaluate the annualized incidences of stroke/systemic embolic event (SEE), major bleeding, intracranial hemorrhage (ICH), heart failure requiring hospitalization (HF), and all-cause mortality. Hazard ratio (HR) for each event was analyzed using the Cox proportional-hazards model. Results Of all patients, 2,970 patients (9.2%) were included in the CA group and 29,305 (90.8%) were included in the No-CA group. The CA group had lower age (mean 78.9 vs 81.7 years), higher prevalence of paroxysmal AF (73.0 vs 39.0%), higher creatinine clearance (mean 53.1 vs 47.9 mL/min) and lower CHA2DS2-VASc (mean 4.2 vs 4.5) and HAS-BLED scores (mean 1.8 vs 1.9) than the No-CA group. Oral anticoagulants (OACs) were administered in 87.3% of the CA group (warfarin, 16.8%; direct OAC, 70.5%) and 92.9% of the No-CA group (warfarin, 26.4%; direct OAC, 66.5%). Compared with the No-CA group, the CA group had lower the annualized incidences (/100 patient-year [95%confidence intervals]) of stroke/SEE (0.74 [0.52, 0.96] vs 1.72 [1.61, 1.83]), major bleeding (0.63 [0.43, 0.84] vs 1.12 [1.03, 1.21]), ICH (0.49 [0.31, 0.67] vs 0.78 [0.71, 0.86]), HF (2.54 [2.12, 2.96] vs 4.44 [4.26, 4.62]), and all-cause mortality (1.45 [1.14, 1.77] vs 3.95 [3.78, 4.11]). Conclusions Elderly NVAF patients with a history of CA had lower adverse incidences compared with patients without a history of CA. A more optimal OAC therapy for elderly NVAF patients with a history of CA should be examined in the future.

Two-year outcomes of more than 30000 elderly patients with atrial fibrillation: results from the All Nippon AF In the Elderly (ANAFIE) Registry.

AimsTo clarify the real-world clinical status and prognosis of elderly and very elderly non-valvular atrial fibrillation (NVAF) patients, more than 30 000 elderly patients with NVAF aged ≥75 years were enrolled in the ANAFIE Registry.Methods and resultsThis multicentre, prospective, observational study followed elderly NVAF patients in Japan for ∼2 years. Among 32 275 patients (mean age, 81.5 years; men, 57.3%; mean CHA2DS2-VASc score, 4.5), 2445 (7.6%) were not receiving oral anticoagulants (OACs) and 29 830 (92.4%) were given OACs. Of these, 21 585 (66.9%) were receiving direct OACs (DOACs) and 8233 (25.5%), warfarin (mean time in therapeutic range: ∼75%). In total, the 2-year incidence rate was 3.01% for stroke/systemic embolic events (SEE); 2.00%, major bleeding; and 6.95%, all-cause death. When compared with the warfarin group, the DOAC group had a lower hazard ratio (HR) for stroke/SEE, major bleeding, and all-cause death after adjusting for confounders. The group without OACs had a higher HR for stroke/SEE and all-cause death, with a lower HR for major bleeding. History of falls within 1 year at enrolment and of catheter ablation were positive and negative independent risk factors, respectively, for stroke/SEE, major bleeding, and all-cause death.ConclusionIn Japan, a large proportion of elderly and very elderly NVAF patients were receiving DOACs, which was significantly associated with lower rates of stroke/SEE, major bleeding, and all-cause death vs. well-controlled warfarin. History of falls and of catheter ablation were independently associated with stroke/SEE, major bleeding, and all-cause death.

Mortality Prediction of the CHA2DS2-VASc Score, the HAS-BLED Score, and Their Combination in Anticoagulated Patients with Atrial Fibrillation.

Background and Objectives: Atrial fibrillation (AF) is associated with increased mortality, predictors of which are poorly characterized. We investigated the predictive power of the commonly used CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥ 75 years [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65–75 years, sex category [female]), the HAS-BLED score (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio [INR], elderly [age ≥ 65 years], drugs/alcohol concomitantly), and their combination for mortality in AF patients. Methods: The PREvention oF thromboembolic events—European Registry in Atrial Fibrillation (PREFER in AF) was a prospective registry including AF patients across seven European countries. We used logistic regression to analyze the relationship between the CHA2DS2-VASc and HAS-BLED scores and outcomes, including mortality, at one year. We evaluated the performance of logistic regression models by discrimination measures (C-index and DeLong test) and calibration measures (Hosmer and Lemeshow goodness-of-fit and integrated discrimination improvement (IDI), with bootstrap techniques for internal validation. Results: In 5209 AF patients with complete information on both scores, average one-year mortality was 3.1%. We found strong gradients between stroke/systemic embolic events (SSE), major bleeding and—specifically—mortality for both CHA2DS2-VASc and HAS-BLED scores, with a similar C-statistic for event prediction. The predictive power of the models with both scores combined, removing overlapping components, was significantly enhanced (p < 0.01) compared to models including either CHA2DS2-VASc or HAS-BLED alone: for mortality, C-statistic: 0.740, compared to 0.707 for CHA2DS2-VASc or 0.646 for HAS-BLED alone. IDI analyses supported the significant improvement for the combined score model compared to separate score models for all outcomes. Conclusions: Both the CHA2DS2-VASc and the HAS-BLED scores predict mortality similarly in patients with AF, and a combination of their components increases prediction significantly. Such combination may be useful for investigational and—possibly—also clinical purposes.

Risk factors associated with stroke/systemic embolic events in elderly non-valvular atrial fibrillation patients in the ANAFIE registry, the largest real-world elderly AF registry

Abstract Background Since prevalence of atrial fibrillation (AF) is increasing by aging, AF in elderly has been recognized as a big burden to keep long lasting healthy life worldwide. CHADS2 and CHA2DS2-VASc scores are commonly used for stroke risk assessment for AF, but predictors for elderly was not well elucidated, especially for very elderly (≥85 years old) patients. Purpose All Nippon AF In the Elderly (ANAFIE) registry was designed to evaluate a real-world treatment status of elderly (≥75 years old) non-valvular AF (NVAF) patients, including anticoagulant therapy and outcomes. The present analysis aimed to identify factors for stroke/systemic embolic events (SEE) of elderly NVAF patients using the dataset of ANAFIE registry, which was conducted in Japan. Methods Total of 32,099 patients aged ≥75 years with NVAF were enrolled in ANAFIE registry, and followed for 2 years. Incidence of stroke/SEE for total population, &amp;lt;85 years old group and ≥85 years old group was estimated using Kaplan-Meier method. Cox proportional hazards model was used to determine independent predictors of stroke/SEE. The factors included in the model were selected by backward elimination procedure. Results Mean age was 81.5 years. 23,738 (74%) was &amp;lt;85 years old and 8,361 (26%) was ≥85 years old. Women were more prevalent in ≥85 years old than in &amp;lt;85 years old group (53.2 vs 39.0%). Mean CHADS2 and CHA2DS2-VASc scores in the ≥85 years group were 3.0 and 4.7, and 2.8 and 4.4 in the &amp;lt;85 years group, respectively. 92.5% of whole population used anti-coagulants including warfarin (27.6%) or direct oral anticoagulants (DOACs) (72.3%). Stroke/SEE occurred in 396 patients at 12 month with 256 in &amp;lt;85 years old and 140 in ≥85 years old group. The cumulative incidence rate of stroke/SEE by Kaplan-Meier method at 12 months was 1.2% in the whole patients, and was higher in ≥85 years than in &amp;lt;85 years old group (1.7% vs 1.1%). In the multivariate analysis using the whole patients, age ≥85 years (hazard ratio [HR]: 1.27), history of major bleeding (HR: 1.93), persistent AF (HR: 1.64), longstanding persistent and permanent AF (HR: 1.61), high systolic blood pressure (130-&amp;lt;140 [HR: 1.43], ≥140 [HR: 1.44]), prior stroke (HR: 2.09), dementia (HR: 1.34), creatinine clearance &amp;lt;30 mL/min (HR: 1.82) emerged as independent predictors. Independent predictors for stroke/SEE were almost similar between &amp;lt;85 and ≥85 years old group except hypertension and diabetes. High blood pressure was associated with stroke/SEE only in patients aged &amp;lt;85 years, and high blood sugar was only associated in patients aged ≥85 years. Conclusion Among elderly NVAF patients in the era of DOACs, higher age (≥85 years), type of AF, prior major bleeding, high blood pressure, prior stroke, dementia, and low creatinine clearance were identified as independent predictors of stroke/SEE. The blood pressure and blood sugar control differently affected &amp;lt;85 years vs ≥85 years old group. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo Co., Ltd.

Comparing clinical outcomes of NOACs with warfarin on atrial fibrillation with Valvular heart diseases: a meta-analysis

BackgroundWarfarin is the standard of care and NOAC (Novel oral anticoagulants) are a group of newer drugs for such purposes. NOAC has a generally better profile (Clear interaction, less side effect, require less monitoring). However, its efficacy on valvular atrial fibrillation remains unclear.MethodWe researched literature articles from Embase, Cochrane and PubMed. Then we meta-analysed these six articles to assess pooled estimate of relative risk (RR) and 95% confidence intervals (Cl) using random-effects model for stroke, systemic embolic event, major bleeding and all-cause mortality. Heterogeneity across study was tested with Cochran’s Q Test and I2 Test. The bias of studies was first tested by examining the symmetry of Funnel Plot. Cochrane’s Collaboration Tool was also used to report any presented bias.ResultsWe collected 496 articles in total and finally we included six articles in our meta-analysis. For SSEE (Stroke, Systemic Embolic Event), the pooled relative risk showed a significantly better clinical outcome of NOAC (RR: 0.66; 95% CI: 0.46 to 0.95). However, there is no significant difference in major bleeding (RR: 0.714, 95% CI:0.46 to 1.11) and all-cause mortality (RR: 0.84, 95% CI: 0.58 to 1.21).ConclusionCompared to Warfarin, NOAC is significantly more protective against the embolic event, but no significant difference in lowering risk of major bleeding, all-cause mortality or all aspects of post-TAVI (Trans-catheter aortic valve implantation).

Relationship between body mass index and outcomes in patients with atrial fibrillation treated with edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial.

To investigate the relationship between body mass index (BMI) and outcomes in patients with atrial fibrillation (AF). In the ENGAGE AF-TIMI 48 trial, patients with AF were randomized to warfarin (international normalized ratio 2.0-3.0) or edoxaban. The cohort (N = 21028) included patients across BMI categories (kg/m2): underweight (<18.5) in 0.8%, normal (18.5 to <25) in 21.4%, overweight (25 to <30) in 37.6%, moderately obese (30 to <35) in 24.8%, severely obese (35 to <40) in 10.0%, and very severely obese (≥40) in 5.5%. In an adjusted analysis, higher BMI (continuous, per 5 kg/m2 increase) was significantly and independently associated with lower risks of stroke/systemic embolic event (SEE) [hazard ratio (HR) 0.88, P = 0.0001], ischaemic stroke/SEE (HR 0.87, P < 0.0001), and death (HR 0.91, P < 0.0001), but with increased risks of major (HR 1.06, P = 0.025) and major or clinically relevant non-major bleeding (HR 1.05, P = 0.0007). There was a significant interaction between sex and increasing BMI category, with lower risk of ischaemic stroke/SEE in males and increased risk of bleeding in women. Trough edoxaban concentration and anti-Factor Xa activity were similar across BMI groups >18.5 kg/m2, while time in therapeutic range for warfarin improved significantly as BMI increased (P < 0.0001). The effects of edoxaban vs. warfarin on stroke/SEE, major bleeding, and net clinical outcome were similar across BMI groups. An increased BMI was independently associated with a lower risk of stroke/SEE, better survival, but increased risk of bleeding. The efficacy and safety profiles of edoxaban were similar across BMI categories ranging from 18.5 to >40.

Valvular Heart Disease Patients on Edoxaban or Warfarin in the ENGAGE AF-TIMI 48 Trial

BackgroundThe use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart disease (VHD) is of substantial interest. ObjectivesThis study explored outcomes in patients with AF with and without VHD in the ENGAGE AF–TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin. MethodsValvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards. ResultsAfter adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio [HR]: 1.40; 95% confidence interval [CI]:1.26 to 1.56; p <0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p <0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction [pint] = 0.26; and for less major bleeding, HR: 0.74; 95% CI: 0.53 to 1.02 in patients with VHD, and HR: 0.82; 95% CI: 0.71 to 0.94, in patients with no VHD; pint = 0.57). ConclusionsThe presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF. (Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs. Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [ENGAGE AF-TIMI 48]; NCT00781391)