Background
A global, randomized clinical trial indicated the efficacy and safety of apixaban in stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). However, data in the elderly ...NVAF patients ≥75 years, especially those on reduced dose, are limited.
Hypothesis
To confirm the current dose reduction criteria of apixaban in elderly NVAF patients.
Method
With a large‐scale, multicenter prospective observational study, one‐year outcomes after administration of on‐label doses of apixaban were analyzed in Japanese NVAF patients aged ≥75 years. Endpoints were stroke or systemic embolism, bleeding requiring hospitalization, total death, and cardiovascular death.
Results
A total of 3031 patients (average age, 81.7 years; female, 48.2%) taking standard (5 mg bid) or reduced dose (2.5 mg bid) of apixaban were enrolled from 110 facilities. Standard and reduced apixaban doses were administered in 1284 (42.4%) and 1747 (57.6%) patients, respectively. Event rates (/100 person‐years) in standard and reduced dose groups were 1.67 and 1.56, respectively, for stroke or systemic embolism, 1.42 and 2.25 for bleeding requiring hospitalization, 1.41 and 4.46 for total death, and 0.41 and 1.36 for cardiovascular death. Reduced apixaban dose was not significantly associated with stroke or systemic embolism and bleeding requiring hospitalization, but was independently associated with total and cardiovascular death.
Conclusions
Incidences of stroke or systemic embolism and bleeding requiring hospitalization were similar between standard and reduced apixaban doses in the elderly NVAF patients. The incidences of total and cardiovascular death were significantly higher in the reduced dose group due to the coexisting higher risks in this group.
Background:The short-term safety and plasma concentrations of edoxaban 15 mg once daily in Japanese patients with non-valvular atrial fibrillation (NVAF) and severe renal impairment (SRI; creatinine ...clearance CLCR ≥15 to <30 ml/min) were compared with those in NVAF patients with normal renal function or mild renal impairment (normal/MiRI; CLCR≥50 ml/min) treated with edoxaban 30 or 60 mg.Methods and Results:In this Phase 3 multicenter open-label 3 parallel-group study, SRI patients received once-daily edoxaban 15 mg (n=50), whereas normal/MiRI patients were randomized to receive either once-daily edoxaban 30 or 60 mg (n=22 and 21, respectively) for 12 weeks. Plasma edoxaban concentrations and biomarkers of blood coagulation and fibrinolysis were measured. Adverse events and thromboembolic events were recorded throughout the study. Rates of any bleeding were comparable between SRI patients receiving edoxaban 15 mg (20.0%) and normal/MiRI patients receiving edoxaban 30 or 60 mg (22.7% and 23.8%, respectively). No major bleeding or thromboembolic events occurred in any treatment group. Similar plasma concentrations and biomarker profiles were observed in SRI patients receiving edoxaban 15 mg and normal/MiRI patients receiving edoxaban 30 or 60 mg.Conclusions:In this 12-week short-term study in Japanese NVAF patients with SRI, edoxaban 15 mg once daily exhibited similar safety, plasma concentration, and biomarker profiles as did the 30-mg and 60-mg doses in patients with normal/MiRI. (Circ J 2015; 79: 1486–1495)
Excess psychological stress is one of the precipitating factors for paroxysmal atrial fibrillation (AF), although the involved mechanisms are still uncertain. To test a hypothesis that one of the ...stress-induced hormones, glucocorticoid, is involved in the pathogenesis of stress-induced AF, we investigated whether the glucocorticoid could alter the temporal profile of cardiac ion channels gene expression, thereby leading to atrial arrhythmogenesis.Dexamethasone (DEX, 1.0 mg/kg) was injected subcutaneously in Sprague-Dawley rats. At predetermined times after DEX injection (0, 1, 3, 6, 12, and 24 hours), the mRNA levels of cardiac ion channel genes (erg, KvLQT1, Kv4.3, Kv4.2, Kv2.1, Kv1.5, Kv1.4, Kv1.2, SUR2A, Kir6.2, Kir3.4, Kir3.1 Kir2.2, Kir2.1, SCN5A, and α1C) were determined using RNase protection assay. DEX induced immediate and transient increase in the mRNA level of Kv1.5 and Kir2.2 with peaks at 6 (5.0 fold) and 3 hours (3.3 fold) after DEX injection, respectively. Patch-clamp studies revealed a significantly increased current density of the corresponding current, IKur and IK1 at 6 hours after DEX injection. Simultaneously, electrophysiological study in isolated perfused hearts showed significantly increased number of repetitive atrial responses induced by single atrial extrastimulus (3.2 ± 2.4 to 26.7 ± 16.4, P = 0.004) with shorting of the refractory period (36.4 ± 4.6 to 27.4 ± 5.5 ms, P = 0.049) after DEX injection.Glucocorticoid immediately modified Kv1.5 and Kir2.2 gene expression at pretranslational levels, thus leading to effective refractory period shortening that could be arrhythmogenic. These results implied that transient glucocorticoid-induced biochemical modification of cardiac ion channels might be one of the mechanisms underlying the stress-induced paroxysmal AF.
Background:In the multinational, double-blind, double-dummy ENGAGE AF-TIMI 48 phase 3 study, once-daily edoxaban was non-inferior to warfarin for prevention of stroke or systemic embolism event (SEE) ...in patients with non-valvular atrial fibrillation (AF). Here, we evaluated the efficacy and safety of edoxaban in patients from East Asia.Methods and Results:Patients aged ≥21 years with documented AF and CHADS score ≥2 were randomized to receive once-daily edoxaban higher-dose (60 mg) or lower-dose (30 mg) regimen or warfarin dose-adjusted to an international normalized ratio of 2.0–3.0. Patients with a creatinine clearance of 30–50 ml/min, weighing ≤60 kg, or receiving strong p-glycoprotein inhibitors at randomization or during the study received a 50% dose reduction of edoxaban or matched placebo. This prespecified subanalysis included 1,943 patients from Japan, China, Taiwan, and South Korea. The annualized rate of stroke/SEE for higher-dose edoxaban was 1.34% vs. 2.62% for warfarin (hazard ratio HR, 0.53; 95% confidence interval CI: 0.31–0.90, P=0.02) and 2.52% for lower-dose edoxaban (HR, 0.98; 95% CI: 0.63–1.54, P=0.93). Compared with warfarin (4.80%), major bleeding was significantly reduced for the higher-dose (2.86%; HR, 0.61; 95% CI: 0.41–0.89, P=0.011) and lower-dose regimens (1.59%; HR, 0.34; 95% CI: 0.21–0.54, P<0.001).Conclusions:Once-daily edoxaban provided similar efficacy to warfarin while reducing major bleeding risk in the East Asian population. (Circ J 2016; 80: 860–869)
The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which ...transforming growth factor-1 (TGF-β1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-β1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6C
monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-β1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.
We sought to determine the efficacy of a new, inexpensive, single-tube 8-color multiparameter flow cytometry (MFC) method (SRL-Flow), which is based on the EuroFlow next-generation flow (NGF) (tube 2 ...only), to assess minimal residual disease (MRD)-negative status. MRD-negative status is considered a treatment milestone in multiple myeloma (MM). We used 45 bone marrow samples from patients with MM, including 11 cases treated with anti-CD38 monoclonal antibody. The SRL-Flow sample preparation protocol was identical to that of EuroFlow-NGF. The antibody panel for SRL-Flow was as follows: CD138
V450
/CD27
V500
/CD38ME (multiepitope)
FITC
/CD56
PE
/CD45
PerCP-Cy5.5
/CD19
PE-Cy7
/cytoplasmic (Cy) immunoglobulin (Ig) κ
APC
/CyIgλ
APC-H7
. To identify abnormal plasma cells (aPCs) of patients with MM who received anti-CD38 monoclonal antibody, we used a panel of anti-CD45 and anti-CD138 antibodies (Abs) rather than a panel of anti-CD45 and anti-CD38 Abs. We comparatively analyzed the total nucleated cell numbers, total PC levels, and MRD levels between the SRL-Flow and EuroFlow-NGF. High correlations (r > 0.9) in total PC and MRD levels were noted among SRL-Flow, original EuroFlow-NGF (2 tubes), and EuroFlow-NGF (tube 2 only), suggesting that SRL-Flow is an inexpensive (< $200 USD/sample as of January of 2019) alternative to EuroFlow-NGF (< $350 USD/sample) for assessing MRD in MM.
•Combined prevalence of frailty and mild cognitive impairment (MCI) was 27% in older cardiac surgery patients.•Physical frailty or MCI alone had no significant risk for the incidence of ...delirium.•Coexistence of physical frailty and MCI poses the greatest risk of delirium.•Additional treatment for such high-risk patients may reduce the incidence.
Frailty and cognitive impairment are well-known risk factors of delirium after cardiac surgery. Frailty is closely associated with cognitive impairment. This study aimed to examine how frailty and cognitive impairment affect the incidence of delirium after cardiac surgery in older patients.
In total, 89 patients (aged ≥65 years) who underwent cardiac surgery between April 2016 and December 2017 were included (74.9 ± 5.5 years, male 64.1%). They were divided according to the combination of frailty and mild cognitive impairment (MCI): Group 1, non-frailty and non-MCI; Group 2, non-frailty and MCI; Group 3, frailty and non-MCI; and Group 4, frailty and MCI. Frailty was defined as a score of at least 3 points according to the Japanese version of the Cardiovascular Health Study criteria, and MCI was defined as a Montreal Cognitive Assessment score less than 26. Delirium was evaluated using the Intensive Care Delirium Screening Checklist, and a score of 4 or higher indicated delirium. Multivariate logistic regression analysis was performed to examine the influence of the combination of frailty and MCI on delirium after cardiac surgery.
In total, 31 patients (34.8%) showed postoperative delirium. Multivariate analysis-adjusted baseline characteristics (reference, Group 1) showed that only Group 4 had a risk of delirium after cardiac surgery (odds ratio, 7.494; 95% confidence interval 1.539–36.494).
Preoperative coexistence of frailty and MCI poses the greatest risk of delirium after cardiac surgery. Therefore, attention should be paid to both physical and cognitive function prior to surgery. Further studies are warranted to investigate the optimal intervention for high-risk patients.
Background
Elderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the ENGAGE AF‐TIMI 48 trial, ...we evaluate clinical outcomes with edoxaban versus warfarin according to age.
Methods and Results
Twenty‐one thousand one‐hundred and five patients enrolled in the ENGAGE AF‐TIMI 48 trial were stratified into 3 prespecified age groups: <65 (n=5497), 65 to 74 (n=7134), and ≥75 (n=8474) years. Older patients were more likely to be female, with lower body weight and reduced creatinine clearance, leading to higher rates of edoxaban dose reduction (10%, 18%, and 41% for the 3 age groups, P<0.001). Stroke or systemic embolic event (1.1%, 1.8%, and 2.3%) and major bleeding (1.8%, 3.3%, and 4.8%) rates with warfarin increased across age groups (Ptrend<0.001 for both). There were no interactions between age group and randomized treatment in the primary efficacy and safety outcomes. In the elderly (≥75 years), the rates of stroke/systemic embolic event were similar with edoxaban versus warfarin (hazard ratio 0.83 0.66–1.04), while major bleeding was significantly reduced with edoxaban (hazard ratio 0.83 0.70–0.99). The absolute risk difference in major bleeding (−82 events/10 000 pt‐yrs) and in intracranial hemorrhage (−73 events/10 000 pt‐yrs) both favored edoxaban over warfarin in older patients.
Conclusions
Age has a greater influence on major bleeding than thromboembolic risk in patients with atrial fibrillation. Given the higher rates of bleeding and death with increasing age, treatment of elderly patients with edoxaban provides an even greater absolute reduction in safety events over warfarin, compared to treatment with edoxaban versus warfarin in younger patients.
Clinical Trial Registration
URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00781391.
The ELDERCARE-AF trial showed that low-dose edoxaban benefits elderly patients with nonvalvular atrial fibrillation considered ineligible for standard oral anticoagulants due to high bleeding risk, ...but whether this applied to patients with extremely low body weight was unclear.
This was a prespecified subanalysis by body weight (≤45, >45 kg) of the phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven ELDERCARE-AF trial, which compared low-dose edoxaban (15 mg once daily) with placebo in Japanese patients considered ineligible for oral anticoagulants at the recommended therapeutic strength or the approved doses. The primary efficacy and safety end points were stroke or systemic embolism and major bleeding (International Society on Thrombosis and Hemostasis definition), respectively. The ≤45-kg weight group included 374/984 patients (38.0%), and the >45-kg group included 610/984 patients (62.0%). The stroke or systemic embolism rate was lower with edoxaban than placebo in both weight groups (≤45 kg: hazard ratio HR, 0.36 95% CI, 0.16-0.80; >45 kg: HR, 0.31 95% CI, 0.13-0.73; interaction
=0.82). Major bleeding incidence was numerically higher with edoxaban than placebo (≤45 kg: HR, 3.05 95% CI, 0.84-11.11; >45 kg: HR, 1.40 95% CI, 0.56-3.48), with no interaction with body weight (interaction
=0.33). All-cause mortality was higher in the ≤45-kg group, with no significant difference between treatment groups.
The benefit of edoxaban 15 mg was consistent in elderly patients with atrial fibrillation and extremely low body weight, though clinicians must remain vigilant about the risk of major bleeding, especially gastrointestinal bleeding.
ClinicalTrials.gov. Identifier: NCT02801669.
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