Purpose
To investigate the distribution of plasma apixaban levels and their relationships with clinical outcomes in elderly patients with atrial fibrillation (AF).
Method
The J-ELD AF Registry is a ...multicenter prospective observational study of Japanese non-valvular AF patients aged ≥75 years taking an on-label dose of apixaban (3015 patients from 110 institutions). Among them, plasma apixaban levels at trough were estimated by anti-Xa assay (Api-AXA) in 943 patients. Patients with standard (5 mg bid;
n
= 431) and reduced (2.5 mg bid;
n
= 512) dose were further divided into two groups with low and high Api-AXA levels (boundary: median value).
Results
The incidence rates (per 100 person-years) of events in the low- and high-Api-AXA groups were as follows: 1.48 and 1.99 (log-rank test,
P
= 0.695) for stroke or systemic embolism, 0.98 and 1.49 (
P
= 0.652) for bleeding requiring hospitalization, and 0.49 and 0.99 (
P
= 0.565) for total deaths in patients with standard dose, versus 0.84 and 1.68 (
P
= 0.414), 0.42 and 4.64 (
P
= 0.004), and 2.52 and 6.65 (
P
= 0.035) in patients with a reduced dose, respectively. In multivariate Cox regression analysis among patients with a reduced dose, a high Api-AXA level was independently associated with bleeding requiring hospitalization (HR 12.12, 95% CI: 1.56–94.22) and nonsignificantly with total deaths.
Conclusions
A high trough apixaban level in patients indicated for standard dose was not associated with adverse events, while a high apixaban level in patients indicated for a reduced dose was associated with bleeding requiring hospitalization.
Implementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding.
We ...conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis.
A total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval CI, 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P = 0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36).
In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.).
Background
We introduce a novel operative technique to dissect lymph nodes adjacent to the recurrent laryngeal nerve, referred to as the “native tissue preservation” technique. Using this technique, ...there was no damage to the recurrent laryngeal nerve, which is maintained in its anatomical position.
Methods
From September 2016 to December 2018, minimally invasive esophagectomy was performed in the left lateral decubitus position in 87 patients with esophageal cancer. The native tissue preservation technique for lymphadenectomy around the recurrent laryngeal nerve was used, and all patients were evaluated for recurrent laryngeal nerve paralysis.
Results
Minimally invasive esophagectomy was completed in all patients without conversion to thoracotomy. Although an extended lymphadenectomy was performed in all patients, there were no grade II or higher complications (Clavien–Dindo classification) and no incidence of recurrent laryngeal nerve paralysis.
Conclusion
The native tissue preservation technique may reduce the incidence of recurrent laryngeal nerve paralysis after minimally invasive esophagectomy with radical lymph node dissection.
Summary Background Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in ...subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes. Methods We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71 683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF–TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity. Findings 42 411 participants received a new oral anticoagulant and 29 272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73–0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38–0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85–0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39–0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01–1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59–0·81 vs 0·93, 0·76–1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84–1·27; p=0·74), and a more favourable bleeding profile (0·65, 0·43–1·00; p=0·05), but significantly more ischaemic strokes (1·28, 1·02–1·60; p=0·045). Interpretation This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk–benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population. Funding None.
This study aimed to evaluate the impact of climate change on flood damage and the effects of mitigation measures and combinations of multiple adaptation measures in reducing flood damage. The ...inundation depth was calculated using a two-dimensional unsteady flow model. The flood damage cost was estimated from the unit evaluation value set for each land use and prefectures and the calculated inundation depth distribution. To estimate the flood damage in the near future and the late twenty-first century, five global climate models were used. These models provided daily precipitation, and the change of the extreme precipitation was calculated. In addition to the assessment of the impacts of climate change, certain adaptation measures (land-use control, piloti building, and improvement of flood control level) were discussed, and their effects on flood damage cost reduction were evaluated. In the case of the representative concentration pathway (RCP) 8.5 scenario, the damage cost in the late twenty-first century will increase to 57% of that in the late twentieth century. However, if mitigation measures were to be undertaken according to RCP2.6 standards, the increase of the flood damage cost will stop, and the increase of the flood damage cost will be 28% of that in the late twentieth century. By implementing adaptation measures in combination rather than individually, it is possible to keep the damage cost in the future period even below that in the late twentieth century. By implementing both mitigation and adaptation measures, it is possible to reduce the flood damage cost in the late twenty-first century to 69% of that in the late twentieth century.
Randomized clinical trials demonstrated the efficacy and safety of apixaban in preventing stroke in patients with atrial fibrillation (AF). However, data on patients with low creatinine clearance ...(CCr), especially CCr 15-29 mL/min, are limited.
The J-ELD AF Registry is a large-scale, multicenter prospective observational study of Japanese nonvalvular AF patients aged ≥75 years taking on-label dose (standard dose of 5 mg bid or reduced dose of 2.5 mg bid) of apixaban. The entire cohort (3,015 patients from 110 institutions) was divided into 3 CCr subgroups: CCr ≥50 mL/min (n = 1,165, 38.6%), CCr 30-49 mL/min (n = 1,395, 46.3%), and CCr 15-29 mL/min (n = 455, 15.1%).
The event incidence rates (/100 person-years) were 1.76, 1.39, and 1.67 for stroke or systemic embolism (log rank P = .762); 1.39, 1.93, and 3.13 for bleeding requiring hospitalization (log rank P = .159); 1.75, 2.76, and 7.87 for total deaths (log rank P < .001); and 0.46, 0.84, and 2.62 for cardiovascular deaths (log rank P < .001), respectively. After adjusting for confounders by Cox regression analysis, CCr 15-29 was an independent risk for total death and cardiovascular death but not for stroke or systemic embolism, or bleeding requiring hospitalization.
The incidence of events in each CCr value group was comparable for stroke or systemic embolism and bleeding requiring hospitalization, and significantly higher for total deaths and cardiovascular deaths only in the CCr 15- to 29-mL/min group, in Japanese nonvalvular AF patients aged ≥75 years.
Atrial fibrillation (AF) is becoming an epidemiologically important syndrome among the developed countries. Although racial differences exist with regard to AF prevalence, it remains unclear whether ...the AF mortality and morbidity rates exhibit racial differences. Medical treatment and management of AF is aimed at improving the clinical course of AF patients who reside in a particular region; therefore, the AF mortality and morbidity rates should be assessed from both global and local viewpoints. AF is a progressive disease that might be first detected as paroxysmal, persistent, or permanent. The associations between AF progression and AF-related cardiovascular morbidities and those between the cardiovascular morbidity and mortality rates of AF are important matters of discussion, as they reflect the rationale of AF therapy. At present, AF patients have a wide variety of backgrounds, and these analyses would require stratification by risks, which would not be free from racial differences. In this review, the mortality and morbidity rates of Japanese AF patients are reviewed and discussed. (Circ J 2013; 77: 864–868)
Background:The incidence rate of ischemic stroke in Japanese non-valvular atrial fibrillation (NVAF) patients without anticoagulation therapy remains unclear.Methods and Results:We performed a pooled ...analysis of 3,588 patients from the Shinken Database (n=1,099), J-RHYTHM Registry (n=1,002), and Fushimi AF Registry (n=1,487) to determine the incidence rate of ischemic stroke in Japanese NVAF patients without anticoagulation therapy. Average patient age was 68.1 years. During the follow-up period (total, 5,188 person-years; average, 1.4 years), 69 patients suffered from ischemic stroke (13.3 per 1,000 person-years; 95% confidence intervals CI: 10.5–16.8). The incidence rates of ischemic stroke were 5.4, 9.3, and 24.7 per 1,000 person-years and 5.3, 5.5, and 18.4 per 1,000 person-years in patients with low (0), intermediate (1), and high (≥2) CHADS2 and CHA2DS2-VASc scores, respectively. History of ischemic stroke or transient ischemic attack (hazard ratio HR, 3.25; 95% CI: 1.86–5.67), age ≥75 years (HR, 2.31; 95% CI: 1.18–4.52), and hypertension (HR, 1.69; 95% CI: 1.01–2.86) were independent risk factors for ischemic stroke.Conclusions:A low incidence rate of ischemic stroke was observed in Japanese NVAF patients except for those with CHADS2 score ≥2. In this pooled analysis, history of ischemic stroke or transient ischemic attack, advanced age, and hypertension were identified as independent risk factors for ischemic stroke. (Circ J 2015; 79: 432–438)
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