Design and rationale for REVERXaL: A real-world study of patients with factor Xa inhibitor-associated major bleeds.

BACKGROUND: The prevalence of anticoagulation treatment is increasing as an aging global population faces a high burden of cardiovascular comorbidities. Direct oral anticoagulants, including factor Xa inhibitors (FXai), are replacing vitamin K antagonists as the most commonly prescribed treatment for reducing risk of thrombotic events. While the risk of FXai-associated spontaneous bleeds is established, less is understood about their management and the effect of treatment on clinical and patient-reported outcomes. The primary objectives of the REVERXaL study are to describe patient characteristics, health care interventions during the acute-care phase, in-hospital outcomes, and associations between timing of reversal/replacement agent administration and in-hospital outcomes. Secondary/exploratory objectives focus on clinical assessments and patient-reported outcome measures (PROMs) at 30 and 90 days. METHODS: REVERXaL is a multinational, observational study of hospitalized patients with FXai-associated major bleeds in Germany, Japan, the United Kingdom, and the United States. The study includes 2 cohorts of approximately 2000 patients each. Cohort A is a historic cohort for whom medical chart data will be collected from hospitalization to discharge for patients admitted for major bleeds during FXai use within 2 years prior to enrollment of Cohort B. Cohort B will prospectively enroll patients administered any reversal/replacement agent during hospitalization to manage FXai-associated major bleeds and will include the collection of clinical outcomes and PROMs data over 3 months. CONCLUSIONS: REVERXaL will generate insights on patient characteristics, treatment approaches, and associated outcomes in patients hospitalized with FXai-associated major bleeds. These data may inform clinical practice and streamline treatment pathways in this population. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; unique identifier: NCT06147830.

Gastrointestinal bleeding in elderly patients with atrial fibrillation: prespecified All Nippon Atrial Fibrillation in the Elderly (ANAFIE) Registry subgroup analysis.

Gastrointestinal (GI) bleeding control is critical in elderly patients with atrial fibrillation (AF) receiving oral anticoagulants (OAC). This subgroup analysis aimed to clarify the actual state and significance of GI bleeding in elderly non-valvular AF (NVAF) patients. We evaluated the incidence and risk factors of GI bleeding during the 2-year follow-up and examined the GI bleeding impact on mortality. Of the 32,275 patients in the ANAFIE Registry, 1139 patients (3.5%) experienced GI bleeding (incidence rate, 1.92 events per 100 person-years; mean follow-up, 1.88 years); 339 upper and 760 lower GI bleeding events occurred. GI bleeding risk factors included age ≥ 85 years, body mass index ≥ 25.0 kg/m2, prior major bleeding, hyperuricaemia, heart failure, P-glycoprotein inhibitor use, GI disease, and polypharmacy (≥ 5 drugs). No significant differences in GI bleeding risk were found between direct OAC (DOAC) vs warfarin users (adjusted hazard ratios [95% confidence interval], 1.01 [0.88-1.15]). The 1-year post-GI bleeding mortality rate was numerically higher in patients with upper (19.6%) than lower GI bleeding (8.9%). In elderly Japanese NVAF patients, this large-scale study found no significant difference in GI bleeding risk between DOAC vs. warfarin users or 1-year mortality after upper or lower GI bleeding.

Prediction of obliteration of unruptured cerebral aneurysm by residual aneurysm volume after flow diverter stent treatment.

Introduction There is no methodology to predict aneurysm occlusion using residual volume after flow diverter stent treatment. We retrospectively examined whether residual aneurysm volume at 6 months postoperatively can predict the degree of aneurysm obliteration at 1 year after flow diverter stent treatment. Materials and Methods This single institution study included 101 consecutive patients who underwent flow diverter stent treatment for unruptured cerebral aneurysm. Based on pre-treatment aneurysm volume, the percentage residual volume was calculated 6 months postoperatively. The volume of the aneurysm was determined using the volume calculation function of the cerebral angiography equipment. 1 year postoperatively, patients were classified into two groups: the good obliteration group (GG; O'KellyMarotta [OKM] grading scale: C and D) and the poor obliteration group (PG; OKM: A and B). Statistical analysis was performed to determine if there was a difference in residual aneurysm volume percentage at 6 months postoperatively between the two groups. Results A total of 20 patients were studied: 6 in the GG and 14 in the PG. Mean residual aneurysm volume at 6 months postoperatively in the GG was 33.1% (±34.7), while that in the PG was 80.6% (±24.8) (P=0.018). A residual aneurysm volume of ≥35.2% at 6 months postoperatively was significantly associated with poor aneurysm obliteration at 1 year postoperatively (AUC=0.88, P=0.008). Conclusions Residual aneurysm volume percentage at 6 months after flow diverter stent treatment might be able to predict the likelihood of aneurysm occlusion at 1 year postoperatively.

Real-World Safety and Effectiveness of a 4-Factor Prothrombin Complex Concentrate in Japanese Patients Experiencing Major Bleeding: A Post-marketing Surveillance Study.

INTRODUCTION: Limited data are available regarding the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) in patients experiencing major hemorrhage or requiring expeditious surgical intervention, both globally and within Japan. METHODS: We executed a prospective, observational post-marketing surveillance study of patients receiving 4F-PCC for the first time between September 19, 2017 and August 15, 2018 in Japan. Patients were subjected to a comprehensive follow-up for a duration of 4 weeks. RESULTS: Of 1381 eligible patients, 1271 (92%) received a vitamin K antagonist. Among these, 58% were aged ≥ 75 years, 49% manifested atrial fibrillation, 17% presented with valvular heart disease, and 6% exhibited venous thromboembolism. The median (range) international normalized ratio was 2.67 (0.96-27.11) at baseline and 1.21 (0.45-6.61) at first measurement post-administration of 4F-PCC. The most common reason for 4F-PCC administration was intracranial hemorrhage (59.6%), followed by gastrointestinal bleeding (6.6%). Hemostatic effectiveness was achieved in 85.8% of patients. The incidences of adverse drug reactions (ADRs) and serious ADRs were 3.9% and 2.8%, respectively. Thromboembolic events (TEEs) occurred in 20 (1.5%) patients, with a mean onset of 10 days. The majority of TEEs were classified as nervous system disorders (55%). At the time of TEE, only 13% of patients resumed anticoagulant therapy. CONCLUSION: The incidence of TEEs following treatment with 4F-PCC did not surpass those observed in phase 3 trials. No novel safety signals were identified. The safety and effectiveness of 4F-PCC in Japanese real-world practice were in harmony with the observations of prior studies.

Age-related variation in coagulation factors in non-valvular atrial fibrillation patients receiving direct oral anticoagulants.

Age is a significant risk factor for ischemic stroke. However, the influence of aging on coagulation parameters in non-valvular atrial fibrillation (NVAF) patients treated with direct oral anticoagulants (DOACs) remains unclear. A total of 775 samples were collected from 224 NVAF patients receiving apixaban, edoxaban or rivaroxaban. The samples were categorized into three age groups: (i) ≤ 64 years, (ii) 65-74 years, and (iii) ≥ 75 years (apixaban: N = 48, 108, 119; edoxaban: N = 63, 68, 126; rivaroxaban: N = 115, 90, 38, respectively). Coagulation parameters including fibrinogen (Fbg), factor II, factor V, factor VII, factor X, and D-dimer, were compared between the three age groups for each drug. The slopes in the correlation between drug concentrations and modified diluted prothrombin time (mdPT) were also assessed. Fbg and factor V increased with age, while factor II and factor X decreased. Factor VII and D-dimer showed no significant differences across age categories. The slope in response to drug concentrations was similar between the age groups. In NVAF patients treated with apixaban, edoxaban and rivaroxaban, some coagulation parameters exhibited age-related variation. However, the response of mdPT to drug concentration was consistent across age categories.

Coronary events in elderly patients with non-valvular atrial fibrillation: a prespecified sub-analysis of the ANAFIE registry.

Real-world data on coronary events (CE) in elderly patients with atrial fibrillation (AF) are lacking in the direct oral anticoagulant era. This prespecified sub-analysis of the ANAFIE Registry, a prospective observational study in > 30,000 Japanese patients aged ≥ 75 years with non-valvular AF (NVAF), investigated CE incidence and risk factors. The incidence and risk factors for new-onset CE (a composite of myocardial infarction [MI] and cardiac intervention for coronary heart diseases other than MI), MI, and cardiac intervention for coronary heart diseases other than MI during the 2-year follow-up were assessed. Bleeding events in CE patients were also examined. Among 32,275 patients, the incidence rate per 100 patient-years was 0.48 (95% confidence interval (CI): 0.42-0.53) for CE during the 2-year follow-up, 0.20 (0.16-0.23) for MI, and 0.29 (0.25-0.33) for cardiac intervention for coronary heart diseases other than MI; that of stroke/systemic embolism was 1.62 (1.52-1.73). Patients with CE (n = 287) likely had lower creatinine clearance (CrCL) and higher CHADS2 and HAS-BLED scores than patients without CE (n = 31,988). Significant risk factors associated with new-onset CE were male sex, systolic blood pressure of ≥ 130 mmHg, diabetes mellitus (glycated hemoglobin ≥ 6.0%), CE history, antiplatelet agent use, and CrCL < 50 mL/min. Major bleeding incidence was significantly higher in patients with new-onset CE vs without CE (odds ratio [95% CI], 3.35 [2.06-5.43]). In elderly patients with NVAF, CE incidence was lower than stroke/systemic embolism incidence. New-onset CE (vs no CE) was associated with a higher incidence of major bleeding.Trial registration: UMIN000024006.

Clinical outcomes and anticoagulation therapy in elderly non-valvular atrial fibrillation and heart failure patients.

AIMS: Atrial fibrillation (AF) and heart failure (HF) often coexist. Older age is strongly associated with stroke, HF, and mortality. The association between coexistence of HF and a risk of clinical outcomes and the effectiveness of anticoagulation therapy including direct oral anticoagulants (DOACs) in elderly patients with AF and HF have not been investigated. We aimed to evaluate 2 years of outcomes and to elucidate the efficacy of DOACs or warfarin in elderly AF patients in the All Nippon AF In the Elderly (ANAFIE) Registry with and without a history of HF. METHODS AND RESULTS: The ANAFIE Registry is a multicentre, prospective observational study following elderly non-valvular AF patients aged ≥75 years for 2 years. Hazard ratios (HRs) were calculated based on the presence or absence of an HF diagnosis and DOAC or warfarin use at enrolment. Among 32 275 eligible patients, 12 116 (37.5%) had been diagnosed with HF. Patients with HF had significantly higher rates of HF hospitalization or cardiovascular death (HR 1.94, P < 0.001), cardiovascular events (HR 1.59, P < 0.001), cardiovascular death (HR 1.49, P < 0.001), all-cause death (HR 1.32, P < 0.001), and net clinical outcome including stroke/systemic embolism, major bleeding, and all-cause death (HR 1.23, P < 0.001), compared with those without HF; however, HRs for stroke/systemic embolism (HR 0.96, P = 0.56) and major bleeding (HR 1.14, P = 0.13) were similar. DOAC use was associated with a low risk of stroke/systemic embolism (HR 0.86, P = 0.19 in HF; HR 0.79, P = 0.016 in non-HF; P for interaction = 0.56), major bleeding (HR 0.71, P = 0.008 in HF; HR 0.75, P = 0.016 in non-HF; P for interaction = 0.74), HF hospitalization or cardiovascular death (HR 0.81, P < 0.001 in HF; HR 0.78, P < 0.001 in non-HF; P for interaction = 0.26), cardiovascular events (HR 0.83, P < 0.001 in HF; HR 0.82, P = 0.001 in non-HF; P for interaction = 0.65), cardiovascular death (HR 0.84, P = 0.12 in HF; HR 0.75, P = 0.035 in non-HF; P for interaction = 0.18), all-cause death (HR 0.89, P = 0.082 in HF; HR 0.80, P = 0.001 in non-HF; P for interaction = 0.091), and net clinical outcome (HR 0.88, P = 0.019 in HF; HR 0.81, P < 0.001 in non-HF; P for interaction = 0.21) compared with warfarin, irrespective of the presence or absence of HF. Analysis using the propensity score matching method showed similar associations. CONCLUSIONS: Non-valvular AF patients aged ≥75 years with a history of HF had higher risks of cardiovascular events and mortality. DOACs were favourable to warfarin regardless of the coexistence of HF. These results might encourage the use of DOACs in elderly patients with non-valvular AF with or without HF.

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity: Prespecified Subgroup Analysis of the ANNEXA-4 Study in Japan.

AIMS: Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor-related acute major bleeding in patients enrolled for ANNEXA-4 in Japan. METHODS: This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment. RESULTS: A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events. CONCLUSION: Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.

Association of the Timing of Atrial Fibrillation Detection and Insular Involvement With the Risk of Embolic Events After Acute Ischemic Stroke.

OBJECTIVE: Atrial fibrillation (AF) detected after insular stroke might arise from autonomic and inflammatory mechanisms triggered by insular damage, and be associated with a low embolic risk. We assessed the association of the timing of AF detection and insular involvement with the risk of embolic events after acute ischemic stroke. METHODS: Acute ischemic stroke patients with AF who underwent brain magnetic resonance imaging at baseline were enrolled. Patients were classified according to the timing of AF detection (AF detected after stroke [AFDAS] or known AF [KAF]) and insular involvement. The primary outcome was embolic events defined as recurrent ischemic stroke, transient ischemic attack, and systemic embolism within 90 days. RESULTS: Of 1,548 patients, 360 had AFDAS with insular cortex lesions (+I), 409 had AFDAS without insular cortex lesions (-I), 349 had KAF+I, and 430 had KAF-I. Cumulative incidence rates of embolic events at 90 days in patients with AFDAS+I, AFDAS-I, KAF+I, and KAF-I were 0.8%, 3.5%, 4.9%, and 3.3%, respectively. Patients with AFDAS-I (adjusted hazard ratio 5.04, 95% confidence interval 1.43-17.75), KAF+I (6.18, 1.78-21.46), and KAF-I (5.26, 1.48-18.69) had a significantly higher risk of embolic events than those with AFDAS+I. INTERPRETATION: Acute ischemic stroke patients with AFDAS and insular cortex lesions had a lower risk of embolic events than those who had AFDAS without insular cortex lesions or those with KAF, regardless of insular involvement. ANN NEUROL 2024;95:338-346.

Cost-effectiveness of left atrial appendage closure with Watchman for non-valvular atrial fibrillation patients in Japan.

AIMS: Left atrial appendage closure (LAAC) has been demonstrated to be cost-saving relative to oral anticoagulants for stroke prophylaxis in patients with non-valvular atrial fibrillation (NVAF) in the United States and Europe. This study assessed the cost-effectiveness of LAAC with the Watchman device relative to warfarin and direct oral anticoagulants (DOACs) for stroke risk reduction in NVAF from a Japanese public healthcare payer perspective. METHODS: A Markov model was developed with 70-year-old patients using a lifetime time horizon. LAAC clinical inputs were from pooled, 5-year PROTECT AF and PREVAIL trials; warfarin and DOAC inputs were from published meta-analyses. Baseline stroke and bleeding risks were from the SALUTE trial on LAAC. Cost inputs were from the Japanese Medical Data Vision database. Probabilistic and one-way sensitivity analyses were performed. RESULTS: Over the lifetime time horizon, LAAC was less costly than warfarin (savings of JPY 1,878,335, equivalent to US $17,600) and DOACs (savings of JPY 1,198,096, equivalent to US $11,226). LAAC also provided 1.500 more incremental quality-adjusted life years (QALYs) than warfarin and 0.996 more than DOACs. In probabilistic sensitivity analysis, LAAC was cost-effective relative to warfarin and DOACs in 99.98% and 99.73% of simulations, respectively. LAAC dominated (had higher cumulative QALYs and was less costly than) warfarin and DOACs in 89.94% and 83.35% of simulations, respectively. CONCLUSIONS: Over a lifetime time horizon, LAAC is cost-saving relative to warfarin and DOACs for stroke risk reduction in NVAF patients in Japan and is associated with improved quality-of-life.

This study examined the cost-effectiveness of left atrial appendage closure (LAAC) compared to oral anticoagulants for stroke risk reduction among individuals with a specific type of irregular heart rhythm called non-valvular atrial fibrillation (NVAF). This study evaluated the cost-effectiveness of LAAC using the Watchman device in comparison to warfarin and direct oral anticoagulants (DOACs) from the perspective of Japan's public healthcare system. To investigate this, a computer-based model was developed involving 70-year-old patients over their lifetime. Data from notable studies such as the PROTECT AF and PREVAIL trials (covering 5 years) for LAAC and published meta-analyses for warfarin and DOACs were incorporated into the model. Baseline stroke and bleeding risks were derived from the SALUTE trial on LAAC. Cost inputs were based on data from the Japanese Medical Data Vision database. Additionally, we performed thorough cost-effectiveness analyses, including probabilistic and one-way sensitivity assessments. Our findings revealed that, over a lifetime, LAAC was more cost-effective than both warfarin and DOACs. Further, LAAC contributed an additional 1.500 quality-adjusted life years (QALYs) compared to warfarin and 0.996 QALYs compared to DOACs. In the long-term, adopting LAAC as an alternative to warfarin and DOACs is a cost-effective strategy for reducing stroke risk in NVAF patients in Japan. Moreover, it is associated with enhanced quality-of-life. These findings hold significant implications for informing decision-making in healthcare policies and clinical practices for NVAF patients.

Idarucizumab for Emergency Reversal of the Anticoagulant Effects of Dabigatran: Final Results of a Japanese Postmarketing Surveillance Study.

INTRODUCTION: Idarucizumab, a monoclonal antibody fragment that rapidly reverses the anticoagulant effects of dabigatran, was approved in Japan in September 2016, at which time an all-case, postmarketing surveillance (PMS) study was initiated to collect data on idarucizumab in Japanese patients. Interim results were published previously, and the final results are reported herein. METHODS: This multicenter, open-label, uncontrolled, non-interventional PMS study was conducted in Japanese patients who received idarucizumab at the approved dose (2 × 2.5 g/50 ml) and had uncontrolled bleeding (group A) or required an emergency procedure (group B). The primary endpoint was the frequency of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effects of dabigatran, within 4 h of idarucizumab administration, based on activated partial thromboplastin time (aPTT). RESULTS: The final analysis included 804 patients. ADRs during the idarucizumab treatment and post-treatment periods were reported in 17 of 542 patients (3.1%) in group A and 12 of 240 patients (5.0%) in group B. Thrombotic events were reported in 22 patients (4.1%) in group A and 15 patients (6.3%) in group B, and hypersensitivity occurred in four (0.7%) and five patients (2.1%), respectively. Among 793 patients evaluated for effectiveness, 78 in group A and 26 in group B had aPTT data at baseline (immediately before idarucizumab administration) and within 4 h of idarucizumab administration; in these patients, median maximum percentage reversal within 4 h of idarucizumab administration was 100%. CONCLUSIONS: The final analysis from the PMS study confirms previous findings suggesting that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients in clinical practice. The results support the continued use of idarucizumab in Japan. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov (NCT02946931).

Atrial fibrillation is an irregular heart rhythm (arrhythmia), and the type of atrial fibrillation not caused by a heart valve problem is known as "non-valvular atrial fibrillation" or NVAF. People with NVAF have an increased risk of ischemic stroke, in which a blood clot (thrombus) blocks an artery in the brain. Drugs that inhibit blood clots, known as anticoagulants, are prescribed to people with NVAF to prevent ischemic stroke. Historically, warfarin has been one of the most prescribed anticoagulant drugs. However, a novel anticoagulant drug, known as dabigatran, has clinical advantages over warfarin and is approved in many countries for people with NVAF. People who take anticoagulants may experience life-threatening bleeding or need urgent surgery, and thus rapid and effective reversal of the anticoagulant effects is critical. The drug idarucizumab specifically binds to dabigatran to reverse its anticoagulant effects in people with uncontrolled bleeding or who require an urgent procedure. Idarucizumab was approved for use in Japan in September 2016. In Japan, drug companies are obligated to collect data after a new drug is launched as an approval condition, which is done through a postmarketing surveillance study. Here, we report the final results of a postmarketing surveillance study conducted between September 2016 and November 2020 to evaluate the safety and effectiveness of idarucizumab in Japanese patients receiving dabigatran. The results of our study show that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients, and support the continued use of idarucizumab in Japan in clinical practice.

Echocardiographic Parameters of Left Atrial Structure and Function and Clinical Outcomes at 2 Years in Elderly Patients With Atrial Fibrillation　- The ANAFIE Echocardiographic Substudy.

BACKGROUND: This prospective ANAFIE Registry substudy investigated the relationship between the echocardiographic parameters of left atrial (LA) structure and function and clinical outcomes at 2 years among atrial fibrillation (AF) patients aged ≥75 years.Methods and Results: Outcomes of 1,474 elderly non-valvular AF (NVAF) patients who underwent transthoracic echocardiography at baseline were analyzed by categories of maximum LA volume index (max. LAVi) and LA emptying fraction (LAEF) total. Baseline mean±standard deviation LAEF total and max. LAVi were 28.2±14.9% and 54.2±25.9 mL/m2, respectively. Proportions of oral anticoagulant (OAC), direct OAC, and warfarin use were 92.7%, 68.7%, and 24.0%, respectively. Patients with LAEF total ≤45.0% (n=1,213) vs. >45.0% (n=224) were at higher risk of cardiovascular events (hazard ratio [HR]: 2.19, P=0.021) and heart failure (HF) hospitalization (HR: 2.25, P=0.045). Risk of all-cause death was higher with max. LAVi >48.0 mL/m2(n=656) vs. ≤48.0 mL/m2(n=621) (HR: 1.69, P=0.048). Subgroups with abnormal LA function and structure had increased incidence of cardiac/cardiovascular events and HF hospitalization. No significant interaction was observed between echocardiographic parameters and OAC type. CONCLUSIONS: Elderly Japanese patients with NVAF and LAEF total ≤45.0% were at higher risk of cardiovascular events and HF hospitalization, and those with max. LAVi >48.0 mL/m2were at higher risk of all-cause death.

The case of treatment for carotid web - Double-layer micromesh stent implantation in our hospital.

Background: A carotid web is a shelf-like structure on the posterior wall of the origin of the internal carotid artery, and it is believed to cause cerebral infarction due to thrombus formed by turbulent flow with stagnation of blood flow. Recently, it has been suggested that recurrent cerebral infarction cannot be prevented in patients with a symptomatic carotid web by conventional medical management alone. However, there is still no consensus on the treatment of carotid webs. Carotid artery stenting (CAS) with the CASPER stent (Microvention, Terumo, Tustin, CA, USA) was performed in six consecutive patients with symptomatic carotid webs, and the results are reported along with a review of the literature. Methods: Six consecutive patients with a diagnosis of internal carotid artery stenosis due to a carotid web on magnetic resonance imaging and digital subtraction angiography (DSA) were included in this study. All patients underwent dual antiplatelet therapy approximately 10 days before surgery and after 6 months, and then, a CASPER stent was implanted under general anesthesia. All patients were evaluated postoperatively by DSA 6 months after treatment. Results: In all patients, no in-stent stenosis was seen 6 months after the operation, and no symptomatic cerebral infarction occurred within 1 year after the procedure. Conclusions: CASPER stent implantation may be effective for treating carotid webs.

Strategy of cerebral endovascular treatment for cervical internal carotid artery stenosis with a persistent primitive hypoglossal artery.

Background: Persistent primitive hypoglossal artery (PPHA) is a rare residual arterial anastomosis. We placed a CASPER stent using Spider FX as an embolic protection device (EPD) in a patient with internal carotid artery (ICA) stenosis and PPHA. There are no reports of carotid artery stenting (CAS) using a CASPER stent for ICA stenosis with PPHA. We report the EPD strategy used in this case and the usefulness and precautions of CASPER stent insertion for cervical ICA stenosis in association with PPHA. Methods: A 9Fr sheath was placed in the right femoral artery and a 9Fr Branchor balloon guide catheter was guided to the common carotid artery. A Spider FX was placed proximal to the bifurcation of the ICA and the PPHA. A 10 mm × 20 mm CASPER stent was deployed at the site of the stricture with no postoperative ischemic complications. Results: There was no intra-stent occlusion, stenosis, or plaque protrusion immediately after surgery, and no postoperative ischemic complications were observed. Conclusion: CASPER stent deployment with the Spider FX in the ICA and PPHA bifurcation can be considered to be an effective treatment method for ICA stenosis associated with PPHA. However, care should be taken in selecting the appropriate EPDs and stents depending on the location of the stenosis and bifurcation of the PPHA.

Coagulation Biomarkers and Clinical Outcomes in Elderly Patients With Nonvalvular Atrial Fibrillation: ANAFIE Subcohort Study.

Background: Little is known about the relationship between coagulation biomarkers and clinical outcomes in patients with atrial fibrillation (AF) treated with anticoagulants, especially direct oral anticoagulants (DOACs) and warfarin. Objectives: This subcohort study evaluated the association between coagulation biomarkers and clinical outcomes in elderly Japanese patients with nonvalvular AF using the ANAFIE (All Nippon AF In the Elderly) Registry. Methods: Patients with a definitive diagnosis of nonvalvular AF and aged ≥75 years at enrollment were included. At enrollment, biomarker levels for D-dimer, thrombin-antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), and soluble fibrin monomer complex (SFMC), along with data on anticoagulant use, were recorded. Results: Of the 3,194 patients, 95.1% were using oral anticoagulants (OACs) (71.7% DOACs, 23.4% warfarin). D-dimer, TAT, and F1+2 levels, as well as the proportion of patients with a positive SFMC, were lower among those receiving OACs compared with those not receiving OACs. In the DOAC group, higher levels of D-dimer (≥1.0 µg/mL) and TAT (>3 ng/mL) were significantly associated with increased incidences of cardiovascular (CV) events (stroke, myocardial infarction, cardiac intervention, heart failure, and CV death), all-cause death, and CV death. In the warfarin group, higher levels of D-dimer were significantly associated with increased rates of all-cause death, higher levels of TAT with increased major bleeding, and positive SFMC with increased major bleeding and CV events. Conclusions: Higher levels of coagulation biomarkers were associated with a higher risk of worse clinical outcomes, and the relationships between the coagulation biomarkers and outcomes differed between the DOAC and warfarin groups. (Prospective Observational Study in Late-Stage Elderly Patients with Non-Valvular Atrial Fibrillation All Nippon AF In Elderly Registry-ANAFIE Registry; UMIN000024006).

Comprehension of Nonvalvular Atrial Fibrillation and Anticoagulant Adherence in Elderly Patients in a Subcohort Study of the All Nippon Atrial Fibrillation in the Elderly Registry.

In this subcohort study of the ANAFIE (All Nippon Atrial Fibrillation In the Elderly) Registry enrolling >30,000 Japanese elderly (aged ≥75 years) patients with nonvalvular atrial fibrillation (NVAF), we assessed the association between patient comprehension of NVAF and adherence to anticoagulant therapy with clinical outcomes. Data from 1,968 patients evaluated for NVAF comprehension by a questionnaire consisting of 4 key questions, and 2,362 patients who completed the Morisky Medication Adherence Scale-8 questionnaire were analyzed. Overall, NVAF comprehension was low (81.9% had <3 points), and compared with high comprehension (score ≥3), low comprehension (0 points: 42.1%) was associated with poor prognosis, nonsignificantly higher risk of stroke or systemic embolic event (adjusted hazard ratio [aHR] 2.60 [95% confidence interval 0.97 to 6.94, p = 0.057]), all-cause death (aHR 1.71 [0.96 to 3.04, p = 0.069]), and significantly higher risk of net clinical outcome (composite of stroke/systemic embolic events, major bleeding, and all-cause death) (aHR 1.63 [1.04 to 2.54, p = 0.032]). Adherence to anticoagulant therapy assessed by Morisky Medication Adherence Scale-8 was high (64.9% had high adherence; 29.2%, had medium adherence), but compared with high adherence (score 8), low adherence (score <6: 5.9%) was associated with poor prognosis, significantly higher risk of ischemic stroke (aHR 2.95 [1.08 to 8.04, p = 0.035]), all-cause death (aHR 1.93 [1.16 to 3.21, p = 0.011]), and net clinical outcome (aHR 1.75 [1.12 to 2.75, p = 0.015]). Overall, NVAF comprehension and adherence showed a weak correlation to anticoagulant therapy at baseline (correlation coefficient 0.049). In conclusion, low NVAF comprehension and low anticoagulant adherence were associated with poor clinical outcomes in elderly patients with NVAF.

Renal Function and Clinical Outcomes Among Elderly Patients With Nonvalvular Atrial Fibrillation From ANAFIE.

Background: Advancing age, decreasing renal function, and atrial fibrillation are strongly associated. Real-world evidence of direct oral anticoagulant (DOAC) use among elderly patients ≥75 years of age with nonvalvular atrial fibrillation and renal dysfunction is limited. Objectives: This study sought to assess 2-year outcomes and anticoagulant treatment, stratified by renal function. Methods: Enrolled patients were divided into 4 subgroups by creatinine clearance (CrCl) to determine the impact of renal dysfunction on clinical outcomes. Results: Of 32,275 patients, 26,202 with CrCl data were analyzed (median follow-up 2.00 [IQR: 1.92-2.00] years); 1.3% of patients had CrCl <15 mL/min, 10.7% had CrCl 15 to <30 mL/min, 33.4% had CrCl 30 to <50 mL/min, 35.8% had CrCl ≥50 mL/min, and 18.9% had unknown CrCl. Cumulative incidences of stroke/systemic embolic events, major bleeding, major plus clinically relevant nonmajor bleeding, cardiovascular death, all-cause death, and net clinical outcomes increased with decreasing CrCl. In multivariable Cox regression analysis, lower CrCl emerged as an independent risk factor for these clinical outcomes, except for major bleeding, compared with CrCl ≥50 mL/min. The effectiveness and safety of DOACs over warfarin were similar or better across 3 CrCl subgroups with CrCl 15 mL/min or more. DOAC use was associated with a lower risk of stroke/systemic embolic events, major bleeding, cardiovascular death, all-cause death, and net clinical outcome compared with warfarin in patients with CrCl 30 to <50 mL/min. Conclusions: Incidences of major clinical outcomes increased with decreasing renal function in elderly nonvalvular atrial fibrillation patients. DOACs were effective and safe even in patients with renal dysfunction (CrCl 15-<50 mL/min). (Prospective Observational Study in Late-Stage Elderly Patients with Non-Valvular Atrial Fibrillation: All Nippon AF In Elderly Registry [ANAFIE Registry]; UMIN000024006).

Relationship Between Direct Oral Anticoagulant Doses and Clinical Outcomes in Elderly Patients With Non-Valvular Atrial Fibrillation　- ANAFIE Registry Sub-Analysis.

BACKGROUND: This sub-analysis of the ANAFIE Registry, a prospective, observational study of >30,000 Japanese non-valvular atrial fibrillation (NVAF) patients aged ≥75 years, assessed the prevalence of direct oral anticoagulant (DOAC) under-dose prevalence, identified the factors of under-dose prescriptions, and examined the relationship between DOAC dose and clinical outcomes.Methods and Results: Patients, divided into 5 groups by DOAC dose (standard, over-, reduced, under-, and off-label), were analyzed for background factors, cumulative incidences, and clinical outcome risk. Endpoints were stroke/systemic embolic events (SEE), major bleeding, and all-cause death during the 2-year follow-up. Of 18,497 patients taking DOACs, 20.7%, 3.8%, 51.6%, 19.6%, and 4.3%, were prescribed standard, over-, reduced, under-, and off-label doses. Factors associated with under-dose use were female sex, age ≥85 years, reduced creatinine clearance, history of major bleeding, polypharmacy, antiplatelet agents, heart failure, dementia, and no history of catheter ablation or cerebrovascular disease. After confounder adjustment, under-dose vs. standard dose was not associated with the incidence of stroke/SEE or major bleeding but was associated with a higher mortality rate. Patients receiving an off-label dose showed similar tendencies to those receiving an under-dose; that is, they showed the highest mortality rates for stroke/SEE, major bleeding, and all-cause death. CONCLUSIONS: Inappropriate low DOAC doses (under- or off-label dose) were not associated with stroke/SEE or major bleeding but were associated with all-cause death.

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.