Effects of paroxetine, a P2X4 inhibitor, on cerebral aneurysm growth and recanalization after coil embolization: the NHO Drug for Aneurysm Study.

OBJECTIVE: Rupture of cerebral aneurysms has a poor prognosis, and growing aneurysms are prone to rupture. Although the number of coil embolization procedures is increasing worldwide, they are more prone to recurrence than clipping surgeries. However, there is still no drug that prevents aneurysm growth or recanalization after coil embolization. The authors have previously focused on the role of hemodynamics in cerebral aneurysm development and reported that inhibition of the P2X4 purinoceptor, by which vascular endothelial cells sense blood flow, reduced the induction and growth of aneurysms in an animal model. In this study, the authors investigated the effects of paroxetine, a P2X4 inhibitor also used as an antidepressant, on aneurysm growth and recanalization after endovascular coiling. METHODS: Using the J-ASPECT Study registry, the largest comprehensive reimbursement database system for acute stroke inpatient care in Japan, the authors searched for patients incidentally taking paroxetine who were registered in the decade 2010-2019 with an unruptured cerebral aneurysm or who underwent aneurysm coiling. They calculated the growth incidence and growth rate by the person-year method and the odds ratio for recanalization within 1 year after coiling and statistically compared to controls. RESULTS: Seventy-eight stroke facilities participated, and 275 patients were identified as potentially eligible. Thirty-seven patients with unruptured aneurysms and 38 after coil embolization met all eligibility criteria. They were compared with 396 control cases of unruptured aneurysms and 308 coil-placement controls. Multivariate analysis showed that paroxetine significantly reduced the incidence of aneurysm growth (number of cases with growth/person/year; incidence rate ratio [IRR] 0.24, 95% CI 0.05-0.66; p = 0.003) and the growth rate (total increase in maximum diameter in millimeters/person/year; IRR 0.57, 95% CI 0.28-0.98; p = 0.04). Paroxetine also significantly reduced the odds of recanalization in the year after coiling (OR 0.21, 95% CI 0.05-0.95; p = 0.04). The authors then performed propensity score matching to reduce bias due to imbalances in patient characteristics between the two groups; the outcome confirmed that paroxetine significantly reduced aneurysm growth incidence (IRR 0.02, 95% CI 0.008-0.05; p < 0.0001) and growth rate (IRR 0.03, 95% CI 0.01-0.06; p < 0.0001) and the 1-year recanalization (OR 0.18, 95% CI 0.03-0.99; p = 0.04). CONCLUSIONS: This observational cohort study suggests that P2X4 inhibitors such as paroxetine may be clinically applicable as prophylaxis against aneurysm rupture and postoperative recanalization.

Global Results of Implantable Loop Recorder for Detection of Atrial Fibrillation After Stroke: Reveal LINQ Registry.

BACKGROUND: We aimed to quantify the incidence of atrial fibrillation (AF) in patients with cryptogenic stroke globally, as well as separately in patients in and outside of Japan, using an implantable loop recorder from a prospective, observational, Reveal LINQ Registry. METHODS AND RESULTS: Patients developing cryptogenic stroke and monitored by implantable loop recorder for searching AF were studied. The primary end point was incidence of AF within 36 months after insertion. Secondary end points were recurrent ischemic stroke/transient ischemic attack and AF-related treatment strategies. A total of 271 patients (61.6±14.3 years, 170 men, 60 from Japan) were enrolled from 12 countries. AF was detected in 28.2% at 36 months. The median time from enrollment to AF detection was 7.9 months. During the first 12 months, the AF detection rate slope was relatively steeper in the Japanese subgroup versus non-Japanese patients. However, by 3 years, the cumulative incidence of AF detection did not differ between groups. Age was the only variable associated with AF detection (hazard ratio, 1.05 [95% CI, 1.02-1.07] per year), trending higher in older age groups. Of the 271 patients, 11 (4.1%) developed recurrent ischemic stroke/transient ischemic attack; AF was detected by implantable loop recorder in only 1 of these patients. Patients with detected AF were more commonly taking oral anticoagulation than those without AF at the last follow-up (64.7% versus 25.3%, P<0.001). CONCLUSIONS: The rate of AF detection was similar to other studies in stroke populations monitored by implantable loop recorders, including CRYSTAL-AF (Cryptogenic Stroke and Underlying Atrial Fibrillation), STROKE-AF (Stroke of Unknown Cause and Underlying Atrial Fibrillation) and PER-DIEM (Post-Embolic Rhythm Detection With Implantable Versus External Monitoring). Patients with detected AF more commonly initiated anticoagulation than those without AF.

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

Background: 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. Methods and Results: 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. Conclusions: 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.

Neurological outcomes of flow-diverter stent placement for middle cerebral artery aneurysms, with reference to the effects of argatroban on ischemic events: patient series.

BACKGROUND: A systematic review and meta-analysis of flow-diverter stents (FDSs) for the treatment of middle cerebral artery (MCA) aneurysms reported concerns about ischemic complications during treatment. The authors report on the intraoperative and postoperative complications of unruptured MCA aneurysms and their control strategies at their hospital, with detailed information on the aneurysms and a review of the previous literature. OBSERVATIONS: Intraoperative and perioperative in-stent thrombus occlusion occurred in 3 (37.5%) of the 8 patients evaluated. In cases with in-stent thrombus formation, rapid administration of 10 mg argatroban led to improvement in blood flow, as seen on angiography. Only 1 patient (12.5%) had a symptomatic stroke postoperatively. This patient was admitted for rehabilitation and drug therapy but was discharged from the hospital 10 days postoperatively with a modified Rankin Scale (mRS) score of 1. The patient had an mRS score of 0 at 90 days after surgery and at the last observation. LESSONS: Ischemic complications require attention during FDS treatment for MCA aneurysms. The use of argatroban in cases of in-stent thrombosis may contribute to a good neurological prognosis. https://thejns.org/doi/10.3171/CASE24237.

Safety and Effectiveness of Four-Factor Prothrombin Complex Concentrate in Special Populations with INR Below 2: A Post-Marketing Surveillance Study.

INTRODUCTION: We previously conducted a prospective, observational post-marketing surveillance study to assess the safety and effectiveness of four-factor prothrombin complex concentrate (4F-PCC) for rapid vitamin K antagonist (VKA) reversal in Japanese patients. METHODS: This subgroup analysis compared the safety, especially thromboembolic events (TEEs), and effectiveness of 4F-PCC by stratifying patients into two subgroups according to baseline international normalized ratio (INR) levels with < 2.0 and ≥ 2.0. RESULTS: Of 1271 eligible patients, 215 (17.9%) had INR < 2.0 and 987 (82.1%) had INR ≥ 2.0. Overall baseline characteristics were similar between groups; age (74.0 years vs 74.0 years), body mass index (22.1 kg/m2 vs 21.9 kg/m2), ratio of inpatients (90.2% vs 88.7%), manifested atrial fibrillation (46.0% vs 48.8%). Median INRs at baseline were 1.72 (minimum 0.92, maximum 1.99) in the INR < 2.0 group and 2.95 (2.00, 27.11) in the INR ≥ 2.0 group. The most common reason for 4F-PCC administration was intracranial hemorrhage (67.0% vs 59.5%), and lesser gastrointestinal bleeding (0.9% vs 7.5%). After 4F-PCC administration (average doses 24.5 IU/kg [INR < 2.0 group] and 29.2 IU/kg [INR ≥ 2.0 group]), INRs were significantly reduced to 1.21 (- 28%) and 1.31 (- 68%), respectively, and resulted in hemostasis in a similarly rapid manner. The incidences of adverse drug reactions were 3.7% in each group. TEEs occurred in 4 (1.9%) patients in the INR < 2.0 group and 11 (1.1%) patients in the INR ≥ 2.0 group and were predominantly composed of stroke, while similar rates (67.0% vs 62.9%) of bleeding events post-anticoagulant resumption were observed between groups. CONCLUSION: This study supports the favorable tolerability and efficacy of 4F-PCC regardless of baseline INR (< 2.0 or ≥ 2.0), with a prompt reduction of INR and substantial hemostatic effectiveness in the real-world setting for patients requiring urgent VKA reversal, although no indicated 4F-PCC dose for VKA reversal exists for INR < 2.0 to date.

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.

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.

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.

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.