Effects of Cardioprotective Drugs on 90-Day Mortality or Heart Transplantation in Patients With Fulminant Myocarditis.

Background: Cardioprotective drugs have not been previously shown to improve the prognosis in patients with fulminant myocarditis presentation (FMP). We aimed to investigate whether cardioprotective drugs, including angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) and ß-blocker, administered during hospitalization improved the prognosis in patients with FMP. Methods and Results: This multicenter cohort study conducted in Japan included 755 patients with clinically diagnosed FMP. Those who died within 14 days of admission were excluded, and 588 patients (median age 53 [37-65] years and 40% female) were evaluated. The primary outcome was the composite of 90-day mortality or heart transplantation. The patients were divided into 4 groups according to whether they were administered ACEI/ARB or ß-blocker during hospitalization. Administration of ACEI/ARB without ß-blocker improved the overall patient outcomes (log-rank test [vs. ACEI/ARB - and ß-blocker -]: ACEI/ARB + and ß-blocker -, P<0.001; ACEI/ARB - and ß-blocker +, P=0.256). Subsequently, a matched cohort of 146 patient pairs was generated for patients with or without ACEI/ARB administration during hospitalization. The outcome-free survival at 90 days was significantly higher in the ACEI/ARB administration group than in the non-administration group (hazard ratio 0.37; 95% confidence interval 0.19-0.71). Conclusions: Administration of ACEI or ARB during hospitalization was associated with favorable outcomes in terms of 90-day mortality and heart transplantation events in patients with clinically diagnosed FMP.

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.

Prediction of heart failure events based on physiologic sensor data in HINODE defibrillator patients.

AIMS: Hospitalizations are common in patients with heart failure and are associated with high mortality, readmission and economic burden. Detecting early signs of worsening heart failure may enable earlier intervention and reduce hospitalizations. The HeartLogic algorithm is designed to predict worsening heart failure using diagnostic data from multiple device sensors. The main objective of this analysis was to evaluate the sensitivity of the HeartLogic alert calculation in predicting worsening heart failure events (HFEs). We also evaluated the false positive alert rate (FPR) and compared the incidence of HFEs occurring in a HeartLogic alert state to those occurring out of an alert state. METHODS: The HINODE study enrolled 144 patients (81 ICD and 63 CRT-D) with device sensor data transmitted via a remote monitoring system. HeartLogic alerts were then retrospectively simulated using relevant sensor data. Clinicians and patients were blinded to calculated alerts. Reported adverse events with HF symptoms were adjudicated and classified by an independent HFE committee. Sensitivity was defined as the ratio of the number of detected usable HFEs (true positives) to the total number of usable HFEs. A false positive alert was defined as an alert with no usable HFE between the alert onset date and the alert recovery date plus 30 days. The patient follow-up period was categorized as in alert state or out of alert state. The event rate ratio was the HFE rate calculated in alert to out of alert. RESULTS: The patient cohort was 79% male and had an average age of 68 ± 12 years. This analysis yielded 244 years of follow-up data with 73 HFEs from 37 patients. A total of 311 HeartLogic alerts at the nominal threshold (16) occurred across 106 patients providing an alert rate of 1.27 alerts per patient-year. The HFE rate was 8.4 times greater while in alert compared with out of alert (1.09 vs. 0.13 events per patient-year; P < 0.001). At the nominal alert threshold, 80.8% of HFEs were detected by a HeartLogic alert [95% confidence interval (CI): 69.9%-89.1%]. The median time from first true positive alert to an adjudicated clinical HFE was 53 days. The FPR was 1.16 (95% CI: 0.98-1.38) alerts per patient-year. CONCLUSIONS: Results suggest that signs of worsening HF can be detected successfully with remote patient follow-up. The use of HeartLogic may predict periods of increased risk for HF or clinically significant events, allowing for early intervention and reduction of hospitalization in a vulnerable patient population.

Time Course of Left Ventricular Strain Assessment via Cardiovascular Magnetic Resonance Myocardial Feature Tracking in Takotsubo Syndrome.

Background: Although takotsubo syndrome (TTS) is characterized by transient systolic dysfunction of the left ventricle (LV), the time course and mechanism of LV function recovery remain elusive. The aim of this study is to evaluate cardiac functional recovery in TTS via serial cardiac magnetic resonance feature tracking (CMR-FT). Methods: In this Japanese multicenter registry, patients with newly diagnosed TTS were prospectively enrolled. In patients who underwent serial cardiovascular magnetic resonance (CMR) imaging at 1 month and 1 year after the onset, CMR-FT was performed to determine the global circumferential strain (GCS), global radial strain (GRS) and global longitudinal strain (GLS). We compared LV ejection fraction, GCS, GRS and GLS at 1 month and 1 year after the onset of TTS. Results: Eighteen patients underwent CMR imaging in one month and one year after the onset in the present study. LV ejection fraction had already normalized at 1 month after the onset, with no significant difference between 1 month and 1 year (55.8 ± 9.2% vs. 58.9 ± 7.3%, p = 0.09). CMR-FT demonstrated significant improvement in GCS from 1 month to 1 year (-16.7 ± 3.4% vs. -18.5 ± 3.2%, p < 0.01), while there was no significant difference in GRS and GLS between 1 month and year (GRS: 59.6 ± 24.2% vs. 59.4 ± 17.3%, p = 0.95, GLS: -12.8 ± 5.9% vs. -13.8 ± 4.9%, p = 0.42). Conclusions: Serial CMR-FT analysis revealed delayed improvement of GCS compared to GRS and GLS despite of rapid recovery of LV ejection fraction. CMR-FT can detect subtle impairment of LV systolic function during the recovery process in patients with TTS.

Multicenter prospective observational study to clarify the current status and clinical outcome in Japanese patients who have an indication for implantable cardioverter defibrillator (ICD) or wearable cardioverter defibrillator (WCD) (TRANSITION JAPAN-ICD/WCD study): Rationale and design of a prospective, multicenter, observational, comparative study.

Background: Despite the positive impact of implantable cardioverter defibrillators (ICDs) and wearable cardioverter defibrillators (WCDs) on prognosis, their implantation is often withheld especially in Japanese heart failure patients with reduced left ventricular ejection fraction (HFrEF) who have not experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) for uncertain reasons. Recent advancements in heart failure (HF) medications have significantly improved the prognosis for HFrEF. Given this context, a critical reassessment of the treatment and prognosis of ICDs and WCDs is essential, as it has the potential to reshape awareness and treatment strategies for these patients. Methods: We are initiating a prospective multicenter observational study for HFrEF patients eligible for ICD in primary and secondary prevention, and WCD, regardless of device use, including all consenting patients. Study subjects are to be enrolled from 31 participant hospitals located throughout Japan from April 1, 2023, to December 31, 2024, and each will be followed up for 1 year or more. The planned sample size is 651 cases. The primary endpoint is the rate of cardiac implantable electronic device implementation. Other endpoints include the incidence of VT/VF and sudden death, all-cause mortality, and HF hospitalization, other events. We will collect clinical background information plus each patient's symptoms, Clinical Frailty Scale score, laboratory test results, echocardiographic and electrocardiographic parameters, and serial changes will also be secondary endpoints. Results: Not applicable. Conclusion: This study offers invaluable insights into understanding the role of ICD/WCD in Japanese HF patients in the new era of HF medication.

Effect of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes treated with an implantable cardioverter-defibrillator: the EMPA-ICD trial.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes. METHODS: A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozin or placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values. RESULTS: In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79. The coefficient for the between-group difference was - 1.07 (95% confidence interval [CI] - 1.29 to - 0.86; P < 0.001). The change in the number of appropriate device discharges during and before treatment was 0.06 in the empagliflozin group and 0.27 in the placebo group, with no significant difference between the groups (P = 0.204). Empagliflozin was associated with an increase in blood ketones and hematocrit and a decrease in blood brain natriuretic peptide and body weight. CONCLUSIONS: In patients with type 2 diabetes treated with ICD/CRT-D, empagliflozin reduces the number of ventricular arrhythmias compared with placebo. Trial registration jRCTs031180120.

Educational status and the risk of adverse outcomes in Asian patients with atrial fibrillation: a report from the prospective APHRS-AF Registry.

BACKGROUND: The aim of this study was to evaluate the impact of educational status (ES) on the clinical course of Asian patients with atrial fibrillation (AF). METHODS: We used data from the prospective APHRS-AF Registry. ES was classified as follows: low (primary school), medium (secondary), and high (University). The primary outcome was a composite of all-cause death, thromboembolic events, acute coronary syndrome, and heart failure. Secondary outcomes were each component of the primary outcome, cardiovascular death, and major bleeding. The one-year risk of primary and secondary outcomes was assessed through Cox-regressions. Adherence to the Atrial fibrillation Better Care (ABC) pathway was assessed. RESULTS: Among 2697 AF patients (69±12 years, 34.8% females), 34.6% had low ES; 37.3% had medium ES; and 28.1% had high ES. Compared to patients with medium-high ES, patients with low ES were older, more often females, with a higher prevalence of cardiovascular risk factors, and a lower ABC pathway adherence (30.4% vs. 40.2%, P<0.001). On multivariable analysis, low ES was associated with a higher risk for the primary outcome (HR 1.52,95%CI 1.11-2.06) and all-cause death (HR 1.76,95%CI 1.10-2.83) than medium-high ES. A significant interaction was found for the risk of composite outcome among the different age strata, with the higher risk in the elderly (P for int=0.008), whereas the beneficial effect of the ABC pathway was irrespective of ES (P for int=0.691). CONCLUSIONS: In Asian AF patients, low ES is associated with high mortality. Efforts to improve education and include ES evaluation in the integrated care approach for AF are necessary to reduce the cardiovascular burden in these patients.

Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

BACKGROUND AND AIMS: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. METHODS: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. RESULTS: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. CONCLUSIONS: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Novel Compound Heterozygous Variants in Trans-2,3-Enoyl-Coenzyme A Reductase-Like Gene Associated With Catecholaminergic Polymorphic Ventricular Tachycardia.

A 10-year-old female patient experienced syncope while swimming, and electrocardiography revealed polymorphic ventricular tachycardia, leading to a diagnosis of catecholaminergic polymorphic ventricular tachycardia. No pathogenic variant was identified in RYR2. Additional comprehensive genetic testing revealed novel compound heterozygous variants in trans-2,3-enoyl-coenzyme A reductase-like gene, which caused a recessive form of catecholaminergic polymorphic ventricular tachycardia.

TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.

While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.

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.

Adverse Events and Clinical Correlates in Asian Patients with Atrial Fibrillation and Diabetes Mellitus: A Report from Asia Pacific Heart Rhythm Society Atrial Fibrillation Registry.

Aims. To evaluate the adverse events (and its clinical correlates) in a large prospective cohort of Asian patients with atrial fibrillation (AF) and diabetes mellitus (DM). Material and Methods. We recruited patients with atrial fibrillation (AF) from the Asia-Pacific Heart Rhythm Society (APHRS) AF Registry and included those for whom the diabetic mellitus (DM) status was known. We used Cox-regression analysis to assess the 1-year risk of all-cause death, thromboembolic events, acute coronary syndrome, heart failure and major bleeding. Results. Of 4058 patients (mean age 68.5 ± 11.8 years; 34.4% females) considered for this analysis, 999 (24.6%) had DM (age 71 ± 11 years, 36.4% females). Patients with DM had higher mean CHA2DS2-VASc (2.3 ± 1.6 vs. 4.0 ± 1.5, p < 0.001) and HAS-BLED (1.3 ± 1.0 vs. 1.7 ± 1.1, p < 0.001) risk scores and were less treated with rhythm control strategies compared to patients without DM (18.7% vs. 22.0%). After 1-year of follow-up, patients with DM had higher incidence of all-cause death (4.9% vs. 2.3%, p < 0.001), cardiovascular death (1.3% vs. 0.4%, p = 0.003), and major bleeding (1.8% vs. 0.9%, p = 0.002) compared to those without DM. On Cox regression analysis, adjusted for age, sex, heart failure, coronary and peripheral artery diseases and previous thromboembolic event, DM was independently associated with a higher risk of all-cause death (HR 1.48, 95% CI 1.00-2.19), cardiovascular death (HR 2.33, 95% CI 1.01-5.40), and major bleeding (HR 1.91, 95% 1.01-3.60). On interaction analysis, the impact of DM in determining the risk of all-cause death was greater in young than in older patients (p int = 0.010). Conclusions. Given the high rates of adverse outcomes in these Asian AF patients with DM, efforts to optimize the management approach of these high-risk patients in a holistic or integrated care approach are needed.

Risk of Death and Cardiovascular Events in Asian Patients With Atrial Fibrillation and Chronic Obstructive Pulmonary Disease: A Report From the Prospective APHRS Registry.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of adverse events in patients with atrial fibrillation (AF); however, few data are available on this topic in Asian populations. METHODS AND RESULTS: Prospective observational study conducted on patients with AF enrolled in the Asia-Pacific Heart Rhythm Society (APHRS) AF Registry. The diagnosis of COPD was based on data reported in the case report form by the investigators. Cox-regression models were used to assess the 1-year risk of a primary composite outcome of all-cause death, thromboembolic events, acute coronary syndrome, and heart failure. Analysis on single outcomes and cardiovascular death was also performed. Interaction analysis was used to assess the risk of composite outcome and all-cause death in different subgroups. The study included 4094 patients with AF (mean±SD age 68.5±12 years, 34.6% female), of whom 112 (2.7%) had COPD. Patients with COPD showed a higher incidence of the primary composite outcome (25.1% versus 6.3%, P<0.001), all-cause death (14.9% versus 2.6%, P<0.001), cardiovascular death (2.0% versus 0.6%, P<0.001), and heart failure (8.3% versus 6.0%, P<0.001). On multiple Cox-regression analysis, COPD was associated with a higher risk of the primary composite outcome (hazard ratio [HR], 3.17 [95% CI, 2.05-4.90]), all-cause death (HR, 3.59 [95% CI, 2.04-6.30]), and heart failure (HR, 3.32 [95% CI, 1.56-7.03]); no statistically significant differences were found for other outcomes. The association between COPD and mortality was significantly modified by the use of beta blockers (Pint=0.018). CONCLUSIONS: In Asian patients with AF, COPD is associated with worse prognosis. In patients with AF and COPD, the use of beta blockers was associated with a lower mortality. REGISTRATION INFORMATION: clinicaltrials.gov Identifier: NCT04807049.

Improved outcomes of cardiac resynchronization therapy with a defibrillator in systolic heart failure: Analysis of the Japan cardiac device treatment registry database.

Background: Temporal change in outcomes of heart failure patients receiving cardiac resynchronization therapy with a defibrillator (CRT-D) is unknown. Methods: We assess outcomes and underlying heart diseases of patients receiving CRT-D with analyzing database of the Japan cardiac device treatment registry (JCDTR) at the implantation year 2011-2015 and New JCDTR at the implantation year 2018-2021. Results: Proportion of nonischemic heart diseases was about 70% in both the groups (JCDTR: 69%; New JCDTR: 72%). Cardiac sarcoidosis increased with the rate of 5% in the JCDTR to 9% in the New JCDTR group. During an average follow-up of 21 months, death from any cause occurred in 167 of 906 patients in the JCDTR group (18%) and 79 of 611 patients in the New JCDTR group (13%) (adjusted hazard ratio [aHR] in the New JCDTR group, 0.72; 95% confidence interval [CI]: 0.55-0.94; p = .017). The superiority was mainly driven by reduction in the risk of noncardiac death. With regard to appropriate and inappropriate implantable cardioverter-defibrillator (ICD) therapy, there was a significant reduction in the New JCDTR group versus the JCDTR group (aHR in the New JCDTR group, 0.76; 95% CI: 0.59-0.98; p = .032 for appropriate ICD therapy; aHR in the New JCDTR group, 0.24; 95% CI: 0.12-0.50; p < .0001 for inappropriate ICD therapy). Conclusions: All-cause mortality was reduced in CRT-D patients implanted during 2018-2021 compared to those during 2011-2015, with a significant reduction in noncardiac death.

Weekday Surgery Associated With Short-Term Outcomes in Patients With Colorectal Cancers.

INTRODUCTION: The "weekday effect" on elective surgery remains controversial. We aimed to examine the association between the day of surgery and short-term outcomes after elective surgery for stage I-III colorectal cancer (CRC). METHODS: We performed a multicenter retrospective analysis of 2574 patients who underwent primary colorectal resection for CRC between January 2017 and December 2019 at 15 institutions belonging to the Hiroshima Surgical Study Group of Clinical Oncology. Patients were divided into two groups according to the day of surgery: Friday and non-Friday (Monday to Thursday). After propensity score matching (PSM), we compared 30-day mortality and postoperative outcomes. RESULTS: Out of the total, 368 patients underwent surgery on Fridays, and the remaining 2206 underwent surgery on non-Fridays. The overall mortality rate was 0.04% (n = 1). In 1685 patients with colon cancer, the proportion of American Society of Anesthesiologists scores was significantly lower in the Friday group than in the non-Friday group before PSM. After PSM of patient, tumor, and operative characteristics, operative time was slightly more prolonged and blood loss was slightly greater in the Friday group; however, these differences were not clinically meaningful. In the 889 patients with rectal cancer, the proportion of patients with abnormal respiratory patterns was significantly lower in the Friday group than in the non-Friday group before PSM. After PSM, the Friday group had a higher incidence of morbidity (≥ Clavien-Dindo 3a), higher incidence of digestive complications, and prolonged postoperative hospital stay. CONCLUSIONS: The results may be useful in determining the day of the week for CRC surgery, which requires more advanced techniques and higher skills.

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.

External Validation of COOL-AF Scores in the Asian Pacific Heart Rhythm Society Atrial Fibrillation Registry.

Background: The COOL-AF (Cohort of Antithrombotic Use and Optimal International Normalized Ratio Levels in Patients with Atrial Fibrillation) risk scores for death, bleeding, and thromboembolic events (TEs) were derived from the COOL-AF cohort from Thailand and require external validation. Objectives: The authors sought to externally validate the COOL-AF scores in the APHRS (Asia-Pacific Heart Rhythm Society) registry and to compare their performance in the ESC-EHRA (European Society of Cardiology-European Heart Rhythm Association) EORP-AF (EURObservational Research Programme in Atrial Fibrillation) General Long-Term Registry. Methods: We studied 3,628 APHRS and 8,825 EORP-AF patients. Receiver operating characteristic (ROC) curves and Cox regression analyses were used to test the predictive value of COOL-AF scores and to compared them with the CHA2DS2-VASc and HAS-BLED scores. Results: Patients in the EORP-AF were older, had a higher prevalence of male sex, and were at higher thromboembolic and hemorrhagic risk than APHRS patients. After 1 year of follow-up in APHRS and EORP-AF, the following events were recorded: 87 (2.4%) and 435 (4.9%) death for any causes, 37 (1.0%) and 111 (1.3%) major bleeding, and 25 (0.7%) and 109 (1.2%) TEs, respectively. In APHRS, the COOL-AF scores showed moderate-to-good predictive value for all-cause mortality (area under the curve [AUC]: 0.77; 95% CI: 0.71-0.83), major bleeding (AUC: 0.68; 95% CI: 0.60-0.76), and TEs (AUC: 0.61; 95% CI: 0.51-0.71), and were similar to the CHA2DS2-VASc and HAS-BLED scores. In EORP-AF, the predictive value of COOL-AF for all-cause mortality (AUC: 0.68; 95% CI: 0.65-0.70) and major bleeding (AUC: 0.61; 95% CI: 0.60-0.62) was modest and lower than in APHRS. In EORP-AF, the COOL-AF score for TE was inferior to the CHA2DS2-VASc score. Conclusions: The COOL-AF risk scores may be an easy tool to identify Asian patients with AF at risk for death and major bleeding and performs better in Asian than in European patients with AF. (Clinical Survey on the Stroke Prevention in Atrial Fibrillation in Asia [AF-Registry]; NCT04807049).

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.