Published papers

Background: Introduction of guideline-directed medical therapy (GDMT) has transformed the care of heart failure (HF) with reduced ejection fraction, establishing four foundational drug classes. Yet, in clinical practice, many patients cannot initiate or maintain all four, and clinicians must pragmatically prioritise agents such as angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter-2 inhibitor, whose comparative impacts are still explored. Moreover, the optimal loop diuretic to pair with modern GDMT, which enhances natriuresis, remains uncertain. Methods: Between January 2022 and February 2024, we conducted a multicentre, open-label, randomised, 2×2 factorial design trial for ambulatory patients with symptomatic HF, elevated natriuretic peptide levels and left ventricular ejection fraction (LVEF) <50%, despite conventional therapies (eg, renin-angiotensin-aldosterone system inhibitors and beta-blockers). The patients were assigned to receive either sacubitril/valsartan or dapagliflozin, and torsemide or furosemide. The primary endpoint was the change in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) over 6 months; a prespecified secondary endpoint was a hierarchical clinical outcome. Results: Of 231 randomised patients (median age 73 years; median LVEF 36%; 84.0% New York Heart Association class II), changes in KCCQ-OSS did not differ between sacubitril/valsartan and dapagliflozin (adjusted mean difference 2.53 points; 95% confidence interval (CI) −1.81 to 6.88; p=0.25) or between torsemide and furosemide (0.25 points; 95% CI −4.10 to 4.59; p=0.91). Hierarchical composite outcome analyses also showed no significant differences between sacubitril/valsartan and dapagliflozin (win ratio, 1.15; 95% CI 0.71 to 1.88), or between torsemide and furosemide (win ratio, 1.15; 95% CI 0.70 to 1.85). Conclusions: This trial found no evidence of benefit of one treatment over another for health status over 6 months. Given the sample size and predefined power, modest differences between treatments cannot be excluded. Trial registration number: UMIN000045229.

Background Current guidelines and quality metrics after percutaneous coronary intervention (PCI) often assign equal weight to nonfatal adverse events, including heart failure hospitalization (HFH), acute coronary syndrome (ACS), and major bleeding, within composite endpoints. Objectives The aim of this study was to quantify and compare the associations of HFH, ACS, and major bleeding with subsequent mortality following PCI. Methods A Japanese multicenter prospective PCI registry (2008-2021) with 2-year postprocedural outcomes was analyzed. The primary outcome was all-cause mortality, with HFH, ACS, and major bleeding as time-varying exposures. Cumulative incidence was estimated with death as a competing risk. Cox proportional hazards models and population attributable fractions were used to assess associations between time-varying events and mortality, adjusting for conventional risk factors. Results Among 10,482 patients (mean age 69 years, 77.5% men) followed for a median of 730 days (Q1-Q3: 730-730 days), 1,021 (9.7%; 95% CI: 9.2%-10.3%) experienced adverse events. Two-year cumulative incidence rates were 4.7% (95% CI: 4.2%-5.1%) for HFH, 3.4% (95% CI: 3.0%-3.7%) for ACS, and 2.5% (95% CI: 2.2%-2.8%) for major bleeding. Cox analysis showed that HFH was associated with mortality (adjusted HR [aHR]: 6.11; 95% CI: 4.76-7.85), followed by ACS (aHR: 3.22; 95% CI: 2.14-4.84) and major bleeding (aHR: 2.62; 95% CI: 1.71-4.02). Population attributable fraction analysis demonstrated that HFH accounted for 20.1% (95% CI: 19.0%-21.0%) of mortality burden, higher than ACS (4.3%; 95% CI: 3.3%-4.9%) and major bleeding (2.9%; 95% CI: 1.9%-3.5%). Conclusions HFH shows stronger associations with mortality than ACS or major bleeding following PCI, suggesting that adverse events should not be weighted equally and underscoring the need to reconsider prioritization in clinical decision-making and endpoint definitions.

BACKGROUND: The absence of practice standards in vasoactive agent usage for acute decompensated heart failure has resulted in significant treatment variability across hospitals, potentially affecting patient outcomes. This study aimed to assess temporal trends and institutional differences in vasodilator and inotrope/vasopressor utilization among patients with acute decompensated heart failure, considering their clinical phenotypes. METHODS: Data were extracted from a government-funded multicenter registry covering the Tokyo metropolitan area, comprising consecutive patients hospitalized in intensive/cardiovascular care units with a primary diagnosis of acute decompensated heart failure between January 2013 and December 2021. Clinical phenotypes, that is, pulmonary congestion or tissue hypoperfusion, were defined through a comprehensive assessment of clinical signs and symptoms, vital signs, and laboratory findings. We assessed the frequency and temporal trends in phenotype-based drug utilization of vasoactive agents and investigated institutional characteristics associated with adopting the phenotype-based approach using generalized linear mixed-effects models, with random intercepts to account for hospital-level variability. RESULTS: Among 37 293 patients (median age, 80 years; 43.7% female), 88.6% and 21.2% had pulmonary congestion and tissue hypoperfusion status, respectively. Throughout the study period, both overall and phenotype-based vasodilator utilizations showed significant declines, with overall usage dropping from 61.4% in 2013 to 48.6% in 2021 (Ptrend<0.001). Conversely, no temporal changes were observed in overall inotrope/vasopressor utilization from 24.6% in 2013 to 25.8% in 2021 or the proportion of phenotype-based utilization. Notably, there was considerable variability in phenotype-based drug utilization among hospitals, with a median ranging from 48.3% to 77.8%. In multivariable-adjusted models, a higher number of board-certified cardiologists were significantly associated with lower rates of phenotype-based vasodilator utilization and reduced inappropriate inotrope/vasopressor utilization, while tertiary care hospitals were linked to more appropriate inotrope/vasopressor utilization. CONCLUSIONS: Substantial variability existed among hospitals in phenotype-based drug utilization of vasoactive agents for patients with acute decompensated heart failure, highlighting the need for standardized treatment protocols.

Aims: Available predictive models for sudden cardiac death (SCD) in heart failure (HF) patients remain suboptimal. We assessed whether the electrocardiography (ECG)-based artificial intelligence (AI) could better predict SCD, and also whether the combination of the ECG-AI index and conventional predictors of SCD would improve the SCD stratification among HF patients. Methods and results: In a prospective observational study, 4 tertiary care hospitals in Tokyo enrolled 2559 patients hospitalized for HF who were successfully discharged after acute decompensation. The ECG data during the index hospitalization were extracted from the hospitals' electronic medical record systems. The association of the ECG-AI index and SCD was evaluated with adjustment for left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) class, and competing risk of non-SCD. The ECG-AI index plus classical predictive guidelines (i.e. LVEF ≤35%, NYHA Class II and III) significantly improved the discriminative value of SCD [receiver operating characteristic area under the curve (ROC-AUC), 0.66 vs. 0.59; P = 0.017; Delong's test] with good calibration (P = 0.11; Hosmer-Lemeshow test) and improved net reclassification [36%; 95% confidence interval (CI), 9-64%; P = 0.009]. The Fine-Gray model considering the competing risk of non-SCD demonstrated that the ECG-AI index was independently associated with SCD (adjusted sub-distributional hazard ratio, 1.25; 95% CI, 1.04-1.49; P = 0.015). An increased proportional risk of SCD vs. non-SCD with an increasing ECG-AI index was also observed (low, 16.7%; intermediate, 18.5%; high, 28.7%; P for trend = 0.023). Similar findings were observed in patients aged ≤75 years with a non-ischaemic aetiology and an LVEF of >35%. Conclusion: To improve risk stratification of SCD, ECG-based AI may provide additional values in the management of patients with HF.

Aims: To help establish optimized treatment strategies for congestion in patients with acute heart failure, this study aimed to provide a detailed summary of real-world diuretic use in hospitalized patients with heart failure requiring urgent therapy in Japan. Methods and results: This observational study used a Japanese medical records database to extract data of patients admitted to hospital with a heart failure diagnosis and an intravenous diuretic prescription from the day before admission to 2 days after. Time from hospital visit to first dose, second dose, and maximum dose of intravenous diuretics were determined. Patients were grouped according to whether they received diuretic modification, defined as an intravenous diuretic dose increase or concomitant use of other diuretics. Results: Overall, 1577 patients were included in the study (without diuretic modification, n = 1140 [72.3%]; with diuretic modification, n = 437 [27.7%]). The study population was 49.5% female (n = 780) and the mean age ± standard deviation was 80.1 ± 12.7 years. Intravenous diuretic treatment was received within 1 h of their hospital visit in 43.5% of patients (686/1577) and ≤2 h in 16.4% of patients (258/1577). Among 437 patients with an inadequate response following their first dose, 42.1% received an intravenous dose titration, 56.5% received combination diuretics, and 1.4% received both. Over half of the patients (59.0% [258/437]) with diuretic modification received it after the first 24 h of the hospital visit. The median time from hospital visit to first dose titration was similar to time to first combination diuretic use (18.6 h and 17.0 h, respectively). The mean ± standard deviation duration of intravenous diuretic use was significantly longer for patients with versus without diuretic modification (6.3 ± 5.2 vs. 3.7 ± 3.2 days), and a significantly greater proportion of patients (44.6% [195/437] vs. 35.0% [399/1140]) received repeated intravenous diuretic administration. Other characteristics/outcomes of intravenous diuretic use were similar with versus without diuretic modification, including in-hospital death (15.6% [68/437] vs. 13.9% [159/1140]) and mean ± standard deviation length of hospitalization (21.9 ± 14.7 days vs. 22.1 ± 21.2 days). Conclusions: In Japan, real-world patterns of intravenous diuretic administration for patients with heart failure remains far from the time-sensitive approach recommended in Japanese, European, and United States guidelines.

Objectives: Cancer and cardiovascular disease (CVD) increasingly coexist, yet patient perspectives on self-care in cardio-oncology remain poorly understood. This study aimed to identify concerns and self-care needs among patients with concurrent cancer and CVD. Methods: We conducted a cross-sectional questionnaire survey of patients with cancer and CVD at Keio University Hospital from August 2024 to August 2025. Participants allocated 100 points between cancer- and CVD-related concerns and ranked five self-care domains (symptom management, medication, diet, social services and anxiety). Self-care interests were scored and evaluated according to cancer treatment status (active vs completed) and age (<70 vs ≥70 years). Results: A total of 72 patients were included (median age 72 years, 47% male); 42% were receiving active cancer treatment. Overall, cancer was prioritised over CVD (median 60 vs 40 points). Actively treated patients placed greater emphasis on cancer than completed-treatment patients (80 vs 50 points, p<0.001). Among five domains, symptom management and medication received greater attention in the active versus completed group (p=0.016 and p=0.047, respectively). Older age was independently associated with lower total self-care interests in multivariable analysis. Conclusions: Oncologic concerns outweigh cardiovascular priorities, particularly during active cancer treatment, with age further limiting self-care engagement. Phase- and age-sensitive self-care programmes are needed in cardio-oncology.

BACKGROUND: The prognostic impact of worsening renal function (WRF) during the vulnerable phase following discharge after hospitalization for acute decompensated heart failure (HF) remains unclear. This study investigated the determinants of WRF 1 year after discharge (1Y-WRF) and its association with clinical outcomes in patients with acute decompensated HF. METHODS: Data were analyzed for 1753 patients hospitalized with acute decompensated HF from WET-HF2 (West Tokyo Heart Failure 2), a multicenter registry. 1Y-WRF was defined as a ≥25% decrease in estimated glomerular filtration rate (eGFR). The primary end point was a composite of all-cause mortality and HF rehospitalization beyond 1 year after discharge. Exploratory subgroup analyses were conducted based on age, sex, left ventricular ejection fraction, diabetes, eGFR, HF rehospitalization, and loop diuretic intensification within 1 year after discharge, anemia, and renin-angiotensin-aldosterone system inhibitors use. RESULTS: Of the 1753 patients (median age 76 years, 39.9% female, median eGFR 50.7 mL/min per 1.73 m2 at discharge), 285 (16.3%) developed 1Y-WRF. Female sex, anemia, higher New York Heart Association class, and higher eGFR at discharge were associated with 1Y-WRF. Over a median follow-up of 1 year, 1Y-WRF was associated with an increased risk of the composite end point (adjusted hazard ratio, 1.34 [95% CI, 1.02-1.75], P=0.035), primarily driven by HF rehospitalization. The adverse prognostic impact was notable in young patients and those with high eGFR and no HF rehospitalization within 1 year after discharge. CONCLUSIONS: In a contemporary cohort of acute decompensated heart failure 1Y-WRF was relatively common and associated with subsequent worse clinical outcomes.

BACKGROUND: The Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire is endorsed for symptom and quality-of-life assessment in atrial fibrillation (AF) but is typically measured once. Because patient-reported health status changes with treatment, serial AFEQT assessments may better reflect disease burden over time. We evaluated whether repeated AFEQT measurements are associated with subsequent outcomes and whether the most recent score is informative. METHODS AND RESULTS: We analyzed a multicenter, prospective registry of stable outpatients with AF referred to 11 hospitals in Japan (2012-2018). Associations of baseline ("prior"), 12-month ("current"), and change in AFEQT overall summary (os) scores with all-cause death and heart failure (HF) hospitalization were examined using multivariable Cox models. Among 2,743 patients (mean [±SD] age 67.8±11.1 years; 31.9% women), 146 (5.3%) experienced HF hospitalization and 134 (4.9%) died over a median follow-up of 4.0 years. Higher current AFEQT-os and change scores, but not prior AFEQT-os, were associated with a lower risk of death/HF hospitalization, with adjusted hazard ratios (95% confidence intervals) per 5-point increase of 0.94 (0.91-0.97) and 0.96 (0.92-0.99), respectively. When modeled together, only current AFEQT-os remained independently associated with outcomes. In time-varying analyses, time-updated AFEQT-os predicted both death/HF hospitalization and all-cause death. CONCLUSIONS: The most recent AFEQT-os is associated with mortality and HF hospitalization, whereas baseline scores provide limited prognostic value. Updating patient-reported health status may help with risk assessment in AF.

BACKGROUND: Although the “I NEED HELP” criteria facilitate timely consideration of advanced heart failure (HF) therapies, patient classification based on the variables included in the criteria are scarcely investigated. This study aimed to identify phenotypically distinct subgroups of patients with advanced HF using unsupervised cluster analysis based on the variables included in these criteria. METHODS: A multicenter registry was used to identify patients hospitalized with HF who met at least 1 I NEED HELP criterion. Latent class analysis was performed on 9 variables from the criteria. RESULTS: A total of 2520 patients (mean age, 74±13years; 40% women) were included in this study. Latent class analysis identified 3 phenotypes: more de novo HF with the lowest number of applicable criteria (phenotype 1, 31%); younger age with the lowest left ventricular ejection fraction and highest number of applicable criteria (phenotype 2, 19%); and older age with more comorbidities and poorer renal function (phenotype 3, 49%). After multivariable adjustment, phenotypes 2 and 3 were associated with a higher incidence of composite all-cause death or rehospitalization for HF (phenotype 2: hazard ratio [HR], 1.96 [95% CI, 1.58–2.42]; phenotype 3: HR, 1.54 [95% CI, 1.28–1.84]; phenotype 1: reference) during the follow-up period (median, 461 [interquartile range, 130–730] days). CONCLUSIONS: This study describes a novel phenotypical classification based on the I NEED HELP criteria, with significantly different prognoses identified for patients with advanced HF. These classifications may facilitate risk stratification in this population with a complicated clinical profile.

Chronic thromboembolic pulmonary disease (CTEPD) is characterized by persistent obstruction of pulmonary arteries with organized thrombotic materials. Patients with CTEPD without pulmonary hypertension (PH) are generally considered unlikely to progress to chronic thromboembolic pulmonary hypertension (CTEPH). Here, we report a case of a 75-year-old woman with essential thrombocythemia harboring JAK2 V617F mutation, who had a history of acute pulmonary embolism. Initial evaluation of contrast-enhanced computed tomography and pulmonary angiography revealed organized thrombi predominantly in the right main and lobar pulmonary arteries, accompanied by perfusion defects on lung perfusion scintigraphy. Right heart catheterization (RHC) showed a mean pulmonary arterial pressure (mPAP) of 18 mmHg, leading to a diagnosis of CTEPD without PH. As the patient declined invasive treatment, she was followed with anticoagulation therapy alone. Three years later, her symptoms worsened, and RHC revealed an elevated mPAP of 33 mmHg, along with slight progression of thrombotic lesions and newly identified calcified deposits. She again refused invasive treatment and died one year later despite medical therapy. This case suggests that the JAK2 V617F mutation could be a risk factor for progression from CTEPD without PH to CTEPH, underscoring the importance of close follow-up and early consideration of invasive treatment in such patients. Learning objective This case highlights that chronic thromboembolic pulmonary disease without pulmonary hypertension can progress to chronic thromboembolic pulmonary hypertension, particularly in patients with high-risk features such as the JAK2 V617F mutation. It underscores the importance of careful long-term follow-up and early consideration of invasive treatment despite initially normal hemodynamics.

Background: Acute coronary syndrome complicated by cardiogenic shock (ACS-CS) remains associated with high mortality despite advances in percutaneous coronary intervention (PCI) and increasing attention to mechanical circulatory support (MCS). Objectives: This study aimed to evaluate temporal trends in patient risk profiles, treatment strategies, and in-hospital outcomes among patients undergoing PCI for ACS-CS. Methods: From 2009 to 2019, 24,527 consecutive PCI procedures were recorded in the Keio Interhospital Cardiovascular Studies-PCI registry, including 870 cases (3.5%) with ACS-CS. Patients were categorized into 4 time periods (T1: 2009-2011; T2: 2012-2013; T3: 2014-2016; T4: 2017-2019). Temporal changes in risk profiles were evaluated using National Cardiovascular Data Registry Catheterization PCI mortality and bleeding risk scores. Trends in MCS use, in-hospital mortality, and post-PCI complications were analyzed. Results: Predicted in-hospital mortality and bleeding risk remained stable over time, at approximately 20% (P for trend = 0.053) and 40% (P for trend = 0.39), respectively. Overall MCS use declined from 66.5% in T1 to 56.7% in T4, primarily due to reduced intra-aortic balloon pump use (46.5% to 31.2%). Despite these changes in management, crude and National Cardiovascular Data Registry risk–adjusted in-hospital mortality remained persistently high at approximately 30% throughout the study period. Conclusions: Among patients with ACS-CS selected for PCI in a multicenter Japanese registry, management strategies changed substantially over the past decade, particularly regarding MCS utilization. However, no significant temporal improvement in in-hospital mortality was observed, underscoring the persistent clinical challenges of this high-risk PCI-treated population.

BACKGROUND: Prognostic implications of mineralocorticoid receptor antagonist (MRA) initiation in the context of worsening renal function (WRF) in patients with acute heart failure (AHF) remain unknown. METHODS: This was a post hoc analysis using data from Japanese AHF registries (NARA-HF [Nara Registry and Analyses for Heart Failure], WET-HF [West Tokyo Heart Failure], REALITY-AHF [Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure]). MRA-naïve patients at baseline were included, comprising 1632 patients with HF with reduced ejection fraction (HFrEF) and 2407 with heart failure with mildly reduced or preserved ejection fraction (HFmr/pEF). They were divided into 3 groups: MRA initiated without WRF (HFrEF, n=590; HFmr/pEF, n=572), MRA initiated with WRF (HFrEF, n=74; HFmr/pEF, n=100), and no MRA initiation (HFrEF, n=968; HFmr/pEF, n=1735). WRF was defined as a 0.3 mg/dL increase from admission to discharge. The composite of death or HF hospitalization after discharge was assessed. RESULTS: During the 1-year follow-up, 369 and 593 events occurred in patients with HFrEF and HFmr/pEF, respectively. Overall, MRA initiation during hospitalization of AHF was independently associated with better prognosis (hazard ratio [HR], 0.81), mainly driven by HF hospitalization. Among patients with HFrEF, the groups with MRA with and without WRF showed a lower incidence of the outcome than the no-MRA group, even after adjusting for risk factors (HR, 0.75 and 0.49, respectively). Among patients with HFmr/pEF, MRA initiation without WRF was independently associated with better prognosis (HR, 0.78), but MRA initiation with WRF was not. CONCLUSIONS: Initiating an MRA during AHF hospitalization was associated with better postdischarge outcomes in HFrEF, irrespective of creatinine elevation, whereas no such consistent association was observed in HFmr/pEF.

Importance Improving health status, including symptoms and quality of life, is a key goal in the management of atrial fibrillation (AF). However, whether improvements in patient-reported health status are associated with subsequent clinical outcomes remains unclear. Objective To evaluate the association between changes in health status and long-term adverse clinical outcomes in patients with AF. Design, Setting, and Participants This cohort study used data from a prospective multicenter registry in Japan that enrolled patients aged 22 to 94 years with newly diagnosed AF or who were newly referred for AF management between September 20, 2012, and May 22, 2018. The registry collected follow-up data for up to 5 years. Eligible patients completed the Atrial Fibrillation Effect on Quality of Life patient-reported outcome measure (PROM) questionnaire at both baseline and 1-year follow-up. Clinical outcomes were assessed for 4 years following the 1-year AF PROM assessment. Data were analyzed between February 7 and July 14, 2025. Exposure One-year change in the AF PROM overall summary score. Main Outcomes and Measures The primary outcome was a composite of all-cause death, heart failure hospitalization, and stroke or transient ischemic attack over 4 years. Multivariable hierarchical regression models adjusted for baseline score, clinical factors, and comorbidities were used to evaluate associations between 1-year change in AF PROM overall summary score and outcomes. Results Among 2744 patients (mean [SD] age, 67.8 [11.1] years; 1868 male [68.1%]; 1357 [49.6%] with paroxysmal AF), 1408 (51.3%) had improved health status (overall summary score increase of ≥5 points), 833 (30.4%) had stable health status, and 503 (18.3%) had worsened health status (overall summary score decrease of ≥5 points). During a mean (SD) follow-up of 3.1 (1.4) years after the 1-year assessment, the primary outcome occurred in 283 patients (10.3%). After adjustment for baseline characteristics (including baseline AF PROM score), improvement in the AF PROM overall summary score was associated with a lower risk of adverse outcomes (per 5-point increase: hazard ratio, 0.93 [95% CI, 0.89-0.96]; P <.001). Conclusions and Relevance This cohort study of patients with AF in Japan found that greater improvements in 1-year AF PROM scores were associated with a lower risk of subsequent adverse clinical events. These findings support the prognostic value of PROMs and highlight the importance of monitoring health status in AF management.

BACKGROUND: SGLT2 (sodium–glucose cotransporter-2) inhibitors (SGLT2is) improve outcomes in heart failure (HF), but evidence in patients with frailty and acute HF (AHF) is limited. This study investigated the association between SGLT2i use at discharge and outcomes in patients with AHF, with a focus on frailty. METHODS: We analyzed 5579 patients hospitalized for AHF enrolled between 2018 and 2024 in the prospective WET-HF2 (West Tokyo Heart Failure 2) registry in Japan (age 79years, 43% women, body mass index 23.1, 23% ischemic cause, left ventricular ejection fraction 45%, 24% SGLT2is at discharge). Frailty was assessed using the Clinical Frailty Scale (≥4; 63%), and complementary analyses were performed using frailty-related factors (low body mass index, reduced activities of daily living, malnutrition, and dementia). The primary outcome was a composite of cardiac death or HF rehospitalization within 1year, which occurred in 766 patients (18%). A propensity score was calculated using variables associated with SGLT2i prescription. RESULTS: After propensity score–based inverse probability of treatment weighting adjustment, SGLT2i use was associated with a lower risk of the primary outcome (hazard ratio [HR], 0.76, P=0.045). This association was more pronounced in patients with frailty (HR, 0.59, P=0.005), but not in patients without frailty (HR, 1.18; Pinteraction=0.010). Analyses using frailty-related factors yielded similar patterns. At 1year, SGLT2i use at discharge was not associated with deterioration in body mass index or nutritional status. CONCLUSIONS: In this observational registry, SGLT2i use at discharge was associated with improved outcomes in patients with AHF, particularly those with frailty, without evidence of nutritional harm. These findings support the potential safety of SGLT2is in patients with frailty and AHF.

Background: Renin-angiotensin system inhibitors (RASI) reduce adverse cardiovascular events in patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤40% and mild or moderate chronic kidney disease (CKD). However, RASI administration rate and its association with long-term outcomes in patients with CKD complicated by HF with LVEF >40% remain unclear. Methods: We analyzed 1923 consecutive patients with LVEF >40% registered within the multicenter database for hospitalized HF. We assessed RASI administration rate and its association with all-cause mortality among patients with mild or moderate CKD (estimated glomerular filtration rate [eGFR]: 30–60 mL/min/1.73 m2). Exploratory subgroups included patients grouped by age (<80, ≥80 years), sex, previous HF hospitalization, B-type natriuretic peptide (higher, lower than median), eGFR (30–44, 45–59 mL/min/1.73 m2), systolic blood pressure (<120, ≥120 mmHg), LVEF (41–49, ≥50%), and mineralocorticoid receptor antagonists (MRA) use. Results: Among patients with LVEF >40%, 980 (51.0%) had mild or moderate CKD (age: 81 [74–86] years; male, 52.6%; hypertension, 69.7%; diabetes, 25.9%), and 370 (37.8%) did not receive RASI. RASI use was associated with hypertension, absence of atrial fibrillation, and MRA use. After multivariable adjustments, RASI use was independently associated with lower all-cause mortality over a 2-year median follow-up (hazard ratio: 0.58, 95% confidence interval: 0.43–0.79, P = 0.001), and the mortality rate difference was predominantly due to cardiac death, consistent in all subgroups. Conclusions: Approximately one-third of HF patients with mild or moderate CKD and LVEF >40% were discharged without RASI administration and demonstrated relatively guarded outcomes.