Published papers

Background: Recently, patients with supra-normal left ventricular ejection fraction (snEF) are reported to have high risk of adverse outcomes, especially in women. We sought to evaluate sex-related differences in the association between LVEF and long-term outcomes in heart failure (HF) patients. Methods: The multicenter WET-HF Registry enrolled all patients hospitalized for acute decompensated HF (ADHF). We analyzed 3943 patients (age 77 years; 40.1% female) registered from 2006 to 2017. According to LVEF the patients were divided into the 3 groups: HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) and preserved EF. The primary endpoint was defined as the composite of cardiac death and ADHF rehospitalization after discharge. Results: In HFmrEF, implementation of guideline-directed medical therapy (GDMT) such as the combination of renin-angiotensin-system inhibitor (RASi) and β-blocker at discharge was significantly lower in women than men even after adjustment for covariates (p = 0.007). There were no such sex-related differences in HFrEF. Female sex was associated with higher incidence of the primary endpoint and ADHF rehospitalization after adjustment for covariates exclusively in HFmrEF. Restricted cubic spline analysis demonstrated a U-shaped relationship between LVEF and the hazard ratio of the primary endpoint showing higher event rate in HFmrEF and HFsnEF in women, but such relationship was not observed in men (p for interaction = 0.037). Conclusions: In women, mrEF and snEF were associated with worse long-term outcomes. Additionally, sex-related differences in the GDMT implementation for HFmrEF highlight the need for further exploration, which might lead to creation of sex-specific guidelines to optimize HF management.

Obesity hypoventilation syndrome is caused by complex interactions between multiple pathological processes, including diminished respiratory drive and sleep-related breathing alterations, leading to structural and functional respiratory impairment and ultimately, pulmonary hypertension. Because pulmonary hypertension is closely associated with obesity hypoventilation syndrome, thoroughly evaluating its etiology is essential, and individualized treatments must be considered. We describe 2 patients with obesity hypoventilation syndrome exhibiting severe pulmonary hypertension with pulmonary vascular resistance exceeding 5 Wood units; both were classified as Group 1 pulmonary hypertension, ie, pulmonary arterial hypertension. Initially admitted to our hospital complaining of dyspnea, both patients commenced pulmonary arterial hypertension therapies in addition to positive airway pressure therapy and diuretics, improving their hemodynamic status, dyspnea, and exercise capacity, and finally enabling their discharge. These findings suggest that pulmonary arterial hypertension can coexist with obesity hypoventilation syndrome, and pulmonary arterial hypertension therapies, introduced with careful consideration, may provide substantial benefits for select patients.

Background: Anthracyclines are known to exhibit dose-dependent cardiotoxicity, leading to cancer therapy-related cardiac dysfunction (CTRCD). The significance of routine global longitudinal strain (GLS) measurements remains uncertain in patients at low or moderate risk for cardiotoxicity. This study aimed to investigate the appropriateness of the contemporary CTRCD surveillance strategy in this population. Methods: We prospectively enrolled women with breast cancer undergoing anthracycline-based chemotherapy at Keio University Hospital from April 2018 to November 2023. Cardiotoxicity risk was assessed using the Heart Failure Association-International Cardio-Oncology Society (HFA-ICOS) tool. GLS was measured by echocardiography at baseline (T0), completion of anthracyclines (T1), and 6 months (T2) and 12 months (T3) after initiating chemotherapy. CTRCD was defined as a > 15% relative decline in GLS from baseline. Repeated GLS measurements were analyzed using linear mixed models with post-hoc Tukey testing. Results: Fifty-eight patients (mean age 53.8 ± 9.3 years) were included, with 53 (91.3%) classified as low or moderate risk. GLS significantly declined at T2 and returned toward baseline at T3. GLS-based CTRCD was observed in 4 (6.9%), 14 (24.1%), and 4 (6.9%) patients at T1, T2, and T3, respectively. The majority of CTRCD cases showed spontaneous recovery by T3. Persistent CTRCD at T3 was limited to a small number of patients and was significantly associated with higher high-sensitivity cardiac troponin T levels at T1 (area under curve = 0.836; 95% CI, 0.674–0.997), with a Youden index-derived cutoff of 0.016 ng/mL by receiver operating characteristic analysis. Conclusions: In breast cancer patients with low to moderate cardiotoxicity risk, early GLS decline following anthracycline exposure was mostly transient. These findings support current surveillance recommendations and suggest a potential role for troponin in identifying patients at risk for persistent dysfunction.

Background Guidelines recommend vericiguat initiation in patients with heart failure (HF) with reduced ejection fraction who have already been prescribed guideline-directed medical therapy (GDMT). However, few studies have examined the safety and tolerability of vericiguat according to baseline GDMT in clinical practice. Methods This retrospective observational study used data from a multicenter registry of patients who initiated vericiguat between June 2021 and September 2023. Patients with left ventricular ejection fraction <45% who had at least one GDMT at baseline were divided into two groups according to the number of GDMTs: the quadruple GDMT and non-quadruple GDMT groups. The association between baseline GDMT and hypotension and drug discontinuation within 90 days after vericiguat initiation was analyzed. Results Among 791 patients included, 398 (50.3%), 220 (27.8%), 127 (16.1%), and 46 (5.8%) patients were prescribed quadruple, triple, double, and single GDMTs, respectively. The median (interquartile range) baseline systolic blood pressure was similar between the non-quadruple GDMT [104 (92–118) mmHg] and the quadruple GDMT [102 (90–115) mmHg] groups ( p = 0.11). Patients in the non-quadruple GDMT group were older, had a lower proportion of a history of HF hospitalization, and higher B-type natriuretic peptide levels. Hypotension occurred in 28.2% in the non-quadruple GDMT group and 22.4% in the quadruple GDMT group ( p = 0.057), and the adjusted odds ratio for hypotension was not different between groups (odds ratio 1.16, 95% confidence interval 0.80–1.67; p = 0.43). Drug discontinuation occurred more frequently in the non-quadruple GDMT group than in the quadruple GDMT group (16.5% vs 10.3%, p = 0.01), with hypotension accounting for a minority of discontinuations. Conclusions Baseline non-quadruple GDMT was not associated with hypotension after vericiguat initiation, suggesting that vericiguat may be safely added even when quadruple GDMT has not been achieved.

Background: Obesity is a risk factor for heart failure (HF) development but is associated with a lower incidence of mortality in HF patients. This obesity paradox may be confounded by unrecognized comorbidities, including cachexia. Methods: A retrospective assessment was conducted using data from a prospectively recruiting multicenter registry, which included consecutive acute heart failure patients. A low, normal, and high body mass index (BMI) was defined as <20 kg/m2, 20–25 kg/m2, and ≥25 kg/m2, respectively. Cachexia was defined as a combination of BMI < 20 kg/m2 and any biochemical abnormalities including albumin, hemoglobin, or C-reactive protein. Patients with either of the three biochemical abnormalities were categorized as those with cachectic biomarkers. Two-year all-cause, cardiac, and noncardiac mortality were evaluated. Results: This study evaluated 3314 patients (mean BMI, 22 ± 4 kg/m2 [low BMI with cachexia, 828 (25%); low BMI without cachexia, 273 (8%); normal BMI, 1584 (48%); high BMI, 629 (19%)]). Overall, an increase of 1 point in BMI was associated with a decreased incidence of all-cause mortality (adjusted hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.90–0.94; p < 0.001). Regardless of the mode of death, the low BMI with cachexia indicated the worst prognosis, while the low BMI without cachexia showed a similar prognosis to the normal BMI. Cachectic biomarkers, which were observed more frequently in the low BMI, predicted a higher incidence of 2-year all-cause mortality across the BMI categories (adjusted HR for the low BMI, 1.90; 95% CI, 1.30–2.77; p = 0.001; adjusted HR for the normal BMI, 1.94; 95% CI, 1.34–2.79; p < 0.001; adjusted HR for the high BMI, 3.60; 95% CI, 1.61–8.08; p = 0.002). Conclusions: BMI could be only a surrogate marker. The cachectic biomarkers may reflect the underlying conditions and contribute to elucidating the obesity paradox. (Figure presented.)

BACKGROUND: Changes in N-terminal pro B-type natriuretic peptide (NT-proBNP) levels and cardiac remodeling from baseline to follow-up in patients with heart failure with reduced ejection fraction (HFrEF) treated with vericiguat remain unclear. METHODS AND RESULTS: The VERIFY-HF registry is a nationwide multicenter retrospective single-arm study of patients with HFrEF newly prescribed vericiguat at 22 hospitals in Japan. In this study, we analyzed baseline and follow-up echocardiography findings of 504 patients. Vericiguat dose-dependently reduced NT-proBNP levels, with a greater reduction in those receiving 7.5 or 10 than ≤5 mg vericiguat (NT-proBNP least-squares geometric mean ratio [3 months/baseline] 0.53 vs. 0.65, respectively; P=0.009). Multivariable analysis revealed that high-dose (7.5 or 10 mg) vericiguat was independently associated with a greater reduction in log-transformed NT-proBNP at 3 months (β=-0.125; 95% confidence interval [CI] -0.247, -0.004; P=0.043). High-dose vericiguat was not significantly associated with changes in left ventricular ejection fraction (LVEF) at 12 months (β=0.53; 95% CI -0.49, 1.6; P=0.30). Overall, reverse remodeling at 12 months was modest (LVEF, +4.7%; left ventricular end-systolic volume index, -6.4 mL/m2) and was predominantly associated with newly initiated β-blockers or renin-angiotensin system inhibitors within 3 months prior to vericiguat administration or prior heart failure hospitalization rather than vericiguat dose. CONCLUSIONS: In this real-world registry study, high-dose vericiguat was associated with sustained dose-dependent reductions in NT-proBNP, but not cardiac reverse remodeling.

Aims: Circulating microRNAs (miRNAs) are informative markers of heart failure (HF); however, sex differences in HF-associated miRNA changes remain unclear. We performed sex-stratified analyses to assess whether HF-associated circulating miRNA changes differ by sex in HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Methods and results: In this prospective multicentre cohort study in Japan, we analysed 235 participants, including 82 controls (41 males and 41 females), 76 patients with HFpEF (39 males and 37 females), and 77 patients with HFrEF (54 males and 23 females). Unbiased whole-blood miRNA sequencing detected 1767 unique miRNAs, of which 229 were retained for the primary analysis after abundance filtering. Age- and body mass index (BMI)-adjusted differential-expression analyses identified 50 miRNAs in males with HFpEF and 59 miRNAs in males with HFrEF, whereas no miRNAs reached statistical significance in females with either HF phenotype. Importantly, HF-associated log2 fold changes in males and females were positively correlated for both HF phenotypes, although the absolute magnitudes of change were greater in males than in females, indicating partly shared directions of change between sexes. Age- and BMI-adjusted permutational multivariate analysis of variance revealed more pronounced phenotype-associated differences in global miRNA profiles in males than in females; these findings were consistent across alternative abundance filters. Conclusion: Sex-stratified analyses of circulating miRNAs in HFpEF and HFrEF showed that HF-associated expression changes were consistently more pronounced in males than in females. These findings highlight the importance of sex stratification when interpreting circulating miRNA alterations in HF. Trial registration number: UMIN000052673 (UMIN Clinical Trials Registry; observational study)

BACKGROUND: – Acute decompensated heart failure (ADHF) exhibits seasonal variations, yet the short-term effects of ambient temperature, independent of seasonality, remain poorly studied. Moreover, temperature-sensitive exacerbation phenotypes are not well defined, limiting the development of effective preventive strategies. We aimed to investigate the effects of ambient temperature on ADHF admissions and clinical presentation profiles. METHODS: – We included 26 874 patients with ADHF who had been registered in the Tokyo Coronary Care Unit Network Database between January 2014 and December 2019. The onset date of ADHF leading to hospitalization, along with clinical characteristics such as age, left ventricular function, cause of ADHF, and hemodynamic profile, was assessed by cardiologists at each participating center. Climate data were obtained from an observatory near the admitting hospital. We used a time-stratified case-crossover design with distributed lag nonlinear models to explore the association between ambient temperature and ADHF admissions over lag days 0 to 5, with stratified analyses by the clinical presentations. RESULTS: – Exposure to extremely low temperatures (−4.5 °C [first percentile]) increased the risk of ADHF (1.80, 95% CI, 1.40–2.31) when referenced to the temperature of lowest risk (29.0 °C [99th percentile]). The excess risk of lower temperature appeared immediately on the day of exposure (lag 0). This risk was larger in patients aged ≥70 years and otherwise consistent across subgroups. Notably, the temperature-risk relationship differed by hemodynamic profiles; risk for ADHF with hypertension rose at low temperatures, whereas ADHF with low blood pressure showed the opposite pattern, with risk increasing at high temperatures (odds ratio, 6.25 [95% CI, 1.07–36.6] at the 99th percentile). CONCLUSIONS: – Low ambient temperature increased ADHF risk, especially in older adults, while temperature effects differed by hemodynamic phenotype. Incorporating temperature exposure into risk assessment may enable targeted prevention of climate-related decompensation. REGISTRATION: – URL: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000015310; Unique identifier: UMIN000013128.

Background: This prospective multicenter study assessed the prevalence of myocardial injury in patients with COVID-19 using cardiac magnetic resonance imaging (CMR). Methods and Results: We prospectively screened 505 patients with moderate to severe COVID-19 disease from 7 hospitals in Japan. Of these patients, 31 (mean [±SD] age 63.5±10.4 years, 23 [74%] male) suspected of myocardial injury, based on elevated serum troponin or B-type natriuretic peptide concentrations either upon admission or 3 months after discharge, underwent CMR 3 months after discharge. The primary endpoint was the presence of myocardial injury, defined by any of the following: (1) contrast enhancement in the left or right ventricle myocardium on late gadolinium enhancement CMR; (2) left or right ventricular dysfunction (defined as <50% and <45%, respectively); and (3) pericardial thickening on contrast enhancement. The mean (±SD) duration between diagnosis and CMR was 117±16 days. The primary endpoint was observed in 13 of 31 individuals (42%), with 8 (26%) satisfying the modified Lake Louise Criteria for the diagnosis of acute myocarditis. Conclusions: This study revealed a high incidence of myocardial injury identified by CMR in patients with moderate to severe COVID-19 and abnormal findings for cardiac biomarkers.

Introduction The current guidelines strongly recommend early initiation of multiple classes of cardioprotective drugs for patients with heart failure with reduced ejection fraction to improve prognosis and health status. However, evidence on the optimal sequencing of approved drugs is scarce, highlighting the importance of individualised treatment plans. Registry data indicate that only a portion of these patients can tolerate all four recommended classes, underscoring the need to establish the favoured sequence when using these drugs. Additionally, the choice between long-acting and short-acting loop diuretics in the present era remains uncertain. This is particularly relevant given the frequent use of angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter 2 inhibitor, both of which potentiate natriuretic effects. Methods and analysis In a prospective, randomised, open-label, blinded endpoint method, LAQUA-HF (Long-acting vs short-acting diuretics and neurohormonal Agents on patients' QUAlity-of-life in Heart Failure patients) will be a 2×2 factorial design, with a total of 240 patients randomised to sacubitril/valsartan versus dapagliflozin and torsemide versus furosemide in a 1:1 ratio. Most enrolment sites have participated in an ongoing observational registry for consecutive patients hospitalised for heart failure involved dedicated study coordinators, and used the same framework to enrol patients. The primary endpoint is the change in patients' health status over 6 months, defined by the Kansas City Cardiomyopathy Questionnaire. Additionally, clinical benefit at 6 months defined as a hierarchical composite endpoint will be assessed by the win ratio as the secondary endpoint. Ethics and dissemination The medical ethics committee Keio University in Japan has approved this trial. All participants provide written informed consent prior to study entry. The results of this trial will be disseminated in one main paper and additional papers on secondary endpoints and subgroup analyses. Trial registration number UMIN000045229

Background: Multidisciplinary self-care education plays a critical role in ensuring the high-quality transitional care of patients hospitalized due to heart failure (HF). However, whether confidence concerning self-care during their index hospitalizations would influence their post-discharge self-care performances and long-term outcomes remains uncertain. Methods: We conducted an assessment of 100 consecutive patients with HF who completed self-care questionnaires both during their hospitalizations and 1 year after discharge. Among these patients hospitalized due to HF, self-care confidence was assessed immediately after they completed their pre-discharge education program. One year after the index hospitalization, we evaluated self-care performance by using the European Heart Failure Self-care Behavior Scale. Logistic regression analysis was employed to identify determinants of poor self-care behavior 1 year after the hospitalization. Additionally, the Cox proportional hazards model with adjustment for the Seattle Heart Failure Model was applied to assess their association with 2-year mortality and readmission risk. Results: The enrolled patients predominantly had HF with reduced ejection fraction (43.0%), and approximately half of the patients had experienced a previous hospitalization due to HF (47.0%). The 3 worst-performing aspects of post-discharge self-care behavior (among the 12 items) were appropriate consultation for fatigue (40.0%), weight gain (52.0%) and application of regular exercise (57.0%). After adjustment, low self-care confidence during the index hospitalization was associated with poor post-discharge self-care performance (OR: 1.11, CI: 1.00–1.21). Poor post-discharge self-care behavior was not associated with worse prognoses over a 2-year follow-up (hazard ratio [HR]: 1.82, CI: 0.85–3.86); however, the association was significant in patients with reduced ejection fraction (HR: 4.04, CI: 1.17–13.89) and previous HF hospitalization (HR: 3.66, CI: 1.46–9.13). Conclusions: Post-discharge self-care performance was associated with self-care confidence during the index HF hospitalization. Effective measures that improve pre-discharge confidence levels in self-care should be considered to enhance the quality of transitional care.

Background: Precise risk stratification in heart failure (HF) patients enables clinicians to tailor the intensity of their management. The Seattle Heart Failure Model (SHFM), which uses conventional clinical variables for its prediction, is widely used. We aimed to externally validate SHFM in Japanese HF patients with a recent episode of acute decompensation requiring hospital admission. Methods and Results: SHFM was applied to 2470 HF patients registered in the West Tokyo Heart Failure and National Cerebral And Cardiovascular Center Acute Decompensated Heart Failure databases from 2006 to 2016. Discrimination and calibration were assessed with the use of the c-statistic and calibration plots, respectively, in HF patients with reduced ejection fraction (HFrEF; <40%) and preserved ejection fraction (HFpEF; ≥40%). In a perfectly calibrated model, the slope and intercept would be 1.0 and 0.0, respectively. The method of intercept recalibration was used to update the model. The registered patients (mean age 74 ± 13 y) were predominantly men (62%). Overall, 572 patients (23.2%) died during a mean follow-up of 2.1 years. Among HFrEF patients, SHFM showed good discrimination (c-statistic = 0.75) but miscalibration, tending to overestimate 1-year survival (slope = 0.78; intercept = −0.22). Among HFpEF patients, SHFM showed modest discrimination (c-statistic = 0.69) and calibration, tending to underestimate 1-year survival (slope = 1.18; intercept = 0.16). Intercept recalibration (replacing the baseline survival function) successfully updated the model for HFrEF (slope = 1.03; intercept = −0.04) but not for HFpEF patients. Conclusions: In Japanese acute HF patients, SHFM showed adequate performance after recalibration among HFrEF patients. Using prediction models to tailor the care for HF patients may improve the allocation of medical resources.

Aims: The precise outcomes for patients with residual pulmonary hypertension (PH) following the optimized treatment of acute decompensated heart failure (ADHF) remain poorly understood. This study aimed to investigate the prognostic association of PH, categorized according to left ventricular ejection fraction (LVEF), in hospitalized ADHF patients. Methods and results: The WET-HF registry is a multicentre, prospective cohort ADHF registry. Patients were classified into four groups according to tricuspid regurgitation velocity (TRV) and LVEF. PH was defined as peak TRV >2.8 m/s. The primary endpoint was a composite of all-cause mortality and heart failure (HF) rehospitalization at 2 years. In total, 1702 patients had nonPH-HF with LVEF <50% (n = 689 [40.5%]), PH-HF with LVEF <50% (n = 291 [17.1%]), nonPH-HF with LVEF ≥50% (n = 453 [26.6%]), and PH-HF with LVEF ≥50% (n = 269 [15.8%]). A significant difference in the composite endpoint was observed between patients with and without PH (42.3% vs. 30.4%, p < 0.001), with no significant interaction between PH and LVEF. Notably, in the nonPH-HF group, there were significant differences in clinical outcomes between patients with more than 30% B-type natriuretic peptide (BNP) improvement and those with less (composite endpoint 27.5% vs. 41.8%, p < 0.001; all-cause mortality 9.4% vs. 24.6%, p < 0.001; HF rehospitalization 20.2% vs. 32.8%, p = 0.001). However, no such difference was evident in the PH-HF group. Conclusions: The prognostic importance of residual PH was comparable across both HF with reduced and preserved ejection fraction patients. While the prognostic significance of BNP improvement on clinical outcomes was attenuated in the presence of residual PH, utilizing residual PH for risk stratification effectively identified patients at increased risk of mortality and rehospitalization following ADHF, irrespective of their LVEF.

© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology Aims: Prognostic models for hospitalized heart failure (HHF) were developed predominantly for patients of European origin in the United States of America; it is unclear whether they perform similarly in other health care systems or for different ethnicities. We sought to validate published prediction models for HHF in the United Kingdom (UK) and Japan. Methods and results: Patients in the UK (n =894) and Japan (n =3158) were prospectively enrolled and were similar in terms of sex (∼60% men) and median age (∼77 years). Models predicted that British patients would have a higher mortality than Japanese, which was indeed true both for in-hospital (4.8% vs. 2.5%) and 180-day (20.7% vs. 9.5%) mortality. The model c-statistics for the published/derivation (range 0.70–0.76) and Japanese (range 0.75–0.77) cohorts were similar and higher than for the UK (0.62–0.75) but models consistently overestimated mortality in Japan. For in-hospital mortality, the OPTIMIZE-HF model performed best, providing similar discrimination in published/derivation, UK and Japanese cohorts [c-indices: 0.75 (0.74–0.77); 0.75 (0.68–0.81); and 0.77 (0.70–0.83), respectively], and least overestimated mortality in Japan. For 180-day mortality, the c-statistics for the ASCEND-HF model were similar in published/derivation (0.70) and UK [0.69 (0.64–0.74)] cohorts but higher in Japan [0.75 (0.71–0.79)]; calibration was good in the UK but again overestimated mortality in Japan. Conclusion: Calibration of published prediction models appears moderately accurate and unbiased when applied to British patients but consistently overestimates mortality in Japan. Identifying the reason why patients in Japan have a better than predicted prognosis is of great interest.

Acute heart failure (AHF) has become a global public health burden largely because of the associated high morbidity, mortality, and cost. The treatment options for AHF have remained relatively unchanged over the past decades. Historically, clinical congestion alone has been considered the main target for treatment of acute decompensation in patients with AHF; however, this is an oversimplification of the complex pathophysiology. Within the similar clinical presentation of congestion, significant differences in pathophysiological mechanisms exist between the fluid accumulation and redistribution. Tissue hypoperfusion is another vital characteristic of AHF and should be promptly treated with appropriate interventions. In addition, recent clinical trials of novel therapeutic strategies have shown that heart failure management is ‘time sensitive’ and suggested that treatment selection based on individual aetiologies, triggers, and risk factor profiles could lead to better outcomes. In this review, we aim to describe the specifics of the ‘time-sensitive’ approach by the clinical phenotypes, for example, pulmonary/systemic congestion and tissue hypoperfusion, wherein patients are classified based on pathophysiological conditions. This mechanistic classification, in parallel with the comprehensive risk assessment, has become a cornerstone in the management of patients with AHF and thus supports effective decision making by clinicians. We will also highlight how therapeutic modalities should be individualized according to each clinical phenotype.

Aims: Furosemide, a short-acting loop diuretic (SD), is the dominant agent prescribed for heart failure (HF) in clinical practice. However, accumulating data suggests that long-acting loop diuretics (LD), such as torsemide or azosemide, might have more favourable pharmacological profiles. This study aimed to investigate the relationship between the type of loop diuretics and long-term outcomes among patients hospitalized for acute HF enrolled in a contemporary multicentre registry. Methods and results: Within the West Tokyo Heart Failure Registry from 2006 to 2017, a total of 2680 patients (60.1% men with a median age of 77 years) were analysed. The patients were characterized by the type of diuretics used at the time of discharge; 2073 (77.4%) used SD, and 607 (22.6%) used LD. The primary endpoint was composite of all-cause death or HF re-admission after discharge, and the secondary endpoints were all-cause death and HF re-admission, respectively. During the median follow-up period of 2.1 years, 639 patients died [n = 519 (25.0%) in the SD group; n = 120 (19.8%) in the LD group], and 868 patients were readmitted for HF [n = 697 (33.6%) in the SD group; n = 171 (28.2%) in the LD group]. After multivariable adjustment, the LD group had lower risk for the composite outcome [hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.66–0.96; P = 0.017], including all-cause death (HR; 0.73; 95% CI; 0.54–0.99; P = 0.044) and HF re-admission (HR, 0.81; 95% CI, 0.66–0.99; P = 0.038), than the SD group. Propensity score matching yielded estimates that were consistent with those of the multivariable analyses, with sub-group analyses demonstrating that use of LD was associated with favourable outcomes predominantly in younger patients with reduced ejection fraction. Conclusions: LD was associated with lower risk of long-term outcomes in patients with HF and a recent episode of acute decompensation.

BACKGROUND: This retrospective observational study investigated the incidence of worsening renal function (WRF) in patients hospitalized for heart failure (HF) and treated with intravenous diuretics in Japan.Methods and Results: Associations between WRF at any point and HF treatments, and the effects of WRF on outcomes were evaluated (Diagnosis Procedure Combination database). Of 1,788 patients analyzed (mean [±SD] age 80.5±10.2 years; 54.4% male), 641 (35.9%) had WRF during a course of hospitalization for worsening HF: 208 (32.4%) presented with WRF before admission (BA-WRF; estimated glomerular filtration rate decreased by ≥25% from baseline at least once between 30 days prior to admission and admission); 44 (6.9%) had WRF that persisted before and after admission (P-WRF); and 389 (60.7%) had WRF develop after admission (AA-WRF). Delayed initial diuretic administration, higher maximum doses of intravenous diuretics during hospitalization, and diuretic readministration during hospitalization were associated with a significantly higher incidence of AA-WRF. Patients with WRF at any time point were at higher risk of death during hospitalization compared with patients without WRF, with adjusted hazard ratios of 3.56 (95% confidence interval [CI] 2.23-5.69) for BA-WRF, 3.23 (95% CI 2.21-4.71) for AA-WRF, and 13.16 (95% CI 8.19-21.15) for P-WRF (all P<0.0001). CONCLUSIONS: Forty percent of WRF occurred before admission for acute HF; there was no difference in mortality between patients with BA-WRF and AA-WRF.