Prognostic Value of Objective Social Isolation and Loneliness in Older Patients With Heart Failure: Subanalysis of FRAGILE-HF and Kitasato Cohort.

BACKGROUND: Social factors encompass a broad spectrum of nonmedical factors, including objective (social isolation [SI]) and perceived (loneliness) conditions. Although social factors have attracted considerable research attention, information regarding their impact on patients with heart failure is scarce. We aimed to investigate the prognostic impact of objective SI and loneliness in older patients with heart failure. METHODS AND RESULTS: This study was conducted using the FRAGILE-HF (Prevalence and Prognostic Value of Physical and Social Frailty in Geriatric Patients Hospitalized for Heart Failure; derivation cohort) and Kitasato cohorts (validation cohort), which included hospitalized patients with heart failure aged ≥65 years. Objective SI and loneliness were defined using the Japanese version of Lubben Social Network Scale-6 and diagnosed when the total score for objective and perceived questions on the Lubben Social Network Scale-6 was below the median in the FRAGILE-HF. The primary outcome was 1-year death. Overall, 1232 and 405 patients in the FRAGILE-HF and Kitasato cohorts, respectively, were analyzed. Objective SI and loneliness were observed in 57.8% and 51.4% of patients in the FRAGILE-HF and 55.4% and 46.2% of those in the Kitasato cohort, respectively. During the 1-year follow-up, 149 and 31 patients died in the FRAGILE-HF and Kitasato cohorts, respectively. Cox proportional hazard analysis revealed that objective SI, but not loneliness, was significantly associated with 1-year death after adjustment for conventional risk factors in the FRAGILE-HF. These findings were consistent with the validation cohort. CONCLUSIONS: Objective SI assessed using the Lubben Social Network Scale-6 may be a prognostic indicator in older patients with heart failure. Given the lack of established SI assessment methods in this population, further research is required to refine such methods.

Bendopnea prevalence and prognostic value in older patients with heart failure: FRAGILE-HF-SONIC-HF post hoc analysis.

AIMS: This study aimed to investigate the prevalence, clinical characteristics, and prognostic value of bendopnea in older patients hospitalized for heart failure. METHODS: This post hoc analysis was performed using two prospective, multicenter, observational studies: the FRAGILE-HF (main cohort) and SONIC-HF (validation cohort) cohorts. Patients were categorized based on the presence of bendopnea, which was evaluated before discharge. The primary endpoint was 2-year all-cause mortality after discharge. RESULTS: Among the 1,243 patients (median age, 81 years; 57.2% male) in the FRAGILE-HF cohort and 225 (median age, 79 years; 58.2% men) in the SONIC-HF cohort, bendopnea was observed in 31 (2.5%) and 10 (4.4%) patients, respectively. Over a 2-year follow-up period, all-cause death occurred in 20.8% and 21.9% of the patients in the FRAGILE-HF and SONIC-HF cohorts, respectively. Kaplan-Meier survival curves demonstrated significantly higher mortality rates in patients with bendopnea than in those without bendopnea in the FRAGILE-HF (log-rank P = 0.006) and SONIC-HF cohorts (log-rank P = 0.014). Cox proportional hazard analysis identified bendopnea as an independent prognostic factor for all-cause mortality in both the FRAGILE-HF (hazard ratio [HR] 2.11, 95% confidence interval [CI] 1.18-3.78, P = 0.012) and SONIC-HF cohorts (HR 4.20, 95% CI 1.63-10.79, P = 0.003), even after adjusting for conventional risk factors. CONCLUSIONS: Bendopnea was observed in a relatively small proportion of older patients hospitalized for heart failure before discharge. However, its presence was significantly associated with an increased risk of all-cause mortality.

This study investigated how common it is for older patients with heart failure to have trouble breathing when they bend forward, and whether this affects their chances of survival. The study found that although this problem is not very common, it is linked to a higher risk of death. Key findings: Only a small number of older patients with heart failure have trouble breathing when they bend forward.However, those who do have this problem are more likely to die.

Chronic Effects of Adaptive Servo-Ventilation Therapy on Mortality and the Urgent Rehospitalization Rate in Patients Experiencing Recurrent Admissions for Heart Failure　- A Multicenter Prospective Observational Study (SAVIOR-L).

BACKGROUND: This study investigated whether the chronic use of adaptive servo-ventilation (ASV) reduces all-cause mortality and the rate of urgent rehospitalization in patients with heart failure (HF).Methods and Results: This multicenter prospective observational study enrolled patients hospitalized for HF in Japan between 2019 and 2020 who were treated either with or without ASV therapy. Of 845 patients, 110 (13%) received chronic ASV at hospital discharge. The primary outcome was a composite of all-cause death and urgent rehospitalization for HF, and was observed in 272 patients over a 1-year follow-up. Following 1:3 sequential propensity score matching, 384 patients were included in the subsequent analysis. The median time to the primary outcome was significantly shorter in the ASV than in non-ASV group (19.7 vs. 34.4 weeks; P=0.013). In contrast, there was no significant difference in the all-cause mortality event-free rate between the 2 groups. CONCLUSIONS: Chronic use of ASV did not impact all-cause mortality in patients experiencing recurrent admissions for HF.

Impact of Multidomain Frailty on the Mode of Death in Older Patients With Heart Failure: A Cohort Study.

BACKGROUND: Although frailty is strongly associated with mortality in patients with heart failure (HF), the risk of which specific cause of death is associated with being complicated with frailty is unclear. We aimed to clarify the association between multidomain frailty and the causes of death in elderly patients hospitalized with HF. METHODS: We analyzed data from the FRAGILE-HF cohort, where patients aged 65 years and older, hospitalized with HF, were prospectively registered between 2016 and 2018 in 15 Japanese hospitals before discharge and followed up for 2 years. All patients were assessed for physical, social, and cognitive dysfunction, and categorized into 3 groups based on their number of frailty domains (FDs, 0-1, 2, and 3). Kaplan-Meier survival analysis was used to evaluate the association between the number of FDs and all-cause mortality, whereas Fine-Gray competing risk regression analysis was used for assessing the impact on cause-specific mortality. RESULTS: We analyzed 1181 patients with HF (81 years old in median, 57.4% were male), 530 (44.9%), 437 (37.0%), and 214 (18.1%) of whom were categorized into the FD 0 to 1, FD 2, and FD 3 groups, respectively. During the 2-year follow-up, 240 deaths were observed (99 HF deaths, 34 cardiovascular deaths, and 107 noncardiovascular deaths), and an increase in the number of FD was significantly associated with mortality (Log-rank: P<0.001). The Fine-Gray competing risk analysis adjusted for age and sex showed that FDs 2 (subdistribution hazard ratio, 1.77 [95% CI, 1.11-2.81]) and 3 (2.78, [95% CI, 1.69-4.59]) groups were associated with higher incidence of noncardiovascular death but not with HF and other cardiovascular deaths. CONCLUSIONS: Although multidomain frailty is strongly associated with mortality in older patients with HF, it is mostly attributable to noncardiovascular death and not cardiovascular death, including HF death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: UMIN000023929.

Cardiac Troponin and Treatment Effects of Omecamtiv Mecarbil: Results From the GALACTIC-HF Study.

BACKGROUND: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329). METHODS: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil. RESULTS: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2). CONCLUSIONS: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI.

Prognostic impact of MitraScore in elderly Asian patients with heart failure: sub-analysis of FRAGILE-HF.

AIMS: MitraScore is a novel, simple, and manually calculatable risk score developed as a prognostic model for patients undergoing transcatheter edge-to-edge repair (TEER) for mitral regurgitation. As its components are considered prognostic in heart failure (HF), we aimed to investigate the usefulness of the MitraScore in HF patients. METHODS AND RESULTS: We calculated MitraScore for 1100 elderly patients (>65 years old) hospitalized for HF in the prospective multicentre FRAGILE-HF study and compared its prognostic ability with other simple risk scores. The primary endpoint was all-cause deaths, and the secondary endpoints were the composite of all-cause deaths and HF rehospitalization and cardiovascular deaths. Overall, the mean age of 1100 patients was 80 ± 8 years, and 58% were men. The mean MitraScore was 3.2 ± 1.4, with a median of 3 (interquartile range: 2-4). A total of 326 (29.6%), 571 (51.9%), and 203 (18.5%) patients were classified into low-, moderate-, and high-risk groups based on the MitraScore, respectively. During a follow-up of 2 years, 226 all-cause deaths, 478 composite endpoints, and 183 cardiovascular deaths were observed. MitraScore successfully stratified patients for all endpoints in the Kaplan-Meier analysis (P < 0.001 for all). In multivariate analyses, MitraScore was significantly associated with all endpoints after covariate adjustments [adjusted hazard ratio (HR) (95% confidence interval): 1.22 (1.10-1.36), P < 0.001 for all-cause deaths; adjusted HR 1.17 (1.09-1.26), P < 0.001 for combined endpoints; and adjusted HR 1.24 (1.10-1.39), P < 0.001 for cardiovascular deaths]. The Hosmer-Lemeshow plot showed good calibration for all endpoints. The net reclassification improvement (NRI) analyses revealed that the MitraScore performed significantly better than other manually calculatable risk scores of HF: the GWTG-HF risk score, the BIOSTAT compact model, the AHEAD score, the AHEAD-U score, and the HANBAH score for all-cause and cardiovascular deaths, with respective continuous NRIs of 0.20, 0.22, 0.39, 0.39, and 0.29 for all-cause mortality (all P-values < 0.01) and 0.20, 0.22, 0.42, 0.40, and 0.29 for cardiovascular mortality (all P-values < 0.02). CONCLUSIONS: MitraScore developed for patients undergoing TEER also showed strong discriminative power in HF patients. MitraScore was superior to other manually calculable simple risk scores and might be a good choice for risk assessment in clinical practice for patients receiving TEER and those with HF.

Predictive value of the Ishii score for sarcopenia and the prognosis of older patients hospitalized with heart failure.

AIMS: Although sarcopenia is common and associated with poor outcomes in patients with heart failure, its simple screening methods remain unclear. We aimed to investigate the predictive value of the Ishii score, which includes age, grip strength, and calf circumference, for sarcopenia and its prognostic predictability in patients with heart failure. METHODS: This was a subanalysis of the FRAGILE-HF study. Receiver operating characteristic curves were used to evaluate the predictive value for sarcopenia. Patients were stratified into the high and low Ishii score groups based on the cutoff values of the Ishii score determined by the Youden index for sarcopenia, and the 1-year mortality rates were compared. RESULTS: Of the 1262 study participants, 936 were evaluated with sarcopenia, and 184 (55 women, 129 men) were diagnosed with sarcopenia. The areas under the receiver operating characteristic curves for sarcopenia were 0.73 and 0.87 for women and men, respectively. The optimal cutoff values for predicting sarcopenia were 165 and 141 for women and men, respectively. Using these cutoff values, the sensitivity and specificity for sarcopenia were 70.9% and 68.5% for women and 88.4% and 69.7% for men, respectively. At 1 year, 151 (low Ishii score group, 98; high Ishii score group, 53) deaths were observed. Adjusted Cox proportional hazards analysis showed that the high Ishii score group was significantly associated with 1-year mortality. CONCLUSION: Among older patients hospitalized for heart failure, the Ishii score is useful for predicting sarcopenia and 1-year mortality. Geriatr Gerontol Int 2024; 24: 147-153.

Association and Prognostic Value of Multidomain Frailty Defined by Cumulative Deficit and Phenotype Models in Patients With Heart Failure.

BACKGROUND: Frailty is associated with a poor prognosis in older patients with heart failure (HF). However, multidomain frailty assessment tools have not been established in patients with HF, and the association between the frailty phenotype and the deficit-accumulation frailty index in these patients is unclear. We aimed to understand this relationship and evaluate the prognostic value of the deficit-accumulation frailty index in older patients with HF. METHODS: We retrospectively analyzed FRAGILE-HF cohort, which consisted of prospectively registered hospitalized patients with HF aged ≥ 65 years. The frailty index was calculated using 34 health-related items. The physical, social, and cognitive domains of frailty were evaluated using a phenotypic approach. The primary endpoint was all-cause mortality. RESULTS: Among 1027 patients with HF (median age, 81 years; male, 58.1%; median frailty index, 0.44), a higher frailty index was associated with a higher prevalence in all domains of cognitive, physical, and social frailty defined by the phenotype model. During the 2-year follow-up period, a higher frailty index was independently associated with all-cause death even after adjustment for Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score plus log B-type natriuretic peptide (per 0.1 increase: hazard ratio, 1.21; 95% confidence interval, 1.07-1.37; P = 0.002). The addition of the frailty index to the baseline model yielded statistically significant incremental prognostic value (net reclassification improvement, 0.165; 95% confidence interval, 0.012-0.318; P = 0.034). CONCLUSIONS: A higher frailty index was associated with a higher prevalence of all domains of frailty defined by the phenotype model and provided incremental prognostic information with pre-existing risk factors in older patients with HF.

Empagliflozin cost-effectiveness analysis in Japanese heart failure with mildly reduced and preserved ejection fraction.

AIMS: Empagliflozin, a sodium-glucose co-transporter 2 inhibitor, was shown to be effective in patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial. The present study aims to evaluate the cost-effectiveness of empagliflozin among Japanese patients with HFpEF. METHODS AND RESULTS: A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin added to standard of care (SoC) compared with SoC alone in patients with HFpEF from the perspective of the Japanese healthcare system and with a lifetime horizon. In addition to clinical events, the progression of disease severity was modelled based on the migration of Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores (KCCQ-CSS). Model inputs, including risk of clinical events, costs, and utilities/disutilities, were derived from EMPEROR-Preserved trial data, a claims database and published literature. The generalizability of model results was investigated by applying various subgroups including age, body mass index (BMI), and region Asia, based on the subgroup analysis of EMPEROR-Preserved data. In the base-case analysis, empagliflozin yielded additional quality-adjusted life years (QALYs; 0.11) with an incremental cost of $1408 per patient for Japanese patients with HFpEF. Incremental cost, mainly derived from drug acquisition cost ($1963 per patient), was largely offset by reduced cost in hospitalization for heart failure (HHF) and cardiovascular death (-$537 per patient and -$166 per patient, respectively). Treatment of empagliflozin provided incremental 0.11 QALYs and 0.08 life years compared with SoC alone. The incremental cost-effectiveness ratio (ICER) was $12 772 (¥1 662 689)/QALY, which was below the Japanese willingness-to-pay (WTP) threshold of $38 408 (¥5 000 000)/QALY. The results were consistent across all the subgroups considered, and empagliflozin was dominant over SoC alone in the region Asia and BMI < 25 kg/m2 subgroups. ICERs for the remaining subgroups ranged from $7520/QALY (¥978 972/QALY, patients with baseline age ≥ 75 years) to $31 049/QALY (¥4 041 896/QALY, patients with baseline New York Heart Association class III/IV). Deterministic sensitivity analysis result showed that the treatment effect on HHF is the biggest driver of the cost-effectiveness analysis, while the ICER will be still under the threshold even if no effect of empagliflozin on HHF was assumed. The probabilistic sensitivity analysis result showed that 64% of simulations were cost-effective based on the Japanese WTP threshold. CONCLUSIONS: Empagliflozin was demonstrated to be cost-effective for patients with HFpEF in Japan based on EMPEROR-Preserved trial data.

Efficacy and Safety of Sacubitril/Valsartan in Japanese Patients With Heart Failure According to Baseline Systolic Blood Pressure　- Results From a Subgroup Analysis of the PARALLEL-HF Study.

BACKGROUND: Lower systolic blood pressure (SBP) is known to be associated with poor prognosis in heart failure (HF). We evaluated the efficacy and safety of sacubitril/valsartan according to baseline SBP tertiles in Japanese patients from the PARALLEL-HF study.Methods and Results: In all, 223 patients were stratified into tertiles according to baseline SBP (≤114 mmHg: n=75; >114 and ≤130 mmHg: n=76; and >130 mmHg: n=72). Patients with lower SBP (≤114 mmHg) had the highest median N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations at baseline (P=0.0184). No significant difference was observed between sacubitril/valsartan and enalapril for the composite outcome of cardiovascular death and HF hospitalization across SBP tertiles (P-interaction=0.2682). Although the P-interaction value was not significant (0.2106), a greater reduction in NT-proBNP with sacubitril/valsartan compared with enalapril was observed in patients with SBP >130 mmHg (P=0.0076). The incidence of hypotension-related events and reduction or discontinuation of treatment due to hypotension-related events was higher in the lower SBP subgroup, and these events were more frequent in the sacubitril/valsartan than enalapril group. CONCLUSIONS: The efficacy of sacubitril/valsartan compared with enalapril was consistent across baseline SBP tertiles in Japanese patients from the PARALLEL-HF study. Hypotension-related events were more common in patients treated with sacubitril/valsartan with lower SBP.

Clinical Use of Oral Opioid Therapy for Dyspnea in Patients With Advanced Heart Failure　- A Single-Center Retrospective Study.

Background: For patients with advanced heart failure, palliative care, including opioids, is needed as a treatment for refractory dyspnea. However, little evidence has been reported on the efficacy and safety of opioids, and their use is not well established. Methods and Results: We have introduced a protocol for the use of opioids for dyspnea in patients with advanced heart failure admitted to Saitama Citizens Medical Center. Following this protocol, differences in clinical variables and outcome were investigated between patients in whom opioids were initiated intravenously or subcutaneously (i.v./s.c. group; n=13) and patients in whom they were initiated orally (oral group; n=18). In a comparison of baseline characteristics, significantly more patients in the oral group had a history of hospitalization for heart failure within the past year, and significantly more patients were treated with dobutamine and tolvaptan. After initiation of opioid treatment, both groups showed improvement in dyspnea; however, serial changes in vital signs were significantly greater in the i.v./s.c. group. The survival rate was significantly higher in the oral group (P<0.0001), with 33% of patients discharged alive. Conclusions: The clinical use of oral opioids using a single-center protocol is reported, suggesting that oral opioids may be practical and effective for dyspnea in patients with advanced heart failure.

Long-Term Treatment With Sacubitril/Valsartan in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction　- Open-Label Extension of the PARALLEL-HF Study.

BACKGROUND: The PARALLEL-HF study assessed the efficacy and safety of sacubitril/valsartan vs. enalapril in Japanese patients with chronic heart failure with reduced ejection fraction (HFrEF). This open-label extension (OLE) assessed long-term safety with sacubitril/valsartan.Methods and Results: This study enrolled 150 patients who received sacubitril/valsartan 50 or 100 mg, b.i.d., in addition to optimal background heart failure (HF) therapy. A dose level of sacubitril/valsartan 200 mg, b.i.d., was targeted by Week 8. At OLE baseline, higher concentrations of B-type natriuretic peptide (BNP) and urine cGMP, and lower concentrations of N-terminal pro B-type natriuretic peptide (NT-proBNP), were observed in the sacubitril/valsartan core group (patients who received sacubitril/valsartan in both the core and extension study) than in the enalapril core group (patients who received enalapril in the core study and were then transitioned to sacubitril/valsartan). The mean exposure to study drug was 98.9%. There was no trend of worsening of HF at Month 12. No obvious changes in cardiac biomarkers were observed, whereas BNP and urine cGMP increased and NT-proBNP decreased in the enalapril core group, which was evident at Weeks 2-4 and sustained to Month 12. CONCLUSIONS: Long-term sacubitril/valsartan at doses up to 200 mg, b.i.d., has a positive risk-benefit profile; it was safe and well tolerated in Japanese patients with chronic HFrEF.

Clinical outcomes of chronic heart failure patients with unsuppressed sleep apnea by positive airway pressure therapy.

Introduction: Heart failure (HF) is an advanced stage of cardiac disease and is associated with a high rate of mortality. Previous studies have shown that sleep apnea (SA) is associated with a poor prognosis in HF patients. Beneficial effects of PAP therapy that is effective on reducing SA on cardiovascular events, were not yet established. However, a large-scale clinical trial reported that patients with central SA (CSA) which was not effectively suppressed by continuous positive airway pressure (CPAP) revealed poor prognosis. We hypothesize that unsuppressed SA by CPAP is associated with negative consequences in patients with HF and SA, including either obstructive SA (OSA) or CSA. Methods: This was a retrospective observational study. Patients with stable HF, defined as left ventricular ejection fraction of ≤50%; New York Heart Association class ≥ II; and SA [apnea-hypopnea index (AHI) of ≥15/h on overnight polysomnography], treated with CPAP therapy for 1 month and performed sleep study with CPAP were enrolled. The patients were classified into two groups according to AHI on CPAP (suppressed group: residual AHI ≥ 15/h; and unsuppressed group: residual AHI < 15/h). The primary endpoint was a composite of all-cause death and hospitalization for HF. Results: Overall, data of 111 patients including 27 patients with unsuppressed SA, were analyzed. The cumulative event-free survival rates were lower in the unsuppressed group during a period of 36.6 months. A multivariate Cox proportional hazard model showed that the unsuppressed group was associated with an increased risk for clinical outcomes (hazard ratio 2.30, 95% confidence interval 1.21-4.38, p = 0.011). Conclusion: Our study suggested that in patients with HF and SA including either OSA or CSA, presence of unsuppressed SA even on CPAP was associated with worse prognosis as compared to those with suppressed SA by CPAP.

Prognostic impact of cachexia by multi-assessment in older adults with heart failure: FRAGILE-HF cohort study.

BACKGROUND: Cachexia substantially impacts the prognosis of patients with heart failure (HF); however, there is no standard method for cachexia diagnosis. This study aimed to investigate the association of Evans's criteria, consisting of multiple assessments, with the prognosis of HF in older adults. METHODS: This study is a secondary analysis of the data from the FRAGILE-HF study, a prospective multicentre cohort study that enrolled consecutive hospitalized patients aged ≥65 years with HF. Patients were divided into two groups: the cachexia and non-cachexia groups. Cachexia was defined according to Evans's criteria by assessing weight loss, muscle weakness, fatigue, anorexia, a decreased fat-free mass index and an abnormal biochemical profile. The primary outcome was all-cause mortality, as assessed in the survival analysis. RESULTS: Cachexia was present in 35.5% of the 1306 enrolled patients (median age [inter-quartile range], 81 [74-86] years; 57.0% male); 59.6%, 73.2%, 15.6%, 71.0%, 44.9% and 64.6% had weight loss, decreased muscle strength, a low fat-free mass index, abnormal biochemistry, anorexia and fatigue, respectively. All-cause mortality occurred in 270 patients (21.0%) over 2 years. The cachexia group (hazard ratio [HR], 1.494; 95% confidence interval [CI], 1.173-1.903; P = 0.001) had a higher mortality risk than the non-cachexia group after adjusting for the severity of HF. Cardiovascular and non-cardiovascular deaths occurred in 148 (11.3%) and 122 patients (9.3%), respectively. The adjusted HRs for cachexia in cardiovascular mortality and non-cardiovascular mortality were 1.456 (95% CI, 1.048-2.023; P = 0.025) and 1.561 (95% CI, 1.086-2.243; P = 0.017), respectively. Among the cachexia diagnostic criteria, decreased muscle strength (HR, 1.514; 95% CI, 1.095-2.093; P = 0.012) and low fat-free mass index (HR, 1.424; 95% CI, 1.052-1.926; P = 0.022) were significantly associated with high all-cause mortality, but there was no significant association between weight loss alone (HR, 1.147; 95% CI, 0.895-1.471; P = 0.277) and all-cause mortality. CONCLUSIONS: Cachexia evaluated by multi-assessment was present in one third of older adults with HF and was associated with a worse prognosis. A multimodal assessment of cachexia may be helpful for risk stratification in older patients with HF.

Teneligliptin, a DPP-4 Inhibitor, Improves Vascular Endothelial Function via Divergent Actions Including Changes in Circulating Endothelial Progenitor Cells.

Purpose: Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endothelial progenitor cells (EPCs) in peripheral blood circulation. However, the underlying mechanisms and effects on vascular endothelial function remain unclear. We evaluated whether the DPP-4 inhibitor teneligliptin increases circulating EPCs by inhibiting stromal-derived factor-1α (SDF-1α) and improves flow-mediated vascular dilatation (FMD) in type 2 diabetes mellitus patients with acute coronary syndrome (ACS) or its risk factors. Patients and Methods: This single-center, open-label, prospective, randomized controlled trial evaluated 17 patients (hemoglobin A1c ≤7.5% and peak creatinine phosphokinase <2000 IU/mL) with ACS or a history of ACS or multiple cardiovascular risk factors. Metabolic variables of glucose and lipids, circulating EPCs, plasma DPP-4 activity, and SDF-1α levels, and FMD were evaluated at baseline and 28 ± 4 weeks after enrollment. Patients were randomly assigned to either the teneligliptin (n = 8) or control (n = 9) groups. Results: The DPP-4 activity (∆-509.5 ± 105.7 vs ∆32.8 ± 53.4 µU/mL) and SDF-1α levels (∆-695.6 ± 443.2 vs ∆11.1 ± 193.7 pg/mL) were significantly decreased after 28 weeks in the teneligliptin group than those in the control group. The number of EPCs showed an increasing trend in the teneligliptin treated group; albeit this did not reach statistical significance. Glucose and lipid levels were not significantly different between the groups before and after 28 weeks. However, FMD was significantly improved in the teneligliptin group when compared to the control group (∆3.8% ± 2.1% vs ∆-0.3% ± 2.9%, P=0.006). Conclusion: Teneligliptin improved FMD through a mechanism other than increasing the number of circulating EPCs.

Cost-effectiveness analysis of empagliflozin in patients with heart failure with reduced ejection fraction in Japan based on the EMPEROR-Reduced trial.

BACKGROUND: Several studies have reported the cost-effectiveness of sodium-glucose co-transporter 2 inhibitors in heart failure patients; however, their economic implications have not been sufficiently elucidated in Japan. METHODS: A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin plus standard of care (SoC) vs. SoC for patients with heart failure with reduced ejection fraction (HFrEF) in Japan. Model inputs, including risk of clinical events, costs, and utilities based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores were derived from EMPEROR-Reduced trial data, published literature, and a claims database. RESULTS: The model predicted lower lifetime hospitalizations for heart failure (HHFs) and additional quality-adjusted life-years (QALYs; 0.21) for empagliflozin plus SoC vs. SoC in the overall population. Increased costs of ¥100,495/patient ($772/patient), primarily driven by higher drug costs of ¥239,558/patient ($1,840/patient), were largely offset by reduced HHF management costs of -¥166,160/patient (-$1,276/patient), yielding an incremental cost-effectiveness ratio (ICER) of ¥469,672/QALY ($3,608/QALY). Results were consistent among subgroups and sensitivity analyses. In probabilistic sensitivity analysis, 82.5 % of runs were below the Japanese ICER reference value of ¥5,000,000/QALY ($38,408/QALY). CONCLUSIONS: Empagliflozin was demonstrated to be cost-effective for HFrEF patients in Japan based on the EMPEROR-Reduced trial data.

Prevalence and prognostic impact of the coexistence of cachexia and sarcopenia in older patients with heart failure.

BACKGROUND: No study with an adequate patients' number has examined the relationship/overlap between sarcopenia and cachexia. We examined the prevalence of the overlap and prognostic implications of sarcopenia and cachexia in older patients with heart failure using well-accepted definitions. METHODS: This was a post-hoc sub-analysis of the FRAGILE-HF study, a prospective, multicenter, observational study conducted at 15 hospitals in Japan. In total, 905 hospitalized older patients were classified into four groups based on the presence or absence of cachexia and/or sarcopenia, which were defined according to the Evans and Asian Working Group for Sarcopenia criteria revised in 2019, respectively. The primary endpoint was 2-year all-cause mortality. RESULTS: Cachexia and sarcopenia prevalence rates were 32.7% and 22.7%, respectively. Patients were classified into the non-cachexia/non-sarcopenia (55.7%), cachexia/non-sarcopenia (21.7%), non-cachexia/sarcopenia (11.6%), and cachexia/sarcopenia (11.0%) groups. During the 2-year follow-up period after discharge, 158 (17.5%) all-cause deaths (124 cardiovascular deaths [CVD] and 34 non-CVD) were observed. The cachexia/sarcopenia group had the lowest body fat mass and exhibited significantly higher mortality rates (log-rank P < 0.001). Cox proportional hazard analysis revealed that cachexia/sarcopenia was an independent prognostic factor after adjusting for known prognostic factors (versus non-cachexia/non-sarcopenia: hazard ratio, 2.78; 95% confidence interval, 1.80-4.29; P < 0.001). Neither cachexia/non-sarcopenia nor non-cachexia/sarcopenia were significantly associated with all-cause mortality compared with non-cachexia/non-sarcopenia. CONCLUSIONS: Cachexia and sarcopenia are prevalent among older hospitalized patients with heart failure; nonetheless, the overlap is not as prominent as previously expected. The presence of cachexia and sarcopenia is a risk factor for all-cause mortality.

Prognostic implications of six-minute walking distance in patients with heart failure with preserved ejection fraction.

BACKGROUND: The incremental prognostic value of the six-minute walking test over conventional risk factors has not been evaluated in an adequate number of patients with heart failure with preserved ejection fraction (HFpEF). Therefore, we aimed to examine its prognostic significance using data from the FRAGILE-HF study. METHODS AND RESULTS: A total of 513 older patients who were hospitalized for worsening heart failure were examined. Patients were classified according to the tertiles of six-minute walking distance (6MWD): T1 (<166 m), T2 (166-285 m), and T3 (≥285 m). During the 2-year follow-up period after discharge, 90 all-cause deaths occurred. Kaplan-Meier curves showed that the T1 group had significantly higher event rates than the other groups (log-rank p = 0.007). Cox proportional hazard analysis revealed that the T1 group was independently associated with lower survival, even after adjusting for conventional risk factors (T3: hazard ratio 1.79, 95% confidence interval 1.02-3.14, p = 0.042). The addition of the 6MWD to the conventional prognostic model showed a statistically significant incremental prognostic value (net reclassification improvement 0.27, 95% confidence interval 0.04-0.49; p = 0.019). CONCLUSIONS: The 6MWD is associated with survival in patients with HFpEF and has an incremental prognostic value over conventional well-validated risk factors.

The interaction between physical frailty and prognostic impact of heart failure medication in elderly patients.

AIMS: Frailty is highly prevalent and associated with poor prognoses in elderly patients with heart failure (HF). However, the potential effects of physical frailty on the benefits of HF medications in elderly patients with HF are unclear. We aimed to determine the influence of physical frailty on the prognosis of HF medications in elderly patients with HF with reduced and mildly reduced ejection fraction (HFr/mrEF). METHODS AND RESULTS: From the combined HF database of the FRAGILE-HF and Kitasato cohorts, hospitalized HF patients with a left ventricular ejection fraction < 50% and age ≥ 65 years were analysed. Patients treated with or without renin-angiotensin-aldosterone system inhibitors (RAASi) and beta-blockers at discharge were compared. Physical frailty was defined by the presence of ≥3 items on the Japanese version of the Cardiovascular Health Study criteria. The primary endpoint was all-cause mortality rate. Among the 1021 enrolled patients, 604 patients (59%) received both RAASi and beta-blockers, and 604 patients (59%) were diagnosed as physically frail. Patients receiving both RAASi and beta-blockers showed a significantly lower 1 year mortality than those not receiving either, even after adjusting for covariates (hazard ratio: 0.50, 95% confidence interval: 0.34-0.75). This beneficial effect of both medications on 1 year mortality was comparable between patients with and without physical frailty (hazard ratio: 0.53 and 0.51, respectively; P for interaction = 0.77). CONCLUSIONS: The presence of physical frailty did not interact with the beneficial prognostic impact of RAASi and beta-blocker combination therapy in elderly patients with HFr/mrEF.

Percutaneous Decannulation for Venoarterial Extracorporeal Membrane Oxygenation Using a Perclose ProGlide Closure Device and a Balloon Catheter Without On-Site Cardiac Surgical Backup.

Surgical decannulation for venoarterial extracorporeal membrane oxygenation (VA-ECMO) is recommended as a standard weaning strategy considering large-sized cannulas (14-22 French) are inserted in VA-ECMO. However, we should be aware of complications such as bleeding and infection when removing an arterial cannula, especially in facilities without on-site cardiac surgical backup. Percutaneous closure devices for femoral arterial access sites are currently approved for the decannulation of a 10-French or smaller sheath. We reported a case of successful weaning off from ECMO using a combination method of a balloon catheter and a Perclose ProGlide closure device. We successfully removed the arterial cannula using this technique for four ECMO-treated patients without vascular complications or blood transfusion. Percutaneous decannulation by this method could reduce the procedural time and adverse events and be safely performed even in facilities without on-site cardiac surgical backup.