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.

Efficacy and Safety of Acute Phase Intensive Electrical Muscle Stimulation in Frail Older Patients with Acute Heart Failure: Results from the ACTIVE-EMS Trial.

As frailty in older patients with acute heart failure (AHF) has an adverse effect on clinical outcomes, the addition of electrical muscle stimulation (EMS) to exercise-based early rehabilitation may improve the effects of treatment. Post hoc analysis was performed on a randomized controlled study for clinical outcomes and prespecified subgroups (ACTIVE-EMS: UMIN000019551). In this trial, 31 AHF patients aged ≥ 75 years with frailty (Short Physical Performance Battery [SPPB] score 4-9) were randomized 1:1 to receive treatment with an early rehabilitation program only (n = 16) or early rehabilitation with add-on EMS therapy (n = 15) for 2 weeks. Changes in physical function and cognitive function between baseline and after two weeks of treatment were assessed. There were no adverse events during the EMS period. The EMS group showed significantly greater changes in quadriceps' isometric strength and SPPB compared to the control group, and EMS therapy showed uniform effects in the prespecified subgroups. There were no significant differences in the changes in other indexes of physical function and cognitive function between groups. There was no significant difference in the rate of heart failure hospitalization at 90 days between groups. In conclusion, older AHF patients with frailty showed greater improvement in lower extremity function with the addition of EMS therapy to early rehabilitation without adverse events.

Prognostic value of postural hypotension in hospitalized patients with heart failure.

Although postural hypotension (PH) is reportedly associated with mortality in the general population, the prognostic value for heart failure is unclear. This was a post-hoc analysis of FRAGILE-HF, a prospective multicenter observational study focusing on frailty in elderly patients with heart failure. Overall, 730 patients aged ≥ 65 years who were hospitalized with heart failure were enrolled. PH was defined by evaluating seated PH, and was defined as a fall of ≥ 20 mmHg in systolic and/or ≥ 10 mmHg in diastolic blood pressure within 3 min after transition from a supine to sitting position. The study endpoints were all-cause death and heart failure readmission at 1 year. Predictive variables for the presence of PH were also evaluated. PH was observed in 160 patients (21.9%). Patients with PH were more likely than those without PH to be male with a New York Heart Association classification of III/IV. Logistic regression analysis showed that male sex, severe heart failure symptoms, and lack of administration of angiotensin-converting enzyme inhibitors were independently associated with PH. PH was not associated with 1-year mortality, but was associated with a lower incidence of readmission after discharge after adjustment for other covariates. In conclusion, PH was associated with reduced risk of heart failure readmission but not with 1-year mortality in older patients with heart failure.

Inaccurate recognition of own comorbidities is associated with poor prognosis in elderly patients with heart failure.

AIMS: A patient's understanding of his or her own comorbidities is part of the recommended patient education for those with heart failure. The accuracy of patients' understanding of their comorbidities and its prognostic impact have not been reported. METHODS AND RESULTS: Patients hospitalized for heart failure (n = 1234) aged ≥65 years (mean age: 80.1 ± 7.7 years; 531 females) completed a questionnaire regarding their diagnoses of diabetes, malignancy, stroke, hypertension, chronic obstructive pulmonary disease (COPD), and coronary artery disease (CAD). The patients were categorized into three groups based on the number of agreements between self-reported comorbidities and provider-reported comorbidities: low (1-2, n = 19); fair (3-4, n = 376); and high (5-6, n = 839) agreement groups. The primary outcome was a composite of all-cause mortality or heart failure rehospitalization at 1 year. The low agreement group had more comorbidities and a higher prevalence of a history of heart failure. The agreement was good for diabetes (κ = 0.73), moderate for malignancy (κ = 0.56) and stroke (κ = 0.50), and poor-to-fair for hypertension (κ = 0.33), COPD (κ = 0.25), and CAD (κ = 0.30). The fair and low agreement groups had poorer outcomes than the good agreement group [fair agreement group: hazard ratio (HR): 1.25; 95% confidence interval (CI): 1.01-1.56; P = 0.041; low agreement group: HR: 2.74: 95% CI: 1.40-5.35; P = 0.003]. CONCLUSIONS: The ability to recognize their own comorbidities among older patients with heart failure was low. Patients with less accurate recognition of their comorbidities may be at higher risk for a composite of all-cause mortality or heart failure rehospitalization.

Impact of Social Frailty in Hospitalized Elderly Patients With Heart Failure: A FRAGILE-HF Registry Subanalysis.

Background Frailty is conceptualized as an accumulation of deficits in multiple areas and is strongly associated with the prognosis of heart failure (HF). However, the social domain of frailty is less well investigated. We prospectively evaluated the clinical characteristics and prognostic impact of social frailty (SF) in elderly patients with HF. Methods and Results FRAGILE-HF (prevalence and prognostic value of physical and social frailty in geriatric patients hospitalized for heart failure) is a multicenter, prospective cohort study focusing on patients hospitalized for HF and aged ≥65 years. We defined SF by Makizako's 5 items, which have been validated as associated with future disability. The primary end point was a composite of all-cause death and rehospitalization because of HF. The impact of SF on all-cause mortality alone was also evaluated. Among 1240 enrolled patients, 825 (66.5%) had SF. During the 1-year observation period after discharge, the rates of the combined end point and all-cause mortality were significantly higher in patients with SF than in those without SF (Log-rank test: both P < 0.05). SF remained as significantly associated with both the combined end point (hazard ratio, 1.30; 95% CI, 1.02-1.66; P = 0.038) and all-cause mortality (hazard ratio, 1.53; 95% CI, 1.01-2.30; P = 0.044), even after adjusting for key clinical risk factors. Furthermore, SF showed significant incremental prognostic value over known risk factors for both the combined end point (net-reclassification improvement: 0.189, 95% CI, 0.063-0.316, P = 0.003) and all-cause mortality (net-reclassification improvement: 0.234, 95% CI, 0.073-0.395, P = 0.004). Conclusions Among hospitalized geriatric patients with HF, two thirds have SF. Evaluating SF provides additive prognostic information in elderly patients with HF. Registration URL: https://upload.umin.ac.jp/. Unique identifier: UMIN000023929.

Aspartate aminotransferase to alanine aminotransferase ratio is associated with frailty and mortality in older patients with heart failure.

Frailty is a common comorbidity associated with adverse events in patients with heart failure, and early recognition is key to improving its management. We hypothesized that the AST to ALT ratio (AAR) could be a marker of frailty in patients with heart failure. Data from the FRAGILE-HF study were analyzed. A total of 1327 patients aged ≥ 65 years hospitalized with heart failure were categorized into three groups based on their AAR at discharge: low AAR (AAR < 1.16, n = 434); middle AAR (1.16 ≤ AAR < 1.70, n = 487); high AAR (AAR ≥ 1.70, n = 406). The primary endpoint was one-year mortality. The association between AAR and physical function was also assessed. High AAR was associated with lower short physical performance battery and shorter 6-min walk distance, and these associations were independent of age and sex. Logistic regression analysis revealed that high AAR was an independent marker of physical frailty after adjustment for age, sex and body mass index. During follow-up, all-cause death occurred in 161 patients. After adjusting for confounding factors, high AAR was associated with all-cause death (low AAR vs. high AAR, hazard ratio: 1.57, 95% confidence interval, 1.02-2.42; P = 0.040). In conclusion, AAR is a marker of frailty and prognostic for all-cause mortality in older patients with heart failure.

Prevalence and prognostic impact of the coexistence of multiple frailty domains in elderly patients with heart failure: the FRAGILE-HF cohort study.

AIMS: To describe the prevalence, overlap, and prognostic implications of physical and social frailties and cognitive dysfunction in hospitalized elderly patients with heart failure. METHODS AND RESULTS: The FRAGILE-HF study was a prospective multicentre cohort study enrolling consecutive hospitalized patients with heart failure aged ≥65 years. The study objectives were to examine the prevalence, overlap, and prognostic implications of the coexistence of multiple frailty domains. Physical frailty, social frailty, and cognitive dysfunction were evaluated by the Fried phenotype model, Makizako's 5 items, and Mini-Cog, respectively. The primary study outcome was the combined endpoint of heart failure rehospitalization and all-cause death within 1 year. Among 1180 enrolled hospitalized patients (median age, 81 years; 57.4% male), physical frailty, social frailty, and cognitive dysfunction were identified in 56.1%, 66.4%, and 37.1% of the patients, respectively. The number of identified frailty domains was 0, 1, 2, and 3 in 13.5%, 31.4%, 36.9%, and 18.2% of the patients, respectively. During follow-up, the combined endpoint occurred in 383 patients. Adjusted hazard ratios for 1, 2, and 3 domains, with 0 domains as the reference, were 1.38 [95% confidence interval (CI) 0.89-2.13; P = 0.15], 1.60 (95% CI 1.04-2.46; P = 0.034), and 2.04 (95% CI 1.28-3.24; P = 0.003), respectively. Incorporating the number of frailty domains into the pre-existing risk model yielded a 22.0% (95% CI 0.087-0.352; P = 0.001) net reclassification improvement for the primary outcome. CONCLUSIONS: The coexistence of multiple frailty domains is prevalent in hospitalized elderly patients with heart failure. Holistic assessment of multi-domain frailty provides additive value to known prognostic factors.

Effects of Acute Phase Intensive Electrical Muscle Stimulation in Frail Elderly Patients With Acute Heart Failure (ACTIVE-EMS): Rationale and protocol for a multicenter randomized controlled trial.

In elderly patients with acute heart failure (AHF), clinical outcome is adversely affected by frailty. Although a number of potentially effective interventions for frailty have been reported, little is known about the effects of rehabilitation programs in frail elderly AHF patients. We postulated that addition of electrical muscle stimulation (EMS), which induces muscle contraction without requiring patient volition, to early rehabilitation would be efficacious in frail elderly AHF patients. The ACTIVE-EMS (Effects of Acute Phase Intensive Electrical Muscle Stimulation in Frail Elderly Patients With AHF; UMIN000019551) trial is a multicenter, randomized controlled trial that will enroll 80 patients from 3 hospitals in Japan. AHF patients age ≥ 75 years positive for frailty, defined as Short Physical Performance Battery score 4 to 9, will be randomly assigned to receive early rehabilitation program only or EMS add-on therapy for 2 weeks. The primary endpoint of the trial is the change in quadriceps isometric strength between baseline and 2 weeks, with changes in physical function and cognitive function, and clinical safety and feasibility of EMS therapy as secondary outcomes. ACTIVE-EMS is the first randomized trial to evaluate the clinical effectiveness of adding EMS therapy to early rehabilitation in frail elderly AHF patients. The results of this study will provide insight for the development of appropriate rehabilitation programs for this high-risk population.

Effects of phase II cardiac rehabilitation on job stress and health-related quality of life after return to work in middle-aged patients with acute myocardial infarction.

The aim of the present study was to clarify the effects of phase II cardiac rehabilitation (CR) on job stress and health-related quality of life (HRQOL) after return to work in middle-aged patients with acute myocardial infarction (AMI). A total of 109 middle-aged outpatients (57 +/- 7 years) who completed a phase I CR program after AMI were enrolled, 72 of whom participated in a phase II CR program for 5 months after hospital discharge (CR group) and 37 who discontinued the phase II CR program after the discharge (non-CR group). Job stress was assessed at 6 months after the AMI using a brief job stress questionnaire containing questions related to job stressors, worksite support, level of satisfaction with work or daily life, and psychological distress. HRQOL was assessed using the short-form 36-item health survey (SF-36) at hospital discharge and at 3 and 6 months after the AMI. There were no significant differences in clinical and occupational characteristics between the CR and non-CR groups. The CR group patients exhibited significantly better results for job stressors and psychological distress and higher SF-36 scores at 6 months after the AMI, as compared with those in the non-CR group. These findings suggest that discontinuing a phase II CR program induced chronic psychosocial stress after return to work in these middle-aged post-AMI patients.

Influence of nifedipine coat-core and amlodipine on systemic arterial stiffness modulated by sympathetic and parasympathetic activity in hypertensive patients.

The aim of this study was to compare the effects of nifedipine coat-core (once daily formulation) and amlodipine on systemic arterial stiffness in patients with hypertension. Study drugs were assigned by the randomized open-label crossover method. After the blood pressure was maintained below 130/85 mm Hg for 8 months by treatment with either drug in 48 hypertensive patients (aged 63.2+/-6.9 years; 64.5% men), they were switched to the other drug for another 8 months. The blood pressure, heart rate, plasma catecholamine level and brachial-ankle pulse wave velocity were measured before and after a bicycle ergometer testing. Heart rate recovery was calculated from the change of the heart rate after treadmill exercise testing. The high-frequency and low-frequency components of the heart rate variability spectrum were analyzed from 24-h Holter electrocardiograms. The change of blood pressure after exercise testing showed no significant difference between the two medications. However, the increases of heart rate, noradrenalin and branchial-ankle pulse wave velocity after exercise were significantly smaller with nifedipine treatment than with amlodipine (P=0.0472, P=0.006 and P=0.0472, respectively). Heart rate recovery was significantly faster with nifedipine treatment (P=0.0280). The nighttime high-frequency component of heart rate variability was significantly larger after nifedipine treatment than after amlodipine (P=0.0259), while the nighttime low/high-frequency ratio was significantly smaller with nifedipine (P=0.0429). Nifedipine reduced functional arterial stiffness and improved heart rate recovery by altering the autonomic activity balance in hypertensive patients.

Comparison of cardiovascular responses between upright and recumbent cycle ergometers in healthy young volunteers performing low-intensity exercise: assessment of reliability of the oxygen uptake calculated by using the ACSM metabolic equation.

OBJECTIVES: To clarify (1) differences in cardiovascular response during low-intensity exercise in the upright versus the recumbent position, and (2) whether the oxygen uptake (V o 2 ) calculated by the American College of Sports Medicine (ACSM) metabolic equation reflects the actual V o 2 at low-intensity testing. DESIGN: Repeated-measures comparison study. SETTING: University research laboratory. PARTICIPANTS: Thirty-one healthy, young volunteers (age, 23+/-2y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Blood pressure, rate pressure product (RPP), V o 2 , oxygen pulse, carbon dioxide output (V co 2 ), and ventilatory equivalent (V e ) were measured during graded exercise testing using upright and recumbent cycle ergometers. The estimated V o 2 was calculated by using the ACSM metabolic equation. RESULTS: Systolic blood pressure, RPP, V o 2 , oxygen pulse, V co 2 , and V e at 15 or 30W were significantly higher in the recumbent position than in the upright one ( P <.05), however, no significant differences were observed at 50 and 70W. The estimated V o 2 during exercise was significantly higher than the actual one, at every level of intensity, from 15 to 70W ( P <.05). CONCLUSIONS: Cardiovascular responses should be carefully monitored even during low-intensity exercise using a recumbent cycle ergometer. The V o 2 estimated using the ACSM metabolic equation did not reflect the actual V o 2 during low-intensity exercise at 70W or less.