Frailty related all-cause mortality or hospital readmission among adults aged 65 and older with stage-B heart failure inpatients

Heart failure (HF) is a highly prevalent, progressive condition and associated with substantial morbidity and mortality. It is an important cause of hospitalization in older adults [1]. Among people > 65 years presenting to primary care facilities with breathlessness on exertion, one in six have unrecognized HF [2]. The prognosis of HF is poor and health care costs are high [1]. Frailty is also highly prevalent in older adults and is associated with a high risk of falling, disability, hospitalization, and mortality [3]. Frailty is a biological syndrome of decreased reserve and resistance to stressors, with the features of weakness, decreased endurance, and slowed performance [4, 5].

Frailty is of particularly concern for patients with HF. HF put the repeatedly exposes geriatric patients to stress and vulnerability, and the prevalence of frailty is higher in these patients than in the general older adults, which may be associated with depression, disability, and cognitive impairment [6‐8]. According to the process of HF development [9], HF is divided into four stages of A (preHF), B (preclinical HF), C (clinical HF), and D (refractory HF). Onset of HF may be delayed or prevented by interventions aimed at treating asymptomatic left ventricular dysfunction [10]. Previous studies have focused on frailty and stage C or D HF, but no previous study has explored frailty and stage-B HF (SBHF), which is a clinically reversible stage.

If frailty can also predict poor outcomes, including all-cause mortality or readmission and the onset of clinical HF in older SBHF inpatients, then interventions targeting frailty will provide a new way to improve outcomes in SBHF inpatients. Therefore, we explored the prognostic value of frailty in older SBHF inpatients using the criteria of the Fried frailty phenotype.

This study explored the prognostic value of frailty, defined by the Fried frailty phenotype, in older SBHF inpatients. We found that frailty could independently predict the 6-month all-cause mortality or readmission and the development clinical HF in older inpatients.

Frailty was common among inpatients with SBHF - our study found that the prevalence of frailty diagnosed by the Fried phenotype was 24.6% in older SBHF inpatients, which was higher than that in people without HF (3%, aged 65–70 years) [17], and lower than that in clinical HF patients (32–76%) [6, 18]. A lower physical activity score, more comorbidities, and other factors in SBHF compared with healthy individuals [19] may account for the increased prevalence of frailty in older SBHF inpatients. Individuals with SBHF have fewer HF-related multisystem complications (systemic inflammation, comorbidity burden, older age, sarcopenic obesity, metabolic impairment, hemodynamic abnormalities, translocation of gut microbiome, etc.), and this along with other related factors [17] may account for the decreased prevalence of frailty in older SBHF inpatients.

Our study demonstrated that frail older SBHF inpatients were more likely to be older, had more comorbidities, lower LVEF, polypharmacy, depression, disability, and cognitive impairment. Among those, polypharmacy, disability, and cognitive impairment were independently associated with frailty. To a certain degree, our results matched the findings of previous studies in clinical HF patients, which also indicated an association between these factors and the development of frailty [5, 20‐23]. The key mechanism underlying this association in clinical HF patients was related to worsening of the decreased reserve and resistance to stressors due to the inflammatory and metabolic disturbances caused by these factors [17]; this may also explain the similar phenomenon found in older SBHF inpatients. These factors should be screened to help identify older SBHF inpatients with a high risk of developing frailty.

We found that frailty could independently predict the 6-month all-cause mortality or hospital readmission in older SBHF inpatients, and this was unaffected by age, sex, NT-pro BNP level and LVEF. This finding was in agreement with the higher risk of readmission and mortality among frail patients with clinical HF [6, 24]. The prognostic value of frailty has been shown in patients with HF, and assessing frailty may help to identify patients with clinical HF who are at a higher risk of disability and adverse clinical outcomes at each stage of the disease [17].

We also explored the prevalence and predictive value of each frailty component in SBHF inpatients. Unintentional weight loss was the only component that predicted mortality or readmission which was different compared to the low physical activity component in clinical HF [6]. Previous studies have recognized the importance of unintentional weight loss in predicting poor outcomes [25]. Malignancy, cardiovascular disease, gastrointestinal disease, endocrinopathies, infectious disease, and psychiatric disease were the common causes of unintentional weight loss [25, 26]. All of the above mentioned causes may be related to higher mortality or readmission in SBHF inpatients. Furthermore, unintentional weight loss in older adults was connected to the physiology of aging and chronic medical conditions and also due to part decreases in lean muscle mass and increases in total body fat. In addition to this, sarcopenia was also prevalent. Sarcopenia is one of the important mechanisms of frailty [17]. Additionally, unintentional weight loss has no predictive value in clinical HF and this is probably due to inaccuracies resulting from its measurement, since edema and the use of diuretics directly influence body weight and are common in clinical HF.

Cardiac cachexia (the cachexia complicating HF) is often associated with anorexia, inflammation, and insulin resistance and is caused by a pathological shift in the balance between anabolism and catabolism and describes a state of unintentional weight loss that cannot be reversed by changes in nutritional intake alone [27]. Skeletal muscle is the most important functional tissue lost in the context of cachexia owing to catabolism and adipose tissue loss. In addition to sarcopenia, exercise capacity also decreased [28]. Cardiac cachexia, sarcopenia and unintentional weight loss are closely associated with frailty and worsen the outcomes of HF. Furthermore, the levels of serum adiponectin were significantly higher in patients with HF and cachexia, suggesting that adiponectin may play a critical role in cardiac remodeling in the presence of cachexia [29]. In particular, cachexia is also a risk factor for cardiovascular disease development. A potential therapeutic strategy in overlapping conditions of frailty, sarcopenia and cachexia included improving appetite, providing additional calories, and exercise training aimed at improving exercise capacity [28]. The treatment of cachexia may be a potential way to improve frailty in HF patients.

Although only 6.5% of older SBHF inpatients developed clinical HF during the follow-up period, we found that frailty could predict clinical HF independently, which may be due to the following reasons. Firstly, pre-clinical diastolic dysfunction predicts a markedly higher risk of progression to HF and death, and its prevalence increases with age, hypertension, atrial fibrillation/flutter, coronary artery disease, history of myocardial infarction, diabetes, and systolic dysfunction [30]. Secondly, exercise is very helpful from a symptomatic perspective, but frail individuals have a lower functional capacity. They more commonly have disabilities, experience falls, exercise ≤5 times per week, and are unable to walk 100 m without help.

Interestingly, the older SBHF inpatients in our study mainly had preserved LVEF and presented with structural and diastolic abnormalities, rather than systolic abnormalities. Since the evidence for interventions in patients with preserved ejection fraction is lacking and inconclusive, our results may suggest that better blood pressure control, exercise, and interventions targeting frailty may improve outcomes or reduce the risk of developing clinical HF in older SBHF inpatients. Nevertheless, it is difficult to achieve blood pressure control in these individuals, and this had been achieved in only half of our older SBHF inpatients with hypertension. Frailty is to a certain is a reversible condition. Interventions for hypertension, atrial fibrillation/flutter, cardiac rehabilitation, physical training, decreased polypharmacy (particularly involving unnecessary medication), and patient education might delay the progress of HF, or even reduce mortality [30].

There were several limitations to our study. First, our subjects were from a single tertiary hospital and none of the subjects had reduced LVEF, which might affect the generalizability of our results. Second, a gold standard measurement for frailty is lacking in China. Third, diabetes was associated with the outcome and the use of SGLT-2 was of great value. However, none of our participants were using SGLT-2, as SGLT-2 was not covered by medical insurance when we recruited the participants. Fourth, our follow-up period was not long enough and the rate of clinical HF development was low. Multicenter studies with a larger sample size, more information about cardiovascular risk factors, a longer follow-up period, and more meaningful and functional outcomes, like all cause death, all cause readmission, HF hospitalization, HF death, medical cost, institutionalization, prospective falls, prospective activity of daily living decline, and home time, are warranted in the future.

Frailty is common among older SBHF inpatients. It can also predict the 6-month mortality or hospital readmission, and the development of clinical HF. Frailty status should be evaluated in older SBHF inpatients to help identify individuals with an increased risk of mortality or readmission, and developing clinical HF and interventions targeting frailty should be applied to help improve outcomes.