Heart Failure With Reduced Ejection Fraction: "The Importance of Being Frail"

Linda R. Peterson, MD; Andrew R. Coggan, PhD


Circulation. 2022;146(2):91-93. 

Oscar Wilde, in his famous play, recognized the Importance of Being Earnest. Cardiologists recognize the importance of exercise training (ET) in the rehabilitation of heart failure with reduced ejection fraction (HFrEF). Pandey et al have now put the spotlight on 'the importance of ' frailty in the response to ET. Frailty is characterized by diminished physiological function, reduced physiologic reserve, and increased vulnerability to acute stressors.[1,2] It appears to affect >1 of every 2 patients.[1,3] This frequency is roughly double that of community-dwelling adults more than 90 years of age.[4] This high burden of frailty in HFrEF has a tremendous monetary and human cost. It is associated with poorer exercise tolerance, poorer quality of life, and a 50% higher risk of hospitalization and death.[5] Paradoxically, frailty is also associated with a lower likelihood of being on goal-directed medical therapy[1] or enrollment in cardiac rehabilitation.[6] It is clear that frailty has a profound effect on patients with HFrEF and exposes an area where more study is needed to test therapies and improve outcomes.

Although aerobic ET improves exercise capacity and other aspects of frailty, how frailty modulates the effectiveness of ET in patients with HFrEF was heretofore unknown. In this issue of Circulation, Pandey et al evaluated the effect of frailty on ET in patients with HFrEF in the HF-ACTION study (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training).[2] The investigators first constructed a new frailty index on the basis of the approach described by Searle et al.[7] Of the 2130 patients with HFrEF, 59% were identified as frail.[2] This is a striking percentage, because one of the entry criteria for HF-ACTION was the ability to perform a cardiorespiratory fitness test, and the mean age was only 60 years.[2] Frail patients were more likely to be male, smokers, and hospitalized in the past 6 months as well as have a higher body mass index, worse New York Heart Association class, and more comorbidities. They also had worse mobility, lower peak oxygen consumption (VO2), and a poorer quality of life compared with nonfrail patients.[2] Although there was no difference in mean systolic blood pressure, frail patients were less likely to take angiotensin converting enzyme inhibitors/angiotensin receptor blockers. This confirms the findings by Khan et al[1] that found frail patients with heart failure were less likely to be on guideline-directed medical therapy despite worse outcomes. Moreover, although the mean left ventricular ejection fraction was <35% in both groups, the frail patients were less likely to have an implanted cardiac defibrillator. The investigators showed that after ET, the primary composite end point (all-cause mortality or all-cause hospitalization) was reduced by 17% (P<0.01) in the frail patients but not in the nonfrail group. The reduction in the primary end point was driven by a 16% reduction (P<0.05) in all-cause hospitalization during the 4-year follow-up and was independent of other markers of severe cardiovascular disease.[2] Frailty status and effect of ET interacted in predicting the primary end point. In contrast, ET did not improve secondary cardiovascular-related end points (such as cardiovascular death or cardiovascular hospitalization) in either group. Both groups saw improvements in peak oxygen consumption and 6-minute walk distance at 3 months (with 6-minute walk but not peak oxygen consumption decreasing at 1 year). However, quality of life improved at 3 months only in the frail group, with this improvement being maintained at 1 year. In short, frail patients with HFrEF appeared to realize more and greater gains than the nonfrail patients.

The investigators spotlighting frailty in HFrEF is commendable. Their study highlights the importance of the high prevalence of frailty in HFrEF. Although this is not a new finding (others have shown frailty rates of 56–63% in clinical trial patients),[1,3] it is remarkable given that in HF-ACTION, the average age was only 60 years and all patients were required to be able to perform a peak oxygen consumption study. This high frailty prevalence in outpatients with HFrEF may be underappreciated by health care professionals and raises the curtain on this question: Should it be part of routine screening?

The importance of screening patients for frailty is brought to center stage because the study by Pandey et al shows that ET was more likely to lower the primary end point—all-cause hospitalization or death—in frail patients compared with nonfrail patients.[2] This is not entirely surprising because frail patients are, by definition, "sicker" overall and have a higher than expected hospitalization/death rate, making an effective therapy, like ET, more likely to show a benefit in this group. However, the finding by Pandey et al is of extreme importance because it affects the high monetary and personal cost of hospitalization and mortality. Heart failure hospitalizations in general and readmissions are on the rise,[8] and all-cause hospitalizations are frequent among patients with heart failure.[9] Countering this trend, Pandey et al showed that ET was associated with a 16% decrease in all-cause hospitalization rates and a 17% decrease in all-cause hospitalization plus mortality in frail patients with HFrEF.[2] It is clear that ET mitigates against poor outcomes, particularly in frail patients. However, the unfortunate paradox is that frail patients—the ones who benefit the most from ET—may be less likely to enroll in ET through cardiac rehabilitation because other chronic medical conditions, such as age and depression (all components of frailty), are each correlated with worse enrollment.[6] This suggests that creating a successful "Act II" to follow Pandy et al should include studies on how to improve frail patient enrollment in effective ET programs whether in traditional cardiac rehabilitation, home-based programs, or novel programs at rehabilitation and skilled nursing facilities.

The fact that the study by Pandey et al did not find a difference in their cardiovascular-based secondary end points only serves to highlight the importance of frailty as a whole-body problem and a risk for all-cause hospitalization. Patients with HFrEF are at increased risk for developing a plethora of other diseases and conditions (including skeletal muscle dysfunction, depression, anemia, endothelial dysfunction, and pulmonary hypertension), many of which can contribute to heart failure symptoms, frailty, poor exercise performance, and all-cause hospitalization or mortality. As the authors point out, there is also significant cross-talk between the heart and other organs, as well as certain pathophysiologic pathways (such as inflammation) that are upregulated in HFrEF and frailty, which affect >1 organ.[10] Taken together, this suggests the importance of improving not just the heart in patients with HFrEF and frailty but also other organ systems[11,12] and comorbidities.

Although depression is an important comorbidity in HFrEF and a frequent component of frailty, one critique of the frailty index created by Pandey et al (on the basis primarily of questionnaires in addition to a few biomarkers and comorbidities) is that it appears to relatively oversample depression and its manifestations. (The authors also acknowledged that they were not able to quantify physical function using phenotypic assessments, eg, grip strength and gait speed).[2] For example, of the 36 items, 10 of them are either "depression" or symptoms typically related to depression.[2] That said, patients with HFrEF are at increased risk of depression, and depression is an important risk factor for hospital admissions.[13] Although data on the effects of antidepressant pharmacotherapy on HFrEF end points are mixed,[13] 1 therapy improves both HFrEF and depression: ET.[14,15] Although Pandey et al did not evaluate a measure of depression separate from the frailty index, they did show improved quality of life in the frail patients after ET.[2] This is consistent with a study of intensive cardiac rehabilitation that showed that cardiac self-efficacy as well as PHQ-9 scores (Patient Health Questionnaire-9; a measure of depression) improve significantly after ET, with patients who had more severe depression reaping the greatest benefits.[15]

In sum, the importance of the study by Pandey et al lies in both its hypothesis-affirming and hypothesis-generating findings. It affirmed that frailty affects the response to ET in patients with HFrEF, such that frail patients realize greater benefits than nonfrail patients. This points to the importance of the prevalence of frailty in HFrEF and getting these patients ET in any way possible. The lack of change in the secondary cardiovascular-related end points with ET generates questions for future studies including the following: (1) Can novel therapies (possibly in addition to ET) improve skeletal muscle and other organs help mitigate against frailty and poor outcomes in HFrEF? and (2) Can treatment of mechanistic pathways common to both frailty and HFrEF improve both and their attendant morbidity and mortality? The importance of this study is in the questions that it answers and in the questions that it generates with the overall aim of improving the lifespan and health span of patients with HFrEF and frailty.