Progression of Physical Frailty and the Risk of All-Cause Mortality: Is There a Point of No Return?

Qian-Li Xue, PhD; Karen Bandeen-Roche, PhD; Jing Tian, MS; Judith D. Kasper, PhD; Linda P. Fried, MD, MPH

Disclosures

J Am Geriatr Soc. 2021;69(4):908-915. 

In This Article

Abstract and Introduction

Abstract

Objectives: To investigate the rate and patterns of accumulation of frailty manifestations in relationship to all-cause mortality and whether there is a point in the progression of frailty beyond which the process becomes irreversible and death becomes imminent (a.k.a. point of no return).

Design: Longitudinal observational study.

Setting: Community or a non-nursing home residential care setting.

Participants: Two thousand five hundred and fifty seven robust older adults identified at baseline in 2011 with follow-up for all-cause mortality between 2011 and 2018.

Measurements: Frailty was measured by the physical frailty phenotype. Cox models were used to study the relationships of the number of frailty criteria (0–5) at each point in time and its accumulation patterns with all-cause mortality. Markov state-transition models were used to study annual transitions between health states (i.e., frailty, recovery, and death) after becoming frail among those with frailty onset (n = 373).

Results: There was a nonlinear association between greater number of frailty criteria and increasing risk of mortality, with a notable risk acceleration after having accumulated all five criteria (hazard ratio (HR) = 32.6 vs none, 95% confidence interval (CI) = 15.7–67.5). In addition, the risk of one-year mortality tripled, and the likelihood of recovery (i.e., reverting to be robust or pre-frail) halved among those with five frailty criteria compared to those with three or four criteria. A 50% increase in mortality risk was also associated with frailty onset without (vs with) a prior history of pre-frailty (HR = 1.51, 95% CI = 1.20–1.90).

Conclusion: Both the number and rate of accumulation of frailty criteria were associated with mortality risk. Although there was insufficient evidence to declare a point of no return, having all five-frailty criteria signals the beginning of a transition toward a point of no return. Ongoing monitoring of frailty progression could aid clinical and personal decision-making regarding timing of intervention and eventual transition from curative to palliative care.

Introduction

Frailty is a debilitating medical condition that places a person in a state of increased systemic vulnerability to intrinsic (e.g., disease pathology, acute infection) or extrinsic (e.g., environmental stressors) insults. It is posited that the progression of frailty consists of a series of transitions between states of dynamic equilibrium of decreasing cellular, molecular, and physiologic integrity even before reaching a critical threshold beyond which frailty becomes clinically observable.[1] Although frailty appears to be reversible,[2,3] with progressive severity, a complete remission becomes an increasingly rare event in the absence of an intervention.[2] If the syndrome of frailty is progressive in nature, like many other chronic diseases and conditions of aging, it is important to know whether there is a point in the progression of frailty beyond which the process becomes irreversible and death becomes imminent (a.k.a. point of no return). In addition, given that the entry point into the "cycle of frailty" tends to be heterogeneous, with studies showing either muscle weakness or exhaustion to be the most common first manifestation[4,5] it is worth investigating whether specific patterns of emergence of frailty manifestations is as relevant as the number of manifestations in determining the point of no return.

To evaluate these questions, we assessed the relationship between frailty progression and the risk of all-cause mortality among older adults aged 65 and older in the United States. Specifically, we evaluated progression in the context of the clinical syndrome of frailty.[6,7] Our primary hypothesis is that there is a threshold relationship between number of frailty manifestations and mortality risk. In addition, we hypothesize that the strength of the association depends on the rate and pattern of accumulation of frailty criteria. The hypothesized relationship has implications for clinical prognostication, potentially guiding clinical and personal decision-making regarding timing of intervention and eventual transition from curative or life-prolonging care to palliative care.

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