Editor's Note: Commentary based on Higueras-Fresnillo S, Cabanas-Sanchez V, Lopez-Garcia E, et al. Physical activity and association between frailty and all-cause and cardiovascular mortality in older adults: population-based prospective cohort study. J Am Geriatr Soc 2018;66:2097-103.

Rationale for Study/Background: Physical activity for the primary and secondary prevention of chronic medical conditions, and in particular cardiovascular disease (CVD) conditions, is highly effective in reducing mortality and improving quality of life.¹ However, physical activity declines with age, while the presence and severity of chronic CVD conditions increases with age. One reason for this decline in physical activity may be increased prevalence of frailty. Frailty, broadly defined as an age-related accumulation of vulnerabilities in the face of stress, is a strong predictor of adverse outcomes, including all-cause and cardiovascular mortality.² Whether physical activity attenuates the increased risk of frailty status for all-cause and cardiovascular mortality is unknown.

Methods: A retrospective analysis of a population-based prospective cohort study of participants in the Universidad Autónoma de Madrid cohort; a large, community-based sample of "noninstitutionalized" individuals ≥ 60 years old representative of those living in Spain (N = 4008).³ The baseline assessment in 2000-2001 included self-reported physical activity as either inactive, occasional, several times per month or several times per week. Due to the small number of responses for the several times per month or several times per week categories, physical activity was converted to a dichotomous variable (active vs. inactive). Frailty was assessed using a modified version of the Fatigue, Resistance, Ambulation, Illness and weight Loss (FRAIL) scale.⁴ The FRAIL scale is scored from 0-5, with a score of 0 indicating robust (or not frail state), 1-2 indicating pre-frail and 3 or more indicating frail. Covariates collected at baseline included age, sex, educational attainment, smoking status, alcohol consumption, height, weight, waist circumference and cognitive impairment (measured by the mini-mental status exam [MMSE]). Patients were followed until 2014 for the outcomes of all-cause and cardiovascular mortality.

Design: Population-based prospective cohort study

Exclusion Criteria: None

Exposure: Self-reported physical activity

Primary outcome(s): All-cause mortality

Secondary outcomes: Cardiovascular mortality

Statistical Analysis: Cox regression models were used to estimate risk-adjusted hazard ratio (HR, 95% CI)

Results: Compared to robust patients, pre-frail and frail patients were more likely to be older, female, have a lower education level, higher body weight and waist circumference, physically inactive, with increasing cognitive impairment. They were also more likely to have not smoked or drank alcohol. As expected, pre-frail and frail patients had greater all-cause mortality after adjustment for age, sex, educational attainment, smoking status, alcohol consumption, BMI, waist circumference and MMSE score (Prefrail HR 1.26, 95% CI:1.12–1.42; Frail HR 2.05, 95% CI:1.71–2.45) and cardiovascular mortality (Prefrail HR=1.40, 95% CI=1.14–1.72; Frail HR 2.32, 95% CI=1.74–3.10) compared to robust patients. Physical activity lowered risk of all-cause mortality and CVD mortality regardless of frailty status with a relative risk reduction between 18% to 38%.

The association between frailty status [per 1-category increase], and all-cause mortality by physical activity status is shown below:

	Hazard for all-cause mortality for each 1-category increase in frailty status
Inactive group	HR 1.26, 95% CI:1.18-1.35
Active group	HR 1.15, 95% CI: 1.05-1.26

Physical activity mildly attenuated the risk of all-cause mortality. However, frailty status did not have an effect modification on physical activity on all-cause mortality (p_interaction =0.69)

Conclusion: Physical activity attenuates the risk of all-cause mortality associated with frailty. Indeed, inactive robust patients had numerically higher risk of all-cause than active pre-frail patients. These results are consistent with prior population-based studies of self-reported exercise and health outcomes.

Limitations of Study: Physical activity was self-reported, and the exposure was not randomized.

Geriatric Perspective for the Cardiovascular Clinician: While increased risk of frailty among older adults with cardiovascular diseases is well-known, this study adds the important perspective that reduced physical activity constitutes an additional parameter of additive risk. Frail patients who are sedentary have the highest risks of all-cause and CV mortality.

This not only sharpens prognostic discrimination, but also implies a treatment priority. Increasing physical activity among adults who are frail and sedentary seems logical. Yet this is inherently difficult as frailty implies a phenotype of exercise intolerance and fatigue. Cardiac rehabilitation (CR) may provide an opportunity to augment physical activity in frail adults with CVD, and trials have highlighted the fact that those who are most frail and sedentary often derive the greatest benefit from CR.⁵

Nonetheless, the fact remains that CR is usually overlooked as an option for older candidates who are also frail.^6,7 The option of CR often seems intimidating or unfeasible to older patients amidst common enfeeblements and logistic limitations. Recently, the NIA funded a trial that is targeting novel approaches for CR in older adults, emphasizing broader notions of risk reduction (i.e., both geriatric and cardiovascular risks) and innovative approaches to home-based CR (using a hybrid model) (R01 AG060499-01).

In parallel, there are many initiatives focused on the biological underpinnings of sarcopenia and frailty.⁸ Whereas some types of frailty may be associated with sedentariness which is entrenched (e.g., frailty associated with end-stage cancer), other types of frailty may be relatively more responsive to exercise and physical activity (perhaps in combination with nutrition and enriching supplements).⁹ While more evidence is necessary, it seems clear that many older frail adults who have been revascularized, better medicated, or who have undergone TAVR benefit from activity in respects to overcoming sedentariness, improving self-confidence, and improving general health.

As fundamental insights are still evolving, it remains especially important that clinicians share clinical decisions with their patients, acknowledging the limits of what is known, and prioritizing patients' individual goals and values. Frail patients who are sedentary may benefit from palliative approaches, but they may also benefit from aggressive approaches to CR. Evolving options for home-based and hybrid-models of CR may help advance the implementation of CR for older populations, who often have significant transportation barriers. However, key issues of safety and efficacy for higher risk patients (i.e., older adults with cognitive, sensory, neurological, orthopedic, or other age-related intricacies) require further study.^10,11

References

1. 2018 Physical Activity Guidelines Advisory Committee. 2018 Physical Activity Guidelines Advisory Committee Scientific Report. Washington, DC: US Department of Health and Human Services, 2018.
2. Afilalo J, Alexander KP, Mack MJ, et al. Frailty assessment in the cardiovascualr care of older adults. J Am Coll Cardiol 2014;63:747-62.
3. Higueras-Fresnillo S, Cabanas-Sanchez V, Lopez-Garcia E, et al. Physical activity and association between frailty and all-cause and cardiovascular mortality in older adults: population-based prospective cohort study. J Am Geriatr Soc 2018;66:2097-103.
4. Morley JE, Malstrom TK, Miller DK. A simple frailty questionnaire (FRAIL) predicts outcomes in middle aged African Americans. J Nutr Health Aging 2012;16:601-8.
5. Baldasseroni S, Pratesi A, Francini S, et al. Cardiac rehabilitation in very old adults: effect of baseline functional capacity on treatment effectiveness. J Am Geriatr Soc 2016;64:1640-5.
6. Suaya JA, Shepard DS, Normand SL, Ades PA, Prottas J, Stason WB. Use of cardiac rehabilitation by Medicare beneficiaries after myocardial infarction or coronary bypass surgery. Circulation 2007;116:1653-62.
7. Krishnamurthi N, Schopfer DW, Ahi T, et al. Predictors of patient participation and completion of home-based cardiac rehabilitation in the Veterans Health Administration for patients with coronary heart disease. Am J Cardiol 2019;123:19-24.
8. Moaddel R, Fabbri E,Khadeer MA, et al. Plasma biomarkers of poor muscle quality in older men and women from the Baltimore Longitudinal Study of Aging. J Gerontol A Biol Sci Med Sci 2016;71:1266-72.
9. Stanaway L, Rutherfurd-Marwick K, Page R, Ali A. Performance and health benefits of dietary nitrate supplementation in older adults: a systematic review. Nutrients 2017;9:E1171.
10. Forman DE, Arena R, Boxer R, et al. Prioritizing functional capacity as a principal end point for therapies oriented to older adults with cardiovascular disease: a scientific statement for healthcare professionals from the American Heart Assocaition. Circulation 2017;135:e894-918.
11. Forman DE, Sanderson BK, Josephson RA, et al. Heart failure as a newly approved diagnosis for cardiac rehabilitation: challenges and opportunities. J Am Coll Cardiol 2015;65:2652-9.

Keywords: Geriatrics, Cardiac Rehabilitation, Cardiovascular Diseases, Secondary Prevention, Body Mass Index, Weight Loss, Frail Elderly, Quality of Life, Transcatheter Aortic Valve Replacement, Risk Factors, Proportional Hazards Models, Risk Reduction Behavior, Cognition

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