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SYSTEMATIC REVIEWS

Effectiveness of interventions to prevent pre-frailty and frailty progression in older adults

a systematic review

Apóstolo, João1; Cooke, Richard2; Bobrowicz-Campos, Elzbieta1; Santana, Silvina3; Marcucci, Maura4,5; Cano, Antonio6; Vollenbroek-Hutten, Miriam7; Germini, Federico5; D’Avanzo, Barbara8; Gwyther, Holly2; Holland, Carol2

Author Information
JBI Database of Systematic Reviews and Implementation Reports: January 2018 - Volume 16 - Issue 1 - p 140-232
doi: 10.11124/JBISRIR-2017-003382
  • Open

Abstract

GRADE Summary of Findings

1. Clinical/medical component

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2. Economic component

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Introduction

Frailty is an age-related state of decreased physiological reserves characterized by a weakened response to stressors and an increased risk of poor clinical outcome.1 Frailty predisposes falls and fractures, disability, dependency, hospitalization and institutional placement, and ultimately leads to death.2 It can be preceded by, but also occurs in the absence of, chronic disease.3,4 According to some authors, this clinical condition results from decrease in reserves across multiple physiological systems that are normally responsible for healthy adaptation to stress.2,5,6 Alternatively, it is considered that frailty is due to critical accumulation of dysregulation in important signaling pathways and subsequent depletion of homeostatic reserve and resilience.2,7,8 Other authors describe this state of increased vulnerability as being associated with the reduced capacity to compensate ageing-related molecular and cellular damage.9 Independently of pathophysiological conceptualization, it is assumed that frailty is a dynamic process that leads to a spiral of decline in various functional domains and that exacerbates risk of geriatric syndromes.2,3,10

The phenotypic markers of frailty, operationalized based on data from the Cardiovascular Health Study (CHS),6 include global weakness with low muscle strength (e.g. poor grip strength), overall slowness (particularly of gait), decreased balance and mobility, fatigability or exhaustion, low physical activity and involuntary weight loss.2,3,6 For diagnostic purposes, at least three of these components must be observed.6 The presence of only one or two of them is considered an indicator of the state of pre-frailty. In a broader approach, it is assumed that frailty can also manifest through cognitive impairment,11-15 although, according to evidence, the decline in cognition is very selective, being limited to executive functions, attention, verbal fluency and processing speed. It is also well documented that frail elders manifest some impairment in activities of daily living and report significant reduction of quality of life.11,16 Furthermore, recent studies have shown that frailty may be related to mood change,15,17 or to social factors such as social support or living alone,11 although the nature of this association, as well as its relevance to the frailty construct, needs to be clarified.16 Based on the comprehensive approach to frailty, several screening and diagnostic instruments have been developed. One of these instruments is the Frailty Index, elaborated within the framework of the Canadian Study of Health and Aging (CSHA).4 This instrument defines frailty in terms of a multidimensional risk state that arises from the interaction of multiple interdependent factors linked to the physical, psychological and social domains of individual functioning, and measures the number of deficits of the person. Presently, several variants of this tool are available in clinical practice.18 The definition of frailty in terms of cumulative deficits is also presented in the Edmonton Frail Scale19 and The Tilburg Frailty Indicator.20 There are also studies that operationalize frailty as a limited set of indicators, such as impairment in activities of daily living (ADLs),21 low physical activity,22 low mobility with poor nutrition23 or others, using for assessment purposes indicator-related scales, measurements or indexes.

Regarding the prevalence of frailty, systematic comparison of numerous studies24 shows that frailty in community dwelling adults aged 65 and over varies from 4% to 17%. In case of pre-frailty, the frequency varies between 19% and 53% in different studies.24 These differences between estimates depend on the operational definition of frailty (based on physical markers or using a broader multidimensional approach) and the population studied (e.g. the results of epidemiological studies can be affected by demographic variables, such as age and gender, as well as the presence of chronic disease or other comorbid conditions).

Because of the frequency of its occurrence and the weight of its consequences, frailty is seen as a threatening condition for older adults, requiring attention from healthcare professionals, social care practitioners, researchers and policy-makers.10,24 The implications of the involvement of these agents can be observed at various levels, with issues related to improving prognosis and preventing deterioration from a pre-frail to frail status of greatest interest and relevance. In relation to interventions, attempts to manage adverse consequences of frailty are often focused on minimization of risk of disability and dependency or the treatment of underlying conditions and symptoms. In a complementary approach, frailty management involves the development of coping strategies, necessary to control potential stress factors or diminish the extent of their impact.25 So far, various types of interventions have been proposed, among them, physical activity, psychosocial intervention, health and social care provision, cognitive stimulation, nutrition, medication/medical maintenance adherence focused intervention, intervention based on information and communication technologies, and multifactorial intervention. The results of studies conducted in this area have indicated that treating frailty in older adults is a realistic therapeutic goal.26-29 However, it is still difficult to determine how effective these types of interventions are and how efficiency can be influenced by other factors, for example, severity of clinical condition, and importantly, which types of interventions are more likely to be effective. It is also unclear whether the interventions for frailty have an impact on clinical outcomes related to drug prescription and analytical parameters (such as results of laboratory analyses, blood tests, etc.).30,31 The focus of attention should also be on economic data, namely, the costs relative to benefits and/or savings associated with implementing interventions for pre-frailty and frailty,32 thus informing clinical decision makers on the likelihood of cost effectiveness.

A preliminary search33 of the JBI Database of Systematic Reviews and Implementation Reports, the Cochrane Database of Systematic Reviews, PROSPERO, CINAHL and MEDLINE, performed during the development of the protocol,34 revealed that there were systematic reviews reporting evidence on the effectiveness of intervention programs in frail older adults.35-38 However, to the best of our knowledge, these reviews have focused only on physical exercise programs and have identified as outcomes of interest physical frailty and/or functional capacity or mobility, without addressing wider domains (e.g. psychological, social) of individual functioning. Additionally, not all of these reviews provided the indication of a clear operational definition or measurement of frailty as a criterion for inclusion, and two of them35,38 were published before 2010. Neither have these reviews provided evidence on the economic effectiveness of the physical exercise-based treatment. Moreover, there is currently no systematic review (neither published nor in progress) on the clinical/medical and economic effectiveness of other types of interventions to prevent or reduce frailty in advanced age. In our opinion, presenting the full spectrum of different types of interventions available in clinical practice could be extremely useful to practitioners for choosing the treatment type. Therefore, it was considered necessary to examine the effectiveness of the interventions to prevent progression of pre-frailty and frailty in older adults, which involves a critical analysis based on scientific evidence. This review was conducted according to an a priori published protocol.34

Review question

The objective of this review was to identify the effectiveness of interventions to prevent progression of pre-frailty and frailty in older adults. More specifically, the review questions were:

  • What is the effectiveness of interventions in preventing or reducing frailty in older adults?
  • How does effectiveness vary with degree of frailty?
  • Are there factors that moderate the effectiveness of interventions?
  • What is the economic evidence of interventions for pre-frailty and frailty?

Inclusion criteria

Participants

This review considered studies that included older adults (female and male) aged 65 years and over, explicitly identified as pre-frail or frail by researchers or associated medical professionals according to a pre-specified scale or index, and who received health care and support services in any type of setting (primary care network, nursing homes, hospitals). This review excluded studies that included participants selected because of one specific illness or that only considered patients with a terminal diagnosis.

Interventions

The clinical/medical component of the review considered studies that evaluated any type of interventions to prevent progression of pre-frailty and frailty in older adults. These interventions included, but were not limited to, physical activity, multifactorial intervention, psychosocial intervention, health and social care provision, cognitive, nutrition or medication/medical maintenance adherence focused interventions.

The economic component of the review considered studies that performed any type of health economic analysis of interventions to prevent progression of pre-frailty and frailty in older adults.

Comparator

The effectiveness of interventions of interest was compared with usual care, alternative therapeutic interventions or no intervention.

Outcomes

The primary outcome of interest was frailty indicated by any validated scale or measurement or index (e.g. Frailty Index, Fried's frailty criteria based on phenotype model or Edmonton Frailty Scale). We also considered outcomes of frailty assessed by a limited set of indicators, since its operational definition was clearly stated by the authors.

Secondary outcomes included degree of change or no change, indicated by any validated scale or measurement or index, in domains of cognition (e.g. assessed by Mini-Mental State Examination), quality of life (e.g. assessed by EuroQol Group 5-Dimension Self-Report Questionnaire), quality-adjusted life year (QALY) (assessed by comparing length of life with commonly used indicators of quality of life), ADL (assessed by Barthel Index, Katz ADL Index or other), caregiver burden (e.g. Caregiver Burden Inventory), functional capacity (e.g. Physical Activity Scale for Elderly), depression and other mental health-related outcomes (e.g. Geriatric Depression Scale), self-perceived health (e.g. Self-Rated Health), and social engagement (e.g. Scale of Gijón). Secondary outcomes also included change or no change in analytical parameters (e.g. measured by clinical tests), drugs and prescriptions (e.g. indicated by medical records), and prevalence of adverse outcomes, such as falls and fractures, mortality, hospitalization, institutionalization, comorbidities (e.g. indicated by medical records or self-reported).

In addition, costs and/or costs relative to benefits and/or savings associated with implementing the interventions for pre-frailty and frailty were considered.

Types of studies

The clinical/medical component of this review considered for inclusion any experimental study designs that were related to the effectiveness of interventions for pre-frailty and frailty, including randomized controlled trials (RCTs), non-randomized trials and quasi-experimental studies. In the case of absence of RCTs, non-randomized trials and quasi-experimental studies, other research designs of quantitative nature, such as cohort studies, were considered for inclusion.

The economic component of this review considered the inclusion of cost effectiveness, cost benefit, cost minimization or cost utility studies. Any quantitative study measuring clinical effectiveness that incorporated economic data was considered. Studies where the effectiveness of the intervention on frailty levels was not measured were excluded.

Methods

Search strategy

The search strategy aimed to find both published and unpublished studies. A three-step search strategy was utilized in this review. An initial limited search of MEDLINE via EBSCOhost Web and CINAHL was undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe the article. A second search using all identified keywords and index terms was then undertaken across all included databases. Thirdly, the reference lists of all identified reports and articles were searched for additional studies. Studies published in English, Portuguese, Spanish, Italian and Dutch, from January 2001 to November 25, 2015, were considered for inclusion in this review. The initial timeframe from 2001 was chosen because it is the year of publication of Fried's8 paper that is seen as seminal for research on frailty condition.

The search for published studies included the following electronic databases: CINAHL, MEDLINE, Scopus, Embase, Cochrane Central Register of Controlled Trials and SciELO.

The searched databases for unpublished studies included: ProQuest Theses and Dissertations, OpenGrey, Banco de teses da CAPES (www.capes.gov.br) and Dissertation Abstracts Online (e-Thos).

The initial keywords used in the exploratory stage of the search for studies in electronic databases were: frailty, elder*, old*, intervention*. To capture all available evidence, in the stage of second search additional keywords, considering various terminology and spelling, were used. These final keywords were: frail*, pre-frail*, elder*, old*, intervention*, therap*, treatment*, program*, effect*, efficacy. A detailed record of the search strategies used in the included databases can be found in Appendix I.

Assessment of methodological quality

Reviewers, in pairs, independently screened titles and abstracts prior to retrieving full texts. The full-texts were assessed for eligibility in respect of type of participants, study design and outcomes. At completion of the search process, each paper selected for retrieval was assessed independently by two reviewers for methodological validity prior to inclusion in this systematic review, as originally outlined in the review protocol.34 Any disagreements that arose between the reviewers were resolved through discussion, or with other reviewers. All authors contributed to paper assessments and critical appraisal.

For the purpose of critical appraisal of the studies focusing on the clinical/medical component of this review, the standardized instruments from the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI) were used.33 These instruments included the JBI Critical Appraisal Checklist for Randomized Control/Pseudo-randomized Trial, the JBI Critical Appraisal Checklist for Comparable Cohort/Case Control and the JBI Critical Appraisal Checklist for Descriptive/Case Series, and were chosen accordingly to the study design.

For the purpose of critical appraisal of the studies focusing on the economic component of this review, the standardized instrument from the Joanna Briggs Institute Analysis of Cost, Technology and Utilization Assessment and Review Instrument (JBI ACTUARI) was used,39 namely, the JBI Critical Checklist for Economic Evaluations.

In order to ensure quality of analyzed evidence, a cut-off point for inclusion of studies focusing on the clinical/medical component was applied. Experimental studies were considered as meeting a minimum of quality when they obtained at least five “Yes” ratings on the JBI Critical Appraisal Checklist for Randomized Control/Pseudo-randomized Trial, the JBI Critical Appraisal Checklist for Comparable Cohort/Case Control or the JBI Critical Appraisal Checklist for Descriptive/Case Series. In relation to studies that focused on the economic component of this review, it was decided to include only those in which the effect on clinical outcomes of the intervention was reported with sufficient methodological quality. Simultaneously, the anticipation of the reduced number of such studies resulted in the decision not to apply any additional cut-off point for the JBI Critical Appraisal Checklist for Economic Evaluations, and to analyze the implications of the possible methodological weaknesses related to the economic component in the discussion section.

Data extraction

Data from studies focusing on the clinical/medical component of this review were extracted using the standardized data extraction tool from JBI SUMARI.33 For data extraction from the studies focusing on the economic component of this review, the standardized data extraction tool from JBI ACTUARI39 was applied. In both cases the data extraction process was conducted by two independent reviewers. Disagreements were resolved by discussion to reach consensus.

The extracted data included specific details about the interventions, populations, study methods and outcomes of significance to the review questions and specific objectives. In case of missing or unclear information, the authors of the included studies were contacted.

Data synthesis

Differences in populations, interventions, comparators and outcomes of the included studies focusing on the clinical/medical component of this review did not allow for direct comparison, and therefore meta-analysis was not possible. Consequently, the results of these studies were synthesized in narrative and tabular form.

Significant variability in study methodology was also observed in the studies focusing on the economic component of this review. Due to this variability, it was not possible to combine the economic results in statistical meta-analysis. Results, therefore, have been presented in narrative and tabular form.

Deviation from the protocol

The secondary outcomes indicated in the protocol of this systematic review34 included the outcome of depression, however in the final report other mental health-related outcomes were additionally considered. This deviation is due to the fact that in some cases the depressive symptomatology was evaluated together with symptoms of anxiety or others.

Results

Study selection

The results of the search and study selection process are presented in Figure 1. A total of 4726 potentially relevant studies were identified in the literature search. Of those, 2227 were duplicates. From the remaining 2499 records, 2121 were excluded after title and abstract assessment, and then 346 were excluded after full-text analysis as they did not meet the inclusion criteria. The methodological quality of the remaining 32 studies was assessed. From those 32 studies, one was a pseudo-randomized control trial with two groups, two were before and after studies, two were pseudo-randomized control trials with one group, and 27 were RCTs. Four of those 32 studies (three RCTs and the pseudo-randomized control trial with two groups) provided data related to both clinical/medical and economic components of the interventions. The assessment of methodological quality focused on the clinical/medical component resulted in the exclusion of 11 studies and inclusion of 21 studies. The reasons for study exclusion are detailed in Appendix II.

Figure 1
Figure 1:
Flowchart of the study selection and inclusion process

All 21 studies21-23,29,32,40-55 included in this review were RCTs. They described a total of 33 interventions. Two of the included RCTs32,44 additionally provided economic data. In one of these studies32 the costs and cost-effectiveness of a multidisciplinary intervention versus usual care were compared. The second study44 analyzed the costs of health services providing geriatric assessment and management with comparison to usual inpatient and outpatient care.

Methodological quality

The reviewers, in teams of two, independently assessed the methodological quality of 32 studies. The authors of 23 studies were contacted to obtain more details in relation to missing or unclear data. Eleven authors replied. Based on the authors’ answers, eight studies were included for further analysis and three studies were excluded as they did not obtain the minimum of five “yes” answers in the critical appraisal checklist. Besides these three studies, eight other failed to reach the cut-off point for inclusion. Appendix II lists the studies that were excluded based on critical appraisal and indicates the reasons for the exclusion. Tables 1 and 2 outline the critical appraisal scores for the included studies.

Table 1
Table 1:
Assessment of methodological quality of clinical/medical component of included studies
Table 2
Table 2:
Assessment of methodological quality of economic component of included studies

On clinical/medical components, there was consensus among the reviewers to include 21 studies,21-23,29,32,40-55 all of them RCTs. None of these studies obtained 10 “yes” answers in the critical appraisal checklist, and the highest score of nine “yes” answers was obtained by only three studies22,44,52 (see Table 1). The methodological weakness most frequently identified was related to use of participant blinding procedures with regards to treatment assignment, namely, in eight studies21,29,32,42-45,49, the participants were not blind to treatment allocation (Q2), and in 10 studies23,40,41,46-48,50,53-55 the information provided about participant blinding was unclear. Due to the nature of the interventions, the practical difficulties of the blinding process were recognized. In relation to persons assessing outcomes, lack of their blinding with regard to treatment assignment (Q5) was pointed out in four studies,22,29,43,46 and in one study,41 information provided about this issue was unclear. In three studies21,29,45 the allocation to treatment groups was not concealed from the allocator (Q3). There were also three studies46,50,55 in which the information about allocation concealment procedure was insufficiently detailed. The lack of detailed description of randomization procedure (Q1) was detected in six studies.21,29,40,46,47,50 The authors of one study41 were not clear about the statistical treatment of the outcomes of people who withdrew (Q4), and in three studies21,48,55 the analysis of drop-outs was not conducted. In four studies42,48,51,54 the control and treatment groups were not comparable at entry and the baseline differences were not considered in statistical analysis (Q6). Non-identical group treatment other than the intervention of interest (Q7) was observed in two studies41,55; from the remaining 19 studies, ten23,40,42,47-51,53,54 did not provide a clear statement about this issue. In all studies the outcomes were measured in the same way for all groups (Q8) and appropriate statistical analyses were used (Q10). In relation to the reliability of outcome measurement (Q9), in 11 studies23,29,32,40-42,45,48-50,54 unclear or insufficient information to judge this issue was provided, and in two studies51,52 the measures used for the outcomes assessment were not culturally adapted or validated (information provided by the authors of these studies).

In relation to the two included studies with an economic component, both32,44 clearly stated the objective of the study and were placed in a particular decision making context (Q1). Both32,44 also reported solid evidence showing that the clinical effectiveness of the examined intervention had been established (Q4). Detailed description of the intervention and comparator (Q2), measures used for costs and outcomes (Q5), and sufficient explanation about how costs and outcomes were valued (Q6) were provided in only one study.32 The second of the included economic studies44 was unclear in relation to these three questions. Relevant costs and outcomes for each examined intervention, defined accordingly to the objective of the study (Q3), were identified in the study examining the multidisciplinary intervention,32 but not in the study focusing on treatment based on geriatric assessment and management.44 Additionally, there was no incremental analysis conducted of costs and consequences in this second study (Q8).44 Neither of these studies32,44 conducted sensitivity analysis to establish validity of economic results (Q9) or presented sufficient information to answer the questions that users/decision makers would want to know when making decisions about the implementation of the examined intervention (Q10). In addition, a clear report about the adjustment of costs and outcomes for differential timing was not provided in either study (Q7). In relation to the generalizability of the results to other settings with similar characteristics, the study analyzing the multidisciplinary intervention32 was unclear about this issue, and in the study examining the costs of geriatric assessment and management,44 transferability of findings was not discussed.

Characteristics of included studies

Date of publication of the included studies ranged from 2002 to 2016 (with the study from 2016 available online in November 2015) and all were published in English. In the sections below the main features of the included studies are summarized. Detailed information about the setting, methods, participants, interventions, outcomes, authors’ conclusions and limitations are provided in Appendix III.

Study settings

Summary information on the setting and geographical location of the included studies is presented in Table 3. Twelve of included studies were undertaken in Europe (three in Sweden,29,40,47 three in Spain,41,46,51 two in the Netherlands,52,54 one in Belgium,21 one in Switzerland,48 one in the United Kingdom43 and one in France22). From the remaining nine studies, five were undertaken in Asia (Taiwan,42,50 Singapore,53 Japan49 and South Korea23), two in the United States of America,44,55 one in Mexico45 and one in Australia.32 Participants were recruited from the community,21,40,42,47,48,50,52,53 through primary health care centers,46,51,54 medical inpatient and/or outpatient clinics or centers,43-45 an emergency department,29 a long-term care institution,41 rehabilitation facilities,32 an association involved in home assistance for the elderly,22 social security lists,45 national registers,23,49 and local advertisements.55 The interventions described in the included studies were undertaken in the community,21-23,32,40,43,45-48,52-55 primary care centers,51 medical centers,44 community hospitals,42,50 an institute of gerontology,49 the community and hospital,29 and elderly care institutions.41

Table 3
Table 3:
Setting, geographical location and characteristics of participants of included studies
Table 3
Table 3:
(Continued) Setting, geographical location and characteristics of participants of included studies
Table 3
Table 3:
(Continued) Setting, geographical location and characteristics of participants of included studies

In relations to studies reporting economic evidence, one32 was conducted in Australia and included participants who sought care at the emergency department and were discharged to their own home. The other study44 was conducted in the United States of America and was set in Veterans Affairs Medical Centers with established inpatients and outpatients programs of evaluation and management.

Participants

The 21 studies analyzed in this review included a total of 5275 older adults. The number of study participants ranged from 24 (in the study comparing a multicomponent exercise program with mobility exercises)41 to 1338 (in the study comparing inpatient care in the evaluation and management unit with usual inpatient care, and outpatient care in the evaluation and management clinics with usual outpatient care).44 In two studies,40,47 the same sample was considered.

The age range of studied samples was reported in seven studies,32,40,42,45,47,50,51,55 and was 65 to 106 years. For the remaining 14 studies the verification of the age-related criterion for inclusion (age of 65 years and over) defined by the authors of this review was based on the analysis of inclusion criteria provided by the authors of primary studies. Sixteen studies21,23,32,41-44,46,48-55 reported the mean age of their samples; however in six of these studies21,23,32,49,52,54 only data calculated separately for each group was provided. A mean age of total samples varied from 70 (± 4.7)53 to 91.9 (± 4.1)41 years. From the remaining five studies, three22,40,47 provided median age that varied from 8422 to 85–8640,47 years, one study indicated an average age of 75–76 years, and in one study29 the information about mean, median or average age was missing. One study45 considered older adults aged 60 years or more as eligible for inclusion; however the age of the included participants ranged from 70 to 90 years, satisfying the inclusion criteria of this review.

Gender was reported in all studies. In a total review sample of 5275 older adults, approximately 49% were women. One study used only male participants52 and one study used only female participants.49 Two studies44,50 included more men than women. In one of these44 only two percent of participants were female. In the second50 the proportion of female and male participants was more balanced, being 48:52. The remaining studies21-23,29,32,40-43,45-48,51,53-55 included more women than men, with the proportion of female participants ranging from 55%29,45 to 98%.48

In ten studies23,32,41,44-46,49,52,54,55 the condition of being frail was mandatory for inclusion. Three studies42,50,53 included both pre-frail and frail older adults, and one study22 only included older adults at risk of frailty. In six studies29,40,43,47,51,55 the baseline level of frailty was assessed but inclusion in the study did not depend on the presence or absence of a frailty condition. However, in one of these studies51 the condition of being at risk of frailty (or not) influenced the treatment of participants who were allocated to the intervention group. There was also one study48 that included older adults at increased risk of falling, with frailty considered as one of the indicators of this risk. The characteristics of the participants and criteria for inclusion and exclusion used in the analyzed studies are described in Table 3.

The economic study examining the cost-effectiveness of a multifactorial interdisciplinary intervention with comparison to usual care32 was conducted with 241 community dwelling older adults, predominantly female (68%) and aged71 to 101 years. All the participants included in this study met the criteria for frailty. The study that analyzed the costs of health services providing geriatric assessment and management with comparison to usual inpatient and outpatient care44 was delivered to 1338 older adults, predominantly male (98%), with a mean age of 74.2 years, and who were hospitalized on a medical or surgical ward. In this study the condition of being frail was not mandatory for inclusion.

Frailty definition

The included studies used different operational definitions of frailty. The definition cited most frequently, in nine studies,32,41,42,45,47-50,53 was the one based on the CHS phenotypic indicators of frailty, including weakness, fatigue/exhaustion, weight loss, low physical activity and slowness. One study additionally considered poor balance.47 Importantly, the operationalization of frailty indicators differed from study to study. For example, in five studies, weakness was measured using grip strength,32,42,45,47,49 and in one study53 through knee extension in the dominant leg. In the remaining three studies,41,48,50 detailed information was not provided. The stratification of weakness measurement by gender was conducted in five studies,32,42,45,47,53 and by body mass index (BMI) in only two studies.42,53 Finally, the cut-off score for grip strength varied from 13 kg47 to 21 kg42 for women and from 21 kg47 to 32 kg42 for men.

One45 of the studies using CHS phenotypic indicators of frailty also used the Frailty Index of Rockwood et al.,56 integrating 34 variables, with a cut-off score of 0.14. Comprehensive assessment of frailty was also conducted by other authors.29,40,43,44,51,54,55 For example, in two studies44,51 frailty was assessed using information on functional and cognitive status, falls, dependence in ADL, depression, malnutrition, incontinence, polypharmacy and comorbidity, and in one study43 changes in functional and cognitive status were considered. Another study54 defined frailty in terms of self-reported scores in the worst quartile of at least two of six COOP-WONCA charts (an instrument used in primary care settings worldwide that allows quick identification of functional health status57), including overall health, physical fitness, changes in health, daily activities, mental health and social activities. In two studies,29,40 frailty measurements took into account eight indicators, such as weakness, fatigue/exhaustion, weight loss, low physical activity, slowness, poor balance, visual impairment and cognitive impairment, with one of these studies40 using complementary measurement of tiredness in daily activities. The last of the listed studies55 identified frailty by the presence of biomedical, functional and psychosocial indicators.

Some studies21-23,46,52 based frailty assessment on a very limited set of indicators. These indicators included: the presence of low gait speed and/or poor physical activity,22 the presence of poor physical activity and self-reported exhaustion,46 the presence of low mobility and poor nutrition,23 the presence of weakness and changes in physical performance (physical frailty),52 and impairment in basic ADL functioning.21Table 4 summarizes information about frailty assessment conducted in the analyzed studies.

Table 4
Table 4:
Definitions of frailty used in the included studies, measured outcomes and assessment tools
Table 4
Table 4:
(Continued) Definitions of frailty used in the included studies, measured outcomes and assessment tools
Table 4
Table 4:
(Continued) Definitions of frailty used in the included studies, measured outcomes and assessment tools
Table 4
Table 4:
(Continued) Definitions of frailty used in the included studies, measured outcomes and assessment tools
Table 4
Table 4:
(Continued) Definitions of frailty used in the included studies, measured outcomes and assessment tools
Table 4
Table 4:
(Continued) Definitions of frailty used in the included studies, measured outcomes and assessment tools

Interventions/comparators

The interventions examined in the included studies were categorized as physical exercise programs (n = 7),41-43,46,49,53,55 nutritional supplementation (n = 3),23,49,53 hormone replacement (n = 1),52 individually tailored management of clinical condition (n = 5),21,29,32,44,50 group sessions (n = 3),40,47,51 home visits (n = 4),40,45,47,54 psychological therapy (n = 1),42 cognitive training (n = 1),53 individual educational session by a geriatrician (n = 1),51 and combined treatment (n = 4).22,48,49,53 Two studies40,47 included the same sample and examined the same experimental interventions (multi-professional senior group meetings with one home visit and single preventive home visit), differing in the measured outcomes and in the time point of the outcomes assessment. Control conditions used for comparison purposes were as follows: usual care,29,32,43-45,51,54 usual care with education,46 education,42,55 usual care with placebo,53 placebo,49,52 screening evaluation without further management of individual needs,50 community services,21,40,47 and mobility exercises.41 In one study48 the control group included participants who discontinued experimental intervention. Finally, in two studies,22,23 detailed description of the control interventions was missing. In one of these studies,23 the preventive effect of protein-energy supplementation was examined and the control group did not receive nutritional supplement. The second study22 investigated the preventive effect of home-based exercise program with dietary protein supplementation, without providing any information about the control intervention. More detailed information regarding both interventions and comparators is provided in Table 5.

Table 5
Table 5:
Characteristics of the interventions described in included studies
Table 5
Table 5:
(Continued) Characteristics of the interventions described in included studies
Table 5
Table 5:
(Continued) Characteristics of the interventions described in included studies
Table 5
Table 5:
(Continued) Characteristics of the interventions described in included studies
Table 5
Table 5:
(Continued) Characteristics of the interventions described in included studies
Table 5
Table 5:
(Continued) Characteristics of the interventions described in included studies

Follow-up and measurement intervals

In ten studies21-23,41,43,45,47,50-52 the outcomes of interest were assessed twice, at baseline and at the end of the intervention or study, with measurement intervals varying from eight to 10 weeks21 to 18 months.51 In eight studies32,40,44,46,48,49,54,55 three assessment sessions were conducted. The largest measurement interval between the baseline and the last follow-up assessments was four years,48 and the smallest one seven months.49 Finally, three studies29,42,53 provided four assessment sessions. In one of these studies42 the outcomes were measured at baseline, after a three-month intervention, and at six and 12 months. The same measurement intervals (at baseline, and three, six and 12 months) were indicated by the authors of another study.53 However in this case the intervention lasted six months so that one of the assessment sessions (at three months) was conducted in the course of the intervention. In the third study29 the outcomes were measured at baseline and at three, six and twelve months after discharge, with the period of the intervention being unclear (for more detailed information see Table 4).

Methods of economic analysis

The aim of the study developed by Fairhall et al.32 was to compare the costs and cost-effectiveness of a multifactorial interdisciplinary intervention targeting identified frailty characteristics versus usual care from the community services and general practitioners. The effectiveness outcome measures included prevalence of frailty (assessed according to CHS criteria) and level of quality of life (assessed based on EuroQol questionnaire including items regarding mobility, self-care, usual activities, pain/discomfort and anxiety/depression), with data being collected at baseline, and at three and 12 months. In addition, quality adjusted life years (QALYs) were calculated based on data obtained from the quality of life measurements. For the calculation of the number of QALYs gained or lost over the 12 months of follow-up, trapezoidal integration (an approach used for measure of the area under a function plotted on a graph) was used. The study authors32 also evaluated health and community resource utilization, that included costs of primary care appointments with general practitioner and nurse or other health professional, costs of hospital-based care, costs of permanent and respite residential care, with high and low care, and costs of home help, transport and meal delivery. The resource use over 12 months was translated into monetary values using local or national prices or unit costs as appropriate. Monetary amounts were presented in 2011 Australian dollars. Finally, complete-case cost-utility and cost-effectiveness of multifactorial interdisciplinary intervention versus usual care were carried out, with the adopted perspective of health and community care funder. These economic evaluations included comparison of the difference in cases of transition out of frailty and in total costs between intervention and the control groups, as well as incremental cost-effectiveness ratios (ICERs) determined to assess the additional expenditure required to achieve additional benefits of the intervention.

Cohen et al.44 compared the costs of an intervention consisting of inpatient and outpatient geriatric evaluation and management versus inpatient and outpatient usual care. The effectiveness of these interventions was measured based on changes in basic and instrumental ADLs, physical performance and quality of life (assessed by Short Form 36 Health Survey). Data about these outcomes was collected at discharge and 12 months. In addition, probability of survival and relative risk of death at one year were calculated. The economic evaluations included utilization and costs of health care services, determined using a computer program at each center, centralized Veterans Affairs databases, and patients’ or caregivers’ reports of non-Veterans Affairs nursing home care. The costs considered in the analyses included overall costs of initial hospitalization and overall costs of health care after discharge (that is, costs of inpatient, outpatient, and long-term care provided by Veteran Affairs Medical Centers, as well as care in private nursing homes, without including the costs of inpatient and outpatient care at non-Veterans Affairs facilities). Detailed information about specific costs was not provided. Monetary amounts were presented in dollars. The authors did not provide information about the adopted perspective.44

Outcomes

The overview of the results on the outcome of frailty, indicated by any validated scale, measurement or index, or assessed by a limited set of indicators, is provided in Table 6. Table 7 summarizes the impact on the secondary outcomes.

Table 6
Table 6:
Effectiveness of interventions described in the included studies for outcome of frailty
Table 6
Table 6:
(Continued) Effectiveness of interventions described in the included studies for outcome of frailty
Table 6
Table 6:
(Continued) Effectiveness of interventions described in the included studies for outcome of frailty
Table 6
Table 6:
(Continued) Effectiveness of interventions described in the included studies for outcome of frailty
Table 6
Table 6:
(Continued) Effectiveness of interventions described in the included studies for outcome of frailty
Table 6
Table 6:
(Continued) Effectiveness of interventions described in the included studies for outcome of frailty
Table 6
Table 6:
(Continued) Effectiveness of interventions described in the included studies for outcome of frailty
Table 6
Table 6:
(Continued) Effectiveness of interventions described in the included studies for outcome of frailty
Table 6
Table 6:
(Continued) Effectiveness of interventions described in the included studies for outcome of frailty
Table 6
Table 6:
(Continued) Effectiveness of interventions described in the included studies for outcome of frailty
Table 6
Table 6:
(Continued) Effectiveness of interventions described in the included studies for outcome of frailty
Table 6
Table 6:
(Continued) Effectiveness of interventions described in the included studies for outcome of frailty
Table 7
Table 7:
Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes
Table 7
Table 7:
(Continued) Effectiveness of interventions described in the included studies for secondary outcomes

Effectiveness of interventions to prevent progression of frailty

Physical exercise programs delivered in class41,42,46,49 or delivered in class and followed by home-based practice53,55 were shown to be effective for preventing the progression of pre-frailty and frailty, at least in some of the frailty indicators (sum of indicators,42,53 weakness,41,55 weight loss,49 slowness/gait speed,41,46,53 gait distance,55 balance,46 exhaustion,49 physical activity,49 activities of daily living,46 and fear of falls55). These positive effects were observed for different types of exercise programs (including Tai Chi,55 resistance training with42 and without41,53 nutrition consultation, and comprehensive multicomponent training46,49) and for different samples (community dwelling older adults,42,49,53,55 older adults aged between 80 years and 90 years contacted through the primary health care center,46 institutionalized older adults aged 85 or over41).

On the other hand, home-based exercise programs43 developed with housebound older adults showed only a non-significant trend to improve mobility. No effects on the prevention of frailty progression were observed for computerized balance training55 performed individually with supervision.

Providing nutritional supplements alone, including milk fat globule membrane (MFGM)49 and protein-energy formula,23 or increasing protein-calorie and micronutrients intake,53 was also shown to be favorable for prevention of frailty progress. Milk fat globule membrane49 provided to frail women from the community improved physical activity immediately after the intervention and reduced long-term exhaustion, but had no significant post-intervention effect on weight. In another study,23 a protein-energy formula provided to community dwelling older adults with low mobility and who were also malnourished (both indicators used for operational definition of frailty), had beneficial effects for energy intake. However, this improvement in energy intake was not associated with significant change in body weight. An intervention based on increase of protein-calorie and micronutrient intake53 provided to pre-frail and frail older adults from the community improved frailty scores from the baseline, with observed change being significant at 12 months, but not at three or six months. The positive effects of this intervention were observed through the increase in long-term physical activity. Regarding body mass index, the highest mean change was observed follow-up at three months; however, this change was not significant.

Hormone replacement with atamestane and/or dehydroepiandrosterone52 and conducted with independently living men without disease or recent hospitalization and with low scores on strength tests was shown to have no influence on frailty measurements.

Interventions based on individually tailored management of clinical condition by a multi-professional team and according to individual needs21,29,32,44,50 were shown to have inconsistent effects on frailty prevalence. A twelve month multifactorial interdisciplinary intervention provided to community dwelling older adults meeting with frailty showed a significant impact on frailty prevalence.32 Improvement in frailty (operationalized in terms of impairment in basic activities of daily living) was also observed in relation to client-centered, individually tailored activity oriented program conducted with community dwelling older adults receiving healthcare support.21 Regarding inpatient care in geriatric evaluation and management units44 that included screening geriatric evaluation and management according to individual care plan developed by a multi-professional team, positive effects were demonstrated on basic ADL and physical performance at discharge, but not at the follow up at 12 months. However, when the same intervention was developed in geriatric clinics with outpatients who had previously received all appropriate hospital services,44 the positive effects were only observed on physical performance at 12 months. On the other hand, a six month intervention based on screening evaluation results,50 developed with pre-frail and frail community dwelling older adults, as well as continuum care29 provided to older adults with at least one chronic disease and dependent in at least one ADL, discharged from emergency departments, were shown to have no effects on frailty status.

Group sessions focused on the ageing process and health,40 conducted with community dwelling older adults resulted in postponing progression in tiredness in daily activities (measured through Mob-T Scale) for up to one year. When tiredness was not included in the analysis and when the follow-up at three months was considered,47 group meetings focused on ageing process and health were shown to have no effect on frailty.

Educational sessions focused on health promotion, disease prevention and self-care,51 provided in groups for participants who were not at risk of frailty, and individually by a geriatrician for participants who were at risk of frailty, showed positive impact for a change of frailty status.

Regarding home visits by nurses provided to community dwelling older adults, positive effects were observed in relation to nine months of weekly nurse home visits focused on life-style changes and accompanied by an alert button,45 but not in relation to nine months of weekly nurse home visits focused on life-style changes without alert button45 or 18 months of nurse home visits focused on designing of care plan.54 The positive impact of the treatment including alert button was observed on the frailty prevalence, namely on the percentage of older adults who developed frailty during the follow up period. The authors45 suggested that a visiting nurse combined with use of technology could produce a sense of security in the patients diminishing the level of risk. They also considered the possibility that the technology could be a tool to make better clinical decisions and to achieve closer patient care.

Favorable effects were also verified for a single preventive home visit by a trained professional40 provided to community dwelling older adults. In this case, the intervention resulted in postponing progression in tiredness in daily activities for up to one year. The authors of the intervention also described the results obtained in the follow–up at three months,47 however the definition of frailty presented in this study did not include tiredness. In this three months follow-up study47 no changes in frailty prevalence were observed.

Cognitive training designed to stimulate short-term memory, and enhance attention, information-processing skills, and reasoning and problem-solving abilities53 reduced the frailty score from baseline at 12 months (six months after the intervention). Regarding frailty components, the significant improvement was observed in knee strength immediately after the intervention (at six months) and in follow-up assessment (at 12 months). Other frailty components remained unchanged.

Problem solving therapy42 was shown to have no effects on frailty.

Combined multidisciplinary treatment, including nutritional supplementation, physical training and cognitive training53 provided to community dwelling older adults, showed a significant positive impact on frailty prevalence in follow up at three-, six- and 12 months. Physical exercise programs with supplementation were also shown to be effective for preventing the progression of frailty in community dwelling older adults, independently of type of supplement used (protein supplement22 or MFGM49). Protein supplementation in combination with exercise prevented decrease in maximal walking time, but had no effects on maximal walking distance and physical activity. In addition, for good compliers, a significant increase in walking outcomes was observed.22 Exercise and MFGM supplementation had positive long-term effects on all frailty indicators, with the exception of muscle strength.49 Finally, long-term music-based multi task exercise48 (also conducted with community dwelling older adults) improved gait speed and handgrip strength. In addition, pre-frail participants from the continued intervention group were more likely to become robust at four years than participants from the discontinued intervention group.

Effectiveness of interventions to prevent deterioration in secondary outcomes

Data for secondary outcomes of interest was presented in 19 studies.21-23,29,32,41-44,46-55 These outcomes included quality of life,21,32,42-44 self-rated health,47,48 depression or other mental health-related outcomes,42,43,48,51 cognition,41,42,48,52 functional capacity/mobility,22,23,41,42,46,48,49 ADLs,22,29,41-43,47,50,52,53 analytical parameters including blood analyses,42,49,52 body composition parameters23,41,42,49,52 and nutrition-related outcomes (body weight, body mass index, fat mass and lean mass, score on nutritional tests, etc.),22,42,48,52 and adverse outcomes23,41,42,44,48,51-54,55 (see Table 7). The presentation of data regarding secondary outcomes followed the categories of interventions provided above.

All physical exercise programs delivered in classes focused on the outcomes of functional capacity/mobility. These were a multicomponent exercise program,41 resistance training with nutrition consultation,42 and a functional circuit-training program.46 All were shown to have beneficial effects on the functional capacity or mobility outcomes. More specifically, the multicomponent exercise program41 provided to institutionalized patients improved Timed Up and Go Test (TUGT)performance with single and dual tasks, as well as rise from chair and balance. This multicomponent exercise program also enhanced high-density muscle cross-sectional area, reduced incidence of falls and postponed deterioration in ADLs.41 The functional circuit-training program46 delivered to frail older adults improved balance and gait performance, lower body strength and physical functions assessed by Modified TUGT. The positive effects of a functional circuit-training program were observed either immediately after the intervention (at week 12) or in follow-up assessments (at week 36). The intervention combining resistance training with nutrition consultation,42 developed with frail older adults from the community, was revealed to be beneficial for balance and lower body strength. The improvement in balance was observed immediately after the intervention, and maintained up to nine months after the intervention. The improvement in lower body strength was observed only immediately after the intervention, showing significant decrease from baseline in follow-up assessment. The resistance training with nutrition consultation42 also had a positive impact on ADLs immediately after the intervention. Moreover, the follow-up assessments revealed that this intervention significantly increased levels of 25(OH) Vitamin D and decreased body mass index and fat free mass. On the other hand, resistance training with nutrition consultation had no influence on quality of life, mental health-related outcomes (assessed based on Primary Care Evaluation of Mental Disorders), cognitive performance (assessed based on Mini-Mental State Examination) or health care resource utilization.42 The physical exercise sessions with placebo supplementation, provided to community dwelling older women,49 were shown to have a positive impact on TUGT scores. In this study49 skeletal muscle mass or leg muscle mass were also measured, but changes observed on these outcomes were not significant.

Regarding two exercise programs delivered in classes and followed by home-based practice (resistance and balance training53 and Tai Chi55), both were examined from the perspective of adverse outcomes (falls incidence53,55 and number of hospitalizations53). The study on Tai Chi55 revealed that this intervention was effective for reducing the risk ratio for falls incidence. In comparison, the resistance and balance training53 was shown to have no impact (either short-term or long-term) on falls incidence or number of hospitalizations. In the study on resistance and balance training,53 outcomes of dependency in ADLs and in instrumental ADLs were also considered. The differences observed between intervention and the control groups in the course of the intervention, immediately after the intervention and at six month follow up, were shown to be non-significant.

The study on computerized balance training55 performed individually with supervision in the sample of community dwelling older adults focused on the outcome of falls incidence. Between-group analysis indicated no significant difference in changes in the fall-related outcomes between the intervention and control groups.

In the study describing a home-based exercise program43 developed with housebound older adults, the outcomes of quality of life, depression and ADLs were considered. Between-group analyses (performed immediately after 12-week intervention and 12 months after randomization) showed no difference on any of these outcomes.

Providing nutritional supplements alone, including MFGM49 and protein-energy formula,23 had significant positive effects on outcomes related to functional capacity/mobility, but not on outcomes related to body composition, including skeletal muscle mass,49 leg muscle mass49 and mid-arm circumference.23 Protein-energy supplementation also had no impact on the serum level of blood urea nitrogen and creatinine clearance. In relation to the intervention increasing protein-calorie and micronutrients intake,53 the secondary outcomes were dependency in ADLs and in instrumental ADLs, self-reported hospitalizations and self-reported falls. Between-group analyses conducted in the course of the intervention, immediately after the intervention and at 12 months showed that the frequency of occurrence of these outcomes in the intervention group was not significantly different to frequency observed in the control condition.

The secondary outcomes of interest examined for the intervention based on hormone replacement with atamestane and/or dehydroepiandrosterone52 included ADLs, cognition, nutrition-related outcomes (such as body mass index, lean body mass and fat body mass), bone mineral density, and serum concentration of total testosterone, estradiol and dehydroepiandrosterone. In addition, data regarding indicators of generalized atherosclerosis was collected. The analysis of differences between placebo and study agent indicated a post-intervention increase in body mass index in the atamestane and dehydroepiandrosterone (DHEA) groups. Comparatively, the body mass index of the placebo group significantly decreased from baseline. The changes on the other outcomes were not statistically significant.

Secondary outcomes examined in the studies describing interventions based on individually tailored management of clinical condition21,29,32,44,50 were: quality of life21,44 and health-related quality of life,32 independency in ADLs,29,50 probability of survival,44 and health care resource utilization.44 The study describing a six-month intervention developed with frail or pre-frail older adults50 examining the outcome of independency in ADLs was revealed to be not effective for this outcome of interest. On the other hand, continuum care by multi-professional team delivered to older adults discharged from emergency departments29 was shown to improve independency in ADLs up to one year and, simultaneously, to postpone dependency in ADLs up to six months. The study presenting data on effectiveness of the multifactorial interdisciplinary intervention for the health-related quality of life32 has shown that the post-intervention changes observed in the intervention group are not significantly different from those observed in the control group. In the study describing client-centered, individually tailored activity oriented program21 data related to different dimensions of quality of life was presented. The client-centered program, as compared to community care as usual, was shown to improve all analyzed dimensions of quality of life, with the exception of mental health for which a score decrease of 0.1 was observed. However, only the change on bodily pain dimension was statistically significant. Finally, the geriatric evaluation and management of clinical conditions developed with inpatients and outpatients from the Veterans Affairs Medical Centers44 were shown to have a significant impact on some dimensions of quality of life, but not on probability of survival, namely, at discharge the participants from the inpatient intervention group, as compared to inpatient usual care, were found to have lower decrease in dimensions of general function and general health, and improvement in dimensions of bodily pain and energy. Between-group differences in bodily pain were maintained 12 months after the intervention. Regarding groups of outpatients, those who received geriatric evaluation and management of clinical condition were shown to have a lower decrease in general health at discharge and at follow-up at 12 months, lower decrease in energy at discharge and improvement in energy at follow-up at 12 months, and improvement in mental health at follow-up at12 months. The study authors44 also evaluated health care resource utilization. The participants in the inpatient intervention group, as compared with the participants in the inpatient control group, spent more days in hospital, had longer initial hospitalization and higher number of medical and surgical consultations, but they spent less days in long-term care. Differences in health care resource utilization between outpatient groups were not significant.

The secondary outcomes included in the study examining the effectiveness of multi-professional senior meetings47 were self-rated health and ADLs. The multi-professional senior meetings, as compared to the ordinary range of community services, delayed deterioration on both self-rated health and ADLs. The significant positive effect on maintaining independency in ADLs was also found when multi-professional senior meetings were compared with a single preventive home visit. The study, describing a group session51 conducted with participants not at risk of frailty and an individual educational session51 by a geriatrician conducted with participants at risk of frailty, focused on the outcome of depression and adverse outcomes such as death, admission to nursing home and admission to home care program. The post-intervention assessment indicated that the proportion of participants at risk of depression was significantly higher in the control group receiving usual care than the intervention groups. Regarding adverse outcomes, the significant differences were found only for the subgroups of participants at risk of frailty, with participants from the control group showing higher risk of death, admission to nursing home or admission to home care program.

The study describing 18-month home visits by nurses54 provided data about healthcare resource utilization (including hospital admittance) and adverse outcomes (such as acute hospital visit, institutionalization and mortality). Between-group analyses revealed no statistically significant difference on any of the outcomes measures. However, when the subgroup analysis based on scores in self-rated health and number of comorbid chronic conditions were conducted, some relevant effects were observed. Namely, participants from the intervention group who achieved the poorest score in self-rated health had a higher risk of hospital admission, and participants from the intervention group that had two or more chronic conditions had a higher risk of acute hospital visits. The study describing single preventive home visit by a trained professional47 presented data on self-rated health and ADLs. The assessment conducted at three months indicated that a single preventive home visit, as compared to the ordinary range of community services, was more likely to postpone deterioration in self-rated health, but not in ADLs.

Six month cognitive training developed with community dwelling frail older adults53 was shown to have no beneficial effects on dependency in ADLs and in instrumental ADLs, self-reported hospitalizations and self-reported falls.

No significant differences on healthcare-resource utilization were also reported in relation to problem solving therapy provided to community dwelling frail older adults.42 On the other hand, in the problem solving therapy group, body mass index and fat free mass decreased significantly from baseline, and the levels of 25(OH) Vitamin D increased significantly (all at 12 months). Moreover, this therapy had significant positive effects on mental health-related outcomes, quality of life and ADLs (all at three months) and functional capacity/mobility (at three, six and 12 months). However, in comparison to the control condition consisting of educational booklets, only follow-up changes on outcomes related to functional capacity/mobility were shown to be significant.42

In relation to combined multidisciplinary interventions the secondary outcomes of interest were self-rated health status,48 cognitive performance,48 mental health-related outcomes,48 nutrition-related outcomes,48 dependency in ADLs and in instrumental ADLs,53 functional capacity/mobility,22,48,49 body composition parameters49 and adverse outcomes.48,53 In the study examining the effectiveness of treatment consisting of nutritional, physical and cognitive components,53 the changes on secondary outcomes (including dependency in ADLs and in instrumental ADLs, self-reported hospitalizations and self-reported falls) were assessed three times, in the course of the intervention (at three months), immediately after the intervention (at six months) and at the follow-up at six months. At no point were significant differences from the control condition (standard care plus placebo) observed. Both studies describing exercise programs with supplementation22,49 focused on the outcomes of functional capacity/mobility. The MFGM supplementation with exercise training provided to women from the community49 was shown to have a positive impact on functional capacity/mobility and some hematological parameters. However, this MFGM/exercise-based intervention49 had no influence on skeletal muscle mass or leg muscle mass. Regarding home-based exercise with dietary protein supplementation,22 there were no significant effects on functional capacity/mobility. On the other hand, home-based exercise with dietary protein supplementation stabilized body mass index and postponed deterioration on the mini nutritional assessment score, and in the instrumental ADLs. Finally, after continued intervention of music-based multitask training,48 the community dwelling older adults who had increased risk of falling had better performance on gait speed (in both single and dual tasks) and balance. They also did better on the TUGT and five-times-sit-to-stand test. The continued intervention of music-based multitask training also significantly reduced risk of falls and multiple falls. However, this intervention had no effect on self-rated health status, cognitive performance (assessed based on Mini-Mental State Examination and Clock-drawing test), levels of depression and anxiety, and nutrition-related outcomes such as body mass index or Mini Nutritional Assessment score.48

The influence of degree of frailty on the effectiveness of interventions

Three studies22,29,44 examined the influence of degree of frailty on the effectiveness of the applied intervention. Eklund et al.29 examined whether the baseline differences in the level of frailty (measured based on CHS criteria) had modifying effects on ADL outcome and found that this confounding variable had no significant impact for the continuum care results. In Cohen et al.,44 subgroup analyses were conducted aiming to show whether the main effects of inpatient and outpatient geriatric evaluation and management depend on the functional status of patients. Functional status included indicators of basic and instrumental ADLs, both used for frailty measurements. Low functional status was defined in terms of assistance required with at least three ADLs, and high functional status in terms of assistance required with less than three ADLs. This variable had no influence on the main effects observed in the study.44 Bonnefoy et al.22 conducted exploratory subgroup analysis comparing good compliers to poor compliers. The authors assessed the participants’ compliance using diaries, participants’ knowledge of exercise during the final evaluation, protein supplement bag counts and interviews of home helpers supervising delivery of the intervention, with a compliance rate of 50% considered as satisfactory. The groups of good and poor compliers differed before the intervention on the Physical Activity Scale for the Elderly score and on walking speed, both considered as frailty indicators. The good compliers had better baseline performance on the Physical Activity Scale for the Elderly and better baseline performance on walking speed. After the four-month home based exercise program with dietary protein supplementation, good compliers, as compared with poor compliers, improved maximum walking distance and maximum walking time in 29.15% (first quartile: 0.0; third quartile: 66.7) and 33.3% (first quartile: -20.0; third quartile: 50.0), respectively. The change in both variables was significantly different from that observed in the control group (maximum walking distance: p = .007; maximum walking time p = .004).

Other factors moderating the effectiveness of interventions

Other factors moderating the effectiveness of interventions were examined in eight studies.22,23,29,42,44,51,54,55 In one of these studies, Bonnefoy et al.22 analyzed the relevance of good compliance to the home based exercise with dietary protein supplementation intervention program. The subgroup of good compliers, identified by the study authors,22 had fewer falls within the six months before the intervention, higher baseline score on the Mini Nutritional Assessment test, higher baseline energy intake, better baseline physical performance and walking speed, and better baseline performance in ADLs and instrumental ADLs. Regarding post-intervention results, good compliers benefited significantly more on the maximum walking distance and maximum walking speed, with improvement about 30% higher than the subgroup of poor compliers. A logistic regression analysis showed that the best predictor of good compliance was the score on the test examining instrumental ADLs (OR for each 1-point increase in instrumental ADLs score = 2.84, 95% CI 1.52; 5.31, p = .0011).

Subgroup analyses examining the potential moderating effect of baseline characteristics were also performed by van Hout et al.54 These authors showed that among participants with the poorest self-rated health (EuroQol Quality of Life Scale score < 55), the participants who received an 18-month intervention consisting of nurse home visits had a significantly higher risk of being admitted to a hospital than those who received usual care (intervention subgroup: OR = 1.95, 95% CI 1.2; 3.1, p = .005). In addition, a higher risk of an acute hospital visit was found among participants included in the intervention group who had two or more chronic disease (OR = 1.6, 95% CI 1.04; 2.4, p = .03). According to study authors54 the higher odds of hospital admittance and acute hospital visits, observed in the subgroups of intervention participants may be explained by an increased awareness of the participants concerning the treatability of their health status, as a result of the nurse assessment.

In Cohen et al.,44 subgroup analyses focused on functional status (for the detailed description see previous section) age (> 75 versus ≤ 75 years), Charlson comorbidity index (low with score ≤ 2, and high with score > 2) and the year of enrollment. According to the study authors,44 none of these baseline characteristics had any modifying effect on the results of the intervention based on inpatient or outpatient geriatric evaluation and management. However, no statistical data corroborating this conclusion was provided.

In the study investigating geriatric intervention in individual sessions or group sessions, with participants determined as at risk or not at risk of frailty, with usual care as a control condition, Monteserin et al.51 performed logistic regression in order to identify multivariate predictors of likelihood of reversing from risk of frailty to healthy status (described by the authors as a “reversible risk of frailty”), evaluating data of patients at risk of frailty only, using information from the comprehensive geriatric assessment. The authors identified the following variables as multivariate predictors of reversible risk of frailty: younger age (OR = .89, 95% CI 0.82; 0.99), low consumption of medication at baseline (OR = .77, 95% CI 0.63; 0.93), not being at risk of depression at baseline (OR = 3.68, 95% CI 1.39; 9.70) and the intervention itself (OR = 3.08, 95% CI 1.21; 7.82).51

To obtain adjusted effects of two exercise approaches (Tai Chi and computerized balance training) on occurrence of falls and injurious falls, Wolf et al.55 examined potential baseline risk factors for falls, including variables such as age, gender, currently working for pay, volunteer status, cognitive status, scores in the depression test, scores in the instrumental ADL test, body mass index, trouble falling asleep, waking up during the night, feeling rested in the morning, cataract history, fallsin previous year, fear of falling and fall efficacy score. Fall occurrence in past year, fear of falling and trouble falling asleep were identified as significant risk factors for fall occurrence. Injurious falls were associated with falls in the last year (RR = 3.104, 95% CI 1.476; 6.530, p = .003) and fear of falling (RR = 1.466, 95% CI 1.039; 2.040, p = .029), but not with trouble falling asleep (RR = 0.915, 95% CI 0.598; 1.399, p = .680). However, there were no significant treatment differences for time to one of more falls before and after adjusting for covariates (see Table 7).55

Chan et al.42 observed that at the end of the three-month intervention the improvement rate in the exercise and nutrition consultation group was 45% and in the problem solving therapy group it was 44%. However, after adjusting the post-treatment results for multiple confounding variables, including baseline characteristics, such as age, gender, Mini-Mental State Examination scores, healthcare resource utilization, EuroQol Quality of Life Scale score, fat free mass, body mass index, one-leg stand and 25 (OH) Vitamin D levels, only improvement in the exercise and nutrition consultation group, as compared to the control group, remained significant.

In the study examining the effectiveness of continuum care provided to the older adults discharged from emergency departments, with usual care as a control condition, Eklund et al.29 tested whether the baseline differences in the Mini-Mental State Examination score or self-rated health had influenced the ADL and frailty outcomes. The authors stated that no modifying effects of the referred variables were found; however no statistical data corroborating this conclusion were provided.

Finally, Kim and Lee23 investigated the preventive effect of protein-energy supplementation among frail older people with low socioeconomic status. To identify the factors that determined the changes in nutritional and functional status during the study period (12 weeks), the authors performed Spearman's correlations, showing that change of physical functioning was significantly correlated with protein intake (rs = .23; p = .037) and mean adequacy ratio calculated from nutrient adequacy ratio for the intake of energy, protein, and 11 micronutrients (rs = .25; p = .023). The study authors also found a significant correlation between change in mid-arm circumference and change in Short Physical Performance Battery (rs = .31; p = .004). On the other hand, no significant correlations between change of physical functioning and energy intake, essential amino acid intake, body weight or mid-arm circumference were found. There was also no correlation between change in Short Physical Performance Battery and change in dietary intake data or body weight.23

Economic evidence of interventions preventing frailty

Two of the included studies32,44 presented economic data. The characteristics of these studies are summarized in Table 8.

Table 8
Table 8:
Characteristics of included studies examining economic data

The study developed by Fairhall et al.32 compared costs and cost-effectiveness of a 12-month multifactorial interdisciplinary intervention targeting identified frailty characteristics versus usual care from the community services and general practitioner. This study included 241 older adults with frailty and with a life expectancy exceeding 12 months. The participants were recruited after discharge from the Division of Rehabilitation and Aged Care Service (Sydney, Australia) between January 2008 and June 2011.32 In the study conducted by Cohen et al.,44 the cost of an intervention consisting of inpatient and outpatient geriatric evaluation and management was examined, and was compared with inpatient and outpatient usual care. This second study had a two-by-two factorial design and included 1388 stabilized patients with frailty from 11 Veterans Affairs Medical Centers (USA) that received either care in an inpatient geriatric unit or usual inpatient care, followed by either care at outpatient geriatric clinic or usual outpatient care. The patients were enrolled in the study between August 1995 and January 1999.44

Data related to economic and health related outcomes reported in both studies are presented in Table 9. In relation to the study developed by Fairhall et al.,32 the total cost of a 12-month multifactorial interdisciplinary intervention targeting identified frailty characteristics was AUD183,422, with an average cost per participant of AUD1528. Between-group differences in costs related with hospital admissions, general practitioner consultations, nursing or other health professional appointments, permanent and respite residential care, transport and home help were not significant. Regarding meal delivery, the mean cost was $255 more in the intervention group (95%CI −89; −421, p = .003), compared with the control group. At 12 months the reduction of frailty prevalence in the intervention group was significantly higher than in the control group (absolute difference: 14.7%, 95%CI 2.4%; 27.0%, p = .02). However, at three months only a marginally significant between-group difference in frailty prevalence was observed (11.3%, 95%CI −23.3%; 0.7%, p = .07). The change in the levels of quality of life measured at three and at 12 months and the controlled for baseline score was not significantly different between the intervention and the control groups (at three months: −0.04, 95%CI −0.10; 0.03, p = .24; at 12 months: 0.01; 95%CI −0.07; 0.10, p = .74).32

Table 9
Table 9:
Costs, quality adjusted life years and outcome data reported in included studies
Table 9
Table 9:
(Continued) Costs, quality adjusted life years and outcome data reported in included studies

According to Fairhall et al.,32 in the sample of all participants, the ICER per additional patient experiencing transition from frailty was $15,955. For the “frail” subgroup, this cost was $41,428; for the “very frail” subgroup (patients met more than three CHS criteria for frailty) the intervention was both more effective and less costly than the control condition. A cost-effectiveness acceptability curve showed that the multifactorial interdisciplinary intervention targeting identified frailty characteristics would be cost-effective, with 80% certainty with decision makers’ willingness to pay $50,000 per extra person transitioning from frailty. In the very frail subgroup this value was reduced to $25,000. The improvement in QALYs was similar in both the intervention and control groups. The lack of significant difference was also shown for the subgroup analysis.

The mean costs of initial hospitalization in geriatric evaluation and management units and in usual inpatient care, calculated by Cohen et al.,44 were of $13,449 (± 621) and $10,758 (± 592), respectively (the authors did not provide the information about currency). The observed difference was significant (p < .001). Care after discharge in the inpatient intervention group was similar to the mean cost calculated for the inpatient control group (p = 0.19). The similarity between the inpatient intervention and the inpatient control groups was also observed for mean total cost of care (p = 0.29). In relation to mean costs of care provided in the outpatient intervention and the outpatient control groups, no significant differences were observed (the mean costs of initial hospitalization: p = 0.72; mean costs of care after discharge: p = 0.88; mean total cost of care: p = 0.69). The results obtained by Cohen et al.44 suggested that the intervention based on geriatric evaluation and management provided during the hospitalization period and/or after discharge was more beneficial for frail patients than usual care, at least for the outcomes of functional capacity and mental health, without an increase in overall costs.

Discussion

This review set out to examine the effectiveness of interventions for frailty in older adults, additionally aiming to determine if there is enough information to provide answers to questions of the impact of levels of frailty on effectiveness of interventions, and what factors modify the effectiveness of interventions. Economic evidence was also queried by including studies that examined issues such as cost effectiveness of interventions, alongside the success of those interventions.

While the literature contained a large number of interventions for frail older adults, it became immediately apparent that there were few studies specifically addressing frailty using validated scales or measurements of frailty as initial measures and primary outcome, with a general older population (e.g. not a population with a specific illness such as cancer). After excluding 2121 records and 346 full-text articles that did not meet the study criteria, 32 studies were assessed for quality. Of these, a further 11 were excluded after careful quality appraisal, with the reasons for exclusion at this stage being related to non-experimental designs and low methodological quality. These issues, along with the large number of studies excluded due to lack of validated before-after measures of frailty, suggest that the field is still at an early stage of development, with observational studies being predominant rather than well-constructed randomized controlled intervention trials. The use of well-validated measures of frailty was explored in full in an umbrella review of reviews on screening tools for frailty58 with the conclusion that while there were effective prognostic tools available, further research was needed to investigate whether psychometric properties of these frailty measures translate into effective tools when embedded in the community-based prevention programs, and specifically for use to measure intervention outcomes.

Nevertheless, this review was able to identify 21 randomized control trials of interventions for frailty that met our inclusion criteria. Within these records, post intervention measurements were repeated a second time in eight studies, with the post intervention period varying, up to a follow-up period of four years. Setting and intervention types were heterogeneous, resulting in an inability to perform meta-analysis. However, the inclusion of such variety in studies enabled an overview of the types of interventions that seemed to have more success in preventing, delaying or reversing frailty than others.

What types of interventions for frailty worked?

Exercise and nutrition interventions were amongst the most successful interventions to reduce frailty. Interventions delivered in group sessions were more successful than exercise interventions delivered one-to-one. In comparison, two systematic reviews analyzing the efficacy of exercise-based interventions on frailty36,37 concluded that these interventions seemed to be beneficial for different physical performance-related outcomes; however it was still unclear what type of exercise, its frequency and duration were most effective. None of these reviews separately discussed the findings related to interventions delivered in group and delivered individually. Thus, more studies on this topic are needed before further conclusion on the most favorable physical exercise program can be drawn.

Exercise plus nutrition was shown to be a good combination of interventions to reduce frailty. Combining exercise with nutrition may benefit patients by leading to a range of improvements in frailty that are not achieved when using either exercise or nutrition. For example, a study by Buigues et al.59 (published after November 2015, the search limit date set for this review) found that patients who received a prebiotic product showed improvements in certain aspects of frailty (exhaustion, muscle strength) but not others (weight loss, walking speed, physical activity). The frailty elements that did not change in this study may have changed if participants had also received a physical exercise intervention.

Group discussions and health educational sessions were shown to have little impact on outcomes apart from self-reported tiredness. Home visit by nurses or other professionals had mixed results. While these studies did not examine the impact of home care provision, or prevention of crises, they demonstrated positive effects on frailty or its components, particularly in one case where an alert button was provided in addition to the visits. Even a single preventive home visit was seen to have an effect, but did not make any difference three months later, suggesting that the frequency of visits may need examining more closely.

The only cognitive training intervention included covered issues related to flexibility, day-to-day coping and compensating or planning, such as working memory, problem solving abilities and attention. This showed a significant impact on frailty indices and frailty reduction lasting up to the follow-up at 12 months. Similarly, a novel intervention using play activities program (described in a study published after November 2015, the search limit date set for this review),60 was shown to have a wide range of impacts on psychological functioning, including frailty, life satisfaction and quality of life. However, another psychological, but non-cognitive, intervention of problem solving “therapy” did not have an impact on frailty. The distinction is important here, with the former addressing cognitive function and providing cognitive stimulation, but the latter focusing on therapeutic problem solving support as related to mood and self-efficacy. However, it is noticeable that cognitive training, while broadly seen as effective and supportive of cognitive reserve and coping and compensation in older age,61 is not a common intervention for frailty. Nevertheless, physical interventions, particularly exercise, are known to have an impact on cognition and brain health in older adults62 and further study is needed to elucidate on the relationship between cognitive change and frailty impact. For example, one study63 demonstrated clear relationships between change in cognition and change in outcome frailty measures, in both positive and negative directions. Finally, the studies demonstrated that combinations of interventions were particularly useful, with evidence for exercise and nutrition and cognitive training standing out as having cumulative impacts on frailty.

Who did frailty interventions work for?

Studies reported a variety of age ranges, gender distribution, and variously included people at risk of frailty, pre-frail and frail people. In terms of age, interventions showed impact across the age ranges. The physical exercise programs were shown to be effective in studies with participants ranging in age from 65 upwards. For example, one study with the “oldest-old” institutionalized participants with a mean age of 91.9 years41 showed significant effects on components of physical frailty such as gait speed and grip strength. Some researchers examined age as a moderator of the impacts in their studies, although few reported detailed comparisons of age groups. In the study43 investigating geriatric intervention in individual sessions or group sessions was found that younger age within their older frail group was a predictor of the likelihood to revert to being robust from a state of frailty, although considerably less so than the impact of the intervention itself. Other studies42,44,55 reported examining the effect of age as one of a set of modifiers in analyses on impact of their intervention, but reported that there were no impacts on frailty outcomes.

No study directly compared effectiveness by gender, although some examined gender as a potential moderator or risk factor. Given that this was often in the context of a range of effects (e.g. Chan et al.33) whether or not gender moderates effects is not yet clear. However, while studies varied in terms of the numbers of men and women recruited into the study, physical activity and physical activity plus nutritional supplementation interventions were effective for both men and women. This is important given the higher prevalence of physical frailty for older women, and related higher falls and fracture risks.6,24,64 However, nutrition supplementation on its own had a less clear impact, with studies that included either 100%49 or a significant majority23 of women having mixed results, but a study with a more even mix of men and women53 showing an overall significant effect on frailty measures. Given the higher evidenced frailty amongst older women, and specific issues such as hormone related muscle mass loss and osteoporosis that are gender related, the usefulness of frailty interventions by gender is a crucial issue for further research.

In addition, other types of interventions varied by their gender distribution of participants, but there was no clear pattern of types of interventions that had different implications for men and women. For example, one study44 with mainly male patients examining inpatient multidisciplinary screening and detailed care plan worked well at least at discharge. A similar study with 55% women29 did not show effects. On the other hand, other multi-disciplinary personalized care support interventions with a mix of male and female patients did work well32 as did those with mainly women patients.21 However, there is no clear reason to hypothesize possible gender related differences in impact for care interventions as there may be for exercise plus nutrition, given the differences in physical frailty development in older women and men.

We examined the influence of initial levels of frailty on the impact of the interventions where this was available. While exercise and nutritional interventions clearly worked across levels of frailty, based on available information on the included participant samples, this was less clear for other types of intervention. Interventions based on individually tailored management in community based older adults seemed to have an impact on frailty outcomes when the participants were indicated as frail,21,32 but not when they were mixed frail and pre-frail,50 although there may have been other less obvious differences between the studies such as context (Belgium and Australia versus Taiwan), adherence to the intervention protocol of the staff delivering it (implementation fidelity),65 or the actual content of the management in the community. For example, the management in the community that occurred in the successful study32 had very salient structured and well supported physical exercise components with individual physiotherapist instruction that was not described in other studies. In a study on continuum care for older adults who were discharged from the emergency department29 no difference in frailty outcomes was seen. However, the authors speculated that the standard of ordinary care for control participants was high and as such may have confounded the results.

Three studies22,29,44 examined whether baseline differences in the level of frailty had modifying effects on intervention outcome measures. There was no impact of initial level of frailty on ADL based outcomes of the continuum care program.29 In another study44 low or normal baseline functional status (again assessed using ADLs) had no influence on the effects of an inpatient geriatric care and management intervention. Bonnefoy et al.'s analysis of good and poor compliers to their exercise plus protein supplementation study also provided insight into the impact of initial levels of frailty.22 The people who turned out to be good compliers had better baseline performance on the Physical Activity Scale for the Elderly and walking speed and improved significantly more than poor compliers and the control group. The difficulty in interpreting this finding is that initial frailty levels and compliance are confounded. The relationship between extent of frailty and amount of improvement possible in an exercise plus supplementation intervention remains unanswered, with calls for studies that carefully examine the impact of level of frailty on prognosis made in previous studies58 being reiterated here in the context of interventions. Nevertheless, it is possible to conclude that impacts are evidenced across the range of not frail, pre-frail and frail older adults, genders and age.

Do frailty interventions have further impacts on secondary outcomes?

In addition to frailty, studies described findings relating to secondary outcomes such as functional and mobility outcomes, quality of life, self-rated health, depression or other mental health-related outcomes, cognition, functional capacity/mobility, ADLs, analytical parameters including blood analyses components, body composition parameters and nutrition-related outcomes, and adverse events. Functional capacity and mobility were common secondary outcomes in the physical exercise41,42,46 and nutrition interventions,23,49 with participants even into extreme old age showing improved indices such as ability to rise from a chair and balance, gait performance and lower body strength, with some improvements still being evident up to nine months later. Exercise interventions producing such changes included resistance training, balance and gait retraining, and strength training. Other related secondary outcomes of the exercise-based programs included better dual task walking performance and reduction of falls.41 Computer based balance training55 and home based exercise plus supplementation22 did not have these positive outcomes for mobility and safety related indices, but some nutrition supplementation interventions examined did so even when applied in the absence of an exercise intervention.

Impact on independence indices such as ADLs was shown for one of the exercise interventions with nutrition consultation42 and by continuum care,29 and postponement of decline in ADLs was shown for a multicomponent exercise program in institutionalized people over the age of 85.41 Impact on ADLs was not reliably shown for exercise and nutrition interventions, multi-professional senior meetings and for problem solving therapy. Other interventions that had no impact on frailty were nevertheless shown to have potential for ADLs, notably, the home-based exercise with dietary protein supplementation postponed deterioration in instrumental ADLs.22

Quality of life was assessed in several studies but was only shown to improve in programs where participants were given individually tailored evaluation and management or personalized care, or specific emotionally based psychological therapy (the problem solving therapy).21,44 Self-rated health was also examined by some studies and only the interventions with a multi-professional seniors meeting and a single preventive home visit showed positive impacts on self-rated health.47 Mental health was also positively affected by the geriatric evaluation and management of clinical conditions developed with inpatients and outpatients from the Veterans Affairs Medical Centers, which also impacted quality of life,44 and the problem solving therapy which was specifically aimed at emotional health.42 In addition, a group session and individual session with a geriatrician also seemed to impact risk of depression with depression being more common in the control group than in the interventions groups.51 Cognitive function was measured only rarely41,42,48,52 and the prevention of its decrease was reported only in the multicomponent exercise-based intervention provided to institutionalized older adults aged over 85 years.

Physiological secondary outcomes were observed for assessments such as overall skeletal or leg muscle mass, but significant changes were not evident.

Impact on adverse outcomes such as falls or hospitalizations was observed in several studies. Tai Chi was confirmed as useful for reducing falls risk,55 but resistance training and computerized balance training was not.55 Likelihood of hospitalization was not clearly reduced by any of the studies, but length of stay and number of consultations were observed to be higher in the inpatient intervention participants, although their overall care utilization was no greater than controls as they spent less time in long term care.44 The individual educational session by a geriatrician conducted with participants at risk of frailty, showed a positive influence on adverse outcomes in that participants from the control group had a higher risk of death or admission to a nursing home or home care program.51

What is the economic evidence regarding interventions for frailty?

Both studies reporting economic analyses32,44 focused on individually tailored management of frailty. The study targeting frailty characteristics with older adults in the community was effective for reducing frailty prevalence and cost savings,32 with average costs incurred in delivering the intervention being $1528 per participant. The obtained data suggested that the examined therapy, as compared to usual care, provided good value for money, especially for very frail persons. The study examining geriatric evaluation and management in inpatient and outpatient care units was shown to have a more favorable impact for frailty outcome than usual care, but only for the hospitalized patients.44 On the other hand, after receiving the individual tailored treatment, both inpatients and outpatients experienced significant improvement in quality of life. Total costs at one year were similar for the intervention (about $36,000) and usual care (about $37,000) groups, with the initial hospitalization of the inpatient subgroup being most costly in the intervention group than in usual care.

Limitations of the included studies

The studies included in this review presented several methodological weaknesses, with the most prominent being lack of participant blinding to treatment allocation, or unclear information about this issue (however, in most cases due to the nature of the applied interventions, the practical difficulties of the blinding process were recognized). Only eight studies provided clear information about the tools used for the assessment, indicating that their versions were culturally adapted or validated, while only nine studies clearly stated about equality of treatment between the intervention and the control groups, other than the intervention in question. Thus, we cannot rule out the possibility of bias arising from selection, performance and detection within the included studies.

In relation to studies reporting data on the economic component of this review, one such study was excluded due to insufficient methodological quality of the clinical/medical component, and only two were included for analysis. Both studies presented data on individually tailored management of the clinical condition. However, due to the different characteristics of the included samples (participants recruited from the community vs inpatient and/or outpatient care) it was not possible to proceed with a meta-analysis and obtain a pooled estimate of effects. In one of these studies44 various methodological weaknesses were observed. In addition, neither of the studies conducted sensitivity analyses to investigate uncertainty in estimates of costs or consequences, and both studies failed to present the issues of concern to users. This clearly reduces the validity of the extracted evidence, and sends a strong message that studies evaluating the economic aspects of interventions for frailty are needed.

Limitations of the review

The current review has some limitations. First, the search was undertaken in 2015 and as such it is over 12 months old. To overcome this limitation, the MEDLINE and CINAHL databases were searched for studies published in English from December 2015 to February 2017, using a phrase AB frail* AND AB (intervention OR treatment OR therapy OR program) AND AB old*. The studies that met inclusion criteria of this review (n = 2) were introduced in the discussion.59,60 However, the review authors did not evaluate the methodological quality of these two studies and therefore their findings need to be treated with some caution. Second, the search was limited to articles published in the languages known by the group members and only papers published in English were included. The exclusion of papers in other languages could have limited access to studies with significant findings related to our aim that were developed in cultural and socio-economic contexts different from those considered in this review. Third, a large number of studies was excluded because of the lack of the operational definition of frailty used to select participants and/or because of the use of different criteria for frailty assessment before and after the intervention. This fact is highly important since it suggests that the possibility that the frailty concept is excessively used for the description of ageing processes, and not only for the description of a specific and assessed age-related state of decreased physiological reserves characterized by a weakened response to stressors and an increased risk of poor clinical outcomes. This fact also reflects the lack of consensus on frailty definition, which limits substantially the capacity to compare the obtained findings and to subsequently generalize them to the different clinical and economic contexts. For example, from 21 studies included in this review only nine used the same overall operational definition of frailty (based on CHS phenotypic indicators), and even those nine studies showed a significant variation on the operationalization of specific indicators used in the assessment and on the definition of cut-off points. Moreover, there were some outcomes (such as ADLs) that in some studies were considered as indicators of frailty,21,44 and in other studies22,29,41,42 as complementary outcomes. We decided to follow the structure proposed in the protocol34 and report these outcomes in separate sections (dedicated to primary versus secondary outcomes), which perhaps made the findings related to specific outcomes more difficult to compare.

Finally, due to the variation in outcomes assessed across included studies, and the reduced number of studies focusing on the same intervention and different characteristics of included samples, we were unable to conduct meta-analyses to more efficiently explore data from the included studies. Consequently, it was impossible to estimate the effect size difference between individuals receiving specific interventions and individuals in control conditions, which reduces the statistical power and generalizability of this review's findings.

Conclusion

This review has demonstrated mixed effectiveness of frailty interventions. We can conclude that physical exercise interventions are generally effective in reducing or reversing/postponing frailty but only where classes or group based interventions are used – evidence for home based or computerized training was not found. Geriatric management and continuum care was not found to be universally effective in terms of changing frailty status but differences between healthcare systems and interventions in the studies that did and did not find effects on frailty need consideration. For example, some authors65 noted that in instances where there were functional improvements, but not changes in frailty status, it might be that the intervention care and the background healthcare were not sufficiently different (particularly in developed countries with a high standard of care) to achieve a change in global physical frailty phenotype scores. Likewise for nutritional supplementation studies, those involving people with poor background nutrition will show greater effects than those in people who are generally well-nourished.

Home visits were widely supported, even at quite a low level such as a single visit, with added features such as provision of an alert button possibly increasing nurse involvement and patient confidence. Secondary impacts on ADLs or physical mobility were commonly supported, suggesting the further impact of successful interventions, but consistency in the range of secondary outcomes assessed was not found. Finally, the impact of frailty interventions on secondary issues such as quality of life, depression or cognition is much needed, and analyses that demonstrate the relationships between changes in frailty as a result of the intervention and these secondary outcomes that contribute to the wellbeing of older persons and costs to healthcare are also called for.

Recommendations for practice

This review has confirmed the view that frailty is malleable, with effects of interventions on frailty assessments demonstrated for men and women, for frail and pre-frail and for some very old participants indeed, including those in hospital or in long term institutional care. This accumulation of findings, albeit from a range of interventions, suggests that intervention for frailty is worthwhile across the range of frail patients, with strong evidence for physical exercise plus nutrition, and other combinations of evidence based intervention such as cognitive training. However, we can also make some suggestions as to what does not work. For example, exercise interventions without group support seemed less likely to work, and multi-disciplinary care worked well for frailty when it included specific interventions such as supported exercise, but not when only continuum care was coordinated. However, such care based interventions that did not have an impact on frailty itself still had other positive impacts, for example, on independent function. The economic evaluations of individually tailored management of frailty condition developed with older adults recruited from different settings (primary care, hospital care) was shown to be dominant as compared to usual care, with the intervention provided to older adults from the community being more effective and more probably cost saving, and the intervention conducted with inpatients and outpatients being more effective and equal cost. However, further research with more rigorous methodology is required to reinforce the current evidence and to increase transferability of findings.

Based on the findings of this systematic review, the following recommendations for practice can be made:

  • Physical exercise programs provided in groups to pre-frail and frail older adults that are institutionalized32 or that live in community42,46,49 are an effective intervention for reducing frailty level (Level of Evidence – 1a) or, at least, for positively changing some of the frailty indicators. Thus, based on current evidence, health professionals are strongly recommended to provide physical exercise program conducted in classes or in groups to prevent progression of pre-frailty and frailty in community dwelling and institutionalized older adults (GRADE A).
  • Physical exercise programs delivered in classes with home-based practice to non-frail, pre-frail and frail older adults from the community53,55 are an effective intervention for reducing frailty level (Level of Evidence – 1c), improving or postponing decline of grip strength, improving gait speed and reducing fear of falling (Level of Evidence – 1c). Thus, based on current evidence, health professionals may provide physical exercise programs conducted in classes with home-based practice to prevent progression of pre-frailty and frailty in community dwelling and non-institutionalized older adults (GRADE B).
  • Physical exercise programs provided individually to non-frail, pre-frail and frail community dwelling older adults43,55 have been shown to have no impact on mobility (Level of Evidence – 1c), functional status or biomedical and psychosocial variables (Level of Evidence – 1c). Thus, based on current evidence, the recommendation of physical exercise programs provided individually for preventing progression of pre-frailty and frailty in community dwelling older adults is not supported.
  • Nutritional supplementation provided to pre-frail and frail older adults from the community23,49,53 is an effective intervention for increasing physical activity (Level of Evidence – 1a), for reducing long-term exhaustion and for improving energy intake (Level of Evidence – 1c); however, it seems to have no impact on body weight. Thus, based on current evidence, health professionals are strongly recommended to provide nutritional supplementation to prevent progression of pre-frailty and frailty in community dwelling older adults (GRADE A).
  • Group sessions for persons not at risk of frailty and individual educational sessions by a geriatrician for persons at risk of frailty, provided to non-institutionalized older adults,51 are an effective intervention for reverting frailty condition (Level of Evidence – 1c), and the group sessions with one home visit conducted with older adults from the community40,47 is an effective therapy for postponing progression in tiredness in daily activities for up to one year (Level of Evidence – 1c/2RCTs). Thus, based on current evidence, health professionals may provide group sessions and individual educational sessions to prevent progression of pre-frailty and frailty in community dwelling and non-institutionalized older adults (GRADE B).
  • Home visit(s) from a nurse or other health professionals, provided to frail45,54 and non-frail40,47 older adults from the community, have been shown to have no impact on frailty core indicators (Level of Evidence – 1c/2RCTs), on disability in ADLs (Level of Evidence – 1c) or on physical and mental component of health status (Level of Evidence – 1c). However, a single preventive home visit by a trained professionals delivered to non-frail older adults from the community40 has been shown to be an effective therapy for postponing progression in tiredness in daily activities for up to one year (Level of Evidence – 1c), and the home visits from a nurse combined with use of alert button provided to frail older adults have been shown to be an effective therapy for reducing frailty prevalence (Level of Evidence – 1c). Thus, based on current evidence, health professionals may provide home visit(s) for preventing progression of pre-frailty and frailty in older adults (GRADE B).
  • Combined multidisciplinary treatment integrating physical activity and nutritional supplementation is an effective intervention for preventing decrease in maximal walking time in community dwelling older adults that are at risk of becoming frail31 (Level of Evidence – 1c), and for improving some frailty indicators in community dwelling women with frailty49 (Level of Evidence – 1c). Combined multidisciplinary treatment including nutritional supplementation, physical training and cognitive training is an effective intervention for reducing frailty level, especially for improving knee strength and energy level, in pre-frail and frail older adults from the community53 (Level of Evidence – 1c). Continued long-term intervention of music-based multitask training provided to community dwelling older adults at increased risk of falling48 is an effective intervention for preventing decline in gait speed and grip strength, and for reverting frailty status in pre-frail persons48 (Level of Evidence – 1c). Thus, based on current evidence, health professionals may provide combined multidisciplinary treatment for preventing progression of pre-frailty and frailty in community dwelling older adults (GRADE B).
  • Cognitive training provided to pre-frail and frail older adults from the community53 is an effective intervention for reducing frailty level and improving knee strength (Level of Evidence – 1c). Thus, based on current evidence, health professionals may provide cognitive training to prevent progression of pre-frailty and frailty in community dwelling older adults (GRADE B).
  • Problem solving therapy provided to frail older adults from the community42 has been shown to have no impact on improvement in frailty, gait speed, grip strength, weight, exhaustion or physical activity level (Level of Evidence – 1c). Thus, based on current evidence, the recommendation of problem solving therapy for preventing progression of pre-frailty and frailty in community dwelling older adults is not supported.
  • Hormone replacement with atamestane and/or dehydroepiandrosterone52 has been shown to have no impact on isometric grip strength, leg extension power or physical performance of frail independently living men (Level of Evidence – 1c). Thus, based on current evidence, the recommendation of the hormone replacement for preventing progression of pre-frailty and frailty in community dwelling older adults is not supported.
  • Individually tailored management of clinical condition is an effective intervention for improving physical performance in frail inpatients and outpaitents44 (Level of Evidence – 1c), and for reducing basic ADL dependency in older adults who are from the community and who have functional problems21 or who are frail and require hospital care44 (Level of Evidence – 1c), but it seems to have no impact on instrumental ADLs44 (Level of Evidence – 1c). On the other hand, individually tailored management of clinical condition has mixed effects for decreasing the core frailty indicators in pre-frail and frail older adults from the community29,32,50 and hospitals29 (Level of Evidence – 1c/3RCTs). In addition, individually tailored management of frailty condition, as compared to usual care, has a high probability to be cost saving when provided to community dwelling older adults32 (Level of Evidence - 6), does not increase the total costs of care when developed with inpatients44 (Level of Evidence - 6), and is equal cost when delivered to oupatients44 (Level of Evidence - 6). Thus, based on current evidence, we recommend adopting individually tailored management of frailty condition on a larger-scale basis (GRADE B).

Recommendations for research

Despite the positive findings, there are still many unresolved issues. The impact of an initial level of frailty or gender on the benefits of different interventions still needs clarification to inform personalized frailty intervention. The interaction between outcomes, such as impact of physical exercise or nutrition on mediators such as cognition, depression or self-efficacy in terms of the outcomes on frailty also needs further investigation. Significantly, in such extensive literature there were remarkably few intervention types that fulfilled the inclusion criterion of measuring frailty before and after an intervention, and few that employed careful RCT methods, preventing full systematic comparison or conclusions. Finally, there is a need for well-conducted economic evaluations of frailty interventions performed in different decision making contexts.

Acknowledgements

We acknowledge the support of the FOCUS project (Frailty management Optimisation through EIPAHA Commitments and Utilisation of Stakeholders input) which is a three-year project co-financed by the Consumers, Health, Agriculture and Food Executive Agency (CHAFEA), under the power delegated by the European Commission (Grant Agreement 664367 - FOCUS).

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Figure

We acknowledge the contribution of other members of Focus project: Alessandro Nobilia, Ana González Segurab, Ana M. Martinez-Arroyoc, Donata Kurpasd, Enrique de la Cruz Martínezb, James Browne, Lex van Velsenf, Maria Bujnowskad, Rachel Shawe, Vicente Gilc, Vicente Llorensc who were co-responsible for elaboration of PICO questions and structuring of PICO components of this systematic review protocol.

a IRCCS Istituto Di RicercheFarmacologiche “Mario Negri”

b EVERIS Spain S.L.U

c ESAM Tecnología S.L.

d Wroclaw Medical University

e Aston Research Centre for Healthy Ageing, Aston University

f Roessingh Research and Development

The authors would like to acknowledge Daniela Cardoso for her contribution to the protocol development, and Ana Gois and Mariana Santos for their collaboration under supervision in the organization of the analyzed materials.

Appendix I: Search strategy

Search – November 25th, 2015

MEDLINE

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CINAHL

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Embase

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Cochrane Central Register of Controlled Trials

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Scopus

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SciELO

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OpenGrey

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Banco de teses da CAPES (www.capes.gov.br)

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Dissertation Abstracts Online (e-Thos)

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ProQuest –Theses and Dissertations

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Appendix II: Excluded studies based on assessment of methodological quality

Pseudo-randomized control trials (one group)

Nomura T, Nagano K, Takato J, Ueki S, Matsuzaki Y, Yasumura S. The development of a Tai Chi exercise regimen for the prevention of conditions requiring long-term care in Japan. Arch Gerontol Geriatr. 2011;52(3):e198–203.

Reason for exclusion: Methodological appraisal value below minimum cut-off score. It was unclear whether the outcomes were measured in a reliable way. The study authors did not describe and did not include in the analysis the outcomes of people who withdrew. The critical appraisal items related with randomization, blinding, allocation and comparability of the groups were not considered as the study was conducted with one group only.

De Vries N, van Ravensberg CD, Hobbelen JS, van der Wees PJ, Olde Rikkert MG, Staal JB, et al. The Coach2Move Approach: Development and Acceptability of an Individually Tailored Physical Therapy Strategy to Increase Activity Levels in Older Adults With Mobility Problems. J Geriatr Phys Ther. 2015;38(4):169–82.

Reason for exclusion: Methodological appraisal value below minimum cut-off score. It was unclear whether the outcomes were measured in a reliable way and whether the appropriate statistical analysis were used. The critical appraisal items related with randomization, blinding, allocation and comparability of the groups were not considered as the study was conducted with one group only.

Before and after studies

Sugimoto H, Demura S, Nagasawa Y, Shimomura M. Changes in the physical functions of pre-frail elderly women after participation in a 1-year preventative exercise program. Geriatr Gerontol Int. 2014;14(4):975–82.

Reason for exclusion: Methodological appraisal value below minimum cut-off score. The composition of the study groups was intentionally different (healthy and pre-frail participants), thus all the critical appraisal items related with randomization, allocation and comparability of the groups were rated negatively. It was unclear whether the appropriate statistical analysis were used.

Yamada M, Arai H, Uemura K, Mori S, Nagai K, Tanaka B, et al. Effect of resistance training on physical performance and fear of falling in elderly with different levels of physical well-being. Age Ageing. 2011;40(5): 637–41.

Reason for exclusion: Methodological appraisal value below minimum cut-off score. The composition of the study groups was intentionally different (robust and frail participants), thus all the critical appraisal items related with randomization, allocation and comparability of the groups were rated negatively. The outcomes of people who withdrew were not described and included in the analysis. It was unclear whether the outcomes were measured in a reliable way.

Pseudo-randomized control trial (two groups)

Yamada M, Arai H, Sonoda T, Aoyama T. Community-based exercise program is cost-effective by preventing care and disability in Japanese frail older adults. J Am Med Dir Assoc. 2012;13(6):507–11.

Reason for exclusion: In addition to lack of group randomization there was unclear information about allocation and blinding procedures, and insufficient data about tools used for the outcomes assessment. It was also unclear whether the groups were treated identically other than for the named interventions.

Randomized controlled trials

Binder E, Schechtman KB, Ehsani AA, Steger-May K, Brown M, Sinacore DR, et al. Effects of exercise training on frailty in community-dwelling older adults: results of a randomized, controlled trial. J Am Geriatr Soc. 2002;50(12):1921–8.

Reason for exclusion: Not all outcomes were measured in the same way for all groups. There was also unclear information about allocation and blinding procedures, and about the treatment of groups other than for the named interventions.

Chin A Paw MJM, de Jong N, Schouten EG, Hiddink GJ, Kok FJ. Physical exercise and/or enriched foods for functional improvement in frail, independently living elderly: a randomized controlled trial. Arch Phys Med Rehabil. 2001;82(6):811–7.

Reason for exclusion: Those assessing outcomes were not blind to treatment allocation. In addition, it was unclear if the assignment to treatment group was truly random, if participants were blinded to treatment allocation, if the allocation to treatment group was concealed from the allocator, if the outcomes of people who withdrew were described and included in the analysis, and if the groups were treated identically other than for the named interventions.

Kono A, Kanaya Y, Fujita T, Tsumura C, Kondo T, Kushiyama K, et al. Effects of a preventive home visit program in ambulatory frail older people: A randomized controlled trial. J Gerontol A Biol Sci Med Sci. 2012;67(3):302–9.

Reason for exclusion: The outcomes were not measured in a reliable way. There was unclear information about allocation and blinding procedures. In addition, it was unclear if the outcomes of people who withdrew were described and included in the analysis and if the control and treatment groups were comparable at entry.

Kwon J, Yoshida Y, Yoshida H, Kim H, Suzuki T, Lee Y. Effects of a combined physical training and nutrition intervention on physical performance and health-related quality of life in prefrail older women living in the community: A randomized controlled trial. J Am Med Dir Assoc. 2015;16(3):263e1–8.

Reason for exclusion: The outcomes of people who withdrew were not described and included in the analysis. It was unclear if the assignment to treatment group was truly random, if participants were blinded to treatment allocation, if the allocation to treatment group was concealed from the allocator, if the groups were treated identically other than for the named interventions, and if the outcomes were measured in a reliable way.

Manor B, Lough M, Gagnon MM, Cupples A, Wayne PM, Lipsitz LA. Functional benefits of Tai Chi training within senior housing facilities. J Am Geriatr Soc. 2014;62(8):1484–9.

Reason for exclusion: The outcomes of people who withdrew were not described and included in the analysis, and the control and treatment groups were not comparable at entry. It was unclear if the assignment to treatment group was truly random, if participants were blinded to treatment allocation, if the allocation to treatment group was concealed from the allocator, and if the groups were treated identically other than for the named interventions. It was also unclear whether the statistical analysis used was appropriate (the authors used the parametric statistical tests in samples with n < 30, without reference to meeting the assumptions underlying these tests).

Rydwik E, Lammes E, Frändin K, Akner G. Effects of a physical and nutritional intervention program for frail elderly people over age 75. A randomized controlled pliot treatment trial. Aging Clin Exp Res. 2008;20(2):159–170.

Reason for exclusion: The allocation to treatment groups was not concealed from the allocator, and the control and treatment groups were not comparable at entry. It was unclear if the assignment to treatment group was truly random, if participants and those assessing outcomes were blinded to treatment allocation, if the groups were treated identically other than for the named interventions, and if the outcomes were measured in a reliable way.

Appendix III: Characteristics of included studies

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Keywords:

frail older adults; frailty; intervention; prevention; systematic review

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