Interventions to prevent, delay or reverse frailty in older people: a journey towards clinical guidelines

The term ‘frailty’ has been used to describe an age-related state of decline and vulnerability characterised by weakness and decreased physiological reserve [1]. Frail older adults are less able to adapt to stressors such as acute illness, surgery, trauma or bereavement, and are at increased risk of falls, institutionalisation, disability and death [2, 3]. The concept of frailty has been operationalised through different definitions to help clinicians, researchers and other stakeholders to identify frail older patients. One of the most commonly adopted definitions is the one used in the Cardiovascular Health Study, known as the Frailty Phenotype or Physical Frailty. It is based on five criteria related to reduced physical reserve, and defines frail and prefrail states based on the number of criteria met [1]. Others sustain a different approach, which views frailty as a multidimensional risk state defined by the accumulation of deficits in different domains, such as cognition and mood, chronic diseases, polypharmacy, functional autonomy and social conditions, using a continuous scale as opposed to category assignment. The Frailty Index by Rockwood et al. [4] is taken as a paradigm of this second approach.

Although the use of different definitions leads to the identification of different target populations and leads to a variation in the estimate of the actual prevalence of frailty [5, 6], the associations between frailty, adverse outcomes, and health and social care utilisation have been invariably demonstrated. This has been common understanding for more than a decade [7] and has led to several initiatives to tackle frailty and its related outcomes.

To add to the international efforts to reduce the impact of frailty, we conducted the FOCUS (Frailty Management Optimisation through EIP-AHA Commitments and Utilisation of Stakeholders Input) project, funded by the European Union’s Third Health Programme (2014–2020) [8, 9]. The project included a series of quantitative and qualitative studies [10‐16] (Table 1), which, through the review and appraisal of the literature and the collection of stakeholder inputs, served the project mission of providing instruments to guide the implementation and scaling up of effective strategies of frailty prevention and management. The development of clinical guidelines represented an ultimate important achievement in the fulfilment of this mission.

At the time of designing our project, we recognised the need to offer patients, their formal and informal carers, healthcare practitioners, and decision-makers a scientific support to their actions, by bringing together scientific evidence and stakeholder perspectives into recommendations that responded to the definition of clinical guidelines [17, 18]. In fact, as the interest in the concept of frailty had also grown outside the internal and geriatric medicine field, we had seen several non-geriatric scientific societies including special considerations on the management of the disease(s) of interest related to older frail patients in their clinical guidelines [19‐22]. However, within the specific field of frailty as a syndrome, when the FOCUS consortium started its work in 2015, there were no clinical guidelines generated from rigorous methods recognised as standards by the scientific community, which would give frailty the dignity of other clinical conditions [23]. Therefore, we translated our FOCUS project mission into the development of evidence- and consensus-based guidelines, intended for all those involved in decision-making and implementation of actions on frailty.

This correspondence article presents the development process of our FOCUS guidelines, providing their justification, with emphasis on their novelty, limitations and implications.

We started by formulating the questions to be answered by the guidelines, based on the PICO format [24] (Table 2). While the project covered the entire spectrum of relevant clinical questions on frailty, including screening and diagnostic strategies [10], we decided to focus the guidelines on the role of interventions to prevent, delay or revert frailty. We framed the guidelines according to a hierarchical structure. We included a first question (General Question, GQ) asking whether the overall current evidence and stakeholder inputs support interventions meant to affect frailty and its course, followed by the addition of sub-questions (Questions 1–3 (Q1–Q3)) focused on specific types of interventions. For each question, two population subgroups were also considered, i.e. frail and prefrail subjects. The choice of the outcome and its definition represented the most sensitive step in the formulation of our PICO questions. We prespecified ‘frailty’ as our primary outcome, in compliance with the FOCUS project mission and the intention to treat frailty as a syndrome; we reflected the choice previously made in the definition of the study inclusion criteria for our systematic review of randomised controlled trials on interventions to prevent or reduce frailty [11]. Specifically, in our systematic review, we included studies that looked at the effect of interventions on frailty defined according to any validated scale, index, indicator or sets of indicators that were explicitly adopted by the authors as a definition for frailty [11]. However, our systematic review and guidelines also considered and evaluated the effect on frailty-related outcomes, which we defined as our secondary outcomes, including cognitive performance, ability to perform activities of daily life and quality of life, among others [11].

We adopted the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group system to assess the certainty of evidence and define the strength of related recommendations [25, 26]. In particular, we followed the Evidence-to-Decision (EtD) framework, which was developed by the GRADE Working Group to support the process of moving from evidence to decisions, in the contexts of making clinical recommendations or coverage, health system, or public health decisions [27]. It has been implemented as an interactive online tool (iEtD) that can support a consensus-based process, which we used [28]. The framework suggests a list of criteria upon which the intervention(s) of interest should be assessed based on research evidence, namely whether the problem is a priority, the magnitude of the desirable and undesirable effects, the certainty of the evidence, how patients (or others affected, such as carers) value the main outcomes, the balance between desirable and undesirable effects, resource use, acceptability, and feasibility [27].

The development of our guidelines was preceded by a series of quantitative and qualitative studies performed within the FOCUS project, reported in separate publications [11‐16], which represented the evidence base for our judgments and recommendations. In particular, we performed a systematic review of randomised controlled trials evaluating interventions on frailty, which represented our quantitative evidence base [11]. As a support to the consensus process, the relevant results of the systematic review were synthesised into tables, one for each of the sub-questions (Additional file 1). The tables focused on the effect of interventions on frailty as an outcome, according to different frailty definitions and based on the typical GRADE Summary of Findings table structure [25]. The effect of interventions on the secondary outcomes was narratively synthesised (Additional file 2). We also performed a realist review [16], using the approach of the Realist and Meta-narrative Evidence Synthesis: Evolving Standards (RAMESES) project [29] and integrating the results of the systematic review with other FOCUS studies, to try to respond to the question “what works, for whom and in what circumstances’; this realist review represented the base for our recommendations on implementation (i.e. the conditions for the intervention to succeed). These and the other FOCUS studies are listed in Table 1, together with their relevance to the EtD criteria used to develop these guidelines.

The guideline panel included the FOCUS project investigators with a background in health and social sciences as well as expertise in frailty, aging and health research methods. Most of them are members of the European Innovation Partnership on Active and Healthy Ageing (EIP-AHA) [30]. Table S1 in the Additional file 3: Table S1 lists the FOCUS investigators, their professional profile and their role in guideline development. We undertook a multistep approach, as schematised in Fig. 1. The technical team (Table S1) conducted a preliminary appraisal of the evidence base upon the iEtD criteria and submitted it to the panel using the iEtD tool. The panel was asked to revise this appraisal and to make their judgment on the existing evidence for each question, upon each criterion. In particular, the judgement was guided by criterion-specific questions (e.g. ‘How substantial are the desirable anticipated effects?’) that the panel had to answer using an ordinal scale. Voting was anonymous. Panel discussion was also encouraged via email. The technical team collated the panel’s judgments and comments. A draft consensus judgement for each criterion and for each question was determined based on the mode and median rating. Any non-coincidence between mode and median rating was considered semi-quantitative proof of skewness of the votes, suggesting the need for discussion with the panel. Even when mode and median coincided, a note (e.g. ‘+’ or ‘–’) was added to the draft consensus statement in the case of significant heterogeneity in the vote distribution.

Of the 13 FOCUS project investigators who were given the role of voting panellists, 11 participated in the voting process. All criteria for all questions were covered by the voting, but with a few missing votes, which were evenly distributed across criteria and questions. We provide an example of the voting outcome, based on the iEtD output and with the addition of the panel’s comments and technical team’s annotations (Additional file 4). The level of agreement was generally very good, but varied slightly across questions and criteria; it was higher for GQ (the highest) and Q1 compared with Q2 and Q3. Although initially all the EtD criteria were judged relevant for guideline development, the FOCUS panellists considered the existing evidence upon the criteria of resource use and cost-effectiveness, as collected in the frame of the FOCUS project, insufficient to use these criteria to justify their recommendations (Additional file 5). Subsequently, the main point raised by the panel during the discussion was the necessity to put more emphasis on what had been learned from the qualitative evidence base, and in particular from our realist review, which combined qualitative and quantitative evidence [16]. This translated into a final version in which the suggestions on how to implement interventions to increase the chance of success were included in the core of the guidelines, rather than only as additional considerations. Finally, the attribute of ‘conditional’ for recommendations, as opposed to ‘strong’, was preferred over ‘weak’ to emphasise that the recommendation is conditional to confirmation from further evidence and/or conditional to implementing facilitators or overcoming barriers.

Table 3 presents the final FOCUS Recommendations (R) on interventions to prevent or delay the progression of frailty, or to reverse frailty, in response to the four questions, i.e. RG (‘G’ for general), R1, R2, and R3. Below, we offer a justification, subgroup considerations and other considerations related to monitoring and evaluation, for each guideline. In Additional file 5 we provide a detailed justification for the judgement on each criterion for each guideline.

This paper presents evidence- and consensus-based clinical guidelines on interventions to prevent or treat frailty, developed in the context of the FOCUS project. This was a core objective of the project, i.e. an ultimate deliverable in which the quantitative and qualitative research studies conducted in context of the project converged, and also represented the content of the service we intended to deliver in our proposal. To achieve such a pivotal objective, we required a solid methodological structure and the involvement of the entire FOCUS consortium to act as the guideline panel. We developed four guidelines based on one overarching question concerning interventions for frailty in general and three sub-questions on specific groups of interventions. Each guideline includes a recommendation on whether and how interventions should be implemented.

Our work has distinctive characteristics among other initiatives that have been undertaken to help clinicians and patients make informed decisions in the context of frailty. For instance, in 2015, the EIP-AHA – Action Group A3 produced a Decalogue on Frailty Prevention as a result of the work conducted by the group in the period 2012–2015, which includes ten key messages focusing on “the main areas of interest that policy makers at Member State level would need to support in order to tackle frailty” [33]. Before that, the British Geriatrics Society, in association with the Royal College of General Practitioners and Age UK, had published Fit for Frail, a comprehensive best practice guidance document for the care of older people living with frailty in community and outpatient settings [34]. Both of these initiatives are consensus-based guides that stemmed from the expertise and experience of the groups’ or societies’ members. Although these documents are useful and translate knowledge into action, they either did not start from a systematic appraisal of the evidence, or the process and evidence was not clearly documented and accessible. More recently, the results of a concurrent initiative – the Asia-Pacific Clinical Practice Guidelines for the Management of Frailty – have been published [35]. Starting from the presentations and discussions at the Asia-Pacific Geriatrics Conference on Geriatrics Beyond Borders: Are We Frailty Ready?, they performed a comprehensive and systematic review and adopted the GRADE approach to develop recommendations that span many aspects of the management of frailty. Two elements, inherent to the FOCUS mission, distinguish ours from these guidelines. First, we had the opportunity to use both quantitative and qualitative evidence in order to combine effect sizes with relevant stakeholders’ inputs and perspectives in the development of our guidelines, according to an integrated knowledge translation strategy. For these reasons, we adopted the EtD framework proposed by the GRADE working group, i.e. because of the relevance given to perspectives and subgroups, and the value assigned to criteria like values, acceptability, feasibility and equity. Secondly, not only did we have a narrower and deeper focus on interventions only, but we specifically reviewed and based our recommendations on interventional studies that explicitly looked at frailty as an outcome, excluding those studies in which interventions were applied to people with or at risk of frailty but assessed upon different outcomes. Although this may have led to the inclusion of a narrower evidence base, our approach intended to give frailty the dignity of a condition. Indeed, the role of frailty as a measurable outcome, and not only as a predictor, to evaluate the impact of interventions or of other types of exposures, has been increasingly recognised in different clinical settings [36, 37]. At the same time, within the selected studies, we did consider other outcomes, thus not overlooking or undervaluing the possibility that interventions can impact other important adverse events to which frail people are vulnerable.

Our work has recognised limitations. The main limitation to the production of definitive guidelines was related to the quantitative evidence base. The evidence available was of low quality due to methodological bias, inconsistencies and imprecision in the existing studies. In addition to the low quality of the collected evidence, there was a high level of methodological heterogeneity, which had already prevented any quantitative synthesis in our systematic review [11]. The diversity of frailty definitions and operationalisations was mostly expected. It is also possible that our choice to include studies in our systematic review in which authors operationalised frailty using a study-specific, pre-specified set of indicators, while valuing the intention of the investigators, increased such heterogeneity. As a result of the heterogeneity and low quality of the collected evidence, which was often coupled with inadequate reporting, we were not able to draw the typical GRADE summary of findings or evidence profile tables [25]. The heterogeneous nature of interventions also represented a challenge to framing the guidelines into questions and grouping the interventions in an appropriate but also user-friendly manner. Finally, we encountered some technical limitations. Firstly, there were time constraints dictated by the FOCUS project timeline, which impeded the possibility of arranging a conference to facilitate the panel discussion. However, the discussion that took place online and by email achieved satisfactory results. Secondly, although extremely useful and user friendly, the EtD tool was limited in terms of flexibility to the development of guidelines for heterogeneous interventions in a field of complex nosography such as frailty in older age.

The ultimate lesson we learned with our 3-year work is that, while stakeholders showed awareness of and place relevance to the challenge represented by age-related frailty, the current scientific quantitative evidence still has important limitations. This was reflected in our guidelines, which could include only weak or conditional recommendations. Even if such types of recommendations might seem less appealing or helpful, they do yield an important message to the clinician and decision-maker, i.e. to be considered when these interventions are adopted, or indeed, to give consideration to when and whether to adopt them. This message reflects the limitations of the scientific literature and important implementation considerations. Our work also conveys an important lesson to the researcher – while the evidence heterogeneity could never be eliminated since it reflects the heterogeneity in the definition of frailty itself, we need more studies which specifically recognise and measure frailty as an outcome as well as greater adherence to high methodological standards. This is true in general, but in particular for studies on comprehensive frailty interventions, which have the potential to be effective, especially when defined holistically, and have so far not been adequately evaluated. We also need more studies to compare different interventions. The fact that most of the studies included in our evidence base compared the experimental intervention with ‘usual practice’, which can differ dramatically from reality to reality, made the findings extremely context bound. This generated the need to include, in our guidelines, not only an answer to the question ‘does it work?’ but also a consideration of the circumstances of success.