Frailty Confers High Mortality Risk across Different Populations: Evidence from an Overview of Systematic Reviews and Meta-Analyses

We performed an overview of systematic reviews and meta-analyses to summarize available data regarding the association between frailty and all-cause mortality. Medline, Embase, CINAHL, Web of Science, PsycINFO, and AMED (Allied and Complementary Medicine) databases were searched until February 2020 for meta-analyses examining the association between frailty and all-cause mortality. The AMSTAR2 checklist was used to evaluate methodological quality. Frailty exposure and the risk of all-cause mortality (hazard ratio [HR] or relative risk [RR]) were displayed in forest plots. We included 25 meta-analyses that pooled data from between 3 and 20 studies. The number of participants included in these meta-analyses ranged between <2000 and >500,000. Overall, 56%, 32%, and 12% of studies were rated as of moderate, low, and critically low quality, respectively. Frailty was associated with increased risk of all-cause mortality in 24/24 studies where the HR/RRs ranged from 1.35 [95% confidence interval (CI) 1.05–1.74] (patients with diabetes) to 7.95 [95% CI 4.88–12.96] (hospitalized patients). The median HR/RR across different meta-analyses was 1.98 (interquartile range 1.65–2.67). Pre-frailty was associated with a significantly increased risk of all-cause mortality in 7/7 studies with the HR/RR ranging from 1.09 to 3.65 (median 1.51, IQR 1.38–1.73). These data suggest that interventions to prevent frailty and pre-frailty are needed.


Rationale
3 Describe the rationale for the review in the context of what is already known.

3
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
N/A Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. 4 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

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Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

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Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).

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Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis.

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Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

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Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

Study selection
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

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Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

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Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 6 (Supple mentary  Table) Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

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Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

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Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).

DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

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Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

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Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.