Study Selection and Characteristics of the Included Trials

Figure 1 details study selection. Our database searches yielded 5917 references, of which 61 articles11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71 met the inclusion criteria. The included trials are summarized by the type of frailty assessment: frailty index (24 trials) (Table 1), frailty phenotype (17 trials) (Table 2), and other assessments (20 trials) (Table 3). Further details of each trial can be found in Appendix Table. The mean age of trial populations ranged from 58.711 to 87.112 years and the proportion of women ranged from 23.429 to 93.3%14 (in particular, one RCT was 100% male15 and the other 100% female16). There were 26 trials evaluating pharmacological interventions (sample size 4017 to 31,98918), 27 trials on non-pharmacological interventions (sample size 3014, 18 to 5145),11 and 8 trials on multicomponent interventions (sample size 17319 to 1464).20

Figure 1

Evidence search and selection.

Table 1 Results from 24 Randomized Controlled Trials using Deficit Accumulation Frailty IndexTable 2 Results from 17 Randomized Controlled Trials using Frailty PhenotypeTable 3 Results from 20 Randomized Controlled Trials using Other Frailty Assessment ToolsQuality of the Included Trials

Most of the included articles have low likelihood of bias. Risk of bias related to blinding of participants and personnel and incomplete outcome data were identified in 18 and 12 trials, respectively. The risk of bias for each included trial is shown in both the Appendix Figure and Table.

Evaluation of Treatment Effect by Deficit Accumulation Frailty IndexPharmacologic Interventions

The included 15 trials assessed whether the effect of the following treatments was different by frailty levels: anticoagulants,21 antihypertensives,22,23,24,25,26 heart failure (HF) medication,27,28,29,30,31 anti-interleukin 1 monoclonal antibody,13 and vaccinations.32,33,34

Anticoagulants

In a trial of 20,867 adults with atrial fibrillation conducted over 34 months across 46 countries,21 edoxaban was associated with lower rates of major bleeding compared with warfarin in patients with frailty index 0.12 to <0.36 (edoxaban 60 mg) and patients with frailty index <0.36 (edoxaban 30 mg), but not in patients with frailty index <0.12 (edoxaban 60 mg) and frailty index 0.36 to <1.0 (edoxaban 30 mg or 60 mg) (p-for-interaction=not reported [NR]). There was a significant treatment effect of edoxaban compared with warfarin on stroke or systemic embolism, but the treatment effect was not different across the frailty spectrum (p-for-interaction=NR).

Antihypertensives

There was a significant treatment effect of antihypertensive medication reduction compared with usual care on systolic blood pressure control,22 indapamide ± perindopril compared with placebo on stroke and cardiovascular events.24 However, there was no significant treatment effect of intensive systolic blood pressure control compared with standard control on syncope and falls,23 indapamide ± perindopril compared with placebo on all-cause mortality24. Furthermore, five trials22,23,24,25,26 have concluded that the effects of antihypertensive medication reduction,22 intensive blood pressure control,23, 25, 26 and indapamide ± perindopril24 compared with control treatment, were similar across frailty levels for cardiovascular events,24, 25 stroke,24 all-cause mortality,