dapagliflozin improved all outcomes examined, regardless of frailty status, and the absolute reductions were larger in frailer patients: HRs for the primary outcomes were 0.72 (95%CI 0.59-0.89) in participants with FI≤0.21, 0.77 (95%CI 0.62 to 0.97) in the more frail group, and 0.71 (95%CI 0.54 to 0.93) in the most frail group.
DELIVER trial: The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial aimed to examine whether SGLT2 inhibitors are effective in patients with heart failure with preserved ejection fraction (HFpEF). Participants (n=6263) were randomly assigned to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. The investigators found that dapagliflozin, compared with placebo, reduced the risk of worsening HF events or cardiovascular death and improved symptoms in the participants.14 In a prespecified analysis published recently, the authors examined the efficacy and safety of dapagliflozin according to frailty status using the Rockwood cumulative deficit approach.15 A 30-item FI was created. Similar to the DAPA HF study, participants were divided into the following 3 subgroups: FI ≤0.210 (FI class 1, not frail); FI 0.211 to 0.310 (FI class 2, moderately frail); and FI ≥0.311 (FI class 3, most frail). The mean FI was 0.248 (SD 0.092). In total, 2354 (37.6%) patients were not frail (FI ≤0.210), 2413 (38.6%) were moderately frail (FI 0.211–0.310), and 1491 (23.8%) were in class 3 frailty (FI ≥0.311; ie, most frail). The analysis showed that the benefit of dapagliflozin was consistent across the range of frailty studied . For the primary composite outcome, compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death across FI classes: the HRs from lowest to highest FI class were 0.85 (95% CI 0.68–1.06), 0.89 (95% CI 0.74–1.08), and 0.74 (95% CI 0.61–0.91), respectively (p for interaction = 0.40). The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with a higher level of frailty: Although patients with a greater degree of frailty had worse Kansas City Cardiomyopathy Questionnaire scores at baseline, their improvement with dapagliflozin was greater compared to patients who were less frail: placebo-corrected improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score at 4 months in FI class 1 was 0.3 (95% CI, −0.9 to 1.4); in class 2, 1.5 (0.3–2.7); and in class 3, 3.4 (1.7–5.1; p value for interaction = 0.021). The authors suggested that these findings should challenge any clinical reluctance to introduce dapagliflozin in patients perceived to be frail.
1.3. Antiplatelets
ASPREE: The Aspirin in Reducing Events in the Elderly (ASPREE) study was a primary prevention trial that investigated whether the daily use of 100 mg of enteric-coated aspirin would prolong the healthy life span of older adults.16 The trial recruited 19,114 participants, 9525 assigned to receive aspirin and 9589 to receive placebo. The primary end point was disability-free survival, which was defined as survival free from dementia or persistent physical disability. The primary composite end point was derived from the first end-point events of death, dementia, or persistent physical disability. The trial found that the use of low-dose aspirin did not differ significantly from placebo in influencing the rate of the primary end point after a median of 4.7 years of follow-up.
In an analysis on the effect of aspirin on all-cause mortality, the investigators found that ASPREE participants who received daily aspirin had higher all-cause mortality. The HR for all-cause mortality in the frail and non-frail were 1.36 (0.85-2.19) and 1.26 (95%CI 1.04-1.53) respectively.17 In this analysis, frailty was assessed at baseline using the adapted Fried frailty criteria, which included body weight, strength, exhaustion, walking speed, and physical activity.17
In a recent published paper in 2022, Ryan and colleagues aimed to adapt the deficit-accumulation FI approach to determine frailty status in ASPREE participants, to characterize the FI in terms of its association with age and physical health, and to compare it to the modified Fried’s frailty phenotype. This study also aimed to validate the ASPREE FI by determining its predictive capacity for dementia-free survival and DFS and persistent physical disability over 5 years. The FI was constructed based on 67 items (n=19 110). The median FI score was 0.10 (interquartile range: 0.07–0.14) at baseline, and the cut-point to define frailty was FI > 0.21 (8.1% of the participants were defined as frail at baseline). Frailty was associated with the primary composite outcome capturing independent life lived free of major disability and dementia, and increased the rate of persistent physical disability (HR 21.3, 95% CI 15.6–28.9). FI strongly associated with a modified Fried’s frailty phenotype (p < .0001, for all comparisons).18
1.4. Anticoagulants
The ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial aimed to compare the efficacy and safety of very-low-dose edoxaban (15mg) vs placebo in very elderly Japanese patients (aged 80 years or older) with AF who were considered ineligible for standard oral anticoagulant (OAC) therapy because of their high bleeding risk.19 The trial found that edoxaban 15 mg was effective at preventing stroke and systemic embolism (SSE) and did not significantly increase the incidence of major bleeding compared with placebo. In that trial, frailty was prospectively assessed using the Japanese version of the Fried’s frailty criteria. Approximately 40% were classified as frail (having a frailty score 3 or higher). Post hoc analysis aimed to compare very-low-dose edoxaban (15mg daily) vs placebo across frailty status among the ELDERCARE-AF participants. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding. A total of 984 patients were randomly assigned to treatment (492 each to the edoxaban and placebo groups); 944 patients (402 frail patients [42.6%]; 542 non-frail patients [57.4%]; mean [SD] age, 86.6 [4.3] years; 541 women [57.3%]) were included in this analysis. The analysis showed that regardless of frailty status ,once-daily 15-mg edoxaban was associated with reduced incidence of stroke or systemic embolism and may be a suitable treatment option for these patients. 20
1.5. Anti-diabetic therapies
ADVANCE trial: The Action in Diabetes and Vascular Disease - Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial was a 2 by 2 factorial design randomised controlled trial of 11,140 participants in 215 collaborating centres in 20 countries.21,22 The trial included two randomised interventions: (1) a double-blind assessment of the effects on vascular disease of a fixed combination of perindopril/indapamide vs placebo and (2) an open-label evaluation of an intensive glucose-lowering regimen (lowering the glycated haemoglobin value to a target of 6.5% or less ) using modified release gliclazide vs standard care. In a post hoc analysis published in 2021, frailty was retrospectively assessed using a 34-item FI.23 In this analysis, the mean FI was 0.17 (SD 0.08), and with the cut point of 0.21, the prevalence of frailty was 25.7% in the study participants. Frailty was treated as a binary variable (frail/ non-frail) in models examining the effect of frailty on the study outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail : HRs for combined major macro- and micro-vascular events 1.03 (95% CI 0.90–1.19) in the frail versus 0.84 (95% CI 0.74–0.94) in the non-frail (P = 0.02). A similar trend was observed with blood pressure intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15–10.63) vs. 4.80 (3.84–5.76) in non-frail (P < 0.001).
2. Trials aiming to improve cognitive function
MAPT: the Multidomain Alzheimer Preventive Trial (MAPT) trial tested the effect of omega 3 polyunsaturated fatty acid supplementation and a multidomain intervention (physical activity, cognitive training, and nutritional advice), alone or in combination, compared with placebo, on cognitive decline.24 It was a 3-year, multicentre, randomised, placebo-controlled superiority trial with four parallel groups at 13 memory centres in France and Monaco. Participants were community-dwelling people aged 70 years or older without dementia, and had either relayed a spontaneous memory complaint to their physician, limitations in one instrumental activity of daily living, or slow gait speed. A total of 1680 participants were randomly assigned (1:1:1:1) to either the multidomain intervention (43 group sessions integrating cognitive training, physical activity, and nutrition, and three preventive consultations) plus omega 3 polyunsaturated fatty acids (ie, two capsules a day providing a total daily dose of 800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid), the multidomain intervention plus placebo, omega 3 polyunsaturated fatty acids alone, or placebo alone. The primary outcome was change from baseline to 36 months on a composite Z score combining four cognitive tests (free and total recall of the Free and Cued Selective Reminding test, ten Mini-Mental State Examination orientation items, Digit Symbol Substitution Test, and Category Naming Test) in the modified intention-to-treat population. The study found that multidomain intervention and polyunsaturated fatty acids, either alone or in combination, had no significant effects on cognitive decline over 3 years in elderly people with memory complaints.
Secondary exploratory analysis from the MAPT 25 aimed to examine whether multidomain intervention and Omega-3 Polyunsaturated Fatty Acids supplementation can modify the cognitive function on elderly according to frail status. Frailty was defined by the adapted Fried’s frailty phenotype, which included 5 components: (i) unintentional weight loss (self-reported unintentional loss of 4.5 kg or more recently); (ii) exhaustion (using two items of the Center for Epidemiologic Studies Depression Scale (16) (CES-D) : during the past week, “I felt that everything I did was an effort” and “I could not get going) ; (iii) weakness (using the handgrip strength ascertained by dynamometer); (iv) slowness (the time needed to cover the four-meter walk) and (v) low energy expenditure (no engagement in physical activities). Participants meeting three or more criteria were classified as frail, those meeting one or two were considered prefrail, and those meeting none as non-frail. This analysis suggested that the beneficial effect of multidomain intervention and n3 PUFA supplementation on cognitive function did not differ between frail and non-frail participants.
3. Clinical trials related to vaccinations:
In an RCT published in 2009, Ridda and colleagues evaluated the immunogenicity of the 7-valent conjugated pneumococcal vaccine (PCV7) versus 23-valent polysaccharide vaccine (23vPPV) and compare the immune response to four serotypes (4, 6B, 18C and 19F), with respect to age or frailty in 241 patients aged 60 years who were previously unvaccinated hospitalized patients. 26 A 40-item FI were constructed prospectively to evaluate frailty in the participants. The presence of any item receives a score of one, and the total score is summed for each patient to give a Frailty Index measure. The minimum possible score is 0 (least frail) and the maximum is 40 (most frail). When examining immunological response at 6 months by frailty, the FI was treated as a binary variable, with a cut-off of 16. Frailty predicted poor immune responses to both polysaccharide and conjugate pneumococcal vaccines. Although there was some variation by serotype, responses after vaccination were lowest in the most frail or aged subjects.
In another double-blind, randomized, active-controlled, multicenter trial conducted by DiazGranados and colleagues,27participants aged ≥65 years were randomized 1:1 to receive a high-dose inactivated influenza vaccine (IIV-HD) or a standard-dose vaccine (IIV-SD) and followed for 6-8 months postvaccination for the occurrence of influenza. Frailty was prospectively measured. The study protocol prespecified several frailty-associated conditions based on deficit accumulation approach. At the time of enrolment, the study site collected the presence or absence of each of the following conditions, based on participant’s self-report: vision loss, hearing loss, impaired mobility, difficulty toileting, difficulty bathing, difficulty dressing, difficulty grooming, difficulty going out, skin problems, resting tremor, changes in sleep, urinary complaints, gastrointestinal problems, and hypertension. When examining the impact of frailty on the efficacy of IIV-HD, frailty was treated as a categorical variable with 4 values: no frailty conditions, one frailty condition, two frailty conditions, and three or more frailty conditions. The study revealed that estimates of relative efficacy consistently favored IIV-HD over IIV-SD, and