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