Results
The search was conducted on 10th of April 2023, and after removing duplicates, 4031 abstracts were screened, 185 full texts were reviewed, and 18 relevant studies were included in this review (Figure 1). We have summarised the findings into four main clinical areas: cardiovascular; cognition; vaccination; cancer and other.
1. Cardiovascular drug trials
1.1. Blood pressure lowering
SPRINT: The Systolic Blood Pressure Intervention Trial (SPRINT) examined whether a lower systolic blood pressure (SBP) target of 120 mm Hg could reduce cardiovascular morbidity and mortality among hypertensive, nondiabetic adults.7 A total of 9361 participants with a SBP of 130 mm Hg or higher and an increased cardiovascular risk (but without diabetes) were randomly assigned to a SBP target of less than 120 mm Hg (intensive treatment) or SBP target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. At 1 year, the mean SBP in the intensive-treatment group was lower compared to the standard-treatment group (121.4 mmHg versus 136.2 mm Hg, respectively). The intervention ceased early after a median follow-up of 3.26 years due to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group: 1.65% per year vs. 2.19% per year, hazard ratio [HR] with intensive treatment 0.75 (95% confidence interval [CI] 0.64 to 0.89, P<0.001). All-cause mortality was also significantly lower in the intensive-treatment group (HR 0.73, 95% CI 0.60 to 0.90, P = 0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group. The SPRINT study protocol included measures of functional status and frailty. However, neither frailty status nor gait speed was a prespecified subgroup in the trial protocol. Frailty was defined using a 36-item frailty index (FI) in 9306 SPRINT participants. Cut-offs used to classify participants were FI ≤ 0.10 (fit), 0.10 < FI ≤ 0.21 (less fit), or FI > 0.21 (frail).8 Overall, the prevalence of frailty was 30.9% (33.4% in the intervention group and 28.4% in the control group). In multivariable analyses, a 1% increase in the FI was associated with increased risk for self-reported falls (HR = 1.030), injurious falls (HR = 1.035), and all-cause hospitalizations (HR = 1.038) (all p values < 0.0001).8 In 2016, Williamson et al reported the results for the prespecified subgroup of SPRINT participants aged 75 years or older with hypertension. The authors concluded that among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Exploratory secondary analyses were conducted to examine modification of the treatment effect by frailty status, and the investigators found thatfrail participants exhibited smaller inter treatment group differences (10.8 mm Hg) compared with less fit participants (11.3 mm Hg) and fit participants (13.5 mm Hg), with no significant difference in adverse events.9
HYVET: The HYpertension in the Very Elderly Trial (HYVET) study was a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over, and obtained frailty adjusted estimates of the effect of treatment with antihypertensive medication on risk of stroke, cardiovascular events, and mortality. Participants in HYVET were randomised 1:1 to active treatment with indapamide sustained release 1.5 mg ± perindopril 2 to 4 mg or to matching placebo. The FI was calculated at entry, based on 60 potential deficits (minimum 30 deficits). The mean value of FI was 0.19 (standard deviation (SD), 0.10). Participants with an FI ≤0.10 were considered as the least frail, while those with FI ≥0.35 were considered the frailest. When examining the effect of frailty on treatment effect, estimated HRs for treatment effect were calculated for 6 FI categories: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6. Cox regression analysis was used to assess the impact of FI at entry to the study on subsequent risk of stroke, total mortality, and cardiovascular events. Models were stratified by region of recruitment and adjusted for sex and age at entry. The investigators found that the point estimates of the HRs for the treatment effect decreased as FI increased, although to varying degrees and with varying certainty. The investigators found no evidence of an interaction between effect of treatment for hypertension and frailty as measured by the FI. Both the frailer and the fitter older adults with hypertension appeared to gain from treatment .
1.2. Heart failure treatment:
TOPCAT: The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial compared the use of spironolactone 15–45 mg daily with placebo in 3445 patients with symptomatic HFpEF from six countries. The primary study outcome was a composite of death from cardiovascular causes, aborted cardiac arrest or hospitalization for the management of heart failure. Secondary outcomes included cardiovascular death, heart failure hospitalization and all-cause mortality. Although the overall study result was neutral with regard to the primary endpoint, spironolactone was associated with a reduction in both cardiovascular death and heart failure hospitalization in a post-hoc analysis of subjects enrolled in the Americas.10 In 2018, Sanders and colleagues retrospectively constructed an FI using 39 clinical, laboratory, and self-reported variables in a subset of 1767 TOPCAT participants.11 The mean FI at baseline was 0.37±0.11. The cut-off to define frailty was FI >0.21. Overall, 94% of the participants were considered frail. When examining the impact of frailty on the study outcomes of cardiovascular death and heart failure hospitalization, the hazard ratios (HR) are represented per 0.10-point increase in FI (Group 1: FI < 0.3 as the reference group; Group 2: FI 0.3–0.4; Group 3: FI 0.4–0.5; and Group 4: FI ≥ 0.5). The investigators found that greater frailty severity was associated with a higher risk of cardiovascular outcomes and mortality, however the benefit of spironolactone on heart failure hospitalisation was not attenuated by frailty severity: HRs for heart failure hospitalisation 1.70 (95%CI 1.26-2.29) in Group 2, 2.11 (95%CI 1.55-2.86) in Group 3, and 4.12 (95%CI 3.01-5.66) in Group 4 (p value for interaction =0.35). A similar association was observed with all-cause mortality: HRs for all-cause mortality 1.32 (95%CI 1.00-1.73) in Group 2, 1.42 (95%CI 1.06-1.89) for Group 3, and 1.81 (95%CI 1.31-2.50) for Group 4. 11
DAPA HF trial: The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial was a randomized, double blind, and placebo controlled to evaluate the efficacy and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors (10 mg of dapagliflozin once daily) compared with matching placebo, added to standard care in patients with heart failure and a reduced ejection fraction (HFrEF).12 A total of 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less were randomly assigned to receive either dapagliflozin or placebo, in addition to recommended therapy, with a median follow up of 18.2 months. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. The study found that among patients with HFrEF, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.12 In a post hoc analysis in 2022, the investigators retrospectively constructed a 32-item FI and examined the efficacy of dapagliflozin according to frailty status.13 A cut-off of FI>0.21 was also applied to define frailty, determining 49.6% of the participants as frail. However, frailty was treated as a categorical variable with three values in the regression models: FI class 1 (FI ≤0.210; not frail), FI class 2 (FI 0.211 to 0.310; more frail), and FI class 3 (FI ≥0.311; most frail). The authors found that