Frailty in clinical drug trials: Frailty assessments, subgroup analyses and outcomes.

INTRODUCTION

Clinical drug trials play a critical role in developing effective and safe therapeutic interventions and treatments. As the world's population ages, frailty is becoming increasingly important, particularly in clinical practice and medical research. There is an urgent need to narrow the evidence practice gap in the treatment of older frail people. The projected global growth of older adults underwrites the need to have greater evidence on how to use medications safely and effectively in this vulnerable group. Although the interest in clinical trials involving frail older patients is increasing, there has been a large evidence gap for such people due to intended (and unintended) exclusion from clinical trials. 1 , 2

Frailty, defined as a state of increased vulnerability and reduced physiological reserve, carries an increased risk of poor outcomes in older adults, including reduced mobility, disability, increased risk of falls, cognitive decline, hospitalization and mortality. 3 , 4 , 5 Although more than 40 frailty definitions have been applied in research, there is still no ‘gold standard’ to define frailty. 6 , 7 , 8 There are three major approaches to defining frailty: (1) the physical frailty phenotype model (also called Fried's frailty criteria), (2) the deficit accumulation model proposed by Rockwood and Mitnitski, which captures mostly multimorbidity, and (3) the mixed physical and psychosocial models, such as the Edmonton Frailty Scale, the Reported Edmonton Frail Scale and the Tilburg Frailty Indicator. 3 , 5 The physical frailty phenotype defines frailty based on five components (unintentional weight loss, weak grip strength, self‐reported exhaustion, slow gait speed and low physical activity), and the presence of three or more of these five components is defined as frailty. 9 The deficit accumulation model (or the Frailty Index [FI]) is constructed based on a set of age‐related deficits, including chronic health conditions, signs, symptoms and functional disabilities. 10 The FI is calculated by dividing the deficits present in an individual by the total number of deficits considered, with a value range from 0 to 1. Besides these two most popular frailty definitions, the Clinical Frailty Scale (CFS) has also been commonly used to assess frailty in older people, especially in clinical settings. 5 , 11 The CFS score ranges from 1 to 9, and a score of 4 or greater indicates a frailty status. 5 , 11 , 12 The Hospital Frailty Risk Score is another emerging frailty assessment tool in hospital settings. 13 The Hospital Frailty Risk Score was developed to assess frailty through the International Classification of Diseases, Tenth Revision, and has been shown to be correlated with Fried's frailty criteria and the FI. 13 In addition, there are many rapid screening tools for frailty such as Fatigue, Resistance, Ambulation, Illnesses, Loss of weight (FRAIL), Program of Research to Integrate Services for the Maintenance of Autonomy (PRISMA‐7), the Tilburg Frailty Index, the Vulnerable Elders Survey, the Self‐Rated Health Deficits Index, the Sherbrooke Postal Questionnaire, the G8 Questionnaire for oncology patients, the Easy Care short version, the Study of Osteoporotic Fractures Index and the Identification of Seniors at Risk. 5 The Asia‐Pacific Clinical Practice Guidelines for the Management of Frailty recommend that when making the decision on a suitable frailty measurement, it is crucial to opt for one that not only effectively identifies frailty and predicts patient outcomes, but is also user‐friendly, extensively validated and aligned with the priorities, resources and objectives of the particular clinical setting. 5

The global incidence of frailty in community‐dwelling older adults has been estimated at 43.4 new cases per 1000 person‐years. 14 The reported prevalence of frailty varies depending on the definitions of frailty, the study settings and study populations. In older community‐dwelling people, the prevalence of frailty ranges from 4.0% to 59.1%, with an overall weighted frailty prevalence of 10.7%. 15 In a recent meta‐analysis of 240 population‐level studies in 1 755 497 participants from 62 countries and territories, the pooled frailty prevalence was 12% (95% confidence interval [CI] 11‐13%) in studies using the physical frailty phenotype definition, and 24% (95% CI 22‐26%) in studies using the deficit accumulation model. 16 In clinical settings and long‐term care settings, the prevalence was reported to be higher. 17 , 18 In a meta‐analysis conducted by Boucher and colleagues in 39 041 266 admissions (median age 80 years, 22 frailty measurement tools) the overall prevalence of moderate and severe frailty ranged from 14.3% to 79.6% in unplanned hospital admissions. 18 In nursing home residents, the pooled estimate of prevalence of frailty was 52.3% (95% CI 37.9‐66.5%). 17

Ageing and frailty are associated with many physiological changes, such as increased body fat, reduced lean body mass and serum albumin, decreased liver function and reduced renal clearance. 19 Older people, especially the frail, usually have increased sensitivity to many drugs due to changes in body compositions and organ functions that lead to altered drug absorption, distribution, metabolism and excretion. 20 , 21 Several studies have assessed the association between frailty and medications in older people. A recent review in 66 studies in 167 888 frail older adults found that the pooled prevalence of polypharmacy in older adults with frailty was 59% (95% CI 55‐64%) and the pooled prevalence of hyperpolypharmacy in older adults with frailty was 22% (95% CI 6‐37%). 22

Clinical drug trials have traditionally focused on younger, healthier participants with less comorbidity who would be able to tolerate the medications, and excluded frail older adults often due to concerns regarding their ability to tolerate and respond to treatments. 1 The exclusion of frail older people from clinical trials is often driven by worries of safety, feasibility and the potential impact of confounding variables on trial outcomes. 23 Frail older people usually have physical limitations, such as reduced mobility and endurance, which may make it difficult for them to participate in clinical trials that require certain physical activities or frequent travel to the study sites during the trial duration. 1 In addition, cognitive impairment in older people can impact their ability to understand and provide informed consent for participation. 1 , 23 However, this exclusion raises concerns about the generalizability of trial results to the broader ageing populations. Efforts are being made to address these issues and include more representative populations in clinical trials. With the ageing population and a change in attitudes to older people (less ageism), frailty has become an increasing issue for drug trials. This has led to a growing recognition in recent years of the importance of including frail older adults in clinical drug trials. Over the past decades, increasing efforts have been made to include frailty assessment and to examine responses to drug effects according to baseline frailty in some randomized controlled trials.

The aim of this review is to provide an overview of how frailty was assessed in published studies related to clinical pharmacological trials, and on the interaction of frailty on the safety and efficacy of the treatments.

METHODS

We searched MEDLINE, EMBASE and Cochrane for studies published in English (from inception to 10 April 2023) that focused on clinical drug trials in older people, using keywords and Medical Subject Headings (MeSH) associated with ‘frailty’, ‘frail elderly’, ‘frail’, ‘pharmacology’, ‘medication’, ‘drug’, ‘clinical pharmacology’, ‘drug trial’, ‘randomised controlled trial’ and ‘clinical trial’. Abstracts were screened and any duplicates removed. We selected randomized controlled drug trials that (1) included older people, (2) included frailty assessment for participants and (3) had subgroup analyses by frailty status. We excluded studies examining the effect of drugs/treatment in frail patients only, with no comparison group of non‐frail patients, studies examining the intervention to improve frailty but not the impact of frailty drug responses, observational studies, studies with no definition for frailty and studies examining the impact of frailty on progression the disease or on changes in biomarkers but not on the drug itself (Figure 1 ).

We extracted information on the study sample size, frailty assessment tools, frailty prevalence, how frailty was treated in subgroup analyses and the study findings into Table 1 . The results of this review were narratively summarized.

RESULTS

A total of 4031 abstracts were screened, 185 full texts were reviewed and 17 relevant studies were included in this review (Figure 1 ). We have summarized the findings into five main clinical areas: cardiovascular, cognition, vaccination, cancer, and other.

Cardiovascular drug trials

Blood pressure lowering

The Systolic Blood Pressure Intervention Trial (SPRINT) examined whether a lower systolic blood pressure (SBP) target of 120 mmHg could reduce cardiovascular morbidity and mortality among hypertensive, nondiabetic adults. 41 A total of 9361 participants with an SBP of 130 mmHg or higher and an increased cardiovascular risk (but without diabetes) were randomly assigned to an SBP target of less than 120 mmHg (intensive treatment) or SBP target of less than 140 mmHg (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 vs 136.2 mmHg, 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% CI 0.64‐0.89, P < 0.001). All‐cause mortality was also significantly lower in the intensive‐treatment group (HR 0.73, 95% CI 0.60‐0.90, 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). 42 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). 42 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 mmHg compared with an SBP target of less than 140 mmHg 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 that frail participants exhibited smaller inter treatment group differences (10.8 mmHg) compared with less fit participants (11.3 mmHg) and fit participants (13.5 mmHg), with no significant difference in adverse events. 24

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. 25 Participants in HYVET were randomized 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 to be 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 six FI categories: 0.1, 0.2, 0.3, 0.4, 0.5 and 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.

Heart failure treatment

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 heart failure with preserved ejection fraction (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. 43 In 2018, Sanders and colleagues retrospectively constructed an FI using 39 clinical, laboratory and self‐reported variables in a subset of 1767 TOPCAT participants. 26 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 HRs 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; 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 hospitalization was not attenuated by frailty severity: HRs for heart failure hospitalization 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. 26

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA‐HF) trial was a randomized, double blind, placebo‐controlled trial 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 with reduced ejection fraction (HFrEF). 44 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. 44 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. 27 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 0.211‐0.310, more frail) and FI class 3 (FI ≥ 0.311, most frail). The authors found that 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.

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 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 heart failure events or cardiovascular death and improved symptoms in the participants. 45 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. 28 A 30‐item FI was created. Similar to the DAPA‐HF study, participants were divided into the following three subgroups: FI ≤ 0.210 (FI class 1, not frail), FI 0.211‐0.310 (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 heart failure 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 was 1.5 (0.3‐2.7) and in class 3 was 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.

Antiplatelets

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. 46 The trial recruited 19 114 participants, with 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. 29 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. 29 At baseline, 2.2% of the participants were classified as frail, 39.0% as prefrail and 58.8% as not frail. The HRs for all‐cause mortality were 1.36 (95% CI 0.85‐2.19) for the frail participants, 1.03 (95%CI 0.88‐1.22) for the prefrail participants and 1.26 (95% CI 1.04‐1.53) for the not frail participants. The P value for interaction was 0.22, which means that there was no significant difference in the effect of aspirin on mortality across the frailty groups.

Anticoagulants

The Edoxaban Low‐Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE‐AF) trial aimed to compare the efficacy and safety of very‐low‐dose edoxaban (15 mg) versus placebo in very old Japanese patients (aged 80 years or older) with atrial fibrillation who were considered ineligible for standard oral anticoagulant therapy because of their high bleeding risk. 47 The trial found that edoxaban 15 mg was effective at preventing stroke and systemic embolism, and did not significantly increase the incidence of major bleeding compared with placebo. In this 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 (15 mg daily) versus 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) and 944 patients (402 frail patients [42.6%], 542 non‐frail patients [57.4%], mean [SD] age, 86.6 [4.3] years, and 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. 30

Antidiabetic therapies

The Action in Diabetes and Vascular Disease—Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial was a 2 by 2 factorial design randomized controlled trial of 11 140 participants in 215 collaborating centres in 20 countries. 48 , 49 The trial included two randomized interventions: (1) a double‐blind assessment of the effects on vascular disease of a fixed combination of perindopril/indapamide versus 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 versus standard care. In a post hoc analysis published in 2021, frailty was retrospectively assessed using a 34‐item FI. 31 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 were 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 hypoglycaemia rates (per 1000 person‐years) were higher in the frail: 8.39 (6.15‐10.63) versus 4.80 (3.84‐5.76) in non‐frail ( P < 0.001).

Trials aiming to improve cognitive function

The Multidomain Alzheimer Preventive Trial (MAPT) tested the effect of omega 3 polyunsaturated fatty acid supplementation and a multidomain intervention (physical activity, cognitive training or nutritional advice), alone or in combination, compared with placebo, on cognitive decline. 50 It was a 3‐year, multicentre, randomized, 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 who had relayed a spontaneous memory complaint to their physician, had limitations in one instrumental activity of daily living or had slow gait speed. A total of 1680 participants were randomly assigned (1:1:1:1) to 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 of docosahexaenoic acid and 225 mg of 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, 10 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 older people with memory complaints.

Secondary exploratory analysis from the MAPT 32 aimed to examine whether multidomain intervention and omega‐3 polyunsaturated fatty acid supplementation can modify cognitive function in older people according to frail status. Frailty was defined by the adapted Fried's frailty phenotype, which included five 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 were considered non‐frail. In subgroup analysis, frail and prefrail participants were combined into one group, in comparison to the non‐frail group. The subgroup analysis suggested that the beneficial effect of multidomain intervention and n3 PUFA supplementation on cognitive function did not differ between the two groups.

Clinical trials related to vaccinations

In a randomised controlled trial (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. 33 A 40‐item FI was constructed prospectively to evaluate frailty in the participants. The presence of any item received a score of 1 and the total score was summed for each patient to give an FI measure. The minimum possible score was 0 (least frail) and the maximum was 40 (most frail). When examining the 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, 34 15 991 participants 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 post vaccination 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 the 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 four 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 favoured IIV‐HD over IIV‐SD, and there was no significant evidence that baseline age, comorbidity, or frailty modified the efficacy of IIV‐HD relative to IIV‐SD.

Drug trials in patients with cancer

The EMN01 study was designed to compare the progression‐free survival (PFS) of older, newly diagnosed multiple myeloma patients treated with triplet versus doublet induction regimens and the PFS following maintenance treatment with lenalidomide ‐ prednisone versus lenalidomide alone. Before treatment, a geriatric assessment to assess patients' frailty status according to the International Myeloma Working Group (IMWG) Frailty Score was performed. In 2015, a frailty scoring system was developed by the IMWG that classifies patients into three frailty subgroups—fit, intermediate and frail—based on age, comorbidities (Charlson comorbidity index, ≤1 vs >1), the Katz Activities of Daily Living scale (>4 vs ≤4) and the Lawton Instrumental Activities of Daily Living scale (>5 vs ≤5). Participants were stratified into three groups according to their frailty status: fit (total score 0), intermediate‐fit (total score 1) and frail (total score > = 2). Post hoc analysis according to frailty status in both induction and maintenance treatment arms showed that fit patients benefit from a full‐dose triplet regimen, while intermediate‐fit and frail patients benefit from gentler regimens. Frail patients had the highest rate of discontinuation due to adverse events and a trend towards a higher discontinuation due to adverse events was found in frail versus fit patients. 35

The ALCYONE was a phase 3 trial in 706 patients with newly diagnosed multiple myeloma who were ineligible for stem‐cell transplantation to receive nine cycles of bortezomib , melphalan and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. 36 The primary end point was PFS. In the primary analysis of the study (median follow‐up 16.5 months), adding daratumumab to bortezomib/melphalan/prednisone (D‐VMP) significantly prolonged PFS over bortezomib/melphalan/prednisone (VMP) and induced deep responses in transplant‐ineligible newly diagnosed multiple myeloma (NDMM) patients. After a median follow‐up of 40.1 months, D‐VMP continued to show significant PFS benefit and significantly prolonged overall survival, even in patients aged ≥75 years. 51 In 2021, Mateos and colleagues conducted subgroup analysis of ALCYONE participants comparing D‐VMP and VMP by frailty status. 52 Frailty scores were calculated retrospectively for all participants based on age (≤75 years = 0 points, 76‐80 years = 1 point, >80 years = 2 points), Charlson Comorbidity Index (CCI; ≤1 = 0 points, > 1 = 1 point) and the Eastern Cooperative Oncology Group performance status (ECOG PS) score (0 = 0 points; 1 = 1 point; ≥2 = 2 points). The sum of scores was used to classify patients as fit (0), intermediate (1) or frail (≥2). When examining the impact of frailty on the intervention, frailty was treated as a binary variable: frail and non‐frail. Those with a frailty status of fit (0) or intermediate (1) were collectively classified as non‐frail. After a median follow‐up of 40.1 months, the PFS benefit of D‐VMP versus VMP was maintained in all frailty subgroups: fit (HR 0.34, 95% CI 0.20‐0.57), intermediate (HR 0.37, 95% CI 0.27‐0.50) and frail (HR 0.51, 95% CI 0.39‐0.68). The study confirmed the clinical benefit of D‐VMP in transplant‐ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.

Auner and colleagues examined the effect of age and frailty on the efficacy and tolerability of once‐weekly selinexor , bortezomib and dexamethasone in participants with previously treated multiple myeloma from the BOSTON trial. 37 Recent US Food and Drug Administration approval (18 December 2020) was granted based on the phase 3 BOSTON trial in 402 patients with previously treated multiple myeloma, which demonstrated that the triplet combination of once‐weekly selinexor with bortezomib and low‐dose dexamethasone (XVd) was superior to the standard twice‐weekly combination of bortezomib and moderate dose dexamethasone (Vd). Among the 402 patients (195 on XVd, 207 on Vd) enrolled in the BOSTON study, 272 were non‐frail (129 in the XVd arm and 143 in the Vd arm) and 130 were considered frail, with 66 in the XVd arm and 64 in the Vd arm. Frailty categories were assigned based on age, CCI and ECOG PS. Frailty was treated as a binary variable: non‐frail (0‐1 points) or frail (≥2 points). The findings indicate that the combination of weekly selinexor with weekly bortezomib and dexamethasone was effective and safe in non‐frail and frail patients. Median PFS was prolonged with XVd compared with Vd, with non‐frail patients having a significantly longer PFS (median 13.24 months) on XVd compared to Vd (median 9.43 months) (HR 0.66, 95% CI 0.47‐0.93), and frail patients showing a trend towards improvement on the triplet (XVd median 13.93 months vs Vd 9.46 months, HR 0.69, 95% CI 0.40‐1.17).

In the phase 3 MAIA study of patients with newly diagnosed multiple myeloma (NDMM) who were not eligible for transplant, daratumumab plus lenalidomide/dexamethasone (D‐Rd) improved PFS versus lenalidomide/dexamethasone (Rd). 38 Facon and colleagues conducted subgroup analysis of the MAIA study by frailty status. 53 Frailty assessment was performed retrospectively using age, CCI and baseline ECOG PS score. Frailty scores were used to classify patients into fit (0), intermediate (1) or frail (≥2) subgroups. Of the randomized patients (D‐Rd n = 368, Rd n = 369), 396 patients were non‐frail (D‐Rd 196 [53.3%], Rd 200 [54.2%]) and 341 patients were frail (172 [46.7%], 169 [45.8%]). The analysis showed that the clinical benefit of D‐Rd in transplant‐ineligible NDMM patients enrolled in MAIA, regardless of frailty status. After a 36.4‐month median follow‐up, the PFS benefit of D‐Rd versus Rd was maintained across subgroups: HR 0.41 (95% CI 0.22‐0.75) in the fit group, 0.53 (95% CI 0.35‐0.80) in the intermediate group and 0.62 (95% CI 0.45‐0.85) in the frail group. 53

Other drug trials

Rizka and colleagues aimed to determine the effect of alphacalcidol (a vitamin D analogue) on inflammatory cytokines (IInterleukin‐6, Interleukin‐10, interferon‐gamma) and T‐cell subsets (CD4/CD8 ratio and CD8+ CD28−) of older people with various stages of frailty syndrome. This was a double‐blind RCT with allocation concealment in 110 older participants, with an aim to examine the effect of 0.5 μg alphacalcidol administration for 90 days on inflammatory cytokines (IL‐6, IL‐10, g‐IFN) from peripheral blood mononuclear cells (PBMC) culture supernatant, as well as CD4/CD8 and CD8+ CD28− percentage using flow cytometry. Frailty was defined by Fried's frailty criteria and in the analysis, frailty was categorized into three groups: fit, prefrail and frail. The study revealed that alphacalcidol improved immune senescence by acting as an anti‐inflammatory agent through increased IL‐10 and decreased IL6/IL‐10 ratio, and also improves cellular immunity through increased CD4/CD8 ratio and decreased CD8+ CD28− subset in older people, and the effect is not influenced by frailty state. 39

In a recent published study, Hanlon and colleagues use individual‐level participant data from industry‐sponsored clinical trials for three exemplar chronic conditions (type 2 diabetes mellitus, rheumatoid arthritis and chronic obstructive pulmonary disease) to construct a frailty index. The authors then examined the prevalence of frailty in these clinical trial populations and examine whether frailty is associated with serious adverse events in the clinical trials studied. The prevalence of frailty in these trials was 7‐21% in type 2 diabetes mellitus trials, 33‐73% in rheumatoid arthritis trials and 15‐22% in chronic obstructive pulmonary disease trials. Across all trials, and after adjusting for age, sex and disease severity, and higher FI predicted increased risk of serious adverse events, the pooled incidence rate ratios (per 0.1‐point increase in FI scale) were 1.46 (95% CI 1.21‐1.75), 1.45 (1.13‐1.87) and 1.99 (1.43‐2.76) for type 2 diabetes mellitus, rheumatoid arthritis and chronic obstructive pulmonary disease, respectively. 40

DISCUSSION AND CONCLUSION

This review shows that frailty has been increasingly and successfully applied in clinical drug trials, especially trials in patients with cardiovascular disease and cancer. In most of the studies in the review, frailty was assessed retrospectively. Only a few studies prospectively included frailty assessment and subgroup analysis by frailty status.

There was heterogeneity in the effect of frailty, depending on the diseases and the treatment types. The effect of frailty on the treatment efficacy was not consistent among the studies in this review. While several trials, such as ADVANCE, SPRINT and ASPREE, showed some reduced effects of the treatment in frail patients, most of the trials showed that the benefits of the treatment are not affected by frailty status. Some even showed that the benefits of the treatment were more significant in frailer patients (DAPA‐HF and DELIVER). There is a need to balance the benefits of medications with the risks of adverse effects. Frail patients are often perceived to be more vulnerable to the adverse effects of medications, and their poor health may make them more likely to experience adverse effects that could negatively impact the outcome of the trials. Additionally, frail patients are often taking multiple medications, which can increase the risk of drug interactions and further increase the risk of adverse effects. Our review suggests that frailty should not be assumed to attenuate the treatment effect, and it is important to include frailty assessment in future RCTs.

One of the most significant challenges of conducting frailty assessments in clinical drug trials is the lack of a standardized definition of frailty. There is currently no universally accepted definition of frailty, leading to confusion among researchers and a lack of comparability between studies. Moreover, frailty exists on a spectrum, and it can be difficult to determine at what point a patient is considered ‘frail’. This lack of standardization makes it challenging for researchers to design clinical drug trials that include frail patients, as it is difficult to determine what criteria should be used to identify patients who are appropriate for inclusion in the study. This review raised a question on the best methods to evaluate frailty. The FI and Fried's frailty phenotype were applied in most of the trials in this review. The FI is one convenient method of quantifying frailty and has excellent predictive value for adverse health outcomes in older people. 10 , 54 The FI is based on the conceptualisation of frailty as an accumulation of deficits throughout life. It is constructed as the proportion of deficits present in an individual out of the total number of age‐related health variables considered, with a value obtained from 0 to 1. This index can be established from almost any sets of health‐related variables and is a feasible way to identify frailty in older hospitalized patients. The FI is good for baseline measurement in clinical trials. In the studies in this review, the deficit accumulation approach (FI) has been predominantly used compared to Fried's frailty phenotype. On the other hand, Fried's frailty phenotype may be more suitable if the investigators aim for repeated measurement of frailty from baseline to follow‐up and with an intention to improve frailty. The frailty phenotypic type may be changed based on the intervention targeted at frailty.

How frailty was treated in statistical analysis was not consistent among the studies. The FI was treated as an ordinal variable (with different levels of frailty) or binary variable (frail/non‐frail) using cut‐offs in some studies, and as a continuous in some other studies. The cut‐point to define frailty of FI > 0.21 was consistently applied to define frailty in most of the studies. Similarly, with Fried's frailty phenotype, some studies categorized participants into two groups of frail/non‐frail, while other studies categorized participants into three groups of fit (or non‐frail), prefrail and frail when conducting statistical analyses.

This review has some limitations. First, the literature search was performed only on the English literature. Additional studies published in other languages and other unpublished studies could have been omitted. Second, only two authors assessed the titles, abstracts and full texts for eligibility, and extracted the data from the selected studies. Potential discrepancies for study selection and data collection between the authors may exist. The strength of this review is its systematic search strategy across the three large databases: MEDLINE, EMBASE and Cochrane.

This review suggests that screening for frailty in participants in clinical drug trials would enable the identification of those that merit closer monitoring for adverse events. Trial data may be harnessed to inform disease management in people living with frailty. Overall, frailty has become an important consideration in clinical drug trials in older people. Including frail older adults in drug trials provides valuable information on the safety and efficacy of treatments and allows researchers to examine the effect of drugs in different frailty subgroups. As such, frailty should continue to be used as a criterion for inclusion in clinical drug trials to ensure that older adults of all frailty levels are appropriately represented in research. There may be significant challenges to conducting frailty assessments in clinical drug trials. Researchers must select appropriate assessment tools and overcome recruitment barriers to effectively assess frailty and ensure the success of clinical drug trials. The development of practical and efficient frailty assessment tools and increased efforts to recruit older adults with frailty can enhance the quality and relevance of clinical drug trials and improve the development of safe and effective treatments in older populations. Implementing strategies to enhance consumer engagement and raise awareness among older patients and clinicians is highly advisable to effectively incorporate frailty assessments into clinical drug trials. This integration can significantly bolster the safety and efficacy of treatments for older people.

AUTHOR CONTRIBUTIONS

Tu N Nguyen is the principal investigator, designed the study and drafted the manuscript. Tu N Nguyen and Fahed Ahmad conducted the literature search and data analysis, and created all figures and tables. Tu N Nguyen, Fahed Ahmad and Richard I Lindley contributed to the interpretation of the results. All authors provided critical feedback and revised the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interest to declare.

ACKNOWLEDGEMENTS

There was no funding provided for this study.

Nguyen TN, Ahmad F, Lindley RI. Frailty in clinical drug trials: Frailty assessments, subgroup analyses and outcomes. Br J Clin Pharmacol. 2025;91(1):8‐22. doi: 10.1111/bcp.16034

DATA AVAILABILITY STATEMENT

Not applicable.

REFERENCES

1. Hempenius L, Slaets JP, Boelens MA, et al. Inclusion of frail elderly patients in clinical trials: solutions to the problems. J Geriatr Oncol. 2013;4(1):26‐31. doi: 10.1016/j.jgo.2012.08.004

2. Lindley RI. Drug trials for older people. J Gerontol A Biol Sci Med Sci. 2012;67(2):152‐157. doi: 10.1093/gerona/glr065

3. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet. 2013;381(9868):752‐762. doi: 10.1016/S0140-6736(12)62167-9

4. Soysal P, Veronese N, Thompson T, et al. Relationship between depression and frailty in older adults: a systematic review and meta‐analysis. Ageing Res Rev. 2017;36:78‐87. doi: 10.1016/j.arr.2017.03.005

5. Dent E, Lien C, Lim WS, et al. The Asia‐Pacific clinical practice guidelines for the Management of Frailty. J Am Med Dir Assoc. 2017;18(7):564‐575. doi: 10.1016/j.jamda.2017.04.018

6. Cesari M, Calvani R, Marzetti E. Frailty in older persons. Clin Geriatr Med. 2017;33(3):293‐303. doi: 10.1016/j.cger.2017.02.002

7. Sobhani A, Fadayevatan R, Sharifi F, et al. The conceptual and practical definitions of frailty in older adults: a systematic review. J Diabetes Metab Disord. 2021;20(2):1975‐2013. doi: 10.1007/s40200-021-00897-x

8. Huang EY, Lam SC. Review of frailty measurement of older people: evaluation of the conceptualization, included domains, psychometric properties, and applicability. Aging Med (Milton). 2021;4(4):272‐291. doi: 10.1002/agm2.12177

9. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146‐M157. doi: 10.1093/gerona/56.3.M146

10. Rockwood K, Mitnitski A. Frailty defined by deficit accumulation and geriatric medicine defined by frailty. Clin Geriatr Med. 2011;27(1):17‐26. doi: 10.1016/j.cger.2010.08.008

11. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ. 2005;173(5):489‐495. doi: 10.1503/cmaj.050051

12. Fehlmann CA, Nickel CH, Cino E, Al‐Najjar Z, Langlois N, Eagles D. Frailty assessment in emergency medicine using the clinical frailty scale: a scoping review. Intern Emerg Med. 2022;17(8):2407‐2418. doi: 10.1007/s11739-022-03042-5

13. Gilbert T, Neuburger J, Kraindler J, et al. Development and validation of a hospital frailty risk score focusing on older people in acute care settings using electronic hospital records: an observational study. Lancet. 2018;391(10132):1775‐1782. doi: 10.1016/S0140-6736(18)30668-8

14. Ofori‐Asenso R, Chin KL, Mazidi M, et al. Global incidence of frailty and prefrailty among community‐dwelling older adults: a systematic review and meta‐analysis. JAMA Netw. 2019;2(8):e198398‐e. doi: 10.1001/jamanetworkopen.2019.8398

15. Collard RM, Boter H, Schoevers RA, Oude Voshaar RC. Prevalence of frailty in community‐dwelling older persons: a systematic review. J Am Geriatr Soc. 2012;60(8):1487‐1492. doi: 10.1111/j.1532-5415.2012.04054.x

16. O'Caoimh R, Sezgin D, O'Donovan MR, et al. Prevalence of frailty in 62 countries across the world: a systematic review and meta‐analysis of population‐level studies. Age Ageing. 2021;50(1):96‐104. doi: 10.1093/ageing/afaa219

17. Kojima G. Prevalence of frailty in nursing homes: a systematic review and meta‐analysis. J Am Med Dir Assoc. 2015;16(11):940‐945. doi: 10.1016/j.jamda.2015.06.025

18. Boucher EL, Gan JM, Rothwell PM, Shepperd S, Pendlebury ST. Prevalence and outcomes of frailty in unplanned hospital admissions: a systematic review and meta‐analysis of hospital‐wide and general (internal) medicine cohorts. EClinicalMedicine. 2023;59:101947. doi: 10.1016/j.eclinm.2023.101947

19. Hilmer SN, Wu H, Zhang M. Biology of frailty: implications for clinical pharmacology and drug therapy in frail older people. Mech Ageing Dev. 2019;181:22‐28. doi: 10.1016/j.mad.2019.111119

20. Hubbard RE, O'Mahony MS, Woodhouse KW. Medication prescribing in frail older people. Eur J Clin Pharmacol. 2013;69(3):319‐326. doi: 10.1007/s00228-012-1387-2

21. Wynne HA, Yelland C, Cope LH, Boddy A, Woodhouse KW, Bateman DN. The association of age and frailty with the pharmacokinetics and pharmacodynamics of metoclopramide. Age Ageing. 1993;22(5):354‐359. doi: 10.1093/ageing/22.5.354

22. Toh JJY, Zhang H, Soh YY, Zhang Z, Wu XV. Prevalence and health outcomes of polypharmacy and hyperpolypharmacy in older adults with frailty: a systematic review and meta‐analysis. Ageing Res Rev. 2023;83:101811. doi: 10.1016/j.arr.2022.101811

23. Ridda I, Lindley R, MacIntyre RC. The challenges of clinical trials in the exclusion zone: the case of the frail elderly. Australas J Ageing. 2008;27(2):61‐66. doi: 10.1111/j.1741-6612.2008.00288.x

24. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged >/=75 years: a randomized clinical trial. JAMA. 2016;315(24):2673‐2682. doi: 10.1001/jama.2016.7050

25. Warwick J, Falaschetti E, Rockwood K, et al. No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double‐blind, placebo‐controlled study of antihypertensives in people with hypertension aged 80 and over. BMC Med. 2015;13:78.

26. Sanders NA, Supiano MA, Lewis EF, et al. The frailty syndrome and outcomes in the TOPCAT trial. Eur J Heart Fail. 2018;20(11):1570‐1577. doi: 10.1002/ejhf.1308

27. Butt JH, Dewan P, Merkely B, et al. Efficacy and safety of Dapagliflozin according to frailty in heart failure with reduced ejection fraction: a post hoc analysis of the DAPA‐HF trial. Ann Intern Med. 2022;175(6):820‐830. doi: 10.7326/M21-4776

28. Butt JH, Jhund PS, Belohlavek J, et al. Efficacy and safety of dapagliflozin according to frailty in patients with heart failure: a prespecified analysis of the DELIVER trial. Circulation. 2022;146(16):1210‐1224. doi: 10.1161/CIRCULATIONAHA.122.061754

29. McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all‐cause mortality in the healthy elderly. New Engl J Med. 2018;379(16):1519‐1528. doi: 10.1056/NEJMoa1803955

30. Akashi S, Oguri M, Ikeno E, et al. Outcomes and safety of very‐low‐dose edoxaban in frail patients with atrial fibrillation in the ELDERCARE‐AF randomized clinical trial. JAMA Netw Open. 2022;5(8):e2228500. doi: 10.1001/jamanetworkopen.2022.28500

31. Nguyen TN, Harris K, Woodward M, et al. The impact of frailty on the effectiveness and safety of intensive glucose control and blood pressure‐lowering therapy for people with type 2 diabetes: results from the ADVANCE trial. Diabetes Care. 2021;44(7):1622‐1629. doi: 10.2337/dc20-2664

32. Tabue‐Teguo M, Barreto de Souza P, Cantet C, et al. Effect of multidomain intervention, Omega‐3 polyunsaturated fatty acids supplementation or their combination on cognitive function in non‐demented older adults according to frail status: results from the MAPT study. J Nutr Health Aging. 2018;22(8):923‐927. doi: 10.1007/s12603-018-1024-6

33. Ridda I, Macintyre CR, Lindley R, et al. Immunological responses to pneumococcal vaccine in frail older people. Vaccine. 2009;27(10):1628‐1636. doi: 10.1016/j.vaccine.2008.11.098

34. DiazGranados CA, Dunning AJ, Robertson CA, Talbot HK, Landolfi V, Greenberg DP. Efficacy and immunogenicity of high‐dose influenza vaccine in older adults by age, comorbidities, and frailty. Vaccine. 2015;33(36):4565‐4571. doi: 10.1016/j.vaccine.2015.07.003

35. Bringhen S, D'Agostino M, Paris L, et al. Lenalidomide‐based induction and maintenance in elderly newly diagnosed multiple myeloma patients: updated results of the EMN01 randomized trial. Haematologica. 2020;105(7):1937‐1947. doi: 10.3324/haematol.2019.226407

36. Mateos M‐V, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. New Engl J Med. 2017;378(6):518‐528. doi: 10.1056/NEJMoa1714678

37. Auner HW, Gavriatopoulou M, Delimpasi S, et al. Effect of age and frailty on the efficacy and tolerability of once‐weekly selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma. Am J Hematol. 2021;96(6):708‐718. doi: 10.1002/ajh.26172

38. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104‐2115. doi: 10.1056/NEJMoa1817249

39. Rizka A, Setiati S, Harimurti K, Sadikin M, Mansur IG. Effect of Alfacalcidol on inflammatory markers and T cell subsets in elderly with frailty syndrome: a double blind randomized controlled trial. Acta Med Indones. 2018;50(3):215‐221.

40. Hanlon P, Butterly E, Lewsey J, Siebert S, Mair FS, McAllister DA. Identifying frailty in trials: an analysis of individual participant data from trials of novel pharmacological interventions. BMC Med. 2020;18(1):309. doi: 10.1186/s12916-020-01752-1

41. Ambrosius WT, Sink KM, Foy CG, et al. The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the systolic blood pressure intervention trial (SPRINT). Clin Trials. 2014;11(5):532‐546. doi: 10.1177/1740774514537404

42. Pajewski NM, Williamson JD, Applegate WB, et al. Characterizing frailty status in the systolic blood pressure intervention trial. J Gerontol A‐Biol Sci Med Sci. 2016;71(5):649‐655. doi: 10.1093/gerona/glv228

43. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383‐1392. doi: 10.1056/NEJMoa1313731

44. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995‐2008. doi: 10.1056/NEJMoa1911303

45. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387(12):1089‐1098. doi: 10.1056/NEJMoa2206286

46. McNeil JJ, Woods RL, Nelson MR, et al. Effect of aspirin on disability‐free survival in the healthy elderly. N Engl J Med. 2018;379(16):1499‐1508. doi: 10.1056/NEJMoa1800722

47. Okumura K, Akao M, Yoshida T, et al. Low‐dose edoxaban in very elderly patients with atrial fibrillation. N Engl J Med. 2020;383(18):1735‐1745. doi: 10.1056/NEJMoa2012883

48. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560‐2572. doi: 10.1056/NEJMoa0802987

49. ADVANCE Management Committee . Study rationale and design of ADVANCE: action in diabetes and vascular disease—preterax and diamicron MR controlled evaluation. Diabetologia. 2001;44(9):1118‐1120. doi: 10.1007/s001250100612

50. Andrieu S, Guyonnet S, Coley N, et al. Effect of long‐term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo‐controlled trial. Lancet Neurol. 2017;16(5):377‐389. doi: 10.1016/S1474-4422(17)30040-6

51. Mateos M‐V, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open‐label, phase 3 trial. Lancet. 2020;395(10218):132‐141. doi: 10.1016/S0140-6736(19)32956-3

52. Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone in transplant‐ineligible newly diagnosed multiple myeloma: frailty subgroup analysis of ALCYONE. Clin Lymphoma Myeloma Leuk. 2021;21(11):785‐798. doi: 10.1016/j.clml.2021.06.005

53. Facon T, Cook G, Usmani SZ, et al. Daratumumab plus lenalidomide and dexamethasone in transplant‐ineligible newly diagnosed multiple myeloma: frailty subgroup analysis of MAIA. Leukemia. 2022;36(4):1066‐1077. doi: 10.1038/s41375-021-01488-8

54. Rockwood K, Andrew M, Mitnitski A. A comparison of two approaches to measuring frailty in elderly people. J Gerontol A Biol Sci Med Sci. 2007;62(7):738‐743. doi: 10.1093/gerona/62.7.738

Associated Data

Data Availability Statement

Not applicable.