Use of antithrombotic therapy and the risk of cardiovascular outcomes and bleeding in cancer patients at the end of life: A Danish nationwide cohort study.

BACKGROUND: Despite uncertain benefit-risk profile near the end of life, antithrombotic therapy (ATT) is prevalent in patients with terminal cancer. OBJECTIVES: To examine adherence and persistence with ATT in terminally ill cancer patients and investigate risks of major and clinically relevant bleeding, venous thromboembolism (VTE), and arterial thromboembolism (ATE) by ATT exposure. METHODS: Using a Danish nationwide cohort of terminal cancer patients, ATT adherence in the year following terminal illness declaration was measured by the proportion of days covered (PDC) by prescription. Discontinuation was defined as a treatment gap of ≥30 days between prescription renewals. One-year cumulative incidences of bleeding complications, VTE, and ATE were calculated, considering the competing risk of death. RESULTS: During 2013-2022, 86,732 terminally ill cancer patients were identified (median age 75 years, 47% female, median survival 57 days). At terminal illness declaration, 37.5% were receiving ATT (66.6% platelet inhibitors, 23.0% direct oral anticoagulants (DOAC), and 10.4% vitamin K antagonists (VKA)). The mean PDC was 88% (SD 30%), highest among platelet inhibitor users (mean PDC 89%) and lowest among VKA users (73%). One-year ATT discontinuation incidence was 7.9% (95% CI 7.7%-8.1%). Most patients continued ATT until death (74.8% platelet inhibitors, 58.8% DOACs, 61.6% VKAs). Patients receiving ATT had a lower one-year VTE risk but higher risks of ATE and major bleeding. CONCLUSION: Despite uncertain benefit-risk profile, most terminally ill cancer patients continue ATT until the end of life. These findings provide insights into current ATT utilisation and discontinuation dynamics in the challenging context of terminal illness.

Association of Glasgow Prognostic Score with frailty, mortality and adverse health outcomes in older patients with cancer: A prospective cohort study.

INTRODUCTION: To balance benefits and risks of cancer treatment in older patients, prognostic information is needed. The Glasgow Prognostic Score (GPS), composed of albumin and C-reactive protein (CRP), might provide such information. This study first aims to investigate the association between GPS and frailty, functional decline, and health-related quality of life (HRQoL) decline as indicators of health problems in older patients with cancer. The second aim is to study the predictive value of GPS for mortality, in addition to clinical predictors. MATERIALS AND METHODS: This prospective cohort study included patients aged ≥70 years with a solid malignant tumor who underwent a geriatric assessment and blood sampling before treatment initiation. GPS was calculated using serum albumin and CRP measured in batch, categorized into normal (0) and abnormal GPS (1-2). Outcomes were all-cause mortality and a composite outcome of decline in daily functioning and/or HRQoL, or mortality at one year follow-up. Daily functioning was assessed by Activities of Daily Living and Instrumental Activities of Daily Living questionnaires and HRQoL by the EQ-5D-3L and EQ-VAS questionnaires. RESULTS: In total, 192 patients with a median age of 77 years (interquartile range 72.3-81.0) were included. Patients with abnormal GPS were more often frail compared to those with normal GPS (79 % vs. 63 %, p = 0.03). Patients with abnormal GPS had higher mortality rates after one year compared to those with normal GPS (48 % vs. 23 %, p < 0.01) in unadjusted analysis. Abnormal GPS was associated with increased mortality risk (hazard ratio 2.8, 95 % CI 1.7-4.8). The area under the receiver operating characteristics curve of age, distant metastasis, tumor site, comorbidity, and malnutrition combined was 0.73 (0.68-0.83) for mortality prediction, and changed to 0.78 (0.73-0.86) with GPS (p = 0.10). The composite outcome occurred in 88 % of patients with abnormal GPS versus 83 % with normal GPS (p = 0.44). DISCUSSION: Abnormal GPS was associated with frailty and mortality. The addition of GPS to clinical predictors showed a numerically superior mortality prediction in this cohort of older patients with cancer, although not statistically significant. While GPS may improve the stratification of future older patients with cancer, larger studies including older patients with similar tumor types are necessary to evaluate its clinical usefulness. TRIAL REGISTRATION: The TENT study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107. Date of registration: 22-10-2019.

Increased 1H-NMR metabolomics-based health score associates with declined cognitive performance and functional independence in older adults at risk of cardiovascular disease.

The 1-HMR metabolomics-based MetaboHealth score, comprised of 14 serum metabolic markers, associates with disease-specific mortality, but it is unclear whether the score also reflects cognitive changes and functional impairment. We aimed to assess the associations between the MetaboHealth score with cognitive function and functional decline in older adults at increased cardiovascular risk. A total of 5292 older adults free of dementia at baseline with mean age 75.3 years (SD = 3.4) from the Prospective Study of Pravastatin in the Elderly (PROSPER). MetaboHealth score were measured at baseline, and cognitive function and functional independence were measured at baseline and every 3 months during up to 2.5 years follow-up. Cognitive function was assessed using the Stroop test (selective attention), the Letter Digit Coding test (LDCT) (processing speed), and the two versions of the Picture Learning test (delayed and immediate; memory). Two tests of functional independence were used: Barthel Index (BI) and instrumental activities at daily living (IADL). A higher MetaboHealth score was associated with worse cognitive function (in all domains) and with worse functional independence. For example, after full adjustments, a 1-SD higher MetaboHealth score was associated with 9.02 s (95%CI 7.29, 10.75) slower performance on the Stroop test and 2.79 (2.21, 3.26) less digits coded on the LDCT. During follow-up, 1-SD higher MetaboHealth score was associated with an additional decline of 0.53 s (0.23, 0.83) on the Stroop test and - 0.08 (- 0.11, - 0.06) points on the IADL. Metabolic disturbance, as reflected by an increased metabolomics-based health score, may mark future cognitive and functional decline.

Risk assessment and management strategies in older patients with acute pulmonary embolism.

INTRODUCTION: Managing older patients with acute pulmonary embolism (PE) is challenging due to their underrepresentation in clinical trials, comorbidities and increased complication risk. This study evaluates risk assessment and management outcomes in older PE patients focussing on home and reperfusion treatment. METHODS: A retrospective analysis was conducted on patients aged ≥70 years diagnosed with acute PE at an academic medical centre (2015-2022). RESULTS: 242 patients with a mean age of 77 years were included. All 59 patients with negative Hestia criteria were discharged ≤24h, and in total 81 patients (35%) received home treatment. Among these 14-day mortality and recurrent venous-thromboembolism were 0% and major bleeding occurred in 1.3% (one patient, 95%CI 0.11-6.1). European Society of Cardiology (ESC) risk-classification showed 9 low-risk PE (3.9%), 199 intermediate-risk (87%), and 20 high-risk PE patients (8.8). In 5 of the 20 high-risk patients, hypotension was mainly caused by another condition, i.e. sepsis. Eight high-risk patients received reperfusion therapy. Fourteen-day mortality was 51% in high-risk patients (95%CI 27-71); 5 out of 8 patients receiving reperfusion treatment died within 5 days. Patients with an Acute Presenting Older Patient (APOP) score of ≥45% had higher 14-day mortality (28%; 95%CI 12-46) compared to <45% (3.2%; 95%CI 0.85-8.3; HR 10.2; 95%CI 2.6-39). CONCLUSION: Selecting for home treatment using Hestia was safe for older PE patients in our cohort. Mortality in the high-risk group was high also when receiving reperfusion treatment. The ESC risk-classification and APOP score identified patients at higher mortality risk, suggesting their potential utility in clinical decision-making.

Association between cognitive functioning and health-related quality of life and its mediation by depressive symptoms in older patients with kidney failure.

BACKGROUND: Impaired cognition, poor health-related quality of life (HRQoL) and depressive symptoms are common in older patients with kidney failure. Understanding what influences HRQoL is important, as older patients regard HRQoL as a health priority. This study examines whether cognitive functioning is associated with HRQoL and whether depressive symptoms mediate this effect in older patients with kidney failure. METHODS: Outpatients aged ≥ 65 years from 35 Dutch and Belgian hospitals with eGFR 20-10 mL/min/1.73 m2 were included from the ongoing DIALOGICA study. Cognitive functioning was assessed using the Montreal Cognitive Assessment. Depressive symptoms were screened with 2 Whooley Questions and thereafter assessed with the 15-item Geriatric Depression Scale. HRQoL was assessed using the 12-item Short-Form Health Survey. To assess whether cognitive functioning is associated with HRQoL, cross-sectional multivariable linear regression analyses were performed. Subsequent mediation analyses were performed with PROCESS using the product method. RESULTS: In total, 403 patients were included, with a mean age of 76.5 years (SD 5.8) and estimated glomerular filtration rate (eGFR) of 14.5 mL/min/1.73 m2 (SD 3.0). Cognitive functioning was associated with mental HRQoL (adjusted ß 0.30, 95% CI 0.05;0.55) but not physical HRQoL (adjusted ß 0.18, 95% CI -0.09;0.44). This effect is mediated by depressive symptoms (adjusted ß 0.14, 95% CI 0.04;0.25). CONCLUSION: Lower cognitive functioning was negatively associated with mental HRQoL, which was mediated by depressive symptoms in older patients with kidney failure. Future research should explore whether cognitive interventions and treatment of depression improve HRQoL in this vulnerable patient population.

Allocation and value of curative oncological treatment in frail and fit older patients with esophageal cancer: An observational cohort study.

INTRODUCTION: The Value-Based Health Care (VBHC) model of care provides insights into patient characteristics, outcomes, and costs of care delivery that help clinicians counsel patients. This study compares the allocation and value of curative oncological treatment in frail and fit older patients with esophageal cancer in a dedicated VBHC pathway. MATERIALS AND METHODS: Data was collected from patients with primary esophageal cancer without distant metastases, aged 70 years or older, and treated at a Dutch tertiary care hospital between 2015 and 2019. Geriatric assessment (GA) was performed. Outcomes included treatment discontinuation, mortality, quality of life (QoL), and physical functioning over a one-year period. Direct hospital costs were estimated using activity-based costing. RESULTS: In this study, 89 patients were included with mean age 75 years. Of 56 patients completing GA, 19 were classified as frail and 37 as fit. For frail patients, the treatment plan was chemoradiotherapy and surgery (CRT&S) in 68% (13/19) and definitive chemoradiotherapy (dCRT) in 32% (6/19); for fit patients, CRT&S in 84% (31/37) and dCRT in 16% (6/37). Frail patients discontinued chemotherapy more often than fit patients (26% (5/19) vs 11% (4/37), p = 0.03) and reported lower QoL after six months (mean 0.58 [standard deviation (SD) 0.35] vs 0.88 [0.25], p < 0.05). After one year, 11% of frail and 30% of fit patients reported no decline in physical functioning and QoL and survived. Frail and fit patients had comparable mean direct hospital costs (€24 K [SD €13 K] vs €23 K [SD €8 K], p = 0.82). DISCUSSION: The value of curative oncological treatment was lower for frail than for fit patients because of slightly worse outcomes and comparable costs. The utility of the VBHC model of care depends on the availability of sufficient data. Real-world evidence in VBHC can be used to inform treatment decisions and optimization in future patients by sharing results and monitoring performance over time. TRIAL REGISTRATION: The study was retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107 (date of registration: 22-10-2019).

The association of inflammatory markers with frailty and in-hospital mortality in older COVID-19 patients.

INTRODUCTION: During the COVID19 pandemic, older patients hospitalized for COVID-19 exhibited an increased mortality risk compared to younger patients. While ageing is associated with compromised immune responses and frailty, their contributions and interplay remain understudied. This study investigated the association between inflammatory markers and mortality and potential modification by frailty among older patients hospitalized for COVID-19. METHODS: Data were from three multicenter Dutch cohorts (COVID-OLD, CliniCo, Covid-Predict). Patients were 70 years or older, hospitalized for COVID-19and categorized into three frailty groups: fit (Clinical frailty score (CFS) 1-3), pre-frail (CFS 4-5), and frail (CFS 6-9). Immunological markers (lymphocyte count, neutrophil count, C-reactive protein, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic inflammation index (SII)) were measured at baseline. Associations with in hospital mortality were examined using logistic regression. RESULTS: A total of 1697 patients were included from COVID-OLD, 656 from Covid-Predict, and 574 from CliniCo. The median age was 79, 77, and 78 years for each cohort. Hospital mortality rates were 33 %, 27 % and 39 % in the three cohorts, respectively. A lower CRP was associated with a higher frailty score in all three cohorts (all p < 0.01). Lymphocyte count, neutrophil count, NLR, PLR, or SII, were similar across frailty groups. Higher CRP levels were associated with increased in-hospital mortality risk across all frailty groups, across all cohorts (OR (95 % CI), 2.88 (2.20-3.78), 3.15 (1.95-5.16), and 3.28 (1.87-5.92)), and frailty did not modify the association between inflammatory markers and in-hospital mortality (all p-interaction>0.05). CONCLUSION: While frailty is a significant factor in determining overall outcomes in older patients, our study suggests that the elevated risk of mortality in older patients with frailty compared to fit patients is likely not explained by difference in inflammatory responses.

DOSAGE study: protocol for a phase III non-inferiority randomised trial investigating dose-reduced chemotherapy for advanced colorectal cancer in older patients.

INTRODUCTION: Treating older adults with chemotherapy remains a challenge, given their under-representation in clinical trials and the lack of robust treatment guidelines for this population. Moreover, older patients, especially those with frailty, have an increased risk of developing chemotherapy-related toxicity, resulting in a decreased quality of life (QoL), increased hospitalisations and high healthcare costs. Phase II trials have suggested that upfront dose reduction of chemotherapy can reduce toxicity rates while maintaining efficacy, leading to fewer treatment discontinuations and an improved QoL. The DOSAGE aims to show that upfront dose-reduced chemotherapy in older patients with metastatic colorectal cancer is non-inferior to full-dose treatment in terms of progression-free survival (PFS), with adaption of the treatment plan (monotherapy or doublet chemotherapy) based on expected risk of treatment toxicity. METHODS AND ANALYSIS: The DOSAGE study is an investigator-initiated phase III, open-label, non-inferiority, randomised controlled trial in patients aged≥70 years with metastatic colorectal cancer eligible for palliative chemotherapy. Based on toxicity risk, assessed using the Geriatric 8 (G8) tool, patients will be stratified to either doublet chemotherapy (fluoropyrimidine with oxaliplatin) or fluoropyrimidine monotherapy. Patients classified as low risk will be randomised between a fluoropyrimidine plus oxaliplatin in either full-dose or with an upfront dose reduction of 25%. Patients classified as high risk will be randomised between fluoropyrimidine monotherapy in either full-dose or with an upfront dose reduction. In the dose-reduced arm, dose escalation after two cycles is allowed. The primary outcome is PFS. Secondary endpoints include grade≥3 toxicity, QoL, physical functioning, number of treatment cycles, dose reductions, hospital admissions, overall survival, cumulative received dosage and cost-effectiveness. Considering a median PFS of 8 months and non-inferiority margin of 8 weeks, we shall include 587 patients. The study will be enrolled in 36 Dutch Hospitals, with enrolment scheduled to start in July 2024. This study will provide new evidence regarding the effect of dose-reduced chemotherapy on survival and treatment outcomes, as well as the use of the G8 to choose between doublet chemotherapy or monotherapy. Results will contribute to a more individualised approach in older patients with metastatic colorectal cancer, potentially leading to improved QoL while maintaining survival benefits. ETHICS AND DISSEMINATION: This trial has received ethical approval by the ethical committee Leiden Den Haag Delft (P24.018) and will be approved by the Institutional Ethical Committee of the participating institutions. The results will be disseminated in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT06275958.

Temporal dynamics of depressive symptoms and cognitive decline in the oldest old: dynamic time warp analysis of the Leiden 85-plus study.

BACKGROUND: The prevalence of depressive symptoms and cognitive decline increases with age. We investigated their temporal dynamics in individuals aged 85 and older across a 5-year follow-up period. METHODS: Participants were selected from the Leiden 85-plus study and were eligible if at least three follow-up measurements were available (325 of 599 participants). Depressive symptoms were assessed at baseline and at yearly assessments during a follow-up period of up to 5 years, using the 15-item Geriatric Depression Scale (GDS-15). Cognitive decline was measured through various tests, including the Mini Mental State Exam, Stroop test, Letter Digit Coding test and immediate and delayed recall. A novel method, dynamic time warping analysis, was employed to model their temporal dynamics within individuals, in undirected and directed time-lag analyses, to ascertain whether depressive symptoms precede cognitive decline in group-level aggregated results or vice versa. RESULTS: The 325 participants were all 85 years of age at baseline; 68% were female, and 45% received intermediate to higher education. Depressive symptoms and cognitive functioning significantly covaried in time, and directed analyses showed that depressive symptoms preceded most of the constituents of cognitive impairment in the oldest old. Of the GDS-15 symptoms, those with the strongest outstrength, indicating changes in these symptoms preceded subsequent changes in other symptoms, were worthlessness, hopelessness, low happiness, dropping activities/interests, and low satisfaction with life (all P's < 0.01). CONCLUSION: Depressive symptoms preceded cognitive impairment in a population based sample of the oldest old.

Person-centred decisions in emergency care for older people living with frailty: principles and practice.

Older people living with frailty are frequent users of emergency care and have multiple and complex problems. Typical evidence-based guidelines and protocols provide guidance for the management of single and simple acute issues. Meanwhile, person-centred care orientates interventions around the perspectives of the individual. Using a case vignette, we illustrate the potential pitfalls of applying exclusively either evidence-based or person-centred care in isolation, as this may trigger inappropriate clinical processes or place undue onus on patients and families. We instead advocate for delivering a combined evidence-based, person-centred approach to healthcare which considers the person's situation and values, apparent problem and available options.

The performance of metabolomics-based prediction scores for mortality in older patients with solid tumors.

Prognostic information is needed to balance benefits and risks of cancer treatment in older patients. Metabolomics-based scores were previously developed to predict 5- and 10-year mortality (MetaboHealth) and biological age (MetaboAge). This study aims to investigate the association of MetaboHealth and MetaboAge with 1-year mortality in older patients with solid tumors, and to study their predictive value for mortality in addition to established clinical predictors. This prospective cohort study included patients aged ≥ 70 years with a solid malignant tumor, who underwent blood sampling and a geriatric assessment before treatment initiation. The outcome was all-cause 1-year mortality. Of the 192 patients, the median age was 77 years. With each SD increase of MetaboHealth, patients had a 2.32 times increased risk of mortality (HR 2.32, 95% CI 1.59-3.39). With each year increase in MetaboAge, there was a 4% increased risk of mortality (HR 1.04, 1.01-1.07). MetaboHealth and MetaboAge showed an AUC of 0.66 (0.56-0.75) and 0.60 (0.51-0.68) for mortality prediction accuracy, respectively. The AUC of a predictive model containing age, primary tumor site, distant metastasis, comorbidity, and malnutrition was 0.76 (0.68-0.83). Addition of MetaboHealth increased AUC to 0.80 (0.74-0.87) (p = 0.09) and AUC did not change with MetaboAge (0.76 (0.69-0.83) (p = 0.89)). Higher MetaboHealth and MetaboAge scores were associated with 1-year mortality. The addition of MetaboHealth to established clinical predictors only marginally improved mortality prediction in this cohort with various types of tumors. MetaboHealth may potentially improve identification of older patients vulnerable for adverse events, but numbers were too small for definitive conclusions. The TENT study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107. Date of registration: 22-10-2019.

Effects of the discontinuation of antihypertensive treatment on neuropsychiatric symptoms and quality of life in nursing home residents with dementia (DANTON): a multicentre, open-label, blinded-outcome, randomised controlled trial.

BACKGROUND: Based on observational studies and randomised controlled trials (RCTs), the benefit-harm balance of antihypertensive treatment in older adults with dementia is unclear. OBJECTIVE: To assess whether discontinuing antihypertensive treatment reduces neuropsychiatric symptoms (NPSs) and maintains quality of life (QoL) in nursing home residents with dementia. DESIGN: Open-label, blinded-outcome RCT. Randomisation 1:1, stratified by nursing home organisation and baseline NPS. Trial registration: NL7365. SUBJECTS: Dutch long-term care residents with moderate-to-severe dementia and systolic blood pressure (SBP) ≤160 mmHg during antihypertensive treatment. Exclusion criteria included heart failure NYHA-class-III/IV, recent cardiovascular events/procedures or life expectancy <4 months (planned sample size n = 492). MEASUREMENTS: Co-primary outcomes NPS (Neuropsychiatric Inventory-Nursing Home [NPI-NH]) and QoL (Qualidem) at 16 weeks. RESULTS: From 9 November 2018 to 4 May 2021, 205 participants (median age 85.8 [IQR 79.6-89.5] years; 79.5% female; median SBP 134 [IQR 123-146] mmHg) were randomised to either antihypertensive treatment discontinuation (n = 101) or usual care (n = 104). Safety concerns, combined with lacking benefits, prompted the data safety and monitoring board to advice a premature cessation of randomisation. At 16-week follow-up, no significant differences were found between groups for NPI-NH (adjusted mean difference 1.6 [95% CI -2.3 to 5.6]; P = 0.42) or Qualidem (adjusted mean difference - 2.5 [95% CI -6.0 to 1.0]; P = 0.15). Serious adverse events (SAEs) occurred in 36% (discontinuation) and 24% (usual care) of the participants (adjusted hazard ratio 1.65 [95% CI 0.98-2.79]). All 32-week outcomes favoured usual care. CONCLUSION: Halfway through this study, a non-significant increased SAE risk associated with discontinuing antihypertensive treatment was observed, and an associated interim analysis showed that significant worthwhile health gain for discontinuation of antihypertensive treatment was unlikely. This unbeneficial benefit-harm balance shows that discontinuation of antihypertensive treatment in this context does not appear to be either safe or beneficial enough to be recommended in older adults with dementia.

Differences in characteristics and outcomes of older patients hospitalized for COVID-19 after introduction of vaccination.

PURPOSE: The aim of the present study was to investigate characteristics and outcomes in vaccinated and unvaccinated older patients hospitalized for COVID-19 infection. METHODS: A retrospective multicentre cohort study among patients aged ≥70 years hospitalized for COVID-19 infection. RESULTS: 263 vaccinated and 82 unvaccinated patients were included. Vaccinated patients were older (median age 79 vs. 76 years; p < 0.001), more patients were male (66.2% vs. 53.7%; p = 0.040), had more comorbidities [median Charlson Comorbidity Index (CCI) 2 vs. 1; p 0.016] and were frailer [Clinical Frailty Scale (CFS) ≥ 4 68% vs. 49%; p 0.015]. Vaccinated patients were admitted earlier after symptom onset (median 5 days vs. 7 days) but were equally ill at time of hospital admission. After correction for frailty, comorbidity and disease severity, risk of in-hospital mortality was three times lower for vaccinated patients (HR 0.30 95% CI 0.16-0.56; p < 0.001) compared to unvaccinated patients. CONCLUSION: Vaccinated patients had lower risk of in-hospital mortality than unvaccinated patients with COVID-19 infection. These findings suggest that vaccinated patients benefit from the protective effect of the vaccine against death during hospital stay, outweighing the increased mortality risk that is associated with older age, greater frailty and more numerous comorbidities. This could be an encouragement for older people to receive age-appropriate vaccines, although no definite conclusions can be drawn for this was no intervention study.

Preparing for future pandemics: frailty associates with mortality in hospitalised older people during the entire COVID-19 pandemic, a Dutch multicentre cohort study.

PURPOSE: Viral mutations and improved prevention or treatment options may have changed the association of frailty with mortality throughout the COVID-19 pandemic. We investigated how associations of frailty with in-hospital mortality changed throughout the pandemic in older people hospitalised for COVID-19. METHODS: The COVID-OLD study included COVID-19 patients aged ≥ 70 years hospitalised during the first (early 2020), second (late 2020), third (late 2021) or fourth wave (early 2022). Based on the clinical frailty scale, patients were categorised as fit (1-3), pre-frail (4-5) or frail (6-9). Associations of frailty with in-hospital mortality were assessed with pairwise comparisons with fit as reference category and modelled using binary logistic regression adjusted for age and sex. RESULTS: This study included 2362 patients (mean age 79.7 years, 60% men). In the first wave, in-hospital mortality was 46% in patients with frailty and 27% in fit patients. In-hospital mortality decreased in each subsequent wave to 25% in patients with frailty and 11% in fit patients in the fourth wave. After adjustments, an overall higher risk of in-hospital mortality was found in frail (OR 2.26, 95% CI: 1.66-3.07) and pre-frail (OR 1.73, 95% CI: 1.27-2.35) patients compared to fit patients, which did not change over time (p for interaction = 0.74). CONCLUSIONS: Frailty remained associated with a higher risk of in-hospital mortality throughout the entire COVID-19 pandemic, although overall in-hospital mortality rates decreased. Frailty therefore remains a relevant risk factor in all stages of a pandemic and is important to consider in prevention and treatment guidelines for future pandemics.

Delirium detection in the emergency department: A diagnostic accuracy meta-analysis of history, physical examination, laboratory tests, and screening instruments.

INTRODUCTION: Geriatric emergency department (ED) guidelines emphasize timely identification of delirium. This article updates previous diagnostic accuracy systematic reviews of history, physical examination, laboratory testing, and ED screening instruments for the diagnosis of delirium as well as test-treatment thresholds for ED delirium screening. METHODS: We conducted a systematic review to quantify the diagnostic accuracy of approaches to identify delirium. Studies were included if they described adults aged 60 or older evaluated in the ED setting with an index test for delirium compared with an acceptable criterion standard for delirium. Data were extracted and studies were reviewed for risk of bias. When appropriate, we conducted a meta-analysis and estimated delirium screening thresholds. RESULTS: Full-text review was performed on 55 studies and 27 were included in the current analysis. No studies were identified exploring the accuracy of findings on history or laboratory analysis. While two studies reported clinicians accurately rule in delirium, clinician gestalt is inadequate to rule out delirium. We report meta-analysis on three studies that quantified the accuracy of the 4 A's Test (4AT) to rule in (pooled positive likelihood ratio [LR+] 7.5, 95% confidence interval [CI] 2.7-20.7) and rule out (pooled negative likelihood ratio [LR-] 0.18, 95% CI 0.09-0.34) delirium. We also conducted meta-analysis of two studies that quantified the accuracy of the Abbreviated Mental Test-4 (AMT-4) and found that the pooled LR+ (4.3, 95% CI 2.4-7.8) was lower than that observed for the 4AT, but the pooled LR- (0.22, 95% CI 0.05-1) was similar. Based on one study the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is the superior instrument to rule in delirium. The calculated test threshold is 2% and the treatment threshold is 11%. CONCLUSIONS: The quantitative accuracy of history and physical examination to identify ED delirium is virtually unexplored. The 4AT has the largest quantity of ED-based research. Other screening instruments may more accurately rule in or rule out delirium. If the goal is to rule in delirium then the CAM-ICU or brief CAM or modified CAM for the ED are superior instruments, although the accuracy of these screening tools are based on single-center studies. To rule out delirium, the Delirium Triage Screen is superior based on one single-center study.

Older people's goals of care in relation to frailty status-the COOP-study.

BACKGROUND: Literature relating older people's goals of care to their varying frailty status is scarce. OBJECTIVE: To investigate goals of care in case of acute and/or severe disease in relationship to frailty status among the general older population. METHOD: Older people aged ≥70 in the Netherlands completed a questionnaire. They were divided into three subgroups based on a self-reported Clinical Frailty Scale: fit (CFS 1-3), mildly frail (CFS 4-5) and severely frail (CFS 6-8). Seven goals were graded as unimportant (1-5), somewhat important (6-7) or very important (8-10): extending life, preserving quality of life (QoL), staying independent, relieving symptoms, supporting others, preventing hospital admission and preventing nursing home admission. RESULTS: Of the 1,278 participants (median age 76 years, 63% female), 57% was fit, 32% mildly frail and 12% severely frail. Overall, participants most frequently considered preventing nursing home admission as very important (87%), followed by staying independent (84%) and preserving QoL (83%), and least frequently considered extending life as very important (31%). All frailty subgroups reported similar preferences out of the surveyed goals as the overall study population. However, participants with a higher frailty status attached slightly less importance to each individual goal compared with fit participants (Ptrend-values ≤ 0.037). CONCLUSION: Preferred goals of care are not related to frailty status, while the importance ascribed to individual goals is slightly lower with higher frailty status. Future research should prioritise outcomes related to the shared goals of fit, mildly frail and severely frail older people to improve personalised medicine for older patients.

Toxicity in Older Patients with Cancer Receiving Immunotherapy: An Observational Study.

BACKGROUND: Checkpoint inhibition has emerged as an effective treatment strategy for a variety of cancers, including in older adults. However, older patients with cancer represent a heterogenous group as they can vary widely in frailty, cognition, and physical status. OBJECTIVE: This study aims to investigate the association between clinical frailty and immune-related treatment toxicity, hospitalization, and treatment discontinuation due to immune-related treatment toxicity in older patients treated with checkpoint inhibitors. METHODS: Patients aged 70 years and older treated with checkpoint inhibitors were selected from the TENT study, IMAGINE study, and "Tolerability and safety of immunotherapy study". Clinical frailty was assessed by the Geriatric-8 test score and World Health Organization (WHO) status. Outcomes were grades 3-5 toxicity, hospitalization, and treatment discontinuation due to toxicity during treatment. RESULTS: Of 99 patients included, 22% had comorbidities. While 33% of the patients were considered frail based on an abnormal Geriatric-8 test score of < 15, physical impairments were considered absent in 51% (WHO score of 0) and mild in 40% (WHO score of 1). Despite the limited sample size of the cohort, consistent trends were observed with patients with an abnormal Geriatric-8 test score of < 15 or a higher WHO score of 1 for having higher odds of toxicity [odds ratio (OR) 2.32 (95% CI 0.41-13.02); OR 1.33 (95% CI 0.45-4.17)], treatment discontinuation due to immune-related treatment toxicity [OR 2.25 (95% CI 0.61-8.31); OR 2.18 (95% CI 0.7-6.73)], and hospitalization due to immune-related treatment toxicity [OR 3.72 (95% CI 0.39-35.4); OR 1.31 (95% CI 0.35-4.9)]. Moreover, in a sub-analysis, we observed that the treatment discontinuation due to immune-related treatment toxicity occurred often in patients with grade 1-2 toxicity as well. CONCLUSIONS: Although not statistically significant, in older patients treated with immunotherapy in a real-life population with cancer, we observed consistent trends towards increased toxicity, hospitalization, and treatment discontinuation with increasing frailty. Larger studies are needed to confirm these exploratory results. Moreover, older patients with a lower toxicity grade 1-2 experienced early treatment discontinuation frequently, suggesting a lower tolerance of toxicity.

Tolerability and effectiveness of palbociclib in older women with metastatic breast cancer.

PURPOSE: Palbociclib has become the standard of care for estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer, but real-world evidence in older women remains scarce. Therefore, we investigated tolerability of palbociclib in older women with metastatic breast cancer. METHODS: Consecutive women aged ≥ 70 with ER+/HER2- metastatic breast cancer, treated with palbociclib in any treatment line in six hospitals, were included. Primary endpoint was grade ≥ 3 palbociclib-related toxicity. Predictors of toxicity were identified using logistic regression models. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier. RESULTS: We included 144 women with a median age of 74 years. Grade 3-4 toxicity occurred in 54% of patients, of which neutropenia (37%) was most common. No neutropenic fever or grade 5 toxicity occurred. Dose reduction during treatment occurred in 50% of patients, 8% discontinued treatment due to toxicity and 3% were hospitalized due to toxicity. Polypharmacy (odds ratio (OR) 2.50; 95% confidence interval (CI) 1.12-5.58) and pretreatment low leukocytes (OR 4.81; 95% CI 1.27-18.21) were associated with grade 3-4 toxicity, while comorbidities were not. In first-line systemic therapy, median PFS was 12 months and median OS 32 months. In second-line, median PFS was 12 months and median OS 31 months. CONCLUSION: Although grade 3-4 toxicity and dose reductions occurred frequently, most were expected and managed by dose reductions, showing that palbociclib is generally well tolerated and thus represents a valuable treatment option in the older population.

Patient-Reported Satisfaction with Thyroid Hormone Replacement Therapy for Subclinical Hypothyroidism in Older Adults: A Pooled Analysis of Individual Participant Data from Two Randomized Controlled Trials.

Background: The benefit of levothyroxine treatment of subclinical hypothyroidism (SCH) is subject to debate. This study compared treatment satisfaction between older adults with SCH using levothyroxine or placebo. Methods: We analyzed pooled individual participant data from two randomized, double-blind, placebo-controlled trials investigating the effects of levothyroxine treatment in older adults with SCH. Community-dwelling participants aged ≥65 years, with SCH (persistent thyrotropin levels 4.60-19.99 mIU/L for >3 months and normal free T4 level), were included. Intervention dose titration until thyrotropin levels normalized, with a mock dose adjustment of placebo. Treatment satisfaction was determined during the final study visit using the Treatment Satisfaction Questionnaire for Medication (TSQM), encompassing perceived effectiveness, side effects, convenience, and global satisfaction, along with the participants' desire to continue study medication after the trial. Results: We included 536 participants. At baseline, the median (interquartile range [IQR]) age was 74.9 (69.7-81.4) years, and 292 (55%) were women. The median (IQR) thyrotropin levels were 5.80 (5.10-7.00) mIU/L at baseline in both groups; at final visit, 4.97 (3.90-6.35) mIU/L in the placebo and 3.24 (2.49-4.41) mIU/L in the levothyroxine group. After treatment, the groups did not differ significantly in global satisfaction (mean difference [CI] -1.1 [-4.5 to 2.1], p = 0.48), nor in any other domain of treatment satisfaction. These results held true regardless of baseline thyrotropin levels or symptom burden. No major differences were found in the numbers of participants who wished to continue medication after the trial (levothyroxine 35% vs. placebo 27%), did not wish to continue (levothyroxine 27% vs. placebo 30%), or did not know (levothyroxine 37% vs. placebo 42%) (p = 0.14). In a subpopulation with high symptom burden from hypothyroid symptoms at baseline, those using levothyroxine more often desired to continue the medication after the trial than those using placebo (mean difference [CI]: -21.1% [-35.6% to -6.5%]). Conclusion: These pooled data from two RCTs showed no major differences in treatment satisfaction between older adults receiving levothyroxine or placebo. This finding has important implications for decision-making regarding initiating levothyroxine treatment for SCH. Our findings generally support refraining from routinely prescribing levothyroxine in older adults with SCH.

Geriatric Assessment in CKD Care: An Implementation Study.

Rationale & Objective: Older people with progressive chronic kidney disease (CKD) have complex health care needs. Geriatric evaluation preceding decision making for kidney replacement is recommended in guidelines, but implementation is lacking in routine care. We aimed to evaluate implementation of geriatric assessment in CKD care. Study Design: Mixed methods implementation study. Setting & Participants: Dutch nephrology centers were approached for implementation of geriatric assessment in patients aged ≥70 years and with an estimated glomerular filtration rate of ≤20 mL/min/1.73 m2. Quality Improvement Activities/Exposure: We implemented a consensus-based nephrology-tailored geriatric assessment: a patient questionnaire and professionally administered test set comprising 16 instruments covering functional, cognitive, psychosocial, and somatic domains and patient-reported outcome measures. Outcomes: We aimed for implementation in 10 centers and 200 patients. Implementation was evaluated by (i) perceived enablers and barriers of implementation, including integration in work routines (Normalization Measure Development Tool) and (ii) relevance of the instruments to routine care for the target population. Analytical Approach: Variations in implementation practices were described based on field notes. The postimplementation survey among health care professionals was analyzed descriptively, using an explanatory qualitative approach for open-ended questions. Results: Geriatric assessment was implemented in 10 centers among 191 patients. Survey respondents (n = 71, 88% response rate) identified determinants that facilitated implementation, ie, multidisciplinary collaboration (with geriatricians) -meetings and reports and execution of assessments by nurses. Barriers to implementation were patient illiteracy or language barrier, time constraints, and patient burden. Professionals considered geriatric assessment sufficiently integrated into work routines (mean, 6.7/10 ± 2.0 [SD]) but also subject to improvement. Likewise, the relevance of geriatric assessment for routine care was scored as 7.8/10 ± 1.2. The Clinical Frailty Score and Montreal Cognitive Assessment were perceived as the most relevant instruments. Limitations: Selection bias of interventions' early adopters may limit generalizability. Conclusions: Geriatric assessment could successfully be integrated in CKD care and was perceived relevant to health care professionals.

The number of older persons with kidney failure is increasing, many of whom have cognitive decline or are dependent on others for daily life tasks. These problems are often overlooked but relevant for future treatment choices, and they affect quality of life. We asked 10 health care centers to use tests and questionnaires to identify these issues, thus being able to offer additional support. We learned that it is possible to use these assessments in practice and that professionals found them relevant. Collaboration with geriatric departments was perceived valuable. However, there are also challenges, such as not having enough time and personnel and burden to patients. Understanding these possibilities and challenges is crucial for improving care for older patients with kidney failure.