Familial longevity is associated with lower baseline bone turnover but not differences in bone turnover in response to rhTSH.

CONTEXT: Offspring from long-lived families have a different thyroid status than controls, characterised by higher circulating levels of thyroid stimulating hormone (TSH) and similar levels of thyroid hormone. Expression of the TSH receptor has previously been observed on various extrathyroidal tissues, including bone. However, potential physiological consequences of differences in circulating TSH as observed in familial longevity on bone tissue remain unclear. OBJECTIVE: Based on the hypothesis that TSH may inhibit bone resorption, we explored whether offspring of long-lived families have lower bone turnover than controls at baseline as well as following a challenge with recombinant human TSH (rhTSH). METHODS: Bone turnover markers CTX and P1NP were measured in fasted morning samples from 14 offspring and 12 controls at baseline and at 24 hour intervals following 0.1 mg rhTSH i.m. administration for four consecutive days. RESULTS: At baseline, mean (SEM) CTX was 0.32 (0.03) ng/ml in offspring and 0.50 (0.04) ng/ml in controls, p < 0.01, whereas mean (SEM) P1NP was 39.6 (3.2) ng/ml in offspring and 61.8 (6.6) ng/ml in controls, p < 0.01. Following rhTSH administration, both CTX and P1NP levels transiently increased over time and normalized towards baseline after 72 h (general linear modelling: CTX time p = 0.01, P1NP time p < 0.01); the response was similar between offspring and controls. CONCLUSIONS: Bone turnover markers were lower at baseline in offspring from long-lived families than in controls but increased similarly following an rhTSH challenge.

Design and rationale of a routine clinical care pathway and prospective cohort study in older patients needing intensive treatment.

BACKGROUND: Treatment decisions concerning older patients can be very challenging and individualised treatment plans are often required in this very heterogeneous group. In 2015 we have implemented a routine clinical care pathway for older patients in need of intensive treatment, including a comprehensive geriatric assessment (CGA) that was used to support clinical decision making. An ongoing prospective cohort study, the Triaging Elderly Needing Treatment (TENT) study, has also been initiated in 2016 for participants in this clinical care pathway, to study associations between geriatric characteristics and outcomes of treatment that are relevant to older patients. The aim of this paper is to describe the implementation and rationale of the routine clinical care pathway and design of the TENT study. METHODS: A routine clinical care pathway has been designed and implemented in multiple hospitals in the Netherlands. Patients aged ≥70 years who are candidates for intensive treatments, such as chemotherapy, (chemo-)radiation therapy or major surgery, undergo frailty screening based on the Geriatric 8 (G-8) questionnaire and the Six-Item Cognitive Impairment Test (6CIT). If screening reveals potential frailty, a CGA is performed. All patients are invited to participate in the TENT study. Clinical data and blood samples for biomarker studies are collected at baseline. During follow-up, information about treatment complications, hospitalisations, functional decline, quality of life and mortality is collected. The primary outcome is the composite endpoint of functional decline or mortality at 1 year. DISCUSSION: Implementation of a routine clinical care pathway for older patients in need of intensive treatment provides the opportunity to study associations between determinants of frailty and outcomes of treatment. Results of the TENT study will support individualised treatment for future patients. TRIAL REGISTRATION: The study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107 . Date of registration: 22-10-2019.

The Prognostic Value of Metabolic Profiling in Older Patients With a Proximal Femoral Fracture.

INTRODUCTION: High mortality rates of approximately 20% within 1 year after treatment are observed for patients with proximal femoral fractures. This preliminary study explores the prognostic value of a previously constructed mortality risk score based on a set of 14 metabolites for the survival and functional recovery in patients with proximal femoral fractures. MATERIALS AND METHODS: A prospective observational cohort study was conducted including patients admitted with a proximal femoral fracture. The primary outcome was patient survival, and the recovery of independence in activities of daily living was included as a secondary outcome. The mortality risk score was constructed for each patient and its prognostic value was tested for the whole population. RESULTS: Data was available form 136 patients. The mean age of all patients was 82.1 years, with a median follow-up of 6 months. Within this period, 19.0% of all patients died and 51.1% recovered to their prefracture level of independence. The mortality score was significantly associated with mortality (HR, 2.74; 95% CI, 1.61-4.66; P < 0.001), but showed only a fair prediction accuracy (AUC = 0.68) and a borderline significant comparison of the mortality score tertile groups in survival analyses (P = 0.049). No decisive associations were found in any of the analyses for the functional recovery of patients. DISCUSSION: These findings support the previously determined prognostic value of the mortality risk score. However, the independent prognostic value when adjusted for potential confounding factors is yet to be assessed. Also, a risk score constructed for this specific patient population might achieve higher accuracies for the prediction of survival and functional recovery. CONCLUSIONS: A modest prediction accuracy was observed for the mortality risk score in this population. More elaborate studies are needed to validate these findings and develop a tailored model for clinical purposes in this patient population.

Geriatric assessment and 1-year mortality in older patients with cancer in the head and neck region: A cohort study.

BACKGROUND: The aim is to describe the association of functional capacity and cognitive functioning with 1-year mortality in older patients with cancer in the head and neck region. METHODS: We performed a cohort study in which all patients aged 70 years and older received a geriatric screening before treatment. Main outcome was 1-year mortality. RESULTS: A total of 102 patients were included. Median age was 78.7 years (interquartile range [IQR], 72.3-84.5), 25% were cognitive impaired, 40% were malnourished, and 28.4% used a walking device. Overall, 1-year mortality was 42.3%. Male sex (hazard ratio [HR], 4.30; 95% confidence interval [CI], 1.35-13.67), malnutrition (HR, 2.55; 95% CI, 1.19-5.16), and using a walking device (HR, 2.80; 95% CI 1.13-6.93) were associated with higher mortality risk, independent of stage and comorbidities. CONCLUSION: In older patients with head and neck cancer, the mortality rates are high. Nutritional status and mobility are determinants of 1-year mortality, independent of tumor stage, age, and comorbidity.

Predictors and Outcomes of Revisits in Older Adults Discharged from the Emergency Department.

OBJECTIVES: To study predictors of emergency department (ED) revisits and the association between ED revisits and 90-day functional decline or mortality. DESIGN: Multicenter cohort study. SETTING: One academic and two regional Dutch hospitals. PARTICIPANTS: Older adults discharged from the ED (N=1,093). MEASUREMENTS: At baseline, data on demographic characteristics, illness severity, and geriatric parameters (cognition, functional capacity) were collected. All participants were prospectively followed for an unplanned revisit within 30 days and for functional decline and mortality 90 days after the initial visit. RESULTS: The median age was 79 (interquartile range 74-84), and 114 participants (10.4%) had an ED revisit within 30 days of discharge. Age (hazard ratio (HR)=0.96, 95% confidence interval (CI)=0.92-0.99), male sex (HR=1.61, 95% CI=1.05-2.45), polypharmacy (HR=2.06, 95% CI=1.34-3.16), and cognitive impairment (HR=1.71, 95% CI=1.02-2.88) were independent predictors of a 30-day ED revisit. The area under the receiver operating characteristic curve to predict an ED revisit was 0.65 (95% CI=0.60-0.70). In a propensity score-matched analysis, individuals with an ED revisit were at higher risk (odds ratio=1.99 95% CI=1.06-3.71) of functional decline or mortality. CONCLUSION: Age, male sex, polypharmacy, and cognitive impairment were independent predictors of a 30-day ED revisit, but no useful clinical prediction model could be developed. However, an early ED revisit is a strong new predictor of adverse outcomes in older adults.

Predicting mortality in acutely hospitalized older patients: a retrospective cohort study.

Acutely hospitalized older patients have an increased risk of mortality, but at the moment of presentation this risk is difficult to assess. Early identification of patients at high risk might increase the awareness of the physician, and enable tailored decision-making. Existing screening instruments mainly use either geriatric factors or severity of disease for prognostication. Predictive performance of these instruments is moderate, which hampers successive interventions. We conducted a retrospective cohort study among all patients aged 70 years and over who were acutely hospitalized in the Acute Medical Unit of the Leiden University Medical Center, the Netherlands in 2012. We developed a prediction model for 90-day mortality that combines vital signs and laboratory test results reflecting severity of disease with geriatric factors, represented by comorbidities and number of medications. Among 517 patients, 94 patients (18.2 %) died within 90 days after admission. Six predictors of mortality were included in a model for mortality: oxygen saturation, Charlson comorbidity index, thrombocytes, urea, C-reactive protein and non-fasting glucose. The prediction model performs satisfactorily with an 0.738 (0.667-0.798). Using this model, 53 % of the patients in the highest risk decile (N = 51) were deceased within 90 days. In conclusion, we are able to predict 90-day mortality in acutely hospitalized older patients using a model with directly available clinical data describing disease severity and geriatric factors. After further validation, such a model might be used in clinical decision making in older patients.

Haemoglobin predicts length of hospital stay after hip fracture surgery in older patients.

OBJECTIVES: Treating anaemia in older patients who have undergone hip fracture surgery is to enhance functional recovery. The relationship between peri-operative haemoglobin levels and outcome after hip fracture surgery are controversial. We assessed whether higher haemoglobin levels predict length of hospital stay after hip fracture surgery in elderly subjects. STUDY DESIGN: A follow-up study in a historical cohort was performed in 317 patients aged 65 years old undergoing hip fracture surgery over the period 2004-2006 at the Leiden University Medical Centre. MEAN OUTCOME MEASURES: Linear regression analysis was used to assess the association between pre- and post-operative haemoglobin level and length of hospital stay after controlling for age and sex. RESULTS: Anaemia after hip fracture surgery was present among 86% of the patients. Length of hospital stay after hip fracture surgery in elderly subjects with post-operative anaemia (10.7 days) was significantly longer than in elderly subjects without post-operative anaemia (7.5 days, p=0.007). Post-operative haemoglobin levels and length of hospital stay were inversely related (p=0.013). The length of hospital stay was not related with pre-operative haemoglobin level. CONCLUSION: Higher postoperative haemoglobin levels predict shorter length of hospital stay after hip fracture surgery in the elderly. A definitive randomized clinical trial has to demonstrate whether this association is causal.

No increased mortality risk in older persons with unexplained anaemia.

BACKGROUND: in older persons, anaemia is associated with a number of unfavourable outcomes. In approximately 30% of older persons with anaemia, the cause of the anaemia is unexplained. We assessed the clinical differences between subjects with explained and unexplained anaemia and investigated whether these subjects have different mortality patterns compared with subjects without anaemia. DESIGN: observational prospective follow-up study. SETTING: the Leiden 85-plus study. PARTICIPANTS: four hundred and ninety-one persons aged 86 years. METHODS: the study population was divided in three groups: (i) no anaemia (reference group, n=377), (ii) explained anaemia (iron deficiency, folate deficiency, vitamin B12 deficiency, signs of myelodysplastic syndrome or renal failure, n=74) and (iii) unexplained anaemia, (n=40). Mortality risks were estimated with Cox-proportional hazard models. RESULTS: haemoglobin levels were significantly lower in subjects with explained anaemia than in subjects with unexplained anaemia (P<0.01). An increased risk for mortality was observed in subjects with explained anaemia [HR: 1.93 (95% CI: 1.47-2.52), P<0.001], but not in subjects with unexplained anaemia [HR: 1.19 (95% CI: 0.85-1.69), P=0.31]. Adjusted analyses (sex, co-morbidity, MMSE, institutionalised and smoking) did not change the observed associations for both explained and unexplained anaemic subjects. CONCLUSION: older subjects with unexplained anaemia had similar survival compared with non-anaemic subjects. Increased mortality risks were observed in subjects with explained anaemia compared with non-anaemic subjects.

White blood cell count and C-reactive protein are independent predictors of mortality in the oldest old.

BACKGROUND: White blood cell (WBC) count is, like C-reactive protein (CRP), a clinical marker of inflammation and predicts cardiovascular disease and mortality in middle-aged populations. Limited data exist on the association between WBC count and mortality in the oldest old. Moreover, because CRP and WBC count are closely linked, it is not known whether WBC count and CRP are independent risk factors for mortality. We assessed the independent predictive value of WBC count and CRP levels in relation to mortality, both vascular and nonvascular, in very old participants. METHODS: A total of 599 women and men were evaluated longitudinally in the Leiden 85-plus Study. Blood samples and medical information were collected at age 85, and all participants were visited annually until age 90 or death. Mortality risks were estimated with Cox proportional hazard models. RESULTS: Increasing WBC count was associated with an increased risk for all-cause mortality (hazard ratio, HR [95% confidence interval, CI] = 1.26 [1.15-1.38]) after adjustment for sex and smoking status. CRP levels were also associated with an increased risk for mortality (HR [95% CI] = 1.22 [1.10-1.35]). The association between increasing WBC count and mortality remained significant after adjustment for CRP levels (HR [95% CI] = 1.20 [1.09-1.33]), whereas also the relation between increasing CRP levels and mortality remained significant after adjustment for WBC count (HR [95% CI] = 1.17 [1.05-1.30]). CONCLUSION: Our results suggest that WBC count and CRP levels both independently predict mortality in the oldest old.

Apolipoprotein e genotype, plasma cholesterol, and cancer: a Mendelian randomization study.

Observational studies have shown an association between low plasma cholesterol levels and increased risk of cancer, whereas most randomized clinical trials involving cholesterol-lowering medications have not shown this association. Between 1997 and 2002, the authors assessed the association between plasma cholesterol levels and cancer risk, free from confounding and reverse causality, in a Mendelian randomization study using apolipoprotein E (ApoE) genotype. ApoE genotype, plasma cholesterol levels, and cancer incidence and mortality were measured during a 3-year follow-up period among 2,913 participants in the Prospective Study of Pravastatin in the Elderly at Risk. Subjects within the lowest third of plasma cholesterol level at baseline had increased risks of cancer incidence (hazard ratio (HR) = 1.90, 95% confidence interval (CI): 1.34, 2.70) and cancer mortality (HR = 2.03, 95% CI: 1.23, 3.34) relative to subjects within the highest third of plasma cholesterol. However, carriers of the ApoE2 genotype (n = 332), who had 9% lower plasma cholesterol levels than carriers of the ApoE4 genotype (n = 635), did not have increased risk of cancer incidence (HR = 0.86, 95% CI: 0.50, 1.47) or cancer mortality (HR = 0.70, 95% CI: 0.30, 1.60) compared with ApoE4 carriers. These findings suggest that low cholesterol levels are not causally related to increased cancer risk.

Diastolic wall shear stress in the internal carotid artery is associated with different cardiovascular risk factors than systolic wall shear stress.

BACKGROUND AND PURPOSE: Wall shear stress (WSS) is the frictional force exerted by the circulating blood on the endothelium. Low systolic WSS is identified as an atherosclerotic risk factor. Recently, also the importance of diastolic WSS has been described. Still, it is unknown whether diastolic WSS carries similar cardiovascular risk factors compared to systolic WSS. METHODS: Of 379 subjects (70-82 years, 56% male) diastolic and systolic WSS in the internal carotid arteries was determined. RESULTS: After adjustment for age and gender, diastolic blood pressure was associated with systolic WSS (p = 0.02). Body mass index was associated with diastolic WSS (p = 0.04). Smoking was associated with diastolic WSS (p = 0.05). Myocardial infarction was associated with both systolic WSS (p = 0.04) and diastolic WSS (p < 0.01). No associations between cholesterol, HDL, LDL, triglycerides, history of diabetes, hypertension, angina pectoris, claudication, stroke, or any vascular disease were found with systolic or diastolic WSS. CONCLUSIONS: Our data indicates different cardiovascular risk factors for diastolic WSS compared to systolic WSS.

Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

BACKGROUND: Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke. METHODS AND FINDINGS: In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672]), fatal CVD (n = 190), death from other CV causes (n = 38), and non-CVD mortality (n = 300), over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis) more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44-2.12) than with risk of nonfatal CVD (1.17, 95% CI 1.04-1.31), in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction). The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001) improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20). CONCLUSIONS: In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.

C-reactive protein and prediction of coronary heart disease and global vascular events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).

BACKGROUND: The role of C-reactive protein (CRP) in predicting vascular events and response to statin therapy remains uncertain. Additional large prospective studies are required. METHODS AND RESULTS: Baseline CRP was related to risk over 3.2 years for primary a combined end point (definite or suspected death from coronary heart disease, nonfatal myocardial infarction, and fatal or nonfatal stroke; n=865 events) and secondary (coronary heart disease events or stroke alone) and tertiary (stroke plus transient ischemic attack) end points in the Prospective Study of Pravastatin in the Elderly at Risk (n=5804 men and women; age, 70 to 82 years). CRP levels were higher in subjects who had a subsequent primary end-point event compared with those who did not (geometric mean; 3.64 mg/L [SD, 3.08 mg/L] versus 3.01 mg/L [SD, 3.05 mg/L]; P<0.0001). CRP correlated positively with body mass index and smoking status and negatively with high-density lipoprotein cholesterol. The unadjusted hazard ratio for the primary end point was 1.48 (95% CI, 1.26 to 1.74) in a comparison of top and bottom thirds for CRP, falling to 1.36 (95% CI, 1.15 to 1.61) with adjustment for established predictors and body mass index. Similar results were obtained for other end points or when results were examined separately by history of vascular disease. However, baseline CRP added minimally to risk prediction beyond conventional predictors and did not relate to the magnitude of pravastatin benefit. CONCLUSIONS: Elevated CRP minimally enhances cardiovascular disease prediction beyond established vascular risk factors and does not predict response to statin therapy in elderly subjects at risk. These data suggest that CRP has limited clinical value in cardiovascular disease risk stratification or predicting response to statin therapy in elderly people.

Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.

BACKGROUND: Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. METHODS: We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. FINDINGS: Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006). Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8), but the hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. INTERPRETATION: Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people.