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Nanchen D.,Leiden University | Nanchen D.,University of Lausanne | Westendorp R.G.J.,Leiden University | Westendorp R.G.J.,Netherlands Consortium for Healthy Aging | And 12 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Subclinical thyroid dysfunction is common in older people. However, its clinical importance is uncertain. Objective: Our objective was to determine the extent to which subclinical hyperthyroidism and hypothyroidism influence the risk of heart failure and cardiovascular diseases in older people. Setting and Design: The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) is an prospective cohort study. Patients: Patients included men and women aged 70-82 yr (n = 5316) with known cardiovascular risk factors or previous cardiovascular disease. Main Outcome Measures: Incidence rate of heart failure hospitalization, atrial fibrillation, and cardiovascular events and mortality according to baseline thyroid status were evaluated. Euthyroid participants (TSH=0.45-4.5 mIU/liter) were compared with those with subclinical hyperthyroidism (TSH <0.45 mIU/liter) and those with subclinical hypothyroidism (TSH ≥4.5 mIU/liter, both with normal free T 4). Results: Subclinical hyperthyroidism was present in 71 participants and subclinical hypothyroidism in 199 participants. Over 3.2 yr follow-up, the rate of heart failure was higher for subclinical hyperthyroidism compared with euthyroidism [age- and sex-adjusted hazard ratio (HR) = 2.93, 95% confidence interval (CI) = 1.37-6.24, P = 0.005; multivariate-adjusted HR = 3.27, 95% CI = 1.52-7.02, P = 0.002). Subclinical hypothyroidism (only at threshold >10 mIU/liter) was associated with heart failure (age- and sex-adjusted HR = 3.01, 95% CI = 1.12-8.11, P = 0.029; multivariate HR = 2.28, 95% CI = 0.84-6.23). There were no strong evidence of an association between subclinical thyroid dysfunction and cardiovascular events or mortality, except in those with TSH below 0.1 or over 10 mIU/liter and not taking pravastatin. Conclusion: Older people at high cardiovascular risk with low or very high TSH along with normal free T4 appear at increased risk of incident heart failure. Copyright © 2012 by The Endocrine Society.


Van Leeuwen N.,Erasmus Medical Center | Lingsma H.F.,Erasmus Medical Center | De Craen A.J.M.,Leiden University | Nieboer D.,Erasmus Medical Center | And 4 more authors.
Epidemiology | Year: 2016

In epidemiology, the regression discontinuity design has received increasing attention recently and might be an alternative to randomized controlled trials (RCTs) to evaluate treatment effects. In regression discontinuity, treatment is assigned above a certain threshold of an assignment variable for which the treatment effect is adjusted in the analysis. We performed simulations and a validation study in which we used treatment effect estimates from an RCT as the reference for a prospectively performed regression discontinuity study. We estimated the treatment effect using linear regression adjusting for the assignment variable both as linear terms and restricted cubic spline and using local linear regression models. In the first validation study, the estimated treatment effect from a cardiovascular RCT was -4.0 mmHg blood pressure (95% confidence interval: -5.4, -2.6) at 2 years after inclusion. The estimated effect in regression discontinuity was -5.9 mmHg (95% confidence interval: -10.8, -1.0) with restricted cubic spline adjustment. Regression discontinuity showed different, local effects when analyzed with local linear regression. In the second RCT, regression discontinuity treatment effect estimates on total cholesterol level at 3 months after inclusion were similar to RCT estimates, but at least six times less precise. In conclusion, regression discontinuity may provide similar estimates of treatment effects to RCT estimates, but requires the assumption of a global treatment effect over the range of the assignment variable. In addition to a risk of bias due to wrong assumptions, researchers need to weigh better recruitment against the substantial loss in precision when considering a study with regression discontinuity versus RCT design. © 2016 Wolters Kluwer Health, Inc.


Birkenhager-Gillesse E.G.,Leiden University | Birkenhager-Gillesse E.G.,Laurens Care Centers | Den Elzen W.P.J.,Leiden University | Achterberg W.P.,Leiden University | And 4 more authors.
Journal of the American Geriatrics Society | Year: 2015

Objectives To examine the association between glycosylated hemoglobin (HbA1c) and incident cardiovascular disease and mortality in 85-year-old individuals without diabetes mellitus from the general population. Design Population-based prospective follow-up study. Setting General population. Participants Individuals without known diabetes mellitus (N = 445, n = 291 female). Measurements HbA1c levels were categorized into three groups (<5.0% (31 mmol/mol), 5.0-5.7% (31-39 mmol/mol; reference), 5.7-6.5% (39-48 mmol/mol)). Results At baseline, a history of myocardial infarction (MI) was more prevalent in subjects in the highest HbA1c group (18%) than in the reference group (7%) (P =.001). Prospectively, those with the highest level of HbA1c at baseline had a risk of incident MI during the 5-year follow-up that was 3.6 (95% confidence interval = 1.5-8.3) times as great as that of the reference group. No association was found between HbA1c level and incident stroke, cardiovascular mortality, or all-cause mortality. Conclusion In individuals aged 85 and older without diabetes mellitus, higher HbA1c is associated with greater risk of MI but not with stroke and mortality. © 2015, The American Geriatrics Society.


Wijsman C.A.,Leiden University | Westendorp R.G.J.,Leiden University | Westendorp R.G.J.,Vitality | Verhagen E.A.L.M.,VU University Amsterdam | And 13 more authors.
Journal of Medical Internet Research | Year: 2013

Background: Lack of physical activity leads to detrimental changes in body composition and metabolism, functional decline, and increased risk of disease in old age. The potential of Web-assisted interventions for increasing physical activity and improving metabolism in older individuals holds great promise but to our knowledge it has not been studied. Objective: The goal of our study was to assess whether a Web-based intervention increases physical activity and improves metabolic health in inactive older adults. Methods: We conducted a 3-month randomized, waitlist-controlled trial in a volunteer sample of 235 inactive adults aged 60-70 years without diabetes. The intervention group received the Internet program Philips DirectLife, which was directed at increasing physical activity using monitoring and feedback by accelerometer and digital coaching. The primary outcome was relative increase in physical activity measured objectively using ankle- and wrist-worn accelerometers. Secondary outcomes of metabolic health included anthropometric measures and parameters of glucose metabolism. Results: In total, 226 participants (97%) completed the study. At the ankle, activity counts increased by 46% (standard error [SE] 7%) in the intervention group, compared to 12% (SE 3%) in the control group (P difference<.001). Measured at the wrist, activity counts increased by 11% (SE 3%) in the intervention group and 5% (SE 2%) in the control group (Pdifference=.11). After processing of the data, this corresponded to a daily increase of 11 minutes in moderate-to-vigorous activity in the intervention group versus 0 minutes in the control group (P difference=.001). Weight decreased significantly more in the intervention group compared to controls (-1.5 kg vs -0.8 kg respectively, P=.046), as did waist circumference (-2.3 cm vs -1.3 cm respectively, P=.036) and fat mass (-0.6% vs 0.07% respectively, P=.025). Furthermore, insulin and HbA1c levels were significantly more reduced in the intervention group compared to controls (both P<.05). Conclusions: This was the first study to show that in inactive older adults, a 3-month Web-based physical activity intervention was effective in increasing objectively measured daily physical activity and improving metabolic health. Such Web-based interventions provide novel opportunities for large scale prevention of metabolic deregulation in our rapidly aging population.


Sabayan B.,Leiden University | Wijsman L.W.,Leiden University | Wijsman L.W.,Netherlands Consortium for Healthy Ageing | Foster-Dingley J.C.,Leiden University | And 15 more authors.
BMJ (Online) | Year: 2013

Objective To investigate the association between visit-to-visit variability in blood pressure and cognitive function in old age (>70 years). Design Prospective cohort study. Setting PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) study, a collaboration between centres in Ireland, Scotland, and the Netherlands. Participants 5461 participants, mean age 75.3 years, who were at risk of cardiovascular disease. Blood pressure was measured every three months during an average of 3.2 years. Visit-to-visit variability in blood pressure was defined as the standard deviation of blood pressure measurements between visits. Main outcome measures Four domains of cognitive function, testing selective attention, processing speed, and immediate and delayed memory. In a magnetic resonance imaging substudy of 553 participants, structural brain volumes, cerebral microbleeds, infarcts, and white matter hyperintensities were measured. Results Participants with higher visit-to-visit variability in systolic blood pressure had worse performance on all cognitive tests: attention (mean difference high versus low thirds) 3.08 seconds (95% confidence interval 0.85 to 5.31), processing speed ?1.16 digits coded (95% confidence interval ?1.69 to ?0.63), immediate memory ?0.27 pictures remembered (95% confidence interval ?0.41 to ?0.13), and delayed memory ?0.30 pictures remembered (95% confidence interval ?0.49 to ?0.11). Furthermore, higher variability in both systolic and diastolic blood pressure was associated with lower hippocampal volume and cortical infarcts, and higher variability in diastolic blood pressure was associated with cerebral microbleeds (all P<0.05). All associations were adjusted for average blood pressure and cardiovascular risk factors. Conclusion Higher visit-to-visit variability in blood pressure independent of average blood pressure was associated with impaired cognitive function in old age.


Poortvliet R.K.E.,Leiden University | Ford I.,University of Glasgow | Lloyd S.M.,University of Glasgow | Sattar N.,University of Glasgow | And 10 more authors.
PLoS ONE | Year: 2012

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70-82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1-1.4; hazard ratio 1.1, 95% confidence interval 1.1-1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2-1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1-1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1-1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1-1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0-1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0-1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0-1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects. © 2012 Poortvliet et al.


Poortvliet R.K.E.,Leiden University | De Ruijter W.,Leiden University | De Craen A.J.M.,Leiden University | Mooijaart S.P.,Leiden University | And 6 more authors.
Journal of Hypertension | Year: 2013

Objective: To evaluate the independent contributions of both the trend in SBP and the SBP value at age 90 to the prediction of mortality in nonagenarians. Methods: The trend in SBP between 85 and 90 years and SBP at age 90 years were assessed in a population-based sample of 271 participants (74 men and 197 women) aged 90 years of the Leiden 85-plus Study, an observational population-based prospective follow-up study (started 1997). Primary endpoint, followed up over 5 years (median 3.6 years), was all-cause mortality. Results: A decreasing trend in SBP between 85 and 90 years (decline 2.9 mmHg/year) was associated with increased mortality compared to an average SBP trend (hazard ratio 1.45, 95% confidence interval 1.02-2.06), independent of SBP at age 90. The effect was stronger in institutionalized participants compared to those living independently [hazard ratio 1.87 (1.10-3.19) and hazard ratio 1.30 (0.81-2.09)]. After analysis with a fully adjusted model, the estimate approached unity [hazard ratio 1.08 (0.60-1.86)]. Overall, 90-year-old participants with SBP of 150 mmHg or less had a 1.62 times increased mortality risk compared to those with SBP more than 150 mmHg (1.21-2.20), independent of the SBP trend in preceding years. This applied to those with and without antihypertensive drugs and those with and without history of cardiovascular disease or noncardiovascular disease. In the fully adjusted model, the estimate was 1.47 (0.90-2.40). Conclusion: In very old age, both decreasing trend in SBP over the previous 5 years and the current SBP value independently contribute to prediction of all-cause mortality. Therefore, in individual patients, all available preceding SBP measurements should be taken into account. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Wijsman C.A.,Leiden University | Van Heemst D.,Leiden University | Hoogeveen E.S.,Leiden University | Slagboom P.E.,Leiden University | And 7 more authors.
Aging Cell | Year: 2013

Glucose metabolism marks health and disease and is causally inferred in the aging process. Ambulant continuous glucose monitoring provides 24-h glucose rhythms under daily life conditions. We aimed to describe ambulant 24-h glucose rhythms measured under daily life condition in relation to calendar and biological age in apparently healthy individuals. In the general population and families with propensity for longevity, we studied parameters from 24-h glucose rhythms; glucose levels; and its variability, obtained by continuous glucose monitoring. Participants were 21 young (aged 22-37 years), 37 middle-aged (aged 44-72 years) individuals from the general population, and 26 middle-aged (aged 52-74 years) individuals with propensity for longevity. All were free of diabetes. Compared with young individuals, middle-aged individuals from the general population had higher mean glucose levels (5.3 vs. 4.7 mmol L-1, P < 0.001), both diurnally (P < 0.001) and nocturnally (P = 0.002). Glucose variability was higher in the middle-aged compared with the young (standard deviation 0.70 vs. 0.57 mmol L-1, P = 0.025). Compared with middle-aged individuals from the general population, middle-aged individuals with propensity for longevity had lower overall mean glucose levels (5.2 vs. 5.4 mmol L-1, P = 0.047), which were more different nocturnally (4.8 vs. 5.2 mmol L-1, P = 0.003) than diurnally (5.3 vs. 5.5 mmol L-1, P = 0.14). There were no differences in glucose variability between these groups. Results were independent of body mass index. Among individuals without diabetes, we observed significantly different 24-h glucose rhythms depending on calendar and biological age. © 2012 The Authors. © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.


Wijsman L.W.,Leiden University | Wijsman L.W.,Netherlands Consortium for Healthy Ageing | Sabayan B.,Leiden University | Van Vliet P.,Leiden University | And 15 more authors.
Annals of Neurology | Year: 2014

Objective Elevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with cognitive impairment, which might be explained by cardiovascular diseases or risk factors. The aim of this study was to investigate the association of NT-proBNP with cognitive function and decline in older adults at high risk of cardiovascular disease. Methods We studied 5,205 men and women (mean age = 75 years) who were recruited into the PROspective Study of Pravastatin in the Elderly at Risk. All participants had pre-existing cardiovascular disease or risk factors thereof. Four domains of cognitive function were tested at baseline and repeated during a follow-up period of 3.2 years. Results Participants with higher NT-proBNP (≥450ng/l) had worse baseline cognitive function, including reaction time (mean difference high vs low group = 3.07 seconds, 95% confidence interval [CI] = 0.83 to 5.32), processing speed (-1.02 digits coded, 95% CI = -1.65 to -0.39), and immediate memory (-0.13 pictures remembered, 95% CI = -0.29 to 0.04). There was no significant difference in delayed memory (-0.14, 95% CI = -0.38 to 0.10) between the NT-proBNP groups. Participants with higher NT-proBNP had a steeper cognitive decline, including reaction time (mean annual change high vs low group = 0.60 seconds, 95% CI = 0.14 to 1.07), processing speed (-0.15 digits coded, 95% CI = -0.25 to -0.05), immediate memory (-0.05 pictures remembered, 95% CI = -0.09 to 0.00), and delayed memory (-0.05 pictures remembered, 95% CI = -0.11 to 0.01). Associations were independent of cardiovascular diseases and risks. Interpretation Higher NT-proBNP associates with worse cognitive function and steeper cognitive decline, independent of cardiovascular diseases and risks. Further studies to unravel the underlying mechanisms are warranted. © 2014 American Neurological Association.


Poortvliet R.K.E.,Leiden University | Blom J.W.,Leiden University | De Craen A.J.M.,Leiden University | Mooijaart S.P.,Leiden University | And 6 more authors.
European Journal of Heart Failure | Year: 2013

AimsTo investigate whether low systolic blood pressure is predictive for increased mortality risk in 90-year-old subjects without heart failure, defined by low levels of NT-proBNP, as well as in 90-year-old subjects with high levels of NT-proBNP.Methods and resultsThis study was embedded in the Leiden 85-plus Study, an observational population-based prospective study. All 90-year-old participants (n = 267) were included between 2002 and 2004 and followed up for mortality for at least 5 years. Differences in mortality risks were compared between participants with low systolic blood pressure (≤150 mmHg) and high systolic blood pressure (>150 mmHg) within strata of low NT-proBNP (<284 pg/mL for women and <306 pg/mL for men = lowest tertile) vs. high NT-proBNP (middle and highest tertile) at age 90 years. During maximal follow-up of 7.2 years, 212 participants (79%) died. Among participants with low NT-proBNP, low systolic blood pressure gave a two-fold increased risk (hazard ratio 2.0, 95% confidence interval 1.1-3.4) compared with participants with high systolic blood pressure. For participants with high NT-proBNP, low systolic blood pressure provided a 1.7 increased mortality risk (95% confidence interval 1.2-2.3) compared with high systolic blood pressure.ConclusionLow systolic blood pressure is predictive for increased mortality risk in 90-year-old subjects, irrespective of the NT-proBNP level. Therefore, the absence or presence of heart failure as determined by NT-proBNP does not influence the prognostic value of low systolic blood pressure with regard to mortality in the oldest old. All rights reserved. © 2012 The Author.

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