BackgroundFalls and consequent injuries are prevalent in older adults. In this group, half of injury-related hospitalizations are associated with falls and the rate of falls increases with age. The... Show moreBackgroundFalls and consequent injuries are prevalent in older adults. In this group, half of injury-related hospitalizations are associated with falls and the rate of falls increases with age. The evidence on the role of blood pressure and the use of antihypertensive treatment on the risk of falls remains unclear in oldest-old adults (>= 85 years).ObjectivesTo examine the association between systolic blood pressure (SBP) and incident falls with medical consequences in oldest-old adults and to analyse whether this association is modified by the use of antihypertensive treatments or the presence of cardiovascular disease.MethodsWe analysed data from the Leiden 85-plus Study, a prospective, population-based cohort study with adults aged >= 85 years and a 5-year follow-up. Falls with medical consequences were reported by the treating physician of participants. We assessed the association between time-updated systolic blood pressure and the risk of falling over a follow-up period of five years using generalized linear mixed effects models with a binomial distribution and a logit link function. Subgroup analyses were performed to examine the role of antihypertensive treatment and the difference between participant with and without cardiovascular disease.ResultsWe analysed data from 544 oldest-old adults, 242 (44.4%) of which used antihypertensives. In 81 individuals (15%) >= 1 fall(s) were reported during the follow-up period. The odds for a fall decreased by a factor of 0.86 (95% CI 0.80 to 0.93) for each increase in blood pressure by 10 mmHg. This effect was specific to blood pressure values above 130mmHg. We did not find any evidence that the effect would be modified by antihypertensive treatment, but that there was a tendency that it would be weaker in participants with cardiovascular disease (OR 0.81, 95% CI 0.72 to 0.90 per 10mmHg) compared to those without cardiovascular disease (OR 0.94, 95% CI 0.84 to 1.05 per 10mmHg).ConclusionOur results point towards a possible benefit of higher blood pressure in the oldest-old with respect to falls independent of the use of antihypertensive treatments. Show less
Spoel, E. van der; Vliet, N.A. van; Poortvliet, R.K.E.; Puy, R.S. du; Elzen, W.P.J. den; Quinn, T.J.; ... ; Heemst, D. van 2023
ContextWith age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown.ObjectiveTo investigate incidence and... Show moreContextWith age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown.ObjectiveTo investigate incidence and determinants of spontaneous normalization of TSH levels in older adults with subclinical hypothyroidism.DesignPooled data were used from the (1) pretrial population and (2) in-trial placebo group from 2 randomized, double-blind, placebo-controlled trials (Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial and Institute for Evidence-Based Medicine in Old Age thyroid 80-plus thyroid trial).SettingCommunity-dwelling 65+ adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom.ParticipantsThe pretrial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free T4 within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included.Main Outcome MeasuresIncidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization.ResultsIn the pretrial phase, TSH levels normalized in 60.8% of participants in a median follow-up of 1 year. In the in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up. Younger age, female sex, lower initial TSH level, higher initial free T4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization.ConclusionBecause TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment. Show less
Ploeg, M.A. van der; Poortvliet, R.K.E.; Bogaerts, J.M.K.; Klei, V.M.G.T.H. van der; Kerse, N.; Rolleston, A.; ... ; TULIPS Consortium 2023
BackgroundIn the general population, an increase in low-density lipoprotein cholesterol (LDL-C) predicts higher cardiovascular disease risk, and lowering LDL-C can prevent cardiovascular disease... Show moreBackgroundIn the general population, an increase in low-density lipoprotein cholesterol (LDL-C) predicts higher cardiovascular disease risk, and lowering LDL-C can prevent cardiovascular disease and reduces mortality risk. Interestingly, in cohort studies that include very old populations, no or inverse associations between LDL-C and mortality have been observed. This study aims to investigate whether the association between LDL-C and mortality in the very old is modified by a composite fitness score.MethodsA 2-stage meta-analysis of individual participant data from the 5 observational cohort studies. The composite fitness score was operationalized by performance on a combination of 4 markers: functional ability, cognitive function, grip strength, and morbidity. We pooled hazard ratios (HR) from Cox proportional-hazards models for 5-year mortality risk for a 1 mmol/L increase in LDL-C. Models were stratified by high/low composite fitness score.ResultsComposite fitness scores were calculated for 2 317 participants (median 85 years, 60% females participants), of which 994 (42.9%) had a high composite fitness score, and 694 (30.0%) had a low-composite fitness score. There was an inverse association between LDL-C and 5-year mortality risk (HR 0.87 [95% CI: 0.80–0.94]; p < .01), most pronounced in participants with a low-composite fitness score (HR 0.85 [95% CI: 0.75–0.96]; p = .01), compared to those with a high composite fitness score (HR = 0.98 [95% CI: 0.83–1.15]; p = .78), the test for subgroups differences was not significant.ConclusionsIn this very old population, there was an inverse association between LDL-C and all-cause mortality, which was most pronounced in participants with a low-composite fitness scores. Show less
Noordam, R.; Brochard, T.A.G.; Drewes, Y.M.; Gussekloo, J.; Mooijaart, S.P.; Dijk, K.W. van; ... ; Heemst, D. van 2023
Background and aims: Mendelian randomization confirmed multiple risk factors for primary events of coronary artery disease (CAD), but no such studies have been performed on recurrent major coronary... Show moreBackground and aims: Mendelian randomization confirmed multiple risk factors for primary events of coronary artery disease (CAD), but no such studies have been performed on recurrent major coronary events despite interesting insights derived from other designs. We examined the associations between genetically-influenced classical cardiovascular risk factors and the risk of recurrent major coronary events in a cohort of CAD patients. Methods: We included all first-time CAD cases (defined as angina pectoris, chronic ischemic heart disease or acute myocardial infarction) of European ancestry from the UK Biobank. Cases were followed till the end of follow-up, death or when they developed a recurrent major coronary event (chronic ischemic heart disease or acute myocardial infarction). Standardized weighted genetic risk scores were calculated for body mass index (BMI), systolic blood pressure, LDL cholesterol and triglycerides. Results: From a total of 22,949 CAD patients (mean age at first diagnosis 59.8 (SD 7.3) years, 71.1% men), 12,539 (54.6%) reported a recurrent major coronary event within a period of maximum 17.8 years. One standard de-viation higher genetically-determined LDL cholesterol was associated with a higher risk of a recurrent major coronary event (odds ratio: 1.08 [95% confidence interval: 1.05, 1.11]). No associations were observed for genetically-influenced BMI (1.00 [0.98, 1.03]), systolic blood pressure (1.01 [0.98, 1.03]) and triglycerides (1.02 [0.995, 1.05]). Conclusions: Despite the use risk-reducing medications following a first coronary event, this study provided ge-netic evidence that, of the classical risk factors, mainly high LDL cholesterol was associated with a higher risk of developing recurrent major coronary events. Show less
Gaalen, M.V.; Voshol, I.E.; Linden, M.C. van der; Gussekloo, J.; Mast, R.C. van der 2023
BackgroundAs unplanned Emergency Department (ED) return visits (URVs) are associated with adverse health outcomes in older adults, many EDs have initiated post-discharge interventions to reduce... Show moreBackgroundAs unplanned Emergency Department (ED) return visits (URVs) are associated with adverse health outcomes in older adults, many EDs have initiated post-discharge interventions to reduce URVs. Unfortunately, most interventions fail to reduce URVs, including telephone follow-up after ED discharge, investigated in a recent trial. To understand why these interventions were not effective, we analyzed patient and ED visit characteristics and reasons for URVs within 30 days for patients aged ≥ 70 years.MethodsData was used from a randomized controlled trial, investigating whether telephone follow-up after ED discharge reduced URVs compared to a satisfaction survey call. Only observational data from control group patients were used. Patient and index ED visit characteristics were compared between patients with and without URVs. Two independent researchers determined the reasons for URVs and categorized them into: patient-related, illness-related, new complaints and other reasons. Associations were examined between the number of URVs per patient and the categories of reasons for URVs.ResultsOf the 1659 patients, 222 (13.4%) had at least one URV within 30 days. Male sex, ED visit in the 30 days before the index ED visit, triage category “urgent”, longer length of ED stay, urinary tract problems, and dyspnea were associated with URVs. Of the 222 patients with an URV, 31 (14%) returned for patient-related reasons, 95 (43%) for illness-related reasons, 76 (34%) for a new complaint and 20 (9%) for other reasons. URVs of patients who returned ≥ 3 times were mostly illness-related (72%).ConclusionAs the majority of patients had an URV for illness-related reasons or new complaints, these data fuel the discussion as to whether URVs can or should be prevented. Show less
Ravensberg, A.J.; Poortvliet, R.K.E.; Puy, R.S. du; Dekkers, O.M.; Mooijaart, S.P.; Gussekloo, J. 2023
Background Many older persons use the thyroid hormone levothyroxine which is often continued for life. Scientifically, there is much uncertainty whether simple continuation is the optimal approach.... Show moreBackground Many older persons use the thyroid hormone levothyroxine which is often continued for life. Scientifically, there is much uncertainty whether simple continuation is the optimal approach. First, the physical need for levothyroxine can decrease with age thereby posing a higher risk of overtreatment and adverse effects. Second, large trials in subclinical hypothyroidism have shown no benefit for the use of levothyroxine. Interestingly, guidelines do not address re-evaluation of the indication. This self-controlled trial aims to determine the effects of discontinuation of levothyroxine treatment in older adults.Methods and analysis Participants are community-dwelling subjects aged ≥60 years using levothyroxine continuously at a stable dosage of ≤150 µg and a level of thyroid-stimulating hormone (TSH) <10 mU/L. After a control period of 12 weeks, levothyroxine treatment is discontinued gradually using a stepwise approach with regular monitoring of thyroid function guided by their GP. The primary outcome is the proportion of participants withdrawn from levothyroxine while maintaining a free T4 level within the reference range and a TSH level <10 mU/L, 52 weeks after the start of discontinuation. Secondary outcomes are compared with the control period (self-controlled) and include among others, the effects on thyroid-specific and general health-related quality of life. Furthermore, patients’ attitudes towards deprescribing and regret regarding discontinuing levothyroxine treatment will be recorded. A total of 513 participants will be recruited to estimate the expected proportion of 50% with a 95% CI ranging from 45% to 55%.Ethics and dissemination Approval was obtained from the institutional Medical Ethics Committee. The Older People Advisory Board Health and Well-being has reviewed the research proposal and their comments were used for improvement. In line with the funding policies of the grant organisation funding this study, the study results will be proactively disseminated to the general public and key public health stakeholders. Show less
Objectives: The benefit-risk ratio of many interventions remains unclear in older adults with dementia. Efforts for more representative trial inclusion are made; however, recruiting and... Show moreObjectives: The benefit-risk ratio of many interventions remains unclear in older adults with dementia. Efforts for more representative trial inclusion are made; however, recruiting and particularly gaining informed consent remains complex. For research participation, dementia compels the designation of a legal guardian (LG) to give proxy consent. To advance future trial development, we aimed to provide more insights into the factors that affect the proxy decision-making process in dementia research. Design: A qualitative analysis of semi-structured interviews about proxy decision-making on participation in dementia research. Setting and Participants: LGs of nursing home residents that gave (n = 19) and refrained from giving (n = 18) proxy consent for a clinical trial (the Danton study) in the Netherlands. Methods: Verbatim transcripts were thematically analyzed by using a preliminary deductive framework with room for induction of additional emerging themes, being an overall abductive approach. Based on that theme list, related factors of the decision-making process were grouped into overarching levels and merged into a step-by-step process. Results: When discussing proxy decision-making on the participation of an older adult with dementia in a clinical trial, LGs described interconnected factors on the level of the study and patient. Past experiences and attitudes of the LG influenced the weighing of these study- and patient-related factors, leading to a preliminary decision. Other proxies and treating health care professionals (HCPs) were named as important other stakeholders of the decision-making process. Conclusions and Implications: When giving proxy consent for research participation, LGs weigh study- and patient-related factors, leading to an initial benefit-risk evaluation. This weighing process is influenced by LG-related factors and can be modulated by other proxies or treating HCPs, leading to a definitive decision. Although insights into these underlying mechanisms could facilitate the proxy decision-making process for both LGs and researchers, treating HCPs could act as an independent party. (c) 2023 The Authors. Published by Elsevier Inc. on behalf of AMDA - The Society for Post-Acute and Long-Term Care Medicine. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Netzer, S.; Chocano-Bedoya, P.; Feller, M.; Janett-Pellegri, C.; Wildisen, L.; Buchi, A.E.; ... ; Rodondi, N. 2023
Background loss of skeletal muscle function, strength and mass is common in older adults, with important socioeconomic impacts. Subclinical hypothyroidism is common with increasing age and has been... Show moreBackground loss of skeletal muscle function, strength and mass is common in older adults, with important socioeconomic impacts. Subclinical hypothyroidism is common with increasing age and has been associated with reduced muscle strength. Yet, no randomized placebo-controlled trial (RCT) has investigated whether treatment of subclinical hypothyroidism affects muscle function and mass. Methods this is an ancillary study within two RCTs conducted among adults aged >= 65 years with persistent subclinical hypothyroidism (thyrotropin (TSH) 4.60-19.99 mIU/l, normal free thyroxine). Participants received daily levothyroxine with TSH-guided dose adjustment or placebo and mock titration. Primary outcome was gait speed at final visit (median 18 months). Secondary outcomes were handgrip strength at 1-year follow-up and yearly change in muscle mass. Results we included 267 participants from Switzerland and the Netherlands. Mean age was 77.5 years (range 65.1-97.1), 129 (48.3%) were women, and their mean baseline TSH was 6.36 mIU/l (standard deviation [SD] 1.9). At final visit, mean TSH was 3.8 mIU/l (SD 2.3) in the levothyroxine group and 5.1 mIU/l (SD 1.8, P < 0.05) in the placebo group. Compared to placebo, participants in the levothyroxine group had similar gait speed at final visit (adjusted between-group mean difference [MD] 0.01 m/s, 95% confidence interval [CI] -0.06 to 0.09), similar handgrip strength at one year (MD -1.22 kg, 95% CI -2.60 to 0.15) and similar yearly change in muscle mass (MD -0.15 m(2), 95% CI -0.49 to 0.18). Conclusions in this ancillary analysis of two RCTs, treatment of subclinical hypothyroidism did not affect muscle function, strength and mass in individuals 65 years and older. Show less
Klei, V.M.G.T.H. van der; Poortvliet, R.K.E.; Bogaerts, J.M.K.; Blom, J.W.; Mooijaart, S.P.; Teh, R.; ... ; Gussekloo, J. 2022
Objectives: Previous findings suggest a vascular foundation underlying apathy, but transdiagnostic and prospective evidence on vascular apathy is scarce. This study examines the association between... Show moreObjectives: Previous findings suggest a vascular foundation underlying apathy, but transdiagnostic and prospective evidence on vascular apathy is scarce. This study examines the association between vascular disease and the presence and development of apathy symptoms in the very old.Methods: Four cohorts of the Towards Understanding Longitudinal International older People Studies (TULIPS)-consortium were included in a two-staged, individual participant data meta-analysis using generalized linear mixed models, Vascular disease was defined as a history of any clinical atherosclerotic pathology (angina pectoris, myocardial infarction, intermittent claudication, transient ischemic attack, stroke or related surgeries) and was related to apathy symptoms as repeatedly measured by the Geriatric Depression Scale (GDS-3A >= 2) over a maximum of 5 years.Results: Of all 1868 participants (median age 85 years old), 53.9% had vascular disease and 44.3% experienced apathy symptoms. Participants with vascular disease had a 76% higher risk of apathy symptoms at baseline (odds ratio (OR) 1.76, 95% confidence interval (CI) 1.32-2.35), irrespective of depressive symptoms and only partially explained by stroke. Conversely, there was no association of vascular disease with the occurrence of apathy symptoms longitudinally, both in those with apathy at baseline (OR 1.00, 95% CI 0.84-1.20) and without (OR 0.96, 95% CI 0.841.09).Conclusions: Vascular disease in the very old is associated with apathy symptoms cross-sectionally, but not proven longitudinally, independent of depressive symptoms. These findings query a vascular cause underlying apathy symptoms. However, the consistency of our cross-sectional findings in direction and magnitude across the TULIPS-consortium do emphasize international relevance of the interplay of vascular factors and apathy in advanced age, which meaning needs further unravelling. Show less
ObjectiveFew prospective studies have assessed whether individuals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a... Show moreObjectiveFew prospective studies have assessed whether individuals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a systematic review of the literature and an individual participant data analysis of multiple prospective cohorts to investigate the association between subclinical thyroid dysfunction and incident diabetes. MethodsWe performed a systematic review of the literature in Medline, Embase, and the Cochrane Library from inception to February 11, 2022. A two-stage individual participant data analysis was conducted to compare participants with subclinical hypothyroidism and subclinical hyperthyroidism vs euthyroidism at baseline and the adjusted risk of developing diabetes at follow-up. ResultsAmong 61 178 adults from 18 studies, 49% were females, mean age was 58 years, and mean follow-up time was 8.2 years. At the last available follow-up, there was no association between subclinical hypothyroidism and incidence of diabetes (odds ratio (OR) = 1.02, 95% CI: 0.88-1.17, I-2 = 0%) or subclinical hyperthyroidism and incidence of diabetes (OR = 1.03, 95% CI: 0.82-1.30, I-2 = 0%), in age- and sex-adjusted analyses. Time-to-event analysis showed similar results (hazard ratio for subclinical hypothyroidism: 0.98, 95% CI: 0.87-1.11; hazard ratio for subclinical hyperthyroidism: 1.07, 95% CI: 0.88-1.29). The results were robust in all sub-group and sensitivity analyses. ConclusionsThis is the largest systematic review and individual participant data analysis to date investigating the prospective association between subclinical thyroid dysfunction and diabetes. We did not find an association between subclinical thyroid dysfunction and incident diabetes. Our results do not support screening patients with subclinical thyroid dysfunction for diabetes. Significance statementEvidence is conflicting regarding whether an association exists between subclinical thyroid dysfunction and incident diabetes. We therefore aimed to investigate whether individuals with subclinical thyroid dysfunction are more prone to develop diabetes in the long run as compared to euthyroid individuals. We included data from 18 international cohort studies with 61 178 adults and a mean follow-up time of 8.2 years. We did not find an association between subclinical hypothyroidism or subclinical hyperthyroidism at baseline and incident diabetes at follow-up. Our results have clinical implications as they neither support screening patients with subclinical thyroid dysfunction for diabetes nor treating them in the hope of preventing diabetes in the future. Show less
Objectives: While randomized controlled trials have proven the benefits of blood pressure (BP) lowering in participating octogenarians, population-based observational studies suggest an association... Show moreObjectives: While randomized controlled trials have proven the benefits of blood pressure (BP) lowering in participating octogenarians, population-based observational studies suggest an association between low systolic blood pressure (SBP) and faster overall decline. This study investigates the effects of BP-lowering treatment, a history of cardiovascular diseases (CVD), and cognitive and physical fitness on the associations between SBP and health outcomes in the very old. Methods: Five cohorts from the Towards Understanding Longitudinal International older People Studies (TULIPS) consortium were included in a two-step individual participant data meta-analysis (IPDMA). We pooled hazard ratios (HR) from Cox proportional-hazards models for 5-year mortality and estimates of linear mixed models for change in cognitive and functional decline. Models were stratified by BP-lowering treatment, history of CVD, Mini-Mental State Examination scores, grip strength (GS) and body mass index (BMI). Results: Of all 2480 participants (59.9% females, median 85 years), median baseline SBP was 149 mmHg, 64.3% used BP-lowering drugs and 47.3% had a history of CVD. Overall, higher SBP was associated with lower all-cause mortality (pooled HR 0.91 [95% confidence interval 0.88-0.95] per 10 mmHg). Associations remained irrespective of BP-lowering treatment, history of CVD and BMI, but were absent in octogenarians with above-median MMSE and GS. In pooled cohorts, SBP was not associated with cognitive and functional decline. Conclusion: While in the very old with low cognitive or physical fitness a higher SBP was associated with a lower all-cause mortality, this association was not evident in fit octogenarians. SBP was not consistently associated with cognitive and functional decline. Show less
Buchi, A.E.; Feller, M.; Netzer, S.; Blum, M.R.; Rodriguez, E.G.; Collet, T.H.; ... ; Aeberli, D. 2022
The effect of levothyroxine (LT4) therapy for subclinical hypothyroidism (SHypo) on appendicular bone geometry and volumetric density has so far not been studied. In a nested study within the... Show moreThe effect of levothyroxine (LT4) therapy for subclinical hypothyroidism (SHypo) on appendicular bone geometry and volumetric density has so far not been studied. In a nested study within the randomized, placebocontrolled Thyroid Hormone Replacement for Subclinical Hypothyroidism (TRUST) trial, we assessed the effect of LT4 therapy on bone geometry as measured by peripheral quantitative computed tomography (pQCT). In the TRUST trial, community-dwelling adults aged >= 65 years with SHypo were randomized to LT4 with dose titration vs. placebo with mock titration. We analyzed data from participants enrolled at the TRUST site in Bern, Switzerland who had bone pQCT measured at baseline and at 1 to 2 years follow-up. The primary outcomes were the annual percentage changes of radius and tibia epi- and diaphysis bone geometry (total and cortical crosssectional area (CSA) and cortical thickness), and of volumetric bone mineral density (bone mineral content (BMC) and total, trabecular and cortical volumetric bone mineral density (vBMD)). We performed linear regression of the annual percentage changes adjusted for sex, LT4 dose at randomization and muscle crosssectional area. The 98 included participants had a mean age of 73.9 (+/- SD 5.4) years, 45.9% were women, and 12% had osteoporosis. They were randomized to placebo (n = 48) or LT4 (n = 50). Annual changes in BMC and vBMD were similar between placebo and LT4-treated groups, without significant difference in bone geometry or volumetric bone mineral density changes, neither at the diaphysis, nor at the epiphysis. For example, in the placebo group, epiphyseal BMC (radius) decreased by a mean 0.2% per year, with a similar decrease of 0.5% per year in the LT4 group (between-group difference in %Delta BMC 0.3, 95% CI -0.70 to 1.21, p = 0.91). Compared to placebo, LT4 therapy for an average 14 months had no significant effect on bone mass, bone geometry and volumetric density in older adults with subclinical hypothyroidism. Trial registration: The trial was registered on ClinicalTrials.gov numbers NCT01660126 (TRUST Thyroid trial) and NCT02491008 (Skeletal outcomes). Show less
Lyko, C.; Blum, M.R.; Abolhassani, N.; Stuber, M.J.; Giovane, C. del; Feller, M.; ... ; Rodondi, N. 2022
Background Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed... Show moreBackground Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4). Objective To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies. Methods We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti-thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. Results Among 660 participants (54% women) >= 65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of -2.07 (95% confidence interval: -6.04 to 1.90) for positive antibodies versus 0.89 (-1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores-adjusted between-group difference 1.75 (-3.60 to 7.09) for positive antibodies versus 1.14 (-1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment. Conclusions Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4. Show less
Background Visual impairment frequently occurs amongst older people. Therefore, the aim of this study was to investigate the predictive value of visual impairment on functioning, quality of life... Show moreBackground Visual impairment frequently occurs amongst older people. Therefore, the aim of this study was to investigate the predictive value of visual impairment on functioning, quality of life and mortality in people aged 85 years. Methods From the Leiden 85-plus Study, 548 people aged 85 years were eligible for this study. Visual acuity was measured at baseline by Early Treatment Diabetic Retinopathy Study charts (ETDRS). According to the visual acuity (VA) three groups were made, defined as no (VA > 0.7), moderate (0.5 <= VA <= 0.7) or severe visual impairment (VA < 0.5). Quality of life, physical, cognitive, psychological and social functioning were measured annually for 5 years. For mortality, participants were followed until the age of 95. Results At baseline, participants with visual impairment scored lower on physical, cognitive, psychological and social functioning and quality of life (p < 0.001). Compared to participants with no visual impairment, participants with moderate and severe visual impairment had an accelerated deterioration in basic activities of daily living (respectively 0.27-point (p = 0.017) and 0.35 point (p = 0.018)). In addition, compared to participants with no visual impairment, the mortality risk was 1.83 (95% CI 1.43, 2.35) for participants with severe visual impairment. Discussion In very older adults, visual impairment predicts accelerated deterioration in physical functioning. In addition, severely visually impaired adults had an increased mortality risk. A pro-active attitude, focussing on preventing and treating visual impairment could possibly contribute to the improvement of physical independence, wellbeing and successful aging in very old age. Show less
Ploeg, M.A. van der; Poortvliet, R.K.E.; Achterberg, W.P.; Mooijaart, S.P.; Gussekloo, J.; Drewes, Y.M. 2022
Background In clinical practice and science, there is debate for which older adults the benefits of cardiovascular preventive medications (CPM) still outweigh the risks in older age. Therefore, we... Show moreBackground In clinical practice and science, there is debate for which older adults the benefits of cardiovascular preventive medications (CPM) still outweigh the risks in older age. Therefore, we aimed to assess how various clinical characteristics influence the judgement of appropriateness of CPM in older adults. Method We assessed the appropriateness of CPM for adults >= 75 years with regard to clinical characteristics (cardiovascular variables, complexity of health problems, age, side effects and life expectancy) using the RAND/ University of California at Los Angeles Appropriateness Method. A multidisciplinary panel, including 11 medical professionals and 3 older representatives of the target population, received an up-to-date overview of the literature. Using 9-point Likert scales (1 = extremely inappropriate; 9 = extremely appropriate), they assessed the appropriateness of starting and stopping cholesterol lowering medication, antihypertensives and platelet aggregation inhibitors, for various theoretical clinical scenarios. There were two rating rounds, with one face-to-face discussion in between. The overall appropriateness judgments were based on the median panel ratings of the second round and level of disagreement. Results The panelists emphasized the importance of the individual context of the patient for appropriateness of CPM. They judged that in general, a history of atherosclerotic cardiovascular disease strongly adds to the appropriateness of CPM, while increasing complexity of health problems, presence of hindering or severe side effects, and life expectancy < 1 year all contribute to the inappropriateness of CPM. Age had only minor influence on the appropriateness judgments. The appropriateness judgments were different for the three types of CPM. The literature, time-to-benefit, remaining life expectancy, number needed to treat, and quality of life, were major themes in the panel discussions. The considerations to stop CPM were different from the considerations not to start CPM. Conclusion Next to the patients' individual context, which was considered decisive in the final decision to start or stop CPM, there were general trends of how clinical characteristics influenced the appropriateness, according to the multidisciplinary panel. The decision to stop, and not start CPM, appeared to be two distinct concepts. Results of this study may be used in efforts to support clinical decision making about CPM in older adults. Show less
IMPORTANCE Intra-articular (IA) glucocorticoid injection is widely used in patients with knee osteoarthritis (OA), but the safety of this technique is in question among physicians. Intramuscular ... Show moreIMPORTANCE Intra-articular (IA) glucocorticoid injection is widely used in patients with knee osteoarthritis (OA), but the safety of this technique is in question among physicians. Intramuscular (IM) glucocorticoid injection could be an alternative approach.OBJECTIVE To investigate whether an IM glucocorticoid injection is noninferior to an IA glucocorticoid injection in reducing knee pain for patients with knee OA in primary care.DESIGN, SETTING, AND PARTICIPANTS The KIS trial, a multicenter, open-label, randomized clinical noninferiority trial including patients with symptomatic knee OA, was conducted in 80 primary care general practices in the southwest of the Netherlands. The study was conducted from March 1, 2018, to July 28, 2020.INTERVENTIONS Patients were randomly allocated to receive an injection of triamcinolone acetonide, 40 mg, either IM in the ipsilateral ventrogluteal region or IA in the knee joint. All patients were followed up for 24 weeks.MAIN OUTCOMES AND MEASURES The pain score at 4 weeks measured with Knee Injury and Osteoarthritis Outcome Score (range, 0-100; 0 indicates extreme pain), with a noninferiority margin of -7 (IM minus IA). A per-protocol analysis was prespecified as the primary analysis.RESULTS A total of 145 patients (94 women [65%]; mean [SD] age, 67 [10] years) were included; of these, 138 patients (IM, 72; IA, 66) were included in the per-protocol analysis. Clinically relevant improvements in knee pain were reached up to 12 weeks after the injection in both groups. At 4 weeks, the estimated mean difference in the Knee Injury and Osteoarthritis Outcome Score between the 2 groups was -3.4 (95% CI, -10.1to 3.3). Noninferiority could not be declared because the lower limit exceeded the noninferiority margin. Intramuscular injection was noninferior to IA injection at 8 (mean difference, 0.7; 95% CI, -6.5 to 7.8) and 24 (mean difference, 1.6; 95% CI, -5.7 to 9.0) weeks. No significant difference was found among all the secondary outcomes. These results were similar for the sensitivity analysis in an intention-to-treat population. The most frequently reported adverse events were hot flush (IM, 7 [10%] vs IA, 14 [21%]) and headache (IM, 10 [14%] vs IA, 12 [18%]), and all events were classified as nonserious.CONCLUSIONS AND RELEVANCE Based on the findings of this trial, among patients with knee OA in primary care, IM glucocorticoid injection could present an inferior effect in reducing pain at 4 weeks compared with IA injection. Noninferiority of an IM injection was observed at 8 and 24 weeks after injection. This trial provides data for shared decision-making, taking into account the advantages and disadvantages of both types of injections. Show less
Puy, R.S. du; Poortvliet, R.K.E.; Mooijaart, S.P.; Stott, D.J.; Quinn, T.; Sattar, N.; ... ; Elzen, W.P.J. den 2022
Context Subclinical thyroid dysfunction and anemia are common disorders, and both have increasing prevalence with advancing age. Objective The aim of this study was to assess whether levothyroxine... Show moreContext Subclinical thyroid dysfunction and anemia are common disorders, and both have increasing prevalence with advancing age. Objective The aim of this study was to assess whether levothyroxine treatment leads to a rise in hemoglobin levels in older persons with subclinical hypothyroidism. Methods This preplanned combined analysis of 2 randomized controlled trials included community-dwelling persons aged 65 years and older with subclinical hypothyroidism who were randomly assigned to levothyroxine or placebo treatment. The levothyroxine dose was periodically titrated aiming at thyroid stimulating hormone (TSH) level within the reference range, with mock titrations in the placebo group. The main outcome measure was the change in hemoglobin level after 12 months. Results Analyses included 669 participants (placebo n = 337, levothyroxine n = 332) with a median age of 75 years (range, 65-97) and mean baseline hemoglobin of 13.8 +/- 1.3 g/dL. Although levothyroxine treatment resulted in a reduction in TSH from baseline after 12 months of follow-up compared with placebo, the change in hemoglobin level was not different between the levothyroxine and the placebo groups (-0.03 g/dL [95% CI, -0.16 to 0.11]). Similar results were found in stratified analyses including sex, age, or TSH levels. No difference in change of hemoglobin levels after 12 months was identified in 69 participants with anemia at baseline (-0.33 g/dL [95% CI, -0.87 to 0.21]). Conclusion In persons aged 65 years and older with subclinical hypothyroidism, treatment with levothyroxine does not lead to a rise in hemoglobin levels, regardless of the presence of anemia. Show less
BackgroundIn non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline... Show moreBackgroundIn non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC). MethodsFor the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naive approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA. ResultsTen of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score. ConclusionANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly. Show less
Vliet, N.A. van; Kamphuis, A.E.P.; Elzen, W.P.J. den; Blauw, G.J.; Gussekloo, J.; Noordam, R.; Heemst, D. van 2022
Context: Thyroid dysfunction is associated with higher anemia prevalence, although causality remains unclear.Objective: This study aimed to investigate the association between thyroid function and... Show moreContext: Thyroid dysfunction is associated with higher anemia prevalence, although causality remains unclear.Objective: This study aimed to investigate the association between thyroid function and anemia.Methods: This cross-sectional and Mendelian randomization study included 445 482 European participants from the UK Biobank (mean age 56.77 years (SD 8.0); and 54.2% women). Self-reported clinical diagnosis of hypothyroidism was stated by 21 860 (4.9%); self-reported clinical diagnosis of hyperthyroidism by 3431 (0.8%). Anemia, defined as hemoglobin level of < 13 g/dL in men and < 12 g/dL in women, was present in 18 717 (4.2%) participants.Results: In cross-sectional logistic regression analyses, self-reported clinical diagnoses of hypo- and hyperthyroidism were associated with higher odds of anemia (OR 1.12; 95% CI, 1.05-1.19 and OR 1.09; 95% CI, 0.91-1.30), although with wide confidence intervals for hyperthyroidism. We did not observe an association of higher or lower genetically influenced thyrotropin (TSH) with anemia (vs middle tertile: OR for lowest tertile 0.98 [95% CI, 0.95-1.02]; highest tertile 1.02 [95% CI, 0.98-1.061), nor of genetically influenced free thyroxine (fT4) with anemia. Individuals with genetic variants in the DIO3OS gene implicated in intracellular regulation of thyroid hormones had a higher anemia risk (OR 1.05; 95% CI, 1.02-1.10); no association was observed with variants in DIO1 or DIO2 genes.Conclusion: While self-reported clinical diagnosis of hypothyroidism was associated with higher anemia risk, we did not find evidence supporting a causal association with variation of thyroid function within the euthyroid range. However, intracellular regulation of thyroid hormones might play a role in developing anemia. Show less
Abstract Background Coronavirus Disease 2019 (COVID-19) reached the Netherlands in February 2020. To minimize the spread of the virus, the Dutch government announced an “intelligent lockdown”.... Show moreAbstract Background Coronavirus Disease 2019 (COVID-19) reached the Netherlands in February 2020. To minimize the spread of the virus, the Dutch government announced an “intelligent lockdown”. Older individuals were urged to socially isolate completely, because they are at risk of a severe disease course. Although isolation reduces the medical impact of the virus, the non-medical impact should also be considered. Aim To investigate the impact of COVID-19 pandemic and associated restrictive measures on the six dimensions of Positive Health in community-dwelling older individuals living in the Netherlands, and to identify differences within subgroups. Methods In May/June 2020, community-dwelling older individuals aged ≥ 65 years completed an online survey based on Huber’s model of Positive Health. Positive Health was measured regarding the appreciation of the six dimensions (categorized as poor/satisfactory/excellent) and a comparison with a year before (categorized as decreased/unchanged/increased) using frequencies (%) and a chi-square test. Results 834 older individuals participated (51% women, 38% aged ≥ 76 years, 35% living alone, 16% self-rated poor health). Most respondents assessed their bodily functions, mental well-being and daily functioning as satisfactory, their meaningfulness and quality of life (QoL) as excellent, and their social participation as poor. 12% of the respondents reported a deterioration of 4–6 dimensions and 73% in 1–3 dimensions, compared to the past year. Deterioration was most frequently experienced in the dimension social participation (73%), the dimension mental well-being was most frequently improved (37%) and quality of life was in 71% rated as unchanged. Women more often observed a deterioration of 4–6 dimensions than men (15% vs. 8%, p = 0.001), and individuals with self-rated poor health more often than individuals with self-rated good health (22% vs. 10%, p < 0.001). Older individuals living alone experienced more frequently a decrease in meaningfulness compared to older individuals living together. Conclusion The COVID-19 pandemic and associated restrictive measures had a substantial impact on all six dimensions of Positive Health in community-dwelling older individuals, especially in women, respondents living alone and respondents with self-rated poor general health. Show less
