Cardiovascular disease and the risk of incident falls and mortality among adults aged ≥ 65 years presenting to the emergency department: a cohort study from national registry data in Denmark.

BACKGROUND: Falls cause 58% of injury-related Emergency Department (ED) attendances. Previous research has highlighted the potential role of cardiovascular risk factors for falls. This study investigated the impact of cardiovascular disease (CVD) risk on three-year incident falls, with presentation to the ED, and mortality. METHODS: A matched cohort study design was employed using national registry data from 82,292 adults (33% male) aged ≥ 65 years living in Denmark who attended the ED in 2013. We compared age and gender matched ED attendees presenting with a fall versus another reason. The cohort was followed for three-year incident falls, with presentation to the ED, and mortality. The impact of falls-related CVDs was also examined. RESULTS: Three-year incident falls was twofold higher among age and gender matched ED attendees aged ≥ 65 years presenting with a fall versus another reason at baseline. A presentation of falls with hip fracture had the highest percentage of incident falls in the 65-74 age group (22%) and the highest percentage mortality in all age groups (27-62%). CVD was not a significant factor in presenting with a fall at the ED, nor did it contribute significantly to the prediction of three-year incident falls. CVD was strongly associated with mortality risk among the ED fall group (RR = 1.81, 95% CI: 1.67-1.97) and showed interactions with both age and fall history. CONCLUSION: In this large study of adults aged ≥ 65 years attending the ED utilising data from national administrative registers in Denmark, we confirm that older adults attending the ED with a fall, including those with hip fracture, were at greatest risk for future falls. While CVD did not predict incident falls, it increased the risk of mortality in the three-year follow up with advancing age. This may be informative for the provision of care pathways for older adults attending the ED due to a fall.

Altered cardiovascular risk pattern of LDL cholesterol in older adults.

PURPOSE OF REVIEW: Elevated serum low-density lipoprotein cholesterol (LDL-C) levels at middle-age constitute a strong risk factor for later cardiovascular events. In older populations, however, LDL-C levels are no longer predictive of cardiovascular mortality or may even seem protective. Whether the altered risk pattern of LDL-C in old age reflects a causal mechanism or is due to confounding and bias is subject to debate. In this review, we briefly discuss the possible explanations for the altered risk pattern of LDL-C observed in old age. RECENT FINDINGS: Using examples from the recent literature we illustrate how LDL-C levels 'lose' their predictive value as a cardiovascular risk factor in old age. We review three potential explanations for the changed cardiovascular risk pattern of LDL-C in older populations: survivorship bias, reverse causation, and effect modification. SUMMARY: The absent or protective effect of LDL-C on cardiovascular mortality in older populations found in observational studies might be explained by survivorship bias, reverse causation, and effect modification. However, this does not necessarily preclude the possibility that (specific) cholesterol-lowering treatment could decrease the risk of morbidity and mortality. Placebo-controlled trials may importantly add to our understanding of who may benefit from lipid-lowering therapy or statins at an older age.

Long-term exposure to elemental components of fine particulate matter and all-natural and cause-specific mortality in a Danish nationwide administrative cohort study.

BACKGROUND: Fine particulate matter (PM2.5) is a well-recognized risk factor for premature death. However, evidence on which PM2.5 components are most relevant is unclear. METHODS: We evaluated the associations between mortality and long-term exposure to eight PM2.5 elemental components [copper (Cu), iron (Fe), zinc (Zn), sulfur (S), nickel (Ni), vanadium (V), silicon (Si), and potassium (K)]. Studied outcomes included death from diabetes, chronic kidney disease (CKD), dementia, and psychiatric disorders as well as all-natural causes, cardiovascular disease (CVD), respiratory diseases (RD), and lung cancer. We followed all residents in Denmark (aged ≥30 years) from January 1, 2000 to December 31, 2017. We used European-wide land-use regression models at a 100 × 100 m scale to estimate the residential annual mean levels of exposure to PM2.5 components. The models were developed with supervised linear regression (SLR) and random forest (RF). The associations were evaluated by Cox proportional hazard models adjusting for individual- and area-level socioeconomic factors and total PM2.5 mass. RESULTS: Of 3,081,244 individuals, we observed 803,373 death from natural causes during follow-up. We found significant positive associations between all-natural mortality with Si and K from both exposure modeling approaches (hazard ratios; 95% confidence intervals per interquartile range increase): SLR-Si (1.04; 1.03-1.05), RF-Si (1.01; 1.00-1.02), SLR-K (1.03; 1.02-1.04), and RF-K (1.06; 1.05-1.07). Strong associations of K and Si were detected with most causes of mortality except CKD and K, and diabetes and Si (the strongest associations for psychiatric disorders mortality). In addition, Fe was relevant for mortality from RD, lung cancer, CKD, and psychiatric disorders; Zn with mortality from CKD, RD, and lung cancer, and; Ni and V with lung cancer mortality. CONCLUSIONS: We present novel results of the relevance of different PM2.5 components for different causes of death, with K and Si seeming to be most consistently associated with mortality in Denmark.

Use of candles and risk of cardiovascular and respiratory events in a Danish cohort study.

Burning candles at home emit small particles and gases that pollute indoor air. Exposure to fine particles in outdoor air has been convincingly linked to cardiovascular and respiratory events, while the associations with fine and ultrafine particles from candle burning remain unexplored. We examined the association between the use of candles and incident cardiovascular and respiratory events. We collected data on 6757 participants of the Copenhagen Aging and Midlife Biobank cohort recruited in 2009 and followed them up for the first hospital contact for incident cardiovascular and respiratory events until 2018. We investigated an association between the self-reported frequency of candle use in wintertime and cardiovascular and respiratory events, using Cox regression models adjusting for potential confounders. During follow-up, 1462 and 834 were admitted for cardiovascular and respiratory events, respectively. We found null associations between candle use and a hospital contact due to cardiovascular and respiratory events, with hazard ratios (HRs) and 95% confidence intervals (CI) of 0.97 (95% CI: 0.84, 1.11) and 0.98 (95% CI: 0.81, 1.18), respectively, among those using candles >4 times/week compared with <1 time/week. For cause-specific cardiovascular diseases, HRs were 1.10 (95% CI: 0.85, 1.43) for ischemic heart disease and 1.18 (95% CI: 0.77, 1.81) for myocardial infarction. For chronic obstructive pulmonary disease, HR was 1.26 (95% CI: 0.81, 1.97). We found no statistically significant associations between candle use and the risk of cardiovascular and respiratory events. Studies with improved exposure assessments are warranted.

Dynamical indicators in time series of healthcare expenditures predict mortality risk of older adults following spousal bereavement.

BACKGROUND: The process of aging renders older people susceptible for adverse outcomes upon stress. Various indicators derived from complex systems theory have been proposed for quantifying resilience in living organisms, including humans. We investigated the ability of system-based indicators in capturing the dynamics of resilience in humans who suffer the adversity of spousal bereavement and tested their predictive power in mortality as a finite health transition. METHODS: Using longitudinal register data on weekly healthcare consumption of all Danish citizens over the age of 65 from January 1st, 2011, throughout December 31st, 2016, we performed statistical comparisons of the indicators 'average', 'slope', 'mean squared error', and 'lag-1 autocorrelation' one year before and after spousal bereavement, stratified for age and sex. The relation between levels of these indicators before bereavement and mortality hazards thereafter was determined by time to event analysis. We assessed the added value for mortality prediction via the time dependent area (AUC) under the receiver operating characteristic curve. RESULTS: The study included 934,003 citizens of whom 51,890 experienced spousal bereavement and 2862 died in the first year thereafter. Healthcare consumption is increased, more volatile and accelerating with aging and in men compared to women (all p-values < 0.001). All dynamic indicators before bereavement were positively related with mortality hazards thereafter (all p-values < 0.001). The average discriminative performance for the 1-year mortality risk of the model with only age as a predictor (AUC: 68.9% and 70.2%) was significantly increased with the addition of dynamical indicators (78.5% and 82.4%) for males and females, respectively. CONCLUSIONS: Dynamic indicators in time series of health care expenditures are strong predictors of mortality risk and could be part of predictive models for prognosis after life stressors, such as bereavement.

Do changes in frailty, physical functioning, and cognitive functioning predict mortality in old age? Results from the Longitudinal Aging Study Amsterdam.

BACKGROUND: The ability to accurately predict survival in older adults is crucial as it guides clinical decision making. The added value of using various health indicators as well as changes in these indicators for predicting mortality remains unclear. The aim of this study was to investigate whether changes in health indicators such as frailty and physical performance improve mortality predictions in old age. METHODS: This is a population based prospective cohort study on 995 community-dwelling people aged 68-92 years from the Longitudinal Aging Study Amsterdam. Two measurements at a three-year interval (1995/1996 and 1998/1999) were available for the frailty index, frailty phenotype, grip strength, walking speed, and Mini-Mental State Examination (MMSE). Cox regression was used to analyze mortality risks associated with the current health status and changes in health, with mortality data up to 2017. The extent to which these health indicators improved mortality predictions compared to models with age and sex only was assessed by the area under the receiver operating characteristic curve (AUC). RESULTS: The AUC of age and sex for five-year mortality was 72.8% (95% CI 69.0 - 76.5) and was the lowest in the oldest old (age > 80.5 years). The added AUC of the current status of health indicators ranged from 0.7 to 3.3%. The added AUC of the three-year change was lower, ranging from -0.0 to 1.1%, whereas the added AUC of three-year change and current status combined was similar to current status alone, ranging from 0.6 to 3.2%. Across age, the added AUC of current status was highest in the oldest old, however there was no such pattern using three-year change. Overall, the frailty index appeared to improve mortality predictions the most, followed by the frailty phenotype, MMSE, grip strength, and walking speed. CONCLUSIONS: Current health status improved mortality predictions better than changes in health. Its contribution was highest in the oldest old, but the added value to models with age and sex only was limited.

The plasticity of late-onset dementia: A nationwide cohort study in Denmark.

INTRODUCTION: The determinants of the secular decline in the incidence of dementia are not clear. The aim of this study was to investigate the influences of four factors-education, wealth, cerebrovascular health, and general health-on the secular decline. METHODS: A cohort study was conducted of all individuals aged ≥65 years in Denmark from 2005 through 2018 (N = 1,757,168). Annual incidence rates of dementia and population attributable risks of the four factors were calculated and birth cohort trends were examined. RESULTS: The incidence of dementia declined by 22.5% in men and 34.2% in women from 2005 through 2018. Population attributable risks of lower education, lower wealth, and stroke likewise declined. Independent of these improvements, the incidence of dementia fell across successive birth cohorts. DISCUSSION: Most of the observed plasticity in late-onset dementia is associated with a risk decline across successive birth cohorts that is independent of improvements in traditional risk factors.

Associations of Cytomegalovirus Infection With All-Cause and Cardiovascular Mortality in Multiple Observational Cohort Studies of Older Adults.

BACKGROUND: Whether latent cytomegalovirus (CMV) infection in older adults has any substantial health consequences is unclear. Here, we sought associations between CMV-seropositivity and IgG titer with all-cause and cardiovascular mortality in 5 longitudinal cohorts. METHODS: Leiden Longevity Study, Prospective Study of Pravastatin in the Elderly at Risk, Longitudinal Study of Aging Danish Twins, and Leiden 85-plus Study were assessed at median (2.8-11.4 years) follow-up . Cox regression and random effects meta-analysis were used to estimate mortality risk dependent on CMV serostatus and/or IgG antibody titer, in quartiles after adjusting for confounders. RESULTS: CMV-seropositivity was seen in 47%-79% of 10 122 white community-dwelling adults aged 59-93 years. Of these, 3519 had died on follow-up (579 from cardiovascular disease). CMV seropositivity was not associated with all-cause (hazard ratio [HR], 1.05; 95% confidence interval [CI], .97-1.14) or cardiovascular mortality (HR, 0.97; 95% CI, .83-1.13). Subjects in the highest CMV IgG quartile group had increased all-cause mortality relative to CMV-seronegatives (HR, 1.16; 95% CI, 1.04-1.29) but this association lost significance after adjustment for confounders (HR, 1.13; 95% CI, .99-1.29). The lack of increased mortality risk was confirmed in subanalyses. CONCLUSIONS: CMV infection is not associated with all-cause or cardiovascular mortality in white community-dwelling older adults.

Long-term air pollution and road traffic noise exposure and COPD: the Danish Nurse Cohort.

BACKGROUND: While air pollution has been linked to the development of chronic obstructive pulmonary disease (COPD), evidence on the role of environmental noise is just emerging. We examined the associations of long-term exposure to air pollution and road traffic noise with COPD incidence. METHODS: We defined COPD incidence for 24 538 female nurses from the Danish Nurse Cohort (age >44 years) as the first hospital contact between baseline (1993 or 1999) and 2015. We estimated residential annual mean concentrations of particulate matter with an aerodynamic diameter <2.5 µm (PM2.5) since 1990 and nitrogen dioxide (NO2) since 1970 using the Danish Eulerian Hemispheric Model/Urban Background Model/Air Geographic Information System modelling system, and road traffic noise (Lden) since 1970 using the Nord2000 model. Time-varying Cox regression models were applied to assess the associations of air pollution and road traffic noise with COPD incidence. RESULTS: 977 nurses developed COPD during a mean of 18.6 years' follow-up. We observed associations with COPD for all three exposures with HRs and 95% CIs of 1.19 (1.01-1.41) per 6.26 µg·m-3 for PM2.5, 1.13 (1.05-1.20) per 8.19 µg·m-3 for NO2 and 1.15 (1.06-1.25) per 10 dB for Lden. Associations with NO2 and Lden attenuated slightly after mutual adjustment, but were robust to adjustment for PM2.5. Associations with PM2.5 were attenuated to null after adjustment for either NO2 or Lden. No potential interaction effect was observed between air pollutants and noise. CONCLUSION: Long-term exposure to air pollution, especially traffic-related NO2, and to road traffic noise were independently associated with COPD.

Differential effects of colorectal cancer screening across sociodemographic groups in Denmark: a register-based study.

INTRODUCTION: Colorectal cancer (CRC) does not affect different sociodemographic groups uniformly. CRC screening programmes could seek to reduce this inequality; however, the screening programmes themselves might be subject to differential participation across sociodemographic groups. This study investigates the sociodemographic inequality at all steps in Denmark's nationwide CRC screening programme: screening participation, faecal immunochemical test (FIT) results, colonoscopy compliance, CRC diagnosis, and cancer stage. MATERIAL AND METHODS: This cohort study includes all first-time invitees from the beginning of the Danish population-based CRC screening programme from 1 March 2014 to 31 December 2017. RESULTS: Sixty-four percent of the invitees participated in the screening programme, and of those 7% were FIT-positive. After being invited to further diagnostic procedures, 90% responded to the invitation, and among those 5% were CRC-positive. Among those diagnosed with CRC, 9% were stage IV. Through multivariable analyses, we identified sociodemographic inequalities in all steps of the screening programme from returning a stool sample to being diagnosed with CRC. Specifically, we identified inequalities across sex, age, migration status, relationship status, the screening status of one's partner, education, income, and use of health services. Women were more likely to participate compared to men (RR = 1.13; 95% CI: 1.12-1.13), but had a lower risk of a positive FIT result (RR = 0.67; 95% CI: 0.66-0.68) and of a CRC diagnosis (RR = 0.88; 95% CI: 0.82-0.93) compared to men. The likelihood of participating as well as the risk of positive FIT results and CRC diagnosis increased with age. CONCLUSION: All steps of the screening programme were subject to sociodemographic inequalities. Interventions are needed to target groups identified as having lower uptake as well as high-risk of being FIT- and/or CRC-positive. These groups include males, individuals aged 60+ years and individuals who do not visit their GP regularly.

Reablement through time and space: a scoping review of how the concept of 'reablement' for older people has been defined and operationalised.

BACKGROUND: While the field of rehabilitation has determined a common definition of professional practice, legislators and healthcare professionals in various Western countries have struggled to reach consensus about how the newer offer of 'reablement' should be organised, operationalised, and understood as a health service for older adults. International research indicates that there is confusion, ambiguity, and disagreement about the terminology and the structure of these programmes, and they may not be adequately supporting older people's self-identified goals. Could an analysis of the concept's genealogy illuminate how reablement can be more effective and beneficial in theory and in practice? METHODS: We conducted a qualitative and quantitative scoping review to determine how reablement has developed through time and space. Eligible articles (N=86) had to focus on any of the defined features of current reablement programmes; there were no restrictions on study designs or publication dates. In articles published from 1947 to 2019, we identified themes and patterns, commonalities, and differences in how various countries described and defined reablement. We also performed an analysis using computer software to construct and visualise term maps based on significant words extracted from the article abstracts. RESULTS: The fundamental principles of reablement have a long history. However, these programmes have undergone a widespread expansion since the mid-2000s with an intention to reduce costs related to providing long-term care services and in-home assistance to growing older populations. Despite theoretical aspirations to offer person-centred and goal-directed reablement, few countries have been able to implement programmes that adequately promote older people's goals, social involvement, or participation in their local community in a safe, culturally sensitive and adaptable way. CONCLUSIONS: Reablement is meant to support older people in attaining their self-defined goals to be both more physically independent at home and socially involved in their communities. However, until legislators, health professionals, and older people can collectively reach consensus about how person-centred reablement can be more effectively implemented and supported in professional home-care practice, it will be difficult to determine a conceptual description of reablement as a service that is unique, separate, and distinct from standard rehabilitation.

Do we know the effects of colorectal cancer screening? A short communication on selective uptake and differential effects of colorectal cancer screening in Scandinavia.

Colorectal cancer (CRC) contributes extensively to the overall cancer burden, with substantial and increasing social inequality in both incidence and survival. In several countries, this social inequality in incidence and survival has been increasing over time, and the increase is expected to continue. To overcome this, it is advised to implement nationwide CRC screening programmes, as these are effective in detecting possible signs of CRC, hence identifying earlier-stage cancer and reducing mortality. However, little is known about the distribution of these effects across population groups. It is possible that the outcomes of CRC screening are not equally distributed among participants, but rather that the screening programme serves some population groups better than others. The aim of this short communication based on published data is to describe the status of selective uptake according to sociodemographic and economic factors in CRC screening in Scandinavia. Furthermore, we raise questions that need to be addressed in future research in order to grasp the full effects of the screening programme and ultimately to ensure high uptake as well as participation in subsequent diagnostic procedures across population groups.

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism.

BACKGROUND: The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 µg daily, or 25 µg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). RESULTS: The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 µg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. CONCLUSIONS: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).

Night work and incidence of Parkinson's disease in the Danish Nurse Cohort.

OBJECTIVES: Evidence on the association between night work and Parkinson's disease (PD) is sparse and conflicting, calling for more definitive studies. METHODS: We included 20 138 female nurses from the Danish Nurse Cohort without PD who at baseline in 1993 and/or 1999 reported their most common current work schedule (day, evening, night, and rotating (a combination of at least two of these)), including information on lifetime cumulative duration (years) of each shift in a 2009 follow-up survey. We obtained information on PD hospital contacts and PD medication until November 2018 via linkage to the Danish National Patient (inpatient from 1977 and outpatient contacts from 1995 onwards) and Prescription Registers starting in 1995. We defined the incidence of PD as the first-ever hospital contact due to PD, or the first-ever redeemed levodopa prescription, whichever came first. We used Cox regression models to calculate HRs and 95% CIs, adjusting for age, smoking status, coffee consumption and use of hormone replacement therapy. RESULTS: We found no significant difference in PD risk among nurses who reported working evening (HR=0.86; 95% CI=0.55 to 1.34), night (HR=1.26; 95% CI=0.79 to 2.02) or rotating shifts (HR=0.83; 95% CI=0.56 to 1.21) at cohort baseline in 1993 or 1999, when compared with permanent day workers. Similarly, persistency of shift work (working the same work schedule for 6+ years) or duration of shift work was not associated with PD risk. CONCLUSIONS: Overall, there was little evidence for an association between various shift work schedules including night work and PD in this cohort of middle-aged female nurses.

Perceived stress and dementia: Results from the Copenhagen city heart study.

Objectives: We investigated if perceived stress in midlife increased the risk of dementia. Furthermore, we explored differences between subgroups related to sex, age and employment status when reporting stress.Methods: In this longitudinal study, we used information on perceived stress from 10,814 participants (mean age 56.7 years). Participants were followed through Danish national registers for development of dementia. Participants were considered at risk of dementia from the date they turned 60 years. Perceived stress was assessed as a combination of self-reported intensity and frequency of stress, and categorized into low (score 0-1), medium (score 2-4), and high stress (score 5-6). We used Poisson regression to estimate incidence rate ratios (IRR) and their 95% confidence intervals (CI) and adjusted for sociodemographic factors and psychiatric morbidity at baseline (main model) as well as cardio/cerebrovascular diseases and health behaviors at baseline (additional model).Results: The mean follow-up time was 13.8 years, and 1,519 participants were registered with dementia. Dementia risk was higher in participants reporting medium stress (IRR = 1.11, 95% CI: 0.99-1.24) and high stress (IRR = 1.36, 95% CI: 1.13-1.65). Adjustment for cardio/cerebrovascular diseases and health behaviors did not alter the results. We did not find strong support for differences between subgroups, although the association between stress and dementia was stronger for those who were employed at the time of reporting high stress.Conclusion: Our results provide empirical support for an effect of perceived stress on the risk of dementia in old age.

Shift work and incidence of dementia: A Danish Nurse Cohort study.

INTRODUCTION: A few studies suggest that working night and rotating shifts increase the risk of dementia. We examined the association between shift work and the incidence of dementia in a cohort of female Danish nurses. METHODS: We linked Danish Nurse Cohort participants, who reported work schedules (day, evening, night, rotating shifts) in 1993 and/or 1999 and their duration in 2009, to Danish registers to obtain information on dementia hospitalizations and prescription medication until November 2018. RESULTS: Among 6048 nurses who reported work schedules in 1993 and 1999, nurses working night shifts ≥6 years had higher dementia incidence (hazard ratio: 2.43, 95% confidence interval: 1.39 to 4.23) than those working day shifts ≥6 years. Among 8059 nurses who reported shift work duration, nurses working night shifts ≥6 years had higher dementia incidence than those working night shifts <1 year (1.47, 1.06 to 2.06). DISCUSSION: Persistent night shift work may increase the risk of dementia.

Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism.

IMPORTANCE: It is unclear whether levothyroxine treatment provides clinically important benefits in adults aged 80 years and older with subclinical hypothyroidism. OBJECTIVE: To determine the association of levothyroxine treatment for subclinical hypothyroidism with thyroid-related quality of life in adults aged 80 years and older. DESIGN, SETTING, AND PARTICIPANTS: Prospectively planned combined analysis of data involving community-dwelling adults aged 80 years and older with subclinical hypothyroidism. Data from a randomized clinical trial were combined with a subgroup of participants aged 80 years and older from a second clinical trial. The trials were conducted between April 2013 and May 2018. Final follow-up was May 4, 2018. EXPOSURES: Participants were randomly assigned to receive levothyroxine (n = 112; 52 participants from the first trial and 60 from the second trial) or placebo (n = 139; 53 participants from the first trial and 86 from the second trial). MAIN OUTCOMES AND MEASURES: Co-primary outcomes were Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire scores for the domains of hypothyroid symptoms and tiredness at 1 year (range, 0-100; higher scores indicate worse quality of life; minimal clinically important difference, 9). RESULTS: Of 251 participants (mean age, 85 years; 118 [47%] women), 105 were included from the first clinical trial and 146 were included from the second clinical trial. A total of 212 participants (84%) completed the study. The hypothyroid symptoms score decreased from 21.7 at baseline to 19.3 at 12 months in the levothyroxine group vs from 19.8 at baseline to 17.4 at 12 months in the placebo group (adjusted between-group difference, 1.3 [95% CI, -2.7 to 5.2]; P = .53). The tiredness score increased from 25.5 at baseline to 28.2 at 12 months in the levothyroxine group vs from 25.1 at baseline to 28.7 at 12 months in the placebo group (adjusted between-group difference, -0.1 [95% CI, -4.5 to 4.3]; P = .96). At least 1 adverse event occurred in 33 participants (29.5%) in the levothyroxine group (the most common adverse event was cerebrovascular accident, which occurred in 3 participants [2.2%]) and 40 participants (28.8%) in the placebo group (the most common adverse event was pneumonia, which occurred in 4 [3.6%] participants). CONCLUSIONS AND RELEVANCE: In this prospectively planned analysis of data from 2 clinical trials involving adults aged 80 years and older with subclinical hypothyroidism, treatment with levothyroxine, compared with placebo, was not significantly associated with improvement in hypothyroid symptoms or fatigue. These findings do not support routine use of levothyroxine for treatment of subclinical hypothyroidism in adults aged 80 years and older. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01660126; Netherlands Trial Register: NTR3851.

Thyroid Function Within the Normal Range, Subclinical Hypothyroidism, and the Risk of Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF. METHODS: We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF. RESULTS: Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease. CONCLUSIONS: In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.