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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 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 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.

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BACKGROUND Estimating life expectancy of older adults informs whether to pursue future investigation and therapy. Several models to predict mortality have been developed but often require data not immediately available during routine clinical care. The HOSPITAL score and the LACE index were previously validated to predict 30-day readmissions but may also help to assess mortality risk. We assessed their performance to predict 1-year and 30-day mortality in hospitalized older multimorbid patients with polypharmacy. METHODS We calculated the HOSPITAL score and LACE index in patients from the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly) trial (patients aged �����70 years with multimorbidity and polypharmacy, admitted to hospital across four European countries in 2016-2018). Our primary and secondary outcomes were 1-year and 30-day mortality. We assessed the overall accuracy (scaled Brier score, the lower the better), calibration (predicted/observed proportions), and discrimination (C-statistic) of the models. RESULTS Within 1��year, 375/1879 (20.0%) patients had��died, including 94 deaths within 30 days. The overall accuracy was good and similar for both models (scaled Brier score 0.01-0.08). The C-statistics were identical for both models (0.69 for 1-year mortality, p��=��0.81; 0.66 for 30-day mortality, p��=��0.94). Calibration showed well-matching predicted/observed proportions. CONCLUSION The HOSPITAL score and LACE index showed similar performance to predict 1-year and 30-day mortality in older multimorbid patients with polypharmacy. Their overall accuracy was good, their discrimination low to moderate, and the calibration good. These simple tools may help predict older multimorbid patients' mortality after hospitalization, which may inform post-hospitalization intensity of care.

Background identifying drug-related hospital admissions (DRAs) in older people is difficult. A standardised chart review procedure has recently been developed. It includes an adjudication team (physician and pharmacist) screening using 26 triggers and then performing causality assessment to determine whether an adverse drug event (ADE) occurred (secondary to an adverse drug reaction, overuse, misuse or underuse) and whether the ADE contributed to hospital admission (DRA). Objective to assess the performance of those triggers in detecting DRA. Design retrospective study using data from the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people) trial. Settings four European medical centres. Subjects multimorbid (≥ 3 chronic medical conditions) older (≥ 70 years) inpatients with polypharmacy (≥ 5 chronic medications) were enrolled in the OPERAM trial (N = 2,008) and followed for 12 months. We included patients with ≥1 adjudicated hospitalisation during the follow-up. Methods the positive predictive value (PPV; number of DRAs identified by trigger/number of triggers) was calculated for each trigger and for the tool as a whole. Results of 1,235 hospitalisations adjudicated for 832 patients, 716 (58%) had at least one trigger; an ADE was identified in 673 (54%) and 518 (42%) were adjudicated as DRAs. The overall PPV of the trigger tool for detecting DRAs was 0.66 [0.62–0.69]. Conclusions this tool performs well for identifying DRAs in older people. Based on our results, a revised version of the tool was proposed but will require external validation before it can be incorporated into research and clinical practice.

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 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).

Objective To examine the effect of optimising drug treatment on drug related hospital admissions in older adults with multimorbidity and polypharmacy admitted to hospital. Design Cluster randomised controlled trial. Setting 110 clusters of inpatient wards within university based hospitals in four European countries (Switzerland, Netherlands, Belgium, and Republic of Ireland) defined by attending hospital doctors. Participants 2008 older adults (≥70 years) with multimorbidity (≥3 chronic conditions) and polypharmacy (≥5 drugs used long term). Intervention Clinical staff clusters were randomised to usual care or a structured pharmacotherapy optimisation intervention performed at the individual level jointly by a doctor and a pharmacist, with the support of a clinical decision software system deploying the screening tool of older person’s prescriptions and screening tool to alert to the right treatment (STOPP/START) criteria to identify potentially inappropriate prescribing. Main outcome measure Primary outcome was first drug related hospital admission within 12 months. Results 2008 older adults (median nine drugs) were randomised and enrolled in 54 intervention clusters (963 participants) and 56 control clusters (1045 participants) receiving usual care. In the intervention arm, 86.1% of participants (n=789) had inappropriate prescribing, with a mean of 2.75 (SD 2.24) STOPP/START recommendations for each participant. 62.2% (n=491) had ≥1 recommendation successfully implemented at two months, predominantly discontinuation of potentially inappropriate drugs. In the intervention group, 211 participants (21.9%) experienced a first drug related hospital admission compared with 234 (22.4%) in the control group. In the intention-to-treat analysis censored for death as competing event (n=375, 18.7%), the hazard ratio for first drug related hospital admission was 0.95 (95% confidence interval 0.77 to 1.17). In the per protocol analysis, the hazard ratio for a drug related hospital admission was 0.91 (0.69 to 1.19). The hazard ratio for first fall was 0.96 (0.79 to 1.15; 237 v 263 first falls) and for death was 0.90 (0.71 to 1.13; 172 v 203 deaths). Conclusions Inappropriate prescribing was common in older adults with multimorbidity and polypharmacy admitted to hospital and was reduced through an intervention to optimise pharmacotherapy, but without effect on drug related hospital admissions. Additional efforts are needed to identify pharmacotherapy optimisation interventions that reduce inappropriate prescribing and improve patient outcomes. Trial registration ClinicalTrials.gov NCT02986425 .

Background Older adults with chronic conditions are at high risk of complications from influenza and pneumococcal infections. Evidence about factors associated with influenza and pneumococcal vaccination among older multimorbid persons in Europe is limited. The aim of this study was to investigate the prevalence and determinants of these vaccinations in this population. Methods Multimorbid patients aged ≥70 years with polypharmacy were enrolled in 4 European centers in Switzerland, Belgium, the Netherlands, and Ireland. Data on vaccinations, demographics, health care contacts, and comorbidities were obtained from self-report, general practitioners and medical records. The association of comorbidities or medical contacts with vaccination status was assessed using multivariable adjusted log-binomial regression models. Results Among 1956 participants with available influenza vaccination data (median age 79 years, 45% women), 1314 (67%) received an influenza vaccination within the last year. Of 1400 patients with available pneumococcal vaccination data (median age 79 years, 46% women), prevalence of pneumococcal vaccination was 21% (n = 291). The prevalence of vaccination remained low in high-risk populations with chronic respiratory disease (34%) or diabetes (24%), but increased with an increasing number of outpatient medical contacts. Chronic respiratory disease was independently associated with the receipt of both influenza and pneumococcal vaccinations (prevalence ratio [PR] 1.09, 95% confidence interval [CI] 1.03–1.16; and PR 2.03, 95%CI 1.22–3.40, respectively), as was diabetes (PR 1.06, 95%CI 1.03–1.08; PR 1.24, 95%CI 1.16–1.34, respectively). An independent association was found between number of general practitioner visits and higher prevalence of pneumococcal vaccination (p for linear trend Conclusion Uptake of influenza and particularly of pneumococcal vaccination in this population of European multimorbid older inpatients remains insufficient and is determined by comorbidities and number and type of health care contacts, especially outpatient medical visits. Hospitalization may be an opportunity to promote vaccination, particularly targeting patients with few outpatient physician contacts.

Objective To evaluate if subclinical thyroid dysfunction is associated with cardiovascular (CV) risk in patients with atrial fibrillation (AF). Methods Swiss-AF is a prospective cohort of community-dwelling participants aged ≥ 65 years with AF. Primary outcome was a composite endpoint of CV events (myocardial infarctions, stroke/transitory ischemic events, systemic embolism, heart failure (HF) hospitalizations, CV deaths). Secondary outcomes were component endpoints, total mortality, and AF-progression. Exposures were thyroid dysfunction categories, TSH and fT4. Sensitivity analyses were performed for amiodarone use, thyroid hormones use, and competing events. Results 2415 patients were included (mean age: 73.2 years; 27% women). 196 (8.4%) had subclinical hypothyroidism and 53 (2.3%) subclinical hyperthyroidism. Subclinical thyroid dysfunction was not associated with CV events, during a median follow-up of 2.1 years (max 5 years): age- and sex-adjusted hazard ratio (adjHR) of 0.99 (95% CI: 0.69–1.41) for subclinical hypothyroidism and 0.55 (95% CI: 0.23–1.32) for subclinical hyperthyroidism. Results remained robust following multivariable adjustment and sensitivity analyses. In euthyroid patients, fT4 levels were associated with an increased risk for the composite endpoint and HF (adjHR: 1.46, 95% CI: 1.04–2.05; adjHR: 1.70, 95% CI: 1.08–2.66, respectively, for the highest quintile vs the middle quintile). Results remained similar following multivariable adjustment and remained significant for HF in sensitivity analyses. No association between subclinical thyroid dysfunction and total mortality or AF-progression was found. Conclusions Subclinical hypothyroidism was not associated with increased CV risk in AF patients. Higher levels of fT4 with normal TSH were associated with a higher risk for HF.

Importance Levothyroxine prescriptions are rising worldwide. However, there are few data on factors associated with chronic use. Objective To assess the prevalence of chronic levothyroxine use, its rank among other chronic drugs and factors associated with chronic use. To assess the proportion of users outside the therapeutic range of thyroid-stimulating hormone (TSH). Design Cohort study (CoLaus|PsyCoLaus) with recruitment from 2003 to 2006. Follow-ups occurred 5 and 10 years after baseline. Participants A random sample of Lausanne (Switzerland) inhabitants aged 35–75 years. Main outcomes We evaluated the prevalence of chronic levothyroxine use and we then ranked it among the other most used chronic drugs. The ranking was compared to data from health insurance across the country. We assessed the association between each factor and chronic levothyroxine use in multivariable logistic regression models. The proportion of chronic levothyroxine users outside the usual TSH therapeutic range was assessed. Results 4,334 participants were included in the analysis (mean±SD age 62.8±10.4 years, 54.9% women). 166 (3.8%) participants were chronic levothyroxine users. Levothyroxine was the second most prescribed chronic drug after aspirin in the cohort (8.2%) and the third most prescribed when using Swiss-wide insurance data. In multivariable analysis, chronic levothyroxine use was associated with increasing age [odds ratio 1.03, 95% confidence interval 1.01–1.05 per 1-year increase]; female sex [11.87 (5.24–26.89)]; BMI [1.06 (1.02–1.09) per 1-kg/m2 increase]; number of concomitant drugs [1.22 (1.16–1.29) per 1-drug increase]; and family history of thyroid pathologies [2.18 (1.37–3.48)]. Among chronic levothyroxine users with thyroid hormones assessment (n = 157), 42 (27%) were outside the TSH therapeutic range (17% overtreated and 10% undertreated). Conclusions In this population-based study, levothyroxine ranked second among chronic drugs. Age, female sex, BMI, number of drugs and family history of thyroid pathologies were associated with chronic levothyroxine use. More than one in four chronic users were over- or undertreated.

Importance Previous trials on the effect of levothyroxine on depressive symptom scores in patients with subclinical hypothyroidism were limited by small sample sizes (N = 57 to 94) and potential biases. Objective To assess the effect of levothyroxine on the development of depressive symptoms in older adults with subclinical hypothyroidism in the largest trial on this subject and to update a previous meta-analysis including the results from this study. Design, Setting, and Participants This predefined ancillary study analyzed data from participants in the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism (TRUST) trial, a double-blind, randomized, placebo-controlled, parallel-group clinical trial conducted from April 2013 to October 31, 2016. The TRUST trial included adults aged 65 years or older diagnosed with subclinical hypothyroidism, defined as the presence of persistently elevated thyroid-stimulating hormone (TSH) levels (4.6-19.9 mIU/L) with free thyroxine (T4) within the reference range. Participants were identified from clinical and general practitioner laboratory databases and recruited from the community in Switzerland, the Netherlands, Ireland, and the UK. This ancillary study included a subgroup of 472 participants from the Netherlands and Switzerland; after exclusions, a total of 427 participants (211 randomized to levothyroxine and 216 to placebo) were analyzed. This analysis was conducted from December 1, 2019, to September 1, 2020. Interventions Randomization to either levothyroxine or placebo. Main Outcomes and Measures Depressive symptom scores after 12 months measured with the Geriatric Depression Scale (GDS-15), with higher scores indicating more depressive symptoms (minimal clinically important difference = 2). Results A total of 427 participants with subclinical hypothyroidism (mean [SD] age, 74.52 [6.29] years; 239 women [56%]) were included in this analysis. The mean (SD) TSH level was 6.57 (2.22) mIU/L at baseline and decreased after 12 months to 3.83 (2.29) mIU/L in the levothyroxine group; in the placebo group, it decreased from 6.55 (2.04) mIU/L to 5.91 (2.66) mIU/L. At baseline, the mean (SD) GDS-15 score was 1.26 (1.85) in the levothyroxine group and 0.96 (1.58) in the placebo group. The mean (SD) GDS-15 score at 12 months was 1.39 (2.13) in the levothyroxine and 1.07 (1.67) in the placebo group with an adjusted between-group difference of 0.15 for levothyroxine vs placebo (95% CI, -0.15 to 0.46; P = .33). In a subgroup analysis including participants with a GDS-15 of at least 2, the adjusted between-group difference was 0.61 (95% CI, -0.32 to 1.53; P = .20). Results did not differ according to age, sex, or TSH levels. A previous meta-analysis (N = 278) on the association of levothyroxine with depressive symptoms was updated to include these findings, resulting in an overall standardized mean difference of 0.09 (95% CI, -0.05 to 0.22). Conclusions and Relevance This ancillary study of a randomized clinical trial found that depressive symptoms did not differ after levothyroxine therapy compared with placebo after 12 months; thus, these results do not provide evidence in favor of levothyroxine therapy in older persons with subclinical hypothyroidism to reduce the risk of developing depressive symptoms. Trial Registration ClinicalTrials.gov Identifier: NCT01853579.

Author(s): Stuber, Mirah J; Moutzouri, Elisavet; Feller, Martin; Del Giovane, Cinzia; Bauer, Douglas C; Blum, Manuel R; Collet, Tinh-Hai; Gussekloo, Jacobijn; Mooijaart, Simon P; McCarthy, Vera JC; Aujesky, Drahomir; Westendorp, Rudi; Stott, David J; Glynn, Nancy W; Kearney, Patricia M; Rodondi, Nicolas | Abstract: BackgroundFatigue often triggers screening for and treatment of subclinical hypothyroidism. However, data on the impact of levothyroxine on fatigue is limited and previous studies might not have captured all aspects of fatigue.MethodThis study is nested within the randomized, placebo-controlled, multicenter TRUST trial, including community-dwelling participants aged ≥65 and older, with persistent subclinical hypothyroidism (TSH 4.60-19.99 mIU/L, normal free thyroxine levels) from Switzerland and Ireland. Interventions consisted of daily levothyroxine starting with 50 μg (25 μg if weight l50 kg or known coronary heart diseases) together with dose adjustments to achieve a normal TSH and mock titration in the placebo group. Main outcome was the change in physical and mental fatigability using the Pittsburgh Fatigability Scale over 1 year, assessed through multivariable linear regression with adjustment for country, sex, and levothyroxine starting dose.ResultsAmong 230 participants, the mean ± standard deviation (SD) TSH was 6.2 ± 1.9 mIU/L at baseline and decreased to 3.1 ± 1.3 with LT4 (n = 119) versus 5.3 ± 2.3 with placebo (n = 111, p l .001) after 1 year. After adjustment we found no between-group difference at 1 year on perceived physical (0.2; 95% CI -1.8 to 2.1; p = .88), or mental fatigability (-1.0; 95% CI -2.8 to 0.8; p = .26). In participants with higher fatigability at baseline (≥15 points for the physical score [n = 88] or ≥13 points for the mental score [n = 41]), the adjusted between-group differences at 1 year were 0.4 (95% CI -3.6 to 2.8, p = .79) and -2.2 (95% CI -8.8 to 4.5, p = .51).ConclusionsLevothyroxine in older adults with mild subclinical hypothyroidism provides no change in physical or mental fatigability.

Background: Subclinical hypothyroidism has been associated with heart failure, but only small trials assessed whether treatment with levothyroxine has an impact on cardiac function.Methods: In a randomized, double-blind, placebo-controlled, trial nested within the TRUST trial, Swiss participants ages ≥65 years with subclinical hypothyroidism (thyroid-stimulating hormone [TSH] 4.60-19.99 mIU/L; free thyroxine level within reference range) were randomized to levothyroxine (starting dose of 50 µg daily) to achieve TSH normalization or placebo. The primary outcomes were the left ventricular ejection fraction for systolic function and the ratio between mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e' ratio) for diastolic function. Secondary outcomes included e' lateral/septal, left atrial volume index, and systolic pulmonary artery pressure.Results: A total of 185 participants (mean age 74.1 years, 47% women) underwent echocardiography at the end of the trial. After a median treatment duration of 18.4 months, the mean TSH decreased from 6.35 mIU/L to 3.55 mIU/L with levothyroxine (n = 96), and it remained elevated at 5.29 mIU/L with placebo (n = 89). The adjusted between-group difference was not significant for the mean left ventricular ejection fraction (62.7% vs 62.5%, difference = 0.4%, 95% confidence interval -1.8% to 2.5%, P = 0.72) and the E/e' ratio (10.6 vs 10.1, difference 0.4, 95% confidence interval -0.7 to 1.4, P = 0.47). No differences were found for the secondary diastolic function parameters or for interaction according to sex, baseline TSH, preexisting heart failure, and treatment duration (P value >0.05).Conclusion: Systolic and diastolic heart function did not differ after treatment with levothyroxine compared with placebo in older adults with mild subclinical hypothyroidism.

Background:\ud L-thyroxine does not improve hypothyroid symptoms among adults with subclinical hypothyroidism (SCH). However, those with greater symptom burden before treatment may still benefit.\ud \ud Objective:\ud To determine whether L-thyroxine improves hypothyroid symptoms and tiredness among older adults with SCH and greater symptom burden.\ud \ud Design:\ud Secondary analysis of the randomized, placebo-controlled trial TRUST (Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism Trial). (ClinicalTrials.gov: NCT01660126)\ud \ud Setting:\ud Switzerland, Ireland, the Netherlands, and Scotland.\ud \ud Participants:\ud 638 persons aged 65 years or older with persistent SCH (thyroid-stimulating hormone level of 4.60 to 19.9 mIU/L for >3 months and normal free thyroxine level) and complete outcome data.\ud \ud Intervention:\ud L-thyroxine or matching placebo with mock dose titration.\ud \ud Measurements:\ud 1-year change in Hypothyroid Symptoms and Tiredness scores (range, 0 to 100; higher scores indicate more symptoms) on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire among participants with high symptom burden (baseline Hypothyroid Symptoms score >30 or Tiredness score >40) versus lower symptom burden.\ud \ud Results:\ud \ud 132 participants had Hypothyroid Symptoms scores greater than 30, and 133 had Tiredness scores greater than 40. Among the group with high symptom burden, the Hypothyroid Symptoms score improved similarly between those receiving L-thyroxine (mean within-group change, −12.3 [95% CI, −16.6 to −8.0]) and those receiving placebo (mean within-group change, −10.4 [CI, −15.3 to −5.4]) at 1 year; the adjusted between-group difference was −2.0 (CI, −5.5 to 1.5; P = 0.27). Improvements in Tiredness scores were also similar between those receiving L-thyroxine (mean within-group change, −8.9 [CI, −14.5 to −3.3]) and those receiving placebo (mean within-group change, −10.9 [CI, −16.0 to −5.8]); the adjusted between-group difference was 0.0 (CI, −4.1 to 4.0; P = 0.99). There was no evidence that baseline Hypothyroid Symptoms score or Tiredness score modified the effects of L-thyroxine versus placebo (P for interaction = 0.20 and 0.82, respectively).\ud \ud Limitation:\ud Post hoc analysis, small sample size, and examination of only patients with 1-year outcome data.\ud \ud Conclusion:\ud In older adults with SCH and high symptom burden at baseline, L-thyroxine did not improve hypothyroid symptoms or tiredness compared with placebo.\ud \ud Primary Funding Source:\ud European Union FP7.

Background A cointervention in a randomized clinical trial ( RCT ) is medical care given in addition to the tested intervention. If cointerventions are unbalanced between trial arms, the results may be biased. We hypothesized that cointerventions would be more adequately reported in RCT s without full blinding or at risk of bias. Methods and Results To describe the reporting of cointerventions and to evaluate the factors associated with their reporting, we did a systematic search of all RCT s evaluating pharmacological interventions on cardiovascular outcomes published in 5 high‐impact journals. The reporting of cointerventions, blinding, and risk of bias were extracted and evaluated independently by 2 reviewers (E.M., L.A.). Cointerventions were inadequately reported in 87 of 123 RCT s (70.7%), with 56 (45.5%) providing no information on cointerventions and 31 (25.2%) providing only partial information. Of the RCT s, 52 (42.3%) had inadequate blinding of participants and/or personnel and 63 (51.2%) of the RCT s were judged at risk of bias. In univariable analysis, the reporting of cointerventions was not associated with blinding of participants and/or personnel (odds ratio [OR], 1.04; 95% CI, 0.47–2.27 for adequately versus inadequately blinded trials) or with risk of bias ( OR, 1.47; 95% CI, 0.67–3.21 for at low risk of bias versus trials at risk of bias). In multivariable analysis, only a follow‐up of OR, 3.63; 95% CI, 1.21–10.91). Conclusions More than two‐thirds of recent major cardiovascular trials did not adequately report cointerventions. The quality of reporting was not better among trials that were not fully blinded or at risk for bias. Registration URL : https://www.crd.york.ac.uk/PROSP​ERO/ . Unique identifier: CRD 42018106771.

OBJECTIVE Data on the association between subclinical thyroid dysfunction and dementia are limited and conflicting. We aimed to determine whether subclinical thyroid dysfunction was associated with dementia and cognitive decline. DESIGN Population-based prospective cohort study. PATIENTS Adults aged 70-79 years with measured thyroid function, but no dementia at baseline, and Modified Mini-Mental State (3MS) at baseline and follow-up. MEASUREMENTS Primary outcome was incident adjudicated dementia, based on 3MS, hospital records, and dementia drugs. Secondary outcome was change in 3MS. Models were adjusted for age, sex, race, education, and baseline 3MS, and then further for cardiovascular risk factors. RESULTS Among 2558 adults, 85% were euthyroid (TSH 0.45-4.49mIU/L), 2% had subclinical hyperthyroidism with mildly decreased TSH (TSH 0.10- 0.44mIU/L), 1% subclinical hyperthyroidism with suppressed TSH (TSH

Previous studies reported lower rates of recurrent venous thromboembolism (rVTE) among statin users, but this association could be influenced by concurrent anticoagulation and confounding by statin indication. This study aimed to confirm the beneficial association between statins and rVTE, stratified according to periods with and without anticoagulation, and additionally employ propensity score weighted approach to reduce risk of confounding by indication. The setting was a prospective multicentre cohort study and the outcome was time to first rVTE in statin vs. non-statin users. 980 participants with acute VTE were enrolled (mean age 75.0 years, 47% women), with median follow-up of 2.5 years. Of 241 (24.3%) statin users, 21 (8.7%) suffered rVTE vs. 99 (13.4%) among 739 non-users. The overall adjusted sub-hazard ratio (aSHR) for rVTE comparing statin users to non-users was 0.72 (95%CI 0.44 to 1.19, p = 0.20). This association was only apparent during periods without anticoagulation (aSHR 0.50, 95%CI 0.27 to 0.92, p = 0.03; vs. with anticoagulation: aSHR 1.34, 95%CI 0.54 to 3.35, p = 0.53). Using propensity scores, the rVTE risk during periods without anticoagulation fell further (aSHR 0.20, 95%CI 0.08 to 0.49, p

Context Both thyroid dysfunction and levothyroxine (LT4) therapy have been associated with bone loss, but studies on the effect of LT4 for subclinical hypothyroidism (SHypo) on bone yielded conflicting results. Objective To assess the effect of LT4 treatment on bone mineral density (BMD), Trabecular Bone Score (TBS), and bone turnover markers (BTMs) in older adults with SHypo. Design and Intervention Planned nested substudy of the double-blind placebo-controlled TRUST trial. Participants with SHypo were randomized to LT4 with dose titration versus placebo with computerized mock titration. Setting and Participants 196 community-dwelling adults over 65 years enrolled at the Swiss TRUST sites had baseline and 1-year follow-up bone examinations; 4 participants withdrew due to adverse events not related to treatment. Main Outcome Measures One-year percentage changes of BMD, TBS, and 2 serum BTMs (serum CTX-1 [sCTX] and procollagen type 1 N-terminal polypeptide [P1NP]). Student’s t-test for unadjusted analyses and linear regression adjusted for clinical center and sex were performed. Results Mean age was 74.3 years ± 5.7, 45.4% were women, and 19.6% were osteoporotic. The unadjusted 1-year change in lumbar spine BMD was similar between LT4 (+0.8%) and placebo-treated groups (–0.6%; between-groups difference +1.4%: 95% confidence interval [CI] –0.1 to 2.9, P = .059). Likewise, there were no between-group differences in 1-year change in TBS (–1.3%: 95% CI –3.1 to 0.6, P = .19), total hip BMD (–0.2%: 95% CI –1.1 to 0.1, P = .61), or BTMs levels (sCTX +24.1%: 95% CI –7.9 to 56.2, P = .14), or after adjustment for clinical centers and sex. Conclusions Over 1-year levothyroxine had no effect on bone health in older adults with SHypo. Registration ClinicalTrial.gov NCT01660126 and NCT02491008

Clinical questionWhat are the benefits and harms of thyroid hormones for adults with subclinical hypothyroidism (SCH)? This guideline was triggered by a recent systematic review of randomised controlled trials, which could alter practice.Current practiceCurrent guidelines tend to recommend thyroid hormones for adults with thyroid stimulating hormone (TSH) levels >10 mIU/L and for people with lower TSH values who are young, symptomatic, or have specific indications for prescribing.RecommendationThe guideline panel issues a strong recommendation against thyroid hormones in adults with SCH (elevated TSH levels and normal free T4 (thyroxine) levels). It does not apply to women who are trying to become pregnant or patients with TSH >20 mIU/L. It may not apply to patients with severe symptoms or young adults (such as those ≤30 years old).How this guideline was createdA guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach.The evidenceThe systematic review included 21 trials with 2192 participants. For adults with SCH, thyroid hormones consistently demonstrate no clinically relevant benefits for quality of life or thyroid related symptoms, including depressive symptoms, fatigue, and body mass index (moderate to high quality evidence). Thyroid hormones may have little or no effect on cardiovascular events or mortality (low quality evidence), but harms were measured in only one trial with few events at two years’ follow-up.Understanding the recommendationThe panel concluded that almost all adults with SCH would not benefit from treatment with thyroid hormones. Other factors in the strong recommendation include the burden of lifelong management and uncertainty on potential harms. Instead, clinicians should monitor the progression or resolution of the thyroid dysfunction in these adults. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of thyroid hormones in multilayered evidence summaries and decision aids available in MAGIC (https://app.magicapp.org/) to support shared decisions and adaptation of this guideline.

Importance: The benefit of thyroid hormone therapy for subclinical hypothyroidism is uncertain. New evidence from recent large randomized clinical trials warrants an update of previous meta-analyses.\ud \ud Objective: To conduct a meta-analysis of the association of thyroid hormone therapy with quality of life and thyroid-related symptoms in adults with subclinical hypothyroidism.\ud \ud Data Sources: PubMed, EMBASE, ClinicalTrials.gov, Web of Science, Cochrane Library, CENTRAL, Emcare, and Academic Search Premier from inception until July 4, 2018.\ud \ud Study Selection: Randomized clinical trials that compared thyroid hormone therapy with placebo or no therapy in nonpregnant adults with subclinical hypothyroidism were eligible. Two reviewers independently evaluated eligibility based on titles and abstracts of all retrieved studies. Studies not excluded in this first step were independently assessed for inclusion after full-text evaluation by 2 reviewers.\ud \ud Data Extraction and Synthesis: Two independent reviewers extracted data, assessed risk of bias (Cochrane risk-of-bias tool), and evaluated the quality of evidence (GRADE tool). For synthesis, differences in clinical scores were transformed (eg, quality of life) into standardized mean differences (SMDs; positive values indicate benefit of thyroid hormone therapy; 0.2, 0.5, and 0.8 correspond to small, moderate, and large effects, respectively). Random-effects models for meta-analyses were applied.\ud \ud Main Outcomes and Measures: General quality of life and thyroid-related symptoms after a minimum follow-up of 3 months.\ud \ud Results: Overall, 21 of 3088 initially identified publications met the inclusion criteria, with 2192 adults randomized. After treatment (range, 3-18 months), thyroid hormone therapy was associated with lowering the mean thyrotropin value into the normal reference range compared with placebo (range, 0.5-3.7 mIU/L vs 4.6 to 14.7 mIU/L) but was not associated with benefit regarding general quality of life (n = 796; SMD, −0.11; 95% CI, −0.25 to 0.03; I2=66.7%) or thyroid-related symptoms (n = 858; SMD, 0.01; 95% CI, −0.12 to 0.14; I2=0.0%). Overall, risk of bias was low and the quality of evidence assessed with the GRADE tool was judged moderate to high.\ud \ud Conclusions and Relevance: Among nonpregnant adults with subclinical hypothyroidism, the use of thyroid hormone therapy was not associated with improvements in general quality of life or thyroid-related symptoms. These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.

BACKGROUND Even though the association between thyroid dysfunction and anemia is commonly described, it is not known whether it is clinically relevant. This study set out to quantify the association of thyroid dysfunction on hemoglobin (Hb) concentration and risk of anemia. A systematic review (MEDLINE and EMBASE, from inception until May 15, 2017) was conducted to interpret the findings in context. METHODS Participants from the EPIC-Norfolk cohort with available baseline thyrotropin (TSH), free thyroxine (fT4), and Hb were included. Euthyroidism was defined as TSH 0.45-4.49 mIU/L (reference category), hypothyroidism as TSH ≥4.50 mIU/L (subclinical [SHypo] with normal fT4 or overt [OHypo] with low fT4), and hyperthyroidism as TSH ≤0.44 mIU/L (subclinical [SHyper] with normal fT4 or overt [OHyper] with elevated fT4). Anemia was defined as Hb

Context Subclinical hypothyroidism (SHypo) has been associated with atherosclerosis, but no conclusive clinical trials assessing the levothyroxine impact on carotid atherosclerosis exist. Objective To assess the impact of treatment of SHypo with levothyroxine on carotid atherosclerosis. Design and Setting Randomized, double-blind, placebo-controlled trial nested within the Thyroid Hormone Replacement for Subclinical Hypothyroidism trial. Participants Participants aged ≥65 years with SHypo [thyroid-stimulating hormone (TSH), 4.60 to 19.99 mIU/L; free thyroxine level within reference range]. Intervention Levothyroxine dose-titrated to achieve TSH normalization or placebo, including mock titrations. Main Outcome Measures Carotid intima media thickness (CIMT), maximum plaque thickness measured with ultrasound. Results One hundred eighty-five participants (mean age 74.1 years, 47% women, 96 randomized to levothyroxine) underwent carotid ultrasound. Overall mean TSH ± SD was 6.35 ± 1.95 mIU/L at baseline and decreased to 3.55 ± 2.14 mIU/L with levothyroxine compared with 5.29 ± 2.21 mIU/L with placebo (P < 0.001). After a median treatment of 18.4 months (interquartile range 12.2 to 30.0 months), mean CIMT was 0.85 ± 0.14 mm under levothyroxine and 0.82 ± 0.13 mm under placebo [between-group difference = 0.02 mm; 95% CI, −0.01 to 0.06; P = 0.30]. The proportion of carotid plaque was similar (n = 135; 70.8% under levothyroxine and 75.3% under placebo; P = 0.46). Maximum carotid plaque thickness was 2.38 ± 0.92 mm under levothyroxine and 2.37 ± 0.91 mm under placebo (between-group difference −0.03; 95% CI, −0.34 to 0.29; P = 0.86). There were no significant interactions between levothyroxine treatment and mean CIMT, according to sex, baseline TSH (categories 4.6 to 6.9, 7.0 to 9.9, and ≥10 mIU/L), or established cardiovascular disease (all P for interaction ≥ 0.14). Conclusion Normalization of TSH with levothyroxine was associated with no difference in CIMT and carotid atherosclerosis in older persons with SHypo.

Author(s): Schneider, Claudio; Feller, Martin; Bauer, Douglas C; Collet, Tinh-Hai; da Costa, Bruno R; Auer, Reto; Peeters, Robin P; Brown, Suzanne J; Bremner, Alexandra P; O'Leary, Peter C; Feddema, Peter; Leedman, Peter J; Aujesky, Drahomir; Walsh, John P; Rodondi, Nicolas | Abstract: ObjectiveGuidelines for thyroid function evaluation recommend testing TSH first, then assessing fT4 only if TSH is out of the reference range (two-step), but many clinicians initially request both TSH and fT4 (one-step). Given limitations of previous studies, we aimed to compare the two-step with the one-step approach in an unselected community-dwelling study population, and develop a prediction score based on clinical parameters that could identify at-risk patients for thyroid dysfunction.DesignCross-sectional analysis of the population-based Busselton Health Study.MethodsWe compared the two-step with the one-step approach, focusing on cases that would be missed by the two-step approach, i.e. those with normal TSH, but out-of-range fT4. We used likelihood ratio tests to identify demographic and clinical parameters associated with thyroid dysfunction and developed a clinical prediction score by using a beta-coefficient based scoring method.ResultsFollowing the two-step approach, 93.0% of all 4471 participants had normal TSH and would not need further testing. The two-step approach would have missed 3.8% of all participants (169 of 4471) with a normal TSH, but a fT4 outside the reference range. In 85% (144 of 169) of these cases, fT4 fell within 2 pmol/l of fT4 reference range limits, consistent with healthy outliers. The clinical prediction score that performed best excluded only 22.5% of participants from TSH testing.ConclusionThe two-step approach may avoid measuring fT4 in as many as 93% of individuals with a very small risk of missing thyroid dysfunction. Our findings do not support the simultaneous initial measurement of both TSH and fT4.

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.

Oxidative stress can contribute to the development of diseases, and may originate from exposures to toxicants commonly found in air pollution and cigarette smoke such as polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs). Yet, associations between these exposures and oxidative stress biomarkers are poorly characterized. We report here novel associations between 14 exposure biomarkers of PAHs and VOCs, and two oxidative stress biomarkers; 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-isoprostaglandin F 2α (8-isoprostane) in urine obtained from smokers participating in an ongoing clinical study (ESTxENDS, NCT03589989). We also assessed associations between six biomarkers of tobacco smoke exposure (metabolites of nicotine and tobacco-specific nitrosamines (TSNAs)) and both oxidative stress biomarkers. We then quantified the relative importance of each family of the 20 exposure biomarkers on oxidative stress. Participating smokers (153 men and 117 women, median age 44 years) had on average smoked 25 [2-62] years and smoked about 17 [5-40] cigarettes per day at the time of the study. Multiple linear regression results showed an association between 8-oxodG concentrations and the following metabolites in decreasing relative importance: PAHs (beta coefficient β = 0.105, p-value 2 = 0.15) > VOCs (β = 0.028, p < 0.001, partial R 2 = 0.09) > nicotine (β = 0.226, p < 0.001, partial R 2 = 0.08); and between 8-isoprostane concentrations and metabolites of PAHs (β = 0.117, p < 0.001, partial R 2 = 0.14) > VOCs (β = 0.040, p < 0.001, partial R 2 = 0.14) > TSNAs (β = 0.202, p = 0.003, partial R 2 = 0.09) > nicotine (β = 0.266, p < 0.001, partial R 2 = 0.08). Behavioral factors known to contribute to oxidative stress, including sleep quality, physical activity, and alcohol consumption, did not play a significant role. Exposures to PAHs and VOCs among smokers were significantly associated with oxidative stress.