Simon P. Mooijaart, MD, PhD1,2; Robert S. Du Puy, MD3; David J. Stott, MD4; et alPa

Author Affiliations Article Information
JAMA. Published online October 30, 2019. doi:10.1001/jama.2019.17274

Key Points
Question Among adults aged 80 years and older with subclinical hypothyroidism, what is the association between treatment with levothyroxine and thyroid-related symptoms?

Findings In this pooled analysis of data from 2 randomized clinical trials that included 251 participants aged 80 years and older, treatment with levothyroxine, compared with placebo, was not significantly associated with improvement in thyroid-related patient-reported quality of life outcome scores (range, 0-100; higher scores indicate worse quality of life; minimal clinically important difference, 9) for hypothyroid symptoms (adjusted between-group difference, 1.3) or tiredness (adjusted between-group difference, 0.1).

Meaning These findings do not support routine treatment with levothyroxine for subclinical hypothyroidism in adults aged 80 years and older.

Abstract
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

Introduction
The prevalence of subclinical hypothyroidism increases with age.1 Subclinical hypothyroidism is defined by elevated levels of thyrotropin (often referred to as thyroid-stimulating hormone [TSH]) simultaneously with free thyroxine (FT4) within the normal range. Some patients with subclinical hypothyroidism report symptoms such as constipation, mental slowness, fatigue, or depressive symptoms.2,3 Subclinical hypothyroidism has also been associated with an increased risk of cardiovascular disease.4

In a 2017 clinical randomized trial of 737 participants aged 65 years and older, treatment with levothyroxine demonstrated no benefit on the primary outcome of thyroid-specific quality of life.5 However, individuals aged 80 years and older with subclinical hypothyroidism have been underrepresented in clinical trials6,7 and outcomes such as quality of life have not been reported for this age group. Because the prevalence of comorbidities and frailty increase with age, it is possible that benefits and harms from managing subclinical hypothyroidism may differ in adults aged 80 years and older compared with younger age groups.8 The lack of evidence for older patients may have contributed to significant treatment variation by primary care clinicians.9

This study combined data from the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial10 and the subgroup of participants in the Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial (TRUST) aged 80 years and older.5 The 2 trials examined the effects of managing subclinical hypothyroidism with levothyroxine on quality of life in adults aged 80 years and older.

Methods
Both clinical trials were approved by the Central Committee on Research Involving Human Subjects in the Netherlands and by the Bern and Lausanne ethics committees and Swissmedic, the Swiss authority on drugs, in Switzerland. One trial was also approved by the Multicenter Research Ethics Committee and the Medicines and Healthcare products Regulatory Agency in the United Kingdom, with cosponsors the National Health Services Greater Glasgow and Clyde and the University of Glasgow, and by the Clinical Research Ethics Committee, Cork, and the Health Products Regulatory Authority (formerly known as the Irish Medicines Board) in Ireland. Written informed consent was obtained from all participants. The study protocol and statistical analysis plans for each trial have been published.10,11 The protocol and statistical analysis plan for the combined analyses are available in Supplement 1 and Supplement 2.

Design
The included studies were randomized, double-blind, placebo-controlled parallel-group trials investigating the effects of levothyroxine treatment for persons with subclinical hypothyroidism aged 80 years and older and aged 65 years and older.10,11 They were conducted with similar study designs and included a prospectively planned combined analysis of all participants aged 80 years and older. The cohorts are presented and analyzed as a single study group throughout this report.

Study Population
One trial recruited community-dwelling participants aged 80 and older years between May 2014 and May 2017, from sites in the Netherlands and Switzerland,10 with a final date of follow-up of May 4, 2018. The other trial recruited community-dwelling participants aged 65 years and older from sites in the Netherlands, Switzerland, Ireland, and the United Kingdom between April 2013 and May 2015, with a final date of follow-up of October 31, 201611; only participants aged 80 years and older from this trial were included in this report. Participants were followed up for a minimum of 12 months and a maximum of 36 months. Information on participant race was collected to evaluate for racial differences in outcomes. Participants selected their race from 8 prespecified options reflecting the most common racial groups in the countries of the study sites.

Inclusion Criteria
Eligibility criteria for both trials have been published.10,11 Individuals with persistent subclinical hypothyroidism aged 80 years and older, defined as elevated thyrotropin levels (4.6-19.9 mIU/L), measured on at least 2 occasions between 3 months and 3 years apart, who had FT4 levels within laboratory reference ranges were eligible. Eligible persons were identified from lists of patients with laboratory test results from hospitals and primary care practices. Exclusion criteria included use of levothyroxine, antithyroid medication, amiodarone, or lithium; recent thyroid surgery or radioiodine therapy; New York Heart Association class IV heart failure; clinical diagnosis of dementia; recent hospitalization for major illness; recent acute coronary syndrome, acute myocarditis, or pancarditis; and terminal illness.

Randomization and Blinding
Participants were randomized in a 1:1 ratio using a computer-based program to receive levothyroxine or placebo using randomly permuted blocks in a block size of 4, stratified by site, sex, and starting dose. Randomization was performed separately for each trial. The independent data center (Robertson Centre for Biostatistics, University of Glasgow, United Kingdom) provided the randomization schedule; the 2 interventions were identically packaged by Mawdsley Brooks & Co (United Kingdom). Participants, general practitioners, and study personnel were blinded to treatment allocation and thyroid function test results throughout the study.

Intervention and Control
The study medication consisted of levothyroxine sodium tablets and matching placebo tablets taken orally once daily. The levothyroxine group started with 50 µg daily (or 25 µg for participants with body weight <50 kg or a history of coronary heart disease) and the placebo group started with a matching placebo for 6 to 8 weeks. The dose of levothyroxine was adjusted in 25-µg increments based on thyrotropin levels measured 6 to 8 weeks after starting the intervention, 6 to 8 weeks after each dose adjustment, and at 12- and 24-month follow-up with the goal of attaining a thyrotropin level within the reference range (0.4-4.6 mIU/L) in the levothyroxine group. An identical schedule for adjusting the dose of the placebo was used to achieve an equal number of titrations between the groups to maintain blinding. Laboratory test results were uploaded in the computer system by laboratory personnel not involved in the study, and study medication was prescribed in a blinded fashion using an automated system, according to the algorithm. The participants, investigators, and treating physicians were unaware of the results of thyrotropin measurements throughout the course of the trial and remained blinded for treatment allocation.

Study Outcomes
Primary outcomes and prespecified secondary outcomes were measured at the 12-month follow-up and at the end of the study, defined as the last study visit for each participant. The co-primary study outcomes were the change from baseline to the 12 month follow-up in the hypothyroid symptoms score (4 items) and tiredness score (7 items) from the Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO)12 questionnaire (range, 0-100; higher scores indicate more symptoms; minimal clinically important difference [MCID], 9).13

Prespecified secondary outcomes differed between the protocol (Supplement 1), which was finalized in June 2016, and the statistical analysis plan (Supplement 2), which was finalized in May 2018 before the results from the trial of patients aged 80 years and older were known to the investigators. The secondary outcomes were prespecified in the statistical analysis plan (Supplement 2) and include change from baseline to 12 months in thyrotropin levels; general quality of life measured using the EuroQol-5D index (range, −0.59 to 1.00; higher scores indicate a better quality of life; MCID, 0.037-0.069)14 and the EuroQol Visual Analogue Scale (range, 0-100; higher scores indicate better quality of life; MICD, 8)15; handgrip strength using the Jamar isometric dynamometer (best of 3 measurements in the dominant hand; MCID, 5.0-6.5 kg16); weight and body mass index (MCID, 5%-10% change for both17,18); waist circumference (MCID, 4 cm19); systolic and diastolic blood pressure (MCID, 5 mm Hg20), FT4 test results; and incidence of falls.

The statistical analysis plan (Supplement 2) also prespecified end-of-study outcomes, which were measured at the final follow-up visit attended by each participant. The prespecified end-of-study outcomes were all of the secondary outcomes listed above in addition to change from baseline in the hypothyroid symptoms and tiredness scores (assessed with the ThyPRO), Barthel Index21 activities of daily living score (range, 0-20; higher scores indicate greater ability to perform activities of daily living; MCID, 1.8522,23), Older Americans Resources and Services24 instrumental activities of daily living score (range, 0-14; higher scores indicate better performance in instrumental activities of daily living; MCID, 125), executive cognitive function measured with the Letter Digit Coding Test26 (the number of correct substitutions of digits and letters in a 90-second period; minimum score, 0; higher scores indicate better cognitive function; MCID, 4 or 10%27), living situation (living independently or not independently and living alone or not living alone), gait speed (MICD for change, 0.1-0.2 m/s28), and ThyPRO-39 questionnaire score. However, the following prespecified outcomes were listed in the statistical analysis plan but were not reported here: FT4 test results, ThyPRO-39 score, gait speed, and falls. Information on gait speed and falls was only available for 1 of the trials.

Adverse Events
The statistical analysis plan (Supplement 2) prespecified the following outcomes, consisting of adverse events, at the end of the study: combined fatal and nonfatal cardiovascular events (defined as acute myocardial infarction, stroke, amputations for peripheral vascular disease, revascularizations for atherosclerotic vascular disease, acute coronary syndrome, and heart failure hospitalizations), fatal cardiovascular events, and mortality. The following safety outcomes were also prespecified in the statistical analysis plan (Supplement 2): hypothyroidism, atrial fibrillation, heart failure, and fractures. Adverse events were reviewed by a blinded adjudication group of 5 investigators. The hyperthyroid symptom score from the ThyPRO questionnaire12 was used to assess for overtreatment or the development of hyperthyroidism.

Sample Size
The sample size was calculated for the primary outcomes of mean change from baseline in the hypothyroid symptoms and tiredness scores at 12 months (pooled data). All sample size calculations were based on statistical power of 0.80 and a 2-sided α of .05. The 2-sided significance level for each primary outcome was .025. The study was considered positive if this level of significance was achieved for either outcome.

Assuming an SD of 26 for the score change for each primary outcome,29 264 participants were required (132 per group) to detect the MCID of 9 on the hypothyroid symptoms and tiredness scores. Assuming a dropout rate of 10% in the first 12 months, the target sample size was 291 participants in the pooled analysis. Originally, the proposed sample size was 900 participants for the primary outcomes of fatal and nonfatal cardiovascular events and mean change in hypothyroid symptoms and tiredness scores on the ThyPRO questionnaire. Due to recruitment difficulty, protocols were amended and fatal or nonfatal cardiovascular events became prespecified secondary outcomes in the protocols and adverse events in the statistical analysis plan (Supplement 2).10,11 Investigators were blinded to this process.

Statistical Methods
Primary outcome and adverse event analyses were performed for participants with data available at the 12-month follow-up. In a preplanned secondary analysis, analyses were repeated for the outcome at the final visit instead of 12 months. Continuous variables measured at baseline and during follow-up were analyzed at each time point, comparing change from baseline between the placebo and levothyroxine groups, using mixed-effects models, adjusting for stratification variables and baseline values and including study as a random effect. Outcomes measured at more than 1 follow-up were also analyzed using linear mixed-effects regression analysis, including data at all time points up to 12 months and repeated analyses including data at all available time points. Additional sensitivity analyses were performed using mixed-effect models and multiple imputations.30 Ten imputed data sets were generated, imputing all missing values of the outcome variable at 12-month follow-up from age, sex, baseline thyrotropin level, baseline measurement of the outcome variable and, if available, measurement of the outcome variable at 6- to 8-week follow-up visits.

Total ThyPRO scores per domain containing missing items were scaled to maintain the maximum possible score for analyses. If more than 50% of the items for a score were missing, the score was considered to be missing. Categorical outcomes were analyzed using Cox proportional hazards regression analysis in models that contained the randomized treatment allocation and stratification variables as covariates. Adjusted differences were analyzed using the Wald test. Corresponding point estimates and 95% CIs for the hazard ratio for treatment were estimated. The assumption of proportionality of hazards was checked, and the assumption was met, using diagnostic plots of the log(−log(survival)) vs log(survival) and of the Schoenfield residuals over time. The 2-sided significance level was .025 for each primary outcome (hypothyroid symptoms and tiredness scores) and .05 for secondary outcomes. Because of the potential for type I error due to multiple comparisons, secondary outcomes should be interpreted as exploratory. All statistical analyses were performed in R, version 3.2.4 (R Development Core Team).

Results
Of 251 randomized participants aged 80 years and older in the combined analyses, 112 (52 from the first trial and 60 from the second) were randomized to receive levothyroxine and 139 (53 from the first trial and 86 from the second) were randomized to receive the placebo. Results are presented for the combined group of participants in the 2 trials and for each trial separately (eTables 1, 3, 4, and 5 and eFigures 1 and 2 in Supplement 3). In one trial, 342 adults aged 80 years and older were screened for eligibility. In the other trial, 2647 participants aged 65 years and older were screened for eligibility (Figure 1; eFigure 1 in Supplement 3). The mean (SD) age of participants was 84.6 (3.6) years and 118 (47%) were women. A higher percentage of participants in the placebo group had a history of ischemic heart disease compared with the levothyroxine group (27.3% vs 20.5%) (Table 1). Mean (SD) thyrotropin at baseline was 6.3 (1.9) mIU/L in the placebo group vs 6.4 (1.8) mIU/L in the levothyroxine group. No other clinically relevant differences between treatment groups at baseline were observed (eTable 1 in Supplement 3).

Dropout rates were similar between the groups (10 participants [8.9%] in the levothyroxine group vs 9 [6.5%] in the placebo group). After 12 months, 122 (88%) participants in the placebo group and 90 (80%) in the levothyroxine group had follow-up laboratory measures available (eTable 2 in Supplement 3). Mean (SD) thyrotropin levels decreased from 6.20 (1.48) mIU/L at baseline to 5.49 (2.21) mIU/L at 12 months in the placebo group and from 6.50 (1.80) mIU/L at baseline to 3.69 (1.81) mIU/L at 12 months in the levothyroxine group (estimated mean between-group difference, −1.9 mIU/L [95% CI, −2.49 to −1.45]; P < .001; Figure 2) in regression models. Thyrotropin levels were significantly different between the placebo and levothyroxine groups at all time points during follow-up (all P < .001), including when the 2 studies were analyzed separately (all P < .01) (eFigure 2 in Supplement 3).

There was no significant association of levothyroxine treatment with change in the hypothyroid symptoms score at the 12-month follow-up (21.7 at baseline and 19.3 at 12 months in the levothyroxine group vs 19.8 at baseline and 17.4 at 12 months in the placebo group; adjusted between-group difference, 1.27 [95% CI, −2.69 to 5.23]; P = .53). There was also no significant association in the tiredness score (25.5 at baseline and 28.2 at 12 months in the levothyroxine group vs 25.1 at baseline and 28.7 at 12 months in the placebo group; adjusted between-group difference, −0.10 [95% CI, −4.51 to 4.31]; P = .96) (Table 2).

Levothyroxine treatment was not significantly associated with changes from baseline to 12 months in general quality of life measured with the EuroQol-5D index (change from 0.785 to 0.754 in the levothyroxine group vs 0.811 to 0.785 in the placebo group; adjusted difference, −0.012 [95% CI, −0.063 to 0.039]) or physical function as measured by handgrip strength at 12 months (change from 25.4 kg to 23.4 kg in the levothyroxine group vs 24.7 kg to 23.0 kg in the placebo group; adjusted between-group difference, −0.27 kg [95% CI, −1.79 to 1.25]) (Table 2).

Treatment with levothyroxine was associated with a statistically significant increase in body mass index (between-group difference, 0.38 [95% CI, 0.08-0.68]; P = .01) and in waist circumference (between-group difference, 1.52 cm [95% CI, 0.09-2.95]; P = .04) compared with placebo (Table 2).

Data for 17 participants (12%) in the placebo group and 22 (20%) in the levothyroxine group who had incomplete follow-up data were imputed. Sensitivity analyses using repeated measures mixed-effect regression models and imputed data for outcomes at 12 months showed similar results (eTable 4 in Supplement 3).

For the end-of-study outcomes, the mean follow-up was 17 months. Treatment with levothyroxine was not significantly associated with thyroid-specific or overall quality of life based on the end-of-study outcomes (Table 3). There was no significant association of levothyroxine treatment with activities of daily living measured using the Barthel Index (from 19.3 at baseline to 19.0 at the end of the study in the levothyroxine group vs from 19.4 to 19.1 in the placebo group; adjusted mean difference, 0.09 [95% CI, −0.33 to 0.52]) or in executive cognitive function measured with the Letter Digit Coding Test (mean between-group difference, 1.24 [95% CI, −0.30 to 2.78]) at the end of the study.

During a mean follow-up of 17 months (median follow-up, 13 months), 9 participants (3.6%) died (1 cardiovascular death). Levothyroxine was not associated with increased rates of fatal or nonfatal cardiovascular events (unadjusted hazard ratio, 0.61 [95% CI, 0.24-1.50]; event rate per 100 person-years of 4.2 in the levothyroxine group and 7.64 in the placebo group) or overall mortality (unadjusted hazard ratio, 1.39 [95% CI, 0.37-5.19]; event rate of 2.99 in the levothyroxine group and 2.02 in the placebo group) (Table 4). A total of 73 participants (29%; 33 [29.5%] in the levothyroxine group and 40 [28.8%] in the placebo group) experienced 1 or more serious adverse events. Adverse events included new-onset atrial fibrillation (10 participants [4.5%]), heart failure (9 [4.1%]), and fractures (9 [4.1%]). Hypothyroidism did not occur in any of the participants. In the levothyroxine group, the most common adverse events were stroke (3 participants [2.2%]), anemia (2 [1.4%]), and pneumonia (2 [1.4%]). In the placebo group, the most common adverse events were pneumonia (4 participants [3.6%]), cardiac failure (2 [1.8%]), and respiratory failure (2 [1.8%]). At the end of the study, treatment discontinuation occurred in 81 participants (32%) during follow-up, whereas total study withdrawal occurred in 19 (8%) participants. There was no significant difference in treatment discontinuation (38 participants [31%] in the levothyroxine group and 43 [34%] in the placebo) or withdrawal (2 participants [3.8%] in the levothyroxine group and 1 [1.9%] in the placebo group) between the groups.

Discussion
In this prospective analysis that combined data from 2 trials of community-dwelling adults aged 80 years and older with subclinical hypothyroidism, levothyroxine treatment, compared with placebo, was not associated with improvement in hypothyroid symptoms or fatigue. There was no association of levothyroxine treatment with risk of adverse events or secondary outcomes, except for with body mass index and waist circumference; however, the magnitude of these associations were small and likely due to chance given the large number of comparisons. There were no differences in dropout rates between treatment groups, suggesting that levothyroxine treatment was not associated with adverse effects.

These findings do not support routine use of levothyroxine for managing subclinical hypothyroidism in adults aged 80 years and older. Consistent with results reported in the current trial, European and US guidelines do not recommend routine treatment for individuals aged 80 years and older with subclinical hypothyroidism.31,32 However, in both guidelines, treatment is recommended for individuals with thyrotropin levels of 10 mIU/L or higher (age is not mentioned), and the European guideline suggests ongoing monitoring of thyroid function in patients older than 80 years with subclinical hypothyroidism. Participants in the current study had only mildly elevated thyrotropin levels and a low symptom burden at baseline, consistent with findings in a population study of older individuals with subclinical hypothyroidism.1 The findings of the present study are thus relevant to the large group of adults aged 80 years and older with few symptoms in whom elevated thyrotropin levels are identified during a routine evaluation.

A Cochrane review of 11 double-blinded randomized clinical trials that examined the effects of thyroid hormone treatment of subclinical hypothyroidism on various outcomes reported no association of thyroid hormone treatment with clinically relevant outcomes.7 However, these 11 randomized clinical trials of 350 participants included few older participants and had outcomes that were diverse with respect to length of follow-up and type of outcome studied, such as lipids, mood, and heart function.7 Results of the current study were consistent with the overall results of the included trial of adults aged 65 years and older, in which levothyroxine treatment was found to have no beneficial effect on thyroid-related symptoms, generic quality of life, cognitive or physical function, and activities of daily living scores, and there was no increase in adverse events.5

Limitations
This study has several limitations. First, there were no preplanned subgroup analyses of participants with high symptom burden or higher elevated thyrotropin level at baseline. Results may not apply to these participants. Second, antithyroid antibody status, which may identify individuals who have an increased risk of progression to overt hypothyroidism, was not available. Third, the study population was homogeneous with respect to race. Fourth, there were participants who discontinued treatment (32%), which may have biased results. However, numbers of and reasons for discontinuation were similar between treatment groups.

Conclusions
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.

Article Information
Corresponding Author: Simon P. Mooijaart, MD, PhD, Department of Gerontology and Geriatrics (C7-Q), Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands ([email protected]).

Accepted for Publication: October 1, 2019.

Published Online: October 30, 2019. doi:10.1001/jama.2019.17274

Author Contributions: Drs Mooijaart and Du Puy had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Mooijaart and Du Puy contributed equally as co-primary authors.

Concept and design: Mooijaart, Stott, Kearney, Rodondi, Westendorp, den Elzen, Ford, Dekkers, Jukema, Smit, Gussekloo.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Mooijaart, Du Puy, Westendorp.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ford, Messow.

Obtained funding: Mooijaart, Stott, Rodondi, Westendorp, Dekkers, Gussekloo.

Administrative, technical, or material support: Mooijaart, Du Puy, Rodondi, Westendorp, den Elzen, Postmus, Poortvliet, Peeters, Kean, Watt, Jukema, Langhorne, Gussekloo.

Supervision: Mooijaart, Stott, Rodondi, Westendorp, Postmus, Ford, Kean, Dekkers, Smit, Gussekloo.

Conflict of Interest Disclosures: Dr Mooijaart reported receiving grants from ZonMW and nonfinancial support from Merck during the conduct of the study. Dr Du Puy reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. Dr Stott reported receiving grants from European Union FP7 and nonfinancial support from Merck Serono during the conduct of the study. Dr Rodondi reported receiving grants from the Swiss National Science Foundation and the Velux Foundation (EU FP7-HEALTH-2011) during the conduct of the study. Dr Poortvliet reported receiving grants from Netherlands Organisation for Health Research and Development (ZonMw) and the European Union FP7-HEALTH-2011 programme during the conduct of the study. Dr van Heemst was supported by the European Commission–funded project THYRAGE (Horizon 2020 research and innovation programme under grant agreement 666869). Dr Collet reported receiving grants from the Swiss National Science Foundation during the conduct of the study. Dr Langhorne reported receiving grants from University of Glasgow during the conduct of the study. Dr J Gussekloo reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. No other disclosures were reported.

Funding/Support: The IEMO trial was supported by research grant (627001001) from ZonMw under the ZonMw programme Evidence-based Medicine in Old age and by grants from the Swiss National Science Foundation (SNSF 320030-150025 and 320030-172676 to Dr Rodondi). The TRUST trial was supported by research grant (278148) from the European Union FP7-HEALTH-2011 program and by grants from the Swiss National Science Foundation (SNSF 320030-150025 to Dr Rodondi) and the Swiss Heart Foundation and Velux Stiftung (grant 974a to Dr Rodondi). Dr Blum’s work was funded by a grant from the Swiss National Science Foundation (P2BEP3-175289). Dr Collet’s research was funded by a grant from the Swiss National Science Foundation (PZ00P3-167826). Study medication (levothyroxine and matching placebo) was supplied free of charge by Merck KGaA.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 4.

Additional Contributions: The authors would like to thank all the participants in the IEMO trial and TRUST; the physicians, nurses, and secretarial staff at the research centers; the general practitioners and laboratories that helped to recruit participants; members of the Independent Data Monitoring Committee (Gary Ford, MD, PhD [Oxford University, UK]; Thompson G. Robinson, MD, PhD [University of Leicester, UK]; Colin Dayan, MD, PhD [Cardiff University, UK]; and Kathleen Bennett, MD, PhD [Trinity College Dublin, Ireland]); members of the study end point committee (Peter Langhorne, MD, PhD [University of Glasgow, UK]; J. Wouter Jukema, MD, PhD [Leiden University Medical Center, the Netherlands]; Tinh-Hai Collet, MD, PhD [University of Lausanne, Switzerland]; Olaf M. Dekkers, MD, PhD [Leiden University Medical Centre, the Netherlands]; and Anne Marie O’Flynn, MD, PhD [University College Cork, Ireland]); members of the TRUST/IEMO Biobank committee (Patricia M. Kearney, MD, PhD [University College Cork, Ireland], H. Anette van Dorland, PhD [University of Bern, Switzerland]; and Wendy P. J. den Elzen, PhD [Leiden University Medical Center, the Netherlands); Mawdsley-Brooks & Co (United Kingdom) for the logistics of handling and distributing the study medication; Merck KGaA for donating the levothyroxine and matching placebo; the staff of the Robertson Centre for Biostatistics for providing the electronic data capture and safeguarding; and Bruce H.R. Wolffenbuttel, MD, PhD (University Medical Center Groningen, the Netherlands), for his help in the recruitment of participants. Members of committees and Dr Wolffenbuttel did not receive payment for their roles. The Robertson Centre and Mawdsley Brooks were paid for services under the funding sources. Merck KGaA did not receive or provide financial contributions.

References
1. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87(2):489-499. doi:10.1210/jcem.87.2.8182