Optimising prescribing in older adults with multimorbidity and polypharmacy in primary care (OPTICA): cluster randomised clinical trial.

OBJECTIVE: To study the effects of a primary care medication review intervention centred around an electronic clinical decision support system (eCDSS) on appropriateness of medication and the number of prescribing omissions in older adults with multimorbidity and polypharmacy compared with a discussion about medication in line with usual care. DESIGN: Cluster randomised clinical trial. SETTING: Swiss primary care, between December 2018 and February 2021. PARTICIPANTS: Eligible patients were ≥65 years of age with three or more chronic conditions and five or more long term medications. INTERVENTION: The intervention to optimise pharmacotherapy centred around an eCDSS was conducted by general practitioners, followed by shared decision making between general practitioners and patients, and was compared with a discussion about medication in line with usual care between patients and general practitioners. MAIN OUTCOME MEASURES: Primary outcomes were improvement in the Medication Appropriateness Index (MAI) and the Assessment of Underutilisation (AOU) at 12 months. Secondary outcomes included number of medications, falls, fractures, and quality of life. RESULTS: In 43 general practitioner clusters, 323 patients were recruited (median age 77 (interquartile range 73-83) years; 45% (n=146) women). Twenty one general practitioners with 160 patients were assigned to the intervention group and 22 general practitioners with 163 patients to the control group. On average, one recommendation to stop or start a medication was reported to be implemented per patient. At 12 months, the results of the intention-to-treat analysis of the improvement in appropriateness of medication (odds ratio 1.05, 95% confidence interval 0.59 to 1.87) and the number of prescribing omissions (0.90, 0.41 to 1.96) were inconclusive. The same was the case for the per protocol analysis. No clear evidence was found for a difference in safety outcomes at the 12 month follow-up, but fewer safety events were reported in the intervention group than in the control group at six and 12 months. CONCLUSIONS: In this randomised trial of general practitioners and older adults, the results were inconclusive as to whether the medication review intervention centred around the use of an eCDSS led to an improvement in appropriateness of medication or a reduction in prescribing omissions at 12 months compared with a discussion about medication in line with usual care. Nevertheless, the intervention could be safely delivered without causing any harm to patients. TRIAL REGISTRATION: NCT03724539Clinicaltrials.gov NCT03724539.

Novel bleeding risk score for patients with atrial fibrillation on oral anticoagulants, including direct oral anticoagulants.

OBJECTIVE: Balancing bleeding risk and stroke risk in patients with atrial fibrillation (AF) is a common challenge. Though several bleeding risk scores exist, most have not included patients on direct oral anticoagulants (DOACs). We aimed at developing a novel bleeding risk score for patients with AF on oral anticoagulants (OAC) including both vitamin K antagonists (VKA) and DOACs. METHODS: We included patients with AF on OACs from a prospective multicenter cohort study in Switzerland (SWISS-AF). The outcome was time to first bleeding. Bleeding events were defined as major or clinically relevant non-major bleeding. We used backward elimination to identify bleeding risk variables. We derived the score using a point score system based on the ß-coefficients from the multivariable model. We used the Brier score for model calibration (<0.25 indicating good calibration), and Harrel's c-statistics for model discrimination. RESULTS: We included 2147 patients with AF on OAC (72.5% male, mean age 73.4 ± 8.2 years), of whom 1209 (56.3%) took DOACs. After a follow-up of 4.4 years, a total of 255 (11.9%) bleeding events occurred. After backward elimination, age > 75 years, history of cancer, prior major hemorrhage, and arterial hypertension remained in the final prediction model. The Brier score was 0.23 (95% confidence interval [CI] 0.19-0.27), the c-statistic at 12 months was 0.71 (95% CI 0.63-0.80). CONCLUSION: In this prospective cohort study of AF patients and predominantly DOAC users, we successfully derived a bleeding risk prediction model with good calibration and discrimination.

Potentially inappropriate medication and attitudes of older adults towards deprescribing.

INTRODUCTION: Multimorbidity and polypharmacy are current challenges when caring for the older population. Both have led to an increase of potentially inappropriate medication (PIM), illustrating the need to assess patients' attitudes towards deprescribing. We aimed to assess the prevalence of PIM use and whether this was associated with patient factors and willingness to deprescribe. METHOD: We analysed data from the LESS Study, a cross-sectional study on self-reported medication and on barriers and enablers towards the willingness to deprescribe (rPATD questionnaire). The survey was conducted among multimorbid (≥3 chronic conditions) participants ≥70 years with polypharmacy (≥5 long-term medications). A subset of the Beers 2019 criteria was applied for the assessment of medication appropriateness. RESULTS: Data from 300 patients were analysed. The mean age was 79.1 years (SD 5.7). 53% had at least one PIM (men: 47.8%%, women: 60.4%%; p = 0.007). A higher number of medications was associated with PIM use (p = 0.002). We found high willingness to deprescribe in both participants with and without PIM. Willingness to deprescribe was not associated with PIM use (p = 0.25), nor number of PIMs (p = 0.81). CONCLUSION: The willingness of older adults with polypharmacy towards deprescribing was not associated with PIM use in this study. These results suggest that patients may not be aware if they are taking PIMs. This implies the need for raising patients' awareness about PIMs through education, especially in females, in order to implement deprescribing in daily practice.

Managing hypertension in frail oldest-old-The role of guideline use by general practitioners from 29 countries.

BACKGROUND: The best management of hypertension in frail oldest-old (≥80 years of age) remains unclear and we still lack guidelines that provide specific recommendations. Our study aims to investigate guideline use in general practitioners (GPs) and to examine if guideline use relates to different decisions when managing hypertension in frail oldest-old. DESIGN/SETTING: Cross-sectional study among currently active GPs from 29 countries using a case-vignettes survey. METHODS: GPs participated in a survey with case-vignettes of frail oldest-olds varying in systolic blood pressure (SBP) levels and cardiovascular disease (CVD). GPs from 26 European countries and from Brazil, Israel and New Zealand were invited. We compared the percentage of GPs reporting using guidelines per country and further stratified on the most frequently mentioned guidelines. To adjust for patient characteristics (SBP, CVD and GPs' sex, years of experience, prevalence of oldest-old and location of their practice), we used a mixed-effects regression model accounting for clustering within countries. RESULTS: Overall, 2,543 GPs from 29 countries were included. 59.4% of them reported to use guidelines. Higher guideline use was found in female (p = 0.031) and less-experienced GPs (p<0.001). Across countries, we found a large variation in self-reported guideline use, ranging from 25% to 90% of the GPs, but there was no difference in hypertension treatment decisions in frail oldest-old patients between GPs that did not use and GPs that used guidelines, irrespective of the guidelines they used. CONCLUSION: Many GPs reported using guidelines to manage hypertension in frail oldest-old patients, however guideline users did not decide differently from non-users concerning hypertension treatment decisions. Instead of focusing on the fact if GPs use guidelines or not, we as a scientific community should put an emphasis on what guidelines suggest in frail and oldest-old patients.

Recommendations for (Discontinuation of) Statin Treatment in Older Adults: Review of Guidelines.

OBJECTIVES: As a person's age increases and his/her health status declines, new challenges arise that may lead physicians to consider deprescribing statins. We aimed to provide insight into recommendations available in international cardiovascular disease prevention guidelines regarding discontinuation of statin treatment applicable to older adults. DESIGN: We systematically searched PubMed, EMBASE, EMCARE, and the websites of guideline development organizations and online guideline repositories for cardiovascular disease prevention guidelines aimed at the general population. We selected all guidelines with recommendations (instructions and suggestions) on discontinuation of statin treatment applicable to older adults, published between January 2009 and April 2019. In addition, we performed a synthesis of information from all other recommendations for older adults regarding statin treatment. Methodological quality of the included guidelines was appraised using the appraisal of guidelines for research & evaluation II (AGREE II) instrument. RESULTS: Eighteen international guidelines for cardiovascular disease prevention in the general adult population provided recommendations for statin discontinuation that were applicable to older adults. We identified three groups of instructions for statin discontinuation related to statin intolerance, and none was specifically aimed at older adults. Three guidelines also included suggestions to consider statin discontinuation in patients with poor health status. Of the 18 guidelines included, 16 made recommendations regarding statin treatment in older adults, although details on how to implement these recommendations in practice were not provided. CONCLUSION: Current international cardiovascular disease prevention guidelines provide little specific guidance for physicians who are considering statin discontinuation in older adults in the context of declining health status and short life expectancy. J Am Geriatr Soc 68:417-425, 2020.

'Optimising PharmacoTherapy In the multimorbid elderly in primary CAre' (OPTICA) to improve medication appropriateness: study protocol of a cluster randomised controlled trial.

INTRODUCTION: Multimorbidity and polypharmacy are major risk factors for potentially inappropriate prescribing (eg, overprescribing and underprescribing), and systematic medication reviews are complex and time consuming. In this trial, the investigators aim to determine if a systematic software-based medication review improves medication appropriateness more than standard care in older, multimorbid patients with polypharmacy. METHODS AND ANALYSIS: Optimising PharmacoTherapy In the multimorbid elderly in primary CAre is a cluster randomised controlled trial that will include outpatients from the Swiss primary care setting, aged ≥65 years with ≥three chronic medical conditions and concurrent use of ≥five chronic medications. Patients treated by the same general practitioner (GP) constitute a cluster, and clusters are randomised 1:1 to either a standard care sham intervention, in which the GP discusses with the patient if the medication list is complete, or a systematic medication review intervention based on the use of the 'Systematic Tool to Reduce Inappropriate Prescribing'-Assistant (STRIPA). STRIPA is a web-based clinical decision support system that helps customise medication reviews. It is based on the validated 'Screening Tool of Older Person's Prescriptions' (STOPP) and 'Screening Tool to Alert doctors to Right Treatment' (START) criteria to detect potentially inappropriate prescribing. The trial's follow-up period is 12 months. Outcomes will be assessed at baseline, 6 and 12 months. The primary endpoint is medication appropriateness, as measured jointly by the change in the Medication Appropriateness Index (MAI) and Assessment of Underutilisation (AOU). Secondary endpoints include the degree of polypharmacy, overprescribing and underprescribing, the number of falls and fractures, quality of life, the amount of formal and informal care received by patients, survival, patients' quality adjusted life years, patients' medical costs, cost-effectiveness of the intervention, percentage of recommendations accepted by GPs, percentage of recommendation rejected by GPs and patients' willingness to have medications deprescribed. ETHICS AND DISSEMINATION: The ethics committee of the canton of Bern in Switzerland approved the trial protocol. The results of this trial will be published in a peer-reviewed journal. MAIN FUNDING: Swiss National Science Foundation, National Research Programme (NRP 74) 'Smarter Healthcare'. TRIAL REGISTRATION NUMBERS: Clinicaltrials.gov (NCT03724539), KOFAM (Swiss national portal) (SNCTP000003060), Universal Trial Number (U1111-1226-8013).

Rationale and design of OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people (OPERAM): a cluster randomised controlled trial.

INTRODUCTION: Multimorbidity and polypharmacy are important risk factors for drug-related hospital admissions (DRAs). DRAs are often linked to prescribing problems (overprescribing and underprescribing), as well as non-adherence with drug regimens for different reasons. In this trial, we aim to assess whether a structured medication review compared with standard care can reduce DRAs in multimorbid older patients with polypharmacy. METHODS AND ANALYSIS: OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people is a European multicentre, cluster randomised, controlled trial. Hospitalised patients ≥70 years with ≥3 chronic medical conditions and concurrent use of ≥5 chronic medications are included in the four participating study centres of Bern (Switzerland), Utrecht (The Netherlands), Brussels (Belgium) and Cork (Ireland). Patients treated by the same prescribing physician constitute a cluster, and clusters are randomised 1:1 to either standard care or Systematic Tool to Reduce Inappropriate Prescribing (STRIP) intervention with the help of a clinical decision support system, the STRIP Assistant. STRIP is a structured method performing customised medication reviews, based on Screening Tool of Older People's Prescriptions/Screening Tool to Alert to Right Treatment criteria to detect potentially inappropriate prescribing. The primary endpoint is any DRA where the main reason or a contributory reason for the patient's admission is caused by overtreatment or undertreatment, and/or inappropriate treatment. Secondary endpoints include number of any hospitalisations, all-cause mortality, number of falls, quality of life, degree of polypharmacy, activities of daily living, patient's drug compliance, the number of significant drug-drug interactions, drug overuse and underuse and potentially inappropriate medication. ETHICS AND DISSEMINATION: The local Ethics Committees in Switzerland, Ireland, The Netherlands and Belgium approved this trial protocol. We will publish the results of this trial in a peer-reviewed journal. MAIN FUNDING: European Union's Horizon 2020 programme. TRIAL REGISTRATION NUMBER: NCT02986425 , SNCTP000002183 , NTR6012, U1111-1181-9400.

The Relation Between Thyroid Function and Anemia: A Pooled Analysis of Individual Participant Data.

Context: Anemia and thyroid dysfunction often co-occur, and both increase with age. Human data on relationships between thyroid disease and anemia are scarce. Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia. Design: Individual participant data meta-analysis. Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n = 42,162). Main Outcome Measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women). Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants [overt hypothyroidism, pooled OR 1.84 (95% CI 1.35 to 2.50), subclinical hypothyroidism 1.21 (1.02 to 1.43), subclinical hyperthyroidism 1.27 (1.03 to 1.57), and overt hyperthyroidism 1.69 (1.00 to 2.87)]. Hemoglobin levels were lower in all groups compared with participants with euthyroidism. In the longitudinal analyses (n = 25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 (95% CI 0.86 to 2.20) for overt hypothyroidism, 1.18 (1.00 to 1.38) for subclinical hypothyroidism, 1.15 (0.94 to 1.42) for subclinical hyperthyroidism, and 1.47 (0.91 to 2.38) for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups. Conclusion: Higher odds of having anemia were observed in participants with both hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.

Development of a standardized chart review method to identify drug-related hospital admissions in older people.

AIMS: We aimed to develop a standardized chart review method to identify drug-related hospital admissions (DRA) in older people caused by non-preventable adverse drug reactions and preventable medication errors including overuse, underuse and misuse of medications: the DRA adjudication guide. METHODS: The DRA adjudication guide was developed based on design and test iterations with international and multidisciplinary input in four subsequent steps: literature review; evaluation of content validity using a Delphi consensus technique; a pilot test; and a reliability study. RESULTS: The DRA adjudication guide provides definitions, examples and step-by-step instructions to measure DRA. A three-step standardized chart review method was elaborated including: (i) data abstraction; (ii) explicit screening with a newly developed trigger tool for DRA in older people; and (iii) consensus adjudication for causality by a pharmacist and a physician using the World Health Organization-Uppsala Monitoring Centre and Hallas criteria. A 15-member international Delphi panel reached consensus agreement on 26 triggers for DRA in older people. The DRA adjudication guide showed good feasibility of use and achieved moderate inter-rater reliability for the evaluation of 16 cases by four European adjudication pairs (71% agreement, κ = 0.41). Disagreements arose mainly for cases with potential underuse. CONCLUSIONS: The DRA adjudication guide is the first standardized chart review method to identify DRA in older persons. Content validity, feasibility of use and inter-rater reliability were found to be satisfactory. The method can be used as an outcome measure for interventions targeted at improving quality and safety of medication use in older people.

Thyroid Dysfunction and Anemia: A Prospective Cohort Study and a Systematic Review.

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 <12 g/dL in women and Hb <13 g/dL in men. In the cross-sectional analyses, multiple linear regression was used to compare Hb across TSH categories. In the prospective analysis, participants with OHypo/OHyper at baseline were excluded, as it was assumed that they were treated for overt thyroid disease. A covariance model was used to determine change in Hb concentration from baseline to last follow-up, and multivariable Cox regression was used to analyze anemia risk. RESULTS: In the cross-sectional population (n = 12,337), the adjusted Hb was 0.22 g/dL lower [confidence interval (CI) 0.07-0.38] in OHypo compared to euthyroids, and 0.08 g/dL lower [CI -0.23 to 0.38] in OHyper. In the prospective analysis, 460/7031 participants developed anemia over a median follow-up of 4.7 years. The adjusted mean Hb change over time was -0.04 g/dL in SHypo [CI -0.14 to 0.06] and 0.05 g/dL in SHyper [CI -0.10 to 0.20]. The adjusted hazard ratio for anemia was 0.99 [CI 0.67-1.48] in SHypo, and 0.52 [CI 0.23-1.16] in SHyper. The systematic review returned no other prospective studies on this association, but cross-sectional and case-control studies showed comparable results. CONCLUSION: In this first prospective population-based cohort, subclinical thyroid dysfunction was not associated with a change in Hb concentration during follow-up and was not an independent risk factor for developing anemia; variations in Hb concentration in patients with overt thyroid dysfunction were not clinically relevant.

Subclinical thyroid dysfunction and cardiovascular diseases: 2016 update.

Subclinical thyroid dysfunction comprises subclinical hypothyroidism (SHypo), defined as elevated thyroid-stimulating hormone (TSH) by normal free thyroxine (FT4), and subclinical hyperthyroidism (SHyper) with decreased or undetectable TSH and normal FT4. Up to 10% of the elderly have SHypo, which is usually asymptomatic. Individual participant data (IPD) analyses of prospective cohort studies from the international Thyroid Studies Collaboration show that SHypo is associated with increased coronary heart disease (CHD) mortality [hazard ratio (HR) 1,58 for TSH ≥ 10 mIU/L, 95% CI 1.10-2.27), as well as increased risk of stroke, and heart failure (HF) for both higher and lower TSH. Small studies found that SHypo affects carotid intima media thickness (CIMT), diastolic function, peripheral vascular resistance, endothelial function, and lipid profile. SHyper is associated with increased risk of atrial fibrillation (AF) (HR 1.68, 95% CI 1.16-2.43) and CHD events (HR 1.21, 95% CI 0.99-1.46). The TSH threshold for initiating treatment is unclear. In the absence of large randomized controlled trials, the best evidence suggests SHypo therapy should be started at TSH ≥ 10 mIU/L, and SHyper therapy at TSH < 0.1 mIU/L. Recommendations on screening are discordant, but most guidelines advocate that thyroid function should be checked in those at risk for hypothyroidism, those over 60, and those with known CHD and HF. This review updates current evidence on the association between thyroid dysfunction and cardiovascular disease, as well as on screening and treatment of subclinical thyroid dysfunction.

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.

Thyroid Function Tests in the Reference Range and Fracture: Individual Participant Analysis of Prospective Cohorts.

Context: Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower thyroid-stimulating hormone (TSH) and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective: To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design: Individual participant data analysis. Setting: Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants: Adults with baseline TSH 0.45 to 4.49 mIU/L. Main Outcome Measures: Primary outcome was incident hip fracture. Secondary outcomes were any, nonvertebral, and vertebral fractures. Results were presented as hazard ratios (HRs) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45 to 0.99 mIU/L; 1.00 to 1.49 mIU/L; 1.50 to 2.49 mIU/L; 2.50 to 3.49 mIU/L; and 3.50 to 4.49 mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results: During 659,059 person-years, 2,565 out of 56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05 to 1.49) for TSH 0.45 to 0.99 mIU/L, 1.19 (1.01 to 1.41) for TSH 1.00 to 1.49 mIU/L, 1.09 (0.93 to 1.28) for TSH 1.50 to 2.49 mIU/L, and 1.12 (0.94 to 1.33) for TSH 2.50 to 3.49 mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 [HR (95% CI) 1.22 (1.11 to 1.35) per one standard deviation increase in FT4]. FT4 only was associated with any and nonvertebral fractures. Results remained similar in sensitivity analyses. Conclusions: Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests.

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 .).