Authors' objectives: BACKGROUND: Subclinical hypothyroidism (SCH) is a hormonal disorder in which the serum thyroid-stimulating hormone levels (TSH) are elevated while the thyroid hormone levels are within the normal reference range. SCH can be treated with hormone replacement therapy using levothyroxine, a synthetic version of the endogenous thyroid hormone thyroxine (T4), to raise low levels of endogenous thyroid hormones. In Switzerland, levothyroxine is approved by the Swiss Agency for Therapeutic Products (Swissmedic) for the treatment of hypothyroidism. There is no standard alternative treatment option for patients diagnosed with SCH. OBJECTIVE: The aim of this health technology assessment (HTA) report is to evaluate the clinical and economic consequences of levothyroxine treatment for patients diagnosed with SCH in Switzerland.

Authors' results and conclusions: RESULTS: Evidence from 28 RCTs based on 22 unique studies was evaluated to inform efficacy and safety outcomes of levothyroxine compared to placebo (n=24 articles) or no treatment (n=4 articles) for the treatment of SCH. Twenty-five RCTs reported TSH level changes and 12 studies reported additional clinical efficacy and safety outcomes. The body of evidence was substantial, and the risk of bias ranged from low to high. Levothyroxine successfully reduced increased levels of TSH in SCH patients. However, levothyroxine treatment did not affect any of the other clinically and patient-relevant efficacy outcomes that were assessed. The evidence base did not show consistent statistically significant changes between the placebo and levothyroxine treated patients in hypothyroid associated symptoms like fatigue, depression, health-related quality of life, neurological, musculoskeletal or cardiovascular outcomes. Some positive trends were reported in individual studies, but these findings were typically inconsistent between studies and not statistically significant. In none of the studies major safety issues were observed. No published study was identified from the cost-effectiveness systematic review. In the budget impact analysis, we calculated the total healthcare cost of levothyroxine for adult SCH patients between ages 18 and 99 years, in Switzerland over a time horizon of five years (years 2020-2024). In the absence of Swiss epidemiological data and on the percentage of SCH patients receiving levothyroxine, we estimated the number of patients receiving levothyroxine for SCH based on general population estimates from the Swiss FSO, and European SCH prevalence rates from the literature. Subsequently we used a percentage range (10%-90%) of the prevalent population that would be eligible for levothyroxine in Switzerland. Costs for the treatment with levothyroxine were calculated as a function of drug unit prices and a standard dosing schedule. The total costs of treatment ranged between 9 Mio CHF and 87 Mio CHF over a time horizon of five years, depending on the percentage of patients that would be treated with levothyroxine. The literature search did not provide evidence indicating that levothyroxine treatment in SCH patients was associated with any important ethical, legal, social or organisation issues. CONCLUSION: Levothyroxine treatment successfully lowers raised levels of serum TSH in SCH patients but evidence of a consistent (positive) treatment effect on other clinical or patient-relevant outcomes like hypothyroid associated symptoms or cardiovascular outcomes is lacking. There are no indications of major safety issues related to levothyroxine treatment. The budget impact analysis showed that depending on the prescription behaviour of physicians the costs of levothyroxine for SCH patients can be substantial (up to 87 Mio CHF over 5 years).

Authors' methods: METHODS: For the clinical review, a systematic literature search of the Pubmed (MEDLINE) and Embase databases was conducted adhering to international methodological standards. Randomized controlled trials (RCTs) in patients diagnosed with SCH who are treated with levothyroxine compared with no treatment or placebo were included. Articles including only women with specific sex hormonal state were out of scope. The search was worldwide and restricted to RCTs published from 2000 onwards. The included studies were critically appraised, and the extracted data was summarised in summary tables and narrative text. For the economic review, cost-effectiveness searches followed the principles of the clinical systematic literature search. A de novo model was developed to calculate the budget impact of levothyroxine for adult SCH patients, between 18 and 99 years of age, in Switzerland over a time horizon of five years (years 2020-2024). Legal, social, ethical, and organisational issues addressed in the studies included in the clinical, cost-effectiveness systematic literature searches were extracted and narratively summarised. In addition, grey literature searches were conducted on this HTA domain.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/levothyroxin.html

URL for protocol: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0035ltsh-hta-protocol.pdf.download.pdf/h0035ltsh-hta-protocol.pdf

Year Published: 2022

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0035ltsh-hta-report.pdf.download.pdf/h0035ltsh-hta-report.pdf

URL for additional information: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-programm.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health