• Laurien E Zijlstra, J Wouter Jukema, WestendorpRudi G JRGJDepartment of Public Health, University of Copenhagen, Copenhagen, Denmark.Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark., Robert S Du Puy, PoortvlietRosalinde K ERKEDepartment of Public Health and Primary Care, Leiden University Medical Center, Leiden, Netherlands., Patricia M Kearney, Linda O'Keeffe, Olaf M Dekkers, Manuel R Blum, Nicolas Rodondi, Tinh-Hai Collet, Terence J Quinn, Naveed Sattar, David J Stott, Stella Trompet, den ElzenWendy P JWPJDepartment of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, Netherlands., Jacobijn Gussekloo, and Simon P Mooijaart.
• Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.
• Front Endocrinol (Lausanne). 2021 Jan 1; 12: 674841.

BackgroundThe cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in cardiovascular side effects from thyroid hormone replacement, undertreatment may also increase the risk of cardiovascular events, especially for patients with cardiovascular disease (CVD).ObjectiveTo determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH.MethodsCombined data of two parallel randomised double-blind placebo-controlled trials TRUST (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial) and IEMO80+ (the Institute for Evidence-Based Medicine in Old Age 80-plus thyroid trial) were analysed as one-stage individual participant data. Participants aged ≥65 years for TRUST (n=737) and ≥80 years for IEMO80+ (n=105) with SCH, defined by elevated TSH with fT4 within the reference range, were included. Participants were randomly assigned to receive placebo or levothyroxine, with titration of the dose until TSH level was within the reference range. Cardiovascular events and cardiovascular side effects of overtreatment (new-onset atrial fibrillation and heart failure) were investigated, including stratified analyses according to CVD history and age.ResultsThe median [IQR] age was 75.0 [69.7-81.1] years, and 448 participants (53.2%) were women. The mean TSH was 6.38± SD 5.7 mIU/L at baseline and decreased at 1 year to 5.66 ± 3.3 mIU/L in the placebo group, compared with 3.66 ± 2.1 mIU/L in the levothyroxine group (p<0.001), at a median dose of 50 μg. Levothyroxine did not significantly change the risk of any of the prespecified cardiovascular outcomes, including cardiovascular events (HR 0.74 [0.41-1.25]), atrial fibrillation (HR 0.69 [0.32-1.52]), or heart failure (0.41 [0.13-1.35]), or all-cause mortality (HR 1.28 [0.54-3.03]), irrespective of history of CVD and age.ConclusionTreatment with levothyroxine did not significantly change the risk of cardiovascular outcomes in older adults with subclinical hypothyroidism, irrespective of a history of cardiovascular disease and age.Clinical Trial Registration[ClinicalTrials.gov], identifier [NCT01660126] (TRUST); Netherlands Trial Register: NTR3851 (IEMO80+).Copyright © 2021 Zijlstra, Jukema, Westendorp, Du Puy, Poortvliet, Kearney, O’Keeffe, Dekkers, Blum, Rodondi, Collet, Quinn, Sattar, Stott, Trompet, den Elzen, Gussekloo and Mooijaart.

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