Levothyroxine Treatment and Cardiovascular Outcomes in Older People With Subclinical Hypothyroidism: Pooled Individual Results of Two Randomised Controlled Trials

Abstract

Background: The 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).

Objective: To determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH.

Methods: Combined 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.

Results: The 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.

Conclusion: Treatment 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+).

Keywords: cardiovascular disease; levothyroxine; older adults; randomised controlled trial; subclinical hypothyroidism.

Conflict of interest statement

SM reported receiving grants from ZonMW and nonfinancial support from Merck during the conduct of the study. RP reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. DS reported receiving grants from European Union FP7 and nonfinancial support from Merck Serono during the conduct of the study. NR reported receiving grants from the Swiss National Science Foundation and the Velux Foundation during the conduct of the study. KP 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. T-HC reported receiving grants from the Swiss National Science Foundation during the conduct of the study. JG reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Zijlstra, Jukema, Westendorp, Du Puy, Poortvliet, Kearney, O’Keeffe, Dekkers, Blum, Rodondi, Collet, Quinn, Sattar, Stott, Trompet, den Elzen, Gussekloo and Mooijaart.

Figures

Figure 1

Flowchart study population. Combined data of the TRUST and IEMO80+ trials will be examined as one-stage individual participant data of these two randomised double-blind placebo-controlled parallel group trials. Cardiovascular disease (CVD) is defined as ischemic heart disease, stroke or transient ischemic attack, heart failure, peripheral vascular disease, revascularisation or atrial fibrillation. Median follow-up was 17-months.

Figure 2

Cardiovascular outcomes stratified for history of cardiovascular disease and age. Cardiovascular disease (CVD) is defined as ischemic heart disease, stroke or transient ischemic attack, heart failure, peripheral vascular disease, revascularisation or atrial fibrillation. Hazard ratios for treatment were obtained from a Cox proportional hazard regression model predicting and were adjusted for study, country, sex and starting dose of levothyroxine.