TY - JOUR
T1 - Levothyroxine Treatment and Cardiovascular Outcomes in Older People With Subclinical Hypothyroidism
T2 - Pooled Individual Results of Two Randomised Controlled Trials
AU - Zijlstra, Laurien E.
AU - Jukema, J. Wouter
AU - Westendorp, Rudi G. J.
AU - du Puy, Robert S.
AU - Poortvliet, Rosalinde K. E.
AU - Kearney, Patricia M.
AU - O’Keeffe, Linda
AU - Dekkers, Olaf M.
AU - Blum, Manuel R.
AU - Rodondi, Nicolas
AU - Collet, Tinh-Hai
AU - Quinn, Terence J.
AU - Sattar, Naveed
AU - Stott, David J.
AU - Trompet, Stella
AU - den Elzen, Wendy P. J.
AU - Gussekloo, Jacobijn
AU - Mooijaart, Simon P.
N1 - Funding Information: The authors would like to thank all the participants in the IEMO trial and TRUST; the physicians, nurses, and secretarial staff at the research centres; 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 [Geneva University Hospitals, 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. Funding Information: The TRUST trial was supported by a research grant (278148) from the European Union FP7-HEALTH-2011 program and by grants from the Swiss National Science Foundation (SNSF 320030-150025 and 320030-172676; to NN, P2BEP3_165409), and the Swiss Heart Publisher Copyright: © Copyright © 2021 Zijlstra, Jukema, Westendorp, Du Puy, Poortvliet, Kearney, O’Keeffe, Dekkers, Blum, Rodondi, Collet, Quinn, Sattar, Stott, Trompet, den Elzen, Gussekloo and Mooijaart.
PY - 2021/5/20
Y1 - 2021/5/20
N2 - 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+).
AB - 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+).
KW - cardiovascular disease
KW - levothyroxine
KW - older adults
KW - randomised controlled trial
KW - subclinical hypothyroidism
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85107283686&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34093444
UR - http://www.scopus.com/inward/record.url?scp=85107283686&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fendo.2021.674841
DO - https://doi.org/10.3389/fendo.2021.674841
M3 - Article
C2 - 34093444
SN - 1664-2392
VL - 12
JO - Frontiers in Endocrinology
JF - Frontiers in Endocrinology
M1 - 674841
ER -