Efficacy and safety of levothyroxine (L-T4) replacement on the exercise capability in chronic systolic heart failure patients with subclinical hypothyroidism: Study protocol for a multi-center, open label, randomized, parallel group trial (ThyroHeart-CHF)

Xuan Zhang, Wen-Yao Wang, Kuo Zhang, Jian Tian, Ji-Lin Zheng, Jing Chen, Shi-Min An, Si-Yuan Wang, Yu-Peng Liu, Yan Zhao, Jing-Jia Wang, Min Yang, Yi-da Tang, Xuan Zhang, Wen-Yao Wang, Kuo Zhang, Jian Tian, Ji-Lin Zheng, Jing Chen, Shi-Min An, Si-Yuan Wang, Yu-Peng Liu, Yan Zhao, Jing-Jia Wang, Min Yang, Yi-da Tang

Abstract

Background: Subclinical hypothyroidism is a common condition in patients with heart failure and is defined as elevated serum thyroid hormone (TSH) with normal circulating free thyroxine (FT4). Evidence on the effect of thyroid hormone treatment is lacking. We designed a randomized controlled trial to compare the efficacy and safety of thyroid hormone supplementation in patients with chronic heart failure complicated with subclinical hypothyroidism.

Methods/design: Eligible participants were identified from the cardiology units of five study centers based on the following criteria: 18 years or older, systolic heart failure with NewYork Heart Association (NYHA) class II-III, left ventricular ejection fraction ≤ 40%, and subclinical hypothyroidism (TSH > 4.78μIU/ml, < 10 μIU/ml + FT4 level within reference range). Eligible patients will be randomly assigned in a 1:1 manner to receive thyroxine replacement therapy plus standard chronic heart failure (CHF) treatment or only standard CHF therapy. Levothyroxine will be administered at an initial dose of 12.5 μg once daily and will be titrated until TSH is within the normal range. The primary endpoints include the difference in distance of the six-minute walk test between 24 weeks and baseline. The secondary endpoints include differences in plasma NT-proBNP levels and serum lipid profiles, changes in the NYHA classification, cardiovascular death, re-hospitalization, differences in echocardiographic and cardiac magnetic resonance imaging measures, and Minnesota Living With Heart Failure Questionnaire (MLHFQ) results between 24 weeks and baseline.

Discussion: ThyroHeart-CHF is designed as a prospective, multi-center, randomized, controlled clinical trial to study the efficacy and safety of thyroid hormone supplementation in patients with chronic heart failure complicated with subclinical hypothyroidism. The study findings will have significant implications for discovering the new therapeutic targets and methods of heart failure.

Trail registration: ClinicalTrials.gov, NCT03096613 . Registered on 30 March 2017.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the institutional review board central committee at Fuwai Hospital, NCCD of China, and complies with the Declaration of Helsinki. Informed consent will be obtained from each participating patient. After the subjects have signed informed consent, patient data will be populated per the protocol. IRB number(Approval No.) of Fu Wai hospital is 2016–798, IRB number of The Second hospital of Tianjin Medical University is KY2017K037, IRB number of The First Hospital of Hebe Medical University is 2,017,001, IRB number of Henan Provincial People’s Hospital is 2017–12, IRB number of Luhe hospital is 2017-LHYW-01.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study Flowchart. TSH serum thyroid hormone, L-T4 levothyroxine, CHF chronic heart failure

References

    1. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002;347:1397–1402. doi: 10.1056/NEJMoa020265.
    1. Tang YD, Kuzman JA, Said S, et al. Low thyroid function leads to cardiac atrophy with chamber dilatation, impaired myocardial blood flow, loss of arterioles, and severe systolic dysfunction. Circulation. 2005;112:3122–3130. doi: 10.1161/CIRCULATIONAHA.105.572883.
    1. Mitchell JE, Hellkamp AS, Mark DB, et al. Thyroid function in heart failure and impact on mortality. JACC Heart Fail. 2013;1:48–55. doi: 10.1016/j.jchf.2012.10.004.
    1. Chen S, Shauer A, Zwas DR, et al. The effect of thyroid function on clinical outcome in patients with heart failure. Eur J Heart Fail. 2014;16:217–226. doi: 10.1002/ejhf.42.
    1. Curotto Grasiosi J, Peressotti B, Machado RA, et al. Improvement in functional capacity after levothyroxine treatment in patients with chronic heart failure and subclinical hypothyroidism. Endocrinol Nutr. 2013;60:427–432. doi: 10.1016/j.endonu.2013.01.013.
    1. AlGhalayini K. Prevalence of hypothyroidism in a cohort of Saudi women with heart failure and effect on systolic and diastolic function. J Pak Med Assoc. 2015;65(12):1300–1304.
    1. Pasqualetti G, Tognini S, Polini A, et al. Subclinical hypothyroidism and heart failure risk in older people. Endocr Metab Immune Disord Drug Targets. 2013;13:13–21. doi: 10.2174/1871530311313010004.
    1. Frey A, Kroiss M, Berliner D, et al. Prognostic impact of subclinical thyroid dysfunction in heart failure. Int J Cardiol. 2013;168:300–305. doi: 10.1016/j.ijcard.2012.09.064.
    1. Wang W, Guan H, Gerdes AM, et al. Thyroid status, cardiac function, and mortality in patients with idiopathic dilated cardiomyopathy. J Clin Endocrinol Metab. 2015;100:3210–3218. doi: 10.1210/jc.2014-4159.
    1. Iervasi G, Molinaro S, Landi P, et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med. 2007;167:1526–1532. doi: 10.1001/archinte.167.14.1526.
    1. Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005;165(21):2460–2466. doi: 10.1001/archinte.165.21.2460.
    1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:e240–e327.
    1. Zhang M, Sara JD, Matsuzawa Y, et al. Clinical outcomes of patients with hypothyroidism undergoing percutaneous coronary intervention. Eur Heart J. 2016;37(26):2055–2065. doi: 10.1093/eurheartj/ehv737.
    1. Gerdes AM, Iervasi G. Thyroid replacement therapy and heart failure. Circulation. 2010;122:385–393. doi: 10.1161/CIRCULATIONAHA.109.917922.
    1. Khalife WI, Tang YD, Kuzman JA, et al. Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2005;289:H2409–H2415. doi: 10.1152/ajpheart.00483.2005.
    1. Committee A ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111–117. doi: 10.1164/ajrccm.166.1.at1102.
    1. Writing Committee Members. ACC/AHA Task Force Members 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Card Fail. 2016;22(9):659–669. doi: 10.1016/j.cardfail.2016.07.001.
    1. Li X, Zhang J, Huang J, et al. A multicenter, randomized, double-blind, parallel-group, placebo-controlled study of the effects of qili qiangxin capsules in patients with chronic heart failure. J Am Coll Cardiol. 2013;62(12):1065–1072. doi: 10.1016/j.jacc.2013.05.035.
    1. Friberg L, Werner S, Eggertsen G, Ahnve S. Rapid down-regulation of thyroid hormones in acute myocardial infarction: is it cardioprotective in patients with angina? Arch Intern Med. 2002;162:1388–1394. doi: 10.1001/archinte.162.12.1388.
    1. Pantos CI, Malliopoulou VA, Mourouzis IS, et al. Long-term thyroxine administration protects the heart in a pattern similar to ischemic preconditioning. Thyroid. 2002;12:325–329. doi: 10.1089/10507250252949469.
    1. Pantos C, Mourouzis I, Markakis K, et al. Thyroid hormone attenuates cardiac remodeling and improves hemodynamics early after acute myocardial infarction in rats. Eur J Cardiothorac Surg. 2007;32:333–339. doi: 10.1016/j.ejcts.2007.05.004.
    1. Weltman NY, Pol CJ, Zhang Y, et al. Long-term physiological T3 supplementation in hypertensive heart disease in rats. Am J Physiol Heart Circ Physiol. 2015;309:H1059–H1065. doi: 10.1152/ajpheart.00431.2015.
    1. Villar HC, Saconato H, Valente O, Atallah ÁN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007;July(3):CD003419.
    1. Stott DJ, Rodondi N, Kearney PM. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376:2534–2544. doi: 10.1056/NEJMoa1603825.
    1. Sato Y, Yoshihisa A, Kimishima Y. Subclinical hypothyriodism is associated with adverse prognosis in heart failure patients. Can J Cardiol. 2018;34(1):80–87. doi: 10.1016/j.cjca.2017.10.021.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅