The Impact of Levothyroxine on Cardiac Function in Older Adults With Mild Subclinical Hypothyroidism: A Randomized Clinical Trial

Abstract

BACKGROUND: Subclinical hypothyroidism has been associated with heart failure, but only small trials assessed whether treatment with levothyroxine has an impact on cardiac function. METHODS: In a randomized, double-blind, placebo-controlled, trial nested within the TRUST trial, Swiss participants ages ≥65 years with subclinical hypothyroidism (thyroid-stimulating hormone [TSH] 4.60-19.99 mIU/L; free thyroxine level within reference range) were randomized to levothyroxine (starting dose of 50 mg daily) to achieve TSH normalization or placebo. The primary outcomes were the left ventricular ejection fraction for systolic function and the ratio between mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e 0 ratio) for diastolic function. Secondary outcomes included e 0 lateral/septal, left atrial volume index, and systolic pulmonary artery pressure. RESULTS: A total of 185 participants (mean age 74.1 years, 47% women) underwent echocardiography at the end of the trial. After a median treatment duration of 18.4 months, the mean TSH decreased from 6.35 mIU/L to 3.55 mIU/L with levothyroxine (n = 96), and it remained elevated at 5.29 mIU/L with placebo (n = 89). The adjusted between-group difference was not significant for the mean left ventricular ejection fraction (62.7% vs 62.5%, difference = 0.4%, 95% confidence interval À1.8% to 2.5%, P = 0.72) and the E/e 0 ratio (10.6 vs 10.1, difference 0.4, 95% confidence interval À0.7 to 1.4, P = 0.47). No differences were found for the secondary diastolic function parameters or for interaction according to sex, baseline TSH, preexisting heart failure, and treatment duration (P value >0.05). CONCLUSION: Systolic and diastolic heart function did not differ after treatment with levothyroxine compared with placebo in older adults with mild subclinical hypothyroidism.

Outcomes of Cardiac Resynchronization Therapy in Patients with Hypothyroidism and Heart Failure

“…A large observational study has corroborated that TRT may minimize the risk of coronary heart disease in younger patients (<70 years) 24 . A recent randomized, double-blind, placebo-controlled clinical trial found no difference in systolic or diastolic heart function after TRT compared with placebo in older adults ( ≥65 years) with subclinical hypothyroidism 25 . No comparison about TRT for SH patients was conducted in this study since no TRT was used for SH.…”

Levothyroxine and the Heart

“…The impairment in systolic and/or diastolic performance observed in patients with subclinical hypothyroidism, compared with healthy controls, has been shown to reverse during treatment with LT4 for periods of up to 1 year (Table 2) [21]. Such effects have been observed in young adults but not in elderly subjects in some randomized trials [35][36][37]. An overview of these and other studies in populations with subclinical hypothyroidism are summarised in Table 3 [32,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51].…”

Levothyroxine in the Older Patient

“…Therefore, it is interesting that a post hoc analysis in subjects with more pronounced symptoms of hypothyroidism at baseline produced a similar lack of clinical benefit of LT4 treatment [26]. Additional sub-analysis from TRUST found no effect of LT4 treatment on cardiac function [27] or bone metabolism [28] in this population. Pooling the data from two randomised trials, including a subgroup from TRUST, involving a total of 251 patients with subclinical hypothyroidism aged ≥80 years also found no significant effect of LT4 on thyroid symptoms or fatigue, relative to placebo [29].…”

“…The randomised evaluations of LT4 have not provided unequivocal evidence for benefit of intervention with LT4 in older patients, especially those with subclinical hypothyroidism [23,24,[26][27][28][29]. It is important to remember that the diagnosis of hypothyroidism and the titration of the LT4 dose were guided in these studies by standard reference ranges for thyrotropin in adults.…”