The TRUST Trial - CardioVascular Imaging ECHO
The TRUST Trial - CardioVascular Imaging ECHO
Coronary heart disease (CHD) and heart failure (HF) are the leading causes of mortality and
 morbidity, particularly with the current context of an aging population. Prospective cohort
 studies, as well as analyses of pooled individual participant data suggest up to a 60-90%
 increase in the risk of CHD or HF events among adults with severe SHypo. However, no large
 randomized controlled trials (RCT) have assessed the impact of thyroid replacement on
 cardiovascular (CV) imaging outcomes. The goals of this proposal are to address the impact of
 thyroid replacement on cardiac function. The investigators will conduct a RCT in 185 patients
 with subclinical hypothyroidism who will be randomly assigned to thyroxine or placebo with an
 average follow-up of 24 months from baseline. The main outcome will be CV imaging modalities
 measured by echocardiography at the close-out visit. Assessment of the impact of thyroid
 replacement on cardiac function and subclinical atherosclerosis within a trial will aid
 decisions and evidence-based guidelines development to treat a potential modifiable risk
 factor, such as SHypo.
Background: Coronary heart disease (CHD) and heart failure (HF) are the leading causes of
 mortality and morbidity, particularly with the current context of an aging population.
 Subclinical hypothyroidism (SHypo), defined as elevated serum TSH levels with normal
 thyroxine values, is common in older adults (5-10%). Prospective cohort studies, as well as
 analyses of pooled individual participant data suggest up to a 60-90% increase in the risk of
 CHD or HF events among adults with severe SHypo. However, no large randomized controlled
 trials (RCT) have assessed the impact of thyroid replacement on cardiovascular (CV) imaging
 outcomes (largest trial to date: 45 participants). Imaging endpoints are especially
 well-suited for early trials with investigational therapies for HF treatment and prevention,
 as well as validated and strong surrogate markers of clinical outcomes.

 Specific Aims: The goals of this proposal are to address the impact of thyroid replacement on
 1) cardiac function as measured by echocardiography.

 Methods: The investigators will conduct a RCT in 185 patients with subclinical hypothyroidism
 who will be randomly assigned to thyroxine or placebo with an average follow-up of 24 months
 from baseline (4 death and 17 withdrawal). The main outcome will be CV imaging modalities
 measured by echocardiography at the close-out visit. Transthoracic echocardiography will be
 performed for the assessment of diastolic function (abnormalities of the pulsed wave mitral
 valve inflow pattern and mitral annulus tissue velocities, left atrial volume index, left
 ventricular [LV] mass index) and cardiac systolic function (LV ejection fraction and regional
 function). Ultrasound of carotid intima media thickness (CIMT) will be used to assess
 subclinical atherosclerosis and plaque burden. All images will be centralized at the core lab
 for a blinded and standardized interpretation.

 Expected value of the proposed project: Controversies persist regarding the indications for
 screening and treatment of SHypo due to the lack of an appropriately powered RCT addressing
 the impact of thyroid replacement on CV outcomes. Assessment of the impact of thyroid
 replacement on cardiac function and subclinical atherosclerosis within a trial will aid
 decisions and evidence-based guidelines development to treat a potential modifiable risk
 factor, such as SHypo. The strengths of this study include the combination of: 1) High
 feasibility of the project in collaboration with the largest RCT on SHypo making it possible
 to investigate the mechanisms of associations with CV disease; 2) Innovative project with
 combined CV imaging to assess cardiac function with thyroid replacement therapy vs. placebo;
 3) Excellent power given the large sample size and participants' older age. The sample size
 for this proposal will be 5-fold higher than previous small trials of thyroid replacement on
 CV outcomes. The collaboration of CV imaging modalities expertise with the ongoing largest
 trial on SHypo, is a unique opportunity to address the clinical and scientific issue of the
 impact of SHypo on the CV system.
Inclusion Criteria:

 -  Community-dwelling patients aged >= 65 years with subclinical hypothyroidism

 -  Written informed consent

 Exclusion Criteria:

 -  Subjects currently under levothyroxine or antithyroid drugs (amiodarone, lithium)

 -  Recent thyroid surgery or radio-iodine (within 12 months)

 -  Grade IV NYHA heart failure

 -  Prior clinical diagnosis of dementia

 -  Recent hospitalization for major illness or elective surgery (within 4 weeks)

 -  Terminal illness

 -  Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
 deficiency or glucose-galactose malabsorption

 -  Subjects who are participating in ongoing RCTs of therapeutic interventions (including
 CTIMPs)

 -  Plan to move out of the region in which the trial is being conducted within the next 2
 years (proposed minimum follow-up period)