Acute and long term effects of thyroid hormone replacement therapy in patients with ST-Elevation Myocardial Infarction (STEMI) and borderline/reduced triiodothyronine levels.
The THIRST Study
(Thyroid Hormone Replacement Therapy in ST elevation myocardial infarction)
Principal investigators: G. Iervasi, A. Pingitore, S. Berti., S. Molinaro, E. Galli, C.N.R. Institute of Clinical Physiology- C.N.R./Tuscany Region G. Monasterio Foundation
Document type: Clinical Study Protocol
Development phase: II
EudraCT: 2009-010869-23
Date of Ethics Committee Approval 26-02-2009 (ASL 1 Massa-Carrara). President of the Committee: MARIELLA IMMACOLATO, MD
Abbreviations
Coronary Artery Disease (CAD)
Coronary Care Unit (CCU)
Free Triiodothyronine (fT3)
Low-T3 Syndrome (LT3S)
Myosin Heavy Chain (MHC)
Reverse triiodothyronine (rT3)
Sarcoplasmic Reticulum Calcium ATP-ase (SERCA)
ST-Elevation Myocardial Infarctio (STEMI)
Thyrotropin or Thyroid stimulating hormone (TSH)
Thyroid Hormones (TH)
Thyroxine (T4)
Triiodothyronine (T3)
Vascular Smooth Muscle Cells (VSMCs)
Introduction
It has long been recognized that thyroid hormone (TH) plays a pivotal role in cardiovascular homeostasis in both physiological and pathological conditions. This is also evident in the case of subclinical TH abnormalities, that are associated with an increase of morbility and mortality in cardiac patients [1,2].
The thyroid gland synthesizes and releases TH mostly as thyroxine (T4), whilst most (> 80%) of triiodothyronine (T3), the biological active form of the hormone, is obtained (at least in humans) by peripheral deiodination of T4 through the action of type I and type II-5’ deiodinase. As in other organs, including the cardiovascular system, T3 cellular actions are mediated by genomic/nuclear and non-nuclear mechanisms. In the heart, T3 modulates transcription of TH responsive genes encoding both structural and regulatory proteins with up regulation of sarcoplasmatic reticulum Ca++-ATPase (SERCA-2), α-Myosin Heavy Chain (α-MHC), Na+/K+ ATP-ase and a down-regulation of β-Myosin Heavy Chain (β-MHC) and phospholamban [3,4].
The net effect of all these activities is that T3 enhances contractile functions (inotropism), diastolic relaxation and favours excitability-contraction coupling [3,4].
T3 non-genomic effects include the induction of vascular smooth muscle cells (VSMCs) relaxation [5], with a consequent reduction in systemic vascular resistances, the modulation of various membrane ion channels, mitochondrial membrane traslocators and of a variety of intracellular signalling pathways [4]
Low T3 syndrome (LT3S) is an alteration of TH plasma levels characterized by decreased serum T3 and free T3 (fT3) levels associated with normal or mildly reduced serum T4 and thyrotropin (TSH, thyroid-stimulating hormone) concentrations, increased reverse-T3 (rT3) plasma levels and is attributable to a reduction of peripheral conversion of T4 to the active TH form T3 [6].
LT3S appears in patients without previous thyroid disorders, but who suffer from severe clinical conditions [6], including severe cardiac disease such as HF [2,7-10], acute myocardial infarction [11-13] or subjected to heart surgery [14].
Even if commonly interpreted as an adaptive process finalized in reducing catabolism and thus energy expenditure [15], LT3S may have potential negative effects, contributing to the progressive myocardial remodeling [16] and deterioration of cardiac function in cardiac disease.
This hypothesis is sustained by evidence showing that: 1) in in vitro and ex vivo experimental studies an altered TH metabolism modifies cardiovascular homeostasis with regards to cardiac protein gene expression [3,4], cardiac histology and cardiomyocyte morphology [17], and myocardial blood flow [18], having important effects on diastolic and systolic myocardial function [3, 4] 2) LT3S (as far as other subclinical thyroid dysfunction) is associated with a worse prognosis in cardiac patients [1,2,7-13,19]; 3) TH replacement therapy exerts some beneficial effects in patients with heart failure or [20-23] or undergoing coronary artery bypass graft [24-27].
All experimental and clinical evidences portend the observation of increased cardiac risk in patients with cardiac disease and even mild alteration of TH metabolism, and offer a mechanistic base for a TH-system based therapy in this subset of patients [10,28]
Thyroid hormone and coronary artery disease
The TH system is transiently down regulated in otherwise euthyroid individuals during the acute phase of myocardial infarction. The changes in TH levels are rapid during the initial 72 hours after pain onset, with maximal changes observed between the 24- to 36-hour periods [2930]]. Low T3 and elevated rT3 levels observed immediately after myocardial infarction are associated with an increased mortality both during the acute phase (in hospital period) and the chronic phase (after hospital discharge) of coronary artery disease (CAD) [12,13].
Interestingly noted, after myocardial infarction, T3 plasma levels tend to remain persistently low after a 12-week period in patients with worse prognosis [12].
These observations, together with recent evidence that mild TSH abnormalities are associated not only with traditional coronary risk factors [30], but also with mortality for coronary artery disease [19,30], supports the hypothesis that even mild TH abnormalities have a role in myocardial response to ischemia.
Many recent experimental studies explored the effects of TH on cardiac remodelling and function, when administered shortly after acute myocardial infarction in rats [31].
TH seems to induce cardio protection against ischemia by improving hemodynamics and reducing the extent of myocardial injury.
There are several mechanisms responsible for these effects:
a) Modification of cardiac gene expression
After acute myocardial infarction, there is a modification of gene expression in viable myocardium with an increase in β-MHC and PLB content and a down-regulation of α-MHC, SERCA-2, TH receptors expression [32]. These changes are similar to those observed in pathologic cardiac hypertrophy and heart failure and represent a “recapitulation of foetal phenotype”, configuring a picture of tissue-specific TH deficiency [33,34]. TH therapy administered in the early phase of ischemic damage is associated as a reverse effect of these alterations [32,35]
B) Reduction of oxidative stress
Oxidative damage with cytoskeleton abnormalities contributing to contractile dysfunction is typical of ischemic injury [36]; TH administration may reduce oxidative stress by increasing the expression and activity of heat shock proteins like HSP27 [37].
C) Anti-apoptotic properties
Short term TH treatment inhibits cardiac myocyte apoptosis in the border area after myocardial infarction in rats by activating Akt signalling pathway in a non-genomic manner [38].
D) Metabolic effects
The effects of TH on glucose and fat metabolism in peripheral tissues are well known.
T3 administration after ischemia/reperfusion in isolated rat hearts increases piruvato-dehidrogenase activity, favouring complete glucose oxidation with a reduction in H+ production, an increase in cardiac workload and contractile efficiency without significant effects on oxygen consumption [39].
Through the regulation of transcriptional factors like P43 and mTFA, TH modulates also mitochondrial chain function, which has a pivotal role in determining post-ischemic myocardial dysfunction [40,41].
All previous observations taken together support the hypothesis that TH action has a protective role in myocardial ischemia, reducing infarct size, favouring a positive remodelling of viable myocardium and enhancing systolic and diastolic function.
In this context, it appears worthwhile to evaluate the safety and the effects of TH treatment in patients with acute myocardial infarction.
Study objectives
The effects of short term TH administration in patients with cardiac disease and LT3S have been already studied in patients undergoing coronary artery bypass graft [24-27] or affected by heart failure of different aetiologies [20-23]. In all these clinical studies except one [27], TH were administered at pharmacological doses in seriously ill patients, with great hemodynamic and/or clinical benefit and without significant side effects.
In spite of numerous experimental evidences [31,32,35-39], no clinical study explored the effects of TH replacement therapy in patients with myocardial infarction and borderline reduced TH plasma levels.
With respect to previous studies, aim of the present study is to investigate the safety and feasibility of thyroid hormone (TH) replacement therapy with synthetic triiodothyronine (Liotir) in patients with STEMI and borderline/reduced TH level
Primary objectives
To investigate:
- the safety and feasibility of synthetic TH replacement therapy with a triiodothyronine analogue (Liotir) in patients with STEMI both in the acute (in hospital period) and chronic phase (after hospital discharge) of coronary artery disease and its association with cardiac function and outcome;
- The effects of TH replacement therapy on clinical outcome in terms of major (cardiac and non cardiac death, reinfarction) and minor (recurrence of angina, coronary revascularization, and hospital re-admission) events.
Secondary objectives
To evaluate the effects of thyroid hormone therapy on:
- Infarct size, regional wall motion abnormalities, systolic and diastolic myocardial function;
- Neuroendocrine imbalance;
- Patients functional capacity, quality of life, cognitive and behavioural status
Investigational plan
Overall study design
This is a phase II, randomized, double blind, placebo-controlled study.
Patients admitted to the Coronary Care Unit (CCU) for chest pain and subsequently proven STEMI [42] undergoing myocardial revascularization of the culprit lesion within a 12-hour period, with borderline/reduced fT3 plasma levels (fT3< 2.2 pg/mL or reduction of fT3 plasma levels more that 20% with respect to entry levels after a 72-hour period of hospitalization) and satisfying the inclusion and exclusion criteria will be randomly allocated with a 1:1 ratio to receive TH replacement therapy with a synthetic thyroid hormone (liothyronine sodium, LIOTIR) or placebo.
In accordance with Good Clinical Practice, all patients will be also treated according to the existing guidelines for management of STEMI [43,44], stable angina [4546] and secondary prevention of coronary artery disease [47].
Treatment with TH analogue or placebo will start during the in hospital period (Acute phase) and will be taken for further 6 months after hospital discharge (Chronic phase).
Patient’s enrollment will last 18 months.
Patients, whenever taking TH analogue or placebo, will be subjected to control of TH plasma levels every day during in hospital stay and at 20 days, 40 days, 2 months, 3 months and six months after hospital discharge and to clinical follow-up visits at 20 days, 3 months and six months after hospital discharge.
Study population
Patients
200 patients with STEMI without a history of previous myocardial infarction and thyroid disease, subjected to coronary revascularization through PTCA and stenting performed within a 12-hour period from the onset of symptoms will be eligible for the study.
All patients should be in good clinical conditions, being ST-elevation myocardial infarction the main pathology, without evidence of clinical/hemodynamic instability.
All patients eligible for the study should present - at admission or within 72 hours after hospital arrival - borderline/reduced plasma levels of triiodothyronine (fT3 <2.2 pg/mL or decrease in fT3 plasma levels more than 20% with respect to the admission levels).
Inclusion and exclusion criteria
Inclusion criteria
- Male and female patients, of all ethnic races, admitted to the CCU for chest pain and subsequently proven STEMI (ST Elevation Myocardial Infarction);
- Age between 30 to 70 years;
- Patients subject to coronary revascularization through PTCA and stenting of the culprit lesion alone.
- PTCA performed within 12 hours from the onset of symptoms
- Evidence of fT3 levels below the lower referral limit (<2.2 pg/mL for our laboratory) or decrease in fT3 plasma levels major than 20% with respect to the admission levels
- Written Signature on Informed Consent Form before randomization
Exclusion criteria
- Previous myocardial infarction
- Previous evidence of moderate-to-severe compromised left ventricular function (Ejection Fraction< 40%)
- Hemodynamic instability, ventricular fibrillation or sustained ventricular tachycardia, cardiogenic shock, decompensate heart failure (NYHA IV class) on admission
- Use of inotropic drugs
- Thyroid disease
- Patients assuming: TH replacemement therapy, anti-thyroid drugs, corticosteroids, amiodarone, oral anticoagulant therapy, oral contraceptives
- Patients presenting atrial fibrillation or with previous documentation of paroxysmal or persistent atrial fibrillation
- Pregnant or breast-feeding women
- Sever systemic diseases including: neoplasia, decompensate diabetes mellitus with glycosylated hemoglobin levels more than 9%, liver cirrhosis, chronic obstructive lung disease with moderate to severe respiratory impairment, chronic kidney failure with creatinine plasma levels more than 3 mg/dL
- Systemic inflammatory/autoimmune disease
- Patients holding mechanical cardiac valves, pace-makers or infusion pumps, magnetic materials like metallic clips and prosthesis
- Patients allergic to synthetic thyroid hormone or any eccipient present in the drug eventually administered
- Patients refusing or unable to supply written Informed Consent.
Study end-points
Primary end-points
To evaluate the effects of TH replacement therapy in patients with STEMI and borderline/reduced fT3 plasma levels on outcome and major (cardiac and non cardiac death, reinfarction) and minor (angina, coronary revascularization, hospitalization) adverse cardiac events.
Secondary end-points
To evaluate the effects of TH replacement therapy in patients with STEMI and borderline/reduced fT3 plasma levels on some aspects of coronary artery disease like: infarct size, wall motion abnormalities, quality of life, systolic and diastolic myocardial function, neuroendocrine imbalance, patients functional capacity, quality of life, cognitive and behavioural status.
Treatments
Substitutive treatment with LIOTIR/placebo
The treatment medications supplied for this trial will be a synthetic analogue of native triiodothyronine (Liothyronine Sodium, LIOTIR) and placebo.
Treatment with Liothyronine Sodium or placebo will start within 72 hours after hospital admission.
Liothyronine Sodium
Liothyronine Sodium is already sold in Italy as LIOTIR. This drug is composed of a solution of sodium liothyronine, ethanol and glycerol in the following concentration (ethanol, 96% vol.; glycerol, 85% vol.).
The drug must be assumed per os as drops dissolved in a small quantity of water, each drop containing 0.7 mcg of sodium liothyronine.
For patients taking Liothyronine Sodium, the maximum daily dosage will be 15 mcg/m2/die, to be assumed in 3 times during the day, at 08:00 a.m., 04:00 p.m. and 10:00 p.m.
Placebo
Placebo consists in a solution of glycerol and ethanol at the same concentration seen in Liothyronine Sodium.
As Liothyronine Sodium, placebo must be assumed per os, as drops dissolved in a small quantity of water and three daily administrations at 08:00 a.m., 04:00 p.m. and 10:00 p.m will be performed.
Treatment duration and management
The maximum treatment duration is 6 months.
Treatment assumption will be interrupted in any case when any of the Interruption Criteria listed below are met.
In order to monitor the safety and effects of TH/placebo replacement therapy, patients will be subjected to clinical follow-up at 20 days, 40 days, 2 months, 3 months and 6 months after discharge.
TH levels will be determined every day during the in-hospital period and at 20 days, 40 days, 2 months, 3 months and 6 months during the follow-up in order to be able to modify the Liothyronine Sodium dosage. An analogous modification of dosage will be performed in patients assuming placebo.
In those patients receiving Lyothironine Sodium, the evidence of borderline/elevated fT3 plasma levels (>/= 4.2 pg/ml) and/or evidence of TSH levels below of the referral limits (0.3 microU/ml) will be followed by the assumption of a half dosage of Liothyronine Sodium for 10 days. After this period, a new TH dosage will be performed and TH treatment will be discontinued in the case of persistent abnormalities of fT3 and/or TSH plasma levels.
Whenever the patient complaints symptoms or signs suggestive for hyperthyroidism (e.g. palpitation, anxiety, significant weight loss, etc), a new TH dosage should be programmed to assess TH status and further clinical or instrumental exam will be performed if necessary.
Treatment assignment
All patients eligible for the study in accordance with the inclusion and exclusion criteria will be randomized to one of the two-treatment group using a computer-generated radomization scheme.
A 1:1 treatment allocation will be adopted.
Randomization data will be kept strictly confidential, only accessible to authorized persons, until the expiry date. The blind experiment can cease only due to adverse side events or if essential for the safety of patients.
Blinding
Liothyronine Sodium and placebo will be supplied as a solution of identical appearance for double blind treatment. The investigator site personnel involved in the monitoring or conducting of the trial will be blinded to the trial drug codes. Trial drug codes will not be available to the above personnel until after the completion of the trial and final data review, except in the case of an emergency.
Interruption or discontinuation of treatment
It will be documented whether or not each patient completed the clinical study. If for any patient either the study treatment or observations were discontinued the reason will be recorded.
Reason that a patient may discontinue participation in this clinical study are considered to constitute one of the following:
- Subject withdrew informed consent
- Unsatisfactory adherence of the patient to study protocol or protocol violation
- Patients’ no longer requiring TH replacement therapy because of persistent normalization of TH plasma levels at follow-up.
- Appearance of clinical status that rend the patient unsuitable to continue the study
- Adverse effects related to TH/placebo administration
- Major (cardiac and non cardiac death, reinfarction) and minor (angina, coronary revascularization, re-hospitalization) adverse events at follow-up
- Necessity of therapy with drugs interfering with TH dosage/metabolism or data interpretation (see section “Concomitant treatments”.
Analysis of data collected will be programmed every six months during the study course to eventually discontinue the study in the case of excess of benefit or adverse events, In the case of occurrence of a major or minor event, the patient will be immediately excluded TH therapy will be promptly stopped and the patient will be excluded from successive follow-up.
Concomitant treatments
All patients enrolled in the study will be also treated according to the existing guidelines for management of STEMI, stable angina and secondary prevention of coronary artery disease [43-47].
Due to their potential interference with TH metabolism and results interpretation patients already assuming the following drugs will be excluded from the study:
- TH replacement therapy, anti-thyroid drugs
- Amiodarone
- Corticosteroids
- Oral anticoagulant therapy
- Sympathomimetic drugs
- Oral contraceptives or estro-progestinic hormone replacement
- Potentially hepatotoxic drugs (e.g. metotrexate)
If treatment with these drugs becomes necessary during follow-up, patients will be automatically excluded from the study.
Pregnancy and breast feeding
Potential fertile women enrolled in the study will undergo a pregnancy test that will exclude any possibility of present pregnancy and must confirm not to intend remaining pregnant during the entire study period. They must confirm to use a safe contraceptive method and not to remain pregnant throughout the entire study period. The responsible physicians following the study will discuss with the patient the most appropriate birth-control methods. In the case of pregnancy, the patient will immediately and automatically be excluded from the protocol and all necessary assistance will be guaranteed for the mother and the child and the pregnancy will be followed until the delivery.