Liothyronine Use Beyond Replacement Therapy,with Caution

Thyroid hormone action has a pivotal role in myocardial function and differentiation. Aside the well-known positive transcriptional regulation of myosin alpha chain (1) and cardiac sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2a) (2), thyroid hormone is a potent signal for differentiation. Conversely its action inhibits the embryonic transcriptional signature, which also occurs in postischemic remodeling (3), a maladaptive event leading to cardiac dilation, heart failure, and increased mortality. This observation represents the premise of the study of Pantos et al. published in the current issue of Thyroid (4). In this pilot double-blind placebo-controlled study, the authors treated patients affected by acute myocardial infarction with pharmacological doses of liothyronine (LT3) during the first 48 hours after primary percutaneous coronary intervention using as primary aim difference in left ventricle ejection fraction between the treatment arms six months after the ischemic event.

The study did not reach statistical significance in the primary endpoint, but the results are nonetheless enticing since the data trend toward an improvement in myocardial function in the LT3-treated group. Specifically, at discharge LT3-treated patients showed smaller left ventricle size, and smaller infarct size at the six-month follow-up visit.

A major strength of this study is the translational approach based on preclinical observations in animal models that guided the choices in LT3 dose and window of treatment. The authors posed extreme attention in the design by limiting the recruitment to patients with single vessel (anterior descending) disease, thus increasing the internal validity of the study. Moreover, the study was double blind placebo-controlled, myocardial function was assessed by state-of-the-art cardiac MRI, and the follow-up (six months) was adequate.

Major caution though should be posed in the evaluation of the data in their entirety. One major limitation is the elimination of four patients with minimal infarction size (<1% of left ventricle volume), which happened to occur all in the placebo group (see article, Fig. 2). When the data were analyzed including these patients all the statistical significance was negated, although the trend toward improvement in myocardium function remained.

Although the authors provide a rationale for not using intention to treat analysis, one could argue the possibility that the lack of exposure to LT3 resulted in much smaller infarct size in a significant minority (20%) of the patients allocated to the placebo group. Similarly, although one cannot draw any conclusion in such a small amount of adverse events/fatalities, the placebo group had lower events (one vs. two deaths, and none vs. one case of sustained atrial fibrillation) as it relates to safety. The increase in heart rate and trend toward increase in transient atrial fibrillation observed during or immediately after the LT3 treatment do not appear concerning.

Overall the results of this pilot study are interesting and could potentially provide the rationale for a larger efficacy (phase 3) trial. In contrast, one should consider the inherent limitations of pilot studies (5) and evaluate the results not limiting the view whether the intervention reached the primary or secondary endpoints, but rather focusing on the effect size of the intervention, and safety and adverse events signals. These data may prove critical in designing further studies and to determine criteria for early termination based on patients' safety. To this end, in the future similar pilot studies (and in general terms all clinical research) publications would be more impactful if the study protocol, amendments, and regulatory documentation were made available as supplemental material to clarify the rationale (and the limitations) of the study design rather than relying to blanket statements such “predetermined analysis” (4).

In conclusion, the data presented in this article are exciting yet extremely preliminary, offering the point estimate and the safety framework to consider designing phase 3 efficacy studies. If successful such studies could generate a paradigm shift in the therapeutic use of thyroid hormone beyond replacement therapy for the treatment of postischemic cardiac remodeling. In a larger context, this study is a proof of concept for exploiting therapeutically the thyroid hormone signaling in other end-organ targets of its action, such as lipid and energy metabolism, steatohepatitis, and mood disorders.