Levothyroxine Fails to Provide Cardiac Benefit in Subclinical Hypothyroidism

Salman Razvi, MD

Results from a new trial indicate hormone therapy with levothyroxine may not have the cardiovascular impact many may have expected based on its placement in guidelines.

Findings from the trial, which was conducted in patients with subclinical hypothyroidism, indicate use of levothyroxine did not result in improvements in cardiac function for patients with acute myocardial infarction.

“The results of this trial demonstrate that there are no significant improvements for patients with heart attacks who are given levothyroxine,” said lead investigator Salman Razvi, MD, senior lecturer and consultant endocrinologist, Newcastle University and the Queen Elizabeth Hospital in Gateshead, in a statement. “On this basis, screening for and subsequent treatment of subclinical hypothyroidism in patients who have had a heart attack to preserve or improve heart function is not justified."

Despite being relatively common among adult populations, treatment of subclinical hypothyroidism remains a challenge in many regards. One of these areas in particular is management of patients with acute myocardial infarction, where an apparent lack of high-quality evidence creates disagreement among clinicians on proper course of treatment. While current guidelines recommend treatment with levothyroxine in these patient populations based on observational studies, some clinicians still decline initiating treatment.

To create a more clear consensus on the effects of levothyroxine on cardiac function in these patients, Razvi and colleagues designed the current study to assess levothyroxine’s impact on left ventricular function in a double-blinded, randomized fashion. Conducted across 6 hospitals in the UK, investigators enrolled a total of 95 patients who were enrolled between February 2015-December 2016.

Of these 95 patients, 46 were randomized to levothyroxine and 49 were randomized to placebo therapy. The mean age of the study participants was 63.5 (SD, 9.5) years, 76.6% were men, and 69.1% had ST-segment elevation myocardial infarction (STEMI). The median serum thyrotropin level was 5.7 mU/L (interquartile range, 4.8-7.3 mU/L) and the mean free thyroxine level was 1.14 (SD, 0.16) ng/dL.

For inclusion in the study, patients needed to be older than 18 years and have serum thyrotropin levels greater than 4.0 mU/L, with normal free thyroxine (FT4) levels on 2 occasions 7 to 10 days apart and with 1 thyrotropin value being below 10 mU/L, and either (STEMI) or non–STEMI (NSTEMI) diagnosed on admission. Additionally, patients were excluded if they were taking medications impacting thyroid function.

Patients randomized to levothyroxine received first dose within 21 days of acute myocardial infarction with a starting dose of 25 μg. From that point, doses were treated at subsequent visit based on thyroid functions tests to aim for serum thyrotropin levels from 0.4-2.5 mU/L.

The primary outcome for the trial was left ventricular ejection fraction at 52 weeks. Investigators assessed left ventricular ejection fraction by magnetic resonance imaging. Investigators noted they planned to adjust these analyses for age, sex, type of acute myocardial infarction, affected coronary artery territory, and baseline left ventricular ejection fraction. Secondary outcomes included left ventricular volumes, infarct size, adverse events, and patient-report outcome measures of health status, health-related quality of life, and depression.

At 52 weeks, data related to the primary outcome measure was available for 85 (89.5%) patients. At baseline, mean left ventricular ejection fraction was 51.3% (SD, 9.1%) compared to 53.8% (9.7%) at 52 weeks. In comparison, left ventricular ejection fraction among the placebo group was 54.0% (7.9%) at baseline and 56.1% (7.9%) at 52 weeks.

Based on an adjusted between-group mean difference of 0.76% (95% CI, -0.93 to 2.46%; P=.37), investigators concluded levothyroxine did not significantly alter left ventricular ejection fraction at 52 weeks. Additionally, results suggested none of the 6 secondary outcomes of the trial showed a significant difference between the levothyroxine and placebo treatment arms.

Of note, 15 (33.3%) and 18 (36.7%) adverse cardiovascular events occurred in the levothyroxine and placebo arms, respectively.

Razvi and colleagues noted multiple limitations within their study. These limitations included the low dose initially offered, patients began treatment an average of 17 days after index event, and 4 in 10 patients with subclinical hypothyroidism had normalized their levels when checked within a few days.

This study, “Effect of Levothyroxine on Left Ventricular Ejection Fraction in Patients With Subclinical Hypothyroidism and Acute Myocardial Infarction,” was published in JAMA.