Intensity of Thyroid Hormone Treatment Tied to Cardiovascular Mortality

Intensity of thyroid hormone treatment was linked with cardiovascular (CV) mortality, according to an observational study.

In more than 700,000 patients who received thyroid hormone treatment and were followed for a median of 4 years, those with exogenous hyperthyroidism (thyrotropin <0.1 mIU/L) had a 39% increased risk for CV mortality after adjusting for known risk factors (HR 1.39, 95% CI 1.32-1.47), reported Maria Papaleontiou, MD, of the University of Michigan in Ann Arbor, and colleagues.

The risk increase was similar in an assessment of hyperthyroidism with free thyroxine (FT₄) measurements; patients with levels >1.9 ng/dL had a 29% increase in risk (HR 1.29, 95% CI 1.20-1.40), they stated in JAMA Network Open.

Hypothyroidism was even more strongly linked with CV mortality, specifically thyrotropin levels of >20 mIU/L were tied to a more than twofold risk increase (HR 2.67, 95% CI 2.55-2.80). And FT₄ levels <0.7 ng/dL were associated with higher risk (HR 1.56, 95% CI 1.50-1.63), Papaleontiou’s group said.

Long-term exogenous hyper- and hypothyroidism have been linked with CV risk and all-cause mortality in previous research, but the current study is one of the first to examine the impact of treatment intensity, they noted. A 2021 study by the current authors indicated that the intensity of thyroid hormone treatment was a modifiable risk factor for incident atrial fibrillation and stroke, but its association with CV is not clear.

“Our study findings have the potential to affect how we think about the risks and benefits associated with thyroid hormone treatment, particularly for vulnerable populations, such as older adults or those with underlying cardiovascular disease,” the authors stated. “These findings emphasize the importance of maintaining euthyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.”

However, they cautioned that the retrospective, observational study did not establish causality.

Synthetic thyroid hormones have consistently been one of the top three most frequently prescribed medications in the U.S. in the past decade, and CV disease remains the leading cause of death, so “an association between the intensity of thyroid hormone treatment and CV death has far-reaching implications for both patients and physicians,” they said.

“Although the variability in thyrotropin and FT₄ levels and thyroid hormone dose adjustments are an inevitable reality for most patients, our study emphasizes the importance of regular monitoring of thyroid function test results and correction of both overtreatment and under-treatment with exogenous thyroid hormones to reduce patient harm, particularly for older adults who are at higher risk for adverse effects,” the authors added.

The retrospective study analyzed data on 705,307 adults who received thyroid hormone treatment from the Veteran’s Health Administration during 2004-2017. The majority of the patients (88.7%) were men. The patients were predominantly white (79%) and the median age was 67. Overall, 75,963 patients (10.8%) died of CV causes.

Among these, 701,929 of the patients had at least two thyrotropin measurements during the study period and 373,981 had at least two FT₄ measurements. The main outcome was death from CV causes, including myocardial infarction, heart failure, and stroke.

The researchers performed survival analyses using Cox proportional hazards regression models with serum thyrotropin and FT₄ levels as time-varying covariates. They adjusted for other risk factors including age, sex, hypertension, diabetes, lipids, smoking, and previous CV disease or arrhythmia. Patients’ cause of death was ascertained by the National Death Index.

Other study limitations included the fact that VA did not accurately capture information on body mass index, obesity, or alcohol use, which are all potential confounders. However, “adjusting for a comprehensive list of cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, and prior history of cardiovascular disease, which represent some of the downstream effects of obesity, partially mitigates this limitation,” the authors argued.

Also, the researchers could not determine how adequately certain risk factors, such as diabetes or hypertension, were treated, and the study did also not account for all medications or supplements patients may have been taking that could have interfered with thyroid hormone metabolism or thyroid function tests.

“Cardiovascular disease remains the leading cause of death in the United States, and its economic impact is enormous,” Papaleontiou and colleagues stated. “Identifying and addressing modifiable risk factors continues to be critically important to reducing the rates of cardiovascular disease and mortality. The emergence of the intensity of thyroid hormone treatment as a potential associated risk factor provides a highly relevant and easily modifiable clinical parameter for patients who receive thyroid hormone treatment.”