A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.
“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, told Medscape Medical News.
Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, agreed that the findings are significant.
“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told Medscape Medical News.
Getting the Balance Right: A Tricky Task
Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.
“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.
In a previous study, Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.
For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone between January 1, 2004, and December 31, 2017 who had a median follow-up of 4 years.
They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.
The mean age of participants was 67 years and 88.7% were male.
Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.
Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio [AHR], 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.
In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.
Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.
The increased mortality risk in relation to TSH levels was more pronounced among older patients compared with FT4 associations, the authors note.
“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.
Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.
Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.
Addressing Over- and Undertreatment Will Avoid Harm
The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.
And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.
“Addressing over- and undertreatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Papaleontiou said.
Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.
“In older persons, over 65-70, the target TSH may be higher [eg, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.
“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Cooper explained.
“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”
The authors have reported no relevant financial relationships.
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