Hypothyroidism Overtreatment Linked to Risk of Atrial Fibrillation

Nancy A. Melville

November 06, 2019

CHICAGO — Low levels of thyroid stimulating hormone (TSH) that result from the over-treatment of hypothyroidism are associated with a significantly increased risk of atrial fibrillation and stroke, according to results from a large, population-based study using data from the Veterans Health Administration.

"Our study provides new insights on the incidence of atrial fibrillation and stroke in patients being treated with exogenous thyroid hormone," lead author Maria Papaleontiou, MD, told Medscape Medical News.

"We found that despite controlling for known cardiovascular risk factors, such as smoking, hypertension, etc, lower serum TSH was associated with both incident atrial fibrillation and stroke," she said.

Papaleontiou, who is an assistant professor of internal medicine, Division of Metabolism, Endocrinology, and Diabetes at the University of Michigan, Ann Arbor, presented the findings at the 89th American Thyroid Association (ATA) Annual Meeting.

The study received funding from the National Institute on Aging and the Michigan Biology of Cardiovascular Aging program.

Endogenous hyperthyroidism has been shown to be associated with cardiovascular risks, however, the effects of exogenous hyperthyroidism, defined as lower TSH levels caused by exogenous factors — specifically medical over-treatment of hypothyroidism — have not been well established.

Levothyroxine for hypothyroidism is the most commonly prescribed medication in the United States, and as over-replacement is known to be very common, the issue is important.

Asked to comment, Mona M. Sabra, MD, said these latest findings underscore the need to avoid hypothyroidism over-treatment, when possible.

"The cardiovascular risk with suppressed TSH levels can be seen with (hypothyroidism) overtreatment as well as hyperthyroidism from Graves disease or other causes of suppressed TSH, and it is also associated with a risk of death," she told Medscape Medical News.

"Therefore, these data suggest that suppressed TSH levels should be treated and avoided when possible," said Sabra, who is a professor of clinical medicine, Endocrine Service, Department of Medicine, Memorial Sloan Kettering and Weill Cornell School of Medicine, New York City.

However, she acknowledged, "In thyroid cancer patients who are at high risk for recurrence, this may not be possible because the risk of cancer may outweigh the risk of suppressed TSH."

Almost a Third of Patients With Hypothyroidism Were Overtreated

For the study, Papaleontiou and colleagues identified 643,054 patients in the Corporate Data Warehouse of the Veterans Health Administration who were treated with thyroid hormone replacement for hypothyroidism from 2004 to 2017.

Treatment included either thyroxine (T4) alone or T4 plus liothyronine (T3) combination, and patients with at least two outpatient TSH measurements were included. Those with thyroid cancer or on medications affecting thyroid function, such as amiodarone, were excluded.

At least one TSH measurement falling below 0.5 mIU/L, indicating over-replacement, occurred in 31.3% (236,930) of patients, which is consistent with rates of over-replacement reported in previous studies.

With a median follow-up of 59 months, atrial fibrillation occurred in 67,772 (10.5%) patients.

Specifically, for a TSH level below 0.1 mIU/L, the odds ratio (OR) for atrial fibrillation was 1.16 (95% CI, 1.10 - 1.22) compared with normal (euthyroid) TSH ranges (0.5-5.5 mIU/L).

However, there was no increased risk of atrial fibrillation for levels between 0.1-0.5 mIU/L (OR, 0.94).

Researchers were also surprised to find a higher risk of atrial fibrillation in those with TSH levels > 5.5 mIU/L (indicating under treatment) (OR, 1.18; 95% CI, 1.52 - 1.21).

Looking at incident cerebrovascular accidents (CVAs), such as ischemic and thrombotic/embolic stroke, among 692,537 patients in the Veteran Affairs cohort, there were 16,878 (2.4%) incident CVAs.

For TSH levels < 0.1 mIU/L, the OR for CVA was 1.16 (95% CI, 1.05 - 1.28) and for TSH levels 0.1-0.5 mIU/L, the OR was 1.11 (95% CI, 1.04 - 1.14), both compared with euthyroid patients.

Again, undertreatment was also associated with higher risk: patients with TSH levels ≥ 5.5 mIU/L had an OR for CVAs of 1.33 (95% CI, 1.27 - 1.39) compared with those with normal TSH levels.

"We are still thinking about how to interpret the unexpected results in those undertreated, as mechanisms remain unclear," Papaleontiou said.

As would be expected, risk factors such as older age and hypertension were associated with atrial fibrillation and, in particular, a prior history of atrial fibrillation was significantly associated with risk for CVA (OR, 1.55).

Lower TSH Level Independently Associated With AF and CVA

The fact that lower TSH was independently associated with the outcomes is particularly important in light of the fact that, in these cases, lower TSH can be seen as a modifiable risk factor, Papaleontiou said.

"The most surprising finding of our study is that low TSH was independently associated with incident stroke in thyroid hormone users, even when controlling for prior history of atrial fibrillation, which is the most common mechanism thought to lead to stroke in hyperthyroidism," she noted.

"This suggests that there may be additional mechanisms leading to increased risk of stroke in patients who are over-replaced with thyroid hormone, and a low TSH is a modifiable factor," Papaleontiou said.

89th Annual Meeting of the American Thyroid Association. Abstract #12. Presented October 31, 2019.

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