A new analysis of the large, randomized TRUST trial shows that L-thyroxine does not improve pronounced symptoms in older people with subclinical hypothyroidism.
The original trial established that the synthetic hormone did not improve symptoms in the overall trial population, a finding that called into question the routine prescribing of thyroid medication for this patient group.
But questions lingered as to whether patients with a higher burden of symptoms might still benefit from treatment with L-thyroxine.
For their research, published in Annals of Internal Medicine, Maria de Montmollin, MD, of the University of Bern (Switzerland), looked at results for 638 subjects randomized to L-thyroxine treatment (50 mcg daily for most patients) or placebo and followed for at least 1 year in the Thyroid Hormone Therapy for Older Adults With Subclinical Hypothyroidism (TRUST) trial (N Engl J Med. 2017;376:2534-2544). All were 65 years or older and met the criteria for subclinical hypothyroidism, defined as persistent elevated TSH levels (4.60-19.99 mIU/L) in combination with a normal free-thyroxine level.
Dr. de Montmollin and her colleagues identified 132 participants with high hypothyroid symptom burden at baseline and 133 patients with high scores for tiredness, using the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. Cutoffs were a baseline symptoms score of higher than 30 (on a 1-100 scale), or a tiredness score of over 40.
At 1 year, researchers saw no statistically significant improvements in either measure for the L-thyroxine treated patients, compared with placebo.
Among the patients with high symptom burden, those on L-thyroxine saw a score improvement of –12.3 points, compared with –10.4 for those on placebo, for an adjusted between-group difference of –2.0 (95% confidence interval, –5.5 to 1.5; P = 0.27). Tiredness scores also improved similarly, dropping 8.9 points for L-thyroxine–treated patients, compared with –10.9 for those receiving placebo, for an adjusted between-group difference of 0.0 (95% CI, –4.1 to 4.0; P = 0.99).
Dr. de Montmollin and colleagues also noted no significant between-group differences in two secondary measures they looked at in the study: patient self-reported quality of life and handgrip strength, an objective measure of weakness.
The results “do not support the hypothesis that the subgroup of adults with SCH [subclinical hypothyroidism] and high symptom burden before treatment benefit from L-thyroxine therapy,” the investigators wrote in their analysis. “This may be because of regression to the mean, the natural history of SCH, or the placebo effect and may explain why many persons with symptomatic SCH and their treating physicians are convinced that L-thyroxine is beneficial,” they added.
In an interview, Dr. de Montmollin commented that treating physicians “should reconsider prescribing or offering L-thyroxine to older adults with SCH, even those with consistent symptoms, because there is no clear evidence for its benefit in treating SCH to date and a risk of harm related to overtreatment is still possible. In addition, it is associated with unnecessary costs for the patient and for the health system.”
The investigators mentioned several limitations to their study, including its post hoc design and a small sample size. Additionally, they wrote, the findings “cannot exclude the possibility that a rare subgroup with greater symptom burden would benefit from L-thyroxine therapy” or that more aggressive treatment leading to lower TSH levels would confer benefit.
The study was sponsored by the National Health Service Greater Glasgow and Clyde Health Board, while the TRUST trial was sponsored by the European Union and with medication donated by Merck. Dr. de Montmollin and her coauthors disclosed no financial ties to industry.
SOURCE: De Montmollin et al. Ann Intern Med 2020 May 5. doi: 10.7326/M19-3193.