Subclinical Hypothyroidism in adults >65

Major randomized control study shows that reducing mean TSH from 6.4 to 3.6 does not improve "symptoms/tiredness" of subclinical hypothyroidism in a group of adults with average age 75. The article was just published in New England Journal of Medicine.

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N E J M

Randomized Trial

April 2017

Background: The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition.

Methods: We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were >65 years of age and who had persisting subclinical hypothyroidism (TSH 4.60-20 with normal FT4). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0-100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points).

Results: The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) TSH was 6.40±2.01 mIU/L at baseline; at 1 year, this level had decreased to 5.48 mIU/L in the placebo group, as compared with 3.63 mIU/L in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found NO DIFFERENCES in the mean change at 1 year in the Hypothyroid Symptoms score or the Tiredness score. No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest.

Conclusions: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism.


More from the article:

Subclinical hypothyroidism is defined as an elevated TSH and normal FT4. Between 8%-18% of adults 65 years of age or older have these biochemical features, and the prevalence is higher among women than among men.

Subclinical hypothyroidism is a possible contributor to many problems in older persons. Thyroid hormones have multiple effects, since they act as an essential regulatory factor in numerous physiological systems, including the vascular tree and the heart, the brain (including cognition), skeletal muscle, and bone. Tiredness is the most important symptom of overt hypothyroidism, but most patients with subclinical hypothyroidism have no symptoms or have nonspecific symptoms. There is a convincing epidemiologic association with subsequent coronary heart disease.

Randomized, controlled trials of levothyroxine replacement for the treatment of subclinical hypothyroidism have been small and have yielded only limited evidence regarding the possible benefits and risks of treatment. We aimed to determine whether there are clinical benefits from levothyroxine replacement in older persons with subclinical hypothyroidism.

We found that levothyroxine had no consistent beneficial effect on thyroid-related symptoms. This finding was true in both older men and older women and for different thyrotropin levels at baseline. Our trial had good statistical power to detect a clinically meaningful effect on thyroid-related quality of life, with 95% confidence intervals that excluded a beneficial effect greater than 2.1 points (on a scale from 0-100) in either of the two primary outcomes. If a symptom benefit was to have occurred, it would have been expected to be seen at 12 months.

Muscle function has been described as being adversely affected by underactive thyroid. However, we found that hand-grip strength did not change from baseline significantly more with levothyroxine treatment than with placebo. Similarly, it has been suggested that the speed of information processing is slowed in persons with subclinical hypothyroidism. However, we found no benefit with levothyroxine with regard to executive cognitive function as measured by the letter–digit coding test. There also was no effect of treatment on blood pressure, weight, waist circumference, body-mass index, or the Barthel Index or Instrumental Activities of Daily Living scores.

Participants were monitored closely for adverse effects from levothyroxine treatment. We found no increase in hyperthyroid symptoms after the initiation of treatment, and there was no significant excess of serious adverse events of special interest, including atrial fibrillation, heart failure, fracture, or new diagnosis of osteoporosis. We believe that the slight excess of patients who had serious adverse events in the placebo group is a CHANCE finding; the events were spread among a range of body systems, and no particular pattern was observed. Observational studies also have not shown any association of treatment of subclinical hypothyroidism with an increased risk of adverse events.

Many older persons with biochemical results that are consistent with subclinical hypothyroidism will have reversion to a euthyroid state if they are followed up without treatment. In total, approximately 3/5 persons that we screened for entry into the trial on the basis of previously elevated thyrotropin levels had reversion to normal thyroid biochemical results and were therefore excluded from the trial. These data are consistent with several other observational and trial cohorts that showed a high proportion of participants with an elevated thyrotropin level having reversion to biochemical euthyroidism during follow-up.

The trial also had certain limitations. First, we chose to set a thyrotropin target of 0.40-4.60 mIU per liter with levothyroxine treatment, which is an approach that reflects recent guidelines, particularly for older persons. However, some authorities have recommended a lower thyrotropin target (e.g., 0.40-2.50 mIU/L). We cannot exclude the possibility that this more aggressive treatment approach might be beneficial. Second, since few participants had a baseline TSH>10, we cannot address whether there are benefits from treatment in this subgroup. Third, the symptom levels at trial entry were low, so we cannot exclude the possibility of benefit in persons with more marked symptoms. Fourth, we did not measure thyroid antibody levels.

Antibody-positive patients are more likely than antibody-negative patients to have progressive hypothyroidism and therefore may be more likely to have a benefit from long-term levothyroxine treatment. Finally, our trial was underpowered to detect any effect of levothyroxine on the incidence of cardiovascular events or mortality. Therefore, we cannot exclude the possibility that treatment with levothyroxine may provide cardiovascular protection or cause harm.

In conclusion, this trial indicated that treatment with levothyroxine in older persons with subclinical hypothyroidism provided no symptomatic benefits.