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Stott DJ, Rodondi N, Kearney PM, et al. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med. 2017 Apr 3. doi: 10.1056/NEJMoa1603825. (Original) PMID: 28402245

Group(s): TRUST Study Group
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DynaMed Plus Topic: Hypothyroidism in adults
DISCIPLINERELEVANCE TO PRACTICEIS THIS NEWS?
Internal Medicine
Endocrine
General Internal Medicine-Primary Care(US)
General Practice(GP)/Family Practice(FP)
Geriatrics**

* Ratings pending – login to http://plus.mcmaster.ca/evidencealerts in a few days if interested.

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Abstract

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 at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). 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 to 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) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter 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 (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). 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. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).


Comments from Clinical Raters
Endocrine
As expected, further confirmation that treating subclinical hypothyroidism does not improve outcomes, but limited power for more important neurocognitive, cardiovascular, or lipid outcomes. It might have been more useful to stick to patients with TSH > 10 who are expected to have a higher risk for developing symptoms, rather than the modest levels represented in this study.
Endocrine
This is not convincing. Even high normal TSH is known to be at least associated with metabolic risk factors, low moods and weight gain. Intake of Levothyroxine too close to factors that are known to impair Levothyroxine absorption in this study may well have influenced the results.
General Internal Medicine-Primary Care(US)
Before rushing to change approaches in elderly patients with elevated TSH but normal T4, one should re-read the Thyroid Association`s review on the topic. Further, if subclinical hypothyroidism is actually a disease, it is likely that any physiologic changes may take a long time to develop (> 1 year) and perhaps longer than 1 year to resolve (if they can be measured at all). This study may very well be correct and, if so, calls into question the entity of "subclinical" hypothyroidism and whether it exists at all or is just a man-made biochemical entity. If correct, we should simply watch unless symptoms or blood tests evolve into clinically overt disease. I`m not certain that one can base clinical actions on this study alone, even though my inclination (and practice) is to wait until there is more to support a disease before treating it.
General Internal Medicine-Primary Care(US)
Few of us realize how nonproductive thyroid testing is, even more so is the "subclinical" approach. I think we're looking at an epiphenomenon, and not even addressing the real underlying issues. At least this article implies a DISCONNECT between symptoms and number and treatment.
General Practice(GP)/Family Practice(FP)
Very good evidence that treating subclinical hypothyroidism in the elderly (and likely in the non-elderly too, but not addressed in this article) is not of value. So, when hypothyroidism is not clinically manifest, avoid treatment of elevated TSH with normal thyroxine. And if symptoms MAY be due to hypothyroidism but testing is consistent with subclinical hypothyroidism, then be sure the treatment resolves the symptoms. If the symptoms persist, they were not due to hypothyroidism and treatment should be stopped.
General Practice(GP)/Family Practice(FP)
Subclinical hypothyroidism among older patients is a common primary care condition. This well conducted randomized clinical trial confirms findings from smaller studies showing a lack of benefit from treatment. These findings could deter over-treatment.
Internal Medicine
As a hospitalist, we may be not dealing with these scenarios; as an internist, this is always a fascinating topic for me and my team. While reading this, I was specifically looking for heart failure and new onset Afib, but was glad to see there is no increase risk. In fact, the numbers look worse in the placebo group without a significant P value. I think this study needs to be expanded to more populations with larger numbers to be assured about adverse events. As a hospitalist, I am always worried about diagnosing subclinical hypothyroidism, and my main concern is adverse events. This is an impressive study and the methods are very well done.
Internal Medicine
Very common clinical scenario; very helpful to finally have an RCT to address.

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