EvidenceAlerts

Thayakaran R, Adderley NJ, Sainsbury C, et al. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ. 2019 Sep 3;366:l4892. doi: 10.1136/bmj.l4892. (Original study)
Abstract

OBJECTIVE: To explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures.

DESIGN: Retrospective cohort study.

SETTING: The Health Improvement Network (THIN), a database of electronic patient records from UK primary care.

PARTICIPANTS: Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017.

EXPOSURE: TSH concentration in patients with hypothyroidism.

MAIN OUTCOME MEASURES: Ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome.

RESULTS: 162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)).

CONCLUSIONS: In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.


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Ratings
Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Endocrine 6 / 7
Cardiology 5 / 7
Internal Medicine 5 / 7
Comments from MORE raters

Endocrine rater

Interesting data, supporting current recommendations to maintain TSH within normal range. It is surprising that outcomes were worse for those with high rather than low TSH.

General Internal Medicine-Primary Care(US) rater

Important reiteration about keeping TSH within normal limits when treating hypothyroidism.

General Internal Medicine-Primary Care(US) rater

Management of hypothyroidism is very common in primary care. This study is observational and potential confounding is a limitation; however, it suggests that our current approach of maintaining TSH in the normal range is appropriate.

General Internal Medicine-Primary Care(US) rater

The research validates current clinical practice, which did not have a good evidence base, namely: treating hypothyroid patients to the same targets as what has been defined as euthyroid.

Internal Medicine rater

In this retrospective study, the authors used a very large database to estimate the effects of hypothyroidism control on cardiovascular events, heart failure, and fragility fractures. The goal TSH for patients treated for hypothyroidism is not in dispute. The great difficulty with this study, which is unavoidable because of its retrospective design, is it is difficult to know whether poor control of thyroid disease is just a proxy for poor compliance with statin, aspirin, hospitals, physician recommendations, smoking or alcohol use. There is already a great deal of (currently conflicting) information in this space. The answers to this question should be determined with an RCT.

Internal Medicine rater

This is a large retrospective cohort study with a limited follow-up interval and adjusted to a limited number of comorbidities. It does, however, provide useful information for clinicians about the benefits of maintaining therapeutic concentrations of TSH to optimize the long-term mortality and morbidity of patients with hypothyroidism.
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