Recent evidence sets therapeutic targets for levothyroxine-treated patients with primary hypothyroidism based on risk of death

Perros, Petros; Nirantharakumar, Krishnarajah

doi:10.1530/eje-20-1229

Cited by 12 publications

(11 citation statements)

References 8 publications

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“…More studies are needed to assess the effect of fT4 levels due to subclinical hypothyroidism treatment on CV events in such patients. This is crucial considering common oversubstitution and overtreatment of subclinical hypothyroidism in patients with known cardiac co-morbidities (42).…”

Section: Discussionmentioning

confidence: 99%

Subclinical thyroid function and cardiovascular events in patients with atrial fibrillation

Moutzouri

Lyko

Feller

et al. 2021

European Journal of Endocrinology

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Objective: To evaluate if subclinical thyroid dysfunction is associated with cardiovascular (CV) risk in patients with atrial fibrillation (AF). Methods: Swiss-AF is a prospective cohort of community-dwelling participants aged ≥ 65 years with AF. Primary outcome was a composite endpoint of CV events (myocardial infarctions, stroke/transitory ischemic events, systemic embolism, heart failure (HF) hospitalizations, CV deaths). Secondary outcomes were component endpoints, total mortality and AF-progression. Exposures were thyroid dysfunction categories, TSH and fT4. Sensitivity analyses were performed for amiodarone use, thyroid hormones use and competing events. Results: 2415 patients were included (mean age 73.2 years; 27% women). 196 (8.4%) had subclinical hypothyroidism and 53 (2.3%) subclinical hyperthyroidism. Subclinical thyroid dysfunction was not associated with CV events, during a median follow-up of 2.1 years (max 5 years): age- and sex- adjusted hazard ratio (adjHR) of 0.99 (95% confidence interval (CI) 0.69-1.41) for subclinical hypothyroidism; and 0.55 (95%CI 0.23-1.32) for subclinical hyperthyroidism. Results remained robust following multivariable adjustment and sensitivity analyses. In euthyroid patients, fT4 levels were associated with an increased risk for the composite endpoint and HF (adjHR 1.46 95%CI 1.04- 2.05; adjHR 1.70 95%CI 1.08-2.66, respectively, for the highest quintile versus the middle quintile). Results remained similar following multivariable adjustment. Results remained significant for HF in sensitivity analyses. No association between subclinical thyroid dysfunction and total mortality or AF-progression was found. Conclusions: Subclinical hypothyroidism was not associated with increased CV risk in AF patients. Higher levels of fT4 with normal TSH were associated with higher risk for HF.

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Section: Discussionmentioning

confidence: 99%

Subclinical thyroid function and cardiovascular events in patients with atrial fibrillation

Moutzouri

Lyko

Feller

et al. 2021

European Journal of Endocrinology

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“…It makes sense not to change T4 and T3 doses simultaneously; the ETA guidelines recommend to adapt first the daily T3 dose [ 1 ]. Maintenance of a normal serum TSH level is prudent because two large independent population studies over the past 2 years have shown that mortality of hypothyroid patients treated with LT4 is increased when the serum TSH exceeds or is reduced outside the normal reference range [ 82 ]. Residual thyroid function (RTF) might be a key factor in the success of combination therapy.…”

Section: How To Make Progress In the Management Of Persistent Symptoms On Lt4 Despite A Normal Tsh?mentioning

confidence: 99%

T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity

Wiersinga

2021

Endocrinol Metab

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Thyroxine (T4)+triiodothyronine (T3) combination therapy can be considered in case of persistent symptoms despite normal serum thyroid stimulating hormone in levothyroxine (LT4)-treated hypothyroid patients. Combination therapy has gained popularity in the last two decades, especially in countries with a relatively high gross domestic product. The prevalence of persistent symptoms has also increased; most frequent are complaints about energy levels and fatigue (80% to 90%), weight management (70% to 75%), memory (60% to 80%), and mood (40% to 50%). Pathophysiological explanations for persistent problems are unrealistic patient expectations, comorbidities, somatic symptoms, related disorders (Diagnostic and Statistical Manual of Mental Disorders [DSM-5]), autoimmune neuroinflammation, and low tissue T3. There is fair circumstantial evidence for the latter cause (tissue and specifically brain T3 content is normalized by T4+T3, not by T4 alone), but the other causes are viewed as more relevant in current practice. This might be related to the 'hype' that has emerged surrounding T4+T3 therapy. Although more and better-designed trials are needed to validate the efficacy of T4+T3 combination, the management of persistent symptoms should also be directed towards alternative causes. Improving the doctor-patient relationship and including more and better information is crucial. For example, dissatisfaction with the outcomes of T4 treatment for subclinical hypothyroidism can be anticipated as recent trials have demonstrated that LT4 is hardly effective in improving symptoms associated with subclinical hypothyroidism.

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“…Light colors indicate CIs. The distance to the final dosage dropped significantly after 2 weeks in DAT groups [goiter t ( 15 ) = 3.16, p = 0.003, cancer t ( 27 ) = 3.52, p = 0.001], but not in controls (n.s.). ( C ) Violin plots showing time to achieve TSH targets (black dots for individual patients).…”

Section: Resultsmentioning

confidence: 96%

“…After 2 weeks, clinicians made significant adjustments toward the “correct” final dosage for patients with DAT [ t (65) = 3.31, p = 0.002], but not for controls [ t (65) = 1.00, p = 0.32]. Subgroup analysis revealed that the effect of DAT was present in both goiter [ t ( 15 ) = 3.16, p = 0.006] and cancer [ t ( 27 ) = 3.52, p = 0.002] groups. The results from control groups indicate that the experienced clinicians were not able to make significant dose adjustments based on the TSH and fT4 values from the first two weeks without assistance of the DAT.…”

Section: Resultsmentioning

confidence: 99%

Patient-Tailored Levothyroxine Dosage with Pharmacokinetic/Pharmacodynamic Modeling: A Novel Approach After Total Thyroidectomy

Brun

Eriksen

Selseth

et al. 2021

Thyroid

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Background: After seven decades of levothyroxine (LT4) replacement therapy, dosage adjustment still takes several months. We have developed a decision aid tool (DAT) that models LT4 pharmacometrics and enables patient-tailored dosage. The aim of this was to speed up dosage adjustments for patients after total thyroidectomy. Methods: The DAT computer program was developed with a group of 46 patients post-thyroidectomy, and it was then applied in a prospective randomized multicenter validation trial in 145 unselected patients admitted for total thyroidectomy for goiter, differentiated thyroid cancer, or thyrotoxicosis. The LT4 dosage was adjusted after only two weeks, with or without application of the DAT, which calculated individual free thyroxine (fT4) targets based on four repeated measurements of fT4 and thyrotropin (TSH) levels. The individual TSH target was either <0.1, 0.1–0.5, or 0.5–2.0 mIU/L, depending on the diagnosis. Initial postoperative LT4 dosage was determined according to clinical routine without using algorithms. A simplified DAT with a population-based fT4 target was used for thyrotoxic patients who often went into surgery after prolonged TSH suppression. Subsequent LT4 adjustments were carried out every six weeks until target TSH was achieved. Results: When clinicians were guided by the DAT, 40% of patients with goiter and 59% of patients with cancer satisfied the narrow TSH targets eight weeks after surgery, as compared with only 0% and 19% of the controls, respectively. The TSH was within the normal range in 80% of DAT/goiter patients eight weeks after surgery as compared with 19% of controls. The DAT shortened the average dosage adjustment period by 58 days in the goiter group and 40 days in the cancer group. For thyrotoxic patients, application of the simplified DAT did not improve the dosage adjustment. Conclusions: Application of the DAT in combination with early postoperative TSH and fT4 monitoring offers a fast approach to LT4 dosage after total thyroidectomy for patients with goiter or differentiated thyroid cancer. Estimation of individual TSH-fT4 dynamics was crucial for the model to work, as removal of this feature in the applied model for thyrotoxic patients also removed the benefit of the DAT.

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Recent evidence sets therapeutic targets for levothyroxine-treated patients with primary hypothyroidism based on risk of death

Cited by 12 publications

References 8 publications

Subclinical thyroid function and cardiovascular events in patients with atrial fibrillation

Subclinical thyroid function and cardiovascular events in patients with atrial fibrillation

T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity

Patient-Tailored Levothyroxine Dosage with Pharmacokinetic/Pharmacodynamic Modeling: A Novel Approach After Total Thyroidectomy

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