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Thyroxine-Triiodothyronine Combination Therapy Versus Thyroxine Monotherapy for Clinical Hypothyroidism: Meta-Analysis of Randomized Controlled Trials

Endocrine Institute (S.G.-G.) and Department of Medicine E (A.F., L.L.), Rabin Medical Center, and Geha Mental Health Center (E.N., A.W.), Petah-Tiqva 49100, Israel; and Sackler Faculty of Medicine (E.N., A.W., L.L.), Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel

Address all correspondence and requests for reprints to: Leonard Leibovici, M.D., Department of Medicine E, Beilinson Campus, Petah-Tiqva 49100, Israel. E-mail: leibovic{at}post.tau.ac.il.

	Abstract

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Context: In some patients symptoms of hypothyroidism persist despite therapy with T₄.

Objective: The objective of the study was to compare the effectiveness of T₄-T₃ combination vs. T₄ monotherapy for the treatment of clinical hypothyroidism in adults.

Data Sources: PubMed, EMBASE, LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched in September 2005. References of all included trials were scanned for additional studies. We put no restrictions on language, year of publication, or publication status.

Study Selection: All randomized trials that compared the effectiveness of T₄-T₃ combination vs. T₄ monotherapy for the treatment of clinical hypothyroidism in adults were included.

Data Extraction: The data were extracted by two independent reviewers.

Data Synthesis: We included 11 studies, in which 1216 patients were randomized. No difference was found in the effectiveness of combination vs. monotherapy in any of the following symptoms: bodily pain [standardized mean difference (SMD) 0.00, 95% confidence interval (CI) –0.34, 0.35], depression (SMD 0.07, 95% CI –0.20, 0.34), anxiety (SMD 0.00, 95% CI –0.12, 0.11), fatigue (SMD –0.12, 95% CI –0.33, 0.09), quality of life (SMD 0.03, 95% CI –0.09, 0.15), body weight, total serum cholesterol, triglyceride levels, low-density lipoprotein, and high-density lipoprotein. Adverse events did not differ between regimens.

Conclusions: T₄ monotherapy should remain the treatment of choice for clinical hypothyroidism.

	Introduction

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HYPOTHYROIDISM IS A common disorder, affecting about 5% of people over the age of 60 yr (1, 2). In the United Kingdom, more than 1% of the population receives T₄ replacement therapy for hypothyroidism (3). T₄ is the replacement medication of choice because it has a half-life of 6 d, providing stable and physiological quantities of T₃ to the body. T₃ therapy is also available. It reaches peak levels 2–4 h after oral administration and has a circulating half-life of 1 d. Thus, steady-state levels cannot be maintained with once-daily dosing of T₃ (4).

Studies of hypothyroid rats (after thyroidectomy or after radioiodine therapy) failed to show normalization in tissue concentration of T₄ and T₃ with T₄ monotherapy. However, normalization was achieved with a combination of T₄ and T₃ (5). In humans, this issue remains controversial. In some patients symptoms of hypothyroidism persist despite T₄ therapy. A survey conducted in the United Kingdom found that 32% of patients treated with T₄ were above the threshold for significant psychiatric morbidity according to the abbreviated General Health Questionnaire (GHQ-12), compared with 26% of controls (3). It is not clear whether this is due to comorbidity or because standard T₄ replacement therapy is in some way inadequate for these patients (6, 7).

Successful treatment of hypothyroidism with the use of replacement therapy should result in improved signs and symptoms as well as normal thyroid hormone levels in peripheral tissues. We performed a systematic review and meta-analysis comparing the effectiveness of T₄-T₃ combination therapy vs. T₄ monotherapy for the treatment of clinical hypothyroidism in adults.

	Materials and Methods

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Search

We searched PubMed, EMBASE, LILACS, and The Cochrane Central Register of Controlled Trials in September 2005. The terms hypothyroidism and similar terms, thyroxine and similar terms, triiodothyronine and similar terms, or combination therapy and similar terms were crossed (8). References of all included trials were scanned for additional studies. We put no restrictions on language, year of publication, or publication status.

Selection

We included all randomized or quasirandomized trials (in which the allocation to study groups is not equivalent to the throw of a coin, e.g. birth date) that compared the effectiveness of T₄-T₃ combination therapy vs. T₄ monotherapy for the treatment of clinical hypothyroidism in adults. Two reviewers independently inspected each reference identified by the search and applied the inclusion criteria. For possibly relevant articles or in cases of disagreement between the two reviewers, we obtained and independently inspected the full article and applied inclusion criteria.

Data abstraction

Two reviewers independently extracted the data and assessed the methodological quality of included trials. In case of any disagreement between the two reviewers, a third reviewer was consulted. We discussed data extraction, documented decisions, and contacted the authors of trials for missing data or clarifications when necessary.

We assessed the quality of the following trial characteristics: allocation concealment, generation of the allocation sequence, and blinding. We graded allocation concealment and generation as adequate, unclear, or inadequate. Adequate allocation concealment was defined as the use of central randomization, numbered or coded bottles or containers, drugs prepared by the pharmacy, serially numbered sealed opaque envelopes, or other convincing measures. Adequate allocation generation was defined as the use of random-number table, random-number generator, computer generated, coin-tossing, or shuffling. We also recorded data on method of analysis (intention to treat or per protocol), number of dropouts, trial design (parallel or crossover design and washout period), length of follow-up until outcome assessment, and the questionnaires used to assess outcomes.

Our predefined primary outcomes were symptoms (bodily pain, fatigue, anxiety, depression, and insomnia) and quality of life. Secondary outcomes included cognitive performance, thyroid function test levels, serum lipids levels, adverse effects, and weight changes. To decide which questionnaires were most appropriate for assessment of the predefined outcomes, we consulted two senior psychiatrists who were blinded to trial results.

Quantitative data synthesis

When an outcome was assessed using different scales and the direction of the scales was different, i.e. higher scores indicated improved outcomes in some scales and worse outcomes in others, we standardized the direction by using the inversion of measurements of one of the two types of scales. We pooled data recorded at the end of follow-up in each trial unless otherwise specified. Weighted mean differences (WMD) and 95% confidence intervals (CIs) were calculated for continuous data measured. All biochemical determinations (including TSH) were expressed in the same units for all trials, and thus, the WMD was used for data synthesis.

If continuous outcomes were conceptually the same but measured using different questionnaires, the standardized mean difference (SMD) was used. Relative risks and 95% CIs were calculated for dichotomous data and pooled using the Mantel-Haenszel method. A fixed-effect model was used unless significant heterogeneity was observed, and then a random effects model was used. Heterogeneity in the results of the trials was assessed using a ² test and the I-square measure of inconsistency. We predefined significant heterogeneity as a ² test P < 0.1 or an I-square measure greater than 50% (9). For our primary analysis, we divided trials into trials with a crossover and noncrossover design to assess whether the results of these two groups of trials differed. Meta-regression was performed to assess the effect of T₃ dosage, percentage of athyreotic patients, and length of follow-up on trial results.

	Results

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Eleven randomized trials, performed between the years 1999 and 2005 (Fig. 1), in which 1216 patients were randomized, were included in the review. Six were crossover trials. Trial characteristics and methodology are presented in Tables 1 and 2, respectively. Details of the questionnaires used to assess outcomes in included trials can be found in the supplemental data published on The Endocrine Society’s web site at http://jcem.endojournals.org (22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37). Appelhof et al. (11) included two arms treated with combination therapy, one with a 10:1 ratio between T₄ and T₃ and the second with a 5:1 ratio, in addition to the arm receiving monotherapy. We included the 10:1 ratio study arm in the meta-analyses because this dose was similar to the doses used in the other studies and to avoid including the monotherapy group twice. Replacing the data from the arm treated with a 10:1 ratio of T₄ and T₃ with results from the 5:1 ratio arm had no substantial effect on the results for any of the outcomes. Saravanan et al. (19) assessed the outcomes at 3 and 12 months, respectively. We included in our review the 3-month results because this was the closest period to that used in the other studies.

View larger version (19K): [in this window] [in a new window]   FIG. 1. Publications identified for study and exclusions. RTC, Randomized controlled study.

No difference was found in the effectiveness of combination therapy or monotherapy in any of the following symptoms: bodily pain (SMD 0.00, 95% CI –0.34, 0.35; four studies, Fig. 2); quality of life (SMD 0.03, 95% CI –0.09, 0.15; Fig. 3); depression (SMD 0.07; 95% CI –0.20, 0.34; all studies, Fig. 4); fatigue (SMD –0.12, 95% CI –0.33, 0.09; six studies, Fig. 5); and anxiety (SMD 0.00, 95% CI –0.12, 0.11; seven studies, Fig. A1 in supplemental data). Due to scarcity of data, we could not assess the effect of combination therapy on sleeping patterns.

View larger version (14K): [in this window] [in a new window]   FIG. 2. The effect of monotherapy and combination therapy on bodily pain.

View larger version (17K): [in this window] [in a new window]   FIG. 3. The effect of the combination therapy vs. monotherapy on quality of life.

View larger version (19K): [in this window] [in a new window]   FIG. 4. The effect of monotherapy and combination therapy on depression.

View larger version (14K): [in this window] [in a new window]   FIG. 5. The effect of monotherapy and combination therapy on fatigue.

Cognitive function was tested in the included trials using two standard, well-validated tests: the Symbol Digit Modalities (31), which assesses cognitive efficiency and ability to undertake a novel task, and the Digit Span Sub-Test (both forward and backward) of the Wechsler Adult Intelligence Scale III (32), which assesses immediate auditory memory, attention, and concentration. Seven studies (11, 12, 13, 15, 17, 18, 20) reported results of the Symbol Digit Modalities Test. No significant difference was detected (WMD 0.15, 95% CI –0.79, 1.08), (Fig. A2 in supplemental data).

Eight studies reported results of the Digit Span Sub-Test (both forward and backward) of the Wechsler Adult Intelligence Scale III (11, 12, 13, 14, 15, 17, 18, 21). No significant difference was found between the two treatment groups: forward subtest, WMD –0.02 (95% CI –0.25, 0.22; Fig. A3 in supplemental data); backward subtest, WMD –0.07 (95% CI –0.30, 0.15; Fig. A4 in supplemental data).

Weight changes

Weight changes were measured in seven studies (11, 13, 14, 18, 19, 20, 21). In three of four studies, weight remained stable or decreased during the study period (11, 14, 18). Bunevicius et al. (13) did not specify weight at baseline. In the study by Clyde et al. (14), baseline mean weight in the two treatment groups was significantly different, and we therefore used the change in weight in each group in the analysis. The weight in the combination group was lower at the end of the study, and this difference reached statistical significance, but the magnitude of the difference is negligible: WMD –0.10 kg; 95% CI –0.13, –0.07 kg; Fig. A5 in supplemental data).

Biochemistry results

The results of the thyroid function tests [TSH, free T₄ (FT4), and total T₃ (TT3), supplemental Figs. A6, A7, and A8] and the serum lipid levels (total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides, supplemental Figs. A9, A10, A11, and A12) are documented in Table 3, and but for levels of T₄ (as expected), no differences were apparent between study groups.

All studies reported adverse effects, which were similar between study groups (relative risk 1.19, 95% CI 0.63, 2.24) (Fig. 6).

View larger version (22K): [in this window] [in a new window]   FIG. 6. Adverse events in the two study arms.

Because eight of the 11 studies were graded A (adequate) for allocation concealment, sensitivity analysis was not performed. Meta-regression demonstrated no association among length of follow-up, percentage of athyreotic patients or dose of T₃, and trial results for the primary outcomes.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
T₄-T₃ combination therapy used as replacement therapy for patients treated for hypothyroidism provided no advantage when compared with standard T₄ monotherapy in the randomized, controlled trials included in the present review. There was no benefit in terms of symptoms (fatigue, bodily pain, anxiety, depression) and no improvement in quality of life. Moreover, the analysis of the impact of combination therapy on cognition shows no improvement in cognitive efficiency and the ability to undertake a novel task, immediate auditory memory, attention, and concentration. Lipid profile was not improved in patients prescribed combination therapy, and there was no significant difference in terms of weight change.

Trials also varied in the T₄ to T₃ ratio, the absolute doses prescribed, and duration of treatment. However, the differences in primary outcomes did not depend on T₃ dose and duration of treatment.

Whether combination therapy offers an advantage is of particular interest for patients who are dissatisfied with monotherapy or continue to be symptomatic despite monotherapy and normalized serum free T₄ and TSH levels. Four trials addressed this group of patients. Walsh et al. (18) found no benefit associated with combination therapy in a subgroup of patients dissatisfied with the results of monotherapy. Appelhof et al. (11) found that results for patients in the highest tertile of SCL-90 (psychiatric Symptoms Checklist) total scores did not differ from the overall results. Bunevicius et al. (12) reported no difference in results for depressed patients, compared with patients without depression, and Rodriguez et al. (21) reported no difference in patients with high and low fatigue levels.

Only one trial (12) found significant benefit of combination therapy over the monotherapy. It was later suggested that this benefit was associated with the cause of hypothyroidism and that only athyreotic thyroid cancer patients benefited from combination therapy, whereas patients with autoimmune thyroiditis did not (13, 38). However in the present review, we were unable to show a relation between the percentages of athyreotic patients included in the study and the effect of combination therapy on symptoms.

Limitations

It should be noted that we used mean (± SD) TSH values in the meta-analysis, although TSH values are not normally distributed. In addition, five of the included studies were crossover studies. Therefore, observations are not independent because the same patients receive both therapies (combination and monotherapy).

Implications for practice and research

Given the conclusive evidence, monotherapy with T₄ should remain the standard treatment for hypothyroidism. It is doubtful whether further trials evaluating combination therapy are needed because the chances that the accumulated evidence will change are low.

	Acknowledgments

 
We are grateful to Drs. P. W. Clyde, B. C. Appelhof, J. P. Walsh, J. A. Levitt, and P. Saravanan for kindly supplying additional data. We thank the Cochrane Endocrine Disorders Group for their guidance and support.

	Footnotes

 
The authors have no conflict of interest to declare.

First Published Online May 2, 2006

Abbreviations: CI, Confidence interval; FT4, free T₄; SMD, standardized mean difference; TT3, total T₃; WMD, weighted mean difference.

Received February 27, 2006.

Accepted April 24, 2006.

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