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Intervention Protocol

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Total thyroidectomy versus subtotal thyroidectomy for Graves' disease

  1. Zi Wei Liu1,*,
  2. Liam Masterson2,
  3. Piyush Jani2,
  4. Brian Fish3,
  5. Krishna Chatterjee3

Editorial Group: Cochrane Metabolic and Endocrine Disorders Group

Published Online: 7 OCT 2013

DOI: 10.1002/14651858.CD010576


How to Cite

Liu ZW, Masterson L, Jani P, Fish B, Chatterjee K. Total thyroidectomy versus subtotal thyroidectomy for Graves' disease (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD010576. DOI: 10.1002/14651858.CD010576.

Author Information

  1. 1

    Broomfield Hospital, Otolaryngology - Head and Neck Surgery, Chelmsford, Essex, UK

  2. 2

    Cambridge University Hospitals NHS Foundation Trust, ENT Department, Cambridge, UK

  3. 3

    Cambridge Biomedical Campus, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

*Zi Wei Liu, Otolaryngology - Head and Neck Surgery, Broomfield Hospital, Court Road, Chelmsford, Essex, CM1 7ET, UK. zwl20cam@gmail.com. ziweiliu@doctors.org.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 7 OCT 2013

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This is not the most recent version of the article. View current version (25 NOV 2015)

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest
 

Description of the condition

Graves' disease accounts for 50% to 80% of cases of hyperthyroidism and has a population prevalence of 0.5% to 2%. It is more common in women, with a female:male ratio of 5:1 (Genovese 2012; Ponto 2012). Five per cent of patients with Graves' disease develop moderate to severe Graves' ophthalmopathy, with older age groups (40 to 80 years) at higher risk of developing eye signs (Laurberg 2012).

Graves' disease is an autoimmune disease caused by production of auto-antibodies against the thyroid-stimulating hormone (TSH) receptor, which stimulates follicular cell production of thyroid hormone. Symptoms include evidence of hyperthyroidism such as irritability, heat intolerance, weight loss and diarrhoea, and a hypervascular, enlarged thyroid may be found on examination. Extrathyroidal manifestations range from ophthalmopathy, dermopathy (pretibial myxoedema) and acropachy, which distinguish Graves' from other causes of hyperthyroidism (Lalwani 2012).

Hyperthyroid states are associated with significant cardiovascular and respiratory adverse events such as atrial fibrillation, congestive cardiac failure, hypercoagulability and stroke. A recent meta-analysis suggested a 20% increase in mortality in patients diagnosed with hyperthyroidism (Brandt 2011).

Graves' disease may be diagnosed by evidence of extrathyroidal manifestations (ophthalmopathy, acropachy and pretibial myxoedema) on examination and biochemical hyperthyroidism (suppressed TSH, high triiodothyronine (T3), thyroxine (T4) or both). If the diagnosis is uncertain, a radionuclide uptake test may be performed which shows diffusely increased uptake throughout the thyroid. Assays for TSH receptor antibody (TRAb) have 98% sensitivity and 100% specificity for Graves' disease, but their use in clinical practice remains variable (Paunkovic 2007).

 

Description of the intervention

Thyroid surgery for Graves' disease commonly falls into one of three categories: 1) total thyroidectomy, which aims to achieve complete macroscopic removal of thyroid tissue; 2) bilateral subtotal thyroidectomy, in which bilateral thyroid remnants are left; 3) unilateral total and contralateral subtotal thyroidectomy, or Dunhill's operation. In subtotal thyroidectomy techniques, less than 2 to 8 g thyroid remnant is recommended, to reduce the risk of recurrent hyperthyroidism (Chi 2005; Hermann 1998).

 

Adverse effects of the intervention

Thyroidectomy for benign disease carries significantly less risk than for thyroid malignancies. Two recent large retrospective case series for total thyroidectomy in benign disease (Bellantone 2002; Efremidou 2009) reported the risk of permanent recurrent laryngeal nerve palsy as 0% to 0.4%, and temporary recurrent laryngeal nerve palsy at 1.3%. Temporary hypocalcaemia was seen in 7.3% of patients, and permanent hypocalcaemia was seen in 0.3% to 3.4%. Haemorrhage requiring repeat surgery was reported to be in the region of 0.2% to 1.5%. The trend was for a decrease in complications over recent years, suggesting surgeon experience and case load may be factors in rates of complications. Subtotal thyroidectomy has been reported to give lower rates of temporary recurrent laryngeal nerve palsy and hypocalcaemia, but outcomes are similar in the long term (Barczynski 2011).

 

How the intervention might work

Total thyroidectomy removes target tissue for the stimulating TSH receptor antibody. It controls hyperthyroidism at the cost of life-long thyroxine replacement. Subtotal thyroidectomy leaves a thyroid remnant and aims to achieve euthyroidism without the need for thyroxine replacement, however a higher rate of recurrent hyperthyroidism is expected.

Graves' ophthalmopathy is thought to be due to common antigens shared between the thyroid and orbit which are both targeted by TSH receptor antibody (TRAb) and a G-protein G2sAb. Total thyroidectomy has been shown to be associated with regression of Graves' opthalmopathy, associated with a concurrent decrease in TRAb and G2sAb post surgery (De Bellis 2012; Leo 2012).

 

Why it is important to do this review

Thyroidectomy for Graves' disease may be indicated in patients who have persistent hyperthyroidism after a trial of antithyroid medication; when a rapid return to euthyroidism is desired; or when radioactive iodine treatment is contraindicated (e.g. in pregnancy).

In recent years we have seen a resurgence of interest in surgical management of Graves' disease. The American Thyroid Association's Hyperthyroidism Management Guidelines 2010 named surgery as one of three first-line treatments for hyperthyroidism associated with Graves' disease alongside radioactive iodine and antithyroid drugs. In studies conducted in patients who have persistent hyperthyroidism after medical treatment, total thyroidectomy is shown to be more cost effective than radioactive iodine or lifelong antithyroid medication (In 2009; Zanocco 2012). Health-related quality of life after surgical ablation of the thyroid has been shown to be comparable to the general population (Al-Adhami 2012). Morbidity associated with thyroidectomy has been shown to be less than previously thought (Bellantone 2002; Efremidou 2009).

Choice of thyroidectomy technique is currently largely a matter of surgeon preference, and a systematic review of the evidence base is required to determine which option offers the best outcome for patients. A previous meta-analysis on this subject was carried out in 2000 (Palit 2000), which only searched MEDLINE and not any other databases. Since that time, data from several new randomised controlled trials have been published, which demonstrates considerable interest in this topic.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest

To assess the effects of total thyroidectomy and subtotal thyroidectomy on Graves' disease and Graves' ophthalmopathy.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled clinical trials.

 

Types of participants

All patient age groups receiving surgical treatment for Graves' disease.

 

Diagnostic criteria

Our criteria for Graves' disease are clinical examination and suppressed TSH and elevated free T4, free T3, or both. Additional diagnostic tests such as radionuclide uptake and TRAb (TSH receptor antibody)/TBII (thyrotropin binding inhibiting immunoglobulins) are noted where performed, but not considered essential for study inclusion.

 

Types of interventions

We will consider studies for inclusion where the surgical interventions listed below are compared. We will exclude studies where only one trial arm contains a surgical intervention, or where surgical interventions are compared to medical interventions.

We plan to investigate the following comparisons of intervention versus control/comparator where the same letters indicate direct comparisons.

 

Intervention

a) Bilateral subtotal thyroidectomy

b) Unilateral total and contralateral subtotal thyroidectomy

 

Comparator

a1) Unilateral total and contralateral subtotal thyroidectomy

a2) Total thyroidectomy

b1) Total thyroidectomy

 

Types of outcome measures

 

Primary outcomes

  • Rate of recurrent hyperthyroidism
  • Adverse effects (e.g. permanent recurrent laryngeal nerve palsy, permanent hypocalcaemia)

 

Secondary outcomes

  • Regression of Graves' ophthalmopathy
  • All-cause mortality
  • Postoperative bleeding
  • Health-related quality of life
  • Health economic outcomes

 
Timing of outcome measurement

All outcomes must have reported measurements at a minimum of three months follow-up.

 
Definition of outcome measurement

  • Rate of recurrent hyperthyroidism: bio-chemically confirmed elevation of T3/T4 with postoperatively suppressed TSH.
  • Regression of Graves' opthalmopathy: a clinically-significant improvement in Graves' ophthalmopathy using a validated scoring system as reported by the authors of the study.
  • Health-related quality of life: measured by a validated instrument.

'Summary of findings' table

We will present a 'Summary of findings' table using the following outcomes listed according to priority:

  1. Rate of recurrent hyperthyroidism
  2. Permanent recurrent laryngeal nerve palsy
  3. Permanent hypocalcaemia
  4. Regression of Graves' ophthalmopathy
  5. All-cause mortality
  6. Health-related quality of life
  7. Health economic outcomes

 

Search methods for identification of studies

 

Electronic searches

We will search the following sources from inception to the present:

  • The Cochrane Library.
  • MEDLINE.
  • EMBASE.

We will also search databases of ongoing trials (ClinicalTrials.gov (www.clinicaltrials.gov/), Current Controlled Trials metaRegister (www.controlled-trials.com/), the EU Clinical Trials register (www.clinicaltrialsregister.eu/) and the WHO International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/)).

For detailed search strategies see Appendix 1. We will continuously apply PubMed's 'My NCBI' (National Center for Biotechnology Information) email alert service to identify newly published studies using a basic search strategy (see Appendix 1). Four weeks before we submit the final review draft to the Cochrane Metabolic and Endocrine Disorders Group (CMED) for editorial approval, we will perform an updated search on all specified databases. If we identify new studies for inclusion we will evaluate these and incorporate findings in our review before submission of the final review draft.

If we detect additional relevant key words during any of the electronic or other searches, we will modify the electronic search strategies to incorporate these terms and document the changes. We will place no restrictions on the language of publication when searching the electronic databases or reviewing reference lists in identified studies.

We will send results of electronic searches to the Cochrane Metabolic and Endocrine Disorders Group for databases which are not available at the editorial office.

 

Searching other resources

We will try to identify other potentially eligible trials or ancillary publications by searching the reference lists of retrieved included trials, (systematic) reviews, meta-analyses and health-technology assessment reports.

 

Data collection and analysis

 

Selection of studies

Two review authors (ZWL, LM) will independently scan the abstract, title, or both sections of every record retrieved, to determine the studies to be assessed further. We will investigate all potentially-relevant articles as full text. Where differences in opinion exist, they will be resolved by a third party. If resolving disagreement is not possible, the article will be added to those 'awaiting assessment' and we will contact study authors for clarification. We will present an adapted PRISMA (preferred reporting items for systematic reviews and meta-analyses) flow-chart of study selection (Figure 1) (Liberati 2009).

 FigureFigure 1. Study flow diagram.

 

Data extraction and management

For studies that fulfil inclusion criteria, two review authors (ZWL, LM) will independently abstract relevant population and intervention characteristics using standard data extraction templates (for details see  Table 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 8; Appendix 9; Appendix 10; Appendix 11; Appendix 12) with any disagreements to be resolved by discussion, or if required by a third party.

We will provide information including trial identifier about potentially-relevant ongoing studies in the table 'Characteristics of ongoing studies' and in the appendix 'Matrix of study endpoints (protocol/trial documents)'. We will try to find the protocol of each included study, either in databases of ongoing trials, in publications of study designs, or both, and specify data in the appendix 'Matrix of study endpoints (protocol/trial documents)'.

We will send an email to all study authors of included studies to ask whether they are willing to answer questions regarding their trials. We will publish the results of this survey in Appendix 13. Thereafter, we will seek relevant missing information on the trial from the primary author(s) of the article, if required.

 

Dealing with duplicate publications and companion papers

In the event of duplicate publications, companion papers or multiple reports of a primary study, we will maximise yield of information by collating all available data. In case of doubt the publication reporting the longest follow-up associated with our primary or secondary outcomes will be given priority.

 

Assessment of risk of bias in included studies

Two review authors (ZWL, LM) will assess the risk of bias of each trial independently. We will resolve possible disagreements by consensus, or with consultation of a third party. In cases of disagreement, the rest of the group will be consulted and a judgement will be made based on consensus.

We will assess risk of bias using The Cochrane Collaboration's tool (Higgins 2011a; Higgins 2011b). We will assess the following criteria:

  • Random sequence generation (selection bias).
  • Allocation concealment (selection bias).
  • Blinding (performance bias and detection bias), separated for blinding of participants and personnel, and blinding of outcome assessment.
  • Incomplete outcome data (attrition bias).
  • Selective reporting (reporting bias).
  • Other bias.

We will assess outcome reporting bias (Kirkham 2010) by integrating the results of 'Examination of outcome reporting bias' (Appendix 8), 'Matrix of study endpoints (protocol/trial documents)' (Appendix 7), and section 'Outcomes (outcomes reported in abstract of publication)' of the 'Characteristics of included studies' table. This analysis will form the basis for the judgement of selective reporting (reporting bias).

We will judge 'Risk of bias' criteria as 'low risk', 'high risk' or 'unclear risk' and evaluate individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We will present a 'Risk of bias' figure and a 'Risk of bias summary' figure.

We will assess the impact of individual bias domains on study results at endpoint and study levels.

For blinding of participants and personnel (performance bias), detection bias (blinding of outcome assessors) and attrition bias (incomplete outcome data) we intend to evaluate risk of bias separately for subjective and objective outcomes (Hróbjartsson 2013). We will consider the implications of missing outcome data from individual participants.

We define the following endpoints as subjective outcomes:

  • Regression of Graves' ophthalmopathy.
  • Health-related quality of life.

We define the following outcomes as objective outcomes:

  • Rate of recurrent hyperthyroidism.
  • Permanent recurrent laryngeal nerve palsy.
  • Permanent hypocalcaemia.
  • All-cause mortality.
  • Health economic outcomes.

 

Measures of treatment effect

We will express dichotomous data as odds ratios (OR) or risk ratios (RR) with 95% confidence intervals (CI). We will express continuous data as mean differences (MD) with 95% CI.

 

Unit of analysis issues

We will take into account the level at which randomisation occurred, such as cluster-randomised trials and multiple observations for the same outcome.

 

Dealing with missing data

We will obtain relevant missing data from authors, if feasible, and carefully evaluate important numerical data such as screened, randomised patients as well as intention-to-treat (ITT), as-treated and per-protocol (PP) populations. We will investigate attrition rates, for example drop-outs, losses to follow-up and withdrawals, and critically appraise issues of missing data and imputation methods (e.g. last observation carried forward (LOCF)).

 

Assessment of heterogeneity

In the event of substantial clinical or methodological or statistical heterogeneity, we will not report study results as meta-analytically pooled effect estimates.

We will identify heterogeneity by visual inspection of the forest plots and by using a standard Chi2 test with a significance level of α = 0.1, in view of the low power of this test. We will examine heterogeneity using the I2 statistic, which quantifies inconsistency across studies to assess the impact of heterogeneity on the meta-analysis (Higgins 2002; Higgins 2003), where an I2 statistic of 75% or more indicates a considerable level of inconsistency (Higgins 2011b).

When we find heterogeneity, we will attempt to determine potential reasons for it by examining individual study and subgroup characteristics.

We expect the following characteristics to introduce clinical heterogeneity:

  • Sex.
  • Age.
  • Previous treatment.

 

Assessment of reporting biases

If we include 10 studies or more for a given outcome, we will use funnel plots to assess small study effects. Owing to several possible explanations for funnel plot asymmetry, we will interpret results carefully (Sterne 2011).

 

Data synthesis

Unless there is good evidence for homogeneous effects across studies, we will primarily summarise low risk of bias data by means of a random-effects model (Wood 2008). We will interpret random-effects meta-analyses with due consideration of the whole distribution of effects, ideally by presenting a prediction interval (Higgins 2009). A prediction interval specifies a predicted range for the true treatment effect in an individual study (Riley 2011). In addition, we will perform statistical analyses according to the statistical guidelines contained in the latest version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

 

Subgroup analysis and investigation of heterogeneity

We will carry out the following subgroup analyses and plan to investigate interaction:

  • Age (depending on data).
  • Gender.
  • Effects of previous treatment.

 

Sensitivity analysis

We will perform sensitivity analyses in order to explore the influence of the following factors on effect sizes:

  • Restricting the analysis to published studies.
  • Restricting the analysis taking into account risk of bias, as specified at Assessment of risk of bias in included studies.
  • Restricting the analysis to very long or large studies to establish how much they dominate the results.
  • Restricting the analysis to studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.

We will also test the robustness of the results by repeating the analysis using different measures of effect size (RR, OR etc.) and different statistical models (fixed-effect and random-effects models).

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest
 

Appendix 1. Search strategies


Search terms and databases

Unless otherwise stated, search terms are free text terms.

Abbreviations:

'$': stands for any character; '?': substitutes one or no character; adj: adjacent (i.e. number of words within range of search term); exp: exploded MeSH; MeSH: medical subject heading (MEDLINE medical index term); pt: publication type; sh: MeSH; tw: text word.

The Cochrane Library

#1 MeSH descriptor Graves disease explode all trees
#2 ((grave* in All Text near/6 diseas* in All Text) or (grave* in All Text near/6 thyrotoxicos* in All Text) or (grave* in All Text near/6 hyperthyr* in All Text))
#3 ((grave* in All Text near/6 orbitopath* in All Text) or (grave* in All Text near/6 ophthalmopath* in All Text))
#4 ((basedow* in All Text and adj6 in All Text and diseas* in All Text) or (basedow* in All Text and adj6 in All Text and syndrom* in All Text) )
#5 (#1 or #2 or #3 or #4)
#6 MeSH descriptor Thyroidectomy explode all trees
#7 thyroidectom* in All Text
#8 (#6 or #7)
#9 (#5 and #8)

MEDLINE

1 exp Graves Disease/
2 (grave* adj6 (diseas* or thyrotoxicos* or hyperthyr*)).tw,ot.
3 (grave* adj6 (orbitopath* or ophthalmopath*)).tw,ot.
4 (basedow* adj6 (diseas* or syndrom*)).tw,ot.
5 or/1-4
6 exp Thyroidectomy/
7 thyroidectom*.tw,ot.
8 6 or 7
9 5 and 8
10 randomized controlled trial.pt.
11 controlled clinical trial.pt.
12 randomi?ed.ab.
13 placebo.ab.
14 clinical trials as topic.sh.
15 randomly.ab.
16 trial.ti.
17 or/10-16
18 Meta-analysis.pt.
19 exp Technology Assessment, Biomedical/
20 exp Meta-analysis/
21 exp Meta-analysis as topic/
22 hta.tw,ot.
23 (health technology adj6 assessment$).tw,ot.
24 (meta analy$ or metaanaly$ or meta?analy$).tw,ot.
25 (search* adj10 (medical databas*or medline or pubmed or embase or cochrane or cinahl or psycinfo or psyclit or healthstar or biosis or current content*)).tw,ot.
26 (systematic adj3 review*).tw,ot.
27 or/18-26
28 17 or 27
29 (comment or editorial or historical-article).pt.
30 28 not 29
31 9 and 30
32 limit 31 to humans

EMBASE

1 exp Graves disease/
2 (grave* adj6 (diseas* or thyrotoxicos* or hyperthyr*)).tw,ot.
3 (grave* adj6 (orbitopath* or ophthalmopath*)).tw,ot.
4 (basedow* adj6 (diseas* or syndrom*)).tw,ot.
5 or/1- 4
6 exp subtotal thyroidectomy/ or exp thyroidectomy/
7 thyroidectom*.tw,ot.
8 6 or 7
9 5 and 8
10 exp Randomized Controlled Trial/
11 exp Controlled Clinical Trial/
12 exp Clinical Trial/
13 exp Comparative Study/
14 exp Drug comparison/
15 exp Randomization/
16 exp Crossover procedure/
17 exp Double blind procedure/
18 exp Single blind procedure/
19 exp Placebo/
20 exp Prospective Study/
21 ((clinical or control$ or comparativ$ or placebo$ or prospectiv$ or randomi?ed) adj3 (trial$ or stud$)).ab,ti.
22 (random$ adj6 (allocat$ or assign$ or basis or order$)).ab,ti.
23 ((singl$ or doubl$ or trebl$ or tripl$) adj6 (blind$ or mask$)).ab,ti.
24 (cross over or crossover).ab,ti.
25 or/10-24
26 exp meta analysis/
27 (metaanaly$ or meta analy$ or meta?analy$).ab,ti,ot.
28 (search$ adj10 (medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo or psyclit or healthstar or biosis or current content$ or systematic$)).ab,ti,ot.
29 exp Literature/
30 exp Biomedical Technology Assessment/
31 hta.tw,ot.
32 (health technology adj6 assessment$).tw,ot.
33 or/26-32
34 (comment or editorial or historical-article).pt.
35 33 not 34
36 25 or 35
37 9 and 36

'My NCBI' alert service

("graves disease"[MeSH Terms] OR ("graves"[All Fields] AND "disease"[All Fields]) OR "graves disease"[All Fields]) AND ("thyroidectomy"[MeSH Terms] OR "thyroidectomy"[All Fields]) AND (Randomized Controlled Trial[ptyp] OR systematic[sb])



 

Appendix 2. Characteristics of included studies table: template


MethodsDelete as appropriate

Parallel/cross-over/cluster/factorial randomised controlled clinical trial (RCT)

Randomisation ratio:

Superiority design

Non-inferiority design (specify 1- or 2-sided confidence interval)

Equivalence design (specify 1- or 2-sided confidence interval)

Controlled clinical trial (CCT)

ParticipantsInclusion criteria:

Exclusion criteria:

Diagnostic criteria:

InterventionsNumber of study centres:

Treatment before study:

Titration period:
(Complex interventions: detailed description of all interventions!)

OutcomesOutcomes reported in abstract of publication:

Study detailsRun-in period:

Study terminated before regular end (for benefit/because of adverse events): yes/no

Publication detailsDelete as appropriate

Language of publication:

Commercial/non-commercial/other funding

Publication status (peer reviewed journal / journal supplement / full article / conference paper / other (specify))

Stated aim of studyQuote from publication: "..."

NotesAbbreviations:



 

Appendix 3. Description of interventions


CharacteristicIntervention(s)Comparator(s)

Study 1Intervention 1Comparator 1

Intervention 2Comparator 2

Footnotes

"-" denotes not reported



 

Appendix 4. Baseline characteristics (I)


CharacteristicIntervention(s) and comparator(s)Duration of intervention (duration of follow-up)Participating populationStudy period [year to year]CountrySettingEthnic groups [%]Duration of disease [mean/range years (SD), or as reported]

Study 1Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Footnotes

"-" denotes not reported

SD: standard deviation



 

Appendix 5. Baseline characteristics (II)


CharacteristicIntervention(s) and comparator(s)Sex [female %]Age [mean/range years (SD), or as reported]Co-medications/Co-interventionsCo-morbidities

Study 1Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Footnotes

"-" denotes not reported

SD: standard deviation



 

Appendix 6. Matrix of study endpoints (publications)


CharacteristicEndpoint reported in publicationEndpoint not reported in publicationTime of measurementa

ExampleReview's primary outcomes

Rate of recurrent hyperthyroidismx6, 12 mo

Adverse effects (e.g. permanent recurrent laryngeal nerve palsy, permanent hypocalcaemia)x0, 6, 12 mo

Review's secondary outcomes

Regression of Graves' ophthalmopathyx12 mo

All-cause mortalityx6, 12 mo

Health-related quality of lifexN/A

Health economic outcomesxN/A

Other than review's primary/secondary outcomes reported in publication (classification: P/S/O)b

Patient satisfaction (S), safety parameters (O)

Subgroups reported in publication

Age < 65 years vs ≥ 65 years, cardiovascular risk factors vs no cardiovascular risk factors


Footnotes

aUnderlined data denote times of measurement for primary and secondary review outcomes, if measured and reported in the results section of the publication (other times represent planned but not reported points in time).

b(P) Primary or (S) secondary endpoint(s) refer to verbatim statements in the publication, (O) other endpoints relate to outcomes which were not specified as 'primary' or 'secondary' outcomes in the publication.

mo: months; N/A: not acknowledged



 

Appendix 7. Matrix of study endpoints (protocol/trial documents)


Characteristic / Study ID (trial identifier)EndpointTime of measurement

ExampleRate of recurrent hyperthyroidisma (P)b12 mo

Adverse effects (e.g. permanent recurrent laryngeal nerve palsy, permanent hypocalcaemia) (S)3, 6, 12 mo

Regression of Graves' ophthalmopathy (P)12 mo

All-cause mortality (S)N/A

Patient satisfaction (O)12 mo

Footnotes

"-" denotes not reported

aEndpoint in bold/italic = review's primary/secondary outcome

b(P) Primary or (S) secondary endpoint(s) refer to verbatim statements in the publication, (O) other endpoints relate to outcomes which were not specified as 'primary' or 'secondary' outcomes in the report.



 

Appendix 8. Examination of outcome reporting bias


CharacteristicClear that outcome was measured and analyseda [trial report states that outcome was analysed but only reports that result was not significant]Clear that outcome was measured and analysedb [trial report states that outcome was analysed but no results reported]Clear that outcome was measuredc [clear that outcome was measured but not necessarily analysed (judgement says likely to have been analysed but not reported because of non-significant results)]Unclear whether the outcome was measuredd [not mentioned but clinical judgement says likely to have been measured and analysed but not reported on the basis of non-significant results]

Study 1

Footnotes

'High risk of bias' categories for outcome reporting bias according to the Outcome Reporting Bias In Trials (ORBIT) study classification system for missing or incomplete outcome reporting in reports of randomised trials (Kirkham 2010).

aClassification 'A' (table 2, Kirkham 2010)

bClassification 'D' (table 2, Kirkham 2010)

cClassification 'E' (table 2, Kirkham 2010)

dClassification 'G' (table 2, Kirkham 2010)



 

Appendix 9. Definition of endpoint measurement


Characteristic

Study ID
Rate of recurrent hyperthyroidismPermanent recurrent laryngeal nerve palsyPermanent hypocalcaemiaRegression of Graves' ophthalmopathyPostoperative bleedingHealth-related quality of lifeHealth economic outcomesSevere/serious adverse events

Study 1

Footnotes

ND: not defined; N/I: not investigated



 

Appendix 10. Adverse events (I)


CharacteristicIntervention(s) and comparator(s)Randomised / Safety [N]Deaths [N]Deaths [%]All adverse events [N]All adverse events [%]Severe/serious adverse events [N]Severe/serious adverse events [%]

Study 1Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Footnotes

"-" denotes not reported



 

Appendix 11. Adverse events (II)


CharacteristicIntervention(s) and comparator(s)Randomised / Safety [N]Left study due to adverse events [N]Left study due to adverse events [%]Hospitalisation [N]Hospitalisation [%]Out-patient treatment [N]Out-patient treatment [%]

Study 1Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Footnotes

"-" denotes not reported



 

Appendix 12. Adverse events (III)


CharacteristicIntervention(s) and comparator(s)Randomised / Safety [N]Specific adverse events [description]Specific adverse events [N]Specific adverse events [%]

Study 1Intervention 1

Intervention 2

Comparator 1

Comparator 2

all:

Footnotes

"-" denotes not reported



 

Appendix 13. Survey of authors providing information on trials


CharacteristicStudy author contactedStudy author repliedStudy author asked for additional informationStudy author provided data

Study 1Y

Footnotes

N: no; Y: yes



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest

Zi Wei Liu (ZWL): protocol draft, search strategy development, acquiring trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.

Liam Masterson (LM): protocol draft, search strategy development, acquiring of trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.

Piyush Jani (PJ): protocol draft, search strategy development, acquiring trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.

Brian Fish (BF): protocol draft, search strategy development, acquiring trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.

Krishna Chatterjee (KC): protocol draft, search strategy development, acquiring trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest

None known.

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Additional references
Al-Adhami 2012
  • Al-Adhami A, Craig W, Krukowski ZH. Quality of life after surgery for Graves' disease: comparison of those having surgery intended to preserve thyroid function with those having ablative surgery. Thyroid 2012;22(5):494-500. [PUBMED: 22420618]
Barczynski 2011
  • Barczyński M, Konturek A, Stopa M, Cichoń S, Richter P, Nowak W. Total thyroidectomy for benign thyroid disease: is it really worthwhile?. Annals of Surgery 2011;254(5):724-9. [PUBMED: 22005150]
Bellantone 2002
  • Bellantone R, Lombardi CP, Bossola M, Boscherini M, De Crea C, Alesina P. Total thyroidectomy for management of benign thyroid disease: review of 526 cases. World Journal of Surgery 2002;26(12):1468-71. [PUBMED: 12360381]
Brandt 2011
  • Brandt F, Green A, Hegedüs L, Brix TH. A critical review and meta-analysis of the association between overt hyperthyroidism and mortality. European Journal of Endocrinology/European Federation of Endocrine Societies 2011;165(4):491-7. [PUBMED: 21724839]
Chi 2005
  • Chi SY, Hsei KC, Sheen-Chen SM, Chou FF. A prospective randomized comparison of bilateral subtotal thyroidectomy versus unilateral total and contralateral subtotal thyroidectomy for graves' disease. World Journal of Surgery 2005;29(2):160-3. [PUBMED: 15650802]
De Bellis 2012
  • De Bellis A, Conzo G, Cennamo G, Pane E, Bellastella G, Colella C. Time course of Graves' ophthalmopathy after total thyroidectomy alone or followed by radioiodine therapy: a 2-year longitudinal study. Endocrine 2012;41(2):320-6. [PUBMED: 22169963]
Efremidou 2009
  • Efremidou EI, Papageorgiou MS, Liratzopoulos N, Manolas KJ. The efficacy and safety of total thyroidectomy in the management of benign thyroid disease: a review of 932 cases. Canadian Journal of Surgery 2009;52(1):39-44. [PUBMED: 19234650]
Genovese 2012
  • Genovese BM, Noureldine SI, Gleeson EM, Tufano RP, Kandil E. What is the best definitive treatment for Graves' disease? A systematic review of the existing literature. Annals of Surgical Oncology 2012;20(2):660-7. [DOI: 10.1245/s10434-012-2606-x]
Hermann 1998
  • Hermann M, Roka R, Richter B, Freissmuth M. Early relapse after operation for Graves' disease: postoperative hormone kinetics and outcome after subtotal, near-total, and total thyroidectomy. Surgery 1998;124(5):894-900. [: 9823404]
Higgins 2002
Higgins 2003
Higgins 2009
Higgins 2011a
  • Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.
Higgins 2011b
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Hróbjartsson 2013
  • Hróbjartsson A, Thomsen AS, Emanuelsson F, Tendal B, Hilden J, Boutron I, et al. Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. Canadian Medical Association Journal 2013;185(4):E201-11.
In 2009
  • In H, Pearce EN, Wong AK, Burgess JF, McAneny DB, Rosen JE. Treatment options for Graves disease: a cost-effectiveness analysis. Journal of the American College of Surgeons 2009;209(2):170-9. [PUBMED: 19632593]
Kirkham 2010
Lalwani 2012
  • Lalwani K. Lange Current Diagnosis and Treatment: Otolaryngology - Head and Neck Surgery. 3rd Edition. McGraw-Hill, 2012.
Laurberg 2012
  • Laurberg P, Berman DC, Bülow Pedersen I, Andersen S, Carlé A. Incidence and clinical presentation of moderate to severe graves' orbitopathy in a Danish population before and after iodine fortification of salt. Journal of Clinical Endocrinology and Metabolism 2012;97(7):2325-32. [PUBMED: 22518849]
Leo 2012
  • Leo M, Marcocci C, Pinchera A, Nardi M, Megna L, Rocchi R. Outcome of Graves' orbitopathy after total thyroid ablation and glucocorticoid treatment: follow-up of a randomized clinical trial. Journal of Clinical Endocrinology and Metabolism 2012;97(1):E44-8. [PUBMED: 22031515]
Liberati 2009
Palit 2000
Paunkovic 2007
  • Paunkovic N, Paunkovic J. The diagnostic criteria of Graves' disease and especially the thyrotropin receptor antibody; our own experience. Hellenic Journal of Nuclear Medicine 2007;10(2):89-94. [PUBMED: 17684583]
Ponto 2012
  • Ponto Ka, Kahaly GJ. Autoimmune thyrotoxicosis: diagnostic challenges. American Journal of Medicine 2012;125(9):S1. [PUBMED: 22938935]
Riley 2011
  • Riley RD, Higgins JP, Deeks JJ. Interpretation of random effects meta-analyses. BMJ 2011;342:d549.
Sterne 2011
  • Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011;343:d4002.
Wood 2008
  • Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 2008;336(7644):601-5.
Zanocco 2012
  • Zanocco K, Heller M, Elaraj D, Sturgeon C. Is subtotal thyroidectomy a cost-effective treatment for Graves disease? A cost-effectiveness analysis of the medical and surgical treatment options. Surgery 2012;152(2):164-72. [PUBMED: 22503512]