Cochrane Library

#1 [mh "Graves disease"]
#2 (grave* near/7 (diseas* or thyrotoxicos* or hyperthyr* or orbitopath* or ophthalmopath*)):ti,ab,kw
#3 (basedow* near/7 (diseas* or syndrom*)):ti,ab,kw
#4 {or #1‐#3}
#5 [mh Radiotherapy]
#6 [mh "Iodine Radioisotopes"]
#7 ((radioiodine or radio‐iodine) near/7 (therap* or treatment*)):ti,ab,kw
#8 (radiotherap* or radio‐therap*):ti,ab,kw
#9 (131‐I near/7 (therap* or treatment*)):ti,ab,kw
#10 (iodine‐131 near/7 (therap* or treatment*)):ti,ab,kw
#11 RAI:ti,ab,kw
#12 {or #5‐#11}
#13 [mh "Antithyroid Agents"]
#14 ((antithyroid* or anti‐thyroid*) near/7 (therap* or treatment* or agent* or drug* or substanc* or compound*)):ti,ab,kw
#15 (carbimazole* or methimazole* or methylthiouracil* or propylthiouracil* or thiouracil*):ti,ab,kw
#16 [mh Carbimazole]
#17 [mh Methimazole]
#18 [mh Methylthiouracil]
#19 [mh Propylthiouracil]
#20 [mh Thiouracil]
#21 {or #13‐#20}
#22 #4 and #12 and #21

MEDLINE (Ovid SP)

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 Radiotherapy/
7. exp Iodine Radioisotopes/tu [Therapeutic Use]
8. ((radioiodine or radio‐iodine) adj6 (therap* or treatment*)).tw,ot.
9. (radiotherap* or radio‐therap*).tw,ot.
10. (131‐I adj6 (therap* or treatment*)).tw,ot.
11. (iodine‐131 adj6 (therap* or treatment*)).tw,ot.
12. RAI.tw,ot.
13. or/6‐12
14. exp Antithyroid Agents/
15. ((antithyroid* or anti‐thyroid*) adj6 (therap* or treatment* or agent* or drug* or substanc* or compound*)).tw,ot.
16. (carbimazole* or methimazole* or methylthiouracil* or propylthiouracil* or thiouracil*).tw,ot.
17. exp Carbimazole/
18. exp Methimazole/
19. exp Methylthiouracil/
20. exp Propylthiouracil/
21. exp Thiouracil/
22. or/14‐21
[23‐33: Cochrane RCT Filter – sensitivity maximizing version 2008]
23. randomized controlled trial.pt.
24. controlled clinical trial.pt.
25. randomized.ab.
26. placebo.ab.
27. drug therapy.fs.
28. randomly.ab.
29. trial.ab.
30. groups.ab.
31. or/23‐30
32. exp animals/ not humans/
33. 31 not 32
34. 5 and 13 and 22 and 33

EMBASE (Ovid SP)

1. exp Graves disease/
2. (basedow adj6 (diseas* or syndrom*)).tw.

3. (graves* adj6 (orbitopath* or ophthalmopath*)).tw.
4. (exophthalmic adj6 (goiter* or goitre* or hyperthyroidism*)).tw.
5. (grave* adj6 (disease* or hyperthyr* or thyrotoxicos*)).tw.
6. or/1‐5
7. exp radiotherapy/
8. exp radioactive iodine/
9. ((radioiodin* or radio‐iodin*) adj6 (therap* or treatment*)).tw.
10. (radiotherap* or radio‐therap*).tw.
11. ((131I or 131‐I) adj6 (therap* or treatment*)).tw.
12. RAI.tw.
13. or/7‐12
14. exp antithyroid agent/
15. ((antithyroid* or anti‐thyroid*) adj6 (therap* or treatment* or agent* or drug* or substanc* or compound*)).tw.
16. exp carbimazole/
17. exp thiamazole/
18. exp methylthiouracil/
19. exp propylthiouracil/
20. exp thiouracil/
21. (carbimazole* or methimazole* or methylthiouracil* or propylthiouracil* or thiouracil*).tw.
22. or/14‐21
23. 6 and 13 and 22
[24:Wong 2006– small drop in sensitivity, substantive gain in specificity filter]
24. random*.tw. or clinical trial*.mp. or exp treatment outcome/
25. 23 and 24
26. limit 25 to embase

ICTRP Search Portal (Standard search)

[searched as one string]

grave* AND radiotherap* OR
grave* AND radio therap* OR
grave* AND iodin* OR
grave* AND radioiodin* OR
grave* AND RAI OR
grave* AND 131* OR
basedow* AND radiotherap* OR
basedow* AND radio therap* OR
basedow* AND iodin* OR
basedow* AND radioiodin* OR
basedow* AND RAI OR
basedow* AND 131*

ClinicalTrials.gov (Advanced search)

Search Terms: (grave OR graves OR basedow OR basedows) AND (radiotherapy OR "radio therapy" OR radioiodine OR "radio iodine" OR "131" OR "131‐I" OR "RAI")

Intervention(s) [route, frequency, total dose/day]

Comparator(s) [route, frequency, total dose/day]

Traisk 2009

A single oral activity of ¹³¹I was administered using the following formula: activity (MBq) = 23.4 x thyroid mass (grams) x 120 (Gy)/estimated uptake (0 h; %) x effective half‐life (days)
The thyroid mass was assessed by thyroid scintigraphy and by palpation; at day 14 after radioiodine therapy, 50 μg L‐thyroxine was added daily

Methimazole was given as 15 mg twice daily; at day 14, 50 μg L‐thyroxine was added daily; methimazole was discontinued after 18 months with an additional month of L‐thyroxine substitution of 100 μg daily, which thereafter was discontinued

Tallstedt 1992^a

A single oral activity of ¹³¹I was administered, based on thyroid size, 24‐hour ¹³¹I uptake, and the measured effective half‐life of the isotope in the thyroid

Oral administration of 10 mg methimazole 4 times daily (40 mg/day). 3 to 5 weeks later thyroxine was added in doses between 0.1 and 0.3 mg/day (mean dose 0.17 mg/day). Methimazole and thyroxine were discontinued simultaneously after 18 months. Propranolol at a dose of 20 to 60 mg 3 to 4 times daily or 50 to 300 mg metoprolol daily in divided doses was given initially until the participants became euthyroid. In cases of adverse reactions to methimazole, the drug was exchanged with propylthiouracil (100 mg 4 times daily)

^aThe participants who were between 20 and 34 years old were randomly assigned to treatment with antithyroid drug plus thyroxine (young medical group) or subtotal thyroidectomy (young surgical group); the participants who were between 35 and 55 years old were randomly assigned to antithyroid drug plus thyroxine (old medical group), subtotal thyroidectomy (old surgical group) or to iodine‐131 (iodine‐131 group)

¹³¹I: iodine‐131 (radioiodine)

Intervention(s) and comparator(s)

Duration of intervention
(duration of follow‐up)

Description of participants

Trial period
[year to year]

Country

Setting

Ethnic groups
[%]

Diagnostic criteria for Graves' disease

Traisk 2009

I: radioiodine

1 day (4 years)

Patients aged 35 to 69 years; symptomatic Graves' hyperthyroidism

Started in May 1996 and the trial was closed in 2003. With the 4‐year clinical follow‐up, the trial was terminated by the end of 2007

Sweden

Outpatients

‐

Serum TSH ≤ 0.1 mIU/L and elevated triiodothyronine and/or free thyroxine, thyroid uptake of iodine‐131, and radionuclide scans compatible with Graves' disease, i.e. an even distribution of radionuclide

C: methimazole

18 months

(4 years)

Tallstedt 1992

I: radioiodine

1 day (24 months^a)

Participants aged 20 to 55 years with hyperthyroidism caused by Graves' disease

1991 (most participants had been followed for at least 24 months)

Sweden

Outpatients

‐

Presence of symptoms and signs of hyperthyroidism, a diffuse goitre, elevated total and free thyroxine and total triiodothyronine concentrations in serum, detectable serum concentrations of thyrotropin‐receptor antibodies, increased uptake of iodine‐131 by the thyroid, and thyroid radionuclide scans showing a diffuse pattern of isotope uptake

C: methimazole

18 months (24 months^a)

‐ denotes not reported

C: comparator; I: intervention; TSH: thyroid‐stimulating hormone

^aDifferent follow‐up times for various outcome measures.

Intervention(s) and
comparator(s)

Sex
[female %]

Age
[mean years (SD)]

Duration of disease
[mean months (SD)]

Co‐medications/Co‐interventions

Comorbidities
[%]

Traisk 2009

I: radioiodine

87

51 (8)

5 (4)

Beta‐blockers were used as pretreatment to radioiodine; L‐thyroxine substitution was administered at day 14 after radioiodine treatment

Current smokers: 36

C: methimazole

91

50 (8)

6 (5)

At day 14, 50 μg of L‐thyroxine was added and increased to 100 μg 2 weeks later; at week 6, the dose of L‐thyroxine was adjusted to normalise the levels of serum T₃ and free T₄ and to bring TSH levels to less than 0.4 mIU/L; a slightly elevated serum free T₄ was accepted up to 20% above the upper normal limit; beta‐blockers were used for symptomatic treatment

Current smokers: 42

Tallstedt 1992

I: radioiodine

85

45 (5)

‐

Unless contraindicated, propanolol or metoprolol was given to all participants; 18 participants were given more than one dose of iodine‐131 from 10 weeks to 23 months; all participants eventually had hypothyroidism and received thyroxine 0.1 ‐ 0.3 mg daily

Smoker: 56

C: methimazole

85

28 (4) & 45 (6)

‐

Thyroxine 0.1 ‐ 0.3 mg daily was added after 3 ‐ 5 weeks; propanolol 60 ‐ 240 mg daily or metoprolol 50 ‐ 300 mg daily was given initially for a few weeks; methimazole and thyroxine were discontinued simultaneously

Smoker: 42

‐ denotes not reported

BMI: body mass index; C: comparator; HbA1c: glycosylated haemoglobin A1c; I: intervention; SD: standard deviation; T₃: triiodothyronine; T₄: thyroxine; TSH: thyroid‐stimulating hormone

Endpoints quoted in trial document(s)
(ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a

Trial results/
publications available
in trial register
Yes/No

Endpoints quoted in publication(s)^b,c

Endpoints quoted in abstract of publication(s)^b,c

Traisk 2009

N/T

Primary outcome measure(s): difference in the proportion of participants with worsening or development of thyroid‐associated ophthalmopathy during a 4‐year follow‐up

Primary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Other outcome measure(s): recurrence of hyperthyroidism (relapse), adverse events, thyroid hormone levels, corticosteroid treatment for thyroid‐associated ophthalmopathy, health‐related quality of life

Other outcome measure(s): worsening or development of thyroid‐associated ophthalmopathy; smoking as a risk factor

Tallstedt 1992

N/T

Primary outcome measure(s): occurrence of ophthalmopathy within 2 years after the initiation of therapy^e

Primary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Other outcome measure(s): recurrent hyperthyroidism; predictive factors of ophthalmopathy; participants assessment of the treatment; sick leave; adverse effects; euthyroidism; health‐related quality of life; costs; laboratory assessments; TSH‐receptor autoimmunity^f

Other outcome measure(s): development or worsening of Graves' ophthalmopathy

‐ denotes not reported

^aTrial document(s) refers to all available information from published design papers and sources other than regular publications (e.g. FDA/EMA documents, manufacturer's websites, trial registers).
^bPublication(s) refers to trial information published in scientific journals (primary reference, duplicate publications, companion documents or multiple reports of a primary trial).
^cOther outcome measures refer to all outcomes not specified as primary or secondary outcome measures.
^dRefers to outcome measures from both of the two publications of Traisk 2009.
^eNot explicitly stated as primary outcome but clear from paragraph 'Statistical Analysis' in the methods section of Tallstedt 1992.

^fRefers to outcome measures from all of the six publications of Tallstedt 1992.

EMA: European Medicines Agency; FDA: Food and Drug Administration (US); mo: month(s); N/T: no trial document available; TSH: thyroid‐stimulating hormone

Outcome

High risk of bias
(category A)^a

High risk of bias
(category D)^b

High risk of bias
(category E)^c

High risk of bias
(category G)^d

Traisk 2009

N/A

Tallstedt 1992

N/A

^aClear that outcome was measured and analysed; trial report states that outcome was analysed but only reports that result was not significant.
(Classification 'A', table 2, Kirkham 2010).

^bClear that outcome was measured and analysed; trial report states that outcome was analysed but no results reported.
(Classification 'D', table 2, Kirkham 2010).
^cClear that outcome was measured; clear that outcome was measured but not necessarily analysed; judgement says likely to have been analysed but not reported because of non‐significant results.
(Classification 'E', table 2, Kirkham 2010).
^dUnclear whether the outcome was measured; not mentioned but clinical judgement says likely to have been measured and analysed but not reported on the basis of non‐significant results.
(Classification 'G', table 2, Kirkham 2010).

N/A: not applicable; ORBIT: Outcome Reporting Bias In Trials

All‐cause mortality

Health‐related quality of life

Adverse events other than development and worsening of Graves' ophthalmopathy [hypothyroidism]

Recurrence of hyperthyroidism [relapse]

Development and worsening of Graves' disease

Individuals in euthyroid state

Bone mineral density

Socioeconomic effects

Traisk 2009

‐

Short‐Form Health Status Survey (SF‐36)

TSH was elevated and/or FT₃, FT₄ or T₃ was below the lower limit of the reference range

‐

The worsening or development and improvement of ophthalmopathy met 2 of the following 4 decisive factors compared with baseline data: 1) change in exophthalmometry readings of 2 mm or more; 2) improvement or deterioration of the patient's eye movements between the 4 scoring levels (no impairment, clearly impaired, diplopia in the primary position, fixation of the globe); 3) changes of visual acuity caused by optic neuropathy; and 4) changes in 2 of the 3 ophthalmopathy activity measures (chemosis, eyelid oedema, and conjunctival redness)

‐

N/I

N/I

Tallstedt 1992

‐

Short‐Form Health Status Survey (SF‐36) and quality of life 2004
(QoL 2004; not a validated instrument)

TSH was elevated and/or FT₃, FT₄ or T₃ were below the lower limit of the reference range

TSH was decreased and/or FT₃, FT₄ or T₃ were above the lower limit of the reference range

The eye examination by the study ophthalmologist included testing of visual acuity, tonometry, Hertel exophthalmometry, slitlamp examination and tests of extraocular‐muscle function with Lee's screen; the results of the examination were summarised as an ophthalmopathy‐index score, which was based on a modification of the American Thyroid Association's classification of ocular changes in Graves' disease; 4 categories of findings (soft tissue involvement, exophthalmos, extraocular muscle involvement and sight loss) were scored from 1 to 3 according to their severity

TSH (0.1 ‐ 4.5 mu/L), T₄ (75 ‐ 150 nmol/L) and T₃ (1.1 ‐ 2.5) nmol/L levels within the normal range

N/I

The costs were assessed by analysing the official hospital reimbursement system for both outpatient and inpatient costs for a period of 2 years from the day of randomisation; sick leave: number of days the participants stayed at home from work due to Graves' disease or other diseases

"‐" denotes not reported

FT₃: free triiodothyronine; FT₄: free thyroxin; N/I: not investigated; T₃: triiodothyronine; T₄: thyroxine; TSH: thyroid‐stimulating hormone

Intervention(s) and comparator(s)

Participants included in analysis
[N]

Deaths
[N]

Deaths
[%]

Participants with at least one adverse event
[N]

Participants with at least one adverse event
[%]

Participants with at least one severe/serious adverse event
[N]

Participants with at least one severe/serious adverse event
[%]

Traisk 2009

I: radioiodine

163

‐

‐

0

0

‐

‐

C: methimazole

150

‐

‐

12

8

‐

‐

Tallstedt 1992^a

I: radioiodine

39

‐

‐

39^b

100

‐

‐

C: methimazole

68

‐

‐

11

16

‐

‐

‐ denotes not reported

^aData from up to 48 months follow‐up.
^bAll participants developed hypothyroidism after the initial or additional treatments and were given T₄; the mean time from the initial treatment until T₄ was prescribed was 3.7 months.

C: comparator; I: intervention; T₄: thyroxine

Intervention(s) and comparator(s)

Participants included in analysis
[N]

Participants discontinuing trial due to an adverse event
[N]

Participants discontinuing trial due to an adverse event
[%]

Traisk 2009

I: radioiodine

163

‐

‐

C: methimazole

150

‐

‐

Tallstedt 1992

I: radioiodine

39

‐

‐

C: methimazole

68

‐

‐

‐ denotes not reported

C: comparator; I: intervention

Instrument

Dimensions (subscales)
[no. of items]

Validated instrument

Answer options

Scores

Minimum score

Maximum score

Weighting
of scores

Direction
of scales

Minimal important difference

SF‐36 (G)

Physical functioning (PF) (10) Role‐physical (RP) (4) Bodily pain (BP) (2) General health (GH) (5) Vitality (VT) (4) Social functioning (SF) (2) Role‐emotional (RE) (3) Mental health (MH) (5) Reported health transition (RHT) (1)

Yes

3‐, 5‐ and 6‐point Likert‐scale

Scores for dimensions
Physical component summary (PCS)

Mental component summary (MCS)

Minimum scores:
scores for dimensions/PCS/MCS:
norm‐based scale

Maximum scores:
scores for dimensions/PCS/MCS:
norm‐based scale

No

Higher values
mean better assessment

PCS: 2 to 3 points MCS: 3 points Dimensions: PF/BT/VT: 2 points, if score < 40; 3 points, if score ≥ 40 RP: 2 points SF/MH: 3 points RE: 4 points

Traisk 2009

Quote from the publication: "Patients who had experienced development or worsening of eye problems at any time point during the 4‐year study period (TAO group) had lower QoL estimated by the SF‐36 questionnaire when no attention was paid to the mode of treatment ... throughout the whole study period, the TAO group had lower MCS and PCS for the first 3 years ... There were no differences in the results of the SF‐36 scores between the two treatment groups ... Already after 3 months, the physical component score reached the average for the Swedish reference population (score 50) and remained at this level throughout the study period (48 months). The mental component score showed some delay in both the radioiodine and medically treated groups to reach the average score of 50 not until 12 months. Thereafter, the mental component score remained rather constant for 3 years or at least until 48 months ... Comparisons between the two groups of patients without TAO showed no significant differences in QoL regardless whether they had been treated with radioiodine or ATDs ... The study also showed that QoL was rather equal in both treatment groups when no attention was paid to the possible influence of TAO ... Patients with TAO generally had significantly lower QoL scores as compared with patients without TAO at several time points, but no consistent treatment‐ or time‐related pattern could be found ... The result of this analysis showed that the SF‐36 due to its generic properties is not an optimal instrument for measuring QoL‐related issues in this population ... Although the SF‐36 is used extensively, it has not been specifically evaluated in a population of GD patients, but neither have other disease‐specific instruments."

Tallstedt 1992^a

Quote from publication: "The Physical Component Summary and Mental Component Summary were not significantly different among the three old‐age groups. Also the sub‐component Summaries of the Physical and Mental Component Summary were similar .... Compared to the Swedish reference population at 50‐74 years, we observed that the Vitality score was lower for all three treatment groups (p < 0.05). The medical group had a significantly lower Mental Component Summary than the reference population ... The radioiodine‐treated group had a significantly lower General Health score (p < 0.05)"

^a145/179 participants with evaluated questionnaires (56 on surgery, 55 on antithyroid drugs, 34 on radioiodine); only figures are provided (Abraham‐Nordling 2005 under Tallstedt 1992).

ATD: antithyroid drug; G: generic; GD: Graves' disease; QoL: quality of life; S: specific; SF: short‐form health survey

Trial author contacted

Trial author replied

Trial author asked for additional information

Trial author provided data

Traisk 2009

Yes (2012)

No

No

No

Tallstedt 1992

Yes (2012)

Yes (2012)

Yes (2012)

Yes (2012); trial author provided the exact number of participants in different thyroid status after treatment for hyperthyroidism

(1) Health‐related quality of life

(2) Development and worsening of Graves' ophthalmopathy

(3) Individuals in euthyroid state

(4) Recurrence of hyperthyroidism (relapse)

(5) Adverse events other than development and worsening of Graves' ophthalmopathy (hypothyroidism, adverse drug effects)

(6) All‐cause mortality

(7) Socioeconomic effects

Trial limitations
(risk of bias)^a

Was random sequence generation used (i.e. no potential for selection bias)?

Unclear

Unclear

Unclear

Unclear

Unclear

N/A

Unclear

Was allocation concealment used (i.e. no potential for selection bias)?

Yes/Unclear

Yes/Unclear

Yes/Unclear

Yes/Unclear

Yes/Unclear

N/A

Yes

Was there blinding of participants and personnel (i.e. no potential for performance bias) or outcome not likely to be influenced by lack of blinding?

No (↓)

Yes/No (↓)

Yes

Yes

Yes

N/A

Yes

Was there blinding of outcome assessment (i.e. no potential for detection bias) or was outcome measurement not likely to be influenced by lack of blinding?

Yes/No (↓)

Yes/No (↓)

Yes

Yes

Yes

N/A

Yes

Was an objective outcome used?

Yes

Yes

Yes

Yes

Yes/No (↓)

N/A

Yes

Were more than 80% of participants enrolled in trials included in the analysis (i.e. no potential reporting bias)?^e

Yes

Yes

Yes

Yes

Yes

N/A

Yes

Were data reported consistently for the outcome of interest (i.e. no potential selective reporting)?

Yes

Yes

Yes

Yes

Yes

N/A

Yes

No other biases reported (i.e. no potential of other bias)?

Yes

Yes

Yes

Yes

Yes

N/A

Yes

Did the trials end up as scheduled (i.e. not stopped early)?

Yes

Yes

Yes

Yes

Yes

N/A

Yes

Inconsistency^b

Point estimates did not vary widely?

N/A

Yes

N/A

No (↓)

N/A

N/A

N/A

To what extent did confidence intervals overlap (substantial: all confidence intervals overlap at least one of the included studies point estimate; some: confidence intervals overlap but not all overlap at least one point estimate; no: at least one outlier: where the confidence interval of some of the studies do not overlap with those of most included studies)?

N/A

Some

N/A

No (↓)

N/A

N/A

N/A

Was the direction of effect consistent?

N/A

Yes

N/A

Yes

N/A

N/A

N/A

What was the magnitude of statistical heterogeneity (as measured by I²) ‐ low (I² < 40%), moderate (I² 40% to 60%), high I² > 60%)?

N/A

Low

N/A

High (↓)

N/A

N/A

N/A

Was the test for heterogeneity statistically significant (P value < 0.1)?

N/A

Not statistically significant

N/A

Statistically significant (↓)

N/A

N/A

N/A

Indirectness^a

Were the populations in included studies applicable to the decision context?

Highly applicable

Highly applicable

Highly applicable

Highly applicable

Highly applicable

N/A

Highly applicable

Were the interventions in the included studies applicable to the decision context?

Highly applicable

Highly applicable

Highly applicable

Highly applicable

Highly applicable

N/A

Highly applicable

Was the included outcome not a surrogate outcome?

Yes

Yes

Yes

Yes

Yes/No (↓)

N/A

Yes

Was the outcome timeframe sufficient?

Sufficient

Sufficient

Sufficient

Sufficient

Sufficient

N/A

Sufficient

Were the conclusions based on direct comparisons?

Yes

Yes

Yes

Yes

Yes

N/A

Yes

Imprecision^c

Was the confidence interval for the pooled estimate not consistent with benefit and harm?

N/A

Yes

N/A

No (↓)

N/A

N/A

N/A

What is the magnitude of the median sample size (high: 300 participants, intermediate: 100 to 300 participants, low: < 100 participants)?^e

Intermediate

Intermediate

Intermediate

Intermediate

Intermediate

N/A

Low (↓)

What was the magnitude of the number of included studies (large: > 10 studies, moderate: 5 to 10 studies, small: < 5 studies)?^e

Small (↓)

Small (↓)

Small (↓)

Small (↓)

Small (↓)

N/A

Small (↓)

Was the outcome a common event (e.g. occurs more than 1/100)?

N/A

Yes

N/A

Yes

N/A

N/A

N/A

Publication bias^d

Was a comprehensive search conducted?

Yes

Yes

Yes

Yes

Yes

N/A

Yes

Was grey literature searched?

No (↓)

No (↓)

No (↓)

No (↓)

No (↓)

N/A

No (↓)

Were no restrictions applied to study selection on the basis of language?

Yes

Yes

Yes

Yes

Yes

N/A

Yes

There was no industry influence on studies included in the review?

Yes

Yes

Yes

Yes

Yes

N/A

Yes

There was no evidence of funnel plot asymmetry?

N/A

N/A

N/A

N/A

N/A

N/A

N/A

There was no discrepancy in findings between published and unpublished trials?

Unclear

Unclear

Unclear

Unclear

Unclear

N/A

Unclear

^aQuestions on risk of bias are answered in relation to the majority of the aggregated evidence in the meta‐analysis rather than to individual trials.
^bQuestions on inconsistency are primarily based on visual assessment of forest plots and the statistical quantification of heterogeneity based on I².

^cWhen judging the width of the confidence interval it is recommended to use a clinical decision threshold to assess whether the imprecision is clinically meaningful.
^dQuestions address comprehensiveness of the search strategy, industry influence, funnel plot asymmetry and discrepancies between published and unpublished trials.
^eDepends on the context of the systematic review area.

(↓): key item for possible downgrading the quality of the evidence (GRADE) as shown in the footnotes of the 'Summary of finding' table(s); GRADE: Grading of Recommendations Assessment, Development and Evaluation; N/A: not applicable