Radioiodine therapy versus antithyroid medications for Graves' disease

Chao Ma; Jiawei Xie; Hui Wang; Jinsong Li; Suyun Chen

doi:10.1002/14651858.CD010094.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial (blank cells indicate that the trial did not measure that particular outcome).

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Analysis 1.1

Comparison 1 Radioiodine versus methimazole, Outcome 1 Development or worsening of Graves' ophthalmopathy.

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Analysis 1.2

Comparison 1 Radioiodine versus methimazole, Outcome 2 Adverse events: hypothyroidism.

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Analysis 1.3

Comparison 1 Radioiodine versus methimazole, Outcome 3 Recurrence of hyperthyroidism (relapse).

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Analysis 1.4

Comparison 1 Radioiodine versus methimazole, Outcome 4 Participants in euthyroid state.

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Radioiodine therapy compared with antithyroid medications for Graves' disease
Patient: participants with Graves' disease Settings: outpatients Intervention: radioiodine Comparison: methimazole
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Methimazole	Radioiodine	Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Health‐related quality of life [measured by the validated questionnaire SF‐36] Follow‐up: 4 years and 14 to 21 years	See comment	See comment	See comment	425 (2)	See comment	2 trials assessed this outcome but no quantitative data for comparisons between intervention groups were provided; trial authors in 1 trial reported that there were no differences in the results of the SF‐36 scores between the 2 treatment groups
Development and worsening of Graves' ophthalmopathy [examination by ophthalmologists] Follow‐up: 2 years and 4 years	186 per 1000	361 of 1000 (260 to 502)	RR 1.94 (1.40 to 2.70)	417 (2)	⊕⊕⊝⊝ low^a	‐
Individuals in euthyroid state [measured by serum thyroid hormone levels within the normal range] Follow‐up: at least 4 years	See comment	See comment	See comment	112 (1)	See comment	No participant who underwent radioiodine treatment achieved an euthyroid state compared to 4/68 participants not becoming euthyroid treated by methimazole (Tallstedt 1992); however, in this trial thyroxine therapy was not introduced early in both treatment arms to avoid hypothyroidism
Recurrence of hyperthyroidism (relapse) [measured by serum thyroid hormone levels above the normal range after withdrawal of methimazole or end of radioiodine treatment] Follow‐up: at least 4 years	256 per 1000	51 of 1000 (3 to 680)	RR 0.20 (0.01 to 2.66)	417 (2)	⊕⊝⊝⊝ very low^b	‐
Adverse events other than development or worsening of Graves' disease (a) Hypothyroidism [measured by TSH and/or thyroid hormones] (b) Drug reactions Follow‐up: (a) at least 2 years (b) at least 4 years	See comment	See comment	See comment	(a) 104 (1) (b) 215 (2)	a) ⊕⊝⊝⊝ very low^c b) ⊕⊝⊝⊝ very low^d	(a) 39 of 41 participants developed hypothyroidism after radioiodine treatment for Graves' disease, compared with 0 of 65 participants receiving methimazole (Tallstedt 1992); however, in this trial thyroxine was not introduced early in both treatment groups in order to avoid hypothyroidism (b) 23 of 215 participants (11%) reported adverse effects likely related to methimazole treatment
All‐cause mortality Follow‐up: at least 4 years and 14 to 21 years	See comment	See comment	See comment	425 (2)	See comment	No quantitative data for all‐cause mortality were reported
Socioeconomic effects [costs per patient, based on the official hospital reimbursement system in Sweden] Follow‐up: 2 years	See comment	See comment	See comment	112 (1)	See comment	Costs for patients without relapse and methimazole treatment were USD 1126/USD 1164 (young/older methimazole group) and for radioiodine treatment USD 1862 Costs for patients with relapse and methimazole treatment were USD 2284/1972 (young/older methimazole group) and for radioiodine treatment USD 2760
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; SF‐36: 36‐item Short Form Health Status Survey; TSH: thyroid‐stimulating hormone
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risk was derived from the event rates in the comparator groups. ^aDowngraded by two levels: one level because of performance and detection bias and one level because of imprecision (see Appendix 12). ^bDowngraded by three levels: two levels because of serious inconsistency and one level because of imprecision (see Appendix 12). ^cDowngraded by three levels: one level because of indirectness and two levels because of imprecision (see Appendix 12). ^cDowngraded by three levels: one level because of risk of bias, one level because of indirectness and one level because of imprecision (see Appendix 12).

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Table 1. Overview of study populations

	Intervention(s) and comparator(s)	Sample size^a	Screened/eligible [N]	Randomised [N]	ITT [N]	Analysed [N]	Finishing trial [N]	Randomised finishing trial [%]	Follow‐up (extended follow‐up)^b
Traisk 2009	Radioiodine	Primary endpoint was the difference in the proportion of participants with worsening or development of thyroid‐associated ophthalmopathy during a 4‐year follow‐up in the 2 groups (intention‐to‐treat analysis). A comparison (0.05, two‐tailed test) of the binomial proportions between 2 groups of 300 patients each would give more than 90% probability (power) to detect a true difference of 10%	482/333	‐	163	163	163	‐	24 months (4 years)
	Methimazole		482/333	‐	150	150	150	‐
	total:			333	313	313	313	94
Tallstedt 1992^e	Radioiodine	‐	179	41	‐	39^f	39	95	At least 24 months (at least 48 months; 3 years; 5 years; 14‐21 years)^g
	Methimazole	‐	179	71		65^f	64	90
	total:			112		104	103	92
*Grand total*	*All radioiodine‐treated participants*			*204*
	*All participants treated with methimazole*			*221*
	*All interventions*			*425*
"‐" denotes not reported ^aInformation about power calculation, sample size etc. in trial publication or report. ^bFollow‐up under randomised conditions until end of trial or, if not available, duration of intervention; extended follow‐up refers to follow‐up of participants once the original study was terminated as specified in the power calculation. ^cEnrollment in the study started in May 1996. By the second half of 2002, it was obvious that the inclusion rate was too slow to obtain the full number of participants within a reasonable period of time and the study was closed in 2003. This meant that with the above specifications and the number of observations obtained so far (333 enrolled participants), the study had a power of about 70%. With the 4‐year clinical follow‐up, the study was terminated by the end of 2007. ^dThe cumulative drop‐out (last observation carried forward) from the ophthalmological follow‐up in the radioiodine group and the medical treatment group, respectively, was as follows: at 1 year, 3% and 1%; at 2 years, 6% and 3%; and at 3 years, 10% and 9%, respectively. At 4 years (i.e. after protocol for ophthalmological follow‐up), 20% of the participants in both groups were still followed by ophthalmologists. ^eParticipants were stratified into two age groups (20 to 34 years (group 1) and 35 to 55 years (group 2)). Participants in group 1 were randomised to treatment with methimazole for 18 months or subtotal thyroidectomy, participants in group 2 to methimazole, subtotal thyroidectomy or radioiodine treatment. Numbers in the table reflect the participants being treated with methimazole or radioiodine. ^fWith regard to occurrence of ophthalmopathy within two years after the initiation of therapy. ^gDifferent follow‐up times according to various publications of extended follow‐up. ITT: intention‐to‐treat

Table 1. Overview of study populations

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Comparison 1. Radioiodine versus methimazole

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Development or worsening of Graves' ophthalmopathy Show forest plot	2	417	Risk Ratio (M‐H, Random, 95% CI)	1.94 [1.40, 2.70]

2 Adverse events: hypothyroidism Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Recurrence of hyperthyroidism (relapse) Show forest plot	2	417	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 2.66]

4 Participants in euthyroid state Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 1. Radioiodine versus methimazole

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