Is radioiodine treatment better than antithyroid drugs for the therapy of Graves' disease?
Graves' disease is an autoimmune disorder, which means that the body's immune systems attacks the body itself by means of antibodies. These antibodies stimulate the thyroid gland to produce and secrete excessive amounts of thyroid hormones (hyperthyroidism). Graves' disease is the most common cause of hyperthyroidism. Other typical characteristics of Graves' disease are goitre and eye disease (Graves' ophthalmopathy or orbitopathy). Currently, antithyroid medications such as methimazole or propylthiouracil and radioactive iodine (radioiodine, given either in a capsule or in a tasteless solution in water) are most often used for the treatment of Graves' disease. Radioiodine destroys most cells in the thyroid gland, so that secretion of thyroid hormones is massively reduced. Antithyroid medications block the production of thyroid hormones, also leading to a decrease in the production of these hormones.
We identified two randomised controlled trials (RCTs) enrolling 425 adult participants with Graves' disease. Altogether 204 participants were randomised to treatment with radioiodine and 221 to methimazole. Follow-up in the included studies was from 2 to 21 years depending on which outcome was investigated.
Study authors reported health-related quality of life to be similar in the radioiodine and methimazole treatment groups, however exact data were not published.
The development and worsening of Graves' opthalmopathy, which is a serious eye disease that happens in some people with Graves' disease, was observed in 361 of 1000 radioiodine-treated persons compared with 186 of 1000 methimazole-treated persons. A high percentage of the study participants were smokers, which is related to the risk of worsening or development of Graves' opthalmopathy.
A normal thyroid gland function (euthyroidism) was not achieved by any participant who was treated with radioiodine compared with 64 of 68 participants (94%) after methimazole treatment. In this study thyroid hormone (thyroxine) therapy was not started early in both treatment arms to accomplish euthyroidism.
A recurrence of hyperthyroidism (relapse of the disease) was seen more often after methimazole treatment, however the size of the effect is unclear because of big differences between the two included studies.
A side effect related to radioiodine therapy was an underactive thyroid gland (hypothyroidism), which was seen in 39 of 41 participants (95%) compared with 0% of participants receiving methimazole. Again, in this study thyroxine therapy, with the aim to avoid hypothyroidism, was not given early in the radioiodine group. Side effects related to methimazole treatment were seen in 23 of 215 participants (11%). The outcomes death from any cause and bone mineral density were not reported in the included studies.
One study reported socioeconomic effects: costs based on the official hospital reimbursement system in Sweden for people without relapse and methimazole treatment were between USD 1126 and USD 1164, and for radioiodine treatment USD 1862. Costs for people with relapse and methimazole treatment were between USD 1972 and USD 2284, and for radioiodine treatment USD 2760.
Quality of the evidence
The overall quality of the evidence was low to very low mainly because there were just one or two studies per outcome and the number of participants was small. Another limitation is that among antithyroid medications only methimazole was investigated, which might limit the applicability of our findings with regard to other medications such as propylthiouracil.
Currentness of evidence
This evidence is up to date as of September 2015.
The only antithyroid drug investigated in the two included trials was methimazole, which might limit the applicability of our findings with regard to other compounds such as propylthiouracil. Results from two RCTs suggest that radioiodine treatment is associated with an increased risk of Graves' ophthalmopathy. Our findings suggest some benefit from radioiodine treatment for recurrence of hyperthyroidism (relapse) but there is uncertainty about the magnitude of the effect size.
Graves' disease is the most common cause of hyperthyroidism. Both antithyroid medications and radioiodine are commonly used treatments but their frequency of use varies between regions and countries. Despite the commonness of the diagnosis, any possible differences between the two treatments with respect to long-term outcomes remain unknown.
To assess the effects of radioiodine therapy versus antithyroid medications for Graves' disease.
We performed a systematic literature search in the Cochrane Library, MEDLINE and EMBASE and the trials registers ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was September 2015 for all databases.
Randomised controlled trials (RCTs) comparing the effects of radioiodine therapy versus antithyroid medications for Graves' disease with at least two years follow-up.
Two authors independently screened titles and abstracts for relevance. One author carried out screening for inclusion, data extraction and 'Risk of bias' assessment and a second author checked this. We presented data not suitable for meta-analysis as descriptive data. We analysed the overall quality of evidence utilising the GRADE instrument.
We included two RCTs involving 425 adult participants with Graves' disease in this review. Altogether 204 participants were randomised to radioiodine therapy and 221 to methimazole therapy. A single dose of radioiodine was administered. The duration of methimazole medication was 18 months. The period of follow-up was at least two years, depending on the outcome measured. For most outcome measures risk of bias was low; for the outcomes health-related quality of life as well as development and worsening of Graves' ophthalmopathy risks of performance bias and detection bias were high in at least one of the two RCTs.
Health-related quality of life appeared to be similar in the radioiodine and methimazole treatment groups, however no quantitative data were reported (425 participants; 2 trials; low quality evidence). The development and worsening of Graves' ophthalmopathy was observed in 76 of 202 radioiodine-treated participants (38%) and in 40 of 215 methimazole-treated participants (19%): risk ratio (RR) 1.94 (95% confidence interval (CI) 1.40 to 2.70); 417 participants; 2 trials; low quality evidence. A total of 35% to 56% of radioiodine-treated participants and 42% of participants treated with methimazole were smokers, which is associated with the risk of worsening or development of Graves' ophthalmopathy. Euthyroidism was not achieved by any participant being treated with radioiodine compared with 64/68 (94%) of participants after methimazole treatment (112 participants; 1 trial). In this trial thyroxine therapy was not introduced early in both treatment arms to avoid hypothyroidism. Recurrence of hyperthyroidism (relapse) in favour of radioiodine treatment showed a RR of 0.20 (95% CI 0.01 to 2.66); P value = 0.22; 417 participants; 2 trials; very low quality evidence. Heterogeneity was high (I² = 91%) and the RRs were 0.61 or 0.06 with non-overlapping CIs. Adverse events other than development of worsening of Graves' ophthalmopathy for radioiodine therapy were hypothyroidism (39 of 41 participants (95%) compared with 0% of participants receiving methimazole, however thyroxine treatment to avoid hypothyroidism was not introduced early in the radioiodine group - 104 participants; 1 trial; very low quality evidence) and drug-related adverse events for methimazole treatment (23 of 215 participants (11%) reported adverse effects likely related to methimazole therapy - 215 participants; 2 trials; very low quality evidence). The outcome measures all-cause mortality and bone mineral density were not reported in the included trials. One trial (174 participants) reported socioeconomic effects: costs based on the official hospital reimbursement system in Sweden for patients without relapse and methimazole treatment were USD 1126/1164 (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.