Abstract: Twenty-six randomised trials involving 3388 participants were included. Overall the quality of trials, as reported, was poor. None of the studies investigated incidence of hypothyroidism, changes in weight, health-related quality of life, ophthalmopathy progression or economic outcomes. Four trials examined the effect of duration of therapy on relapse rates, and when using the titration regimen 12 months was superior to six months, but there was no benefit in extending treatment beyond 18 months. Twelve trials examined the effect of block-replace versus titration block-regimens. The relapse rates were similar in both groups at 51% in the block-replace group and 54% in the titration block-group (OR 0.86, 95% confidence interval (CI) 0.68 to1.08) though adverse effects (rashes (10% versus 6%) and withdrawing due to side effects (16% versus 9%)) were significantly higher in the block-replace group. Three studies considered the addition of thyroxine with continued low dose antithyroid therapy after initial therapy with antithyroid drugs. There was significant heterogeneity between the studies and the difference between the two groups was not significant (OR 0.58, 95% CI 0.05 to 6.21). Four studies considered the addition of thyroxine alone after initial therapy with antithyroid drugs. There was no significant difference in the relapse rates between the groups after 12 months follow-up (OR 1.15, 95% CI 0.79 to 1.67). Two studies considered the addition of immunosuppressive agents. The results which were in favour of the interventions would need to be validated in other populations. The evidence suggests that the optimal duration of antithyroid drug therapy for the titration regimen is 12 to 18 months. The titration (low dose) regimen had fewer adverse effects than the block-replace (high dose) regimen and was no less effective. Continued thyroxine treatment following initial antithyroid therapy does not appear to provide any benefit in terms of recurrence of hyperthyroidism. Immunosuppressive therapies need further evaluation.

Plain-language summary: Twenty-six RCTs involving 3388 participants were identified. The majority of participants in all the studies were female (83% in the studies reporting sex distribution). The mean age was 40 years. The duration of follow up was between two to five years in eleven trials. In high dose ('block-replace') versus low dose ('titration') studies the duration of therapy was six months in two studies, 18 months in four studies and 12 months in the remaining trials. The main outcome was the relapse rate of hyperthyroidism over one year after completion of drug treatment and this was the primary outcome in all the studies assessed. There were no deaths reported in any of the studies. None of the studies detailed incidence of hypothyroidism, changes in weight during the course of therapy, health-related quality of life, ophthalmopathy progression or economic outcomes. The evidence (based on four studies) suggests that the optimal duration of antithyroid drug therapy for the low dose regimen is 12 to 18 months. The low dose regimen had fewer adverse effects than the high dose regimen and was no less effective in trials (based on 12 trials) of equal duration. Continued thyroxine treatment following initial antithyroid therapy does not appear to provide any benefit in terms of recurrence of hyperthyroidism. Studies using immunosuppressive agents need further validation of safety and efficacy in controlled trials among different populations. Data regarding side effects and number of participants withdrawn from therapy due to side effects were available in seven studies. The number of participants reporting rashes was significantly higher in the high versus low dose group (10% versus 6%). The number of participants withdrawing due to side effects were also significantly higher in the high versus low dose group (16% versus 9%).