A Systematic Review of Drug Therapy for Graves' Hyperthyroidism

Home , Carbimazole, Liothyronine, Propylthiouracil

European Journal of Endocrinology (2005) 153 489–498 ISSN 0804-4643

REVIEW A systematic review of drug therapy for Graves’ hyperthyroidism Prakash Abraham, Alison Avenell, Christine M Park, Wendy A Watson and John S Bevan Department of Endocrinology, Health Services Research Unit, Aberdeen Royal Inﬁrmary, Foresterhill, Aberdeen AB25 2ZN, UK (Correspondence should be addressed to P Abraham; Email: [email protected])

Abstract We assessed the effects of dose, regimen and duration of anti-thyroid drug therapy for Graves’ thyrotoxicosis on recurrence of hyperthyroidism, course of ophthalmopathy, adverse effects, health-related quality of life and economic outcomes. We undertook a systematic review and meta-analyses of randomised controlled trials (RCTs). We identified RCTs regardless of language or publication status by searching six databases, and trial registries. Dual, blinded data abstraction and quality assessment were undertaken. Trials included provided therapy for at least 6 months with follow-up at least 1 year after drug cessation. Fixed or random effects meta-analyses were used to combine study data. Twelve trials compared a Block-Replace regimen (requiring a higher dose of anti-thyroid drug treatment) with a Titration regimen. Overall, there was no significant difference between the regimens for relapse of hyperthyroidism (relative risk (RR) ¼ 0.93, 95% confidence interval (CI) 0.84 to 1.03). Par- ticipants were more likely to withdraw due to adverse events with a Block-Replace regimen (RR ¼ 1.89, 95% CI 1.25 to 2.85). Prescribing replacement thyroxine, either with the anti-thyroid drug treatment, or after this was completed, had no significant effect on relapse. Limited evidence suggested 12–18 months of anti-thyroid drug treatment should be used. The titration regimen appeared as effective as the Block-Replace regimen, and was associated with fewer adverse effects. However, relapse rates over 50% and high participant drop-out rates in trials mean that the results should be interpreted with caution, and may suggest that other strategies for the management of Graves’ disease, such as radioiodine, should be considered more frequently as first-line therapy. There were no data on the course of ophthalmopathy, health-related quality of life and economic outcomes.

European Journal of Endocrinology 153 489–498

Introduction The preferred regimen and duration of therapy remain unresolved with varying duration from 6 to Hyperthyroidism is common, affecting approximately 24 months with either the Block-Replace or the 2% of women and 0.2% of men (1). The most Titration regimen. We undertook a substantial update common cause of hyperthyroidism is Graves’ disease to a Cochrane systematic review (2) assessing the (1). Methimazole, carbimazole and propylthiouracil effects of anti-thyroid drug regimen and duration in are the main drug treatments, blocking thyroid hor- the treatment of Graves’ hyperthyroidism. mone synthesis. They may also help control thyrotoxicosis by immune suppression. Propylthiouracil Methods additionally inhibits the peripheral conversion of thyroxine (T4) to triiodothyronine. Methimazole is the PA was involved in protocol development, searching for active metabolite of carbimazole, and since the conver- trials, quality assessment of trials, data abstraction and sion of carbimazole to methimazole is virtually com- data analysis. A A was involved in protocol develop- plete, equivalent doses are thought to be comparable. ment, quality assessment of trials, data abstraction Anti-thyroid drug therapy can be given either by the and data analysis. W A W was involved in searching Block-Replace regimen (where a higher dose of anti- for trials, quality assessment of trials and data abstrac- thyroid drug is used with a replacement dose of thyroid tion. C M P undertook quality assessment of trials and hormone) or by the Titration regimen (where the anti- data abstraction. J S B provided clinical input, and res- thyroid drug dose is reduced by titrating treatment olution of differences of opinion. No Ethics approval against thyroid hormone concentrations). was required.

q 2005 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.01993 Online version via www.eje-online.org

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Search strategy for identification of studies Any differences were resolved by discussion between the reviewers. We identified relevant studies regardless of language or publication status by searching The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2004), MEDLINE (1966 to July 2004), EMBASE (1980 Quantitative data synthesis to July 2004), BIOSIS (1985 to July 2004), CINAHL Where appropriate, the results of comparable groups of (1982 to July 2004), HEALTHSTAR (1975 to June trials were combined for relative risks (RRs) using fixed- 2002) and trial registries. We contacted authors of pub- effects models, and results are presented with 95% lished trials and thyroid researchers and checked the confidence intervals (CIs). Heterogeneity between com- references of retrieved studies and reviews for additional parable trials was assessed by the I2 statistic (3). trials. Three trialists provided additional data. Random effects models were used where I2 was 50% or more. Pre-specified subgroup and sensitivity ana- Selection lyses were undertaken. We included all published and unpublished, randomised and quasi-randomised controlled trials (RCTs) of patients of any age receiving anti-thyroid drug treat- Results ment for Graves’ hyperthyroidism, where Graves’ hyperthyroidism had been adequately defined. We Trial flow pre-specified a minimum duration for drug treatment Twenty-three RCTs were included in the review (Fig. 1). of 6 months and a minimum duration of follow-up of All studies included adults only. Overall 83% of 1 year from completion of drug therapy to assess the participants were women, and the weighted mean age pre-specified outcomes. was 40 years. We sought trials of carbimazole, propylthiouracil, methimazole, lithium or perchlorate. We pre-specified the comparisons of Block-Replace vs Titration regimen; short-term (6 months) vs long-term (over 6 months) regimens; high-dose drug therapy (equivalent to 40 mg carbimazole or more) vs low-dose (equivalent to 30 mg carbimazole or less); and continued thyroid hormone replacement with or without continued anti-thyroid medication. The main outcome measures were recurrence of hyperthyroidism, incidence of hypothyroidism and mor- tality. Additional outcome measures sought were the course of ophthalmopathy (need for corticosteroids, radiotherapy, visual compromise); adverse effects (agranulocytosis, drug rash, hepatitis, vasculitis); symptoms of hyperthyroidism (anxiety, tachycardia, heat intoler- ance, diarrhoea, oligomenorrhoea); thyroid antibody status; weight change; frequency of outpatient visits and thyroid function tests; health-related quality of life; economic outcomes; compliance; and necessity for surgery or radioiodine.

Validity assessment Quality assessment of RCTs included allocation concealment, whether intention-to-treat analysis was undertaken, comparability of groups at baseline, and blinding of outcome assessors. The summary risk of bias was based on the concealment of allocation.

Data abstraction Two reviewers independently abstracted the data and assessed the methodological quality of the studies. Figure 1 Flow of studies through the meta-analysis.

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Duration of anti-thyroid therapy (Table 1, Fig. 2) In one study (4, 5) the longer-duration Titration regimen (18 months) had significantly fewer relapses than the 6 month group (RR ¼ 0.63, 95% CI 0.41 to 0.99). One study (6) found there was no significant difference between 12 and 6 months (RR ¼ 0.86, 95% CI 0.52 to 1.43) using the Block-Replace regi- Methodological rating for men. concealment of allocation Two other studies used longer durations of Titration regimen, comparing 12 months with 24 months (7) and 18 months with 42 months of therapy (8). Com- bining these showed no significant difference between the longer and shorter durations of treatment (% (numbers)) (RR ¼ 0.88, 95% CI 0.67 to 1.16). Relapse rates f assignment, or states ‘random’ but no description given;

Block-Replace vs Titration regimen (Table 2, Figs 3 and 4) The anti-thyroid drug used was carbimazole in eight studies (9–16). The dose ranged between 30 and 60 mg/day in the Block-Replace arms of all these studies except for one study (11), where a dose of at close of study 100 mg/day was used. Methimazole was used in three studies (17–20) where doses of 30–60 mg/day were used in the Block-Replace arms of the trials. One Patients randomised/assessed study (21) used either propylthiouracil or methimazole but the doses were not reported. The duration of therapy was 6 months in two studies (11, 19), 18 months in four studies (9, 10, 15, 20) and 12 follow-up months in the remaining trials (duration of therapy Duration of in one study (21) is unknown). Including all trials, irrespectively of length of follow- up, there was no signiﬁcant difference in the relapse rates between the Block-Replace (322 of 636; 51%) therapy Duration of 2:6 months 2:92/72 2:36 (26/72) 2:6 months 2:29/28 2:86 (24/28) 2:6 months 2:57/48 2:58 (28/48) and Titration (332 of 614; 54%) regimens 2:6 months 2:NS/59 2:41 (20/49) (RR ¼ 0.93, 95% CI 0.84 to 1.03) when the losses to follow-up were not considered. However, there were T4 1:12 months 1 year 1:NS/51 1:35 (18/51) C large losses to follow-up, with 234 and 223 in the þ Block-Replace and Titration groups respectively. Excluding one study (17, 18) with a loss to follow-up of 44% had no major effect on the overall results (RR ¼ 0.91, 95% CI 0.81 to 1.03). When analysis was carried out making the extreme assumption of relapsed hyperthyroidism in participants lost to follow-up there was a signiﬁcant difference between the two groups, with relapse rates of 63% (549 of 870) in the Block-Replace group and 68% (566 of 837) in the Titration group (RR ¼ 0.93, 95% CI 0.87 France CBZ 30–50 mg titrated 1:42 months 2 years 1:82/62 1:29 (18/62) B UK CBZ 60, then 40 mg Spain CBZ 30 mg titrated 1:24 months 5 years 1:27/24 1:83 (20/24) B to 0.99). Therefore the true relapse rates with either France CBZ 60 mg titrated 1:18 months 2 years 1:57/46 1:37 (17/46) B

of these anti-thyroid drug regimen would be between . 51 and 68%. . et al .

Data regarding side-effects and number of partici- et al. et al

pants withdrawn from therapy due to side-effects Trials comparing long vs shorter duration of anti-thyroid therapy. et al were available in seven studies (11, 13, 14, 16–19). The number of participants reporting rashes was sig- Maugendre (1999) (8) Weetman (1994) (6) Garcia-Mayor (1992) (7) Allannic (1990,1991) (4, 5) C, quasi-randomised (alternate allocation to groups). niﬁcantly higher in the Block-Replace trial arms Table 1 Trial LocationAbbreviations: CBZ: carbimazole; Intervention T4:Methodological levothyroxine; rating NS: for not concealment stated. of allocation: A, method did not allow disclosure of assignment; B, small, but possible chance of disclosure o

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Figure 2 Long vs shorter duration of anti-thyroid therapy – participants relapsing. (Allannic et al. (1990,1991) (4, 5), Weetman et al. (1994) (6), Garcia-Mayor et al. (1992) (7), Maugendre et al. (1999) (8)).

(10%, 63 of 616) as compared with the Titration arms of this study also yielded no significant difference in the (5%, 31 of 622) (RR ¼ 2.04, 95% CI 1.36 to 3.06). relapse rates. The Block-Replace regimens also had more patients with agranulocytosis compared with the titration group (nine vs three). There was one further report of Initial anti-thyroid drug therapy followed by agranulocytosis in one study (20) but the treatment T4 compared with no T4 (Table 3, Fig. 5) group was not mentioned. The number of participants Three studies (25–29) gave anti-thyroid drugs for withdrawing due to side-effects was also significantly 12–18 months and then randomised into groups higher on the Block-Replace regimen (RR ¼ 1.89, receiving either T4 or no treatment. One study (25, 95% CI 1.25 to 2.85). The study (11) using the highest 26) randomised the T4 group further at the end of dose of 100 mg carbimazole had 7 of 17 patients in the the first year into groups either stopping or continuing Block-Replace regimen withdrawing due to side-effects T4 (only the results of the initial randomisation with including two cases of agranulocytosis and five with results at the end of the first year were considered in rashes, compared with one case of agranulocytosis the analysis). One study (13) had a factorial randomis- from participants on the Titration regimen. ation such that following a period of anti-thyroid drugs (Block-Replace compared with Titration) one group continued T4 for 1 year and the second group had no Initial and continued low-dose anti-thyroid therapy after anti-thyroid medications. On combining drug therapy followed by additional T4 the results of these four studies for T4 there was no compared with no additional T4 (Table 3, statistically significant difference in the relapse rates Fig. 5) between the two groups after 12 months of follow-up Combining the data from three studies (22–24) adding (RR ¼ 1.09, 95% CI 0.86 to 1.39). in T4 led to fewer relapses (RR ¼ 0.65, 95% CI 0.14 to 3.00, random effects model). There was marked hetero- Drug choice geneity (I2 ¼ 88%) with the result being largely influ- enced by one study (22) where the relapses in the T4 Among the studies that reported rashes, 7% (19 of group were less than 2% compared with 35% in the 264) participants on carbimazole developed rashes, placebo group. A sensitivity analysis with the exclusion and 12% (82 of 714) of participants on methimazole.

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Table 2 Trials comparing Block-Replace vs Titration regimens.

Patients Methodological Duration of Duration of randomised/ Relapses rating for therapy follow-up assessed at rates concealment Trial Location Intervention (mean (S.D.)) (mean (S.D.)) close of study (% (numbers)) of allocation

Benker et al. European 1: MMI 12 months 4.3 (1.3) years 1: 258/147 1: 54 (85/147) A (1998) (17) multicentre 40 mg þ T4 1: 251/144 2: 58 (84/144) (6 countries) 2: MMI 10 mg titrated Edmonds & Tellez UK 1: CBZ 12 months 2 years 1: 49/34 1: 50 (17/34) A (1994) (16) 60 mg þ T4 2: 46/36 2: 67 (24/36) 2: CBZ 60 mg titrated Goni-Iriarte et al. Spain 1: CBZ 14 (5) months 3 years 1: 30/28 1: 61 (17/28) B (1995) (12) 30 mg þ T4 2: 46/35 2: 63 (22/35) 2: CBZ 40 mg titrated Grebe et al. New Zealand 1: CBZ 100 mg 6 months 24 months 1: 17/9 1: 66 (6/9) B (1998) (11) 2: CBZ 25 mg 2: 20/16 2: 94 (15/16) titrated Jorde et al. Norway 1: MMI 6 months 24 months 1: 29/19 1: 58 (11/19) B (1995) (19) 60 mg þ T4 2: 27/22 2: 77 (17/22) 2: MMI 30 mg titrated Leclere French 1: CBZ 60 mg þ 18 months 3 years 1: 123/98 1: 40 (39/98) B (1994) (10) multicentre T4 or T3 2: 123/98 2: 47 (46/98) 2: CBZ 60 mg titrated Lucas et al. Spain 1: CBZ 18 months 4.9 (1.6) years 1: 30/30 1: 67 (20/30) A (1997) (9) 60 mg þ T4 2: 30/30 2: 60 (18/30) 2: CBZ 60 mg titrated McIver et al. UK 1: CBZ 18 months 1 year 1: 59/13 1: 61 (8/13) B (1996) (15) 40 mg þ T4 2: 52/17 2: 47 (8/17) 2: CBZ 40 mg titrated Nedrebo et al. Norway 1: CBZ 12 months 13.4–41.7 1: 110/98 1: 48 (47/98) B (2002) (13) multicentre 40 mg þ T4 months 2: 108/91 2: 45 (41/91) 2: CBZ titrated Rittmaster et al. Canada 1: MMI 18 months 27 months 1: 98/98 1: 58 (57/98) B (1998) (20) 30 mg þ T4 2: 51/51 2: 59 (30/51) 2: MMI 30 mg titrated Tuncel et al. Turkey 1: PTU or NS 9–30 1: NS/34 1: 15 (5/34) B (2000) (21) MMI þ T4 months 2: NS/39 2: 18 (7/39) 2: PTU or MMI titrated Wilson et al. UK 1: CBZ 12 months 1 year 1: 33/28 1: 36 (10/28) B (1996) (14) 60 mg þ T3 2: 44/35 2: 57 (20/35) 2: CBZ 45 mg titrated

Abbreviations: CBZ: carbimzole; MMI: methimazole; PTU: propylthiouracil; T4: levothyroxine; T3: liothyronine; NS: not stated. Methodological rating for concealment of allocation: A, method did not allow disclosure of assignment; B, small, but possible chance of disclosure of assignment, or states ‘random’ but no description given; C, quasi-randomised (alternate allocation to groups).

Five cases of agranulocytosis occurred in participants quality of life, use of healthcare resources, or undertook on methimazole and four cases in participants on car- an economic evaluation. bimazole (two participants were taking very high doses of 100 mg carbimazole/day). Discussion

Other outcomes The optimal medical therapy for Graves’ hyperthyroidism remains a subject of debate. There are several None of the trials reported the effects of the different choices to be made when considering the drug treat- treatment regimens on progress of ophthalmopathy, ment of Graves’ hyperthyroidism: which drug, dose

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Figure 3 Block-Replace vs Titration regimen – participants relapsing. (Benker et al. (1998) (17), Edmonds & Tellez (1994) (16), Grebe et al. (1998) (11), Jorde et al. (1995) (19), Leclere (1994) (10), Lucas et al. (1997) (9), McIver et al. (1996) (15), Nedrebo et al. (2002) (13), Rittmaster et al. (1998) (20), Tuncel et al. (2000) (21), Wilson et al. (1996) (14)). and duration of therapy, whether to add T4, and when Longer-term follow-up data (2–5 years after com- to discontinue therapy. This review examines the evi- pletion of anti-thyroid drug therapy) showed no evidence dence from the RCTs conducted in this field. The results to suggest that the Block-Replace therapy reduces need to be interpreted with some caution as several of relapse rates when compared with the standard Titration the trials had large losses to follow-up. In the Block- regimen. None of the studies examined differences in the Replace vs Titration regimens, there was a total loss rates of ophthalmopathy progression or looked at any to follow-up of 27%. The reasons for the large loss to quality of life indicators. There was in fact a significantly follow-up are unclear and may include: patients feeling higher rate of drug withdrawal due to side-effects (16 vs relatively well a few weeks after commencement of 9%), a significantly higher incidence of rashes (10 vs 5%) therapy and attainment of euthyroidism; relatively and more episodes of agranulocytosis (nine vs three) younger age group of patients likely to have work in the Block-Replace group. The use of higher doses and other commitments such that once euthyroidism (carbimazole 100 mg daily) in one study (11) led to is attained, they fail to comply with therapy and have unacceptably high rates of side-effects, including a 12% a variable lag period before a relapse occurs; other (2 of 17) incidence of agranulocytosis, a potentially motives leading to poor compliance with therapy life-threatening complication. Seven of the 17 (46%) par- including maintenance of weight loss in young to ticipants withdrew from the Block-Replace group due to middle aged women; and different health systems in the side-effects (11). The increased side-effects of the different countries with varying follow-up mechanisms. higher drug doses required for the Block-Replace regi- With regard to the duration of therapy, there is some men and the lack of evidence in the longer term about evidence that 12-18 months of drug therapy is more its effectiveness over the Titration regimen would preju- effective than shorter durations. This is stronger dice choice in favour of the Titration regimen. Some of with use of the Titration regimen (4, 5) than for the reasons that the Block-Replace regimen is preferred the Block-Replace regimen (6), although the latter include the better maintenance of the euthyroid state study was a quasi-randomised study. Two of the and concerns regarding the effects of transient periods studies (7, 8) using longer durations of therapy of hypothyroidism on quality of life and in Graves’ did not show any clear evidence of benefit in extending ophthalmopathy where hypothyroidism may be detri- therapy beyond 18 months, although the CIs were mental to the progression of the eye disease. Unfortu- wide. nately none of the RCTs looked at this issue and there is

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Table 3 Trials comparing additional T4 vs none.

Patients Methodological rating Duration of Duration of randomised/assessed Relapse rates for concealment of Trial Location Intervention therapy follow-up (mean) at close of study (% (numbers)) allocation

Combined ATD and T4 Hashizume et al. Japan MMI for 6 months then 12 months (then 3 years 1: 60/60 1: 2 (1/60) B (1991) (22) 1: MMI 10 mg þ T4 T4 or placebo 2: 49/49 2: 35 (17/49) 2: MMI 10 mg þ placebo alone for 3 years) Pfeilschifter & Zeigler Germany CBZ till euthyroid then 12 months 12 months 1: NS/28 1: 61 (17/28) B (1997) (24) 1: CBZ 10 mg þ T4 2: NS/22 2: 23 (5/22) 153 to keep TSH , 0.03 mU/l 2: CBZ 10 mg and T4 if TSH . 4 mU/l Raber et al. (2000) (23) Austria MMI for 9 months then 6 months 12–31 months 1: 31/31 1: 45 (14/31) B 1: MMI 10 mg þ T3 2: 44/44 2: 52 (23/44) 2: No treatment Continued T4 alone Glinoer et al. Belgium MMI 150–30 mg (or PTU) 12 months 12 months 1: NS/42 1: 29 (12/42) B (2001) (28); Glinoer multicentre with T4 as needed 2: NS/40 2: 27 (11/40) et al. (2000) (29) for euthyroidism for 15 months then 1: T4 100 mg 2: Placebo Hoermann et al. (2002) Multicentre ATD for 12–15 months, 12 months 12 months 1: 114/NS 1: 16 (18/114) A (25); Quadbeck et al. Germany, euthyroid off ATD for 1 month then 2: 111/NS 2: 16 (18/111) (2003) (26) Hungary, 1: T4 to keep TSH , 0.3 Austria 2: No treatment rgteayfrGae’hyperthyroidism Graves’ for therapy Drug Nedrebo et al. (2002) Norway CBZ titrated (or CBZ 40 mg þ T4) 12 months 13.4–41.7 months 1: 108/93 1: 47 (44/93) B (13) multicentre for 12 months then 2: 110/96 2: 46 (44/96) 1: T4 alone 2: No treatment Mastorakos et al. Greece ATD for 18 months, euthyroid 12 months 12 months 1:33/NS 1: 42 (14/33) B (2003) (27) off ATD for 1 month then 2: 37/NS 2: 24 (9/37)

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Abbreviations: CBZ: carbimazole; MMI: methimazole; PTU: propylthiouracil; T4: levothyroxine; T3: liothyronine; ATD: antithyroid drugs; TSH: thyrotropin-stimulating hormone; NS: not stated. Methodological rating for concealment of allocation: A, method did not allow disclosure of assignment; B, small, but possible chance of disclosure of assignment, or states ‘random’ but no description; C, quasi-randomised (alternate allocation to groups). www.eje-online.org 495 via freeaccess 496 P Abraham and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 153

Figure 4 Block-replace vs Titration regimen – participants with rashes and withdrawals due to side-effects. (Benker et al. (1998) (17), Edmonds & Tellez (1994) (16), Grebe et al. (1998) (11), Jorde et al. (1995) (19), Leclere (1994) (10), Nedrebo et al. (2002) (13), Wilson et al. (1996) (14)).

a need for well-designed adequately powered trials which this modality of treatment, creating a stable situation look at the benefits of the Block-Replace regimen on the earlier in the course of therapy and saving several quality of life and progression of ophthalmopathy. years of regular outpatient clinic visits and possible There is no clear evidence in favour of giving upsets caused by relapses of hyperthyroidism. The thyroid hormone supplementation following the initial possibility of long-term low-dose continuous anti-thyr- treatment of Graves’ thyrotoxicosis with anti-thyroid oid use has also been suggested in a recent trial with medication. The discrepant result from one study (22) over 10 years of follow-up for 26 patients on low- could be due to higher iodine intake in Japan and/or dose methimazole (32). differences in immunological or genetic factors (30). The trials which have subsequently tried to reproduce this study have all used differing protocols and Evidence-based recommendations none has used the original protocol used by Hashizume . The Titration regimen is just as effective as the et al. (22). Block-Replace regimen and, with a significantly The relapse rates obtained in our review were 51% lower incidence of adverse effects, should be con- for the Block-Replace regimen and 54% for the sidered as the first-line regimen in most Titration regimen. The relapse rates were 63 and situations. 68% for the Block-Replace and Titration regimens . The evidence suggests the optimal duration of respectively when intention-to-treat analysis was car- anti-thyroid drug therapy for the Titration regi- ried out making the extreme assumption of relapsed men is 12–18 months. hyperthyroidism in all drop-outs. It can be presumed . There is no benefit from continued T4 replace- that the true relapse rate for the anti-thyroid drug regi- ment after a course of anti-thyroid treatment. mens is in the range of 51–68%. It could be argued . Radioiodine treatment should be discussed at an that with such relapse rates, radioiodine therapy early stage – patients may choose this option should be considered at an earlier stage in the UK, as when they are made aware of the likelihood of appears to be the trend among American thyroidolo- relapse and the need for prolonged outpatient gists (31). It is possible that patients may also choose clinic attendance with anti-thyroid drug treatment.

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Figure 5 Additional T4 vs none – participants relapsing. (Hashizume et al. (1991) (22), Pfeilschifter & Zeigler (1997) (24), Raber et al. (2000) (23), Glinoer et al. (2001) (28), Hoermann et al. (2002) (25), Nedrebo et al. (2002) (13), Mastorakos et al. (2003) (27)).

. Adequately powered trials which will look at the References benefits of Block-Replace and Titration regimens on the progression of ophthalmopathy and qual- 1 Franklyn JA. The management of hyperthyroidism. New England ity of life are needed. Journal of Medicine 2002 330 1731–1738. 2 Abraham P, Avenell A, Watson WA, Park CM & Bevan JS. Antith- yroid drug regimen for treating Graves’ hyperthyroidism. The Cochrane Database of Systematic Reviews 2005 2. 3 Higgins JPT, Thompson SG, Deeks JJ & Altman DG. Measuring inconsistency in meta-analyses. British Medical Journal 2003 Acknowledgements 327 557–560. 4 Allannic H, Fauchet R, Orgiazzi J, Madec AM, Genetet B, Lorcy Y, We are grateful to Prof. Adrian Grant, Ms Sheila Wal- Le Guerrier AM, Delambre C & Derennes V. Antithyroid drugs and lace and Ms Cynthia Fraser for their advice; to Dr Graves’ disease: a prospective randomized evaluation of the effi- Amalia Mayo and Ms Aurelie Desbois for undertaking cacy of treatment duration. Journal of Clinical Endocrinology and translations; and to Dr R Hoermann, Dr J Leclere and Metabolism 1990 70 675–679. Dr B G Nedebro for providing further information 5 Allannic H, Lorcy Y, Leguerrier AM, Delambre C, Stetieh H, Madec AM & Orgiazzi J. Antithyrodiens de synthese et maladie about their trials. We thank the Medical Research de Basedow ou le choix d’une strategie therapeutique. Presse Med- Council and the Grampian University Hospitals NHS icale 1991 20 649–651. Trust Endowments for funding. The Health Services 6 Weetman AP, Pickerill AP, Watson P, Chatterjee VK & Research Unit is funded by the Chief Scientist Office of Edwards OM. Treatment of Graves’ disease with the block-replace the Scottish Executive Health Department. The study regimen of antithyroid drugs: the effect of treatment duration and immunogenetic susceptibility on relapse. Quarterly Journal of funders had no role in the study design; collection, ana- Medicine 1994 87 337–341. lysis and interpretation of data; writing of the report; 7 Garcia-Mayor RVPC, Luna-Cano R, Perez-Mendez LF, Galofre JC & and in the decision to submit the paper for publication. Andrade A. Antithyroid drug and Graves’ hyperthyroidism. The views expressed are those of the authors. Significance of treatment duration and TRAb determination on All authors contributed to the writing and revision of lasting remission. Journal of Endocrinological Investigation 1992 this paper. 15 815–820.

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