Antithyroid Drugs in the Management of Patients with Graves’ Disease: An Evidence-Based Approach to Therapeutic Controversies

David S. Cooper

Division of Endocrinology, Sinai Hospital of Baltimore, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21215

Address all correspondence and requests for reprints to: David S. Cooper, M.D., Johns Hopkins University School of Medicine, Division of Endocrinology, Sinai Hospital of Baltimore, 2401 West Belvedere Avenue, Hoffberger Building, Suite 56, Baltimore, Maryland 21215. E-mail: dcooper{at}lifebridgehealth.org.


    Introduction
 Top
 Introduction
 Methods
 Conclusion
 References
 
Antithyroid drugs have been in use for over half a century, and much is now known about their mechanism of action, pharmacokinetics, and clinical pharmacology (1). Somewhat surprisingly perhaps, clinicians are still challenged on a regular basis by numerous questions related to their optimal use. Choice of antithyroid agent, duration of use, proper dosage, patient selection for primary antithyroid drug therapy, and pretreatment of patients before radioiodine administration are just some of the issues that confront busy practitioners on an almost daily basis. Although there have been published guidelines addressing the general subject of hyperthyroidism therapy (2, 3, 4), they are not evidenced-based, nor do they confront these specific, practical questions. To try to address these specific issues in a rigorous way, the following discussion will use an evidence-based approach. The American Academy of Family Physicians (5) and most other organizations rate levels of evidence according to the following scheme.

Level A: a high-quality randomized controlled trial (RCT) that considers all important outcomes, and high-quality metaanalysis (quantitative systematic review) using comprehensive search strategies.
• Level B (other evidence): a well-designed, nonrandomized clinical trial; and a nonquantitative systematic review with appropriate search strategies and well-substantiated conclusions. Level B includes lower quality RCTs, clinical cohort studies, and case-controlled studies with nonbiased selection of study participants and consistent findings. Other evidence, such as high-quality, historical, uncontrolled studies, or well-designed epidemiological studies with compelling findings, is also included.
• Level C: consensus viewpoint or expert opinion.

The cases of two prototypical patients that are likely to be seen frequently in any busy clinical endocrinologist’s office will be presented. A series of questions about each case will be raised and then answered using level A evidence, wherever possible. Unfortunately, for many of the questions under consideration, the highest levels of evidence are not available, and data that are less rigorously obtained must be used. A 1998 British review (6) discussed some of the same issues using a similar format.


    Methods
 Top
 Introduction
 Methods
 Conclusion
 References
 
MEDLINE was used to search the English-language literature from 1980 through 2002, with Graves’ disease, hyperthyroidism, antithyroid drugs, propylthiouracil, methimazole, carbimazole, and randomized controlled trials used as search terms. Reference lists from review articles, book chapters, and textbooks were also included in the search to find older papers. Whenever possible, papers that describe the results of RCTs were used to answer the questions; data from case series and retrospective cohort studies were included in the absence of randomized trials or to supplement information from randomized trials.

Case 1

A 20-yr-old unmarried woman presents with typical symptoms and signs of Graves’ disease. She has mild periorbital edema, mild proptosis, and a thyroid gland that is 1.5-fold enlarged. Her initial thyroid function tests reveal the following: free T4 (fT4), 2.3 ng/dl (normal, 0.8–1.8 ng/dl); T3, 250 ng/dl (normal, 80–180 ng/dl); and TSH, below 0.005 mU/liter (normal, 0.5–4.0 mU/liter). The 24-h radioiodine uptake is 40% (normal, 10–25%), and the scan shows a homogeneous pattern. After discussing various options for therapy, the patient decides that she would feel most comfortable with a course of antithyroid drug therapy.

Given this information, the following questions arise:

  1. Which drug should be used to treat this patient, propylthiouracil (PTU) or methimazole?
  2. For how long should she be treated to optimize the chances of remission?
  3. Does the drug dose influence the chances of remission? What dose should be used initially to get her disease under control?
  4. Would the coadministration of T4 during or after antithyroid drug therapy enhance her chances of remission?
  5. Is the patient a good candidate for primary antithyroid drug therapy, or is she unlikely to achieve a remission, making radioiodine a better initial therapeutic choice?

Discussion

1. Which drug should be used to treat this patient, PTU or methimazole? This question really represents a number of subsidiary questions. For example, which drug is more effective and works more rapidly? Which drug has the least toxicity? Which drug has the better patient compliance? Which drug costs less? Which drug has fewer effects on the subsequent effectiveness of radioactive iodine therapy, should it be needed later on?

1a. Which drug is more effective? One often quoted retrospective study examined the rate of normalization of serum T4 and T3 in patients who had been prescribed either methimazole 10 mg three times a day (n = 66) or PTU 100 mg three times a day (n = 17) (7). The data suggested that methimazole led to a more rapid normalization of thyroid function compared with PTU, but, given the retrospective design, it is unclear whether the patients in each group were truly equivalent at baseline and how drug assignment was made. There are three prospective RCTs in which PTU and methimazole were compared head-to-head. In one small study, 29 patients were randomly assigned to receive PTU 100 mg every 8 h or methimazole 30 mg once a day (8). Twenty-two patients completed the study in which thyroid function was monitored monthly. Serum fT4 and T3 normalized more quickly with methimazole, although the results were statistically significant only for serum T3 levels. In another study, 94 patients were randomly assigned to receive methimazole 10 mg every 12, 8, or 6 h, or PTU 100 mg every 12, 8, or 6 h (9). The primary outcome measure was the lowest serum fT4 level achieved at 12 wk of therapy. At the end of 12 wk, almost all patients had a normal fT4 level except those who received the lowest doses of both drugs. The conclusion was that both drugs were equivalent in terms of efficacy. However, in this study serum T3 levels were not measured, and the rate of response was not assessed. The third study involved 71 patients with Graves’ disease who were randomized to receive methimazole 15 mg/d vs. PTU 150 mg/d for 12 wk (10). fT4 and T3 were monitored monthly. Not unexpectedly, fT4 and T3 values were lower at every time point in the methimazole group, likely because the dose of PTU was subtherapeutic in many cases. Indeed, at 12 wk only 19% of PTU-treated patients were biochemically euthyroid vs. 77% of methimazole-treated patients. In summary, although the data point toward methimazole was somewhat more effective, there is only one small prospective randomized trial comparing the two drugs at therapeutically equivalent doses at clinically relevant time points.

1b. Which drug is less toxic? Both PTU and methimazole are associated with minor reactions (rash, urticaria, gastrointestinal upset) approximately 1–5% of the time (11, 12). Werner et al. (12) reported on the side effects of 389 consecutively treated patients treated with high or low doses of either PTU or methimazole. There were no statistically significant differences between the two drugs in minor side effects, including arthralgias, rash, or gastric intolerance. However, with methimazole, the rate of drug side effects may be dose related, whereas data relating dose to side effects with PTU are less clear-cut (1). Therefore, very low doses of methimazole (e.g. 5–10 mg/d) may be associated with fewer minor side effects than any PTU dose. Similarly, the rates of agranulocytosis for both drugs range from 0.2–0.5%, but the number of reported cases of this severe side effect are very small in patients receiving methimazole doses of less than 10 mg/d (13). Furthermore, rare but major side effects including drug-induced hepatitis and antineutrophil cytoplasmic antibody-positive vasculitis are virtually exclusively seen in patients taking PTU (11). Therefore, overall, it would appear that methimazole is a safer drug, especially when given in doses below 10 mg/d, a dose that is adequate in patients with mild to moderate disease.

1c. Which drug is associated with greater patient compliance? No one has studied overall medication compliance rates in hyperthyroidism, but one might imagine that hyperthyroid patients might be particularly unreliable in taking prescribed medications. One RCT compared patients receiving methimazole 30 mg/d as a single dose (n = 12) to patients receiving PTU 100 mg every 6 h (n = 10) (8). At the end of 3 months, compliance rates (defined by >80% of medication having been taken, assessed by pill count) were 83% for methimazole vs. 53% for PTU (P < 0.01). In all likelihood, the major advantage of methimazole over PTU in terms of compliance is the fact that it is effective when given in a single daily dose (14).

1d. Which drug costs less? This is a difficult question to answer, because the retail price probably varies considerably and many patients have prescription plans that cover all or part of the charges. A survey using a website that compares drug prices among national chains and mail order vendors (www.destinationrx.com, searched 3/6/03) yielded the following information: for PTU 300 mg/d, the typical starting dose, the charge for 180 tablets (1-month supply) was $21.81. The average charge for a 1-month supply of Tapazole 30 mg/d (e.g. three 10-mg tablets/d) was $86.08 (range, $83 to $90), and the monthly charge for generic methimazole 30 mg/d was $62.30 (range, $61 to $63.13). But, the commonly accepted potency ratio of 10:1 between methimazole and PTU is probably an underestimation, with a 30:1 ratio a more likely estimate (1). If so, a starting dose of 10 mg of methimazole daily would be equivalent to 300 mg of PTU a day and is adequate for many patients. The mean monthly charge for Tapazole 10 mg/d averages $28.69 (range, $27.67 to $30), and the mean monthly charge for generic methimazole is $20.85 (range, $20.33 to $21.05). Therefore, at lower doses, the cost of methimazole and PTU is similar, but at higher doses Tapazole and methimazole are more expensive.

1e. What are the effects of PTU and methimazole on the efficacy of subsequent radioactive iodine therapy? That antithyroid drugs have an effect on radioiodine outcomes has been known for many decades. Yet, a survey of members of the American Thyroid Association suggested that approximately 30% of clinicians routinely use antithyroid drugs to render patients euthyroid before administering radioactive iodine (15). Then too, there is another large group of patients who are treated with antithyroid drugs as primary therapy, who then subsequently relapse and are offered radioiodine treatment. These patients also have been exposed to antithyroid drugs before therapeutic radioiodine.

There have been a number of retrospective studies that indicate an effect of PTU to significantly lower the efficacy of subsequent radioiodine treatment, but there have been no prospective randomized prospective controlled trials (16, 17, 18, 19) (Fig. 1AGo). In contrast, there have been two retrospective (18, 20) and two prospective RCTs (21, 22) comparing the effectiveness of radioactive iodine after methimazole pretreatment vs. no pretreatment (Fig. 1BGo). None of the four studies involving methimazole demonstrated an alteration in the effectiveness of radioactive iodine therapy. Therefore, methimazole would be preferable if one chose to pretreat a patient with antithyroid drugs before radioiodine therapy. In the case of PTU pretreatment, the dose of radioactive iodine could be increased by 25% to overcome the putative radioresistant effects of PTU, as was the case with methylthiouracil pretreatment in an older study (23).



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FIG. 1. A, Failure rates after radioiodine therapy in patients who had received PTU therapy before radioiodine administration. B, Failure rates after radioiodine therapy in patients who had received methimazole therapy before radioiodine administration. MMI, methimazole; RAI, radioactive iodine.

 
2. How long should the patient be treated to maximize the chances of remission? Retrospective studies have suggested that the chances of remission increase the longer antithyroid drugs are administered (24, 25). For example, one study showed that the remission rate was significantly higher when patients received antithyroid drugs for more than 2 yr compared with those patients who only received drug treatment for 1 yr (24). Unfortunately, randomized prospective trials have not confirmed this impression (Fig. 2Go). One study did show that the relapse rate was significantly lower after 18 months of treatment compared with 6 months of treatment (26). However, subsequent randomized studies found no differences between 12 vs. 24 months (27), 6 vs. 12 months (using a block replace regimen) (28), and 18 vs. 42 months (29). Therefore, treating for longer than 12–18 months is not likely to yield a higher remission rate compared with longer treatment periods.



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FIG. 2. Relapse rates among patients in four prospective trials comparing different durations of therapy with antithyroid drugs. Numbers on the bars refer to the number of months of therapy in each treatment arm. *, P < 0.05.

 
3a. Does the antithyroid drug dose influence the chances of remission? It has been hypothesized that antithyroid drugs may have immunosuppressive effects (30). If this is the case, then higher doses of drug may lead to higher rates of remission. One randomized prospective trial comparing traditional drug doses to high-dose treatment showed a higher remission rate in those patients receiving doses of methimazole greater than 60 mg/d or PTU greater than 600 mg/d (plus supplemental T4 or T3 therapy to maintain a euthyroid state) (31). However, the follow-up time was less than 2 yr after drug discontinuation. Four more recent RCTs (32, 33, 34, 35) found no significant difference in remission rates between patients receiving high-dose antithyroid drugs supplemented with either T4 or T3, compared with a lower dose regimen titrated to maintain normal thyroid function. Follow-up times ranged from 1 yr (33) to 4–5 yr (34, 35). One study comparing a high-dose to a low-dose regimen found no differences in remission rates after 2 yr of follow-up, but it did find a longer relapse-free survival in the high-dose group (27 vs. 9.6 wk; P < 0.04) (36). In most of the studies examining the effects of high drug dosages, patients randomized to the high dose arm had more side effects (31, 36, 37). Thus, the recent evidence suggests that there is no advantage but potential harm with high-dose therapy.

3b. What antithyroid drug dose should be used initially? It is logical that higher drug doses might induce more rapid responses, because thyroid hormone synthesis is being impaired to a greater degree. In fact, studies comparing high-dose drug therapy with low-dose drug therapy confirm this, although the differences are not as dramatic as one might think. For example, in the largest study, the European Multicentre Trial (37), 68% of patients taking methimazole 10 mg/d were euthyroid within 3 wk vs. 83% of patients receiving 40 mg/d (P < 0.01). At 6 wk, the percentages were 85% and 92%, respectively (P < 0.01).

Page et al. (38) used carbimazole, an antithyroid agent that is metabolized to methimazole, to compare rates of response to high- and low-dose antithyroid drug therapy. This is one of the few studies to relate the rate of response to the baseline severity of the hyperthyroidism. Patients were assigned to receive either 20 or 40 mg of carbimazole (equivalent to approximately 15 and 30 mg of methimazole, respectively). Baseline serum T4 levels were divided retrospectively into quartiles, with a mean value of 21 µg/dl. The authors observed that a 20-mg/d dose of carbimazole was too low in the more severely hyperthyroid patients (T4 > 21 µg/dl), with the majority still hyperthyroid at 4 wk (Fig. 3Go). In contrast, this dose was adequate for most of the less severely hyperthyroid patients (T4 < 21 µg/dl). Doses of 40 mg/d were appropriate for the majority of the patients with severe hyperthyroidism, but caused hypothyroidism in over 50% of the less severely ill patients. Therefore, the underlying disease activity and the starting dose are both important considerations. For a patient with mild to moderate disease, an initial methimazole dose of 10–20 mg would be appropriate in most cases.



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FIG. 3. Rates of hyperthyroidism ({blacksquare}) or hypothyroidism ({square}) in patients receiving carbimazole (CBZ) 20 or 40 mg/d, divided according to baseline T4 levels below or above 21 µg/dl. [Adapted from Page et al.: Clin Endocrinol (Oxf) 45:511–516, 1996 (38 )].

 
4. Would coadministration of T4 during or after antithyroid drug therapy enhance the chances of remission? Hashizume et al. (39) randomized patients to receive antithyroid drug therapy for 6 months, supplemented by exogenous T4 or placebo for 1 yr, followed by continued T4 or placebo for another 3 yr. The results strongly suggested that relapse rates after a course of antithyroid drug therapy could be dramatically improved with T4 administration (1.7% in the T4 group vs. 35% in the placebo arm). This effect was hypothesized to be due to suppression of endogenous TSH, with decreased expression of putative thyroidal antigens. Unfortunately, subsequent trials with similar, although not identical, designs have failed to corroborate the initial results (34, 40, 41, 42, 43, 44, 45, 46, 47). Therefore, there is currently no rationale for using T4 in combination with antithyroid drugs to enhance remission rates.

5. Is the patient a good candidate for primary antithyroid drug therapy, or is she unlikely to achieve a remission, making radioiodine a better choice? Many retrospective studies have been conducted to try to address the question of whether there are baseline predictors that might help to identify those patients who are most likely to have a remission after a course of antithyroid drugs (1). To summarize the studies briefly, almost all of them show the highest remission rates in patients with relatively small goiters in whom thyroid function tests are only slightly deranged (e.g. Refs. 48, 49, 50). Factors such as age, sex, the presence of ophthalmopathy, smoking history, and prior history of relapse have not consistently been shown to predict success or failure with sufficient sensitivity or specificity to be useful in individual patient management. The absence of circulating anti-TSH receptor antibodies at baseline has been shown to be predictive of remission (51), but negative titers are seen mainly in patients with the mildest disease in any case. In accord with this observation, one retrospective (48) and one prospective study (52) demonstrated that patients with higher baseline anti-TSH receptor antibody titers are more likely to relapse.

In the European Multicentre Trial cited above, baseline factors were examined to see whether any of them might predict the likelihood of subsequent remission (35). A total of 313 patients were followed for a mean of 4.3 yr with a mean relapse rate of 58% (58% in the group receiving 10 mg/d vs. 57% in the group receiving 40 mg/d). There were no differences at baseline between those who eventually relapsed and those who had a sustained remission in age, goiter size, eye findings, thyroid function tests, or history of prior relapse. Anti-TSH receptor antibody measurements were not reported, nor did the authors perform subgroup analysis retrospectively to see whether patients with the mildest disease or smallest goiters might have had higher remission rates compared with those with the most severe disease or largest goiters. In summary, the large body of retrospective data are likely correct: severe disease and large goiter are poor prognostic features for achieving a remission, but this has been difficult to demonstrate in prospective studies.

Case 2

A 60-yr-old woman noted a 6-month history of a 20-lb weight loss, nervousness, and palpitations. On physical exam, she was found to be in atrial fibrillation with a rate of 110 beats/min. There was no proptosis, and extraocular movements were full. The thyroid was not palpable. The rest of the exam was unremarkable except for a fine tremor. Thyroid function tests were as follows: fT4, 2.6 ng/dl (0.8–1.8); T3, 250 ng/dl (80–180); and TSH, below 0.005 mU/liter (0.5–4.0). A thyroid scan showed a normal sized gland, homogeneous uptake, with a 37% 24-h radioiodine uptake.

Radioiodine therapy was recommended for this patient.

  1. Should she be treated with antithyroid drugs before or after radioiodine to prevent worsening of her thyroid function and cardiac status?
  2. Will treating her with antithyroid drugs after radioiodine therapy lead to more rapid disease control?

Discussion

1. Should she be pretreated with antithyroid drugs to prevent worsening of her thyroid function and cardiac status? Many physicians recommend antithyroid drug treatment before or after radioiodine therapy in the hope that it will prevent postradioiodine exacerbation of thyroid function (15). Worsening of thyroid function has been documented to occur in older studies 1–2 wk after treatment (53, 54) and is likely related to radiation-induced thyroiditis. However, more recent studies (55, 56) have shown that worsening of thyroid function can also occur 6–12 wk after radioiodine, in this case perhaps related to the increase in serum anti-TSH receptor antibody titers that occurs 3–6 months after treatment (57).

In an analysis of the older literature, McDermott et al. (58) found 16 cases of thyroid storm occurring after radioiodine therapy. This problem developed an average of 6 d after radioiodine therapy and carried a 25% mortality. The authors also calculated that the frequency of radioiodine-related thyroid storm was 0.34% (10 cases of approximately 2975 patients treated), but the frequency of severe exacerbations that did not meet the criteria for thyroid storm was 0.88% (26 cases of 2975 patients treated with radioiodine). In view of this information, some experts have recommended antithyroid drug pretreatment before radioiodine administration, especially the elderly or those who have underlying cardiovascular disease (3). However, it has not been demonstrated whether such pretreatment does in fact reduce postradioiodine thyroid storm, clinical worsening, or untoward cardiovascular events.

In one prospective controlled trial (59), 70 patients were randomized to receive either carbimazole 30 mg/d before radioiodine treatment, followed by 6 wk of carbimazole therapy after radioiodine (n = 36), or propranolol 60 mg/d before and 6 wk after radioiodine therapy (n = 34). After radioiodine, one patient in each group developed a transient exacerbation (clinical worsening in one patient in the carbimazole group, paroxysmal atrial fibrillation in one patient in the propranolol group). In a retrospective study (55), 36% of patients not pretreated with an antithyroid drug had a transient increase in fT4 after radioiodine therapy, vs. 53% of a group given antithyroid drugs before radioiodine. However, in the untreated group, serum fT4 levels were higher and rose to much higher levels when the postradioiodine worsening occurred, compared with fT4 values in the pretreated group, whose biochemical exacerbations were far less severe.

In a recent randomized trial, 28 patients were treated with radioiodine without antithyroid drug pretreatment, and 28 patients were treated with methimazole until they were euthyroid (for a median of 12 wk) before radioiodine (60). The drug was stopped 4 d before radioiodine treatment in this group. In the patients who were not pretreated, thyroid function (fT4 and T3) gradually fell over the ensuing 1-month follow-up period. In contrast, in the pretreatment group after methimazole discontinuation, serum fT4 and T3 values rose by 36 and 70%, respectively, in the 4 d before radioiodine administration (Fig. 4Go). Nevertheless, at all time points after radioiodine administration, serum fT4 and T3 values were lower in the pretreated group compared with the nonpretreated group. After radioiodine therapy, a small subset of patients (two in the nonpretreatment group, three in the pretreatment group) had progressive increases in serum fT4 and T3 over the ensuing 30 d, but serum hormonal values during these exacerbations were lower in the patients that had been pretreated vs. those that had not.



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FIG. 4. Changes in thyroid hormone levels in patients with Graves’ hyperthyroidism who were treated with radioiodine or methimazole-radioiodine. Negative numbers indicate days before treatment. *, P < 0.01 for the comparison with the value on the day the drugs were interrupted (day -4). {dagger}, P < 0.05 for the comparison with the value on d 2 after radioiodine administration. §, P < 0.01 for the comparison with the value on the day of radioiodine administration (d 0). [Reproduced with permission from V.A. Andrade et al. J Clin Endocrinol Metab 84:4012–4016, 1999 (60 ). © The Endocrine Society.]

 
A similar pattern was seen in another randomized trial comparing methimazole pretreatment with no pretreatment before radioiodine (56). Again, several patients in each group had progressive worsening of thyroid function after radioiodine, but thyroid hormone levels were much higher in the patients who did not receive antithyroid drug pretreatment (Fig. 5Go). In neither of these two relatively small studies were there any significant clinical events, but patients who were elderly or who had underlying comorbidities were excluded from both trials.



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FIG. 5. Changes in fT4 levels in five patients experiencing worsening thyrotoxicosis after radioiodine therapy, including three pretreated patients ({diamond}) and two nonpretreated patients ({circ}). The normal range for fT4 is shown by cross-hatching. [Reproduced with permission from H.B. Burch et al. J Clin Endocrinol Metab 86:3016–3021, 2001 (56 ). © The Endocrine Society.]

 
Some investigators have opined that the increases in thyroid function after antithyroid drug withdrawal are potentially dangerous and dictate against using antithyroid drugs in this context in most patients (61). In response to this concern, a recent randomized trial demonstrated that a 2- to 3-wk course of lithium carbonate (900 mg/d) starting the day after methimazole withdrawal can prevent the increases in serum thyroid hormone levels that occur when methimazole is discontinued (62).

In conclusion, it is still not proven that antithyroid drug pretreatment prevents radioiodine-related exacerbations. However, in those few patients who manifest worsened thyroid function after radioiodine, the severity of such biochemical abnormalities is far less in those patients who had been pretreated with antithyroid drugs. If the inevitable mild increase of thyroid function after cessation of antithyroid drugs is perceived to be a clinical problem for some fragile patients, lithium therapy could be considered.

2. Will treating her with antithyroid drugs after radioiodine therapy lead to more rapid disease control? Antithyroid drug therapy given after ablative therapy may hasten the return to a euthyroid state. It is also possible that postradioiodine exacerbations of thyroid function might be prevented; prior studies have reported that methimazole administration before and/or after radioiodine treatment prevented the rise in TSH receptor antibody titers at 3–6 months that was seen in patients who received radioiodine alone (63, 64, 65). There have been two randomized studies (66, 67) that examined the effects of posttreatment antithyroid drug administration, but they were largely intended to address rates of normalization of thyroid function and long-term cure rates, rather than acute exacerbations. In one prospective study, 112 patients were randomized to receive PTU 300 mg/d, saturated solution of potassium iodide 10 drops/d, or no treatment after radioiodine (66). There was no difference in thyroid function among the three groups 6 wk after radioiodine treatment, suggesting no benefit to treating patients with PTU (or saturated solution of potassium iodide) after radioiodine therapy. Furthermore, there was a higher failure rate in those subjects who were randomized to receive PTU. In contrast, a second trial randomized 159 patients to receive either methimazole administered in a block-replace regimen or no treatment after radioiodine therapy (67). Patients receiving methimazole became euthyroid sooner (2 wk vs. 8 wk; P < 0.02) than those who received no therapy. In neither of these two prospective studies were clinically significant exacerbations reported in any of the treatment arms (66, 67). In contrast to two retrospective studies showing a negative effect on cure rates of methimazole given after radioiodine (20, 65), the prospective randomized trial of methimazole showed no effect on long-term radioiodine success rates (67).

Lithium might also be useful in this context. A recent RCT comparing lithium 900 mg/d for 6 d starting on the day of radioiodine administration also resulted in significantly earlier control hyperthyroidism (68). However, again no postradioiodine exacerbations were noted in either treatment arm, so that the idea that lithium might prevent such events remains unproven. No significant differences in overall cure rates were observed in this study, similar to another study that examined the effects of lithium after radioiodine therapy (69).


    Conclusion
 Top
 Introduction
 Methods
 Conclusion
 References
 
This review was intended to update clinicians on some of the unsettled issues in the management of patients with Graves’ disease with antithyroid drugs. In general, methimazole is the preferred drug in the management of hyperthyroidism due to Graves’ disease (Table 1Go). There is no benefit to larger doses, longer treatment regimens, or concomitant use of T4 (Table 2Go). Selection of the correct dose at the beginning of therapy requires clinical experience and judgment. It is difficult to know in advance which patients are likely to remit, but mild disease, a small goiter, and the absence of circulating anti-TSH receptor antibodies are good prognostic signs.


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TABLE 1. Antithyroid drug comparisons

 

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TABLE 2. Controversies about antithyroid drug use

 
There are few data showing that antithyroid drug treatment prevents clinical or biochemical exacerbations after radioiodine (Table 2Go). However, when there are biochemical exacerbations, they are less severe in patients who have been pretreated. Discontinuation of antithyroid drugs before radioiodine does result in a mild deterioration of thyroid function, but the clinical significance is uncertain. Lithium therapy after antithyroid drug discontinuation prevents this rise in thyroid hormone levels, and also leads to more rapid control of thyroid function after radioiodine. Finally, it is obvious that although much is known about the appropriate use of antithyroid drugs in the management of Graves’ disease, this topic is fertile ground for additional clinical research.


    Footnotes
 
Abbreviations: fT4, Free T4; PTU, propylthiouracil; RCT, randomized controlled trial.

Received February 5, 2003.

Accepted April 10, 2003.


    References
 Top
 Introduction
 Methods
 Conclusion
 References
 

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