Has the time come for favouring one antithyroid drug over the other (MMI versus PTU) in the treatment of Graves- disease?

TOPIC: A ntithyroid drugs for treatment of hyperthyroidism due to Graves- disease

Title: Comparison of methimazole & propylthiouracil in patients with hyperthyroidism caused by Graves- disease.

Authors: Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N (and the working group of the Japan Thyroid Association for the guideline of the treatment of Graves- disease).

Reference: Journal of Clinical Endocrinology & Metabolism, 92: 2157-2162, 2007

Summary

Background

Available data do not allow a clear-cut evidence-based choice of type of antithyroid drug (ATD) or initial drug dose in the treatment of hyperthyroidism due to Graves- disease (GD).

Purpose

To compare, in a randomized prospective non-blinded study with three arms, methimazole (MMI) 30 mg daily with MMI 15 mg daily, or propylthiouracil (PTU) 300 mg daily. Main outcome measures were time to normalization of thyroid function and frequency of adverse reactions.

Patients: A cohort of 396 patients with untreated and first occurrence of GD was investigated, among whom 303 patients were evaluated for thyroid function and 371 patients for adverse events. Recruitment was from 4 Japanese hospitals.

Methods

Serum free T 4 and free T 3 measured at 4, 8, and 12 weeks after initiation of therapy. Evaluation of adverse effects – by interview, clinical investigation and hepatic and hematological variables – at 2, 4, 8, & 12 weeks.

Results

After 12 weeks with MMI 30 mg/day, significantly more patients (97%) had normalized serum free T 4 than those who received PTU 300 mg/day (78%) or MMI 15 mg/day (86%). This was mainly due to a difference in those with the highest serum free T 4 values. A similar tendency was observed for serum free T 3 , although less pronounced. Number of patients with adverse effects, especially mild hepatotoxicity, were significantly higher in the PTU group (52%) than in the MMI groups, and were higher in the group with MMI 30 mg/d (30%) than in the group with MMI 15 mg/d (14%).

Conclusions

The present study, in an iodine-sufficient area, suggests that 15 mg of MMI daily will normalize thyroid function in the majority of patients with GD with the lowest risk of adverse events. If hyperthyroidism is pronounced, 30 mg of MMI daily should be used. PTU should not be used as the first drug of choice due to its adverse effect profile.

Commentary

As evidenced by questionnaire studies carried out fifteen years ago, and despite more than half a century of its use, there remain quite profound regional/continental differences in the use and type of antithyroid drug (ATD), and also differences as to whether ATD or radioactive iodine (RAI) should be the preferred first choice for the treatment of hyperthyroidism due to Graves- disease (GD). Although the most recent issues of thyroid/endocrine textbooks state that the choice is mainly based on personal preference and experience of physicians, they generally suggest that there are many reasons to prefer MMI.

Accepting that it is highly unlikely that this influenced the overall conclusions of the study by Nakamura et al., the study was unblinded and we do not know whether variables such as age, sex, family history of thyroid disease, initial thyroid function, initial TSH-receptor antibody levels, serum free T4/free T3 ratio, thyroid size, thyroid flow and degree of hypoechogenicity (at ultrasound), were comparable in the three groups. These and other variables are, to an unknown degree, associated with the effects of ATD. Additionally, knowledge of iodine status in this group of patients would help in interpreting the potential validity of the findings for populations from regions which differ in iodine sufficiency.

Whether present findings also apply to toxic nodular goiter, and whether there is also a potential dose-response relationship for PTU (as was the case for MMI) remains unclarified. Again, can the findings be generalized to cover populations with low or borderline iodine intake?

What about adverse effects? First, both white blood cell count and hepatic function may be altered by hyperthyroidism per se . In the present study, there was no account of pre-treatment values. Possibly this could account for the unusually high frequency of -hepatotoxicity-. Second, the unprecedented high incidence of adverse effects (52% with PTU) is most likely due to a more rigorous definition of adverse effects than normally used. Most of us operate with a figure of 5-10% of GD patients having adverse effects due to ATD. On the other hand the definitions were independent of treatment group and therefore the relative difference seems valid. Third, noting the high frequency of adverse effects, it is striking that none seemed to have taste-related disorders, which, especially with PTU is one of the more common adverse effects in our experience.

A logical consequence of the existing literature – including the present study – is to recommend MMI and not PTU as the first drug of choice for adult non-pregnant hyperthyroid patients with GD. In the vast majority of cases, an initial dose of 15 mg daily (given as one or two divided doses) seems to offer the best balance between time needed to normalize thyroid function and risks of side effects. In case of adverse effects, a majority of adult patients are probably better off given RAI than PTU. Importantly, present study cannot clarify whether routine monitoring of hematological and/or liver function parameters should be offered.

Summary and commentary prepared by Laszlo Heged-s (related to Chapter 11 of TDM) Full paper obtainable at: http://jcem.endojournals.org/cgi/content/full/92/6/

Has the time come for favouring one antithyroid drug over the other (MMI versus PTU) in the treatment of Graves- disease?

TOPIC: A ntithyroid drugs for treatment of hyperthyroidism due to Graves- disease

Title: Comparison of methimazole & propylthiouracil in patients with hyperthyroidism caused by Graves- disease.

Authors: Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N (and the working group of the Japan Thyroid Association for the guideline of the treatment of Graves- disease).

Reference: Journal of Clinical Endocrinology & Metabolism, 92: 2157-2162, 2007

Summary

Background

Available data do not allow a clear-cut evidence-based choice of type of antithyroid drug (ATD) or initial drug dose in the treatment of hyperthyroidism due to Graves- disease (GD).

Purpose

To compare, in a randomized prospective non-blinded study with three arms, methimazole (MMI) 30 mg daily with MMI 15 mg daily, or propylthiouracil (PTU) 300 mg daily. Main outcome measures were time to normalization of thyroid function and frequency of adverse reactions.

Patients: A cohort of 396 patients with untreated and first occurrence of GD was investigated, among whom 303 patients were evaluated for thyroid function and 371 patients for adverse events. Recruitment was from 4 Japanese hospitals.

Methods

Serum free T 4 and free T 3 measured at 4, 8, and 12 weeks after initiation of therapy. Evaluation of adverse effects – by interview, clinical investigation and hepatic and hematological variables – at 2, 4, 8, & 12 weeks.

Results

After 12 weeks with MMI 30 mg/day, significantly more patients (97%) had normalized serum free T 4 than those who received PTU 300 mg/day (78%) or MMI 15 mg/day (86%). This was mainly due to a difference in those with the highest serum free T 4 values. A similar tendency was observed for serum free T 3 , although less pronounced. Number of patients with adverse effects, especially mild hepatotoxicity, were significantly higher in the PTU group (52%) than in the MMI groups, and were higher in the group with MMI 30 mg/d (30%) than in the group with MMI 15 mg/d (14%).

Conclusions

The present study, in an iodine-sufficient area, suggests that 15 mg of MMI daily will normalize thyroid function in the majority of patients with GD with the lowest risk of adverse events. If hyperthyroidism is pronounced, 30 mg of MMI daily should be used. PTU should not be used as the first drug of choice due to its adverse effect profile.

Commentary

As evidenced by questionnaire studies carried out fifteen years ago, and despite more than half a century of its use, there remain quite profound regional/continental differences in the use and type of antithyroid drug (ATD), and also differences as to whether ATD or radioactive iodine (RAI) should be the preferred first choice for the treatment of hyperthyroidism due to Graves- disease (GD). Although the most recent issues of thyroid/endocrine textbooks state that the choice is mainly based on personal preference and experience of physicians, they generally suggest that there are many reasons to prefer MMI.

Accepting that it is highly unlikely that this influenced the overall conclusions of the study by Nakamura et al., the study was unblinded and we do not know whether variables such as age, sex, family history of thyroid disease, initial thyroid function, initial TSH-receptor antibody levels, serum free T4/free T3 ratio, thyroid size, thyroid flow and degree of hypoechogenicity (at ultrasound), were comparable in the three groups. These and other variables are, to an unknown degree, associated with the effects of ATD. Additionally, knowledge of iodine status in this group of patients would help in interpreting the potential validity of the findings for populations from regions which differ in iodine sufficiency.

Whether present findings also apply to toxic nodular goiter, and whether there is also a potential dose-response relationship for PTU (as was the case for MMI) remains unclarified. Again, can the findings be generalized to cover populations with low or borderline iodine intake?

What about adverse effects? First, both white blood cell count and hepatic function may be altered by hyperthyroidism per se . In the present study, there was no account of pre-treatment values. Possibly this could account for the unusually high frequency of -hepatotoxicity-. Second, the unprecedented high incidence of adverse effects (52% with PTU) is most likely due to a more rigorous definition of adverse effects than normally used. Most of us operate with a figure of 5-10% of GD patients having adverse effects due to ATD. On the other hand the definitions were independent of treatment group and therefore the relative difference seems valid. Third, noting the high frequency of adverse effects, it is striking that none seemed to have taste-related disorders, which, especially with PTU is one of the more common adverse effects in our experience.

A logical consequence of the existing literature – including the present study – is to recommend MMI and not PTU as the first drug of choice for adult non-pregnant hyperthyroid patients with GD. In the vast majority of cases, an initial dose of 15 mg daily (given as one or two divided doses) seems to offer the best balance between time needed to normalize thyroid function and risks of side effects. In case of adverse effects, a majority of adult patients are probably better off given RAI than PTU. Importantly, present study cannot clarify whether routine monitoring of hematological and/or liver function parameters should be offered.

Summary and commentary prepared by Laszlo Heged-s (related to Chapter 11 of TDM) Full paper obtainable at: http://jcem.endojournals.org/cgi/content/full/92/6/