Thursday, October 29, 2009

Carbimazole and Thyroxine in the Treatment of Graves' Disease

A 43-year-old Malay woman, AS, has been diagnosed with Graves Disease 4 years ago. She is under follow up at a specialist clinic and has been on t. carbimazole 15 mg tds and t. levothyroxine 0.1 mg od (levothryroxine was added 4 months ago). [Note: this is an actual case at a district hospital]

Issue of interest:

In Graves’ disease, hyperthyroidism results from the action of thyroid stimulating antibodies directed against the thyrotropin receptor on the surface of the thyroid cells. These immunoglobulin G (Ig G antibodies) bind to the surface of thyroid cells and stimulate those cells to overproduce thyroid hormones.

Carbimazole is a thionamide that blocks thyroid hormone synthesis; on the other hand, levothyroxine is the drug of choice for hormone replacement therapy in the treatment of hypothyroidism.
What is the rationale of adding levothyroxine to carbimazole in AS?

Findings:

Carbimazole is given 20-60 mg/day as 2-3 divided doses until patient becomes euthyroid (usually after 4-8 weeks). For maintenance dose, the dosage of carbimazole is gradually reduced to maintain normal thyroid activity. Therapy is usually continued for 12-18 months.

The evidence that high doses of antithyroid drug have an immunosuppressive effect has led to implementation of block-replacement regimen by some clinicians. In this regimen, the dose of carbimazole is maintained at initially high level (20-60 mg/day) and supplemental thyroxine (50-150 mcg/day) is given in order to prevent an underactive thyroid induced by the high carbimazole dosage. (prevention of iatrogenic hypothyroidism). Therapy is usually continued for 12-18 months.



Caveats:
A systematic review of 12 trials that compared a Block-Replace regimen (requiring a higher dose of anti-thyroid drug treatment) with a Titration regimen showed that there was no significant difference between the regimens for relapse of hyperthyroidism (relative risk (RR) = 0.93, 95% confidence interval (CI) 0.84 to 1.03). Participants were more likely to withdraw due to adverse events with a Block-Replace regimen (RR = 1.89, 95% CI 1.25 to 2.85).

In 8 out of the 12 studies, the ant-thyroid drug used was carbimazole, the dose ranged between 30 and 60 mg/day in the Block-Replace arms of all these studies except for one study, where a dose of 100 mg/day was used.



References:
  1. DiPiro J et al. Pharmacotherapy handbook. 6th ed. USA: McGraw-Hill; 2006, p. 196-200.

  2. Lucas A, Salinas I, Rius F, Pizarro E, Granada ML, Foz M, and Sanmartl A. Medical therapy of Graves’ disease: Does thyroxine prevent recurrence of hyperthyroidism? Journey of Clinical Endocrinology and Metabolism 1997 [cited 28 October 2009]; 82(8): 2410-2413. Available from: URL: http://www.eje-online.org/cgi/content/abstract/131/2/120

  3. Lexi-Comp Drug Information Handbook. 18th ed.

  4. BNF 57.

  5. Abraham P, Avenell A, Park CM, Watson WA, and Bevan JS. A systematic review of drug therapy for Graves’ hyperthyroidism. European Journal of Endocrinology 2005 [cited 28 October 2009];153 (4): 484-498. Available from: URL: http://eje-online.org/cgi/content/full/153/4/489

4 comments:

  1. Thanks for GW for raising this issue.

    The systematic review (Reference 5)actually saying that in overall, there was no significant difference between the regimens for relapse of hyperthyroidism (relative risk (RR) = 0.93, 95% confidence interval (CI) 0.84 to 1.03). Participants were more likely to withdraw due to adverse events with a Block-Replace regimen (RR = 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. The titration regimen appeared as effective as the Block-Replace regimen, and was associated with fewer adverse effects.
    Just a reminder, this systematic review has a relapse rates over 50% and high participant drop-out rates in trials mean that the results ned to be interpreted carefully.

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    I cross-checked with Micromedex(R) Healthcare Series Vol. 142 expires 12/2009 in my hospital and I found :

    The use of levothyroxine (thyroxine) for adjunct treatment in thyrotoxicosis, has actually inconclusive in the efficacy, and FDA has no approval for this indication for both adult and paediatric.

    Or in other words: Thyroid hormones used with antithyroid drugs to treat thyrotoxicosis may prevent goitrogenesis and hypothyroidism. Conflicting results during combination therapy of thyroid and antithyroid agents in the treatment of hyperthyroidism (Rittmaster et al, 1996, Hashizume et al, 1991)

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    (Rittmaster et al, 1996) : Adding levothyroxine to methimazole did not cause a greater decrease in thyroid-stimulating hormone (TSH) receptor antibody concentration than methimazole alone in an 18-month comparative study in 70 patients with GRAVES' DISEASE . All patients received methimazole alone until they were euthyroid; they were then randomized to 1 of 3 regimens: 1) Group 1 remained on methimazole alone at a dosage to maintain a TSH level of 0.3 to 5.4 milliunits/L (n=24); 2) Group 2 received methimazole 30 milligrams/day plus enough levothyroxine to maintain a TSH level of 2 to 5.4 milliunits/L (n=23); 3) Group 3 received methimazole 30 milligrams/day plus enough levothyroxine to maintain a TSH level of 0.6 milliunits/L or less (n=23). There was a significant decrease in TSH receptor antibody (TSI) levels from baseline in all 3 groups, but there were no significant differences in the degree of TSI reduction among the 3 groups at 6 or 18 months. Thyroid-binding, inhibitory IG (TBII) was significantly higher in Group 3 than Group 1 at 6 months, but at 18 months, all 3 groups had similar TBII levels. The degree of reduction in TBII over the 18-month study was also similar among the 3 groups. The authors predicted no difference in remission rates among the groups of patients, but long- term follow-up is needed to make that conclusion.

    (Hashizume et al, 1991): Levothyroxine, when administered during antithyroid therapy, was effective for reducing the amount of antibodies produced to thyroid-stimulating hormone (TSH) receptors and the recurrence of hyperthyroidism. In a randomized trial, 60 patients received 10 milligrams of methimazole daily with either levothyroxine 100 micrograms/day or placebo for 1 year. The frequency of recurrence of hyperthyroidism and the amount of antibodies produced to TSH receptors were significantly reduced in the levothyroxine-treated patients .
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  2. Sorry, forget to include the references:

    Rittmaster RS, Zwicker H, Abbott EC, et al: Effect of methimazole with or without exogenous L-thyroxine on serum concentrations of thyrotropin (TSH) receptor antibodies in patients with Graves' disease. J Clin Endocrinol Metab 1996; 81:3283-3288.

    Hashizume K, Ichikawa K, Sakurai A, et al: Administration of thyroxine in treated graves' disease. N Engl J Med 1991; 324:947-953.

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