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Three Part Question

In treating [children with Graves’ hyperthyroidism] is [block and replace regimen better than titration] at achieving [higher medium to long term remission rates]?

Clinical Scenario

You see a 12 year old girl with Graves’ hyperthyroidism in the clinic. She has relapsed on titration of her carbimazole. Hence, the Consultant changes her treatment regimen to block and replace ( combination of high dose carbimazole and thyroxine ) . You wonder whether block and replace regimen (combination of high dose anti thyroid drug with thyroxine replacement ) is better than dose titration regimen ( low dose anti thyroid drug ) at reducing relapses and achieving long term remission ( greater than 2 years ).

Search Strategy

Cochrane.
Medline via NHS evidence from 1950 to date, search date 12th September 2012.
Embase via NHS evidence from 1950 to date, search date 12th September 2012.
Pubmed via NCBI from 1883 to date, search date 12th September 2012.

Separate searches for Grave’s disease, “block and replace or block-replace” and “titration” were run. The three searches were then combined.

Search Outcome

1 relevant meta-analysis on Cochrane.
7 articles were found on Medline, 1 further article on Embase and 1 further article on Pub Med via NCBI which was an electronic article ahead of print.
All relevant articles were reviewed and references searched.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Lucas et al. 1997 Spain	60 patients aged 7-57years, with a new diagnosis of Grave’s disease were recruited. N=30 received high dose ATD* and n=30 received low dose ATD. Patients were treated for 18.4± 2.6 months.	RCT	Relapse of hyperthyroidism at 24 months. Remission at 4.9±1.6 years.	Block-replace n/N=20/30, titration n/N= 18/20. Odds ratio is 1.33 and 95% CI is 0.47-3.76 for relapse in study completers (no drop out). P value is 0.467	No mention of assessor’s blinding. Exclusion criteria not mentioned The mean age of patients was 36 ± 11.5. No break up to specify number of children included
Rittmaster et al. 1998 Canada	199 patients aged 10-72years, with a new diagnosis of Grave’s disease were recruited. There were 50 drop outs and 149 patients were followed up. The patients were divided into 3 groups. Group1(n=51) received high dose ATD, group2(n=50) received low dose ATD and T4 sufficient to maintain normal to high TSH, group 3(n=48) received low dose ATD and T4 sufficient to maintain low TSH. Group 2 and 3 were reassigned to Group A and B depending on TSH achieved <1 and >1 respectively. Patients were treated for 18months.	RCT	Relapse of hyperthyroidism at 24months. Remission rate at 27months	Block-replace n/N= 57/98, titration n/N= 30/51. Odds ratio is 0.97 and 95% CI is 0.49-1.93 in study completers and also after assuming relapse in all drop outs. P value is 1	No details of randomization and did not follow intention to treat. Exclusion criteria not mentioned. High number of drop outs. The drug used was methimazole, which is not used in the UK Mean age of patients was 38years. Number of children not known.

Comment(s)

63% of patients relapsed and there was no difference in relapse rate between the two groups in the first study. In the second study although there was a delay in time to relapse in the block and replace group where sufficient T4 was used to maintain a low TSH. The relapse rate was 58%. There was no difference in remission rates in the two groups at 2 year follow up. There are no studies to date which have addressed the above question, exclusively, in a paediatric population. Although the above studies included children, the mean age of the study population was in the 30s. These studies and similar studies in adult population suggest that there is no difference in relapse rate or long term remission rates between the two forms of drug regimens. Nearly 50% of the patients treated with anti thyroid drugs achieved long term remission in most studies. The author of the meta-analysis concluded that the dose titration regimen for 12-18months is preferred in adults, due to reduced incidence of side effects. The high doses of ATDs used in block and replace regimen are more likely to cause side effects and the most worrying one being agranulocytosis or granulocytopenia. However, the evidence on which the meta-analyses concluded this has been criticized by some ( S Razvi and others, 2006 ). The hyperthyroidism management guidelines published by the American Thyroid Association and American Association of clinical endocrinologists supports the recommendation of the meta-analysis to use titration regimen, in both adults and children. Block and replace is recommended by some authors due to ease of monitoring and fewer hospital visits ( Raza J, 1999 ). It is also the preferred mode of treatment for patients with fluctuating thyroid functions during treatment and for those with eye disease and risk of complications. There is no consensus on the preferred drug regimen to date. Block and replace seems to the preferred regimen in UK whereas the titration regimen is more popular in the USA. The National Institute of Health Research ( NIHR ) is currently recruiting children for a UK multicentre study comparing the two approaches to treatment with Anti Thyroid Drugs. The main outcomes are remission rates, biochemical stability and frequency and nature of drug side effects.

Clinical Bottom Line

There is no difference in relapse or long term remission rates in either approach in adult studies. Paediatric studies are underway. No consensus on preferred drug regimen.

References

1. A. LUCAS, I. SALINAS, F. RIUS, E. PIZARRO, M.L. GRANADA, M. FOZ, AND A. SANMARTÍ Medical Therapy of Graves’ Disease: Does Thyroxine Prevent Recurrence of Hyperthyroidism? Journal of Clinical Endocrinology and Metabolism 1997 Aug;82(8):2410-3.
2. ROGER S. RITTMASTER, E. CARL ABBOTT, ROBERT DOUGLAS, MORRIS L. GIVNER, LEA LEHMANN, SETHU REDDY, SONIA R. SALISBURY, ALLAN H. SHLOSSBERG, MENG H. TAN, AND SAMUEL E. YORK Effect of Methimazole, with or without L-Thyroxine, on Remission Rates in Graves’ Disease Journal of Clinical Endocrinology and Metabolism 1998 Mar;83(3):814-8.
3. Abraham P, Avenell A, Park CM, Watson WA, Bevan JS. (2010) Antithyroid drug regimen for treating Graves’ hyperthyroidism. Cochrane Database of Systematic Reviews
4. Daniels GH The American Thyroid Association and American Association of Clinical Endocrinologists\' Guidelines for Hyperthyroidism and Other Causes of Thyrotoxicosis: An Appraisal. Endocrine Practice 2011
5. Raza J, Hindmarsh PC, Brook CG Thyrotoxicosis in children: thirty years\' experience Acta Paediatrica 1999, 88, 937-41
6. Razvi S, Vaidya B, Perros P, Pearce SH What is the evidence behind the evidence-base? The premature death of block-replace antithyroid drug regimens for Graves\' disease European journal of Endocrinology 2006 Jun;154(6):783-6.
7. Schenk D, Donaldson M, Cheetham T Which antithyroid drug regimen in Paediatric Graves\' disease? Clinical Endocrinology (Oxf) 2012 Jul 20. doi: 10.1111/j.1365-2265.2012.04509.x. [Epub ahead of print]