An Evidence-Based Study Comparing The Effectiveness Of 
Block & Replace Versus Titration Methods Of Antithyroid Drug Treatment In Graves’ Disease

Tutor : Dr Rona
Group Members :
Iheoma Amaechi 
Zareena Chaudhury 
Adj Dufu
Stephen Fenn
Ben Fisher
Daphne Hazel 
Charles Olojugba 
Aymer Postgate

Contents

Subject		Page	
			
Introduction		1	
Methods		2	
Results		4	
Conclusion		7	
Appendices		8	

Introduction

Hyperthyroidism is defined as a state of overactivity of the thyroid gland. It is a common condition affecting females five times as often as males.

The commonest cause of hyperthyroidism is Graves’ disease, an autoimmune condition in which serum IgG antibodies bind to TSH receptors, thus stimulating excess thyroid hormone production.

There are three main treatment options for the treatment of Graves’ disease, all of which aim to produce a euthyroid state :

.	Antithyroid drugs (Thionamides)
.	Radio-iodine
.	Surgery

Drug therapy

Antithyroid drug therapy is often used as the initial treatment and there are two main regimes in common usage throughout the world :

.	Gradual dose titration
	A dose of Antithyroid drug is given in order to achieve, and then maintain, a euthyroid state. Eventually the drug is discontinued.
	
.	Block & Replace (B&R)
	A large, blocking dose of Antithyroid drug is given to completely suppress thyroid activity. The Thyroid hormones are then replaced by giving T3 or T4.

There are three main Antithyroid drugs in use :

.	Carbimazole 	- most commonly used in the UK.
.	Methimazole 	- a metabolite of Carbimazole which is assumed to 				   function similarly.
.	Propylthiouracil - more commonly used in the US.

Reasons for choosing this study

	Graves’disease is commonly seen in the Endocrine Clinics at St Thomas’ Hospital and, while the Titration regimen has been used successfully for many years, the effectiveness of the B&R regimen has yet to be investigated.
	Initial literature studies and discussions with physicians suggested that there existed some evidence that the B&R regimen resulted in higher remission rates then the current Titration regimen.
	We decided to perform an evidence-based study to determine the most effective Antithyroid drug regimen in the treatment of Graves’ disease. It is hoped that the results of our analysis will enable the Endocrine Department to more easily assess the two treatments.

Methods

Selection of Papers.

	A ‘textword’ search of the Medline databases (1980-96) was carried out using words connected to the subject. Although Medline allowed a quick search of the journals, care was needed when selecting the search terms to ensure that all relevant papers were found.

	Search terms :

Block and replace
Block-replace
Block-replacing
Block and replacement

Graves’ disease
Carbimazole
Methimazole
Propylthiouracil

Initially, we only looked for randomised control trials which compared the relapse rates of the B&R and titration regimens. Unfortunately, only three suitable papers were found, so it was decided to widen our search to include all studies of Antithyroid drug treatments in order to provide enough data for analysis.

	The new searches produced thirty papers covering the desired topic and we obtained copies of the eighteen which were held by the UMDS libraries (appendix 1.1). A summary sheet (appendix 1.2) was then completed for each paper.

	Using these summaries, we checked each paper against our inclusion criteria to assess suitability for further analysis.

Inclusion Criteria -

Relapse Rates given for a specific treatment.
Treatment with Carbimazole, Propylthiouracil or Methylmethimazole.
Addition of T3 or T4 for B&R regimens.
Human population.

Of the eighteen papers collected, seven were excluded for various reasons.

Study 3 - Although this gave the relapse rates, without the original papers, it was impossible to tell whether our inclusion criteria could be applied.
Study 7 - No relapse rates for each treatment type were given.
Study 13 - No specific relapse rates were given.
Study 15 - Only 53 patients (48%) had finished the therapy at time of the report.
Study 16 - No relapse rates for each treatment type given.
Study 17 - No relapse rates were given.
Study 18 - No relapse rates were given.

Assumptions

Although the remaining eleven papers were found to be suitable for analysis, there were many parameters which differed between papers.

 Parameters :

Population
Severity of initial disease.
Drug
Dose
Treatment length
Time to relapse measurement
Method of relapse assessment

By looking at the comments made by these and other studies, we concluded that these differences were not significant enough to prevent us combining all the studies to produce one large population for analysis. 

Statistical Analysis

A 2x2 table showing the relapse rates for each treatment could be created for the three RCTs and then all eleven studies combined. These data could then be analysed using the Odds Ratio and Chi-squared tests.

Odds Ratio testing - this tests the relationship between the parameters being studied and the results seen, i.e. does the treatment affect the relapse rate? A value of less than one suggests such a link exists and that the relapse rate does depend on the treatment given. The 95% Confidence Interval is also calculated to test the significance of this relationship.

Chi-squared (2) test - this test compares the observed results with the results expected if there is no link between treatment and relapse rate. The significance of the 2 value is found using a table, and the p-value used to express the result, i.e. a p-value of less than 0.01 suggests that there is less than a 1% chance that the observed results were due to random effects, or a greater than 99% chance that they are due to the relationship between the treatment and the relapse rates.

	There was insufficient detail in the studies to allow complete analysis of the effects of the different variables on the relapse rates, but the effect of treatment length on relapse rate was statistically analysed.

An important part of the analysis was to check if the proposed new treatment, B&R, produced more side effects than the present treatment.

Results

In order to closely match the populations and treatments analysed, the three RCTs were grouped together to provide one population for analysis (appendix 2.1). Chart 1 summarises the results.

Chart 1 - OR and 95% CI for RCTs

As can be seen from Chart 1, the Odds Ratio is only significant Study 6, but when taking the results as a whole, the three RCTs demonstrate that the B&R relapse rate is significantly lower than the Titration regimen’s rate (Odds Ratio = 0.50).

This analysis only included 133 patients, so it was decided to group all the data from the eleven studies and analyse it. Several of the papers suggested that the relapse rate was unaffected by the treatment variables discussed earlier (population, drug, etc.), so it seemed reasonable to combine all the studies into one population and apply the same tests.

	Titration			Block & Replace			
Study	No. in Study	No. Relapsed	Relapse Rate	No. in Study	No. Relapsed	Relapse Rate	
1	32	27	84%	-	-	-	
2	116	76	66%	-	-	-	
4	94	45	48%	-	-	-	
5	-	-	-	47	28	60%	
6	48	28	58%	65	16	25%	
8	36	22	61%	34	19	56%	
9	-	-	-	156	58	37%	
10	-	-	-	65	32	49%	
11	-	-	-	100	38	38%	
12	41	14	34%	9	2	22%	
14	-	-	-	72	31	43%	
							
Total	367	212	58%	548	224	41%	
							
			Total number of patients  =	915	

Table 1 -  data for all eleven studies.

Note -	1) Study 8 excludes those patients changed to Propylthiouracil
	2) Study 9 excludes those patients on low-dose Methylmethimazole B&R

Although there is an obvious difference in the overall relapse rates (41% vs. 58%), statistical analysis was necessary to assess the significance of this difference.

Odds Ratio	= 0.51	
95% Confidence Interval	= 0.39 - 0.66	
		
2	= 24.46	
p	< 0.001	

As the 95% confidence interval for the Odds Ratio excludes and is less than one, there is a significant link between the type of treatment and the relapse rate. This is also shown by the Chi-squared p-value being less than 0.001.

Effect of Treatment Length

Several studies mentioned that treatment length is a very important factor in determining the relapse rate, especially for Titration regimens. To assess this, the relapse rate for each treatment type and length of treatment ( <12 months or 12 months) was calculated and statistically analysed.

Analysis (appendix 2.3) shows that only the Titration regimen demonstrated a difference in the relapse rate between <12 months and 12 months of treatment (Odds Ratio=0.5). It also shows a difference in the relapse rates when comparing B&R with Titration for both treatments <12 months and those 12 months in length (Odds Ratios of 0.38 and 0.34 respectively).
	So, although Titration is more effective when used for 12 months, it is still not as effective as B&R. This last effect is well recognised as being partly due to the time needed to reach a euthyroid state with the Titration regime.

Side Effects

The thionamide Antithyroid drugs used to treat hyperthyroidism are associated with side effects in between 5 and 25% of cases.  These side effects are usually minor, and include mild arthralgia, pruritis, gastritis, headache, skin rashes and dermatitis.  Less commonly, serious side effects can occur, including toxic hepatitis, agranulocytosis and asthma. It is important to take these side effects into consideration when comparing the efficacy of the two treatments. 

There is some general consensus in past studies that the Antithyroid drugs exhibit a dose dependant toxicity, and that consequently the B&R regimen, which uses higher doses of these drugs, is more prone to side effects than is the titration method.  This assertion was supported by the conclusions of the International Symposium of the European Thyroid Association in 1991.  

Odds Ratio	= 0.30	
95% Confidence Interval	= 0.16 - 0.55	
		
2	= 15.49	
p	< 0.001	
Of the eleven studies reviewed, only five mentioned side effects.  Two of these noted no dose dependant toxicity.  However, one study found a significant (P=0.0038) dose-dependant effect on the frequency of side effects, between different doses of Methimazole (10mg/day vs. 40mg/day) with the B&R regimen.  In order to address this discrepancy we took the data from all five of the studies that mentioned side effects and statistical analysis was performed to see if there was a significant difference in the frequency of side effects between the two treatment methods.

The average frequency of side effects was 16.5% for B&R and 5.6% for Titration. The above results show that there is a significant difference in the rate of side effects between the two treatments.

Conclusion

The evidence suggests that patients undergoing Block & Replace treatment have a relative risk reduction of 29% compared with those on gradual dose Titration treatment.

Associated with this, however, we found that the higher doses of thionamides used in B&R were associated with a higher rate of side effects. It is not possible to say, however, whether these side effects are severe enough to restrict the general use of the B&R  regimen. It is also possible that one particular regime (drug, dose, treatment length, etc.) is responsible for the high side effects rate seen for B&R. Perhaps, with careful selection of the treatment parameters, the risk of side effects can be reduced while still maintaining the lower relapse rates seen with the treatment.

Limitations

.	Only locally held, English language papers were selected
.	We assumed that the different drugs gave similar results.
.	The treatment length varied between the papers.
.	The criteria for the diagnosis of relapse may have varied.

Although there is little evidence to suggest these limitations have affected our results, a prospective, large randomised control trial would be useful to assess the importance of these limitations and test the conclusions we have drawn from the data analysis.

Appendix 1.1

1	Once daily, low does, short term antithyroid drug treatment of Graves’ disease is followed by an unacceptably high relapse rate.	
	New Zealand M J 104(907):97-8, 1991	
2	Drug therapy for Graves’ disease in blacks - very low remission	
	SAMT 74(5):284-6,1988	
3	Meta-analysis evaluation of the impact of thyrotropin receptor antibodies on long term remission after medical therapy of Graves’ disease.	
	J Clin Endo & Met 78(1):98-102, 1994	
4	Antithyroid drugs and Graves’ disease: A prospective randomised evaluation of the efficacy of treatment duration.	
	J Clin Endo & Met 70(3):675	
5	The prognostic value of TSH receptor binding and thyroid stimulating antibodies following antithyroid drug treatment of Graves’ disease.	
	Acta Endocrinologica 121:666-70, 1989	
6	Comparison of effects of high and low dosage regimens of antithyroid drugs in the management of Graves’ hyperthyroidism.	
	J Clin Endo & Met 57(3):563, 1983	
7	Prospective multicentre study on the prediction of relapse after antithyroid drug treatment in patients with Graves’ disease.	
	Acta Endocrinologica 120:689-701, 1989	
8	Treatment of Graves’ disease by Carbimazole: high dose with thyroxine compared to titration dose.	
	European J Endo. 131:120-4, 1994	
9	A prospective randomised trial of antithyroid drug dose in Graves’ disease therapy.	
	J Clin Endo & Met 76(6):1516	
10	Prediction of outcome in Graves’ disease after Carbimazole treatment.	
	Quarterly J Med 59(228):409-19, 1986	
11	Treatment of Graves’ disease with the block-replace regimen of antithyroid drugs: the effect of treatment duration and immunogenetic susceptibility on relapse.	
	Quarterly J Med 87:337-41, 1994	
12	Role of TSH measurements in predicting the outcome of treatment for Graves’ disease following drug therapy.	
	Postgrad Med J 71(834):222-3, 1995	
13	Reassessment of antithyroid drug therapy of Graves’ disease.	
	Annual Review Med 44:323-34, 1993	
14	Prediction of remission after antithyroid drug treatment in Graves’ disease	
	Quarterly J Med 66(250):175-89, 1988	
15	Lack of effect of thyroxine in patients with Graves’ hyperthyroidism who are treated with an antithyroid drug.	
	New England J Med 334(4):220-4, 1996	
16	Antithyroid drugs in the treatment of hyperthyroidism of Graves’ disease: long-term follow-up of 434 patients.	
	Clin Endo 31:209-18, 1989	
17	Comparison of standardised initial doses of 2 antithyroid drugs in the treatment of Graves’ disease.	
	J Internal Med 239:525-9, 1996	
18	Higher than conventional doses of Carbimazole in the treatment of thyrotoxicosis.	
	Clin Endo 29:281-8, 1988	

Reviewer’s Name : 		
Paper Title : 	
	
Journal & Reference : 	
	
Authors : 		
Type of Study :	
			
Date & Length :
of Study 	
			
Source of Population :	
	Age range :		
Ethnicity / Country :	
	Newly Diagnosed :	Yes / No / Unknown	
Previous Treatment :	

				
	Group One	Group Two	Group Three	
Drugs Used : 1

2

Dose & Timing : 1

2
				
Duration : 1
 of Therapy           
2
				
Original Size :
 				
Time Relapse : 1
Measured       2
3				
Number Completed : 1 
2 
3
				
Relapse Number : 1
or Rate         2
3

 Conclusions Made : 	

	
Comments Made : 
(i.e. iodine intake)	

	
Appendix 1.2

Appendix 2.1
Odds Ratio Testing for RCT Study 6									
									
	Relapse	Remission	Total						
B&R	16	49	65						
Titration	28	20	48						
									
Odds Ratio =	0.233236							
ln (OR) =	-1.4557							
SE [ln(OR)] =	0.410637							
95% CI [ln (OR)] =	-2.26055	to	-0.65086					
95% CI (OR) =	0.104293	to	0.521599					
	Result : The difference is	significant.					
									
Odds Ratio Testing for RCT Study 8									
									
	Relapse	Remission	Total						
B&R	19	15	34						
Titration	22	14	36						
									
Odds Ratio =	0.806061							
ln (OR) =	-0.2156							
SE [ln(OR)] =	0.485985							
95% CI [ln (OR)] =	-1.16813	to	0.736934					
95% CI (OR) =	0.310949	to	2.08952					
	Result : The difference is	not significant.			
									
Odds Ratio Testing for RCT Study 12									
									
	Relapse	Remission	Total						
B&R	2	7	9						
Titration	14	27	41						
									
Odds Ratio =	0.55102							
ln (OR) =	-0.59598							
SE [ln(OR)] =	0.866789							
95% CI [ln (OR)] =	-2.29489	to	1.102923					
95% CI (OR) =	0.100773	to	3.012959					
	Result : The difference is	not significant.			
									
Odds Ratio Testing for Total RCTs									
									
Observed results						Expected results			
	Relapse	Remission	Total	R Rate			Relapse	Remission	
B&R	37	71	108	34.26%		B&R	46.81545	61.18455	
Titration	64	61	125	51.20%		Titration	54.18455	70.81545	
									
Odds Ratio =	0.496699					1.853611	1.418293	
ln (OR) =	-0.69977					1.60152	1.225405	
SE [ln(OR)] =	0.270426							
95% CI [ln (OR)] =	-1.22981	to	-0.16974		Chi-squared =	6.098829	
95% CI (OR) =	0.29235	to	0.843887			p <	0.02	
	Result : The difference is	significant				
Appendix 2.2

Odds Ratio Testing for Total Results									
						Expected results			
	Relapse	Remission		R Rate					
B&R	224	324		40.88%			Relapse	Remission	
Titration	212	155		57.77%		B&R	261.1235	286.8765	
						Titration	174.8765	192.1235	
Odds Ratio =	0.505474							
ln (OR) =	-0.68226					5.136575	4.675463	
						7.669873	6.981346	
SE [ln(OR)] =	0.136818						
95% CI [ln (OR)] =	-0.95042	to	-0.41409		Chi-squared =	24.46326	
95% CI (OR) =	0.386578	to	0.660939			p <	0.001	
									
	Result : The difference is	significant.					

Appendix 2.3
Odds Ratio Testing for Length of Treatment (Titration)									
									
	Relapse	Remission				Expected results			
> 12 mths	163	149					Relapse	Remission	
< 12 mths	55	25				< 12 mths	173.5102	138.4898	
						> 12 mths	44.4898	35.5102	
Odds Ratio =	0.497254							
ln (OR) =	-0.69865					0.577512	0.723549	
SE [ln(OR)] =	0.266511					2.252296	2.821842	
95% CI [ln (OR)] =	-1.22102	to	-0.17629					
95% CI (OR) =	0.294931	to	0.838373		Chi-squared =	6.375199	
	Result : The difference is	significant.			p <	0.02	
									
Odds Ratio Testing for Length of Treatment (B&R)									
						Expected results			
	Relapse	Remission					Relapse	Remission	
> 12 mths	180	493				< 12 mths	186.0977	486.9023	
< 12 mths	52	114				> 12 mths	45.90226	120.0977	
									
Odds Ratio =	0.800437					0.168377	0.064355	
ln (OR) =	-0.2226					0.682638	0.26091	
SE [ln(OR)] =	0.188644							
95% CI [ln (OR)] =	-0.59234	to	0.147145		Chi-squared =	1.17628	
95% CI (OR) =	0.553031	to	1.158522			p <	0.3	
	Result : The difference is	not significant.			
									
Odds Ratio Testing for < 12 months									
									
	Relapse	Remission				Expected results			
B&R	52	62					Relapse	Remission	
Titration	55	25				< 12 mths	62.87629	51.12371	
						> 12 mths	44.12371	35.87629	
Odds Ratio =	0.381232							
ln (OR) =	-0.96435					1.712368	2.106016	
SE [ln(OR)] =	0.305846					2.440125	3.001073	
95% CI [ln (OR)] =	-1.56381	to	-0.36489					
95% CI (OR) =	0.209338	to	0.694273		Chi-squared =	9.259583	
	Result : The difference is	significant.			p <	0.005	
									
Odds Ratio Testing for >= 12 months									
									
	Relapse	Remission				Expected results			
B&R	172	262					Relapse	Remission	
Titration	157	130				< 12 mths	198.0388	235.9612	
						> 12 mths	130.9612	156.0388	
Odds Ratio =	0.543589							
ln (OR) =	-0.60956					3.293456	2.76415	
SE [ln(OR)] =	0.153924					4.980347	4.179934	
95% CI [ln (OR)] =	-0.91125	to	-0.30787					
95% CI (OR) =	0.402021	to	0.73501		Chi-squared =	15.21789	
	Result : The difference is	significant.			p <	0.001