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Title: Cost-Utility Analysis Comparing Radioactive Iodine, Antithyroid Drugs and Total 1
Thyroidectomy for Primary Treatment of Graves’ Disease 2
3
Authors: Peter J Donovan,1,2
Donald SA McLeod,2,3,4
Richard Little,5 Louisa Gordon
4,6 4
5
1. Department of Clinical Pharmacology, Royal Brisbane and Women’s Hospital, 6
Herston, QLD, Australia 7
2. School of Medicine and Biosciences, University of Queensland, Herston, QLD, 8
Australia 9
3. Department of Endocrinology and Diabetes, Royal Brisbane and Women’s Hospital, 10
Herston, QLD, Australia 11
4. Population Health Department, QIMR Berghofer Medical Research Institute, 12
Herston, QLD, Australia 13
5. Consultant Health Economist, Cambridge, England 14
6. Griffith University, Centre for Applied Health Economics, Logan Campus, University 15
Dr, Meadowbrook QLD, Australia 16
17
Corresponding author’s postal and email address: 18
Dr Peter Donovan 19
Department of Clinical Pharmacology 20
Level 1 Ned Hanlon Building 21
Royal Brisbane and Women’s Hospital 22
Butterfield St, Herston QLD, Australia 4029 23
25
Short title: Cost-utility Analysis of Graves’ Disease Therapies 26
27
Key Words: Cost-effectiveness, Cost-utility, Graves’ disease, hyperthyroidism, radioactive 28
iodine, antithyroid drugs, thyroidectomy 29
30
Word count: 2740 (excluding abstract, references, title page, and tables) 31
32
Page 1 of 29 Accepted Preprint first posted on 15 September 2016 as Manuscript EJE-16-0527
Copyright © 2016 European Society of Endocrinology.
2
Abstract 33
Objective: Little data exists about the most cost-effective primary treatment for Graves’ 34
disease. We performed a cost-utility analysis comparing radioactive iodine [RAI]; 35
antithyroid drugs [ATD]); and total thyroidectomy (TT) as first-line therapy for Graves’ 36
disease in England and Australia. 37
Methods: We used a Markov model to compare lifetime costs and benefits (quality adjusted 38
life-years [QALYs]). The model included efficacy, rates of relapse and major complications 39
associated with each treatment, and alternative second-line therapies. Model parameters 40
were obtained from published literature. One-way sensitivity analyses were conducted. 41
Costs were presented in 2015£ or Australian Dollars (AUD). 42
Results: RAI was the least expensive therapy in both England (£5,425; QALYs 34.73) and 43
Australia (AUD5,601; 30.97 QALYs). In base case results, in both countries, ATD was a cost-44
effective alternative to RAI (£16,866; 35.17 QALYs; incremental cost-effectiveness ratio 45
[ICER] £26,279 per QALY gained England; AUD8,924; 31.37 QALYs; ICER AUD9,687 per QALY 46
gained Australia), while RAI dominated TT (£7,115; QALYs 33.93 England; AUD15,668; 30.25 47
QALYs Australia). In sensitivity analysis, base case results were stable to changes in most 48
cost, transition probabilities and health-relative quality of life (HRQoL) weights; however, in 49
England, the results were sensitive to changes in the HRQoL weights of hypothyroidism and 50
euthyroidism on ATD. 51
Conclusions: In this analysis, RAI is the least expensive choice for first-line treatment 52
strategy for Graves’ disease. In England and Australia, ATD is likely to be a cost-effective 53
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alternative, while TT is unlikely to be cost-effective. Further research into HRQoL in Graves’ 54
disease could improve the quality of future studies. 55
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Introduction 56
Graves’ disease is the most common cause of hyperthyroidism with an incidence of 0.8 57
cases per 1000 women annually in the United Kingdom.1 The three standard primary 58
treatments have different profiles of potential benefits and harms for patients: radioactive 59
iodine (RAI) is associated with lower rates of relapse than ATD but more potential to cause 60
Graves’ ophthalmopathy (GO);2, 3
antithyroid drugs (ATD) can lead to long-term remission 61
(with no deficits in quality of life and no long-term costs), but has high rates of relapse and is 62
associated with potentially catastrophic side effects (e.g., agranulocytosis); surgery (total 63
thyroidectomy – TT) has the highest cure rates, but largest upfront costs and more potential 64
long-term side-effects (hypoparathyroidism, recurrent laryngeal nerve palsy, scar).4 65
Therefore, to properly assess the cost-effectiveness of the primary therapies for Graves’ 66
disease, modelling lifelong costs and effectiveness (measured by quality of life in quality 67
adjusted life years – QALYs) is necessary. The few published cost-effectiveness analyses 68
examining Graves’ disease management have important limitations including only short-69
term assessment of costs and benefits and/or assessment treatment options not consistent 70
with contemporary management (i.e. subtotal thyroidectomy).5-8
71
The primary aim of this study was to perform a cost-utility analysis comparing RAI, ATD and 72
TT from the perspective of the government contribution to the healthcare sector, in both 73
England and Australia. 74
Methods 75
Model Structure 76
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We conducted a cost-utility analysis using TreeAge Pro 2015 R2 (TreeAge Software; 77
Williamstown, Massachusetts, United States of America [USA]). One model with the same 78
structure was constructed for England and Australia, with the only differences being the 79
inputs of costs, life-expectancy data and discount rates. Figure 1 shows a simplified version 80
of the model. We used a Markov cohort, which is cyclical and tracks key clinical options and 81
outcomes of persons with Graves’ disease following each of the three treatments. 82
Given peak age of onset of Graves’ disease is described as 40 to 60 years,9 and to capture 83
the impact of it on younger patients, a 40-year-old female was selected as the base case 84
patient. Life-expectancy data was obtained from recognised country-specific sources.10, 11
85
The Markov cycle length was three months, given that all transient or short-term states 86
(e.g., transient hypoparathyroidism and symptomatic hyperthyroidism) should be near or 87
fully resolved within this timeframe. The maximum time horizon of the model was until age 88
100 years. Discount rates for costs and benefits beyond the first year were 3.5% per year 89
for both in England and 5% in Australia, according to country-specific guidelines.12, 13
90
Carbimazole was used as the ATD of choice. In the base case analysis, for model simplicity 91
all of the ATD cohort that relapsed after initial remission were treated with long-term ATD, 92
rather than definitive therapy (e.g., RAI or TT); sensitivity analyses examined for differing 93
proportions of RAI and TT given as second line treatment in patients with relapse after initial 94
ATD therapy. If RAI did not produce remission, retreatment with RAI (up to three doses) 95
was included in the model, consistent with American Thyroid Association guidelines.8 96
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Rates of minor complications that are short-lived, have little effect on quality of life or lead 97
to a change in treatment (e.g., minor rash or elevated liver enzymes from ATD), are rare 98
(e.g., fulminant liver failure from propylthiouracil) or for which evidence to support 99
causation is limited (e.g., RAI causing secondary cancers) were not included.3, 9
Although 100
GO can occur at any time, only the excess risk of GO associated with RAI was included in the 101
model.2 Additionally, although many women with Graves’ disease are of child-bearing age, 102
this aspect was excluded from this model, as, in patients where pregnancy is desired in the 103
short-term, RAI is contraindicated due to potential teratogenicity.8 104
Clinical Estimates 105
We performed a literature review using PubMed and EMBASE to identify rates of efficacy, 106
relapse, complications and HRQoL values, associated with each treatment option, with 107
various combinations of the following search terms (PubMed terms only shown): 108
hyperthyroid*, Graves, thyrotoxicosis, "Graves Disease"[Mesh], Graves 109
Disease/therapy"[MeSH], anti-thyroid drug, carbimazole, propylthiouracil, methimazole, 110
("Antithyroid Agents"[Pharmacological Action], recurrence, radioiodine OR radioactive*, 111
"Iodine Isotopes/therapeutic use"[MeSH], "Iodine Isotopes/therapy"[MeSH], complication, 112
thyroidectomy[MeSH Terms], "cost utility", "cost-utility", QALY, EQ-5D, "quality adjusted life 113
year", "quality-adjusted life year", "Quality of Life"[MeSH], "cost effective*", "cost-114
effective*", "cost utility", "cost-utility", "Cost-Benefit Analysis"[MeSH], “economic 115
evaluation”. Additional publications were obtained by targeted searches of the references 116
of identified studies. Where more than one potential publication was identified, meta-117
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analyses and randomised trials were preferred.2, 3, 14
If only cohort studies were identified, 118
data from studies with larger populations and longer durations of follow-up were included.15
119
Table 1 shows a summary of the transition probabilities included in the model and their 120
sensitivity analysis ranges. Transition probabilities are the probability of a patient 121
transitioning from one Markov state to another, during a single Markov cycle (e.g., the 122
probability that a patient transitions from active hyperthyroidism to hypothyroidism with 123
TT, without having suffered any other complication of surgery, is 62.2% (see Table 1)). 124
Costs 125
Unit costs were identified using recognised sources and presented in 2015 values (Pounds 126
[Sterling]; £ in England and 2015 Australian Dollars [AUD]) – see Table 2. Where unit costs 127
were not readily available, estimates were obtained from published literature or by currency 128
conversion, with costs from prior to 2015 adjusted to present values, where possible.6, 16, 17
129
The perspective taken for this analysis was of each Governments’ contribution to 130
healthcare. 131
Long-term costs of medications, medical practitioner visits and pathology associated with all 132
treatments and their complications were included in the model, with the proposed follow-133
up visit schedule similar to previously published CEA and recognised treatment guidelines – 134
see Table 3.5, 8
135
Health-related Quality of Life Estimates 136
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Effectiveness was evaluated by using HRQoL estimates (health utilities) from the published 137
literature to generate quality-adjusted life-years obtained – Table 1. The preferred 138
methods for obtaining HRQoL estimates to be included in the model were (in descending 139
order of preference, consistent with country-specific guidelines12, 13
): 140
• Preference-based methods with direct elicitation of HRQoL weights from prospective 141
studies (e.g. time trade-off, standard gamble, multi-attribute utility indices with 142
preference-based methodology [e.g. Euro-Quality of Life – 5 Dimensions (EQ-5D)] 143
• Studies using the SF-36 (Short Form 36) questionnaire and conversion of these 144
scores to EQ-5D weights using a published, validated algorithm24
145
• HRQoL weights based on expert judgement, weights from previously published cost-146
effectiveness analysis or generated as part of this study (using Delphi methodology, 147
seven specialist endocrinologists came to consensus values, after taking into 148
consideration the other HRQoL weights used in the model). 149
Incremental Cost Effectiveness Ratio 150
The model aggregates the costs and patient outcomes using an expected values analysis, 151
calculating the incremental cost-effectiveness ratios (ICER) using the following formula (ICER 152
of ATD over RAI as an example): 153
���� = ����� ������� − ����� �������
������������� − Total��������
In the main model, the ICER is calculated using the best available estimates, called the ‘base 154
case’, while uncertainty and variation in these estimates are tested in sensitivity analyses 155
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(see below). The results were assessed for dominance (a dominant option is both less costly 156
and more effective than another option) and extended dominance (where a treatment 157
option is more costly and less effective than a combination of two other options). The 158
National Institute of Health and Care Excellence (NICE) in England suggest a cost-159
effectiveness threshold of £20,000-30,000 per QALY gained.12
We chose a pre-specified 160
threshold £30,000 per QALY gained in this analysis for England (and AUD 50,000), consistent 161
with this guidance.12
162
Sensitivity Analyses 163
We performed one-way sensitivity analyses, where the value of a single parameter is 164
changed across a range of values (the sensitivity analysis range) with different ICER values 165
calculated. Comparing these values to the base case ICER can be used to assess how stable 166
the results are to these changes, particularly in reference to the pre-specified thresholds for 167
cost-effectiveness. Sensitivity analysis ranges of transition probabilities were based on 95% 168
confidence intervals (CI) from published literature (where available). Cost estimates were 169
varied from 50% to 150% of base case values. As no published data was available to assist 170
with choice of sensitivity analysis ranges, the chosen ranges were arbitrary but were 171
considered to be plausible. Age at entry to the cohort ranging from 20 to 60 years was also 172
assessed. 173
174
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Results 175
Base Case 176
RAI was the least expensive therapy in both England (£5,425; QALYs 34.73) and Australia 177
(AUD5,601, 30.97 QALYs). In both countries, ATD was a cost-effective alternative to RAI 178
(£16,866, 35.17 QALYs, incremental cost-effectiveness ratio [ICER] £26,279 per QALY gained 179
England; AUD8,924; 31.37 QALYs; ICER AUD9,687 per QALY gained Australia), while RAI 180
dominated TT (£7,115; QALYs 33.93 England; AUD15,668; 30.25 QALYs Australia). 181
Sensitivity Analysis 182
Table 4 outlines the results of selected one-way sensitivity analysis. ATD was a cost-183
effective alternative to RAI in most sensitivity analyses (i.e., the calculated ICER ranges 184
remained below the thresholds of cost-effectiveness – £30,000 in England, AUD50,000 in 185
Australia), with the exceptions of HRQoL weights attached to hypothyroidism post RAI, 186
remission post ATD and euthyroidism on ATD (where the calculated ICER ranges extended 187
beyond these thresholds). ATD became more cost-effective (ICER became lower) as the 188
proportion of the cohort that received second-line RAI increased following relapse after 189
initially achieving remission with ATD. RAI was dominant over TT (i.e., RAI was less costly 190
and more effective) in sensitivity analysis of all parameters assessed. 191
Discussion 192
In our base case analysis, in England and Australia, RAI was the least expensive option for 193
the primary treatment of Graves’ disease, while ATD was a cost-effective alternative to it. 194
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TT was more expensive and less effective than RAI (i.e., TT was dominated by RAI). These 195
results were stable to changes in many key parameters and structural uncertainty tested in 196
sensitivity analyses. Although TT was dominated and ATD was cost-effective in both 197
countries, the ICERs were different, with the cost per QALY gained being much less in 198
Australia than England. These differences, as would be expected, are driven largely by 199
differences in unit costs, because, other than life-expectancy, discount rates, and cost 200
differences, the structure of the two models are identical. The main differences appear to 201
be the cost of carbimazole (with the cost in England being about 10-fold higher than 202
Australia, after adjustment for purchasing power parity), the cost of specialist endocrinology 203
follow-up (2.5-fold higher) and TT costs (0.6-fold lower). In both models, all of these unit 204
costs were obtained from reliable sources and likely reflect the true cost to the respective 205
Governments, and hence, are likely to represent true differences in the cost-effectiveness in 206
these two countries. 207
This study is the first, using a lifetime horizon, to assess the cost-effectiveness of the three 208
first-line therapies in Graves’ disease in England and Australia. Our results are consistent 209
with a single centre United Kingdom study that assessed cost per cure from hyperthyroidism 210
(not just Graves’ disease), which captured all medical costs for two years post diagnosis.6 211
That study demonstrated that RAI was substantially cheaper over a short-term horizon than 212
ATD or TT per cure; however, it did not assess long-term costs or quality of life. Our results 213
are not consistent with a 2012 cost-effectiveness analysis from the USA that suggested 214
surgery (subtotal thyroidectomy) was more effective and minimally more costly that RAI for 215
Graves’ disease.7 We did not consider subtotal thyroidectomy as a treatment choice, given 216
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it is not a recommended therapy for Graves’ disease due to high rates of relapse.8 Other 217
differences in our study were the inclusion of long-term costs, more recent data sources for 218
transition probabilities and HRQoL weights, and the costs of medical services identified in 219
England and Australia were much less than those in the previous study.7 220
Although the results of this study were stable to variation in most key parameters, results 221
were sensitive to changes in some HRQoL weights, particularly the weights attached to 222
hypothyroidism post-RAI, remission following ATD and euthyroidism while on ATD. This 223
sensitivity is potentially important for a number of reasons. Firstly, in both countries, ATD 224
ranged from being cost-effective compared with RAI, to being dominated by it across a 225
relatively modest sensitivity analysis range. Similarly, in England, but not Australia, as the 226
HRQoL of euthyroidism on ATD therapy decreased across its modest sensitivity analysis 227
range, ATD became less cost-effective (with an ICER as high as £91,303 per QALY gained). 228
Secondly, there are limited high quality data (e.g., from prospective studies using 229
preference-based methods) to support many of the HRQoL weights used in this study and in 230
particular, two of the weights were derived using expert opinion, albeit, the consensus 231
opinion of seven specialist endocrinologists. Thus, further research into HRQoL estimates in 232
thyroid disease (e.g., hypothyroidism, euthyroidism on ATD therapy), to obtain validated 233
weights using more accepted methodologies (e.g., EQ-5D) could improve the accuracy of 234
future economic models. 235
Our base case analysis included long-term ATD therapy as the treatment of choice for most 236
patients with relapsed Graves’ disease. However, base case results were highly sensitive to 237
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the proportion of RAI therapy given as second line, as, with increasing proportions, ATD 238
became highly cost-effective in both England and Australia (with ICERs down to £7,319 and 239
AUD4,928). Therefore, given the uncertainty about long-term quality of life, if ATD is chosen 240
as first-line therapy, second-line RAI (rather than long-term ATD therapy or TT) would 241
appear to be the most cost cost-effective therapy in the event of relapsed Graves’ disease. 242
There are a number of other limitations to this study. Firstly, the acquisition of unit cost 243
data, particularly in England, was problematic, as lists of unit costs, particularly for 244
pathology and radiology services, are not readily available. However, findings were 245
insensitive to a wide range of changes in unit costs and therefore appear to be stable to 246
these uncertainties. Secondly, although a thorough sensitivity analysis was performed, its 247
extent was limited by the available data. For example, the sensitivity analysis ranges for 248
HRQoL and cost data were arbitrary and although we believe them to be plausible, this is 249
open to interpretation. Thirdly, there are situations where a particular therapy may not be 250
a valid first-line choice, which have not been accounted for in this model. For example, the 251
use of RAI in women of childbearing potential, particularly those that are interested in 252
pregnancy in the short-term is contraindicated due to possible teratogenicity, while 253
thyroidectomy might be favoured in large goitres or if there are concerns about thyroid 254
cancer.8 In addition, despite the inclusion of GO in the model, many clinicians might be 255
reluctant to give RAI if a patient had severe, active GO, preferring an alternative therapy 256
that does not have the potential to cause worsening symptoms.8 Fourthly, this study was 257
performed from the perspective of the government contribution to the healthcare sectors in 258
each country and thus ignores any costs borne by patients (e.g., out-of-pocket medication 259
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costs), their preferred choice of therapy and any anxiety that may be experienced (e.g., as a 260
result of possible future cancer risk from RAI). Further, the results of our study may not be 261
readily generalizable to other countries, given that local practice and the costs of medical 262
services are likely to differ. 263
Finally, the choice of cost-effectiveness threshold (i.e., how much one is willing to pay for 264
one extra QALY) is potentially important, particularly in the English analysis. NICE guidance 265
recommends a cost-effectiveness threshold of £20,000 to £30,000 per QALY gained.12
If the 266
threshold was rigidly set at £20,000 per QALY gained, ATD may not to be cost-effective in 267
England, because in the base case and in most one-way sensitivity analyses, the ICER 268
estimates sit between £20,000 to £30,000 per QALY gained. NICE guidance suggests that a 269
threshold of £30,000 per QALY gained may be used where there is some uncertainty around 270
the true ICER and HRQoL capture, which there is in this study. We therefore believe that 271
our pre-specified threshold of £30,000 per QALY gained is reasonable. 272
In conclusion, in this cost-utility analysis, RAI is the least costly first-line treatment of Graves’ 273
disease in both England and Australia, while ATD, but not TT, may be a cost-effective 274
alternative. These results are robust to substantial sensitivity analysis of cost and transition 275
probabilities. However, the results are potentially sensitive to changes in some HRQoL 276
weights, particularly hypothyroidism post definitive therapy and euthyroidism on ATD 277
therapy. Where ATD is chosen as first-line, RAI as second-line therapy in the event of a 278
relapsed Graves’ disease is likely to be more cost-effective than long-term ATD or TT. 279
Further research into the HRQoL of many of the disease states associated with Graves’ 280
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disease and its treatment complications, and taking a wider (e.g., societal) perspective for 281
analysis could add to the quality, robustness and comparability of future CEA in Graves’ 282
disease. 283
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Declaration of interest 284
The authors declare that there is no conflict of interest that could be perceived as 285
prejudicing the impartiality of the research reported. 286
287
Funding 288
An NHMRC Early Career Fellowship (APP1092153) supports Donald McLeod. 289
290
Acknowledgements 291
The authors would like to acknowledge Prof. Emma Duncan, Assoc. Prof. Michael d’Emden, 292
Drs Syndia Lazarus, Donald Perry-Keene, Catherine Baskerville, and Michael Keogh for their 293
assistance with proving health-related quality of life values used in this analysis. 294
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379
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Simplified version of the Markov model. ATD – antithyroid drugs, GO – Graves’ ophthalmopathy, RAI – radioactive iodine
Figure 1
152x182mm (600 x 600 DPI)
Page 21 of 29
Table 1 – Transition Probabilities and Health-Related Quality of Life Weights
Parameter Value Sensitivity
Analysis Range
Reference
Transition Probabilities
ATD
Failure of ATD 5% over 1.5 years 0-20% Assumption
Agranulocytosis 0.35% over 13 years 0.29-0.42% 15
Hypothyroidism 2.9% over 10.2 years 0-8.6% 25
Relapse post remission with ATD 52.8% over 3.73 years (reverts
to zero after 5 years)
49.0-56.6% 3
Radioactive Iodine
Hypothyroid post RAI 72.3% over 10 years 68.7-75.9% 26
Persistent Graves’ disease post first
dose RAI
14.4% over 0.25 years 11.6-17.3% 26
Hypothyroid post second dose 77.5% over 0.25 years 73.2-81.7% 27
Hypothyroid post third dose 100% over 0.25 years - Assumption, 27
Symptomatic GO Rate of 5.8% over 1.21 years
(reverts to zero after 15
months)
2.5-9.1% 2
Resolution of GO symptoms 99% resolution in 3 years 50-99.99% 14
Total Thyroidectomy
Hypothyroidism, no complications 62.2% over 0.25 years 57.1-67.4% 4
Hypoparathyroidism 33.0% over 0.25 years
(resolves in 92%)
28.0-38.0% 4
RLN palsy 4.7% over 0.25 years
(resolves in 69%)
2.4-6.9% 4
Health-related Quality of Life Weights
Remission 1.00 0.98-1.0 24, 28
Euthyroidism while on ATD 0.98 0.96-1.0 24, 28
Hypothyroidism after RAI (treated) 0.97 0.945-0.995 Expert opinion
using Delphi
methodology
Page 22 of 29
Parameter Value Sensitivity
Analysis Range
Reference
Hypothyroidism after TT (treated) 0.95 0.92-0.96 Expert opinion
using Delphi
methodology
Graves’ ophthalmopathy 0.88 0.86-0.90 7, 28
Hypoparathyroidism 0.89 0.87-0.92 29
Dysphonia from RLN palsy 0.89 0.87-0.92 29
Thyrotoxicosis 0.81 0.78-0.82 24, 28
Agranulocytosis 0.46 (for 7 days) 0.46-1.0 30
Page 23 of 29
Table 2 – Unit Costs in England and Australia
England (2015 £) Australia (2015 AUD) References
Interventions and Medications
Administration of RAI for treatment of
Graves’ (including I-131, per dose
thyroid uptake scan, physician visits and
ATD)
556.85 341.15 6, 17
Thyroxine 4.04 (28 tablets) 24.02 (200 tablets) 18, 19
Same day admission for treatment of
Graves’ ophthalmopathy with
intravenous methylprednisolone
461 999 17, 20
ATD (carbimazole 5mg) 76.49 (100 tablets) 31.38 (200 tablets) 18, 19
Admission with agranulocytosis 959 5,076 20, 21
Total thyroidectomy 2,345 8,344 20, 21
Calcium carbonate (1.5g tablets) 8.7 (100 tablets) 14.65 (120 tablets) 18, 19
Calcitriol (0.25mcg tablets) 25.76 (100 tablets) 30.62 (100 tablets) 18, 19
Total Thyroidectomy with Complications
(i.e. RLN palsy or hypoparathyroidism)
2,794 15,355
20, 21
Pathology and Other Investigations
Thyroid Function Tests (TFTs) 12.93 34.80 6, 16
Calcium studies (ionised) 4.47 9.70 17, 22
Electrolytes and renal function tests 8.16 17.70 17, 22
Thyroid uptake scan 243.51 175.40 6, 16
Medical Attendances
Specialist physician – initial
(subsequent)
187.00 (93.00) 150.90 (75.50) 21, 22
Specialist surgeon – initial (subsequent) 140 (81.00) 85.55 (43.00) 21, 22
Ophthalmologist – initial (subsequent) 104 (59.00) 85.55 (43.00) 21, 22
General Practitioner 45.00 37.05 21, 22
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Table 3 – Follow-up Schedule and Healthcare Utilisation
State Medical practitioner visits Pathology
per visit
Medications
Hypothyroidism after
any treatment
Every 6 months for 12 months
(general practitioner)
TFTs Thyroxine 150mcg/day
GO Review with specialist
ophthalmologist (once every 3
months while active)
6 x weekly intravenous
infusions of
methylprednisolone23
(day admission to
hospital)
Initiation of ATD (first-
line therapy for 18
months)
Every 6 weeks for 6 months
(physician)
Thyroid
function
tests (TFTs)
Carbimazole – 6 per day
for 6 weeks, then 3 per
day for 6 weeks, then 2
per day for 3 months,
then 1 per day thereafter Then every 3 months for 12 months TFTs
Continue lifelong ATD
Initially as per initiation of ATD (for
first 18 months, then every 6
months (physician)
TFTs Carbimazole – as above
Then every 12 months (general
practitioner)
TFTs
Post TT (no other
complications)
Initial 1 visit 2 months post-
operatively (surgeon)
Thyroxine 150mcg/day
Then every 6 months for 12 months
(general practitioner)
TFTs
Then every 12 months (general
practitioner)
TFTs
Hypoparathyroidism
(permanent) after TT
Initial 1 visit 2 months post-
operatively (surgeon)
Thyroxine 150mcg/day,
one calcium carbonate
(600mg) twice daily and
one calcitriol twice daily) Then every 6 weeks for 6 months
(physician)
TFTs,
calcium
studies
Then every 3 months for 12 months
(physician)
TFTs,
calcium
studies
Then every 6 months (physician) TFTs,
calcium
studies
Page 25 of 29
State Medical practitioner visits Pathology
per visit
Medications
RLN palsy after TT Beyond first Markov cycle, no
medical costs in addition to post TT
hypothyroidism are likely to be
expended even if RLN palsy remains
permanent
Thyroxine 150mcg/day
Page 26 of 29
Table 4 – One-way Sensitivity Analysis Results
Parameter Range Tested ICER £/QALY (over RAI) ICER AUD/QALY (over RAI)
ATD TT ATD TT
HRQoL weight
Hypothyroidism post RAI 0.945-0.995 13,314-RAI
dominant (above
0.986)
RAI dominant 4,974-RAI
dominant (above
0.986)
RAI dominant
Hypothyroidism post TT 0.92-0.96 25,499-25,690 RAI dominant 9,409-10,629 RAI dominant
Hyperthyroidism 0.78-0.82 26,203-26,453 RAI dominant 9,657-9,756 RAI dominant
Remission 0.98-1.0 26,279-34,783 RAI dominant 9,687-13,057 RAI dominant
Euthyroid 0.96-1.0 15,855-91,303 RAI dominant 5,978-29,542 RAI dominant
Hypoparathyroidism 0.87-0.92 26,237-26,317 RAI dominant 9,679-9,701 RAI dominant
Recurrent laryngeal nerve
palsy
0.87-0.92 26,255-26,296 RAI dominant 9,678-9,693 RAI dominant
Graves’ ophthalmopathy 0.86-0.90 26,255-26,296 RAI dominant 9,681-9,692 RAI dominant
Agranulocytosis 0.46-1.0 26,279-26,279 RAI dominant 9,687-9,687 RAI dominant
Transition probabilities
Failure rate of primary
ATD therapy
0-20% 24,730-33,583 RAI dominant 8,460-15,444 RAI dominant
Relapse rate following
remission with ATD
95% CI 25,465-27,069 RAI dominant 9,313-10,051 RAI dominant
Hypothyroidism post ATD 95% CI 25,357-26,762 RAI dominant 9,354-9,862 RAI dominant
Excess risk of GO with RAI 95% CI 26,594-26,954 RAI dominant 9,026-10,330 RAI dominant
GO resolves in three years 50-99.9% 26,233-26,283 RAI dominant 9,639-9,692 RAI dominant
Rate of hypothyroidism
post RAI
95% CI 26,178-26,375 RAI dominant 9,653-9,720 RAI dominant
Failure rate of first dose
RAI
95% CI 26,052-26,583 RAI dominant 9,540-9,884 RAI dominant
Failure rate of second dose
RAI
95% CI 26,196-26,360 RAI dominant 9,639-9,734 RAI dominant
Rate of relapse after
achieving euthyroid state
95% CI 25,266-27,496 RAI dominant 9,189-10,286 RAI dominant
Page 27 of 29
with RAI
Rate of RLN palsy 95% CI 26,257-26,301 RAI dominant 9,669-9,705 RAI dominant
Rate of
hypoparathyroidism
95% CI 26,262-26,295 RAI dominant 9,653-9,720 RAI dominant
Rate of agranulocytosis 95% CI 26,262-26,294 RAI dominant 9,666-9,705 RAI dominant
Costs
Total Cost of RAI 50-150% 24,352-28,205 RAI dominant 8,263-11,110 RAI dominant
Cost of uncomplicated TT 50-150% 26,225-26,332 RAI dominant 9,506-9,868 RAI dominant
Cost of TT resulting in RLN
palsy or
hypoparathyroidism same
as uncomplicated TT
- 26,278 RAI dominant 9,504 RAI dominant
Treatment cost of
agranulocytosis
0 to base case 26,278-26,279 RAI dominant 9,683-9,689 RAI dominant
Carbimazole cost 50-150% 25,581-26,976 RAI dominant 8,230-11,143 RAI dominant
Total Cost of treatment of
GO with
methylprednisolone
50-150% 26,355-26,202 RAI dominant 9,156-10,218 RAI dominant
Other
Age, at entry to model 20-60 21,690-29,055 RAI dominant 7,933-10,736 RAI dominant
Proportion having second
line RAI (remainder ATD
long-term)
0-100% 7,319-26,279 RAI dominant 4,928-9,687 RAI dominant
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