Cost–utility analysis comparing radioactive iodine, anti-thyroid drugs and total thyroidectomy for primary treatment of Graves’ disease

in European Journal of Endocrinology

Objective

Little data is in existence about the most cost-effective primary treatment for Graves’ disease. We performed a cost–utility analysis comparing radioactive iodine (RAI), anti-thyroid drugs (ATD) and total thyroidectomy (TT) as first-line therapy for Graves’ disease in England and Australia.

Methods

We used a Markov model to compare lifetime costs and benefits (quality-adjusted life-years (QALYs)). The model included efficacy, rates of relapse and major complications associated with each treatment, and alternative second-line therapies. Model parameters were obtained from published literature. One-way sensitivity analyses were conducted. Costs were presented in 2015£ or Australian Dollars (AUD).

Results

RAI was the least expensive therapy in both England (£5425; QALYs 34.73) and Australia (AUD5601; 30.97 QALYs). In base case results, in both countries, ATD was a cost-effective alternative to RAI (£16 866; 35.17 QALYs; incremental cost-effectiveness ratio (ICER) £26 279 per QALY gained England; AUD8924; 31.37 QALYs; ICER AUD9687 per QALY gained Australia), while RAI dominated TT (£7115; QALYs 33.93 England; AUD15 668; 30.25 QALYs Australia). In sensitivity analysis, base case results were stable to changes in most cost, transition probabilities and health-relative quality-of-life (HRQoL) weights; however, in England, the results were sensitive to changes in the HRQoL weights of hypothyroidism and euthyroidism on ATD.

Conclusions

In this analysis, RAI is the least expensive choice for first-line treatment strategy for Graves’ disease. In England and Australia, ATD is likely to be a cost-effective alternative, while TT is unlikely to be cost-effective. Further research into HRQoL in Graves’ disease could improve the quality of future studies.

Abstract

Objective

Little data is in existence about the most cost-effective primary treatment for Graves’ disease. We performed a cost–utility analysis comparing radioactive iodine (RAI), anti-thyroid drugs (ATD) and total thyroidectomy (TT) as first-line therapy for Graves’ disease in England and Australia.

Methods

We used a Markov model to compare lifetime costs and benefits (quality-adjusted life-years (QALYs)). The model included efficacy, rates of relapse and major complications associated with each treatment, and alternative second-line therapies. Model parameters were obtained from published literature. One-way sensitivity analyses were conducted. Costs were presented in 2015£ or Australian Dollars (AUD).

Results

RAI was the least expensive therapy in both England (£5425; QALYs 34.73) and Australia (AUD5601; 30.97 QALYs). In base case results, in both countries, ATD was a cost-effective alternative to RAI (£16 866; 35.17 QALYs; incremental cost-effectiveness ratio (ICER) £26 279 per QALY gained England; AUD8924; 31.37 QALYs; ICER AUD9687 per QALY gained Australia), while RAI dominated TT (£7115; QALYs 33.93 England; AUD15 668; 30.25 QALYs Australia). In sensitivity analysis, base case results were stable to changes in most cost, transition probabilities and health-relative quality-of-life (HRQoL) weights; however, in England, the results were sensitive to changes in the HRQoL weights of hypothyroidism and euthyroidism on ATD.

Conclusions

In this analysis, RAI is the least expensive choice for first-line treatment strategy for Graves’ disease. In England and Australia, ATD is likely to be a cost-effective alternative, while TT is unlikely to be cost-effective. Further research into HRQoL in Graves’ disease could improve the quality of future studies.

Introduction

Graves’ disease is the most common cause of hyperthyroidism with an incidence of 0.8 cases per 1000 women annually in England (1). The three standard primary treatments have different profiles of potential benefits and harms for patients: radioactive iodine (RAI) is associated with lower rates of relapse than anti-thyroid drugs (ATDs) but more potential to cause Graves’ ophthalmopathy (GO) (2, 3); ATDs can lead to long-term remission (with no deficits in quality of life and no long-term costs), but has high rates of relapse and is associated with potentially catastrophic side effects (e.g. agranulocytosis); surgery (total thyroidectomy – TT) has the highest cure rates, but largest upfront costs and more potential long-term side effects (hypoparathyroidism, recurrent laryngeal nerve palsy and scar) (4). Therefore, to properly assess the cost-effectiveness of the primary therapies for Graves’ disease, modelling lifelong costs and effectiveness (measured by quality of life in quality-adjusted life-years – QALYs) is necessary. The few published cost-effectiveness analyses examining Graves’ disease management have important limitations including only short-term assessment of costs and benefits and/or assessment treatment options not consistent with contemporary management (i.e. subtotal thyroidectomy) (5, 6, 7, 8).

The primary aim of this study was to perform a cost–utility analysis comparing RAI, ATD and TT from the perspective of the government contribution to the healthcare sector, in both England and Australia.

Methods

Model structure

We conducted a cost–utility analysis using TreeAge Pro 2015 R2 (TreeAge Software, Williamstown, MA, USA). One model with the same structure was constructed for England and Australia, with the only differences being the inputs of costs, life-expectancy data and discount rates. Figure 1 shows a simplified version of the model. We used a Markov cohort, which is cyclical and tracks key clinical options and outcomes of persons with Graves’ disease following each of the three treatments.

Figure 1
Figure 1

Simplified version of the Markov model. ATD, antithyroid drugs; GO, Graves’ ophthalmopathy; RAI, radioactive iodine.

Citation: European Journal of Endocrinology 175, 6; 10.1530/EJE-16-0527

Given peak age of onset of Graves’ disease is described as 40–60 years (9), and to capture the impact of it on younger patients, a 40-year-old female was selected as the base case patient. Life-expectancy data was obtained from recognised country-specific sources (10, 11). The Markov cycle length was three months, given that all transient or short-term states (e.g. transient hypoparathyroidism and symptomatic hyperthyroidism) should be near or fully resolved within this time frame. The maximum time horizon of the model was until age 100 years. Discount rates for costs and benefits beyond the first year were 3.5% per year in England and 5% in Australia, according to country-specific guidelines (12, 13). Carbimazole was used as the ATD of choice. In the base case analysis, for model simplicity all of the ATD cohort that relapsed after initial remission were treated with long-term ATD, rather than definitive therapy (e.g. RAI or TT); the effect of differing proportions of RAI and TT as second-line therapy was assessed in sensitivity analysis in patients with relapse after initial ATD therapy. If RAI did not produce remission, retreatment with RAI (up to three doses) was included in the model, consistent with American Thyroid Association guidelines (8).

Rates of minor complications that are short-lived, have little effect on quality of life or lead to a change in treatment (e.g. minor rash or elevated liver enzymes from ATD), are rare (e.g. fulminant liver failure from propylthiouracil) or for which evidence to support causation is limited (e.g. RAI causing secondary cancers) were not included (3, 9). Although GO can occur at any time, only the excess risk of GO associated with RAI was included in the model (2). Additionally, although many women with Graves’ disease are of childbearing age, this aspect was excluded from this model, as, in patients where pregnancy is desired in the short-term, RAI is contraindicated due to potential teratogenicity (8).

Clinical estimates

We performed a literature review using PubMed and EMBASE to identify rates of efficacy, relapse, complications and HRQoL values, associated with each treatment option, with various combinations of the following search terms (PubMed terms only shown): hyperthyroid*, Graves, thyrotoxicosis, ‘Graves Disease’[Mesh], ‘Graves Disease/therapy’[MeSH], anti-thyroid drug, carbimazole, propylthiouracil, methimazole, (‘Antithyroid Agents’[Pharmacological Action], recurrence, radioiodine OR radioactive*, ‘Iodine Isotopes/therapeutic use’[MeSH], ‘Iodine Isotopes/therapy’[MeSH], complication, thyroidectomy[MeSH Terms], ‘cost utility’, ‘cost-utility’, QALY, EQ-5D, ‘quality adjusted life year’, ‘quality-adjusted life year’, ‘Quality of Life’[MeSH], ‘cost effective*’, ‘cost-effective*’, ‘cost utility’, ‘cost-utility’, ‘Cost-Benefit Analysis’[MeSH] and ‘economic evaluation’. Additional publications were obtained by targeted searches of the references of identified studies. Where more than one potential publication was identified, meta-analyses and randomised trials were preferred (2, 3, 14). If only cohort studies were identified, data from studies with larger populations and longer durations of follow-up were included (15).

Table 1 shows a summary of the transition probabilities included in the model and their sensitivity analysis ranges. Transition probabilities are the probability of a patient transitioning from one Markov state to another, during a single Markov cycle (e.g. the probability that a patient transitions from active hyperthyroidism to hypothyroidism with TT, without having suffered any other complication of surgery, is 62.2% (Table 1)).

Table 1

Transition probabilities and health-related quality-of-life weights.

Parameter valueSensitivity analysis rangeReference
Transition probabilities
 ATD
  Failure of ATD5% over 1.5 years0–20%Assumption
  Agranulocytosis0.35% over 13 years0.29–0.42%(15)
  Hypothyroidism2.9% over 10.2 years0–8.6%(25)
  Relapse post remission with ATD52.8% over 3.73 years (reverts to zero after 5 years)49.0–56.6%(3)
 Radioactive Iodine
  Hypothyroid post-RAI72.3% over 10 years68.7–75.9%(26)
  Persistent Graves’ disease post first dose RAI14.4% over 0.25 years11.6–17.3%(26)
  Hypothyroid post second dose77.5% over 0.25 years73.2–81.7%(27)
  Hypothyroid post third dose100% over 0.25 yearsAssumption (27)
  Symptomatic GORate of 5.8% over 1.21 years (reverts to zero after 15 months)2.5–9.1%(2)
  Resolution of GO symptoms99% resolution in 3 years50–99.99%(14)
 Total thyroidectomy
  Hypothyroidism, no complications62.2% over 0.25 years57.1–67.4%(4)
  Hypoparathyroidism33.0% over 0.25 years (resolves in 92%)28.0–38.0%(4)
  RLN palsy4.7% over 0.25 years (resolves in 69%)2.4–6.9%(4)
 Health-related quality–of-life weights
  Remission1.000.98–1.0(24, 28)
  Euthyroidism while on ATD0.980.96–1.0(24, 28)
  Hypothyroidism after RAI (treated)0.970.945–0.995Expert opinion using Delphi methodology
  Hypothyroidism after TT (treated)0.950.92–0.96Expert opinion using Delphi methodology
  Graves’ ophthalmopathy0.880.86–0.90(7, 28)
  Hypoparathyroidism0.890.87–0.92(29)
  Dysphonia from RLN palsy0.890.87–0.92(29)
  Thyrotoxicosis0.810.78–0.82(24, 28)
  Agranulocytosis0.46 (for 7 days)0.46–1.0(30)

Costs

Unit costs were identified using recognised sources and presented in 2015 values (Pounds (Sterling); £ in England and 2015 Australian Dollars (AUD)) – see Table 2. Where unit costs were not readily available, estimates were obtained from published literature or by currency conversion, with costs from before 2015 adjusted to present values, where possible (6, 16, 17). The perspective taken for this analysis was of each governments’ contribution to healthcare.

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)556.85341.15(6, 17)
 Thyroxine4.04 (28 tablets)24.02 (200 tablets)(18, 19)
 Same day admission for treatment of Graves’ ophthalmopathy with intravenous methylprednisolone461999(17, 20)
 ATD (carbimazole 5 mg)76.49 (100 tablets)31.38 (200 tablets)(18, 19)
 Admission with agranulocytosis9595076(20, 21)
 Total thyroidectomy23458344(20, 21)
 Calcium carbonate (1.5 g tablets)8.7 (100 tablets)14.65 (120 tablets)(18, 19)
 Calcitriol (0.25 μg tablets)25.76 (100 tablets)30.62 (100 tablets)(18, 19)
 Total thyroidectomy with complications (i.e. RLN palsy or hypoparathyroidism)279415 355(20, 21)
Pathology and other investigations
 Thyroid function tests (TFTs)12.9334.80(6, 16)
 Calcium studies (ionised)4.479.70(17, 22)
 Electrolytes and renal function tests8.1617.70(17, 22)
 Thyroid uptake scan243.51175.40(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 practitioner45.0037.05(21, 22)

Long-term costs of medications, medical practitioner visits and pathology associated with all treatments and their complications were included in the model, with the proposed follow-up visit schedule similar to previously published CEA and recognised treatment guidelines – see Table 3 (5, 8).

Table 3

Follow-up schedule and healthcare utilisation.

StateMedical practitioner visitsPathology per visitMedications
Hypothyroidism after any treatmentEvery 6 months for 12 months (general practitioner)TFTsThyroxine 150 μg/day
GOReview with specialist ophthalmologist (once every 3 months while active)6× weekly intravenous infusions of methylprednisolone (23) (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 monthsTFTs
Continue lifelong ATDInitially as per initiation of ATD (for first 18 months, then every 6 months (physician))TFTsCarbimazole – as above
Then every 12 months (general practitioner)TFTs
Post TT (no other complications)Initial 1 visit 2 months post-operatively (surgeon)Thyroxine 150 μg/day
Then every 6 months for 12 months (general practitioner)TFTs
Then every 12 months (general practitioner)TFTs
Hypoparathyroidism (permanent) after TTInitial 1 visit 2 months post-operatively (surgeon)Thyroxine 150 μg/day, one calcium carbonate (600 mg) 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
RLN palsy after TTBeyond first Markov cycle, no medical costs in addition to post-TT hypothyroidism are likely to be expended even if RLN palsy remains permanentThyroxine 150 μg/day

Health-related quality-of-life estimates

Effectiveness was evaluated by using HRQoL estimates (health utilities) from the published literature to generate QALYs obtained – Table 1. The preferred methods for obtaining HRQoL estimates to be included in the model were (in descending order of preference, consistent with country-specific guidelines (12, 13)):

  • Preference-based methods with direct elicitation of HRQoL weights from prospective studies (e.g. time trade-off, standard gamble, multi-attribute utility indices with preference-based methodology (e.g. Euro-Quality of Life – 5 Dimensions (EQ-5D)))
  • Studies using the SF-36 (Short Form 36) questionnaire and conversion of these scores to EQ-5D weights using a published, validated algorithm (24)
  • HRQoL weights based on expert judgement, weights from previously published cost-effectiveness analysis or generated as part of this study (using Delphi methodology, seven specialist endocrinologists came to consensus values, after taking into consideration the other HRQoL weights used in the model).

Incremental cost-effectiveness ratio

The model aggregates the costs and patient outcomes using an expected values analysis, calculating the incremental cost-effectiveness ratios (ICER) using the following formula (ICER of ATD over RAI as an example):

E0001

In the main model, the ICER is calculated using the best available estimates, called the ‘base case’, while uncertainty and variation in these estimates are tested in sensitivity analyses (see below). The results were assessed for dominance (a dominant option is both less costly and more effective than another option) and extended dominance (where a treatment option is more costly and less effective than a combination of two other options). The National Institute of Health and Care Excellence (NICE) in England suggest a cost-effectiveness threshold of £20 000–30 000 per QALY gained (12). We chose a pre-specified threshold £30 000 per QALY gained in this analysis for England (and AUD 50 000), consistent with this guidance (12).

Sensitivity analyses

We performed one-way sensitivity analyses, where the value of a single parameter is changed across a range of values (the sensitivity analysis range) with different ICER values calculated. Comparing these values to the base case ICER can be used to assess how stable the results are to these changes, particularly in reference to the pre-specified thresholds for cost-effectiveness. Sensitivity analysis ranges of transition probabilities were based on 95% confidence intervals from published literature (where available). Cost estimates vary from 50 to 150% depending on base case values. As no published data was available to assist with choice of sensitivity analysis ranges, the chosen ranges were arbitrary but were considered to be plausible. Age at entry to the cohort ranging from 20 to 60 years was also assessed.

Results

Base case

RAI was the least expensive therapy in both England (£5425; QALYs 34.73) and Australia (AUD5601, 30.97 QALYs). In both countries, ATD was a cost-effective alternative to RAI (£16 866, 35.17 QALYs, ICER £26 279 per QALY gained England; AUD8924; 31.37 QALYs; ICER AUD9687 per QALY gained Australia), while RAI dominated TT (£7115; QALYs 33.93 England; AUD15 668; 30.25 QALYs Australia).

Sensitivity analysis

Table 4 outlines the results of selected one-way sensitivity analysis. ATD was a cost-effective alternative to RAI in most sensitivity analyses (i.e. the calculated ICER ranges remained below the thresholds of cost-effectiveness – £30 000 in England, AUD50 000 in Australia), with the exceptions of HRQoL weights attached to hypothyroidism post-RAI, remission post-ATD and euthyroidism on ATD (where the calculated ICER ranges extended beyond these thresholds). ATD became more cost-effective (ICER became lower) as the proportion of the cohort that received second-line RAI increased following relapse after initially achieving remission with ATD. RAI was dominant over TT (i.e. RAI was less costly and more effective) in sensitivity analysis of all parameters assessed.

Table 4

One-way sensitivity analysis results.

ParameterRange testedICER £/QALY (over RAI)ICER AUD/QALY (over RAI)
ATDTTATDTT
HRQoL weight
 Hypothyroidism post-RAI0.945–0.99513 314-RAI dominant (above 0.986)RAI dominant4974-RAI dominant (above 0.986)RAI dominant
 Hypothyroidism post-TT0.92–0.9625 499–25 690RAI dominant9409–10 629RAI dominant
 Hyperthyroidism0.78–0.8226 203–26 453RAI dominant9657–9756RAI dominant
 Remission0.98–1.026 279–34 783RAI dominant9687–13 057RAI dominant
 Euthyroid0.96–1.015 855–91 303RAI dominant5978–29 542RAI dominant
 Hypoparathyroidism0.87–0.9226 237–26 317RAI dominant9679–9701RAI dominant
 Recurrent laryngeal nerve palsy0.87–0.9226 255–26 296RAI dominant9678–9693RAI dominant
 Graves’ ophthalmopathy0.86–0.9026 255–26 296RAI dominant9681–9692RAI dominant
 Agranulocytosis0.46–1.026 279–26 279RAI dominant9687–9687RAI dominant
Transition probabilities
 Failure rate of primary ATD therapy0–20%24 730–33 583RAI dominant8460–15 444RAI dominant
 Relapse rate following remission with ATD95% CI25 465–27 069RAI dominant9313–10 051RAI dominant
 Hypothyroidism post-ATD95% CI25 357–26 762RAI dominant9354–9862RAI dominant
 Excess risk of GO with RAI95% CI26 594–26 954RAI dominant9026–10 330RAI dominant
 GO resolves in three years50–99.9%26 233–26 283RAI dominant9639–9692RAI dominant
 Rate of hypothyroidism post-RAI95% CI26 178–26 375RAI dominant9653–9720RAI dominant
 Failure rate of first dose RAI95% CI26 052–26 583RAI dominant9540–9884RAI dominant
 Failure rate of second dose RAI95% CI26 196–26 360RAI dominant9639–9734RAI dominant
 Rate of relapse after achieving euthyroid state with RAI95% CI25 266–27 496RAI dominant9189–10 286RAI dominant
 Rate of RLN palsy95% CI26 257–26 301RAI dominant9669–9705RAI dominant
 Rate of hypoparathyroidism95% CI26 262–26 295RAI dominant9653–9720RAI dominant
 Rate of agranulocytosis95% CI26 262–26 294RAI dominant9666–9705RAI dominant
Costs
 Total cost of RAI50–150%24 352–28 205RAI dominant8263–11 110RAI dominant
 Cost of uncomplicated TT50–150%26 225–26 332RAI dominant9506–9868RAI dominant
 Cost of TT resulting in RLN palsy or hypoparathyroidism same as uncomplicated TT26 278RAI dominant9504RAI dominant
 Treatment cost of agranulocytosis0 to base case26 278–26 279RAI dominant9683–9689RAI dominant
 Carbimazole cost50–150%25 581–26 976RAI dominant8230–11 143RAI dominant
 Total cost of treatment of GO with methylprednisolone50–150%26 355–26 202RAI dominant9156–10 218RAI dominant
Other
 Age, at entry to model20–6021 690–29 055RAI dominant7933–10 736RAI dominant
 Proportion having second-line RAI (remainder ATD long-term)0–100%7319–26 279RAI dominant4928–9687RAI dominant

Discussion

In our base case analysis, in England and Australia, RAI was the least expensive option for the primary treatment of Graves’ disease, while ATD was a cost-effective alternative to it. TT was more expensive and less effective than RAI (i.e. TT was dominated by RAI). These results were stable to changes in many key parameters and structural uncertainty tested in sensitivity analyses. Although TT was dominated and ATD was cost-effective in both countries, the ICERs were different, with the cost per QALY gained being much less in Australia than England. These differences, as would be expected, are driven largely by differences in unit costs, because, other than life expectancy, discount rates and cost differences, the structure of the two models are identical. The main differences appear to be the cost of carbimazole (with the cost in England being about 10-fold higher than Australia, after adjustment for purchasing power parity), the cost of specialist endocrinology follow-up (2.5-fold higher) and TT costs (0.6-fold lower). In both models, all of these unit costs were obtained from reliable sources and likely reflect the true cost to the respective governments, and hence, are likely to represent true differences in the cost-effectiveness in these two countries.

This study is the first, using a lifetime horizon, to assess the cost-effectiveness of the three first-line therapies in Graves’ disease in England and Australia. Our results are consistent with a single centre England study that assessed cost per cure from hyperthyroidism (not just Graves’ disease), which captured all medical costs for two years post diagnosis (6). That study demonstrated that RAI was substantially cheaper over a short-term horizon than ATD or TT per cure; however, it did not assess long-term costs or quality of life. Our results are not consistent with a 2012 cost-effectiveness analysis from the United States that suggested surgery (subtotal thyroidectomy) was more effective and minimally more costly that RAI for Graves’ disease (7). We did not consider subtotal thyroidectomy as a treatment choice, given it is not a recommended therapy for Graves’ disease due to high rates of relapse (8). Other differences in our study were the inclusion of long-term costs, more recent data sources for transition probabilities and HRQoL weights, and the costs of medical services identified in England and Australia were much less than those in the previous study (7).

Although the results of this study were stable to variation in most key parameters, results were sensitive to changes in some HRQoL weights, particularly the weights attached to hypothyroidism post-RAI, remission following ATD and euthyroidism while on ATD. This sensitivity is potentially important for a number of reasons. First, in both countries, ATD ranged from being cost-effective compared with RAI, to being dominated by it across a relatively modest sensitivity analysis range. Similarly, in England, but not Australia, as the HRQoL of euthyroidism on ATD therapy decreased across its modest sensitivity analysis range, ATD became less cost-effective (with an ICER as high as £91 303 per QALY gained). Secondly, there are limited high-quality data (e.g. from prospective studies using preference-based methods) to support many of the HRQoL weights used in this study and in particular, two of the weights were derived using expert opinion, albeit, the consensus opinion of seven specialist endocrinologists. Thus, further research into HRQoL estimates in thyroid disease (e.g. hypothyroidism, euthyroidism on ATD therapy) to obtain validated weights using more accepted methodologies (e.g. EQ-5D) could improve the accuracy of future economic models.

Our base case analysis included long-term ATD therapy as the treatment of choice for most patients with relapsed Graves’ disease. However, base case results were highly sensitive to the proportion of RAI therapy given as second line, as, with increasing proportions, ATD became highly cost-effective in both England and Australia (with ICERs down to £7319 and AUD4928). Therefore, given the uncertainty about long-term quality of life, if ATD is chosen as first-line therapy, second-line RAI (rather than long-term ATD therapy or TT) would appear to be the most cost cost-effective therapy in the event of relapsed Graves’ disease.

There are a number of other limitations to this study. First, the acquisition of unit cost data, particularly in England, was problematic, as lists of unit costs, particularly for pathology and radiology services, are not readily available. However, findings were insensitive to a wide range of changes in unit costs and therefore appear to be stable to these uncertainties. Secondly, although a thorough sensitivity analysis was performed, its extent was limited by the available data. For example, the sensitivity analysis ranges for HRQoL and cost data were arbitrary and, although we believe them to be plausible, this is open to interpretation. Thirdly, there are situations where a particular therapy may not be a valid first-line choice, which are not accounted for in this model. For example, the use of RAI in women of childbearing potential, particularly those that are interested in pregnancy in the short-term is contraindicated due to possible teratogenicity, while thyroidectomy might be favoured in large goitres or if there are concerns about thyroid cancer (8). In addition, despite the inclusion of GO in the model, many clinicians might be reluctant to give RAI if a patient had severe, active GO, preferring an alternative therapy that does not have the potential to cause worsening symptoms (8). Fourthly, this study was performed from the perspective of the government contribution to the healthcare sectors in each country and thus ignores any costs borne by patients (e.g. out-of-pocket medication costs), their preferred choice of therapy and any anxiety that may be experienced (e.g. as a result of possible future cancer risk from RAI). Further, the results of our study may not be readily generalizable to other countries, given that local practice and the costs of medical services are likely to differ.

Finally, the choice of cost-effectiveness threshold (i.e. how much one is willing to pay for one extra QALY) is potentially important, particularly in the English analysis. NICE guidance recommends a cost-effectiveness threshold of £20 000 to £30 000 per QALY gained (12). If the threshold was rigidly set at £20 000 per QALY gained, ATD may not be cost-effective in England, because in the base case and in most one-way sensitivity analyses, the ICER estimates sit between £20 000 and £30 000 per QALY gained. NICE guidance suggests that a threshold of £30 000 per QALY gained may be used where there is some uncertainty around the true ICER and HRQoL capture. As there is uncertainty in both these in our study, we believe that our pre-specified threshold of £30 000 per QALY gained is reasonable.

In conclusion, in this cost–utility analysis, RAI is the least costly first-line treatment of Graves’ disease in both England and Australia, while ATD, but not TT, may be a cost-effective alternative. These results are robust to substantial sensitivity analysis of cost and transition probabilities. However, the results are potentially sensitive to changes in some HRQoL weights, particularly hypothyroidism post definitive therapy and euthyroidism on ATD therapy. Where ATD is chosen as first-line, RAI as second-line therapy in the event of a relapsed Graves’ disease is likely to be more cost-effective than long-term ATD or TT. Further research into the HRQoL of many of the disease states associated with Graves’ disease and its treatment complications, and taking a wider (e.g. societal) perspective for analysis could add to the quality, robustness and comparability of future CEA in Graves’ disease.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

An NHMRC Early Career Fellowship (APP1092153) supports Donald McLeod.

Acknowledgements

The authors acknowledge Prof E Duncan; Associate Professor Michael d’Emden; and Drs S Lazarus, D Perry-Keene, C Baskerville and M Keogh for their assistance with proving health-related quality-of-life values used in this analysis.

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    • Export Citation
  • 5

    InHPearceENWongAKBurgessJFMcAnenyDBRosenJE. Treatment options for Graves disease: a cost-effectiveness analysis. Journal of the American College of Surgeons2009209170–179.e171–e172. (doi:10.1016/j.jamcollsurg.2009.03.025)

    • Search Google Scholar
    • Export Citation
  • 6

    PatelNNAbrahamPBuscombeJVanderpumpMPJ.The cost effectiveness of treatment modalities for thyrotoxicosis in a U.K. center. Thyroid200616593598. (doi:10.1089/thy.2006.16.593)

    • Search Google Scholar
    • Export Citation
  • 7

    ZanoccoKHellerMElarajDSturgeonC.Is subtotal thyroidectomy a cost-effective treatment for Graves disease? A cost-effectiveness analysis of the medical and surgical treatment options. Surgery2012152164172. (doi:10.1016/j.surg.2012.02.020)

    • Search Google Scholar
    • Export Citation
  • 8

    Bahn ChairRSBurchHBCooperDSGarberJRGreenleeMCKleinILaurbergPMcDougallIRMontoriVMRivkeesSAHyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid201121593646. (doi:10.1089/thy.2010.0417)

    • Search Google Scholar
    • Export Citation
  • 9

    BrentGA.Clinical practice. Graves’ disease. New England Journal of Medicine200835825942605. (doi:10.1056/NEJMcp0801880)

  • 10

    United Kingdom National Life Tables 1980–82 to 2011–13. Newport UK: Office of National Statistics 2013.

  • 11

    3302.0.55.001 – Life Tables States Territories and Australia 2011–2013. Canberra Australia: Australian Bureau of Statistics 2013.

  • 12

    Guide to the methods of technology appraisal 2013. London UK: National Institute for Health and Care Excellence 2013.

  • 13

    Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory Committee. Canberra Australia: Department of Health and Aging 2015.

  • 14

    JarhultJRudbergCLarssonESelvanderHSjovallKWinsaBRastadJKarlssonFAGroupTEOS.Graves’ disease with moderate-severe endocrine ophthalmopathy-long term results of a prospective, randomized study of total or subtotal thyroid resection. Thyroid20051511571164. (doi:10.1089/thy.2005.15.1157)

    • Search Google Scholar
    • Export Citation
  • 15

    TajiriJNoguchiS.Antithyroid drug-induced agranulocytosis: special reference to normal white blood cell count agranulocytosis. Thyroid200414459462. (doi:10.1089/105072504323150787)

    • Search Google Scholar
    • Export Citation
  • 16

    CurtisL Ed. Unit Costs of Health and Social Care 2013. University of Kent Canterbury UK: Personal Social Services Research Unit 2013.

  • 17

    Purchasing Power Parity Dataset. Paris, France: Organisation of Economic Co-operation and Development (OECD)2015.

  • 18

    CommitteeJF.British National Formulary. London UK: British Medical Association and Royal Pharmaceutical Society of Great Britain 2015.

  • 19

    Pharmacuetical Benefits Schedule. Canberra Australia: Department of Health and Aging 2015.

  • 20

    Australian refined diagnosis-related groups (AR-DRG) – Cost Weights for AR-DRG Version 6.0x (20112012) current version. Bruce Australia: Australian Institute of Health and Welfare 20112012.

  • 21

    National tariff payment system 2014/15. London, UK: National Health Service2015.

  • 22

    Medical Benefits Schedule. Department of Health and Aging 2015.

  • 23

    BartalenaLBaldeschiLDickinsonAJEcksteinAKendall-TaylorPMarcocciCMouritsMPPerrosPBoboridisKBoschiAConsensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid200818333346. (doi:10.1089/thy.2007.0315)

    • Search Google Scholar
    • Export Citation
  • 24

    AraRBrazierJ.Deriving an algorithm to convert the eight mean SF-36 dimension scores into a mean EQ-5D preference-based score from published studies (where patient level data are not available).Value Health20081111311143. (doi:10.1111/j.1524-4733.2008.00352.x)

    • Search Google Scholar
    • Export Citation
  • 25

    AziziFAtaieLHedayatiMMehrabiYSheikholeslamiF.Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine. European Journal of Endocrinology2005152695701. (doi:10.1530/eje.1.01904)

    • Search Google Scholar
    • Export Citation
  • 26

    Hernandez-JimenezSPachon-BurgosAAguilar-SalinasCAAndradeVReynosoRRiosAReza-AlbarranAAMehtaRGonzalez-TrevinoOGomez-PerezFJRadioiodine treatment in autoimmune hyperthyroidism: analysis of outcomes in relation to dosage. Archives of Medical Research200738185189. (doi:10.1016/j.arcmed.2006.09.007)

    • Search Google Scholar
    • Export Citation
  • 27

    MetsoSJaatinenPHuhtalaHLuukkaalaTOksalaHSalmiJ.Long-term follow-up study of radioiodine treatment of hyperthyroidism. Clinical Endocrinology200461641648. (doi:10.1111/j.1365-2265.2004.02152.x)

    • Search Google Scholar
    • Export Citation
  • 28

    ElberlingTVRasmussenAKFeldt-RasmussenUHordingMPerrildHWaldemarG.Impaired health-related quality of life in Graves’ disease. A prospective study. European Journal of Endocrinology2004151549555. (doi:10.1530/eje.0.1510549)

    • Search Google Scholar
    • Export Citation
  • 29

    SejeanKCalmusSDurand-ZaleskiIBonnichonPThomopoulosPCormierCLegmannPRichardBBertagnaXYVidal-TrecanGM.Surgery versus medical follow-up in patients with asymptomatic primary hyperparathyroidism: a decision analysis. European Journal of Endocrinology2005153915927. (doi:10.1530/eje.1.02029)

    • Search Google Scholar
    • Export Citation
  • 30

    PerlisRHGanzDAAvornJSchneeweissSGlynnRJSmollerJWWangPS.Pharmacogenetic testing in the clinical management of schizophrenia: a decision-analytic model. Journal of Clinical Psychopharmacology200525427434. (doi:10.1097/01.jcp.0000177553.59455.24)

    • Search Google Scholar
    • Export Citation

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     European Society of Endocrinology

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    Simplified version of the Markov model. ATD, antithyroid drugs; GO, Graves’ ophthalmopathy; RAI, radioactive iodine.

  • 1

    VanderpumpMPTunbridgeWMFrenchJMAppletonDBatesDClarkFGrimley EvansJHasanDMRodgersHTunbridgeFThe incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clinical Endocrinology1995435568. (doi:10.1111/j.1365-2265.1995.tb01894.x)

    • Search Google Scholar
    • Export Citation
  • 2

    AcharyaSHAvenellAPhilipSBurrJBevanJSAbrahamP.Radioiodine therapy (RAI) for Graves’ disease (GD) and the effect on ophthalmopathy: a systematic review. Clinical Endocrinology200869943950. (doi:10.1111/j.1365-2265.2008.03279.x)

    • Search Google Scholar
    • Export Citation
  • 3

    SundareshVBritoJPWangZProkopLJStanMNMuradMHBahnRS.Comparative effectiveness of therapies for Graves’ hyperthyroidism: a systematic review and network meta-analysis. Journal of Clinical Endocrinology and Metabolism20139836713677. (doi:10.1210/jc.2013-1954)

    • Search Google Scholar
    • Export Citation
  • 4

    GuoZYuPLiuZSiYJinM.Total thyroidectomy vs bilateral subtotal thyroidectomy in patients with Graves’ diseases: a meta-analysis of randomized clinical trials. Clinical Endocrinology201379739746. (doi:10.1111/cen.12209)

    • Search Google Scholar
    • Export Citation
  • 5

    InHPearceENWongAKBurgessJFMcAnenyDBRosenJE. Treatment options for Graves disease: a cost-effectiveness analysis. Journal of the American College of Surgeons2009209170–179.e171–e172. (doi:10.1016/j.jamcollsurg.2009.03.025)

    • Search Google Scholar
    • Export Citation
  • 6

    PatelNNAbrahamPBuscombeJVanderpumpMPJ.The cost effectiveness of treatment modalities for thyrotoxicosis in a U.K. center. Thyroid200616593598. (doi:10.1089/thy.2006.16.593)

    • Search Google Scholar
    • Export Citation
  • 7

    ZanoccoKHellerMElarajDSturgeonC.Is subtotal thyroidectomy a cost-effective treatment for Graves disease? A cost-effectiveness analysis of the medical and surgical treatment options. Surgery2012152164172. (doi:10.1016/j.surg.2012.02.020)

    • Search Google Scholar
    • Export Citation
  • 8

    Bahn ChairRSBurchHBCooperDSGarberJRGreenleeMCKleinILaurbergPMcDougallIRMontoriVMRivkeesSAHyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid201121593646. (doi:10.1089/thy.2010.0417)

    • Search Google Scholar
    • Export Citation
  • 9

    BrentGA.Clinical practice. Graves’ disease. New England Journal of Medicine200835825942605. (doi:10.1056/NEJMcp0801880)

  • 10

    United Kingdom National Life Tables 1980–82 to 2011–13. Newport UK: Office of National Statistics 2013.

  • 11

    3302.0.55.001 – Life Tables States Territories and Australia 2011–2013. Canberra Australia: Australian Bureau of Statistics 2013.

  • 12

    Guide to the methods of technology appraisal 2013. London UK: National Institute for Health and Care Excellence 2013.

  • 13

    Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory Committee. Canberra Australia: Department of Health and Aging 2015.

  • 14

    JarhultJRudbergCLarssonESelvanderHSjovallKWinsaBRastadJKarlssonFAGroupTEOS.Graves’ disease with moderate-severe endocrine ophthalmopathy-long term results of a prospective, randomized study of total or subtotal thyroid resection. Thyroid20051511571164. (doi:10.1089/thy.2005.15.1157)

    • Search Google Scholar
    • Export Citation
  • 15

    TajiriJNoguchiS.Antithyroid drug-induced agranulocytosis: special reference to normal white blood cell count agranulocytosis. Thyroid200414459462. (doi:10.1089/105072504323150787)

    • Search Google Scholar
    • Export Citation
  • 16

    CurtisL Ed. Unit Costs of Health and Social Care 2013. University of Kent Canterbury UK: Personal Social Services Research Unit 2013.

  • 17

    Purchasing Power Parity Dataset. Paris, France: Organisation of Economic Co-operation and Development (OECD)2015.

  • 18

    CommitteeJF.British National Formulary. London UK: British Medical Association and Royal Pharmaceutical Society of Great Britain 2015.

  • 19

    Pharmacuetical Benefits Schedule. Canberra Australia: Department of Health and Aging 2015.

  • 20

    Australian refined diagnosis-related groups (AR-DRG) – Cost Weights for AR-DRG Version 6.0x (20112012) current version. Bruce Australia: Australian Institute of Health and Welfare 20112012.

  • 21

    National tariff payment system 2014/15. London, UK: National Health Service2015.

  • 22

    Medical Benefits Schedule. Department of Health and Aging 2015.

  • 23

    BartalenaLBaldeschiLDickinsonAJEcksteinAKendall-TaylorPMarcocciCMouritsMPPerrosPBoboridisKBoschiAConsensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid200818333346. (doi:10.1089/thy.2007.0315)

    • Search Google Scholar
    • Export Citation
  • 24

    AraRBrazierJ.Deriving an algorithm to convert the eight mean SF-36 dimension scores into a mean EQ-5D preference-based score from published studies (where patient level data are not available).Value Health20081111311143. (doi:10.1111/j.1524-4733.2008.00352.x)

    • Search Google Scholar
    • Export Citation
  • 25

    AziziFAtaieLHedayatiMMehrabiYSheikholeslamiF.Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine. European Journal of Endocrinology2005152695701. (doi:10.1530/eje.1.01904)

    • Search Google Scholar
    • Export Citation
  • 26

    Hernandez-JimenezSPachon-BurgosAAguilar-SalinasCAAndradeVReynosoRRiosAReza-AlbarranAAMehtaRGonzalez-TrevinoOGomez-PerezFJRadioiodine treatment in autoimmune hyperthyroidism: analysis of outcomes in relation to dosage. Archives of Medical Research200738185189. (doi:10.1016/j.arcmed.2006.09.007)

    • Search Google Scholar
    • Export Citation
  • 27

    MetsoSJaatinenPHuhtalaHLuukkaalaTOksalaHSalmiJ.Long-term follow-up study of radioiodine treatment of hyperthyroidism. Clinical Endocrinology200461641648. (doi:10.1111/j.1365-2265.2004.02152.x)

    • Search Google Scholar
    • Export Citation
  • 28

    ElberlingTVRasmussenAKFeldt-RasmussenUHordingMPerrildHWaldemarG.Impaired health-related quality of life in Graves’ disease. A prospective study. European Journal of Endocrinology2004151549555. (doi:10.1530/eje.0.1510549)

    • Search Google Scholar
    • Export Citation
  • 29

    SejeanKCalmusSDurand-ZaleskiIBonnichonPThomopoulosPCormierCLegmannPRichardBBertagnaXYVidal-TrecanGM.Surgery versus medical follow-up in patients with asymptomatic primary hyperparathyroidism: a decision analysis. European Journal of Endocrinology2005153915927. (doi:10.1530/eje.1.02029)

    • Search Google Scholar
    • Export Citation
  • 30

    PerlisRHGanzDAAvornJSchneeweissSGlynnRJSmollerJWWangPS.Pharmacogenetic testing in the clinical management of schizophrenia: a decision-analytic model. Journal of Clinical Psychopharmacology200525427434. (doi:10.1097/01.jcp.0000177553.59455.24)

    • Search Google Scholar
    • Export Citation