Effectiveness data

The analysis is based on a double blind, randomised clinical trial in 682 patients (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes, TEMPO).⁹ In this trial patients with active disease for whom previous disease modifying antirheumatic drugs (DMARDs) other than methotrexate had failed were randomised to receive etanercept 25 mg (subcutaneously twice a week), methotrexate (up to 20 mg every week), or etanercept plus methotrexate for a period of 2 years. Patients previously exposed to methotrexate were included provided they were deemed to be appropriate candidates for methotrexate treatment at the time of enrolment in the study.

All randomised patients who had received a first treatment were included in the cost effectiveness analysis (intention to treat analysis, n = 682). Table 1⇓ shows the demographics of the sample used in this analysis.

The model

Development of the disease is represented using a Markov model¹⁰ with five main functional states and cut off points at HAQ 0.6, 1.1, 1.6, 2.1. Each state is further separated into two substates representing high and low disease activity. All resulting 10 states are further subdivided according to those receiving study treatment or not. Changes in disease status are modelled as transitions between the states at intervals of 1 year (cycles). Costs and utility are assigned to each of the 20 states and the model estimates expected costs and QALYs for defined cohorts of patients over given periods of time.

Disease progression

Transition probabilities for the first 2 years are calculated based on the observed transitions in the clinical trial for patients with a HAQ measurement at both the start and the end of each year. Transition probabilities beyond the trial are based on the average reported annual progression of HAQ (0.03). Scott and colleagues have published a comprehensive review of studies investigating changes in HAQ and found a mean annual increase of 0.031.¹¹

Mortality

A number of studies have shown increased mortality in patients with RA, but reports have not been consistent. Standardised mortality ratios have been reported to range from 1.16 to 3.0,^12,13 and a link with disease activity has been shown.^14,15 Recent studies in North America and the UK recorded standardised mortality ratios of 1.32 and 3.08,^12,15–,¹⁷ whereas studies in Norway and Sweden reported 1.57 and 2.0, respectively.^18,19 Studies in early RA, on the other hand, including the Lund cohort study, did not show evidence of any increased mortality during the first 10 years of follow up.^20,21

The model therefore includes normal mortality adjusted for age and sex in the two early HAQ states (<1.1), whereas in the three more advanced states, we adjust normal mortality with a relative risk of 1.3 and 2.0 in states with low and high disease activity, respectively.

Disease activity

In clinical trials, disease activity is currently measured with the Disease Activity Score (DAS) or 28 joint count DAS (DAS28), and low disease activity has been defined as a DAS28 score of ⩽3.2.²² However, DAS28 is a recent scoring method and has not been included in cohort studies or registries in the past. Also, it is difficult to assess DAS28 in population surveys, as it requires clinical and laboratory measurements. As an alternative, the patient global visual analogue scale (global VAS) has been used when assessing disease activity and severity—for example, in registries, with high disease activity being defined as a VAS of ⩾40.²³ We have confirmed this cut off point by correlating the patient global VAS with the DAS28 in the TEMPO trial and found that a DAS28 of 3.2 corresponds to a score of 41 on the global VAS.

Utility and resource utilisation survey

In 1997 a survey in 1016 patients with confirmed RA, representing an estimated 90–95% of patients in the area, was carried out by the department of rheumatology at Malmö University Hospital.²⁴ In 2002 a follow up survey answered by 616 patients included a questionnaire on resource consumption and work capacity, as well as the EQ-5D (EuroQol).^25,26 The mean age of the patients was 64.5 years, 74% were female, and the mean disease duration was 16.7 years.

Utilities

Utility scores were derived from the five dimensional health state classification of the EQ-5D and related to both HAQ scores and disease activity using multiple regression.

The TEMPO trial included the EuroQol VAS, and we investigated the differences in scores between the treatment groups using regression analysis, controlling for functional status (HAQ) and disease activity.

Resource utilisation

Direct resource utilisation included all healthcare and community services as well as investments, devices, transportation, and informal help. Indirect costs included early retirement due to RA, long and short term sick leave, loss of leisure time. Early retirement due to RA has been shown to be one of the most important cost drivers in economic evaluations in RA. To increase the sample size and to account for potential regional variations we combined the Malmö data with early retirement data for 1810 patients in the Stockholm area, currently followed up in the National Swedish RA registry.²⁷

Unit costs and valuation

Costs for healthcare and community services were obtained from the county councils of southern Sweden²⁸ and the national price list for drugs.²⁹ The annual cost of etanercept and methotrexate in Sweden is €16 000 and €78, respectively, excluding monitoring costs. Mean annual labour cost by sex (mean salary plus employers’ costs) for 2001 was available from the statistical yearbook 2003³⁰ and inflated to 2004. Informal help and care was valued as leisure time, using the estimated net income after tax in Sweden (35% of full labour cost).

The analysis is performed from the societal perspective and includes all costs, regardless of the payer. The full patient dataset of costs and utilities is incorporated into the model and bootstrapping is used for the simulations. Costs and effects are discounted by 3%.

Cost effectiveness simulations

Transitions for all patients in the clinical trial are used directly during the first 2 years and the model then extrapolates to 10 (5) years. All patients in the trial had high disease activity at baseline according to our definition. We first present an analysis of the trial effect only, without any assumptions about treatment continuation. Thus, at the end of the trial, patients stop treatment and follow the annual disease progression with standard treatment (+0.03 HAQ). Patients in the etanercept and etanercept plus methotrexate groups revert to their baseline HAQ and DAS28 scores over the next cycle, except if scores had deteriorated during the trial. In the latter case, patients remain at the level reached at the end of the trial. The same logic is applied to patients withdrawing from treatment during the trial. Patients in the methotrexate group in states 3 to 5 revert to a slightly higher HAQ score than at baseline (+0.005/year). The rationale for this is the difference in radiological progression in the groups. Sharp scores remained stable and even slightly improved in patients treated with etanercept or with etanercept plus methotrexate, but progressed by 2.8 points a year in patients treated with methotrexate. This corresponds to approximately 35% of the mean annual progression of 1.6–1.9% of maximum possible damage estimated by Scott and colleagues.¹¹ Using a correlation of 0.5 between Sharp and HAQ scores after 5 years of disease duration calculated by the same authors, we estimated the effect on the annual HAQ progression to be 15–20% in patients with ⩾5 years’ disease duration and an HAQ score >1.1.

We also present an analysis with treatment continuation for the full 5 or 10 years, using the second year of the trial to make assumptions. HAQ scores during this year were stable for patients receiving treatment, and the withdrawal rates were 22%, 16%, and 13% in the methotrexate, etanercept, and etanercept plus methotrexate arms, respectively. We thus used the group-specific transitions from the second year of the trial for the extrapolation, and assumed that dropouts accounted for treatment failure due to lack of efficacy or adverse events.

The uncertainty in the cost effectiveness results is dealt with by using acceptability curves.^31,32 In these calculations, a threshold for the willingness to pay for a QALY is defined and the probability estimated of the cost per QALY gained falling below this threshold, using the full range of patient level data. Acceptability curves are created with Monte Carlo simulation. We used bootstrapping to estimate the uncertainty around the model inputs (transition probabilities, costs, utilities).³³ In each Monte Carlo simulation, 1 of 1000 bootstrap estimates for each measure is drawn at random and used.

Utilities

Utility scores correlated significantly with both HAQ and disease activity (p<0.001). Patients with high disease activity had consistently lower utilities at the same HAQ level (table 2⇓).

The EuroQol VAS scores in TEMPO indicated similar results, but as expected, the VAS shows a substantial ceiling and floor effect. However, across all functional states, patients in the TEMPO trial treated with etanercept had consistently higher scores, as shown in table 3⇓. The difference was estimated by regression analysis, and utility scores were subsequently adjusted by 0.04 for patients in the etanercept plus methotrexate group, and by 0.02 in the etanercept group, compared with methotrexate alone.

Costs

Table 4⇓ shows that total costs correlated significantly with HAQ but not with disease activity (when controlling for HAQ), although a trend was found. An exception to this was short and medium term sick leave (<12 months), which correlated significantly with disease activity, but not with HAQ. When patients aged 65 years or less were included, costs for sick leave were estimated at €2262 and €4686 for patients with low and high disease activity, respectively. The effect of age and disease duration on costs was not significant when HAQ was included.

Modelling results

Table 5⇓ presents the base case with 2 years’ treatment. Excluding study treatment, mean direct costs for each patient are €49 353, €52 377, and €54 531 in the etanercept plus methotrexate, etanercept, and methotrexate groups, respectively. Patient-borne costs were €8715, €9127, and €9331, while indirect costs were €102 224, €105 835, and €108 059. Of these latter, sick leave amounted to €30 798, €31 443, and €31 709. Thus, the cost offset with etanercept plus methotrexate compared with methotrexate alone was €11 013, compensating in part for the treatment cost of €25 339.

The number of QALYs over 10 years was estimated at 3.46, 3.23, and 3.08 in the three groups respectively, leading to a QALY gain with etanercept plus methotrexate compared with methotrexate alone of 0.38. This would be equivalent to 4 months in full health.

In the base case, the incremental cost per QALY for etanercept plus methotrexate compared with methotrexate alone was estimated to be €37 331. When patients continue treatment beyond the trial, cost effectiveness ratios increased from €37 331 to €46 494 per QALY gained for up to 10 years and to €47 316 per QALY gained for 5 years’ treatment (table 6⇓).

Sensitivity analyses

Our results are most sensitive to assumptions about the cost of the treatment and the difference in utility between the treatment groups (table 7⇓). Utility, being highly sensitive to changes in HAQ or in disease activity, is an expression of treatment effectiveness, and results are thus sensitive to changes in effectiveness. Faster disease progression leads to lower cost effectiveness ratios, as costs in patients receiving standard treatment increase more rapidly. A higher dropout rate decreases treatment costs, but increases overall costs. Higher costs for patients with high disease activity have a very limited effect, as has RA-specific mortality. Cost effectiveness ratios are somewhat lower for patients of working age, as the potential for cost offsets is larger.

Using a threshold value of €50 000 for the willingness to pay for a QALY gained, the probability that 2 years’ treatment with etanercept plus methotrexate is acceptable is 88%. With 10 years’ treatment, the probability is 71%. For a threshold of €82 000, the probability is 99% and 98%, respectively (fig 1⇓).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

 Uncertainty in the cost effectiveness estimates (acceptability curves) of a 2 or 10 year intervention with etanercept plus methotrexate in patients with active RA over 10 years. Acceptability curves are generated by Monte Carlo simulation, using individually drawn bootstrap estimates (1000 in this case) from the entire distribution of costs and utilities in the different Markov states. Different levels of willingness to pay for a QALY are defined and the probabilities of the cost effectiveness ratio falling below these different thresholds estimated. The probability that a 2 year treatment with etanercept plus methotrexate in a cohort of patients such as that included in the TEMPO trial is acceptable when the willingness to pay for a QALY is €50 000 is 88%. For a 10 year treatment, the probability is 71%. For a threshold value of €82 000, the probability is 99 and 98%, respectively.