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ARD Online First, published on January 13, 2016 as 10.1136/annrheumdis-2015-208317 Clinical and epidemiological research
EXTENDED REPORT
Disease activity-guided dose optimisation of adalimumab and etanercept is a cost-effective strategy compared with non-tapering tight control rheumatoid arthritis care: analyses of the DRESS study Wietske Kievit,1 Noortje van Herwaarden,2 Frank HJ van den Hoogen,2,3 Ronald F van Vollenhoven,4 Johannes WJ Bijlsma,5 Bart JF van den Bemt,6,7 Aatke van der Maas,2 Alfons A den Broeder2 Handling editor Tore K Kvien ▸ Additional material is published online only. To view, please visit the journal online (http://dx.doi.org/10.1136/ annrheumdis-2015-208317). For numbered affiliations see end of article. Correspondence to Dr Wietske Kievit, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands;
[email protected] Received 27 July 2015 Revised 7 December 2015 Accepted 20 December 2015
To cite: Kievit W, van Herwaarden N, van den Hoogen FHJ, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/ annrheumdis-2015-208317
ABSTRACT Background A disease activity-guided dose optimisation strategy of adalimumab or etanercept (TNFi (tumour necrosis factor inhibitors)) has shown to be noninferior in maintaining disease control in patients with rheumatoid arthritis (RA) compared with usual care. However, the cost-effectiveness of this strategy is still unknown. Method This is a preplanned cost-effectiveness analysis of the Dose REduction Strategy of Subcutaneous TNF inhibitors (DRESS) study, a randomised controlled, openlabel, non-inferiority trial performed in two Dutch rheumatology outpatient clinics. Patients with low disease activity using TNF inhibitors were included. Total healthcare costs were measured and quality adjusted life years (QALY) were based on EQ5D utility scores. Decremental cost-effectiveness analyses were performed using bootstrap analyses; incremental net monetary benefit (iNMB) was used to express cost-effectiveness. Results 180 patients were included, and 121 were allocated to the dose optimisation strategy and 59 to control. The dose optimisation strategy resulted in a mean cost saving of −€12 280 (95 percentile − €10 502; −€14 104) per patient per 18 months. There is an 84% chance that the dose optimisation strategy results in a QALY loss with a mean QALY loss of −0.02 (−0.07 to 0.02). The decremental cost-effectiveness ratio (DCER) was €390 493 (€5 085 184; dominant) of savings per QALY lost. The mean iNMB was €10 467 (€6553–€14 037). Sensitivity analyses using 30% and 50% lower prices for TNFi remained cost-effective. Conclusions Disease activity-guided dose optimisation of TNFi results in considerable cost savings while no relevant loss of quality of life was observed. When the minimal QALY loss is compensated with the upper limit of what society is willing to pay or accept in the Netherlands, the net savings are still high. Trial registration number NTR3216; Post-results.
are widely used, with adalimumab and etanercept being the two most frequently used2; they are among the highest selling drugs worldwide.3 However, TNFi are associated with a (dose-dependent) increased risk of infections and non-melanoma skin cancer.4–7 Furthermore, TNFi treatment is costly: approximately €14 000 yearly per patient.8 Improving the usage of TNFi is therefore warranted. Previous research showed that dose reduction or discontinuation of TNFi without deterioration of disease activity is possible in a relevant proportion of patients.9–11 A promising strategy might be to taper the TNFi until it is stopped, while carefully monitoring the disease, and increase the dose or restart when necessary. The Dose REduction Strategy of Subcutaneous TNF inhibitors (DRESS) study indeed showed that a disease activity-guided dose optimisation strategy of adalimumab or etanercept in RA is non-inferior to standard tight control without tapering with regard to major flaring.12 The strategy resulted in the successful dose reduction or stopping in two-thirds of patients. Before such a strategy should be widely implemented in daily practice, we need to know about the cost-effectiveness of such a strategy. Although titrating patients to the lowest dose may save medication costs, it may also lead to increased number of patient contacts and consequently increased healthcare costs. Furthermore, flares that occur after dose reduction might be short-lived and easily treated, or could be prolonged, compromising quality of life. However, if the loss in quality of life is compensated with large cost saving, we might consider it a costeffective intervention. The aim of this study is therefore to relate a difference in costs to difference in quality adjusted life years (QALYs) between a disease activity-guided TNFi dose optimisation strategy and tight control RA care without protocollised tapering from a societal perspective, as a preplanned secondary analysis of the DRESS study.
INTRODUCTION Tumour necrosis factor inhibitors (TNFi) are effective in the treatment of rheumatoid arthritis (RA), decreasing disease activity and functional disability and slowing joint damage progression.1 Different TNFi
METHODS Study design and participants The DRESS study was a pragmatic, open label, randomised, controlled, non-inferiority (NI) trial,
Kievit W, et al. Ann Rheum Dis 2016;0:1–6. doi:10.1136/annrheumdis-2015-208317
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Clinical and epidemiological research stratified by TNFi. The rationale and design, and primary outcomes have been described extensively elsewhere12 13 and are summarised here. Consenting patients with RA using adalimumab or etanercept in any stable dose and interval for at least 6 months, with stable low disease activity at two subsequent visits, were enrolled. Low disease activity was determined by rheumatologist and measured using the DAS28-CRP. The study was performed at the Sint Maartenskliniek in Nijmegen and Woerden, the Netherlands, from December 2011 through May 2014, and was approved by the local ethics committee and registered in the Dutch trial register (CMO region Arnhem-Nijmegen; NL37704.091.11, http://www.trialregister. nl;NTR 3216). Patients were randomly assigned to the dose optimisation or control group stratified for TNFi. Random sized blocks (block size 3–12) were used, and a ratio of dose optimisation versus control condition is 2:1. For more details, see elsewhere.12 13
Procedures Patients allocated to the control group continued a standardised tight control treatment protocol, aimed at maintaining at least low disease activity. Visits were planned once in three months and patients were encouraged to contact the outpatient clinic when experiencing more symptoms. In the dose optimisation group, patients received identical care as the control group, with the addition of a dose reduction advice. This advice consisted of stepwise increasing the interval between injections every 3 months. For adalimumab, the steps were (1) 40 mg every 21 days, (2) 40 mg every 28 days and (3) stop. For etanercept, the steps were: (1) 50 mg every 10 days, (2) 50 mg every 14 days and (3) stop. In both groups, treatment was changed in case of a disease activity flare. A flare was defined using a validated criterion: as a DAS28-CRP increase >1.2 or a DAS28-CRP increase >0.6 and current DAS28-CRP ≥3.2 compared with baseline DAS28-CRP.14 A regular treatment protocol was followed, including bridging with glucocorticoids or adding or switching conventional synthetic/biologic disease modifying antirheumatic drugs (c/bDMARDs) in the control group. In the dose optimisation group, the last effective interval was reinstated. If despite this the flare persisted, TNFi was increased until the shortest registered interval, thereafter treatment was switched following the same escalation protocol as the control group. Bridging with glucocorticoids was also allowed.
Outcomes For this cost-effectiveness analysis, we report on quality of life, measured with the EuroQol-5D5L (EQ5D-5L)15 and healthcare usage with related costs from a medical and societal perspective. Based on the EQ5D-5L questionnaire answers, utilities were calculated using the Dutch tariffs for the EQ5D-3L16 and the Dutch crosswalk value set to converse EQ5D-3L utilities to EQ5D-5L utilities.17 To derive QALYs area under the curve was calculated using the trapezium rule; using this method missing EQ5D values were linear interpolated between available time points on patient level. Volumes of care were determined in both dose optimisation and control group. Consultations, including telephonic consultations, with the rheumatologist or rheumatology nurse, travelling distance and hospital admissions related to RA were collected. Medication use was registered based on the medical chart, and RA-related absence from work was administered with a patient questionnaire. Because most resource usage was based on electronic record, there were no missing values to be considered. 2
The cost prices for common items like outpatient visits were based on the Dutch Guideline for Cost Analyses.18 Cost prices for medication were retrieved from the Dutch national tariff list.8 For detailed information on the prices used, we would like to refer to the online supplementary appendix. For the valuation of absenteeism from work, we used the friction cost method (3 months friction period). The base year for all prices was 2014. Prices retrieved from other years were converted to 2014 using the general Dutch price index rate. Costs were not discounted, because of the short time horizon of 18 months.
Cost-effectiveness analysis The cost-effectiveness analysis is following a superiority design; and analyses were done on an intention-to-treat basis. Differences in costs and QALYs between intervention and control group (reference) were analysed for the study period of 18 months. A decremental cost-effectiveness ratio (DCER) was calculated by dividing the cost savings by the QALY loss related to the optimisation strategy. Ninety-five per cent uncertainty boundaries in the DCER were determined non-parametrically using bootstrapping (1000 replications). The incremental Net Monetary Benefit (iNMB) per patient for the dose optimisation strategy compared with the usual care strategy was calculated for varying levels of willingness to accept (WTA) in euro’s per QALY lost, using the formula: WTA*incremental QALYs – incremental costs. This results in the net amount of money saved, when the possible loss of QALY is corrected for a certain amount of money; this can then be done for different WTA levels per QALY lost.19 As we wanted to anticipate to lower TNFi drug costs in the future due to the introduction of biosimilars and other market effects on drug pricing, we performed a sensitivity analyses with two different drug prices, namely −30% and −50% of the current TNFi-related costs.
RESULTS Patients A total of 180 patients were enrolled, 121 patients in the optimisation group and 59 patients in the control group (figure 1). Baseline characteristics were similar between the two groups, except for higher prevalence of DMARD co-medication in the control group (table 1). Almost no data were missing; 2% of the planned visits and 3–7% missing per baseline variable, thus multiple imputation was deemed unnecessary. There were no differences in missing levels by randomisation group.
Healthcare usage Medication use is summarised in table 2. At 18 months, in the dose optimisation group TNFi was successfully discontinued in 20% (95% CI 13% to 28%) and tapered in 43% (95% CI 34% to 53%) patients, whereas in 37% (95% CI 28% to 46%) patients no dose reduction was possible. There was no difference between adalimumab or etanercept concerning the percentages of patients in whom no dose reduction was possible, 38% and 36%, respectively. The mean cumulative TNFi dose over the whole study period in the dose optimisation group was 45% (median with IQR 27–65%) of the defined daily dose (DDD, etanercept 50 mg/week and adalimumab 40 mg per 2 weeks). In the control group, 7% (95% CI 2% to 17%) discontinued TNFi (all because of adverse effects), 8% (95% CI 3% to 19%) tapered TNFi because of low disease activity and 85% (95% CI 73% to 92%) did not dose reduce. The cumulative TNFi dose over 18 months expressed as % of DDD was 100% in most of Kievit W, et al. Ann Rheum Dis 2016;0:1–6. doi:10.1136/annrheumdis-2015-208317
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Clinical and epidemiological research
Figure 1 (A) Results of the 1000 bootstrapped replications, presented in cost-effectiveness planes. It graphically presents the uncertainty around the cost-effectiveness ratio. (B) Mean incremental net monetary benefit on the y-axis with the lower and upper limit of 95% percentile, plotted against different levels of euro per quality adjusted life years (QALY) that could be chosen as willingness to accept (WTA) on the x-axis. iNMB, incremental net monetary benefit. the control patients, namely in 76% (n=41/54, five missing for cumulative dose). Concerning co-medication, there were some differences. Intramuscular and/or intra-articular glucocorticoid injections were given in 35% (95% CI 27% to 45%) in the dose optimisation group and in 24% (95% CI 14% to 37%) in the control group ( p value 0.26). DMARDs were reduced or discontinued more often in the control group compared with the dose optimisation group, 27% (95% CI 17% to 40%) vs 10% (95% CI 5% to 17%) ( p
