Abatacept or infliximab for patients with rheumatoid arthritis and inadequate response to methotrexate: an Italian trial-based and real-life cost-consequence analysis M. Benucci1, W.B. Stam2, I. Gilloteau3, K. Sennfält3, A. Leclerc3, A. Maetzel4, C. Lucioni5

1Rheumatology Unit, Department of Internal Medicine, Hospital S. Giovanni di Dio, Azienda Sanitaria di Firenze, Florence, Italy; 2Stam-Consulting, Houten, the Netherlands; 3Bristol-Myers Squibb, Rueil Malmaison, France; 4Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada; 5Springer Healthcare, Italy. Abstract Objectives In the 1-year, double-blind, placebo-controlled ATTEST trial, efficacy of abatacept or infliximab versus placebo was reported in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). The current study estimated trial-based and real-life costs of abatacept and infliximab for achieving pre-defined remission or low disease activity state (LDAS).

Methods Quantity of drug, serious adverse event (SAE) rates and time (months) in remission or LDAS were taken from ATTEST for the trial-based calculation to derive a cost per remitting/LDAS patient and a cost per patient-month in remission/LDAS. Trial-based and real-life scenarios were performed.

Results The annual trial-based costs per remitting/LDAS patient were €70.238/€37.208 for abatacept and €85.565/€46.602 for infliximab. In the first 6 months of the ATTEST trial, costs per patient-month in remission/LDAS were higher for abatacept (€11.024 and €6.018, respectively), relative to infliximab (€8.347 and €4.174, respectively). Over the full 12-month trial period cost per month in remission/LDAS estimates were only slightly in favour of infliximab (€6.959/€3.625) relative to abatacept (€7.297/€3.909). Assuming extension of treatment under real life conditions the cost per month in remission/LDAS turned substantially in favour of abatacept (€5.321/€2.819), as compared to infliximab (€7.189/€3.916). The higher initiation cost for abatacept to achieve remission/LDAS would be offset after a total 14.6 and 16.1 months of treatment, respectively, if treatment extended beyond 6 months under real-life conditions. These results proved to be robust when it was assumed that the (i) sharing of vials across patients completely averted infliximab wastage, (ii) AE risks were similar and (iii) onset of response was slower for abatacept.

Conclusion Our findings suggest a lower cost-consequence for abatacept during real-life treatment.

Key words abatacept, infliximab, economics, rheumatoid arthritis, Italy

Clinical and Experimental Rheumatology 2013; 31: 575-583. Cost consequence of abatacept or infliximab in Italy / M. Benucci et al.

Maurizio Benucci, MD Introduction in Treating RA) trial is a randomised, Wiro B. Stam, PhD A growing body of evidence indicates double blind, double dummy, placebo- Isabelle Gilloteau, MSc that treatment of rheumatoid arthritis and active comparator (infliximab)- Karin Sennfält, PhD (RA) should aim to control inflamma- controlled, 12-month global trial in Adriana Leclerc, MD Andreas Maetzel, MD, PhD tion and should start immediately upon patients with an inadequate response Carlo Lucioni, MSc diagnosis, as this leads to improved (IR) to MTX (5). This study demon- Please address correspondence to: long-term clinical outcomes and a re- strated that after 6 months of treatment Wiro B. Stam, PhD, duced disease burden (1). Accordingly, both biologics performed better than Lupine-oord 53, the recent European League Against placebo, to a similar extent, in terms of 3991VH Houten, the Netherlands. Rheumatism (EULAR) recommenda- patients reaching LDAS and remission. E-mail: [email protected] tions and consensus group formulated a However, a more durable response for Received on July 3, 2012; accepted in “treatment to target strategy” that is fo- abatacept was observed upon prolonged revised form on February 5, 2013. cused on obtaining remission or at least treatment for another 6 months resulting © Copyright Clinical and a low disease activity state (LDAS) in a numerically higher proportion of Experimental Rheumatology 2013. preferably within 3 months of initiating patients achieving LDAS and remission an RA treatment regimen (1, 2). In order than on infliximab. Furthermore, abata- to reach this goal, frequent treatment cept displayed lower rates of serious adjustments are recommended as nec- adverse events (SAEs) and infections essary. This paradigm shift in the treat- and lower discontinuation rates due to ment of RA from a focus on reducing AEs and SAEs. Modest differences in symptoms to disease remission has ar- outcomes may translate into favour- gued for intensive treatment and timely able economic consequences for one consideration of combination therapy. biologic vs. another which is even more Based on EULAR recommendations, critical for higher priced drugs like bio- methotrexate (MTX) is recommended logical DMARDs. A cost-consequence as the initial disease-modifying anti- analysis between abatacept and inflixi- rheumatic drug (DMARD) drug of mab has been performed based on the choice and is considered as the an- ATTEST trial to assess respective cost chor drug for combination therapy (2). per responder and cost per month in Abatacept is approved for use as first LDAS/remission from the perspective line biologic in patients with an inad- of the Italian payer. equate response to one or more con- ventional DMARDs including MTX or Methods a TNF-alpha inhibitor. This approval Structure offers rheumatologists an additional The ATTEST trial evaluated abata- treatment option after MTX failure with cept and infliximab, each in combina- a mode of action different from TNF- tion with MTX, in patients with active alpha inhibitors. RA who had an inadequate response to Given that biological agents are con- MTX. The objective of this trial was to sidered expensive drugs, any final deci- evaluate the efficacy of abatacept and sions on which agent to use after MTX infliximabversus placebo; ATTEST was failure will most likely consider the as- a randomised active and placebo con- sociated costs in addition to relative dif- trolled trial, where placebo treatment ferences in efficacy and safety. Recent- was limited to days 1–197 to provide in- ly, two head-to-head studies have been ternal validity to the trial design and the reported comparing either subcutane- clinical response rates of the two active ously administered abatacept (AMPLE treatment groups. In ATTEST, abatacept trial [3]) or tocilizumab (ADACTA trial was administered by intravenous (IV) [4]) with adalimumab. For other biolog- infusion 10 mg/kg on days 1, 15, and Competing interests: icals, however, direct comparisons are 29, then every 28 days, or a stable dose W. Stam and A. Maetzel have collaborated lacking, which complicates a thorough of infliximab 3 mg/kg on days 1, 15, 43, on this project as part of a consulting assessment of the relative value of the and 85, then every 56 days, according to agreement with BMS Europe; multiple therapies available for RA. Al- the US/EU label at the time of the study, I. Gilloteau is employed by BMS; A. Leclerc and K. Sennfält were employees though not designed as a head-to-head or matching placebo. After 6 months, of BMS at the time of the study; comparison, the ATTEST (Abatacept placebo treated patients were reallocated the other co-authors have declared no or infliximab versus placebo, a Trial to abatacept, though these patients were competing interests. for Tolerability, Efficacy and Safety excluded from the analysis at 1 year.

576 Cost consequence of abatacept or infliximab in Italy / M. Benucci et al.

The trial analyses allowed an evaluation of the patients’ disease status according to DAS28 based on erythrocyte sedi- mentation rates (DAS28-ESR) and ACR response rates at 6 and 12 months of pa- tients that were treated with abatacept or infliximab from trial start. At 6 months, the outcomes for abatacept and inflixi- mab were compared to placebo. Both periods are characterised by a different Fig. 1. Presentation of the different scenarios considered in the cost-consequence analysis. infusion frequency: 8 and 5 times in the first 6-month period and 6 and 3 times in and infliximab, and iii) a scenario to first 12 months of treatment, the dose the last 6 months for abatacept and inf- evaluate the effect of a response onset and infusion frequency of the biologics liximab, respectively (Table I). during the first 6-month ATTEST pe- were in accordance with the label and Where available and applicable, trial riod that was assumed to be slower for as applied in the ATTEST trial. During data are used in the cost/consequence abatacept relative to infliximab. the first 6 months of the ATTEST trial, analysis. These data are complement- patients either received 6 infusions of ed with local registry data (mainly for Source data for the analysis infliximab at a dose of 3 mg/kg or 8 in- real-life dose regimen) or data from – Efficacy outcomes fusions of abatacept. In ATTEST, abata- additional sources (mainly for adverse Percentages of responders in either cept was administered a dose of either events and costs) where applicable. LDAS or remission were obtained 500 mg or 750 mg depending on body This allowed simulation of a ‘real-life’ from the ATTEST trial (Table I). In AT- weight (5). In the trial, 25% of patients extrapolation scenario. For the bene- TEST, disease activity was assessed weighed less than 60 kg and were ad- fits, the time in remission and in LDAS by DAS28-ESR, which is a recognised ministered 500 mg abatacept, whereas was considered. The current analysis and validated score (1, 2). LDAS and the other 75% weighed >60 kg and re- assumes that the decision to prescribe remission were defined as DAS28 ceived a dose of 750 mg (5, 8). Hence, a biologic has been taken and conse- (ESR) ≤3.2 and DAS28 (ESR) <2.6, the average dose of 687.5 mg required quently it does not focus on the oppor- respectively. From these efficacy data on average 2.75 vials of abatacept. It is tunity cost of allocating resources to the time in remission or LDAS was cal- worth noticing that for abatacept only alternative therapy choices, but solely culated by multiplying time (either 6 or complete vials are administered. Inflix- on the cost per consequence for each 12 months) with the responder percent- imab was administered on days 1, 15, possible alternative. For this analysis age (Table I). For the base case, it was and 43 and every following 56 days at a only direct medical costs are accounted assumed that the effects became estab- dose of 3 mg/kg (5). Based on an aver- for and expressed in association with lished immediately after treatment start. age body weight of 72.6 kg in ATTEST, the efficacy and safety benefits. Since the onset of action of biological this corresponded with an average dose agents with a cell-based mode of action of 218 mg. For the model it was as- Scenarios such as abatacept has been suggested to sumed that 50% of patients required 2 The current analysis differentiates 3 be slower as compared to infliximab (6, vials of 100 mg infusion, whereas the main scenarios corresponding to 3 dif- 7), an additional scenario was evaluated remaining 50% required 3 vials result- ferent analysis periods (Fig. 1): a) a which assumed a slower onset of action ing in an average of 2.5 vials per infu- scenario based on the first 6 months for abatacept. This scenario assumed a sion to be used in the economic calcula- of the ATTEST trial, b) a full ATTEST delay in response onset for abatacept of tion. This can be considered a conserva- trial scenario based on the 12-month 1 month after that of infliximab. This tive assumption, since the median body ATTEST period, and c) a ‘real life’ delay of 1 month was based on the dif- weight in the ATTEST trail was 71 kg scenario which could start after either ference observed for ACR data before indicating that a greater proportion of the 6- or 12-month ATTEST period and day 85 of the ATTEST trial after which patients required 3 vials of infliximab which applies real-life data on the use response levels of abatacept and inflixi- as compared to 2 vials (5, 8). of infliximab and abatacept. mab were similar (5). Since DAS scores It is well established that clinical effi- Additional sub-scenarios were defined were not reported (5), it was assumed cacy of infliximab declines upon pro- to evaluate the impact of assump- that the difference in response kinetics longed use and dose escalation is com- tions that were more conservative for was reflected by the reported ACR re- monly applied (9-11), either through abatacept: i) a “zero wastage” scenario sponder rates. an increase in dose, a reduction of the where vial optimisation for infliximab interval between infusions or a com- was assumed to result in no wastage of – Dose regimen bination of both. For Italy, Favalli et infliximab, i.e. dose was not rounded The dose regimens of abatacept and al. (12) demonstrated that in clinical up to the next vial; ii) a scenario which infliximab were defined by the dose practice the interval between infu- assumed similar AE rates for abatacept and the frequency of dosing. For the sions was reduced to 50 days and the

577 Cost consequence of abatacept or infliximab in Italy / M. Benucci et al.

Table I. Source data for the analysis.

Abatacept Infliximab Source

Remission Responders at month 6, % 11.3% 12.8% ATTEST (5) Responders at month 12, % 18.7% 12.2% Δ (95%CI): 6.5% (-2.2–15.2)* Time (months) 1st 6 months 0.68 0.77 Calculated Total time months (1 year) 1.8 1.5

LDAS Responders at month 6, % 20.7% 25.6% ATTEST (5) Outcomes Responders at month 12, % 35.3% 22.4% Δ (95%CI): 12.9% (2.1–23.7)* Time (months) 1st 6 months 1.24 1.54 Calculated Total time months (1 year) 3.36 2.88

Trial-based scenario Dose per infusion (mg) 687.5 218 ATTEST (5, 8) Vials per infusion, n 2.75 2.5 Calculated Infusion frequency months 1–6 8 5 ATTEST (5) Infusion frequency months 7–12 6 3 ATTEST (5)

Dose regimen Real-life scenario Vials per infusion, n 2.7 2.8 Abatacept (14), infliximab (12) Infusion frequency 6.5 3.7 Abatacept (5), infliximab (12)

Trial-based scenario Serious infections 1.9% 8.5% ATTEST (5) SAE’s (other than serious infections) 7.7% 9.7%

Real-life scenario Serious infections (annual) 1.5% 3.7% Cochrane meta-analysis (15) SAE’s (other than serious infections) (annual) 6.4% 10.9% Adverse events

Drug Cost per vial €378.00 €570.68 List prices** Administration i.v. infusion €18.91 €26.37 (16, 17)

SAE Hospitalisation: serious infections €5.908 €5.908 DRG 079: respiratory inflammation with Costs complications (18) Hospitalisation: SAE (other than infection) €4.183 €4.183 DRG 240: connective tissue disease with complications (18)

*ATTEST was not designed to demonstrate non-inferiority or superiority abatacept versus infliximab. **In the analysis net prices (including all government measures and mandatory discounts to NHS) were considered. i.v.: intravenous. average infliximab dose was increased – Adverse events similar as to that applied for the AT- up to 3.57 mg/kg. These figures cor- Adverse events (AEs) that involved TEST based scenarios described above. respond to 2.8 vials of infliximab per hospitalisation were incorporated in Although most data on adverse events infusion and 3.7 infusions on average the analysis. Hospitalisations due to come from pooled relative short-term per 6 months. The dose escalation of serious infections were considered trials on the use of biologics across infliximab taken from these Italian reg- separate from other serious adverse different indications, this can be con- istry data (12) was applied in the ‘real- events (SAEs), since both are believed sidered as the best evidence available. life’ scenario. In contrast to infliximab to incur different costs. The 1-year The Cochrane review group synthesised and as suggested in US real-life data, probabilities for serious infections as available evidence in a network meta- the average dose of abatacept as well reported in the trial (5) were incorpo- analysis and calculated a SAE rate of 79 as the time interval between infusions rated in the ATTEST based scenarios. per 1.000 (95%CI 53–118) for abatacept is consistent over time in accordance Furthermore, the risk for SAEs other compared to 118 per 1.000 in the control with label (13). Consequently, in the than serious infections was calculated group. For serious infections, the calcu- absence of Italian real-life data, the ap- by subtracting the serious infection rate lated rates were 15 per 1.000 (95%CI plied dosing regimen of abatacept was from the SAE risk, as reported in the 8–28) (abatacept) vs. 26 per 1.000 (con- chosen according to label for the real- ATTEST trial (Table I). trol). For infliximab, SAEs rates were life scenario. For abatacept the average For the real-life scenario, the risks for 146 per 1.000 (95%CI 116–185) vs. 118 number of vials per infusion (2.7) for serious infections and SAEs other than per 1.000 in the control group, and the the real-life scenario was according to serious infections were obtained from rates of serious infections were 37 per the weight distribution of RA patients a Cochrane network meta-analysis (Ta- 1.000 (95%CI 26–54) vs. 26 per 1.000 in included in an observational Italian ble I) (15). The calculation to discrimi- the control group (15). Of all biologics study (14) which was almost similar to nate the risks for serious infections and evaluated, abatacept and anakinra were the trial-based analysis. SAEs other than serious infections was associated with a significantly lower

578 Cost consequence of abatacept or infliximab in Italy / M. Benucci et al. risk of serious adverse events compared to most other biologics.

– Costs Both biological DMARDs are commer- cialised in vials (100mg vial for inflixi- mab, 250 mg vial for abatacept). The drug acquisition costs for abatacept and infliximab represent the ex-factory drug price costs for the hospital including all government measures and mandatory discounts to Italian NHS. Administra- tion costs for the infusion of infliximab and abatacept were obtained from re- ports by Iannazzo et al. (16) and Be- Fig. 2. Cost consequence results upon prolonged use of abatacept and infliximab under real-life condi- nucci et al. (17), respectively. AE costs tions. were obtained from the national 2010 DRG (18). Since most observed seri- the cost per month in remission/LDAS Real-life extrapolation scenarios ous infections in trials were respiratory were therefore higher for abatacept Real-life extrapolation scenarios took tract infections (5), the DRG 079 tariff (€11.024/€6.018), as compared to in- into account dose escalation for inf- of respiratory inflammation with -com fliximab (€8.347/€4.174). liximab. Three different scenarios were plications was applied as a proxy for the evaluated: a) real-life base case – no average costs incurred by the healthcare Full ATTEST trial: month 1 to 12 vial sharing across patients as a base system for treating serious infections. Inclusion of month 7–12 of the ATTEST case – b) vial sharing across patients, For SAE other than serious infections, trial period by an analysis of the full and c) assuming similar SAE probabil- the DRG 240 tariff for connective tissue 12-month trial period yielded cost per ities for both agents. disease with complications was applied month in remission/LDAS estimates to reflect the average costs to the health- that were only slightly in favour of inf- a) Real-life base case scenario care system. Annual costs of AEs were liximab (€6.959/€3.625) as compared (per 6 months treatment continuation) obtained by multiplying annual prob- to abatacept (€7.297/€3.909). Howev- with individual dosing and no vial abilities with DRG tariffs. Also for the er, this results in a larger reduction of sharing across patients ATTEST trial we used annual probabili- the cost per month in remission/LDAS In this scenario, each patient on inflixi- ties and did not discriminate between for abatacept (by 34%/35%) than for mab was assumed to use a whole vial AE rates for the first 6 months and the infliximab (only 17%/13%) relative package. So, for example, a patient second 6 months. It was assumed that to the first 6 months of treatment sce- requiring a dose of 250 mg infliximab the annual costs for AEs were equally nario. For the full ATTEST period the would require 3 vials of 100 mg cor- distributed per 6 months. 12-month cost per remitting patient/ responding with wastage of 50 mg in- LDAS responder was lower for abata- fliximab. The average number of vials Results cept (€70.238/€37.208) relative to in- used was based on the weight distri- With respect to the cost-consequence fliximab (€85.565/€46.602). bution of people in the ATTEST trial. results (Table II), there were several For each 6 months of treatment con- differences across the scenarios. Scenario first 6 months: tinuation under real-life conditions, the slower time of onset of abatacept cost consequence results per month in Month 1 to 6 of the ATTEST trial relative to infliximab remission/LDAS were substantially in Drug acquisition costs were the main Importantly, this scenario did not af- favour of abatacept (€5.321/€2.819, driver of the total costs during this pe- fect total costs of the 6 and 12 months respectively), as compared to inflixi- riod: 96% and 91% of the total costs ATTEST scenarios, but mainly in- mab (€7.189/€3.916) (Fig. 2). The for abatacept and infliximab treated creased the initial costs per month in higher initiation costs for abatacept to patients, respectively. Total costs dur- remission/LDAS for abatacept for the achieve remission/LDAS would be off- ing the first 6 months were higher for first 6 months of the ATTEST period set rapidly, i.e. after a total of 14.6/16.1 abatacept (€7.474) relative to inflixi- (€13.229/€7.222) and to a lesser ex- months of treatment if treatment after 6 mab (€6.411) due to the higher ac- tent the costs per month in remission/ months would be prolonged under real- quisition cost. Since the proportion LDAS for the full 12-month trial period life conditions. of LDAS/remission patients after 6 (€7.786/€4.166), when compared to For the scenario that assumed a delay months of treatment was relatively sim- the base case scenario, which assumed in the onset of the abatacept response, ilar for infliximab and abatacept (Table no difference in the time of onset for treatment prolongation up to a total I), the cost-consequence expressed as both agents (Table II). 21.7/22.7 months under real-life condi-

579 Cost consequence of abatacept or infliximab in Italy / M. Benucci et al.

Table II. Overall costs and cost consequence results for different scenarios.

Category Item Abatacept Infliximab

ATTEST Real life ATTEST Real life (extrapolation)

ATTEST 1st Full ATTEST (per 6 months) ATTEST 1st Full ATTEST Base case: ‘Zero wastage’ Individual 6 months (12 months) 6 months (12 months) individual (per 6 months) dosing and dosing similar AE risk (per 6 months) (per 6 months)

Drug costs € 7.106 €12.436 €5.669 €5.825 €9.320 €4.828 €4.483 €4.828 Admin. costs €151 €265 €123 €132 €211 €98 €98 €98

Costs AE costs €217 € 434 €178 €454 €908 €337 €337 €178 Total costs €7.474 €13.135 €5.970 €6.411 €10.439 €5.263 €4.918 €5.103

Per month €11.024 €7.297 €5.321 €8.347 €6.959 €7.189 €6.718 €6.972 Remission (€13.299)* (€7.786)*

Cost Per month €6.018 €3.909 €2.819 €4.174 €3.625 €3.916 €3.659 €3.797 * *

consequence In LDAS (€7.222) (€4.166)

*Assuming response onset for abatacept 1 month after treatment initiation. tions was required to offset the higher the drug costs for infliximab to €4.483 €5.321/€2.819) remained strongly in 6-month initiation cost for abatacept per 6 months and improved the cost favour of abatacept under real-life con- for achieving remission/LDAS. per month in remission/LDAS for inf- ditions. liximab (€6.718/€3.659). Even in this b) Real-life scenario with scenario, abatacept performed better Discussion vial sharing across patients with cost per month in remission/LDAS The current cost-consequence analy- In contrast to abatacept, where only for abatacept of €5.321/€2.819. This sis modelled the cost per month in complete vials are used for infusion, scenario confirms the robustness of the LDAS and cost per month in remission infliximab is dosed on a mg/kg basis cost-consequence benefits of abatacept achieved with abatacept or infliximab. and supplied in 100 mg vials, which relative to infliximab in real-life clini- The clinical results from the ATTEST can lead to considerable wastage. For cal practice. trial were used to derive the expected example, for a person weighing 75 kg time in remission or LDAS during the dosed at 3.57 mg/kg a total amount of c) Real-life scenario assuming no initial 6 months of treatment and dur- 268 mg infliximab per infusion would difference in adverse events risks ing a full 12-month period of treatment. need 3 vials and potentially waste 32 between infliximab and abatacept The ATTEST trial evaluated efficacy mg infliximab per infusion. In Ital- The majority of the studies incorporated and safety of two biological agents in a ian clinical practice, several patients in the network meta-analysis of Singh et randomised setting. Furthermore, dose are often scheduled for infusion at the al. (15) were of a relative short duration information from an Italian registry same time in order to optimise vial us- (median duration of 6 months). A recent study for infliximab was used to calcu- age and reduce wastage (12). To ac- updated Cochrane analysis produced late the expected real-life costs for inf- count for such vial optimisation, an slightly different SAE rates still favour- liximab from an Italian healthcare sys- additional theoretical scenario was ing abatacept relative to infliximab, but tem perspective. In the absence of head- defined that assumed zero wastage of results no longer reached significance to-head comparative long-term safety infliximab. This scenario can be- con (19). Since there is a general lack of data, Cochrane network meta-analysis sidered “theoretical”, as zero wast- comparative long-term data regarding data on AEs across biologics were used age is unlikely in clinical practice, but the safety of biologics, differences in as providing the best available data for supports testing the robustness of the SAE risk during prolonged use can be real-life extrapolation analyses. real-life findings. For this scenario, considered uncertain. To evaluate the The costs per month in remission or the infliximab dose administered was impact of AE risk, a scenario was de- LDAS were higher for abatacept dur- based on the average body weight of fined where the SAE risk for infliximab ing the first 6 months of treatment com- patients in the ATTEST trial while as- was assumed to be similar to that of pared to infliximab. However, these suming zero wastage. Hence, based on abatacept: serious infections 1.5% and cost differences were reduced over the the average body weight of 72.6 kg other SAE 6.4%. Table II demonstrates subsequent 6 months in the trial-based and a real-life dose of 3.57 mg/kg, this that even with similar SAE risk for in- scenario. The cost per month in remis- would equal 259 mg corresponding to fliximab and abatacept, the cost-conse- sion/LDAS turned in favour of abata- 2.6 vials of infliximab per infusion. As quence expressed as cost per month in cept when applying a real-life scenario a consequence, this scenario lowered remission/LDAS (€6.972/€3.797 vs. where the infliximab dose is escalated.

580 Cost consequence of abatacept or infliximab in Italy / M. Benucci et al.

Accordingly, if treatment after 6 months difference in the proportion of patients abatacept has been suggested to display is prolonged under real-life conditions, reaching remission at 12 months in the a slower response onset compared to the higher initial (first 6 months of treat- ATTEST trial included the point of no anti-TNF inhibitors, this is challenged ment) costs for abatacept per month in difference (Table I), and therefore it by recent head-to-head data, where LDAS and remission will be offset after cannot be excluded that the difference subcutaneously administered abatacept a total 16.1 and 14.6 months of treat- in efficacy was a random observation. was compared to the TNF inhibitor, ment, respectively. Although the cost However, the observation that a sig- adalimumab (3). In this trial there was differences between abatacept and inf- nificantly higher proportion of patients only a slight, statistically insignificant liximab for the real-life scenario decline in the abatacept group as compared to advantage for adalimumab in ACR20 when vial optimisation was assumed, infliximab arm shift from LDAS toa response rates and DAS28 scores at 2 a conservative “no wastage” scenario state of remission during month 7 to weeks after treatment initiation. Since still favoured abatacept for long-term 12 of the ATTEST trial (21) makes this subcutaneous and intravenous admin- use: cost per month in remission/LDAS unlikely. Still, decisions based on the istered abatacept display similar ACR for infliximab (€6.718/€3.659) versus cost/month in remission would have response kinetics (22), a response delay €5.321/€2.819 for abatacept. The more been less certain than those based on of 1 month for abatacept versus inflixi- durable efficacy of abatacept over time month in LDAS had this been a proba- mab can be considered conservative. as observed in the ATTEST trial result- bilistic model. The slower response onset for abatacept ed in cost consequence benefits, which In order to provide useful results, the did not affect the total treatment costs, were higher when patients continued outcomes provided by any cost con- but increased the cost per month in re- on abatacept vs. infliximab. Therefore, sequence model will need to be trust- mission/LDAS for abatacept during the based on the trial data, abatacept is like- worthy, given the uncertainties in the ATTEST period. However, these higher ly to be an economically attractive al- data used as well as around the use of initiation costs were still offset by pro- ternative for prolonged treatment of RA. both biologicals in real-life clinical longed treatment under real-life condi- Despite a comprehensive and transpar- practice. Therefore, the robustness of tions. ent presentation of the costs and con- the model outcomes was evaluated for The 12-month efficacy data from- AT sequences of both interventions, it is scenarios that incorporated different TEST were assumed to also reflect the not possible to provide an incremental data sources and real life use patterns efficacy of infliximab and abatacept for assessment of the value for money of of both infliximab and abatacept. For the real-life scenario. Therefore, the abatacept when using such a cost con- the main scenario, it was assumed that real-life scenario implicitly assumes sequence approach (20). Accordingly, the onset of response was immediately that a dose escalation of infliximab is it has been argued that the disaggre- upon treatment start for both abatacept not associated with increased efficacy. gated presentation of cost and conse- and infliximab. Although this assump- This assumption might bias against quences bears a potential risk for non- tion is unrealistic and overestimates the infliximab if dose escalation would transparent decision making. This al- treatment effect expressed as months in be associated with improved efficacy. lows for a decision maker to select the remission/LDAS for the first 6 months, Although dose increases are common outcomes and consequences which are it does so for both treatments; therefore, in patients treated with infliximab and most relevant for his or her individual this assumption was unlikely to impact observational studies (9) suggested that perspective, but which are not neces- the results. However, it has been argued a dose increase of infliximab was asso- sarily aligned with the optimal decision that abatacept displays a slower onset ciated with improved clinical efficacy from a societal perspective. However, of the response compared to infliximab this was refuted by randomised trial by the consequences considered in the (6, 7). Consequently, it could be argued Pavelka et al. (23). They demonstrated current analysis, time in LDAS and re- that an immediate onset of the response that a dose increase in RA patients with mission, are well aligned with the treat- for both agents would bias in favour of an inadequate response to prolonged ment to target strategy as formulated by abatacept. Therefore, a scenario was use of infliximab did not lead to a EULAR and therefore individual bias defined where abatacept’s onset of re- greater proportion of patients reaching is unlikely to affect decision making. sponse was delayed by 1 month relative remission as defined by DAS28 score. As for any model analysis, underlying to that for infliximab. Since the- AT Furthermore, the dose of infliximab assumptions and simplifications were TEST trial (21) did not report the pro- (3.57 mg/kg) as reported in the Italian made, which should be acknowledged portion of patients reaching LDAS/re- registry (12) and applied for the real life as these might caution any conclusions. mission on other time points than 6 and scenario represented a 19% increase in The current analyses do not incorpo- 12 months after treatment initiation, the dose compared to the ATTEST trial and rate any uncertainty in the estimates as reported ACR rates were used as a proxy can be considered to be conservative derived from the ATTEST trial and the to assess the response delay. According estimate of real-world dosing in light of Cochrane meta-analysis and therefore to the ACR20 figures presented in the other evidence. An analysis of multiple the analysis calculated expected values ATTEST trial (21), the 1-month delay observational studies (9) demonstrated only. In this perspective it should be is believed to represent the maximum that dose escalation of infliximab of at noted that the confidence interval of the response delay for abatacept. Although least 25% was common. Therefore, the

581 Cost consequence of abatacept or infliximab in Italy / M. Benucci et al.

19% dose increase of infliximab ap- intravenous infusion. Future analysis to methotrexate. Ann Rheum Dis 2008; 67: plied in the real-life scenario can be should determine whether the current 1096-103. 6. RUBBERT-ROTH A, BURMESTER GR: Clini- considered conservative and is more cost consequence outcomes would also cal trials: how to cope with medical needs, likely to bias in favour of infliximab. apply for subcutaneously administered ethics and timelines. Ann Rheum Dis 2010; Furthermore, the robustness of the abatacept for which 1 year data of a 69: 1-3. analysis is underscored by the observed direct comparison against adalimumab 7. KIELY PD, DEIGHTON C, DIXEY J, OSTOR AJ: Biologic agents for rheumatoid arthritis- beneficial cost consequence results for have been recently reported (3). Once -negotiating the NICE technology appraisals. abatacept under real-life conditions the full 24-month data of this AMPLE Rheumatology (Oxford) 2012; 51: 24-31. where vial sharing optimised cost ef- study (3) are available, it will be of inter- 8. Clinical study report ATTEST trial: Trial registration number NCT00095147. 2007. ficient use of infliximab. est to evaluate the cost consequences of 9. ARIZA-ARIZA R, NAVARRO-SARABIA F, HER- In contrast to abatacept, infliximab is subcutaneously administered abatacept NANDEZ-CRUZ B, RODRIGUEZ-ARBOLEYA considered to increase the risk for se- against adalimumab. Also differences L, NAVARRO-COMPAN V, TOYOS J: Dose es- rious infections and for that reason re- in adherence to therapy, which was calation of the anti-TNF-alpha agents in pa- tients with rheumatoid arthritis. A systematic ceived a black box warning from the shown to be under 50% for infliximab review. Rheumatology (Oxford) 2007; 46: FDA (19). Recently, a large Italian reg- in the Italian setting (26), might affect 529-32. istry study has demonstrated that long- the cost-consequence results once these 10. AGARWAL SK, MAIER AL, CHIBNIK LB et al.: term anti-TNF treatment, and espe- data become available for abatacept. Pattern of infliximab utilization in rheuma- toid arthritis patients at an academic medical cially infliximab, was associated with a center. Arthritis Rheum 2005; 53: 872-8. higher risk for serious infections (24). Conclusions 11. BLOM M, KIEVIT W, KUPER HH et al.: On the other hand, a large observation- The results of these analyses dem- Frequency and effectiveness of dose increase of adalimumab, etanercept, and infliximab al study has recently confirmed abata- onstrated that relative to infliximab, in daily clinical practice. Arthritis Care Res cept’s favourable profile regarding se- abatacept is a favourable treatment (Hoboken) 2010; 62: 1335-41. rious infections relative to infliximab for patients failing MTX, both from a 12. FAVALLI EG, MARCHESONI A, COLOMBO (25). In this study, however, the me- clinical and economic perspective, in GL, SINIGAGLIA L: Pattern of use, economic burden and vial optimization of infliximab dian exposure time was only 7 months the Italian healthcare setting. Our find- for rheumatoid arthritis in Italy. Clin Exp (25). Similarly, the AE rates applied ings suggest a lower cost-consequence Rheumatol 2008; 26: 45-51. for the real-life scenario as reported by for abatacept during real-life treatment. 13. SIMONS W, TRIVEDI DN, ROSENBLATT LC: the Cochrane network meta-analysis Future long-term comparative data Real World Treatment patterns of patients with rheumatoid arthrits receiving two in- (15) were mainly based on trials with might be used to confirm the validity fusable biologics: abatacept and infliximab. a relatively short duration (median 6 of extrapolation of the ATTEST results EULAR 2009. SAT0120. 2009. months) and included trials outside the and also establish whether similar find- 14. PUNZI L, MATUCCI CM, CANTINI F et al.: RA indication. Therefore, due the lack ings will be obtained for subcutane- Treatment patterns of anti-TNF agents in Italy: an observational study. Reumatismo of long-term comparative data, the in- ously administered abatacept. 2011; 63: 18-28. cidence of SAEs within the RA indica- 15. SINGH JA, WELLS GA, CHRISTENSEN R et tion upon prolonged use of biologicals References al.: Adverse effects of biologics: a network remains uncertain from either observa- 1. SMOLEN JS, ALETAHA D, BIJLSMA JW et al.: meta-analysis and Cochrane overview. Treating rheumatoid arthritis to target: rec- Cochrane Database Syst Rev 2011; (2): tional or from controlled trials. Also a ommendations of an international task force. CD008794. recent alternative Cochrane analysis Ann Rheum Dis 2010; 69: 631-7. 16. IANNAZZO S, ZANIOLO O, D’ARPINO D: has produced slightly different SAE 2. SMOLEN JS, LANDEWÉ R, BREEDVELD FC Un modello di Budget Impact per la valutazi- rates, which still favoured abatacept et al.: EULAR recommendations for the one economica di tocilizumab come prima management of rheumatoid arthritis with linea biologica nei pazienti con artrite reu- relative to infliximab, but to a lesser synthetic and biological disease-modifying matoide di grado moderato o servero. Italian extent, and results were non-significant antirheumatic drugs. Ann Rheum Dis 2010; Journal of Public Health 2010; 7 (Suppl. 2): (19). To account for the uncertainty 69: 964-75. S44-S53. 3. WEINBLATT ME, SCHIFF M, VALENTE R 17. BENUCCI M, LI GF, SABADINI L, SAVIOLA around a difference in adverse event et al.: Head-to-head comparison of subcu- G, BAIARDI P, MANFREDI M: The economic rates upon prolonged use of abatacept taneous abatacept versus adalimumab for burden of biological therapy in rheumatoid and infliximab an additional ‘real-life’ rheumatoid arthritis: findings of a phase arthritis in clinical practice: cost-effective- scenario assuming no difference was IIIb, multinational, prospective, randomized ness analysis of sub-cutaneous anti-TNF- study. Arthritis Rheum 2013;65: 28-38. alpha treatment in Italian patients. Int J Im- explored. This scenario demonstrated 4. GABAY C, EMERY P, van VOLLENHOVEN R munopathol Pharmacol 2009; 22: 1147-52. that the cost consequence results were et al.: Tocilizumab (TCZ) monotherapy is 18. Tariffa Unica Conventionale 2010. 2011. insensitive to changes in SAE rates in superior to adalimumab (ADA) monotherapy 19. SINGH JA, WELLS GA, CHRISTENSEN R et accordance with the drug acquisition in reducing disease activity in patients with al.: Adverse effects of biologics: a network rheumatoid arthritis (RA): 24-week data from meta-analysis and Cochrane overview. costs being the main driver of the over- the phase 4 ADACTA trial. 2012 p. 172. Cochrane Database Syst Rev 2012; (3): all costs and durability of response as 5. SCHIFF M, KEISERMAN M, CODDING C et CD008794. the main driver for cost offsets. al.: Efficacy and safety of abatacept or inf- 20. COAST J: Is economic evaluation in touch The current cost consequence analysis liximab vs placebo in ATTEST: a phase III, with society’s health values? 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increasing magnitude of response over time Increasing the infliximab dose in rheuma- 25. CURTIS JR, XIE F, CHEN L et al.: The compar- in measures of rheumatoid arthritis disease toid arthritis patients: a randomised, double ative risk of serious infections among rheu- activity: results from the ATTEST trial. Ann blind study failed to confirm its efficacy.Ann matoid arthritis patients starting or switching Rheum Dis 2008; 67: 337. Rheum Dis 2009; 68: 1285-9. biological agents. Ann Rheum Dis 2011; 70: 22. GENOVESE MC, COVARRUBIAS A, LEON G 24. ATZENI F, SARZI-PUTTINI P, BOTSIOS C et 1401-6. et al.: Subcutaneous abatacept versus intra- al.: Long-term anti-TNF therapy and the risk 26. IANNONE F, GREMESE E, ATZENI F et al.: venous abatacept: a phase IIIb noninferiority of serious infections in a cohort of patients Longterm retention of tumor necrosis fac- study in patients with an inadequate response with rheumatoid arthritis: comparison of tor-alpha inhibitor therapy in a large italian to methotrexate. Arthritis Rheum 2011; 63: adalimumab, etanercept and infliximab in the cohort of patients with rheumatoid arthritis 2854-64. GISEA registry. Autoimmun Rev 2012; 12: from the GISEA registry: an appraisal of pre- 23. PAVELKA K, JAROSOVA K, SUCHY D et al.: 225-9. dictors. J Rheumatol 2012; 39: 1179-84.

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