Model
We have developed a cost-consequence model as cost of reaching response to compare direct health costs of ITP treatment with eltrombopag and rixutimab from the perspective of Spanish public Hospitals. As in a similar study comparing romiplostim and rituximab [27], only direct hospital health costs of patients treated with eltrombopag and rituximab have been considered. Grade 1 (petechial) bleedings, which are treated by the patients themselves or at the primary care services, have not been contemplated.
To allow the comparison with this similar study that evaluated the cost per response of romiplostim and rituximab [27], a time horizon of 26 weeks (half a year) has been set. As shown in Fig. 1, it was split into two periods. The first one comprised 8 weeks during which all patients were treated and the response evaluated. This was followed by a period of 18 weeks in which: a) only patients responding to eltrombopag continued to be treated and b) patients on rituximab were treated according to previously described bases [26]. This structure is coherent with the previously mentioned study carried out in Spain [27], so that, it may support decision-making.
As time horizon is less than a year, we did not consider to apply discounting to costs or effects.
In this way, along the 26 weeks, the model accumulates treatment costs (drugs plus administration), follow-up costs and the costs produced by bleedings, to calculate the final cost per responding patient to both treatment alternatives.
Studied population
Considering that eltrombopag is indicated for patients of more than one year of age with chronic ITP who are refractory to other treatments [25], and that, although rituximab is not officially approved for this disease, it is indicated for adult patients in the illnesses in which it is approved [28], we have limited our analysis to adults with chronic-refractory ITP.
To determine the effectiveness of these treatments we have carried out a literature review of chronic ITP treatment, published in English and Spanish between 2000 and 2017. As a result, we have identified a paper focused on a group of Spanish patients treated with eltrombopag [29]. As no similar paper has been found for rituximab (Spanish patients with chronic-refractory ITP) we have used the data from the Arnold DM, et al systematic review [32].
In order to estimate rituximab dosage, we have used the Dubois & Dubois formula to determine the body surface of patients [30]. Height and weight have been determined according to microdata from the Spanish results of the European Health Survey 2014 (basal data shown in Table 1) [31].
Table 1
Basal characteristics of the population used in the model.
Variable | Value | Reference |
Sex (women %) | 63% | Gonzalez-Lopez TJ, et al. 2015 [29]. |
Average age (years) | 60 | Gonzalez-Lopez TJ, et al. 2015 [29]. |
Average women weight (Kg) | 65.75 | European Survey of Health in Spain. INE 2014; 2015 Oct 21 [31]. |
Average men weight (Kg) | 79.90 | European Survey of Health in Spain. INE 2014; 2015 Oct 21 [31]. |
Average women height (cm) | 161 | European Survey of Health in Spain. INE 2014; 2015 Oct 21 [31]. |
Average men height (cm) | 173 | European Survey of Health in Spain. INE 2014; 2015 Oct 21 [31]. |
Estimate of response
No study or Phase 3 clinical trial related to rituximab response was found in Spain; therefore, the more consistent data for this treatment derive from the indicated systematic review [32]. Additionally, we used a retrospective French model to evaluate the need for re-treatment and its effectiveness [26].
Table 2 shows response rates used in the model, their sources and the criteria employed to evaluate response. Re-treatment rates and their response are in Table 3.
Table 2
Response rates according to treatment.
Treatment/kind of response | Response rate | Response criteria (Platelets x 109/l) | Ref. |
Eltrombopag/Full response | 77.31% | ≥ 100 | Gonzalez-Lopez TJ, et al. 2015 [29]. |
Eltrombopag/Partial response | 11.54% | < 100 & ≥30 | Gonzalez-Lopez TJ, et al. 2015 [29]. |
Eltrombopag/No response | 11.15% | < 30 | Gonzalez-Lopez TJ, et al. 2015 [29]. |
Rituximab/Response | 62.50% | ≥ 50 | Arnold DM, et al. 2007 [32]. |
Rituximab/No response | 37.50% | < 50 | Arnold DM, et al. 2007 [32]. |
Ref, reference. |
Table 3
Re-treatment/kind of response | Brah S, et al. 2012 [26]. |
Patients responding to first treatment: Eltrombopag |
No re-treatment | 75% |
Re-treatment/Partial response | 21.43% |
No response | 3.57% |
Patients responding to first treatment: Rituximab |
No re-treatment | 63.64% |
Response | 27.27%% |
No response | 9.09% |
Bleeding estimate
As absence of bleeding and petechial bleeding do not involve hospital attention –they are cared for at primary care services-, the model only considers 2, 3 and 4-grade bleedings (WHO bleeding scale [33], Additional file 1).
There is a relationship between a low platelet count and an increased risk of bleeding. In this way, patients who do not respond to treatment will have a lower count and an increased risk of bleeding compared to responding patients. To simulate these bleeding risks, we have used the RAISE trial data [19], assuming that non-responding patients behave in the same way as the placebo arm in relation to the risk of bleeding while responding patients present a similar risk decrease to that on the treatment arm of the trial.
This assumption seems to be valid considering the effectiveness of eltrombopag and the duration of this trial, which is equivalent to that of the model (six months). The bleeding rates used in the model are in Table 4. Grade 4 bleedings are potentially life threatening, with a mortality rate of 40%; 80% of patients who survive after such a bleeding need rehabilitation [34].
Table 4
Bleeding rates on the basis of response.
Kind of bleeding | Responding patients | Non-responding patients |
Grade 2 | 13.19% | 22.95% |
Grade 3 | 4.40% | 14.75% |
Grade 4 | 0.55% | 3.28% |
Resources and costs
In order to make a cost estimation we used an average of the official lists of prices of the different Spanish regions (Additional file 2. Prices are actualized to 2018 euro (€2018).
As both alternatives are hospital formulary drugs, prices to wholesaler have been used, thus avoiding the extra costs involved by distribution channels and chemist stores.
Table 5 shows the laboratory prices of the different drugs as they appear in BotPlusWeb Portalfarma (online drugs database of the General Council of Official Pharmaceutical Associations, https://botplusweb.portalfarma.com, accessed 1 June 2018).
Table 5
Price of drugs used for the model.
Drug | Price (€) |
Eltrombopag 25 mg x 28 pills | 843.62 |
Eltrombopag 50 mg x 28 pills | 1687.24 |
Mabthera 100 mg solution x 2 vials | 495.18 |
Mabthera 500 mg solution x 1 vial | 1234.53 |
Truxima 100 mg solution x 2 vials | 420.90 |
Truxima 500 mg solution x 1 vial | 1049.35 |
In order to calculate the cost of the drugs, we considered the cost per mg and applied it to doses as described in the trials. Each rituximab treatment comprises 4 cycles of 375 mg for each square meter of body surface [32], implying a daily dose of 25 mg for 17.13% of the patients, a dose of 50 mg for 40.89% and a dose of 75 mg for 41.98% [19]. In the case of rituximab, an extra administration cost must be added; as the drug is administered in hospital, we have assumed it is equivalent to day-hospital costs.
Table 6 shows costs and their use in the model. Eltrombopag response is monitored weekly during the first 8 weeks and then once a month after week 8. For rituximab, monitoring is carried out weekly for the first 4 weeks and once a month after that. We assumed that a grade 2 bleeding cost is 0.6 times the cost of a specialist consultation plus 0.3 times the cost of an urgency consultation. For grade 3 bleedings we assumed a diagnosis related group (DRG) 174 (gastrointestinal bleeding) cost; for grade 4 bleedings we assumed a cost of 0.2 times DRG 810 (medical intracranial hemorrhage) plus 0.8 times the cost of DRG 833 (surgical intracranial hemorrhage) and the cost of rehabilitation when applying. This rehabilitation process after a grade 4 bleeding, when needed, was assumed to last 6 months and to include a monthly visit to the physiotherapy consultant, five physiotherapy and speech therapy sessions every week and three weekly occupational therapy sessions [35].
Table 6
Costs included in the model.
Concept | Cost (€) |
Specialist consultation | 96.95 |
Urgency consultation | 234.80 |
DRG 174 (GI bleeding) | 5015.89 |
DRG 810 (medical IC hemorrhage) | 7305.87 |
DRG 833 (surgical IC hemorrhage) | 25515.31 |
Physiotherapy consultation | 21.46 |
Speech therapy consultation | 20.65 |
Occupational therapy consultation | 19.58 |
Day-hospital consultation | 306.36 |
6-month rehabilitation | 4004.46 |
Costs for calculated event | |
Bleeding grade 2 | 128.61 |
Bleeding grade 3 | 5015.89 |
Bleeding grade 4 | 23795.57 |
DRG, diagnosis related group; GI, gastrointestinal; IC, intracranial. |
Sensitivity analysis
In order to analyze the effect of the different variables on the model results we have carried out 15 sensitivity analyses, described in Table 7.
Table 7
List of carried out sensitivity analyses.
Analysis | Description |
Base case | • Body surface after EHIS 2014 data • Eltrombopag dose after RAISE trial (56.21 mg/day) • Re-treatment with rituximab after retrospective study. • Both full and partial responses to eltrombopag are considered as response • Average value of rituximab efficacy • Rituximab administration cost (= 1 day-hospital consultation) • Monthly monitoring of rituximab after the first 4 weeks of response evaluation • Rituximab, Mabthera price |
SA 1 | • Body surface 1.70 m2 |
SA 2 | • Eltrombopag dose 50 mg /day |
SA 3 | • Eltrombopag dose 25 mg /day |
SA 4 | • Eltrombopag dose 75 mg /day |
SA 5 | • No re-treatment with rituximab |
SA 6 | • Re-treatment with rituximab only for the responding group. |
SA 7 | • Re-treatment with rituximab only for the non-responding group. |
SA 8 | • Only full responses to eltrombopag are considered. |
SA 9 | • Decrease of rituximab efficacy to the lower threshold of the confidence interval |
SA 10 | • Increase of rituximab efficacy to the upper threshold of the confidence interval |
SA 11 | • Rituximab administration cost (= specialist consultation) |
SA 12 | • Twice-a-month rituximab monitoring after the first 4 weeks of response evaluation |
SA 13 | • 10% decrease in bleeding costs |
SA 14 | • 10% increase in bleeding costs |
SA 15 | • Rituximab, Truxima price |
EHIS, European Health Interview Survey; SA, sensitivity analysis. |