Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by a platelet count less than 100 x 109 platelets/liter; this is due to platelet destruction and inadequate production1,2. Diagnosis is reached by exclusion of other diseases associated with thrombocytopenia. The annual ITP incidence rate is 3-4/100,000 in adults, increasing in older patients3. This condition is classified as newly diagnosed ITP when the evolution is shorter than 3 months from diagnosis, persistent if the duration of disease is 3-12 months and chronic when it lasts for more than 12 months1. Although 1/3 of affected persons are asymptomatic and patients with a platelet count over 50 x 109 platelets/liter do not require treatment, this long-lasting disease may threaten life due to bleeding caused by thrombocytopenia; it negatively impacts quality of life and imparts a high economic burden on the healthcare system1,2.

Classical guidelines recommended corticosteroids as first-line treatment for adult ITP followed by splenectomy as second-line treatment and the use of the anti-CD20 chimeric monoclonal antibody rituximab or a thrombopoietin receptor agonist (TPO-RA) in cases of failure or contraindication2,4.

Splenectomy achieves a 60% response after 5 years5. However, this treatment produces important adverse effects mainly derived from surgery, as well as risk of infection, thrombosis and cancer6. In contrast, rituximab and TPO-RAs cause few toxicities and spare a splenectomy. The first option permits lasting responses after a short treatment, with approximately 60% initial responses and a third of patients in remission after one year7. The second involves long-term treatments, but with high response rates (75-95%), and it has fewer side effects than rituximab and the potential of drug discontinuation7–12. Hence, those formerly considered third-line treatments have become extensively used13. In fact, the last recommendations indicate that, even if corticoids remain at the first-line treatment, in view of the lack of randomized trials directly comparing splenectomy, rituximab and TPO-RAs, all three can be used as second-line options7.

TPO-RAs, including eltrombopag and romiplostim, stimulate platelet production, increasing platelet count9,14. Unlike romiplostim subcutaneous administration, eltrombopag oral administration requires no sanitary assistance15.

The aim of this paper is to provide data for clinical decisions according to their economic implications through the per-head cost of responding patients to oral TPO-RA eltrombopag and rituximab for treating chronic ITP in the context of the Spanish Health Service.

The average cost per patient after a 6-month treatment was €13,089.40 for eltrombopag and €11,852.60 for rituximab. Itemized costs show that the greater response rate of the first involves a decrease in bleeding costs (€811.27 with rituximab, €499.97 with eltrombopag). Due to the lower efficacy of rituximab, the average cost of response is €14,732.65 with eltrombopag and €18,964.15 with rituximab (29% higher with the latter).

Tables 1, 2 and 3 show the base case and sensitivity analysis results. The cost of eltrombopag is always lower, excluding the sensitivity analysis in which the patient received a daily dose of 75 mg of eltrombopag —a scenario where eltrombopag global cost is €5,039.58 over rituximab, but when response cost is considered, the difference is reduced to only €48 higher than that of rituximab.

Patient refusal and hazards derived from surgery plus lifelong increased risk of infection, thromboembolic events and malignancy after splenectomy have increased the use of TPO-RAs and rituximab26,27. The last American Hematology Association guideline for ITP treatment update recommends rituximab over splenectomy and places splenectomy and TPO-RAs at the same level7. The preference between rituximab and TPO-RAs is under discussion in patients unresponsive to steroids or suffering from persistent ITP7. Hence, the cost and effectiveness of both types of treatment must be carefully evaluated to make appropriate medical decisions. We selected TPO-RA eltrombopag for this study over romiplostim due to its oral, out-of-hospital administration, in contrast to the subcutaneous administration of romiplostim, which needs sanitary assistance.

Here, we show that the cost of a 6-month treatment is similar using rituximab and eltrombopag, €11,852.60 and €13,089.40, respectively. Both treatments accomplish responses and have low side effects, but lower beneficial effects have been observed with rituximab13. Therefore, as the response to treatment with eltrombopag is greater, the cost per-responding patient is smaller, even though the treatment cost itself is higher, turning the budget to €14,732.65 for eltrombopag and €18,964.15 for rituximab in that period of time. These results are indirectly consistent with those from other economic evaluations in Spain showing that eltrombopag was cost-effective against romiplostim and romiplostim was cost-effective against rituximab16,25. Additionally, a recent meta-analysis indirectly comparing rituximab and TPO-RAs eltrombopag and romiplostim treatment for persistent or chronic ITP suggests that the second type of treatment is superior to the former when considering response (platelet ≥ 50 × 109/L), clinically significant and severe bleeding28. Additionally, although treatment with eltrombopag is considered chronic, there is evidence that suggests that it is possible to discontinue the treatment19.

Another issue to consider is that the rituximab administration route is intravenous or subcutaneous after the first dose, and it has to be monitored at the hospital for undesired side effects versus oral administration at home in the case of eltrombopag. Therefore, treatment with eltrombopag lessens the workload at day hospitals, allowing resources to be focused on other patients who need day-hospital facilities for the administration of their treatments (such as chemotherapy). A limitation of this study is that the model does not take into account the adverse effects caused by treatments, which may potentially be more severe in the first perfusions of the monoclonal antibody than in the case of the thrombopoietin receptor agonist.

As data for rituximab do not inform of splenectomized patients, our model considers the Spanish average of 22% splenectomized patients, but it cannot itemize the splenectomized group of patients. Clinical studies have shown that eltrombopag is more effective in non-splenectomized patients12,29,30, so an increase in the number of splenectomized patients could mean a decrease in the response rate.

A final limitation is related to the use of rituximab at a lower dose (100 mg). In the absence of efficacy data at this dose, this option has not been considered for the present analysis (it should be noted that the use of data that are not sufficiently comprehensible would in turn imply another limitation). Additionally, using a standard dose of rituximab of 375 mg is consistent with a similar article in which rituximab was evaluated against romiplostim16, and may allow comparison between both.

In conclusion, the treatment budget of rituximab, considering monitoring and bleeding costs, is higher than that of eltrombopag. This, together with long response rates and the reduced undesirable effects, supports the recommendation of the latter treatment over rituximab. This type of analysis should be required to guide healthcare policies and treatment decision-making.

No funding.

No conflicts of interest.

Financial activities outside the submitted work: José Ramón González-Porras has received fees for consulting services by Amgen, Novartis, SOBI, Grifols and CSL Behring and speaking honoraria from Novonordisk, Shire, SOBI, Roche, Daiichi Sankyo, Pfizer, Rovi, Amgen, and Novartis. Francisco Javier Parrondo-García has received consultancy fees from Takeda Farmacéutica España, Tesaro España, Pierre Fabre España, Servier España, Bristol-Myers Squibb S.L., Lilly S.A., Biogen Spain S.L., ViiV Healthcare Spain and Pfizer SLU. Eduardo Anguita has received speaking honoraria and support for attending conferences from Amgen and Novartis.

This work was an oral presentation at the LXI National Conference of SEHH and XXXV Congress of SETH, Valencia, October 24-26, 2019.

The cost for responding primary immune thrombocytopenia patient in the Spanish Health Service.

Our data favor eltrombopag over rituximab for primary immune thrombocytopenia treatment in Spain.