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Authors; Khai Tran, and Mê-Linh Lê.
Immune thrombocytopenia (ITP) affects approximately 5 in 100,000 children per year, with a peak incidence occurring in children between 2 and 5 years of age.1,2 ITP is an autoimmune disorder characterized by accelerated destruction of platelets, a risk of increased bleeding caused by platelet deficiencies (i.e., platelet count drops below 10 to 20 × 109 platelets/L).3 Of the cases, 75% to 80% can be self-resolved within 6 months,3 with some resolving within a year after diagnosis.4 Approximately 20% to 30% of pediatric ITP patients could not have spontaneous remission and the disease became chronic.3 Most patients present with mild bruising, and about 3% had serious bleeding from the nose, mucosa, and gastrointestinal tract.5 Intracranial hemorrhage is the most serious complication of ITP, with the rates ranging from 0.17% to 0.6% among cases.1,6,7 The cause of ITP remains unclear, although it can be triggered by viral infection, environmental factors, or immune defect.8
There are various ITP therapies available for preventing bleeding episodes by increasing platelet counts. Three commonly used first-line treatments for ITP are glucocorticoids, IV immunoglobulin, and anti-D immunoglobulin.8 Glucocorticoids (e.g., prednisone or dexamethasone) have both rapid and delayed effects in increasing platelet counts, but most patients relapse after the steroids are discontinued.9 Prolonged use of glucocorticoids has been associated with adverse side effects of steroids.9 IV immunoglobulin has been shown to be superior to glucocorticoids or no treatment in early recovery of platelet counts within 24 hours of administration.9 The exact mechanism of action of immunoglobulin is not well understood, although evidence has suggested that immunoglobulin slows down the destruction of platelets by inhibiting macrophage-induced phagocytosis.9 Anti-D immunoglobulin is an antibody against the Rhesus (Rh)-positive blood type. It works by binding to Rh-positive red blood cells, the complex of which then binds to the Fc receptors on macrophages, which induces the destruction of red blood cells, thus sparing the removal of antibody-coated platelets.9 Anti-D antibody is ineffective in patients with Rh-negative blood types and is contraindicated in patients with anemia.9
In patients having inadequate response to first-line therapies and still being treated with ITP for more than 3 to 6 months, second-line drugs may be considered.10 They are rituximab, thrombopoietin receptor (TPO-R) agonists, and splenectomy.10 Splenectomy is highly effective for inducing remission ITP and does not require maintenance therapy.10 Although highly effective, splenectomy is associated with increased risk of infections, especially bacterial sepsis.10 It is recommended to delay splenectomy in children for at least 12 months after initial ITP diagnosis, because some patients can achieve remission regardless of the choice of therapy.11 Rituximab is a monoclonal antibody to CD20, which targets and destroys autoantibody-producing B lymphocytes.9 The initial response rate of rituximab in children with chromic ITP is 40% to 50%, and the response rate at 2 to 5 years follow-up was only 25%.12,13 TPO-R agonists such as eltrombopag (EPAG) and romiplostim (ROMI), which stimulate megakaryocytes to increase the production of platelets, are emerging effective drugs for treatment of chronic ITP.14 EPAG (brand name Revolade) has been approved by Health Canada for the treatment of ITP in adult and pediatric patients who have had an insufficient response to corticosteroids or immunoglobulins.15 ROMI (brand name Nplate) has also been approved by Health Canada for the treatment of ITP in adult patients, but not in children, with chronic ITP.16 The advantage of EPAG over ROMI is that EPAG is administered orally, while ROMI is administered weekly via injection.10 Evidence has shown that both EPAG and ROMI appear to be effective treatment options for children with chronic ITP, but the their long-term efficacy and safety remain unclear.17 Other drugs including mycophenolate mofetil, mercaptopurine, cyclosporin, and dapsone has been used to treat pediatric ITP, but the rate of efficacy of these drugs was generally low.10
Numerous studies have assessed the cost-effectiveness of various therapies in the treatment of ITP.18-25 However, these studies did not consider pediatric patients.
The aim of this report is to summarize the evidence regarding the cost-effectiveness of dapsone, rituximab, and TPO-R agonists for pediatric patients with ITP.
A limited literature search was conducted by an information specialist on key resources including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were thrombocytopenia and specific treatments (dapsone, rituximab, and thrombopoietin receptor agonists). CADTH-developed search filters were applied to limit retrieval to economic studies. Comments, newspaper articles, editorials, letters, and conference abstracts were excluded. Where possible, retrieval was limited to the human population. The search was completed on March 28, 2022 and limited to English-language documents published since January 1, 2012.
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Selection Criteria.
Articles were excluded if they did not meet the selection criteria outlined in Table 1, or they were published before 2012.
The included publication was critically appraised by 1 reviewer using the Drummond checklist26 for economic evaluations. Summary scores were not calculated for the included study; rather, the strengths and limitations were described narratively.
A total of 157 citations were identified in the literature search. Following screening of titles and abstracts, 148 citations were excluded and 9 potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 8 publications were excluded for various reasons, and 1 publication (i.e., economic evaluation) met the inclusion criteria and was included in this report. Appendix 1 presents the PRISMA27 flow chart of the study selection.
Additional details regarding the characteristics of the included publication are provided in Appendix 2.
The economic evaluation study by Tremblay et al. (2018)28 used a cost-consequence model to assess the cost-effectiveness in response to different treatment outcomes. The clinical data were obtained from 2 randomized placebo-controlled trials.29,30 The indirect treatment comparison (ITC) was used to indirectly compared the clinical data of the comparators. All cost data were from US-based sources and US health care inflation of 3.6% was applied when there were no up-to-date data. No currency conversion was required. The analyses were conducted from a general US payer’s perspective over a 26-week time horizon. As the model horizon was less than 1 year, discounting was not applied.
The economic evaluation study28 was conducted by authors from US.
Patients considered in the economic evaluation study28 were children with chronic ITP who had insufficient response to corticosteroids, immunoglobulins, or splenectomy from 2 randomized placebo-controlled trials.29,30 The 2 studies had some notable differences in baseline characteristics including ethnic origins, the amount of time since diagnosis, and proportion of male patients.
EPAG was the intervention, while ROMI and watch-and-rescue (W&R) were selected as comparators. W&R treatment was based on the placebo groups of the respective trials. Those patients would receive rescue therapy as needed.
The outcomes in the economic evaluation study28 were incremental cost-effectiveness ratio (ICER), which was calculated as the incremental cost per responder, per severe bleeding event avoided, per bleeding event avoided, and per patient.
Additional details regarding the strengths and limitations of included economic evaluation study28 are provided in Appendix 3.
The included economic evaluation study28 clearly stated the objective, the economic importance of the research question, the rational for choosing the alternative comparators (i.e., EPAG versus ROMI and EPAG versus W&R), and the type of economic evaluation (i.e., cost-consequence analysis) that was conducted. The model was constructed from a general US payer’s perspective with a time horizon of 26 weeks. For data collection, the study clearly stated the source of effectiveness estimates with details of the design and findings (i.e., from 2 randomized placebo-controlled trials.29,30) The ITC technique was used to compare efficacy data between 2 trials, although there were some notable differences in baseline characteristics between trials that may affect the findings. The study clearly stated the outcome measures for economic evaluation (i.e., incremental cost per responder, incremental cost per severe bleeding event avoided, incremental cost per bleeding event avoided, and incremental cost per patient). A decision-tree model was presented with all parameters employed in the analysis. For the analysis and interpretation of results, the study clearly stated the time horizon of costs and benefits, statistical tests and confidence intervals, justification for the choice of variables for sensitivity analysis, and the ranges over which the variables were varied. Discounting was not applicable as the time horizon was less than 1 year. The study reported incremental analysis and presented major outcomes in a disaggregated as well as aggregated form. Probabilistic sensitivity analyses (PSA) were used to address uncertainty in the analysis, with a wide range of willingness-to-pay (WTP) thresholds. The conclusion in the study was based on the data reported and was accompanied by the appropriate caveats. Overall, the study was of moderate methodological quality with respect to the study design, data collection, and analysis and interpretation of results.
Appendix 4 presents the main study findings and authors’ conclusions.
No cost-effectiveness studies of dapsone versus rituximab or other TPO-R agonists were identified; therefore, no summary can be provided.
No cost-effectiveness studies of rituximab versus dapsone or other TPO-R agonists were identified; therefore, no summary can be provided.
For overall response (i.e., platelet counts ≥ 50 × 109/L without rescue medication use in the preceding 4 weeks), patients in the EPAG group had higher response rates compared to those in the ROMI group (difference of 2.3%) and W&R group (difference of 53.9%). There were fewer incidence in severe bleeding, overall bleeding, use of rescue medication in the EPAG group compared with ROMI and W&R groups. For total costs, EPAG was estimated to cost US$34,506 less than ROMI, and US$33,830 more than W&R. EPAG’s lower cost compared to ROMI was largely due to lower drug costs, administration costs, costs of severe bleeding, costs of moderate bleeding, and costs of adverse events.
Cost-effectiveness analysis using ICER revealed that EPAG was dominant (i.e., less expensive, and more effective) over ROMI when assessing incremental cost per responder, per severe bleeding event avoided, per bleeding event avoided, and per patient. Uncertainty in the results was assessed via PSA, whose results were consistent with base case findings. The PSA results showed that the probabilities that EPAG being cost-effective for treating children with chronic IPT were close or equal to 100% at all WTP thresholds ranging from US$25,000 to US$10,000,000, from a general US payer’s perspective. Compared with W&R, EPAG had higher total cost but had improved clinical outcomes (e.g., overall response, bleeding, and mortality). Regarding cost per severe bleeding avoided, EPAG had an ICER of US$354,197. The PSA results showed that EPAG had an ICER of 0.8% under a WTP threshold of US$100,000.
One limitation of the economic evaluation study28 was that there was no head-to-head trials that compared EPAG and ROMI to assess their relative efficacy and safety. The ITC technique with some inherent limitations was used to adjust the ROMI efficacy data to match the EPAG data. The technique can be biased by both observed and unobserved differences in baseline characteristics between trials. Another limitation was that this study could not include rituximab and splenectomy, the 2 common treatments for chronic ITP, as comparators, due to unavailable data. The study used a relatively short time horizon in the model, and did not consider the indirect costs (i.e., societal perspective) in the model. Health-related quality of life was not included in the analyses. As the model was constructed from a US payer’s perspective, the findings of the study may not be applicable to the Canadian context. No evidence regarding the cost-effectiveness of dapsone or rituximab was identified.
This report identified 1 economic evaluation study28 using a cost-consequence model to compare the cost-effectiveness of EPAG versus ROMI in pediatric patients with chronic ITP. The study found that EPAG was dominant over ROMI (less expensive and more effective) when assessing cost per responder, cost per severe bleeding event avoided, cost per overall bleeding event avoided, and cost per patient. This was largely driven by lower drug and administrative costs and fewer severe bleeding outcomes. No cost-effectiveness studies of dapsone or rituximab for pediatric patients with ITP were identified. Future studies are needed to verify the cost-effectiveness of EPAG using different perspectives and longer time horizons, and to evaluate the cost-effectiveness of other ITP therapies including dapsone and rituximab.
eltrombopag
indirect treatment comparison
immune thrombocytopenia
probabilistic sensitivity analyses
romiplostim
thrombopoietin receptor
watch-and-rescue
willingness-to-pay
Selection of Included Studies.
Characteristics of Included Economic Evaluation.
Note that this appendix has not been copy-edited.
Strengths and Limitations of Economic Evaluation Using the Drummond Checklist.
Note that this appendix has not been copy-edited.
Cost-consequence analysis of EPAG vs. ROMI or EPAG vs. W&R
Efficacy Outcomes
Costs (US$)
ICER
PSA Results — ICER for Costs per Severe Bleeding Avoided
“EPAG was the preferred TPO-R agonist to treat chronic ITP when indirectly compared to ROMI, largely driven by its favorable severe bleeding outcomes and lower drug and administration costs.”28 (p. 715)
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