This decision tree model estimates the cost per response and incremental cost per additional responder for romiplostim, eltrombopag, and “watch and rescue” for immune thrombocytopenia.
Objectives: This analysis estimated the cost per response and the incremental cost per additional responder of romplostim, eltrombopag, and the “watch-and-rescue” (monitoring until rescue therapies are required) strategy in adults with chronic immune thrombocytopenia (ITP).
Study Design: The decision tree is designed to estimate the total cost per response for romiplostim, eltrombopag, and watch and rescue over a 24-week time horizon; cost-effectiveness was evaluated in terms of incremental cost per additional responder.
Methods: Model inputs including response rates, bleeding-related episode (BRE) rates, and costs were estimated from registrational trial data, an independent Bayesian indirect comparison, database analyses, and peer-reviewed publications. Costs were applied to the proportions of patients with treatment response and nonresponse (based on platelet count). The total cost per response and the incremental cost per additional responder for each treatment were calculated. Sensitivity analyses and alternative analyses were performed.
Results: With higher total costs and greater treatment efficacy, romiplostim and eltrombopag had a lower 24-week cost per response and a lower average number of BREs than watch and rescue. Eltrombopag was weakly dominated by romiplostim. The incremental cost-effectiveness ratio of romiplostim versus watch and rescue was $46,000 per additional responder. The model results are most sensitive to response rates of romiplostim and watch and rescue and the BRE rate for splenectomized nonresponders. Alternative analyses results were similar to the base case.
Conclusions: In adults with chronic ITP, romiplostim represents an efficient way to achieve response, with lower costs per response than eltrombopag; both romiplostim and eltrombopag had lower costs per response than watch and rescue.
Am J Manag Care. 2018;24(Spec Issue No. 8):SP294-SP302Takeaway Points
Chronic immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count and increased risk of bleeding. Two thrombopoietin-receptor agonists (TPO-RAs), romiplostim (once-weekly subcutaneous injection)1 and eltrombopag (once-daily oral agent),2 are indicated for the treatment of adults with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.1-4 In clinical practice, patients are sometimes monitored until rescue therapies, like intravenous (IV) immunoglobulin, are required, commonly referred to as the “watch-and-rescue” strategy.
Although some patients undergo splenectomy to treat their ITP, nonsplenectomized patients account for the majority of adult patients with ITP seen by clinical practices in the United States.5 The primary goal of ITP therapy is to help achieve a platelet count that prevents major bleeding.6 Both of the available TPO-RAs have been shown to increase and maintain platelet counts3,4 and reduce the incidence of bleeding-related episodes (BREs). A BRE is defined as the occurrence of a bleeding event and/or use of rescue therapy, including intravenous immunoglobulin (IVIg), anti-D, corticosteroids, platelet transfusions, and dosage increases.7,8 There is limited evidence related to the economics of TPO-RA therapy currently available in published literature.9,10 This analysis was designed to evaluate the cost-effectiveness (in terms of incremental cost per additional responder) and cost per treatment response of the 2 TPO-RAs and the watch-and-rescue strategy for treating adults with chronic ITP in the United States.
Overview and Model Structure
The target patient population consists of both splenectomized (51%) and nonsplenectomized (49%) adults with chronic ITP. Model comparators included romiplostim, eltrombopag, and watch and rescue. The model was developed in Microsoft Excel 2010 using Visual Basic for Applications (Microsoft Corp; Redmond, Washington).
The model begins with the decision to treat patients with ITP with either romiplostim or eltrombopag or to adopt the watch and rescue strategy. The analysis was based on a decision tree that stratified patients into response or no response, followed by the presence or absence of a BRE (Figure 1). Costs were applied to each group of patients in the decision tree. The patients were followed over a 24-week time horizon, consistent with the trial durations for romiplostim and eltrombopag.3,4 For each strategy, the average number of BREs, BRE costs, percentage of patients who responded, and total costs, including drug, physician, and lab test costs, were estimated. The total cost per response for each treatment was calculated. Cost-effectiveness was evaluated in terms of incremental cost per additional responder from the US payer perspective.
Treatment Response Rates
Overall platelet response was defined in the romiplostim trials as the percentage of patients with a platelet count ≥50 × 109/L for at least 4 weeks during the trial, excluding responses within 8 weeks after use of rescue medications.3,11 Overall platelet response was defined in the eltrombopag trial as the percentage of patients: (1) with a platelet count of 50-400 × 109/L for at least 4 consecutive weeks during treatment, including all data up to time of withdrawal for patients who prematurely withdrew, excluding responses during rescue treatment and up to the time platelet counts fell below 50 × 109/L after cessation of rescue treatment; or (2) with a platelet count of 50-400 × 109/L for at least 6 of the last 8 weeks of treatment, excluding premature withdrawals and patients using rescue therapy at any time on treatment.11-13 In the model, treatment response was defined by overall platelet response based on the number of weeks with a platelet count ≥50 × 109/L. The response rates for romiplostim were estimated using trial data.3,13 The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Task Force on Indirect Treatment Comparisons Good Research Practices report suggests that data from head-to-head trials are preferred in economic evaluations of active comparators; in the absence of these data, evidence from an indirect treatment comparison may be considered.14 The results from an independent Bayesian indirect comparison analysis suggested that the overall response rate with romiplostim was significantly higher than with eltrombopag (odds ratio [OR], 0.15).11 Accordingly, the eltrombopag response rates (51.9% for nonsplenectomized and 35.5% for splenectomized patients) were estimated using the romiplostim response rates (87.8% for nonsplenectomized and 78.6% for splenectomized patients) and the OR of 0.15 estimated from Cooper et al.11 The watch-and-rescue response rates for nonsplenectomized and splenectomized patients of 14.5% and 4.8%, respectively, were estimated from pooled placebo response rates.3,4 Response rates are presented in Table 1 [part A and part B].1-4,8,11,15-18
A BRE was defined as a discrete and identifiable event of bleeding and/or the use of rescue therapy occurring within close proximity of one another (3 days).8 A composite end point, such as a BRE, tends to be more clinically relevant because the bleeding events in phase 3 trials are likely to be confounded by increased use of rescue medication in the placebo arms.8 According to Weitz et al, applying the BRE method to the romiplostim trial shows that treatment was associated with a reduction in the rate of unique clinical episodes related to bleeding compared with placebo. In the model, BREs were estimated from a post hoc analysis of 2 phase 3 placebo-controlled studies of romiplostim in patients with chronic ITP and were calculated by pooling the placebo and romiplostim data.8 BREs were assumed to depend on response and splenectomy status only. Because there were no published BRE data for eltrombopag, BRE rates were assumed to be the same as those for romiplostim and watch and rescue (Table 1).
Wholesale acquisition costs of eltrombopag (tablet strengths, 12.5 mg, 25 mg, 50 mg, and 75 mg) and romiplostim were obtained from the EncoderPro database.15 Although the romiplostim prescribing information indicates that the maximum weekly dose of romiplostim is 10 mcg/kg per week,1 in clinical trials of romiplostim, the maximum allowed dose was 15 mcg/kg per week.3 Accordingly, in the base-case analysis, the maximum weekly dose of romiplostim was allowed to exceed 10 mcg/kg and an alternative analysis limiting the maximum weekly dose to 10 mcg/kg was also performed. It was assumed that patients in the watch and rescue treatment arm do not incur drug acquisition costs. Drug acquisition costs and dosing parameters for romiplostim and eltrombopag are presented in Table 1.
In the real-world setting, patients are on different tablet strengths of eltrombopag. Therefore, the proportions of patients utilizing the various eltrombopag tablet strengths were estimated from published literature (21.5% on 25 mg, 37.5% on 50 mg, and 41.0% on 75 mg).4 The average cost of eltrombopag ($4.008 per mg) was estimated by calculating a weighted average of the unit costs and proportion of patients on each tablet strength. Patients on romiplostim incurred a weekly drug acquisition cost, whereas patients on eltrombopag incurred a daily drug acquisition cost. Both responders and nonresponders were assumed to receive treatment for the entire model horizon and accordingly incurred 24 weeks of drug costs.
The average treatment cost per BRE (Table 1) was estimated from a retrospective study of a large US administrative healthcare claims database that was sponsored by Amgen.16 Adult patients with newly diagnosed ITP were identified between the years 2007 and 2012 by having at least 2 outpatient claims separated by at least 30 days or 1 inpatient claim with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code 287.31 for primary ITP. A BRE was defined as ≥1 actual bleeding event and/or use of rescue therapy (IV immunoglobulin and anti-D; IV steroids; and/or platelet transfusion). In the study, Lin et al did not consider an increase in dose or frequency of a concurrent ITP medication as rescue therapy. Average BRE costs for both nonsplenectomized and splenectomized patients were estimated; however, due to the high variability of the estimates, the difference in BRE costs between the 2 patient groups was not statistically significant. Therefore, the average total cost among both splenectomized and nonsplenectomized patients was used in the base-case analysis.16
The costs and frequency of physician office visits for administration of romiplostim and monitoring patients with chronic ITP, platelet count tests for patient monitoring, and hepatic function panels for patients on eltrombopag are also presented in Table 1.1,2,17,18 The total costs of physician office visits and lab tests were calculated by multiplying the frequency of testing by the time horizon and the cost of individual visits. All cost estimates are presented in 2015 US dollars.
In the model, the total costs at 24 weeks, proportion of patients with response, and average number of BREs were calculated for each comparator. The 24-week cost per response for each comparator was calculated by dividing the total cost at 24 weeks by the proportion of patients with response. The cost-effectiveness of the 2 TPO-RAs and the watch and rescue strategy for treating adults with chronic ITP in the United States was evaluated in terms of incremental cost per additional responder. An alternative analysis was also performed using incremental cost per BRE avoided as the outcome of interest.
When conducting cost-effectiveness analyses (CEAs), if a strategy is both more costly and less effective compared with an alternative strategy, then it is said to be dominated by the alternative strategy and no incremental cost-effectiveness ratio (ICER) is calculated.19,20 If a more costly strategy provides additional benefit, then the 2 strategies are compared by dividing the additional cost (ie, incremental cost) by the additional benefit (ie, incremental effectiveness).19,20 Weak dominance (also called extended dominance) occurs when the ICER for a strategy is greater (ie, the strategy is less cost-effective) than that of a more costly alternative.19-21 Strategies that are weakly dominated are excluded, and then ICERs of the remaining strategies are recalculated.19,20 Given the 24-week time horizon of the model, costs and outcomes were not discounted.
Deterministic, or 1-way, sensitivity analyses (DSAs) were performed to assess how changes in key model parameters, and parameter uncertainty, impact cost-effectiveness results. In the sensitivity analyses, parameters were varied using 95% CIs derived from the clinical trial data or database analyses (Table 1). The model was analyzed with each parameter varied individually to its corresponding upper or lower limit, and results were calculated. Results of the DSA are presented visually in the form of tornado diagrams. The DSA was performed with incremental cost per additional responder as the outcome measure. Alternative analyses examining the impact of differing assumptions related to romiplostim dosing, response rates, nonsplenectomized patients, and frequency of platelet count tests and physician visits were also performed.
The total 24-week costs per patient ranged from $19,500 for watch and rescue to $53,300 for romiplostim (Table 222). Compared with the watch and rescue strategy, use of either of the 2 TPO-RAs was associated with fewer BREs and thus a lower BRE treatment cost ($18,800 for watch and rescue; $13,700 for eltrombopag; and $7700 for romiplostim) and was associated with a lower cost per response ($204,400 for watch and rescue; $118,100 for eltrombopag; and $64,200 for romiplostim). With better treatment efficacy, romiplostim was associated with a lower cost per response than eltrombopag. The incremental cost per additional responder is presented in Table 3.22 Eltrombopag was weakly dominated by romiplostim, and the ICER for romiplostim versus watch and rescue was $46,000 per additional responder.
Given that romiplostim and watch and rescue are the 2 strategies on the cost-effectiveness frontier, the DSA was performed comparing romiplostim with watch and rescue only. Results of the DSA indicated that model results were most sensitive to the response rate of patients on romiplostim, the response rate of patients on watch and rescue, and the BRE rate for splenectomized nonresponders (Figure 2). Varying the response rate for patients on romiplostim to the lower and upper bounds of the 95% CI yielded ICERs of $62,100 and $39,200, respectively. Varying the response rate of patients on watch and rescue to the lower and upper bounds of the 95% CI yielded ICERs of $41,700 and $58,200, respectively. Varying the BRE rate for splenectomized nonresponders to the lower and upper bounds of the 95% CI yielded ICERs of $47,800 and $43,900, respectively.
Results of all alternative analyses are presented in Table 2 (cost per response), Table 3 (incremental cost per additional responder), and Table 4 (incremental cost per BRE avoided). When a maximum dosage of 10 mcg/kg/week for romiplostim (ie, with top-coding) was considered and the corresponding response rate was included in the analyses, the cost per response for romiplostim increased from $64,200 (base-case) to $65,500 and the cost per response for eltrombopag increased from $118,100 (base-case) to $130,600. The cost per response for watch and rescue remained unchanged. The ICER for romiplostim versus watch and rescue was $47,000 per additional responder; eltrombopag was weakly dominated by romiplostim.
When the eltrombopag response rates were estimated using registrational trial data, the cost per response for eltrombopag decreased from $118,100 (base-case) to $73,100, and the cost per response results for the other strategies remained unchanged. As in the base-case analysis, eltrombopag was weakly dominated by romiplostim and the ICER for romiplostim relative to watch and rescue did not change from the base-case result.
When the patient population was limited to nonsplenectomized patients only, results were similar to those of the base-case analysis. The incremental cost per additional responder for romiplostim relative to watch and rescue was $47,200; eltrombopag continued to be weakly dominated by romiplostim. Cost per response estimates were $118,600 for watch and rescue, $94,300 for eltrombopag, and $59,000 for romiplostim.
When the frequency with which patients received platelet count tests and physician visits was increased to weekly during weeks 5 to 24, the cost per response for romiplostim increased from $64,200 (base-case) to $65,600; the cost per response for eltrombopag increased from $118,100 (base-case) to $120,900; and the cost per response for watch and rescue increased from $204,400 (base-case) to $216,900. The incremental cost per additional responder for romiplostim relative to watch and rescue remained unchanged from the base case; eltrombopag continued to be weakly dominated by romiplostim.
When the watch and rescue patients were not assigned costs for physician visits and platelet test counts throughout the 24-week period, the cost per response for watch and rescue decreased from $204,400 (base-case) to $196,900, and the cost per response results for the other strategies remained unchanged. The incremental cost per additional responder for romiplostim relative to watch and rescue increased from $46,000 (base-case) to $47,000, and eltrombopag continued to be weakly dominated by romiplostim.
When the eltrombopag response rates were estimated from Bussel et al,22 eltrombopag was weakly dominated by romiplostim and the incremental cost per additional responder for romiplostim relative to watch and rescue did not change from the base-case result. The cost per response for eltrombopag decreased from $118,100 (base case) to $82,200, and the cost-per-response results for the other strategies remained unchanged. Additionally, when the eltrombopag response rates were varied according to the lower and upper bounds of the CIs for the base case scenario (20.18% to 55.24% for splenectomized patients; 28.85% to 75.77% for nonsplenectomized patients), eltrombopag remained weakly dominated by romiplostim. Accordingly, the ICER for romiplostim relative to watch and rescue remained unchanged from the base-case scenario.
Lastly, when cost-effectiveness was assessed in terms of incremental cost per BRE avoided (Table 4), the ICER for romiplostim relative to watch and rescue was $18,300, and eltrombopag was weakly dominated by romiplostim.
The cost per response and the incremental cost per additional responder were evaluated for 2 TPO-RA treatments and a watch and rescue strategy in both splenectomized and nonsplenectomized adults with chronic ITP. The use of either TPO-RA resulted in lower costs per treatment response and fewer BREs than the watch and rescue strategy. In the base-case analysis, eltrombopag was weakly dominated by romiplostim and the ICER of romiplostim relative to watch and rescue was $46,000 per additional responder. DSA results suggest that model results are most sensitive to the response rates of romiplostim and the watch and rescue strategy, as well as the BRE rate for splenectomized nonresponders.
Results of alternative analyses examining (1) a maximum dosage of 10 mcg/kg/week for romiplostim (ie, with top-coding) and corresponding response rate, (2) eltrombopag response rates estimated using registrational trial data, (3) nonsplenectomized patients only, (4) additional platelet count tests and physician visits for patients on all treatments, (5) zero platelet count tests and physician visits for patients on the watch and rescue strategy, and (6) eltrombopag response rates estimated from Bussel et al22 yielded similar results to the base case. An alternative analysis examining the incremental cost per BRE avoided found that eltrombopag was weakly dominated by romiplostim and the ICER of romiplostim relative to watch and rescue was $18,300.
Results of this analysis should be interpreted in light of the following assumptions and limitations. The efficacy of eltrombopag was estimated using an OR obtained from an independent Bayesian indirect comparison performed by Cooper et al,11 who noted that the clinical trials included in the analysis may have differed in terms of study population and design.23 Despite these differences, Cooper et al concluded that the romiplostim and eltrombopag clinical trials included in the indirect comparison were sufficiently similar. Nonresponders were assumed to continue treatment for 24 weeks, which may overestimate drug costs. BRE rates were assumed to depend on platelet levels, independent of whether patients were on active TPO-RA treatment or watch and rescue. Adverse events were not included in the model due to limited evidence in the literature. Rituximab was not included in the model due to inconsistent use in treatment and the identification of literature to determine doses per patient that prevent bleeding events or predict a response. In the model, patients on watch and rescue were assumed to incur zero medication costs; however, in the real-world setting, patients might be receiving concurrent medication other than the TPO-RAs. Therefore, the model is likely to underestimate the total costs for patients on watch and rescue. There are currently no well-established willingness-to-pay thresholds for the incremental cost per additional responder in this clinical context; accordingly, it is ultimately up to the payer to determine whether TPO-RAs are cost-effective in the treatment of ITP. Finally, patients receiving TPO-RAs were assumed to be 100% compliant according to product labels. The eltrombopag prescribing information states that, due to drug—drug and drug–food interactions, patients must not take or ingest any antacids, dairy products, or mineral supplements within 4 hours of administration.2 Noncompliance with these recommendations would cause a significant reduction of eltrombopag bioavailability,2 consequently impacting the efficacy of the drug. According to the results for other drugs with similar drug—drug and drug–food interactions,24,25 in which noncompliance was about 30%, it is unlikely that patients will be 100% compliant; however, data on eltrombopag compliance are not currently available.
In adults with chronic ITP, romiplostim represents an efficient way to achieve response, with lower costs per response than eltrombopag and watch and rescue. Eltrombopag was weakly dominated by romiplostim, and the ICER for romiplostim versus watch and rescue was $46,000 per additional responder.
The authors would like to acknowledge Mark Bensink of Amgen, Inc, for his contribution to this manuscript.Author Affiliations: Optum (KF, AP), Boston, MA; Amgen, Inc (XL, AS, XZ, MC, XW, KC, ME, DC), Thousand Oaks, CA; Pharmerit International (JL), Bethesda, MA; Creative-Ceutical (RZ), Chicago, IL.
Source of Funding: Funding for this study was provided by Amgen, Inc. The role of Amgen, Inc, as study sponsor included the provision of data and review of and comment on the draft and final manuscript.
Author Disclosures: Ms Fust reports employment with Optum and a paid consultancy to Amgen, Inc, which commercializes romiplostim, 1 of the 2 TPO-RAs under discussion in this manuscript, at the time of the study. Dr Parthan reports employment with Optum, which received funding from Amgen to conduct the study. Dr Li reports employment with and stock ownership in Amgen during study development. Dr Zhang reports employment with Amgen. Dr Campioni, Ms Cetin, Dr Eisen, and Dr Chandler report employment with and stock ownership in Amgen. Dr Lin reports employment with Amgen during study development. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Prior Presentation: Results of this analysis for nonsplenectomized patients only were presented at the 57th Annual Meeting of the American Society of Hematology (Orlando, FL; December 2015). Results including splenectomized patients have not been presented or published previously.
Authorship Information: Concept and design (KF, AP, XL, XZ, MC, JL, KC, ME, DC); acquisition of data (DC); analysis and interpretation of data (KF, AP, XL, AS, XZ, MC, JL, XW, RZ, KC, ME, DC); drafting of the manuscript (KF, AP, KC, DC); critical revision of the manuscript for important intellectual content (AP, XL, AS, XZ, MC, JL, RZ, KC, ME, DC); statistical analysis (XL, XZ, RZ, ME); obtaining funding (JL); and supervision (AS).
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