Cost-Effectiveness of Thrombopoietin Mimetics in Patients with Thrombocytopenia: A Systematic Review.

OBJECTIVES: Thrombopoietin (TPO) mimetics are a potential alternative to platelet transfusion to minimize blood loss in patients with thrombocytopenia. This systematic review aimed to evaluate the cost-effectiveness of TPO mimetics, compared with not using TPO mimetics, in adult patients with thrombocytopenia. METHODS: Eight databases and registries were searched for full economic evaluations (EEs) and randomized controlled trials (RCTs). Incremental cost-effectiveness ratios (ICERs) were synthesized as cost per quality-adjusted life year gained (QALY) or as cost per health outcome (e.g. bleeding event avoided). Included studies were critically appraised using the Philips reporting checklist. RESULTS: Eighteen evaluations from nine different countries were included, evaluating the cost-effectiveness of TPO mimetics compared with no TPO, watch-and-rescue therapy, the standard of care, rituximab, splenectomy or platelet transfusion. ICERs varied from a dominant strategy (i.e. cost-saving and more effective), to an incremental cost per QALY/health outcome of EUR 25,000-50,000, EUR 75,000-750,000 and EUR > 1 million, to a dominated strategy (cost-increasing and less effective). Few evaluations (n = 2, 10%) addressed the four principal types of uncertainty (methodological, structural, heterogeneity and parameter). Parameter uncertainty was most frequently reported (80%), followed by heterogeneity (45%), structural uncertainty (43%) and methodological uncertainty (28%). CONCLUSIONS: Cost-effectiveness of TPO mimetics in adult patients with thrombocytopenia ranged from a dominant strategy to a significant incremental cost per QALY/health outcome or a strategy that is clinically inferior and has increased costs. Future validation and tackling the uncertainty of these models with country-specific cost data and up-to-date efficacy and safety data are needed to increase the generalizability.

Cost-effectiveness of second-line therapies in adults with chronic immune thrombocytopenia.

Major options for second-line therapy in adults with chronic immune thrombocytopenia (ITP) include splenectomy, rituximab, and thrombopoietin receptor agonists (TRAs). The American Society of Hematology guidelines recommend rituximab over splenectomy, TRAs over rituximab, and splenectomy or TRAs while noting a lack of evidence on the cost-effectiveness of these therapies. Using prospective, observational, and meta-analytic data, we performed the first cost-effectiveness analysis of second-line therapies in chronic ITP, from the perspective of the U.S. health system. Over a 20-year time-horizon, our six-strategy Markov model shows that a strategy incorporating early splenectomy, an approach at odds with current guidelines and clinical practice, is the cost-effective strategy. All four strategies utilizing TRAs in the first or second position cost over $1 million per quality-adjusted life-year, as compared to strategies involving early use of splenectomy and rituximab. In a probabilistic sensitivity analysis, early use of splenectomy and rituximab in either order was favored in 100% of 10 000 iterations. The annual cost of TRAs would have to decrease over 80% to begin to become cost-effective in any early TRA strategy. Our data indicate that effectiveness of early TRA and late TRA strategies is similar with the cost significantly greater with early TRA strategies. Contrary to current practice trends and guidelines, early use of splenectomy and rituximab, rather than TRAs, constitutes cost-effective treatment in adults with chronic ITP.

Cost-effectiveness analysis of rhTPO and rhIL-11 in the treatment of chemotherapy-induced thrombocytopenia in hematological tumors based on real-world data.

BACKGROUND: Chemotherapy-induced thrombocytopenia (CIT) is a common adverse reaction to chemotherapy that can lead to treatment delay, platelet transfusion, thereby increasing treatment costs, reducing chemotherapy effectiveness and affecting prognosis. Based on real-world data, this study analyzed the safety, efficacy, and economic of recombinant human thrombopoietin (rhTPO) and recombinant human interleukin-11 (rhIL-11) in the treatment of CIT in hematological tumors from the perspective of the health care system. METHODS: We retrospectively collected the data of hematological tumor patients treated with rhTPO and rhIL-11 due to thrombocytopenia caused by chemotherapy. The propensity score matching (PSM) method was used to balance the baseline information of the two groups and they were further stratified according to the degree of thrombocytopenia (grade I-II and grade III-IV). The platelet compliance rate at 2 weeks of treatment was used as the efficacy evaluation index, and the cost-effectiveness method was used to evaluate the economic value of the two drugs in the treatment of thrombocytopenia based on drug effectiveness. Univariate and probabilistic sensitivity analyses were performed. RESULTS: A total of 1,571 patients met the inclusion and exclusion criteria, and 476 patients were included after 1:1 PSM. For patients with grade I-II thrombocytopenia, no significant difference in the platelet compliance rate was found between the two groups after 1 and 2 weeks of treatment. The platelet compliance rate in the rhTPO group was higher than that in the rhIL-11 group for patients with grade III-IV thrombocytopenia. Cost-effectiveness analysis (CEA) showed that the incremental cost-effectiveness ratio (ICER) for the rhTPO and rhIL-11 groups was 226,615.8. The ICER value was sensitive to the platelet compliance rate of the two groups, the cost of rhTPO, the cost of platelet transfusion in the rhTPO group. Probabilistic sensitivity analysis showed that when willingness to pay was less than approximately 220,000 yuan, rhIL-11 economy presented 100% better than that of rhTPO. CONCLUSIONS: In CIT treatment for hematological tumors, rhTPO yielded a higher platelet compliance rate than rhIL-11 treatment, especially for patients with grade III-IV thrombocytopenia. However, whether rhTPO has economic advantages still requires further exploration.

The Clinical Efficacy and Economic Benefits of Recombinant Human Thrombopoietin for the Treatment of Chemotherapy or Chemoradiotherapy-Induced Thrombocytopenia.

Even though cytopenia caused by either chemotherapy or radiotherapy is a common complication in cancer patients, chemoradiotherapy remains an essential treatment for the majority of patients. The purpose of this study was to look into the clinical efficacy and cost-effectiveness of recombinant human thrombopoietin (rhTPO) in treating chemo- or chemoradiotherapy-induced grade II, III, and IV thrombocytopenia. From December 2019 to November 2020, 233 lung cancer patients admitted to our hospital with chemotherapy- or chemoradiotherapy-induced thrombocytopenia were enrolled and treated with rhTPO. The study's findings revealed a significant disparity in the use of concurrent chemoradiotherapy in patients with grade II, III, and IV thrombocytopenia. All costs, including rhTPO treatment costs, platelet costs, drug costs, and nondrug costs, tended to rise as the severity of thrombocytopenia increased. In the treatment of chemotherapy or radiotherapy-induced thrombocytopenia, rhTPO has shown good clinical efficacy. In the treatment of grade II thrombocytopenia, rhTPO has a favorable economic evaluation. As a result, early intervention and thrombocytopenia treatment should be provided, which warrants further clinical investigation.

Thrombopoietin receptor agonist discontinuation rates and reasons among patients with immune thrombocytopenia: a study of administrative claims linked with medical chart review.

Administrative claims provide a rich data source for retrospective studies of real-world clinical practice, yet some important data may be inconsistent or unavailable. This study explored factors influencing discontinuation of thrombopoietin receptor agonists (TPO-RAs) among patients with immune thrombocytopenia (ITP), by adding medical chart abstraction for additional details. Adult (≥ 18 years) patients with continuous commercial or Medicare Advantage with Part D health insurance coverage were included. Inclusion criteria were ≥ 1 claim for eltrombopag or romiplostim and ≥ 2 diagnoses of ITP between December 31, 2017, and January 1, 2020. Providers were asked to provide access to medical charts for abstraction. The analyses included only patients who discontinued TPO-RA and described patient characteristics, treatment patterns, platelet values, and reasons for discontinuation. Among 207 ITP patients treated with a TPO-RA, 137 (66%) discontinued treatment during the observation period. The mean TPO-RA treatment duration was 185 days. Mean platelet count at the time of discontinuation was 197 × 109/L. The most common reason for discontinuation was improvement of the patient's condition (42%). Other reasons included worsening of ITP/lack of response (12%), adverse events (12%), and cost-related or social reasons (23%). No reason was reported for 10%. Notably 26% of patients who discontinued remained off all ITP therapy for the remainder of the study, with a mean treatment-free period of 262 days. These results emphasize that some patients with ITP are able to discontinue TPO-RA therapy and achieve durable treatment-free periods.

Systematic literature review and meta-analysis on use of Thrombopoietic agents for chemotherapy-induced thrombocytopenia.

BACKGROUND: Currently, there are no approved options to prevent or treat chemotherapy-induced thrombocytopenia (CIT). We performed a systematic literature review and meta-analysis on use of thrombopoietic agents for CIT. PATIENTS AND METHODS: We searched Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed, EMBASE, ClinicalTrials.gov, and health technology assessments from January 1995 to March 2021 for studies evaluating thrombopoietic agents for CIT, including recombinant human thrombopoietin (rhTPO), megakaryocyte growth and development factor (MGDF), romiplostim, and eltrombopag. Random effects meta-analyses were conducted for efficacy and safety endpoints. RESULTS: We screened 1503 titles/abstracts, assessed 138 articles, and abstracted data from 39 publications (14 recombinant human thrombopoietin, 7 megakaryocyte growth and development factor, 9 romiplostim, 8 eltrombopag, and 1 romiplostim/eltrombopag). Random effects meta-analyses of data from multiple studies comparing thrombopoietic agents versus control (comparator, placebo, or no treatment) showed that thrombopoietic agents did not significantly improve chemotherapy dose delays and/or reductions (21.1% vs 40.4%, P = 0.364), grade 3/4 thrombocytopenia (39.3% vs 34.8%; P = 0.789), platelet transfusions (16.7% vs 31.7%, P = 0.111), grade ≥ 2 bleeding (6.7% vs 16.5%; P = 0.250), or thrombosis (7.6% vs 12.5%; P = 0.131). However, among individual studies comparing thrombopoietic agents with placebo or no treatment, thrombopoietic agents positively improved outcomes in some studies, including significantly increasing mean peak platelet counts (186 x 109/L with rhTPO vs 122 x 109/L with no treatment; P < 0.05) in one study and significantly increasing platelet count at nadir (56 x 109/L with rhTPO vs 28 x 109/L with not treatment; P < 0.05) in another study. Safety findings included thrombosis (n = 23 studies) and bleeding (n = 11), with no evidence of increased thrombosis risk with thrombopoietic agents. CONCLUSION: Our analyses generate the hypothesis that thrombopoietic agents may benefit patients with CIT. Further studies with well-characterized bleeding and platelet thresholds are warranted to explore the possible benefits of thrombopoietic agents for CIT.

Assessment of romiplostim immunogenicity in pediatric patients in clinical trials and in a global postmarketing registry.

Development of first-generation thrombopoietins (TPOs) was halted due to antibodies that neutralized endogenous TPO, causing protracted thrombocytopenia in some patients. The second-generation TPO receptor agonist romiplostim, having no homology to TPO, was developed to circumvent potential immunogenicity. We examined the development of binding and neutralizing antibodies to romiplostim and TPO among pediatric patients with primary immune thrombocytopenia (ITP) in 5 clinical trials and a global postmarketing registry. In the trials, 25 of 280 (8.9%) patients developed anti-romiplostim binding antibodies. The first positive result was detected 67 weeks (median) after romiplostim treatment was initiated. The median romiplostim dose was 8 µg/kg, and the median platelet count was 87 × 109/L. Most patients who developed anti-romiplostim binding antibodies (18 of 25 [72%]) had ≥90% of platelet assessments showing a response. Anti-romiplostim neutralizing antibodies developed in 8 of 280 (2.9%) patients. The development of anti-romiplostim neutralizing antibodies was unrelated to the romiplostim dose, and most patients who developed the antibodies (7 of 8 [88%]) had platelet response. Nine of 279 (3.2%) patients developed anti-TPO binding antibodies, and 1 (0.4%) developed transient anti-TPO neutralizing antibodies. In 8 patients who developed anti-romiplostim neutralizing antibodies, no TPO cross-reactivity was observed. In the postmarketing registry, 3 of 19 (15.8%) patients developed anti-romiplostim binding antibodies; 1 (5.3%) patient developed anti-romiplostim neutralizing antibodies. These results suggest that immunogenicity to romiplostim occurs infrequently in pediatric patients with ITP and is generally not associated with loss of platelet response or other negative clinical sequelae.

Cost-minimization analysis comparing eltrombopag vs romiplostim for adults with chronic immune thrombocytopenia.

BACKGROUND: Promacta (eltrombopag; EPAG) and Nplate (romiplostim; ROMI) have not been compared in head-to-head trials for treatment of chronic immune thrombocytopenia (cITP); however, indirect treatment comparisons have indicated similar efficacy and safety outcomes, and the drugs are generally accepted as therapeutic alternatives. OBJECTIVE: To determine which of the 2 therapies would result in the lowest overall cost from a US health plan perspective, under the assumption of equivalent clinical efficacy and safety. METHODS: A cost-minimization model was developed in Microsoft Excel. The model incorporated only costs that differ between the treatments, including drug acquisition, administration, and monitoring costs, over a 52-week horizon. Average dosing for EPAG and ROMI was taken from the long-term EXTEND trial and from a published metaanalysis of 14 clinical trials, respectively. ROMI is injectable and EPAG is oral, so only ROMI had administration costs. The model assumed patients used 25 mg EPAG tablets and the 250 µg vial size of ROMI. ROMI wastage was included in drug acquisition costs by rounding up average dose to the nearest whole vial. Monitoring requirements were determined from US prescribing information, with platelet monitoring assumed equal, and hepatic panel testing every 4 weeks for EPAG. The model was adjustable to commercial, Medicare, and Medicaid plan perspectives, with optional inclusion of drug wastage, monitoring, or administration costs. RESULTS: The base case used a commercial plan perspective, with average dosing of 51.5 mg/day for EPAG and 4.20 µg/kg/week for ROMI. The analysis found a cost difference per treated patient of $64,770 in favor of EPAG on an annual basis. Breakdown by unique costs for EPAG included drug-acquisition cost of $123,135 and monitoring cost of $705. Breakdown by unique costs for ROMI included drug-acquisition cost of $183,234, with wastage of $63,179 and administration cost of $5,377. Based on a hypothetical commercial plan with 1 million members and an estimated 11 patients with cITP receiving ROMI, potential annual savings for switching all patients from ROMI to EPAG is $712,473 or $0.06 per member per month. EPAG remained the less costly option for all plan types and assumptions. A sensitivity analysis found that the result was most sensitive to drug pricing and wastage inputs. CONCLUSIONS: Because of lower drug-acquisition costs (including drug wastage) and administration costs, treatment of cITP with EPAG is associated with a lower net cost per patient than ROMI. DISCLOSURES: This study was funded by Novartis Pharmaceuticals Corporation. Proudman, Lucas, and Nellesen are employees of Analysis Group, Inc., which received funding from Novartis Pharmaceuticals Corporation to conduct this study. Patwardhan was employed by Novartis Pharmaceuticals Corporation at the time of this study; Allen is an employee of Novartis. This research was presented as an e-poster at the AMCP 2020 Virtual, April 2020.

Ex Vivo Manufacture of Megakaryocytes and Platelets from Stem Cells: Recent Advances Toward Transfusion in Humans.

The generation of ex vivo functional megakaryocytes (MK) and platelets is an important issue in transfusion medicine as donor dependence implies in limitations, such as shortage of eligible volunteers. Indeed, platelet transfusion is still a procedure that saves the lives of patients with defective platelet production. Recent technological development has enabled the isolation and expansion of stem cells that can be used as a source for the production of functional platelets for transfusion. In this review, we discuss recent approaches of in vitro or ex vivo production of MK and platelets, suggesting that, in the near future, donor-independent sources may become a possibility. The feasibility of using these cells in the clinic may be safer, and in vitro manipulation could generate universally compatible products, solving problems related to platelet refractoriness. However, functionality and survival testing of these products in human beings are scarce; therefore, additional studies are needed to consolidate this purpose.

Successful treatment of refractory secondary immune thrombocytopenia (antiphospholipid antibody syndrome-associated) with the combination of rituximab and romiplostim at the cost of severe bone pain: A case report and review of literature.

INTRODUCTION: Immune thrombocytopenia is an autoimmune disorder associated with increased thrombocyte destruction and impaired production in the bone marrow. Proposed mechanisms include an antibody or autoreactive T-cell-associated autoimmunity and thrombopoietin deficiency among others. Clinical manifestations are predominantly mucocutaneous hemorrhages including petechiae, purpura, mucosal bleeding in the urinary or the gastrointestinal tracts, menorrhagia, and epistaxis. The purpose of the treatment is to prevent bleeding rather than normalizing the platelet counts. First-line treatments include corticosteroids ± intravenous immunoglobulin and Anti-D which mainly decrease antibody-mediated platelet destruction and increase the number of peripheral Tregs. Second-line and subsequent therapies include splenectomy, chimeric anti-CD20 antibody (rituximab), which eliminates B cells and act as an immunomodulatory agent, and Thrombopoietin receptor agonists (romiplostim), which promote platelet production. CASE REPORT: We describe a 40-year-old male patient diagnosed with immune thrombocytopenia that was refractory to first-line corticosteroid and intravenous immunoglobulin and second-line romiplostim monotherapy treatments.Management and outcome: The patient was given the romiplostim and rituximab combination which not only successfully treated thrombocytopenia but also resulted in grade 3 bone pains and the patient's subsequent refusal to continue therapy. DISCUSSION: Common adverse effects of rituximab are infusion reactions and prolonged immunosuppression; those of romiplostim include thrombosis, headaches, arthralgia-myalgia, and gastrointestinal symptoms. This case shows that romiplostim has not caused any discernible side effects when given alone, while combination with rituximab resulted in severe bone and joint pains. We hypothesize that this combination regimen shows a synergistic effect both in terms of efficacy and adverse-effect probability and/or severity.

Cost-per-responder analysis for eltrombopag and rituximab in the treatment of primary immune thrombocytopenia in Spain.

OBJECTIVE: Splenectomy, thrombopoietin receptor agonists and rituximab are  the second-line treatments for steroid-resistant adult primary immune  thrombocytopenia. The last two are becoming the most widely used treatments  to avoid splenectomy adverse effects and inconveniences. However, the choice  between rituximab and thrombopoietin receptor agonists is unclear. Therefore,  the treatment cost may be of particular interest to prioritize the therapy option.  Our aim is to determine the cost per responding-patient after 6 months of use of rituximab compared to thrombopoietin receptor agonists eltrombopag in the  treatment of chronic primary immune thrombocytopenia in the Spanish National  Health Service. METHOD: A 26-week decision tree model was developed to assess the cost of  treatment response of adult patients with chronic-refractory primary immune  thrombocytopenia to eltrombopag and rituximab from the perspective of the  Spanish National Health System. Effectiveness was obtained from the literature,  and cost was obtained from the official rates. Costs were expressed in € (2018).  Due to the short period of assessment, no discount rate was applied. RESULTS: The average cost per patient after 6 months of treatment was slightly  higher for eltrombopag (€13,089.40) than for rituximab (€11,852.60). However, the greater response rate of eltrombopag decreases the bleeding costs, resulting in a 29% higher cost per responding-patient with rituximab (€18,964.15) than  for eltrombopag (€14,732.65). This result is consistent with the results of the 15 sensitivity analyses carried out where eltrombopag always represents a lower  cost per responding patient, except in the sensitivity analysis in which treatment with eltrombopag is performed at its maximum dose (75mg). Only in this case,  the cost per responder of eltrombopag is €48 more expensive than that of  rituximab. Likewise, the greatest difference in favor of eltrombopag occurs in the scenario that uses the minimum dose of this drug -25mg- (eltrombopag  €7,622.14 compared to €18,964.15 for rituximab). Thus, the cost per  responding patient is lower in eltrombopag even if a second cycle of retreatment with rituximab is not performed (€14,732.65 versus €15,298.61). CONCLUSIONS: The treatment cost of rituximab, including monitoring and bleeding costs, is higher than eltrombopag, favoring the latter over  rituximab treatment.

Objetivo: La esplenectomía, los agonistas del receptor de trombopoyetina y el  rituximab son los tratamientos de segunda línea para la trombocitopenia inmune primaria. Los dos últimos se están convirtiendo en los más utilizados para evitar  los efectos adversos de la esplenectomía. Sin embargo, la elección entre ambos  no está clara. El coste puede ser de interés para priorizar el tratamiento.  Nuestro objetivo es determinar el coste por paciente respondedor después de 6  meses de tratamiento de la trombocitopenia inmune primaria crónica con  rituximab frente al agonista del receptor de trombopoyetina eltrombopag en el  Sistema Nacional de Salud español.Método: Se desarrolló un modelo de árbol de decisión de 26 semanas para  evaluar el coste de la respuesta al tratamiento con eltrombopag y rituximab en  pacientes adultos con trombocitopenia inmune primaria crónica refractaria a  esteroides. Debido al corto periodo de evaluación, no se aplicó tasa de  descuento.Resultados: El coste medio por paciente tras 6 meses de tratamiento fue  ligeramente superior para eltrombopag (13.089,40 €) que para rituximab  (11.852,60 €). Sin embargo, la mayor tasa de respuesta de eltrombopag disminuye los costes de hemorragia, lo que se traduce en un coste por paciente  respondedor un 29% mayor con rituximab (18.964,15 €) que con eltrombopag  (14.732,65 €). Este resultado concuerda con los de los 15 análisis de  sensibilidad realizados, donde eltrombopag siempre representa un menor coste  por paciente respondedor, excepto cuando el tratamiento con eltrombopag se  realiza en su dosis máxima (75 mg). Sólo en este caso, el coste por respondedor a eltrombopag es 48 € más caro que el del rituximab. En coherencia con lo  anterior, la mayor diferencia a favor de eltrombopag se da en el escenario que  utiliza la dosis mínima de éste ­25 mg­ (eltrombopag 7.622,14 € frente a  18.964,15 € de rituximab). Así, el coste por paciente respondedor es menor en  eltrombopag aunque no se realice un segundo ciclo de retratamiento con  rituximab (14.732,65 € frente a 15.298,61 €).Conclusiones: El coste del tratamiento con rituximab, incluidos los costes de  monitorización y sangrado, es más alto que el de eltrombopag, lo cual favorece  a este último por encima de rituximab.

Assessment of romiplostim immunogenicity in adult patients in clinical trials and in a global postmarketing registry.

Antibodies to first-generation recombinant thrombopoietin (TPO) neutralized endogenous TPO and caused thrombocytopenia in some healthy subjects and chemotherapy patients. The second-generation TPO receptor agonist romiplostim, having no sequence homology to TPO, was developed to avoid immunogenicity. This analysis examined development of binding and neutralising antibodies to romiplostim or TPO among adults with immune thrombocytopenia (ITP) in 13 clinical trials and a global postmarketing registry. 60/961 (6·2%) patients from clinical trials developed anti-romiplostim-binding antibodies post-baseline. The first positive binding antibody was detected 14 weeks (median) after starting romiplostim, at median romiplostim dose of 2 µg/kg and median platelet count of 29.5 × 109 /l; most subjects had ≥98·5% of platelet assessments showing response. Neutralising antibodies to romiplostim developed in 0·4% of patients, but were unrelated to romiplostim dose and did not affect platelet count. Thirty-three patients (3·4%) developed anti-TPO-binding antibodies; none developed anti-TPO-neutralising antibodies. In the global postmarketing registry, 9/184 (4·9%) patients with spontaneously submitted samples had binding antibodies. One patient with loss of response had anti-romiplostim-neutralising antibodies (negative at follow-up). Collectively, anti-romiplostim-binding antibodies developed infrequently. In the few patients who developed neutralising antibodies to romiplostim, there was no cross-reactivity with TPO and no associated loss of platelet response.

The Cost-effectiveness of Eltrombopag for the Treatment of Immune Thrombocytopenia in the United States.

PURPOSE: Eltrombopag was evaluated as a second-line treatment for adult chronic immune thrombocytopenia (ITP) in the 2006 Phase III RAISE (Eltrombopag for Management of Chronic Immune Thrombocytopenia) randomized, placebo-controlled trial. More than 80% of patients reached satisfactory platelet counts within 2 weeks. However, the economic value of eltrombopag as a second-line treatment for ITP remains to be formally assessed. This study aimed to estimate the cost-effectiveness of treating ITP with a comparable thrombopoietin receptor agonist (eltrombopag vs romiplostim). METHODS: A Markov model was implemented over a lifetime time horizon to estimate the benefits and costs of each treatment. The model featured 3 health states based on current guidelines: (1) on treatment; (2) treatment failure/discontinuation; and (3) mortality. In line with therapeutic goals in ITP, model patients could experience 3 events: no bleeding, mild/moderate bleeding, or severe bleeding. Data on eltrombopag use were obtained from an open-label extension of previous Phase II/III trials, including RAISE. Romiplostim data were obtained from Phase III trials and an extension study. Lifetime overall survival was extrapolated by using treatment-specific mortality rates derived from severe bleeding and natural mortality rates. The costs of drugs, routine care, bleeding episodes, adverse events, and mortality were represented in the model. FINDINGS: Eltrombopag-treated patients gained 17.58 life years and 14.68 quality-adjusted life years, whereas romiplostim-treated patients gained 17.52 life years and 14.67 quality-adjusted life years. The total lifetime cost of eltrombopag treatment was estimated at $1.58 million versus $2.13 million for romiplostim. Sensitivity analyses supported base case findings. Deterministic sensitivity analysis predicted the greatest sensitivity to the rates of severe bleeding, discontinuation, and natural mortality. Probabilistic sensitivity analysis showed that eltrombopag would be an efficient use of resources at a $50,000 threshold in 52.8% of cases. In all probabilistic iterations, the total cost of eltrombopag treatment was lower than with romiplostim, primarily because of lower drug costs. IMPLICATIONS: Clinical data were applied in an economic analysis, and eltrombopag exhibited economic dominance compared with romiplostim, driven largely by the reduced costs of primary therapy. This model was limited by a lack of specific patient-level data and robust data on the duration of secondary therapy, as well as by the fact that utilization values are likely conservative estimates for routine care use.

Assessment of Self-Administration of Romiplostim in Patients with Immune Thrombocytopenic Purpura after Receipt of Home Administration Training Materials: a Cross-Sectional Study.

INTRODUCTION: Romiplostim is a subcutaneously administered thrombopoietin-receptor agonist approved in the European Union for self-administration (or administration by a caregiver) in selected adult patients with chronic primary immune thrombocytopenia refractory to other treatments. To mitigate the risk of medication errors due to self-administration, the manufacturer has implemented additional risk minimisation measures (RMM) in the form of a Home Administration Training (HAT) pack to support the training of both healthcare professionals (HCPs) (guide and checklist for patient selection and training) and patients (a preparation mat, quick guide booklet, step-by-step guide, self-administration diary and DVD/video). OBJECTIVE: The primary objective was to estimate the proportion of patients/caregivers who administered romiplostim correctly after HAT pack training. METHODS: A multicentre observational study was conducted to evaluate the effectiveness of the HAT pack by recording data on a standardised collection form during direct observation of patients/caregivers in the act of administering romiplostim at the first standard-of-care visit 4 weeks after training with the HAT pack. RESULTS: Among the 40 patients/caregivers enrolled across 12 study centres in eight European countries, 35 [87.5%; 95% confidence interval (CI) 73.9-94.5] administered romiplostim correctly, and five (12.5%; 95% CI 5.5-26.1) did not. CONCLUSION: The correct administration of romiplostim by most patients/caregivers supports the effectiveness of the HAT pack as an additional risk minimisation tool in the population and setting of this study.

Cost per response analysis of strategies for chronic 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.

A decision framework for treating chronic immune thrombocytopenia with thrombopoietin receptor agonists.

Aim: Eltrombopag and romiplostim are comparable second-line therapies in chronic immune thrombocytopenia. Treatment decisions are made in different contexts. A framework was created to outline decision pathways for physicians and payers. Materials & methods: The costs of drugs, administration, routine care, bleeding, other adverse events and mortality were included in the year-long calculation of total costs from a US private payer perspective. Treatment parameters and outcome data were obtained from relevant clinical trials. Results: The total cost per year, per patient of eltrombopag was US$51,000 versus US$76,000 for romiplostim. Drug costs and costs associated with bleeding-related events were the main drivers of cost difference. Conclusion: This framework facilitates decision-making in the management of chronic immune thrombocytopenia with eltrombopag and romiplostim.

Comparative treatment-related adverse event cost burden in immune thrombocytopenic purpura.

AIMS: Real-world evidence on the safety profile and costs associated with immune thrombocytopenic purpura (ITP) treatment in adults is lacking. This study quantifies and compares adverse event (AE) crude rates and costs associated with ITP treatments as found in claims data. MATERIALS AND METHODS: A retrospective claims-based analysis was conducted using IMS Pharmetrics Plus database. Included patients were ≥18 years old, with a diagnosis of ITP (2007-2012); an ITP-related claim for anti-D, intravenous immunoglobulin (IVIG), rituximab, romiplostim, or eltrombopag; and 1-year continuous enrollment (3-years for rituximab) during follow-up. AEs and event costs were identified during active treatment, defined from the first claim of each drug to a pre-defined treatment gap or end of study period. Descriptive statistics were reported with Wilcoxon rank-sum significance tests. RESULTS: A total of 2,518 patients were identified (mean age = 50.8 (±16.3 years); 55.8% male). Of all patients, 22.8% experienced any AE. Significantly fewer anti-D patients had any AE (13.8% vs IVIG: 21.1%, rituximab: 29.4%, romiplostim: 28.1%, eltrombopag: 22.4%). Nausea/vomiting and arthralgia/musculoskeletal pain were most common across treatments, and hemolytic events did not differ significantly across treatments. Most costly AEs were urinary tract infection, aseptic meningitis, and fever ($5000+/case); headache, nasal congestion, and hemolytic event were $4,000-5,000/case. Cost per AE did not differ by treatment. LIMITATIONS AND CONCLUSIONS: Although lower than trial-based AE rates, claims for ITP treatment-related AEs are common, with higher numbers for rituximab and lower numbers for anti-D. This disparity suggests a possible differential cost burden overall that future analysis should explore.

Apreciación crítica del estudio "efectividad y seguridad de romiplostim comparado con eltrombopag para el tratamiento de pacientes con púrpura trombocitopénica inmune que fallaron a otros tratamientos previos" / Critical appraisal of the study "effectiveness and safety of romiplostim compared to eltrombopag for the treatment of patients with immune thrombocytopenic purpura who failed other previous treatments"

INTRODUCCIÓN: La trombocitopenia idiopática (TIP) o púrpura trombocitopénica inmunológica o autoinmune, es un trastorno hemorrágico crónico en el cual existe un aumento de la destrucción de plaquetas y reducción de su producción y supervivencia, llevando a complicaciones hemorrágicas de leves a severas que pueden causar incluso la muerte. El control de la TIP puede lograrse mediante un tratamiento secuencial que va desde el inicio con corticoesteroides, seguido de la esplenectomía, hasta el empleo de inmunosupresores y anticuerpos monoclonales en caso de no respuesta. En Colombia, eltrombopag (Revolade®) está indicado para el tratamiento de TIP crónica a fin de incrementar el recuento plaquetario y reducir o prevenir hemorragias en pacientes con respuesta insuficiente al tratamiento con corticoides o inmunoglobulinas, o que han presentado eventos adversos serios con estos. No obstante, AMGEN Biotecnológica S.A.S. ha nominado romiplostim (Nplate®) como medicamento susceptible de incluirse en el plan de beneficios, basado en evidencia favorable derivada de una evaluación indirecta de efectividad y seguridad de romiplostim comparado con eltrombopag para el tratamiento de TIP. OBJETIVO: Realizar una apreciación crítica del informe de "Efectividad y seguridad de romiplostim comparado con eltrombopag para el tratamiento de pacientes con púrpura trombocitopénica inmune que fallaron a otros tratamientos previos". METODOLOGÍA: Siguiendo la metodología propuesta por el Instituto de Evaluación Tecnológica en Salud (IETS), inicialmente se realizó una reunión con expertos clínicos y pacientes para exponer los resultados que presenta el informe de evaluación de efectividad y seguridad, a fin de discutir los desenlaces y comparadores utilizados y, eventualmente, identificar en consenso posibles omisiones por parte de los autores de la evaluación. Luego se realizó una réplica del protocolo de búsqueda en las diferentes bases de datos de donde se seleccionaron los artículos para el análisis. El objetivo de esta réplica era actualizar la búsqueda ejecutada por los autores de la evaluación, a fin de corroborar su correspondencia con los estudios reportados en el informe e identificar posibles estudios que hayan sido publicados en fecha posterior al periodo contemplado en la evaluación de efectividad y seguridad, y que aporten evidencia relevante. Finalmente se realizó una discusión amplia de los nuevos estudios identificados, así como de las conclusiones derivadas de la reunión con expertos, a fin de sintetizar la evidencia disponible sobre el tema, considerar las particularidades de la práctica clínica en Colombia. RESULTADOS: Pese a que los reportes sobre efectividad y seguridad de romiplostim y eltrombopag son escasos, y no se han realizado comparaciones directas entre ambos medicamentos, existen algunos estudios de buena calidad que demuestran su efectividad para el tratamiento de TIP en adultos. Así mismo, a nivel de seguridad, ambos medicamentos muestran un balance riesgo beneficio favorable. En la evaluación objeto de esta apreciación crítica se utiliza un método potente de comparación indirecta entre romiplostim y eltrombopag. La literatura revisada en dicha evaluación es de alta calidad, de modo que sus resultados se consideran robustos. Los resultados muestran mayor efectividad para romiplostim que para eltrombopag, con un perfil de seguridad relativamente idéntico para los dos medicamentos evaluados. Estos resultados no fueron refutados en el proceso de apreciación crítica. Tras la réplica actualizada del protocolo de búsqueda no se identificó nueva literatura con resultados contrarios a los presentados en el informe de evaluación original. De la reunión con expertos clínicos (hematólogos) y pacientes se determinó que los desenlaces y comparadores utilizados son adecuados y no omiten alternativas relevantes. No obstante, los expertos clínicos refieren que sus pacientes han tenido respuesta positiva al tratamiento de segunda línea tanto con eltrombopag como con romiplostim y que la elección de uno u otro medicamento no obedece a consideraciones de efectividad (pues, en su experiencia, ambas presentan efectividades similares), sino a consideraciones relacionadas con la zona de residencia del paciente y la facilidad de la vía de administración. CONCLUSIONES: Tanto romiplostim como eltrombopag son medicamentos eficaces para el tratamiento de segunda línea de TIP. Pese a que la evidencia disponible muestra una mejor respuesta plaquetaria global con romiplostim, no existe diferencia significativa en el sostenimiento de esta respuesta. Adicionalmente, en la elección de una u otra alternativa de tratamiento deben primar las características clínicas, sociales y preferencias específicas de cada paciente. Romiplostim puede ser más adecuado en pacientes tolerantes a la administración subcutánea y con fácil acceso a centros de salud con personal entrenado para la toma de pruebas de laboratorio previas a la aplicación, de modo que sea posible llevar estricto control del recuento plaquetario, efectos secundarios y características clínicas del paciente para decidir la continuidad o suspensión del medicamento. Eltrombopag, por su parte, por tratarse de un medicamento que se administra por vía oral es más recomendable en pacientes con tripanofobia o que residen en zonas rurales o cabeceras municipales pequeñas y que, por tanto, no tienen acceso a la supervisión de personal de salud entrenado. Se considera que la evaluación original es una evaluación de alta calidad y sus conclusiones son concordantes con lo encontrado en la revisión sistemática pero deben ser interpretadas con precaución, debido a que las mismas se basaron únicamente en los reportes de la literatura internacional y no se tuvo en cuenta el contexto del país, por ejemplo, no se tuvieron en cuenta las ventajas o desventajas inherentes a la vía de administración de los fármacos. Esta tecnología resultaría en una ampliación de las alternativas de tratamiento de TIP en el país, de modo que ello constituye una mejora en el espectro de opciones para los pacientes y, por tanto, se puede mejorar su calidad de vida.(AU)

Apreciación crítica de la evaluación económica de romiplostim como primera línea de tratamiento en pacientes adultos con trombocitopenia inmune primaria (TIP) en pacientes esplenectomizados refractarios a otros tratamientos y como segunda línea / Critical appraisal of the economic evaluation of romiplostim as first line treatment in adult patients with primary immune thrombocytopenia (IPT) in splenectomized patients refractory to other treatments and as second line

INTRODUCCIÓN: El Instituto de Evaluación Tecnológica en Salud ­ IETS mediante el contrato interadministrativo No. 243 de 2016 suscrito con el Ministerio de Salud y Protección Social (MinSalud) acordó realizar una apreciación crítica de las evaluaciones de tecnologías enviadas por terceros. En este contexto, el IETS y el MinSalud definieron llevar a cabo una apreciación crítica de los documentos enviados como soporte para la nominación de cinco tecnologías priorizadas por el MinSalud en el año 2016, y que es un proceso posterior a una evaluación inicial de la calidad de los reportes de dichas evaluaciones. Dentro estas cinco tecnologías priorizadas se encuentra el romiplostim, nominada por Novartis de Colombia S.A. En este documento se presenta una apreciación crítica llevada a cabo sobre la evaluación económica de esta tecnología, titulada Análisis costo-efectividad de romiplostim como primera línea de tratamiento en pacientes adultos con trombocitopenia inmune primaria (TIP) en pacientes esplenectomizados refractarios a otros tratamientos y como segunda línea en pacientes no esplenectomizados en los que la cirugía está contraindicada en Colombia incluyendo lo reportado en el informe enviado. Sin embargo, para esta apreciación crítica no se contó con el modelo analítico que fue utilizado en dicho análisis de costo-efectividad. HORIZONTE TEMPORAL: El análisis se efectúa para un horizonte de toda la vida (se asume un máximo de 65 años, horizonte temporal suficiente para cubrir los costos y los beneficios asociados a los tratamientos). PERSPECTIVA: En el informe se menciona que la perspectiva abordada fue la del sistema de salud colombiano. COMENTARIOS: No se llevó a cabo una revisión de literatura económica que diera cuenta del estado de la investigación acerca de la costo-efectividad del romiplostim, tal y como lo indican las recomendaciones del Manual del IETS. No es claro cómo fueron incorporadas dos poblaciones diferentes dentro del modelo de Markov. No se explican las características de cada estado de salud ni cómo llegaron al diseño del modelo de Markov. El estado de salud "muerte", (de acuerdo con la gráfica que reportan en la evaluación económica) no parece haber sido programado como un estado de salud (y este es, idealmente, el estado de salud absorbente) sino como un evento aleatorio. De manera que no es posible saber si los pacientes salían del modelo, o sí quedaron en un loop dentro de la modelación. No se describió porque la duración de cada ciclo dentro del modelo es de un mes. No se observa un nodo de decisión en la representación gráfica del modelo. Y, de ser probable que el estado de salud "muerte" sí haya sido programado, y que el nodo de azar sí haya sido debidamente identificado y programado, esto no es lo que refleja la gráfica que muestra esta evaluación económica. Esto genera una dificultad al momento de enfrentarse a la lectura del reporte. Se señaló que la edad promedio de los pacientes que entraban al modelo fue de 35 años, pero como se ha mencionado anteriormente, no existe consistencia entre esta información y el horizonte temporal reportado. Es probable que los desarrolladores de esta evaluación económica, al asumir una expectativa de vida de 65 años, solo hayan modelado entonces un horizonte temporal de 30 años. Pero, nuevamente: esa no es la expectativa de vida de la población colombiana y, en caso de ser la expectativa de vida atribuible a un paciente con TIP, esto no fue claramente justificado. La explicación acerca de que los pacientes no respondedores al tratamiento inicial con romiplostim o eltrombopag, podían pasar a un siguiente tratamiento (de manera secuencial hasta agotar el total de alternativas disponibles) o quedar únicamente en observación (con terapia de rescate si era necesario), permite suponer que por ejemplo, tanto "quedar en observación" o "con terapia de rescate" hubieran podido ser estados de salud, pero no se justificó porque solo fueron considerados como eventos aleatorios. No es claro por qué no fueron utilizados los datos del DANE para los datos de mortalidad del modelo, sino que fueron utilizados datos de la Superintendencia Financiera, y no se citó la fuente bibliográfica para esa información. CÁLCULO E INTERPRETACIÓN DE RESULTADOS: El análisis costo-efectividad incremental (RCEI) del uso de Romiplostim vs Eltrombopag se estima empleando como medida de efectividad el tiempo (en años) en respuesta plaquetaria ganados y el costo incremental (ahorro) con el uso de Romiplostim. Resultando en una RCEI dominante. CONCLUSIÓN: Los resultados de esta apreciación crítica permiten concluir que existen limitaciones en el desarrollo metodológico de esta evaluación económica que van en detrimento de la fiabilidad de sus resultados. Con la información presentada en el reporte de esta evaluación no es posible garantizar la replicabilidad de sus métodos. No se ofreció justificación sólida acerca de por qué no se utilizaron AVAC como desenlace principal y, adicionalmente, la información de efectividad de los desenlaces que utilizaron (tiempo en respuesta en años y tiempo de respuesta ganado) contradice los resultados de la evaluación de efectividad y seguridad que desarrolló previamente a la evaluación económica. El reporte de esta evaluación económica tampoco justificó no haber llevado a cabo análisis de sensibilidad determinísticos y probabilísticos. En suma, no es posible obtener una conclusión confiable acerca de la relación de costoefectividad del romiplostim comparado con eltrombopag con la información proporcionada en este reporte de evaluación económica y, en su lugar, se recomienda realizar una evaluación económica de novo que permita determinar si el romiplostim es una alternativa costo-efectiva para el país.

Eficacia y seguridad de eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de medula ósea / Efficacy and safety of eltrombopag in patients with severe medullary aplasia, non-tributary to immunosuppressive triple therapy and bone marrow transplantation

INTRODUCCIÓN: Antecedentes: El presente dictamen responde a la solicitud de evaluación de tecnología sanitaria del uso fuera del petitorio de Eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de médula ósea. Aspectos Generales: La trombopeyetina es un factor humoral o citoquina, el cual estimula la producción de trombocitos (plaquetas), proliferación de megacariocitos de la médula ósea y por ende liberación de plaquetas en un mecanismo llamado trombopoyesis. El rol principal de las plaquetas es proveer la interacción y activación de factores de coagulación en la cascada de coagulación. Los pacientes con anemia aplásica exhiben altos niveles de trombopoyetina y pero aún así presentan trombocitopenia debido a una supresión o falla por parte de la producción de plaquetas en la médula ósea. Tecnología Sanitaria de Interés: Eltrombopag (ETP), Revolade o Promacta (GlaxoSmithKline lnc) es un medicamento agonista del receptor de la trombopoyetina (TPOr) que promueve la diferenciación megacariocítica, la proliferación y la producción de plaquetas. Es un agente hematopoyético que actúa como agonista no peptídico del receptor de la trombopoyetina. Interacciona con el dominio transmembrana e induce a la proliferación y diferenciación de los megacariocitos produciendo, a consecuencia de ello, un incremento en el recuento plaquetario. METODOLOGÍA: Estrategia de Búsqueda: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad de Eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de médula ósea. Para la búsqueda primaria se revisó en primer lugar la información disponible por entes reguladoras y normativas de autorización comercial como la Administración de Drogas y Alimentos (FDA) de Estados Unidos, la Agencia de Medicamentos Europea (EMA) y la Dirección General de Medicamentos y Drogas (DIGEMID) en el Perú. Seguidamente, se emplearon los motores de búsqueda de los metabuscadores Translating Research into Practice (TRIPDATABASE), Epistemonikos y Health Systems Evidence (HSE). Asimismo, se buscó información generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como el National Institute for Health and Care Excellence (NICE) del Reino Unido, National Guideline Clearinghouse (NGC) de Estados Unidos, Canadian Agency for Drugs and Technologies in Health (CADTH) de Canadá, Scottish Medicines Consortium (SMC) de Escocia, Haute Authorité de Santé (HAS) de Francia, el Instituto de Evaluación de Tecnologías Sanitarias (IETS) de Colombia, el Instituto de efectividad clínica y sanitaria (IECS) de Argentina. Finalmente, se realizó una búsqueda dentro de las bases de datos Pubmed, EMBASE, y The Web of Science que a su vez fue complementada con una búsqueda en www.clinicaltrials.gov y www.clinicaltrialsregister.eu. RESULTADOS: Sinopsis de la Evidencia: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de eficacia y seguridad de eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de médula ósea. En la presente sinopsis se describe la evidencia encontrada a la fecha. Guías de práctica clínica: No se encontraron guías de práctica clínica de buena calidad que recomienden eltrombopag en AAS. Evaluaciones de tecnologías sanitarias: El grupo evaluador de NICE revisó este año (2016) la evidencia disponible para AAS con eltrombopag. Sin embargo es observable que tanto la CADTH de Canada, la SMC de Escocia, el IECS Argentina, IETS Colombia, y la HAS de Francia los cuales son referentes internacionales de evaluaciones de tecnologías sanitarias, no han realizado aún evaluaciones ni han emitido recomendaciones para el uso de eltrombopag en AAS. Ensayos clínicos: Se encontraron los ensayos clínicos fase II de Olnes et al., 2012 y Desmond et al., 2014. Ensayos clínicos no-publicados: Se encontraron tres estudios en progreso en la página de clinicaltrials.gov que corresponden a NCT01891994, NCT 01703169, y NCT 02148133. Otros documentos adicionales: Documento de recomendación como Guía de la BCSH. CONCLUSIONES: El presente dictamen responde a la solicitud de evaluación de tecnología sanitaria del uso fuera del petitorio de Eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de médula ósea. Se encontraron dos ensayos clínicos fase II, no-aleatorizados, abiertos y de un solo brazo y tres ensayos clínicos en proceso no-publicados, los cuales evaluaron la respuesta hematológica a eltrombopag en la población de interés. La evidencia generada por éstos contiene limitaciones severas para la interpretación y generalización de los resultados para la población de interés. El Instituto de Evaluación de Tecnologías en Salud e Investigación ­IETSI, aprueba el uso de Eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de médula ósea. La vigencia del presente dictamen preliminar es de un año. En los subsiguientes meses a la publicación del presente dictamen, se evaluará la nueva evidencia publicada en la literatura internacional, y se analizarán los datos clínicos de todos aquellos pacientes que hayan recibido eltrombopag en el contexto del presente dictamen, con el fin de establecer el impacto del mismo. Esta información será tomada en cuenta para actualizar el presente dictamen al culminar su vigencia.