Cost-per-responder analysis comparing romiplostim to rituximab in the treatment of adult primary immune thrombocytopenia in Spain

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Utilidad del vídeo-electroencefalograma precoz" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1085 "Ancho" => 1656 "Tamanyo" => 81779 ] ] "descripcion" => array:1 [ "en" => "Kaplan–Meier survival curves based on EEG in 22 patients. Group 1, intermittent line: EEG of poor prognosis. Group 0, continuous line: EEG of good prognosis or uncertain prognosis. The estimated RR using Cox regression was 2.59 (95% CI: 0.342–19.629; p=ns). 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Marcacuzco Quinto, Alejandro Manrique Municio, Luis C. Jimenez Romero, Carmelo Loinaz Segurola, Jorge Calvo Pulido, Iago Justo Alonso, Alvaro Garcia-Sesma Perez-F, Manuel Abradelo de Usera, Felix Cambra Molero, Oscar Caso M, Enrique Moreno Gonzalez" "autores" => array:11 [ 0 => array:2 [ "nombre" => "Alberto A." "apellidos" => "Marcacuzco Quinto" ] 1 => array:2 [ "nombre" => "Alejandro" "apellidos" => "Manrique Municio" ] 2 => array:2 [ "nombre" => "Luis C." 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Fernanda López, María Eva Mingot, David Valcárcel, Vicente Vicente García, Allison Perrin, Ignasi Campos Tapias" "autores" => array:6 [ 0 => array:3 [ "nombre" => "M. Fernanda" "apellidos" => "López" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "María Eva" "apellidos" => "Mingot" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "David" "apellidos" => "Valcárcel" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Vicente" "apellidos" => "Vicente García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "Allison" "apellidos" => "Perrin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "aff0025" ] ] ] 5 => array:4 [ "nombre" => "Ignasi" "apellidos" => "Campos Tapias" "email" => array:1 [ 0 => "ignasic@amgen.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "f" "identificador" => "aff0030" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:6 [ 0 => array:3 [ "entidad" => "Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Hospital Regional Universitario Carlos Haya, Málaga, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Hospital Vall d’Hebron, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Hospital Universitario Morales Meseguer, Murcia, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "LA-SER Analytica, Nueva York, United States" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Global Health Economics, Amgen (Europe) GmbH, Zug, Switzerland" "etiqueta" => "f" "identificador" => "aff0030" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Coste por paciente con respuesta a romiplostim y rituximab en el tratamiento de la trombocitopenia inmune primaria en España" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2632 "Ancho" => 2174 "Tamanyo" => 162878 ] ] "descripcion" => array:1 [ "en" => "Decision-making flowchart: in this model, squares represent decision nodes, circles represent probability nodes and triangles represent variables." ] ] ] "textoCompleto" => "IntroductionPrimary immune thrombocytopenia, also known as idiopathic thrombocytopenic purpura (ITP), is an acquired autoimmune disease characterised by isolated thrombocytopenia, with a peripheral platelet count <100×109/L. Diagnosis of ITP is made by exclusion when there are no other identifiable causes. The disease is characterised by increased platelet destruction mediated by autoantibodies and a deficiency in their production.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Although incidence rates vary widely in the published literature, ITP is generally considered a rare disease.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> In recent publications, an incidence of 3.9 for every 100,000 persons/year is estimated.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a> The number of affected persons is small, and patients with platelet counts higher than 50×109/L rarely need treatment<a class="elsevierStyleCrossRef" href="#bib0005">1</a>; however, this disorder may have major clinical and economic consequences, especially those related to haemorrhages and the deterioration of quality of life (QoL). Although many patients experience no symptoms or only minor haematomas, other cases may experience severe haemorrhages that may be intracranial, gastrointestinal or extensive mucocutaneous haemorrhages.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In addition, the physical symptoms are the main factor involved in the deterioration of QoL, and patients with ITP obtain bad scores on scales that assess aspects such as discomfort, psychological symptoms, fear, reduced social activity or reduced ability to work.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5</a>Corticosteroids (occasionally administered together with intravenous immunoglobulin [IV Ig]) are the standard first-line of treatment; however, in refractory patients or patients with relapses, the second-line treatment was preferably limited to splenectomy until a few years ago.Romiplostim is a thrombopoietin receptor agonist indicated for splenectomised adult patients with chronic ITP who are refractory to other medications (such as corticosteroids and IV Ig), or as a second-line treatment for non-splenectomised adult patients for whom surgery is contraindicated.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Thrombopoietin receptor agonists increase platelet production through the activation of the thrombopoietin receptor, which is the key mediator of platelet production.<a class="elsevierStyleCrossRefs" href="#bib0005">1,7</a> Rituximab, a chimeric anti-CD20 monoclonal antibody, is indicated in adult patients with non-Hodgkin's lymphoma, chronic lymphocytic leukaemia and rheumatoid arthritis,<a class="elsevierStyleCrossRef" href="#bib0040">8</a> and, although it is not indicated in the manufacturer's technical data sheet, it is frequently used as a second-line treatment in adults with ITP.<a class="elsevierStyleCrossRefs" href="#bib0005">1,7</a> Its main mechanism of action is characterised by a depletion of B lymphocytes with CD20+, which are involved in platelet destruction, mediated by immune mechanisms through the production of antiplatelet autoantibodies.It has been reported that the treatment of chronic ITP in adults is expensive, particularly in patients with a severe form of the disease.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> At present, the cost-consequence ratio of romiplostim and rituximab in patients with ITP in Spain is unknown. This has prompted us to conduct this analysis in order to assess clinical and economic implications and, in particular, to estimate the response rate and cost per patient for these two agents.MethodsStructure of the economic modelA cost-consequence model was designed (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) to compare the total direct costs of patients treated with romiplostim and rituximab. The parameters of the model considered drug costs, treatment duration, effectiveness of therapeutic alternatives and the use of healthcare resources. The cost-consequence analysis was chosen to present the results in a disaggregated manner, which allows the observer to independently assign the importance of the consequences for each alternative. These analyses are becoming more highly appreciated and are being applied more often in countries where the number of health technology assessments are increasing; in addition, they are usually more comprehensible to healthcare decision-makers compared to other types of pharmacoeconomic analyses.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> The model was developed from the perspective of the Spanish National Healthcare System; therefore, only direct health costs were considered. The results and costs of patients (refractory to the first-line treatment) treated with romiplostim or rituximab were assessed. Splenectomy was not considered a third alternative in the decision-making process, since those patients, who were suitable candidates for splenectomy, would already have undergone the procedure. The analysis aimed at assessing the costs associated with each treatment intervention, including drug costs, medical visits, laboratory tests and costs related to treatments for bleeding-related episodes (BRE) in patients who did not respond. The proportion of patients whose platelet response was attributable to either of the treatments was determined 8 weeks following the start of treatment, based on international treatment guidelines.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> As described by Weitz et al.,<a class="elsevierStyleCrossRef" href="#bib0055">11</a> based on a pooled data analysis of the romiplostim and placebo groups in the pivotal romiplostim trials, the patients who did not respond experienced BREs, which agglutinated the patients with bleeding episodes and those who needed rescue medication. The severity of a BRE was defined by the need for hospitalisation and the use of rescue medication.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> The BREs were classified as ambulatory BREs and BREs that required hospitalisation. For the 18-week period contemplated in the model (the period in which patients were classified depending on whether or not they responded to the treatment), the risk of BREs was calculated using the number of BREs and the number of weeks per patient of follow-up.<a class="elsevierStyleCrossRef" href="#bib0055">11</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Clinical informationTo obtain the platelet response (defined as ≥50×109platelets/L<a class="elsevierStyleCrossRef" href="#bib0005">1</a>), duration of the response, sample size, security profile, stratification among splenectomised and non-splenectomised patients and the characteristics of the population, a systematic review of the medical literature was performed with the aim of identifying randomised, controlled, phase III clinical trials of rituximab and romiplostim in the treatment of adult patients with ITP published from 2000 to January 2011. The databases consulted for the review of the medical literature were MEDLINE, EMBASE, EMBASE Alert, BIOSIS Previews, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Derwent Drug File, Health Technology Assessment Database and SciSearch. Clinical trials, comparative studies, observational studies, systematic reviews and meta-analyses published in English were included. The keywords used in the search of the medical literature appear in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Two independent reviewers (along with a third reviewer for conflict resolution) assessed the titles, abstracts and articles retrieved from searches and excluded irrelevant publications based on the following exclusion criteria: publications not about ITP; those related to immune thrombocytopenia secondary to a disease, non-specific for rituximab or romiplostim; reports that were not published in the English language; paediatric studies; publications of case reports/letters to the publisher with no abstracts available; duplicate publications; laboratory research; and economic studies or studies on QoL.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Economic informationUse of drugsThe romiplostim dosage consisted of one subcutaneous injection of 250μg once a week until a response to treatment was observed. The rituximab dosage consisted of a cycle of four weekly doses of 375mg/m2. The required doses for each drug were estimated based on an average patient weight of 76.23kg12 and height of 161.57cm,<a class="elsevierStyleCrossRef" href="#bib0060">12</a> resulting in a body surface area (calculated according to the DuBois and DuBois formula<a class="elsevierStyleCrossRef" href="#bib0065">13</a>) of 1.81m2.A sustained platelet response is not always obtained after the first cycle of rituximab.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In a retrospective study of patients with ITP performed at a hospital in France,<a class="elsevierStyleCrossRef" href="#bib0070">14</a> 28.57% of the responder patients and 36.36% of the patients who did not respond to rituximab received an additional cycle of this drug. Based on that study, a second cycle of rituximab with the mentioned percentages was administered 6 months after the beginning of the treatment in this model.Use of medical resources<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the details of the frequency of visits to health professionals, the laboratory tests and the visits for the administration of romiplostim and rituximab. The frequency of BREs, required treatments and their costs are summarised in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>. The unit costs of these resources were obtained from Spanish official reimbursement lists (<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0075">15–21</a> The model excluded the costs of adverse effect (AE) treatment due to the limited evidence available on AE rates and their minimum impact estimated on global results.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Results of the modelThe results of the model estimated the average cost per patient with ITP and the average cost per responder patient for each arm of the treatment. The costs included the interventions that patients underwent as well as those related to the lack of response. The results were stratified by splenectomised and non-splenectomised patients, and they were defined by categories of resources used (for example, drug costs, drug administration costs, office visits, tests, etc.) (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Sensitivity analysisSensitivity analyses were conducted to evaluate the effects of the potential variability of the platelet response with both drugs and the treatment patterns with rituximab:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.Platelet response to romiplostim and rituximab, variable at ±10%</li><li class="elsevierStyleListItem" id="lsti0010">2.Percentage of patients with an additional cycle of rituximab in a 6-month period:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015">a.0% of patients received a second cycle of rituximab.</li><li class="elsevierStyleListItem" id="lsti0020">b.28.57% of patients with response and 56.27%<a class="elsevierStyleCrossRef" href="#bib0110">22</a> of patients without response received a second cycle of rituximab.</li><li class="elsevierStyleListItem" id="lsti0025">c.28.57% of patients with response and 0% of patients without response received a second cycle of rituximab.</li></ul></li></ul>ResultsSystematic review of the clinical data found in the medical literatureFrom a total of 478 identified publications, we selected 80 studies about rituximab and 26 about romiplostim, according to the aforementioned inclusion/exclusion criteria.The effectiveness data for romiplostim were obtained from 2 phase III randomised controlled trials.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> Overall platelet response was 79% in the splenectomised patients (n=42), 88% in the non-splenectomised patients (n=41) and 83% in the total of patients (splenectomised and non-splenectomised; n=83) (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).<a class="elsevierStyleCrossRef" href="#bib0115">23</a> The overall platelet response was defined as the sum of all the transitory and sustained response rates (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>). The response was considered a overall platelet response when, after 24 weeks of observation, the platelet count ≥50×109platelets/L was sustained for a minimum of 4 weeks.<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>A systematic review of the medical literature did not identify any phase III randomised controlled clinical trials for rituximab. Since the systematic review of Arnold et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> provided the most consistent data (it included effectiveness results from studies that considered overall platelet response to be platelet counts >50×109/L), it was selected for the information on rituximab effectiveness. The 62.5% overall response rate, with a mean response duration of 10.5 months, was based on the pooled effectiveness data of 313 patients from 19 studies (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>). The review by Arnold et al. did not give details of the platelet response rates separately for splenectomised and non-splenectomised patients. Therefore, the analysis assumed that both subgroups had the same response rate to rituximab (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>). Based on the selected studies and on the most solid comparable data available on the effectiveness of romiplostim and rituximab, the most adequate time horizon established for the model was 6 months.Analysis of mean cost per responder patientFor the total population (splenectomised and non-splenectomised patients), mean cost per patient after 6 months of treatment was €16,289 and €13,459 for romiplostim and rituximab, respectively (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). The use of romiplostim reduced the costs of drug administration, hospitalisations related to BRE and the use of IV Ig compared to rituximab.The mean cost per responder patient was 10% more in patients treated with rituximab than in those treated with romiplostim (€21,535 and €19,625, respectively). This increase in cost was mainly due to an inferior response rate to rituximab (62.5 in contrast with the 83% response to romiplostim).In splenectomised patients, the treatment costs were similar for romiplostim and rituximab. The cost of rituximab per responder patient was 6% higher. In non-splenectomised patients, the rituximab treatment cost per responder patient was 14% higher. In addition to the purchase costs of the drug, the main components of the total costs were drug administration costs, the use of IV Ig and BRE-related hospitalisations for patients without response (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).Sensitivity analysisSensitivity analyses were performed to assess the effects of variability on the efficacy of romiplostim and rituximab and retreatment patterns with rituximab. These sensitivity analyses showed that, although the results could be sensitive to the platelet response rates and to the percentage of patients who received additional cycles of rituximab, the results of the model were generally solid. The average cost per responder patient remained, in general, higher for rituximab compared with romiplostim (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>).<elsevierMultimedia ident="tbl0030"></elsevierMultimedia>DiscussionThe results of this pharmacoeconomic analysis show that the highest rate of response associated with romiplostim produces a lower cost per responder patient compared with rituximab treatment in adult patients with ITP in Spain. In addition, the use of romiplostim reduces the cost of administering the drug, the BRE-related hospitalisations and the use of IV Ig compared with rituximab; the costs associated with treating BREs were responsible for a greater cost increase between both treatments. Therefore, it is possible to state that the cost of treatment per responder patient is lower with the thrombopoietin agonist mainly due to its greater efficacy (83% with romiplostim versus 62.5% with rituximab), and secondarily, to a lower incidence of haemorrhagic complications and coadjuvant treatments (Ig, hospitalisations and other health resources). The results of the model are consistent with the recent cost analysis conducted by Khellaf et al.,<a class="elsevierStyleCrossRef" href="#bib0045">9</a> which showed the impact hospitalisations and the use of IV Ig can have on total treatment costs in patients with ITP. In this study, the annual mean cost per patient was €7293 for the overall population, although it could increase up to €15,334 and €26,581 in groups of patients with at least one hospitalisation or hospitalisation with use of IV Ig, respectively. In these subgroups, 33% and 43% of the costs were produced by IV Ig administration. In a similar way, Brosa et al.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> concluded that the cost by response to treatment is much lower in the patients treated with romiplostim compared to patients who were given placebo and concurrent treatment. An analysis between rituximab and romiplostim in a 6-month time-frame conducted in France also determined a lower cost per response to romiplostim from the perspective of the French national health system. This supports the results presented in this analysis.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> The results of the study are also supported by another pharmacoeconomic analysis that assesses the cost-effectiveness ratio of romiplostim in the treatment of adult patients with ITP compared with eltrombopag or the standard treatment, including rituximab, which shows the dominance of romiplostim in those comparisons.<a class="elsevierStyleCrossRef" href="#bib0135">27</a>The results of the model may vary due to the potential need to administer one or two cycles of rituximab for early relapses or a lack of response. Several studies show that additional cycles of rituximab may be necessary to maintain a sustained platelet response.<a class="elsevierStyleCrossRefs" href="#bib0070">14,28</a> Therefore, if the cost analyses were to consider only one dose of rituximab, the results may not reflect the true patterns of current treatments and, consequently, the estimated cost would be lower than the supposedly actual cost. Brah et al.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> specified that 28.57% of the relapsed patients after an initial response to rituximab, and 36.36% of non-responder patients should receive a second cycle of rituximab. This data agree with the opinion of the experts who validated the assumptions of the model.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Nevertheless, it is important to note that treatment practices are evolving with the availability of thrombopoietin analogues, which could result in the reduction of additional cycles of rituximab.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> The response rate to rituximab has a greater impact in the cost per responder patient than the percentage of patients who receive a second cycle of rituximab. Since the response rate assumed for rituximab was conservative, from the perspective of romiplostim, favouring rituximab,<a class="elsevierStyleCrossRef" href="#bib0120">24</a> and although the results were sensitive to the percentage of rituximab patients who received a second cycle of the treatment, it can be considered that the pharmacoeconomic analysis between romiplostim and rituximab is solid.The analysis has limitations because of the heterogeneity of the studies and the definition of the global response used to support the solidity of the efficacy variables of romiplostim and rituximab. The variables for romiplostim were obtained from phase III clinical trials, whereas the variables for rituximab were obtained from a systematic review of the medical literature. Although the systematic review of the specialised literature did not identify any phase III randomised controlled clinical trials for rituximab, it did identify a phase II single-arm trial<a class="elsevierStyleCrossRef" href="#bib0140">28</a> and two systematic reviews of the medical literature,<a class="elsevierStyleCrossRefs" href="#bib0120">24,30</a> which provided valid response rates for the design of the model. Based on the higher consistency of the data, those data related to efficacy were selected from the systematic review conducted by Arnold et al.,<a class="elsevierStyleCrossRef" href="#bib0120">24</a> which defined the overall platelet response as a platelet count >50×109/L. A meta-analysis recently published by Auger et al.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> in non-splenectomised patients supports the selected data. Although Arnold et al. provided the most solid efficacy data for the rituximab group, it is important to point out the differences between the studies considered for romiplostim and for rituximab. Unlike the pivotal analyses for romiplostim,<a class="elsevierStyleCrossRef" href="#bib0115">23</a> there is no detailed information provided for rituximab about the frequency of platelet response measurements; for that reason, it is not clear whether the platelet count was evaluated once or multiple times to determine the response of rituximab. This lack of comparable data is a consequence of the heterogeneous platelet response definitions and the population characteristics between the romiplostim and rituximab studies, which would probably result in criteria discrepancies when assessing patient characteristics, clinical results and platelet responses. These discrepancies were already pointed out in a report made by Rodeghiero et al.<a class="elsevierStyleCrossRef" href="#bib0160">32</a>Since data from prospective trials usually differs from real clinical practice, and with the purpose of considering the peculiarities of each country, the analysis used real clinical practice data based on medical literature<a class="elsevierStyleCrossRefs" href="#bib0055">11,23,24</a> and on the opinion of experts.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> It is important to consider not only the heterogeneity among patients, but also the variability in the clinical practices of different practitioners. The sensitivity analyses incorporated to assess these parameters demonstrate that, as a whole, the results of the model are solid. In addition, the model did not include all the costs that could potentially be evaluated. For example, it did not consider the possible severe adverse events derived from the use of rituximab or romiplostim, which may have led to additional use of resources. As mentioned before, it is difficult to make direct and accurate comparisons of these events between treatments and, for that reason, they were excluded from the analysis. However, there was a greater possibility that the inclusion of adverse events would be more detrimental for the rituximab results than for the romiplostim results.Finally, it must be noted that the analysis establishes a time-frame of 6 months for treatment and, therefore, conclusions may not be extrapolated to longer treatment periods. Although ideally the analysis should be conducted for a longer period of time, the available data limited the analysis to the current time-frame. With that purpose, similar studies should be conducted to evaluate the long-term efficacy of romiplostim and rituximab. In accordance with this, a study has been published showing that, 3–5 years after rituximab administration, its efficacy is sustained in only 20% of the patients.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> This loss of response over time is not observed with romiplostim, whose efficacy remained stable in patients with a long-term follow-up, while being treated with thrombopoietin agonist.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>ConclusionThe results consider the most relevant comparisons between romiplostim and rituximab from the pharmacoeconomic perspective in Spain. In conclusion, the use of romiplostim reduces the cost of administering the drug, BRE-related hospitalisations and the use of IV Ig in comparison with rituximab, for the treatment of adult patients with ITP. The cost per patient who responds to rituximab is 10% higher compared with romiplostim (€21,535 vs €19,625, respectively) in a 6-month treatment period.This pharmacoeconomic analysis shows that, because of the better efficacy profile for romiplostim compared to rituximab, which leads to a reduction in the BREs and associated costs and, ultimately, to a lower cost per responder patient compared to rituximab, romiplostim is an effective option for the use of health-care system resources in Spain.FundingAmgen S.A., Spain, made an unconditional financial contribution to this project.Conflict of interestIgnasi Campos Tapias works for Amgen S.A. Allison Perrin works for LA-SER. Amgen S.A. engaged the services of LA-SER for the development and adaptation of this model, as well as for the coordination of the manuscript preparation. María Fernanda López Fernández, María Eva Mingot Castellano, David Valcárcel and Vicente Vicente cooperated in the Spanish model adaptation and development of the manuscript; these professionals received fees as experts in the adaptation of the global model to the local level." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres597542" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec612230" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres597541" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Fundamento y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Materiales y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec612231" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Structure of the economic model" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical information" ] 2 => array:3 [ "identificador" => "sec0025" "titulo" => "Economic information" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Use of drugs" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Use of medical resources" ] ] ] 3 => array:2 [ "identificador" => "sec0040" "titulo" => "Results of the model" ] 4 => array:2 [ "identificador" => "sec0045" "titulo" => "Sensitivity analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0050" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Systematic review of the clinical data found in the medical literature" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Analysis of mean cost per responder patient" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Sensitivity analysis" ] ] ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0080" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0085" "titulo" => "Conflict of interest" ] 11 => array:2 [ "identificador" => "xack201112" "titulo" => "Acknowledgements" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-04-18" "fechaAceptado" => "2013-11-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec612230" "palabras" => array:4 [ 0 => "Idiopathic thrombocytopenic purpura" 1 => "Costs and costs analysis" 2 => "Rituximab" 3 => "Romiplostim" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec612231" "palabras" => array:4 [ 0 => "Púrpura trombocitopénica idiopática" 1 => "Costes y análisis de costes" 2 => "Rituximab" 3 => "Romiplostim" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Background and objectiveRomiplostim, a thrombopoietin-receptor agonist, is approved for second-line use in idiopathic thrombocytopenic purpura (ITP) patients where surgery is contraindicated. Anti-CD20 rituximab, an immunosuppressant, is currently used off-label. This analysis compared the cost per responder for romiplostim versus rituximab in Spain. Materials and methodA decision analytic model was constructed to estimate the 6-month cost per responding patient (achieving a platelet count ≥50×109/L) according to the most robust published data. A systematic literature review was performed to extract response rates from phase 3 randomised controlled trials. Romiplostim patients received weekly injections; rituximab patients received 4 weekly intravenous infusions. Medical resource costs were obtained from Spanish reimbursement lists. Treatment non-responders incurred bleeding-related event (BRE) management costs as reported in clinical trials. Medical resource utilisation and clinical practice were based on Spanish treatment guidelines and validated by local clinical experts. ResultsThe literature review identified phase 3 romiplostim trials with a response rate of 83%. Due to a lack of phase 3 controlled rituximab trials, a systematic review of studies was selected as the best source, reporting a response rate of 62.5%. The mean cost per patient for romiplostim was €16,289 and €13,459 for rituximab. Rituximab resulted in a 10% higher cost per responder (€21,535 versus €19,625 for romiplostim). Romiplostim use reduced drug administration, intravenous immunoglobulin, and bleeding-related costs compared to rituximab. ConclusionsDue to its high level of efficacy leading to lower BRE costs, romiplostim represents an efficient use of resources for adult ITP patients in the Spanish Healthcare System." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Fundamento y objetivoRomiplostim, agonista del receptor de la trombopoyetina, está aprobado para el tratamiento de segunda línea en pacientes con trombocitopenia inmune primaria (PTI). El tratamiento con rituximab no es infrecuente, aunque esta indicación no esté recogida en la ficha técnica. Este análisis compara el coste por paciente respondedor a romiplostim frente a rituximab en España. Materiales y métodoSe ha diseñado un modelo para estimar el coste de 6 meses de tratamiento por paciente que responde (recuento plaquetario ≥50×109/L). Este modelo toma las referencias conforme a los datos publicados más sólidos. Los pacientes tratados con romiplostim recibieron inyecciones semanales; los pacientes tratados con rituximab recibieron 4 infusiones intravenosas semanales. Los precios se obtuvieron de las listas de reembolso españolas. Los pacientes sin respuesta incurrieron en gastos por el tratamiento de episodios relacionados con sangrado (ERS), tal como se notificó en los ensayos clínicos. La utilización de recursos médicos y la práctica clínica se basaron en las guías de tratamiento españolas y fueron validadas por expertos locales. ResultadosLas tasas de respuesta para romiplostim y rituximab fueron del 83 y 62,5%, y el coste medio por paciente fue de 16.289€ y13.459€, respectivamente. Con rituximab el coste por paciente respondedor fue un 10% superior (21.535€) comparado con romiplostim (19.625€). Romiplostim redujo el coste de administración de fármacos, el uso de inmunoglobulina intravenosa y los costes relacionados con ERS comparado con rituximab. ConclusionesRomiplostim representaría una opción terapéutica eficiente en comparación con rituximab para el tratamiento de pacientes adultos con PTI crónica en el Sistema Nacional de Salud español." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Fundamento y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Materiales y método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: López MF, Mingot ME, Valcárcel D, Vicente García V, Perrin A, Campos Tapias I. Coste por paciente con respuesta a romiplostim y rituximab en el tratamiento de la trombocitopenia inmune primaria en España. Med Clin (Barc). 2015;144:389–396." ] ] "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2632 "Ancho" => 2174 "Tamanyo" => 162878 ] ] "descripcion" => array:1 [ "en" => "Decision-making flowchart: in this model, squares represent decision nodes, circles represent probability nodes and triangles represent variables." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "We should take into account that other more detailed keywords have also been used for study type to guarantee that all the relevant studies were obtained. The search also included truncated words and spelling variations." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Disease field \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Immune/autoimmune/idiopathic/immune thrombocytopenia with immune mediation/autoimmune thrombocytopenia, primary immune thrombocytopenia, ITP, Werlhof's disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Rituximab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rituximab, Mabthera®, Rituxan®, anti-CD20 monoclonal antibody, IDEC-C2B8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Romiplostim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Romiplostim, AMG 531, Nplate® \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Study type \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Clinical trial, randomised controlled trial, comparative study, registry study, observational study, review, systematic review, meta-analysis, summary of conferences \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab977338.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Systematic review: keywords." ] ] 2 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "QW: once a week." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Dosage/costs</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Administration costs \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total cost per dose \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency of laboratory tests<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>/costs per unit<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a></th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Frequency of doctor visits<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>/costs per unit<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Romiplostim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.5μg/kg QW<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> (1×vial of 250μg per dose) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€602.50/vial<a class="elsevierStyleCrossRef" href="#tblfn0025">e</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€15.82<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€618 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Platelet count \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€12.5/8.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€12.5/80.46 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Rituximab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">375mg/m2, 4 infusions per week<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> (7×vials of 100mg per dose) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€250.81/vial<a class="elsevierStyleCrossRef" href="#tblfn0025">e</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€222.12<a class="elsevierStyleCrossRef" href="#tblfn0030">f</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€1978 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Platelet count \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€9.5/8.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€6/80.46 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab977339.png" ] ] ] "notaPie" => array:6 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Opinion of experts, López et al.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Gisbert and Brosa.<a class="elsevierStyleCrossRef" href="#bib0175">35</a>" ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "Kuter et al.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>" ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "Arnold et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>" ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "e" "nota" => "Spanish General Council of Pharmaceutical Associations (Consejo General de Colegios Oficiales de Farmacéuticos).<a class="elsevierStyleCrossRef" href="#bib0075">15</a>" ] 5 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "f" "nota" => "Decree 160/2010<a class="elsevierStyleCrossRef" href="#bib0080">16</a>, Resolution SLT/383/2009<a class="elsevierStyleCrossRef" href="#bib0085">17</a>, Decree 87/2009<a class="elsevierStyleCrossRef" href="#bib0090">18</a>, Resolution 882/2010<a class="elsevierStyleCrossRef" href="#bib0095">19</a>, Order SAN/8/2007<a class="elsevierStyleCrossRef" href="#bib0100">20</a>, Legislative Decree 1/2005.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>" ] ] ] "descripcion" => array:1 [ "en" => "Costs and use of resources in the model." ] ] 3 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "BRE: bleeding-related episode; IV Ig: intravenous immunoglobulin." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">BRE \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk of haemorrhage<a class="elsevierStyleCrossRef" href="#tblfn0035">a</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cost \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Ambulatory BREs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">90.53% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Ambulatory minor BREs (no immunoglobulin treatment required) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.80% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Visit to the doctor+prednisone<a class="elsevierStyleCrossRef" href="#tblfn0035">a</a> (2mg/kg/day for 2 weeks)<a class="elsevierStyleCrossRef" href="#tblfn0040">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€102 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Ambulatory mild BREs (no immunoglobulin treatment required) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">92.20% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ambulatory visit+IV Ig<a class="elsevierStyleCrossRefs" href="#tblfn0035">a,c</a> (1g/kg/day for 2 days)<a class="elsevierStyleCrossRef" href="#tblfn0040">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€5584 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">BREs leading to hospitalisation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15.57% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Intracranial haemorrhage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.14% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hospitalisation+IV Ig<a class="elsevierStyleCrossRefs" href="#tblfn0035">a,c</a> (1g/kg/day for 2 days)<a class="elsevierStyleCrossRef" href="#tblfn0040">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€11,023 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Gastrointestinal haemorrhage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21.43% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€8424 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Other major haemorrhages \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">71.43% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€6546 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab977336.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "a" "nota" => "Weitz et al.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>" ] 1 => array:3 [ "identificador" => "tblfn0040" "etiqueta" => "b" "nota" => "Provan et al.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>" ] 2 => array:3 [ "identificador" => "tblfn0045" "etiqueta" => "c" "nota" => "Pullarkat et al.<a class="elsevierStyleCrossRef" href="#bib0180">36</a>" ] ] ] "descripcion" => array:1 [ "en" => "Risk of bleeding-related episodes and associated treatments." ] ] 4 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Costs expressed in Euros." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Romiplostim</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Rituximab<a class="elsevierStyleCrossRef" href="#tblfn0050">a</a></th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-splenectomised+splenectomised \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Splenectomised \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-splenectomised \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-splenectomised+splenectomised \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Splenectomised \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-splenectomised \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top">Costs</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Drug \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€13,843 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13,344 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14,342 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9234 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9234 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9234 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Drug administration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€363 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">350 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">377 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1168 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1168 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1168 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Tests \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€102 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">102 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">102 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">77 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">77 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Visits to the doctor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€1006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">805 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">805 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">805 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Haemorrhagic episodes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">113 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">113 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">113 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Rescue therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€924 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1176 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">671 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2062 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2062 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2062 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Total cost/patient \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€16,289 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16,043 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16,535 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13,459 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13,459 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13,459 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Response rate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">83% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">79% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">88% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62.5% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cost/responder patient \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">€19,625 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20,411 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18,833 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">21,535 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">21,535 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">21,535 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab977337.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0050" "etiqueta" => "a" "nota" => "Data were not available for rituximab in splenectomised and non-splenectomised patients separately. As a consequence, it was assumed that the patients treated with rituximab had the same response rates." ] ] ] "descripcion" => array:1 [ "en" => "Mean cost per responder patient for 6 months of romiplostim and rituximab." ] ] 5 => array:7 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group of patients \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Response rate \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Definition of global response \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Reference \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top">Romiplostim</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Non-splenectomised \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">88% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Overall platelet response: The rate of sustained response+the rate of transient response. Sustained response: 6 or more platelet responses per week (platelet count ≥50×109/L) during the last 8 weeks of the treatment.Transient response: 4 or more platelet responses per week in the absence of a sustained response between week 2 and week 25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Kuter et al.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Splenectomised \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">79% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Note: The patients received weekly doses of romiplostim or a placebo for 24 weeks, and they were subject to a follow-up as far as week 36 or until the platelet count fell below 50×109/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top">Rituximab</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Non-splenectomised \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Overall platelet response: >50×109/L. In contrast with the pivotal studies for romiplostim, there is no detailed information on the frequency of the platelet response measurement; therefore, it is not clear if the platelet count was evaluated once or multiple times to determine the response. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Arnold et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Splenectomised \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Note: Mean time until response was 5.5 weeks; the duration of the mean response was 10.5 months; the median follow-up was 9.5 months. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab977335.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Platelet response rates." ] ] 6 => array:7 [ "identificador" => "tbl0030" "etiqueta" => "Table 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "NA: not applicable; NS: non-splenectomised; S: splenectomised.Costs expressed in Euros." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameter \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Value of base case \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Value of sensitivity \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cost/responder patient (romiplostim) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cost/responder patient (rituximab) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Analysis of base case \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19,625 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">21,535 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Romiplostim platelet response \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS: 88%; S: 79% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS: 79%; S: 72% (10% reduction) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">21,127 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS: 97%; S: 87% (10% increase) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18,187 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Rituximab platelet response \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">62.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">56% (10% reduction) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24,641 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">69% (10% increase) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18,994 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Platelet response in rituximab treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Responder patients 28.57%; non-responder patients 36.36% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Responder patients: 0%; non-responder patients: 0%Responder patients: 28.57%; non-responder patients: 56.25%Responder patients: 28.57%; non- responder patients: 0% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NANANA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17,54922,47919,809 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab977334.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Sensitivity analysis." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:36 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "International consensus report on the investigation and management of primary immune thrombocytopenia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. 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Original article

Cost-per-responder analysis comparing romiplostim to rituximab in the treatment of adult primary immune thrombocytopenia in Spain

Coste por paciente con respuesta a romiplostim y rituximab en el tratamiento de la trombocitopenia inmune primaria en España

M. Fernanda Lópeza, María Eva Mingotb, David Valcárcelc, Vicente Vicente Garcíad, Allison Perrine, Ignasi Campos Tapiasf,

Corresponding author

ignasic@amgen.com

Corresponding author.

a Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain

b Hospital Regional Universitario Carlos Haya, Málaga, Spain

c Hospital Vall d’Hebron, Barcelona, Spain

d Hospital Universitario Morales Meseguer, Murcia, Spain

e LA-SER Analytica, Nueva York, United States

f Global Health Economics, Amgen (Europe) GmbH, Zug, Switzerland

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Primary immune thrombocytopenia&#44; also known as idiopathic thrombocytopenic purpura &#40;ITP&#41;&#44; is an acquired autoimmune disease characterised by isolated thrombocytopenia&#44; with a peripheral platelet count &#60;100<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#46; Diagnosis of ITP is made by exclusion when there are no other identifiable causes&#46; The disease is characterised by increased platelet destruction mediated by autoantibodies and a deficiency in their production&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Although incidence rates vary widely in the published literature&#44; ITP is generally considered a rare disease&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In recent publications&#44; an incidence of 3&#46;9 for every 100&#44;000 persons&#47;year is estimated&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> The number of affected persons is small&#44; and patients with platelet counts higher than 50<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L rarely need treatment<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#59; however&#44; this disorder may have major clinical and economic consequences&#44; especially those related to haemorrhages and the deterioration of quality of life &#40;QoL&#41;&#46; Although many patients experience no symptoms or only minor haematomas&#44; other cases may experience severe haemorrhages that may be intracranial&#44; gastrointestinal or extensive mucocutaneous haemorrhages&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In addition&#44; the physical symptoms are the main factor involved in the deterioration of QoL&#44; and patients with ITP obtain bad scores on scales that assess aspects such as discomfort&#44; psychological symptoms&#44; fear&#44; reduced social activity or reduced ability to work&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Corticosteroids &#40;occasionally administered together with intravenous immunoglobulin &#91;IV Ig&#93;&#41; are the standard first-line of treatment&#59; however&#44; in refractory patients or patients with relapses&#44; the second-line treatment was preferably limited to splenectomy until a few years ago&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Romiplostim is a thrombopoietin receptor agonist indicated for splenectomised adult patients with chronic ITP who are refractory to other medications &#40;such as corticosteroids and IV Ig&#41;&#44; or as a second-line treatment for non-splenectomised adult patients for whom surgery is contraindicated&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Thrombopoietin receptor agonists increase platelet production through the activation of the thrombopoietin receptor&#44; which is the key mediator of platelet production&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;7</span></a> Rituximab&#44; a chimeric anti-CD20 monoclonal antibody&#44; is indicated in adult patients with non-Hodgkin&#39;s lymphoma&#44; chronic lymphocytic leukaemia and rheumatoid arthritis&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and&#44; although it is not indicated in the manufacturer&#39;s technical data sheet&#44; it is frequently used as a second-line treatment in adults with ITP&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;7</span></a> Its main mechanism of action is characterised by a depletion of B lymphocytes with CD20&#43;&#44; which are involved in platelet destruction&#44; mediated by immune mechanisms through the production of antiplatelet autoantibodies&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">It has been reported that the treatment of chronic ITP in adults is expensive&#44; particularly in patients with a severe form of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> At present&#44; the cost-consequence ratio of romiplostim and rituximab in patients with ITP in Spain is unknown&#46; This has prompted us to conduct this analysis in order to assess clinical and economic implications and&#44; in particular&#44; to estimate the response rate and cost per patient for these two agents&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Structure of the economic model</span><p id="par0025" class="elsevierStylePara elsevierViewall">A cost-consequence model was designed &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; to compare the total direct costs of patients treated with romiplostim and rituximab&#46; The parameters of the model considered drug costs&#44; treatment duration&#44; effectiveness of therapeutic alternatives and the use of healthcare resources&#46; The cost-consequence analysis was chosen to present the results in a disaggregated manner&#44; which allows the observer to independently assign the importance of the consequences for each alternative&#46; These analyses are becoming more highly appreciated and are being applied more often in countries where the number of health technology assessments are increasing&#59; in addition&#44; they are usually more comprehensible to healthcare decision-makers compared to other types of pharmacoeconomic analyses&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The model was developed from the perspective of the Spanish National Healthcare System&#59; therefore&#44; only direct health costs were considered&#46; The results and costs of patients &#40;refractory to the first-line treatment&#41; treated with romiplostim or rituximab were assessed&#46; Splenectomy was not considered a third alternative in the decision-making process&#44; since those patients&#44; who were suitable candidates for splenectomy&#44; would already have undergone the procedure&#46; The analysis aimed at assessing the costs associated with each treatment intervention&#44; including drug costs&#44; medical visits&#44; laboratory tests and costs related to treatments for bleeding-related episodes &#40;BRE&#41; in patients who did not respond&#46; The proportion of patients whose platelet response was attributable to either of the treatments was determined 8 weeks following the start of treatment&#44; based on international treatment guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> As described by Weitz et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> based on a pooled data analysis of the romiplostim and placebo groups in the pivotal romiplostim trials&#44; the patients who did not respond experienced BREs&#44; which agglutinated the patients with bleeding episodes and those who needed rescue medication&#46; The severity of a BRE was defined by the need for hospitalisation and the use of rescue medication&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The BREs were classified as ambulatory BREs and BREs that required hospitalisation&#46; For the 18-week period contemplated in the model &#40;the period in which patients were classified depending on whether or not they responded to the treatment&#41;&#44; the risk of BREs was calculated using the number of BREs and the number of weeks per patient of follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Clinical information</span><p id="par0030" class="elsevierStylePara elsevierViewall">To obtain the platelet response &#40;defined as &#8805;50<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span><span class="elsevierStyleHsp" style=""></span>platelets&#47;L<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#41;&#44; duration of the response&#44; sample size&#44; security profile&#44; stratification among splenectomised and non-splenectomised patients and the characteristics of the population&#44; a systematic review of the medical literature was performed with the aim of identifying randomised&#44; controlled&#44; phase III clinical trials of rituximab and romiplostim in the treatment of adult patients with ITP published from 2000 to January 2011&#46; The databases consulted for the review of the medical literature were MEDLINE&#44; EMBASE&#44; EMBASE Alert&#44; BIOSIS Previews&#44; Cochrane Central Register of Controlled Trials&#44; Cochrane Database of Systematic Reviews&#44; Database of Abstracts of Reviews of Effects&#44; Derwent Drug File&#44; Health Technology Assessment Database and SciSearch&#46; Clinical trials&#44; comparative studies&#44; observational studies&#44; systematic reviews and meta-analyses published in English were included&#46; The keywords used in the search of the medical literature appear in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Two independent reviewers &#40;along with a third reviewer for conflict resolution&#41; assessed the titles&#44; abstracts and articles retrieved from searches and excluded irrelevant publications based on the following exclusion criteria&#58; publications not about ITP&#59; those related to immune thrombocytopenia secondary to a disease&#44; non-specific for rituximab or romiplostim&#59; reports that were not published in the English language&#59; paediatric studies&#59; publications of case reports&#47;letters to the publisher with no abstracts available&#59; duplicate publications&#59; laboratory research&#59; and economic studies or studies on QoL&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Economic information</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Use of drugs</span><p id="par0035" class="elsevierStylePara elsevierViewall">The romiplostim dosage consisted of one subcutaneous injection of 250<span class="elsevierStyleHsp" style=""></span>&#956;g once a week until a response to treatment was observed&#46; The rituximab dosage consisted of a cycle of four weekly doses of 375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#46; The required doses for each drug were estimated based on an average patient weight of 76&#46;23<span class="elsevierStyleHsp" style=""></span>kg<span class="elsevierStyleSup">12</span> and height of 161&#46;57<span class="elsevierStyleHsp" style=""></span>cm&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> resulting in a body surface area &#40;calculated according to the DuBois and DuBois formula<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&#41; of 1&#46;81<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">A sustained platelet response is not always obtained after the first cycle of rituximab&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In a retrospective study of patients with ITP performed at a hospital in France&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> 28&#46;57&#37; of the responder patients and 36&#46;36&#37; of the patients who did not respond to rituximab received an additional cycle of this drug&#46; Based on that study&#44; a second cycle of rituximab with the mentioned percentages was administered 6 months after the beginning of the treatment in this model&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Use of medical resources</span><p id="par0045" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the details of the frequency of visits to health professionals&#44; the laboratory tests and the visits for the administration of romiplostim and rituximab&#46; The frequency of BREs&#44; required treatments and their costs are summarised in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46; The unit costs of these resources were obtained from Spanish official reimbursement lists &#40;<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;21</span></a> The model excluded the costs of adverse effect &#40;AE&#41; treatment due to the limited evidence available on AE rates and their minimum impact estimated on global results&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results of the model</span><p id="par0050" class="elsevierStylePara elsevierViewall">The results of the model estimated the average cost per patient with ITP and the average cost per responder patient for each arm of the treatment&#46; The costs included the interventions that patients underwent as well as those related to the lack of response&#46; The results were stratified by splenectomised and non-splenectomised patients&#44; and they were defined by categories of resources used &#40;for example&#44; drug costs&#44; drug administration costs&#44; office visits&#44; tests&#44; etc&#46;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Sensitivity analysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">Sensitivity analyses were conducted to evaluate the effects of the potential variability of the platelet response with both drugs and the treatment patterns with rituximab&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Platelet response to romiplostim and rituximab&#44; variable at &#177;10&#37;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Percentage of patients with an additional cycle of rituximab in a 6-month period&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">a&#46;</span><p id="par0070" class="elsevierStylePara elsevierViewall">0&#37; of patients received a second cycle of rituximab&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">b&#46;</span><p id="par0075" class="elsevierStylePara elsevierViewall">28&#46;57&#37; of patients with response and 56&#46;27&#37;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> of patients without response received a second cycle of rituximab&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">c&#46;</span><p id="par0080" class="elsevierStylePara elsevierViewall">28&#46;57&#37; of patients with response and 0&#37; of patients without response received a second cycle of rituximab&#46;</p></li></ul></p></li></ul></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Results</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Systematic review of the clinical data found in the medical literature</span><p id="par0085" class="elsevierStylePara elsevierViewall">From a total of 478 identified publications&#44; we selected 80 studies about rituximab and 26 about romiplostim&#44; according to the aforementioned inclusion&#47;exclusion criteria&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The effectiveness data for romiplostim were obtained from 2 phase III randomised controlled trials&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Overall platelet response was 79&#37; in the splenectomised patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42&#41;&#44; 88&#37; in the non-splenectomised patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41; and 83&#37; in the total of patients &#40;splenectomised and non-splenectomised&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>83&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> The overall platelet response was defined as the sum of all the transitory and sustained response rates &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46; The response was considered a overall platelet response when&#44; after 24 weeks of observation&#44; the platelet count &#8805;50<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span><span class="elsevierStyleHsp" style=""></span>platelets&#47;L was sustained for a minimum of 4 weeks&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">A systematic review of the medical literature did not identify any phase III randomised controlled clinical trials for rituximab&#46; Since the systematic review of Arnold et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> provided the most consistent data &#40;it included effectiveness results from studies that considered overall platelet response to be platelet counts &#62;50<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#41;&#44; it was selected for the information on rituximab effectiveness&#46; The 62&#46;5&#37; overall response rate&#44; with a mean response duration of 10&#46;5 months&#44; was based on the pooled effectiveness data of 313 patients from 19 studies &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46; The review by Arnold et al&#46; did not give details of the platelet response rates separately for splenectomised and non-splenectomised patients&#46; Therefore&#44; the analysis assumed that both subgroups had the same response rate to rituximab &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46; Based on the selected studies and on the most solid comparable data available on the effectiveness of romiplostim and rituximab&#44; the most adequate time horizon established for the model was 6 months&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Analysis of mean cost per responder patient</span><p id="par0100" class="elsevierStylePara elsevierViewall">For the total population &#40;splenectomised and non-splenectomised patients&#41;&#44; mean cost per patient after 6 months of treatment was &#8364;16&#44;289 and &#8364;13&#44;459 for romiplostim and rituximab&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; The use of romiplostim reduced the costs of drug administration&#44; hospitalisations related to BRE and the use of IV Ig compared to rituximab&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The mean cost per responder patient was 10&#37; more in patients treated with rituximab than in those treated with romiplostim &#40;&#8364;21&#44;535 and &#8364;19&#44;625&#44; respectively&#41;&#46; This increase in cost was mainly due to an inferior response rate to rituximab &#40;62&#46;5 in contrast with the 83&#37; response to romiplostim&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In splenectomised patients&#44; the treatment costs were similar for romiplostim and rituximab&#46; The cost of rituximab per responder patient was 6&#37; higher&#46; In non-splenectomised patients&#44; the rituximab treatment cost per responder patient was 14&#37; higher&#46; In addition to the purchase costs of the drug&#44; the main components of the total costs were drug administration costs&#44; the use of IV Ig and BRE-related hospitalisations for patients without response &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Sensitivity analysis</span><p id="par0115" class="elsevierStylePara elsevierViewall">Sensitivity analyses were performed to assess the effects of variability on the efficacy of romiplostim and rituximab and retreatment patterns with rituximab&#46; These sensitivity analyses showed that&#44; although the results could be sensitive to the platelet response rates and to the percentage of patients who received additional cycles of rituximab&#44; the results of the model were generally solid&#46; The average cost per responder patient remained&#44; in general&#44; higher for rituximab compared with romiplostim &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">The results of this pharmacoeconomic analysis show that the highest rate of response associated with romiplostim produces a lower cost per responder patient compared with rituximab treatment in adult patients with ITP in Spain&#46; In addition&#44; the use of romiplostim reduces the cost of administering the drug&#44; the BRE-related hospitalisations and the use of IV Ig compared with rituximab&#59; the costs associated with treating BREs were responsible for a greater cost increase between both treatments&#46; Therefore&#44; it is possible to state that the cost of treatment per responder patient is lower with the thrombopoietin agonist mainly due to its greater efficacy &#40;83&#37; with romiplostim versus 62&#46;5&#37; with rituximab&#41;&#44; and secondarily&#44; to a lower incidence of haemorrhagic complications and coadjuvant treatments &#40;Ig&#44; hospitalisations and other health resources&#41;&#46; The results of the model are consistent with the recent cost analysis conducted by Khellaf et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> which showed the impact hospitalisations and the use of IV Ig can have on total treatment costs in patients with ITP&#46; In this study&#44; the annual mean cost per patient was &#8364;7293 for the overall population&#44; although it could increase up to &#8364;15&#44;334 and &#8364;26&#44;581 in groups of patients with at least one hospitalisation or hospitalisation with use of IV Ig&#44; respectively&#46; In these subgroups&#44; 33&#37; and 43&#37; of the costs were produced by IV Ig administration&#46; In a similar way&#44; Brosa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> concluded that the cost by response to treatment is much lower in the patients treated with romiplostim compared to patients who were given placebo and concurrent treatment&#46; An analysis between rituximab and romiplostim in a 6-month time-frame conducted in France also determined a lower cost per response to romiplostim from the perspective of the French national health system&#46; This supports the results presented in this analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The results of the study are also supported by another pharmacoeconomic analysis that assesses the cost-effectiveness ratio of romiplostim in the treatment of adult patients with ITP compared with eltrombopag or the standard treatment&#44; including rituximab&#44; which shows the dominance of romiplostim in those comparisons&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The results of the model may vary due to the potential need to administer one or two cycles of rituximab for early relapses or a lack of response&#46; Several studies show that additional cycles of rituximab may be necessary to maintain a sustained platelet response&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;28</span></a> Therefore&#44; if the cost analyses were to consider only one dose of rituximab&#44; the results may not reflect the true patterns of current treatments and&#44; consequently&#44; the estimated cost would be lower than the supposedly actual cost&#46; Brah et al&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> specified that 28&#46;57&#37; of the relapsed patients after an initial response to rituximab&#44; and 36&#46;36&#37; of non-responder patients should receive a second cycle of rituximab&#46; This data agree with the opinion of the experts who validated the assumptions of the model&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Nevertheless&#44; it is important to note that treatment practices are evolving with the availability of thrombopoietin analogues&#44; which could result in the reduction of additional cycles of rituximab&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The response rate to rituximab has a greater impact in the cost per responder patient than the percentage of patients who receive a second cycle of rituximab&#46; Since the response rate assumed for rituximab was conservative&#44; from the perspective of romiplostim&#44; favouring rituximab&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> and although the results were sensitive to the percentage of rituximab patients who received a second cycle of the treatment&#44; it can be considered that the pharmacoeconomic analysis between romiplostim and rituximab is solid&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The analysis has limitations because of the heterogeneity of the studies and the definition of the global response used to support the solidity of the efficacy variables of romiplostim and rituximab&#46; The variables for romiplostim were obtained from phase III clinical trials&#44; whereas the variables for rituximab were obtained from a systematic review of the medical literature&#46; Although the systematic review of the specialised literature did not identify any phase III randomised controlled clinical trials for rituximab&#44; it did identify a phase II single-arm trial<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> and two systematic reviews of the medical literature&#44;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;30</span></a> which provided valid response rates for the design of the model&#46; Based on the higher consistency of the data&#44; those data related to efficacy were selected from the systematic review conducted by Arnold et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> which defined the overall platelet response as a platelet count &#62;50<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#46; A meta-analysis recently published by Auger et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> in non-splenectomised patients supports the selected data&#46; Although Arnold et al&#46; provided the most solid efficacy data for the rituximab group&#44; it is important to point out the differences between the studies considered for romiplostim and for rituximab&#46; Unlike the pivotal analyses for romiplostim&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> there is no detailed information provided for rituximab about the frequency of platelet response measurements&#59; for that reason&#44; it is not clear whether the platelet count was evaluated once or multiple times to determine the response of rituximab&#46; This lack of comparable data is a consequence of the heterogeneous platelet response definitions and the population characteristics between the romiplostim and rituximab studies&#44; which would probably result in criteria discrepancies when assessing patient characteristics&#44; clinical results and platelet responses&#46; These discrepancies were already pointed out in a report made by Rodeghiero et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Since data from prospective trials usually differs from real clinical practice&#44; and with the purpose of considering the peculiarities of each country&#44; the analysis used real clinical practice data based on medical literature<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;23&#44;24</span></a> and on the opinion of experts&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> It is important to consider not only the heterogeneity among patients&#44; but also the variability in the clinical practices of different practitioners&#46; The sensitivity analyses incorporated to assess these parameters demonstrate that&#44; as a whole&#44; the results of the model are solid&#46; In addition&#44; the model did not include all the costs that could potentially be evaluated&#46; For example&#44; it did not consider the possible severe adverse events derived from the use of rituximab or romiplostim&#44; which may have led to additional use of resources&#46; As mentioned before&#44; it is difficult to make direct and accurate comparisons of these events between treatments and&#44; for that reason&#44; they were excluded from the analysis&#46; However&#44; there was a greater possibility that the inclusion of adverse events would be more detrimental for the rituximab results than for the romiplostim results&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Finally&#44; it must be noted that the analysis establishes a time-frame of 6 months for treatment and&#44; therefore&#44; conclusions may not be extrapolated to longer treatment periods&#46; Although ideally the analysis should be conducted for a longer period of time&#44; the available data limited the analysis to the current time-frame&#46; With that purpose&#44; similar studies should be conducted to evaluate the long-term efficacy of romiplostim and rituximab&#46; In accordance with this&#44; a study has been published showing that&#44; 3&#8211;5 years after rituximab administration&#44; its efficacy is sustained in only 20&#37; of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> This loss of response over time is not observed with romiplostim&#44; whose efficacy remained stable in patients with a long-term follow-up&#44; while being treated with thrombopoietin agonist&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conclusion</span><p id="par0145" class="elsevierStylePara elsevierViewall">The results consider the most relevant comparisons between romiplostim and rituximab from the pharmacoeconomic perspective in Spain&#46; In conclusion&#44; the use of romiplostim reduces the cost of administering the drug&#44; BRE-related hospitalisations and the use of IV Ig in comparison with rituximab&#44; for the treatment of adult patients with ITP&#46; The cost per patient who responds to rituximab is 10&#37; higher compared with romiplostim &#40;&#8364;21&#44;535 vs &#8364;19&#44;625&#44; respectively&#41; in a 6-month treatment period&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">This pharmacoeconomic analysis shows that&#44; because of the better efficacy profile for romiplostim compared to rituximab&#44; which leads to a reduction in the BREs and associated costs and&#44; ultimately&#44; to a lower cost per responder patient compared to rituximab&#44; romiplostim is an effective option for the use of health-care system resources in Spain&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Funding</span><p id="par0155" class="elsevierStylePara elsevierViewall">Amgen S&#46;A&#46;&#44; Spain&#44; made an unconditional financial contribution to this project&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interest</span><p id="par0160" class="elsevierStylePara elsevierViewall">Ignasi Campos Tapias works for Amgen S&#46;A&#46; Allison Perrin works for LA-SER&#46; Amgen S&#46;A&#46; engaged the services of LA-SER for the development and adaptation of this model&#44; as well as for the coordination of the manuscript preparation&#46; Mar&#237;a Fernanda L&#243;pez Fern&#225;ndez&#44; Mar&#237;a Eva Mingot Castellano&#44; David Valc&#225;rcel and Vicente Vicente cooperated in the Spanish model adaptation and development of the manuscript&#59; these professionals received fees as experts in the adaptation of the global model to the local level&#46;</p></span></span>"
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          "titulo" => "Introduction"
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              "titulo" => "Systematic review of the clinical data found in the medical literature"
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              "titulo" => "Analysis of mean cost per responder patient"
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              "titulo" => "Sensitivity analysis"
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    "fechaRecibido" => "2013-04-18"
    "fechaAceptado" => "2013-11-28"
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Idiopathic thrombocytopenic purpura"
            1 => "Costs and costs analysis"
            2 => "Rituximab"
            3 => "Romiplostim"
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          "palabras" => array:4 [
            0 => "P&#250;rpura trombocitop&#233;nica idiop&#225;tica"
            1 => "Costes y an&#225;lisis de costes"
            2 => "Rituximab"
            3 => "Romiplostim"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Romiplostim&#44; a thrombopoietin-receptor agonist&#44; is approved for second-line use in idiopathic thrombocytopenic purpura &#40;ITP&#41; patients where surgery is contraindicated&#46; Anti-CD20 rituximab&#44; an immunosuppressant&#44; is currently used off-label&#46; This analysis compared the cost per responder for romiplostim versus rituximab in Spain&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A decision analytic model was constructed to estimate the 6-month cost per responding patient &#40;achieving a platelet count &#8805;50<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#41; according to the most robust published data&#46; A systematic literature review was performed to extract response rates from phase 3 randomised controlled trials&#46; Romiplostim patients received weekly injections&#59; rituximab patients received 4 weekly intravenous infusions&#46; Medical resource costs were obtained from Spanish reimbursement lists&#46; Treatment non-responders incurred bleeding-related event &#40;BRE&#41; management costs as reported in clinical trials&#46; Medical resource utilisation and clinical practice were based on Spanish treatment guidelines and validated by local clinical experts&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The literature review identified phase 3 romiplostim trials with a response rate of 83&#37;&#46; Due to a lack of phase 3 controlled rituximab trials&#44; a systematic review of studies was selected as the best source&#44; reporting a response rate of 62&#46;5&#37;&#46; The mean cost per patient for romiplostim was &#8364;16&#44;289 and &#8364;13&#44;459 for rituximab&#46; Rituximab resulted in a 10&#37; higher cost per responder &#40;&#8364;21&#44;535 versus &#8364;19&#44;625 for romiplostim&#41;&#46; Romiplostim use reduced drug administration&#44; intravenous immunoglobulin&#44; and bleeding-related costs compared to rituximab&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Due to its high level of efficacy leading to lower BRE costs&#44; romiplostim represents an efficient use of resources for adult ITP patients in the Spanish Healthcare System&#46;</p></span>"
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          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background and objective"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Materials and method"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Fundamento y objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Romiplostim&#44; agonista del receptor de la trombopoyetina&#44; est&#225; aprobado para el tratamiento de segunda l&#237;nea en pacientes con trombocitopenia inmune primaria &#40;PTI&#41;&#46; El tratamiento con rituximab no es infrecuente&#44; aunque esta indicaci&#243;n no est&#233; recogida en la ficha t&#233;cnica&#46; Este an&#225;lisis compara el coste por paciente respondedor a romiplostim frente a rituximab en Espa&#241;a&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materiales y m&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se ha dise&#241;ado un modelo para estimar el coste de 6 meses de tratamiento por paciente que responde &#40;recuento plaquetario &#8805;<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#41;&#46; Este modelo toma las referencias conforme a los datos publicados m&#225;s s&#243;lidos&#46; Los pacientes tratados con romiplostim recibieron inyecciones semanales&#59; los pacientes tratados con rituximab recibieron 4 infusiones intravenosas semanales&#46; Los precios se obtuvieron de las listas de reembolso espa&#241;olas&#46; Los pacientes sin respuesta incurrieron en gastos por el tratamiento de episodios relacionados con sangrado &#40;ERS&#41;&#44; tal como se notific&#243; en los ensayos cl&#237;nicos&#46; La utilizaci&#243;n de recursos m&#233;dicos y la pr&#225;ctica cl&#237;nica se basaron en las gu&#237;as de tratamiento espa&#241;olas y fueron validadas por expertos locales&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Las tasas de respuesta para romiplostim y rituximab fueron del 83 y 62&#44;5&#37;&#44; y el coste medio por paciente fue de 16&#46;289<span class="elsevierStyleHsp" style=""></span>&#8364; y13&#46;459<span class="elsevierStyleHsp" style=""></span>&#8364;&#44; respectivamente&#46; Con rituximab el coste por paciente respondedor fue un 10&#37; superior &#40;21&#46;535<span class="elsevierStyleHsp" style=""></span>&#8364;&#41; comparado con romiplostim &#40;19&#46;625<span class="elsevierStyleHsp" style=""></span>&#8364;&#41;&#46; Romiplostim redujo el coste de administraci&#243;n de f&#225;rmacos&#44; el uso de inmunoglobulina intravenosa y los costes relacionados con ERS comparado con rituximab&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Romiplostim representar&#237;a una opci&#243;n terap&#233;utica eficiente en comparaci&#243;n con rituximab para el tratamiento de pacientes adultos con PTI cr&#243;nica en el Sistema Nacional de Salud espa&#241;ol&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0055">Please cite this article as&#58; L&#243;pez MF&#44; Mingot ME&#44; Valc&#225;rcel D&#44; Vicente Garc&#237;a V&#44; Perrin A&#44; Campos Tapias I&#46; Coste por paciente con respuesta a romiplostim y rituximab en el tratamiento de la trombocitopenia inmune primaria en Espa&#241;a&#46; Med Clin &#40;Barc&#41;&#46; 2015&#59;144&#58;389&#8211;396&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Decision-making flowchart&#58; in this model&#44; squares represent decision nodes&#44; circles represent probability nodes and triangles represent variables&#46;</p>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">We should take into account that other more detailed keywords have also been used for study type to guarantee that all the relevant studies were obtained&#46; The search also included truncated words and spelling variations&#46;</p>"
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Immune&#47;autoimmune&#47;idiopathic&#47;immune thrombocytopenia with immune mediation&#47;autoimmune thrombocytopenia&#44; primary immune thrombocytopenia&#44; ITP&#44; Werlhof&#39;s disease&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Study type&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">QW&#58; once a week&#46;</p>"
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                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Dosage&#47;costs</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Administration costs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total cost per dose&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Romiplostim&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg QW<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> &#40;1<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>vial of 250<span class="elsevierStyleHsp" style=""></span>&#956;g per dose&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;602&#46;50&#47;vial<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;15&#46;82<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">&#8364;618</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Platelet count&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;12&#46;5&#47;8&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;12&#46;5&#47;80&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Rituximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#44; 4 infusions per week<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a> &#40;7<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>vials of 100<span class="elsevierStyleHsp" style=""></span>mg per dose&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;250&#46;81&#47;vial<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;222&#46;12<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">f</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">&#8364;1978</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Platelet count&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;9&#46;5&#47;8&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;6&#47;80&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab977339.png"
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Opinion of experts&#44; L&#243;pez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Gisbert and Brosa&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Kuter et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Arnold et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0025"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Spanish General Council of Pharmaceutical Associations &#40;Consejo General de Colegios Oficiales de Farmac&#233;uticos&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p>"
            ]
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              "identificador" => "tblfn0030"
              "etiqueta" => "f"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Decree 160&#47;2010<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#44; Resolution SLT&#47;383&#47;2009<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#44; Decree 87&#47;2009<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#44; Resolution 882&#47;2010<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&#44; Order SAN&#47;8&#47;2007<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&#44; Legislative Decree 1&#47;2005&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p>"
            ]
          ]
        ]
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Costs and use of resources in the model&#46;</p>"
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        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">BRE&#58; bleeding-related episode&#59; <span class="elsevierStyleSmallCaps">IV</span> Ig&#58; intravenous immunoglobulin&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">BRE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk of haemorrhage<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cost&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Ambulatory BREs</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90&#46;53&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ambulatory minor BREs &#40;no immunoglobulin treatment required&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;80&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Visit to the doctor<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>prednisone<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">a</span></a> &#40;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for 2 weeks&#41;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ambulatory mild BREs &#40;no immunoglobulin treatment required&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">92&#46;20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ambulatory visit<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IV Ig<a class="elsevierStyleCrossRefs" href="#tblfn0035"><span class="elsevierStyleSup">a&#44;c</span></a> &#40;1<span class="elsevierStyleHsp" style=""></span>g&#47;kg&#47;day for 2 days&#41;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;5584&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">BREs leading to hospitalisation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#46;57&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Intracranial haemorrhage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;14&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hospitalisation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IV Ig<a class="elsevierStyleCrossRefs" href="#tblfn0035"><span class="elsevierStyleSup">a&#44;c</span></a> &#40;1<span class="elsevierStyleHsp" style=""></span>g&#47;kg&#47;day for 2 days&#41;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;11&#44;023&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Gastrointestinal haemorrhage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21&#46;43&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;8424&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Other major haemorrhages&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">71&#46;43&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;6546&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab977336.png"
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          "notaPie" => array:3 [
            0 => array:3 [
              "identificador" => "tblfn0035"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Weitz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0040"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Provan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0045"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0045">Pullarkat et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Risk of bleeding-related episodes and associated treatments&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Costs expressed in Euros&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Romiplostim</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Rituximab<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a></th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-splenectomised<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>splenectomised&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Splenectomised&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-splenectomised&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-splenectomised<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>splenectomised&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Splenectomised&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-splenectomised&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleItalic">Costs</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;13&#44;843&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#44;344&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&#44;342&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9234&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9234&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9234&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Drug administration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;363&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">350&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">377&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1168&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1168&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1168&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">77&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">77&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">77&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Visits to the doctor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;1006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">805&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">805&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">805&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Haemorrhagic episodes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">113&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">113&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">113&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rescue therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8364;924&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1176&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">671&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2062&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2062&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2062&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Total cost&#47;patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">&#8364;16&#44;289</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">16&#44;043</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">16&#44;535</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">13&#44;459</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">13&#44;459</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">13&#44;459</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Response rate</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">83&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">79&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">88&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cost&#47;responder patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">&#8364;19&#44;625</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">20&#44;411</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">18&#44;833</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">21&#44;535</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">21&#44;535</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">21&#44;535</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab977337.png"
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0050"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0050">Data were not available for rituximab in splenectomised and non-splenectomised patients separately&#46; As a consequence&#44; it was assumed that the patients treated with rituximab had the same response rates&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Mean cost per responder patient for 6 months of romiplostim and rituximab&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Response rate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Definition of global response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Reference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Romiplostim</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Non-splenectomised&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">88&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Overall platelet response&#58; The rate of sustained response<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>the rate of transient response&#46; Sustained response&#58; 6 or more platelet responses per week &#40;platelet count &#8805;50<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#41; during the last 8 weeks of the treatment&#46;Transient response&#58; 4 or more platelet responses per week in the absence of a sustained response between week 2 and week 25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Kuter et al&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Splenectomised&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">79&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Note&#58; The patients received weekly doses of romiplostim or a placebo for 24 weeks&#44; and they were subject to a follow-up as far as week 36 or until the platelet count fell below 50<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Rituximab</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Non-splenectomised&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Overall platelet response&#58; &#62;50<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#46; In contrast with the pivotal studies for romiplostim&#44; there is no detailed information on the frequency of the platelet response measurement&#59; therefore&#44; it is not clear if the platelet count was evaluated once or multiple times to determine the response&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Arnold et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Splenectomised&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Note&#58; Mean time until response was 5&#46;5 weeks&#59; the duration of the mean response was 10&#46;5 months&#59; the median follow-up was 9&#46;5 months&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab977335.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Platelet response rates&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">NA&#58; not applicable&#59; NS&#58; non-splenectomised&#59; S&#58; splenectomised&#46;</p><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Costs expressed in Euros&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Parameter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Value of base case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Value of sensitivity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cost&#47;responder patient &#40;romiplostim&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cost&#47;responder patient &#40;rituximab&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Analysis of base case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19&#44;625&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21&#44;535&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Romiplostim platelet response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS&#58; 88&#37;&#59; S&#58; 79&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS&#58; 79&#37;&#59; S&#58; 72&#37; &#40;10&#37; reduction&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21&#44;127&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS&#58; 97&#37;&#59; S&#58; 87&#37; &#40;10&#37; increase&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&#44;187&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Rituximab platelet response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">56&#37; &#40;10&#37; reduction&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&#44;641&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">69&#37; &#40;10&#37; increase&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&#44;994&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Platelet response in rituximab treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Responder patients 28&#46;57&#37;&#59; non-responder patients 36&#46;36&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Responder patients&#58; 0&#37;&#59; non-responder patients&#58; 0&#37;Responder patients&#58; 28&#46;57&#37;&#59; non-responder patients&#58; 56&#46;25&#37;Responder patients&#58; 28&#46;57&#37;&#59; non- responder patients&#58; 0&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NANANA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&#44;54922&#44;47919&#44;809&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab977334.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Sensitivity analysis&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:36 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "International consensus report on the investigation and management of primary immune thrombocytopenia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46; Provan"
                            1 => "R&#46; Stasi"
                            2 => "A&#46;C&#46; Newland"
                            3 => "V&#46;S&#46; Blanchette"
                            4 => "P&#46; Bolton-Maggs"
                            5 => "J&#46;B&#46; Bussel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2009-06-225565"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2010"
                        "volumen" => "115"
                        "paginaInicial" => "168"
                        "paginaFinal" => "186"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19846889"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The incidence of idiopathic thrombocytopenic purpura among adults&#58; a population-based study and literature review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "P&#46;E&#46; Abrahamson"
                            1 => "S&#46;A&#46; Hall"
                            2 => "M&#46; Feudjo-Tepie"
                            3 => "F&#46;S&#46; Mitrani-Gold"
                            4 => "J&#46; Logie"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1600-0609.2009.01247.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Haematol"
                        "fecha" => "2009"
                        "volumen" => "83"
                        "paginaInicial" => "83"
                        "paginaFinal" => "89"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19245532"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            2 => array:3 [
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