Cost-effectiveness analysis of interferon beta-1b as treatment for patients with clinically isolated syndrome suggestive of multiple sclerosis in Spain

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Piñol" "autores" => array:1 [ 0 => array:3 [ "nombre" => "C." "apellidos" => "Piñol" "email" => array:1 [ 0 => "carme.pinyol@gmail.com" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "INNOVA Strategic Consulting, Barcelona, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Análisis de coste-efectividad del interferón beta-1b en el tratamiento de pacientes con síndrome desmielinizante aislado indicativo de esclerosis múltiple en España" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1019 "Ancho" => 2172 "Tamanyo" => 175298 ] ] "descripcion" => array:1 [ "en" => "Results from the probabilistic sensitivity analysis. QALY, quality-adjusted life years." ] ] ] "textoCompleto" => "IntroductionMultiple sclerosis (MS) is an inflammatory disease of the central nervous system characterised by progressive demyelination. Most MS patients present severe physical disability and cognitive impairment.<a class="elsevierStyleCrossRef" href="#bib0210">1</a>According to a recent study conducted in La Rioja, Spain, MS has a prevalence of 65 cases per 100000 population and predominantly affects young women.<a class="elsevierStyleCrossRef" href="#bib0215">2</a> The mean annual cost per patient with MS amounts to €24272, with direct costs representing around 60% of the total cost.<a class="elsevierStyleCrossRef" href="#bib0220">3</a>The first manifestation of the disease in 85% of the young adults who develop clinically definite MS (CDMS) is an event resulting from isolated demyelination of the optic nerves, brainstem, or spinal cord.<a class="elsevierStyleCrossRefs" href="#bib0210">1,4</a> This event is called ‘clinically isolated syndrome’, or CIS.Disease-modifying treatments (DMT) such as interferon beta-1b (IFNβ-1b) are the standard first-line of treatment for MS outbreaks, since they have been shown to reduce the exacerbation rate and slow disease progression in clinical trials.<a class="elsevierStyleCrossRefs" href="#bib0210">1,5–7</a>According to the Betaferon® in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT)<a class="elsevierStyleCrossRef" href="#bib0245">8</a> trial, early treatment after a CIS suggestive of MS reduces the risk of conversion to CDMS by 41% compared with delayed treatment. Furthermore, several studies have shown that early treatment reduces the risk of disease progression by 40% to 45% compared with delayed treatment.<a class="elsevierStyleCrossRefs" href="#bib0240">7–10</a>Whereas the cost-effectiveness of treatments for MS has been thoroughly studied, this is not the case for CIS suggestive of MS.<a class="elsevierStyleCrossRefs" href="#bib0260">11–15</a>The aim of this study was to estimate the cost-effectiveness in Spain of IFNβ-1b in patients with a CIS suggestive of MS.Material and methodsDescription of the modelWe used MS Excel® to create a Markov model to estimate the costs and benefits of a hypothetical cohort of 1000 patients (mean age: 30 years, 70% of whom were women, in line with the population of the BENEFIT study) with a CIS who were treated with IFNβ-1b (250mg every other day) either right after a CIS suggestive of MS (early treatment) or at onset of CDMS (delayed treatment).<a class="elsevierStyleCrossRefs" href="#bib0250">9,10</a> We used the model to simulate results for time horizons from 2 years to lifetime. Patient's lifespans were divided into 6-month cycles. During each cycle, patients may experience a wide range of clinical events including an increase in Expanded Disability Status Scale (EDSS) scores, an MS relapse, or survival and gain of life years. Each health state had a unique set of probabilities of either remaining in the same health state or changing to other health state during each cycle (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Health states were defined according to the level of disability as measured by the EDSS,<a class="elsevierStyleCrossRef" href="#bib0285">16</a> the occurrence of a second event leading to a diagnosis of CDMS, and death. The different EDSS categories (EDSS 0; 1–1.5; 2–2.5; 3–5.5; 6; 6.5–7.5; 8–9.5; and 10) were determined by examining the data on probabilities of transition available in the literature (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0230">5,6,17–22</a> These categories were later discussed by clinical experts to identify the ones that represented the main disability markers.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The model included 2 types of relapses: conversion from CIS to CDMS and relapses after diagnosis of CDMS. Probability of relapse for CDMS patients in both treatment groups (early and delayed) was obtained from the literature (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0290">17</a> In order to account for the effect of treatment with IFNβ-1b, we applied the reduction in relapse rate estimated in the IFNβ-1b clinical trial to both groups.<a class="elsevierStyleCrossRefs" href="#bib0230">5,6</a>Two types of mortality were included in the model: all-cause mortality and mortality due to MS. All-cause mortality was estimated using the probability of death by age and sex, which was extracted from the mortality rate tables published by Spain's National Statistics Institute.<a class="elsevierStyleCrossRef" href="#bib0320">23</a> When patients scored 10 (death) on the EDSS, mortality was considered to be due to MS.Patients could discontinue treatment at any time during the time horizon to reflect the real-world situation. Additionally, we assumed that IFNβ-1b treatment was suspended when a patient scored 7 on the EDSS, based on clinical expert opinion.At the end of the model simulation, we calculated the costs and benefits of all the cycles to make cost and benefit estimations for early vs. delayed treatment. Diagnoses of CDMS were established according to the diagnostic criteria developed by Poser et al.<a class="elsevierStyleCrossRef" href="#bib0325">24</a> and McDonald et al.<a class="elsevierStyleCrossRef" href="#bib0330">25</a>In every cycle, patients who remained alive accrued 6 months of life which were later adjusted by the utility corresponding to their health state and occurrence of a relapse (when appropriate). Results from these calculations were expressed as quality-adjusted life years (QALYs). At the end of the model, QALYs of all cycles included in the time horizon were added up for each group to calculate the incremental cost-utility ratio (ICUR). The ICUR was calculated as the difference between early treatment and delayed treatment using the following formula:<elsevierMultimedia ident="eq0005"></elsevierMultimedia>Likewise, we calculated the incremental cost-effectiveness ratio (ICER) considering the relapses avoided for each treatment group.We used a 50-year time horizon in the analysis, since the mean age of the patients who participated in the BENEFIT<a class="elsevierStyleCrossRef" href="#bib0245">8</a> trial was 30 years, and the average life expectancy in Spain is around 80 years.<a class="elsevierStyleCrossRef" href="#bib0335">26</a>The model was created from a Spanish societal perspective. Furthermore, we undertook an additional analysis from the perspective of the Spanish National Health System (SNHS). All costs were calculated in 2013 euros, and costs and results were discounted at an annual rate of 3%.<a class="elsevierStyleCrossRef" href="#bib0340">27</a>Data sourcesThe main data source for our model was the BENEFIT clinical trial.<a class="elsevierStyleCrossRef" href="#bib0245">8</a> This trial assessed the impact of IFNβ-1b treatment after CIS (early treatment) compared with the impact of delaying IFNβ-1b treatment until diagnosis of CDMS (delayed treatment).<a class="elsevierStyleCrossRefs" href="#bib0250">9,10</a> The BENEFIT study was a prospective, placebo-controlled trial conducted in 98 centres from 20 countries. We recruited a total of 468 patients with a symptomatic CIS lasting for more than 24hours and radiological findings of one or more silent lesions to the central nervous system. Patients were randomly assigned to receive either IFNβ-1b (250mg every other day) or a placebo during the first 2 years. Patients included in the placebo group continued receiving the placebo until they were diagnosed with CDMS according to the Poser et al.<a class="elsevierStyleCrossRef" href="#bib0325">24</a> criteria or until the end of the placebo-controlled phase (2 years). Patients who completed the placebo-controlled phase were offered the possibility of being treated with IFNβ-1b for up to 5 years from randomisation. The results obtained at the end of the study period showed that the number of patients developing CDMS was significantly lower in the IFNβ-1b group than in the placebo group (28% vs. 45%, P<.0001).<a class="elsevierStyleCrossRef" href="#bib0250">9</a> The results obtained at 5 years showed that the risk of conversion to CDMS in patients who started IFNβ-1b treatment after a CIS decreased by 37% (P=.003) in comparison with patients treated with a placebo.<a class="elsevierStyleCrossRef" href="#bib0255">10</a>We used data from the BENEFIT trial corresponding to the first 2 years for the placebo group and the first 5 years for the IFNβ-1b group to calculate the 10-year probability of conversion from CIS to MS in both groups. We used the Kaplan–Meier survival curve for this purpose (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). We did not extrapolate data beyond the 10-year time frame. For cycles in the model after that time frame, we used the probability of conversion for the respective tenth year cycle.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Treatment discontinuation rates were obtained from data extrapolated from the Stockholm Swedish MS Registry<a class="elsevierStyleCrossRef" href="#bib0345">28</a> and applied to both early and delayed treatment groups. Registry data were adjusted using Weibull distributions and extrapolated to calculate the treatment distribution rates for a period of 50 years. The treatment discontinuation rate increased with time and at approximately half the time horizon all patients had discontinued treatment. This rate was similar in both groups. Furthermore, we assumed that once patients suspended treatment (not including changes in treatment), they did it until the end of the time horizon.Healthcare and non-healthcare costs (informal care and loss of productivity) of MS treatment were estimated based on data published by Kobelt et al.<a class="elsevierStyleCrossRef" href="#bib0350">29</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Costs for patients with MS calculated according to EDSS scores were also used for patients with a CIS. We assumed one adverse event (that is, an event motivating an unscheduled medical consultation, which was assigned the unitary cost of a medical appointment) per year attributable to IFNβ-1b treatment. Annual cost of purchasing IFNβ-1b (administration not included) was obtained from the General Council of Official Colleges of Pharmacists (CGCOF) website.<a class="elsevierStyleCrossRef" href="#bib0355">30</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>We used the EuroQol-5 Dimensional Questionnaire data collected every 6 months during the BENEFIT trial to estimate the specific utility value of each EDSS health state of the model. We calculated the mean value for each EDSS health state using the conversion algorithm developed by Dolan.<a class="elsevierStyleCrossRef" href="#bib0360">31</a> Utilities of the health states for a period beyond the follow-up phase of the BENEFIT trial were estimated using published data based on EDSS scores and occurrence of relapses.<a class="elsevierStyleCrossRefs" href="#bib0365">32,33</a>Model analysisThe analysis of the base case assessed the ICUR and ICER by comparing the differences between costs per QALYs or relapses avoided in early vs. delayed treatment from a societal perspective. This same analysis was conducted from the SNHS perspective.A probabilistic sensitivity analysis was performed to determine the robustness of the model using a second-order Monte Carlo simulation. We used the beta distribution for the results from the BENEFIT trial for likelihood of effectiveness (EDSS/disability progression, relapse rate, conversion to CDMS) and utility values, and the gamma distribution for costs.ResultsIn the base case (with a 50-year time horizon), both the ICUR and the ICER of early treatment with IFNβ-1b vs. delayed treatment were dominant (ie, less costly and more efficient) from the societal perspective (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Both Poser and McDonald diagnostic criteria were used.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>From the SNHS perspective, ICUR was €40701.9/QALY and ICER €13.07/relapse avoided (including healthcare costs only) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).The number of relapses (conversions from CIS to CDMS and relapses after CDMS diagnosis) was lower in the early treatment group than in the delayed treatment group, which proves that early treatment with IFNβ-1b after a CIS is beneficial (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Early treatment incurred higher healthcare costs (€30038 difference), whereas delayed treatment incurred higher non-healthcare costs (€39875 difference) over the 50-year horizon. In both groups, costs due to early retirement accounted for more than 96% of the total costs resulting from loss of productivity. After adding healthcare and non-healthcare costs together, delayed treatment incurred higher total costs (€9837 difference) than early treatment (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a> shows the results of the Monte Carlo simulation used for the sensitivity analysis. Incremental costs and incremental QALYs are charted in the cost-effectiveness scatter plot as individual dots for each of the 1000 simulated patients. This figure shows that more than half of the dots are located in the right lower quadrant of the plot, which indicates lower costs and greater effectiveness, while all the dots indicating higher costs (right upper quadrant) have an ICUR of less than €30000/QALY (the cost-effectiveness threshold used in Spain).<a class="elsevierStyleCrossRef" href="#bib0375">34</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>DiscussionOur study assessed the cost-effectiveness of early IFNβ-1b treatment of patients with a CIS vs. delayed treatment until CDMS diagnosis. Our analyses showed that from a societal perspective and using either Poser or McDonald diagnostic criteria, early treatment was associated with lower costs and greater effectiveness when compared with delayed treatment.Although QALYs are the most common denominator in ICER, other cost-effectiveness measurements included in this model also provide useful information on the importance of early treatment. For example, early treatment also proved to be less costly and more effective when we defined effectiveness as the total number of relapses in the MS group. This supported the conclusion that early treatment has a high cost-benefit ratio in terms of relapse burden in the MS group since it delays conversion to CDMS.There is limited information in the literature about the cost-effectiveness of early treatment for a CIS. Lazzaro et al.<a class="elsevierStyleCrossRef" href="#bib0380">35</a> showed that early treatment with IFNβ-1b, in comparison with delayed treatment, was dominant from the societal perspective in Italy, which goes in line with our results. Iskedjian et al.<a class="elsevierStyleCrossRef" href="#bib0385">36</a> also made an economic evaluation of a DMT after a CIS and found that treatment with IFNβ-1b was cost-effective from the Canadian societal perspective. However, in the model used in that study, results of health-related benefits were not presented as costs per QALY; therefore, those results are not directly comparable to ours. Two more studies with comparable data from the societal perspective have recently been published.<a class="elsevierStyleCrossRefs" href="#bib0390">37,38</a> Pan et al.<a class="elsevierStyleCrossRef" href="#bib0390">37</a> published their results using the same model adapted to the USA, which showed an ICER of $46357 per QALY gained and $30967 per life year gained. However, a study adapting this model to Sweden<a class="elsevierStyleCrossRef" href="#bib0395">38</a> found that early treatment with IFNβ-1b dominated delayed treatment when effectiveness was measured in terms of QALYs gained. These 2 reports showed results using this model; however conclusions differ when comparing Sweden and Spain on the one hand (with similar results) to the USA on the other, probably due to healthcare system as well as medical care cost differences between these 2 European countries and the USA.Despite some limitations and uncertainties in their economic models, several studies have shown that disease progression is associated with increased costs<a class="elsevierStyleCrossRefs" href="#bib0400">39,40</a> resulting from the greater need for costly DMT, which effectively reduces relapse rates and slows MS progression, and early treatment with a DMT, which has been proposed to delay conversion to CDMS in patients with a CIS. Therefore, stabilisation of the disease at low functional grades of disability should aim to not only improve patients’ quality of life but also provide socio-economic benefits. Delaying disease progression as early as possible results in improved quality of life and functional independence, and lower costs for healthcare systems, society, and patients.<a class="elsevierStyleCrossRef" href="#bib0410">41</a>This analysis has some limitations. Firstly, the impact of IFNβ-1b treatment on MS progression is based on data from the BENEFIT clinical trial exclusively, as no data on long-term outcomes of early vs. delayed treatment after a CIS were available in the literature. Therefore, results of our model should be extrapolated to real populations with caution. Second, and due to the lack of data on patients with CIS, we assumed that costs and utilities were similar for patients in the same EDSS category, whether they had a CIS or CDMS. In addition, there is also uncertainty as to the most suitable EDSS threshold for discontinuing DMT. Our threshold is based on data extrapolated from the BENEFIT trial and expert opinion. Furthermore, we assumed that once patients discontinued treatment, they remained untreated until the end of the time horizon. However, in real life, some patients may have changed treatment. Also, and due to the lack of long-term data on the risk of adverse events of DMT, we assumed one event per person per year, based on expert opinion. However, this may have resulted in excessive additional costs. Lastly, MS patients treated with INFB-1b may develop neutralising anti-interferon beta antibodies, which could reduce the clinical efficacy of INFB-1b. The potential impact of antibodies on DMT treatment efficacy was not included in this model due to the lack of data.In conclusion, the results of our model show that early treatment with IFNβ-1b after a CIS vs. delayed treatment is efficient from the societal perspective, whether we use QALYs or relapses avoided as denominator (dominant in both cases). However, it may not be efficient from the SNHS perspective since the model does not consider non-healthcare costs (informal carers and medical leaves) or use QALY as denominator.Conflicts of interestDuring the drafting of the model, the author was working for Bayer, the company marketing the drug. The contractual relationship terminated before the manuscript was prepared." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres635432" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec647949" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres635431" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec647950" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Description of the model" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Data sources" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Model analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 9 => array:2 [ "identificador" => "xack214123" "titulo" => "Acknowledgements" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-09-23" "fechaAceptado" => "2015-03-05" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec647949" "palabras" => array:6 [ 0 => "Efficiency" 1 => "Costs" 2 => "Multiple sclerosis" 3 => "Expanded Disability Syndrome Scale" 4 => "Interferon beta 1b" 5 => "Clinically isolated syndrome" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec647950" "palabras" => array:6 [ 0 => "Eficiencia" 1 => "Costes" 2 => "Esclerosis múltiple" 3 => "Expanded Disability Syndrome Scale" 4 => "Interferón beta 1b" 5 => "Síndrome desmielinizante aislado" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionThe BENEFIT study has demonstrated the benefits of early treatment with interferon beta 1b (IFNβ-1b). The objective of this study was to estimate the efficiency of early vs. delayed IFNβ-1b treatment in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) in Spain. MethodsA Markov model reflecting the social perspective was developed with time horizons ranging from 2 years to lifetime. A cohort of 1000 patients with CIS, whose health status had been measured on the Expanded Disability Symptom Scale (EDSS), included patients who received early IFNβ-1b treatment and those who did not. Data from the BENEFIT study were used to model EDSS progression and transitions to MS. Costs were estimated from published literature. Patient utilities were derived from EQ-5D data and published data. Mortality was estimated using life tables and EDSS data. Costs (€ at 2013 rates) and outcomes were discounted at 3% per annum. A probabilistic sensitivity analysis was performed. ResultsIn the base case, both the incremental cost utility ratio (ICUR) and the incremental cost effectiveness ratio (ICER) of IFNβ-1b vs. no treatment were dominant (more effective and less costly) from a social perspective. From the perspective of the Spanish Health System, the ICUR was € 40702/QALY and the ICER was € 13/relapse avoided. ConclusionEarly treatment with IFNβ-1b after a CIS vs. delayed treatment is efficient from a social perspective, but it may not be efficient from the perspective of the NHS which does not take non health-related costs into account." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónEl estudio BENEFIT ha mostrado los beneficios del uso precoz del interferón beta 1b (IFNβ-1b). El objetivo del trabajo fue estimar la eficiencia del tratamiento precoz vs. diferido del IFNβ-1b en pacientes con un síndrome desmielinizante aislado (SDA) indicativo de esclerosis múltiple (EM) en España. MétodosSe desarrolló un modelo de Markov desde la perspectiva social, con un horizonte temporal de 2 años hasta toda la vida. Una cohorte de 1.000 pacientes con SDA y estados de salud definidos por la Expanded Disability Syndrome Scale (EDSS) fue tratada o no con IFNβ-1b al inicio. Los datos del BENEFIT se usaron para la progresión en la EDSS y las transiciones a EM. Los costes se estimaron de la literatura. Las utilidades derivaron del EQ-5D y publicaciones y la mortalidad de tablas de mortalidad y de la EDSS. Costes (€ de 2013) y resultados se descontaron al 3% anual. Se realizó un análisis de sensibilidad probabilístico. ResultadosEn el caso base, tanto la razón de coste utilidad incremental (RCUI) como la razón de coste efectividad incremental (RCEI) del IFNβ-1b vs. no tratamiento fueron dominantes (más eficaz y menos costoso) bajo la perspectiva social. Bajo la perspectiva del SNS, la RCUI fue de 40.702 €/AVAC y la RCEI de 13 €/recaída evitada. ConclusiónEl tratamiento precoz con IFNβ-1b después de un SDA frente al tratamiento diferido es eficiente desde la perspectiva social, pero puede no ser eficiente desde la perspectiva del SNS al no tener en cuenta los costes no sanitarios." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Piñol C. Análisis de coste-efectividad del interferón beta-1b en el tratamiento de pacientes con síndrome desmielinizante aislado indicativo de esclerosis múltiple en España. Neurología. 2016;31:247–254." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "Previous versions of this study (2009 data) have been published as: Arbizu T, Piñol C, Casado V, Caloyeras JP. Coste utilidad de interferón beta en el tratamiento de pacientes con síndrome desmielinizante aislado sugestivo de esclerosis múltiple en España. XXVIII Jornadas de la Asociación de Economía de la Salud. Málaga, 17–19 de junio 2009. Gaceta Sanitaria. 2009;23 Espec Cong 2:65. Arbizu T, Piñol C, Casado V. Cost-utility of interferon beta-1b in the treatment of patients with a clinical isolated syndrome suggestive of multiple sclerosis in Spain. ISPOR 12th Annual European Congress. Paris, France, 24–27 October 2009. Value in Health. 2009;12(7):A370." ] ] "multimedia" => array:8 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2235 "Ancho" => 1658 "Tamanyo" => 288768 ] ] "descripcion" => array:1 [ "en" => "Markov model health states. Treat. disc. at 5 y: treatment discontinuation at 5 years; CDMS, clinically definite multiple sclerosis; EDSS, Expanded Disability Status Scale; CIS, clinically isolated syndrome. a A patient can transition to ‘death’ from any health state during any cycle of the model. b Patients discontinuing treatment in the CIS branch during the fifth year are removed from the model at the end of the fifth year. c No transitions occur from EDSS 6 health state to EDSS 6.5–7.5 health state. The user of the model decides the score threshold to consider non-recurring MS (ie, 6, 6.5, 7, or 7.5) and the EDSS 6–7.5 health states are proportionally divided according to the EDSS score chosen." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 853 "Ancho" => 1649 "Tamanyo" => 86997 ] ] "descripcion" => array:1 [ "en" => "Extrapolated survival data from the BENEFIT study. Data from the BENEFIT trial corresponding to the first 2 years for the placebo group and the first 5 years for the active treatment group. MS, multiple sclerosis; IFNβ, interferon beta-1b; CIS, clinically isolated syndrome." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1019 "Ancho" => 2172 "Tamanyo" => 175298 ] ] "descripcion" => array:1 [ "en" => "Results from the probabilistic sensitivity analysis. QALY, quality-adjusted life years." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Taken from The IFNB Multiple Sclerosis Study Group,<a class="elsevierStyleCrossRef" href="#bib0230">5</a> The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group,<a class="elsevierStyleCrossRef" href="#bib0235">6</a> Weinshenker et al.,<a class="elsevierStyleCrossRef" href="#bib0295">18</a> Runmarker and Andersen,<a class="elsevierStyleCrossRef" href="#bib0300">19</a> Goodkin et al.,<a class="elsevierStyleCrossRef" href="#bib0305">20</a> Weinshenker and Ebers,<a class="elsevierStyleCrossRef" href="#bib0310">21</a> and Weinshenker et al.<a class="elsevierStyleCrossRef" href="#bib0315">22</a>" "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">Delayed treatment<a class="elsevierStyleCrossRef" href="#tblfn0010">b</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">Early treatment \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="3" align="left" valign="top">Likelihood of transition to the next disability level every 6 months</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">EDSS health state<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.026 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.018 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1–1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.026 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.018 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2–2.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.026 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.018 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3–5.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.054 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.037 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6–7.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.021 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.015 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">8–10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.006 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.004 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Likelihood of relapse at 6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.453 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.282 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042493.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "EDSS 0, 1–1.5, and 2–2.5 result from subdividing the 0–2.5 health state found in the references mentioned previously. The probability of progressing from a 0–2.5 health state mentioned in the references was similarly applied to every health state defined in our model." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Delayed treatment=no disease-modifying treatment before developing clinically definite multiple sclerosis." ] ] ] "descripcion" => array:1 [ "en" => "Main clinical data obtained from the literature." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Taken from Kobelt et al.<a class="elsevierStyleCrossRef" href="#bib0350">29</a> and the CGCOF.<a class="elsevierStyleCrossRef" href="#bib0355">30</a>EDSS, Expanded Disability Status Scale; IFNβ-1b, interferon beta-1b; OTC, over the counter." "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 " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Total costs (thousands of 2013 €)</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">Delayed treatment<a class="elsevierStyleCrossRef" href="#tblfn0015">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">Early treatment \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="3" align="left" valign="top">Healthcare costs</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Services \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14880 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11912 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Investments \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28647 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25572 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Other treatments with OTC drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10151 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9039 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Tests \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13333 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12941 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Outpatient care \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33277 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29921 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hospitalisation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49087 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">44762 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cost of a relapse \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14411 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12044 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Costs of IFNβ-1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">170840 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">218017 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cost per adverse event \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1646 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2100 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total healthcare costs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">336271 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">366309 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Non-healthcare costs</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Informal care \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">159047 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">131533 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Early retirement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">154182 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">142330 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Short-term leave \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6107 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5598 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total non-healthcare costs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">319336 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">279461 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Total costs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">655607 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">645770 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042494.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "Delayed treatment=no disease-modifying treatment before developing clinically definite multiple sclerosis." ] ] ] "descripcion" => array:1 [ "en" => "Costs (in thousands of 2013 euros)." ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "QALY, quality-adjusted life years; ICER, incremental cost-effectiveness ratio; ICUR, incremental cost-utility ratio; SNHS, Spanish National Health System." "tablatextoimagen" => array:2 [ 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 " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Societal perspective</th></tr><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 " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">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">QALYs \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">Relapses \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">ICUR (€/QALY) \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">ICER (€/relapse avoided) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Early \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">645707 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15.42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16202 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dominant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dominant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Delayed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">655607 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14.68 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18501 \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></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042496.png" ] ] 1 => 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 " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">SNHS perspective</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">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">QALYs \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">Relapses \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">ICUR (€/QALY) \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">ICER (€/relapse avoided) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Early \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">366309 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15.42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16202 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40702 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Delayed \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">336271 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14.68 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">18501 \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></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1042492.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Baseline results of the cost-effectiveness analysis." ] ] 6 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "EDSS, Expanded Disability Status Scale; CDMS, clinically definite multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; IFNβ-1b, interferon beta-1b; CIS, clinically isolated syndrome." "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-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Result \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">IFNβ-1b</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">Delayed treatment<a class="elsevierStyleCrossRef" href="#tblfn0020">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">Early treatment \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patients still in the CIS group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025">b</a> diagnosis (N) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">891 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">826 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025">b</a> diagnosis (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">89.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">82.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Total time (years) in:</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CIS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4884 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10188 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">38212 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32982 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CIS+CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">43096 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">43171 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Mean utility value at the end of the last cycle of the model<a class="elsevierStyleCrossRef" href="#tblfn0030">c</a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CIS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.67 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.70 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.49 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CIS+CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.50 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">QALY</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CIS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.71 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CDMS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11.51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.71 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CIS+CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14.68 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15.42 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Mean EDSS score at the end of the last cycle of the model<a class="elsevierStyleCrossRef" href="#tblfn0030">c</a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CIS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#tblfn0020">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.21 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.73 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CIS+CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5.09 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.64 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; 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"vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/21735808/0000003100000004/v1_201605130036/S2173580816300104/v1_201605130036/en/main.assets" "Apartado" => array:4 [ "identificador" => "9491" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original Articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735808/0000003100000004/v1_201605130036/S2173580816300104/v1_201605130036/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580816300104?idApp=UINPBA00004N"]

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Análisis de coste-efectividad del interferón beta-1b en el tratamiento de pacientes con síndrome desmielinizante aislado indicativo de esclerosis múltiple en España

C. Piñol

INNOVA Strategic Consulting, Barcelona, Spain

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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">Multiple sclerosis &#40;MS&#41; is an inflammatory disease of the central nervous system characterised by progressive demyelination&#46; Most MS patients present severe physical disability and cognitive impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">According to a recent study conducted in La Rioja&#44; Spain&#44; MS has a prevalence of 65 cases per 100<span class="elsevierStyleHsp" style=""></span>000 population and predominantly affects young women&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">2</span></a> The mean annual cost per patient with MS amounts to &#8364;24<span class="elsevierStyleHsp" style=""></span>272&#44; with direct costs representing around 60&#37; of the total cost&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The first manifestation of the disease in 85&#37; of the young adults who develop clinically definite MS &#40;CDMS&#41; is an event resulting from isolated demyelination of the optic nerves&#44; brainstem&#44; or spinal cord&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">1&#44;4</span></a> This event is called &#8216;clinically isolated syndrome&#8217;&#44; or CIS&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Disease-modifying treatments &#40;DMT&#41; such as interferon beta-1b &#40;IFN&#946;-1b&#41; are the standard first-line of treatment for MS outbreaks&#44; since they have been shown to reduce the exacerbation rate and slow disease progression in clinical trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">1&#44;5&#8211;7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">According to the Betaferon<span class="elsevierStyleSup">&#174;</span> in Newly Emerging Multiple Sclerosis for Initial Treatment &#40;BENEFIT&#41;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">8</span></a> trial&#44; early treatment after a CIS suggestive of MS reduces the risk of conversion to CDMS by 41&#37; compared with delayed treatment&#46; Furthermore&#44; several studies have shown that early treatment reduces the risk of disease progression by 40&#37; to 45&#37; compared with delayed treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">7&#8211;10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Whereas the cost-effectiveness of treatments for MS has been thoroughly studied&#44; this is not the case for CIS suggestive of MS&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">11&#8211;15</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The aim of this study was to estimate the cost-effectiveness in Spain of IFN&#946;-1b in patients with a CIS suggestive of MS&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Description of the model</span><p id="par0040" class="elsevierStylePara elsevierViewall">We used MS Excel<span class="elsevierStyleSup">&#174;</span> to create a Markov model to estimate the costs and benefits of a hypothetical cohort of 1000 patients &#40;mean age&#58; 30 years&#44; 70&#37; of whom were women&#44; in line with the population of the BENEFIT study&#41; with a CIS who were treated with IFN&#946;-1b &#40;250<span class="elsevierStyleHsp" style=""></span>mg every other day&#41; either right after a CIS suggestive of MS &#40;early treatment&#41; or at onset of CDMS &#40;delayed treatment&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">9&#44;10</span></a> We used the model to simulate results for time horizons from 2 years to lifetime&#46; Patient&#39;s lifespans were divided into 6-month cycles&#46; During each cycle&#44; patients may experience a wide range of clinical events including an increase in Expanded Disability Status Scale &#40;EDSS&#41; scores&#44; an MS relapse&#44; or survival and gain of life years&#46; Each health state had a unique set of probabilities of either remaining in the same health state or changing to other health state during each cycle &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">Health states were defined according to the level of disability as measured by the EDSS&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">16</span></a> the occurrence of a second event leading to a diagnosis of CDMS&#44; and death&#46; The different EDSS categories &#40;EDSS 0&#59; 1&#8211;1&#46;5&#59; 2&#8211;2&#46;5&#59; 3&#8211;5&#46;5&#59; 6&#59; 6&#46;5&#8211;7&#46;5&#59; 8&#8211;9&#46;5&#59; and 10&#41; were determined by examining the data on probabilities of transition available in the literature &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">5&#44;6&#44;17&#8211;22</span></a> These categories were later discussed by clinical experts to identify the ones that represented the main disability markers&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The model included 2 types of relapses&#58; conversion from CIS to CDMS and relapses after diagnosis of CDMS&#46; Probability of relapse for CDMS patients in both treatment groups &#40;early and delayed&#41; was obtained from the literature &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">17</span></a> In order to account for the effect of treatment with IFN&#946;-1b&#44; we applied the reduction in relapse rate estimated in the IFN&#946;-1b clinical trial to both groups&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Two types of mortality were included in the model&#58; all-cause mortality and mortality due to MS&#46; All-cause mortality was estimated using the probability of death by age and sex&#44; which was extracted from the mortality rate tables published by Spain&#39;s National Statistics Institute&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">23</span></a> When patients scored 10 &#40;death&#41; 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patients who remained alive accrued 6 months of life which were later adjusted by the utility corresponding to their health state and occurrence of a relapse &#40;when appropriate&#41;&#46; Results from these calculations were expressed as quality-adjusted life years &#40;QALYs&#41;&#46; At the end of the model&#44; QALYs of all cycles included in the time horizon were added up for each group to calculate the incremental cost-utility ratio &#40;ICUR&#41;&#46; The ICUR was calculated as the difference between early treatment and delayed treatment using the following formula&#58;<elsevierMultimedia ident="eq0005"></elsevierMultimedia></p><p id="par0075" class="elsevierStylePara elsevierViewall">Likewise&#44; we calculated the incremental cost-effectiveness ratio &#40;ICER&#41; considering the relapses avoided for each treatment group&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">We used a 50-year time horizon in the analysis&#44; since the mean age of the patients who participated in the BENEFIT<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">8</span></a> trial was 30 years&#44; and the average life expectancy in Spain is around 80 years&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">26</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The model was created from a Spanish societal perspective&#46; Furthermore&#44; we undertook an additional analysis from the perspective of the Spanish National Health System &#40;SNHS&#41;&#46; All costs were calculated in 2013 euros&#44; and costs and results were discounted at an annual rate of 3&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Data sources</span><p id="par0090" class="elsevierStylePara elsevierViewall">The main data source for our model was the BENEFIT clinical trial&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">8</span></a> This trial assessed the impact of IFN&#946;-1b treatment after CIS &#40;early treatment&#41; compared with the impact of delaying IFN&#946;-1b treatment until diagnosis of CDMS &#40;delayed treatment&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">9&#44;10</span></a> The BENEFIT study was a prospective&#44; placebo-controlled trial conducted in 98 centres from 20 countries&#46; We recruited a total of 468 patients with a symptomatic CIS lasting for more than 24<span class="elsevierStyleHsp" style=""></span>hours and radiological findings of one or more silent lesions to the central nervous system&#46; Patients were randomly assigned to receive either IFN&#946;-1b &#40;250<span class="elsevierStyleHsp" style=""></span>mg every other day&#41; or a placebo during the first 2 years&#46; Patients included in the placebo group continued receiving the placebo until they were diagnosed with CDMS according to the Poser et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">24</span></a> criteria or until the end of the placebo-controlled phase &#40;2 years&#41;&#46; Patients who completed the placebo-controlled phase were offered the possibility of being treated with IFN&#946;-1b for up to 5 years from randomisation&#46; The results obtained at the end of the study period showed that the number of patients developing CDMS was significantly lower in the IFN&#946;-1b group than in the placebo group &#40;28&#37; vs&#46; 45&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">9</span></a> The results obtained at 5 years showed that the risk of conversion to CDMS in patients who started IFN&#946;-1b treatment after a CIS decreased by 37&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;003&#41; in comparison with patients treated with a placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">10</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">We used data from the BENEFIT trial corresponding to the first 2 years for the placebo group and the first 5 years for the IFN&#946;-1b group to calculate the 10-year probability of conversion from CIS to MS in both groups&#46; We used the Kaplan&#8211;Meier survival curve for this purpose &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; We did not extrapolate data beyond the 10-year time frame&#46; For cycles in the model after that time frame&#44; we used the probability of conversion for the respective tenth year cycle&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Treatment discontinuation rates were obtained from data extrapolated from the Stockholm Swedish MS Registry<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">28</span></a> and applied to both early and delayed treatment groups&#46; Registry data were adjusted using Weibull distributions and extrapolated to calculate the treatment distribution rates for a period of 50 years&#46; The treatment discontinuation rate increased with time and at approximately half the time horizon all patients had discontinued treatment&#46; This rate was similar in both groups&#46; Furthermore&#44; we assumed that once patients suspended treatment &#40;not including changes in treatment&#41;&#44; they did it until the end of the time horizon&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Healthcare and non-healthcare costs &#40;informal care and loss of productivity&#41; of MS treatment were estimated based on data published by Kobelt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">29</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Costs for patients with MS calculated according to EDSS scores were also used for patients with a CIS&#46; We assumed one adverse event &#40;that is&#44; an event motivating an unscheduled medical consultation&#44; which was assigned the unitary cost of a medical appointment&#41; per year attributable to IFN&#946;-1b treatment&#46; Annual cost of purchasing IFN&#946;-1b &#40;administration not included&#41; was obtained from the General Council of Official Colleges of Pharmacists &#40;CGCOF&#41; website&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">30</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">We used the EuroQol-5 Dimensional Questionnaire data collected every 6 months during the BENEFIT trial to estimate the specific utility value of each EDSS health state of the model&#46; We calculated the mean value for each EDSS health state using the conversion algorithm developed by Dolan&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">31</span></a> Utilities of the health states for a period beyond the follow-up phase of the BENEFIT trial were estimated using published data based on EDSS scores and occurrence of relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">32&#44;33</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Model analysis</span><p id="par0115" class="elsevierStylePara elsevierViewall">The analysis of the base case assessed the ICUR and ICER by comparing the differences between costs per QALYs or relapses avoided in early vs&#46; delayed treatment from a societal perspective&#46; This same analysis was conducted from the SNHS perspective&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">A probabilistic sensitivity analysis was performed to determine the robustness of the model using a second-order Monte Carlo simulation&#46; We used the beta distribution for the results from the BENEFIT trial for likelihood of effectiveness &#40;EDSS&#47;disability progression&#44; relapse rate&#44; conversion to CDMS&#41; and utility values&#44; and the gamma distribution for costs&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0125" class="elsevierStylePara elsevierViewall">In the base case &#40;with a 50-year time horizon&#41;&#44; both the ICUR and the ICER of early treatment with IFN&#946;-1b vs&#46; delayed treatment were dominant &#40;ie&#44; less costly and more efficient&#41; from the societal perspective &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Both Poser and McDonald diagnostic criteria were used&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">From the SNHS perspective&#44; ICUR was &#8364;40<span class="elsevierStyleHsp" style=""></span>701&#46;9&#47;QALY and ICER &#8364;13&#46;07&#47;relapse avoided &#40;including healthcare costs only&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The number of relapses &#40;conversions from CIS to CDMS and relapses after CDMS diagnosis&#41; was lower in the early treatment group than in the delayed treatment group&#44; which proves that early treatment with IFN&#946;-1b after a CIS is beneficial &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">Early treatment incurred higher healthcare costs &#40;&#8364;30<span class="elsevierStyleHsp" style=""></span>038 difference&#41;&#44; whereas delayed treatment incurred higher non-healthcare costs &#40;&#8364;39<span class="elsevierStyleHsp" style=""></span>875 difference&#41; over the 50-year horizon&#46; In both groups&#44; costs due to early retirement accounted for more than 96&#37; of the total costs resulting from loss of productivity&#46; After adding healthcare and non-healthcare costs together&#44; delayed treatment incurred higher total costs &#40;&#8364;9837 difference&#41; than early treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a> shows the results of the Monte Carlo simulation used for the sensitivity analysis&#46; Incremental costs and incremental QALYs are charted in the cost-effectiveness scatter plot as individual dots for each of the 1000 simulated patients&#46; This figure shows that more than half of the dots are located in the right lower quadrant of the plot&#44; which indicates lower costs and greater effectiveness&#44; while all the dots indicating higher costs &#40;right upper quadrant&#41; have an ICUR of less than &#8364;30<span class="elsevierStyleHsp" style=""></span>000&#47;QALY &#40;the cost-effectiveness threshold used in Spain&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">34</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discussion</span><p id="par0150" class="elsevierStylePara elsevierViewall">Our study assessed the cost-effectiveness of early IFN&#946;-1b treatment of patients with a CIS vs&#46; delayed treatment until CDMS diagnosis&#46; Our analyses showed that from a societal perspective and using either Poser or McDonald diagnostic criteria&#44; early treatment was associated with lower costs and greater effectiveness when compared with delayed treatment&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Although QALYs are the most common denominator in ICER&#44; other cost-effectiveness measurements included in this model also provide useful information on the importance of early treatment&#46; For example&#44; early treatment also proved to be less costly and more effective when we defined effectiveness as the total number of relapses in the MS group&#46; This supported the conclusion that early treatment has a high cost-benefit ratio in terms of relapse burden in the MS group since it delays conversion to CDMS&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">There is limited information in the literature about the cost-effectiveness of early treatment for a CIS&#46; Lazzaro et al&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">35</span></a> showed that early treatment with IFN&#946;-1b&#44; in comparison with delayed treatment&#44; was dominant from the societal perspective in Italy&#44; which goes in line with our results&#46; Iskedjian et al&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">36</span></a> also made an economic evaluation of a DMT after a CIS and found that treatment with IFN&#946;-1b was cost-effective from the Canadian societal perspective&#46; However&#44; in the model used in that study&#44; results of health-related benefits were not presented as costs per QALY&#59; therefore&#44; those results are not directly comparable to ours&#46; Two more studies with comparable data from the societal perspective have recently been published&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">37&#44;38</span></a> Pan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">37</span></a> published their results using the same model adapted to the USA&#44; which showed an ICER of &#36;46<span class="elsevierStyleHsp" style=""></span>357 per QALY gained and &#36;30<span class="elsevierStyleHsp" style=""></span>967 per life year gained&#46; However&#44; a study adapting this model to Sweden<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">38</span></a> found that early treatment with IFN&#946;-1b dominated delayed treatment when effectiveness was measured in terms of QALYs gained&#46; These 2 reports showed results using this model&#59; however conclusions differ when comparing Sweden and Spain on the one hand &#40;with similar results&#41; to the USA on the other&#44; probably due to healthcare system as well as medical care cost differences between these 2 European countries and the USA&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Despite some limitations and uncertainties in their economic models&#44; several studies have shown that disease progression is associated with increased costs<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">39&#44;40</span></a> resulting from the greater need for costly DMT&#44; which effectively reduces relapse rates and slows MS progression&#44; and early treatment with a DMT&#44; which has been proposed to delay conversion to CDMS in patients with a CIS&#46; Therefore&#44; stabilisation of the disease at low functional grades of disability should aim to not only improve patients&#8217; quality of life but also provide socio-economic benefits&#46; Delaying disease progression as early as possible results in improved quality of life and functional independence&#44; and lower costs for healthcare systems&#44; society&#44; and patients&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">41</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">This analysis has some limitations&#46; Firstly&#44; the impact of IFN&#946;-1b treatment on MS progression is based on data from the BENEFIT clinical trial exclusively&#44; as no data on long-term outcomes of early vs&#46; delayed treatment after a CIS were available in the literature&#46; Therefore&#44; results of our model should be extrapolated to real populations with caution&#46; Second&#44; and due to the lack of data on patients with CIS&#44; we assumed that costs and utilities were similar for patients in the same EDSS category&#44; whether they had a CIS or CDMS&#46; In addition&#44; there is also uncertainty as to the most suitable EDSS threshold for discontinuing DMT&#46; Our threshold is based on data extrapolated from the BENEFIT trial and expert opinion&#46; Furthermore&#44; we assumed that once patients discontinued treatment&#44; they remained untreated until the end of the time horizon&#46; However&#44; in real life&#44; some patients may have changed treatment&#46; Also&#44; and due to the lack of long-term data on the risk of adverse events of DMT&#44; we assumed one event per person per year&#44; based on expert opinion&#46; However&#44; this may have resulted in excessive additional costs&#46; Lastly&#44; MS patients treated with INFB-1b may develop neutralising anti-interferon beta antibodies&#44; which could reduce the clinical efficacy of INFB-1b&#46; The potential impact of antibodies on DMT treatment efficacy was not included in this model due to the lack of data&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">In conclusion&#44; the results of our model show that early treatment with IFN&#946;-1b after a CIS vs&#46; delayed treatment is efficient from the societal perspective&#44; whether we use QALYs or relapses avoided as denominator &#40;dominant in both cases&#41;&#46; However&#44; it may not be efficient from the SNHS perspective since the model does not consider non-healthcare costs &#40;informal carers and medical leaves&#41; or use QALY as denominator&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">During the drafting of the model&#44; the author was working for Bayer&#44; the company marketing the drug&#46; The contractual relationship terminated before the manuscript was prepared&#46;</p></span></span>"
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            1 => "Costs"
            2 => "Multiple sclerosis"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The BENEFIT study has demonstrated the benefits of early treatment with interferon beta 1b &#40;IFN&#946;-1b&#41;&#46; The objective of this study was to estimate the efficiency of early vs&#46; delayed IFN&#946;-1b treatment in patients with clinically isolated syndrome &#40;CIS&#41; suggestive of multiple sclerosis &#40;MS&#41; in Spain&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A Markov model reflecting the social perspective was developed with time horizons ranging from 2 years to lifetime&#46; A cohort of 1000 patients with CIS&#44; whose health status had been measured on the Expanded Disability Symptom Scale &#40;EDSS&#41;&#44; included patients who received early IFN&#946;-1b treatment and those who did not&#46; Data from the BENEFIT study were used to model EDSS progression and transitions to MS&#46; Costs were estimated from published literature&#46; Patient utilities were derived from EQ-5D data and published data&#46; Mortality was estimated using life tables and EDSS data&#46; Costs &#40;&#8364; at 2013 rates&#41; and outcomes were discounted at 3&#37; per annum&#46; A probabilistic sensitivity analysis was performed&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">In the base case&#44; both the incremental cost utility ratio &#40;ICUR&#41; and the incremental cost effectiveness ratio &#40;ICER&#41; of IFN&#946;-1b vs&#46; no treatment were dominant &#40;more effective and less costly&#41; from a social perspective&#46; From the perspective of the Spanish Health System&#44; the ICUR was &#8364; 40<span class="elsevierStyleHsp" style=""></span>702&#47;QALY and the ICER was &#8364; 13&#47;relapse avoided&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Early treatment with IFN&#946;-1b after a CIS vs&#46; delayed treatment is efficient from a social perspective&#44; but it may not be efficient from the perspective of the NHS which does not take non health-related costs into account&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El estudio BENEFIT ha mostrado los beneficios del uso precoz del interfer&#243;n beta 1b &#40;IFN&#946;-1b&#41;&#46; El objetivo del trabajo fue estimar la eficiencia del tratamiento precoz vs&#46; diferido del IFN&#946;-1b en pacientes con un s&#237;ndrome desmielinizante aislado &#40;SDA&#41; indicativo de esclerosis m&#250;ltiple &#40;EM&#41; en Espa&#241;a&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se desarroll&#243; un modelo de Markov desde la perspectiva social&#44; con un horizonte temporal de 2 a&#241;os hasta toda la vida&#46; Una cohorte de 1&#46;000 pacientes con SDA y estados de salud definidos por la Expanded Disability Syndrome Scale &#40;EDSS&#41; fue tratada o no con IFN&#946;-1b al inicio&#46; Los datos del BENEFIT se usaron para la progresi&#243;n en la EDSS y las transiciones a EM&#46; Los costes se estimaron de la literatura&#46; Las utilidades derivaron del EQ-5D y publicaciones y la mortalidad de tablas de mortalidad y de la EDSS&#46; Costes &#40;&#8364; de 2013&#41; y resultados se descontaron al 3&#37; anual&#46; Se realiz&#243; un an&#225;lisis de sensibilidad probabil&#237;stico&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">En el caso base&#44; tanto la raz&#243;n de coste utilidad incremental &#40;RCUI&#41; como la raz&#243;n de coste efectividad incremental &#40;RCEI&#41; del IFN&#946;-1b vs&#46; no tratamiento fueron dominantes &#40;m&#225;s eficaz y menos costoso&#41; bajo la perspectiva social&#46; Bajo la perspectiva del SNS&#44; la RCUI fue de 40&#46;702 &#8364;&#47;AVAC y la RCEI de 13 &#8364;&#47;reca&#237;da evitada&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El tratamiento precoz con IFN&#946;-1b despu&#233;s de un SDA frente al tratamiento diferido es eficiente desde la perspectiva social&#44; pero puede no ser eficiente desde la perspectiva del SNS al no tener en cuenta los costes no sanitarios&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0035">Please cite this article as&#58; Pi&#241;ol C&#46; An&#225;lisis de coste-efectividad del interfer&#243;n beta-1b en el tratamiento de pacientes con s&#237;ndrome desmielinizante aislado indicativo de esclerosis m&#250;ltiple en Espa&#241;a&#46; Neurolog&#237;a&#46; 2016&#59;31&#58;247&#8211;254&#46;</p>"
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        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Previous versions of this study &#40;2009 data&#41; have been published as&#58;</p> <p class="elsevierStyleNotepara" id="npar0045">Arbizu T&#44; Pi&#241;ol C&#44; Casado V&#44; Caloyeras JP&#46; Coste utilidad de interfer&#243;n beta en el tratamiento de pacientes con s&#237;ndrome desmielinizante aislado sugestivo de esclerosis m&#250;ltiple en Espa&#241;a&#46; XXVIII Jornadas de la Asociaci&#243;n de Econom&#237;a de la Salud&#46; M&#225;laga&#44; 17&#8211;19 de junio 2009&#46; Gaceta Sanitaria&#46; 2009&#59;23 Espec Cong 2&#58;65&#46;</p> <p class="elsevierStyleNotepara" id="npar0050">Arbizu T&#44; Pi&#241;ol C&#44; Casado V&#46; Cost-utility of interferon beta-1b in the treatment of patients with a clinical isolated syndrome suggestive of multiple sclerosis in Spain&#46; ISPOR 12th Annual European Congress&#46; Paris&#44; France&#44; 24&#8211;27 October 2009&#46; Value in Health&#46; 2009&#59;12&#40;7&#41;&#58;A370&#46;</p>"
      ]
    ]
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        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "figura" => array:1 [
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Markov model health states&#46; Treat&#46; disc&#46; at 5 y&#58; treatment discontinuation at 5 years&#59; CDMS&#44; clinically definite multiple sclerosis&#59; EDSS&#44; Expanded Disability Status Scale&#59; CIS&#44; clinically isolated syndrome&#46;</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span> A patient can transition to &#8216;death&#8217; from any health state during any cycle of the model&#46;</p> <p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">b</span> Patients discontinuing treatment in the CIS branch during the fifth year are removed from the model at the end of the fifth year&#46;</p> <p id="spar0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">c</span> No transitions occur from EDSS 6 health state to EDSS 6&#46;5&#8211;7&#46;5 health state&#46; The user of the model decides the score threshold to consider non-recurring MS &#40;ie&#44; 6&#44; 6&#46;5&#44; 7&#44; or 7&#46;5&#41; and the EDSS 6&#8211;7&#46;5 health states are proportionally divided according to the EDSS score chosen&#46;</p>"
        ]
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      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Extrapolated survival data from the BENEFIT study&#46; Data from the BENEFIT trial corresponding to the first 2 years for the placebo group and the first 5 years for the active treatment group&#46; MS&#44; multiple sclerosis&#59; IFN&#946;&#44; interferon beta-1b&#59; CIS&#44; clinically isolated syndrome&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Results from the probabilistic sensitivity analysis&#46; QALY&#44; quality-adjusted life years&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Taken from The IFNB Multiple Sclerosis Study Group&#44;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">5</span></a> The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS&#47;MRI Analysis Group&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">6</span></a> Weinshenker et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">18</span></a> Runmarker and Andersen&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a> Goodkin et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">20</span></a> Weinshenker and Ebers&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">21</span></a> and Weinshenker et al&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">22</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
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                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">Delayed treatment<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</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">Early treatment&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="3" align="left" valign="top"><span class="elsevierStyleBold">Likelihood of transition to the next disability level every 6 months</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">EDSS health state</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;026&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>1&#8211;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;026&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2&#8211;2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;026&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>3&#8211;5&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;054&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;037&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>6&#8211;7&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>8&#8211;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Likelihood of relapse at 6 months</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;453&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;282&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1042493.png"
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          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">EDSS 0&#44; 1&#8211;1&#46;5&#44; and 2&#8211;2&#46;5 result from subdividing the 0&#8211;2&#46;5 health state found in the references mentioned previously&#46; The probability of progressing from a 0&#8211;2&#46;5 health state mentioned in the references was similarly applied to every health state defined in our model&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Delayed treatment<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>no disease-modifying treatment before developing clinically definite multiple sclerosis&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Main clinical data obtained from the literature&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
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            "identificador" => "at2"
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            "rol" => "short"
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Taken from Kobelt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">29</span></a> and the CGCOF&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">30</span></a></p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">EDSS&#44; Expanded Disability Status Scale&#59; IFN&#946;-1b&#44; interferon beta-1b&#59; OTC&#44; over the counter&#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  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Total costs &#40;thousands of 2013 &#8364;&#41;</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">Delayed treatment<a class="elsevierStyleCrossRef" href="#tblfn0015"><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">Early treatment&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="3" align="left" valign="top"><span class="elsevierStyleItalic">Healthcare costs</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Services&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14<span class="elsevierStyleHsp" style=""></span>880&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11<span class="elsevierStyleHsp" style=""></span>912&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Investments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28<span class="elsevierStyleHsp" style=""></span>647&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25<span class="elsevierStyleHsp" style=""></span>572&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Other treatments with OTC drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10<span class="elsevierStyleHsp" style=""></span>151&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9039&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " 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="char" valign="top">13<span class="elsevierStyleHsp" style=""></span>333&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12<span class="elsevierStyleHsp" style=""></span>941&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Outpatient care&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33<span class="elsevierStyleHsp" style=""></span>277&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29<span class="elsevierStyleHsp" style=""></span>921&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hospitalisation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">49<span class="elsevierStyleHsp" style=""></span>087&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">44<span class="elsevierStyleHsp" style=""></span>762&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cost of a relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14<span class="elsevierStyleHsp" style=""></span>411&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12<span class="elsevierStyleHsp" style=""></span>044&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Costs of IFN&#946;-1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">170<span class="elsevierStyleHsp" style=""></span>840&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">218<span class="elsevierStyleHsp" style=""></span>017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cost per adverse event&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1646&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Total healthcare costs</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">336<span class="elsevierStyleHsp" style=""></span>271&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">366<span class="elsevierStyleHsp" style=""></span>309&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="3" 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="3" align="left" valign="top"><span class="elsevierStyleItalic">Non-healthcare costs</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Informal care&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">159<span class="elsevierStyleHsp" style=""></span>047&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">131<span class="elsevierStyleHsp" style=""></span>533&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Early retirement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">154<span class="elsevierStyleHsp" style=""></span>182&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">142<span class="elsevierStyleHsp" style=""></span>330&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Short-term leave&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6107&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5598&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Total non-healthcare costs</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">319<span class="elsevierStyleHsp" style=""></span>336&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">279<span class="elsevierStyleHsp" style=""></span>461&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="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Total costs</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">655<span class="elsevierStyleHsp" style=""></span>607&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">645<span class="elsevierStyleHsp" style=""></span>770&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1042494.png"
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Delayed treatment<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>no disease-modifying treatment before developing clinically definite multiple sclerosis&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Costs &#40;in thousands of 2013 euros&#41;&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">QALY&#44; quality-adjusted life years&#59; ICER&#44; incremental cost-effectiveness ratio&#59; ICUR&#44; incremental cost-utility ratio&#59; SNHS&#44; Spanish National Health System&#46;</p>"
          "tablatextoimagen" => array:2 [
            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  " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Societal perspective</th></tr><tr title="table-row"><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">Costs &#40;&#8364;&#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">QALYs&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">Relapses&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">ICUR &#40;&#8364;&#47;QALY&#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">ICER &#40;&#8364;&#47;relapse avoided&#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-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Early&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">645<span class="elsevierStyleHsp" style=""></span>707&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;42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16<span class="elsevierStyleHsp" style=""></span>202&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dominant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dominant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Delayed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">655<span class="elsevierStyleHsp" style=""></span>607&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18<span class="elsevierStyleHsp" style=""></span>501&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></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1042496.png"
              ]
            ]
            1 => 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  " colspan="6" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">SNHS perspective</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">Costs &#40;&#8364;&#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">QALYs&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">Relapses&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">ICUR &#40;&#8364;&#47;QALY&#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">ICER &#40;&#8364;&#47;relapse avoided&#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-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Early&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">366<span class="elsevierStyleHsp" style=""></span>309&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;42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16<span class="elsevierStyleHsp" style=""></span>202&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40<span class="elsevierStyleHsp" style=""></span>702&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Delayed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">336<span class="elsevierStyleHsp" style=""></span>271&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18<span class="elsevierStyleHsp" style=""></span>501&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></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1042492.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Baseline results of the cost-effectiveness analysis&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">EDSS&#44; Expanded Disability Status Scale&#59; CDMS&#44; clinically definite multiple sclerosis&#59; RRMS&#44; relapsing-remitting multiple sclerosis&#59; SPMS&#44; secondary progressive multiple sclerosis&#59; IFN&#946;-1b&#44; interferon beta-1b&#59; CIS&#44; clinically isolated syndrome&#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-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Result&nbsp;\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">IFN&#946;-1b</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">Delayed treatment<a class="elsevierStyleCrossRef" href="#tblfn0020"><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">Early treatment&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-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Patients still in the CIS group</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a> diagnosis &#40;N&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">891&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">826&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a> diagnosis &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">89&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">82&#46;6&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="3" 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="3" align="left" valign="top"><span class="elsevierStyleItalic">Total time &#40;years&#41; in&#58;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CIS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4884&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>188&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025"><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">38<span class="elsevierStyleHsp" style=""></span>212&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32<span class="elsevierStyleHsp" style=""></span>982&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CIS<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025"><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">43<span class="elsevierStyleHsp" style=""></span>096&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43<span class="elsevierStyleHsp" style=""></span>171&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="3" 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="3" align="left" valign="top"><span class="elsevierStyleItalic">Mean utility value at the end of the last cycle of the model</span><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">c</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CIS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;67&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025"><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">0&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CIS<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025"><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">0&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;50&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="3" 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="3" align="left" valign="top"><span class="elsevierStyleItalic">QALY</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CIS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CDMS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#46;51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#46;71&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CIS<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025"><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">14&#46;68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&#46;42&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="3" 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="3" align="left" valign="top"><span class="elsevierStyleItalic">Mean EDSS score at the end of the last cycle of the model</span><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">c</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CIS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</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">2&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CDMS<a class="elsevierStyleCrossRef" href="#tblfn0025"><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">5&#46;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;73&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 21735808
Original language: English

DOI:10.1016/j.nrleng.2015.03.005

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Year/Month	Html	Pdf	Total

2024 October	12	7	19
2024 September	59	6	65
2024 August	37	5	42
2024 July	13	7	20
2024 June	20	4	24
2024 May	18	7	25
2024 April	35	9	44
2024 March	57	6	63
2024 February	143	7	150
2024 January	25	9	34
2023 December	17	21	38
2023 November	14	9	23
2023 October	27	17	44
2023 September	21	5	26
2023 August	23	6	29
2023 July	21	5	26
2023 June	20	11	31
2023 May	28	9	37
2023 April	41	7	48
2023 March	18	2	20
2023 February	15	10	25
2023 January	30	10	40
2022 December	45	6	51
2022 November	44	7	51
2022 October	30	11	41
2022 September	25	27	52
2022 August	30	37	67
2022 July	20	8	28
2022 June	26	6	32
2022 May	46	9	55
2022 April	52	18	70
2022 March	40	10	50
2022 February	30	11	41
2022 January	61	17	78
2021 December	35	12	47
2021 November	22	9	31
2021 October	41	6	47
2021 September	22	11	33
2021 August	25	19	44
2021 July	28	5	33
2021 June	26	14	40
2021 May	32	16	48
2021 April	29	19	48
2021 March	32	14	46
2021 February	13	4	17
2021 January	19	13	32
2020 December	17	3	20
2020 November	26	4	30
2020 October	17	7	24
2020 September	25	14	39
2020 August	24	3	27
2020 July	29	7	36
2020 June	24	4	28
2020 May	23	14	37
2020 April	22	0	22
2020 March	29	4	33
2020 February	27	8	35
2020 January	25	9	34
2019 December	30	7	37
2019 November	17	11	28
2019 October	16	5	21
2019 September	18	12	30
2019 August	16	1	17
2019 July	32	17	49
2019 June	49	23	72
2019 May	123	9	132
2019 April	56	19	75
2019 March	12	3	15
2019 February	20	9	29
2019 January	11	10	21
2018 December	7	7	14
2018 November	17	1	18
2018 October	21	8	29
2018 September	21	1	22
2018 August	5	9	14
2018 July	10	2	12
2018 June	12	5	17
2018 May	22	3	25
2018 April	3	3	6
2018 March	11	2	13
2018 February	7	2	9
2018 January	13	1	14
2017 December	7	1	8
2017 November	16	2	18
2017 October	8	4	12
2017 September	11	4	15
2017 August	15	2	17
2017 July	12	1	13
2017 June	20	4	24
2017 May	23	2	25
2017 April	11	4	15
2017 March	15	3	18
2017 February	13	2	15
2017 January	18	4	22
2016 December	19	7	26
2016 November	26	1	27
2016 October	44	2	46
2016 September	32	7	39
2016 August	23	1	24
2016 July	30	6	36
2016 June	25	7	32
2016 May	24	13	37

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