ORIGINALES

 

Cost-minimization analysis in the treatment of spasticity in children with cerebral palsy with botulinum toxin type A: an observational, longitudinal, retrospective study

Análisis de minimización de costes del tratamiento de la espasticidad en niños con parálisis cerebral con toxina botulínica tipo A: un estudio observacional, longitudinal, retrospectivo

 

 

Gloria Tapias¹, Mar García-Romero², Carlos Crespo^3,4, Maribel Cuesta³, Carles Forné³ and Samuel Ignacio Pascual-Pascual²

¹Ipsen Pharma S.A., Barcelona.
²Paediatric Neurology Unit, Hospital Universitario Materno Infantil La Paz, Madrid.
³Department of Health Economics and Outcomes Research, Oblikue Consulting S.L., Barcelona.
⁴Department of Statistics, Universitat de Barcelona, Barcelona. Spain.

This study has been funded by Ipsen Pharma.

Correspondence

 

 

---

ABSTRACT

Objective: Cost-minimization analysis of onabotulinumtoxinA and abobotulinumtoxinA, taking into account the real dose administered to children with spasticity associated with dynamic equinus foot deformity due to cerebral palsy.
Method: A single centre, observational, longitudinal, and retrospective study which included spastic paediatric patients aged 2-to-18-years and treated with onabotulinumtoxinA or abobotulinumtoxinA from December 1995 to October 2012, in the Paediatric Neurology Unit of a first-level Spanish hospital. A longitudinal analysis of spasticity severity was made to confirm the similar effectiveness of both treatments. Cost minimization was analyzed using the dose administered and the direct costs (pharmacological and medical visits costs) from the perspective of the National Health System (in 2016 euros).
Results: We analyzed 895 patients with paediatric spasticity: 543 were treated only with onabotulinumtoxinA, 292 only with abobotulinumtoxinA, and 60 with both treatments. The mean doses administered were 5.44 U/kg (SD = 2.17) for onabotulinumtoxinA, and 14.73 U/kg (5.26) for abobotulinumtoxinA. The total annual direct cost (pharmacological and medical visits) was € 839.56 for onabotulinumtoxinA and € 631.23 for abobotulinumtoxinA, which represents a difference of € 208.34 per year in favour of treatment with abobotulinum-toxinA.
Conclusions: It has been shown that in real clinical practice, the cost per patient and year for treatment of paediatric spasticity was lower when abobotulinumtoxinA was used.

Key words: Botulinum toxins; Paediatric spasticity; Clinical practice dose; Equinus foot; Spain.

---

RESUMEN

Objetivo: Estudio de minimización de costes de onabotulinumtoxinA y de abobotulinumtoxinA, teniendo en cuenta la dosis real administrada, en niños con espasticidad asociada con la deformidad dinámica del pie equino debida a parálisis cerebral.
Método: Estudio unicéntrico, observacional, longitudinal y retrospectivo que incluyó pacientes pediátricos espásticos entre 2 y 18 años tratados con onabotulinumtoxinA o abobotulinumtoxinA, entre diciembre del 1995 y octubre del 2012, en el Servicio de Neurología Pediátrica de un hospital español de primer nivel. Se realizó un análisis longitudinal de la gravedad de la espasticidad para confirmar la similar efectividad de ambos tratamientos y proceder al análisis de minimización de costes que contempló las dosis infiltradas y los costes directos (costes farmacológicos y de visitas) desde la perspectiva del Sistema Nacional de Salud (euros 2016).
Resultados: Se analizaron 895 pacientes con espasticidad infantil, 543 fueron tratados únicamente con onabotulinumtoxinA, 292 con abobotulinumtoxinA y 60 con ambos tratamientos. Las dosis medias infiltradas obtenidas fueron de 5,44 U/kg (DE = 2,17) para las infiltraciones con onabotulinumtoxinA y de 14,73 U/kg (5,26) para las infiltraciones con abobotulinumtoxinA. El coste directo anual total (farmacológico y visitas) fue de 839,56 € para onabotulinumtoxinA y de 631,23 € para abobotulinumtoxinA, lo que supone una diferencia de 208,34 € al año a favor del tratamiento con abobotulinumtoxinA.
Conclusiones: Se ha mostrado que en práctica clínica real el coste por paciente y año del tratamiento de la espasticidad infantil resulta más económico con la utilización de abobotulinumtoxinA.

Palabras clave: Toxinas botulínicas; Espasticidad infantil; Dosis práctica clínica; Pie equino; España.

---

 

Contribution to scientific literature

The main contribution of this study is that its outcomes correspond to the treatment of paediatric spasticity with botulinum toxin type A in real clinical practice with Spanish patients.

The treatment of paediatric spasticity with Dysport^® represents potential savings in the pharmacological cost per patient, compared with treatment with Botox^®.

 

Introduction

Spasticity is a motor disorder, characterized by a velocity-dependent increase in the tonic stretch reflex, which might cause pain and disability due to the damage or lesion of the central nervous system part which controls voluntary movement¹. This damage interrupts major signals between the nervous system and the muscles, creating an imbalance which increases muscular activity and/or causes spasms. Spasticity can cause difficulties in movements, posture and balance. It can affect the ability to move one or various limbs or one side of the body. Moreover, sometimes spasticity is so severe that it affects daily activities, sleep patterns, and child care.

The main objective of treatment is an improvement in motor function, pain reduction, and preventing complications, with the primary aim of improving the health-related quality of life of patients².

Alongside motor rehabilitation, botulinum toxin type A (TBA) is considered one of the main treatments of choice for focal spastic and dystonia syndromes, regardless of their causes^2-4. Since over a decade ago, TBA has been used in adults and children with neurological conditions that present spasms, muscular hypertonia and/or dystonia.

Clinical trial data have demonstrated that the different pharmacological formulations of TBA present a similar effectiveness and safety profile⁵.

In Spain, three TBA formulations are currently available, with a similar effectiveness and safety profile: Dysport^®abobotulinumtoxinA (Ipsen Pharma), Botox^®onabotulinumtoxinA (Allergan) and Xeomin^®incobotulinumtoxinA (Merz Pharma)⁶. Each formulation has specific clinical recommendations, based on the scientific information available; and their biochemical profiles are different⁷. Their units are specific for each preparation, and not interchangeable with other botulinum toxin compounds^8-10. So far there have been two studies conducted in Spain that analyze the costs of using TBA. However, these assessments were made based on the recommended dose for each indication according to the product specifications^11,12. However, the real doses used for TBA in clinical practice in Spain are unknown; and therefore, it is impossible to conduct a real quantification of costs of the different treatments marketed for TBA.

The objective of this study was to compare the costs and effectiveness of Botox^® and Dysport^®, considering the real dose administered to children with spasticity associated with the dynamic equinus foot deformity due to cerebral palsy (Xeomin^® was excluded, because it has not been approved for treatment of paediatric spasticity). To that aim, a longitudinal analysis of spasticity severity was conducted, in order to confirm that both treatments had similar effectiveness, and subsequently conduct the cost-minimization analysis.

 

Material and Methods

Design and Study Population

An observational, longitudinal and retrospective study was conducted in a cohort of 936 patients with paediatric spasticity treated with Botox^® or Dysport^®, between December, 1995 and October, 2012, at the Paediatric Neurology Unit of a first-level Spanish hospital. From the total number of patients registered, 895 were adequate for assessment according to selection criteria (Figure 1): Spastic patients <18-year-old on treatment with TBA with the principal study variables on record (dates of birth, dates of visits, doses administered and weight).

 

 

Muscles analyzed

The analysis focused on four muscle groups (round pronators, adductors, semitendinous and triceps surae); because these are the most frequently injected muscles, and their spasticity affects patients' autonomy, and therefore their own quality of life, as well as that of their caregivers.

Spasticity Severity

Spasticity severity was collected according to the Ashworth Scale¹³, an ordinal scale with 5 categories (from 0: no spasticity, to 4: severe spasticity). The spasticity of each one of the muscles analyzed was determined by using the maximum spasticity of bilateral muscles.

As a measure associated to spasticity severity, and by indication of the clinicians in the study, the equinovarus foot support was also analyzed, measured in an ordinal scale with 5 categories (from 1: complete equinus support, to 5: initial heel support).

Doses administered

The doses administered were determined by the maximum doses injected in the left and right muscles (considering that dose=0 if not administered in the lateral muscle). Once the dose was determined, it was divided by the weight of the patient in the relevant visit, thus obtaining the dosing per kilo (U/kg) administered per patient.

Costs

The analysis was conducted from the perspective of the National Health System (NHS), considering direct costs only: pharmacological costs (manufacturer's selling price)¹⁴ and costs of visits¹⁵ in 2016 euros. The unit costs of Botox^® and Dysport^® correspond to the mean of the different formulations (Table 1).

The total annual pharmacological costs for each TBA according to the real doses used in clinical practice were obtained by multiplying the mean doses per kilo by the unit cost of the corresponding TBA formulations. The resulting sum was multiplied by the mean weight of patients and the mean number of visits per year according to treatment.

For calculating the annual costs of visits, the expected number of visits per patient in one year was used (for administration and follow-up). A specific cost was applied to the first visit, and another cost to follow-up visits, according to the published costs of healthcare resources¹⁵.

Base-case for cost-minimization analysis

The base-case analysis was conducted taking the profile of the patient whose cost was estimated based on the doses recorded for each muscle, as well as the patient weights recorded throughout follow-up. A subgroup analysis was conducted, based on the muscle group involved.

Sensitivity Analysis

In order to assess the impact of the uncertainty of the estimations obtained upon the outcomes of the study, and therefore assess their robustness, various sensitivity analyses were conducted, modifying the main variables:

- The combination of vials considered was the one with highest reduction in the total cost per dose administered.

- A sensitivity analysis of extremes was conducted, assuming the scenario with the lowest Botox^® dose and the maximum Dysport^® dose (Scenario A). On the other hand, the scenario considering the highest Botox^® dose and the lowest Dysport^® dose was also analyzed (Scenario B).

- Finally, a hypothetical scenario was assumed, with the profile of a "typical patient", whose cost was calculated for a mean weight of 22 kilos and four visits per year (two of them with drug administration) for both patient groups, and assuming injection in each one of the four muscle groups with the mean dose observed in the sample.

Statistical Analysis

A descriptive analysis was conducted, where quantitative variables were analyzed through mean and standard deviations (SD), and median and interquartile ranges (IR); frequency tables were used for categorical variables.

Group comparison was conducted through nonparametric techniques (Mann-Whitney's U Test) for continuous variables, and Chi Square Test for categorical variables.

A longitudinal analysis of spasticity severity was conducted to confirm the severity of treatments, and dichomotous variables were created: 1 if muscle spasticity improved during the treatment period, 0 in the opposite case. Logistical regression models were adjusted, where the variable for response was the improvement in spasticity, and the treatment (Botox^®/Dysport^®) was used as independent variable, adjusted by initial spasticity and time of follow-up. Model calibration was assessed with the Hosmer-Lemeshow C-Test¹⁶. In the outcomes, adjusted odds-ratio (OR) are shown, and with their respective confidence intervals (CIs).

The level of statistical significance was established in 0.05 for all the analysis. The 3.2.3 version of the R statistical package was used.¹⁷.

 

Results

Characteristics of patients and visits

The present study analyzed 895 patients with paediatric spasticity in total: 543 of them were treated with Botox^® only, 292 with Dysport^® and 60 with both treatments (Botox^® was used in the initial administration visits, and Dysport^® was used at the final follow-up). The injections of those patients who received both treatments were distributed accordingly. No differences were observed in the mean age at their first visit, or in their mean weight (Table 2).

Regarding the time between visits, statistically significant differences were observed between the two groups of patients: those treated with Botox^® attended visits more frequently (p<0,001). Differences in frequency of visits were still observed between patients treated with Dysport^® and Botox^®, when considering only those visits with administration (p<0.01) (Table 2).

No differences were observed in the initial spasticity of patients from both groups in any muscle, except for triceps surae (chi-square test, p value = 0.01). No differences were observed in the severity of equinus foot.

Effectiveness of treatments

The longitudinal analysis with the initial and final measures of spasticity showed a non-significant tendency in favour of Dysport^® vs. Botox^®. A non-significant tendency was also observed in favour of Dysport^® in equinus foot (Table 2).

Doses administered

The mean doses injected to patients were calculated for the four muscles analyzed and by TBA (Table 3). These mean doses must be understood as doses administered in each injection, and not per visit. For the base-case analysis of costs, it was convenient to have data regarding the mean doses injected in each visit in any of the muscles. In this case, the mean figures obtained were 5.44 U/kg (2.17) for Botox^® injections, and 14.73 U/kg (5.26) for Dysport^® injections (Table 3).

Costs

The mean pharmacological cost per patient and year was 480,00€ for Botox^® and 287,36€ for Dysport^®, which represents annual savings in favour of Dysport^® of 192,64€ in the pharmacological cost, assuming that no fraction of the TBA vials gets wasted (Table 3). The annual cost per visits for one patient was 359,56€ for Botox^® and 343,87€ for Dysport^®. The total annual direct cost obtained was 839,56€ for Botox^® and 631,23€ for Dysport^®, representing a difference of 208,34€ per year in favour of treatment with Dysport^® (Figure 2).

The analysis stratified by muscle group revealed that the annual pharmacological savings are still in favour of Dysport^® for the four muscles: from 58,03€ in the case of injections in the round pronators, to 164,15€ if the muscles injected were the triceps surae (Table 3). This outcome shows that the treatment for any combination of the four muscle groups will also be cheaper with Dysport^®.

Sensitivity Analysis

Taking into account that the non-injected content of the vials gets discarded, the annual pharmacological savings in favour of Dysport^® would be 59,60€ (Table 3). Considering both the pharmacological cost and the cost for patient follow-up, the annual savings would still be in favour of Dysport^® by 75,29€.

In the analysis for Scenario A (favourable to Botox^®), there were potential pharmacological savings of 158,29€ per patient and year in favour of Dysport^®. In Scenario B (favourable to Dysport^®), pharmacological savings rose up to 227,60€ per patient and year in favour of Dysport^® (Table 3). Given that the outcomes in both scenarios did not change the conclusions of the primary analysis, it was not necessary to conduct a probabilistic sensitivity analysis.

Finally, if the "typical patient" profile is considered, the potential pharmacological savings with Dysport^®would be 295,15€ per patient and year (Table 3 and Figure 2), and the annual direct cost would be 1.015,88€ for Botox^® and 720,73€ for Dysport^®.

 

Discussion

This study has used real life records of patients treated for Paediatric Spasticity at the Paediatric Neurology Unit of a first-level Spanish hospital, in order to conduct a cost-minimization analysis from the perspective of the NHS. It has been estimated that potential savings of 208,34€ could be obtained per patient and year, if the treatment of Paediatric Spasticity was conducted entirely with Dysport^® instead of treating with Botox^®. Besides, it has been demonstrated that treatment with Dysport^®for spasticity in any combination of the muscle groups studied would represent savings for the payer. Sensitivity analyses have shown that, even changing the initial analysis parameters, the difference in costs would still be favourable to Dysport^®.

Tapias et al. conducted a budget impact analysis based on extrapolated prevalence data with a 3-year time horizon (2012-2014), in order to analyze the impact on the NHS budget of an increase in the use of Dysport^®vs. Botox^® and Xeomin^®11. However, this assessment was conducted accepting the dosing recommended by each indication according to the product specifications. In other study, the authors estimated the cost of treatment with TBA per patient in the indications shared by the three medications available in Spain¹². For Paediatric Spasticity, where only Botox^® and Dysport^® are indicated, the authors reached the conclusion that the use of Botox^® would represent 10%-40% annual savings per patient, based on the administered doses recommended in product specifications¹². The present study, with the dosing observed in real clinical practice, shows that those savings would not be offered by using Botox^®, but by using Dysport^®, reaching 40% savings per patient and year in terms of pharmacological cost, and 25% in total direct costs per patient and year. In the scenario of incomplete use of the vial, savings are reduced, due to the higher diversity in Botox^® presentations, but they still favour the use of Dysport^®: 11% savings in pharmacological cost per patient and year; 8% savings in total direct costs per patient and year. Said results highlight that it is useful to have real information about the treatment in clinical practice, because the doses recommended in the product specifications are noticeably different from the doses really administered in daily clinical practice. Therefore, according to the common paradigm of clinical care, the doses initially injected in each muscle were those recommended by guidelines and consensus. The following dose injected in each muscle was adjusted according to the results observed in the previous injection, and whether there were adverse effects or not, never exceeding the total dose recommended^1,3.

Different studies show that both treatments are very similar in terms of effectiveness and safety^18-23 as long as they are adequately administered^23-26. However, due to the fact that the TBA concentration is not the same in both products²⁷, toxins are not comparable. Besides, the dilution and injection techniques lead to a greater alteration in these disparities. There is also a significant variation in doses depending on the specific preparation used, the muscle injected, disease severity, and treatment duration²⁸.

The main contribution by this study is that its data source was a real record of Spanish patients with Paediatric Spasticity. Therefore, its results correspond to real clinical practice in the treatment of spasticity with TBA.

The cost analysis conducted presents limitations. One of them is the lack of external validation of its outcomes. Precisely due to the fact that patients have been treated and followed up in the Paediatric Neurology Unit of one single centre, they cannot be representative of the population of children with spasticity. In order to overcome this limitation, it is necessary to conduct larger controlled studies (international multicenter clinical trials). However, the conservative assumptions as well as all sensitivity analyses conducted point out that the use of Dysport^® is beneficial for the NHS with equal effectiveness.

Another limitation is a consequence of the protocol of spasticity treatment with TBA. The doses administered not only depend on spasticity severity, but also of its evolution and the doses previously administered. Though no differences in effectiveness have been observed throughout the follow-up period, spasticity could present different evolution patterns from the first to the last record. An indepth longitudinal analysis, taking into account all spasticity measures, would be convenient in order to describe the different profiles of evolution of spasticity severity and of the TBA doses administered.

Although the retrospective design could involve the risk of selection of one product or the other, the treatment indications and the selection of botulinum toxin have been the same for both marketed products in any indication of spasticity, without any preference of one over the other for spasticity severity or location reasons. The higher number of cases treated with Botox^® is due to the fact that it was marketed in Spain some years before Dysport^®. We think that the high number of injections with one product and the other will reduce the weight of any potential bias, which, if present, would be involuntary.

It is worth clarifying that no concomitant medication was taken into account, because very few patients received oral antispastic medication. In childhood, these are only used for severe spastic quadriplegia, at low doses, because they will usually cause adverse effects -particularly sedation- which will limit dose escalation. That is why these data, which do not modify the analysis, were not recorded.

A forth limitation presented by these data is the spastic severity scale used. The Ashworth Scale can be used as a measure of the ordinal level of resistance to passive movement, but it presents certain limitations as a scale for measuring spasticity²⁹. As pointed out in the study by Bakheit et al.³⁰, clinicians as a rule will assess treatment effectiveness with deterioration level scales, and functional response measures are rarely used in clinical practice. The conclusion is that the use of these measures should be encouraged, in order to assess if the muscle tone reduction translates into a functional benefit for patients and their caregivers³⁰.

A fifth limitation could arise of assuming that no TBA gets wasted during treatment sessions. Due to the dosing variability, and the fact that there are fixed TBA presentations, even though there is a variety available, it is logical to think that part of the vial contents must be discarded. Besides, TBA must only be used for treatment of one single patient, during one single session, and any rests of the product that have not been used must be inactivated^8,9. In order to take into account the potential TBA waste during clinical practice, all vials used during the period of the study should have been registered; but this information is not available. In order to overcome this limitation, an analysis has been conducted for the TBA waste scenario.

This study offers the first data in real clinical practice about the patterns of treatment and use of resources in patients with Paediatric Spasticity in one Spanish centre. It has been shown that the cost of treatment with Dysport^® is cheaper per patient and year. The potential savings in annual pharmacological costs is of approximately 193€ per patient. The outcomes correspond to the dosing used in clinical practice in a hospital and with paediatric patients; therefore, any potential extrapolations to the whole population should be cautiously approached. It is necessary to conduct larger controlled studies in order to compare the effectiveness of different treatments with TBA and other focal treatments, paying special attention to individual evaluation and functional benefits, as well as its duration, potential concomitant and subsequent treatments, side effects, and cost-effectiveness.

 

Contribution by the authors

Gloria Tapias developed the idea for the project including this study. Dr. Pascual-Pascual provided the anonymized data record which made possible the analysis of doses. Carlos Crespo, Maribel Cuesta and Carles Forné conducted the statistical and cost analysis. Dr. García-Romero was involved in writing the manuscript. All authors have read and approved the final version of the manuscript.

 

Acknowledgments

The authors would like to thank Gemma Lairisa, Lina Ruiz and Eduardo Belenguer from Ipsen Pharma for their contribution in reviewing the manuscript.

 

Conflict of interests

Dr. Pascual-Pascual has received fees from Allergan and from Ipsen Pharma for lectures and training courses. Dr. García-Romero declares no conflict of interest associated with this article. Gloria Tapias is working for Ipsen Pharma, which is the company sponsoring the study. Carles Forné and Maribel Cuesta are working for Oblikue Consulting, a consulting company that received a grant from Ipsen Pharma for conducting this study. Carlos Crespo was working in Oblikue Consulting at the time of conducting the statistical and cost analysis.

 

Bibliography

1. Pascual-Pascual SI, Herrera-Galante A, Póo P, García-Aymerich V, Aguilar-Barberá M, Bori-Fortuny I, et al. Guía terapéutica de la espasticidad infantil con toxina botulínica. Rev Neurol. 2007;44(5):303-9.         [ Links ]

2. Merello M. Fisiopatología, clínica y tratamiento de la espasticidad. Arch Neurol Neuroc Neuropsiq. 2008;7(2):29-62.         [ Links ]

3. Heinen F, Desloovere K, Schroeder AS, Berweck S, Borggraefe I, van Campenhout A, et al. The updated European Consensus 2009 on the use of Botulinum toxin for children with cerebral palsy. Eur J Paediatr Neurol. 2010;14(1):45-66.         [ Links ]

4. Strobl W, Theologis T, Brunner R, Kocer S, Viehweger E, Pascual-Pascual I, et al. Best clinical practice in botulinum toxin treatment for children with cerebral palsy. Toxins (Basel). 2015;7(5):1629-48.         [ Links ]

5. Rosales RL, Chua-Yap AS. Evidence-based systematic review on the efficacy and safety of botulinum toxinA therapy in post-stroke spasticity. J Neural Transm. 2008;115(4):617-23.         [ Links ]

6. Mense S. Neurobiological basis for the use of botulinum toxin in pain therapy. J Neurol. 2004;251 Suppl 1:I1-7.         [ Links ]

7. Peng Chen Z, Morris JG, Rodriguez RL, Shukla AW, Tapia-Núñez J, Okun MS. Emerging Opportunities for Serotypes of Botulinum Neurotoxins. Toxins (Basel). 2012;4:1196-1222.         [ Links ]

8. Ficha Técnica de Dysport^®. Ministerio de Sanidad, Servicios Sociales e Igualdad. Agencia española de medicamentos y productos sanitarios (Internet). Disponible en: http://www.aemps.gob.es/cima/fichasTecnicas.do?metodo=buscar (Acceso en febrero de 2014).         [ Links ]

9. Ficha técnica de Botox^®. Ministerio de Sanidad, Servicios Sociales e Igualdad. Agencia española de Medicamentos y productos sanitarios (Internet).Disponible en: http://www.aemps.gob.es/cima/fichasTecnicas.do?metodo=buscar (Acceso en febrero de 2014).         [ Links ]

10. Ficha Técnica de Xeomin^®. Ministerio de Sanidad, Servicios Sociales e Igualdad. Agencia española De medicamentos y productos sanitarios (Internet). Disponible en: http://www.aemps.gob.es/cima/fichasTecnicas.do?metodo=buscar (Acceso en febrero de 2014).         [ Links ]

11. Tapias G, Ilgrande A, Espinós B. Análisis de impacto presupuestario del uso de la toxina botulínica tipo A (TBA) en el Sistema Nacional de Salud en España. Pharmacoecon Span Res Artic. 2013;10(4):119-129.         [ Links ]

12. de Andrés-Nogales F, Morell A, Aracil J, Torres C, Oyagüez I, Casado MA. Análisis de costes del uso de toxina botulínica A en España. Farm Hosp. 2014;38(3):193-201.         [ Links ]

13. Ashworth B. Preliminary trial of carisoprodal in multiple sclerosis. Practitioner. 1964 Apr;192:540-2.         [ Links ]

14. Consejo General del Colegio Oficial de Farmacéuticos. Base de datos del medicamento (Base de Datos en Internet). www.botplusweb.portalfarma.com. 2014. Disponible en: https://botplusweb.portalfarma.com/ (Acceso en marzo de 2016).         [ Links ]

15. Gisbert R, Brosa M. Base de datos de costes sanitarios Español: eSalud. (Base de datos en Internet). Disponible en: http://www.oblikue.com/bddcostes/ (Acceso en marzo de 2016).         [ Links ]

16. Hosmer DW, Lemeshow S. Applied logistic regression (2^nd ed). Wiley, New York, NY, 2000.         [ Links ]

17. R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. Vienna, Austria. 2015. Disponible en: http://www.R-project.org/.         [ Links ]

18. Pascual-Pascual SI, Pascual-Castroviejo I. Safety of botulinum toxin type A in children younger than 2 years. Eur J Paediatr Neurol. 2009;13(6):511-5.         [ Links ]

19. Gaber TA, Basu B, Shakespeare D, Singh R, Salam S, McFarlane J. Botulinum Toxin in the management of hitchhiker's toe. NeuroRehabilitation. 2011;28(4):395-9.         [ Links ]

20. Mohammadi B, Balouch SA, Dengler R, Kollewe K. Long-term treatment of spasticity with botulinum toxin type A: an analysis of 1221 treatments in 137 patients. Neurol Res. 2010;32(3):309-13.         [ Links ]

21. Sobolewski P. The application of botulinum toxin type A in the treatment of spastic paraparesis. Przegl Lek. 2007;64 Suppl 2:3-7.         [ Links ]

22. Sheean G. Botulinum toxin treatment of adult spasticity: a benefit-risk assessment. Drug Saf. 2006;29(1):31-48.         [ Links ]

23. Slawek J, Bogucki A, Reclawowicz D. Botulinum toxin type A for upper limb spasticity following stroke: an open-label study with individualised, flexible injection regimens. Neurol Sci. 2005;26(1):32-9.         [ Links ]

24. Ravenni R, De Grandis D, Mazza A. Conversion ratio between Dysport and Botox in clinical practice: an overview of available evidence. Neurol Sci. 2013; 34(7):1043-8.         [ Links ]

25. Wissel J, Entner T. Botulinum toxin treatment of hip adductor spasticity in multiple sclerosis. Wien Klin Wochenschr. 2001;113 Suppl 4:20-4.         [ Links ]

26. Stawek J, Car H, Bonikowski M, Bogucki A, Koziorowski D, Potulska-Chromik A, et al. Are botulinum toxin type A preparations really the same medication? A comparison of three botulinum toxin A for variations in labelled neurological indications. Neurol Neurochir Pol. 2010;44(1):43-64.         [ Links ]

27. Frevert J. Content of Botulinum Neurotoxin in Botox^®/Vistabel^®, Dysport^®/Azzalure^®, and Xeomin^®/Bocouture^®. Drugs R D. 2010;10(2):67-73.         [ Links ]

28. Baba Y, Osborne MD, Wszolek ZK, Kwolek A, Druzbicki M. Treatment of spasticity with botulinum toxin. Ortop Traumatol Rehabil. 2004;6(5):665-72.         [ Links ]

29. Pandyan AD, Johnson GR, Price CI, Curless RH, Barnes MP, Rodgers H. A review of the properties and limitations of the Ashworth and modified Ashworth Scales as measures of spasticity. Clin Rehabil. 1999;13(5):373-83.         [ Links ]

30. Bakheit AM, Zakine B, Maisonobe P, Aymard C, Fhedoroff K, Hefter H, et al. The profile of patients and current practice of treatment of upper limb muscle spasticity with botulinum toxin type A: an international survey. Int J Rehabil Res. 2010;33(3):199-204.         [ Links ]

 

 

Correspondence:
Correo electrónico: gloria.tapias@ipsen.com
(Gloria Tapias).

Recibido el 4 de diciembre de 2015;
aceptado el 10 de mayo de 2016.