A cost-utility analysis of sacral anterior root stimulation (SARS) compared with medical treatment in patients with complete spinal cord injury with a neurogenic bladder

Accepted Manuscript Title: A cost-utility analysis of sacral anterior root stimulation (SARS) compared to medical treatment in complete spinal cord injured patients with a neurological bladder. Author: Camille Morlière, Elise Verpillot, Laurence Donon, Louis-Rachid Salmi, Pierre-Alain Joseph, Jean-Rodolphe Vignes, Antoine Bénard PII: DOI: Reference:

S1529-9430(15)01233-4 http://dx.doi.org/doi: 10.1016/j.spinee.2015.08.023 SPINEE 56529

To appear in:

The Spine Journal

Received date: Revised date: Accepted date:

4-3-2015 16-6-2015 11-8-2015

Please cite this article as: Camille Morlière, Elise Verpillot, Laurence Donon, Louis-Rachid Salmi, Pierre-Alain Joseph, Jean-Rodolphe Vignes, Antoine Bénard, A cost-utility analysis of sacral anterior root stimulation (SARS) compared to medical treatment in complete spinal cord injured patients with a neurological bladder., The Spine Journal (2015), http://dx.doi.org/doi: 10.1016/j.spinee.2015.08.023. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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TITLE PAGE

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Title A cost-utility analysis of sacral anterior root stimulation (SARS) compared to medical treatment in complete spinal cord injured patients with a neurological bladder.

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Authors Camille Morlière 1, Elise Verpillot 2, Laurence Donon 3, Louis-Rachid Salmi Joseph 5,6, Jean-Rodolphe Vignes 7,8, Antoine Bénard 1,2.

2,4

, Pierre-Alain

1 CHU Bordeaux, Pôle de santé publique, Service d’information médicale, USMR & CIC 1401 module EC, F-33000 Bordeaux, France 2 INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, F-33000 Bordeaux, France. 3 CHU Bordeaux, Service d'urologie andrologie et transplantation rénale, F-33000 Bordeaux, France. 4 CHU Bordeaux, Pôle de santé publique, Service d’information médicale, UMES, F-33000 Bordeaux, France ; 5 CHU Bordeaux, Service de Médecine physique et de réadaptation, F-33000 Bordeaux, France ; 6 Univ. Bordeaux, Unité EA 4136 Handicap et système nerveux, F-33000 Bordeaux, France. 7 CHU Bordeaux, Service de neurochirurgie A, F-33000 Bordeaux, France ; 8 Univ. Bordeaux, F-33000 Bordeaux, France. Corresponding author Antoine Bénard, MD, PHD. Pôle de Santé Publique du CHU de Bordeaux USMR & CIC 1401 module EC Isped, Université de Bordeaux, CS61292 - case 75. 146, rue Léo Saignat 33076 Bordeaux, France Tel: +33 5 57571181 Fax: +33 5 57571578 E-mail: [email protected]

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Acknowledgements

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The authors would like to acknowledge Elisabeth Fenwick (Director, Health Economics at

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ICON plc) for her precious advices in the elaboration of our model. They thank Mark Strong

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(Clinical Senior Lecturer in Public Health, University of Sheffield) for his advices on Visual

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Basic in Excel and on SAVI. They thank Dr. Véronique Gilleron, Dr. Aude Kostrzewa, Nathalie

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Ong and Eric Frison (CHU Bordeaux, Pôle de santé publique, Service d’information médicale) 1 Page 1 of 20

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for having conducted the simulations using the 2013 French prospective payment system

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(PMSI) classification.

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Finally, the authors would like to taknk the French study group on SARS: Angers: Philippe

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Menei (CHU Angers); Le Mans: Paul Colombel (Hôpital du Mans), Guy Egon (Centre de

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l’Arche), Berck-sur-Mer: Christophe Delecourt (Institut Calot), Patrick Belletante, Jean-

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Gabriel Previnaire (Fondation Franco-Américaine), Elisabeth Hode (Hôpital de Montreuil);

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Bordeaux: Michel Barat, Jean-Rodolphe Vignes (CHU Bordeaux), David Goossens (La Tour de

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Gassie, Bruges); Brest: Phong Dam-Hieu, Marie-Pierre Dorval-Rannou (CHU Brest), Olivier

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Remy-Neris (Hôpital Morvan); Créteil: Philippe Decq (Hôpital Henri Mondor); Brie-Comte-

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Robert: Serdar Kocer, Thierry Albert (Centre rééducation Coubert), Limoges: Pierre

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Dudognon, Jean-Yves Salle, Jean-Christophe Daviet, Jean-Jacques Moreau, François Caire,

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Martine Rabiller (CHU Limoges); Lyon: Patrick Mertens (Hôpital Wertheimer), Alain Ruffion,

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Kathleen Charvier (Hôpital Henry Gabrielle); Montpellier: Luc Bauchet (CHU Montpellier),

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Hélène Rouays-Mabit, Charles Fattal (Centre Propara); Nancy: Catherine Pinelli (CHU Nancy),

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Jean-Marie Beis, Loïc Le Chapelain, Jean-Marie Andre, Marie-Odile Thisse (Centre

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réadaptation Lay St Christophe); Nantes: Roger Robert, Olivier Hamel (Hôpital Hôtel Dieu

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Nantes); Poitiers: Gilles Kemoun, Claire Guillou, Françoise Lapierre, Philippe Rigoard, Anne

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Delaubier (CHU Poitiers); Rouen: François Proust (CHU Rouen), Françoise Beuret Blanquart

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(Centre les Herbiers Boisguillaume); Saint-Etienne: Christophe Nuti, Vincent Gautheron,

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Jacques Brunon, Bruno Fernandez, François Vassal (CHU Saint Etienne); Toulouse: Jacques

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Lagarrigue, Xavier Game, Philippe Marque, Evelyne Castel-Lacanal (CHU Rangueil Toulouse).

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ABSTRACT

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350 words (limit: 350)

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Background context: Sacral anterior root stimulation (SARS) and posterior sacral rhizotomy restores

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the ability to urinate on demand with low residual volumes, a key for preventing urinary complications

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which account for 10% of the causes of death in patients with spinal cord injury (SCI) with a

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neurological bladder. Nevertheless, comparative cost-effectiveness results on a long-time horizon are

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lacking to adequately inform decisions of reimbursement.

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Purpose: To estimate the long-term cost-utility of SARS using the Finetech-Brindley device

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compared to medical treatment (anticholinergics + catheterization). 2 Page 2 of 20

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Study design / Settings: Markov model elaborated with a 10-year time-horizon. Four irreversible

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states: 1) initial treatment; 2) year 1 of surgery for urinary complication; 3) year >1 of surgery for

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urinary complication 4) death. Reversible states: urinary calculi; Finetech-Brindley device failures.

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Patient Sample: Theoretical cohorts of patients with a complete spinal cord lesion since ≥1 year, and

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a neurological bladder.

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Outcome Measures: Effectiveness was expressed as quality adjusted life years (QALY). Costs were

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valued in EUR 2013 in the perspective of the French health system.

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Methods: A systematic review and meta-analyses were performed to estimate transition probabilities

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and Quality Ajusted Life Years (QALYs). Costs were estimated from the literature, and through

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simulations using the 2013 French prospective payment system (PMSI) classification. Probabilistic

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analyses were conducted to handle parameters uncertainty.

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Results: In the base case analysis (2.5% discount rate), the cost-utility ratio was 12 710 EUR/QALY

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gained. At a threshold of 30,000 EUR/QALY the probability of SARS being cost-effective compared

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to medical treatment was 60%. If the French Healthcare System reimbursed SARS for 80 patients/year

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during 10 years (anticipated target population) the expected incremental net health benefit would be

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174 QALYs, and the expected value of perfect information (EVPI) would be 4.735 million EUR. The

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highest partial EVPI is reached for utility values and costs (1.3 to 1.6 million EUR).

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Conclusions: Our model shows that SARS using Finetech-Brindley device offers the most important

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benefit and should be considered cost-effective at a cost-effectivness threshold of 30,000 EUR/QALY.

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Despite a high uncertainty, EVPI and partial EVPI may indicate that further research would not be

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profitable to inform decision making.

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KEYWORDS (6-10)

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Spinal Cord Injuries; Urinary Bladder, Neurogenic; Cost Effectiveness; Implantable Neurostimulator;

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Electrical Stimulation Therapy; Neurosurgical Procedures; Markov Chains; Probabilistic Models.

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INTRODUCTION

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Paraplegia and tetraplegia caused by complete spinal cord injury (SCI) are a chronic condition. Over

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the last 4 decades, thanks to major improvements in emergency care and rehabilitation, there has been

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a 40% decline in mortality during the critical first year after injury [1]. In patients surviving the acute

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phase post injury, medical management is focused on the improvement of quality of life and the

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prevention of specific co-morbidities. Among these, neurological bladder, characterized by detrusor

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hyperreflexia +/- detrusor-sphincter dyssynergia, still represents 10% of the causes of death and

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around 20 times more deaths than in the general population of the same age and gender [2, 3].

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Reference treatment of neurological bladder without complication has not radically evolved in the past

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decades and still associates anticholinergics and urinary voiding techniques, predominantly

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intermittent catheterization [4]. This therapeutic strategy is reimbursed by the healthcare system in

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France but exhibits relatively poor clinical results in treating post-voiding residue and high intravesical

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pressure, yielding incontinence (loss of self-esteem), cystitis, vesicouretral reflux and urinary stones

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[5-9]. The presence of such complications, especially if they are repetitive, is an indication for surgical

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procedures such as sphincterotomy and continent or non-continent urinary diversion [4]. A key issue

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to prevent such an evolution is to promptly restore complete and voluntary micturition (CVM) after

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the diagnosis of neurological bladder. Sacral anterior root stimulation (SARS) and posterior sacral

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rhizotomy with the Brindley-Finetech device is one of the few therapeutic innovations in the field of

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neurological bladder. It restores the ability to urinate on demand with consistently low residual

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volumes. This lowers the intra-vesical pressure and the risk of urinary tract infection and reduces the

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need for catheterization [10, 11]. In a previous comparative cost-effectiveness research we showed that

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SARS was five-time more effective than anticholinergics and urinary voiding techniques to restore

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CVM [12]. We also produced a valid and precise estimate of the cost of SARS on the first year of

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treatment, which is a limiting factor for its use in clinical practice as not reimbursed by health systems.

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However, we did not produced, as others cost studies on the same topic [13, 14], comparative cost-

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effectiveness results on a long time horizon which could adequately inform decision-makers. Indeed,

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the efficacy of SARS in preventing long term complications of neurological bladder in SCI may

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reduce related costs and counterbalance the first year of treatment’s cost, while improving quality of

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life. The objective of our study was to extrapolate the results of our comparative cost-effectiveness

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analysis published in 2013 in order to estimate the long-term cost-utility of SARS using Brindley-

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Finetech device compared to reference medical treatment in complete spinal cord injured patients with

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a neurological bladder.

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METHODS

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Description and justification of the decision model 4 Page 4 of 20

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For the purpose of our study we elaborated a Markov chain decision-analytic model. Compared

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strategies are as defined in our observational study [12]: SARS using Finetech-Brindley device versus

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reference medical treatment (anticholinergics and urinary voiding techniques). Treatment by

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Botulinum Toxin was excluded. As it is not reimbursed by the healthcare system in France it could not

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be considered as a reference treatment in our analysis. Indweling catheters were excluded as well as

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not recommended anymore. Target population is represented by patients with a complete traumatic

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cervical or thoracic spinal cord lesion since ≥1 year, and suffering from a neurological bladder. Mean

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age at the entrance of our model is 41 years.

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Health states in both compared strategies are: 1) initial treatment; 2) year 1 of surgery for urinary

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complication; 3) year >1 of surgery for urinary complication 4) death. All these health states are

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mutually exclusive and irreversible. We decided to create a tunnel state for surgery because its cost is

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due only on the first year. We also integrated reversible conditions in the three first irreversible states.

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These reversible conditions were: kidney stone, bladder stone and, specifically in the SARS strategy,

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Finetech-Brindley device failures (receiver, cable or external transmitter). Model structure is shown on

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figure 1.

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Cycles’ duration was one year and time horizon 10 years. A 10-year time horizon seemed justified for

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three reasons: 1) Finetech-Brindley is a rather robust device. Indeed, the implanted parts of the device

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are a subcutaneous receiver and cables, all passive, simple and replaceable [15]; 2) increasing time

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horizon over 10 years would have been unreasonably in favour of SARS as production cost for this

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therapeutic strategy are mostly due on the first year of treatment (cost of the device and

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hospitalisations). The more the time horizon is long, the more these costs are amortized; 3) due to

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potential future therapeutic innovations, the comparators in our model would be obsolete beyond this

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time horizon.

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The possible progression of the cohorts through our model is based on a key assumption: we

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considered that patients capable of CVM under SARS no longer have urinary disorders. This

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assumption is based on the numerous long-term surveys on SARS where a large majority of patients

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retrieve a quasi-normal micturition: normal post-voiding residue and intravesical pressure, thus

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preventing possible urinary complications due to neurological bladder [10, 16, 17]. It is the result of

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CVM measurement 12 months after the initiation of SARS reported in our previous observational

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comparative cost-effectiveness research [12] that we extrapolated on a long-term horizon through our

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model. We have used this result to identify three categories of patients in our model: 1) SARS capable

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of CVM (SARS success); 2) SARS incapable of CVM (SARS failure); 3) reference medical treatment.

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Under our assumption, SARS patients incapable of CVM come back to the reference medical

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treatment. Consequently, categories 2 and 3 experience the same progression in our model (figure 1).

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Concerning transition to the surgery for urinary complication health state, SARS patients incapable of

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CVM and patients receiving the medical treatment may transit to sphincterotomy, continent urinary

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diversion with or without bladder augmentation, non-continent urinary diversion. These are the

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surgery techniques usually used in France in case of complicated urinary disorders in SCI patients.

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SARS capable of CVM may transit to the urological surgery health state but, as considered as no

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longer having urinary disorders CVM, only to sphincterotomy. Other irreversible health state such as

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bladder cancer and renal failure were not taken into account because they occur more than ten years

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after SCI, beyond the time horizon of our model [18, 19].

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Reversible urinary conditions taken into account in our model are kidney stones and bladder stones

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because they are curable within the duration of a cycle and because they have a significant impact on

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the cost of care for an individual patient. As they are acute and quickly curable, we considered that

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they had no significant impact on quality adjusted life years (QALY). SARS patients capable of CVM,

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as considered as no longer having urinary disorders CVM, are not susceptible to develop these kinds

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of conditions. However, they may experience Brindley-Finetech device failure (receiver, cable or

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external transmitter). Urinary tract infections are not taken into account directly in our model but

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through the cost and utility associated to health states. Vesico-ureteral reflux is taken into account

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through the surgery for urinary complication health state as they represent an indication for surgery

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when they are repetitive. As Brindley-Finetech device and surgical site infections most often occur

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during the first year after implantation [10, 20-23], we did not take them into account in our model.

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However, post-surgical infections occurring during the first year after implantation were taken into

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account in the cost calculation in our previous comparative cost-effectiveness research.

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We made the assumption that all the transition probabilities in our model, except transition to death,

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were constant over time.

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Since our model is an extrapolation of our observational comparative cost-effectiveness research, it

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begins at the end of the one-year follow-up in this study and is elaborated on the costs and quality of

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life reported in it. We did observe a small difference of quality of life (as measured by Qualiveen,

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IPSU index) in favour of SARS during the first year of treatment but not clinically significant [12].

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Therefore, we made the assumption that there was no difference in terms of QALY between the

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compared strategies at the entrance of our model. We also made the hypothesis that, within a ten-year

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time horizon, the transition to death is different neither between SARS and medical treatment, nor

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between the initial health state and the surgery health state.

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Given these characteristics, Markov chain was preferred to other decision models (such as decision

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tree or discrete event simulation). Indeed, a decision tree would have been too much busy for

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representing the different pathways of figure 1 in a ten-year time horizon. Furthermore, no data such

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as determinants of urinary function prognosis or predictive factors of urinary complications are 6 Page 6 of 20

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available in complete spinal cord injured patients with a neurological bladder. This kind of data is

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needed to build more sophisticated models such as discrete event simulation.

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Valuation of transition probabilities and utilities

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A systematic review and meta-analysis were performed to estimate transition probabilities and utility

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values associated to each health states.

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The primary bibliographic search was conducted using Medline and Scopus databases on March 2013.

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We used a very sensitive approach focused on the following keywords: spinal cord

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injuries and neurogenic bladder. Since Finetech-Brindley device was first used in 1978, we restricted

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our search on papers published after January 1980. Search limits focused on English, French or

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Spanish, on humans and excluded case reports and editorials.

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Complementary researches were conducted on October 2013 on Medline only and followed the same

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process as the main bibliographic search. They were focused on topics not fully documented in the

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primary search: quality of life, mortality and frequency of sphincterotomy in SARS (see appendix for

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details on research algorithms).

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References were imported on EndNote X.5. Search for duplicates was carried out on this software.

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Review of titles and abstracts was carried out by two independent reviewers (Camille Morlière and

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Antoine Bénard). References were retained if they were selected by at least one of them. Selection was

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focused on the population (exclusion of studies during the first 12 months post-injury only, animal

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studies, studies on children or pregnant women, and post-mortem studies), the pathology (exclusion of

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non-traumatic or only incomplete SCI), the voiding technique (exclusion of indwelling catheters,

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suprapubic catheter and suprapubic cystostomy), the comparators (only anticholinergics or SARS), the

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type of study (exclusion of case reports, commentaries and correspondences and studies on

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urodynamic, diagnostic, physiopathology or histochemistry). We also excluded literature reviews

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published before 1985.

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The fulltext of selected references was then read independently by the two reviewers and relevant data

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were extracted using a formatted data sheet on Microsoft Excel 2010. For transition probabilities, data

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of interest were sample size, number of events and duration of follow-up; for utilities, data of interest

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were sample size, mean and standard deviation.

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If at least two estimates were available for the same parameter, we conducted a meta-analysis using a

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fixed effect model (inverse variance weighting) [24].

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Quality of life estimates as measured by the Short Form 36® Health Survey (SF-36) were transformed

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to utility values using the algorithm proposed by Ara et al. [25]. As the variance of health utilities

7 Page 7 of 20

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derived from mapping algorithm is usually underestimated, we used a correction based on the

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coefficient of determination (R²) derived from the ordinary least squares method [26].

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Valuation of ressources

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Costs were valued in EUR 2013 in the perspective of the French health system. We used two sources

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of information. For the cost of irreversible health states (except death) we used the estimates reported

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in our previous comparative cost-effectiveness research [12] but recalculated in the perspective of the

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French Health System and using a multiple imputation method to deal with missing data. As these

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costs were valued in 2011, we discounted them until 2013 using a 4% rate. Costs estimated in the

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reference medical treatment arm in our comparative cost-effectiveness research were assigned, in our

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model, to the cohorts of patients receiving the reference medical treatment and those treated with

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SARS but incapable of CVM. The same estimates from which we substracted the cost of

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catheterization were assigned to the cohort of patients treated with SARS and capable of CVM.

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Estimations of the costs of surgery interventions (associated to surgery year one) and of the reversible

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conditions were performed through simulations using the 2013 French inpatient prospective payment

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system (PMSI) classification. Simulations were based on the medical acts of interest (i.e.: ablation of

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urinary calculus, extracorporeal kidney lithotripsy, continent or non-continent urinary diversion…)

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and diagnosis reflecting the clinical condition of our target population (paraplegia, tetraplegia,

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excluding all other neurological conditions). When several costs were available for the same condition,

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we calculated an unweighted mean as we had no information on the frequency of use of each medical

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acts in the population of analysis.

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Model validation

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The structure and assumptions of our model were validated by a committee comprised of an urologist,

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a physiatrist, an epidemiologist, an economist and a neurosurgeon on February 2014. These specialists

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are part of the authors of this article.

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Analytic methods

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Costs and QALYs were discounted at a 2.5% rate. This choice was guided by the recent (2013) report

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from the Commissariat Général au Plan et à la Prospective entitled cost benefit assessments of public

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investments [27].

8 Page 8 of 20

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Since cycles’ duration was one year, we had to proceed to a half-cycle correction for which we used

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the life table method [28]. Parameter uncertainty was handled through a probabilistic analysis (5000

3

samplings). Gamma distributions were used for costs and, beta distributions were used for utility

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values and transition probabilities. The method of moments was used to calculate distributions

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parameters [29].

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Scenario analyses were conducted for other discount rate values (1% and 6%) and considering a 75%

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proportion of patients retrieving CVM one year after SARS implantation.

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For each scenario analysis, the following results were produced: cost-utility ratio and its distribution

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on a cost-effectiveness plan; incremental net health and monetary benefit (INHB and INMB,

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respectively); cost-effectiveness acceptability curve (CEAC); and expected value of perfect

11

information (EVPI) or expected opportunity loss surrounding the decision made with the information

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provided by our model. Expected value of perfect partial information (EVPPI), that is EVPI for a

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single or a group of parameters, was computed only for the main analysis and using the Sheffield

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Accelerated Value of Information online tool (http://savi.shef.ac.uk/SAVI/) [4]. Value of information

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analyses were carried out based on a hypothetic size of the target population of 80 individuals per year

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during 10 years, and on a cost-effectiveness threshold of 30 000 EUR/QALY which is approximately

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the gross domestic product per capita per year in France. All the analyses, except EVPPI, were

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conducted on Microsoft Excel 2010®.

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RESULTS

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The primary bibliographic search retrieved 601 references in the Medline database and 1455 in

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Scopus. From the Medline references, 77 were excluded after reading the title and 383 after reading

23

the abstracts. These figures were 823 and 544 regarding the references extracted from Scopus. To the

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229 references selected after reading the abstract, 14 were added after the complementary researches.

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After careful double and independent reading of these 243 articles’ full text, 23 were selected for the

26

valuation of transition probabilities and utility.

27

Costs, transition probabilities, and utilities, along with their distribution parameters, and the sources of

28

information, are presented in table 1. This table is divided in four parts: 1) cost of treatments at the

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entrance of our model; 2) Parameters associated to the cohort of patients with medical treatment or

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SARS incapable of CVM; 3) Parameters associated to the cohort of patients with SARS capable of

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CVM; 4) Parameters associated to the two cohorts of patients.

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Data from the literature have been used for the estimation of all parameters except the cost of

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reversible conditions and urinary surgical interventions which were determined by simulation as

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described in the methods. Utility values associated to the initial treatment health state were extracted

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from a single article where SF-36 figures were reported in SCI patients with and without urinary 9 Page 9 of 20

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disorder. These figures correspond to the key assumption of our model. A probability distribution was

2

available for all parameters except for costs estimated through simulation and transition probabilities

3

to death.

4 5

Results of the base case analysis

6

The base case analysis was conducted using a 2.5% discount rate and a 60% efficacy of SARS (i.e.:

7

CVM restored one year after the implantation). This analysis yielded an incremental cost-utility ratio

8

(ICUR) of 12,710 EUR/QALY gained. The distribution of the 5,000 ICURs resulting from the

9

probabilistic analysis is presented on figure 2. On this cost-effectiveness plan, 28% of the ICURs are

10

situated on the South-Est quadrant (SARS less costly and more utile than reference medical

11

treatment), and 50% on the North-Est quadrant (SARS more costly and more utile than reference

12

medical treatment). The cost-effectiveness acceptability curve resulting from this analysis is presented

13

on figure 3. The probability of SARS using Finetech-Brindley device being cost-utile compared to the

14

reference medical treatment is 60% for a cost-effectiveness threshold of 30,000 EUR/QALY, reaching

15

a maximum of 74% for a cost-effectiveness threshold of 100,000 EUR/QALY. Based on these results,

16

If SARS using Finetech-Brindley device is reimbursed for 80 patients per year during 10 years, and

17

for a cost-effectiveness threshold of 30,000 EUR/QALY, the expected value of INHB (E(INHB)) is

18

+174 QALY, and the EVPI reaches 4,735 million EUR (table 2). The calculation of EVPPI for 11

19

groups of parameters is presented on figure 4. The highest EVPPI is reached for utility values in

20

patients with reference medical treatment without urinary complication (1,586 million EUR) and costs

21

of routine care with SARS (1,551 million EUR).

22

Results of the scenario analyses

23

Under the scenario of a 60% efficacy of SARS, the ICUR was 9,004 EUR/QALY with a 1% discount

24

rate, and 21,833 EUR/QALY with a 6% discount rate. The cost-effectiveness acceptability curve

25

resulting from these two scenario analyses is presented on figure 3. The probability of SARS using

26

Finetech-Brindley device being cost-utile compared to the reference medical treatment was 64% and

27

54% with discount rates of 1% and 6%, respectively. The value of information analyses, using the

28

same cost-effectiveness threshold and size of the target population as presented earlier, revealed an

29

E(INHB) of +240 QALY, and an EVPI of 4,412 million EUR with a 1% discount rate, and an

30

E(INHB) of +68 QALY, and an EVPI of 4,950 million EUR with a 6% discount rate (table 2).

31

In the scenario analyses based on a 75% efficacy of SARS, estimated ICURs were -738 EUR/QALY,

32

2,239 EUR/QALY, and 9,563 EUR/QALY with discount rates of 1, 2.5 and 6%, respectively. The

33

distribution of the 5,000 ICURs resulting from the probabilistic analysis with a 2.5% discount rate is

34

presented on figure 5. On this cost-effectiveness plan, 36% of the ICURs are situated on the South-Est

35

quadrant (SARS less costly and more utile than reference medical treatment), and 42% on the North10 Page 10 of 20

1

Est quadrant (SARS more costly and more utile than reference medical treatment). The cost-

2

effectiveness acceptability curves are presented on figure 6. The probability of SARS using Finetech-

3

Brindley device being cost-utile compared to the reference medical treatment was 71%, 69% and 64%

4

with discount rates of 1, 2.5, and 6%, respectively. The value of information analyses revealed an

5

E(INHB) of +424 QALY, +352 QALY, and +232 QALY, respectively. EVPI were 4,170 million

6

EUR, 4,250 million EUR, and 4,381 million EUR, respectively (table 2).

7 8

DISCUSSION

9

We acknowledge potential limitations to our model. First of all, it is a model so a simplification of

10

reality. We made the hypothesis that transition probabilities (except mortality) were constant over

11

time. Data from the literature did not allow us to assume an increase or decrease of transition

12

probabilities over time. However, since the transition probabilities in our model are rather low (around

13

1%), we suppose that changing probabilities over cycles would not have greatly modified our results.

14

The algorithm we used to transform SF-36 figures into utility values overestimates to lowest utility

15

values and underestimates the highest ones. This must not represent an issue in our model since the

16

utility values we estimated are intermediate. We considered a same utility value whatever the

17

urological surgery. It is likely that sphincterotomy has less impact on quality of life than urinary

18

diversions but literature data were lacking to take that into account. We considered that patients treated

19

with SARS but incapable of CVM received the reference medical treatment. This ignores the effect of

20

rhizotomy which abolishes reflex incontinence and, as a consequence, the need for anticholinergics

21

[16, 30], but probably with little consequences on costs and QALY. These two last limitations are

22

again a simplification of reality but both are in disfavor of SARS, thus reinforcing the results or our

23

model showing its cost-utility. Another limitation of our model comes from the use of only one survey

24

for the valuation of utilities in the initial treatment health state. Our systematic review did not identify

25

any article reporting utility measured through the EQ-5D instrument. Only SF-36 results were

26

available, and only for patients with medical treatment. We chose to use only one reference because

27

SF-36 figures measured by the same investigators, at the same time, were available for both patients

28

presenting and not presenting urinary disorders, a key assumption of our model. We think that this

29

reinforces the validity of using this single study in our analysis. Globally, the quality of the available

30

literature data was limited. We lacked studies, randomized or not, comparing SARS and medical

31

treatment in parallel groups. We can rely on long-term longitudinal cohort studies but all non

32

comparative. However, spinal cord injured patients are rather similar between each other. Hence,

33

between-study comparability may be achieved.

34

The strengths of our study rely on a thorough systematic literature review conducted according to

35

international guidelines. Besides the cost-effectiveness figures we produced through our model, the 11 Page 11 of 20

1

probability estimates may represent a useful source of information for clinicians. Our model also relies

2

on two key parameters that have been measured with precision and validity. In our previous

3

comparative cost-effectiveness research, the most costly resources (surgery and re-education) were

4

extracted from participating hospital medico-administrative database; and CVM was measured by uro-

5

dynamic examination: after intravesical saline serum instillation (300 mL), patients had to empty their

6

bladder in less than 5 minutes (≤50 mL left) without catheterization [12]. This rigorous method of

7

measure of SARS efficacy may explain why the 60% probability we used in our main analysis is

8

lower than those reported in the literature, from 71% to 91% [10, 21, 23, 31-33]. This explains why we

9

conducted a scenario analysis using a 75% efficacy of SARS. This also justifies why we hypothesized

10

that the probability of reversible urinary complication was null in SARS patients capable of CVM

11

even if we cannot completely exclude this risk. Indeed, the low risk of urinary complication that may

12

persist in SARS patients capable of CVM is taken into account in our model through SARS patients

13

incapable of CVM in whom we attributed the same probability than in patients receiving the reference

14

medical treatment. As a consequence, the probability of urinary complication in all SARS patients in

15

our model is 40% (i.e.: 1 - SARS efficacy) the probability in patients receiving the reference medical

16

treatment. Finally, during the elaboration and analysis of our model we always paid attention to

17

transparency (justification of our model’s hypotheses, verifiability of data sources, and presentation to

18

a validation committee). Furthermore, our model (on an Excel file) is available for further verification

19

of the reproducibility of our analyses.

20

Our study consists in an original approach to extrapolate the results of an observational study in a

21

long-term horizon taking into account all available evidence, in order to produce cost-effectiveness

22

results to adequately inform decision makers. To our knowledge there are no other decision models for

23

the long-term cost-effectiveness evaluation of SARS using Finetech-Brindley device in SCI. Given its

24

strengths and limitations, we believe that our model may be useful for decision-makers in France but

25

also in other countries. Even if we estimated costs in the perspective of the French health system, we

26

believe that these parameters can be easily replaced in order to fit our model to other systems. This

27

model may also be used for the cost-effectiveness evaluation of other treatments of urinary disorders

28

in SCI, such as botulinum toxin injections for example. The results of our probabilistic decision model

29

showed that SARS using Finetech-Brindley device is cost-effective at a threshold of 30 000

30

EUR/QALY gained. Indeed, in all our analyses, the probability of SARS using Finetech-Brindley

31

device being cost-utile compared to the reference medical treatment was systematically >50%.

32

Nevertheless, a high uncertainty does exist as the probability of SARS being cost-utile does not exceed

33

71% in the most optimistic scenario. Based on these figures, if SARS using Finetech-Brindley device

34

was added on the list of reimbursable health products in the French Health System, the expected

35

opportunity loss surrounding this decision (EVPI) would be between 4.5 and 5 million EUR. The

36

groups of parameters which account for most of this expected opportunity loss are utility values during 12 Page 12 of 20

1

the initial treatment (medical or SARS) without urinary complication and cost of routine care. The

2

calculation of the Expected Value of Sample Information and Expected Net Gain would have enable

3

us to appreciate the benefits of new studies to reduce the uncertainty surrounding a decision to fund

4

SARS within the French Health System. However, given the value of EVPI and EVPPI, the Expected

5

Net Gain would have been presumably lower than the cost of such studies. So far, to inform the

6

decision to fund SARS within the French Health System, the available evidence is represented by our

7

results. They must be useful for decision-maker and physicians to improve the care of patients with

8

spinal cord injury, within the budgetary limits of health systems.

9 10 11

13 Page 13 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50

REFERENCES 1. Strauss DJ, Devivo MJ, Paculdo DR, Shavelle RM. Trends in life expectancy after spinal cord injury. Arch Phys Med Rehabil. 87 (2006) 1079-1085. 2. Lidal IB, Snekkevik H, Aamodt G, Hjeltnes N, Biering-Sorensen F, Stanghelle JK. Mortality after spinal cord injury in Norway. J Rehabil Med. 39 (2007) 145-151. 3. Soden RJ, Walsh J, Middleton JW, Craven ML, Rutkowski SB, Yeo JD. Causes of death after spinal cord injury. Spinal Cord. 38 (2000) 604-610. 4. Bladder management for adults with spinal cord injury: a clinical practice guideline for health-care providers. J Spinal Cord Med. 29 (2006) 527-573. 5. El-Masri WS, Chong T, Kyriakider AE, Wang D. Long-term follow-up study of outcomes of bladder management in spinal cord injury patients under the care of the Midlands Centre for Spinal Injuries in Oswestry. Spinal Cord. 50 (2012) 14-21. 6. Ku JH, Jung TY, Lee JK, Park WH, Shim HB. Risk factors for urinary stone formation in men with spinal cord injury: a 17-year follow-up study. BJU Int. 97 (2006) 790-793. 7. Ord J, Lunn D, Reynard J. Bladder management and risk of bladder stone formation in spinal cord injured patients. J Urol. 170 (2003) 1734-1737. 8. Weld KJ, Dmochowski RR. Effect of bladder management on urological complications in spinal cord injured patients. J Urol. 163 (2000) 768-772. 9. Weld KJ, Graney MJ, Dmochowski RR. Differences in bladder compliance with time and associations of bladder management with compliance in spinal cord injured patients. J Urol. 163 (2000) 1228-1233. 10. Kutzenberger J, Domurath B, Sauerwein D. Spastic bladder and spinal cord injury: seventeen years of experience with sacral deafferentation and implantation of an anterior root stimulator. Artif Organs. 29 (2005) 239-241. 11. Vignes JR, Bauchet L, Ohanna F. Dorsal rhizotomy combined with anterior sacral root stimulation for neurogenic bladder. Acta Neurochir Suppl. 97 (2007) 323-331. 12. Benard A, Verpillot E, Grandoulier AS, Perrouin-Verbe B, Chene G, Vignes JR. Comparative cost-effectiveness analysis of sacral anterior root stimulation for rehabilitation of bladder dysfunction in spinal cord injured patients. Neurosurgery. 73 (2013) 600-608; discussion 608. 13. Creasey GH, Dahlberg JE. Economic consequences of an implanted neuroprosthesis for bladder and bowel management. Arch Phys Med Rehabil. 82 (2001) 1520-1525. 14. Wielink G, Essink-Bot ML, Van Kerrebroeck PEV, et al. Sacral rhizotomies and electrical bladder stimulation in spinal cord injury. 2. Cost-effectiveness and quality of life analysis. European Urology. 31 (1997) 441-446. 15. Brindley GS, Polkey CE, Rushton DN. Sacral anterior root stimulators for bladder control in paraplegia. Paraplegia. 20 (1982) 365-381. 16. Brindley GS. The first 500 patients with sacral anterior root stimulator implants: general description. Paraplegia. 32 (1994) 795-805. 17. Van Kerrebroeck PEV, Van der Aa HE, Bosch JLHR, et al. Sacral rhizotomies and electrical bladder stimulation in spinal cord injury. Part I: Clinical and urodynamic analysis. European Urology. 31 (1997) 263-271. 18. Kalisvaart JF, Katsumi HK, Ronningen LD, Hovey RM. Bladder cancer in spinal cord injury patients. Spinal Cord. 48 (2010) 257-261. 19. Sekar P, Wallace DD, Waites KB, et al. Comparison of long-term renal function after spinal cord injury using different urinary management methods. Arch Phys Med Rehabil. 78 (1997) 992-997. 20. Brindley GS. The first 500 sacral anterior root stimulators: implant failures and their repair. Paraplegia. 33 (1995) 5-9. 21. Egon G, Barat M, Colombel P, Visentin C, Isambert JL, Guerin J. Implantation of anterior sacral root stimulators combined with posterior sacral rhizotomy in spinal injury patients. World Journal of Urology. 16 (1998) 342-349. 14 Page 14 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

22. van der Aa HE, Hermens H, Alleman E, Vorsteveld H. Sacral anterior root stimulation for bladder control in patients with a complete lesion of the spinal cord. Acta Neurochir (Wien). 134 (1995) 88-92. 23. Van Kerrebroeck PE, Koldewijn EL, Rosier PF, Wijkstra H, Debruyne FM. Results of the treatment of neurogenic bladder dysfunction in spinal cord injury by sacral posterior root rhizotomy and anterior sacral root stimulation. J Urol. 155 (1996) 1378-1381. 24. Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. Methods for meta-analysis in medical research. New-York: Wiley; 2000. 25. Ara R, Brazier J. Deriving an algorithm to convert the eight mean SF-36 dimension scores into a mean EQ-5D preference-based score from published studies (where patient level data are not available). Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 11 (2008) 1131-1143. 26. Chan KK, Willan AR, Gupta M, Pullenayegum E. Underestimation of Uncertainties in Health Utilities Derived from Mapping Algorithms Involving Health-Related Quality-of-Life Measures: Statistical Explanations and Potential Remedies. Medical decision making : an international journal of the Society for Medical Decision Making. 34 (2014) 863-872. 27. Quinet E. Cost benefit assessments of public investments [Report]. Paris: Commissariat général à la stratégie et à la prospective; 2013. 28. Barendregt JJ. The life table method of half cycle correction: getting it right. Medical decision making : an international journal of the Society for Medical Decision Making. 34 (2014) 283-285. 29. Briggs A, Claxton K, Sculpher M. Decision modelling for health economic evaluation. Oxford: Oxford University Press; 2006. 30. Van Kerrebroeck PE. Neuromodulation and other electrostimulatory techniques. Scand J Urol Nephrol Suppl. (2002) 82-86. 31. Creasey GH. Electrical stimulation of sacral roots for micturition after spinal cord injury. Urol Clin North Am. 20 (1993) 505-515. 32. Creasey GH, Grill JH, Korsten M, et al. An implantable neuroprosthesis for restoring bladder and bowel control to patients with spinal cord injuries: a multicenter trial. Arch Phys Med Rehabil. 82 (2001) 1512-1519. 33. van der Aa HE, Alleman E, Nene A, Snoek G. Sacral anterior root stimulation for bladder control: clinical results. Arch Physiol Biochem. 107 (1999) 248-256.

32 33

15 Page 15 of 20

1

Appendices

2

Search algorithms in Medline

3

1

((("spinal cord injuries"[MeSH Terms] AND "urinary bladder, neurogenic"[MeSH Terms])

4

AND ("1980/01/01"[PDAT] : "2013/03/31"[PDAT])) AND ("english"[Language] OR

5

"french"[Language] OR "spanish"[Language])) NOT ("case reports"[Publication Type] OR

6

"editorial"[Publication Type]) AND "humans"[MeSH Terms] NOT case report [Title].

7

2

(EQ-5D OR SF-36 OR SF-6D) AND ("spinal cord injuries"[MeSH Terms]);

8

3

(("Spinal

9

cord

injuries"

"2013/03/31"[PDAT]))

AND

AND

"life

expectancy"

("english"[Language]

AND OR

("1980/01/01"[PDAT] "french"[Language]

: OR

10

"spanish"[Language])) NOT ("case reports"[Publication Type] OR "editorial"[Publication

11

Type]) AND "humans"[MeSH Terms] NOT case report[Title] ;

12

4

Sphincterotomy AND Sacral stimulation

13 14 15

Search algorithm in Scopus

16

TITLE-ABS-KEY(spinal cord injury) AND TITLE-ABS-KEY(neurogenic bladder) AND

17

(EXCLUDE(PUBYEAR,

1979)

OR

EXCLUDE(PUBYEAR,

1978)

OR

18

EXCLUDE(PUBYEAR,

1977)

OR

EXCLUDE(PUBYEAR,

1976)

OR

19

EXCLUDE(PUBYEAR,

20

TO(SUBJAREA,

"MEDI")

OR

LIMIT-TO(SUBJAREA,

21

TO(SUBJAREA,

"HEAL")

OR

LIMIT-TO(SUBJAREA,

22

TO(SUBJAREA, "NURS")) AND (LIMIT-TO(DOCTYPE, "ar") OR LIMIT-TO(DOCTYPE,

23

"re")) AND (LIMIT-TO(LANGUAGE, "English") OR LIMIT-TO(LANGUAGE, "French") OR

24

LIMIT-TO(LANGUAGE, "Spanish")).

1975)

OR

EXCLUDE(PUBYEAR,

1974))

AND

(LIMIT-

"NEUR")

OR

LIMIT-

"PHAR")

OR

LIMIT-

25

16 Page 16 of 20

1 2 3

Figure 1. Graphical representation of the model

4 5

Figure 2. Cost-effectiveness plane. Probabilistic analysis with a 2.5% discount rate and a 60%

6

efficacy of SARS

7 8

Figure 3. Cost-effectiveness acceptability curve. Probabilistic analysis with a 60% efficacy of

9

SARS and discount ratee of 1, 2.5 and 6%

10 11

Figure 4. Expected Value of Perfect Partial Information for groups of parameters.

12 13

Figure 5. Cost-effectiveness plane. Probabilistic analysis with a 2.5% discount rate and a 75%

14

efficacy of SARS

15 16

Figure 6. Cost-effectiveness acceptability curve. Probabilistic analysis with a 75% efficacy of

17

SARS and discount ratee of 1, 2.5 and 6%

18 19

Table 1. Model parameters values and sources of information. Parameters

Value

Distribution parameters α

β

Stan err

COST OF TREATMENTS AT THE ENTRANCE OF OUR MODEL SARS Medical treatment

35,543.8

3,9

8,450.0

2,6

SARS EFFICACY

17 Page 17 of 20

Probability that CVM is restored 1 year after SARS implantation

0.6

15

10

PARAMETERS ASSIGNED TO THE COHORT OF PATIENTS WITH MEDICAL TREATMENT OR SARS INCAPABLE OF CVM Cost of routine care (initial treatment or surgery)

2,6

8,450.0

Cost of surgical interventions Sphincterotomy

794.0

Continent diversion

6,475.6

Non-continent diversion

8,202.7

Cost of reversible conditions Kidney stone

899.1

Bladder stone

1,398.6 0.554

11

9

Sphincterotomy

0.0024

13

5,292

Continent diversion

0.0016

19

11,744

Non-continent diversion

0.0008

35

45,040

Initial treatment to kidney stone

0.0054

8

1,522

Initial treatment to bladder stone

0.0045

12

2,526

Surgery to kidney stone

0.0036

1

276

Surgery to bladder stone

0.0282

8

259

Utility associated to initial treatment health state Transition probabilities to urological surgery

Transition probabilities to reversible conditions

PARAMETERS ASSIGNED TO THE COHORT OF PATIENTS WITH SARS CAPABLE OF CVM Cost of routine care (initial treatment and surgery) Cost of sphincterotomy

2,6

4,014.6 794.0

Cost of reversible conditions

18 Page 18 of 20

Cost of receiver failure

5,560.2

Cost of cable failure

3,154.6

Cost of external transmitter failure

963.0 0.674

16

8

0.0083

17

1,985

Receiver failure

0,0077

28

3,622

Transmitter failure

0,0267

7

241

Cable failure

0,0036

14

3,738

0.348

16

31

Utility associated to initial treatment health state Transition probabilities to urological surgery in patients with medical treatment or SARS incapable of CVM Sphincterotomy Transition from initial treatment or surgery to reversible conditions

PARAMETERS ASSIGNED TO THE TWO COHORTS OF PATIENTS Utility assigned to surgical health state Mortality according to model cycles’ number Cycles 1-3

0.12

Cycles 4-8

0.16

Cycles 9 and 10

0.21

1 2

* Simulations using the 2013 French prospective payment system classification Costs are valued in EUR 2013

3 4

Table 2. Main results of the base case and scenario analyses Efficacy of SARS

Discount rate (%)

ICUR (EUR/QALY)

pCU

If SARS using Finetech-Brin patients per y and for a cost-effectiveness E(INHB) (QALY)

1,0

9,004

0.64

+240

2,5

12,710

0.60

+174

60%

19 Page 19 of 20

75%

1 2 3

6,0

21,833

0.55

+68

1,0

- 738

0.71

+424

2,5

2,239

0.69

+352

6,0

9,563

0.64

+232

ICER: Incremental cost-utility r atio; pCU: probability of SARS using Finetech-Bridley device being cost-utile comared to reference medical treatment; E(INHB): Expected incremental net health benefit

4

20 Page 20 of 20