Cost analysis of the treatments for patients with advanced Parkinson's disease: SCOPE study

Abstract

Objective:

To perform a comparative long-term analysis of the associated healthcare costs for the therapeutic options in advanced Parkinson’s Disease (PD): deep brain stimulation (DBS), continuous duodenal levodopa-carbidopa infusion (CDLCI), and continuous subcutaneous apomorphine infusion (CSAI).

Methods:

Resource use associated with the pre-treatment period, procedure, and follow-up was assessed for the three therapies from the perspective of the Spanish national healthcare system. Resources consumption was measured with a Healthcare Resources Questionnaire (at nine advanced PD centres). Unit costs (Euro-Spain 2010) were applied to measure resource use to obtain the average total cost for each therapy over 5 years.

Results:

Mean cumulative 5-year cost per patient was significantly lower with DBS (€88,014) vs CSAI (€141,393) and CDLCI (€233,986) (p < 0.0001). DBS was associated with the lowest cumulative costs from year 2, with a yearly average cost of €17,603 vs €46,797 for CDLCI (p = 0.001) and €28,279 for CSAI (p = 0.008). For every patient treated annually with CDLCI, two could be treated with DBS (or €29,194 could be saved) and for every patient treated with CSAI, €10,676 could be saved with DBS. The initial DBS investment (32.2% of the total 5-year costs) was offset by decreases in anti-Parkinsonian drugs and follow-up costs. CDLCI and CSAI required constant drug use (i.e., levodopa and carbidopa for CDLCI, apomorphine for CSAI), representing ∼95% of their total 5-year cost.

Limitations:

All costs were based on a questionnaire, not on actual clinical data. The study is not a cost-effectiveness analysis as there is a lack of comparable outcomes data. An expert panel was used due to the complexity and variability in the treatment of advanced PD. The sample size was relatively small.

Conclusions:

Overall, DBS requires less use of health resources than CDLCI or CSAI in advanced PD patients, mostly pharmacological. The initial DBS investment was offset at year 2 by reductions in the ongoing consumption of anti-Parkinsonian medication. For every patient treated annually with CDLCI or CSAI, substantial cost savings could be made with DBS.

Keywords::

• Apomorphine infusion pump
• Deep brain stimulation
• Duodenal levodopa infusion
• Economic analysis
• Parkinson’s disease

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder of the central nervous system with motor, cognitive, behavioural, and autonomic symptoms. The number of individuals with PD over the age of 50 years in the world’s 10 most populous nations in 2005 was between 4.1–4.6 million and will double to between 8.7–9.3 million by 20301. In Spain, with a population of ∼47 million people2 and considering the different incidence and prevalence rates published3–6, the average incidence of PD has been estimated at ∼6400 new cases/year, and the average prevalence at 150,000 people1. It is estimated that 30% of patients are in an advanced stage of the disease7.

After the first 5 years from PD diagnosis, 40% of patients experience fluctuations and dyskinesias (difficulties with movement) despite best medical treatment, which increase in severity and frequency over time8. Additional treatment options to maintain symptom control are needed, but it can be challenging to achieve a medication regimen that keeps the patient mobile but does not create side-effects that impact the patient’s quality-of-life and outweigh the benefits of treatment9. In these advanced PD patients who are refractory to pharmacological treatment, the following three treatments are recommended: deep brain stimulation (DBS), continuous duodenal levodopa–carbidopa infusion (CDLCI), and continuous subcutaneous apomorphine infusion (CSAI)10.

DBS is a medical device therapy in which a neurostimulator is connected to two leads inserted into the brain to provide electrical stimulation (i.e., bilateral stimulation of the subthalamic nucleus [STN], globus pallidus, or ventral intermediate thalamic nucleus). The stimulation modulates the signals responsible for the symptoms of PD, and can be non-invasively adjusted to meet patients’ needs. Unlike the other two therapies, DBS is supported by level I evidence. Overall, data have demonstrated a good long-term safety profile, significant improvement of motor symptoms and quality-of-life, and a reduction of daily ‘off’ time and dyskinesias when implanted in the STN in well-selected patients11–24. A reduction in oral drug treatment has also been found18,23. CDLCI is a pharmacological/medical device combination therapy in which an external pump continuously delivers levodopa/carbidopa via a catheter inserted directly into the duodenum during the day (oral medication may be taken at night if required). This results in less variability in levodopa concentrations and is associated with fewer motor fluctuations and dyskinesias than oral levodopa administration24–26. CSAI is a pharmacological/medical device combination therapy that uses an external pump to subcutaneously administer apomorphine via intermittent bolus injection or continuous pump infusion, usually during the waking day hours (but sometimes at night if patients suffer from poor quality sleep or pain27). CSAI has shown efficacy in the reduction of ‘off’ episodes24,28–30. It is important to note that these three therapies are not necessarily equivalent treatments and therefore not recommended for all patients with advanced PD; one option may be preferable over another in specific clinical situations. Adequate patient selection allows the optimization of results obtained with the three therapeutic options. The three therapies have no clear positioning in the treatment pathway of advanced PD patients, leaving neurologists with the decision about each therapy’s suitability for their advanced PD patients. Beyond the patient’s clinical status, criteria supporting treatment decision-making include patients’ and physicians’ preferences, previous hospital experience, availability of the treatments, and treatment costs.

No comparative economic evaluation of the three treatment options exists. Cost-effectiveness analyses of these therapies are hindered by the lack of comparable outcomes data. Thus, this study was designed to address the gap in comparative economic data on the three treatment options to support payers and physicians in making treatment decisions for this patient population. The SCOPE (eStudio COstes Parkinson Enfermedad) study is a quantitative evaluation of the long-term (5 years) healthcare costs associated with the use of DBS, CDLCI, and CSAI in patients in advanced PD, from the perspective of the Spanish National Health System (NHS).

Methods

A comparative costing study was undertaken to assess the healthcare costs associated with the use of DBS, CDLCI, and CSAI in patients in advanced PD over a time horizon of 5 years, from the perspective of the Spanish NHS. Costs for the whole treatment period were considered, including: (1) costs of the pre-treatment/pre-operative period; (2) costs of the procedure/treatment administration; and (3) costs of follow-up (separately for up to month 6, and from 6 months onwards to 5 years). To measure the healthcare resources associated with therapies used in advanced PD, a protocol and a detailed Healthcare Resources Questionnaire (HRQ) (see below) were designed with input from a panel of Spanish advanced PD experts. A micro-costing approach was used to estimate the quantity of each health resource consumed.

In the management of chronic diseases such as PD, all the medium- and long-term costs should be considered along with the initial acquisition costs. In addition, the existing literature for DBS states that the average battery life of a non-rechargeable neurostimulator is 4–5 years12,31, at which point a new intervention to replace the neurostimulator is required. This time period was confirmed by the expert panel. Consequently, the time period of the study was set at 5 years, to take into account all of the medium- and long-term costs and a replacement cycle. According to recommendations for economic evaluations in Spain32, both social and NHS perspectives are recommended. In the present case, considering the use of resources was taken from an expert panel of NHS clinicians and indirect costs cannot be assumed, it was decided that the perspective of the Spanish NHS was the most appropriate. Therefore, unit costs from the Spanish health resources database (Spanish Cost Database, e-salud33) were assigned to the resource use identified to obtain the total cost for each of the three therapies for the 5-year period.

The SCOPE Study was evaluated and approved by the Ethics Committee of Clinical Research of the Hospital Clinic i Provincial, Barcelona.

Healthcare resources estimates

The main investigators, together with a panel of 11 experts from nine centres in five Spanish regions (Andalucía, Canarias, Cataluña, Comunidad de Madrid and Comunidad Valenciana) developed a research protocol and a detailed Healthcare Resources Questionnaire (HRQ). A panel of experts was included as there is an absence of advanced PD practice guidelines in Spain, and a panel is representative of the clinical judgements and practice variability in situations where no clinical guidelines exist34. Centres reported a minimum of 3-years’ experience in each technique. (It should be noted, however, that the length of experience varied between centres and also between treatments; two of the centres had more than 10 years of experience in DBS.) All experts also were specialists in the treatment of advanced PD patients with experience in at least two of the three therapies evaluated. Based on 2009 information, 217 advanced PD patients were estimated to be treated annually with these three therapies in the nine centres.

The HRQ was designed to collect healthcare resources associated with DBS, CDLCI and CSAI. Costs tend to be higher in the first 6 months after administration of the therapy, when patients consume more healthcare resources (extra visits, hospitalization, dose adjustments, etc.)35–37. Consequently, it was decided to divide the HRQ into four sections: (1) pre-treatment/preoperative period; (2) procedure/treatment administration; (3) follow-up period from patient’s discharge to month 6; and (4) follow-up period from month 6 to year 5 (Table 1). For example, in the pre-treatment period, the HRQ contained questions on what type of specialist visits the patients underwent, need for hospitalization, and length of stay.

Table 1.  Healthcare resources identified for every phase and for each therapy used to treat advanced Parkinson’s disease.

1. Pre-treatment/pre-operative period (from acceptance of receiving therapy to hospitalization^a)
• Specialist visits • Hospitalization • Laboratory/diagnostic tests	• Additional visits to each specialist due to the therapy (neurosurgery, psychiatry…; not due to Parkinson’s disease progression) • Y/N, service and length of stay • Y/N, number per type
2. Procedure/treatment administration (from patient’s hospitalization to discharge^a)
• Hospitalization • Procedure administration time • Specialists in the surgery room • Material (devices, disposable materials) • Laboratory/diagnostic tests • Anti-Parkinsonian treatment^b • Complications	• Y/N, service and length of stay • Hours/minutes • Number per each type (Specialized Nurse, Anaesthesiologist, etc.) • Number per each type • Y/N, number per type • Average reduction rate in anti-Parkinsonian drug use • Y/N, resource needs
3. Follow-up period: patient’s discharge^a to Month 6
• Specialist and urgency visits • Hospitalization • Laboratory/diagnostic tests • Complications • Anti-Parkinsonian treatment^b pharmacological treatment (non-anti-Parkinsonian drugs)	• Number per each type (neurosurgery, psychiatry, etc.) • Y/N, service and length of stay • Number per each type (x-ray, MRI, etc.) • Y/N, resource needs • Average reduction rate in anti-Parkinsonian drug use
4. Follow-up period: from Month 6 to Year 5
• Specialist and urgency visits	• Number per each type (neurosurgery, psychiatry, etc.)
• Hospitalization	• Y/N, service and length of stay
• Laboratory/diagnostic tests	• Number per each type (x-ray, MRI, etc.)
• Complications	• Y/N, resource needs
• Anti-Parkinsonian treatment from month 6 to year 5^b	• Average reduction rate in anti-Parkinsonian drug use
• DBS battery replacement^c	• When the replacement is done and description of all the resources needed

DBS, deep brain stimulation.

^aAlthough the terms hospitalization and discharge are used to determine the main different phases, these therapies can be administrated in an Outpatient Hospital Service. This data was also collected in the HRQ.

^bIn addition to the pharmacological cost of the evaluated therapies, the use of other anti-Parkinsonian drugs was compared before and after the procedure administration to analyse potential savings.

^cFor DBS, the battery replacement of the device was taken into account at year 5.

The experts were asked to answer the HRQ, on paper or via face-to-face interview, based on their experience and knowledge regarding the therapies, such that the quantitative information obtained would describe real clinical experience for the most frequent patient profile in the selected centres.

Due to the fact that treatment regimens in this patient population are characterized by high variability and complexity, making it difficult to capture drug use, the HRQ did not include direct questions regarding the baseline doses and details of consumption by patients of classical anti-Parkinsonian drugs (selegiline, rasigiline or amantadine, dopaminergic agonists, levodopa, and others). The changes in anti-Parkinsonian drug treatments and associated potential cost reductions or increases with the evaluated therapies were assessed in the HRQ. For each of the treatment phases, it was asked whether anti-Parkinsonian medication was reduced or increased and, if so, by what percentage. This information was then linked to the average drug cost per year for advanced PD patients for conservative (medical) treatment in Spain, as estimated in a published economic evaluation38 for calculation of average drug costs over 5 years for each of the treatment options. The cost did not include that for apomorphine or levodopa/carbidopa.

Unit costs

Once all health resources associated with the therapies were identified and quantified, their cost per unit was obtained from the Spanish health resources database (Spanish Cost Database, e-salud33). When more than one cost was found for a certain resource, the average value was used. In cases where no specific cost was found, experts were consulted in order to choose the cost of a similar resource. All the costs were expressed in Euro-Spain 201033.

The costs of the DBS neurostimulator and all of its components were included, provided by Medtronic (2010 costs). The costs of the devices and components for CDLCI and CSAI (infusion pump, catheters, etc.) were not included as their unit costs were not publicly available; thus it was assumed that they were provided free of charge by the supplier, and therefore their cost to the healthcare system was zero.

Following health economic evaluation guidelines and considering the duration of the analysis, which was longer than 1 year in this study, an annual discount rate of 3% was applied32 to convert the future expected costs into a present value amount.

Analyses

The data analysis was performed with the SPSS 15.0 software package for Windows. The non-parametric Kruskal–Wallis one-way analysis of variance by ranks was applied in order to test the statistical differences of mean costs among the three therapies (multiple comparisons)39. The Mann–Whitney U-test was used in order to determine the statistical differences of mean costs among the two therapies with lower costs39; for this reason, only statistical differences of average costs of DBS vs CSAI were obtained. A two-tailed probability level of 5% (p < 0.05) was considered significant. The analysis results are presented as mean ± standard error of the mean (95% confidence interval [CI]).

In order to obtain a more robust estimation of the costs, a bootstrap analysis was also performed using a sample size of 50 and a re-sample of 1000, calculating the main statistics expressed as median (mean; 2.5 percentile; 97.5 percentile).

Additionally to the main analysis, six different alternative scenarios were proposed to test the sensitivity of the results to the changes in some parameters32 (Table 2). In scenarios 2, 3, and 5, the sensitivity of the results of the analysis was tested based on two values (min, max).

Table 2.  Sensitivity analysis.

Scenarios	Min value	Max value
1. No cost of anti-Parkinsonian drugs Costs of anti-Parkinsonian drugs were not considered (i.e. €0)
2. Costs of anti-Parkinsonian drugs (€/day) Costs were applied by extracting their values from published studies38, with a minimum (€9.38) and maximum (€55.05) patient daily cost for anti-Parkinsonian drugs.	€9.38	€55.05
3. Discount rate As recommended in the economic evaluation guidelines30, results were discounted applying a minimum (0%) and a maximum (5%) discount rate.	0%	5%
4. Two replacements of the DBS neurostimulator in 5 years According to clinical experience, battery replacement for non-rechargeable DBS neurostimulators is generally required between the fourth and fifth year11,32 depending on the programme settings tailored by patients. In this scenario, results were tested considering two battery replacements over the 5-year period.
5. Type of DBS neurostimulator The costs of the most recent DBS stimulators were included in the analysis, instead of the cost of the traditional non-rechargeable dual channel stimulator	Non-rechargeable, dual channel implantable neurostimulator for DBS^a	(a) Rechargeable, dual channel implantable neurostimulator for DBS that is suitable for patients with high energy needs who are willing and who able to keep their system recharged.^b (b) Smaller non-rechargeable, dual channel implantable neurostimulator for DBS that is suitable for patients with moderate energy needs^b
6. Reduction of CDLCI and CSAI costs—breakeven point Two univariate sensitivity analyses were performed in order to find the breakeven point, defined as the reduction of CSAI and CDLCI therapies drug acquisition costs necessary to obtain the same 5 year mean cost as DBS

DBS, deep brain stimulation; CDLCI, continuous duodenal levodopa-carbidopa infusion; CSAI, continuous subcutaneous infusion of apomorphine.

^aThe Medtronic Kinetra® neurostimulator is a legacy, non-rechargeable, dual channel implantable neurostimulator for deep brain stimulation (DBS).

^b(a) The Medtronic Activa® RC neurostimulator is a rechargeable, dual channel implantable neurostimulator for DBS that is suitable for patients with high energy needs who are willing and who able to keep their system recharged; (b) the Medtronic Activa® PC neurostimulator is a smaller non-rechargeable, dual channel implantable neurostimulator for DBS that is suitable for patients with moderate energy needs.

Results

Over 5 years, DBS required the greatest use of surgical and anaesthesia resources (as expected), but necessitated fewer medical visits than CDLCI or CSAI (Table 3). Fewer diagnostic tests were needed with CSAI compared with DBS or CDLCI. The unit costs of the healthcare resources included in the HRQ are shown in Table 4. Table 5 shows the average cost per patient associated with the three alternative therapies in the baseline scenario for the four different phases. As expected, during the pre-treatment phase costs were similar for the three therapies. During phase 2 (procedure/treatment administration), DBS was associated with higher costs due to device acquisition and implant procedure cost. However, from discharge to 5 years follow-up, DBS was associated with significantly lower costs compared to CDLCI and CSAI (p < 0.0001). The costs for DBS were also significantly lower than CSAI for phases 3 (discharge from hospital to 6 months) (p = 0.023) and 4 (month 6 to year 5) (p < 0.0001). This suggests that, in the long-term, DBS is a less costly therapy vs CDLCI and CSAI. The yearly average cost of DBS was €17,603 compared to €46,797 for CDLCI (p = 0.001) and €28,279 for CSAI (p = 0.008). In fact, for every patient treated annually with CDLCI, two patients could be treated with DBS (or €29,194 could be saved) and for every patient treated with CSAI, €10,676 could be saved if DBS was chosen.

Table 3.  Cumulative use of resources during the 5-year follow-up period (average values).

Resource use	DBS	CDLCI	CSAI
Average number of medical visits
Surgeon	0.00	0.14	0.00
Gastroenterologist	0.00	2.47	0.00
Psychiatrist	0.14	0.14	1.17
Nurses	2.37	26.35	17.53
Anaesthetist	0.71	0.43	0.00
Neuropsychologist	0.86	0.86	3.67
Dermatologist	0.00	0.00	1.31
Neurosurgeon	12.17	0.31	0.00
Neurologist	19.98	24.75	28.71
Emergency room	0.09	1.68	1.07
Average hospitalization days
Neurology unit	5.46	12.73	6.41
Neurosurgery unit	5.04	1.02	0.11
Outpatient care unit	0.00	1.71	0.00
Intensive care unit	0.93	0.06	0.00
Average number of diagnostic tests
Blood tests	3.43	3.99	2.08
Electrocardiography	2.00	2.31	0.59
Computerized tomography (abdominal + head)	1.84	0.14	0.00
Endoscopy	0.00	0.21	0.00
Abdominal X-ray	2.12	7.56	0.11
Thorax X-ray	0.00	0.57	0.00
MRI	1.51	0.29	0.00
Coombs Test	0.00	0.00	0.67
Type of anaesthesia: number of times required on average
Local anaesthesia	0.94	0.44	0.00
General anaesthesia	2.00	0.20	0.00
Sedation	0.86	0.82	0.00
Average resources related to surgery (hours)
Operating room	10.20	0.00	0.00
Endoscopy room	0.00	2.80	0.00
Anaesthesiologist	13.70	2.05	0.00
Gastroenterologist	0.00	3.58	0.00
Surgeon/Neurosurgeon/Neurologist	26.61	0.00	1.00
Radiologist	0.00	0.14	0.00
Nurse	14.18	7.69	1.00
Endoscopist	0.00	1.34	0.00
Neurophysiologist	1.57	0.57	0.00
Surgeon’s Assistant	1.11	0.00	0.00
Psychologist	0.86	0.00	0.00
Therapy: number of items required on average
Duodopa: number of cartridges (cartridge 0.5/2 g/100 ml)	0.00	1752.26	0.00
Apomorphine: number of ampoules (ampoules 50 mg/5 ml)	0.00	0.00	3038.49
DBS neurostimulator	1.70	0.00	0.00
Electrodes	2.00	0.00	0.00
Extensions	2.00	0.00	0.00
Days of antiparkinsonian treatment^38	985.74	903.15	1123.46
Silicone patches	0.00	0.00	1.70

DBS, deep brain stimulation; CDLCI, continuous duodenal levodopa-carbidopa infusion; CSAI, continuous subcutaneous apomorphine infusion.

Table 4.  Unit costs of healthcare resources included in the HRQ (€, 2010).

Resource	Average unit cost (€)
Visits to specialists
Surgery	47.95
Gastroenterologist	78.87
Psychiatrist	40.38
Nurses	20.56
Anaesthetist	39.38
Neuropsychologist	91.09
Dermatologist	28.93
Neurosurgeon	77.94
Neurologist	91.09
Urgencies/emergency room	112.50
Rheumatologist	79.95
Hospitalization (cost/day)
Neurology	272.44
Neurosurgery	496.28
Outpatient Care	167.50
Intensive care unit (ICU)	1,085.81
Gastroenterology	307.61
Diagnostic tests
Laboratory tests	10.51
Electrocardiogram	18.97
Abdominal CT	124.83
Endoscopy	35.69
Abdominal X-ray	13.01
Thorax X-ray	19.54
Magnetic resonance	187.17
Cranial tomography	256
Coombs test	10.51
Electromyography	163.98
Ultrasound	11.46
Resources related to surgery
Operating room (cost/hour)	547.83
Endoscopy room (cost/hour)	375.96
Local anaesthesia	47.20
General anaesthesia	188.64
Sedation	47.20
Anaesthetist (cost/hour)	34.14
Gastroenterologist (cost/hour)	37.94
Surgeon (cost/hour)	41.50
Radiologist (cost/hour)	37.94
Nurse (cost/hour)	19.47
Endoscopist (cost/hour)	37.94
Neurophysiology (cost/hour)	41.5
Surgeon’s assistant (cost/hour)	37.94
Psychologist (cost/hour)	37.94
Cost related to therapies Continuous duodenal levodopa/carbidopa infusion (20/5 mg/ml, pack with 7 intestinal gel cartridges of 100 ml) Apomorphine (5 ampoules of 10 mg/ml) DBS system Silicone patches (patches 3 units for 20 days) Pharmacological cost/day anti-Parkinsonian treatment	756^a 151.75^a 17,163.6^b 10.69^a 38.9^c

DBS, deep brain stimulation.

^aRetail prices extracted from Official Database of Medicines in http://www.portalfarma.com (taxes included).

^bOfficial fees provided by Medtronic Ibérica S.A. (taxes included). The system included two electrodes, the extension wires, and the dual program neurostimulator (Kinetra®). In the sensitivity analysis, the costs of the new DBS family Activa® PC and Activa® RC were included, instead of the cost of Kinetra®: average unit costs of DBS system with Activa PC®: €19,555.5; Average costs per patient of DBS system with Activa RC®: €29,605.9. These systems also included two electrodes, the extension wires, and the dual program neurostimulator (Activa PC® or Activa RC®). In the DBS family Activa® RC, the charger costs was also included.

^cAverage anti-Parkinsonian pharmacological treatment cost per day38.

Table 5.  Results of the baseline scenario expressed as mean ± standard error. Costs per patient (€, 2010).

Phases	Average costs
	DBS (n = 7)^a	CDLCI (n = 9)^a	CSAI (n = 7)^a
1. Pre-treatment period to hospitalization^b	1141 ± 411	1705 ± 357	1231 ± 267
2. Hospitalization period to discharge^b	27,236 ± 3105^c	3165 ± 501^c	785 ± 197^c
3. Discharge^b to 6 months post-op	4768 ± 918^c,d	25,521 ± 2381^c	12,094 ± 2158^c,d
4. From month 6 to year 5	54,869 ± 4190^c,d	203,596 ± 8737^c	127,284 ± 9184^c,d
Total cost per 5 years	88,014 ± 2580^c,d	233,986 ± 10,552^c	141,393 ± 9945^c,d
Average cost per year	17,603 ± 516^c,d	46,797 ± 2110^c	28,279 ± 1989^c,d

DBS, deep brain stimulation; CDLCI, continuous duodenal levodopa-carbidopa infusion; CSAI, continuous subcutaneous infusion of apomorphine.

^an = number of expert observations collected for the specific therapy.

^bAlthough the terms hospitalization and discharge are used to determine the main different phases, these therapies can be administrated in an Outpatient Hospital Service.

^cComparison of the three therapies (p < 0.05).

^dDBS vs CSAI comparison (p < 0.05).

DBS was associated with lower cumulative costs compared with CDLCI over the whole 5-year period (p < 0.0001) (Figure 1). In addition, from year 2 there was a significant difference in costs between DBS and CSAI, in favour of DBS (p = 0.008). At year 5, the mean cumulative costs per patient for DBS amounted to €88,014 ± 2580, significantly lower than for CSAI (€141,393 ± 9945) and CDLCI (€233,986 ± 10,552) (p < 0.0001) (Figure 1). For DBS, the high initial investment required during the first two phases (pre-treatment period to discharge; 32.2% of the total 5-year cost) was offset at the end of the first year when compared to CDLCI (p = 0.001) and from year 2 for CSAI comparison (p = 0.008), by decreases in anti-Parkinsonian pharmacological treatment and follow-up costs. The majority of the DBS costs were incurred within the initial 6 months. Around 95% of the total 5-year cost of CDLCI and CSAI was related to constant pharmacological costs, mainly acquisition costs for the levodopa-carbidopa intestinal gel cartridges (84.4%) and apomorphine ampoules (65.7%). In contrast, for DBS anti-Parkinsonian drugs represented only 43% of the total (Figure 2). Results from the bootstrap analysis were very similar to the deterministic analysis (Table 6).

Figure 1.  Cumulative annual costs for deep brain stimulation (DBS), continuous duodenal levodopa-carbidopa infusion (CDLCI), and continuous subcutaneous infusion of apomorphine (CSAI) (€, 2010). * All differences were statistically significant (p < 0.05) for multiple comparisons (among the three therapies) and for the DBS vs CSAI comparison (p < 0.05).

Figure 2.  Costs distribution of deep brain stimulation (DBS), continuous duodenal levodopa-carbidopa infusion (CDLCI), and continuous subcutaneous infusion of apomorphine (CSAI) over the 5 year period (€, 2010).

Table 6.  Results of the bootstrap analysis.* Results are expressed as median (mean; 2.5 percentile; 97.5 percentile).

Phases	DBS	CDLCI	CSAI
1. Pre-treatment period hospitalization	1143 (1155; 1021; 1570)	1700 (1705; 1584; 2041)	1231 (1224; 1134; 1495)
2. Hospitalization period to discharge	27,319 (27,285; 26,412; 29,762)	3175 (3181; 3003; 3717)	786 (790;717;999)
3. Discharge post-op to 6 months	4757 (4782; 4514; 5612)	25,551 (25,649; 24,760; 28,176)	12,083 (12,100;11,410;14,158)
4. From month 6 to year 5	54,738 (54,786; 53,502; 58,512)	203,522 (203,518; 200,647; 212,420)	127,226 (126,960; 123,839; 135,635)
Total cost per 5 years	88,045 (88,009; 86,441; 92,398)	233,984 (234,054; 231,045; 243,091)	141,234 (141,076; 137,817; 149,905)

*The primary benefit of a bootstrap technique is that it is a non-parametric technique, so requires no assumptions as to the shape of the sampling distribution of the statistic of interest. Using the bootstrap approach, repeated random samples of the same size (in this case, the sample size was 50), as the original sample are drawn with replacement from the data. As such, the fact that an observation has been selected for inclusion in a re-sample does not preclude it from being selected again for the same re-sample. The statistic of interest is calculated from each re-sample, and these bootstrap estimates of the original statistic are then used to build up an empirical distribution for the statistic. The number of bootstrap re-samples, B, required depends on the application, but typically B should be at least 1000 when the distribution is to be used to construct confidence intervals.

In the sensitivity analyses (scenarios outlined in Table 1), DBS therapy was the least costly therapy compared to CDLCI and CSAI (p < 0.0001) for the three therapies comparison in both scenarios, even when considering different values for the costs of anti-pPrkinsonian drugs (p = 0.001 for DBS vs CSAI in scenario 1; p = 0.003 and p = 0.008, respectively, for the two DBS vs CSAI comparisons in scenario 2) (Table 7). In scenario 3, different discount rates were applied: by varying the discount rate from 0% to 5%, DBS proportionally remained the least costly therapy compared to CDLCI and CSAI (p < 0.0001 for the three therapies comparison; p = 0.008 for DBS vs CSAI). Considering a different battery replacement cycle for DBS, assuming a total of two battery replacements in the 5 year period in scenario 4, DBS remained the least expensive therapy compared to CDLCI and CSAI (p < 0.0001 for the three therapies comparison and for DBS vs CSAI). In scenario 5, the cost of new, differently-priced neurostimulators (either a rechargeable, dual channel implantable neurostimulator for DBS suitable for patients with high energy needs who are willing and able to keep their system recharged, or a smaller non-rechargeable, dual channel implantable neurostimulator for DBS suitable for patients with moderate energy needs) was considered. Even when this cost was taken into account, DBS remained the least expensive therapy (p < 0.0001 for the three therapies comparison and for DBS vs CSAI). In scenario 6, a progressive univariate reduction of CDLCI and CSAI drug acquisition costs was applied in order to achieve the breakeven point. Results showed that the drug acquisition cost of CDLCI must be reduced by 78.5% from its current value to obtain a similar 5-year cost to DBS. Considering CSAI, a 57.2% reduction in the price of apomorphine would bring the mean 5-year cost of CSAI to the same level as DBS (for example, the price of apomorphine ampoules must be ∼€13 instead of the current price of €30.4).

Table 7.  Results of the sensitivity analysis (average ± standard error) (€, 2010). The results show 5-year total costs.

Scenarios	Average costs per patient (€ 2010)
	DBS	CDLCI	CSAI
Main analysis	88,014 ± 2580^a b	233,986 ± 10,552^a	141,393 ± 9945^a b
1. Without including the costs of anti-Parkinsonian drugs	50,061 ± 4480^a b	200,342 ± 2526^a	96,095 ± 7155^a b
2. Costs of oral anti-Parkinsonian drugs Min daily cost €9.38 Max daily cost €55.05	59,206 ± 3167^a b 103,730 ± 4786^a b	208,448 ± 3966^a 247,918 ± 14,348^a	107,010 ± 7515^a b 160,150 ± 11,772^a b
3. Discount rate Min 0% Max 5%	90,251 ± 2757^a b 86,639 ± 2473^a b	247,645 ± 11,130^a 225,724 ± 10,203^a	149,932 ± 10,546^a b 135,228 ± 9582^a b
4. Replacement cycle: 2 replacements considered in the 5-year period	101,260 ± 2580^a b	233,986 ± 10,552^a c	141,393 ± 9945^a b c
5. Cost of next generation non-rechargeable stimulator Cost of next generation rechargeable stimulator	91,960 ± 2461^a b 82,950 ± 2850^a b	233,986 ± 10,552^a c	141,393 ± 9945^a b c
6. Progressive reduction of CDLCI and CSAI pharmacological costs to reach the breakeven point.		A 78.5% reduction in CDLCI cost is needed to obtain the same 5-year total costs results as DBS	A 57.2% reduction in Apomorphine is needed to obtain the same 5-year total costs results as DBS

DBS, deep brain stimulation; CDLCI, continuous duodenal levodopa-carbidopa infusion; CSAI, continuous subcutaneous apomorphine infusion.

^aComparison of the three therapies (p < 0.05).

^bDBS vs CSAI comparison (p < 0.05).

^cSame results as main analysis.

Discussion

This study is the first to compare the resource use and costs of DBS vs CDLCI and CSAI, the key three treatment options in advanced PD. It is also the only study in Spain to estimate the resources and costs related to advanced PD management with the three therapies. Results of the current evaluation show that, despite requiring an initial investment of 32.2% of the total cost, DBS was associated with the lowest costs during the whole 5-year period compared to CDLCI (p = 0.001) and from year 2 compared to CSAI (p = 0.008). During the total 5-year period, compared with the amount necessary to treat one patient with CDLCI, at least two patients could be treated if DBS was chosen (or €145,972 could be saved) and €53,379 could be saved vs treatment with CSAI. Comparison of costs over a 5-year period enabled the medium- and long-term costs associated with advanced PD to be captured; results show that the breakeven of the initial DBS investment occurred in the first and second year of treatment, respectively, when compared with CDLCI and CSAI.

The study did not include indirect costs, as the Spanish NHS perspective was selected. Pharmacological costs accounted for ∼95% of the total cost of CDLCI and CSAI, while for DBS they represented 43% of the total. These results were obtained considering one battery replacement in the 5-year period and without including acquisition costs for CDLCI and CSAI devices and components (infusion pump, catheters, etc.; only drug costs). If these costs had been included, results would have been even more favourable for DBS. The bootstrap analysis confirmed that the deterministic cost results were robust. Additionally, DBS showed the lowest costs in all the scenarios considered in the sensitivity analysis, even with the most unfavourable assumptions. Other alternative scenarios were tested in the sensitivity analysis: a second battery replacement during DBS therapy and a reduction of CDLCI and CSAI pharmacological costs. In all of these scenarios, DBS remained the least costly therapy.

Several published international economic evaluations of DBS conducted in other countries have applied different approaches, as presented in the review by Puig-Junoy & Puig Peiró.40 which identified five cost studies35,36,41–43 and five complete economic evaluations of DBS compared to optimal medical therapy37,38,44–46. As in our study, the evidence shows a reduction in medication costs associated with DBS.

Regarding the other two therapies, only one Swedish study from 2008 estimated the annual cost of CDLCI47. Cost estimates oscillated between €40,000 and €80,000 according to the dosage used. These results corroborate the CDLCI results of our study, as we observed an average drug cost of €44,839 per patient per year and the intestinal gel cartridges of CDLCI represented 84.4% of this total drug cost.

There are certain limits to the current study. For example, all costs were based on a questionnaire, not on actual clinical data. In addition, the study is not a cost-effectiveness analysis; however, cost-effectiveness analyses of these therapies are hindered by the lack of comparable outcomes data24, and the results of this study are the first step towards supporting payers and physicians in making treatment decisions for this patient population. Furthermore, the decision to use an expert panel (due to the complexity and variability in the treatment of advanced PD) may be considered a limitation. However, an expert panel can contribute to mapping complex treatment processes, and provide estimates of healthcare resources44. It is worth mentioning that the 11 experts of the panel can be considered representative of the clinical practice of advanced PD in Spain, as both neurologists and neurosurgeons from nine centres located in five different Spanish regions were involved, with experience on at least two of the three therapies evaluated in this analysis. While clinical practice for treating PD might be different for settings outside Spain, it can be assumed to be similar enough for the significant results and large cost savings observed for DBS to be relevant across Europe. A further limitation is the relatively small sample size; nevertheless, all results were checked with non-parametric contrast hypothesis tests. For multiple comparisons, all results became statistically significant, except for the pre-treatment period to hospitalization. When statistical differences of mean costs among the two therapies with lower costs were compared, results showed that DBS became significantly less expensive than CSAI in year 2.

Conclusions

This study showed that DBS is the least costly therapy for advanced PD under the Spanish NHS perspective, compared to CDLCI and CSAI. The initial investment for the DBS implant is offset by a reduction in the consumption of other healthcare resources by patients over the years, resulting in the lowest cumulative costs over a 5-year period. For every patient treated annually with CDLCI or CSAI, substantial cost savings could be made with DBS. In contrast, CDLCI and CSAI require a more important and constant use of relatively similar health resources, with pharmacological costs being the main source.

Transparency

Declaration of funding

This research was funded by Medtronic International Sarl, Tolochenaz, Switzerland.

Declaration of financial/other relationships

FV received honoraria from Medtronic for this study and has received honoraria for lectures or advice from: Bohringer Ingelheim España, Abbot Laboratories (Manufacture and Commercialization of Duodopa [CDLCI]), Italfarmaco (Commercialization of Apomorphine [CSAI] in Spain), Medtronic Ibérica, UCB Pharmaceuticals and Novartis. JP-J received honoraria for consultancy from Medtronic for this study. RP-P received honoraria for consultancy from Medtronic for this study and participated in the study while working at the Centre for in Health and Economics (CRES), Universitat Pompeu Fabra, prior to joining the Office of Health Economics (OHE), London. OHE receives an annual conditional research grant from the Association of the British Pharmaceutical Industry (ABPI). The ABPI Code of Practice for the pharmaceutical industry regulates marketing of prescription medicines by companies based in the UK. Duodopa is produced and commercialized by Abbott, a member company of the ABPI. Abbott did not have any input in this study. The views expressed in this paper are those of the authors and are not necessarily those of either OHE or ABPI or Abbott. Neither OHE nor ABPI are in a position to endorse the findings of this report, which was funded by Medtronic Ibérica, S.A. Paloma González and Cristina Canal work for Medtronic Ibérica SA.

Acknowledgements

This paper was edited by an English-speaking professional medical writer, Deborah Nock (DPP-Cordell, Saxthorpe, UK), funded by Medtronic International Sarl, Tolochenaz, Switzerland.