Cost-Effectiveness of Device-Aided Therapies in Parkinson’s Disease: A Structured Review

INTRODUCTION

Parkinson’s disease (PD) is a progressive neurodegenerative disease, mostly affecting older people, with a clear impact on quality of life [1]. In the early stages the disease can be managed well with oral therapies at a relatively low cost, but as the disease progresses into more advanced stages, the effect of these therapies diminishes and associated costs of treatment increase. The impact on societal burden of advanced PD may be considerable as the top 20%of patients incurring most costs, often those in advanced stages of the disease, are responsible for 70%of secondary care costs associated with the disease (£16,500 ( 22,493) per patient per year in the UK) [2]. As the incidence of PD is rising sharply, with a continuous growth in prevalence that is expected to double within the next 25 years [3], costs associated with treatment and the burden this places on society is becoming increasingly relevant.

Oral dopaminergic treatment is effective for alleviating the early symptoms of PD. However, despite optimal dopaminergic treatment most patients in moderate to advance stages of PD experience progressively increasing disabilities [4]. At this stage of the disease motor fluctuations are almost inevitable with levodopa treatment [5], and calls for the initiation of device-aided therapies once the criteria for these therapies are met [6]. Moreover, motor fluctuations are often accompanied by non-motor fluctuations, adding to a separate complexity and the decline in perceived quality of life [7]. When fluctuations occur, treatment aims should shift from oral medication to more continuous dopaminergic stimulation in the form of device-aided therapies [8], not in the least as these therapies also have a positive effect on many non-motor symptoms, and thus improve quality of life for PD patients [9, 10]. Currently available device-aided therapies are deep brain stimulation (DBS), intrajejunal Levodopa-carbidopa infusion (IJLI) and continuous subcutaneous apomorphine infusion (CSAI).

DBS, of either the subthalamic nucleus (STN) or globus pallidus internus (GPI), was approved by the US Food and Drug Administration in 2002 as a treatment option for PD, although the technique had been in use since the 1980s [11]. Randomized clinical trials have confirmed its effectiveness in improvement of motor and non-motor symptoms as well as quality of life in moderated and advanced stages of PD [9, 10, 12, 13]. Also for CSAI and IJLI numerous studies have shown that these two treatments are clinically useful and efficacious in improving levodopa induced dyskinesias and other motor complications of PD [14]. In addition, all three device-aided treatments have a differential effect on non-motor symptoms of PD [9, 10]. Despite the clear effectiveness of device-aided therapies in the management of both motor and non-motor symptoms in advanced PD, concerns continue to exist regarding the high costs associated with these therapies. Here, economic evaluations are useful to assess their cost-effectiveness, aiding in decision-making of when to introduce these therapies in PD patients, in addition to the choice of device-aided therapy type.

Therefore, we aimed to perform a systematic re-view of the available literature on economic analyses of device-aided therapies in patients with PD. Additionally, we looked at ongoing efforts to reduce the costs associated with these therapies.

METHODS

In this systematic review, we aimed to address the following clinical questions:

References used in the current review were identified by performing a systematic search in the PubMed and Web of Science databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15]. The search query was based on the PICO strategy and included 1) Population: advanced PD; 2) Intervention: CSAI, IJLI, or DBS; 3) Context/setting: all countries; and 4) Outcomes: cost-effectiveness of device-aided therapies. We determined time horizon of the intervention of at least one year. The time span of the search ranged from 1988 to April 2020. For PubMed, we used the Medical Subject Heading (MeSH) term “Parkinson’s disease” combined with the terms “Apomorphine”, “Levodopa Infusion” or “Deep Brain Stimulation”, and “Cost” (Table 1). All MeSH terms were expanded to include all subheadings to identify all relevant articles. All potentially eligible manuscripts were considered regardless of publication type or language. The final search was performed in April 2020. In addition, reference lists of identified articles were screened for further potentially relevant papers. Articles were selected based on the following eligibility criteria: (1) original research, and (2) performed in PD patients. The search query is shown in Table 1 and the study selection process is shown in Fig. 1.

Fig. 1

Study selection process.

As universal guidelines on what is considered cost-effective are lacking, and marked differences in reimbursement policies exist between countries, we decided to use the gross domestic product per capita (GDP) as a threshold for cost-ineffectiveness [16]. The GDP of each country in the year in which a study was performed was used to determine whether the device-aided therapy studied was cost-effective (defined by a cost beneath the GDP of the respective country). Information on GDP was downloaded from the Organisation for Economic Co-operation and Development [17]. All costs not provided in euro were converted to euro based on the average exchange rate for the year (http://www.xe.com) in which the analysis for each included manuscript was conducted.

In addition to the aforementioned aims we have included manuscripts identifying implementation barriers of device-aided therapies in PD. For this, articles were selected based on their relevance and these were not included in the systematic search as this was not the primary aim of this review.

RESULTS

An overview of cost-effectiveness for the respective device-aided therapies is provided in Table 2. In total, 248 articles were retrieved from the database search by the query. Based on the selection process, 30 articles were included (Fig. 1); 30 on cost-eff-ectiveness analyses for the device-aided therapies and a further three manuscripts on current efforts to reduce costs in these therapies.

DISCUSSION

Based on the available evidence all three device-aided therapies in PD, DBS, CSAI and IJLI, are able to improve quality of life compared to best medical treatment with oral therapies, with improvements between 0.88 and 1.26 QALY in the studies with long temporal horizons. This improvement appears to be more pronounced for IJLI than CSAI and DBS, although studies directly comparing these three device-aided therapies are few. Nonetheless, these improvements in quality of life are substantial and certainly merit serious consideration in view of the prevailing cost-effectiveness criteria. Based on the criteria used in the current review we have shown that DBS is a cost-effective device-aided treatment for PD, but this picture is less uniform for the infusion therapies.

Whether or not therapies are deemed cost-effective often depends on health authority regulations in individual countries. In the UK, where many of the in-cluded studies in this review were performed, the National institute for Health and Care excellence (NICE) will often only appraise a technology or new medication if the ICER is less than £20,000 per QALY gained, and it is unlikely to approve interventions with an ICER of £30,000 or over per QALY gained. Exceptions are made if a therapy has a very clear treatment effect and offers additional effects beyond standard therapy [49]. However, this situation is not uniform and the ‘willingness to pay’ per QALY differs vastly across countries [50]. In 2018, the range of costs per QALY for diseases in general that different European countries were willing to pay ranged from $19,006 (€ 16,107) in Poland to $180,653 (€ 153,096) in Belgium [50], although these numbers do not need necessarily apply to PD. As such, it is unlikely that all device-aided therapies will be approved in every country in Europe, mainly IJLI which is the most expensive device-aided therapy. Although fixed criteria to assess whether an intervention is cost-effective are lacking and differ from country to country, some studies have proposed, e.g., the one by Laupacis et al., that treatment was considered cost-effective if the costs were below € 50,000/QALY [51]. Other approaches, including the one we deployed in the current review, suggest that the ICER should be below the gross domestic product (GDP) of a country per capita [16]. GDP as a benchmark to evaluate cost-effectiveness of a therapy has been promoted by the World Health Organization’s Choosing Interventions that are Cost–Effective (WHO-CHOICE) project [52]. However, it has been also argued that the thresholds based on per capita GDP had major shortcomings and should be abandoned as guides for policy-makers [53]. Thus, the appropriate measure and threshold of cost-effectiveness remains controversial and there are still no established and commonly accepted criteria. Furthermore, it is a commonplace that therapies that are considered sufficiently promising and therefore get funded often develop (due to scientific and technological progress) and become more cost effective over time [54]. That is why it may be reasonable to fund some particularly beneficial therapies even despite their relative low cost-effectiveness rate. Practical applicability of a therapy may create an incentive to develop it further to become more cost-effective, while its rejection due to insufficient cost-effectiveness (irrespective of its medical effects) usually impairs its potential for improvement, including cost-benefit ratios. It entails that even a relatively low cost-effectiveness of a therapy may, at least in some cases, be compensated by strictly medical effectiveness accompanied by a potential for further technological development reducing its costs.

In addition to the ICER for the three device-aided therapies being within the ‘willingness-to-pay’ limits per QALY for most countries for which such data is available, the introduction of these therapies in the complicated stages of PD may have further benefits. Although not usually included in the cost-effectiveness analyses as an outcome, some authors have suggested that cost savings might be achieved by a reduction in care giver burden and indirect costs associated with care. For example, Heald and colleagues demonstrated that in the UK the prescription of non-oral medication (apomorphine and rotigotine in this study) resulted in a reduced annual admission rate of up to 28%[2]. In this respect, it is interesting to note that Findley et al. found that cost of care for patients with advanced PD, calculated as direct non-medical and indirect costs, accounted for over 85%of total costs [55]. More specifically, the authors observed that direct non-medical costs of professional care in the UK accounted for 50%of costs, indirect informal care 43%, whereas only 7%of total costs could be attributed to directly incurring medical costs. The latter was determined mostly by hospitalisation, followed by health professional visits and testing. In addition, when a caregiver is considered in cost-effectiveness analyses, one study looking at IJLI has shown that the gain in QALYs allows patients to remain independent for longer and, thereby, reduce societal and informal care burden. In terms of costs, this resulted in an additional € 5,500 reduction in ICER [26].

Interestingly, most cost-effectiveness analyses in device-aided therapies have focused on the impro-vement of motor function as a driver for the improvement in quality of life and QALYs. Non-motor symptoms, however, have an at least equal, if not more important contribution to quality of life in PD [56]. Future analyses should include improvements of non-motor symptoms in their analyses as it is known that all device-aided therapies improve non-motor burden and have a differential effect on the spectrum of non-motor symptoms that improve, along with an associated improvement in quality of life [9, 10, 12, 57]. In addition, indirect costs, such as a reduction in caregiver burden and reduced medical care costs, among others related to a reduction in hospital admissions, should be taken into account in future studies.

At first glance, when comparing the three device-aided therapies, DBS appears to be the most cost-effective therapies. However, certain limitations to this conclusion should be acknowledged. First and foremost, it should be realised that the patients that receive DBS, compared to those selected for infusion therapies, show certain differences in demographic characteristics. Patients selected for DBS are often younger and with a shorter disease duration than those selected for CSAI, and especially IJLI [9, 10], and per DBS protocols patients with cognitive decline or depression are not selected for DBS [58]. These latter restrictions are less stringent for the infusion therapies. As all these factors contribute to quality of life, both through increasing motor and non-motor burden with increasing age and disease duration, the improvements observed on quality of life after introduction of these therapies is unlikely to be comparable across groups. Additionally, and unlike the case for IJLI and CSAI, Dams et al. reported that DBS can be efficiently applied at an earlier stage of disease [36], as also recommended in guidelines. Despite the consistent observations that DBS is more costly then oral treatment, expenses can be justified by the gain in health advantages. The authors demonstrated that DBS can be applied in early stages of PD for a generally acceptable price of € 22,700/QALY gained [36].

Choosing which device-aided treatment option is most suitable is not just a question of health economics, but requires a careful process, in which the patient’s and carers’ preferences and the clinician’s expertise contribute equally to the decision. Nonetheless, the implementation of device-aided therapies in PD appears to be challenging and during this process one is regularly confronted with implementation barriers occurring in clinical practice [59]. First of all, even though PD patients need to be involved in a shared-decision making process, they often feel ill-equipped and unsupported by medical specialists, although this is country and healthcare system specific and need not apply to all situations [60]. Furthermore, selecting eligible patients for advanced therapies often appears to be a challenging task in clinical practice. The selection for all device-aided therapies in PD should carefully assess the following factors: disease duration, age, levodopa responsiveness, type and severity of levodopa-unresponsive symptoms, cognitive and psychiatric issues, comorbid disorders, and for DBS also brain magnetic resonance imaging (MRI) findings [61]. Moreover, neurologists regularly mention limited decision-making capabilities in PD patients as an additional barrier in patients with advanced PD, where increasing disease severity and associated cognitive deficits further complicate these capabilities [62]. Other factors of influence include the patient’s place of residence, where, for example, patients in rural areas often have limited access to specialised centres providing device-aided therapies for PD [63]. This may lead to delayed referral and delayed consideration for non-oral treatments, causing a general under-treatment of advanced PD [60]. Related to this, patients are often first seen by a general neurologist, who may not have specialised knowledge regarding advanced treatments in PD, further influenced by the lack of access to multidisciplinary team care and lack of experience with device-aided therapies and their beneficial effects [64]. Finally, from both a patient’s and health care professional’s perspective, potential post-interventional adverse events might represent an additional barrier in choosing device-aided therapies (Table 3). Examples include the greater risk of falling and hallucinations in DBS, potentially leading to longer hospitalization, local nodules at infection site, haemolytic anaemia, fatigue, dizziness, orthostatic hypotension, and electrocardiographic changes in CSAI [65, 66], and the development of polyneuropathy in IJLI treated patients [67]. Related to this, there is limited unbiased and comparable information for all three options, as no randomized controlled trials directly comparing the device-aided therapies have been conducted [59]. However, trials with such comparisons are underway and the results are awaited with great interest [68].

CONCLUSIONS

In summary, of the device-aided therapies DBS is clearly cost-effective, as these costs are around or below the GDP of the countries where the studies looking at this have been performed. For the infusion therapies this picture is less uniform, although current studies seem to support that long-term use of these latter therapies favours their cost-effectiveness profile. Nonetheless, universally acceptable cost thresholds for device-aided therapies are lacking. Additionally, often indirect, improvement of factors other than motor improvement used as the primary endpoint to determine effectiveness, may justify the use of infusion therapies in PD. Moreover, several studies regarding cost-effectiveness for device-aided therapies in PD with a temporal window of over five years show that the ICER was within, or at least near, the respective countries’ GDP per capita, the threshold that remains the prevailing measure of assessing cost-effectiveness for public policy decisions. This suggests that further improvement to the delivery of infusion therapies is likely to make them cost-effective in the long-run. Several studies suggest that societal costs and costs associated with care burden with these therapies and other indirect costs, often not taken into account in cost-effectiveness analyses, decrease compared to best medical therapy. Although DBS appears to be the most cost-effective of the three device-aided therapies, caution should be observed when comparing to the infusion therapies. Often the PD patient populations for DBS and infusion therapies differ, as e.g., per DBS inclusion criteria patients with cognitive problems or depression are excluded, but are often, to a certain extent, allowed for patients on infusion therapies. In addition to the recent efforts that have been made to reduce the direct costs of the infusion therapies, other factors need to be taken into account. As most analyses performed to date have only looked at the effectiveness based on motor improvement, future cost-effectiveness analyses should additionally look at non-motor effects and associated improvements in quality of life and reductions in both direct and indirect costs.

CONFLICT OF INTEREST

No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures of all authors (for the preceding 12 months)

KS received a fellowship grant from Department of Neurology, Christian-Albrechts University, Kiel Germany, Research fellowship from European Academy of Neurology.

DvW received a fellowship grant, and consultancy and speaker fees from Britannia Pharmaceuticals, speaker fees from Bial Pharmaceuticals, and consultancy fees from Invisio Pharma.

TP received grants from National Science Centre (Poland), Ministry of Science and Higher Education (Dialogue Program), and Boards: Council of the Polish National Agency of Academic Exchange, Polish National Committee for Ethical Review of Animal Experimentation, Bioethical Committee of the Silesian Medical Chamber, Boethical Committee of the Silesian Medical University, Council of the Kukuczka Academy of Physical Education in Katowice. Financial Fees from SPCG Law Firm (Katowice Branch Office).

AC received scholarship by the Konrad-Adenauer Foundation.

CRB has nothing to disclose.

PMM has received honoraria from National School of Public Health (ISCIII) and Editorial Viguera for lecturing in courses or publications; from International Parkinson and Movement Disorder Society (IPMDS) for management of the Program on Rating Scales; and from Bial for advice in a clinical-epidemiological study. Grants from the IPMDS for attending the IPMDS International Congress 2019, and for development and validation of the MDS-NMS.

PO Advisory board/expert advice: AbbVie, Bial, Britannia, Evolan, Global Kinetics, Kyowa-Kirin, Lobsor, Neuroderm, Nordic Infucare, UCB, Stada, Zambon, PD Neurotechnology

Honoraria for lectures: AbbVie, Bial, Kyowa-Kirin, PD Neurotechnology, Zambon

Grants (Investigator Initiated): AbbVie, Bial, Global Kinetics Academic grants: Swedish Parkinson Academy, Hardebo Foundation, Lund University Medical Faculty, Swedish Parkinson Foundation, Southern Swedish Health Care Region, Skåne University Hospital donations.

KRC received grants (Investigator Initiated) from: Britania Pharmaceuticals, AbbVie, UCB, GKC, Bial, Aacdemic grants: EU, IMI EU, Horizon 2020, Parkinson’s UK, NIHR, PDNMG, EU (Horizon 2020), Kirby Laing Foundation, NPF, MRC, Wellcome Trust. Advisory board: AbbVie, UCB, GKC, Bial, Cynapsus, Novartis, Lobsor, Stada, Medtronic, Zambon, Profile, Sunovion, Roche, Therevance, Scion, Britannia. Honoraria for lectures: AbbVie, Britannia, UCB, Mundipharma, Zambon, Novartis, Boeringer Ingelheim.