Evaluating the cost effectiveness of donepezil in the treatment of Alzheimer's disease in Germany using discrete event simulation

Alzheimer's disease (AD) is an incurable neurodegenerative disease characterized by cognitive decline, impairment of daily activities and neuropsychiatric symptoms. AD patients lose the ability to perform higher-level daily activities and decrease to being no longer able to perform basic daily necessities such as eating or grooming [1]. Mood swings, apathy, psychosis or agitation are behavioral symptoms commonly observed with AD patients. With increasing severity of the disease dealing with the patients' symptoms can become an increasing burden to caregivers.

A recent study reported the prevalence of dementia in Germany a under 1% of 60-64 year olds and significantly increasing to roughly 20% for those over the 85-89 year olds, up to three quarters of whom had AD [2]. Recent estimates for Germany placed the number of individuals with moderate of severe dementia at just over 1 million, with a projected increase of AD patients in Germany of over 2 million by 2050 [2]. Against the background of an aging population, the German Federal Government has recently intensified its focus on dementia. In 2008, the "Leuchtturmprojekt Demenz" with a budget of 13 million Euro was initiated to improve the evidence-based medical and care service provision for dementia patients [3].

Despite the fact that the benefit of cholinesterase inhibitors have been established by numerous studies [4, 5] and that they are a recommended treatment for AD [6], physicians may hesitate to treat patients accordingly given drug acquisition cost considerations [7]. Research on the cost effectiveness of cholinesterase inhibitors is therefore important to provide decision makers with the best possible economic evidence to determine whether concerns over drug acquisition costs are legitimate.

Over the last decade, numerous studies have measured the cost-effectiveness of treatments for AD [8, 9], most evaluating the cost-effectiveness of cholinesterase inhibitors. Eight studies have investigated donepezil [10‐17], with all but one indicating that donepezil was cost-effective. In Germany, a recent study showed that donepezil was also cost-effective in the German setting, with a base case estimated cost-effectiveness ratio of €4,264 per CDR--Clinical Dementia Rating Scale gained [18].

Previous cost-effectiveness studies have modeled AD progression in terms of cognitive function alone, functional status alone, a single global severity measure, or progression to the need for "Full Time Care". Our study uses an alternative modeling approach to estimate disease progression in terms of correlated changes in cognition, behavior and function. The model was initially constructed for analyses set in the UK [19].

The discrete event simulation developed for the evaluation of donepezil's cost-effectiveness in the UK [19, 20] was adapted for Germany. The model calculates outcomes from the perspective of both the statutory health insurance and care insurance (Gesetzliche Krankenversicherung/Soziale Pflegeversicherung, GKV/SPV), and from the societal perspective. The GKV/SPV perspective encompasses direct medical costs borne by statutory healthcare insurance including drug costs, costs for monitoring and service provision as well as patient care costs borne by long-term care insurance. The societal perspective comprises both direct and indirect costs, the latter including costs of caregiver time. A discount rate of 3.0% was used for both costs and benefits [21]. In the base case analyses, the time horizon is 10 years in order to capture all potential benefits over the course of the disease.

In patients with mild to moderately severe AD (26 ≥ MMSE ≥ 10), donepezil dominates no treatment from both the GKV/SPV perspective, with savings averaging €7,007 per patient (€7,323 undiscounted). From the societal perspective where savings increase to €9,893 per patient (€10,384 undiscounted) (Table 4), donepezil treatment is associated with an increase in QALYs averaging 0.13 per patient (0.14 undiscounted). For caregivers, donepezil treatment increases QALYs by 0.01 compared to caregivers of untreated patients (0.02 undiscounted). Donepezil also increases the amount of time patients spend with MMSE scores above 10 by an average of 24 weeks per patient, NPI scores below 28 by almost 6 weeks, and ADL/IADL scores below 50 by more than 7 and 3 weeks, respectively. In patients with moderate including moderately-severe AD (20 > MMSE ≥ 10), donepezil also dominates memantine, although savings are smaller, averaging €1,960 per patient (€2,097 undiscounted) from the GKV/SPV- and €2,825 per patient (€3,012 undiscounted) from the societal perspective. QALY gains are clearly smaller, with donepezil associated with an average QALY gain of 0.01 per patient versus memantine (0.01 undiscounted), and caregiver QALYs gained at less than < 0.001. The reduction in time patients spend institutionalized also falls by just over 10 days per patient. For patients with moderately severe AD, donepezil still dominates no treatment, although consistent with findings in the UK [20]. Cross reference Getsios 2010, per patients savings were lower at €8,043, as were both patient and caregiver QALYs gained, at 0.120 and 0.013, respectively. Memantine also led to lower overall costs and improved QALYs relative to no treatment, although both savings and QALYs gained, although savings were 35% lower compared to those with donepezil, and QALYs gained 13% lower.

In one-way sensitivity analyses key parameters such as caregiver time, costs, utilities, institutionalization and treatment effects were varied. Regardless of the variation, donepezil remained dominant compared to both no therapy and memantine. Rates of treatment discontinuation and the duration of treatment had the strongest influence on the extent of savings and health benefits (Table 5).

In probabilistic sensitivity analyses, donepezil dominates no treatment in almost all replications from both the health care payer and societal perspectives (Figure 2). Versus memantine, donepezil dominates in 70% of replications, and leads to savings in 95% of replications (Figure 3). For the analyses versus memantine, at a threshold of 10,000 Euro/QALY, donepezil was cost-effective from both perspectives in over 90% of replications.

The discrete event simulation developed for donepezil provides a flexible framework for the assessment of treating AD patients with donepezil. By integrating patients' individual characteristics, heterogeneity in the population, disease progression and outcomes can be captured. Disease progression was modeled not solely relying on 1 year RCT data, but also using longer term CERAD registry data, which allows for a more realistic representation of the disease course. The model allows for analysis of population subgroups, with different settings for time horizon, treatment duration, discontinuation rules, and treatment effects. Cost, utility and caregiver inputs can be specified for different severity ranges and locations of care, or can be specified using predictive equations, making adaptation of the model and incorporation of new data easier.

The analyses for Germany indicate that donepezil is clearly cost-effective in the treatment of patients with mild to moderately-severe AD. In the base case and all one-way sensitivity analyses, donepezil dominated no treatment and memantine in all scenarios evaluated. Results of the probabilistic sensitivity analyses were also highly favorable with donepezil dominating no treatment in virtually all replications, and leading to savings in the comparison with memantine in 95% of replications. With the availability of generic cholinesterase inhibitors, cost savings should be even greater, although the contribution of the cost of treatment with donepezil to overall costs is modest, representing less than 2.5% of total costs in patients with mild to moderately-severe AD.

Our model differs from most previous economic models in AD in that we model disease progression over several domains using continuous scales, rather than using a single domain and/or limiting outcomes to a small number of discrete health states. Although more favorable overall with donepezil predicted to dominate no treatment, the results of this study are much more in line with previous findings for Germany [19], where a base-case ICER of €4,264 per QALY for donepezil versus placebo was estimated. That study also indicated that starting treatment early leads to cost reductions and therefore improved cost-effectiveness. The more favorable predictions from our simulation are chiefly a result of the greater sensitivity of our model in capturing changes in cognition, and in the case of indirect costs, the consideration of not only cognition, but also patient function and behavioral symptoms.

The current simulation is not without limitations. For example, the longest-duration of head to head clinical trial data available was for 1 year versus placebo [29]. With the assumption that continued treatment after 1 year serves as a maintenance function only with no further slowing of the rate of disease progression, we have adopted a conservative approach consistent with most other modeling studies in this area. Furthermore, we assume that all benefits are lost within 6 weeks if treatment is discontinued. Comparisons with memantine are subject to even greater uncertainty, as no head-to-head trial data are available, requiring indirect comparisons based on pooled trial results. Clearly, incorporation of head to head clinical trial data versus memantine would strengthen comparisons and yield more robust results. In addition, the current analyses evaluate memantine monotherapy versus donepezil monotherapy. Although memantine also be used as an add-on treatment to cholinesterase inhibitors, this was not evaluated, as the focus of these analyses was on the cost-effectiveness of donepezil, and not memantine.

The source population for the trial data was not German, though it was weighted for the age and sex distribution of German AD patients when defining the simulated population. Other limitations of the data revolve around assigning costs and utilities associated with different degrees of disease severity. A recent review paper on health utilities [53] used in economic evaluations, noted the limited amount of data on severity specific health utilities in populations with AD, and the poor correlation between patient-based utilities, and those derived by caregiver proxy.

The cost data for Germany are based entirely on MMSE ranges (i.e., they do not consider behavior or function). Furthermore published German cost data for AD at the time of the analysis were scant, with only one publication providing suitable information [47]. A number of studies on dementia and AD costs were published in 2011 [52, 54‐56]. Those studies that did report costs by severity of disease [52, 54, 55], all found that costs increase markedly with increased disease severity, consistent with the data used in the current model and therefore would not alter our conclusions. The one study that examined costs in patients with AD, for example [54] found that the annual costs of the disease average €13,080 per patient per year (€ 2009), but approached €25,000 per patient for those at the most severe stages of the disease, compared to well under €7,000 per patient for those at the most mild stages. Finally, although wide variation exists in the valuation of informal care, with donepezil dominant over no treatment and memantine, even when these costs are considered, the method of assigning costs to caregiver time would only influence the extent of savings associated with donepezil. Of note, however, the hourly costs assigned to caregiver time are substantially lower than those used in recent German costing studies in dementia [52, 54, 55].

These analyses indicate that donepezil is highly cost-effective in the treatment of mild to moderate AD in Germany, and is likely associated with significant cost savings when compared to untreated patients. While benefits over memantine are modest, the base case and sensitivity analyses results suggest a high likelihood that donepezil would lead to cost savings if used in place of memantine.

This research was funded by Eisai GmbH, Germany. Eisai GmbH was informed throughout the process of data collection and analyses, and contributed to the research through critical review of results and manuscript.