Adherence to Cholinesterase Inhibitors in Alzheimer's Disease: A Review

The effectiveness of any treatment is dependent upon the required medications being administered as prescribed. However, treatment adherence (or compliance), defined as ‘the extent to which a patient's behaviour matches agreed recommendations from the prescriber' [1], is a major problem in the management of many medical conditions [1,2].

Alzheimer's disease (AD) is the most common cause of dementia worldwide, with global prevalence estimated to be as high as 24 million, and predicted to double every 20 years through to 2040 [3,4]. AD is a chronic neurodegenerative condition characterised by a progressive deterioration of cognitive function [3,4]. From onset, AD causes progressive deficits in memory, language, judgement, decision making, orientation and learning [3,4].

The mainstays of treatment for the relief of mild-to-moderate AD symptoms are the cholinesterase inhibitors (ChEIs) donepezil, galantamine and rivastigmine [5,6]. Sustained use of these agents for 3 or more months may delay the worsening of cognitive, functional and behavioural symptoms of AD [5,7]. However, treatment management is a major challenge in AD, with non-adherence to treatment often a barrier to effective therapy [8,9].

The aim of this non-systematic literature review is to highlight some of the challenges associated with adherence to ChEIs, since these are by far the most commonly prescribed medications for patients with AD, and to discuss strategies addressing these issues in clinical practice.

A search of the online PubMed literature database (http://www.ncbi.nlm.nih.gov/pubmed) was performed in December 2011 using combinations of the following terms: Alzheimer's disease; cholinesterase inhibitors; adherence; compliance; persistence; caregiver, and non-adherence. In order to focus the search on up-to-date information, articles were limited to those published in the last 10 years. Only articles published in the English language were included. The search results were then manually assessed for relevance using the titles and abstracts of the publications. Further relevant references were selected from the bibliographies of identified papers. A summary of the key studies can be found in table 1.

ChEIs cannot reverse AD or prevent its natural progression, instead they provide relief from symptoms [5,10]. With all three approved agents (donepezil, galantamine and rivastigmine), modest improvements in measures of disease severity last for approximately 6 months, but seldom result in recovery of lost function [5,7]. Rigorous reviews of clinical trial data for each of the three available oral ChEIs show that they all reduce the rate of cognitive function decline and dementia severity, and improve performance in activities of daily living in people with mild-to-moderate AD [10,11,12]. However, functional capacities lost (e.g. the ability to manage finances or drive) are rarely recovered [5,7,10,11,12]. Owing to its dual action on both acetylcholinesterase and butyrylcholinesterase, it has been suggested that rivastigmine may also reduce behavioural symptoms in mild-to-moderate AD (galantamine and donepezil act solely on acetylcholinesterase) [13].

AD has a major impact on the quality of life (QoL) of both the patient and the caregiver [14,15,16]. Given the short life expectancy following a diagnosis of AD (median 3-8 years [17]), and the progressive nature of the disease, treatments that stabilise symptoms or delay their progression, even for 6-12 months, can have important benefits on QoL for patients and their caregivers [14,15]. An observational study of 445 patients with AD found that the use of ChEIs for at least 1 year was associated with a decreased risk of rapid cognitive deterioration and institutionalisation [18]. It follows that patients who manage to adhere to AD therapies for longer have a greater chance of slowing or delaying progression of their symptoms and increasing their QoL [8]. Furthermore, a delay in institutionalisation of patients may also lead to savings in healthcare costs [19,20].

Published data on treatment adherence and persistence (the length of time from initiation to discontinuation of treatment) in AD reveal conflicting results. In part, this may be owing to different methodological processes, such as the length of time taken to signify treatment discontinuation (e.g. 30, 60 or 90 days between prescription refills) or the environmental settings in which adherence has been studied (table 1). Many studies investigating treatment adherence or persistence in patients with AD have been performed using retrospective analyses of administrative health databases or pharmacy claims [21,22,23,24,25,26,27,28,29,30,31,32]. It should be noted that in all of these studies, evaluation of adherence is based on drug dispensation and not actual drug intake by the patient.

In one retrospective analysis of a managed healthcare plan in the US between 2006 and 2008, only 58.2% of the 3,091 patients with AD identified were adherent to oral AD medications (including all three ChEIs or the N-methyl-D-aspartate antagonist, memantine, which is indicated for use in moderate-to-severe AD) over the 12-month follow-up period [21]. In this study, a number of variables were associated with better adherence to oral AD medication, including being male, age ≥86 years, and using a lower formulary tier AD medication [21]. Unfortunately, the database had no information on caregiver support, medication management interventions, or use of adherence aids that may have affected adherence in this cohort. Conversely, in a retrospective community-based survey of dispensing records performed over a 9-year period in Canada, 93.5% adherence to ChEIs was observed [23]. However, as mentioned previously, treatment adherence was measured based on drug dispensation rather than the amount of drug actually administered to the patient, and in addition, home delivery was the most frequent way to dispense treatments, making adherence to treatment easier and more convenient for the caregiver. This may have led to an overestimation of actual adherence to treatment.

In a recent study aimed at assessing actual medication administration/intake, adherence over a period of 6 months was assessed in a small cohort (n = 31) of ambulatory patients with AD using electronic monitoring (a medication vial with a microprocessor in the lid recording the time of every opening) [33]. On average, median compliance to ChEIs was 94% (range 49-99%) but was variable between patients, with 10 patients (32%) <80% compliant for a period of at least 1 month out of the 6 months studied (fig. 1) [33]. This study highlights that adherence rates may differ significantly between individual patients with AD.

Persistence is reported to be a particular problem in AD [8], perhaps more so than is adherence. Indeed, two treatment reviews performed in Canada assessing oral ChEIs showed that only 40-54% of patients achieved persistence at 12 months after initiation of therapy [25,27]. Additionally, in a French study, 1-year persistence of ChEI treatment was estimated at 45.3% of 942 patients. The authors concluded that to optimise persistence with ChEIs, patients presenting with more severe symptoms and/or those aged over 80 years should be especially monitored [29].

In summary, evidence reported in the literature to date indicates that although day-to-day adherence to ChEIs can sometimes be high, there is a great deal of intra-individual and inter-study variation. In addition, persistence with medications over time may be poor. Understanding the reasons for poor treatment adherence and persistence in patients with AD is crucial for determining effective strategies to address and improve outcomes of this problem.

As treatment adherence is presently suboptimal in AD, the potential benefits of the available effective therapies are not being fully experienced, either by patients or caregivers [8]. Non-adherence to treatment can either occur as the result of a considered deliberate decision (intentional non-adherence) or can happen unintentionally (unintentional non-adherence) due to misunderstanding instructions, forgetfulness or unforeseen circumstances. Furthermore, within these categories, patient, caregiver and prescriber factors all exert influences on medication adherence (fig. 2) [1].

Intentional non-adherence is based on patient, caregiver or prescriber beliefs and perceptions about the illness and the treatments available for it. It is clear from the literature that few studies have investigated illness perceptions specifically in dementia or AD, and none have specifically investigated the impact of illness perceptions on treatment adherence [34,35,36].

Patient Beliefs

Patient understanding and beliefs about their illness may impact on their likelihood both to seek help for their symptoms and also to adhere to any recommended therapies. A review of qualitative research proposed that three phases of decision making are important regarding medication adherence in older people: faith in the prescriber's ability to correctly diagnose and select treatment; testing of the effectiveness of the medication on symptom relief and adverse effects, and patients' beliefs about the illness itself [37]. Any one of these can influence attitudes to treatment and adherence. For example, in one study, patients with mild-to-moderate AD did not perceive themselves as being ill and assessed their condition as stable or improving [35]; such misconceptions may alter a patient's acceptance for taking medications. As such, there is clearly a need to educate patients both about the disease itself and available treatment options.

Along with beliefs about the disease itself, there is an expectation among patients with AD (along with their caregivers) for symptom improvement following treatment, and disease stabilisation is not necessarily valued. This may discourage persistence with any medications, such as ChEIs, that treat only the symptoms of disease [5,8].

Caregiver Beliefs

Cultural beliefs may also impact on treatment decisions [38,39]. One study showed that Hispanic and Chinese caregivers were more likely than caregivers from other cultural groups to believe that AD is part of the normal ageing process - such attitudes may delay help seeking by these caregivers, the patients and other family members [39].

Another study specific to AD assessed the attitudes of first-degree relatives (not necessarily caregivers) towards future availability of suitable treatments for the symptoms of AD [36]. The results suggested a positive attitude to AD pharmacological treatments in general. As ChEIs cannot reverse the disease, it is very important that caregiver expectations of treatment outcome are realistic. Indeed, a large perception difference has been reported between physicians and caregivers of patients with AD regarding many aspects of care (including disease aetiology, pathogenesis, dosage and treatment recommendations and adherence) [40]. This highlights the need to improve the communication process between prescribers and caregivers in order to optimise clinical management of AD, which may include increased adherence to effective therapies [40]. Furthermore, in a recent study, overall caregiver satisfaction with treatment for AD did not correlate with patient compliance to treatment, but it did correlate with the changes in patient's cognitive impairment, a factor that also influences caregiver's burden [14]. It therefore follows that improvements in adherence to ChEIs would have a positive impact on caregiver burden.

Prescriber Beliefs

In addition to patient and caregiver attitudes, the attitudes and beliefs of prescribing physicians are also likely to impact on treatment adherence and persistence in AD. Massoud et al. [41] suggested that physicians may not persist with AD treatments because they do not regard stabilisation of the disease as a great benefit. However, as discussed previously, in a condition such as AD, where there is a steady deterioration in a patient's cognitive and functional abilities, treatments that stabilise symptoms or delay progression, even for 6-12 months, can have important benefits on QoL for both patients and their caregivers [8,14,15]. Physician education on the value of disease stabilisation and symptom relief, to both patients and caregivers, may therefore help to relieve caregiver burden.

The chronic nature of AD and the associated deficits in cognitive and physical functions make patients particularly susceptible to treatment non-adherence [8]. Other factors involved in unintentional non-adherence include those related to the medication itself, as well as caregiver and prescriber factors.

Patient Factors

In the early stages of AD, patients are involved in the management of their own medications [42]. However, as people age and the disease progresses, they have increasing physical, visual and cognitive limitations that relate directly to their ability to follow medication regimens; unfortunately, many patients do not realise the extent of these problems, considering themselves able to take their own medicines even when they are unable [43]. Numerous limitations associated with progressive AD, including memory problems, polypharmacy, and physical problems, such as reading labels and swallowing difficulties, are all likely to have an impact on treatment adherence in AD [44,45]. Additionally, many patients with AD also require medications for comorbid conditions, resulting in complex treatment regimens that are also known to decrease adherence [46].

In addition to physical limitations, the patient's tolerability of any given agent may also affect adherence, with decreased adherence likely to result from poor drug tolerability [47]. The most common adverse events associated with all three of the oral ChEIs are gastrointestinal side effects [47]. The development of novel pharmacological treatments or applications for AD may improve drug tolerability. For example, it is reported that the risk for gastrointestinal adverse events is lower with transdermal rivastigmine than with the oral formulation [48].

Caregiver Factors

Family caregivers play a role in medication management from an early onset of AD [42]. However, older caregivers are themselves likely to be affected by a range of adherence factors common in the elderly population, such as polypharmacy, comorbid conditions and declining physical and visual abilities. As a result, elderly caregivers often experience difficulties with scheduling, administration and safety issues [8]. Indeed, one study reports that 12% of caregivers were estimated to have dementia themselves, with 20% treated for psychiatric conditions such as depression, a condition which is known to affect adherence to medication [8,49]. Caregiver underestimation of patients' cognitive impairments and overestimation of their ability to correctly administer their own medications, particularly in the early stages of disease, are also likely to impact on adherence [42]. Furthermore, given the burden and limitations faced by many caregivers, their personal preferences for dosing schedule and route of medication administration also have the potential to inadvertently impact on treatment adherence. As such, treatment schedules, such as once-daily dosing, and delivery routes that allow ease of administration are likely to be seen as advantageous. For example, >70% of caregivers have reported a preference for transdermal over oral delivery of rivastigmine [50,51,52].

Prescriber Factors

Prescriber factors that impact on unintentional treatment adherence in AD may include their compliance with published medical guidelines. Such adherence to medical guidelines is known to vary from country to country. For example, in the UK, uptake of new medications is slower than in many other countries; this is possibly owing to concerns about drug efficacy and safety [53]. Thus, new medications associated with better adherence may not be made available to all patients.

The frequency and quality of contact between the prescriber and the patient/caregiver are also major determinants of medication adherence, with good communication and frequent visits between patient and physician as a major factor for good adherence [8,40].

To date, strategies developed to increase treatment adherence in AD have focused on new drug delivery methods [54]. Concepts suggested include extended release, orally disintegrating or sublingual tablet formulations, intranasal or short- and long-acting intramuscular or transdermal forms, and nanotechnology-based delivery systems [54]. Of these, both extended-release tablets (galantamine) and transdermal application (rivastigmine) are already available. Donepezil is also available in a once-daily dosing formulation. Transdermal patch administration of rivastigmine has been shown to be of particular benefit compared with rivastigmine capsules because of increased tolerance, smooth and consistent drug delivery, easier access to optimal dose through simple titration steps, and the potential for improved efficacy at lower doses with this mode of administration [48,52,55,56]. It will be of interest to investigate how these strategies impact on patient and caregiver behaviour in the future.

Video home monitoring and reminder systems have also been tested as a means for improving compliance in cognitively impaired patients [57,58]. For example, in a cohort of 8 patients with mild dementia, those monitored using 2-way video technology demonstrated stable treatment adherence, whilst adherence in unmonitored patients decreased significantly over the treatment period [57]. However, these systems can be expensive and impractical to install and manage. Automated reminder devices may be easier to apply to the growing population of patients with AD, but do not have the benefit of increasing human contact with the patient [59].

Additional strategies to improve adherence to treatment in AD need to be developed and validated. These should focus on the specific patient, caregiver and prescriber factors that have been highlighted previously (table 2). We suggest that, in addition to the development of pharmacological strategies, interventions should also include education of physicians, patients and caregivers in order to address any unrealistic beliefs and expectations around the course of disease and benefits of any treatments. Particular emphasis should also be made to any cultural beliefs about AD, whilst the importance of treatment adherence should be stressed to both patient and caregiver. Good communication and frequent contact between patient, caregiver and physician is also of importance for all aspects of disease management.

By delaying the progression of AD symptoms, even for a few months, ChEIs can improve QoL for patients with AD and their caregivers. However, in order to achieve maximum benefit from these agents, as with any other medication, it is important that medication schedules are fully adhered to.

Important determinants of adherence to treatments in patients with AD include patient, caregiver and prescriber factors. Along with the physical, cognitive and psychological characteristics of caregivers and patients, their beliefs about AD and expectations about the efficacy of treatment may also be key determinants of adherence and should be addressed in any interventions aimed at improving it. The pharmacological development of ChEIs in order to improve treatment adherence, efficacy and tolerability has been reported in the literature. Consequently, a number of studies have reported on the benefits of transdermal drug delivery of rivastigmine in patients with AD. Further research is required to determine the extent to which such interventions improve adherence in this patient population.

R.B. is an employee of Atlantis Healthcare, and J.W. is a consultant for Atlantis Healthcare. Atlantis Healthcare was commissioned by Novartis to develop a carer support programme for patients prescribed the rivastigmine patch. Editorial assistance was provided by Fishawack Communications; this was funded by Novartis Pharma AG.