Aim of this publication
Alzheimer’s disease (AD) is associated with progressive deterioration of cognitive and functional abilities (Fig. 1). To date, there is no cure and no validated disease-modifying treatment. Therefore, the aim of therapy is to maintain the patient’s independence as long as possible, and to reduce the burden of care. Data from long-term observational studies of antidementia drugs on deterioration rates suggest that persistent use of the available drugs can slow the clinical progression of AD as assessed by cognitive, functional and global outcome measures, possibly even in advanced cases (Rountree et al. 2009). The N-methyl-d-aspartate (NMDA) receptor antagonist memantine is able to preserve everyday competence including cognitive abilities, social behavior, basic everyday activities and communication. There is evidence that therapy with a combination of cholinesterase inhibitors and memantine has positive effects on different aspects of the disease, which exceed those of monotherapy. Physicians in daily practice need recommendations when and how to treat the individual AD patient. The goal of this publication is to review the existing evidence concerning the therapy of AD with a combination of memantine and a ChEI, particularly donepezil, and derive recommendations for clinical practice, based on the results of a scientific symposium sponsored by Merz Pharmaceuticals.
Due to the demographic situation in industrialized nations, AD will become an ever increasing health care challenge in the next decades. The annual number of AD cases probably will double over the next 50 years. Its prevalence in the U.S. could quadruple to more than ten million cases by 2050 (Lopez et al. 2010). These data underscore the need for effective treatment. AD not only affects cognition. The detection of non-cognitive disturbances is important, because they will increase impairment in activities of daily living, accelerate cognitive decline, lead to early institutionalization, and have a negative impact on the patient’s quality of life (Gonzalez-Salvador et al. 2000; Lyketsos et al. 1997; Mok et al. 2004; Stern et al. 1997). Early diagnosis and treatment are important, and also cost effective, as they may delay admission to nursing homes and improve patients‘ and caregivers‘ quality of life (Cummings et al. 2008; Lopez-Pousa et al. 2008).
Current therapeutic options
At the moment, two classes of drugs are licensed for the treatment of AD: Cholinesterase inhibitors (ChEIs) and the N-methyl-d-aspartate (NMDA) receptor antagonist memantine. ChEIs such as donepezil, galantamine and rivastigmine are indicated for the treatment of mild to moderate AD, where they exert a small but robust effect. There is some evidence for an effect of ChEI in the severe stage (MMSE < 10), and donepezil has been licensed for this stage in the U.S.
Memantine is efficacious and approved for the treatment of patients with moderate to severe AD. In placebo-controlled studies, it showed a low incidence of adverse events (Farlow et al. 2008; Parminder et al. 2008). There is no pharmacological or clinical evidence for drug-drug interactions between memantine and ChEIs. In an in-vitro study, memantine did not inhibit ChEI activity within and beyond therapeutic concentrations. In in-vivo studies, it does not interact with licensed ChEIs. Therefore memantine can be administered along with donepezil, galantamine or rivastigmine (Dekundy A. 2003).
Preclinical data supporting combination therapy
Degeneration of cholinergic nuclei localized in the basal forebrain occurs in the course of AD. Impairment of the cholinergic system is followed by cognitive decline. Consistent with these findings, compounds which increase cholinergic neurotransmission have shown to be effective. Additionally, excessive activation of NMDA receptors causes impaired function and death of nerve cells contributing to the manifestation of symptoms of AD. Memantine as an NMDA receptor antagonist can prevent the pathological stimulation of NMDA receptors.
Usually, glutamate transmits phasic signals via the NMDA receptor and glutamate is rapidly recycled in the cells. In AD, ß-amyloid oligomers inhibit glutamate recycling and directly stimulate the NMDA receptor in a tonic manner. The resulting tonic NMDA receptor activation masks signal transmission with the consequence of inhibited postsynaptic signal detection. Disruption of glutamatergic neurotransmission is thought to contribute to the widespread loss of neurons in regions critical for learning and memory via a process known as excitotoxicity. Excitotoxicity can develop due to the presence of excess tonic glutamate in the synapse or due to direct activation/increased sensitivity of NMDA receptors due e.g. to b-amyloid. In either case, an overabundance of calcium enters the cell via the NMDA receptor and inappropriately triggers calcium-dependent cellular processes, ultimately contributing to cell death (Farlow et al. 2004).
Memantine is believed to normalize glutamatergic neurotransmission by blocking tonic overactivation of NMDA receptors. Animal models revealed the potential for neuroprotection in affected areas (Farlow et al. 2004; Dekundy 2006). Combining memantine and donepezil improved cognitive performance in a triple transgenic mouse model (Martinez-Coria, H. et al. 2009).
Combination therapy in randomized trials
Randomized, placebo controlled, double blind clinical trials (RCT) are considered the gold standard for clinical trials in Evidence Based Medicine due to their high internal validity. To date there are two trials with this design evaluating combination therapy with donepezil and memantine. Tariot et al. (2004) performed a study in 404 patients with AD who were on stable doses of donepezil and received either placebo or 20 mg of memantine over 24 weeks. Dementia severity, measured by the Mini Mental State Examination (MMSE), was moderate to severe (placebo group: mean score 10.2 (SD 2.98), memantine group: mean score 9.9 (SD 3.13). At week 24, cognitive function of patients receiving the combination of memantine and donepezil significantly improved. The effect size for cognition was d = 0.21, and a responder analysis showed cognitive deterioration in 9 % for patients treated with memantine and donepezil vs. 17% for patients treated with placebo and donepezil (IQWIG, 2011). Activities of daily functioning (the second primary outcome variable) remained stable for a longer period of time in these patients compared to patients treated with donepezil alone (Fig. 2). A significant difference in favor of memantine plus donepezil treatment was also observed on the Clinician’s Interview-based Impression of Change Plus Caregiver Input, Neuropsychiatric Inventory (NPI) and Behavioral Rating Scale for Geriatric Patients (all secondary outcome variables).
Post-hoc analyses examined these results in detail and identified specific areas in which combination therapy produced better results, namely memory and praxis at week 24 when compared to donepezil monotherapy. Patients treated with memantine and donepezil also showed less decline in language function (Schmitt et al. 2006, Fig. 3). In addition, combination therapy in this group compared to donepezil monotherapy had a significant positive impact on the domains ‘agitation’, ‘aggression’ and ‘irritability’. Patients suffering from gitation/aggression at study entry improved significantly at week 24, and those who were free of agitation/aggression at baseline developed significantly less agitation/aggression by week 24 (Cummings et al. 2006).
The second randomizedcontrolled trial was performed by Porsteinsson et al. (2008). The authors included 433 patients with mild to moderate AD (MMSE 10-22) who were on stable doses of ChEIs (donepezil, rivastigmine or galantamine) and added placebo or memantine over 24 weeks (MMSE: placebo group mean score 17.0 (SD 3.64), memantine group mean score 16.8 (SD 3.67)). The primary outcome variables were cognition (ADAS-cog) and CIBIC-Plus. Secondary outcome variables included measures of cognition, function and behavior. When compared to baseline, there was no statistically significant difference between the groups in this trial across all outcome variables at week 24. Regarding cognition, there were several numerical advantages not reaching statistical significance. Reasons for the negative outcome of this trial could lie in the facts that decline in the “ChEI plus placebo” group was smaller than expected, that patients were pre-treated with any ChEI, as opposed to donepezil-only in the study by Tariot et al. (2004), and that the trial involved mild-stage patients, in whom memantine is less efficacious (see discussion: “When to start combination therapy”). A post-hoc analysis indeed showed a significant effect on cognition in the subgroup of ‘moderate’ patients, with an effect size of 0.17 (IQWIG, 2009). A later responder analysis of the moderate subgroup revealed that 25 % in the memantine combination therapy group, but 32 % in the ChEI group showed a ‘clinically significant cognitive deterioration’.
A pooled analysis of both combination therapy studies showed odds ratios of 0.62 for cognitive deterioration, 0.66 for deterioration of general impression (CIBIC plus), and 0.81 for deterioration of activities of daily living, each in favor of combination therapy. These findings proved to be robust in sensitivity analyses that considered drop-outs as non-responders (IQWIG, 2011).
Combination therapy was well tolerated in the above mentioned trials. In the trial of Tariot et al. (2004), adverse events occurred in a similar proportion of patients in both treatment groups. In the study of Porsteinsson et al. (2008), overall type and frequency of AEs were also similar between groups (Tab. 1). Therefore, the benefit-risk ratio for combination therapy seems to be favorable.
Memantine in long-term trials
Due to ethical reasons RCTs result in a limitation of both patient numbers and length of follow up. In addition, the patients included in such studies seldom reflect the population encountered in routine practice. Therefore, observational studies are necessary to evaluate the long-term treatment effects of combination therapy, e.g. progression of disease or time to nursing home admission.
One observational, open label, longitudinal study conducted at a memory disorders clinic in the U.S.A. demonstrated that the use of a ChEI along with memantine (n = 116) achieved a significant reduction in cognitive and functional decline compared with ChEI monotherapy (n = 122) or no antidementia treatment (n = 144) over a mean period of 30 months (Atri et al. 2008). The authors of this study concluded that combination therapy with a ChEI and memantine is clinically effective in non-institutionalized patients. Additionally, they found that patients receiving combination therapy had a significantly lower rate of deterioration in the domain of “daily function” compared to untreated patients and patients receiving ChEI monotherapy. The latter two groups did not significantly differ from each other. The authors concluded that clinical benefits are increasing over time and that the additional effects of combination therapy are clinically relevant.
Another long-term open-label study, based on the analysis of two different prospective observational cohort studies, was conducted to examine the effects of ChEIs and memantine on the time to institutionalization and life expectancy (Lopez et al. 2009). A total of 943 patients participated in this trial. All patients had a baseline assessment and at least one follow-up evaluation (follow-up time ranged from 0.8 to 18 years). A total of 149 patients were treated with combination therapy, 387 patients received monotherapy with ChEIs and 416 patients did not receive any antidementia drug. Patients who received ChEIs had a significant delay on nursing home admission compared to those who had never taken cognitive enhancers. Adding memantine significantly augmented the effect (Fig. 4). There was more than a threefold decrease in the risk of being admitted to a nursing home in the combination group compared to the ChEI group. Based on these results, the authors concluded that the addition of memantine to ChEI treatment generates additional benefits in extending the time to institutionalization without prolonging live-span or the end stage of the disorder.
Once AD is diagnosed, development of a treatment plan for the best possible management of the disease is essential. In the absence of a cure for AD, the treatment goal is to effectively employ currently available agents. Combination therapy is one important treatment approach in AD management.
Disease stages for combination therapy
Combination therapy is possible for patients with moderate to severe AD.
Explanatory statement: In the U.S., the license for donepezil was extended to the severe stage of AD in 2007, based on several studies that showed treatment effects in this stage (Feldman et al. 2001; Tariot et al. 2001; Winblad et al. 2006; Black et al. 2007). Thus the present licensing covers a combination therapy of donepezil and memantine in the moderate and severe stage. In other countries, licensing for galantamine, rivastigmine and donepezil covers the moderate stage. In the SERAD study, positive effects in the severe stage were also shown for galantamine (Burns et al. 2009). With costs dropping after the introduction of generic ChEIs, combination therapy with ChEI and memantine will likely be considered more often.
Rationale for the use of combination therapy
The multifaceted nature of AD and the pharmacological differences among available agents support the use of combination therapy. Combination therapy is well tolerated.
Explanatory statement: The concept of combination therapy with a ChEI and memantine is based on the fact that the two drugs have different and complementary mechanisms of action, and that there is evidence for a positive effect when memantine is given in addition to a ChEI. In terms of cost effectiveness, precise data are not available, but there is no reason to assume that an increment in treatment effect would not confer a comparable effect on the costs of care.
When to start combination therapy
Based on the available trial data, the recommended time to start combination therapy is at the transition from the mild to the moderate stage, i.e. at a MMSE score of 19–20. Starting add-on therapy before this point seems to have no beneficial effect. Starting add-on therapy too late would mean to dismiss the chance for better acute treatment effect and better long-term outcome.
Explanatory statement: In clinical practice, antidementia treatment of AD patients is frequently started with a ChEI, and switched to memantine or later supplemented by memantine. Possible reasons for this schedule include the concept that ChEI are more efficacious in the early, and memantine in the later stage of AD, the desire to keep memantine as a reserve when dementia progresses despite ChEI treatment, and the assumption that risks and costs are lower in monotherapy than in combination therapy. An alternative approach is to start combination therapy relatively early, e.g. at a MMSE score of 19–20 as suggested above.
The available evidence suggests that memantine monotherapy and combination therapy is efficacious from the moderate stage onwards. The average effect sizes are approximately d = 0.2. In one open-label long-term observational trial, the effect size of combination therapy compared to ChEI therapy increased with time, i.e. from a Cohen’s d of 0.1 during the first year to 0.49 in the fourth year (Atri et al. 2008).
The randomized trial data cited here provide evidence for a statistically and clinically significant effect of emantine when combined with donepezil. However, starting therapy too early seems to have no beneficial effect. A recent review concluded that there is no evidence for an efficacy of memantine before the moderate AD stage (Schneider et al., 2011). One memantine monotherapy (Bakchine et al., 2007) and two combination therapy trials with donepezil (Porsteinsson et al., 2008) and galantamine (Peters et al., 2009) which failed to show significant treatment effects may have done so because they included subgroups of mild AD patients. For example, in the case of Peters et al., the mean MMSE score was 21.7 ± 2.3.
Possible disease-modifying effects of combination therapy
At present, it cannot be determined to which degree combination therapy has truly disease-modifying and/or sustained symptomatic drug effects. A more effective symptom control could also support a more favorable disease course due to better function.
Explanatory statement: Preclinical data show a neuroprotective effect of memantine, which can prevent the pathological stimulation of NMDA receptors commonly seen in AD (see section ‘preclinical data supporting combination therapy’). Whether this translates to a disease-modifying effect in clinical practice, i.e. slowing the progression of AD, has not been proven, due to the limited duration of placebo-controlled trials. However, the above-mentioned two large observational studies (Atri et al. 2008, Lopez et al. 2009) showed markedly better long-term outcomes of memantine/ChEI combination therapy than ChEI monotherapy or no drug treatment. In the trial of Atri et al., combination therapy – unlike the other two groups – showed increasing effect-size of benefits over time for both cognitive and functional domains. These findings support a possible neuroprotective or disease-modifying effect. Yet interpretation of these data is fraught with the pitfalls of interpreting open-label clinical trial data.
Successful symptomatic treatment could also have a positive effect on the disease course (Patel et al. 2011). Rather than sustaining AD in a passive manner, AD patients are engaged in a constant process of adaptation. The individual’s capacity to cope with increasing impairments is therefore of great relevance for the accumulating burden of disease. Less impairment and longer periods above given thresholds of impairment support patients’ efforts to adapt. A relatively better cognitive status may also confer greater resilience towards some behavioral and psychological symptoms of dementia (BPSD).
The patient’s and caregiver’s perspective
It might be more appealing for patients and their families to engage in an AD treatment in expectation of a significant effect on the probability to live at home in a familiar environment longer. Furthermore, the cost-benefit discussion for a treatment with CHEIs and memantine might appear in a new light when it can be presumed that institutionalization costs are less with combination therapy.
Explanatory statement: Although AD is a chronic disease with an average duration of five to eight years, drug-intervention trials were limited to a maximal duration of 1–2 years. Among other reasons, long-term placebo controlled trials are ethically difficult because ChEIs and memantine are established treatment options in AD. To date, important outcomes such as need for institutionalization were not studied as an endpoint in placebo-controlled trials. In a long-term observational study, Lopez et al. (2009) found that patients receiving combination therapy were more easily cared for by their caregivers and consequently remained at home for a longer period of time. Combination therapy seems to allow subjects to maintain better communication skills and to enhance physical health prior to the institutionalization period.
On the basis of the available literature, combination therapy consisting of a ChEI and memantine should be implemented when patients progress form “mild” to “moderate” stage, i.e. at a MMSE score of about 19 to 20. Combination therapy showed a beneficial short-term effect in controlled clinical trials. In two long term open-label observational studies, combination therapy was superior to both, no therapy and monotherapy with ChEI in slowing the progression of cognitive and functional decline. At the moment it cannot be determined whether combination therapy has a disease-modifying potential or only a more pronounced symptomatic effect. However, the available data provide evidence that combination therapy can improve function and long-term outcome.
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