Farlow MR, Grossberg GT, Meng X, et al. Rivastigmine transdermal patch and capsule in Alzheimer's disease: influence of disease stage on response to therapy

Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
International Journal of Geriatric Psychiatry (Impact Factor: 2.87). 12/2011; 26(12):1236-43. DOI: 10.1002/gps.2669
Source: PubMed


The cholinesterase inhibitor rivastigmine is approved for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). This exploratory, hypothesis-forming analysis assessed response to rivastigmine according to severity of dementia at baseline.
This was a retrospective analysis of a large randomized, placebo-controlled trial (ENA713D2320). AD patients treated with 9.5 mg/24 h rivastigmine patch, 17.4 mg/24 h rivastigmine patch, rivastigmine capsule (12 mg/day), or placebo were stratified according to baseline Mini-Mental State Examination (MMSE) scores: ≥7 to ≤12 (severe disease), ≥13 to ≤15 (moderately severe), ≥16 to ≤18 (moderate), or ≥19 to ≤25 (mild to moderate). Changes from baseline at Week 24 on Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) were assessed.
Based on baseline MMSE scores, 141, 228, 333, and 348 patients had severe, moderately severe, moderate, and mild to moderate dementia. Worsening of ADAS-cog, ADCS-CGIC, and ADCS-ADL scores in patients receiving placebo were greater in patients with more severe dementia. Significant improvements versus placebo were seen with rivastigmine patch and/or capsule on ADAS-cog, ADCS-CGIC, and ADCS-ADL scores in patients with severe, moderately severe, and moderate AD (all p < 0.05). However, no significant improvements were seen in rivastigmine-treated patients with mild to moderate AD.
Rivastigmine benefits AD patients across dementia stages. Similar to previous cholinesterase inhibitor studies, greatest treatment effects with rivastigmine patch and capsule were seen in patients with more advanced dementia, most likely driven by greater placebo decline in this population.

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    • "Since the third CCCDTD, new information has emerged on the indication for severe AD (commonly considered MMSE <10). RCTs have demonstrated efficacy in severe AD for donepezil [48-52], rivastigmine (secondary analysis only) [53] and galantamine (MMSE 5 to 12) [54]. The DOMINO trial assigned 295 community-dwelling patients with moderate or severe AD (MMSE 5 to 13) stabilized on donepezil to continued donepezil monotherapy, combined donepezil and memantine therapy, memantine monotherapy, or no active therapy for 52 weeks. "
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    ABSTRACT: While there have been no new medications approved for the treatment of Alzheimer's disease (AD) or other dementias in Canada since 2004, the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD) reviewed and updated the clinical practice guidelines on the pharmacological management of dementia that were published previously. This review focused on the literature for the pharmacological treatment of dementia based on studies published since the third CCCDTD in 2006. A literature search of English-language medical databases was preformed for studies pertaining to the pharmacological treatment of AD and other dementias that examined the management of cognitive and functional impairment, as well as neuropsychiatric symptoms. All previous recommendations were reviewed, and only those that required updating based on new published studies were revised. Several new recommendations were also added. Recommendations were rated for quality of evidence and were approved by consensus. There were 15 revised or new recommendations approved by consensus. The revised recommendations included acknowledging that cholinesterase inhibitors (ChEIs) possess a class effect and any of the agents can be used for AD across the spectrum of severity and with co-existing cerebrovascular disease. There was insufficient evidence to recommend for or against the use of ChEIs in combination with memantine for the primary indication of treating neuropsychiatric symptoms, or for the treatment of vascular dementia. Recommendations for the discontinuation of cognitive enhancers were revised and clarified, as well as the risks associated with discontinuing these drugs. ChEIs were recommended as a treatment option for dementia with Parkinson's disease. Risks associated with use of antipsychotics for neuropsychiatric symptoms were strengthened, and guidelines regarding the use of antidepressants for affective disturbances in dementia were weakened, and are now considered an option but not a firm recommendation. Valproate was recommended not to be used, and there was insufficient evidence to recommend for or against the use of selective serotonin reuptake inhibitors or trazodone for the treatment of agitation and aggression. In spite of the lack of new therapeutic agents for the treatment of dementia, recent studies have helped to clarify and strengthen recommendations to optimize the pharmacological management of these illnesses.
    Full-text · Article · Jul 2013 · Alzheimer's Research and Therapy
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    • "Post-hoc analyses pooling subgroup data of patients with a MMSE score of 10–12 and 10–14 [38] [39] from four of the principal galantamine trials [40] [41] [42] [43] observed positive effects on cognitive, functional , and behavioral measures. A single RCT was conducted for rivastigmine on severe patients [44] showing efficacy of the drug also in patients with MMSE from 0 to 10. Pooled-analyses reported that rivastigmine might be more effective in patients with moderate-severe AD than with mild (MMSE 10–12) [20] [24] [25] [45]. "
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    ABSTRACT: BACKGROUND: Randomized clinical trials have evaluated the efficacy of acetylcholinesterase inhibitors (AChE-Is) and memantine across a wide range of Alzheimer's disease (AD) severity. However, these drugs are prescribed and reimbursed according to precise upper and lower cut off scores of cognitive tests. OBJECTIVES: To verify whether the efficacy of pharmacological treatment had any dependence on the severity of dementia in AD patients. METHODS: Published English-language randomized, placebo-controlled trials evaluating the efficacy of AChE-Is or memantine at any dose, over any length of time, in patients with any severity of dementia due to AD were included. Cognitive, behavioral, and functional outcomes were extracted from each study and multiple outcomes from the same trial were pooled to obtain a unique indicator of efficacy for cognition, functional impairment, and behavioral and psychological disturbances. The existence of a relationship between size of the treatment effect and severity of dementia, measured with the Mini-Mental State Examination, was determined using parametric and non-parametric correlation analyses. RESULTS: Both AChE-Is and memantine had significant effects on cognition. Functional and psycho-behavioral outcomes were reported less frequently but also showed significant efficacy of treatment. High heterogeneity among studies was found within and between the different drugs. The efficacy of all drugs except memantine was independent from dementia severity in all domains. Memantine effect on functional impairment was better in more severe patients. CONCLUSIONS: The modest beneficial effects of anti-dementia drugs on cognition are independent from dementia severity. Memantine is more effective on functional incompetence only in severe patients.
    Full-text · Article · Feb 2013 · Journal of Alzheimer's disease: JAD
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    • "The cholinesterase inhibitor, rivastigmine, is approved for the symptomatic treatment of mild to moderate AD and Parkinson’s disease dementia,2 and can be administered by transdermal patches or orally as capsules or solution.3 Rivastigmine shows a dose-dependent efficacy pattern across its therapeutic oral dose range of 6–12 mg/day. "
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    ABSTRACT: The aim of this study was to assess the sociodemographic and clinical characteristics of patients with Alzheimer's disease who switched from any oral cholinesterase inhibitor to rivastigmine patches. An observational, retrospective, multicenter study was conducted in patients with a diagnosis of Alzheimer's disease who had switched to rivastigmine patches within the previous year in the routine clinical practice of 150 neurologists. Sociodemographic, clinical, and therapeutic data were collected in one office visit. Stepwise logistic regression models were used to find associations. Data were obtained from a total of 1022 patients and their caregivers, and showed a mean age of 78.4 ± 6.62 years, 62.61% being women, and mostly having a family caregiver. The switch to rivastigmine patches was mainly instigated on the initiative of the physician (82.39%) or on request of the caregiver (21.23%) or patient (10.37%). Reasons for the switch included improving ease of administration (56.65%), tolerability (36.79%), efficacy (31.60%), and adherence (18.59%). Prior treatment with oral rivastigmine versus donepezil or galantamine increased the probability of switching in order to improve ease of administration (odds ratio, oral rivastigmine versus donepezil 4.20, P < 0.0001; odds ratio, oral rivastigmine versus galantamine 3.55, P < 0.0001). Conversely, previous treatment with donepezil or galantamine produced an approximate four-fold increase in the odds of switching due to lack of efficacy. A higher level of education as well as more concomitant diseases increased the probability of switching because of intolerance. Improved ease of administration was the main reason for switching to transdermal rivastigmine. Other reasons involved in the decision to switch to rivastigmine patches included sociodemographic and clinical characteristics, including the educational level of patients and caregivers, number of concomitant diseases, and previous treatment for Alzheimer's disease.
    Preview · Article · Jan 2013 · Patient Preference and Adherence
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