Efficacy and tolerability of rivastigmine patch therapy in patients with mild-to-moderate Alzheimer's dementia associated with minimal and moderate ischemic white matter hyperintensities: A multicenter prospective open-label clinical trial

Kyung Won Park, Eun-Joo Kim, Hyun Jeong Han, Yong S Shim, Jae C Kwon, Bon D Ku, Kee Hyung Park, Hyon-Ah Yi, Kwang K Kim, Dong Won Yang, Ho-Won Lee, Heeyoung Kang, Oh Dae Kwon, SangYun Kim, Jae-Hyeok Lee, Eun Joo Chung, Sang-Won Park, Mee Young Park, Bora Yoon, Byeong C Kim, Sang Won Seo, Seong Hye Choi, Kyung Won Park, Eun-Joo Kim, Hyun Jeong Han, Yong S Shim, Jae C Kwon, Bon D Ku, Kee Hyung Park, Hyon-Ah Yi, Kwang K Kim, Dong Won Yang, Ho-Won Lee, Heeyoung Kang, Oh Dae Kwon, SangYun Kim, Jae-Hyeok Lee, Eun Joo Chung, Sang-Won Park, Mee Young Park, Bora Yoon, Byeong C Kim, Sang Won Seo, Seong Hye Choi

Abstract

Background and objective: Studies investigating the impact of white matter hyperintensities (WMHs) on the response of acetylcholinesterase inhibitors in patients with Alzheimer's disease (AD) have presented inconsistent results. We aimed to compare the effects of the rivastigmine patch between patients with AD with minimal WMHs and those with moderate WMHs.

Methods: Three hundred patients with mild to moderate AD were enrolled in this multicenter prospective open-label study and divided into two groups. Group 1 comprised patients with AD with minimal WMHs and group 2 comprised those with moderate WMHs. The patients were treated with a rivastigmine patch for 24 weeks. Efficacy measures were obtained at baseline and after 24 weeks. The primary endpoint was the change in the AD Assessment Scale-Cognitive subscale (ADAS-Cog) from the baseline to the end of the study.

Results: Of the 300 patients, there were 206 patients in group 1 and 94 patients in group 2. The intention-to-treat group comprised 198 patients (group 1, n = 136; group 2, n = 46) during the 24-week study period. Demographic factors did not differ between group 1 and group 2. There were no significant differences in change in ADAS-cog between group 1 (-0.62±5.70) and group 2 (-0.23±5.98) after the 24-week rivastigmine patch therapy (p = 0.378). The patients in group 1 had a 0.63-point improvement from baseline on the Frontal Assessment Battery, while group 2 had a 0.16-point decline compared to baseline at the end of the study (p = 0.037). The rates of adverse events (AEs) (42.6 vs. 40.3%) and discontinuation due to AEs (10.3% vs. 4.3%) did not differ between the groups.

Conclusions: Although the efficacy and tolerability of rivastigmine patch therapy were not associated with WMH severity in patients with AD, some improvement in frontal function was observed in those with minimal WMHs.

Trial registration: ClinicalTrials.gov NCT01380288.

Conflict of interest statement

Competing Interests: KWP received funding from Novartis for this study. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Figures

Fig 1. Flow chart of the study…
Fig 1. Flow chart of the study design and patient participation.
Fig 2. Changes from the baseline at…
Fig 2. Changes from the baseline at 24 weeks in the ADAS-cog, MMSE, FAB, CGA-NPI, CDR-SB, ADCS-ADL, and Mini-Zarit (ITT-LOCF population) in the patients from groups 1 and 2.

References

    1. Yamada M, Mimori Y, Kasagi F, Miyachi T, Ohshita T, Sudoh S, et al.Incidence of dementia, Alzheimer disease, and vascular dementia in a Japanese population: Radiation Effects Research Foundation adult health study. Neuroepidemiology. 2008; 30(3): 152–160. doi:
    1. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR. Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol. 1981; 10(2): 122–126. doi:
    1. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology. 1998; 50(1): 136–145.
    1. Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ. 1999; 318(7184): 633–638.
    1. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology. 2000; 54(12): 2269–2276.
    1. Heyman A, Fillenbaum GG, Welsh-Bohmer KA, Gearing M, Mirra SS, Mohs RC, et al. Cerebral infarcts in patients with autopsy-proven Alzheimer's disease: CERAD, part XVIII. Consortium to Establish a Registry for Alzheimer's Disease. Neurology. 1998; 51(1): 159–162.
    1. Breteler MM. Vascular risk factors for Alzheimer's disease: an epidemiologic perspective. Neurobiol Aging. 2000; 21(2): 153–160.
    1. de la Torre JC. Vascular basis of Alzheimer's pathogenesis. Ann N Y Acad Sci. 2002; 977: 196–215.
    1. Selden NR, Gitelman DR, Salamon-Murayama N, Parrish TB, Mesulam MM. Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain. Brain. 1998; 121 (Pt 12): 2249–2257.
    1. Swartz RH, Sahlas DJ, Black SE. Strategic involvement of cholinergic pathways and executive dysfunction: Does location of white matter signal hyperintensities matter? J Stroke Cerebrovasc Dis. 2003; 12(1): 29–36. doi:
    1. Sadoshima S, Ibayashi S, Fujii K, Nagao T, Sugimori H, Fujishima M. Inhibition of acetylcholinesterase modulates the autoregulation of cerebral blood flow and attenuates ischemic brain metabolism in hypertensive rats. J Cereb Blood Flow Metab. 1995; 15(5): 845–851. doi:
    1. Tanaka K, Ogawa N, Asanuma M, Hirata H, Kondo Y, Nakayama N, et al.Effects of the acetylcholinesterase inhibitor ENA-713 on ischemia-induced changes in acetylcholine and aromatic amine levels in the gerbil brain. Arch Int Pharmacodyn Ther. 1993; 323: 85–96.
    1. Tsujimoto S, Sakaki T, Morimoto T, Tominaga M. The effect of acetylcholinesterase inhibitor (SDZ ENA 713) for r-CBF and focal cerebral ischaemia. Acta Neurochir (Wien). 1993; 124(2–4): 127–131.
    1. Tanaka K, Mizukawa K, Ogawa N, Mori A. Post-ischemic administration of the acetylcholinesterase inhibitor ENA-713 prevents delayed neuronal death in the gerbil hippocampus. Neurochem Res. 1995; 20(6): 663–667.
    1. Kumar V, Anand R, Messina J, Hartman R, Veach J. An efficacy and safety analysis of Exelon in Alzheimer's disease patients with concurrent vascular risk factors. Eur J Neurol. 2000; 7(2): 159–169.
    1. Farlow MR, Doraiswamy PM, Meng X, Cooke K, Somogyi M. The effect of vascular risk factors on the efficacy of rivastigmine patch and capsule treatment in Alzheimer's disease. Dement Geriatr Cogn Dis Extra. 2011; 1(1): 150–162. doi:
    1. Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of ischemic score in differentiation of dementias. Ann Neurol. 1980; 7(5): 486–488. doi:
    1. Fukui T, Hieda S, Bocti C. Do lesions involving the cortical cholinergic pathways help or hinder efficacy of donepezil in patients with Alzheimer's disease? Dement Geriatr Cogn Disord. 2006; 22(5–6): 421–431. doi:
    1. Fukui T, Taguchi S. Do vascular lesions and related risk factors influence responsiveness to donepezil chloride in patients with Alzheimer's disease? Dement Geriatr Cogn Disord. 2005; 20(1): 15–24. doi:
    1. Connelly PJ, Prentice NP, Fowler KG. Hypertension, white matter change and response to cholinesterase inhibitors in Alzheimer's disease. Int J Geriatr Psychiatry. 2005; 20(7): 623–628. doi:
    1. Devine ME, Fonseca JA, Walker RW, Sikdar T, Stevens T, Walker Z. Cerebral white matter changes and rate of progression of dementia during cholinesterase inhibitor treatment: a retrospective cohort study. Int J Geriatr Psychiatry. 2007; 22(11): 1120–1126. doi:
    1. Marcus J, Gardener H, Rundek T, Elkind MS, Sacco RL, Decarli C, et al. Baseline and longitudinal increases in diastolic blood pressure are associated with greater white matter hyperintensity volume: the northern Manhattan study. Stroke. 2011; 42(9): 2639–2641. doi:
    1. Wang R, Fratiglioni L, Laukka EJ, Lövdén M, Kalpouzos G, Keller L, et al. Effects of vascular risk factors and APOE ε4 on white matter integrity and cognitive decline. Neurology. 2015; 84(11): 1128–1135. doi:
    1. Oertel W, Ross JS, Eggert K, Adler G. Rationale for transdermal drug administration in Alzheimer disease. Neurology. 2007; 69(4 Suppl 1): S4–S9. doi:
    1. Winblad B, Cummings J, Andreasen N, Grossberg G, Onofrj M, Sadowsky C, et al. A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease-rivastigmine patch versus capsule. Int J Geriatr Psychiatry. 2007; 22(5): 456–467. doi:
    1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984; 34(7): 939–944.
    1. Kang Y. A normative study of the korean-mini mental state examination (K-MMSE) in the elderly. Korean Journal of Psychology. 2006; 25(2): 1–12.
    1. Noh Y, Lee Y, Seo SW, Jeong JH, Choi SH, Back JH, et al. A new classification system for ischemia using a combination of deep and periventricular white matter hyperintensities. J Stroke Cerebrovasc Dis. 2014; 23(4): 636–642. doi:
    1. Mohs RC, Rosen WG, Davis KL. The Alzheimer's disease assessment scale: an instrument for assessing treatment efficacy. Psychopharmacol Bull. 1983; 19(3): 448–450.
    1. Choi SH, Park KW, Na DL, Han HJ, Kim EJ, Shim YS, Lee JH; Expect Study Group. Tolerability and efficacy of memantine add-on therapy to rivastigmine transdermal patches in mild to moderate Alzheimer's disease: a multicenter, randomized, open-label, parallel-group study. Curr Med Res Opin. 2011. 27(7):1375–1383. doi:
    1. Morris JC. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr. 1997; 9 Suppl 1: 173–176; discussion 7–8.
    1. Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a Frontal Assessment Battery at bedside. Neurology. 2000; 55(11): 1621–1616.
    1. Kang SJ, Choi SH, Lee BH, Jeong Y, Hahm DS, Han IW, et al. Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI). J Geriatr Psychiatry Neurol. 2004; 17(1): 32–35. doi:
    1. Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997; 11 Suppl 2: S33–S39.
    1. Zarit SH, Reever KE, Bach-Peterson J. Relatives of the impaired elderly:correlates of feelings of burden. Gerontologist. 1980;20:649–655.
    1. Rapoport SI. Functional brain imaging in the resting state and during activation in Alzheimer's disease. Implications for disease mechanisms involving oxidative phosphorylation. Ann N Y Acad Sci. 1999; 893: 138–153.
    1. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV. Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet. 2002; 359(9314): 1283–1290. doi:
    1. Thomas DA, Libon DJ, Ledakis GE. Treating dementia patients with vascular lesions with donepezil: a preliminary analysis. Appl Neuropsychol. 2005; 12(1): 12–8. doi:
    1. Rombouts SA, Barkhof F, Van Meel CS, Scheltens P. Alterations in brain activation during cholinergic enhancement with rivastigmine in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2002; 73(6): 665–671. doi:
    1. Venneri A, Shanks MF, Staff RT, Pestell SJ, Forbes KE, Gemmell HG, et al. Cerebral blood flow and cognitive responses to rivastigmine treatment in Alzheimer's disease. Neuroreport. 2002; 13(1): 83–87.
    1. Lojkowska W, Ryglewicz D, Jedrzejczak T, Minc S, Jakubowska T, Jarosz H, et al. The effect of cholinesterase inhibitors on the regional blood flow in patients with Alzheimer's disease and vascular dementia. J Neurol Sci. 2003; 216(1): 119–126.
    1. Schmitt FA, Farlow MR, Meng X, Tekin S, Olin JT. Efficacy of rivastigmine on executive function in patients with Parkinson's disease dementia. CNS Neurosci Ther. 2010;16(6):330–336. doi:
    1. Moretti R, Torre P, Antonello RM, Cazzato G. Rivastigmine in subcortical vascular dementia: a comparison trial on efficacy and tolerability for 12 months follow-up. Eur J Neurol. 2001; 8(4): 361–362.
    1. Moretti R, Torre P, Antonello RM, Cazzato G, Bava A. Rivastigmine in subcortical vascular dementia: an open 22-month study. J Neurol Sci. 2002; 203–204: 141–146.
    1. Moretti R, Torre P, Antonello RM, Cazzato G, Griggio S, Ukmar M, et al. Rivastigmine superior to aspirin plus nimodipine in subcortical vascular dementia: an open, 16-month, comparative study. Int J Clin Pract. 2004; 58(4): 346–353.
    1. Ballard C, Sauter M, Scheltens P, He Y, Barkhof F, van Straaten EC, et al. Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study. Curr Med Res Opin. 2008; 24(9): 2561–2574. doi:
    1. Winblad B, Grossberg G, Frölich L, Farlow M, Zechner S, Nagel J, et al. IDEAL: a 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease. Neurology. 2007; 69(4 Suppl 1): S14–S22. doi:
    1. Nakamura Y, Strohmaier C, Tamura K, Kataoka N, Nakano M, Oda S et al.A 24-Week, Randomized, Controlled Study to Evaluate the Tolerability, Safety and Efficacy of 2 Different Titration Schemes of the Rivastigmine Patch in Japanese Patients with Mild to Moderate Alzheimer's Disease. Dement Geriatr Cogn Dis Extra. 2015. 29;5(3):361–374. doi:

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する