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ARTICLES: B. Winblad, K. Engedal, H. Soininen, F. Verhey, G. Waldemar, A. Wimo, A.-L. Wetterholm, R. Zhang, A. Haglund, and P. Subbiah A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD Neurology 2001; 57: 489-495 [Abstract] [Full text] [PDF]

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Reply to Dr. Deleu's letter

B Winblad, "G Waldemar, A Wimo, P Subbiah, R Zhang"   (6 November 2001)

A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD

Dirk DeLeu   (6 November 2001)

Reply to Dr. Deleu's letter 6 November 2001
B Winblad Karolinska Institutet Huddinge Sweden, "G Waldemar, A Wimo, P Subbiah, R Zhang" Send Correspondence to journal: Re: Reply to Dr. Deleu's letter bengt.winblad{at}neurotec.ki.se B Winblad, et al.	We thank Dr Deleu for his interest in, and comments on our paper. However, we disagree with a number of the points he raises. Exclusion criteria are vital to ensure the safety of the patients enrolled in clinical trials. An example would be patients with unstable or life-threatening conditions are generally excluded from all clinical trials. Furthermore, the exclusion of patients with conditions (or receiving medications) that may interfere with the study drug were required in order to observe the true effects of the medication in this study. Contrary to Dr Deleu’s comments, the efficacy and tolerability of donepezil has been demonstrated in patients representative of those treated during routine clinical practice, and with significant comorbidity. [2, 4, 6] Moreover, in the study by Greenberg et al, patients receiving donepezil 5 mg/day for 6 weeks demonstrated a mean improvement of 1.5 ADAS-cog points, compared with a decline of 0.62 points for placebo. [2] Although direct comparisons cannot be made, this is similar to the mean improvement of approximately 1.6–1.8 points observed in patients treated with donepezil 5 mg/day, at 6 Weeks, in pivotal trials. Furthermore, when Greenberg et al examined the response of patients who would have been excluded from earlier trials, these patients responded to treatment with donepezil approximately as well as the other patients in this study [2] While the treatment difference at Week 52 LOCF just failed to reach significance on the Gottries-Brĺne-Steen (GBS) scale (p = 0.054), a significant treatment difference was obtained using the observed cases analysis at Week 52. [1] In addition, a significant treatment difference at end point was observed on an alternative measure of dementia symptoms, the Global Deterioration Scale. More specific measures of cognition (the Mini-Mental State Examination) and function (the Progressive Deterioration Scale) also confirmed the beneficial effects of treatment with donepezil, with significant treatment differences observed at end point. [1] Furthermore, we also believe that the treatment difference observed on the GBS total score at Week 52 (6.2 points, or a 21% benefit with donepezil over placebo) could be detected by clinicians and caregivers, since a difference of 10-15% on this measure is thought to be clinically relevant, as discussed in our paper. [1] The 9.6% alluded to by Dr Deleu is the difference between the proportion of donepezil (31.2%) versus placebo- treated (21.6%) patients that improved on the GBS at Week 52. This treatment difference (9.6%) should be viewed in relation to the response in the placebo group, and as such, it should be interpreted that donepezil -treated patients are 44% more likely to improve than placebo-treated patients. Moreover, other data from this trial indicate that caregivers of donepezil-treated patients spent less time assisting patients with activities of daily living than those caring for placebo-treated patients. [7] The adverse events (AEs) observed in our study were generally mild and transient and rarely led to discontinuation or severe events. [1] Regarding Dr Deleu’s interest in the incidence of anxiety, asthenia, vertigo and syncope, each of these AEs occurred with a relatively low incidence in donepezil-treated patients. The majority of donepezil-treated patients were administered 10 mg/day during the trial, so a comparison of the incidence of AEs between doses (5 and 10 mg/day) was not possible. However, these four AEs led to a reduction in dose from 10 to 5 mg/day in very few donepezil-treated patients (anxiety 0 patients, asthenia 3 patients, vertigo 1 patient and syncope 1 patient). Therefore, there does not appear to be a meaningful association between dose and these AEs in this study. We believe that donepezil has an important role to play in the management of AD, which is supported by clinically meaningful data that demonstrates that donepezil can delay clinically evident functional decline and institutionalisation. [8, 9] References 1. Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489–495. 2.Greenberg SM, Tennis MK, Brown LB, et al. Donepezil therapy in clinical practice. A randomized crossover study. Arch Neurol 2000;57:94–99. 3. Wolfson C, Wolfson DB, Asgharian M, et al. for the Clinical Progression of Dementia Study Group. A reevaluation of the duration of survival after the onset of dementia. N Engl J Med 2001;344:1111–1116. 4. Matthews HP, Korbey J, Wilkinson DG, Rowden J. Donepezil in Alzheimer's disease: eighteen month results from Southampton Memory Clinic. Int J Geriatr Psychiatry 2000;15:713–720. 5. McRae T, Orazem J. A large, community-based, open-label trial of donepezil in the treatment of Alzheimer's disease. J Am Geriatr Soc 1999;47:S63. 6. Triau E, Boada M, Sakka P, et al. Efficacy and safety of donepezil hydrochloride in patients with AD: preliminary findings from a large, multinational experience study. J Neurol 2001;248(Suppl 2): II/1-II/208. 7. Mastey V, Wimo A, Winblad B, et al. Donepezil reduces the time caregivers spend providing care: Results of a one-year, double-blind, randomized trial in patients with mild to moderate Alzheimer’s disease. J Am Geriatr Soc 2001;49:S20. 8. Mohs RC, Doody RS, Morris JC, et al. A 1-year placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001;57:481–488. 9. McRae T, Knopman D, Duttagupta S, et al. Donepezil delays time to nursing home placement in patients with Alzheimer’s disease. J Am Geriatr Soc 2001;49:S132.
A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD 6 November 2001
Dirk DeLeu Sultan Qaboos University Sultanate of Oman Send Correspondence to journal: Re: A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD dtodeleu{at}squ.edu.om Dirk DeLeu	In their recently published 1-year prospective, double blind, placebo controlled study; Winblad et al. [1] examined the long-term clinical efficacy and safety of donepezil in mild to moderate AD. I congratulate the investigators for their effort. Unfortunately, it remains puzzling to me why the investigators restricted the entry criteria and consequently selected a population not representative of general clinical practice. By excluding patients with frequently coexisting medical conditions such as diabetes, chronic obstructive pulmonary disease, endocrine diseases etc. the demonstrable effect of the treatment is not obscured by comorbid conditions and is therefore probably the greatest possible effect which can be observed. One clinical trial revealed that including patients with significant comorbidity reduced the beneficial effect of donepezil with almost 50% of that observed in trials with more rigorous entry criteria. [2] In addition, the strict lack of any significant effect at the end point (last-observation-carried-forward) on the primary efficacy parameter raises questions. Furthermore it is questionable whether the magnitude of change taken at its highest value (week 52 (6.2 units or 9.6%)) is detectable by the physician and caregivers. From this trial it is also clear that donepezil-treated patients were more subjected to adverse events, particularly, anxiety, asthenia, vertigo and syncope, critical to a geriatric population. It would have been interesting to know whether these adverse events were dose-related since in some of these patients the dose was reduced back to 5 mg/day. Although median survival of patients with probable AD is reported to be only 3.1 years after onset of the disease, [3] the financial burden for treating AD during that short period might be substantial. Unless clinical studies can demonstrate convincing, meaningful and consistent data on delay in progress to severe dependency or institutionalisation, the role of cholinesterase inhibitors, remains questionable. References: 1)Winblad B, Engedal K, Soininen H, et al. A 1-year, randomised, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001:57:489-495. 2)Greenberg SM, Tennis MK, Brown LB, et al. Donepezil therapy in clinical practice. A randomised crossover study. Arch Neurol 2000:57:94- 99. 3)Wolfson C, Wolfson DB, Asgharian M, et al. for the Clinical Progression of Dementia Study Group. A reevaluation of the duration of survival after the onset of dementia N Engl J Med 2001:244:1111-1116.