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The Cognitive Effects of Cholinesterase Inhibitor Treatment in Every- Day Practice

Posted on: Wednesday, 13 July 2005, 03:01 CDT

Key words: Alzheimer's disease - Cholinesterase inhibitors - Donepezil - Galantamine - Mixed dementia - Rivastigmine

ABSTRACT

Objective: Cholinesterase inhibitors (ChEIs) are the treatment of choice in Alzheimer's disease (AD). Their efficacy has been proven in many clinical trials. The aim of the present study was to confirm their cognitive benefit in every day practice as to whether it is similar to that expected from clinical trials.

Patients and methods: We reviewed the files of 41 patients suffering from AD or mixed dementia and treated by ChEIs in terms of every day practice.

Results: During the first year MMSE scores remained better than or at baseline levels. Following that a gradual decline was noted. However, at any time point, the observed scores were significantly better than the expected ones calculated according to the pre- treatment rate of decline. The post-treatment rate of decline was significantly better than the pre-treatment one, while progression to the next stage of dementia was delayed by 8 months.

Conclusion: The present observations from every-day practice indicate that there is a small but significant effect of ChEIs in cognition, similar to that observed in clinical trials. Furthermore, a small but significant delay in dementia progression may occur after treatment with ChEIs.

Introduction

The release of cholinesterase inhibitors (ChEIs), namely tacrine, donepezil, rivastigmine and galantamine constitute a significant progress in Alzheimer's disease (AD) therapeutics1 since, in a good number of clinical trials, they have been shown to produce modest but statistically significant benefits in cognitive function, activities of daily living and behavioural symptoms2-4. Thus, ChEIs are now considered as the agents of choice in AD5-7. There is evidence that they are also effective in vascular or mixed dementia8- 11. Clinical studies, although well designed and performed, are usually executed in specialized centres, according to rigid protocols (fixed dosages, predefined intervals in dose escalation). However, in every-day practice, individualization according to each patient's response, compliance and tolerance is the rule. The aim of the present study was to evaluate the short and long term efficacy of ChEIs in cognition, in terms of every-day practice and to find out whether this is comparable to that expected from the findings of clinical trials.

Patients and methods

We retrospectively reviewed the files of demented patients already examined, diagnosed and treated by us, in the general neurology outpatient department of our institution. As results from the organization of health services in Greece, such departments, in addition to being tertiary academic settings, they are also close to the practice of every-day neurology in the community, since patients have free access without referral. Inclusion criteria were:

(a) Diagnosis of either 'pure' AD or AD with cerebrovascular lesions, fulfilling the NINCDS-ADRDA (probable) or the NINDS-AIREN criteria respectively12,13.

(b) Follow up of at least 24 months.

(c) Patients should have been treated with ChEIs only; those receiving vitamin E, nootropics or other cognition-enhancing drugs were excluded.

The cognitive status was assessed initially and during follow-up examinations by the Mini Mental State Examination (MMSE)14. Finally 41 patients fulfilled the inclusion criteria (follow-up 24-72 months).

Statistical analysis

The MMSE scores at follow-up examinations were compared with the baseline (pre-treatment) score. The pre-treatment rate of deterioration was measured for each patient according to the formula (MMSE^sub 0^-30)/disease duration (where MMSE^sub 0^ refers to the baseline score). Following that, the expected MMSE score (assuming that no treatment was used) was calculated at various points of time for each patient according to the pre-treatment deterioration rate and was compared with the observed MMSE score. Thus, each patient served as control for him(her)self. Using the above pre-treatment deterioration rate, we also calculated the expected time for progression to the next level of dementia (i.e. if the patient had moderate dementia indicated by 10 < MMSE < 20, which was the expected time to reach moderate dementia indicated by MMSE ≤ 10). This expected time of progression was compared with the observed one. The post-treatment deterioration rate was calculated for each patient according to the formula (MMSE^sub final^-MMSE^sub 0^)/treatment duration. Since this calculation refers to the entire treatment period and thus, could be affected by the initial favourable period, we also calculated the deterioration rate after the 1st and after the 2nd year of treatment. These post-treatment deterioration rates were compared with the pre-treatment one. All of the above comparisons were performed by the Wilcoxon matched pairs test.

In patients showing an initial stabilization or improvement of MMSE score, the period that MMSE remained at or above baseline was defined as the post-treatment 'stabilization' period. The correlation of maximum MMSE gain or post-treatment stabilization period with MMSE^sub 0^, age or disease duration was tested by the Spearman correlation coefficient.

The level of statistical significance was set at 0.05.

Results

Clinical data of patients are summarized in Table 1 and their treatment in Table 2. Titration was performed at 4-12-week intervals according to patients' tolerance and compliance. If required (due to tolerance reasons), the dosage was decreased to the previous level for at least 3 months before a new attempt of increase was made. Gastrointestinal symptoms or dizziness were the most frequent complaints (n = 14), but they were minimized or disappeared after slowing of titration rate and/or reduction of the maximum dosage in all but one patient. Two patients without obvious heart disease reported fainting episodes that disappeared after reduction of maximum dosage. In 9 patients, a switch from the first to a second ChEI seemed reasonable, and was attempted successfully in 5; poor compliance did not allow the switch in the remaining 4. One patient switched from tacrine to donepezil, due to hepatic intolerance of the former, 2 patients changed from rivastigmine to galantamine for efficacy reasons, 1 patient was switched from rivastigmine to donepezil due to intolerance of the former (dizziness) and 1 patient was switched from donepezil to rivastigmine for efficacy reasons. Of the 41 patients with 24-month follow-up, 40, 31 and 26 patients reached 30, 60 and 72-month follow-up, respectively. Of the 15 dropouts, 10 were due to poor compliance, four were due to both low efficacy and poor compliance and only one was due to intolerance (dizziness).

Maximum mean improvement was noted at month 3 (0.9 MMSE point, 95% confidence interval: 0.01-1.8, p < 0.05) (Figure 1). Mean MMSE scores remained above the baseline levels during the 1st year, followed by a gradual decline and from the 18th month onwards, patients were significantly worse as compared to baseline. However, at each point of time after treatment initiation, and even after the 18th month, MMSE scores were higher than the expected according to the pre-treatment rate of decline.

Roughly, 2/3 of patients showed at least stabilization of their MMSE scores for a median period of 12 months (quartiles: 6-18) (Figure 2). Those with a greater post-treatment gain in MMSE score also had longer periods of stabilization (R^sub s^ = 0.55, p < 0.01). Unfortunately, 1/3 of the patients did not show the initial 'honeymoon' period, but continued to deteriorate despite treatment. In about half of these patients, however, the rate of decline was lower than the pre-treatment rate, possibly indicating a minimal, yet insufficient degree of response.

Table 1. Clinical characteristics of patients

As compared to the pre-treatment rate of progression, ChEIs achieved a more favourable rate of decline and the statistical significance remained even after the 1st year (Figure 3A). Comparison of the observed vs. expected time to reach the next stage of dementia showed a significant delay of 8 months (95% confidence interval 0.02-16 months) (Figure 3B). Age, gender and disease duration did not affect the degree of response. However, the delay of progression to the next stage of dementia was significantly greater in the mild stage of the disease (Figure 3C). A worse pre- treatment rate of decline tended to be followed by a higher increase in MMSE scores during the first months after treatment (R^sub s^ = - 0.36, p = 0.074).

Table 2. Cholinesterase inhibitors used

Figure 1. Mean ( standard error) MMSE change after treatment for all patients

Figure 2. 'Pie'-chart of patients categorized according to their response to treatment [percentage (95% confidence interval)]. Significant (clinically relevant) improvement is defined as maximum gain of more than 2 MMSE points. A gain of 1 or 2 MMSE points is defined as mild improvement. Deterioration with a rate worse than the pre-treatment rate of progression is defined as severe deterioration, while the one with a better rate is defined as mild deterioration. All patients with mild deterioration lost less than 3 MMSE points per year, while all patients with severe deterioration lost more than 5 MMSE points per year

Although galantamine and donepezil tended t\o show a higher MMSE gain as compared to rivastigmine (Figure 4), rivastigmine remained near the baseline level for a more prolonged period of time; none of these differences reached statistical significance. Patients requiring a switch to another ChEI actually did worse as compared to patients that responded and remained throughout the study on the same drug.

Discussion

The present study, does not include any placebo group, since the proven efficacy of ChEIs makes this option unethical. One may also argue against the small and retrospective character of the study, which is based on data collected by physicians that treated patients in the past, according to widely accepted diagnostic and therapeutic guidelines suggested for every day neurological practice5,6, however, not following a specific protocol. Nevertheless, this might be exactly the advantage of this type of study, reflecting the results of ChEI treatment in every-day practice. Thus dosage and titration rates were flexible and collective data of the three ChEIs used today are given, including patients with a switch from one drug to another.

Figure 3. (A) Mean ( standard error) rate of progression before treatment, during the entire post-treatment period and after 1st or 2nd year of treatment. The negative sign denotes cognitive decline. The p values are the results of comparison with the pre-treatment deterioration rate using the Wilcoxon matched pairs test. (B) Mean ( standard error) time needed to reach the next stage of dementia (Wilcoxon matched pairs test). (C) The delay is significantly greater in the mild (MMSE ≥ 20) as compared to the moderate or moderately severe stage (10 < MMSE < 20).

Figure 4. Mean ( standard error) MMSE change in those treated with one drug without needing to switch, and in those that switching was deemed necessary.

As expected from clinical trials2-4, in the present study a statistically significant benefit was observed during the initial treatment period. It has been suggested that for such a benefit to be clinically meaningful (and not only statistically significant) the cognitive gain should be ≥ 4 points of the ADAS-cog15, which approximately means more than 1-2 MMSE points. Most authors agree that the benefit currently achieved by ChEIs may have a 'ceiling' effect, with a mean maximum gain of 3-4 ADAS-cog points or 1-2 MMSE points i.e., just reaching the limit of a clinically meaningful effect1,7. However, many clinicians feel that the threshold of a clinically relevant gain is even higher, at about 3 MMSE points16. Thus, the initial cognitive benefit achieved by these drugs should be better viewed as a period of clinical stabilization17. This does not exclude a significant improvement in some patients; however, a dramatic improvement should not be expected in most and up to 50% of patients may show inadequate or no response1. This is comparable to our percentage of patients with no change or deterioration of MMSE after treatment (41%) and argues against a significant selection bias from inclusion of patients with a better outcome.

The initial period of stabilization, as assessed by various cognitive scales including MMSE, seems to have a duration of 9-12 months2-4 and the results of the present study are compatible with this notion. According to a meta-analysis, the mean percentage of patients with a gain ≥ 4 ADAS-cog points may be as low as 14%18. However, in the present study, the percentage of patients with an initial gain of > 2 MMSE points was much higher (32%).

An interesting finding is that the rate of dementia progression is reduced after treatment initiation and that this reduction is still present after the 1st year. The latter is a possible indication that even when the 'honey-moon' (stabilization) period has ended and the patients gradually deteriorate, they may do so with a rate significantly lower than the pre-treatment rate. This may be due to a symptomatic effect, while the speculated, yet unproven neuroprotective effect of ChEIs19,20 might also participate; whatever the cause, there seems to be a small but significant delay of progression to the next stage of dementia. The observation that patients with mild dementia show a greater delay of progression as compared to patients with more advanced disease is in agreement with previous findings indicating that, for optimal results, treatment should start as soon as possible2,3,21.

Conclusion

In summary, the cognitive benefits of ChEIs seen in every day practice are similar to those observed in clinical trials, provided that widely accepted guidelines are used. Furthermore, these drugs seem to slow the rate of cognitive decline in AD and may delay dementia deterioration. Further studies are required to clarify the issue of a possibly reduced rate of dementia deterioration after ChEI treatment.

References

1. Moghul S, Wilkinson D. Use of acetylcholinesterase inhibitors in Alzheimer's disease. Expert Rev Neurotherapeutics 2001;1:61-9

2. Farlow M, Anand R, Messina J, et al. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. Eur Neurol 2000;44:236-41

3. Raskind MA, Peskind ER, Wessel T, et al. Galantamine in AD. A 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology 2000;54:2261-8

4. 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;57:489-95

5. Waldemar G, Dubois B, Emre M, et al. Diagnosis and management of Alzheimer's disease and other disorders associated with dementia. The role of neurologists in Europe. Eur J Neurol 2000;7:133-44

6. Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1154-66

7. NICE (National Institute of Clinical Excellence). Guidance on the use of donepezil, rivastigmine and galantamine for the treatment of Alzheimer's disease [online]. Available from http:// www.nice.org.uk [accessed 2001]

8. Kumar V, Anand R, Messina J, et al. An efficacy and safety analysis of Exelon in Alzheimer's disease patients with concurrent vascular risk factors. Eur J Neurol 2000;7:159-69

9. Moretti R, Torre P, Antonello RM, Cazzato G. Rivastigmine in subcortical vascular dementia: an open 22-month study. J Neurol Sci 2002;203-204:141-6

10. Erkinjuntti T, Kurz A, Gauthier S, et al. Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet 2002;359:1283-90

11. Black S, Roman G, Geldmacher DS, et al. Efficacy and tolerability of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized, placebo- controlled clinical trial. Stroke 2003;34:2323-32

12. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease. Report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 1984;34:939-44

13. Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43:250-60

14. Folstein M, Folstein S, McHugh PR. Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-98

15. McLendon BM, Doraiswamy PM. Defining meaningful change in Alzheimer's disease trials: the donepezil experience. J Geriatr Psychiatry Neurol 1999;12:39-48

16. Burback D, Molnar FJ, St John P, Man-Son-Hing M. Key methodological features of randomized controlled trials of Alzheimer's disease therapy: minimal clinically important difference, sample size and trial design. Dementia Geriatr Cogn Disord 1999;10:534-40

17. Giacobini E. Cholinesterase inhibitor therapy stabilizes symptoms of Alzheimer's disease. Alzheimer Dis Assoc Disord 2000;14:S3-S10

18. Lanctt KL, Hermann N, Yau KK, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. Can Med Assoc J 2003;169:557-64

19. Giacobini E. Cholinesterase inhibitors: from the Calabar bean to Alzheimer therapy. In: Cholinesterases and cholinesterase inhibitors. London: Martin Dunitz Ltd; 2000. p. 181-226

20. Arias E, Als E, Gabilan NH, et al. Galantamine prevents apoptosis induced by β-amyloid and thapsigargin: involvement of nicotinic acetylcholine receptors. Neuropharmacology 2004;46:103-14

21. Doody RS, Geldmacher DS, Gordon B, et al. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer's disease. Arch Neurol 2001;58:427-33

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2944_4, Accepted for publication: 14 April 2005

Published Online: 06 May 2005

doi: 10.1185/030079905X46359

E. Kapaki and G. P. Paraskevas

Athens National University, School of Medicine, Department of Neurology, Eginition Hospital, 74 Vas. Sophias Ave., Athens 11528, Greece

Address for correspondence: Professor Elisabeth Kapaki, Assistant Professor of Neurology, Athens National University, Department of Neurology, Eginition Hospital, 74 Vas. Sophias Ave., Athens 11528, Greece. Tel: +30210 7289125; Fax: +30210 9811638; email: ekapaki@med.uoa.gr

Copyright Librapharm Jun 2005

Source: Current Medical Research and Opinion

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