Cholinesterase Debate

1. Cholinesterase Debate

13. British Columbia is Special Because�. Only province with no pharmacare coverage Two tier medicine exists We have politicians who are able to deflect responsibility and not be held accountable

15. Alois Alzheimer: 100 years

16. Neurofibrillary Tangles

17. Efficacy-Cognitive Improvement

18. Efficacy Clinical Global Impression

19. Number Needed to Treat for Benefit Numbers needed to treat to benefit were 7 (CI95%: 6, 9) for stabilization or better 12 (CI95%: 9, 16) for minimal improvement or better 42 (CI95%: 26, 114) for marked improvement

20. Tolerability

21. 1-year Preservation of Function Study with Donepezil Design 1-year, randomized, placebo-controlled, double-blind Subjects 431 patients with mild-to-moderate AD Aged 49-94, mean MMSE 17.1 Primary Outcome �Time to clinically evident functional decline�, defined by: Decline in ? 1 basic ADL present at baseline Decline of ? 20% of the instrumental ADL present at baseline Increase ? 1 point from baseline in global CDR score (Clinical Dementia Rating scale)

22. Time to Clinically Evident Functional Decline*

24. Rivastigmine-Placebo Group Does Not Catch Up To Treated Group Slide 38: Rivastigmine on Cognition: greater long-term benefits when therapy starts earlier These results represent the first evidence showing that rivastigmine is effective in the long-term treatment of mild to moderately-severe AD patients. Furthermore, they suggest rivastigmine treatment should be started as early as possible in order to gain the maximum benefit (Messina et al., 2000). Patients who participated in Study B352 were followed through week 52 in the open-label extension Study B353. This figure illustrates the mean change in ADAS-Cog scores over time, from baseline through the end of the double-blind study (week 26), and through a total of 52 weeks in the study. At week 26, all patients were restarted on rivastigmine and adjusted to their optimal dose (up to 6 mg b.i.d.). Due to the open-label design of Study B353, a placebo-control group was no longer available after week 26. Therefore, a model was created based on data from the first 26 weeks for the original placebo group, to estimate the expected change in cognition in the placebo group through 52 weeks. The change in this projected placebo group is depicted by the dashed line. The decline of 7 points in the projected placebo group is consistent with the cognitive decline observed after 1 year in untreated community-based patients with AD (Stern et al., 1994). In the extension study, the original 6�12 mg/day group remained above baseline on the ADAS-Cog through 38 weeks. The original 1�4 mg/day and placebo groups improved after restarted on rivastigmine, but did not reach the level of cognitive improvement observed in the original 6�12 mg/day group. Compared with the projected placebo group, all three randomization groups showed a statistically significant improvement in cognition at week 52 versus projected placebo. Although all patients were re-adjusted to their optimal rivastigmine dose (up to 6 mg b.i.d.) in the extension phase, patients originally randomized to placebo did not catch up to the original rivastigmine groups. Of interest, the decline seen in the original 6�12 mg/day group after 52 weeks was less than the decline seen in the placebo group after 26 weeks. The results suggest that although patients who start treatment later demonstrate cognitive improvement, they may not attain the level of cognitive benefit seen in patients who begin therapy earlier.Slide 38: Rivastigmine on Cognition: greater long-term benefits when therapy starts earlier These results represent the first evidence showing that rivastigmine is effective in the long-term treatment of mild to moderately-severe AD patients. Furthermore, they suggest rivastigmine treatment should be started as early as possible in order to gain the maximum benefit (Messina et al., 2000). Patients who participated in Study B352 were followed through week 52 in the open-label extension Study B353. This figure illustrates the mean change in ADAS-Cog scores over time, from baseline through the end of the double-blind study (week 26), and through a total of 52 weeks in the study. At week 26, all patients were restarted on rivastigmine and adjusted to their optimal dose (up to 6 mg b.i.d.). Due to the open-label design of Study B353, a placebo-control group was no longer available after week 26. Therefore, a model was created based on data from the first 26 weeks for the original placebo group, to estimate the expected change in cognition in the placebo group through 52 weeks. The change in this projected placebo group is depicted by the dashed line. The decline of 7 points in the projected placebo group is consistent with the cognitive decline observed after 1 year in untreated community-based patients with AD (Stern et al., 1994). In the extension study, the original 6�12 mg/day group remained above baseline on the ADAS-Cog through 38 weeks. The original 1�4 mg/day and placebo groups improved after restarted on rivastigmine, but did not reach the level of cognitive improvement observed in the original 6�12 mg/day group. Compared with the projected placebo group, all three randomization groups showed a statistically significant improvement in cognition at week 52 versus projected placebo. Although all patients were re-adjusted to their optimal rivastigmine dose (up to 6 mg b.i.d.) in the extension phase, patients originally randomized to placebo did not catch up to the original rivastigmine groups. Of interest, the decline seen in the original 6�12 mg/day group after 52 weeks was less than the decline seen in the placebo group after 26 weeks. The results suggest that although patients who start treatment later demonstrate cognitive improvement, they may not attain the level of cognitive benefit seen in patients who begin therapy earlier.

25. I wanted to show you a little about the MRI volumetrics, as this is a very new approach, and very important in attempting to demonstrate dz-modifying effects of treatment. On the top, you see coronoal views of the brain, at the level of the hippocampus, one of the most important structures in memory, and one which has been demonstrated to preferentially atrophy in AD,. Below, you see a close-up, where the hippocampus has been manually outline using a computer. What you see, from left to right is that between time 0 and 36 months, the hippocampus of this AD patient has significantly atrophied. So this is one of the measures that we are performing in the 1-year MCI study, as well some of our other studies. 24-week, RCT parallel group 6-week, single-blind placebo washout Subjects 67 mild to moderate AD patients received donepezil Treatment Donepezil: 5 mg/day Days 1-28, then 10 mg/day Outcomes Hippocampal volumes (MRI) NAA (N-Acetylaspartate) (MRS) � a measure of viability of neurons (possibly less available energy) ADAS-cog I wanted to show you a little about the MRI volumetrics, as this is a very new approach, and very important in attempting to demonstrate dz-modifying effects of treatment. On the top, you see coronoal views of the brain, at the level of the hippocampus, one of the most important structures in memory, and one which has been demonstrated to preferentially atrophy in AD,. Below, you see a close-up, where the hippocampus has been manually outline using a computer. What you see, from left to right is that between time 0 and 36 months, the hippocampus of this AD patient has significantly atrophied. So this is one of the measures that we are performing in the 1-year MCI study, as well some of our other studies. 24-week, RCT parallel group 6-week, single-blind placebo washout Subjects 67 mild to moderate AD patients received donepezil Treatment Donepezil: 5 mg/day Days 1-28, then 10 mg/day Outcomes Hippocampal volumes (MRI) NAA (N-Acetylaspartate) (MRS) � a measure of viability of neurons (possibly less available energy) ADAS-cog

26. Donepezil-treated Patients Had Significantly Less Reduction From Baseline in Hippocampal Volume 24-week, RCT parallel group 6-week, single-blind placebo washout Subjects 67 mild to moderate AD patients received donepezil Treatment Donepezil: 5 mg/day Days 1-28, then 10 mg/day Outcomes Hippocampal volumes (MRI) NAA (N-Acetylaspartate) (MRS) � a measure of viability of neurons (possibly less available energy) ADAS-cog 24-week, RCT parallel group 6-week, single-blind placebo washout Subjects 67 mild to moderate AD patients received donepezil Treatment Donepezil: 5 mg/day Days 1-28, then 10 mg/day Outcomes Hippocampal volumes (MRI) NAA (N-Acetylaspartate) (MRS) � a measure of viability of neurons (possibly less available energy) ADAS-cog

27. AD2000: longer term study in mod-severeAD of donepezil Two year, double blind, RCT in AD on donepezil versus placebo in a family practice setting in the UK: Findings: donepezil produced small improvements in cognition and activities of daily living in patients with moderate AD. However this was interpreted to be not clinically significant as no delay in NHP, loss of milestones, or reduction in caregiver costs was found ISSUES: a) not clear if groups were matched b) large dropout ( 40% 1-yr; 77% 2-year, 96% 3-year) c) 51% of total sample--CVD

28. Cholinesterase Inhibitors selectively benefit multiple cognitive domains (1-Year) Treated patients showed less decline on: overall cognition naming visuospatial and visuoconstructive skills executive functions

29. Multiple Cognitive Domains (2-Years) Treated patients showed less decline on: overall cognition memory naming executive functions

30. Function (1- & 2-Years)

31. Ballard et al BMJ, 2005 Cholinesterase Inhibitors: Patients and Families� Point of View Questionnaire posted to UK Alzheimer�s Society and memory clinics Asked: �whether, taking everything into consideration, they felt that the drug treatment they received had worked� and to give 5 ways it had helped 2295 respondents with treatment exposure 68% stated that the drug treatment had worked Examples of benefits: Increased awareness and activity Improved conversation Better quality of life Increased confidence Taking more interest in things Results similar to Australian survey indicating 70% felt drugs had worked

32. Translating Study Results to Real Patients More than 150 scales have been developed to measure possible changes Comparing statistical significance to clinical relevance Important to have realistic expectation; Assess regularly Consider functional status Consider co-morbid illness

33. What I tell Patients Not memory pills; repetitive questions continue Behavior and function pills Stability (no decline) positive result Rule of thirds Not disease modifying agents; honeymoon of 2 to 3 years Document target symptom for monitoring

34. This Patient and Others After 12 to 16 weeks; improvement 69 yr old women traveling in Europe 82 yr old man with Lewy body dementia and hallucinations 86 year retired judge after 5 years of treatment

35. 10 Years Later- Where are we? More than 80 studies show improvement compared to placebo Benefits seen in first 2 years with waning after this Some Dementias eg. LBD show dramatic improvement Degree of improvement and clinical relevance of improvement best judged by patient , family and attending physician Side effects relatively mild