Page 26 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

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rivastigmine 6-12mg/day (but not 1-4mg/day). A third trial reported statistically significant
differences in cognitive and behavioral measures between rivastigmine 6mg/day and placebo; similar
differences were not observed for patients treated with rivastigmine 4mg/day.

No rivastigmine trial specifically reported the effect of drug treatment on caregiver burden,

institutionalization, or death.

Tacrine vs. placebo

A fair-rated meta-analysis pooled individual patient data on 1,984 patients with probable AD from 12
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published and unpublished placebo-controlled trials. Dosages in the component trials varied from 20
mg/day to 160 mg/day. Trials lasted 3 to 36 weeks. Pooled results at 12 weeks presented a small

beneficial effect of tacrine over placebo for cognitive function (MMSE: + 0.62 points, 95% CI: 0.23 –
1.00; P = 0.002), clinical global impression (CGI: OR 1.58, 95% CI: 1.18-2.11; P = 0.002), and

behavioral disturbance (ADAS: 0.58 points, 95% CI: 0.17-1.00; P = 0.006). No significant difference
could be detected in functional autonomy at 6 weeks (PDS: 0.75 points, 95% CI: -0.34 – 1.93; P = 0.21).
The authors did not report if the component studies were critically appraised for methodological quality

before inclusion. In studies without a dose titration phase (i.e., no active drug run-in phase before
randomization) before the efficacy study, significantly more patients on tacrine than on placebo withdrew

from the study (OR: 3.63, 95% CI: 2.80 - 4.71; no absolute numbers reported).

Four placebo-controlled trials met our eligibility criteria. 58, 67-69 We excluded three of these studies for
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poor methodological quality because of high overall 67, 68 or high differential loss to follow-up. In all
three trials, the high attrition rate reflected frequent adverse events, in particular elevated liver function
tests in tacrine-treated patients. The fourth study compared three fixed dosing regimens (20mg/day,

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40mg/day, 80mg/day) to placebo in 468 patients with mild to moderate Alzheimer’s disease. We were
unable to determine the differential loss to follow-up from the provided data. Thus, differential loss to
follow-up may exceed our cut-off level of 15 percentage points. The differential loss to follow-up

because of adverse events in this study was 18 percentage points (placebo: 7%; tacrine: 25%). Efficacy
results reported statistically significant improvements only for tacrine at 80 mg/day on the CGIC (P =

0.015), ADAS-total (P = 0.029), and caregiver-rated CGIC (P = 0.028) compared to placebo. No
significant differences could be detected for ADAS-cog, MMSE, PDS, or for dosages less than 80 mg/day
on CGIC.

Alzheimer's Drugs Page 26 of 205