Demographics and baseline characteristics
Ninety-five of 100 patients enrolled at baseline were evaluated at 6 months. Five patients had discontinued; three due to adverse events (diarrhoea n = 2, weight loss n = 1) and two withdrew consent. The remaining patients tended to be elderly women with mild AD (Table ), the majority of whom (63%) were dosed at 10 mg donepezil after the initial 3-month follow-up.
Baseline characteristics of patients with mild-moderate Alzheimer's disease who were treated with donepezil for 6 months, by ADAS-Cog response group
ADAS-Cog response at 6 months
The most common response on the ADAS-Cog at 6 months was no change from baseline (56%, mean change = -0.1, ± 2.0). Patients who showed worsening (24%; mean change = 8.0, ± 4.7) outnumbered those who had improved (20%; -6.2, ± 1.7) Patients who improved on the ADAS-Cog were slightly older than those in the other response groups, but there was no clear effect of initial conditions – i.e. those who responded showed no statistically significant differences from non-responders in baseline clinical or demographic measures (Table ).
Comparison of ADAS-Cog response with other outcomes at 6 months
The most common response on the patient/caregiver-GAS (PGAS) at 6 months was no change (i.e., within the range -3 to + 3) which was twice as common as improvement (60% versus 31%; Figure , Panel A). Overall, the PGAS response did not correlate well with the ADAS-Cog response (Table ). Only 42% of patients, mostly in the no change/no change group (33%), were similarly classified by the ADAS-Cog and the PGAS (Figure , Panel A). At a group level, patients with ADAS-Cog improvement had net improvement on the PGAS (mean change = 7.0 ± 9.1) compared with patients who had ADAS-Cog worsening (5.4 ± 11.2). At the individual level, however, there were differences in classification: while no one who was classified as improved on the ADAS-Cog was rated as having worsened clinically, 7/23 people who worsened on the ADAS-Cog were rated by patient/caregivers as having improved. This appears to reflect not just the broader range of domains considered in the PGAS, but also differing accounts of treatment. For example, considering only the PGAS-cognition goals (n = 81 patients), a similar pattern obtains (Figure , Panel B).
Figure 1 Distribution of patients by ADAS-Cog and patient/caregiver-GAS response after 6 months of donepezil therapy. Patient responses on the ADAS-Cog at 6 months were categorized as improved (change from baseline ≤ -4 points), no change (-3 to 3) or (more ...)
Spearman correlation coefficients comparing mean changes on the ADAS-Cog, CIBIC-Plus, PGAS and CGAS with mean changes on other outcomes at 6 months
At 6-months, overall responses on the clinic-GAS (CGAS) tended towards improvement (45%), followed by no change (32%) and worsening (23%). Mean change from baseline on the CGAS corresponded with the ADAS-Cog response by group (from 5.5 ± 9.1 for ADAS-Cog improved to 0.9 ± 12.4 for ADAS-Cog worsening), but the correlation between measures was low (Table ). Here too, agreement (41%) was concentrated primarily in the no change/no change group (20%; Figure , Panel A). Patients who improved on the ADAS-Cog were also more likely to have CGAS improvement (11/19), and again – as with the PGAS – less agreement was evident with ADAS-Cog worsening. Of the 23 patients worsened by ≥ 4 points, clinicians rated 9 as improved and 5 as showing no change. A similar pattern to the PGAS was also seen when we considered only cognition goals. ADAS-Cog improvement usually indicates clinical ratings of improvement or no change; whereas ADAS-Cog worsening can be seen in many people rated as showing clinical improvement (Figure , Panel B).
Figure 2 Distribution of patients by ADAS-Cog and clinician-GAS response after 6 months of donepezil therapy. Patient responses on the ADAS-Cog at 6 months were categorized as improved (change from baseline ≤ -4 points), no change (-3 to 3) or worsened (more ...)
In contrast with the ADAS-Cog, the CIBIC-Plus account of change at 6 months was more evenly distributed: 35% improved, 31% had no change and 34% worsened (see Figure ). For each ADAS-Cog response group, the mean CIBIC-Plus score changed in the corresponding direction (from 3.6 ± 1.0 for ADAS-Cog improved to 4.2 ± 1.3 for ADAS-Cog worsening), but the correlation between the CIBIC-Plus and the ADAS-Cog change scores was low-moderate (Table ). Concordance between the CIBIC-Plus and the ADAS-Cog (i.e., improved on both, no change on both or worsening on both), occurred in 45% of patients, mostly in the 22% with no change by either measure (Figure ). Clinical impressions showed less variability when the ADAS-Cog indicated improvement than for any other response. By contrast, 7/23 patients with ADAS-Cog deterioration had CIBIC-Plus scores that showed improvement, including 4 who were rated as "much" improved (CIBIC-Plus = 2). Most patients (32/53, 60%) characterized as "no change" on the ADAS-Cog were either improved (n = 16) or worsened (n = 16) on the CIBIC-Plus.
Figure 3 Distribution of patients by ADAS-Cog and CIBIC-Plus response after 6 months of donepezil therapy. Patient responses on the ADAS-Cog at 6 months were categorized as improved (change from baseline ≤ -4 points), no change (-3 to 3) or worsened (≥ (more ...)
A small group of patients (15%) demonstrated consistency of response across all measure at 6 months: 5 patients who improved on the ADAS-Cog also improved on the clinical measures, 8 patients were consistent "no changers," and 1 patient worsened on all four measures. It is also notable that when the ADAS-Cog indicated improvement, only one patient worsened on more than one clinical measure, whereas 10 patients with ADAS-Cog worsening showed improvement on at least two of the three clinical measures (including 6 patients who improved on all of the clinical measures).
At 6 months, the ADAS-Cog correlated better with the MMSE than with any other outcome measure (Table ). Here, the CIBIC-Plus correlated better than the ADAS-Cog with all other outcome measures, including PGAS and CGAS.