Cholinesterase Inhibitors

Rivastigmine

The most recently approved CHE-I, rivastigmine, is also approved for the treatment of mild to moderate AD. The largest CHE-I clinical database - more than 3000 patients has been amassed during US and international trials of this agent.

A 26 week, multicenter, double-blind, placebo-controlled, maximum-tolerated dosage design (N=699) was utilized by Bloom and colleagues¹³. A diagnosis of mild-moderate AD was required for study inclusion. This population was more medically frail than most previous trials of CHE-I inhibitors; medical comorbidity was present in 94% of the subjects and 93% were receiving other medications.

Patients were randomized to receive placebo (N=235), low dose rivastigmine (N=233:1-4mg/day), or high dose rivastigmine (N=231: 6-12mg/day). The initial 7 weeks were a fixed dose titration phase, followed by flexible dosing in weeks 8-26. At endpoint, the mean daily doses were 3.5mg/day in the low-dose group and 9.7mg/day in the high-dose group.

Trial completion rates were as follows: placebo (84%), low-dose (85%), and high-dose (65%). Gastrointestinal adverse effects were significantly increased in the high-dose group and may have been exacerbated by the initial forced dose titration. In the high-dose arm, 66 patients withdrew related to adverse effects, as compared with the low-dose and placebo groups where 19 and 17 patients respectively withdrew due to adverse effects. Nausea was reported in 48% of patients in the high dose group with 21% of patients reporting weight losses of >= 7% of baseline weight. No evidence of hepatotoxicity, significant changes in ECG or laboratory results was reported.

On the ADAS-Cog, the mean drug-placebo difference was 4.94 points for the 6-12mg/day group¹³ - the largest drug-placebo difference reported to date for a CHE-I, however, these results have not been replicated in subsequent trials.

ADAS-Cog: Mean change from baseline scores13

More than half of the patients (56%) in the high dose group showed either improvement or no change from baseline, as compared to 27% of patients in the placebo group who did not decline over the period.

Patients in both the low-dose and high-dose groups demonstrated significantly less decline during the study period as compared to placebo on the CIBIC-Plus. Only the high-dose rivastigmine group showed a significant treatment effect on the PDS, a measure of ADL function.

Rosler et al.¹⁵ reported on the results of an international rivastigmine trial of identical length and design as the U.S. trial described above. Over 700 patients were randomized to the three treatment groups. Similar tolerability and safety data was reported, however, a lesser drug-placebo difference for the high-dose group at endpoint was noted due to slower deterioration in the placebo group. There was no significant difference found in endpoint ADAS-Cog scores between the placebo and low dose groups. The mean decrease on the high dose group ADAS-Cog was 0.26 points vs. 0.79 points for the high-dose group in the U.S. study. Only the high-dose rivastigmine group demonstrated statistically significant differences versus placebo on the CIBIC-plus and PDS rating scales.