Rivastigmine: Sustained Benefits for Parkinson's Disease Dementia

Abstract & Commentary

By Claire Henchcliffe, MD, DPhil, Assistant Professor, Department of Neurology, Weill Medical College, Cornell University. Dr. Henchcliffe is on the speaker's bureau for GlaxoSmithKline, Teva/Eisai, and Boehringer Ingelheim.

Synopsis: Rivastigmine demonstrated clinically significant benefits for up to one year in patients with dementia associated with Parkinson's disease.

Source: Poewe W, et al. Long-Term Benefits of Rivastigmine in Dementia Associated with Parkinson's Disease: An Active Treatment Extension Study. Mov Disord. 2006;21:456-461.

This 24-week open-label treatment extension trial aimed to determine whether 3-12 mg/day of rivastigmine had sustained benefit and continued safety in patients with dementia associated with Parkinson's disease (PDD), following an initial double-blind 24-week trial.1 Of 541 initial subjects, 433 patients completed the double-blind phase, and 329 of these, plus 5 retrieved dropout subjects, entered the open-label phase. These subjects were of mean age 72.4 ± 6.6 years, mean Parkinson's disease (PD) duration 8.8 ± 5.5 years, mean PDD duration 1.2 ± 1.6 years, mean time from PD diagnosis to first dementia symptom 6.7 ± 4.8 years, baseline Mini Mental State Examination 19.5 ± 3.8 points, and mean Unified Parkinson's Disease Rating Scale (UPDRS) motor score of 32.7 ± 13.4 points. A total of 273/329 patients (81.7%) completed the open-label phase (83.9% from the initial rivastigmine arm, 78.0% from the initial placebo arm). Mean rivastigmine dose at trial completion was 7.9mg/day. For the 176 patients completing 48 weeks of rivastigmine treatment, mean Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) scores were 22.5 ± 9.6 (baseline), 19.3 ± 9.6 (week 24), and 20.4 ± 11.2 (week 48): a mean improvement of 2.0 ± 7.3 (95% CI 0.8-3.1). For the 97 patients initially on placebo followed by open-label rivastigmine, ADAS-cog scores were 23.3 ± 10.3 (baseline), 23.6 ± 11.7 (24 weeks), and 20.8 ± 11.1 (week 48): a mean improvement of 2.2 ± 8.2, 95% CI 0.5-3.9. Improvements were also observed for secondary outcome measures, including the Alzheimer's Disease Cooperative Study Activities of Daily Living scale. The UPDRS motor score did not change significantly over the course of the study. Overall, 75.4% of patients reported adverse effects in the extension phase, leading to withdrawal in 11.4%. These were most frequently nausea (18.6%), vomiting (11.1%), tremor (6.9%), falls (4.8%), confusional state (5.1%), and hallucinations (4.8%). Parkinsonian symptoms worsened in 18%, mostly with tremor.

Commentary

Dementia in PD is common, with reported prevalence rates of approximately 40%. Patients with PDD have a cholinergic deficit, and the nucleus basalis of Meynert is involved in the underlying pathophysiologic process, providing the rational for symptomatic treatment with a cholinomimetic agent. However, there are multiple processes at play in PDD, including cortical involvement of PD, and Alzheimer Disease-type pathology in some. Rivastigmine is a centrally acting inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) and is approved by the FDA for the treatment of mild to moderate Alzheimer's dementia (AD). A supplemental new drug application is being sought from the FDA for treatment of PPD.2 The ADAS-cog is an 11-item, 70 point mental status examination of language, praxis, memory, and orientation. The mean decrease of 2 points over 48 months suggests a modest but significant effect, although use of a scale designed for AD may not be an ideal measure in PDD. The study design of course has some limitations, and there may have been patient selection bias in the second phase: the subset of subjects continuing from the rivastigmine arm of the original 24-week trial had experienced a greater improvement in ADAS-cog than the entire group. Interestingly, the effect of rivastigmine on cognition varied considerably between patients, reflecting clinical practice. This may reflect the heterogeneity of PDD included in this research trial. It emphasizes the need for studies designed to dissect out predictors of drug responses, whether by imaging, pharmacogenetics, or by other means. Nonetheless, the drug was well-tolerated. Therefore, with appropriate discussion of patients' and caregivers' preferences, instituting rivastigmine for symptomatic treatment of PDD may be worthwhile, with the caveat that it is not a golden bullet.

References

1. Emre M, et al. Rivastigmine for Dementia Associated with Parkinson's Disease. N Engl J Med. 2004;351:2509-2518.

2. Food and Drug Administration. Peripheral and Central Nervous System Drugs Advisory Committee; Notice of Meeting for May 17, 2006. Assessed May 9, 2006, at www.fda.gov/OHRMS/DOCKETS/98fr/E6-3021.pdf