By Lynda Nwabuobi, MD

Assistant Professor of Clinical Neurology, Assistant Attending Neurologist, New York Presbyterian/Weill Cornell Medical College

SYNOPSIS: Individuals with Parkinson’s disease dementia and orthostatic hypotension (OH) showed more robust cognitive improvement from rivastigmine vs. those without OH. The anti-OH effect of rivastigmine probably mediates this better response.

SOURCE: Espay AJ, Marsili L, Mahajan A, et al. Rivastigmine in Parkinson’s disease dementia with orthostatic hypotension. Ann Neurol 2021;89:91-98.

Orthostatic hypotension (OH) is a common nonmotor symptom in Parkinson’s disease (PD), with an overall prevalence of 30%, which increases to 65% as the disease progresses. Untreated, it can independently contribute to cognitive impairment in PD individuals, presumably as the result of a reduction in cerebral perfusion pressure. In individuals with Parkinson’s disease dementia (PDD), the presence of untreated OH could negatively affect the efficacy of cholinesterase inhibitors used to treat PDD. Rivastigmine is approved for the treatment of cognitive impairment in patients with PDD. Using available clinical trial datasets, Espay et al tested the hypothesis that the cognitive effect of rivastigmine is not as effective in patients with PDD with OH vs. those without OH.

The authors performed a post-hoc analysis on three studies of rivastigmine in PDD in which orthostatic blood pressure measurements were recorded: a 24-week randomized, double-blind, placebo-controlled trial of patients with PDD at least two years after diagnosis; a 24-week open-label extension (a total of 48 weeks) in the same population; and a 76-week trial comparing the rivastigmine capsule vs. the transdermal patch. The main outcome was change from baseline in the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog) in patients with OH vs. patients without OH treated with rivastigmine compared to placebo. A secondary endpoint was change in Mini-Mental State Examination (MMSE) from baseline. The 76-week study used the Mattis Dementia Rating Scale (MDRS) as the outcome measure. The 24-week study was used for the main analysis because it was the only study with a placebo comparator. Statistical analysis included analysis of covariance (ANCOVA) model, with 95% confidence intervals for the difference between the treatment groups; P values were provided without adjustment for multiple comparisons.

In the rivastigmine vs. placebo study, the mean maintenance daily dose of rivastigmine for the 10 weeks preceding the study endpoint at week 24 was 8.7 mg (standard deviation [SD] = 3.4 mg); 9.8% of all OH patients were receiving OH treatment. There was a larger improvement in ADAS-Cog in the OH group at 24 weeks (5.6 ± 1.2 vs. 1.9 ± 0.9; P = 0.0165). MMSE also was significantly better with rivastigmine compared to placebo, but only in patients with OH (2.2 ± 4.7 vs. -0.7 ± 3.9; P < 0.001). At 48 weeks, with both groups on rivastigmine, the favorable effect of rivastigmine on ADAS-Cog in the OH group was attenuated (3.2 ± 2.1 vs. -1.1 ± 1.1, P = 0.0741). In the rivastigmine patch vs. capsule study, the daily dose during the maintenance time period ranged from 8.80 mg/day to 8.87 mg/day in patients who received the rivastigmine capsule and from 9.20 cm2 to 9.40 cm2 in patients who received the rivastigmine patch (10 cm2 patch releases 9.5 mg/24 hours). At week 76, the change in MDRS was significantly better for OH patients compared with individuals without OH, but only for those on rivastigmine capsules (10.6 ± 2.9 vs. -1.5 ± 3.0 on transdermal patch; P = 0.031).

At the end of the 24-week study, the prevalence of OH among the patients with OH at baseline declined to 28.3% in the rivastigmine group and 44.6% in the placebo group. Of the OH-negative patients, 5% converted to OH in the placebo arm compared to 1.7% in the rivastigmine arm. Syncope was more common in the OH placebo group (9.2%) compared to the OH rivastigmine group, which included no cases of syncope.

COMMENTARY

Contrary to their hypothesis, Espay et al found rivastigmine produced a greater cognitive benefit in PDD patients with OH vs. individuals without OH, despite similar severity of cognitive impairment at baseline. Also, it appeared to produce a protective effect of reducing OH, given the lower prevalence at the end of the 24-week study and no episodes of syncope in the rivastigmine group. This paradoxical effect may be explained by an anti-OH effect of the medication, as seen in a related ganglionic acetylcholinesterase inhibitor, pyridostigmine, which has been shown to reduce OH. These findings suggest a potential role of rivastigmine as an adjunct treatment for OH in PD. Other researchers should conduct a subanalysis on whether treatment with OH medications contributed to the amount of cognitive improvement seen in OH patients. If this is the case, it brings up the question whether all PDD patients should be on OH medications to boost the effectiveness of cholinesterase inhibitors.