Rivastigmine Prevents Falls in Patients With PD

Pauline Anderson

February 04, 2016

Treatment with high doses of the acetylcholinesterase inhibitor rivastigmine (Exelon, Novartis Pharmaceuticals) reduces falls in patients with Parkinson's disease (PD), a new phase 2 study suggests.

"The intervention improved measures of gait stability, gait variability, walking speed, and balance, and that all equated with a reduction in fall rates," said lead author Emily J. Henderson, MD, registrar in geriatric medicine, Royal United Hospital, Somerset, and clinical research fellow, University of Bristol, United Kingdom.

"The results are very encouraging and really exciting, but they need to be reproduced in larger phase 3 trials before rivastigmine can be recommended to prevent falls in day-to-day routine clinical practice," she told Medscape Medical News.

The study was published online January 12 in The Lancet Neurology.

In PD, a loss of cholinergic function contributes to freezing and other gait changes, postural instability, and cognitive dysfunction. Rivastigmine, an acetylcholinesterase inhibitor, is approved by the US Food and Drug Administration for the treatment of PD dementia but not for gait.

The study included 130 patients with moderate but stable PD without dementia who had had a median of five falls in the previous year. Participants were randomly assigned to placebo or rivastigmine, with the dose being titrated up from 3 mg per day to a target dose of 12 mg per day.

For the primary analysis, researchers measured gait instability while participants walked 18 m wearing an accelerometer around their waist. They explained that they were uncertain if the study would be sufficiently powered to directly detect a difference in fall rate and that gait variability serves as a marker of fall risk.

Patients who needed walking aids were excluded from the study because such aids might have interfered with the accelerator signals.

Dr Henderson and her colleagues looked at step time variability during normal walking, during walking while listing words beginning with the same letter (simple dual task), and during walking while listing words beginning with alternate letters (complex dual task).

The study showed that at 32 weeks, rivastigmine was associated with a 28% greater reduction in step-time variability (geometric mean ratio [GMR], 0.72; 95% confidence interval [CI], 0.58 - 0.89; P = .002) compared with placebo, after adjustment for age, cognition, step-time variability, and number of previous falls.

Step time variability during the simple task was only somewhat improved compared with placebo (a 21% reduction; adjusted GMR, 0.79; 95% confidence interval [CI], 0.62 - 0.99; P = .045).

There was no significant between-group difference in the complex dual task (reduction of 19%; GMR, 0.81; 95% CI, 0.60 - 1.09; P = .17).

"We haven't at this stage done more mechanistic analysis of the dual task," so it's difficult to explain why the change in that task wasn't significant, said Dr Henderson. "But the important take-home feature is that we saw a similar sort of improvement in all three conditions."

Number of Falls

From patient diaries, the researchers gathered information on the number of falls per month. They found that patients in the treatment group had a reduction of 45% in this rate after adjustment for age, baseline cogitation, falls in the previous year, and baseline step-time variability during normal walking.

The drug did not have significant effects on episodes of freezing of gait or on neuropsychological outcomes, such as fear of falling, anxiety, or depression.

The secondary measure of cognitive and executive function also did not significantly improve. However, Dr Henderson speculated that this may have been due to the insensitivity of the measurement instrument or the study being underpowered to detect these changes.

Researchers looked at adverse events over 12 months, which included 4 months beyond the intervention period. Both groups reported a high number of adverse events, but gastrointestinal adverse effects, such as nausea and vomiting, were more common in the treatment group.

Only two adverse events in the rivastigmine group — both worsening of parkinsonism — were linked to the treatment.

The authors suggested that in future, the administration of rivastigmine through patches might improve tolerability.

A post hoc analysis of masking success indicated that more participants in the treatment group correctly guessed their allocation than would be expected by chance. Dr Henderson noted that few trials even look at masking.

"It's quite a challenge in any drug trial to keep participants and researchers blinded when side effects can occur," she said. "If it [knowing the allocation] did introduce any bias, it wouldn't have affected our primary outcome because that was measured by an accelerometer, so we think it's highly unlikely it would have influenced the fall rate."

Urgent Need

There's a "very large and urgent need" to identify strategies to improve balance and gait in patients with PD and cognitive impairment that can be implemented throughout the disease course, said Dr Henderson. She noted that cognitive impairment is "very common" in early stages of the disease.

Rivastigmine is already used to treat PD dementia. The drug augments cognition by preventing the breakdown of acetylcholinesterase.

In directly affecting attention, it's possible that patients with PD taking this drug are able to pay more attention to their walking and therefore fall less often, said Dr Henderson. Alternatively, she said, the drug may stabilize gait by directly affecting some brainstem pathways.

Although physical therapies, particularly tai chi and strength and balance interventions, help prevent falls, "they require patients to be very motivated and committed and relatively cognitively intact," said Dr Henderson. And strategies such as brain stimulation require patients to be relatively healthy, with few comorbidities.

In an accompanying editorial, Caroline Moreau, Department of Neurology, University of Lille Nord de France, and colleagues say the findings "provide valuable arguments in favor of high-dose rivastigmine" in patients with "high level" gait disorders. The results, they said, have been "long awaited" since there are no available pharmacologic treatments for poor postural stability in PD.

The editorial writers note that cardiac adverse events were not more frequent in the rivastigmine group and that the two groups didn't differ significantly in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score.

But they point out that questions still remain. One is whether rivastigmine has different effects on static postural stability (assessed with the retropulsion test in the MDS-UPDRS) compared with dynamic postural stability (stride-to-stride variability during gait).

And although the authors assessed mood with the Geriatric Depression Scale, "it would have been useful to investigate apathy," they write, adding that an earlier double-blind placebo-controlled study of patients with PD and predementia apathy showed that rivastigmine was associated with a lower overall apathy score and caregiver burden.

Reached for an additional comment, Michael S. Okun, MD, professor and chairman of University of Florida Health Neurology, Gainesville, and the national medical director of the National Parkinson Foundation, said that cholinergic deficiency has long been considered a large contributor to walking problems in PD.

"The idea of a replacement therapy that may improve fall risk is, on the surface, very appealing."

However, Dr Okun pointed out that the beneficial effect disappeared in study patients doing a complex dual task, and that the analysis excluded patients requiring walking aids, which he felt reduced the impact of the results.

"Though [this is] an interesting finding, we must keep in mind that most people are unconsciously performing complex dual tasks during walking, and therefore the findings are probably not compelling enough to change clinical practice."

The study authors, editorialists, and Dr Okun have disclosed no relevant financial relationships.

Lancet Neurol. Published online January 12, 2016. Abstract Editorial

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