ARTICLE IN BRIEF
Rivastigmine, a cholinesterase inhibitor, was associated with a reduced risk for falls among patients with Parkinson's disease. But independent commentators say a phase 3 study is needed to replicate and confirm the findings.
The third randomized trial to find that a cholinesterase inhibitor appears to reduce the risk of falls in Parkinson's disease (PD) has now sparked the design of a phase 3 trial to determine whether such medications merit clinical use to prevent falls.
The primary endpoints in the phase 2, single-center trial of rivastigmine, published in the January 12 online edition of Lancet Neurology, were differences in step- time variability (a measure of gait stability) at 32 weeks, adjusted for such potential confounders as baseline age, cognition, and number of falls in the previous year. Compared with 59 patients randomized to placebo, the 55 patients assigned to rivastigmine showed a significant reduction in step-time variability for normal walking (0.72, 95% CI 0.58 - 0.88; p=0.002) — that is, their gait was more stabile.
The median fall rate, a secondary endpoint, was 0.50 per month (IQR 0.14 - 0.89) in the rivastigmine group (excluding an outlier patient who had 1,122 falls during the treatment period), compared with 1.14 (0.26 - 2.76) in the placebo group. After adjusting for potential confounders, the rivastigmine group had a 45 percent reduction in the rate of falls per month.
Gastrointestinal side-effects were more common in the rivastigmine group than in the placebo group (p<0.0001); 20 (31percent) patients in the rivastigmine group versus three (5 percent) in the placebo group had nausea and 15 (17 percent) versus three (5 percent) had vomiting.
The current report is the third trial to report the reduced risk for falls. An earlier study, published last August in the journal European Neurology, also tested the effects of rivastigmine on falling, as well as on cognitive dysfunction. That trial involved 176 PD patients. Conducted by researchers at Binzhou Medical College in Weihai, China, the randomized study found that the number of falls per person and the incidence of falls of patients in the rivastigmine group were significantly lower than those in the placebo group (p<0.01).
Donepezil, another cholinesterase inhibitor, was similarly found in a 2010 randomized trial to significantly reduce the frequency of falls per day, by 50 percent among unsteady patients with PD, although that crossover trial involved just 23 patients who reported falling or nearly falling more than twice a week. The study found that donepezil cut the frequency of falls per day by about half, from 0.25 + 0.08 falls per day on placebo to 0.13 + 0.03 on donepezil.
“It's nice to see that a clinical trial of another cholinesterase inhibitor has shown some confirmation of our findings with donepezil,” said Kathryn A. Chung, MD, an associate professor of neurology at Oregon Health & Science University in Portland and first author of a 2010 Neurology study on cholinesterase inhibitors for reducing PD-related falls. “This group took a deeper dive into it by trying to show that improvements in gait parameters and balance maintenance are a possible means by which falls are prevented. I applaud them for looking at things more mechanistically.”
Together with the findings from her study and from the Chinese trial of rivastigmine, the new results suggest that cholinesterase inhibition may represent a significant new approach to preventing falls in PD patients, Dr. Chung said.
“This is a paradigm shift,” she told Neurology Today. “By no means are we advocating acetylcholinesterase inhibitor medication for trying to improve gait and balance and to prevent falls. However, this may be a new approach that could spur better treatment. But first what needs to be done is a large multicenter, randomized phase 3 study.”
The first author of the new rivastigmine study said a phase 3 study is being planned. “We are now going to perform the phase 3 trial with falls as the primary outcome measure,” Emily Henderson, MRCP, a clinical research fellow at the School for Social and Community Medicine at the University of Bristol, UK, told Neurology Today.
Degeneration of cerebral cholinergic circuits was first proposed as a possible cause of falls in PD in a 2009 paper published in Neurology. The paper presented results of a cross-sectional PET imaging study of 44 patients with PD without dementia and 15 control subjects. The study found reduced cortical acetylcholinesterase (AChE) hydrolysis rates in the PD fallers (-12.3%), followed by PD non-fallers (6.6%), compared with control subjects. (p=0.0004). Thalamic AChE activity was also lower in the PD fallers group (-11.8%, p=0.008). No significant difference, however, was found in nigrostriatal dopaminergic activity between PD fallers and non-fallers.
When Dr. Chung's paper was published a year later, it was accompanied by a somewhat skeptical editorial by J. Eric Ahlskog, PhD, MD, a professor of neurology at the Mayo Clinic in Rochester, MN. “If donepezil is so efficacious for falls,” Dr. Ahlskog wrote, “why has this not been recognized in clinical practice?” He concluded that the findings — “suggestive but hardly definitive” — required replication and further delineation.
Dr. Chung said she and her colleagues are now in the midst of another donepezil trial for preventing falls in PD that will be similar in size to the new rivastigmine study, with about 60 patients, investigating gait and balance in addition to falls.
“Before last year, my 2010 study was the only clinical trial suggesting that cholinesterase inhibitors might reduce falls,” she said. “Because it involved only a single site with a small population, there was some incredulousness initially. People wanted to see more confirmation. Now we have two more studies that are supportive.”
Although 70 percent of PD patients have at least one fall per year and 39 percent fall recurrently, as the new study noted, “few efficacious interventions are available.” Presently neurologists are generally limited to prescribing physical and occupational therapy, modifications of the home environment, minimization of medications associated with an increased risk of falls, and the proper treatment of painful arthritis and other associated problems, Dr. Chung said.
Several movement disorders specialists who were not involved with the current report agreed that the phase 2 study was well done, and that a phase 3 study was needed to replicate and confirm the results.
“I'm impressed that they recruited 130 subjects at a single center,” said John G. Nutt, MD, FAAN, a professor of neurology and emeritus director of the Parkinson's Program at Oregon Health & Science University. Dr. Nutt was a coauthor on Dr. Chung's 2010 paper and is also collaborating on the larger trial of donepezil now underway.
He added, however, that he remains cautious about prescribing cholinergic inhibitors as a means to prevent falls until phase 3 trial results are available.
“There may be a subset of patients with more severe cholinergic deficits for whom these drugs are effective. This subgroup could perhaps be identified by PET scanning or transcranial magnetic stimulation,” Dr. Nutt said.
Roger Albin, MD, a professor of neurology and co-director of the Udall Center at the University of Michigan Medical School, agreed that the study was well designed and the authors were properly circumspect in their interpretation.
“Their interpretation, that it justifies going to a larger, phase 3 trial, is appropriate,” said Dr. Albin, who was the senior author of the 2009 PET imaging paper that first proposed that cholinergic stimulation might prevent falls in PD.
He also agreed with Dr. Nutt that only a subset of patients, those in whom cholinergic terminals are deficient, are likely to benefit from therapy aimed at raising acetylcholine levels.
“It would be better,” he said, “to do trials in only those who are likely to benefit. One thing that is very clear in the literature on falls, not just in PD, is that cognitive function matters a lot. If you have reduced attentional function, you're more fall-prone.”
For now, Dr. Nutt emphasized, the only appropriate clinical use for cholinesterase inhibitors remains slowing the progression of dementia.
“We're using cholinesterase inhibitors for people with cognitive problems more than we did in the past,” he said. “I would be reluctant to say it's time to use these drugs on everybody who falls. They do have side effects. They sometimes increase tremor, which patients may complain about. And they may cause some nausea. There's the unlikely but possible complication of cardiac arrhythmia. A subset of patients do come back after I prescribe them, however, and say, ‘I'm remembering better, I'm functioning better.’”