'Never Events' Common for Patients with Comorbid Parkinson, Dementia


Almost 45% of those who received an antidementia treatment experienced the never event of co-administration of a high-potency anticholinergic medication and an acetylcholinesterase inhibitor.

Dr Allison W. Willis

Allison W. Willis, MD, MS, from the Department of Neurology in the Perelman School of Medicine at the University of Pennsylvania

Allison W. Willis, MD, MS

New study results have shown that those with Parkinson disease, dementia medication use varies by race/ethnicity and sex, as does potentially inappropriate prescribing habits, which were found to be common among those being treated for cognitive impairment.1

In the cross-sectional analysis that included data from 268,407 Medicare beneficiaries with Parkinson disease, it was revealed that nearly 45% of those who received an antidementia treatment experienced the never event of co-administration of a high-potency anticholinergic medication and an acetylcholinesterase inhibitor (ACHEI). Never events are described as adverse events that are serious, largely preventable, and of concern to both the public and health care providers for the purpose of public accountability.2

Corresponding author Allison W. Willis, MD, MS, from the Department of Neurology in the Perelman School of Medicine at the University of Pennsylvania, and colleagues assessed each beneficiary’s use of a dementia drug, specific dementia medication, and concurrent exposure to a high-potency anticholinergic drug and an ACHEI). Drug claims were inquired about to identify the drugs of interest, and the fill date and days’ supply variables were used to calculate the potential boundaries of exposure for each drug.

"The biggest clinical implications of this research are that our current provider workforce may not be well prepared to provide the safest care to individuals with neurodegenerative disease," Willis told NeurologyLive. "The medications we examined in this Parkinson cohort are also problematic for older adults, adults with dementia. The number of persons who are older, have Parkinson disease or have dementia is rising rapidly; providing safer and effective care will likely reduce excess costs and improve patient outcomes."

Of the 64,017 individuals with Parkinson disease who were being treated for dementia with an ACHEI, 81.3% (n = 52,069) experienced at least 1 concurrent use of an anticholinergic event. Additionally, 68% (n = 43,554) had a concurrent prescription fill with a low-potency anticholinergic therapy, 7.6% (n = 4892) did so with a mid-potency anticholinergic drug, and 44.5% (n = 28,495) of those receiving an ACHEI had a simultaneous prescription of a high-potency anticholinergic drug—a never event.

Willis and colleagues wrote that “considering the possibility that there was an intention to stop the anticholinergic drug therapy (such as verbal or written communication to the beneficiary) that was not reflected in claims data, we determined how frequently sequential high-potency anticholinergic—ACHEI events occurred. Sequential high-potency anticholinergic–ACHEI event was defined as a second concurrent prescription filling, immediately after the first, of a high-potency anticholinergic drug and an ACHEI (donepezil, rivastigmine, or galantamine).”

Although investigators allowed for the switching of 1 high-potency anticholinergic drug to another, they found that consecutive high-potency anticholinergic—ACHEI events were common. Ultimately, 84.9% (n = 17.149) of those who filled a prescription for donepezil and a high-potency anticholinergic drug experienced ≥1 event, and 84.1% (n = 7305) of high-potency anticholinergic-rivastigmine events occurred more than once.

"Sadly, I was not surprised," Willis said. "I have seen this prescribing error in patients coming to my clinical frequently over the years. The geographic variation deserves further study, we can learn from provider networks that are less often making this error."

Hispanic (adjusted odds ratio [aOR], 1.11; 95% CI, 1.00 to 1.23) and women (aOR, 1.30; 95% CI, 1.25 to 1.35) beneficiaries had greater odds of experiencing a never event than other subgroups. Black beneficiaries were less likely to have concurrent high-potency anticholinergic and ACHEI prescription (aOR, 0.83; 95% CI, 0.77 to 0.89) compared with white beneficiaries.

The co-administration never event was negatively associated with age, though it was associated with comorbid depression (aOR, 1.62; 95% CI, 1.57 to 1.68), chronic obstructive pulmonary disease (AOR, 1.12; 95% CI, 1.03-1.17), hypertension (AOR, 1.13; 95% CI, 1.09-1.19), chronic kidney disease (AOR, 1.08; 95% CI, 1.03- 1.12), diabetes (AOR, 1.07; 95% CI, 1.03-1.11), and heart failure (AOR, 1.06; 95% CI, 1.02-1.11). Cerebrovascular events, ischemic heart disease, and hyperlipidemia were not associated with co-administration.

Statistically significant clusters of the prevalence of this prescribing error were seen across the United States (Moran I = 0.24; P <.001), with clusters of high prevalence in the southern and midwestern states, and clusters of low prevalence of inappropriate prescribing were present in the northwest and the northeast US regions.

“In determining whether anticholinergic drug exposure has a causal role in clinical dementia in Parkinson disease, future studies may take a clinical trial approach, in which high-potency anticholinergic medications are replaced with lower-potency alternatives, and the change in cognitive testing and cognitive trajectory are measured,” Willis and co-authors wrote. “Such an approach will allow the calculation of anticholinergic drug safety in terms that are easily understood, such as number needed to harm. In addition, pragmatic approaches to practitioner education may lessen negative patient outcomes in the future.”

In an accompanying editorial,3 Hess et. al. noted that although polypharmacy and inappropriate medication prescribing are a major issue in the treatment of older patients, an issue “arises in defining the co-administration of an anti-dementia drug and a medication with high ACH activity as a prescribing error or a never event in all clinical circumstances. Across the literature in this area, the most important principle repeatedly emphasized was that these resources are intended to identify potentially inappropriate medication (not inappropriate medications), and the recommendations and ratings provided cannot replace patient-specific clinical judgment.”

Additionally, Hess et. al. noted that although Willis and colleagues note that every high-potency anticholinergic drug have low-potency, nonanticholinergic, and non-drug alternatives to them, “the other effective pharmacologic options were not available for the treatment of severe Parkinson disease psychosis in the year of study.” As an example, they point to pimavanserin tartrate, which is now approved for the treatment of psychosis in Parkinson disease and has no reported ACH affinity.

Hess et. al. acknowledged that psychotic symptoms are an independent risk factor of mortality in Parkinson disease, and the management of psychosis in these patients “may have outweighed the concern for potential worsening of cognition in many individuals described.”

"My own patient interactions prompted this research. I am a clinician-scientist—I have a clinic and a research lab," Willis explained. "I have had numerous encounters over the years with long-standing patients who have had a sudden worsening of their symptoms in relation to being prescribed a sedative, anticholinergic, narcotic or hypnotic by another physician. However, it is not widely appreciated that some medications should be avoided in patients with Parkinson disease."


1. Mantri S, Fullard M, Gray SL, et al. Patterns of dementia treatment and frank prescribing errors in older adults with Parkinson disease. JAMA Neurol. Epub October 1, 2018. doi:10.1001/jamaneurol.2018.2820.

2. Half of US Hospitals Reporting to Leapfrog Say They Won’t Bill for a Never Event [press release]. Washington, DC: Leapfrog Group. Published September 26, 2007. web.archive.org/web/20110709195830/http://www.leapfroggroup.org/media/file/Release_-_Adoption_of_Leapfrog_Never_Events_Policy_2007.pdf. Accessed September 27, 2018.

3. Hess CW, Okun MS, Ramirez-Zamora A. Challenges in defining inappropriate medication use in Parkinson disease dementia. JAMA Neurol. Epub October 1, 2018. doi: 10.1001/jamaneurol.2018.2826.

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