By Andrea Lee, MD
Assistant Professor of Clinical Neurology and Assistant Attending Neurologist, New York-Presbyterian/Weill Cornell Medical College
SYNOPSIS: This retrospective cohort study of patients with Parkinson’s disease ages 65 years or older residing in Medicare-certified long-term care facilities revealed pimavanserin use vs. nonuse is associated with an increased risk of 30-day hospitalization and higher 90-, 180-, and 365-day mortality.
SOURCE: Hwang YJ, Alexander GC, An H, et al. Risk of hospitalization and death associated with pimavanserin use in older adults with Parkinson disease. Neurology 2021;97:e1266-e1275.
This was a propensity score-based retrospective cohort study of pimavanserin users and nonusers with Parkinson’s disease (PD). The authors accrued information on residents of Medicare-certified long-term care facilities between Nov. 1, 2015, and Dec. 31, 2018, using the Minimum Data Set (MDS) 3.0, which was linked with Medicare claims data. The MDS is a federally required clinical assessment of all individuals residing in Medicare-certified long-term care facilities. The clinical assessment is performed on admission to the long-term care facilities, periodically, and on discharge. The MDS contains information on long-term care residents’ clinical, psychosocial, and functional characteristics.
The study cohort included long-term care residents 65 years of age and older diagnosed with PD. The authors defined the diagnosis of PD as ICD-10-CM diagnosis code G20 (PD) or receipt of a prescription for carbidopa or levodopa. From the cohort of long-term care residents with PD, those with a new outpatient prescription for pimavanserin from May 1, 2016, to Dec. 31, 2018, were accrued into the user group. After the index date for each pimavanserin user and 10 nonusers was identified, the following subjects were excluded: those without continuous enrollment in Medicare Parts A, B, and D for the six months prior to the index date, those without at least one MDS assessment in the six months prior to or one month after the index date, and those who were residing in skilled nursing facilities or hospitalized on the index date. After applying exclusion criteria, the final study cohort included 2,186 pimavanserin users and 18,212 nonusers.
The authors concluded that there was a higher risk of 30-day hospitalization with pimavanserin use vs. nonuse (inverse probabilities of treatment weights [IPTW]-adjusted hazard ratio [aHR], 1.24; 95% confidence interval [CI], 1.06-1.43). There was no association of pimavanserin use with 90-day hospitalization (aHR, 1.10; CI, 0.99-1.24) or with 30-day mortality (aHR, 0.76; CI, 0.56-1.03). Pimavanserin use vs. nonuse was associated with increased 90-day mortality (aHR, 1.20; CI, 1.02-1.41) that persisted after 180 days (aHR, 1.28; CI, 1.13-1.45) and one year (aHR, 1.56; CI ,1.42-1.72).
In PD, a variety of nonmotor symptoms are common. These include dementia and psychosis. In patients with long-term PD, as many as 80% experience dementia
and as many as 60% experience psychosis. In PD, dementia is known to be associated with psychosis, and the use of antipsychotics for PD treatment is common. A study reported that, of newly diagnosed PD patients, approximately one-third were prescribed an antipsychotic within seven years, and another study reported a six-year cumulative probability of initiating antipsychotic treatment at 50%.1-3 Given that a previous study showed typical and atypical antipsychotics more than doubled mortality risk in patients with PD, the authors aimed to assess the risk of hospitalization and death associated with pimavanserin.3
Pimavanserin is a novel antipsychotic approved by the U.S. Food and Drug Administration (FDA) for the management of hallucinations and delusions in patients with PD. Pimavanserin blocks serotonin 5-HT2A receptors and does not have affinity for dopaminergic, histaminergic, muscarinic, or adrenergic receptors. Its lack of dopamine receptor affinity compared to typical or atypical antipsychotics (dopamine receptor affinity is well known to worsen motor symptoms of parkinsonism) makes it a particularly promising antipsychotic in this challenging patient population. Safety signals concerning a possible effect on mortality were observed previously in randomized and observational studies and spontaneous adverse event reporting of pimavanserin. A Phase III randomized trial of 199 patients reported serious adverse events in 11 (11%) patients in the pimavanserin group compared to 4 (4%) in the placebo group. The trend in deaths also was unfavorable, with two deaths in the pimavanserin group vs. one death in the placebo group. In the long-term open-label population, 11% of 497 patients treated with pimavanserin died, but no comparison group was available.
The results of this current study are important because of earlier signals of potential harm associated with pimavanserin, as well as continued uncertainty regarding its safety for the management of hallucinations and delusions in patients with PD. Although the FDA approved the use of pimavanserin among those with PD in 2016, it also published a black-box warning for increased risk of mortality in older adults with dementia, similar to other antipsychotics that have been used off-label in patients with PD and associated with increased risk of mortality.
This is the first cohort study that examined the risk of hospitalization and death associated with pimavanserin use compared to nonuse in older adults with PD, and the results may help to inform decisions about the risk/benefit balance of pimavanserin in clinical practice. While the study was not designed to assess the specific causes of the increased morbidity and mortality documented, prior work has found that the relationship between antipsychotics and risk of mortality may be driven by several factors, including higher rates of sudden cardiac death, acute myocardial infarction, acute kidney injury, pneumonia, falls, and fractures in older adults. Future studies may be warranted to elucidate the putative mechanisms for the risks of hospitalization and death associated with pimavanserin use.
- Marras C, Kopp A, Qiu F, et al. Antipsychotic use in older adults with Parkinson’s disease. Mov Disord 2007;22:319-323.
- Wang M-T, Lian P-W, Yeh C-B, et al. Incidence, prescription patterns, and determinants of antipsychotic use in patients with Parkinson’s disease. Mov Disord 2011;26:1663-1669.
- Weintraub D, Chiang C, Kim HM, et al. Association of antipsychotic use with mortality risk in patients with Parkinson disease. JAMA Neurol 2016;73:535-541.