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Parkinson's disease patients using pimavanserin (Nuplazid), a novel antipsychotic used to help manage Parkinson's hallucinations and delusions, had an increased risk of 30-day hospitalization and higher mortality for up to a year, a large real-world study showed.

Pimavanserin use was tied to a higher risk of 30-day hospitalization (adjusted HR 1.24, 95% CI 1.06-1.43) in a retrospective analysis of Parkinson's patients in long-term care facilities, reported Y. Joseph Hwang, MD, MSc, of Johns Hopkins University in Baltimore, and colleagues.

Pimavanserin also was associated with an increased mortality at 90 days (adjusted HR 1.20, 95% CI 1.02-1.41), which persisted at 180 days (adjusted HR 1.28, 95% CI 1.13-1.45) and at 1 year (adjusted HR 1.56, 95% CI 1.42-1.72), they wrote in .

" previously were associated with increased risks of mortality in patients with Parkinson's disease," Hwang said. "We sought to evaluate such risks associated with pimavanserin, a novel antipsychotic," he told MedPage Today.

"We primarily used a propensity score-based weighting method to balance the pimavanserin user and non-user groups with respect to carefully selected clinical characteristics including demographics, comorbidities, and concomitant medications," Hwang added.

People with Parkinson's disease are at an increased risk of developing dementia and behavioral abnormalities including psychosis, noted Farwa Ali, MBBS, of the Mayo Clinic in Rochester, Minnesota, in an . A prospective longitudinal study of community-dwelling Parkinson's patients found that 60% developed hallucinations and delusions over 12 years, she pointed out.

"Pimavanserin has been approved by the FDA for Parkinson's disease psychosis, but its safety has been called into question based on compared to a rather modest benefit seen in a , the duration of which limits determination of long-term safety," Ali wrote.

The drug carries a stating elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. In 2018, after several hundred were submitted to the federal government, the FDA conducted a post-marketing review of the drug. , the agency did not identify any new or unexpected safety findings or findings inconsistent with the drug label's safety profile.

In their study, Hwang and colleagues evaluated Medicare claims data for Parkinson's patients living in long-term care facilities between 2015 and 2018, comparing 2,186 people who were prescribed pimavanserin and 18,212 who were not. They calculated hospitalization and mortality rates from the date of pimavanserin prescription. Pimavanserin users continued the drug over the entire observed study period.

The researchers used propensity score-based inverse probability of treatment weighting (IPTW) to balance pimavanserin users and non-users on 24 baseline characteristics. After IPTW, the two groups were well balanced and showed no meaningful differences in age, sex, comorbidity burden, or other factors linked to hospitalization or mortality risk. The researchers also calculated to assess the effect of unmeasured confounding on their results.

Mean age in the balanced groups was about 79, and 43% of the cohort was male. Overall, pimavanserin use was associated with a higher risk of 30-day hospitalization, but not with 90-day hospitalization.

During 1-year of follow-up, 26.4% of pimavanserin users died compared with 25.4% of non-users, and cumulative mortality was significantly greater among pimavanserin users. While mortality HRs were higher at 90, 180, and 365 days among pimavanserin users, there was no difference in 30-day mortality between users and non-users.

The E-value for 30-day hospitalization was 1.79, suggesting an unmeasured confounder needed to be associated with both pimavanserin use and hospitalization by that magnitude to explain away the observed association entirely, Hwang and colleagues reported. The E-value of 90-day mortality risk was 1.69; for 180-day mortality it was 1.88, and for 1-year mortality it was 2.06.

"The study confirms previous concerns regarding safety of pimavanserin and more importantly brings to attention the importance of carefully considering risks and benefits of pharmacotherapy in Parkinson's disease psychosis, clear communication with patients and families, and close observation to ensure safety," Ali observed.

The researchers "astutely discuss some very important points that should be considered when critically analyzing data regarding mortality risk in this population," she noted.

"While robust analyses were conducted to ensure pimavanserin users and non-users were comparable, Hwang et al. did find that pimavanserin users were more likely to concomitantly use other antipsychotic drugs, which has been demonstrated as increasing the mortality risk," Ali wrote. The effect of polypharmacy and use of other antipsychotics is difficult to quantify and may influence the results, she added.

Participants were living in long-term facilities and may have had more severe or later-stage disease, conferring higher mortality risk, Ali continued. "As such, results may not be generalizable to community-dwelling Parkinson's disease patients," she wrote. "These factors are important to consider while making individual patient management decisions."

The findings also are subject to residual confounding, Hwang and colleagues noted. "Moreover, while we developed models to maximize the strength of causal inference, our comparison group was pimavanserin non-users and the very reason for prescription of pimavanserin could have predisposed its users to the outcomes of hospitalization and death, introducing confounding by indication," they acknowledged.

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