Risk of Mortality Associated with Pimavanserin Compared with Atypical Antipsychotics in Patients with Parkinson's Disease—related Psychosis

Background: Pimavanserin is the only drug approved in the United States (US) to treat hallucinations and delusions associated with Parkinson's disease psychosis (PDP); other atypical antipsychotics are sometimes used off-label in patients with PDP. In the US, all antipsychotic drugs carry a boxed warning in their approved labeling concerning an increased risk of death in older patients with dementia-related psychosis.

Objectives: To compare mortality risk among patients with PDP after initiation of pimavanserin with mortality risk after initiation of comparator atypical antipsychotics and to evaluate whether mortality risk varies over time or across subgroups.

Methods: A retrospective cohort of patients aged ≥ 65 years and diagnosed with Parkinson's disease (PD) and psychosis initiating pimavanserin or a comparator antipsychotic (clozapine, quetiapine, risperidone, olanzapine, aripiprazole, brexpiprazole) were identified in 2016-2019 Medicare claims data. Differences in treatment group characteristics were balanced with 1:1 propensity score (PS) matching. Incidence of all-cause mortality between the two groups was compared with hazard ratios (HR) and 95% confidence intervals (CI) estimated with Cox proportional hazard models. Time period-specific models evaluated changes in risk over time. Analyses were repeated in subgroups, including long-term care (LTC) or skilled nursing facility (SNF) residents on the index date. A sensitivity analysis included patients without a recorded psychosis diagnosis.

Results: We identified 2,892 pimavanserin initiators and 19,083 comparator initiators (overall 47% female, mean age = 80.9 years, LTC/SNF residents = 30%). Most patients also had dementia (79%). Overall, deaths were observed in 14.5% of the cohort. Before PS matching, pimavanserin users generally had fewer severe comorbidities and more PD medication use than comparator users. PS matching resulted in 2,891 patients in both groups, and all measured covariates were well balanced. The matched HR for mortality for pimavanserin vs. comparator was 0.78 (95% CI, 0.67-0.91), with the lowest observed time period-specific HRs in the first 180 days. In LTC/SNF residents (90% of whom had dementia), the HR was 0.78 (95% CI, 0.60-1.01). In sensitivity analyses not requiring a recorded psychosis diagnosis, the HR was 0.76 (95% CI, 0.68-0.85).

Conclusions: This retrospective, active-comparator, new-user study suggests a lower mortality risk among patients treated with pimavanserin compared with those treated with other atypical antipsychotic drugs. Although PS matching balanced all measured characteristics, the potential for confounding remains; however, this observed association with lower mortality was consistent across subgroups and sensitivity analyses.